HUT76055A - Pharmaceutical composition containing terfenadine carboxylate and its use - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to a method for treating patients with allergic disease, such as GG-wX C / ηJ - / 7 SIL.X-f fafixsui (for τ 10 mg to 50 mg of 5 µg per bar of terfenadine carboxylate). -1- r vp 77 male '■' // E-7

Description

Treatment of allergic diseases with terfenadine carboxylate

Terfenadine, α- [4- (1,1-dimethylethyl) phenyl] -4- (hydroxydiphenylmethyl) -1-piperidin-butanol, is a known antihistamine, commercially available as Seldane®, 60 mg b.i.d. recommended dose. (See PHYSICIAN'S DESK REFERENCE, 47th Edition, 1993, Supplement A, pp. A119-A121, Medical Economics Data, a division of the Medical Economics Company, Inc., Montvale, New Jersey). Terfenadine was discovered by Call et al. ('217 patents), which is disclosed in U.S. Patent No. 3,878,217, issued April 15, 1975. Sokren and Heel summarize the pharmacodynamic properties and therapeutic effects of terfenadine in Drugs 29, 34-56 (1985).

Terfenadine accounts for 99% of the first metabolism, two primary metabolites, one active acid metabolite (terfenadine carboxylate) and the other an inactive desalkylated metabolite. Terfenadine carboxylate, i.e. 4- {1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] butyl} -α, a-dimethylbenzene acetic acid, is an antihistamine having oral activity. U.S. Patent No. 4,254,129, issued March 3, 1981 to Carr et al.

The antagonism of histamine-induced rashes has long been accepted as a demonstration of the activity of doses of histamine antagonists. Huther has described the effect of different doses of terfenadine on the antagonism of histamine-induced rash 9 9 · s and has been studied in humans. In a study by Huther et al., A single oral dose contains 20, 60 and 200 mg of terfenadine per tablet. In the experiments, skin rashes were induced by intradermal injection of 2 pg histamine. The results of the experiments showed that the reduction in histamine rash size was dose-dependent, with a maximum effect at 60 mg and a maintenance dose of 200 mg. Doses of terfenadine multiplex at doses of 20, 40, or 60 mg every 8 hours were studied by Huther et al., And 60 mg every 12 hours for 2-3 days were shown to be effective. Maximum histamine-induced rash inhibition showed 60 mg b.i.d. and 60 mg t.i.d. dose and no difference was observed between 60 mg b.i.d. and t.i.d. dose range. Huther described in his study that doses of terfenadine lower than 60 mg (single dose b.i.d. or t.i.d.) showed reduced histamine-induced rash inhibition.

Recent studies have shown that significant hepatic dysfunction patients (alcoholic cirrhosis, hepatitis) have produced electrocardiographic QT prolongation (eg, hypokalemia, ventricular tachycardia. [See Seldane® Prescribing

Information, PHYSICIAN'S DESK REFERENCE, 47th Edition, 1993, Supplement A, p. A119-A121, Medical Economics Data, a division of the Medical Economics Company, Inc., Montvale, New Jersey.]

62 238 / SM

Summary of the Invention

The present invention is a method of treating patients suffering from allergic diseases by administering to the patients 10 mg to 50 mg of terfenadine carboxylate daily.

The present invention also provides a pharmaceutical unit dosage form comprising 5 mg to 50 mg of terfenadine carboxylate in admixture with a pharmaceutically acceptable carrier.

Detailed Description of the Invention

Terfenadine carboxylate, i.e., 4- {1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] butyl} -α, α-dimethylbenzene-acetic acid, was obtained on March 3, 1981. U.S. Patent No. 4,254,129 to Carr et al., '129 patents.

According to the invention, terfenadine carboxylate is used as an antagonist of the histamine H 1 receptor and thereby reduces the symptoms associated with allergic diseases caused by histamine. Histamine-induced allergic disorders are diseases or conditions that have an allergic component to histamine, such as seasonal allergic rhinitis, perennial rhinitis, idiopathic urticaria, asthma and the like. According to the invention, terfenadine carboxylate is also effective in reducing symptoms associated with non-histamine allergic diseases, such as tinnitus, movement disorders, colds and the like. The reduction in the symptoms of allergic disorders with the treatment method of the present invention shows that the severity of the symptoms is better than would be expected without treatment and does not necessarily result in the complete cessation of the disease or curative.

62 238 / SM

As used herein, the term "patient" refers to adult persons suffering from an allergic disease caused by histamine. It is to be understood that, for the purposes of the present invention, the term "adult" refers to persons 12 years of age or older who are typically treated with a dose of antihistamine for adults with allergic disorders.

The selection and identification of patients who can be treated with the method of the present invention for success will be obvious to one skilled in the art. The practitioner can readily identify which patients suffer from an allergic disorder, whether histamine-induced or non-histamine-induced, through clinical tests, physical examinations, and medical and family history.

The daily dose of terfenadine carboxylate according to the invention is 10 mg to 50 mg daily. A preferred daily dose is 20 mg to 40 mg. A particularly preferred daily dose is 30 mg.

It will be appreciated that the daily dose may be administered to the patient in single or multiple dose units. For example, each dose may be administered in one, two, three or four dosage units. Typically, these dosage units are of equal strength and each dose may be administered at a scheduled time over a period of 24 hours. For example, a daily dose that is required once a day can be given every 24 hours; the daily dose, which is twice daily, may be administered every 12 hours; the daily dose, which is required three times a day, may be given every 8 hours; a daily dose that is four times a day can be given every 6 hours.

In a preferred embodiment of the invention, terfenadine carboxylate is administered to the patient in a dosage of 5 mg to 25 mg twice daily. More preferably, terfenadine carboxylate is administered in a dose of 10 mg to 20 mg per day two 62.238 / SM • · · ·

- 5 times. Most preferably, terfenadine carboxylate is administered in a dose of 15 mg twice daily (15 mg b.i.d.).

The terfenadine carboxylate may be administered in any form or manner in accordance with the present invention so as to provide an effective amount of the bioavailability of the compound, including the oral and parenteral routes of administration. For example, terfenadine carboxylate can be administered orally, subcutaneously, transdermally, intranasally, and the like. Preferably, oral administration is preferred. One of ordinary skill in the art will readily select the appropriate route of administration depending upon the characteristics of the compound selected, the disease status being treated, the disease progression, and other relevant circumstances.

The compounds of the invention, alone or in a pharmaceutical composition, may be administered in admixture with a pharmaceutically acceptable carrier or diluent, and the amount and route of administration will be selected by those of ordinary skill in the art. Terfenadine carboxylate is effective on its own, but can be formulated and administered in the form of a pharmaceutically acceptable salt of the active ingredient increases stability, crystallization becomes convenient, solubility, and the like are increased. During administration, the individual polymorph, solvate or terfenadine carboxylate [i.e., (R) -4- {1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] butyl} -ac, dimethylbenzene acetic acid or (S) -4- {1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] butyl} -α, α-dimethylbenzene acetic acid] individual optical isomers.

The present invention also provides a composition comprising terfenadine carboxylate and one or two inert carriers. These compositions are, for example, test compositions

62 238 / SM

- 6 standard, convenient to prepare bulls for use in formulations or pharmaceuticals. An assayable amount of terfenadine carboxylate is one that is readily measurable, well known, and readily available to one of ordinary skill in the art using standard assays and techniques.

The test amount of terfenadine carboxylate is generally from 0.001% to 75% by weight of the composition. Suitable excipients are any material which does not degrade or covalently react with terfenadine carboxylate. Examples of suitable inert carriers are water; aqueous buffers, such as those used in High Performance Liquid Chromatography (HPLC); an organic solvent such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable carriers or diluents.

More particularly, the present invention relates to a pharmaceutical composition comprising 5 mg to 50 mg of terfenadine carboxylate in solid unit dosage form together with a pharmaceutically acceptable carrier. The term "solid dosage unit form" means a solid dosage form suitable for oral administration, such as tablets, capsules and the like, as well as solid dosage forms suitable 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 diluent may be a solid, semi-solid, or liquid material that serves as a vehicle for the active ingredient or as a vehicle for uptake. Suitable carriers or diluents are well known in the pharmaceutical art. Pharmaceutical formulations adapted for oral or parenteral administration may be administered to the patient in the form of tablets, capsules, solutions, suspensions, transdermal patches, or the like.

62 238 / SM

Terfenadine carboxylate can be administered orally, for example, using an inert diluent or a digestible carrier. The active ingredient is filled into gelatin capsules or compressed into tablets. For oral therapeutic administration, terfenadine carboxylate is incorporated in a diluent and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like. The formulations should contain at least 4% of the active ingredient according to the invention, but may be varied depending upon the dosage form and may conveniently be set at 4% to 70% by weight of the unit. The amount of active ingredient in the pharmaceutical composition is selected such that it is present in an amount suitable for the mode of administration. Preferred compositions and preparations according to the invention contain from 15 mg to 30 mg of active ingredient per oral dosage unit. The most preferred dosage unit for oral administration is 15 mg to 30 mg of active ingredient.

Tablets, pills, capsules and other pharmaceutical forms may also contain one or more adjuvants: such as binders such as microcrystalline cellulose, gum tragacanth or gelatin; diluents such as starch or lactose; disintegrating agents such as alginic acid, Primogel ™, wheat starch; carbonate salts such as sodium bicarbonate or calcium carbonate and the like; lubricants such as magnesium stearate or Sterotex ™, glycans, igya colloidal silicon dioxide, sweeteners, igya sucrose or saccharin; flavors such as peppermint, methyl salicylate or orange flavor. If the dosage form is a capsule, it will contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage forms may contain various substances that modify the physical form of the dosage unit, e.g. 62.238 / SM • · · ·

- 8 coatings. In this way, tablets or pills are coated with sugar, saliva or other enteric coating agents. Syrups may contain, in addition to the active ingredient, sucrose as a sweetening agent, certain preservatives, dyes, colorings and perfumes. The materials used in the various formulations should be pharmaceutically pure and non-toxic in the amounts used. Preferred diluents include wheat starch, gelatin, lactose, magnesium stearate, and sodium bicarbonate.

Oral dosage units can be converted into immediate and sustained release forms. These formulations may be prepared by conventional methods and procedures providing the desired solubility and bioavailability characteristics.

Terfenadine carboxylate may be formulated as a solution or suspension for oral or parenteral administration. These formulations contain at least 0.1% terfenadine carboxylate, but may be varied from 0.1% to 50% by weight of the formulation. The amount of terfenadine carboxylate in such formulations may be adjusted to provide a suitable dosage for oral or parenteral administration.

The solutions or suspensions may also contain one or more adjuvants, such as sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents, such as benzyl alcohol or methyl paraben, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.

For the administration of terfenadine carboxylate in a transdermal dosage form, the dosage form is prepared by conventional techniques well known in the art such that

62.238 / SM, the terfenadine carboxylate is transferred into containers of various polymeric matrix materials. Such polymeric matrix materials include pressure-sensitive acrylates, silicone, polyurethane, ethylene-vinyl acetate copolymers, polyolefins and rubber adhesive stickers, pharmacologically pure silicone fluids, and drug-pure silicone elastomers well known in the art. the preparation.

It is a further object of the present invention to formulate terfenadine carboxylate with a number of other active ingredients, generally combined antihistamines such as a decongestant including pseudoephedrine and related compounds; analgesics such as acetaminophen and related substances, non-steroidal anti-inflammatory drugs such as ibuprofen and the like.

Claims (19)

PATENT CLAIMS CLAIMS 1. A method of treating an allergic patient comprising administering to the patient a daily dose of from 10 mg to 50 mg of terfenadine carboxylate. The method of claim 1, wherein the patients suffering from seasonal allergic rhinitis are treated. 3. A process according to claim 2 wherein the amount of terfenadine carboxylate is from 20 mg to 40 mg. 4. A process according to claim 3 wherein 30 mg of terfenadine carboxylate is used. 5. A method of treating patients with an allergic disease comprising administering to the patients terfenadine carboxylate 5 mg to 25 mg twice daily. 6. The method of claim 5, wherein the patient is suffering from seasonal allergic rhinitis. The process according to claim 6, wherein the amount of terfenadine carboxylate is from 10 mg to 20 mg. 8. A process according to claim 7 wherein 15 mg of terfenadine carboxylate is used. A solid dosage form pharmaceutical composition comprising 5 mg to 50 mg of terfenadine carboxylate in admixture with a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 9, wherein the amount of terfenadine carboxylate is 15 mg. 62.238 / SM »'<* The pharmaceutical composition of claim 9, wherein the amount of terfenadine carboxylate is 30 mg. Use of a pharmaceutical composition for the treatment of patients suffering from an allergic disease comprising administering to the patients 10 mg to 50 mg of terfenadine carboxylate per day. Use according to claim 12, wherein the allergic disease is seasonal allergic rhinitis. The use of claim 13, wherein the amount of terfenadine carboxylate is 20 mg to 40 mg. The method of claim 14, wherein the amount of terfenadine carboxylate is 30 mg. Use of a pharmaceutical composition for the treatment of patients suffering from allergic diseases by administering to the patients terfenadine carboxylate 5 mg to 25 mg twice daily. The method of claim 16, wherein the patients suffering from seasonal allergic thrinitis are treated. The method of claim 17, wherein 10 mg to 20 mg of terfenadine carboxylate is used. The method of claim 18, wherein 15 mg of terfenadine carboxylate is used.