SI9200365A - Pharmaceutical composition on benzopyran derivatives basis - Google Patents

Abstract

A pharmaceutical composition comprising trans(3S,4R)-3,4-dihydro-2,2-diméthyle-4-(2-oxopipéridine-1-yl)-6-pent afluoroéthyle-2H-1-benzopyran-3-ol('Compound I'), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor, wherein the composition comprises 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of Compound I; a method for preparing such a composition and the use of such a composition in medicine.

Description

SMITHKLINE BEECHAM p.l.c.

Pharmaceutical composition based on benzopyran derivatives

The present invention relates to a pharmaceutical composition, to methods for the preparation of such a composition and to the use of such a composition in medicine.

European Patent Application Publication Number 0376524 describes certain benzopyran derivatives which are said to be potentially useful as bronchodilators in the treatment of respiratory tract disorders, such as reversible airway obstruction and asthma, and in the treatment of hypertension.

EP 0376524 also discloses trans (3S, 4R) -3,4-dihydro-2,2-dimethyl-4- (2-oxopiperidin-1-yl) -6-pentafluoroethyl-2H-1-benzopyran-3-ol (Compound I).

We have now found that a recognizable and specific pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is particularly useful for the treatment of people with respiratory tract disorders such as reversible airway obstruction and asthma: the hypotensive activity of such a composition is greatly reduced.

Therefore, one aspect of the present invention is a pharmaceutical composition comprising Compound I, or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable carrier, characterized in that the composition contains 0.2 to 0.9 mg or 1.1 down, 9 mg or 2.1 to 3.0 mg of compound I.

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Individual compositions contain 0.3 to 0.8 mg, 0.4 to 0.7 mg, 0.2 to 0.5 mg, 0.5 to 0.9 mg 1.1 to 1.5 mg, 1.5 to 1.9 mg, 2.1 to 2.5 mg or 2.5 to 3.0 mg of the active compound.

Examples of compositions are those containing 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9,1,1, 1,5,1,9 ,

2,1,2,5 or 3,0 mg of the active compound.

Suitable pharmaceutically acceptable salts include those described in EP0376524. In general, compound I is not in salt form.

Suitable pharmaceutically acceptable solvates include those described in EP0376524, in particular hydrates.

Compound I or a pharmaceutically acceptable salt or solvate thereof can be prepared using known methods, for example, those described in EP0376524. The descriptions in EP0376524 are incorporated herein by reference.

In one aspect, the invention provides a process for the preparation of a pharmaceutical composition containing 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of compound I or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate, and optionally a pharmaceutically acceptable carrier, comprising formulating compound I or a pharmaceutically acceptable salt or solvate thereof, and optionally including admixing a pharmaceutically acceptable carrier.

The composition of the present invention is preferably adapted for oral administration. Of course, it can also be adapted for other routes of administration, e.g. for parenteral administration, sublingual or transdermal administration.

The composition may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

In order to achieve consistency of administration, it is desirable that the composition of the present invention be in unit dosage form.

The unit dosage forms for oral administration may be tablets and capsules and may contain conventional carriers such as binders, such as e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, e.g. lactose, sugar, corn starch,

-I 1 P C 9 £ I 1 έα »calcium phosphate, sorbitol or glycine; tablet lubricants, e.g. magnesium stearate; disintegrating agents, e.g. starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents, such as sodium lauryl sulfate.

Solid oral compositions may be prepared by conventional methods of mixing, filling or tabletting. Repeated mixing operations can be used to distribute the active substance over those compositions where large quantities of fillers are used. Such procedures are, of course, common in the art. The tablets may be coated by well known methods in conventional pharmaceutical practice, especially enteric coatings.

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Oral liquid preparations may take the form of, e.g. emulsions, syrups or elixirs, or may be present as a dry product for reconstitution with water or other suitable carrier before use. Such liquid preparations may contain conventional additives such as suspending agents, e.g. sorbitol, syrup, methyl cellulose, gelatin, hydroxy ethyl cellulose, carboxy methyl cellulose, aluminum stearate gel, hydrogenated edible fats; emulsifying agents, e.g. lecithin, sorbitan monooleate, or acacia; non-aqueous carriers (which may contain edible oils), e.g. almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol or ethyl alcohol; preservatives, e.g. methyl or propyl p-hydroxybenzoate or sorbic acid: and, if desired, conventional flavoring or coloring agents.

For parenteral administration, liquid unit dosage forms are prepared using the compound and a sterile vehicle and, depending on the concentration used, can be either suspended or dissolved in the carrier. In the preparation of solutions, the compound can be dissolved in water for injection and filter sterilized before filling into a vial or ampoule and sealed. Preferably, adjuvants such as topical anesthetic, preservative and buffering agents can be dissolved in the carrier. To increase stability, the composition may be frozen after filling into a vial and removing the water under vacuum. Parenteral suspensions are prepared essentially in the same way except that the compound is suspended in the vehicle instead of dissolved and sterilization cannot be carried out by filtration. The compound may be sterilized before being suspended in a sterile vehicle by exposure to ethylene oxide. Preferably, a surfactant or wetting agent is incorporated into the composition to facilitate even distribution of the compound.

The compositions of the present invention, especially for the treatment of reversible airway obstruction and asthma, may be conveniently present for administration to the respiratory tract as a snuff or aerosol, or a spray or microfine powder for blowing powder, alone or in combination with an inert carrier such as lactose . In such a prime they have

- b Β «In the iMS, the active compound particles have a favorable diameter of less than 50 μτη, preferably less than 10 μτη, e.g. diameters in the range 1-50 μια, 1-10 μια, or 1 - 5 μτη. Where appropriate, small amounts of other anti-asthmatics and bronchodilators may be included, e.g. sympathomimetic amines such as isoprenaline, isoetarin, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH.

The compositions may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight of the active material, depending on the administration process. The preferred area for inhaled administration is 10-99%, especially 60-99%, e.g. 90.95 or 99%.

The present invention further provides a pharmaceutical composition, in particular a composition for inhalation administration, containing 0.2 to 3.0 mg of compound I or a pharmaceutically acceptable salt or solvate thereof in the form of a microfume powder, and optionally a pharmaceutically acceptable carrier. Suitable carriers are those commonly used in the art, e.g. lactose.

Preferably, the composition for inhalation administration contains 0.2 to 0.9 mg, e.g. 0.2 to 0.5 mg or 0.2.0.3.0.4 or 0.5 mg of the active compound.

Microfine powder formulations may be conveniently administered in aerosol as a metered dose or by a suitable respirator-activated device.

Suitable metered dose aerosol formulations include conventional propellants, co-solvents such as ethanol, surfactants such as oleyl alcohol, lubricants such as oleyl alcohol, desiccants such as calcium sulfate, and density regulators such as sodium chloride.

Suitable spray solutions are isotonic sterilized solutions, optionally floured, e.g. pH between 4 - 7 containing up to 20 mg / ml of the compound, but more generally 0.1 to 10 mg / ml, for use with standard spray equipment.

The compositions of the present invention can be prepared and formulated according to conventional methods such as those described in standard reference texts, e.g. in British and US Pharmacopoeia, Remington's Pharmaceutical Sciences (Cats Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press), and Harry's Cosmeticology (Leonard Hill Books).

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The present invention further relates to a method for treating respiratory tract disorders such as reversible airway obstruction and in particular asthma in humans, where the method involves administering a total daily dose of 0.2 to 0.9 mg or 1.1 to 1.9 mg. , or

2.1 to 3.0 mg of compound I or a pharmaceutically acceptable salt or solvate thereof to a person in need.

The drug may be administered 1 to 6 times daily, more typically 2 to 4 times daily, preferably 1 to 2 times daily, to ensure that the total daily dose is 0.2 to 0.9 mg, 1 , 1 to 1.9 mg or 2.1 to 3.0 mg.

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It should be appreciated that the entose dose for use in the process of the invention may contain less than the stated total daily dose (e.g., less than 0.2 to 0.9 mg) of the active compound to achieve the required total daily dose.

The present invention also provides a pharmaceutical composition comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of compound I or a pharmaceutically acceptable salt or solvate thereof, and for this pharmaceutically acceptable carrier for use as an active therapeutic substance.

In particular, the present invention is a pharmaceutical composition containing 0.2 to 0.9 mg or 1.1 to 1.9 or 2.1 to 3.0 mg of compound I or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of respiratory tract disorders. The present invention also relates to the use of a pharmaceutical composition containing 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of compound I or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier for the manufacture of a medicament for the treatment of respiratory tract disorders.

The following example illustrates but does not limit it in any sense.

Example

Male Sprague-Dawley rats were anesthetized using urethane and prepared to determine airway resistance (R _aw ), dynamic pulmonary indulgence (C _dyn ), and blood pressure as described by NE Bowring et. al., 1991, Pulmonary Pharmacology 4, 99-105.

Rats were challenged with methacholine aerosol for 2 minutes at 15 minute intervals, using a concentration (0.25 to 2.5 mol) sufficient to increase the resistance by about 100% and reduce the yield by about 40%. When a consistent response is established, compound I is administered intravenously 2 minutes before the metacholine challenge, with the challenge repeated at 15 minute intervals until its effect on R _aw and C _dyn returns to close values before compound I, followed by a higher dose of compound I. Blood pressure is measured just before each metacholin challenge. When the dose of compound I is high enough to counteract the effect on blood pressure, this effect is maximal within 2 minutes. The results are averages of 5 ± SN and are expressed as percentage drops in blood pressure or inhibition of responses before Compound I to the metacholine challenge.

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Claims (13)

Patent claims A pharmaceutical composition comprising trans (3S, 4R) -3,4-dihydro-2,2-dimethyl-4 (2-oxopiperidin-1-yl) -6-pentafluoroethyl-2H-1-benzopyran-3-ol (Compound I) or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable carrier, characterized in that the composition contains 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2, 1 to 3.0 mg of compound I. I Composition according to claim 1, characterized in that it contains 0.3 to 0.8 mg, 0.4 to 0.7 mg, 0.2 to 0.5 mg, 0.5 to 0.9 mg, 1 , 1 to 1.5 mg, 1.5 to 1.9 mg, 2.1 to 2.5 mg or 2.5 to 3.0 mg of the active compound. Composition according to claim 1 or claim 2, characterized in that it contains 0,2, 0,3, 0,4,0,5, 0,6,0,7,0,8,0,9,1, 1,1,5,1,9,2,1,2,5 or 3.0 mg of the active compound. Composition according to any one of claims 1 to 3, characterized in that it is adapted for oral administration, parenteral administration, sublingual or transdermal administration. Composition according to any one of claims 1 to 4, characterized in that it is adapted for oral administration. Composition according to any one of claims 1 to 5, characterized in that it is in unit dosage form. Composition according to any one of Claims 1 to 6, characterized in that it is adapted for administration to the respiratory tract as a snuff, an aerosol, a spray solution or as a microfine blowing powder. 8. A pharmaceutical composition for inhalation administration comprising 0.2 to 0.3 mg of trans (3S, 4R) -3,4-dihydro-2,2-dimethyl-4- (2-oxopiperidine-1- yl) -6-pentafluoroethyl-2H-1-benzopyran-3-ol (Compound I) or a pharmaceutically acceptable salt or solvate thereof in the form of a microfine powder and optionally a pharmaceutically acceptable carrier. 9 1 1 9 Γ Ο Μ 8 · JUt * - · '*. » Composition according to claim 8, characterized in that it contains 0.2 to 0.9 mg or 0.2 to 0.5 mg of the active compound. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 9, containing trans (3S, 4R) -3,4-dihydro-2,2-dimethyl-4- (2-oxopiperidin-1-yl) 6-pentafluoroethyl -2H-1-benzopyran-3-ol ('compound Γ) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof and, optionally, a pharmaceutically acceptable carrier, characterized in that the compound I or its pharmaceutically acceptable salt or formulation thereof a pharmaceutically acceptable solvate and optionally admix a pharmaceutically acceptable carrier. 11. A pharmaceutical composition comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of trans (3S, 4R) -3,4-dihydro- 2,2-dimethyl-4- (2-oxopiperidin-1-yl) 6-pentafluoroethyl-2H-1-benzopyran-3-ol (Compound I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier therefor , for use as an active therapeutic substance. 12. A pharmaceutical composition comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of trans (3S, 4R) -3,4-dihydro- 2,2-dimethyl-4- (2-oxopiperidin-1-yl) 6-pentafluoroethyl-2H-1-benzopyran-3-ol (Compound I) or a pharmaceutically acceptable cox or a pharmaceutically acceptable solvate thereof for use in the treatment of respiratory disorders tract. Use of a pharmaceutical composition containing 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg trans (3S, 4R) -3,4-dihydro-2,2-dimethyl-4- (2-oxopiperidin-1-yl) -6-pentafluoroethyl-2H-1-benzopyran-3 -ol (Compound I) or a pharmaceutically acceptable salt or solvate thereof, and 'therefor a pharmaceutically acceptable carrier, for the preparation of a medicament for the treatment of disorders of the respiratory tract.