WO1995010278A1 - Treatment of allergic disorders with terfenadine carboxylate - Google Patents
Treatment of allergic disorders with terfenadine carboxylate Download PDFInfo
- Publication number
- WO1995010278A1 WO1995010278A1 PCT/US1994/011155 US9411155W WO9510278A1 WO 1995010278 A1 WO1995010278 A1 WO 1995010278A1 US 9411155 W US9411155 W US 9411155W WO 9510278 A1 WO9510278 A1 WO 9510278A1
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- WIPO (PCT)
- Prior art keywords
- amount
- terfenadine carboxylate
- terfenadine
- carboxylate
- patient
- Prior art date
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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
Definitions
- Terfenadine -[4-( 1,1-dimethylethyl)phenyl ]-4- (hydroxydiphenylmethyl)-l-piperidinebutanol, is a known antihistaminic agent which is currently available commercially under the name Seldane ® with a recommended dosage of 60 mg b.i.d. (See PHYSICIAN'S DESK REFERENCE, 47th Edition, 1993, Supplement A, pp. A119-A121, Medical Economics Data, a division of Medical Economics Company, Inc., Montvale, New Jersey. Terfenadine is disclosed in the Carr et al. '217 patent [U.S. Patent No. 3,878,217; issued April 15, 1975]. Sorken and Heel have provided a review of the pharmacodynamic properties and therapeutic efficacy of terfenadine [ Drugs 9, 34-56 (1985)].
- Terfenadine undergoes extensive (99%) first pass metabolism to two primary metabolites, an active acid metabolite (Terfenadine carboxylate) and an inactive dealkylated metabolite.
- Terfenadine carboxylate is 4-[l- hydroxy-4-[ 4-(hydroxydiphenylmethyl)-l-piperidinyl ]butyl ]- ⁇ , ⁇ -dimethyl-benzeneacetic acid and has been disclosed in the Carr et al. '129 patent [U.S. Patent No. 4,254,129, issued March 3, 1981] as an antihistaminic agent having oral activity.
- Huther et al. [ Eur. J. Clin. Pharmacol. 12, 195-99 (1977)] have described the effects of various doses of terfenadine on the antagonism of histamine-induced skin wheals in studies carried out in man. In a study described by Huther et al., the effects of single oral doses of 20, 60, and 200 mg terfenadine tablets on skin wheals induced by intradermal injections of 2 ⁇ g histamine were studied.
- the results of this study shows a dose-dependent reduction in the size of the histamine wheal with a maximal effect being reached at the 60 mg dose and being maintained at the 200 mg dose.
- the effects of multiple doses of terfenadine (20, 40 or 60 mg every 8 hours and 60 mg every 12 hours over 2 or 3 days) were also studied by Huther et al. Again, maximal inhibition of histamine-induced skin wheal was produced by 60 mg b.i.d. and 60 mg t.i.d. with no difference being observed between the 60 mg b.i.d. and t.i.d. dosage regimens.
- the present invention provides a method of treating a patient suffering from an allergic disorder comprising administering daily to said patient an amount of terfenadine carboxylate from about 10 mg to about 50 mg.
- the present invention further provides a pharmaceutical composition in solid unit dosage form comprising an amount of terfenadine carboxylate from about 5 mg to about 50 mg in admixture with a pharmaceutically acceptable carrier.
- Terfenadine carboxylate,4-[l-hydroxy-4-[4- (hydroxydiphenylmethyl )-l-piperidinyl ]butyl ]- ⁇ , ⁇ -dimethyl- benzeneacetic acid may be prepared as described in the Carr et al. '129 patent [U.S. Patent No. 4,254,129, issued March 3, 1981] .
- Terfenadine carboxylate is used according to the present invention as a histamine Hi-receptor antagonist and as such will provide relief of symptoms associated with histamine-mediated allergic disorders in patients suffering therefrom.
- Histamine-mediated allergic disorders are diseases or conditions which have a histamine-mediated allergic component such as, for example, seasonal allergic rhinitis, perennial rhinitis, idiopathic urticaria, asthma and the like.
- Terfenadine carboxylate also is effective according to the present invention in providing relief of symptoms associated with non-histamine-mediated allergic disorders such as tinnitus, motion sickness, common cold, and the like.
- Relief of symptoms of an allergic disorder by treatment according to the present invention refers to a decrease in symptom severity over that expected in the absence of treatment and does not necessarily indicate a total elimination or cure of the disease.
- the term "patient” refers to an adult person who is suffering from a histamine-mediated allergic disorder. It is understood that for purposes of the present invention, the term “adult” refers to a person of 12 years of age or older who would typically be treated for allergic disorders with an antihistamine dosage as recommended for adults.
- terfenadine carboxylate is administered to a patient in a daily amount of from about 10 mg to about 50 mg.
- a preferred daily dose is from about 20 mg to about 40 mg.
- the most preferred daily dose is about 30 mg.
- the daily dose may be administered to a patient according to a dosage regimen in single or multiple dosage units.
- a daily dose may be administered in a regimen requiring one, two, three, or four unit doses.
- these unit doses will be of equal strength and will be administered on a time schedule so that each dose is approximately equally spaced throughout the day.
- a daily dose requiring a once a day dosage regimen may be administered about every 24 hours; a daily dose requiring a twice-a-day dosage regimen may be administered about every 12 hours; a daily dose requiring a three times-a-day dosage regimen may be administered about every 8 hours; a daily dose requiring a four times-a-day dosage regimen may be administered about every 6 hours.
- terfenadine carboxylate is administered to a patient in a unit dose of from about 5 mg to about 25 mg taken twice daily. More preferably, terfenadine carboxylate is administered to a patient in a unit dose of from about 10 mg to about 20 mg taken twice daily. Most preferably, terfenadine carboxylate is administered to a patient in a unit dose of about 15 mg taken twice daily (15 mg b.i.d.).
- Terfenadine carboxylate can be administered according to the present invention in any form or mode which makes the compound bioavailable in effective amounts, including oral and parenteral routes.
- terfenadine carboxylate can be administered orally, subcutaneously, transdermally, intranasally, and the like. Oral administration is preferred.
- One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected the disease state to be treated, the stage of the disease, and other relevant circumstances.
- the compounds can be administered alone or in the form of a pharmaceutical composition in combination with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the chosen route of administration and standard pharmaceutical practice.
- Terfenadine carboxylate while effective itself, may be formulated and administered in the form of its pharmaceutically acceptable acid addition salt for purposes of stability, convenience of crystallization, increased solubility and the like.
- an individual polymorph, solvate or individual optical isomer of terfenadine carboxylate i.e., (R)-4-[l-hydroxy-4-[4- (hydroxydiphenylmethyl)-l-piperidinyl]butyl ]-_., ⁇ -dimethyl- benzeneacetic acid or (S)-4-[l-hydroxy-4-[ 4- (hydroxydiphenylmethyl)-l-piperidinyl]butyl ]- ⁇ fCt-dimethyl- benzeneacet ⁇ c acid] may be used.
- the present invention contemplates compositions comprising terfenadine carboxylate in admixture or otherwise in association with one or more inert carriers.
- compositions are useful, for example, as assay standards, as convenient means of making bulk shipments, or as pharmaceutical compositions.
- An assayable amount of terfenadine carboxylate is an amount which is readily measurable by standard assay procedures and techniques as are well known and appreciated by those skilled in the art. Assayable amounts of terfenadine carboxylate will generally vary from about 0.001% to about 75% of the composition by weight.
- Inert carriers can be any material which does not degrade or otherwise covalently react with terfenadine carboxylate.
- Suitable inert carriers are water; aqueous buffers, such as those which are generally useful in High Performance Liquid Chromatography (HPLC) analysis; organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable carriers or excipients.
- HPLC High Performance Liquid Chromatography
- the present invention contemplates a pharmaceutical composition in solid unit dosage form comprising an amount of terfenadine carboxylate from about 5 mg to about 50 mg in admixture with a pharmaceutically acceptable carrier.
- solid unit dosage form contemplates a solid dosage form for oral administration such as a tablet, capsule, and the like, as well as solid dosage forms for parenteral administration such as a transdermal patch, and the like.
- the pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art.
- the carrier or excipient may be a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art.
- the pharmaceutical composition may be adapted for oral or parenteral use and may be administered to the patient in the form of tablets, capsules, solutions, suspensions, transdermal patch, and the like.
- Terfenadine carboxylate may be administered orally, for example, with an inert diluent or with an edible carrier. It may be enclosed in gelatin capsules or compressed into tablets.
- terfenadine carboxylate may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
- These preparations should contain at least 4% of the compound of the invention, the active ingredient, but may be varied depending upon the particular form and may conveniently be between about 4% to about 70% of the weight of the unit.
- the amount of the compound present in compositions is such that a suitable dosage will be obtained upon administration.
- Preferred compositions and preparations according to the present invention are prepared so that an oral unit dosage form contains between about 15 mg to about 30 mg. Most preferred unit doses for oral administration are those which contain about 15 mg to about 30 mg.
- the tablets, pills, capsules, and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, PrimogelTM, corn starch, carbonate salts such as sodium bicarbonate or calcium carbonate, and the like; lubricants such as magnesium stearate or SterotexTM; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.
- binders such as microcrystalline cellulose, gum tragacanth or gelatin
- excipients such as starch or lactose, disintegrating agents such as alginic acid, PrimogelTM, corn starch, carbonate salts such as sodium bicarbonate or calcium carbonate, and the like
- lubricants such as magnesium stearate or Ste
- the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil.
- a liquid carrier such as polyethylene glycol or a fatty oil.
- Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
- tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
- a syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
- Preferred excipients are corn starch, gelatin, lactose, magnesium stearate and sodium bicarbonate.
- Oral unit dosage forms may be formulated to provide immediate or sustained release characteristics. These forms may be formulated according to conventional techniques and procedures to give the desirable dissolution and bioavailability characteristics.
- terfenadine carboxylate may be incorporated into a solution or suspension for oral or parenteral administration. These preparations should contain at least 0.1% of terfenadine carboxylate, but may be varied to be between 0.1 and about 50% of the weight thereof. The amount of terfenadine carboxylate in such compositions is such that a suitable dosage will be obtained upon oral or parenteral administration.
- the solutions or suspensions may also include the one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben? antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
- sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
- antibacterial agents such as benzyl alcohol or methyl paraben? antioxidants such as ascorbic acid or sodium bisulfite
- chelating agents such as ethylene diaminetetraacetic acid
- Transdermal dosage forms for administering terfenadine carboxylate can be prepared by conventional techniques well known in the art of pharmaceutical science such as by incorporating terfenadine carboxylate into various polymeric reservoir matrix materials.
- These polymeric matrix materials may include pressure sensitive acrylic, silicone, polyurethane, ethylene vinyl acetate copolymers, polyolefins, and rubber adhesive matrices, medical grade silicone fluids, and medical grade silicone elastamers, which are well known_ in the art for forming reservoirs for transdermal delivery of drugs.
- terfenadine carboxylate may be formulated with a variety of other active ingredients which are commonly combined with antihistamines, such as a decongestant, including pseudoephedrine and the like; analgesics such as acetaminophen and the like, non- steroidal antiinflammatory agents such as ibuprofen and the like.
- antihistamines such as a decongestant, including pseudoephedrine and the like
- analgesics such as acetaminophen and the like, non- steroidal antiinflammatory agents such as ibuprofen and the like.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP94930547A EP0723446A1 (en) | 1993-10-15 | 1994-09-30 | Treatment of allergic disorders with terfenadine carboxylate |
AU79630/94A AU7963094A (en) | 1993-10-15 | 1994-09-30 | Treatment of allergic disorders with terfenadine carboxylate |
JP7511873A JPH09506078A (en) | 1993-10-15 | 1994-09-30 | Method for treating allergic diseases with terfenadine carboxylate |
NO961496A NO961496L (en) | 1993-10-15 | 1996-04-15 | Treatment of allergic diseases with terfenadine carboxylate |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13754593A | 1993-10-15 | 1993-10-15 | |
US08/137,545 | 1993-10-15 | ||
US25521694A | 1994-06-07 | 1994-06-07 |
Publications (1)
Publication Number | Publication Date |
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WO1995010278A1 true WO1995010278A1 (en) | 1995-04-20 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/US1994/011155 WO1995010278A1 (en) | 1993-10-15 | 1994-09-30 | Treatment of allergic disorders with terfenadine carboxylate |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0815860A2 (en) * | 1992-08-03 | 1998-01-07 | Sepracor, Inc. | Terfenadine carboxylate and the treatment of allergic disorders |
US6039974A (en) * | 1997-08-26 | 2000-03-21 | Hoechst Marion Roussel, Inc. | Pharmaceutical composition for combination of piperidinoalkanol-decongestant |
US6113942A (en) * | 1995-02-28 | 2000-09-05 | Aventis Pharmaceuticals Inc. | Pharmaceutical composition for piperidinoalkanol compounds |
US6509353B1 (en) | 1998-04-14 | 2003-01-21 | Sepracor Inc. | Methods and compositions using terfenadine metabolites in combination with leukotriene inhibitors |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2453854A1 (en) * | 1979-04-10 | 1980-11-07 | Richardson Merrell Inc | NOVEL O- (4-DIPHENYLMETHYLPIPERIDINO) -1-PHENYLALCANOLS DERIVATIVES, ESPECIALLY USEFUL AS ANTIHISTAMINS, AND THEIR PREPARATION PROCESS |
WO1993023047A1 (en) * | 1992-05-11 | 1993-11-25 | Merrell Dow Pharmaceuticals Inc. | Use of terfenadine derivatives as antihistaminics in a hepatically impaired patient |
WO1994003170A1 (en) * | 1992-08-03 | 1994-02-17 | Sepracor Inc. | Terfenadine metabolites and their optically pure isomers for treating allergic disorders |
-
1994
- 1994-09-30 WO PCT/US1994/011155 patent/WO1995010278A1/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2453854A1 (en) * | 1979-04-10 | 1980-11-07 | Richardson Merrell Inc | NOVEL O- (4-DIPHENYLMETHYLPIPERIDINO) -1-PHENYLALCANOLS DERIVATIVES, ESPECIALLY USEFUL AS ANTIHISTAMINS, AND THEIR PREPARATION PROCESS |
WO1993023047A1 (en) * | 1992-05-11 | 1993-11-25 | Merrell Dow Pharmaceuticals Inc. | Use of terfenadine derivatives as antihistaminics in a hepatically impaired patient |
WO1994003170A1 (en) * | 1992-08-03 | 1994-02-17 | Sepracor Inc. | Terfenadine metabolites and their optically pure isomers for treating allergic disorders |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0815860A2 (en) * | 1992-08-03 | 1998-01-07 | Sepracor, Inc. | Terfenadine carboxylate and the treatment of allergic disorders |
EP0815860A3 (en) * | 1992-08-03 | 1998-01-14 | Sepracor, Inc. | Terfenadine carboxylate and the treatment of allergic disorders |
EP1214937A2 (en) * | 1992-08-03 | 2002-06-19 | Sepracor Inc. | Terfenadine carboxylate and the treatment of dermal irritation |
EP1214937A3 (en) * | 1992-08-03 | 2002-10-30 | Sepracor Inc. | Terfenadine carboxylate and the treatment of dermal irritation |
EP1688142A1 (en) * | 1992-08-03 | 2006-08-09 | Sepracor Inc. | Terfenadine carboxylate and the treatment of dermal irritation |
US6113942A (en) * | 1995-02-28 | 2000-09-05 | Aventis Pharmaceuticals Inc. | Pharmaceutical composition for piperidinoalkanol compounds |
US8129408B2 (en) | 1995-02-28 | 2012-03-06 | Aventisub Ii Inc. | Pharmaceutical composition for piperidinoalkanol compounds |
US6039974A (en) * | 1997-08-26 | 2000-03-21 | Hoechst Marion Roussel, Inc. | Pharmaceutical composition for combination of piperidinoalkanol-decongestant |
US6509353B1 (en) | 1998-04-14 | 2003-01-21 | Sepracor Inc. | Methods and compositions using terfenadine metabolites in combination with leukotriene inhibitors |
US8404715B2 (en) | 1998-04-14 | 2013-03-26 | Sunovion Pharmaceuticals Inc. | Methods and compositions using racemic, (R)-, and (S)-fexofenadine in combination with leukotriene inhibitors |
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