WO2012052478A2 - Topical gel composition - Google Patents
Topical gel composition Download PDFInfo
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- WO2012052478A2 WO2012052478A2 PCT/EP2011/068261 EP2011068261W WO2012052478A2 WO 2012052478 A2 WO2012052478 A2 WO 2012052478A2 EP 2011068261 W EP2011068261 W EP 2011068261W WO 2012052478 A2 WO2012052478 A2 WO 2012052478A2
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- WIPO (PCT)
- Prior art keywords
- gel composition
- topical gel
- skin
- carbomer
- brimonidine
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
Definitions
- Parabens are esters of para-hydroxybenzoic acid. They are used primarily for their bactericidal and fungicidal properties. Examples of parabens include methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben and their salts. Because of their low costs, long history of safe use and the inefficacy of natural alternatives, parabens are widely used as preservatives in the cosmetic and pharmaceutical industries. See Darbre et al., 24 J. Appl. Toxicol. 5-13 (2004) and references therein.
- Carbomer is a generic name of Carbopol ® , a trademarked product from
- Carbomer and Carbopol ® are used interchangeably in the present application, referring to a synthetic polymer of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol. It can be a homopolymer of acrylic acid, cross-linked with an allyl ether pentaerythritol, allyl ether of sucrose, or allyl ether of propylene.
- Carbomers have been used as vehicles for drug delivery. They have a long history of safe and effective use in topical gels, creams, lotions, and ointments, as supported by extensive toxicology studies. They have been shown to have extremely low irritancy properties and are non- sensitizing with repeat usage.
- Carbomers or carbomer copolymers have been used in topical formulations, e.g., for thickening, emulsifying or suspending.
- Brimonidine is a selective alpha-2-adrenergic agonist. It has been used as either monotherapy or as adjunctive therapy to lower intraocular pressure (IOP) in the treatment of glaucoma and ocular hypertension (OHT) since its approval in 1996.
- IOP intraocular pressure
- OHT ocular hypertension
- Brimonidine has also been found to be useful in treating various skin disorders, such as rosacea, erythema caused by rosacea, see, e.g., U.S. Ser. No. 10/853,585 to DeJovin et al.; U.S. Ser. No. 10/626,037 to Scherer; U.S. Ser. No. 12/193,098 to Theobald et al;
- telangiectasias see, e.g., U.S. Patent Application Publication No. 2006/0264515.
- Topical gel compositions comprising brimonidine, carbomer and paraben(s) for the treatment of skin disorders have been described, see for example, U.S. Ser. No. 10/853,585 to DeJovin et al; U.S. Ser. No. 12/193,098 to Theobald et al, etc.
- crystalline particles of methylparaben have been unexpectedly observed in some brimonidine topical gel formulations and placebo formulations containing carbomer and methylparaben.
- embodiments of the present invention relate to a topical gel composition
- a topical gel composition comprising:
- topical gel composition has a pH of 4.5 to 7.5; and wherein when the concentration of paraben is greater than 0.15% (w/w), the concentration of carbomer is less than 1.25%>(w/w).
- embodiments of the present invention relate to a topical gel composition
- a topical gel composition comprising:
- topical gel composition has a pH of 4.5 to 7.5, and wherein when the concentration of paraben is greater than 0.15% (w/w), the concentration of carbomer is less than 1.25%>(w/w).
- composition comprising:
- one or more second preservatives selected from the group consisting of sodium benzoate, phenoxyethanol, benzyl alcohol, imidazolidinyl urea and diazolidinyl urea;
- the pH of the topical gel composition is adjusted to a pH of 5.0 to 6.5 by an adequate amount of sodium hydroxide aqueous solution.
- embodiments of the present invention relate to a method of treating or preventing a skin disorder in a subject.
- the method comprises topically administering to a skin area of the subject a topical gel composition according to an embodiment of the present invention, wherein the skin area is, or is prone to be, affected by the skin disorder.
- erythema or a symptom associated therewith encompasses skin redness or rash resulting from any causes. For example, it can be caused by skin injury, surgery and other procedures on the skin, infection, inflammation, emotion, exercise, heat (erythema ab igne), cold, photosensitivity, radiation therapy, allergy, hot flush diseases, medications, etc.
- erythema or a symptom associated therewith examples include, but are not limited to, photosensitivity, erythema multiforme, and erythema nodusum, and their associated symptoms.
- Photosensitivity is caused by a reaction to sunlight, which often occurs when some factors, such as an infection or a medication, increase the sensitivity to ultraviolet radiation. However, photosensitivity can also occur without any increased sensitivity to ultraviolet radiation.
- Erythema multiforme is characterized by raised spots or other lesions on the skin, which are usually caused by a reaction to medications, infections, or illness. Most erythema multiforme is associated with herpes simplex or mycoplasma infections. Erythema nodosum is a form of erythema that is accompanied by tender lumps, usually on the legs below the knees, and may be caused by certain medications or diseases.
- the term "erythema or a symptom associated therewith” includes erythema of rosacea, i.e., erythema or a symptom associated therewith in a patient with rosacea.
- Rosacea is an inflammatory skin disorder that generally affects the cheeks, nose, chin, and forehead of a patient.
- the major symptom of rosacea is erythema, i.e., the abnormal redness of the skin.
- erythema or a symptom associated therewith encompasses different degrees or grades of erythema or a symptom associated therewith, from mild to severe.
- a skin area that is affected by erythema or that is prone to be affected by erythema can be identified using any diagnostic signs or means known in the art, and can be treated by methods according to embodiments of the present invention.
- telangiectasia or a symptom associated therewith refers to a visible, permanent abnormal dilation of blood vessels, such as arterioles and venules.
- a visible blood vessel is a blood vessel visually discernable as a line to an observer without the aid of magnifying equipment (other than spectacles normally used by the observer).
- a telangiectatic blood vessel can have a diameter of at least about 0.5 mm.
- Telangiectasias can be associated with numerous conditions, syndromes, diseases, and disorders. For example, a facial telangiectasia can be associated with age, sun exposure, and alcohol use.
- telangiectasias include, in non-limiting example, scleroderma, hereditary hemorrhagic telangiectasia (Olser-Rendu syndrome), ataxia-telangiectasia, spider angioma, cutis marmorata telangiectasia congenita, Bloom syndrome, Klippel-Trenaunay- Weber syndrome, Sturge-Weber disease, xeroderma pigmentosa, nevus flammeus, generalized essential telangiectasias (GET), angioma serpiginosum, spider naevi, CREST syndrome, basal cell carcinoma, and unilateral syndromed telangiectasia.
- Olser-Rendu syndrome hereditary hemorrhagic telangiectasia
- ataxia-telangiectasia spider angioma
- Bloom syndrome Klippel-Trenaun
- telangiectasia or a symptom associated therewith includes telangiectasia associated with rosacea, i.e., telangiectasia or a symptom associated therewith in a patient with rosacea.
- telangiectasia or a symptom associated therewith includes sun-induced/photodamage telangiectasia.
- telangiectasia or a symptom associated therewith encompasses different degrees or grades of telangiectasia or symptoms associated therewith, from mild to severe.
- a skin area that is affected by telangiectasia or that is prone to be affected by telangiectasia can be identified using any diagnostic signs or means known in the art, and can be treated by methods according to embodiments of the present invention.
- brimonidine refers to the compound (5-bromo- quinoxalin-6-yl)-(4,5-dihydro-lH- imidazol-2-yl)-amine having the structure of Formula (I):
- any pharmaceutically acceptable salt of the compound such as brimonidine tartrate.
- pharmaceutically acceptable salt(s) means those salts of a compound of interest that are safe and effective for topical use in mammals and that possess the desired biological activity.
- Pharmaceutically acceptable salts include salts of acidic or basic groups present in the specified compounds.
- Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide,
- Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.
- hydrate means a compound of interest, or a pharmaceutically acceptable salt thereof that further includes a stoichiometric or non- stoichiometric amount of water bound to it by non-covalent intermolecular forces.
- topical gel composition or “topical gel formulation,” as used herein, means any gel formulation or composition which is pharmaceutically and/or cosmetically acceptable for topical delivery of the specified compound(s) according to embodiments of the invention.
- composition is intended to encompass a product comprising the specified ingredient in the specified amount, as well as any product which results, directly or indirectly, from combinations of the specified ingredient in the specified amount.
- the term "subject” means any animal, preferably a mammal, most preferably a human, to whom will be or has been administered compounds or topical formulations according to embodiments of the invention.
- the term "mammal” as used herein, encompasses any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., more preferably a human.
- a subject is in need of, or has been the object of observation or experiment of, treatment or prevention of a skin disorder, such as rosacea, erythema of rosacea, telangiectasia, psoriasis, purpura, erythema of acne, eczema, non- rosacea-related inflammation of the skin, flushing, skin sagging, creasing and/or wrinkling, or a symptom associated therewith.
- a skin disorder such as rosacea, erythema of rosacea, telangiectasia, psoriasis, purpura, erythema of acne, eczema, non- rosacea-related inflammation of the skin, flushing, skin sagging, creasing and/or wrinkling, or a symptom associated therewith.
- “treatment” or “treating” refers to an amelioration, prophylaxis, or reversal of a disease
- treatment refers to an amelioration, prophylaxis, or reversal of at least one measurable physical parameter related to the disease or disorder being treated, not necessarily discernible in or by the mammal.
- treatment or “treating” refers to inhibiting or slowing the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both.
- treatment or “treating” refers to delaying the onset of a disease or disorder.
- compounds of interest are administered as a
- preventative measure refers to a reduction of the risk of acquiring a given disease or disorder.
- prevention or “preventing” refers to a reduction of the risk of acquiring a given disease or disorder.
- the specified compounds are administered as a preventative measure to a subject having a predisposition to a disease or disorder even though symptoms of the disease or disorder are absent or minimal.
- methylparaben crystalline particles have been observed in brimonidine topical gel formulations containing 0.2% (w/w) or more methylparaben, particularly in batch sizes of 300 g to 250 kg. See Example 1 below. This observation is surprising in view of the solubility of methylparaben. According to a Material Safety Data Sheet (MSDS) of methylparaben the solubility of methylparaben in water is about 0.25% (w/w) at 20 °C or about 0.30% (w/w) at 25 °C.
- MSDS Material Safety Data Sheet
- methylparaben in propylene glycol is 1 in 5 at 25 °C.
- methylparaben crystalline particles in the composition is completely unexpected.
- the methylparaben crystalline particles observed in the brimonidine topical gel and placebo compositions may have been caused by one or more reasons, such as recrytallization of methylparaben during the manufacturing process, or recrystallization of methylparaben during storage resulting from excipient-excipient interaction.
- recrytallization of methylparaben during the manufacturing process or recrystallization of methylparaben during storage resulting from excipient-excipient interaction.
- Embodiments of the present invention relate to an improved topical gel composition that is substantially free of crystalline particles and has microbiological quality over an extended period of storage.
- the improved topical gel composition according to an embodiment of the present invention comprises:
- topical gel composition has a pH of 4.5 to 7.5, and wherein when the concentration of paraben is greater than 0.15% (w/w), the concentration of carbomer is less than 1.25%>(w/w).
- the topical gel composition comprises 0.05 to 0.20%) (w/w) methylparaben.
- the amount of paraben in the composition is about 0.05%, 0.075%, 0.10%, 0.125% , 0.15% or 0.20%(w/w).
- Suitable second preservatives that can be used in embodiments of the present invention include any preservatives that are suitable for topical application.
- the second preservatives include, but are not limited to, sodium benzoate, phenoxyethanol, benzyl alcohol, imidazolidinyl urea, or diazolidinyl urea. Additional examples of the second preservatives may include, quaternary ammonium compounds, such as
- benzalkonium chloride benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride
- alcoholic agents such as, chlorobutanol
- antibacterial esters such as esters of parahydroxybenzoic acid
- other anti-microbial agents such as chlorhexidine, chlorocresol, benzoic acid, polymyxin, mupirocin, erythromycin, clindamycin, gentamicin, polymyxin, bacitracin, silver sulfadiazine, etc.
- the second preservative is effective in inactivating challenge doses of Gram-negative and Gram-positive microorganisms, as well as yeast.
- the amount of the one or more second preservatives in the composition is greater than 0.3%, 0.35%, 0.4%, 0.45% or 0.5% (w/w).
- the carbomer is a synthetic polymer of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol. It can be a homopolymer of acrylic acid, cross-linked with an allyl ether pentaerythritol, allyl ether of sucrose, or allyl ether of propylene.
- carbomers that can be used in the present invention include, but are not limited to, carbomer 910, 934P, 940, 941, 1342, Carbopol® 974P (carbomer 974P), and Carbopol® 980 (carbomer 980).
- the carbomer is carbomer 934P, carbomer 974P, or carbomer 980.
- the amount of the carbomer in the composition is about 0.8%, 0.85%, 0.95%, 1.05%, 1.15%, 1.25%, 1.35%, 1.45% or 1.5% (w/w).
- Polyols in gel formulations can serve one or more functions such as solubilizing agents, moisturizers, emollients, skin humectant, skin-penetration agents, etc.
- Suitable polyols that can be used in embodiments of the present invention include, but are not limited to, glycerine, propylene glycol, dipropylene glycol, hexylene glycol, butylene glycol, and liquid polyethylene glycols, such as polyethylene glycol 200 to 600, and glycerol.
- paraben used in the topical gel composition is substantially soluble in at least one of the polyols used in the composition.
- the polyol is propylene glycol.
- an organic constituent other than polyol can also be used in the topical formulation according to embodiments of the present invention.
- the amount of the organic constituent, such as polyol, in the composition is about 4.5%, 5.0%, 5.5%, 6.0%>, or 6.5% (w/w).
- a topical gel composition according to
- embodiments of the invention further comprises a water dispersible form of titanium dioxide (Ti02), preferably at an amount that is sufficient to mask the color of brimonidine or another colored ingredient in the formulation, but would not cause irritation to the skin.
- Ti02 may cause mild irritation and reddening to the eyes, thus eye contact with the Ti02 - containing topically administrable composition should be avoided.
- Titanium dioxide imparts a whiteness to the topically administrable composition and helps to increase the opacity and reduce the transparency of the composition. Titanium dioxide absorbs, reflects, or scatters light (including ultraviolet radiation in light), which can help protect products from deterioration. Titanium dioxide can also be used as a sunscreen to protect the user from the harmful effects of ultraviolet radiation that is part of sunlight.
- the amount of water dispersible form of titanium dioxide in the composition is about 0.04%, 0.0425%, 0.0525%), 0.0625%, 0.0725% or 0.08% (w/w).
- a topical gel formulation according to an embodiment of the present invention further comprises an active pharmaceutical ingredient, such as an alpha adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, , that is effective to prevent or treat a skin disorder.
- an active pharmaceutical ingredient such as an alpha adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, , that is effective to prevent or treat a skin disorder.
- Alpha adrenergic receptor agonists are well known in the art.
- the alpha adrenergic receptor agonist may be an alpha- 1 or alpha-2
- the alpha adrenergic receptor agonists included in the invention may or may not show selectivity for either the alpha- 1 or alpha-2 adrenergic receptors. For example, some may be considered as being both alpha- 1 and alpha-2 adrenergic receptor agonists. More preferably, the alpha adrenergic receptor agonist may be a selective alpha- 1 or a selective alpha-2 adrenergic receptor agonist
- Examples of selective alpha- 1 adrenergic receptor agonists include
- oxymetazoline phenylephrine, and methoxyamine.
- selective alpha-2 adrenergic receptor agonists include brimonidine, tetrahydrozaline, naphazoline, xylometazoline, epinephrine, and norepinephrine.
- the active pharmaceutical ingredient comprises 0.05 to 5% (w/w) brimonidine.
- the active pharmaceutical ingredient can optionally include one or more pharmaceutically active ingredients in addition to brimonidine, including, but not limited to, medications used to treat the skin disorder or the underlying disease that causes the skin disorder, antihistamines to control itching, antibiotics, corticosteroids, intravenous immunoglobulins, acetaminophen, etc.
- the brimonidine is brimonidine tartrate.
- the amount of brimonidine in the topical gel composition is about 0.05% to 0.1%, 0.1% to 0.4%, 0.4% to 0.7%, 0.7% to 1%, 1% to 2%, 2% to 3%, 3% to 4%, or 4% to 5% (w/w).
- the amount of brimonidine tartrate in the composition is about 0.1 to 0.6% (w/w).
- a topical gel composition comprises:
- one or more second preservatives selected from the group consisting of sodium benzoate, phenoxyethanol, benzyl alcohol, imidazolidinyl urea and diazolidinyl urea;
- the pH of the topical gel composition is adjusted to 5.0 to 6.5 by an adequate amount of sodium hydroxide aqueous solution.
- the composition further comprises 4.5%) to 6.5%) (w/w) a second polyol, such as glycerol.
- the one or more second preservatives comprise greater than 0.3%> (w/w) phenoxyethanol when 0.15% (w/w) or less methylparaben is used in the formulation.
- a topical gel composition according to embodiments of the present invention can comprise additional pharmaceutically acceptable excipients, such as those listed in Remington: The Science and Practice of Pharmacy, 866-885 (Alfonso R. Gennaro ed., 19th ed., 1995); Ghosh, T. K. et al., Transdermal and Topical Drug Delivery Systems (1997), hereby incorporated herein by reference.
- additional excipients include, but are not limited to, protectives, adsorbents, antioxidants, local anesthetics, buffering agents, surfactants, flavorants, fragrances, dyes, etc.
- Suitable protective agents and/or cosmetic agents, and adsorbents can include, but are not limited to, dusting powders, zinc stearate, collodion, dimethicone, silicones, zinc carbonate, aloe vera gel and other aloe products, vitamin E oil, allantoin, petrolatum, titanium dioxide, and zinc oxide.
- Suitable antioxidants can include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid.
- Suitable buffering agents can include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, lactic acid buffers, sodium buffer, and borate buffers.
- a topical gel composition according to embodiments of the present invention can further include local anesthetics and analgesics, such as camphor, menthol, lidocaine, dibucaine, and pramoxine; antifungals, such as ciclopirox, chloroxylenol, triacetin, sulconazole, nystatin, undecylenic acid, tolnaftate, miconazole, clotrimazole, oxiconazole, griseofulvin, econazole, ketoconozole, and amphotericin B.
- local anesthetics and analgesics such as camphor, menthol, lidocaine, dibucaine, and pramoxine
- antifungals such as ciclopirox, chloroxylenol, triace
- a topical gel composition according to embodiments of the present invention can further include one or more antiseptics, such as iodine, povidine-iodine, benzalkonium chloride, benzoic acid, nitrofurazine, benzoyl peroxide, hydrogen peroxide,
- one or more antiseptics such as iodine, povidine-iodine, benzalkonium chloride, benzoic acid, nitrofurazine, benzoyl peroxide, hydrogen peroxide,
- the topical gel composition according to embodiments of the present invention can be prepared by mixing the ingredients of the composition according to known methods in the art, for example, methods provided by standard reference texts such as,
- the pH of the topical gel formulations of the invention are preferably within a physiologically acceptable pH, e.g., within the range of about 4.5 to about 7.5, more preferably, of about 5.0 to about 6.5, such as pH 5.1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, or 6.5.
- a physiologically acceptable pH e.g., within the range of about 4.5 to about 7.5, more preferably, of about 5.0 to about 6.5, such as pH 5.1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, or 6.5.
- an effective amount of a buffer is included. Acids or bases can be used to adjust the pH as needed.
- embodiments of the present invention relate to a method of treating or preventing a skin disorder, such as rosacea, erythema of rosacea,
- telangiectasia telangiectasia, psoriasis, purpura, erythema of acne, eczema, non-rosacea-related inflammation of the skin, flushing, skin sagging, creasing and/or wrinkling, or a symptom associated therewith, in a subject by topically administering to a skin area of the subject a topical gel composition according to an embodiment of the present invention, wherein the skin area is, or is prone to be, affected by the skin disorder.
- the relevant disclosures e.g., on using brimonidine to treat the one or more of skin disorders, in U.S. Ser. No.
- the topically administrable composition comprises about 0.1% to 0.6% (w/w), such as about 0.1%, 0.15%, 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55% or about 0.6%, by weight of brimonidine tartrate.
- the topical gel compositions of the invention can be topically applied directly to the affected area in any conventional manner known in the art, e.g., by dropper, applicator stick, or cotton swab, as a mist via an aerosol applicator, via an intradermal or transdermal patch, or by simply spreading a formulation of the invention onto the affected area with fingers, a sponge, a pad, or wipes.
- the amount of a topical formulation of the invention applied to the affected skin area ranges from about 0.0001 g/cm2 of skin surface area to about 0.05 g/cm2, preferably, 0.002 g/cm2 to about 0.005 g/cm2 of skin surface area.
- one to four applications per day are recommended during the term of treatment.
- Methods of the present invention can be used in conjunction with one or more other treatments and medications for the skin disorder, such as the medications used to treat the underlying disease that causes the skin disorder, antihistamines to control itching, antibiotics, corticosteroids, intravenous immunoglobulins, acetaminophen, etc.
- the other medicament or treatment can be administered to the subject simultaneously with, or in a sequence and within a time interval of, the administration of brimonidine, such that the active ingredients or agents can act together to treat or prevent the skin disorder.
- the other medicament or treatment and brimonidine can be administered in the same or separate formulations at the same or different times.
- Any suitable route of administration can be employed to deliver the additional treatment or medication including, but not limited to, oral, intraoral, rectal, parenteral, topical, epicutaneous, transdermal, subcutaneous, intramuscular, intranasal, sublingual, buccal, intradural, intraocular, intrarespiratory, or nasal inhalation.
- crystals are crystals of methylparaben (hereinafter abbreviated as POBM or MPOB), which is a preservative used in the composition.
- methylparaben hereinafter abbreviated as POBM or MPOB
- methylparaben was first dissolved in propylene glycol at 50°C (122-140°F) in
- POBM methylparaben
- the methylparaben concentration in the supernatant was measured and found to be about
- methylparaben also named methyl parahydroxybenzoate (POBM)
- POBM methyl parahydroxybenzoate
- microbiological quality of the formulations was also analyzed by using acceptance-test criteria in preservative-efficacy testing (PET) in the United States Pharmacopeia (USP) and the European Pharmacopoeia ( ⁇
- Phenoxyethanol 0.3 month storage at RT
- Carbopol ® 980 1.25
- Phenoxyethanol 0.3 after one month
- Carbopol ® 980 0.8 storage at RT
Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2814975A CA2814975A1 (en) | 2010-10-21 | 2011-10-19 | Topical gel composition |
JP2013534308A JP2013540142A (en) | 2010-10-21 | 2011-10-19 | Topical gel composition |
MX2013004472A MX2013004472A (en) | 2010-10-21 | 2011-10-19 | Topical gel composition. |
SG2013026679A SG189338A1 (en) | 2010-10-21 | 2011-10-19 | Topical gel composition |
EP11771146.5A EP2605753A2 (en) | 2010-10-21 | 2011-10-19 | Topical gel composition |
BR112013009577A BR112013009577A2 (en) | 2010-10-21 | 2011-10-19 | topical gel composition and method |
RU2013123043/15A RU2013123043A (en) | 2010-10-21 | 2011-10-19 | GEL COMPOSITION FOR LOCAL USE |
CN2011800509124A CN103313700A (en) | 2010-10-21 | 2011-10-19 | Topical gel composition |
AU2011317642A AU2011317642A1 (en) | 2010-10-21 | 2011-10-19 | Topical gel composition |
KR1020137012906A KR20130101552A (en) | 2010-10-21 | 2011-10-19 | Topical gel composition |
ZA2013/02812A ZA201302812B (en) | 2010-10-21 | 2013-04-18 | Topical gel composition |
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US40538210P | 2010-10-21 | 2010-10-21 | |
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FR1058611A FR2966365B1 (en) | 2010-10-21 | 2010-10-21 | TOPICAL GEL COMPOSITION |
US61/405,382 | 2010-10-21 |
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EP (1) | EP2605753A2 (en) |
JP (1) | JP2013540142A (en) |
KR (1) | KR20130101552A (en) |
CN (1) | CN103313700A (en) |
AU (1) | AU2011317642A1 (en) |
BR (1) | BR112013009577A2 (en) |
CA (1) | CA2814975A1 (en) |
IL (1) | IL225775A0 (en) |
MX (1) | MX2013004472A (en) |
RU (1) | RU2013123043A (en) |
SG (1) | SG189338A1 (en) |
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Cited By (4)
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WO2013010032A1 (en) * | 2011-07-14 | 2013-01-17 | Allergan, Inc. | Gel compositions of oxymetazoline and methods of use |
CN103919717A (en) * | 2014-04-15 | 2014-07-16 | 天津中医药大学 | Brimonidine d-tartrate ophthalmic gel preparation as well as preparation method and application thereof |
EP3476393A4 (en) * | 2016-06-28 | 2019-07-17 | Doris Maria Hexsel | Use of an active substance in the treatment of telangiectatic melasma |
US11185532B2 (en) | 2019-05-01 | 2021-11-30 | Clexio Biosciences Ltd. | Methods of treating pruritus |
Families Citing this family (3)
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CN104666239A (en) * | 2013-11-27 | 2015-06-03 | 杭州赛利药物研究所有限公司 | Brimonidine tartrate gel and preparation method thereof |
CN110882211A (en) * | 2019-12-31 | 2020-03-17 | 深圳市瀚德标检生物工程有限公司 | Hydroxyphenyl ester gel and preparation method thereof |
CN116159018A (en) * | 2023-03-01 | 2023-05-26 | 中国药科大学 | Novel external brimonidine gel |
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- 2011-10-19 AU AU2011317642A patent/AU2011317642A1/en not_active Abandoned
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- 2011-10-19 EP EP11771146.5A patent/EP2605753A2/en not_active Withdrawn
- 2011-10-19 JP JP2013534308A patent/JP2013540142A/en active Pending
- 2011-10-19 RU RU2013123043/15A patent/RU2013123043A/en unknown
- 2011-10-19 CA CA2814975A patent/CA2814975A1/en not_active Abandoned
- 2011-10-19 KR KR1020137012906A patent/KR20130101552A/en not_active Application Discontinuation
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2013010032A1 (en) * | 2011-07-14 | 2013-01-17 | Allergan, Inc. | Gel compositions of oxymetazoline and methods of use |
CN103919717A (en) * | 2014-04-15 | 2014-07-16 | 天津中医药大学 | Brimonidine d-tartrate ophthalmic gel preparation as well as preparation method and application thereof |
EP3476393A4 (en) * | 2016-06-28 | 2019-07-17 | Doris Maria Hexsel | Use of an active substance in the treatment of telangiectatic melasma |
US11185532B2 (en) | 2019-05-01 | 2021-11-30 | Clexio Biosciences Ltd. | Methods of treating pruritus |
US11903928B2 (en) | 2019-05-01 | 2024-02-20 | Clexio Biosciences Ltd. | Methods of treating pruritus |
Also Published As
Publication number | Publication date |
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SG189338A1 (en) | 2013-05-31 |
KR20130101552A (en) | 2013-09-13 |
EP2605753A2 (en) | 2013-06-26 |
WO2012052478A3 (en) | 2012-06-14 |
ZA201302812B (en) | 2014-06-25 |
JP2013540142A (en) | 2013-10-31 |
AU2011317642A1 (en) | 2013-05-02 |
IL225775A0 (en) | 2013-09-30 |
CA2814975A1 (en) | 2012-04-26 |
CN103313700A (en) | 2013-09-18 |
RU2013123043A (en) | 2014-12-10 |
MX2013004472A (en) | 2013-10-25 |
BR112013009577A2 (en) | 2016-07-12 |
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