WO1998037889A1 - Use of descarboethoxyloratadine for the manufacture of a medicament for the treatment of urinary incontinence, motion sickness and vertigo - Google Patents
Use of descarboethoxyloratadine for the manufacture of a medicament for the treatment of urinary incontinence, motion sickness and vertigo Download PDFInfo
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- WO1998037889A1 WO1998037889A1 PCT/US1998/003532 US9803532W WO9837889A1 WO 1998037889 A1 WO1998037889 A1 WO 1998037889A1 US 9803532 W US9803532 W US 9803532W WO 9837889 A1 WO9837889 A1 WO 9837889A1
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- acceptable salt
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
Definitions
- the present invention relates to methods for treating urinary incontinence , vertigo and motion sickness .
- Urinary incontinence such as incontinence caused by bladder detrusor muscle instability, is a prevalent problem that affects people of all ages and levels of physical health, both in healthcare settings and in the community at large.
- urinary incontinence afflicts 15-30% of 5 elderly people living at home, one-third of those living in acute-care settings, and at least one-half of those in long- term care institutions (Resnick, R.M. , Lancet 346:94 (1995)). Medically, it predisposes persons to urinary tract infections, pressure ulcers, perineal rashes, and urosepsis.
- urinary incontinence is associated with embarrassment, social stigmatization, depression, and with the risk of institutionalization (Herzo et al . , Annu . Rev . Gerontol . Geriatr . 9 . :74 (1989)). Economically, the costs are great; in the United States alone, over $15 billion is spent 5 per annum managing incontinence.
- Treatments for incontinence include drugs with bladder relaxant properties, i.e., which help to control bladder detrusor muscle overactivity. Such drugs are effective in 80 to 85% of patients with uninhibited bladder contractions. 0 Anticholinergic medications represent the mainstay of this type of treatment.
- the major proportion of the neurohu oral stimulus for physiologic bladder contraction is acetylcholine-induced stimulation of post ganglionic muscarinic receptor sites on bladder smooth muscle.
- anticholinergics such as propantheline bromide and glycopyrrolate, and combination smooth muscle relaxant/anticholinergics such as racemic oxybutynin and dicyclomine, have been used to treat urge incontinence. (See, e.g., ein, A.
- muscarinic receptor antagonists block its binding to uscarinic cholinergic receptors at certain neuroeffector sites such as in the urinary bladder (see Goodman & Gilman's, The Pharmacological Basis of Therapeutics , 9th Ed. p. 148 (1996) ) .
- Scopolamine a muscarinic antagonist
- Muskat et al . state that when the drug is administered by an oral or systemic route, it causes severe side-effects and also discuss the contradictory reports regarding the transdermal administration of scopolamine.
- Maleat et al . report that although scopolamine is known to cause cycloplegia and dryness of the mouth, the side-effects in its study were not so severe to require discontinuation of the medication (id. at 1990) .
- Scopolamine is also reported as being used widely for motion sickness and as effective for the treatment of vertigo (Id.). However, it has also been reported that scopolamine has unwanted sedative effects (see Lathers et al . , TiPS 10:243-250 (1989)).
- Certain first generation Hj-receptor antihistamines such as diphenylpyraline and promethazine have been reported as having significant affinity for the muscarinic receptors (Kubo et al . , Japan J. Pharmacol . 43_:277-282 (1987)).
- Some first generation receptor antihistamines such as dimenhydrinate, cyclizine and meclizine, have also been found to be effective for treating either vertigo or motion sickness (Jd; Wood, C. , Drugs 37:471-479 (1979); Cohen et al . , Archives of Neurology 27 . : 129-135 (1972); see also Goodman & Gilman's, The Pharmacological Basis of Therapeutics , 9th Ed. p. 588, 592 (1996)).
- the second generation H,-receptor antihistamines such as terfenadine, astemizole and loratadine, while having fewer sedative effects, are reported as having weak or no effect on muscarinic receptors (Goodman & Gilman's, The Pharmacological Basis of Therapeutics , 9th Ed. p. 588 (1996); Simons, F.E., Drugs Safety 10(5) :350-380 (1994)). This is consistent with the findings that such compounds do not possess any significant anticholinergic affects (see Simons, F.E., Drug Safety 10(5) :350-380 (1994); Roman et al . , Clinical Reviews in Allergy 11:89-110 (1993)). Quercia et al .
- Astemizole has been reported to alleviate chronic vertigo (see Mitchelson F. , Drugs 43 (4) :443-463 (1992)). However, astemizole and terfenadine have also been reported as ineffective at preventing motion sickness (Cheung et al . , J. Cl n . Pharmacol . 12:163-175 (1992)). Kohl et al . (J. Clin . Pharmacol . 11:934-946 (1991)) reported moderate efficacy of a single 300 mg dose of terfenadine (which is five fold higher than the recommended single dose) for motion sickness and pronounced individual response differences.
- Kubo et al . (Japan J. Pharmacol . 11:277-282 (1987)) state that the anti-motion sickness activity of some of the H, receptor antagonists may be related to their antimuscarinic ability.
- Kubo et al . also state that since histamine H, receptor blockade is suggested to be associated with the sedative activity, a drug which has both antimuscarinic and antihistaminic effects may be more effective in the treatment of motion sickness.
- Loratadine binds preferentially to peripheral rather than to central H j receptors (Quercia et al . , Hosp . Formul . . 28:137-153 (1993)). Loratadine is well absorbed but is extensively metabolized (Hubert, et al . , J. Clin . Pharmacol . 27: 694-98 (1987)). The main metabolite, descarboethoxyloratadine, which has been identified, is reported to be pharmacologically active (Clissold, Drugs 3_7:42-57 (1989)). it is also reported as having antihistaminic activity in U.S. Patent No. 4,659,716. This patent recommends an oral dosage range of 5 to 100 g/day and preferably 10 to 20 g/day.
- the second generation H, antagonists such as loratadine, possess no or weak anticholinergic effects.
- astemizole and terfenadine have been known to cause severe cardiac electrophysiologic adverse side-effects. These adverse side-effects are associated with a prolonged QT interval, and include, but are not limited to, ventricular fibrillation and cardiac arrhythmias, such as ventricular tachyarrhythmias or torsade de pointes.
- ketoconazole, itraconazole, and/or erythromycin interfere with cytochrome P450, and thereby inhibit the metabolism of non-sedative antihistamines such as terfenadine, astemizole, and loratadine (see Andersen et al . , Arch . Dermatol . 131:468-473 (1995)).
- non-sedative antihistamines such as terfenadine, astemizole, and loratadine (see Andersen et al . , Arch . Dermatol . 131:468-473 (1995)).
- Brandes et al . (Cancer Res . (52) :3796-3800 (1992)), showed that the propensity of drugs to promote tumor growth in vivo correlated with potency to inhibit concanavalin A stimulation of lymphocyte mitogenesis. Brandes et al . , (J . Nat ' l Cancer Inst . 86(10) -.111-115 (1994)), assessed loratadine in an in vitro assay to predict enhancement of in vivo tumor growth. This reference also reported that loratadine (at a dose of about 10 mg/day) and astemizole are associated with growth of both melanoma and fibrosarcoma tumors, in vivo .
- the present invention provides methods for the effective treatment of urinary incontinence, vertigo and motion sickness based on the unexpected finding that a metabolite of loratadine, descarboethoxyloratadine ("DCL") , provides a superior treatment of urinary incontinence, and vestibular disorders, such as vertigo and motion sickness, than drugs previously associated with the treatment of such disorders.
- the methods of the present invention comprise administering a therapeutically effective amount of DCL.
- DCL is 8-chloro-6, 11-dihydro-ll- (4- piperidylidene) -5H-benzo[5, 6]cyclohepta[ 1, 2-b]pyridine, and has the following structure:
- the invention relates to a method for treating urinary incontinence which comprises administering to a human in need of such treatment a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof.
- the present invention provides a method for treating vertigo comprising administering to a human in need of such treatment a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof.
- the present invention provides a method for treating motion sickness comprising administering to a human in need of such treatment a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof .
- DCL can be used in accordance with this invention to effectively treat urinary incontinence while substantially reducing or avoiding the adverse side-effects associated with existing drugs for the treatment of urinary incontinence such as scopolamine and racemic oxybutynin.
- DCL can also be used in accordance with this invention to effectively treat vertigo and motion sickness, including, but not limited to, space motion sickness (or space adaptation syndrome) and sea sickness, while substantially reducing the adverse side-effects that primarily arise from drugs that are associated with the treatment of vertigo and motion sickness, such as scopolamine and meclizine.
- the adverse effects include, but are not limited to, xerostomia, mydriasis, drowsiness, nausea, constipation, palpitations and tachycardia.
- DCL also has the additional therapeutic benefit of not causing side-effects associated with certain second generation antihistamines such as cardiac arrythmia, associated with astemizole and terfenadine, or the potential to promote tumors, associated with loratadine.
- the present invention also encompasses compositions for use in the methods for treating motion sickness, comprising a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of ephedrine, and a pharmaceutically acceptable carrier.
- compositions for use in the methods of the present invention for treating motion sickness comprising a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of a drug selected from the group consisting of amphetamines, amphetamine salts and amphetamine analogs, and a pharmacologically acceptable carrier.
- compositions for use in the methods for treating motion sickness comprising a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of an amphetamine agent, and a pharmaceutically acceptable carrier.
- the present invention also encompasses compositions for use in the methods of the present invention for treating motion sickness, comprising a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of a psychostimulant, and a pharmaceutically acceptable carrier.
- the present invention provides a method for treating motion sickness comprising administering to a human in need of such treatment a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a decongestant.
- the present invention provides a method for treating motion sickness comprising administering to a human in need of such treatment a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of ephedrine. Additionally, the present invention is directed to a method for treating motion sickness comprising administering to a human in need of such treatment a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a drug selected from the group consisting of amphetamines, amphetamine salts and amphetamine analogs.
- the present invention is also directed to a method for treating motion sickness comprising administering to a human in need of such treatment a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an amphetamine agent.
- the present invention provides a method for treating motion sickness, comprising administering to a human in need of such treatment a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a psychostimulant.
- DCL may be administered parenterally, rectally, intravesically, transdermally, orally, intravascularly, by inhalation, or by aerosol, at a rate of about 0.1 mg to about 100 mg per day.
- Oral and transdermal are the preferred routes for the treatment of vertigo and motion sickness.
- Oral, intravenous and intravesically are the preferred routes for the treatment of urinary incontinence at the same dosage range.
- Figure 1 represents the effect of loratadine on the delayed rectifying K + current (I Kr ) in rabbit ventricular myocytes .
- Figure 2 represents the effect of DCL on the delayed rectifying K + current (I Kr ) in rabbit ventricular myocytes.
- the present invention encompasses a method for treating urinary incontinence which comprises administering to a human in need of such treatment a therapeutically effective amount of DCL, or a pharmaceutically acceptable salt thereof.
- the present invention also encompasses a method for treating vertigo which comprises administering to a human in need of such treatment a therapeutically effective amount of DCL, or a pharmaceutically acceptable salt thereof.
- Another embodiment of the present invention is a method of treating motion sickness which comprises administering to a human in need of such treatment, a therapeutically effective amount of DCL, or a pharmaceutically acceptable salt thereof.
- DCL to treat motion sickness is that it lacks sedative effects.
- the present invention also relates to methods for treating urinary incontinence, vertigo and/or motion sickness while avoiding the adverse effects associated with existing drugs used to treat these indications.
- the present invention also encompasses the use of DCL, or compositions containing DCL, to treat the above-described conditions while avoiding cardiac arrhythmias and tumor promotion.
- the present invention also relates to the use of DCL to treat such conditions in a human having a higher then normal propensity for or incidence of cancer.
- the present invention also relates to methods of treating urinary incontinence, vertigo, motion sickness while avoiding adverse events associated with co-administration of a drug that inhibits cytochrome, P450, including, but not limited to, ketoconazole, itraconazole, erythromycin, and others known by those skilled in the art.
- the present invention is also related to a method for treating urinary incontinence, vertigo and/or motion sickness in a patient having a higher than normal propensity for Long QT Syndrome as a result of either genetic and/or environmental factors.
- the present invention also involves compositions having anticholinergic activity for use in such methods which comprise a therapeutically effective amount of DCL, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- compositions for use in the methods for treating motion sickness comprising a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of ephedrine, and a pharmaceutically acceptable carrier.
- the present invention also encompasses compositions for use in the methods for treating motion sickness, comprising a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of a drug selected from the group consisting of amphetamines, amphetamine salts, and amphetamine analogs, and a pharmaceutically acceptable carrier.
- compositions for use in the methods for treating motion sickness comprising a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of an amphetamine agent, and a pharmaceutically acceptable carrier.
- compositions for use in the methods for treating motion sickness comprising a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of a psychostimulant, including, but not limited to, pemoline and methylphenidate and a pharmaceutically acceptable carrier.
- the present invention provides a method for treating motion sickness comprising administering to a human in need of such treatment a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a decongestant such as, but not limited to, pseudoephedrine and phenylpropanolamine.
- a decongestant such as, but not limited to, pseudoephedrine and phenylpropanolamine.
- the administration of DCL and decongestant in the methods of the present invention for treating motion sickness may be either concurrent or sequential, i.e., DCL and decongestant may be administered as a combination, concurrently but separately, or by the sequential administration of DCL and decongestant or the sequential administration of decongestant and DCL.
- the present invention provides a method for treating motion sickness comprising administering to a human in need of such treatment a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of ephedrine.
- the administration of DCL and ephedrine in the methods of the present invention for treating motion sickness may be either concurrent or sequential, i.e., DCL and ephedrine may be administered as a combination, concurrently but separately, or by the sequential administration of DCL and ephedrine or the sequential administration of ephedrine and DCL.
- the present invention provides a method for treating motion sickness comprising administering to a human in need of such treatment a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a drug selected from the group consisting of amphetamines, amphetamine salts, and amphetamine analogs.
- the administration of DCL and such a drug in the methods of the present invention for treating motion sickness may be either concurrent or sequential, i.e., DCL and the drug may be administered as a combination, concurrently but separately, or by the sequential administration of DCL and the drug or the sequential administration of the drug and DCL.
- the present invention provides a method for treating motion sickness comprising administering to a human in need of such treatment a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an amphetamine agent.
- the administration of DCL and amphetamine agent in the methods of the present invention for treating motion sickness may be either concurrent or sequential, i . e . , DCL and amphetamine agent may be administered as a combination, concurrently but separately, or by the sequential administration of DCL and amphetamine agent or the sequential administration of amphetamine agent and DCL.
- the present invention provides a method for treating motion sickness comprising administering to a human in need of such treatment a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a psychostimulant, including, but not limited to, pemoline and methylphenidate.
- a psychostimulant including, but not limited to, pemoline and methylphenidate.
- the administration of DCL and a psychostimulant in the methods of the present invention for treating motion sickness may be either concurrent or sequential, i.e., DCL and psychostimulant may be administered as a combination, concurrently but separately, or by the sequential administration of DCL and psychostimulant or the sequential administration of psychostimulant and DCL.
- adverse effects refers to the side-effects associated with administration of drugs used to treat urinary incontinence and/or vertigo and/or motion sickness, which are not part of the desired therapeutic effect of the drug.
- adverse effects include, for illustrative purposes, drowsiness, epistaxis, xerostomia, mydriasis, cycloplegia, unstable cardiovascular status such as tachycardia and cardiac arrhythmia, increased ocular pressure, nausea, constipation, decreased sweating, impotence, and/or dermal manifestations such as urticaria.
- cardiac arrhythmias includes, but is not limited to, Long QT Syndrome, ventricular tachyarrhythmias, torsade de pointes and ventricular fibrillation.
- epistaxis refers to nosebleeds, e.g., hemorrhage from the nose. Epistaxis is a side effect of anticholinergics in children.
- xerostomia refers to dryness of the mouth due to lack of normal secretion.
- mydriasis refers to dilation of the pupil, and often results in blurred vision.
- cycloplegia refers to paralysis of the ciliary muscle; paralysis of accommodation.
- urinary excretions means the inability to prevent the discharge of urinary excretions, and includes, but is not limited to, bladder detrusor muscle instability incontinence, stress incontinence, urge incontinence, overflow incontinence, enuresis, and post-prostectomy incontinence.
- enuresis refers to the involuntary discharge of urine
- nocturnal enuresis refers to involuntary discharge of urine during sleep.
- vertiggo means an abnormal sensation of rotary movement associated with difficulty with balance, gait and navigation in the environment.
- the term also includes a disturbance in which the individual has a subjective impression of movement in space or of objects moving around the individual, usually with a loss of equilibrium. This results from a disturbance somewhere in the equilibratory apparatus: vestibule; semicircular canals, 8th nerve; vestibular nuclei in the brainstem and their temporal lobe connections; and eyes. This term includes, but is not limited to, vertigo which results from Meniere's disease.
- Meniere's Disease means disorders characterized by recurring prostrating vertigo, sensory hearing loss, and tinnitus, associated with generalized dilation of the membranous labyrinth.
- motion sickness means a disorder caused by repetitive angular and linear acceleration and deceleration and excessive stimulation of the vestibular apparatus by motion.
- the disorder is characterized primarily by nausea and vomiting.
- the term includes, but is not limited to space motion sickness, also referred to as space adaptation syndrome.
- DCL can be used to treat urinary incontinence, vertigo and motion sickness by administration to a patient using any suitable route of administration.
- a preferred method of administration is oral administration.
- Another preferred route of administration is intravenous administration.
- a particularly preferred method of administration for the treatment of vertigo and motion sickness is transdermal administration.
- DCL is preferably administered as a pharmaceutical formulation (composition) .
- phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- salts refers to the relatively non-toxic, inorganic and organic salts of DCL.
- Representative salts include the bromide, chloride, hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate salts and the like. (See, e . g. , Berge et al .
- Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual) , rectal, vaginal, parenteral (including subcutaneous, intramuscular, intravenous) , intravascularly , intravesically, by aerosol and/or transdermal administration. Additionally, the drug may be administered directly into the bladder through the urethra, i.e., intravesically, as described by Massad et al . , J. Urol . 148:595-597 (1992). The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
- the amount of active ingredient which is combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, and the particular mode of administration.
- the amount of active ingredient which may be combined with a carrier material to produce a single dosage form preferably will be that amount of DCL which produces a therapeutic effect.
- the amount of the active ingredient will range from about 1 % to about 99 % of the total formulation, preferably from about 5 % to about 70 %, and most preferably from about 10 % to about 30 %.
- Methods of preparing these formulations or compositions include the step of bringing into association DCL with a pharmaceutically acceptable carrier and, optionally, one or more accessory ingredients.
- the formulations are prepared by uniformly and intimately bringing into association DCL with liquid carriers, or finely divided solid carriers, or both, and any optional accessory ingredients, and then, if necessary, shaping the product.
- pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the DCL from one organ, or portion of the body, to another organ or portion of the body.
- a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the DCL from one organ, or portion of the body, to another organ or portion of the body.
- Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
- materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
- Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth) , powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as a gelatin and glycerin, or sucrose and acacia) , or as soft elastic gelatin capsules, and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
- DCL may also be administered as a bolus, electuary or paste.
- the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or may also be mixed with one or more of any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds;
- compositions may also comprise buffering agents.
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
- lactose-free compositions containing DCL are administered.
- Release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions of the present invention.
- antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA) , butylated hydroxytoluene (BHT) , lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA) , sorbitol, tartaric acid, phosphoric acid, and the like.
- water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate sodium sulfite and the like
- oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA) , butylated hydroxytoluen
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose) , lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose) , and/or surface-active or dispersing agents.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered DCL moistened with an inert, liquid diluent.
- compositions of the present invention may also be formulated in a soft elastic gelatin capsule unit dosage form by using conventional methods, well-known in the art (see, e . g. , Ebert, Phar . Tech . 1(5) :44-50(1977) ) .
- Soft elastic gelatin capsules have a soft, globular, gelatin shell somewhat thicker than that of hard gelatin capsules, wherein a gelatin is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
- the hardness of the capsule shell may be changed by varying the type of gelatin and the amounts of plasticizer and water.
- the soft gelatin shells may contain a preservative to prevent the growth of fungi, such as methyl- and propylparabens and sorbic acid.
- The. active ingredient may be dissolved or suspended in a liquid vehicle or carrier, such as vegetable or mineral oils, glycols such as polyethylene glycol and propylene glycol, triglycerides , surfactants such as polysorbates, or a combination thereof.
- the tablets, and other dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
- compositions of the present invention may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may also be administered by controlled release means and delivery devices such as those in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,796; and PCT published application WO 92/20377.
- compositions of the present invention may also optionally contain opacifying agents and may be formulated such that they release the active ingredient (s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
- opacifying agents include polymeric substances and waxes.
- the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
- Liquid dosage forms for oral administration of DCL include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils) , glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
- the oral compositions of the present invention can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
- Suspensions in addition to the active DCL, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- Formulations of the pharmaceutical compositions of the present invention for rectal and vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate.
- Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
- Dosage forms for the topical or transdermal administration of DCL include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
- the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
- Formulations of the present invention in the form of ointments, pastes, creams and gels may contain, in addition to DCL, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and/or zinc oxide, or mixtures thereof.
- excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and/or zinc oxide, or mixtures thereof.
- Powders and sprays may contain, in addition to DCL, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
- Sprays may additionally contain customary propellants, such as, for example, chlorofluorohydrocarbons , volatile unsubstituted hydrocarbons, hydrocarbon ethers and compressed gases.
- Transdermal patches have the added advantage of providing controlled delivery of the active DCL of the present invention to the body.
- dosage forms may be made by dissolving or dispersing the DCL in the proper medium.
- Absorption enhancers may also be used to increase the flux of the DCL across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the DCL in a polymer matrix or gel.
- the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art. Where necessary, the pharmaceutical compositions of the present invention are sterile or can be sterilized before administration to a patient.
- the DCL compositions of the present invention are provided in tablet or capsule form.
- the capsules or tablets are preferably formulated with from about 0.1 mg to about 100 mg of DCL, more preferably with from about 0.5 mg to about 50 mg of DCL, and even more preferably with from about 1 mg to about 25 mg of DCL.
- the DCL preparations of the present invention are provided in soft elastic gelatin capsule form.
- the soft elastic gelatin capsules are preferably formulated with from about 0.1 mg to about 100 mg of DCL, more preferably with from about 0.5 mg to about 50 mg of DCL, and even more preferably with from about 1 mg to about 25 mg of DCL.
- Actual dosage levels of DCL in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
- the selected dosage level and frequency of administration will depend upon a variety of factors including the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the DCL, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
- the dosage regimen is likely to vary with pregnant women, nursing mothers and children relative to healthy adults.
- a physician having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
- the physician could start doses of the compound employed in the pharmaceutical composition of the present invention at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
- a suitable daily dose of DCL will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
- the total daily dose of DCL for the conditions described herein may be from about 0.1 mg to about 100 mg, more preferably from about 0.5 mg to about 50 mg, and more preferably from about 1 mg to about 25 mg.
- a suitable oral daily dose range of decongestant, ephedrine, amphetamines, amphetamine salts, amphetamine analogs, amphetamine agents or psychostimulant is from about 1 mg to about 300 mg. Further, a suitable oral daily dose of such agents can also be readily determined by those skilled in the art.
- the effective daily dose of the active DCL may be administered as two or three sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
- the invention is further illustrated by reference to the following examples, which are provided by way of illustration and not by way of limitation.
- Loratadine can be synthesized, for example, by methods disclosed in U.S. patent No. 4,282,233.
- the metabolites are prepared similarly, by reaction steps conventional in the art, as described in U.S. patent No. 4,659,716 which is incorporated here by reference in its entirety.
- One common method of preparing DCL is to reflux loratadine in the presence of sodium hydroxide and ethanol as depicted below.
- Loratadine (4.0 g) was added to a solution of sodium hydroxide (5.9 g) in 280 mL of absolute ethanol and the mixture was stirred at reflux for four days. The mixture was cooled and concentrated to remove ethanol. The residue was diluted with water and aqueous layer was extracted with methylene chloride five times. The combined organic layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated to give 2.82 g (87%) of pure loratadine derivative (or metabolite) as a pale-tan solid.
- the aim of this study was to assess the affinity of six compounds for human m, , m 2 and m 3 muscarinic receptor subtypes in radioligand binding assays.
- the method used herein is similar to that disclosed in D ⁇ rje et al. The Journal of Pharmacology and Experimental Therapeutics 256: 2 727-733 (1991) .
- Samples were prepared and evaluated in a concentration range (0.1-3000 nM, half-log dilutions) on human recombinant m,-m 3 receptors expressed in mammalian CHO cells. These data were generated from binding inhibition of radiolabelled ligand, where [ 3 H]pirenzepine was used for m,, [ 3 H]AF-DX 384 was used for m 2 , and [ 3 H]4-DAMP (4-diphenylacetoxy-N- methylpiperidine) was used for m 3 .
- the radioligands were from DuPont NEN; the cold ligands were from Sigma or RBI.
- the drugs tested in this experiment were astemizole; norastemizole; loratadine; DCL, (S) (-) terfenadine carboxylate, and (S) (-) terfenadine.
- the specific radioligand binding to the receptors was defined as the difference between total binding and nonspecific binding determined in the presence of an excess of unlabelled ligand. Results were expressed as a percentage of control specific binding obtained in the presence of the compounds .
- IC 50 values concentration required to inhibit 50% of specific binding
- nH Hill coefficients
- DCL has a greater affinity at ,, m 2 , m 3 receptors than loratadine (the parent drug) or other second or third generation antihistamines.
- the present invention is based upon, inter alia , the surprising antimuscarinic affinity of DCL. Without being limited by theory, it is believed that the antimuscarinic affinity of DCL leads to its usefulness in the methods of treatment and compositions described herein.
- lymphocyte mitogenesis Inhibition of lymphocyte mitogenesis was used to screen the potencies of loratadine and DCL as tumor promoting
- DCL is 5-7 fold less active than loratadine at promoting tumor growth.
- CYP3A4 is involved in many drug-drug interactions and quantitation of inhibition of CYP3A4 by loratadine or DCL provides an indication of the potential for the occurrence of adverse effects due to such drug-drug interactions. Inhibition was studied by measuring the metabolism of the model substrate testosterone by cDNA-derived human CYP3A4 in microsomes prepared from a human lymphoblastoid cell line designated h3A4v3.
- the inhibition study consisted of the determination of the 50% inhibitory concentration (IC 50 ) for the test substance.
- IC 50 50% inhibitory concentration
- Testosterone metabolism was assayed by the production of the 6 ( ⁇ ) -hydroxytestosterone metabolite. This metabolite was readily quantitated via HPLC separation with absorbance detection.
- test substances were stored at room temperature.
- test substances were dissolved in ethanol for addition to the incubations.
- the addition of acid was not found to be needed.
- the solvent concentration was constant for all concentrations of the test substance.
- test substance concentrations were 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003 and 0 ⁇ M. Each test concentration was tested in duplicate incubations in accordance with the method below:
- the sample was dissolved in methanol and injected into a 4.6 x 250 mm 5u C18 HPLC column and separated at 50°C with a mobile phase methanol/water at a flow rate of 1 ml per min.
- the retention times were approximately 6 min for the 6 ( ⁇ ) -hydroxy, 8 min for 11 ( ⁇ ) -hydroxy and 12 min for testosterone.
- the product and internal standard were detected by their absorbance at 254 nm and quantitated by correcting for the extraction efficiency using the absorbance of the 11 ( ⁇ ) -hydroxy peak and comparing to the absorbance of a standard curve for 6 ( ⁇ ) -hydroxytestosterone.
- the concentration of 6 ( ⁇ ) -hydroxytestosterone metabolite in each replicate incubation was determined and the percentage inhibition relative to solvent control was calculated.
- the IC 50 was calculated by linear interpolation.
- the IC 50 for loratadine was calculated to be 30 ⁇ M.
- the IC 50 for DCL was calculated to be 23 ⁇ M. This study demonstrates that there is little difference between the actions of loratadine and DCL on the inhibition of cytochrome P4503A4, and thus confirms that both do not themselves contribute to the potential for the occurrence of adverse effects due to drug-drug interactions.
- Useful pharmaceutical dosage forms for administration of the compounds used in the methods of the present invention can be illustrated as follows:
- a mixture of active ingredient in a digestible oil such as soybean oil, lecithin, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 0.1 to 25 milligrams of the active ingredient.
- the capsules are washed and dried.
- Compressed DCL tablets are prepared using conventional direct compression techniques, such that each dosage unit contains 0.1 mg to 25 mg of DCL.
- tablets are prepared using 10 mg DCL, 80 mg microcrystalline cellulose, 5 mg stearic acid and 1 mg colloidal silica. All of the ingredients are blended in a suitable blender. The resulting mixture is compressed into tablets, using a 9/32-inch (7 mm) punch. Tablets and capsules of other strengths may be prepared by altering the ratio of active ingredient to the excipients or to the final weight of the tablet.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
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JP53776198A JP2001515475A (en) | 1997-02-28 | 1998-02-24 | Use of descarboethoxyloratadine for the manufacture of a medicament for the treatment of urinary incontinence, motion sickness and vertigo |
NZ337400A NZ337400A (en) | 1997-02-28 | 1998-02-24 | Use of descarboethoxyloratadine for the manufacture of a medicament for the treatment of urinary incontinence, motion sickness and vertigo |
EP98906665A EP0975344A1 (en) | 1997-02-28 | 1998-02-24 | Use of descarboethoxyloratadine for the manufacture of a medicament for the treatment of urinary incontinence, motion sickness and vertigo |
BR9807796-1A BR9807796A (en) | 1997-02-28 | 1998-02-24 | Processes to treat urinary incontinence, vertigo and motion sickness, and pharmaceutical composition. |
CA002282396A CA2282396A1 (en) | 1997-02-28 | 1998-02-24 | Use of descarboethoxyloratadine for the manufacture of a medicament for the treatment of urinary incontinence, motion sickness and vertigo |
AU61828/98A AU740504B2 (en) | 1997-02-28 | 1998-02-24 | Use of descarboethoxyloratadine for the manufacture of a medicament for the treatment of urinary incontinence, motion sickness and vertigo |
NO994165A NO994165L (en) | 1997-02-28 | 1999-08-27 | Use of descarboethoxyloratadine for the manufacture of a medicament for the treatment of urinary incontinence, travel sickness and dizziness |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US08/808,116 US5939426A (en) | 1997-02-28 | 1997-02-28 | Methods for treating urinary incontinence using descarboethoxyloratadine |
US08/808,116 | 1997-02-28 |
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WO1998037889A1 true WO1998037889A1 (en) | 1998-09-03 |
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PCT/US1998/003532 WO1998037889A1 (en) | 1997-02-28 | 1998-02-24 | Use of descarboethoxyloratadine for the manufacture of a medicament for the treatment of urinary incontinence, motion sickness and vertigo |
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US (2) | US5939426A (en) |
EP (1) | EP0975344A1 (en) |
JP (1) | JP2001515475A (en) |
KR (1) | KR20000075572A (en) |
CN (1) | CN1252722A (en) |
AU (1) | AU740504B2 (en) |
BR (1) | BR9807796A (en) |
CA (1) | CA2282396A1 (en) |
NO (1) | NO994165L (en) |
NZ (2) | NZ337400A (en) |
WO (1) | WO1998037889A1 (en) |
Cited By (1)
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EP1614421A3 (en) * | 1997-02-07 | 2006-02-15 | Sepracor, Inc. | Lactose-free, non-hygroscopic and anhydrous pharmaceutical compositions of descarboethoxyloratadine |
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EP1041981A2 (en) * | 1997-12-31 | 2000-10-11 | Sepracor, Inc. | $i(S)-PROCYCLIDINE FOR TREATING URINARY INCONTINENCE |
US6132758A (en) | 1998-06-01 | 2000-10-17 | Schering Corporation | Stabilized antihistamine syrup |
US6100274A (en) * | 1999-07-07 | 2000-08-08 | Schering Corporation | 8-chloro-6,11-dihydro-11- ](4-piperidylidine)-5H-benzo[5,6]cyclohepta[1,2-bpyridine oral compositions |
AR025964A1 (en) * | 1999-10-08 | 2002-12-26 | Schering Corp | NASAL TOPICAL TREATMENT |
US6114346A (en) * | 1999-10-22 | 2000-09-05 | Schering Corporation | Treating sleep disorders using desloratadine |
AU2276801A (en) | 1999-12-20 | 2001-07-03 | Schering Corporation | Extended release oral dosage composition |
SK287684B6 (en) * | 1999-12-20 | 2011-06-06 | Schering Corporation | Sustained release solid oral pharmaceutical dosage composition |
US7405223B2 (en) | 2000-02-03 | 2008-07-29 | Schering Corporation | Treating allergic and inflammatory conditions |
US6773421B2 (en) * | 2001-12-14 | 2004-08-10 | Kimberly-Clark Worlwide, Inc. | Combination for managing the involuntary loss of bladder control |
AU2004206846B2 (en) * | 2003-01-16 | 2009-05-28 | University Of Rochester | Quaternary antimuscarinic compounds for the treatment of bladder diseases |
JP2007519643A (en) * | 2004-01-30 | 2007-07-19 | 北京佗林医▲葯▼科技有限公司 | Pleurotus extract, piperidone derivatives, and their use for the preparation of antihypertensive drugs |
US20070281960A1 (en) * | 2004-07-16 | 2007-12-06 | Amar Lulla | Anti-Histaminic Composition |
MX2007004976A (en) * | 2004-10-25 | 2007-06-14 | Schering Corp | M1 and/or m3 receptor antagonists in combination with other actives for treating respiratory disorders. |
JP2009530364A (en) * | 2006-03-20 | 2009-08-27 | ファイザー・リミテッド | Amine derivatives |
US20090082385A1 (en) * | 2007-09-26 | 2009-03-26 | Protia, Llc | Deuterium-enriched desloratidine |
US8741930B2 (en) * | 2008-10-24 | 2014-06-03 | Bridge Pharma, Inc. | Treating xerophthalmia with norketotifen |
US8765787B2 (en) * | 2008-11-21 | 2014-07-01 | Bridge Pharma, Inc. | Methods of treatment of xerophthalmia with self-preserving ocular formulations of norketotifen |
IT201900012645A1 (en) * | 2019-07-23 | 2021-01-23 | Eros Zanotti | A pharmaceutical composition for use in the treatment of motion sickness |
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WO1996020708A1 (en) * | 1994-12-30 | 1996-07-11 | Sepracor, Inc. | Methods and compositions for treating allergic rhinitis and other disorders using descarboethoxyloratadine |
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-
1998
- 1998-02-24 NZ NZ337400A patent/NZ337400A/en unknown
- 1998-02-24 BR BR9807796-1A patent/BR9807796A/en not_active IP Right Cessation
- 1998-02-24 AU AU61828/98A patent/AU740504B2/en not_active Ceased
- 1998-02-24 JP JP53776198A patent/JP2001515475A/en active Pending
- 1998-02-24 CN CN98804326A patent/CN1252722A/en active Pending
- 1998-02-24 KR KR1019997007632A patent/KR20000075572A/en not_active Application Discontinuation
- 1998-02-24 CA CA002282396A patent/CA2282396A1/en not_active Abandoned
- 1998-02-24 EP EP98906665A patent/EP0975344A1/en not_active Withdrawn
- 1998-02-24 NZ NZ513650A patent/NZ513650A/en not_active Application Discontinuation
- 1998-02-24 WO PCT/US1998/003532 patent/WO1998037889A1/en not_active Application Discontinuation
-
1999
- 1999-08-27 NO NO994165A patent/NO994165L/en not_active Application Discontinuation
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2002
- 2002-05-16 US US10/146,415 patent/US20020183241A1/en not_active Abandoned
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Also Published As
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US5939426A (en) | 1999-08-17 |
NO994165L (en) | 1999-10-25 |
NZ337400A (en) | 2001-09-28 |
AU6182898A (en) | 1998-09-18 |
BR9807796A (en) | 2000-02-15 |
NZ513650A (en) | 2001-09-28 |
CA2282396A1 (en) | 1998-09-03 |
US20020183241A1 (en) | 2002-12-05 |
KR20000075572A (en) | 2000-12-15 |
NO994165D0 (en) | 1999-08-27 |
CN1252722A (en) | 2000-05-10 |
AU740504B2 (en) | 2001-11-08 |
EP0975344A1 (en) | 2000-02-02 |
JP2001515475A (en) | 2001-09-18 |
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