SK65794A3 - Pharmaceutical mixture, method of its preparing and using - 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

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

BACKGROUND OF THE INVENTION

Published European Patent Application No. EP 0376524 discloses certain benzopyran derivatives which disclose, inter alia, their possible use as bronchodilators in the treatment of respiratory-tract diseases such as repeated airway obstruction and asthma as well as the treatment of high pressure.

EP 0376524 also discloses a compound trans (3S, 4R) -

3,4-dihydro-2,2-dimethyl-4- (2-oxopiperidin-1-yl) -6-pentafluoroethyl-2H-1-benzopyran-3-ol (Compound I).

It has now been found that discreet and particular pharmaceutical compositions comprising Compound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, are particularly useful for treating people with respiratory-tract disorders such as recurrent airway obstruction and asthma; the pressure reducing effects are greatly reduced.

SUMMARY OF THE INVENTION

Accordingly, one aspect of the present invention is that it provides a pharmaceutical composition comprising Compound I, a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate, as well as a pharmaceutically acceptable carrier, wherein the composition comprises 0.2 to 0.9 mg or 1 mg. , 1 to

1.9 mg or 2.1 to 3.0 mg of Compound I.

Particular compositions comprise 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, 5 to

1.9 mg, 2.1 to 2.5 mg, or 2.5 to 3.0 mg of the active ingredient.

Examples of compositions include 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 active ingredient.

Pharmaceutically acceptable salts include those described in EP0376524. Compound I is generally not in the form of a salt.

Pharmaceutically acceptable solvates are described in EP 0376527 in particular as hydrates.

Compound I, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, can be prepared using known methods, for example those described in EP 0376524. The teachings of EP0376524 are also incorporated herein by reference.

Another aspect of the invention is to provide a process for the preparation of a pharmaceutical composition consisting 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 pharmaceutically acceptable solvate and, as appropriate, a pharmaceutically acceptable carrier, comprising formulating Compound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and, as appropriate, admixing a pharmaceutically acceptable carrier.

In particular, the composition of the invention is adapted for oral administration. However, it can also be adapted for other modifications, such as parental, sublingual, or transdermal administration.

The composition may be in the form of tablets, capsules, powder, granules, lozenges, suppositories, reconstituting powders or liquid preparations for oral or sterile parental solutions or suspensions.

In order to achieve a suitable consistency of administration, it is preferred that the composition of the invention is in unit dosage form.

The dosage unit for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents such as syrup, acacia gelatin, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tablet lubricants such as magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or a pharmaceutically acceptable humectant such as sodium lauryl sulphate.

Solid oral compositions may be prepared by conventional methods of mixing, filling and tabletting. Repeated mixing operations can be used to distribute the active ingredient through compositions containing large amounts of fillers. These operations are, of course, conventional in the art. The tablets may be coated by well known methods in conventional pharmaceutical practice, particularly by enteric coating.

Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or may be presented as a dry product for mixing with water or other suitable means before use. Such liquid preparations may contain various conventional additives as suspending agents - for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose aluminum stearate gel, hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan, monooleate or acacia gelatin; non-aqueous binders (which may contain edible oils) such as almond oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol or ethyl alcohol esters; preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid; and, where appropriate, conventional flavoring or coloring agents.

In the case of parenteral administration, the unit doses are composed of the compound and the sterile binder, and - depending on the concentration used, they can either be dissolved or dispersed in the binder. In preparing solutions, the composition can be dissolved in water for injection, sterilized through a filter, before being filled into a suitable vial or vial and sealed. Preferred adjuvants such as a local anesthetic, preservatives and buffering agents can also be dissolved in the binder. In order to increase stability, the composition can be frozen after filling into a vial and water removed under vacuum. Parental suspensions are prepared in substantially the same manner, except that the compound is dispersed in solution instead of being dissolved, and sterilization cannot be achieved by filtration. The compound may be sterilized with ethylene oxide before dispersing it in a sterile binder. It is preferred that it comprises a surfactant or wetting agent to ensure uniform distribution of the compound in the composition.

In particular, in the event of repeated airway and asthma blocking, the composition of the invention may be suitably administered to the respiratory tract as inhalation powder, aerosol or nebulizer solution, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. . In such a case, the particles of the active ingredient have a diameter of less than 50 gm exceptionally less than 10 gm, for example diameters in the range of 1 to 50 gm, 1 to 10 gm or 1 to 5 gm. Where appropriate, small amounts of other anti-asthmatic agents and bronchodilators may be included, for example sympathomimetic amines such as isoprenaline, isoetarin, salbutamol, pheneprine and ephedrine; xanthine derivatives such as theophylline and aminoiniophylline and corticosteroids such as prednisolone and adrenaline scimulants such as ACTH.

The composition may contain from 0.1% to 99% by weight, preferably from 10% to 60% by weight, of the active material based on the weight of the composition depending on the mode of administration. A preferred range for administration by inhalation is 10 to 99%, in particular 60 to 99%, for example 90, 95 or 99% by weight.

The invention further provides a pharmaceutical composition, in particular a composition for inhalation, comprising from 0.2 to 3.0 mg of Compound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the form of a microfine powder and optionally a pharmaceutically acceptable carrier. Suitable carriers include those commonly used in the art, for example lactose.

Preferably, the composition for inhaled administration contains 0.2 to 0.9 mg, for example 0.2 to 0.5 mg or 0.2, 0.3, 0.4 or 0.5 mg of the active ingredient.

The microfine powder may suitably be administered in an aerosol as a metered dose or using a suitable respiratory-promoting device.

Suitable metered aerosol doses include conventional propellants, cosolvents such as ethanol, surfactants such as oleyl alcohol, lubricants such as oleyl alcohol, desiccants such as calcium sulfate, and density modifiers such as sodium chloride.

Suitable nebulizer solutions are isotonic sterilized solutions, usually buffered solutions, for example between pH 4 to 7, containing up to 20 mg. ml of compound, more generally 0.1 to 10 mg. ml ^-1 for use in a standard nebulizer.

The compositions of the invention can be prepared and mixed according to conventional methods also described in standard reference texts, for example, British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martinadale The Extra Pharmacopoeia (London, Pharmaceutical Press) and Harry's Cosmetics (Leonard Hill Books).

The present invention further provides a method of treating respiratory-tract disorders such as recurrent airway obstruction and especially asthma in humans, wherein a total daily dosage of 0.2 to 0.9 mg or 1.1 to 1.9 mg is required. or 2.1 to 3.0 mg of Compound I, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the human in need thereof.

The medicament may be administered from 1 to 6 times a day, usually 2 to 4 times a day, preferably 1 or 2 times a day, provided that the total daily dose is 0.2 to 0.9 mg, 1.1 to 6 times daily.

1.9 mg or 2.1 to 3.0 mg.

It would be appreciated that a unit dose for use in the method of the invention could contain less than said total daily dose (e.g., less than 0.2 to 0.9 mg) of the active ingredient to achieve the desired total daily dose.

in

The present invention also provides a pharmaceutical composition consisting of 0.2 to 0.9 mg or 1.1 to 1.9 mg;

2.1 to 3.0 mg of Compound I or a pharmaceutically acceptable salt thereof

or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier for use as an active therapeutic substance.

In particular, however, the present invention provides, in particular, 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 thereof, or a pharmaceutically acceptable solvate thereof for use in the treatment of respiratory-tract disorders. The present invention also encompasses the use of a pharmaceutical composition comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 0.9 mg

3.0 mg of compound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate or pharmaceutically acceptable carrier thereof, for the manufacture of a medicament for the treatment of respiratory-tract disorders.

The following example illustrates the invention but does not limit it in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example

Male Sprague-Dawley rats were anesthetized with urethane and prepared to determine airway resistance (R _{& w} ). dynamic lung compliance (? dyn) ^and blood pressure as described by NE Bowring et al., 1991, Pulmonary Pharmacology 4, 99-105.

Rats were exposed to an aerosol of methacholine at a concentration of (0.25-2.5 moles) sufficient to increase resistance by 100% and reduce compliance by 40% for 15 minutes at 15 minute intervals. Upon reaching a fixed response, compound 1 was intravenously administered two minutes prior to methacholine treatment, and the treatment was repeated at 15 minute intervals until its effect on R _aw and C (jy _n returned to near pre-compound I values to give higher compound values I. Blood pressure was measured only before each treatment with methacholine After the dose of Compound I was large enough to produce an effect on blood pressure, this effect occurred within a maximum of two minutes, the results being an average of 5 +/- SE and expressed as a percentage decrease in blood pressure or attenuation of methacholine responses prior to administration of compound I.

Claims (13)

PATENT CLAIMS A pharmaceutical composition comprising trans (3S, 4R) -3,4-dihydro-2,2-dimethyl-4- (2-oxopiperidin-1-yl) -6-penxafluoroexyl-2H-1-benzopyran-3-ol (compound I) ) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and optionally a pharmaceutically acceptable carrier, characterized in that it comprises 0.2 to 0.9 mg * - or 1.1 to 1.9 mg or 2.1 to 3, 0 mg of compound I. 2. A composition according to claim 1 comprising 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 1.5 mg 2.5 mg or 2.5 to 3.0 mg of active ingredient. Composition according to claim 1 or 2, characterized in that it comprises 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 ingredient. 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 the form of a unit dose. Composition according to any one of claims 1 to 6, characterized in that it is adapted for administration to the respiratory xacx as an inhalation powder, aero 10 salt, a nebulizer solution or a micro-powder for insufflation. A pharmaceutical composition for inhaled administration comprising 0.2 to 3.0 mg trans (3S, 4R) -3,4-dihydro-2,2-dimethyl-4- (2-oxopiperidin-1-yl) -6-pentafluoroethyl -2-benzopyran-3-ol (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof in the form of a microfine powder and optionally a pharmaceutical carrier received _e Ný. P * · The composition of claim 8, comprising 0.2 to 0.9 mg or 0.2 to 0.5 mg of the active ingredient. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 9 α-containing 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 thereof, or a pharmaceutically acceptable solvate thereof, and optionally a pharmaceutically acceptable carrier, which comprises mixing compound I or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, and optionally admixing an acceptable carrier. A method of treating respiratory-tract disorders such as repeated airway obstruction in humans, comprising administering a total daily dose of 0.2 to 0.9 mg or 1.1 to 0.9 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 thereof, or a pharmaceutically acceptable solvate thereof for a human in need thereof. 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 thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier and for use as an active therapeutic substance. A pharmaceutical composition comprising 0.2 to 0.9 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-oxopiperidine) (1-yl) -6-pentafluoro- In _N , ethyl-2H-1-benzopyran-3-ol (compound I) or a pharmacologically acceptable salt thereof or a pharmaceutically acceptable solvate thereof for use in the treatment of respiratory-tract disorders. Use of 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 thereof, or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier in the manufacture of a medicament for treating respiratory-tract disorders.