CA2703109C - Compositions and methods for treating purpura - Google Patents
Compositions and methods for treating purpura Download PDFInfo
- Publication number
- CA2703109C CA2703109C CA2703109A CA2703109A CA2703109C CA 2703109 C CA2703109 C CA 2703109C CA 2703109 A CA2703109 A CA 2703109A CA 2703109 A CA2703109 A CA 2703109A CA 2703109 C CA2703109 C CA 2703109C
- Authority
- CA
- Canada
- Prior art keywords
- receptor agonist
- adrenergic receptor
- alpha
- selective
- agents
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
Abstract
Embodiments of the present invention are directed to compositions and methods for the treatment of purpura.
Preferred compositions comprise an a adrenergic receptor agonist selected from selective .alpha.1 adrenergic receptor agonist, selective .alpha.2 adrenergic receptor agonist, non-selective .alpha.1/.alpha.2 adrenergic receptor agonist, agents with .alpha.2 adrenergic receptor agonist activity and combinations thereof, in a pharmaceutically acceptable carrier in order to treat and improve the cosmetic appearance of hemorrhagic (purpuric) lesions in the skin.
Preferred compositions comprise an a adrenergic receptor agonist selected from selective .alpha.1 adrenergic receptor agonist, selective .alpha.2 adrenergic receptor agonist, non-selective .alpha.1/.alpha.2 adrenergic receptor agonist, agents with .alpha.2 adrenergic receptor agonist activity and combinations thereof, in a pharmaceutically acceptable carrier in order to treat and improve the cosmetic appearance of hemorrhagic (purpuric) lesions in the skin.
Description
A. Title: Compositions and Methods for Treating Purpura =
G. Brief summary of the invention 100011 Embodiments of the present invention are directed to the use of an a adrenergic agonist for the treatment of vascular extravasation into the skin and particularly for the sequelae manifesting as cutaneous petechiae, purpura or ecchymoses. The a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective at/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof. The a adrenergic agonist may be administered to a patient in need thereof in a composition comprising a therapeutically effective amount of the a adrenergic agonist, such as a composition for topical administration.
[00021 Further embodiments of the present invention are directed to the treatment of purpura in a subject comprising administering a therapeutically effective amount of an a adrenergic agonist to said subject, wherein the purpura is treated. In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective ct2 adrenergic receptor agonist, non-selective ai/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof. In certain embodiments, the a adrenergic agonist may be administered to a patient in need thereof in a composition comprising a therapeutically effective amount of the a adrenergic agonist, In certain embodiments, the composition may be suitable for topical administration or local administration.
[00031 Further embodiments of the present invention are directed to the inhibition of purpura in a subject undergoing a surgical procedure comprising administering a therapeutically effective amount of an a adrenergic agonist to said subject prior to, during or following the surgical procedure, wherein the extent or amount of purpura generated following the surgical procedure is inhibited or decreased. In certain embodiments, the a adrenergic agonist may be selected from a selective ai adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with az adrenergic receptor agonist activity and combinations thereof. In certain embodiments, the a adrenergic agonist may be administered to a patient in a composition comprising a therapeutically effective amount of the a adrenergic agonist. In certain embodiments, the composition may be suitable for topical administration or local administration.
H. Description of Drawings: Not Applicable I. Detailed Description =
(00041 Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.
Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods, devices, and materials are now described. Nothing herein is to be-construed as an admission that the invention is not entitled to antedate such disalosure by virtue of prior invention.
100051 Optical Isomers--Diastereomers--Geometric Isomers¨Tautomers. Compounds described herein may contain an asymmetric center and may thus exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereomers. The present invention includes all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers. The formulas are shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of such formulas and pharmaceutically acceptable salts thereof. Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of
G. Brief summary of the invention 100011 Embodiments of the present invention are directed to the use of an a adrenergic agonist for the treatment of vascular extravasation into the skin and particularly for the sequelae manifesting as cutaneous petechiae, purpura or ecchymoses. The a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective at/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof. The a adrenergic agonist may be administered to a patient in need thereof in a composition comprising a therapeutically effective amount of the a adrenergic agonist, such as a composition for topical administration.
[00021 Further embodiments of the present invention are directed to the treatment of purpura in a subject comprising administering a therapeutically effective amount of an a adrenergic agonist to said subject, wherein the purpura is treated. In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective ct2 adrenergic receptor agonist, non-selective ai/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof. In certain embodiments, the a adrenergic agonist may be administered to a patient in need thereof in a composition comprising a therapeutically effective amount of the a adrenergic agonist, In certain embodiments, the composition may be suitable for topical administration or local administration.
[00031 Further embodiments of the present invention are directed to the inhibition of purpura in a subject undergoing a surgical procedure comprising administering a therapeutically effective amount of an a adrenergic agonist to said subject prior to, during or following the surgical procedure, wherein the extent or amount of purpura generated following the surgical procedure is inhibited or decreased. In certain embodiments, the a adrenergic agonist may be selected from a selective ai adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with az adrenergic receptor agonist activity and combinations thereof. In certain embodiments, the a adrenergic agonist may be administered to a patient in a composition comprising a therapeutically effective amount of the a adrenergic agonist. In certain embodiments, the composition may be suitable for topical administration or local administration.
H. Description of Drawings: Not Applicable I. Detailed Description =
(00041 Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.
Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods, devices, and materials are now described. Nothing herein is to be-construed as an admission that the invention is not entitled to antedate such disalosure by virtue of prior invention.
100051 Optical Isomers--Diastereomers--Geometric Isomers¨Tautomers. Compounds described herein may contain an asymmetric center and may thus exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereomers. The present invention includes all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers. The formulas are shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of such formulas and pharmaceutically acceptable salts thereof. Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of
-2-enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or on a chiral HPLC column. Further, any enantiomer or diastereomer of a compound of the general formula may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
[0006] It must also be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise.
Thus, for example, reference to a "cell" is a reference to one or more cells and equivalents thereof known to those skilled in the art, and so forth.
[0007] As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%.
[0008] "Administering" when used in conjunction with a therapeutic means to administer a therapeutic directly into or onto a target tissue or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted.
Thus, as used herein, the term "administering", when used in conjunction with an ai or a2 adrenergic receptor agonist or composition thereof, can include, but is not limited to, providing an al or a2 adrenergic receptor agonist or composition thereof into or onto the target tissue; or providing an al or a2 adrenergic receptor agonist or composition thereof systemically to a patient by, e.g., intravenous injection whereby the therapeutic reaches the target tissue.
Administering an al or a2 adrenergic receptor agonist or composition thereof may be accomplished by local administration, such as injection directly into or around the site of purpura, topical administration, or by either method in combination with other known techniques [0009] The term "improves" is used to convey that the present invention changes either the appearance, form, characteristics and/or the physical attributes of the tissue to which it is being provided, applied or administered. The change in form may be demonstrated by any of the following alone or in combination: enhanced appearance of the skin; decrease in vascular extravasation into the skin; decrease in cutaneous petechiae, purpura or ecchymoses; decrease in pigmentation; and hastening the resolution of the purpuric/hemorrhagic skin lesions.
[0006] It must also be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise.
Thus, for example, reference to a "cell" is a reference to one or more cells and equivalents thereof known to those skilled in the art, and so forth.
[0007] As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%.
[0008] "Administering" when used in conjunction with a therapeutic means to administer a therapeutic directly into or onto a target tissue or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted.
Thus, as used herein, the term "administering", when used in conjunction with an ai or a2 adrenergic receptor agonist or composition thereof, can include, but is not limited to, providing an al or a2 adrenergic receptor agonist or composition thereof into or onto the target tissue; or providing an al or a2 adrenergic receptor agonist or composition thereof systemically to a patient by, e.g., intravenous injection whereby the therapeutic reaches the target tissue.
Administering an al or a2 adrenergic receptor agonist or composition thereof may be accomplished by local administration, such as injection directly into or around the site of purpura, topical administration, or by either method in combination with other known techniques [0009] The term "improves" is used to convey that the present invention changes either the appearance, form, characteristics and/or the physical attributes of the tissue to which it is being provided, applied or administered. The change in form may be demonstrated by any of the following alone or in combination: enhanced appearance of the skin; decrease in vascular extravasation into the skin; decrease in cutaneous petechiae, purpura or ecchymoses; decrease in pigmentation; and hastening the resolution of the purpuric/hemorrhagic skin lesions.
-3-[0010] The term "inhibiting" includes the administration of a compound of the present invention to prevent the onset of the symptoms, alleviating the symptoms, or eliminating the disease, condition or disorder.
[0011] The term "patient" and "subject" are interchangeable and may be taken to mean any living organism which may be treated with compounds of the present invention. As such, the terms may include, but are not limited to, any animal, mammal, primate or human, and preferably human.
[0012] The term "pharmaceutical composition" shall mean a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.
[0013] By "pharmaceutically acceptable", it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof [0014] "Pharmaceutically acceptable salt" is meant to indicate those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et a/. (1977) J. Pharm. Sciences, Vol 6. 1-19, describes pharmaceutically acceptable salts in detail.
[0015] For the purposes of this invention, a "salt" as used herein is any acid addition salt, preferably a pharmaceutically acceptable acid addition salt, including but not limited to, halogenic acid salts such as, for example, hydrobromic, hydrochloric, hydrofluoric and hydroiodic acid salt; an inorganic acid salt such as, for example, nitric, perchloric, sulfuric and phosphoric acid salt; an organic acid salt such as, for example, sulfonic acid salts (methanesulfonic, trifluoromethan sulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic), acetic, malic, fiimaric, succinic, citric, benzoic, gluconic, lactic, mandelic, mucic, pamoic, pantothenic, oxalic and maleic acid salts; and an amino acid salt such as aspartic
[0011] The term "patient" and "subject" are interchangeable and may be taken to mean any living organism which may be treated with compounds of the present invention. As such, the terms may include, but are not limited to, any animal, mammal, primate or human, and preferably human.
[0012] The term "pharmaceutical composition" shall mean a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.
[0013] By "pharmaceutically acceptable", it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof [0014] "Pharmaceutically acceptable salt" is meant to indicate those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et a/. (1977) J. Pharm. Sciences, Vol 6. 1-19, describes pharmaceutically acceptable salts in detail.
[0015] For the purposes of this invention, a "salt" as used herein is any acid addition salt, preferably a pharmaceutically acceptable acid addition salt, including but not limited to, halogenic acid salts such as, for example, hydrobromic, hydrochloric, hydrofluoric and hydroiodic acid salt; an inorganic acid salt such as, for example, nitric, perchloric, sulfuric and phosphoric acid salt; an organic acid salt such as, for example, sulfonic acid salts (methanesulfonic, trifluoromethan sulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic), acetic, malic, fiimaric, succinic, citric, benzoic, gluconic, lactic, mandelic, mucic, pamoic, pantothenic, oxalic and maleic acid salts; and an amino acid salt such as aspartic
-4-or glutamic acid salt. The acid addition salt may be a mono- or di-acid addition salt, such as a di-hydrohalogenic, di-sulfuric, di-phosphoric or di-organic acid salt.
100161 Unless otherwise indicated, the term "skin" means that outer integument or covering of the body, consisting of the dermis and the epidermis and resting upon subcutaneous tissue.
100171 As used herein, the term "therapeutic" means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient.
In part, embodiments of the present invention are directed to the treatment of purpura or the decrease in vascular extravasation.
100181 A "therapeutically effective amount" or "effective amount" of a composition is a predetermined amount calculated to achieve the desired effect, i.e., to decrease, block, or reverse purpura. The activity contemplated by the present methods includes both medical therapeutic and/or prophylactic treatment, as appropriate. As used herein, "therapeutically effective amount"
refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following as specified in the particular methodology: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reducing the severity of the pathology and/or symptomatology). The specific dose of a compound administered according to this invention to obtain therapeutic and/or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated.
The compounds are effective over a wide dosage range and, for example, dosages will normally fall within the range of from about 0.0025% to about 5%, more usually in the range of from about 0.005% to about
100161 Unless otherwise indicated, the term "skin" means that outer integument or covering of the body, consisting of the dermis and the epidermis and resting upon subcutaneous tissue.
100171 As used herein, the term "therapeutic" means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient.
In part, embodiments of the present invention are directed to the treatment of purpura or the decrease in vascular extravasation.
100181 A "therapeutically effective amount" or "effective amount" of a composition is a predetermined amount calculated to achieve the desired effect, i.e., to decrease, block, or reverse purpura. The activity contemplated by the present methods includes both medical therapeutic and/or prophylactic treatment, as appropriate. As used herein, "therapeutically effective amount"
refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following as specified in the particular methodology: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reducing the severity of the pathology and/or symptomatology). The specific dose of a compound administered according to this invention to obtain therapeutic and/or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated.
The compounds are effective over a wide dosage range and, for example, dosages will normally fall within the range of from about 0.0025% to about 5%, more usually in the range of from about 0.005% to about
-5-2%, more usually in the range of from about 0.05% to about 1 %, and more usually in the range of form about 0.1% to about 0.5% by weight. However, it will be understood that the effective amount administered will be determined by the physician in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. A therapeutically effective amount of compound of this invention is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue.
[0019] The terms "treat," "treated," or "treating" as used herein refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects.
[0020] Generally speaking, the term "tissue" refers to any aggregation of similarly specialized cells which are united in the performance of a particular function.
[0021] As used herein, "a adrenergic agonist" refers to an a adrenergic agonist, a prodrug, congener or pharmaceutically acceptable salt thereof and may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof. An a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine,
[0019] The terms "treat," "treated," or "treating" as used herein refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects.
[0020] Generally speaking, the term "tissue" refers to any aggregation of similarly specialized cells which are united in the performance of a particular function.
[0021] As used herein, "a adrenergic agonist" refers to an a adrenergic agonist, a prodrug, congener or pharmaceutically acceptable salt thereof and may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof. An a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine,
-6-=
=
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine. Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. Selective a2 adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine.
Agents with a2 adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
[00221 Embodiments of the present invention are directed to the use of an a adrenergic agonist, or pharmaceutically acceptable salt thereof, for the treatment of vascular extravasation into the skin and particularly for the sequelae manifesting as cutaneous petechiae, purpura or ecchymoses. In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and a combination thereof. Preferably, the a adrenergic agonist is administered to a patient in a composition, preferably for topical or local administration to a patient in need thereof. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoprotereno I, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol,
=
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine. Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. Selective a2 adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine.
Agents with a2 adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
[00221 Embodiments of the present invention are directed to the use of an a adrenergic agonist, or pharmaceutically acceptable salt thereof, for the treatment of vascular extravasation into the skin and particularly for the sequelae manifesting as cutaneous petechiae, purpura or ecchymoses. In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and a combination thereof. Preferably, the a adrenergic agonist is administered to a patient in a composition, preferably for topical or local administration to a patient in need thereof. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoprotereno I, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol,
-7-moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof.
Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, al-adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine. Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine.
Agents with az adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
100231 Embodiments of the present invention are directed toward the use of composition comprised of an a adrenergic agonist, which may be selected from a selective ai adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and a combination thereof in a pharmaceutically acceptable carrier in order to treat and improve the cosmetic appearance of these hemorrhagic lesions. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol, dip ivefri n, pseudo ephedrine, mephentermine, phenylpropano (amine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, meth ylpheni date, mi vazero I, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline,
Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, al-adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine. Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine.
Agents with az adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
100231 Embodiments of the present invention are directed toward the use of composition comprised of an a adrenergic agonist, which may be selected from a selective ai adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and a combination thereof in a pharmaceutically acceptable carrier in order to treat and improve the cosmetic appearance of these hemorrhagic lesions. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol, dip ivefri n, pseudo ephedrine, mephentermine, phenylpropano (amine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, meth ylpheni date, mi vazero I, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline,
-8-methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, al-adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine. Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine. Agents with a2 adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
100241 As used herein, the term "purpura" refers to any accumulation of blood in the skin due to vascular extravasation, irrespective of size or cause. As used herein, "purpura" refers to medical conditions commonly referred to as "petechiae" (pinpoint spots), "ecchymoses" (larger macular (flat) patches) and "purpura" (larger spots).
[0025] Purpura, in general, is hemorrhage of blood out of the vascular spaces and into the surrounding tissues of the skin or mucous membranes. This hemorrhage results in a collection of blood in the dermis of the skin that is visible initially as a dark purple/red discoloration that changes color as it breaks down and is resorbed.
[0026] In particular, purpura can be characterized as flat (macular or non-palpable) or raised (palpable or papular). The definition of macular purpuric subtypes include: Petechiae-defined as small purpura (less than 4 millimeters (mm) in diameter, purpura-defined as greater than 4 mm and less than I cm (centimeter) in diameter, and ecchymoses-defined as greater than 1 cm in diameter. The size divisions are not absolute but are useful rules of thumb and there is often a range in size of clinical purpuras in any one specific condition.
[0027] A bruise, also called a contusion or ecchymosis, is an injury to biological tissue in which the capillaries are damaged, allowing blood to seep into the surrounding tissue. Bruising is usually caused by a blunt impact and its likelihood and its severity increases as one ages due to thinning and loss of elasticity of the skin.
100241 As used herein, the term "purpura" refers to any accumulation of blood in the skin due to vascular extravasation, irrespective of size or cause. As used herein, "purpura" refers to medical conditions commonly referred to as "petechiae" (pinpoint spots), "ecchymoses" (larger macular (flat) patches) and "purpura" (larger spots).
[0025] Purpura, in general, is hemorrhage of blood out of the vascular spaces and into the surrounding tissues of the skin or mucous membranes. This hemorrhage results in a collection of blood in the dermis of the skin that is visible initially as a dark purple/red discoloration that changes color as it breaks down and is resorbed.
[0026] In particular, purpura can be characterized as flat (macular or non-palpable) or raised (palpable or papular). The definition of macular purpuric subtypes include: Petechiae-defined as small purpura (less than 4 millimeters (mm) in diameter, purpura-defined as greater than 4 mm and less than I cm (centimeter) in diameter, and ecchymoses-defined as greater than 1 cm in diameter. The size divisions are not absolute but are useful rules of thumb and there is often a range in size of clinical purpuras in any one specific condition.
[0027] A bruise, also called a contusion or ecchymosis, is an injury to biological tissue in which the capillaries are damaged, allowing blood to seep into the surrounding tissue. Bruising is usually caused by a blunt impact and its likelihood and its severity increases as one ages due to thinning and loss of elasticity of the skin.
-9-[0028] While not wishing to be bound by theory, we believe that by virtue of the fact that these compounds cause local vasoconstriction and a shunting of the blood back to deeper vessels due to their activity at the vascular a adrenergic receptors, their use may decrease the accumulation of blood (and hemosiderin, which is responsible for a long-lasting deep brown color) in the skin, resulting in a cosmetic improvement in these conditions.
[0029] Initially classified as either a or i3 subtype receptors based on anatomical location and functional considerations, in recent years, and with newer molecular genetic techniques, the simple model of two adrenergic receptors (adrenergic receptors) that mediate the vascular response to catecholamines has been replaced. The concept of "generic" a receptors, responsible mostly for "excitatory" functions such as vasoconstriction, uterine and urethral contraction and "generic" p receptors, responsible mostly for "inhibitory" functions such as vasodilatation, bronchodilation, uterine and urethral relaxation (though notably inotropic for the heart) has been further refined and specific receptor subtypes, localizations and functions have been elucidated.
The current model is that of a complex family of structurally related receptors consisting of at least six a receptor subtypes (alA (ala/c), a113, al D, a2A (a24/D), a213/
112c) and at least three f3 receptor subtypes (pi, P2, 133), with additional conformational variants such as aiL
and f34 bringing the total number of functional adrenergic receptor conformations to at least 11.
[0030] These adrenergic receptors are all members of the G-protein-coupled receptor (GPCR) superfamily of proteins and modulate their effects through a classic 7-transmembrane protein second-messenger system. Their final local and systemic effects however are myriad, as noted above, including vasoactive properties ranging from vasoconstriction to vasodilatation and occur through a wide variety of intracellular mechanisms, that are governed by local receptor subtype concentration, relative receptor subtype distribution throughout the body, ligand binding characteristics and other factors (e.g. local temperature, hypoxia). Elegant in vitro, in vivo and ex vivo studies in a variety of vascular tissues and species reveal that the contraction of peripheral vascular smooth muscle is primarily mediated by al A and aiD
receptor subtypes, though does vary somewhat in different vascular regions. a2 receptor studies suggest that D2A/D
and a2B effects are also of importance, particularly on the arterial side, and that the CtIvi) and a2c effects are of importance on the venular side, though variations based on the experimental model employed arc well reported. The actual physiologic and clinical responses to stimulating or inhibiting these receptors selectively is, however, difficult to predict.
[0029] Initially classified as either a or i3 subtype receptors based on anatomical location and functional considerations, in recent years, and with newer molecular genetic techniques, the simple model of two adrenergic receptors (adrenergic receptors) that mediate the vascular response to catecholamines has been replaced. The concept of "generic" a receptors, responsible mostly for "excitatory" functions such as vasoconstriction, uterine and urethral contraction and "generic" p receptors, responsible mostly for "inhibitory" functions such as vasodilatation, bronchodilation, uterine and urethral relaxation (though notably inotropic for the heart) has been further refined and specific receptor subtypes, localizations and functions have been elucidated.
The current model is that of a complex family of structurally related receptors consisting of at least six a receptor subtypes (alA (ala/c), a113, al D, a2A (a24/D), a213/
112c) and at least three f3 receptor subtypes (pi, P2, 133), with additional conformational variants such as aiL
and f34 bringing the total number of functional adrenergic receptor conformations to at least 11.
[0030] These adrenergic receptors are all members of the G-protein-coupled receptor (GPCR) superfamily of proteins and modulate their effects through a classic 7-transmembrane protein second-messenger system. Their final local and systemic effects however are myriad, as noted above, including vasoactive properties ranging from vasoconstriction to vasodilatation and occur through a wide variety of intracellular mechanisms, that are governed by local receptor subtype concentration, relative receptor subtype distribution throughout the body, ligand binding characteristics and other factors (e.g. local temperature, hypoxia). Elegant in vitro, in vivo and ex vivo studies in a variety of vascular tissues and species reveal that the contraction of peripheral vascular smooth muscle is primarily mediated by al A and aiD
receptor subtypes, though does vary somewhat in different vascular regions. a2 receptor studies suggest that D2A/D
and a2B effects are also of importance, particularly on the arterial side, and that the CtIvi) and a2c effects are of importance on the venular side, though variations based on the experimental model employed arc well reported. The actual physiologic and clinical responses to stimulating or inhibiting these receptors selectively is, however, difficult to predict.
-10-100311 Though initially felt to modulate their effects purely through their vasoconstrictive properties, in recent years it has been demonstrated that several of the a vasoconstrictors also exhibit significant anti-inflammatory properties. In upper respiratory tract infections, oxymetazoline and xylometazoline have been shown to inhibit neutrophilic phagocytosis and oxidative burst, resulting in a decrease in microbial killing, decreased generation of pro-inflammatory cytokines, and decreased inflammation.
Oxymetazoline has also recently been shown to have significant effects on the arachadonic acid cascade, strongly inhibiting 5-lipoxygenase activity thus decreasing the synthesis of the highly proinflammatory leukotriene 134. A potential clinical role for oxymetazoline, or other agents of this class, as inhibitors of inflammation and oxidative-stress dependent reactions in inflammatory and/or infectious skin conditions is intriguing, but has yet to be investigated.
[00321 Further embodiments of the present invention provide methods and compositions for treating purpura and other conditions of the skin characterized by intradermal cutaneous hemorrhages (e.g., petechiae, purpura, ecchymoses) by administering an a adrenergic receptor agonist to a patient in need thereof. In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof. In certain embodiments, a therapeutically effective amount of selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective ai/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozo line, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, arnidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof. Selective ai adrenergic receptor agonist may be selected
Oxymetazoline has also recently been shown to have significant effects on the arachadonic acid cascade, strongly inhibiting 5-lipoxygenase activity thus decreasing the synthesis of the highly proinflammatory leukotriene 134. A potential clinical role for oxymetazoline, or other agents of this class, as inhibitors of inflammation and oxidative-stress dependent reactions in inflammatory and/or infectious skin conditions is intriguing, but has yet to be investigated.
[00321 Further embodiments of the present invention provide methods and compositions for treating purpura and other conditions of the skin characterized by intradermal cutaneous hemorrhages (e.g., petechiae, purpura, ecchymoses) by administering an a adrenergic receptor agonist to a patient in need thereof. In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof. In certain embodiments, a therapeutically effective amount of selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective ai/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozo line, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, arnidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof. Selective ai adrenergic receptor agonist may be selected
-11-from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, al -adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride. Selective az adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine. Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine. Agents with a2 adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
[0033] Another embodiment of the present invention provides methods and compositions for treating other conditions of the skin characterized by intradermal hemorrhage and skin discoloration due to the resorption of the intracutaneous blood accumulation comprising administering an a adrenergic receptor agonist to a patient in need thereof.
In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective al/a2 adrenergic receptor agonist, agents with az adrenergic receptor agonist activity and combinations thereof.
In certain embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, am idephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline,
[0033] Another embodiment of the present invention provides methods and compositions for treating other conditions of the skin characterized by intradermal hemorrhage and skin discoloration due to the resorption of the intracutaneous blood accumulation comprising administering an a adrenergic receptor agonist to a patient in need thereof.
In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective al/a2 adrenergic receptor agonist, agents with az adrenergic receptor agonist activity and combinations thereof.
In certain embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, am idephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline,
-12-tizanidine and combinations thereof. Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazol ine, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, al -adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride. Selective az adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, aradrenergic receptor agonist is preferably brimonidine. Non-selective cti/az adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine. Agents with az adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroarnphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
[00341 Another embodiment of the present invention provides methods and compositions for improvement of bruising comprising administering an a adrenergic receptor agonist to a patient in need thereof. In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective al/az adrenergic receptor agonist, agents with az adrenergic receptor agonist activity and combinations thereof. In certain embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, elonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, i soprotereno I, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), eth ylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetarnine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof. Selective al
[00341 Another embodiment of the present invention provides methods and compositions for improvement of bruising comprising administering an a adrenergic receptor agonist to a patient in need thereof. In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective al/az adrenergic receptor agonist, agents with az adrenergic receptor agonist activity and combinations thereof. In certain embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, elonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, i soprotereno I, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), eth ylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetarnine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof. Selective al
-13-=
adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, a1-adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride.
Selective a2 adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine.
Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine.
Agents with a2 adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
100351 Other embodiments of the present invention are methods and compositions for treating the cutaneous manifestations of intrinsic (chronological) and extrinsic (e.g. caused by sun exposure, smoking, etc) aging of the skin including, but not limited to, purpura (or "bruising"), skin wrinkling, sallow-yellow skin discoloration, dark circles under the eyes, bruising, bruising caused by laser administration, and hyperpigmentation comprising administering an a adrenergic receptor agonist to a patient in need thereof.
In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof.
In certain embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, x ylometazo line, methoxamine, metaraminol, midodrine, desgl ym idodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, phenylpropanol amine, propylhexadrine,
adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, a1-adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride.
Selective a2 adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine.
Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine.
Agents with a2 adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
100351 Other embodiments of the present invention are methods and compositions for treating the cutaneous manifestations of intrinsic (chronological) and extrinsic (e.g. caused by sun exposure, smoking, etc) aging of the skin including, but not limited to, purpura (or "bruising"), skin wrinkling, sallow-yellow skin discoloration, dark circles under the eyes, bruising, bruising caused by laser administration, and hyperpigmentation comprising administering an a adrenergic receptor agonist to a patient in need thereof.
In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof.
In certain embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, x ylometazo line, methoxamine, metaraminol, midodrine, desgl ym idodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, phenylpropanol amine, propylhexadrine,
-14-amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof. Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylom etazo line, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, al-adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine. Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine. Agents with a2 adrenergic receptor agonist activity may be selected from phenylpropanolarnine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemo line, and tizanidine.
100361 Further embodiment of the present invention provides methods and compositions for decreasing bruising caused by laser by administering an a adrenergic receptor agonist to a patient in need thereof prior to or soon after laser treatment. In certain embodiments, the a adrenergic agonist may be selected from a selective at adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof. In certain embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient.
In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidcphrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-m ethyldopa, epinephrine, norepinephrine, i soproterenol, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine,
100361 Further embodiment of the present invention provides methods and compositions for decreasing bruising caused by laser by administering an a adrenergic receptor agonist to a patient in need thereof prior to or soon after laser treatment. In certain embodiments, the a adrenergic agonist may be selected from a selective at adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof. In certain embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient.
In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidcphrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-m ethyldopa, epinephrine, norepinephrine, i soproterenol, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine,
-15-= CA 2703109 2017-03-03 ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a -methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof.
Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, ar-adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine. Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine.
Agents with az adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
1003711 Further embodiments of the present invention provide methods and compositions for resolving purpura using such a laser or a non-laser light source in combination with an al adrenergic receptor agonist, an a2 adrenergic receptor agonist or a combination thereof to a patient in need thereof prior to, during or following the use of such a laser.
In certain embodiments, the a adrenergic agonist may be selected from a selective ai adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective al/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof.
In certain embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol,
Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, ar-adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine. Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine.
Agents with az adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
1003711 Further embodiments of the present invention provide methods and compositions for resolving purpura using such a laser or a non-laser light source in combination with an al adrenergic receptor agonist, an a2 adrenergic receptor agonist or a combination thereof to a patient in need thereof prior to, during or following the use of such a laser.
In certain embodiments, the a adrenergic agonist may be selected from a selective ai adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective al/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof.
In certain embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol,
-16-.
dipivefrin, pseudo ephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof. Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazo line, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, a1-adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine. Non-selective al /a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine. Agents with a2 adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methatnphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
[00381 Further embodiments of the present invention provide methods and compositions for treatment of purpura conditions caused by a surgical procedure involving physical trauma to the skin and/or cutaneous vasculature. As used herein, the term surgical procedure refers to any intervention that may result in an injury to biological tissue in which the skin, cutaneous and subcutaneous vascular and surrounding tissues might sustain injury that would allow blood to seep into the surrounding tissue. Such interventions include, but are not limited to needle-sticks (e.g. for phlebotomy or infusion), injection of therapeutic agents (e.g.
vaccines or sclerotherapy, injection of neurotoxins or fillers for soft-tissue augmentation, cold-steel surgery (e.g.
"incisional" or "excisional" surgery), "minimally-invasive" procedures (e.g.
laparoscopic, arthroscopic procedures, liposuction), laser, thermal, intense pulsed light (IPL), other electromagnetic radiation-based procedures, radiofrequency, chemical, electro-surgical and ultrasonic procedures. In such embodiments, a therapeutically effective amount of the a adrenergic receptor agonist, is administered to a patient prior to, during and/or after said surgical
dipivefrin, pseudo ephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof. Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazo line, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, a1-adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine. Non-selective al /a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine. Agents with a2 adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methatnphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
[00381 Further embodiments of the present invention provide methods and compositions for treatment of purpura conditions caused by a surgical procedure involving physical trauma to the skin and/or cutaneous vasculature. As used herein, the term surgical procedure refers to any intervention that may result in an injury to biological tissue in which the skin, cutaneous and subcutaneous vascular and surrounding tissues might sustain injury that would allow blood to seep into the surrounding tissue. Such interventions include, but are not limited to needle-sticks (e.g. for phlebotomy or infusion), injection of therapeutic agents (e.g.
vaccines or sclerotherapy, injection of neurotoxins or fillers for soft-tissue augmentation, cold-steel surgery (e.g.
"incisional" or "excisional" surgery), "minimally-invasive" procedures (e.g.
laparoscopic, arthroscopic procedures, liposuction), laser, thermal, intense pulsed light (IPL), other electromagnetic radiation-based procedures, radiofrequency, chemical, electro-surgical and ultrasonic procedures. In such embodiments, a therapeutically effective amount of the a adrenergic receptor agonist, is administered to a patient prior to, during and/or after said surgical
-17-procedure, such that the formation of purpura (extent, duration, amount, size) is inhibited or decreased. In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective ai/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof. In certain embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol, dip i vefrin, pseudoephedrine, mephentermine, phenylpropanolamine, prop ylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof. Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, x ylometazo line, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, aradrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine. Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephenterrnine. Agents with a2 adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroaniphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexi dine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
[0039] Further embodiments of the present invention provide methods and compositions for preventing purpura caused by a surgical procedure involving physical trauma to the skin
[0039] Further embodiments of the present invention provide methods and compositions for preventing purpura caused by a surgical procedure involving physical trauma to the skin
-18-and/or cutaneous vasculature, such as, for example, external blunt-force trauma, internal blunt-force trauma (e.g. liposuction trauma or surgical undermining trauma), "sharp"
trauma (e.g. skin incision, skin puncture, needle stick), laceration, dermabrasion, chemical burn, thermal burn, and electrical burn. In such embodiments, a therapeutically effective amount of the a adrenergic receptor agonist, is administered to a patient prior to, during and/or after said surgical procedure, such that the formation of purpura (extent, duration, amount, size) is prevented. In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective az adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with az adrenergic receptor agonist activity and combinations thereof.
In certain embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, _ tetrahydrozoline, phenylephrine, xylometazol ine, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof. Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidothine, cirazoline, and amidephrine. In further embodiments, a1-adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride. Selective az adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, aradrenergic receptor agonist is preferably brimonidine. Non-selective ailaz adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephenterrnine. Agents with az adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
trauma (e.g. skin incision, skin puncture, needle stick), laceration, dermabrasion, chemical burn, thermal burn, and electrical burn. In such embodiments, a therapeutically effective amount of the a adrenergic receptor agonist, is administered to a patient prior to, during and/or after said surgical procedure, such that the formation of purpura (extent, duration, amount, size) is prevented. In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective az adrenergic receptor agonist, non-selective a1/a2 adrenergic receptor agonist, agents with az adrenergic receptor agonist activity and combinations thereof.
In certain embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is administered. In certain embodiments, the a adrenergic receptor agonist is administered topically or locally to the patient. In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, _ tetrahydrozoline, phenylephrine, xylometazol ine, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof. Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidothine, cirazoline, and amidephrine. In further embodiments, a1-adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride. Selective az adrenergic receptor agonist may be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, aradrenergic receptor agonist is preferably brimonidine. Non-selective ailaz adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephenterrnine. Agents with az adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
-19-(deoxyepinephrine), ethylnorepinephrine, levartereno I (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
[0040] Further embodiments of the present invention provide compositions comprising at least one al adrenergic receptor agonist and/or at least one a2 adrenergic receptor agonist, alone or in combination, into a cosmetic, pharmaceutical or dermatological composition for decreasing and/or preventing purpura and other conditions of the skin characterized by intradermal cutaneous hemorrhages and to administer said compositions to a mammal, notably a human, in order to treat or prevent the disease states indicated above.
[0041] Further embodiments of the present invention provide compositions comprising at an a adrenergic receptor agonist in a cosmetic, pharmaceutical or dermatological composition for decreasing and/or preventing purpura and other conditions of the skin characterized by intradermal cutaneous hemorrhages. In certain embodiments, the a adrenergic receptor agonist may be selected from a selective al adrenergic receptor agonist, selective ct2 adrenergic receptor agonist, non-selective ai/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof. In some embodiments, the composition may further comprise other agents known to be effective in treating purpura.
[00421 Embodiments of the present invention are directed to methods for treating purpura and other conditions of the skin characterized by intradermal cutaneous hemorrhages in a patient in need of such treatment, comprising the administration, preferably topical or local, of a therapeutically effective amount of a composition comprising an a-adrenergic receptor agonist.
In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a3/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof.
[0043] In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, i soprotereno 1, dip ivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine),
[0040] Further embodiments of the present invention provide compositions comprising at least one al adrenergic receptor agonist and/or at least one a2 adrenergic receptor agonist, alone or in combination, into a cosmetic, pharmaceutical or dermatological composition for decreasing and/or preventing purpura and other conditions of the skin characterized by intradermal cutaneous hemorrhages and to administer said compositions to a mammal, notably a human, in order to treat or prevent the disease states indicated above.
[0041] Further embodiments of the present invention provide compositions comprising at an a adrenergic receptor agonist in a cosmetic, pharmaceutical or dermatological composition for decreasing and/or preventing purpura and other conditions of the skin characterized by intradermal cutaneous hemorrhages. In certain embodiments, the a adrenergic receptor agonist may be selected from a selective al adrenergic receptor agonist, selective ct2 adrenergic receptor agonist, non-selective ai/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof. In some embodiments, the composition may further comprise other agents known to be effective in treating purpura.
[00421 Embodiments of the present invention are directed to methods for treating purpura and other conditions of the skin characterized by intradermal cutaneous hemorrhages in a patient in need of such treatment, comprising the administration, preferably topical or local, of a therapeutically effective amount of a composition comprising an a-adrenergic receptor agonist.
In certain embodiments, the a adrenergic agonist may be selected from a selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a3/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof.
[0043] In embodiments of the present invention, the a adrenergic agonist may be selected from oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, epinephrine, norepinephrine, i soprotereno 1, dip ivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine),
-20-= CA 2703109 2017-03-03 lofexidine, methamphetamine, a ¨methylnorepinephrine, meth ylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof.
[00441 Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrah ydrozol ine, phenyl ephrine, xylometazol ine, methox amine, met araminol , midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, a 1-adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride.
[0045] Selective az adrenergic receptor agonist may be selected from brimonidine, clonidine, guarifacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine.
[0046] Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine.
100471 Agents with a2 adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethyl norepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
[0048] Preferably, the composition comprises at least one selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective ai/az adrenergic receptor agonist, and agents with a2 adrenergic receptor agonist activity formulated in a pharmaceutically acceptable medium. For example, a gel, cream, lotion or solution which may be administered by spreading the gel, cream, lotion or solution onto or surrounding the affected area.
[0049] Other embodiments may also include combinations of therapeutically effective amounts of combinations of a selective ai adrenergic receptor agonist, a selective az adrenergic receptor agonist, a non-selective a1/a2 adrenergic receptor agonist, and agents with az adrenergic receptor agonist activity. The therapeutically effective amount of each agent may be significantly decreased when used in combination with other a-adrenergic receptor agonist than when used as the sole active agent.
[00501 Preferred embodiments may also include enhancers of cutaneous penetration or inhibitors or regulators of cutaneous penetration as required to increase therapeutic efficacy
[00441 Selective al adrenergic receptor agonist may be selected from oxymetazoline, tetrah ydrozol ine, phenyl ephrine, xylometazol ine, methox amine, met araminol , midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, a 1-adrenergic receptor agonist is preferably oxymetazoline, tetrahydrozoline, and phenylephrine hydrochloride.
[0045] Selective az adrenergic receptor agonist may be selected from brimonidine, clonidine, guarifacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine.
[0046] Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine.
100471 Agents with a2 adrenergic receptor agonist activity may be selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethyl norepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a ¨methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, and tizanidine.
[0048] Preferably, the composition comprises at least one selective al adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective ai/az adrenergic receptor agonist, and agents with a2 adrenergic receptor agonist activity formulated in a pharmaceutically acceptable medium. For example, a gel, cream, lotion or solution which may be administered by spreading the gel, cream, lotion or solution onto or surrounding the affected area.
[0049] Other embodiments may also include combinations of therapeutically effective amounts of combinations of a selective ai adrenergic receptor agonist, a selective az adrenergic receptor agonist, a non-selective a1/a2 adrenergic receptor agonist, and agents with az adrenergic receptor agonist activity. The therapeutically effective amount of each agent may be significantly decreased when used in combination with other a-adrenergic receptor agonist than when used as the sole active agent.
[00501 Preferred embodiments may also include enhancers of cutaneous penetration or inhibitors or regulators of cutaneous penetration as required to increase therapeutic efficacy
-21-and/or decrease systemic absorption and any potential undesirable systemic effects of the active agent(s).
[0051] Further embodiments of the present invention provide methods of treating such conditions by administering one or more ai-adrenergic receptor agonists alone or in combination with one or more and a2-adrenergic receptor agonists (alone or in combination) with active agents for preventing and/or treating other skin complaints, conditions and afflictions. Examples of these agents include: (i) antirosacea agents such as metronidazole, precipitated sulfur, sodium sulfacetamide, or azelaic acid; (ii) antibacterial agents (antibiotics) such as clindamycin phosphate, erythromycin, or antibiotics from the tetracycline family; (iii) antimycobacterial agents such as dapsone; (iv) antiacne agents such as retinoids, or benzoyl peroxide; (v) antiparasitic agents such as metronidazole, permetluin, crotamiton or pyrethroids; (vi) antifungal agents such as compounds of the imidazole family such as miconazole, clotrimazole, econazole, ketoconazole, or salts thereof, polyene compounds such as amphotericin B, compound of the allylamine family such as terbinafine; (vii) steroidal anti-inflammatory agents such as hydrocortisone triamcinolone, fluocinonide, betamethasone valerate or clobetasol propionate, or non-steroidal anti-inflammatory agents such as ibuprofen and salts thereof, naproxen and salts thereof, or acetaminophen; (viii) anesthetic agents such as lidocaine, prilocaine, tetracaine, hydrochloride and derivatives thereof; (ix) antipruriginous agents such as thenaldine, trimeprazine, or pramoxine; (x) antiviral agents such as acyclovir; (xi) keratolytic agents such as alpha- and beta-hydroxy acids such as glycolic acid or salicylic acid, or urea; (xii) anti-free radical agents (antioxidants) such as vitamin E (alpha tocopherol) and its derivatives, vitamin C
(ascorbic acid), vitamin A (retinol) tretinoin, retinal and their derivatives, vitamin K., superoxide dismutase and derivatives of plants, particularly of the genus Arnica, such as sesquiterpene lactones (xiii) antiseborrheic agents such as zinc pyrithione and selenium sulfide; (xiv) antihistamines such as cyproheptadine or hydroxyzine; (xv) tricyclic antidepressants such as doxepin hydrochloride and (xvi) combinations thereof.
[0052] For example, in some aspects, the invention is directed to a pharmaceutical composition comprising a selective al adrenergic receptor agonist, a selective a2 adrenergic receptor agonist, a non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof and a pharmaceutically acceptable carrier or
[0051] Further embodiments of the present invention provide methods of treating such conditions by administering one or more ai-adrenergic receptor agonists alone or in combination with one or more and a2-adrenergic receptor agonists (alone or in combination) with active agents for preventing and/or treating other skin complaints, conditions and afflictions. Examples of these agents include: (i) antirosacea agents such as metronidazole, precipitated sulfur, sodium sulfacetamide, or azelaic acid; (ii) antibacterial agents (antibiotics) such as clindamycin phosphate, erythromycin, or antibiotics from the tetracycline family; (iii) antimycobacterial agents such as dapsone; (iv) antiacne agents such as retinoids, or benzoyl peroxide; (v) antiparasitic agents such as metronidazole, permetluin, crotamiton or pyrethroids; (vi) antifungal agents such as compounds of the imidazole family such as miconazole, clotrimazole, econazole, ketoconazole, or salts thereof, polyene compounds such as amphotericin B, compound of the allylamine family such as terbinafine; (vii) steroidal anti-inflammatory agents such as hydrocortisone triamcinolone, fluocinonide, betamethasone valerate or clobetasol propionate, or non-steroidal anti-inflammatory agents such as ibuprofen and salts thereof, naproxen and salts thereof, or acetaminophen; (viii) anesthetic agents such as lidocaine, prilocaine, tetracaine, hydrochloride and derivatives thereof; (ix) antipruriginous agents such as thenaldine, trimeprazine, or pramoxine; (x) antiviral agents such as acyclovir; (xi) keratolytic agents such as alpha- and beta-hydroxy acids such as glycolic acid or salicylic acid, or urea; (xii) anti-free radical agents (antioxidants) such as vitamin E (alpha tocopherol) and its derivatives, vitamin C
(ascorbic acid), vitamin A (retinol) tretinoin, retinal and their derivatives, vitamin K., superoxide dismutase and derivatives of plants, particularly of the genus Arnica, such as sesquiterpene lactones (xiii) antiseborrheic agents such as zinc pyrithione and selenium sulfide; (xiv) antihistamines such as cyproheptadine or hydroxyzine; (xv) tricyclic antidepressants such as doxepin hydrochloride and (xvi) combinations thereof.
[0052] For example, in some aspects, the invention is directed to a pharmaceutical composition comprising a selective al adrenergic receptor agonist, a selective a2 adrenergic receptor agonist, a non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof and a pharmaceutically acceptable carrier or
-22-diluent, or an effective amount of a pharmaceutical composition comprising a compound as defined above.
[00531 The compositions may be formulated to be administered orally, ophthalmically, intravenously, intramuscularly, intra-arterially, intramedularry, intrathecally, intraventricularly, transdermally, subcutaneously, intraperitoneally, intravesicularly, intranasally, eternally, topically, sublingually, or rectally, preferably topically or locally.
[0054a] Embodiments of the invention include compositions comprising an a adrenergic receptor agonist, preferably a selective al adrenergic receptor agonist, a selective az adrenergic receptor agonist, a non-selective u1/a2 adrenergic receptor agonist, agents with az adrenergic receptor agonist activity and combinations thereof. Preferably the compositions may be administered topically or locally. The compounds of the present invention can be administered in the conventional manner by any route where they are active. Administration can be systemic, topical, or oral. For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, or ocular routes, or intravaginally, intravesicularly, by inhalation, by depot injections, or by implants.
Thus, modes of administration for the compounds of the present invention (either alone or in combination with other pharmaceuticals) can be, but are not limited to, sublingual, injectable (including short-acting, depot, implant and pellet forms injected subcutaneously or intramuscularly), or by use of vaginal creams, suppositories, pessaries, vaginal rings, rectal suppositories, intrauterine devices, and transdermal forms such as patches and creams.
[0054b] In an embodiment the a adrenergic agonist may be in a solution, gel, lotion, cream, ointment, foam, emulsion, micro-emulsion, milk, serum, aerosol, spray, dispersion, microcapsule, vesicle or microparticle thereof, soap or cleansing bar.
[0055] One of ordinary skill in the art will understand and appreciate the dosages and timing of said dosages to be administered to a patient in need thereof. The doses and duration of treatment may vary, and may be based on assessment by one of ordinary skill in the art based on monitoring and measuring improvements in skin tissues. This assessment may be made based on outward physical signs of improvement, such as decreased redness, or other physiological signs or markers. The doses may also depend on the condition or disease being treated, the degree of the condition or disease being treated and further on the age and weight of the patient.
100561 Specific modes of administration will depend on the indication. The selection of the specific route of administration and the dose regimen may be adjusted or titrated by the clinician according to methods known to the clinician in order to obtain the optimal clinical
[00531 The compositions may be formulated to be administered orally, ophthalmically, intravenously, intramuscularly, intra-arterially, intramedularry, intrathecally, intraventricularly, transdermally, subcutaneously, intraperitoneally, intravesicularly, intranasally, eternally, topically, sublingually, or rectally, preferably topically or locally.
[0054a] Embodiments of the invention include compositions comprising an a adrenergic receptor agonist, preferably a selective al adrenergic receptor agonist, a selective az adrenergic receptor agonist, a non-selective u1/a2 adrenergic receptor agonist, agents with az adrenergic receptor agonist activity and combinations thereof. Preferably the compositions may be administered topically or locally. The compounds of the present invention can be administered in the conventional manner by any route where they are active. Administration can be systemic, topical, or oral. For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, or ocular routes, or intravaginally, intravesicularly, by inhalation, by depot injections, or by implants.
Thus, modes of administration for the compounds of the present invention (either alone or in combination with other pharmaceuticals) can be, but are not limited to, sublingual, injectable (including short-acting, depot, implant and pellet forms injected subcutaneously or intramuscularly), or by use of vaginal creams, suppositories, pessaries, vaginal rings, rectal suppositories, intrauterine devices, and transdermal forms such as patches and creams.
[0054b] In an embodiment the a adrenergic agonist may be in a solution, gel, lotion, cream, ointment, foam, emulsion, micro-emulsion, milk, serum, aerosol, spray, dispersion, microcapsule, vesicle or microparticle thereof, soap or cleansing bar.
[0055] One of ordinary skill in the art will understand and appreciate the dosages and timing of said dosages to be administered to a patient in need thereof. The doses and duration of treatment may vary, and may be based on assessment by one of ordinary skill in the art based on monitoring and measuring improvements in skin tissues. This assessment may be made based on outward physical signs of improvement, such as decreased redness, or other physiological signs or markers. The doses may also depend on the condition or disease being treated, the degree of the condition or disease being treated and further on the age and weight of the patient.
100561 Specific modes of administration will depend on the indication. The selection of the specific route of administration and the dose regimen may be adjusted or titrated by the clinician according to methods known to the clinician in order to obtain the optimal clinical
-23-response. The amount of compound to be administered may be that amount which is therapeutically effective. The dosage to be administered may depend on the characteristics of the subject being treated, e.g., the particular animal or human subject treated, age, weight, health, types of concurrent treatment, if any, and frequency of treatments, and can be easily determined by one of skill in the art (e.g, by the clinician).
[0057] A preferable route of administration of the compositions of the present invention may be topical or local.
[0058] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
[0059] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or acetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
[0060] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting
[0057] A preferable route of administration of the compositions of the present invention may be topical or local.
[0058] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
[0059] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or acetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
[0060] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting
-24-agents and suspending agents are exemplified by those already mentioned above.
Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
100611 The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
The emulsions may also contain sweetening and flavoring agents.
100621 Pharmaceutical formulations comprising the compounds of the present invention and a suitable carrier may also be any number of solid dosage forms which include, but are not limited to, tablets, capsules, cachets, pellets, pills, powders and granules;
topical dosage forms which include, but are not limited to, solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels and jellies, and foams; and parenteral dosage forms which include, but are not limited to, solutions, suspensions, emulsions, and dry powder;
comprising an effective amount of a polymer or copolymer of the present invention. It is also known in the art that the active ingredients can be contained in such formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like. The means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman &
Gilman '.s The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980) can be consulted.
100631 The compounds of the present invention can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
The compounds can be administered by continuous infusion over a period of about 15 minutes to about 24 hours.
Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as
Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
100611 The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
The emulsions may also contain sweetening and flavoring agents.
100621 Pharmaceutical formulations comprising the compounds of the present invention and a suitable carrier may also be any number of solid dosage forms which include, but are not limited to, tablets, capsules, cachets, pellets, pills, powders and granules;
topical dosage forms which include, but are not limited to, solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels and jellies, and foams; and parenteral dosage forms which include, but are not limited to, solutions, suspensions, emulsions, and dry powder;
comprising an effective amount of a polymer or copolymer of the present invention. It is also known in the art that the active ingredients can be contained in such formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like. The means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman &
Gilman '.s The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980) can be consulted.
100631 The compounds of the present invention can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
The compounds can be administered by continuous infusion over a period of about 15 minutes to about 24 hours.
Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as
-25-suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
[00641 For oral administration, the compounds can be formulated readily by combining these compounds with pharmaceutically acceptable carriers well known in the art. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline. Some examples of the materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt, gelatin, talc;
excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide;
alginic acid; pyrogen-free water; isotonic saline, Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharniaceutical preparations for oral use can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, marmitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as, but not limited to, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
[00651 Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added
[00641 For oral administration, the compounds can be formulated readily by combining these compounds with pharmaceutically acceptable carriers well known in the art. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline. Some examples of the materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt, gelatin, talc;
excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide;
alginic acid; pyrogen-free water; isotonic saline, Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharniaceutical preparations for oral use can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, marmitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as, but not limited to, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
[00651 Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added
-26-to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
[0066] Pharmaceutical preparations which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as, e.g., lactose, binders such as, e.g., starches, and/or lubricants such as, e.g., talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.
[0067] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
[0068] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
[0069] For buccal or sublingual administration, the compositions can take the form of tablets, flash melts or lozenges formulated in any conventional manner.
[0070] For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[0071] The compounds of the present invention can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
[0066] Pharmaceutical preparations which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as, e.g., lactose, binders such as, e.g., starches, and/or lubricants such as, e.g., talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.
[0067] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
[0068] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
[0069] For buccal or sublingual administration, the compositions can take the form of tablets, flash melts or lozenges formulated in any conventional manner.
[0070] For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[0071] The compounds of the present invention can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
-27-[0072] In addition to the formulations described previously, the compounds of the present invention can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
[00731 Depot injections can be administered at about 1 to about 6 months or longer intervals. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
10074] In transdermal administration, the compounds of the present invention, for example, can be applied to a plaster, or can be applied by transdermal, therapeutic systems that are consequently supplied to the organism.
[0075] Pharmaceutical and therapeutic compositions of the compounds also can comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as, e.g., polyethylene glycols.
(00761 (0077] While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts which can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not limit the scope of the invention. Various modifications and combinations of the illustrative embodiments, as well as other embodiments of the invention, will be apparent to persons skilled in the art upon reference to the description.
100781 In order to evaluate the effect of topically applied al and a2 adrenergic agonists on the resolution of purpura, purpuric macules/ patches were experimentally created on the trunk of
[00731 Depot injections can be administered at about 1 to about 6 months or longer intervals. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
10074] In transdermal administration, the compounds of the present invention, for example, can be applied to a plaster, or can be applied by transdermal, therapeutic systems that are consequently supplied to the organism.
[0075] Pharmaceutical and therapeutic compositions of the compounds also can comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as, e.g., polyethylene glycols.
(00761 (0077] While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts which can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not limit the scope of the invention. Various modifications and combinations of the illustrative embodiments, as well as other embodiments of the invention, will be apparent to persons skilled in the art upon reference to the description.
100781 In order to evaluate the effect of topically applied al and a2 adrenergic agonists on the resolution of purpura, purpuric macules/ patches were experimentally created on the trunk of
-28-a volunteer. Seven sites were marked, and utilizing a pulsed-dye laser (585 nm) and laser light parameters known to be purpurogenic, purpuric macules/ patches were successfully induced at each site. Immediately after the laser energy was delivered, the topical application of commercially available al and/or 0.2 adrenergic agonist preparations was begun. The preparations were applied to the skin and gently rubbed on the skin over and immediately surrounding the laser treatment sites every 6-8 hours (3-4 times/ day). The applied solution was allowed to air-dry without any dressing. The areas were followed clinically and photographically. The evaluated compounds were:
100791 Site 1: Oxymetazoline hydrochloride (0.05%): A solution of oxymetazoline hydrochloride 0.05% (Akin Original 12 Hour Nasal Spray (Schering-Plough Healthcare Products) containing: oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution, edetate disodium, polyethylene glycol, povidone, propylene glycol, purified water, sodium phosphate dibasic, sodium phosphate monobasic.
100801 Site 2: Naphazoline hydrochloride (0.03%): A solution of naphazoline hydrochloride 0.03% (Clear Eyes Maximum Redness Relief (Prestige Brands Inc.) containing:
naphazoline hydrochloride 0.03%, glycerin 0.5%, benzalkonium chloride, boric acid, edetate disodium, purified water, sodium borate).
100811 Site 3: Tetrahydrozoline hydrochloride (0.05%): A solution of tetrahydrozoline hydrochloride 0.05% (Visine Original (Pfizer Consumer Healthcare) containing:
tetrahydrozoline hydrochloride 0.05%, benzalkonium chloride, boric acid, edetate disodium, purified water, sodium borate, sodium chloride).
100821 Site 4: Phenylephrine hydrochloride (1.0%): A solution of phenylephrine hydrochloride 1.0% (Neo-Synephrine Extra Strength Spray (Bayer HealthCare) containing:
phenylephrine hydrochloride 1.0%, anhydrous citric acid, benzalkonium chloride, sodium chloride, sodium citrate, water).
[0083] Site 5: Brimonidine tartrate (0.2%): A solution of brimonidine tartrate 0.2%
(Bausch & Lomb Inc.) containing: brimonidine tartrate 0.02%, citric acid, polyvinyl alcohol, sodium chloride, sodium citrate, purified water, benzalkonium chloride (0.005%).
100841 Site 6: Oxymctazoline hydrochloride 0.05% and brimonidine tartrate 0.2%: The solution of oxymetazoline hydrochloride 0.05% (Afi=in Original 12 Hour Nasal Spray (Schering-Plough Healthcare Products) containing: oxymetazoline hydrochloride 0.05%,
100791 Site 1: Oxymetazoline hydrochloride (0.05%): A solution of oxymetazoline hydrochloride 0.05% (Akin Original 12 Hour Nasal Spray (Schering-Plough Healthcare Products) containing: oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution, edetate disodium, polyethylene glycol, povidone, propylene glycol, purified water, sodium phosphate dibasic, sodium phosphate monobasic.
100801 Site 2: Naphazoline hydrochloride (0.03%): A solution of naphazoline hydrochloride 0.03% (Clear Eyes Maximum Redness Relief (Prestige Brands Inc.) containing:
naphazoline hydrochloride 0.03%, glycerin 0.5%, benzalkonium chloride, boric acid, edetate disodium, purified water, sodium borate).
100811 Site 3: Tetrahydrozoline hydrochloride (0.05%): A solution of tetrahydrozoline hydrochloride 0.05% (Visine Original (Pfizer Consumer Healthcare) containing:
tetrahydrozoline hydrochloride 0.05%, benzalkonium chloride, boric acid, edetate disodium, purified water, sodium borate, sodium chloride).
100821 Site 4: Phenylephrine hydrochloride (1.0%): A solution of phenylephrine hydrochloride 1.0% (Neo-Synephrine Extra Strength Spray (Bayer HealthCare) containing:
phenylephrine hydrochloride 1.0%, anhydrous citric acid, benzalkonium chloride, sodium chloride, sodium citrate, water).
[0083] Site 5: Brimonidine tartrate (0.2%): A solution of brimonidine tartrate 0.2%
(Bausch & Lomb Inc.) containing: brimonidine tartrate 0.02%, citric acid, polyvinyl alcohol, sodium chloride, sodium citrate, purified water, benzalkonium chloride (0.005%).
100841 Site 6: Oxymctazoline hydrochloride 0.05% and brimonidine tartrate 0.2%: The solution of oxymetazoline hydrochloride 0.05% (Afi=in Original 12 Hour Nasal Spray (Schering-Plough Healthcare Products) containing: oxymetazoline hydrochloride 0.05%,
-29-benzalkonium chloride solution, edetate disodium, polyethylene glycol, povidone, propylene glycol, purified water, sodium phosphate dibasic, sodium phosphate monobasic was applied first, then was followed by the application of the solution of brimonidine tartrate 0.2% (Bausch &
Lomb Inc.) containing: brimonidine tartrate 0.02%, citric acid, polyvinyl alcohol, sodium chloride, sodium citrate, purified water, benzalkonium chloride (0.005%).
[0085] Site 7: No treatment after laser light delivered. ("Control") [0086] The sites were followed clinically and photographically 1, 3, 4, 6, 11 and 13 days after the creation of the purpura. In each of the sites treated with at least one of the a agonist preparations, the resolution of the purpura was more rapid than in the non-treated control site.
This effect was most pronounced on site 2 (naphazoline 0.03%), site 4 (phenylephrine 1.0%), site 1 (oxymetazoline 0.05%), and site 6 (oxymetazoline hydrochloride 0.05% +
brimonidine tartrate 0.2%). No local or systemic side effects were noted, and in particular, there was no rebound erythema or edema noted.
[0087] These trials demonstrate that selective at adrenergic receptor agonists and selective a2 adrenergic receptor agonists, used separately or in combination, when topically applied to and around a treatment site after a procedure that can/will induce purpura, will reduce the size and appearance of the purpuric macules/ patches and is an effective treatment to hasten their resolution.
[0088] In order to evaluate the effect of topically applied at and (12 adrenergic agonists on the prevention of laser-induced purpura on normal non-actinically damaged skin, seven sites on the trunk of a volunteer were marked and treated with the topical application of a commercially available al and/or a2 agonist preparation. Six (of the seven) marked sites were pretreated with the topical application of at least one of the testing preparations. The preparations were applied to the skin and gently rubbed on the skin over and immediately surrounding the laser treatment sites 3 hours prior to and 1 hour prior to the delivery of the laser energy.
The applied solution was allowed to air-dry without any dressing. Utilizing a pulsed-dye laser (585 nrn) and laser light parameters known to be purpurogenic, purpuric macules/patches were successfully induced at each site. After the delivery of the laser energy, each spot received only topical petrolatum jelly 3-4 times/day and no additional application of any testing compound. The sites were
Lomb Inc.) containing: brimonidine tartrate 0.02%, citric acid, polyvinyl alcohol, sodium chloride, sodium citrate, purified water, benzalkonium chloride (0.005%).
[0085] Site 7: No treatment after laser light delivered. ("Control") [0086] The sites were followed clinically and photographically 1, 3, 4, 6, 11 and 13 days after the creation of the purpura. In each of the sites treated with at least one of the a agonist preparations, the resolution of the purpura was more rapid than in the non-treated control site.
This effect was most pronounced on site 2 (naphazoline 0.03%), site 4 (phenylephrine 1.0%), site 1 (oxymetazoline 0.05%), and site 6 (oxymetazoline hydrochloride 0.05% +
brimonidine tartrate 0.2%). No local or systemic side effects were noted, and in particular, there was no rebound erythema or edema noted.
[0087] These trials demonstrate that selective at adrenergic receptor agonists and selective a2 adrenergic receptor agonists, used separately or in combination, when topically applied to and around a treatment site after a procedure that can/will induce purpura, will reduce the size and appearance of the purpuric macules/ patches and is an effective treatment to hasten their resolution.
[0088] In order to evaluate the effect of topically applied at and (12 adrenergic agonists on the prevention of laser-induced purpura on normal non-actinically damaged skin, seven sites on the trunk of a volunteer were marked and treated with the topical application of a commercially available al and/or a2 agonist preparation. Six (of the seven) marked sites were pretreated with the topical application of at least one of the testing preparations. The preparations were applied to the skin and gently rubbed on the skin over and immediately surrounding the laser treatment sites 3 hours prior to and 1 hour prior to the delivery of the laser energy.
The applied solution was allowed to air-dry without any dressing. Utilizing a pulsed-dye laser (585 nrn) and laser light parameters known to be purpurogenic, purpuric macules/patches were successfully induced at each site. After the delivery of the laser energy, each spot received only topical petrolatum jelly 3-4 times/day and no additional application of any testing compound. The sites were
-30-followed clinically and photographically 1, 3, 4, 6, 11 and 13 days after the creation of the purpura. The evaluated compounds were:
[0089] Site 8: Oxymetazoline hydrochloride (0.05%): A solution of oxymetazoline hydrochloride 0.05% (Afrin Original 12 Hour Nasal Spray (Schering-Plough Healthcare Products) containing: oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution, edetate disodium, polyethylene glycol, povidone, propylene glycol, purified water, sodium phosphate dibasic, sodium phosphate monobasic.
[0090] Site 9: Naphazoline hydrochloride (0.03%): A solution of naphazoline hydrochloride 0.03% (Clear Eyes Maximum Redness Relief (Prestige Brands Inc.) containing:
naphazoline hydrochloride 0.03%, glycerin 0.5%, benzalkonium chloride, boric acid, edetate disodium, purified water, sodium borate).
[0091] Site 10: Tetrahydrozoline hydrochloride (0.05%): A solution of tetrahydrozoline hydrochloride 0.05% (Visine Original (Pfizer Consumer Healthcare) containing:
tetrahydrozoline hydrochloride 0.05%, benzalkonium chloride, boric acid, edetate disodium, purified water, sodium borate, sodium chloride).
[0092] Site 11: Phenylephrine hydrochloride (1.0%): A solution of phenylephrine hydrochloride 1.0% (Neo-Synephrine Extra Strength Spray (Bayer HealthCare) containing:
phenylephrine hydrochloride 1.0%, anhydrous citric acid, benzalkonium chloride, sodium chloride, sodium citrate, water).
[0093] Site 12: Brimonidine tartrate (0.2%): A solution of brimonidine tartrate 0.2%
(Bausch & Lomb Inc.) containing: brimonidine tartrate 0.02%, citric acid, polyvinyl alcohol, sodium chloride, sodium citrate, purified water, benzalkonium chloride (0.005%).
[0094] Site 13: oxymetazoline hydrochloride 0.05% and brimonidine tartrate 0.2%: The solution of oxymetazoline hydrochloride 0.05% (Afrint Original 12 Hour Nasal Spray (Schering-Plough Healthcare Products) containing: oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution, edetate disodium, polyethylene glycol, povidone, propylene glycol, purified water, sodium phosphate dibasic, sodium phosphate monobasic was applied first, then was followed by the application of the solution of brimonidine tartrate 0.2% (Bausch &
Lomb Inc.) containing: brimonidine tartrate 0.02%, citric acid, polyvinyl alcohol, sodium chloride, sodium citrate, purified water, benzalkonium chloride (0.005%).
[0095] Site 14: No treatment after laser light delivered. ("Control-)
[0089] Site 8: Oxymetazoline hydrochloride (0.05%): A solution of oxymetazoline hydrochloride 0.05% (Afrin Original 12 Hour Nasal Spray (Schering-Plough Healthcare Products) containing: oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution, edetate disodium, polyethylene glycol, povidone, propylene glycol, purified water, sodium phosphate dibasic, sodium phosphate monobasic.
[0090] Site 9: Naphazoline hydrochloride (0.03%): A solution of naphazoline hydrochloride 0.03% (Clear Eyes Maximum Redness Relief (Prestige Brands Inc.) containing:
naphazoline hydrochloride 0.03%, glycerin 0.5%, benzalkonium chloride, boric acid, edetate disodium, purified water, sodium borate).
[0091] Site 10: Tetrahydrozoline hydrochloride (0.05%): A solution of tetrahydrozoline hydrochloride 0.05% (Visine Original (Pfizer Consumer Healthcare) containing:
tetrahydrozoline hydrochloride 0.05%, benzalkonium chloride, boric acid, edetate disodium, purified water, sodium borate, sodium chloride).
[0092] Site 11: Phenylephrine hydrochloride (1.0%): A solution of phenylephrine hydrochloride 1.0% (Neo-Synephrine Extra Strength Spray (Bayer HealthCare) containing:
phenylephrine hydrochloride 1.0%, anhydrous citric acid, benzalkonium chloride, sodium chloride, sodium citrate, water).
[0093] Site 12: Brimonidine tartrate (0.2%): A solution of brimonidine tartrate 0.2%
(Bausch & Lomb Inc.) containing: brimonidine tartrate 0.02%, citric acid, polyvinyl alcohol, sodium chloride, sodium citrate, purified water, benzalkonium chloride (0.005%).
[0094] Site 13: oxymetazoline hydrochloride 0.05% and brimonidine tartrate 0.2%: The solution of oxymetazoline hydrochloride 0.05% (Afrint Original 12 Hour Nasal Spray (Schering-Plough Healthcare Products) containing: oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution, edetate disodium, polyethylene glycol, povidone, propylene glycol, purified water, sodium phosphate dibasic, sodium phosphate monobasic was applied first, then was followed by the application of the solution of brimonidine tartrate 0.2% (Bausch &
Lomb Inc.) containing: brimonidine tartrate 0.02%, citric acid, polyvinyl alcohol, sodium chloride, sodium citrate, purified water, benzalkonium chloride (0.005%).
[0095] Site 14: No treatment after laser light delivered. ("Control-)
-31-[0096] In each of the sites treated with at least one of the a agonist preparations prior to the delivery of the laser energy, the purpuric macule/patch created was smaller than in the non pre-treated site. The time course of the resolution of the purpura was shortened as well. This effect was more pronounced on the sites pretreated with oxymetazoline hydrochloride 0.05%, naphazoline hydrochloride 0.03%, tetrahydrozoline hydrochloride 0.05%, and phenylephrine hydrochloride 1.0%, and was observed, though less pronounced, on the site pretreated with brimonidine tartrate 0.2% alone, and the site pretreated with oxymetazoline hydrochloride 0.05%
+ brimonidine tartrate 0.2%). No local or systemic side effects were noted, and in particular, there was no rebound erythema or edema noted.
[0097] These trials demonstrate that selective al adrenergic receptor agonists and selective a2 adrenergic receptor agonists, used separately or in combination, when topically applied prior to a procedure that can/will induce purpura, will reduce the size and appearance of the purpuric macules/ patches and is an effective treatment to hasten their resolution.
[0098] The use of a topically applied a2 adrenergic agonist for the treatment and prevention of solar purpura ("actinic purpura", "Bateman's purpura"): In order to evaluate the effect of topically applied al and a2 adrenergic agonists on the prevention and treatment of solar purpura, a 78 year old male volunteer with a diagnosis of solar purpura of the forearms treated with a topically applied a2 adrenergic agonist containing solution. The test area comprised the right extensor forearm from the wrist to the elbow. Photos were taken and baseline scores for the solar purpura on his right dorsal forearm from the wrist to the elbow were measured 6 times over a 91 day period before initiating treatment. Two measurements were taken to approximate the area of each purpuric patch. The measurements ranged from 0 cm2 to 9.98 cm2 and the mean over 6 measurements was 3.67 cm2. (See Table 1) [0099] A solution of brimonidine tartrate 0.2% (Bausch & Lomb Inc.) containing:
brimonidine tartrate 0.02%, citric acid, polyvinyl alcohol, sodium chloride, sodium citrate, purified water, and benzalkonium chloride (0.005%) was applied by the patient to the right dorsal foreami twice daily (morning and evening). The solution was applied with a cotton ball to the skin of the entire right extensor forearm from the wrist to the elbow. The sites were followed clinically and photographically.
+ brimonidine tartrate 0.2%). No local or systemic side effects were noted, and in particular, there was no rebound erythema or edema noted.
[0097] These trials demonstrate that selective al adrenergic receptor agonists and selective a2 adrenergic receptor agonists, used separately or in combination, when topically applied prior to a procedure that can/will induce purpura, will reduce the size and appearance of the purpuric macules/ patches and is an effective treatment to hasten their resolution.
[0098] The use of a topically applied a2 adrenergic agonist for the treatment and prevention of solar purpura ("actinic purpura", "Bateman's purpura"): In order to evaluate the effect of topically applied al and a2 adrenergic agonists on the prevention and treatment of solar purpura, a 78 year old male volunteer with a diagnosis of solar purpura of the forearms treated with a topically applied a2 adrenergic agonist containing solution. The test area comprised the right extensor forearm from the wrist to the elbow. Photos were taken and baseline scores for the solar purpura on his right dorsal forearm from the wrist to the elbow were measured 6 times over a 91 day period before initiating treatment. Two measurements were taken to approximate the area of each purpuric patch. The measurements ranged from 0 cm2 to 9.98 cm2 and the mean over 6 measurements was 3.67 cm2. (See Table 1) [0099] A solution of brimonidine tartrate 0.2% (Bausch & Lomb Inc.) containing:
brimonidine tartrate 0.02%, citric acid, polyvinyl alcohol, sodium chloride, sodium citrate, purified water, and benzalkonium chloride (0.005%) was applied by the patient to the right dorsal foreami twice daily (morning and evening). The solution was applied with a cotton ball to the skin of the entire right extensor forearm from the wrist to the elbow. The sites were followed clinically and photographically.
-32-1001001 Seven days after starting, the patient returned for evaluation. The total area of purpura on the right dorsal forearm were measured and equaled 1.48 cm2 (a decrease of 60%
compared to mean baseline). The patient continued to apply brimonidine 0.2%
solution to the right dorsal forearm twice daily (morning and evening).
1001011 Fourteen days after starting, the patient returned for evaluation. The total area of purpura on the right dorsal forearm were measured and equaled 0.35 cm2 (a decrease of 90%
compared to mean baseline). The patient continued to apply brimonidine 0.2%
solution to the right dorsal forearm twice daily (morning and evening).
[00102] Twenty four days after starting, the patient returned for evaluation.
The total area of purpura on the right dorsal forearm were measured and equaled 5.72 cm2 (an increase of 34% compared to mean baseline). The patient reported that he had recently been gardening and had noted significant increase in the purpura after this activity despite continuing the topical medication. The patient continued to apply brimonidine 0.2% solution to the right dorsal forearm twice daily (morning and evening).
[00103] Thirty six days after starting, the patient returned for evaluation.
The total area of purpura on the right dorsal forearm were measured and equaled 2.52 cm2 (a decrease of 31%
compared to mean baseline).
TABLE 1:
Day Purpura Area(cm2) Effect Notes 0 3.67 Baseline 7 1.48 60% from Baseline 14 0.35 90% from Baseline 24 5.72 1 34% from Baseline I in purpura noted after gardening 36 2.52 I 31% from Baseline [00104] This trial demonstrates that the selective a2 adrenergic receptor agonist 0.2%
brimonidine tartrate when topically applied twice daily to areas effected by solar ("actinic" or "senile" or "Bateman's") purpura reduces the size and appearance of purpuric macules/ patches.
Though significant intervening trauma to the region being treated (e.g. trauma to the arms from gardening) may still induce purpura, it is shown to be an effective treatment to hasten the resolution and decrease the appearance of purpura in actinically damaged or otherwise atrophic/damaged skin and cutaneous vessels.
compared to mean baseline). The patient continued to apply brimonidine 0.2%
solution to the right dorsal forearm twice daily (morning and evening).
1001011 Fourteen days after starting, the patient returned for evaluation. The total area of purpura on the right dorsal forearm were measured and equaled 0.35 cm2 (a decrease of 90%
compared to mean baseline). The patient continued to apply brimonidine 0.2%
solution to the right dorsal forearm twice daily (morning and evening).
[00102] Twenty four days after starting, the patient returned for evaluation.
The total area of purpura on the right dorsal forearm were measured and equaled 5.72 cm2 (an increase of 34% compared to mean baseline). The patient reported that he had recently been gardening and had noted significant increase in the purpura after this activity despite continuing the topical medication. The patient continued to apply brimonidine 0.2% solution to the right dorsal forearm twice daily (morning and evening).
[00103] Thirty six days after starting, the patient returned for evaluation.
The total area of purpura on the right dorsal forearm were measured and equaled 2.52 cm2 (a decrease of 31%
compared to mean baseline).
TABLE 1:
Day Purpura Area(cm2) Effect Notes 0 3.67 Baseline 7 1.48 60% from Baseline 14 0.35 90% from Baseline 24 5.72 1 34% from Baseline I in purpura noted after gardening 36 2.52 I 31% from Baseline [00104] This trial demonstrates that the selective a2 adrenergic receptor agonist 0.2%
brimonidine tartrate when topically applied twice daily to areas effected by solar ("actinic" or "senile" or "Bateman's") purpura reduces the size and appearance of purpuric macules/ patches.
Though significant intervening trauma to the region being treated (e.g. trauma to the arms from gardening) may still induce purpura, it is shown to be an effective treatment to hasten the resolution and decrease the appearance of purpura in actinically damaged or otherwise atrophic/damaged skin and cutaneous vessels.
-33-[001051 The use of a topically applied al adrenergic agonist for the treatment and prevention of solar purpura: In order to evaluate the effect of topically applied al adrenergic agonists on the prevention and treatment of solar purpura, two patient volunteers with the diagnosis of solar purpura of the forearms were treated with a topically applied selective al adrenergic agonist containing solution.
1001061 Subject 1 is a 78 year old man with a long-standing history of solar purpura on his forearms. The test area comprised the left dorsal (extensor) forearm from the wrist to the elbow. Pretreatment photos were taken and baseline measurements of the solar purpura on the left extensor forearm from the wrist to the elbow were measured. Two measurements were taken to approximate the area of each purpuric patch. The total area of purpura was 8.94 cm2. (SEE
TABLE 2) [00107] A solution of oxymetazoline hydrochloride 0.05% (Afrin Original 12 Hour Nasal Spray (Schering-Plough Healthcare Products) containing: oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution, edetate disodium, polyethylene glycol, povidone, propylene glycol, purified water, sodium phosphate dibasic, sodium phosphate monobasic (0.005%)) was applied by the patient to the left dorsal forearm twice daily (morning and evening). The solution was applied with a cotton ball to the skin of the entire extensor forearm from the wrist to the elbow. The sites were followed clinically and photographically.
[00108] Seventeen days later, the patient returned for evaluation. The total area of purpura on the left extensor forearm were measured and equaled 9.95 cm2 (an increase of 11%
compared to baseline). The patient continued to apply oxymetazoline solution 0.05% to the left dorsal forearm twice daily (morning and evening).
[00109] Twenty nine days after starting, the patient returned for evaluation.
The total area of purpura on the left extensor forearm were measured and equaled 5.73 cm2 (a decrease of 36% compared to baseline). The patient continued to apply oxymetazoline solution 0.05% to the left dorsal forearm twice daily (morning and evening).
[00110] Forty four days after starting, the patient returned for evaluation.
The total area of purpura on the left extensor forearm were measured and equaled 5.6 cm2 (a decrease of 37%
compared to baseline). The patient continued to apply oxymetazoline solution 0.05% to the left dorsal forearm twice daily (morning and evening).
1001061 Subject 1 is a 78 year old man with a long-standing history of solar purpura on his forearms. The test area comprised the left dorsal (extensor) forearm from the wrist to the elbow. Pretreatment photos were taken and baseline measurements of the solar purpura on the left extensor forearm from the wrist to the elbow were measured. Two measurements were taken to approximate the area of each purpuric patch. The total area of purpura was 8.94 cm2. (SEE
TABLE 2) [00107] A solution of oxymetazoline hydrochloride 0.05% (Afrin Original 12 Hour Nasal Spray (Schering-Plough Healthcare Products) containing: oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution, edetate disodium, polyethylene glycol, povidone, propylene glycol, purified water, sodium phosphate dibasic, sodium phosphate monobasic (0.005%)) was applied by the patient to the left dorsal forearm twice daily (morning and evening). The solution was applied with a cotton ball to the skin of the entire extensor forearm from the wrist to the elbow. The sites were followed clinically and photographically.
[00108] Seventeen days later, the patient returned for evaluation. The total area of purpura on the left extensor forearm were measured and equaled 9.95 cm2 (an increase of 11%
compared to baseline). The patient continued to apply oxymetazoline solution 0.05% to the left dorsal forearm twice daily (morning and evening).
[00109] Twenty nine days after starting, the patient returned for evaluation.
The total area of purpura on the left extensor forearm were measured and equaled 5.73 cm2 (a decrease of 36% compared to baseline). The patient continued to apply oxymetazoline solution 0.05% to the left dorsal forearm twice daily (morning and evening).
[00110] Forty four days after starting, the patient returned for evaluation.
The total area of purpura on the left extensor forearm were measured and equaled 5.6 cm2 (a decrease of 37%
compared to baseline). The patient continued to apply oxymetazoline solution 0.05% to the left dorsal forearm twice daily (morning and evening).
-34-[00111] Eighty one days after starting, the patient returned for evaluation.
The total area of purpura on the left extensor forearm were measured and equaled 1.44 cm2 (a decrease of 84%
compared to baseline). The patient continued to apply oxymetazoline solution 0.05% to the left dorsal forearm twice daily (morning and evening).
[001.12] Ninety one days after starting, the patient returned for evaluation.
The total area of purpura on the left extensor foreami were measured and equaled 0.42 cm2 (a decrease of 95%
compared to baseline). The patient stopped applying the oxymetazoline containing solution on study day 91.
[00113] Seven days after stopping the oxymetazoline, the total area of purpura on the left extensor forearm was measured and equaled 1.96 cm2. (an increase of 366% from the point of stopping medication (day 91 measurement)).
[00114] Fourteen days after stopping the oxymetazoline, the total area of purpura on the left extensor forearm was measured and equaled 0.46 cm2. (an increase of 10%
from the point of stopping medication (day 91 measurement)).
[00115] Twenty four days after stopping the oxymetazoline, the total area of purpura on the left extensor forearm was measured and equaled 2.22 cm2. (an increase of 428% from the point of stopping medication (day 91 measurement)).
TABLE 2:
Day Purpura Area(cm2) Effect Notes 0 8.94 Baseline 17 9.95 11% from Baseline 29 5.73 36% from Baseline 44 5.6 37% from Baseline 81 1.44 84% from Baseline 91 0.42 95% from Baseline Medication Discontinued Day 98 1.96 1 366% from Baseline 7Days off Medication 112 0.46 1. 10% from Baseline 14 Days off Medication 122 2.22 1 428% from Baseline 24 Days off Medication [00116] The patient stated that he felt that there were fewer new purpuric macules/
patches while he was using the medication, and he felt that when purpura occurred they seemed
The total area of purpura on the left extensor forearm were measured and equaled 1.44 cm2 (a decrease of 84%
compared to baseline). The patient continued to apply oxymetazoline solution 0.05% to the left dorsal forearm twice daily (morning and evening).
[001.12] Ninety one days after starting, the patient returned for evaluation.
The total area of purpura on the left extensor foreami were measured and equaled 0.42 cm2 (a decrease of 95%
compared to baseline). The patient stopped applying the oxymetazoline containing solution on study day 91.
[00113] Seven days after stopping the oxymetazoline, the total area of purpura on the left extensor forearm was measured and equaled 1.96 cm2. (an increase of 366% from the point of stopping medication (day 91 measurement)).
[00114] Fourteen days after stopping the oxymetazoline, the total area of purpura on the left extensor forearm was measured and equaled 0.46 cm2. (an increase of 10%
from the point of stopping medication (day 91 measurement)).
[00115] Twenty four days after stopping the oxymetazoline, the total area of purpura on the left extensor forearm was measured and equaled 2.22 cm2. (an increase of 428% from the point of stopping medication (day 91 measurement)).
TABLE 2:
Day Purpura Area(cm2) Effect Notes 0 8.94 Baseline 17 9.95 11% from Baseline 29 5.73 36% from Baseline 44 5.6 37% from Baseline 81 1.44 84% from Baseline 91 0.42 95% from Baseline Medication Discontinued Day 98 1.96 1 366% from Baseline 7Days off Medication 112 0.46 1. 10% from Baseline 14 Days off Medication 122 2.22 1 428% from Baseline 24 Days off Medication [00116] The patient stated that he felt that there were fewer new purpuric macules/
patches while he was using the medication, and he felt that when purpura occurred they seemed
-35-to resolve more quickly. The patient had no side effects, either local or systemic, during the treatment.
[00117] Subject 2 is an 87 year old woman with a long history of cosmetically disturbing solar purpura on her forearms who wanted to improve the appearance solar (decrease the purpura). The test area comprised the left dorsal (extensor) forearm from the wrist to the elbow.
Pretreatment photos were taken and baseline measurements of the solar purpura on the left extensor forearm from the wrist to the elbow were measured. Two measurements were taken to approximate the area of each purpuric patch. The total area of purpura was 1.72 cm2. (SEE
TABLE 3) [00118] A solution of oxymetazoline hydrochloride 0.05% (Afrin Original 12 Hour Nasal Spray (Schering-Plough Healthcare Products) containing: oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution, edetate disodium, polyethylene glycol, povidone, propylene glycol, purified water, sodium phosphate dibasic, sodium phosphate monobasic (0.005%)) was applied by the patient to the left dorsal forearm once daily (morning). The solution was applied with a cotton ball to the skin of the entire extensor forearm from the wrist to the elbow. The sites were followed clinically and photographically.
[00119] 7 days later, the patient was reevaluated. The total area of purpura on the left dorsal forearm measured 0 cm2 (a decrease of 100% compared to baseline). The patient continued to apply oxymetazoline solution 0.05% to the left extensor forearm once daily (morning).
[00120] 31 days after starting, the patient was reevaluated. The total area of purpura on the left dorsal forearm measured 0 cm2 (a decrease of 100% compared to baseline). The patient continued to apply oxymetazoline solution 0.05% to the left extensor forearm once daily (morning).
[00121] 36 days after starting, the patient was reevaluated. The total area of purpura on the left extensor forearm measured 0.36 cm2 (a decrease of 79% compared to baseline).
Day Purpura Area(cm2) Effect Notes 0 1.72 Baseline 7 0.00 100% from Baseline 31 0.00 100% from Baseline
[00117] Subject 2 is an 87 year old woman with a long history of cosmetically disturbing solar purpura on her forearms who wanted to improve the appearance solar (decrease the purpura). The test area comprised the left dorsal (extensor) forearm from the wrist to the elbow.
Pretreatment photos were taken and baseline measurements of the solar purpura on the left extensor forearm from the wrist to the elbow were measured. Two measurements were taken to approximate the area of each purpuric patch. The total area of purpura was 1.72 cm2. (SEE
TABLE 3) [00118] A solution of oxymetazoline hydrochloride 0.05% (Afrin Original 12 Hour Nasal Spray (Schering-Plough Healthcare Products) containing: oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution, edetate disodium, polyethylene glycol, povidone, propylene glycol, purified water, sodium phosphate dibasic, sodium phosphate monobasic (0.005%)) was applied by the patient to the left dorsal forearm once daily (morning). The solution was applied with a cotton ball to the skin of the entire extensor forearm from the wrist to the elbow. The sites were followed clinically and photographically.
[00119] 7 days later, the patient was reevaluated. The total area of purpura on the left dorsal forearm measured 0 cm2 (a decrease of 100% compared to baseline). The patient continued to apply oxymetazoline solution 0.05% to the left extensor forearm once daily (morning).
[00120] 31 days after starting, the patient was reevaluated. The total area of purpura on the left dorsal forearm measured 0 cm2 (a decrease of 100% compared to baseline). The patient continued to apply oxymetazoline solution 0.05% to the left extensor forearm once daily (morning).
[00121] 36 days after starting, the patient was reevaluated. The total area of purpura on the left extensor forearm measured 0.36 cm2 (a decrease of 79% compared to baseline).
Day Purpura Area(cm2) Effect Notes 0 1.72 Baseline 7 0.00 100% from Baseline 31 0.00 100% from Baseline
36 0.36 79% from Baseline [00122] The patient stated that she felt that there were fewer new purpuric patches while she was using the medication, and in her estimation the purpura that did occur seemed to resolve more quickly. The patient had no side effects, either local or systemic, during the treatment.
[00123] These trials demonstrate that the selective ct1 adrenergic receptor agonist oxymetazoline hydrochloride when topically applied once or twice daily to areas effected by solar purpura dramatically reduces the size and appearance of purpuric macules/patches and may eliminate them. Though continuing trauma to the region being treated (e.g.
trauma to the arms from gardening) may still induce purpura, this treatment is shown to be an effective treatment to hasten the resolution and decrease the appearance of purpura in actinically damaged or otherwise atrophic/damaged skin and cutaneous vessels.
[00123] These trials demonstrate that the selective ct1 adrenergic receptor agonist oxymetazoline hydrochloride when topically applied once or twice daily to areas effected by solar purpura dramatically reduces the size and appearance of purpuric macules/patches and may eliminate them. Though continuing trauma to the region being treated (e.g.
trauma to the arms from gardening) may still induce purpura, this treatment is shown to be an effective treatment to hasten the resolution and decrease the appearance of purpura in actinically damaged or otherwise atrophic/damaged skin and cutaneous vessels.
-37-
Claims (80)
1. Use of an .alpha. adrenergic receptor agonist selected from a selective .alpha.1 adrenergic receptor agonist and a selective .alpha.2 adrenergic receptor agonist or a combination thereof to treat non-thrombocytopenic purpura in a subject.
2. Use of an a adrenergic receptor agonist selected from a selective al adrenergic receptor agonist and a selective .alpha.2 adrenergic receptor agonist or a combination thereof for the production of a medicament to treat non-thrombocytopenic purpura in a subject.
3. The use of claim 1 or 2, wherein the .alpha. adrenergic receptor agonist is for topical application to the skin of the subject.
4. The use of claim 1 or 2, wherein the .alpha. adrenergic receptor agonist is for local delivery to the subject.
5. The use of claim 1 or 2, wherein the selective .alpha.1 adrenergic receptor agonist is oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine or combinations thereof.
6. The use of claim 1 or 2, wherein the selective .alpha.1-adrenergic receptor agonist is oxymetazoline, tetrahydrozoline, phenylephrine hydrochloride or combinations thereof.
7. The use of claim 1 or 2, wherein the selective .alpha.2 adrenergic receptor agonist is brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, .alpha.-methyldopa, or combinations thereof.
8. The use of claim 1 or 2, wherein the selective .alpha.2-adrenergic receptor agonist is brimonidine.
9. The use of claim 1 or 2 in combination with at least one other active agent defined as antibacterial agents, antiparasitic agents, antifungal agents, anti-inflammatory agents, antihistamines, anti-pruriginous agents, anesthetics, antiviral agents, keratolytic agents, anti free-radical agents, antioxidants, vitamin K, vitamin E, vitamin C, vitamin A, superoxide dismutase derivatives of plants, sesquiterpene lactones, antiseborrheic agents, antidandruff agents, antiacne agents, sunscreens and sun blocking agents, or active agents which modify at least one of cutaneous differentiation, proliferation, and pigmentation.
10. The use of claim 1 or 2, wherein said .alpha. adrenergic receptor agonist is for administration in a pharmacologically acceptable form defined by solutions, gels, lotions creams, ointments, foams, emulsions, microemulsions, milks, serums, aerosols, sprays, dispersions, microcapsules, vesicles and microparticles thereof, soaps, or cleansing bars.
11. Use of an .alpha. adrenergic receptor agonist selected from a selective .alpha.1 adrenergic receptor agonist, a selective .alpha.2 adrenergic receptor agonist and combinations thereof for decreasing non-thrombocytopenic purpura in a subject.
12. Use of an a adrenergic receptor agonist selected from a selective .alpha.1 adrenergic receptor agonist, a selective .alpha.2 adrenergic receptor agonist and combinations thereof for the production of a medicament for decreasing non-thrombocytopenic purpura in a subject.
13. The use of claim 11 or 12, wherein the a adrenergic receptor agonist is for topical application to the skin of the subject.
14. The use of claim 11 or 12, wherein the .alpha. adrenergic receptor agonist is for local delivery to the subject.
15. The use of claim 11 or 12, wherein the selective .alpha.1 adrenergic receptor agonist is oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine or combinations thereof.
16. The use of claim 11 or 12, wherein the selective .alpha.1-adrenergic receptor agonist is oxymetazoline, tetrahydrozoline, phenylephrine hydrochloride or combinations thereof.
17. The use of claim 11 or 12, wherein the selective .alpha.2 adrenergic receptor agonist is brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, .alpha.-methyldopa, or combinations thereof.
18. The use of claim 11 or 12, wherein the selective .alpha.2-adrenergic receptor agonist is brimonidine.
19. The use of claim 11 or 12 in combination with at least one other active agent defined as antibacterial agents, antiparasitic agents, antifungal agents, anti-inflammatory agents, antihistamines, anti-pruriginous agents, anesthetics, antiviral agents, keratolytic agents, anti free-radical agents, antioxidants, vitamin K, vitamin E, vitamin C, vitamin A, superoxide dismutase derivatives of plants, sesquiterpene lactones, antiseborrheic agents, antidandruff agents, antiacne agents, sunscreens and sun blocking agents, or active agents which modify at least one of cutaneous differentiation, proliferation, and pigmentation.
20. The use of claim 11 or 12, wherein said a adrenergic receptor agonist is for administration in a pharmacologically acceptable form defined by solutions, gels, lotions, creams, ointments, foams, emulsions, microemulsions, milks, serums, aerosols, sprays, dispersions, microcapsules, vesicles and microparticles thereof, soaps, or cleansing bars.
21. Use of an .alpha. adrenergic receptor agonist selected from a selective .alpha.1 adrenergic receptor agonist, a selective .alpha.2 adrenergic receptor agonist and combinations thereof for decreasing purpura at a site of a surgical procedure in a subject.
22. Use of an .alpha. adrenergic receptor agonist selected from a selective .alpha.1 adrenergic receptor agonist, a selective .alpha.2 adrenergic receptor agonist and combinations thereof for the production of a medicament for decreasing purpura at a site of a surgical procedure in a subject.
23. The use of claim 21 or 22, wherein the a adrenergic receptor agonist is for topical application to said site of said surgical procedure.
24. The use of claim 21 or 22, wherein the .alpha. adrenergic receptor agonist is for local delivery to the site of said surgical procedure.
25. The use of claim 21 or 22, wherein the selective .alpha.1 adrenergic receptor agonist is oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine or combinations thereof.
26. The use of claim 21 or 22, wherein the selective .alpha.1-adrenergic receptor agonist is oxymetazoline, tetrahydrozoline, phenylephrine hydrochloride or combinations thereof.
27. The use of claim 21 or 22, wherein the selective .alpha.2 adrenergic receptor agonist is brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, .alpha.-methyldopa, or combinations thereof.
28. The use of claim 21 or 22, wherein the selective .alpha.2-adrenergic receptor agonist is brimonidine.
29. The use of claim 21 or 22 further in combination with at least one other active agent defined as antibacterial agents, antiparasitic agents, antifungal agents, anti-inflammatory agents, antihistamines, anti-pruriginous agents, anesthetics, antiviral agents, keratolytic agents, anti free-radical agents, antioxidants, vitamin K, vitamin E, vitamin C, vitamin A, superoxide dismutase derivatives of plants, sesquiterpene lactones, antiseborrheic agents, antidandruff agents, antiacne agents, sunscreens and sun blocking agents, or active agents which modify at least one of cutaneous differentiation, proliferation, and pigmentation.
30. The use of claim 21 or 22, wherein said a adrenergic receptor agonist is for administration in a pharmacologically acceptable form defined by solutions, gels, lotions, creams, ointments, foams, emulsions, microemulsions, milks, serums, aerosols, sprays, dispersions, microcapsules, vesicles and microparticles thereof, soaps, and cleansing bars.
31. The use of claim 21 or 22, wherein said surgical procedure is a laser treatment.
32. The use of claim 21 or 22, wherein said a adrenergic receptor agonist is for administration prior to said surgical procedure.
33. The use of claim 21 or 22, wherein said a adrenergic receptor agonist is for administration during said surgical procedure.
34. The use of claim 21 or 22, wherein said a adrenergic receptor agonist is for administration after said surgical procedure.
35. The use of claim 1 or 2, wherein non-thrombocytopenic purpura is from physical trauma induced purpura or solar purpura.
36. The use of claim 11 or 12, wherein non-thrombocytopenic purpura is from physical trauma induced purpura or solar purpura.
37. Use of an .alpha. adrenergic receptor agonist selected from a selective .alpha.1 adrenergic receptor agonist, a selective .alpha.2 adrenergic receptor agonist, and a non-selective .alpha.1/.alpha.2 adrenergic receptor agonist, or a combination thereof for topical administration, for treating or preventing non-thrombocytopenic purpura from a vascular extravasation condition comprising capillary damage in a subject before, during or after a procedure wherein the procedure involves physical trauma to the skin and/or cutaneous vasculature.
38. Use of an .alpha. adrenergic receptor agonist selected from a selective .alpha.1 adrenergic receptor agonist, a selective .alpha.2 adrenergic receptor agonist, and a non-selective .alpha.1/.alpha.2 adrenergic receptor agonist, or a combination thereof for topical administration, for the production of a medicament for treating or preventing non-thrombocytopenic purpura from a vascular extravasation condition comprising capillary damage in a subject before, during or after a procedure wherein the procedure involves physical trauma to the skin and/or cutaneous vasculature.
39. The use of claim 37 or 38, wherein the procedure comprises the injection of a neurotoxin or filler for soft-tissue augmentation.
40. The use of claim 37 or 38, wherein the procedure comprises the injection of a filler for soft-tissue augmentation.
41. The use of claim 37 or 38, wherein the a adrenergic receptor agonist is for administration before, or after the procedure.
42. The use of claim 37 or 38, wherein the a adrenergic receptor agonist is for administration during the procedure.
43. The use of claim 37 or 38, wherein the purpura comprises petechiae or ecchymoses.
44. The use of claim 37 or 38, wherein the a adrenergic receptor agonist is oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, amethyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine, ethylnorepinephrine, levarterenol, lofexidine, methamphetamine, .alpha.-methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine or combinations thereof.
45. The use of claim 37 or 38, wherein the .alpha. adrenergic receptor agonist is an .alpha.1 adrenergic receptor agonist.
46. The use of claim 45, wherein the al adrenergic receptor agonist is an .alpha.1 adrenergic receptor agonist defined by oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, or amidephrine.
47. The use of claim 46, wherein the .alpha. adrenergic receptor agonist is phenylephrine.
48. The use of claim 37 or 38, wherein the .alpha. adrenergic receptor agonist is an .alpha.2 adrenergic receptor agonist.
49. The use of claim 48, wherein the .alpha.2 adrenergic receptor agonist is an .alpha.2 adrenergic receptor agonist defined as brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, or .alpha.-methyldopa.
50. The use of claim 49, wherein the .alpha.2 adrenergic receptor agonist is brimonidine.
51. The use of claim 37 or 38, wherein said use is for administration of a formulation comprising the .alpha. adrenergic receptor agonist and a polymeric material.
52. The use of claim 37 or 38, wherein said use is for administration of a formulation comprising the .alpha. adrenergic receptor agonist and a gel phase carrier.
53. The use of claim 52, wherein the gel phase carrier comprises a material comprising calcium carbonate, calcium phosphate, a sugar, a starch, a cellulose derivative, a gelatin, or a polymer.
54. The use of claim 53, wherein the gel phase carrier comprises a sugar.
55. Use of an .alpha. adrenergic receptor agonist selected from a selective .alpha. adrenergic receptor agonist, a selective .alpha.2 adrenergic receptor agonist, and a non-selective .alpha.1/.alpha.2 adrenergic receptor agonist, or a combination thereof for preventing non-thrombocytopenic purpura in a subject undergoing injection of a filler for soft tissue augmentation.
56. Use of an a adrenergic receptor agonist selected from a selective .alpha.1 adrenergic receptor agonist, a selective .alpha.2 adrenergic receptor agonist, and a non-selective .alpha.1/.alpha.2 adrenergic receptor agonist, or a combination thereof for the production of a medicament for preventing non-thrombocytopenic purpura in a subject undergoing injection of a filler for soft tissue augmentation.
57. The use of claim 55 or 56, wherein the .alpha. adrenergic receptor agonist is for administration before, during or after the injection of the filler.
58. The use of claim 55 or 56, wherein the .alpha. adrenergic receptor agonist is for administration during the injection of the filler.
59. The use of claim 55 or 56, wherein the .alpha. adrenergic receptor agonist is for administration by injection during injection of the filler.
60. The use of claim 55 or 56, wherein the purpura comprises petechiae or ecchymoses.
61. The use of claim 55 or 56, wherein the a adrenergic receptor agonist is oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, amethyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine, ethylnorepinephrine, levarterenol, lofexidine, methamphetamine, a-methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine or combinations thereof.
62. The use of claim 55 or 56, wherein the .alpha. adrenergic receptor agonist is .alpha.1 adrenergic receptor agonist.
63. The use of claim 62, wherein the .alpha. adrenergic receptor agonist is oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, or amidephrine.
64. The use of claim 63, wherein the .alpha.1 adrenergic receptor agonist is phenylephrine.
65. The use of claim 55 or 56, wherein the .alpha. adrenergic receptor agonist is .alpha.2 adrenergic receptor agonist.
66. The use of claim 65, wherein the .alpha.2 adrenergic receptor agonist is brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, or .alpha.-methyldopa.
67. The use of claim 66, wherein the .alpha.2 adrenergic receptor agonist is brimonidine.
68. The use of claim 55 or 56, for administration by injection of a formulation comprising the .alpha.
adrenergic receptor agonist and a polymeric material.
adrenergic receptor agonist and a polymeric material.
69. The use of claim 55 or 56, for administration by injection of a formulation comprising the .alpha.
adrenergic receptor agonist and a gel phase carrier.
adrenergic receptor agonist and a gel phase carrier.
70. The use of claim 69, wherein the gel phase carrier comprises calcium carbonate, calcium phosphate, a sugar, a starch, a cellulose derivative, a gelatin, or a polymer.
71. The use of claim 70, wherein the gel phase carrier comprises a sugar.
72. A composition for treating or preventing non-thrombocytopenic purpura in a subject undergoing injection of a filler for soft tissue augmentation, the composition comprising:
a gel phase carrier; and a therapeutically effective amount of an .alpha. adrenergic receptor agonist selected from a selective .alpha.1 adrenergic receptor agonist, a selective .alpha.2 adrenergic receptor agonist, and a non-selective .alpha.1/.alpha.2 or a combination thereof.
a gel phase carrier; and a therapeutically effective amount of an .alpha. adrenergic receptor agonist selected from a selective .alpha.1 adrenergic receptor agonist, a selective .alpha.2 adrenergic receptor agonist, and a non-selective .alpha.1/.alpha.2 or a combination thereof.
73. The composition of claim 72, wherein the .alpha. adrenergic receptor agonist is oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, amethyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine, ethylnorepinephrine, levarterenol, lofexidine, methamphetamine, a-methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine or combinations thereof.
74. The composition of claim 72, wherein the .alpha. adrenergic receptor agonist is .alpha.1 adrenergic receptor agonist.
75. The composition of claim 72, wherein the .alpha.1 adrenergic receptor agonist is oxymetazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, or amidephrine.
76. The composition of claim 75, wherein the .alpha.1 adrenergic receptor agonist is phenylephrine.
77. The composition of claim 72, wherein the .alpha. adrenergic receptor agonist is a2 adrenergic receptor agonist.
78. The composition of claim 77, wherein the .alpha.2 adrenergic receptor agonist is brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, or .alpha.-methyldopa.
79. The composition of claim 78, wherein the .alpha.2 adrenergic receptor agonist is brimonidine.
80. Use as defined in claim 9, 19 or 29, wherein the active agents comprise retinol, retinal, alpha hydroxyl acids, beta hydroxyl acids or a combination thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US98856407P | 2007-11-16 | 2007-11-16 | |
US60/988,564 | 2007-11-16 | ||
PCT/US2008/083774 WO2009065116A1 (en) | 2007-11-16 | 2008-11-17 | Compositions and methods for treating purpura |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2703109A1 CA2703109A1 (en) | 2009-05-22 |
CA2703109C true CA2703109C (en) | 2017-07-18 |
Family
ID=40639204
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2703109A Active CA2703109C (en) | 2007-11-16 | 2008-11-17 | Compositions and methods for treating purpura |
Country Status (19)
Country | Link |
---|---|
US (4) | US8114898B2 (en) |
EP (3) | EP3498299A1 (en) |
JP (2) | JP5670196B2 (en) |
KR (1) | KR101577471B1 (en) |
CN (1) | CN101896204B (en) |
AU (1) | AU2008322411C1 (en) |
BR (1) | BRPI0819075A2 (en) |
CA (1) | CA2703109C (en) |
DK (1) | DK2818184T3 (en) |
ES (1) | ES2709120T3 (en) |
HR (1) | HRP20190214T1 (en) |
HU (1) | HUE042931T2 (en) |
IL (1) | IL205704A (en) |
MX (1) | MX2010005331A (en) |
PL (1) | PL2818184T3 (en) |
PT (1) | PT2818184T (en) |
SI (1) | SI2818184T1 (en) |
TR (1) | TR201901431T4 (en) |
WO (1) | WO2009065116A1 (en) |
Families Citing this family (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8410102B2 (en) * | 2003-05-27 | 2013-04-02 | Galderma Laboratories Inc. | Methods and compositions for treating or preventing erythema |
US7812049B2 (en) * | 2004-01-22 | 2010-10-12 | Vicept Therapeutics, Inc. | Method and therapeutic/cosmetic topical compositions for the treatment of rosacea and skin erythema using α1-adrenoceptor agonists |
EP3498299A1 (en) | 2007-11-16 | 2019-06-19 | Aclaris Therapeutics, Inc. | Compositions and methods for treating purpura |
JP5580210B2 (en) * | 2007-12-21 | 2014-08-27 | ガルデマ ラボラトリーズ インコーポレイテッド | Preoperative treatment |
WO2010136585A2 (en) * | 2009-05-29 | 2010-12-02 | Galderma Research & Development | Combination of adrenergic receptor agonist -1 or -2, preferably brimonidine with fillers, preferablyhyaluronic acid |
FR2953410B1 (en) | 2009-12-09 | 2012-02-24 | Univ Claude Bernard Lyon | PHARMACEUTICAL OR VETERINARY ANTIVIRAL COMPOSITIONS |
US20110172180A1 (en) | 2010-01-13 | 2011-07-14 | Allergan Industrie. Sas | Heat stable hyaluronic acid compositions for dermatological use |
US9114188B2 (en) | 2010-01-13 | 2015-08-25 | Allergan, Industrie, S.A.S. | Stable hydrogel compositions including additives |
JP2013521300A (en) | 2010-03-03 | 2013-06-10 | ネオキュティス エスアー | Compositions and methods for the treatment of skin diseases and disorders using antimicrobial peptide sequestering compounds |
KR20150058551A (en) | 2010-03-26 | 2015-05-28 | 갈데르마 리써어치 앤드 디벨로프먼트 | Improved methods and compositions for safe and effective treatment of telangiectasia |
MX2012010824A (en) | 2010-03-26 | 2012-10-10 | Galderma Res & Dev | Improved methods and compositions for safe and effective treatment of erythema. |
CA2819383C (en) * | 2010-05-28 | 2019-01-15 | Nexgen Dermatologics, Inc. | Compositions and methods for treating bruises |
EP2608794A4 (en) * | 2010-08-26 | 2014-01-22 | Univ Northeastern | Methods and compositions for preventing or treating obesity |
US20120076738A1 (en) * | 2010-09-28 | 2012-03-29 | Michael Graeber | Combination treatment for dermatological conditions |
US20120082625A1 (en) * | 2010-09-28 | 2012-04-05 | Michael Graeber | Combination treatment for rosacea |
CA2814975A1 (en) | 2010-10-21 | 2012-04-26 | Galderma S.A. | Topical gel composition |
EP2629757A2 (en) | 2010-10-21 | 2013-08-28 | Galderma S.A. | Brimonidine gel compositions and methods of use |
US8053427B1 (en) | 2010-10-21 | 2011-11-08 | Galderma R&D SNC | Brimonidine gel composition |
DK2645993T3 (en) * | 2010-12-03 | 2017-02-13 | Allergan Inc | Pharmaceutical cream compositions comprising oxymetazoline |
WO2012083397A1 (en) | 2010-12-22 | 2012-06-28 | Silvestre Labs Químia E Farmaceutica Ltda. | Guanabenz-containing compound for the treatment of primary cutaneous amyloidosis |
RU2648439C2 (en) | 2011-02-15 | 2018-03-26 | Аллерган, Инк. | Pharmaceutical cream composition of oxymetazoline for treating symptoms of rosacea |
JP6423152B2 (en) * | 2011-03-07 | 2018-11-14 | スリーエム イノベイティブ プロパティズ カンパニー | Microneedle device and method |
FR2977493B1 (en) * | 2011-07-05 | 2014-02-14 | Galderma Res & Dev | NOVEL STABLE ANESTHETIC COMPOSITION FOR REDUCING SKIN REACTIONS |
WO2013052770A1 (en) | 2011-10-05 | 2013-04-11 | Sanders Jennifer L | Methods and compositions for treating foot or hand pain |
US9283217B2 (en) | 2011-11-10 | 2016-03-15 | Allergan, Inc. | Pharmaceutical compositions comprising 7-(1 H-imidazol-4-ylmethyl)-5,6,7,8-tetrahydro-quinoline for treating skin diseases and conditions |
US20150306065A1 (en) * | 2012-10-03 | 2015-10-29 | Bioprojet | A Combination of Adrenaline with an Antidepressant for Use in the Treatment of Shocks |
JP6188933B2 (en) | 2013-10-07 | 2017-08-30 | テイコク ファーマ ユーエスエー インコーポレーテッド | Methods and compositions for transdermal delivery of non-sedating amounts of dexmedetomidine |
KR101948779B1 (en) | 2013-10-07 | 2019-05-21 | 테이코쿠 팔마 유에스에이, 인코포레이티드 | Dexmedetomidine transdermal delivery devices and methods for using the same |
TWI629066B (en) | 2013-10-07 | 2018-07-11 | 帝國製藥美國股份有限公司 | Methods and compositions for treating attention deficit hyperactivity disorder, anxiety and insomnia using dexmedetomidine transdermal compositions |
AU2015274532B2 (en) | 2014-06-11 | 2020-06-11 | Epi Health, Llc | Stabilized oxymetazoline formulations and their uses |
CN107427479B (en) * | 2014-11-14 | 2021-03-30 | 芙丽雅国际公司 | System and method for preventing hair loss |
WO2016201286A1 (en) | 2015-06-11 | 2016-12-15 | Applied Biology, Inc. | Treatment of sexual dysfunction |
WO2017105819A1 (en) * | 2015-12-16 | 2017-06-22 | Laitram, L.L.C. | Modular conveyor belt with attached plates |
CN110050032B (en) | 2016-12-08 | 2022-06-28 | 帝斯曼知识产权资产管理有限公司 | Thermoplastic composition, moulded parts made thereof and use thereof in automotive and electrical and electronic applications |
EP3678648B1 (en) * | 2017-09-08 | 2023-07-26 | Insignis Therapeutics, Inc. | Methods of using dipivefrin |
US11738022B2 (en) | 2017-11-10 | 2023-08-29 | The University Of Colorado, A Body Corporate | Methods for inducing pupil dilation |
IL287130B (en) | 2019-05-01 | 2022-08-01 | Clexio Biosciences Ltd | Methods of treating pruritus |
CN113876764B (en) * | 2021-10-29 | 2023-04-14 | 山东良福制药有限公司 | Application of pharmaceutical composition containing tretinoin in preparation of medicine for treating idiopathic thrombocytopenic purpura |
Family Cites Families (259)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2128827A (en) | 1938-03-09 | 1938-08-30 | Frank B Killian | Method and apparatus for manufacturing thin rubber articles |
CA807629A (en) | 1966-06-30 | 1969-03-04 | Eigen Edward | Lotion and detergent compositions |
JPS4838158B1 (en) | 1970-10-05 | 1973-11-15 | ||
CA949965A (en) | 1971-12-03 | 1974-06-25 | Robert H. Marchessault | Method of preparing cross-linked starch and starch derivatives |
US3949073A (en) | 1974-11-18 | 1976-04-06 | The Board Of Trustees Of Leland Stanford Junior University | Process for augmenting connective mammalian tissue with in situ polymerizable native collagen solution |
US4060081A (en) | 1975-07-15 | 1977-11-29 | Massachusetts Institute Of Technology | Multilayer membrane useful as synthetic skin |
US4233360A (en) | 1975-10-22 | 1980-11-11 | Collagen Corporation | Non-antigenic collagen and articles of manufacture |
CA1073360A (en) | 1975-10-22 | 1980-03-11 | John R. Daniels | Non-antigenic collagen and articles of manufacture |
JPS581933Y2 (en) | 1979-04-23 | 1983-01-13 | 株式会社日本製鋼所 | Cable clamp device |
US4279812A (en) | 1979-09-12 | 1981-07-21 | Seton Company | Process for preparing macromolecular biologically active collagen |
JPS6052129B2 (en) | 1979-10-04 | 1985-11-18 | 呉羽化学工業株式会社 | Manufacturing method of medical collagen fiber |
US4424208A (en) | 1982-01-11 | 1984-01-03 | Collagen Corporation | Collagen implant material and method for augmenting soft tissue |
US4582640A (en) | 1982-03-08 | 1986-04-15 | Collagen Corporation | Injectable cross-linked collagen implant material |
IT1229075B (en) | 1985-04-05 | 1991-07-17 | Fidia Farmaceutici | Topical compsn. contg. hyaluronic acid deriv. as vehicle |
US4501306A (en) | 1982-11-09 | 1985-02-26 | Collagen Corporation | Automatic syringe filling system |
SE442820B (en) | 1984-06-08 | 1986-02-03 | Pharmacia Ab | GEL OF THE CROSS-BOND HYALURONIC ACID FOR USE AS A GLASS BODY SUBSTITUTE |
SE456346B (en) | 1984-07-23 | 1988-09-26 | Pharmacia Ab | GEL TO PREVENT ADHESION BETWEEN BODY TISSUE AND SET FOR ITS PREPARATION |
US4605691A (en) | 1984-12-06 | 1986-08-12 | Biomatrix, Inc. | Cross-linked gels of hyaluronic acid and products containing such gels |
US4582865A (en) | 1984-12-06 | 1986-04-15 | Biomatrix, Inc. | Cross-linked gels of hyaluronic acid and products containing such gels |
US4636524A (en) | 1984-12-06 | 1987-01-13 | Biomatrix, Inc. | Cross-linked gels of hyaluronic acid and products containing such gels |
SE8501022L (en) | 1985-03-01 | 1986-09-02 | Pharmacia Ab | FORMAT CREATES AND PROCEDURES FOR ITS PREPARATION |
US4713448A (en) | 1985-03-12 | 1987-12-15 | Biomatrix, Inc. | Chemically modified hyaluronic acid preparation and method of recovery thereof from animal tissues |
US4642117A (en) | 1985-03-22 | 1987-02-10 | Collagen Corporation | Mechanically sheared collagen implant material and method |
US4803075A (en) | 1986-06-25 | 1989-02-07 | Collagen Corporation | Injectable implant composition having improved intrudability |
FR2608456B1 (en) | 1986-12-18 | 1993-06-18 | Mero Rousselot Satia | MICROCAPSULES BASED ON GELATIN AND POLYSACCHARIDES AND PROCESS FOR OBTAINING THEM |
US5385938B1 (en) | 1986-12-23 | 1997-07-15 | Tristrata Inc | Method of using glycolic acid for treating wrinkles |
US5091171B2 (en) | 1986-12-23 | 1997-07-15 | Tristrata Inc | Amphoteric compositions and polymeric forms of alpha hydroxyacids and their therapeutic use |
US4853216A (en) * | 1987-04-02 | 1989-08-01 | Bristol-Myers Company | Process and composition for the topical application of alpha1 adrenergic agonist for pilomotor effects |
FR2623167B2 (en) | 1987-08-14 | 1992-08-07 | Genus Int | IMPROVEMENT IN ARTICLES WITH ELASTIC ARTICULATIONS RIGIDIFYING ON THEIR TENSIONING |
US5017229A (en) | 1990-06-25 | 1991-05-21 | Genzyme Corporation | Water insoluble derivatives of hyaluronic acid |
US6174999B1 (en) | 1987-09-18 | 2001-01-16 | Genzyme Corporation | Water insoluble derivatives of polyanionic polysaccharides |
IT1219587B (en) | 1988-05-13 | 1990-05-18 | Fidia Farmaceutici | SELF-CROSS-LINKED CARBOXYLY POLYSACCHARIDES |
US5643464A (en) | 1988-11-21 | 1997-07-01 | Collagen Corporation | Process for preparing a sterile, dry crosslinking agent |
US5614587A (en) | 1988-11-21 | 1997-03-25 | Collagen Corporation | Collagen-based bioadhesive compositions |
US5565519A (en) | 1988-11-21 | 1996-10-15 | Collagen Corporation | Clear, chemically modified collagen-synthetic polymer conjugates for ophthalmic applications |
US5162430A (en) | 1988-11-21 | 1992-11-10 | Collagen Corporation | Collagen-polymer conjugates |
SE462587B (en) | 1988-11-30 | 1990-07-23 | Wiklund Henry & Co | DEVICE FOR MARKING THE WORK PAPER WITH WRITTEN OR OTHER SIGNS |
JPH02215707A (en) | 1989-02-15 | 1990-08-28 | Chisso Corp | Skin cosmetic |
DE69019779T2 (en) | 1989-05-19 | 1995-12-14 | Hayashibara Biochem Lab | Alpha-glycosyl-L-ascorbic acid and its production and uses. |
EP0416250A3 (en) | 1989-08-01 | 1991-08-28 | The Research Foundation Of State University Of New York | N-acylurea and o-acylisourea derivatives of hyaluronic acid |
US5356883A (en) | 1989-08-01 | 1994-10-18 | Research Foundation Of State University Of N.Y. | Water-insoluble derivatives of hyaluronic acid and their methods of preparation and use |
CA2023922A1 (en) | 1989-09-05 | 1991-03-06 | James M. Curtis | Method of manufacturing an implantable article provided with a micropillared surface |
JP2832848B2 (en) | 1989-10-21 | 1998-12-09 | 株式会社林原生物化学研究所 | Crystal 2-O-α-D-glucopyranosyl-L-ascorbic acid, its production method and use |
US5143724A (en) | 1990-07-09 | 1992-09-01 | Biomatrix, Inc. | Biocompatible viscoelastic gel slurries, their preparation and use |
US5246698A (en) | 1990-07-09 | 1993-09-21 | Biomatrix, Inc. | Biocompatible viscoelastic gel slurries, their preparation and use |
JP3115625B2 (en) | 1991-03-30 | 2000-12-11 | 帝國製薬株式会社 | Topical patch containing lidocaine |
US5314874A (en) | 1991-04-19 | 1994-05-24 | Koken Co., Ltd. | Intracorporeally injectable composition for implanting highly concentrated cross-linked atelocollagen |
JP3267972B2 (en) | 1992-02-28 | 2002-03-25 | コラーゲン コーポレイション | High concentration homogenized collagen composition |
IT1260154B (en) | 1992-07-03 | 1996-03-28 | Lanfranco Callegaro | HYALURONIC ACID AND ITS DERIVATIVES IN INTERPENETRATING POLYMERS (IPN) |
JP3366994B2 (en) | 1993-01-20 | 2003-01-14 | イー アール スクイブ アンド サンズ インコーポレーテッド | Fiber |
WO1994021299A1 (en) | 1993-03-19 | 1994-09-29 | Medinvent | A composition and a method for tissue augmentation |
US5531716A (en) | 1993-09-29 | 1996-07-02 | Hercules Incorporated | Medical devices subject to triggered disintegration |
US5616568A (en) | 1993-11-30 | 1997-04-01 | The Research Foundation Of State University Of New York | Functionalized derivatives of hyaluronic acid |
CA2146090C (en) | 1994-05-10 | 1998-11-24 | Mark E. Mitchell | Apparatus and method of mixing materials in a sterile environment |
US5616689A (en) | 1994-07-13 | 1997-04-01 | Collagen Corporation | Method of controlling structure stability of collagen fibers produced form solutions or dispersions treated with sodium hydroxide for infectious agent deactivation |
AU706434B2 (en) | 1994-10-18 | 1999-06-17 | Ethicon Inc. | Injectable liquid copolymers for soft tissue repair and augmentation |
US20050186673A1 (en) | 1995-02-22 | 2005-08-25 | Ed. Geistlich Soehne Ag Fuer Chemistrie Industrie | Collagen carrier of therapeutic genetic material, and method |
US5972326A (en) | 1995-04-18 | 1999-10-26 | Galin; Miles A. | Controlled release of pharmaceuticals in the anterior chamber of the eye |
FR2733427B1 (en) | 1995-04-25 | 2001-05-25 | W K Et Associes | INJECTABLE BIPHASIC COMPOSITIONS CONTAINING HYALURONIC ACID, ESPECIALLY USEFUL IN REPAIRING AND AESTHETIC SURGERIES |
FR2733426B1 (en) | 1995-04-25 | 1997-07-18 | Debacker Yves | MEDICAL DEVICE FOR FILLING SKIN VOLUME DEFORMATIONS SUCH AS WRINKLES AND SCARS BY INJECTION OF 2 DIFFERENT PHYSICO-CHEMICAL FORMS OF A BIOLOGICAL POLYMER |
US5643586A (en) * | 1995-04-27 | 1997-07-01 | Perricone; Nicholas V. | Topical compositions and methods for treatment of skin damage and aging using catecholamines and related compounds |
US6214331B1 (en) | 1995-06-06 | 2001-04-10 | C. R. Bard, Inc. | Process for the preparation of aqueous dispersions of particles of water-soluble polymers and the particles obtained |
US5827937A (en) | 1995-07-17 | 1998-10-27 | Q Med Ab | Polysaccharide gel composition |
US5571503A (en) | 1995-08-01 | 1996-11-05 | Mausner; Jack | Anti-pollution cosmetic composition |
US6063405A (en) | 1995-09-29 | 2000-05-16 | L.A.M. Pharmaceuticals, Llc | Sustained release delivery system |
US6833408B2 (en) | 1995-12-18 | 2004-12-21 | Cohesion Technologies, Inc. | Methods for tissue repair using adhesive materials |
IT1277707B1 (en) | 1995-12-22 | 1997-11-11 | Chemedica Sa | OPHTHALMIC FORMULATION BASED ON SODIUM HYALURONATE FOR USE IN OCULAR SURGERY |
US5980948A (en) | 1996-08-16 | 1999-11-09 | Osteotech, Inc. | Polyetherester copolymers as drug delivery matrices |
US6066325A (en) | 1996-08-27 | 2000-05-23 | Fusion Medical Technologies, Inc. | Fragmented polymeric compositions and methods for their use |
IT1287967B1 (en) | 1996-10-17 | 1998-09-10 | Fidia Spa In Amministrazione S | PHARMACEUTICAL PREPARATIONS FOR LOCAL ANESTHETIC USE |
FR2759576B1 (en) | 1997-02-17 | 1999-08-06 | Corneal Ind | PRE-DESCEMETIC SCLERO-KERATECTOMY IMPLANT |
FR2759577B1 (en) | 1997-02-17 | 1999-08-06 | Corneal Ind | DEEP SCLERECTOMY IMPLANT |
US5935164A (en) | 1997-02-25 | 1999-08-10 | Pmt Corporaton | Laminated prosthesis and method of manufacture |
FR2764514B1 (en) | 1997-06-13 | 1999-09-03 | Biopharmex Holding Sa | IMPLANT INJECTED IN SUBCUTANEOUS OR INTRADERMAL WITH CONTROLLED BIORESORBABILITY FOR REPAIR OR PLASTIC SURGERY AND AESTHETIC DERMATOLOGY |
US7192984B2 (en) | 1997-06-17 | 2007-03-20 | Fziomed, Inc. | Compositions of polyacids and polyethers and methods for their use as dermal fillers |
US6391336B1 (en) | 1997-09-22 | 2002-05-21 | Royer Biomedical, Inc. | Inorganic-polymer complexes for the controlled release of compounds including medicinals |
FR2780730B1 (en) | 1998-07-01 | 2000-10-13 | Corneal Ind | INJECTABLE BIPHASIC COMPOSITIONS, ESPECIALLY USEFUL IN RESTORATIVE AND AESTHETIC SURGERIES |
ITPD980169A1 (en) | 1998-07-06 | 2000-01-06 | Fidia Advanced Biopolymers Srl | AMIDES OF HYALURONIC ACID AND ITS DERIVATIVES AND PROCESS FOR THEIR PREPARATION. |
US6630457B1 (en) | 1998-09-18 | 2003-10-07 | Orthogene Llc | Functionalized derivatives of hyaluronic acid, formation of hydrogels in situ using same, and methods for making and using same |
IT1303738B1 (en) | 1998-11-11 | 2001-02-23 | Aquisitio S P A | CARBOXYLATE POLYSACCHARIDE CROSS-LINKING PROCESS. |
DK172900B1 (en) | 1998-12-18 | 1999-09-27 | Per Julius Nielsen | Preparation and kit for use in intraocular surgery |
GB9902652D0 (en) | 1999-02-05 | 1999-03-31 | Fermentech Med Ltd | Process |
US6767928B1 (en) | 1999-03-19 | 2004-07-27 | The Regents Of The University Of Michigan | Mineralization and biological modification of biomaterial surfaces |
US6444647B1 (en) | 1999-04-19 | 2002-09-03 | The Procter & Gamble Company | Skin care compositions containing combination of skin care actives |
US6372494B1 (en) | 1999-05-14 | 2002-04-16 | Advanced Tissue Sciences, Inc. | Methods of making conditioned cell culture medium compositions |
US6335023B1 (en) * | 1999-06-30 | 2002-01-01 | Ruey J. Yu | Oligosaccharide aldonic acids and their topical use |
US6521223B1 (en) | 2000-02-14 | 2003-02-18 | Genzyme Corporation | Single phase gels for the prevention of adhesions |
US6682760B2 (en) | 2000-04-18 | 2004-01-27 | Colbar R&D Ltd. | Cross-linked collagen matrices and methods for their preparation |
KR20010096388A (en) | 2000-04-19 | 2001-11-07 | 진세훈 | Human glans enhancing materials and glans enhancing method |
FR2811671B1 (en) | 2000-07-17 | 2003-02-28 | Corneal Ind | POLYMER (S) HYDROGEL, BIODEGRATION RESISTANT, PREPARATION AND USE AS TISSUE REGENERATION SUPPORT |
FR2811996B1 (en) | 2000-07-19 | 2003-08-08 | Corneal Ind | CROSS-LINKING OF POLYSACCHARIDE (S), PREPARATION OF HYDROGEL (S); POLYSACCHARIDE (S) AND HYDROGEL (S) OBTAINED, THEIR USES |
WO2002009792A1 (en) | 2000-07-28 | 2002-02-07 | Anika Therapeutics, Inc. | Bioabsorbable composites of derivatized hyaluronic acid |
JP2004507503A (en) * | 2000-08-28 | 2004-03-11 | センション,インコーポレイテッド | Use of threo-methylphenidate to enhance memory |
US6620196B1 (en) | 2000-08-30 | 2003-09-16 | Sdgi Holdings, Inc. | Intervertebral disc nucleus implants and methods |
US6773723B1 (en) | 2000-08-30 | 2004-08-10 | Depuy Acromed, Inc. | Collagen/polysaccharide bilayer matrix |
JP4187917B2 (en) | 2000-09-08 | 2008-11-26 | 独立行政法人科学技術振興機構 | Method for producing glycosaminoglycan-collagen complex for tissue regeneration matrix |
US6924273B2 (en) | 2000-10-03 | 2005-08-02 | Scott W. Pierce | Chondroprotective/restorative compositions and methods of use thereof |
AU2001294459A1 (en) | 2000-10-06 | 2002-04-15 | Jagotec Ag | A controlled-release, parenterally administrable microparticle preparation |
KR100375299B1 (en) | 2000-10-10 | 2003-03-10 | 주식회사 엘지생명과학 | Crosslinked derivatives of hyaluronic acid by amide formation and their preparation methods |
WO2003053325A2 (en) | 2000-12-13 | 2003-07-03 | Purdue Research Foundation | Microencapsulation of drugs by solvent exchange |
US6979440B2 (en) | 2001-01-29 | 2005-12-27 | Salvona, Llc | Compositions and method for targeted controlled delivery of active ingredients and sensory markers onto hair, skin, and fabric |
US7119062B1 (en) | 2001-02-23 | 2006-10-10 | Neucoll, Inc. | Methods and compositions for improved articular surgery using collagen |
TW574301B (en) | 2001-05-02 | 2004-02-01 | Ind Tech Res Inst | Manufacturing method of epoxide crosslinked polysaccharides matrix |
JP4490095B2 (en) | 2001-06-29 | 2010-06-23 | メドグラフト マイクロテック インコーポレイテッド | Biodegradable injectable implants and related methods of manufacture and use |
US6749841B2 (en) | 2001-07-26 | 2004-06-15 | Revlon Consumer Products Corporation | Stabilized aqueous acidic antiperspirant compositions and related methods |
JP4230135B2 (en) | 2001-08-21 | 2009-02-25 | 独立行政法人科学技術振興機構 | Method for producing glycosaminoglycan-collagen complex cross-linked by multifunctional cross-linking agent |
US6824786B2 (en) * | 2001-11-27 | 2004-11-30 | Ruey J. Yu | Compositions comprising phenyl-glycine derivatives |
US20060189516A1 (en) | 2002-02-19 | 2006-08-24 | Industrial Technology Research Institute | Method for producing cross-linked hyaluronic acid-protein bio-composites |
JP3916516B2 (en) | 2002-06-10 | 2007-05-16 | 独立行政法人科学技術振興機構 | Scaffolding material for hard tissue-soft tissue interface regeneration |
US6780366B2 (en) | 2002-08-15 | 2004-08-24 | Mentor Corporation | Drip retainer |
KR100523953B1 (en) | 2002-08-27 | 2005-10-25 | 주식회사 엘지생명과학 | Microbeads of natural polysaccharide and hyaluronic acid and processes for preparing the same |
KR100507545B1 (en) | 2002-09-03 | 2005-08-09 | 주식회사 엘지생명과학 | Hyaluronic acid derivatives and processes for preparing them |
US20040127932A1 (en) | 2002-09-12 | 2004-07-01 | Shah Tilak M. | Dip-molded polymeric medical devices with reverse thickness gradient, and method of making same |
EP1555957A4 (en) * | 2002-10-04 | 2010-11-24 | Nanomatrix Inc | Sealants for skin and other tissues |
DE10246340A1 (en) | 2002-10-04 | 2004-04-29 | Wohlrab, David, Dr. | Combination preparation of hyaluronic acid and at least one local anesthetic and its use |
US20050271596A1 (en) * | 2002-10-25 | 2005-12-08 | Foamix Ltd. | Vasoactive kit and composition and uses thereof |
US20040101959A1 (en) | 2002-11-21 | 2004-05-27 | Olga Marko | Treatment of tissue with undifferentiated mesenchymal cells |
EP1581270A2 (en) | 2002-12-30 | 2005-10-05 | Angiotech International Ag | Silk-containing stent graft |
TWI251596B (en) | 2002-12-31 | 2006-03-21 | Ind Tech Res Inst | Method for producing a double-crosslinked hyaluronate material |
US7931637B2 (en) * | 2002-12-31 | 2011-04-26 | Marine Polymer Technologies, Inc. | Hemostatic compositions and uses therefor |
WO2004073759A1 (en) | 2003-02-19 | 2004-09-02 | Aventis Pharmaceuticals Holdings Inc. | Composition and method for intradermal soft tissue augmentation |
JP2006521180A (en) | 2003-03-25 | 2006-09-21 | バイオキュア・インコーポレーテッド | Medical device with hydrogel yarn |
US20040220259A1 (en) * | 2003-04-04 | 2004-11-04 | Yu Ruey J. | Topical treatment of dermatological disorders associated with reactive or dilated blood vessels |
FR2861734B1 (en) | 2003-04-10 | 2006-04-14 | Corneal Ind | CROSSLINKING OF LOW AND HIGH MOLECULAR MASS POLYSACCHARIDES; PREPARATION OF INJECTABLE SINGLE PHASE HYDROGELS; POLYSACCHARIDES AND HYDROGELS OBTAINED |
AU2003901834A0 (en) | 2003-04-17 | 2003-05-01 | Clearcoll Pty Ltd | Cross-linked polysaccharide compositions |
JP2004323453A (en) | 2003-04-25 | 2004-11-18 | Chisso Corp | Decomposable gel and method for producing the same |
CN100352031C (en) | 2003-05-13 | 2007-11-28 | 三益半导体工业株式会社 | Wafer demounting method, wafer demounting device, and wafer demounting and transferring machine |
US7439241B2 (en) * | 2003-05-27 | 2008-10-21 | Galderma Laboratories, Inc. | Compounds, formulations, and methods for treating or preventing rosacea |
US20050020600A1 (en) * | 2003-07-23 | 2005-01-27 | Scherer Warren J. | Methods of treating cutaneous flushing using selective alpha-2-adrenergic receptor agonists |
CA2534033A1 (en) | 2003-07-30 | 2005-02-10 | Anteis S.A. | Complex matrix for biomedical use |
ES2406555T3 (en) | 2003-10-29 | 2013-06-07 | Teijin Limited | Composed of hyaluronic acid, hydrogel thereof and material to treat joints |
EP1691852A2 (en) | 2003-11-10 | 2006-08-23 | Angiotech International AG | Medical implants and fibrosis-inducing agents |
US20070224278A1 (en) | 2003-11-12 | 2007-09-27 | Lyons Robert T | Low immunogenicity corticosteroid compositions |
US20090148527A1 (en) | 2007-12-07 | 2009-06-11 | Robinson Michael R | Intraocular formulation |
US20050101582A1 (en) | 2003-11-12 | 2005-05-12 | Allergan, Inc. | Compositions and methods for treating a posterior segment of an eye |
US20060141049A1 (en) | 2003-11-12 | 2006-06-29 | Allergan, Inc. | Triamcinolone compositions for intravitreal administration to treat ocular conditions |
WO2005051451A2 (en) | 2003-11-20 | 2005-06-09 | Angiotech International Ag | Electrical devices and anti-scarring agents |
US8124120B2 (en) | 2003-12-22 | 2012-02-28 | Anika Therapeutics, Inc. | Crosslinked hyaluronic acid compositions for tissue augmentation |
WO2005066215A1 (en) | 2003-12-30 | 2005-07-21 | Genzyme Corporation | Cohesive gels form cross-linked hyaluronan and/or hylan, their preparation and use |
US8524213B2 (en) | 2003-12-30 | 2013-09-03 | Genzyme Corporation | Polymeric materials, their preparation and use |
DE102004002001A1 (en) | 2004-01-14 | 2005-08-11 | Reinmüller, Johannes, Dr.med. | Agent for the treatment of inflammatory diseases |
US7812049B2 (en) * | 2004-01-22 | 2010-10-12 | Vicept Therapeutics, Inc. | Method and therapeutic/cosmetic topical compositions for the treatment of rosacea and skin erythema using α1-adrenoceptor agonists |
CA2536096A1 (en) | 2004-01-30 | 2005-08-18 | Angiotech International Ag | Compositions and methods for treating contracture |
FR2865737B1 (en) | 2004-02-03 | 2006-03-31 | Anteis Sa | BIOCOMPATIBLE RETICLE GEL |
US20050222101A1 (en) * | 2004-03-30 | 2005-10-06 | Jeffrey Hutterer | Method and composition for treatment of skin conditions |
US20050226936A1 (en) | 2004-04-08 | 2005-10-13 | Q-Med Ab | Method of soft tissue augmentation |
US8288362B2 (en) | 2004-05-07 | 2012-10-16 | S.K. Pharmaceuticals, Inc. | Stabilized glycosaminoglycan preparations and related methods |
US20050256204A1 (en) * | 2004-05-11 | 2005-11-17 | Bitter Patrick H Sr | Topical phenyl-epinephrine Rosacea treatment |
EP1750769B1 (en) | 2004-05-20 | 2013-01-23 | Mentor Worldwide LLC | Methods for making injectable polymer hydrogels |
ES2609105T3 (en) | 2004-05-20 | 2017-04-18 | Mentor Worldwide Llc | Covalent linking method of hyaluronic acid and chitosan |
CN101027065A (en) | 2004-06-15 | 2007-08-29 | 陈献 | Phospholipid compositions and methods for their preparation and use |
US7906140B2 (en) * | 2004-06-17 | 2011-03-15 | Virun, Inc. | Compositions for mucosal delivery of agents |
JP2008509935A (en) | 2004-08-13 | 2008-04-03 | アンジオテック インターナショナル アーゲー | Compositions and methods using hyaluronic acid and hyaluronic acid inhibitors |
US20060040895A1 (en) | 2004-08-19 | 2006-02-23 | Kipling Thacker | Aesthetic use of hyaluronan |
US7288263B2 (en) | 2004-09-13 | 2007-10-30 | Evera Laboratories, Llc | Compositions and methods for treatment of skin discoloration |
US7414021B2 (en) | 2004-10-01 | 2008-08-19 | Vincent Carmine Giampapa | Method and composition for restoration of age related tissue loss in the face or selected areas of the body |
KR100762928B1 (en) | 2004-10-29 | 2007-10-04 | 재단법인서울대학교산학협력재단 | Nonwoven Nanofibrous Membranes of Silk Fibroin for Guided Bone Tissue Regeneration and Their Preparation Method |
US20060105022A1 (en) | 2004-11-15 | 2006-05-18 | Shiseido Co., Ltd. | Process for preparing crosslinked hyaluronic acid gel |
DK1817347T3 (en) | 2004-11-24 | 2017-08-14 | Albumedix As | Process for Crosslinking Hyaluronic Acid with Divinyl Sulfone |
FR2878444B1 (en) | 2004-11-30 | 2008-04-25 | Corneal Ind Soc Par Actions Si | VISCOELASTIC SOLUTIONS COMPRISING SODIUM HYALURONATE AND HYDROXYPROPYLMETHYLCELLULOSE, PREPARATION AND USES |
WO2006067608A1 (en) | 2004-12-22 | 2006-06-29 | Laboratoire Medidom S.A. | Aqueous formulations based on sodium hyaluronate for parenteral use |
WO2006105450A2 (en) * | 2005-03-30 | 2006-10-05 | Revance Therapeutics, Inc. | Compositions and methods for treating acne |
US20060257488A1 (en) | 2005-05-10 | 2006-11-16 | Cytophil, Inc. | Injectable hydrogels and methods of making and using same |
EP1726299A3 (en) | 2005-05-27 | 2007-04-18 | StratoSphere Pharma AB | Cores and microcapsules suitable for parenteral administration as well as process for their manufacture |
US7491709B2 (en) | 2005-07-01 | 2009-02-17 | Wayne Carey | Treatment with hyaluronic acid |
CN102266274B (en) | 2005-08-11 | 2016-05-18 | 株式会社林原 | Agent for enhancing collagen production and uses thereof |
JP4982718B2 (en) | 2005-08-31 | 2012-07-25 | 株式会社林原 | Composition for oral intake for beautiful skin |
EP3015101B1 (en) | 2005-10-03 | 2019-08-21 | PINSKY, Mark A. | Non-phospholipid liposomes comprising hyaluronic acid |
US20070082070A1 (en) * | 2005-10-11 | 2007-04-12 | Stookey Evangeline L | Treating skin disorders |
NZ568694A (en) * | 2005-11-09 | 2011-09-30 | Zalicus Inc | Method, compositions, and kits for the treatment of medical conditions |
EP1968499A1 (en) | 2005-12-14 | 2008-09-17 | Anika Therapeutics Inc. | Bioabsorbable implant of hyaluronic acid derivative for treatment of osteochondral and chondral defects |
US20070203095A1 (en) | 2005-12-14 | 2007-08-30 | Anika Therapeutics, Inc. | Treatment of arthritis and other musculoskeletal disorders with crosslinked hyaluronic acid |
FR2894827B1 (en) | 2005-12-21 | 2010-10-29 | Galderma Res & Dev | PHARMACEUTICAL OR COSMETIC PREPARATIONS FOR TOPICAL AND / OR PARENTERAL APPLICATION, PROCESSES FOR THEIR PREPARATION, AND USES THEREOF |
FR2895907B1 (en) | 2006-01-06 | 2012-06-01 | Anteis Sa | VISCOELASTIC GEL FOR DERMATOLOGICAL USE |
US20070184087A1 (en) | 2006-02-06 | 2007-08-09 | Bioform Medical, Inc. | Polysaccharide compositions for use in tissue augmentation |
US20070212385A1 (en) | 2006-03-13 | 2007-09-13 | David Nathaniel E | Fluidic Tissue Augmentation Compositions and Methods |
CA2645324A1 (en) | 2006-03-15 | 2007-09-27 | Surmodics, Inc. | Hydrophobic derivatives of natural biodegradable polysaccharides and uses thereof |
FR2900575B1 (en) | 2006-05-05 | 2008-10-17 | Anteis Sa | BIOCOMPATIBLE CONTROLLED RELEASE GEL, PREPARATION METHOD AND USE THEREOF |
EP2019647A4 (en) | 2006-05-19 | 2010-04-28 | Univ Boston | Novel hydrophilic polymers as medical lubricants and gels |
US20070298005A1 (en) | 2006-06-22 | 2007-12-27 | Marie-Josee Thibault | Injectable composition for treatment of skin defects or deformations |
WO2008003321A2 (en) | 2006-07-07 | 2008-01-10 | Novozymes Biopolymer A/S | Compositions with several hyaluronic acid fractions for cosmetic use |
AR062046A1 (en) | 2006-07-25 | 2008-08-10 | Osmotica Pharmaceutical Argentina S A | OPHTHALMIC SOLUTIONS |
US20100035838A1 (en) | 2006-09-19 | 2010-02-11 | Geoffrey Kenneth Heber | Cross-linked polysaccharide gels |
FR2908415B1 (en) | 2006-11-10 | 2009-01-23 | Abr Dev Sarl | RETICULATED HYALURONIC ACID AND PROCESS FOR PREPARING THE SAME |
FR2909560B1 (en) | 2006-12-06 | 2012-12-28 | Fabre Pierre Dermo Cosmetique | HYALURONIC ACID GEL FOR INTRADERMAL INJECTION |
CA2672495C (en) | 2006-12-11 | 2017-01-17 | Chi2Gel Ltd. | Novel injectable chitosan mixtures forming hydrogels |
KR100759091B1 (en) | 2006-12-13 | 2007-09-17 | 조강선 | Dermal filler composition |
DK2107913T3 (en) | 2006-12-22 | 2012-05-21 | Croma Pharma Ges M B H | Use of thiolated polysaccharides for tissue building |
US20080188416A1 (en) | 2007-02-05 | 2008-08-07 | Freedom-2, Inc. | Tissue fillers and methods of using the same |
CA2677498C (en) | 2007-02-05 | 2016-05-17 | Carbylan Biosurgery, Inc. | Polymer formulations for delivery of bioactive agents |
US7776840B2 (en) | 2007-02-21 | 2010-08-17 | Cutanea Life Sciences, Inc. | Methods of use of biomaterial and injectable implant containing biomaterial |
US7939578B2 (en) | 2007-02-23 | 2011-05-10 | 3M Innovative Properties Company | Polymeric fibers and methods of making |
US8642067B2 (en) | 2007-04-02 | 2014-02-04 | Allergen, Inc. | Methods and compositions for intraocular administration to treat ocular conditions |
US11078262B2 (en) | 2007-04-30 | 2021-08-03 | Allergan, Inc. | High viscosity macromolecular compositions for treating ocular conditions |
US20100323985A1 (en) | 2007-05-11 | 2010-12-23 | Marc Moutet | Pharmaceutical or cosmetic preparations for topical and/or parenteral application, preparation methods thereof and use of same |
EP2155149A2 (en) | 2007-05-11 | 2010-02-24 | Galderma Research & Development | Pharmaceutical or cosmetic preparations for topical and/or parenteral application, preparation methods thereof and use of same |
AU2008256864A1 (en) | 2007-05-23 | 2008-12-04 | Allergan, Inc. | Coated hyaluronic acid particles |
CA2687990A1 (en) | 2007-05-23 | 2008-12-04 | Allergan, Inc. | Cross-linked collagen and uses thereof |
WO2008157608A1 (en) | 2007-06-18 | 2008-12-24 | Cartlix, Inc. | Composite scaffolds for tissue regeneration |
WO2009005790A2 (en) | 2007-06-29 | 2009-01-08 | Carbylan Biosurgery, Inc. | Sterile thiol-derivatized hyaluronic acid polymer compositions and uses thereof |
EP2520309A1 (en) | 2007-07-27 | 2012-11-07 | Humacyte, Inc. | Compositions and methods for soft tissue augmentation |
US20090060852A1 (en) | 2007-07-27 | 2009-03-05 | Jack Dejovin | Compounds, Formulations and Methods for Reducing Skin Wrinkles, Creasing and Sagging |
US20120071437A1 (en) | 2007-07-30 | 2012-03-22 | Allergan, Inc. | Tunable crosslinked polysaccharide compositions |
US20110077737A1 (en) | 2007-07-30 | 2011-03-31 | Allergan, Inc. | Tunably Crosslinked Polysaccharide Compositions |
US8318695B2 (en) | 2007-07-30 | 2012-11-27 | Allergan, Inc. | Tunably crosslinked polysaccharide compositions |
FR2920000B1 (en) | 2007-08-13 | 2010-01-29 | Oreal | COSMETIC OR PHARMACEUTICAL COMPOSITION CONTAINING HYALURONIC ACID, AND COSMETIC PROCESS FOR DECREASING SIGNS OF AGING |
AU2008289178A1 (en) | 2007-08-16 | 2009-02-26 | Carnegie Mellon University | Inflammation-regulating compositions and methods |
KR100813224B1 (en) | 2007-08-24 | 2008-03-13 | 한양대학교 산학협력단 | Thermo-reversible coacervate combination gels for protein delivery |
FR2920968B1 (en) | 2007-09-14 | 2009-11-13 | Oreal | COSMETIC PROCESS FOR AESTHETIC TREATMENT AND / OR REPAIR OF SKIN |
US8697044B2 (en) | 2007-10-09 | 2014-04-15 | Allergan, Inc. | Crossed-linked hyaluronic acid and collagen and uses thereof |
US7910134B2 (en) | 2007-10-29 | 2011-03-22 | Ayman Boutros | Alloplastic injectable dermal filler and methods of use thereof |
EP3498299A1 (en) | 2007-11-16 | 2019-06-19 | Aclaris Therapeutics, Inc. | Compositions and methods for treating purpura |
US8394782B2 (en) | 2007-11-30 | 2013-03-12 | Allergan, Inc. | Polysaccharide gel formulation having increased longevity |
US8394784B2 (en) | 2007-11-30 | 2013-03-12 | Allergan, Inc. | Polysaccharide gel formulation having multi-stage bioactive agent delivery |
US20090143348A1 (en) | 2007-11-30 | 2009-06-04 | Ahmet Tezel | Polysaccharide gel compositions and methods for sustained delivery of drugs |
FR2924615B1 (en) | 2007-12-07 | 2010-01-22 | Vivacy Lab | HYDROGEL COHESIVE BIODEGRADABLE. |
US9161970B2 (en) | 2007-12-12 | 2015-10-20 | Allergan, Inc. | Dermal filler |
JP5580210B2 (en) * | 2007-12-21 | 2014-08-27 | ガルデマ ラボラトリーズ インコーポレイテッド | Preoperative treatment |
US20090169615A1 (en) | 2007-12-26 | 2009-07-02 | Pinsky Mark A | Collagen Formulations for Improved Skin Care |
US20090291986A1 (en) | 2008-05-22 | 2009-11-26 | Apostolos Pappas | Composition and method of treating facial skin defect |
US20090297632A1 (en) | 2008-06-02 | 2009-12-03 | Waugh Jacob M | Device, Methods and Compositions to Alter Light Interplay with Skin |
WO2010003797A1 (en) | 2008-07-09 | 2010-01-14 | Novozymes Biopharma Dk A/S | Hyaluronic acid for corneal wound healing |
US8357795B2 (en) | 2008-08-04 | 2013-01-22 | Allergan, Inc. | Hyaluronic acid-based gels including lidocaine |
EP3184552B1 (en) | 2008-09-02 | 2020-08-12 | Tautona Group LP | Threads of hyaluronic acid, methods of making thereof and uses thereof |
EP2341953B1 (en) | 2008-09-04 | 2018-11-21 | The General Hospital Corporation | Hydrogels for vocal cord and soft tissue augmentation and repair |
GB0816496D0 (en) | 2008-09-10 | 2008-10-15 | Zhao Xiaobin | Hyaluronic acid cryogel |
CN102164606B (en) | 2008-09-30 | 2014-04-16 | 电气化学工业株式会社 | Light-stabilized pharmaceutical composition |
US20100098794A1 (en) | 2008-10-17 | 2010-04-22 | Armand Gerard | Topical anti-wrinkle and anti-aging moisturizing cream |
US20100111919A1 (en) | 2008-10-31 | 2010-05-06 | Tyco Healthcare Group Lp | Delayed gelation compositions and methods of use |
US9248165B2 (en) | 2008-11-05 | 2016-02-02 | Hancock-Jaffe Laboratories, Inc. | Composite containing collagen and elastin as a dermal expander and tissue filler |
FR2938187B1 (en) | 2008-11-07 | 2012-08-17 | Anteis Sa | INJECTABLE COMPOSITION BASED ON HYALURONIC ACID OR ONE OF ITS HEAT-STERILIZED SALTS, POLYOLS AND LIDOCAINE |
AU2009311234B2 (en) | 2008-11-07 | 2013-05-02 | Klox Technologies Inc. | Combination of an oxidant and a photoactivator for the healing of wounds |
ITRM20080636A1 (en) | 2008-11-28 | 2010-05-29 | Univ Palermo | PROCEDURE FOR THE PRODUCTION OF FUNCTIONAL DERIVATIVES OF HYALURONIC ACID AND RELATIVE HYDROGELS. |
WO2010065784A2 (en) | 2008-12-03 | 2010-06-10 | Jakk Group, Inc. | Methods, devices, and compositions for dermal filling |
PL2236523T3 (en) | 2009-03-30 | 2018-07-31 | Scivision Biotech Inc. | Method for producing cross-linked hyaluronic acid |
WO2010115081A2 (en) | 2009-04-02 | 2010-10-07 | Allergan, Inc. | Hair-like shaped hydrogels for soft tissue augmentation |
US9371402B2 (en) | 2009-04-09 | 2016-06-21 | Scivision Biotech Inc. | Method for producing cross-linked hyaluronic acid |
IT1395392B1 (en) | 2009-08-27 | 2012-09-14 | Fidia Farmaceutici | VISCOELASTIC FROSTS LIKE NEW FILLERS |
US20110171311A1 (en) | 2010-01-13 | 2011-07-14 | Allergan Industrie, Sas | Stable hydrogel compositions including additives |
US20110172180A1 (en) | 2010-01-13 | 2011-07-14 | Allergan Industrie. Sas | Heat stable hyaluronic acid compositions for dermatological use |
US20110171286A1 (en) | 2010-01-13 | 2011-07-14 | Allergan, Inc. | Hyaluronic acid compositions for dermatological use |
US9114188B2 (en) | 2010-01-13 | 2015-08-25 | Allergan, Industrie, S.A.S. | Stable hydrogel compositions including additives |
CA2792729C (en) | 2010-03-12 | 2016-06-28 | Allergan Industrie, Sas | Fluid compositions for improving skin conditions |
CA2794254C (en) | 2010-03-22 | 2018-09-04 | Allergan, Inc. | Polysaccharide and protein-polysaccharide cross-linked hydrogels for soft tissue augmentation |
US8883139B2 (en) | 2010-08-19 | 2014-11-11 | Allergan Inc. | Compositions and soft tissue replacement methods |
US9005605B2 (en) | 2010-08-19 | 2015-04-14 | Allergan, Inc. | Compositions and soft tissue replacement methods |
US8697057B2 (en) | 2010-08-19 | 2014-04-15 | Allergan, Inc. | Compositions and soft tissue replacement methods |
EP2979709B1 (en) | 2010-10-20 | 2017-08-02 | Allergan Holdings France S.A.S. | Threads of cross-linked hyaluronic acid and use thereof |
US9299476B2 (en) | 2010-10-22 | 2016-03-29 | Newsouth Innovations Pty Limited | Polymeric material |
FR2968305B1 (en) | 2010-12-06 | 2014-02-28 | Teoxane | PROCESS FOR PREPARING RETICULATED GEL |
FR2968306B1 (en) | 2010-12-06 | 2014-02-28 | Teoxane | PROCESS FOR PREPARING RETICULATED GEL |
US9408797B2 (en) | 2011-06-03 | 2016-08-09 | Allergan, Inc. | Dermal filler compositions for fine line treatment |
US9149422B2 (en) | 2011-06-03 | 2015-10-06 | Allergan, Inc. | Dermal filler compositions including antioxidants |
US20130096081A1 (en) | 2011-06-03 | 2013-04-18 | Allergan, Inc. | Dermal filler compositions |
US9393263B2 (en) | 2011-06-03 | 2016-07-19 | Allergan, Inc. | Dermal filler compositions including antioxidants |
US20130116190A1 (en) | 2011-09-06 | 2013-05-09 | Allergan, Inc. | Hyaluronic acid-collagen matrices for tissue engineering |
US20130244943A1 (en) | 2011-09-06 | 2013-09-19 | Allergan, Inc. | Hyaluronic acid-collagen matrices for dermal filling and volumizing applications |
US20130116411A1 (en) | 2011-09-06 | 2013-05-09 | Allergan, Inc. | Methods of making hyaluronic acid/collagen compositions |
US20140011980A1 (en) | 2012-07-03 | 2014-01-09 | Allergan, Inc. | Methods for sterilizing compositions and resulting compositions |
-
2008
- 2008-11-17 EP EP18202816.7A patent/EP3498299A1/en active Pending
- 2008-11-17 EP EP14170999.8A patent/EP2818184B1/en active Active
- 2008-11-17 CN CN200880116406.9A patent/CN101896204B/en active Active
- 2008-11-17 EP EP08850846.0A patent/EP2207424B1/en active Active
- 2008-11-17 HU HUE14170999A patent/HUE042931T2/en unknown
- 2008-11-17 WO PCT/US2008/083774 patent/WO2009065116A1/en active Application Filing
- 2008-11-17 PT PT14170999T patent/PT2818184T/en unknown
- 2008-11-17 CA CA2703109A patent/CA2703109C/en active Active
- 2008-11-17 JP JP2010534258A patent/JP5670196B2/en active Active
- 2008-11-17 BR BRPI0819075-5A2A patent/BRPI0819075A2/en not_active IP Right Cessation
- 2008-11-17 DK DK14170999.8T patent/DK2818184T3/en active
- 2008-11-17 TR TR2019/01431T patent/TR201901431T4/en unknown
- 2008-11-17 AU AU2008322411A patent/AU2008322411C1/en active Active
- 2008-11-17 US US12/272,253 patent/US8114898B2/en active Active
- 2008-11-17 SI SI200832035T patent/SI2818184T1/en unknown
- 2008-11-17 MX MX2010005331A patent/MX2010005331A/en active IP Right Grant
- 2008-11-17 PL PL14170999T patent/PL2818184T3/en unknown
- 2008-11-17 KR KR1020107013170A patent/KR101577471B1/en active IP Right Grant
- 2008-11-17 ES ES14170999T patent/ES2709120T3/en active Active
-
2010
- 2010-05-11 IL IL205704A patent/IL205704A/en active IP Right Grant
-
2012
- 2012-01-06 US US13/345,472 patent/US8673953B2/en active Active
-
2014
- 2014-02-16 US US14/181,706 patent/US9265761B2/en active Active
- 2014-10-02 US US14/505,100 patent/US20150018358A1/en not_active Abandoned
- 2014-10-21 JP JP2014214612A patent/JP5938082B2/en active Active
-
2019
- 2019-01-31 HR HRP20190214TT patent/HRP20190214T1/en unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2703109C (en) | Compositions and methods for treating purpura | |
DK2663727T3 (en) | Centering Device | |
Del Rosso | Advances in understanding and managing rosacea: part 2: the central role, evaluation, and medical management of diffuse and persistent facial erythema of rosacea | |
US20050020600A1 (en) | Methods of treating cutaneous flushing using selective alpha-2-adrenergic receptor agonists | |
US20120058056A1 (en) | Treatment of cutaneous hemangioma | |
US20140329874A1 (en) | Alpha adrenergic agonists for the treatment of tissue trauma | |
TWI464147B (en) | Use of indolyl and indolinyl hydroxamates for treating heart failure or neuronal injury | |
EP3651767A1 (en) | Methods and compositions for reducing side effects in chemotherapeutic treatments | |
CA3026974A1 (en) | Compositions comprising timolol and their use in the treatment of rosacea by topical administration | |
WO2019093359A1 (en) | Agent for increasing blood flow volume in peripheral capillary | |
CN116983415A (en) | Composition for preventing and treating subcutaneous telangiectasis, telangiectasis and related secondary diseases and application thereof | |
US20170027922A1 (en) | Use of naratriptan in the treatment of rosacea | |
Wankhede et al. | Tinea Capitis: Causal Organisms, Prognosis and Therapy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |
Effective date: 20131004 |