Aerosol pharmaceutical composition, a canister for storing and delivering pharmaceutical aerosol composition, a method of treating respiratory diseases, a method of obtaining a composition

 

(57) Abstract:

The invention relates to an aerosol composition used for the administration of drugs by inhalation, and means for receiving, storage and delivery. The composition comprises a monohydrate beclomethasone, the particles of which are generally less than 20 microns, at least 0,015% water by weight of the composition, in addition to the water of crystallization associated in the specified monohydrate, and a fluorocarbon or containing hydrogen harperperennial media. A method of treating respiratory diseases includes an introduction by inhalation an effective amount of a pharmaceutical aerosol composition. The container consists of a container, covered with a metering valve and contains a pharmaceutical aerosol composition. The container is able to withstand the vapor pressure of the propellant used. The method of obtaining the composition is a dispersion of the active component with additional water. The obtained aerosol compositions are stable. The container is able to withstand the vapor pressure of the propellant used. 4 C. and 15 C.p. f-crystals.

This invention relates to improvements farmacocinetica, used for the introduction of beclomethasone by inhalation.

Beclomethasone is 9-chloro-16-methyl-1,4-pregnadien-11, 17, 21-triol-3, 20-dione -17, 21-dipropionate formula (I).

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It is known that corticosteroid of formula (I) exhibits a local anti-inflammatory activity, described and claimed in UK patent CB 1047519. It was found that when the automatic treatment conditions effective is the introduction of compounds in the form of dry powders or aerosols with a small particle size of the drug, usually obtained by micronization. However, it is known that the particle size of conventional compositions containing anhydrous beclomethasone increases during storage due to the formation of the solvate to such an extent that the particles become too large to penetrate into the bronchial system.

It was proposed that a large number of potential solutions to this problem. For compositions containing beclomethasone, in the form of dry powders was suggested that the problem can be solved by using beclomethasone in the form of its monohydrate (patent UK CB 2107715). It is proposed to use in aerosol compositions crushed acetate the solvate (DE-3018550), the solvate C5-8alkanes (European patent EP-0039369), MES diisopropyl ether (European patent EP-0172672) and the solvate alcohols C1-5(WO 86/03750). Patent UK CB 2076422 discloses a method of obtaining harperperennial aerosols, which includes a low temperature (-5 to -40oC) stage, which also stated that inhibits the growth of crystals.

It is known that the presence of water in a conventional aerosol compositions is due to the large number of potential problems, and usually believe that these drugs are mostly not contain water. Strict exclusion of atmospheric moisture in the synthesis and storage of such compositions complicates obtaining aerosols containing the drug and increases the cost of the final product.

Now discovered that certain new aerosol compositions containing beclomethasone and water, surprisingly, are stable.

According to one aspect of the invention an aerosol composition containing:

(a) monohydrate beclomethasone, and the size of almost all particles monohydrate is less than 20 microns;

(b) at least 0,015% (by weight of the composition) water additives water of crystallization, Ellen.

The monohydrate beclomethasone can be obtained by known methods, for example, by the method described in UK patent CB 2107715. The particle size of the crystalline monohydrate can be reduced by conventional means, for example, crushing on micron colloidal mill, the particle size should be such as to ensure penetration of almost all of the medicinal product into the lungs during inhalation aerosol composition. Thus, it is desirable that the particle size ranged from 1 to 10 μm, for example, from 1 to 5 microns.

It is desirable that the final spray composition contains from 0.005 to 10% (weight/weight), preferably from 0.005 to 5% (weight/weight), particularly preferably from 0.01 to 1.0% (weight/weight) monohydrate beclomethasone relative to the total weight of the composition.

Aerosol compositions according to the invention contain at least 0,015% (for example, of 0.015 to 0.1%) water by weight of the composition (excluding water of crystallization associated with the monohydrate beclomethasone), preferably at least 0.02 percent (for example, 0,025%), with more added water by weight. Surprisingly discovered that the aerosol composition is pulverized on the micron mill monohydrate beclomethasone and FPO which does not contain water, for example, less than 0,005% by weight, give the crystal growth during storage and unusable. Preferred compositions according to the invention contain at least 0,026%, for example, 0,026 to 0.08% water by weight in addition to the water of crystallization associated in the monohydrate beclomethasone.

However, as will be clear to experts, the solubility of individual fluorocarbon containing hydrogen chargerbulletin propellants vary and accordingly the minimum amount of added water required for stabilization of aerosol compositions according to the invention will depend on the particular propellant used. Thus, aerosol composition, including, for example, a monohydrate beclomethasone and 1,1,1,2-Tetrafluoroethane as propellant, preferably contain at least 0,026% weight. (for example, of 0.03 to 0.08%) added water. Aerosol composition, including the monohydrate beclomethasone and 1,1,1,2,3,3-heptagon-n-propane as a propellant contain at least 0,015% weight. (for example, 0.02 to 0.05%) of added water.

The carrier used in the invention can be any fluorocarbon, or containing hydrogen hortonplea predpochtitelno propellant should not dissolve the monohydrate beclomethasone. Suitable carrier materials include, for example, C1-4chlorofluorocarbons, such as CH2ClF, CClF2-CHClF, CF3CHClF, CHF2CClF2, CHClFCHF2, CF3CH2Cl and CClF2CH3; C1-4the fluorocarbons, such as CHF2CHF2, CF3CH2F, CHF2CH3and CF3CHFCF3; and perfluorocarbon compounds such as CF3CF3and CF3CF2CF3.

When using a mixture of fluorocarbons or hydrogen-contain chlorofluorocarbons, they can be mixtures of the above compounds or mixtures (preferably binary) with other fluorocarbons or chlorofluorocarbons, for example, CHClF2CH2F2and CF3CH3. It is preferable to use as the propellant separate fluorocarbon compound or hydrogen-containing chlorofluorocarbon. Particularly preferred carriers are C1-4the hydrogen-containing fluorocarbons such as 1,1,1,2-Tetrafluoroethane (CF3CH2F) and 1,1,1,2,3,3,3-heptathlon-n-propane (CF3CHFCF3).

Preferably, the compositions of the invention do not contain components that can cause a decrease in the amount of ozone in the stratosphere. In particular, it is desirable that th is s without hydrogens, such as CC3F, CC2F2and CF3CC3. The expression "mainly contain no" here means less than 1 % weight. from the content of the fluorocarbon compounds or chlorophenolates media, in particular less than 0.5%, for example 0.1% or less.

The propellant may optionally contain adjuvant with higher polarity and/or a higher boiling point than the propellant. Polar adjuvants that can be used include aliphatic alcohols (for example, C2-6) and polyols such as ethanol, isopropanol and propylene glycol, preferably ethanol. Usually to increase the stability of the dispersion may need a very small amount of polar adjuvants (for example, 0.05 to 3.0 wt%), the use of quantities of more than 5% (weight/weight) can lead to the dissolution of the drug product. Compositions corresponding to the present invention preferably may contain less than 1 wt%, such as 0.1% polar adjuvant. However, preferred compositions of the invention generally not contain polar adjuvants, especially ethanol. Suitable volatile adjuvants include saturated hydrocarbons such as propane, n-butane, isobutane, pentane and isopentane, and alkyl, efio 30% of volatile unsaturated hydrocarbon, C1-6.

Optional aerosol compositions according to the invention can additionally contain one or more surfactants. These surfactants should be physiologically suitable for administration by inhalation. This category includes such surface-active substances, such as oleic acid, sarbatorile (SpanR85), servicemanual, sorbitanoleat, polyoxyethylene(20) sorbitanoleat, polyoxyethylene(20)servicemanual, natural lecithin, alaipayuthey(2) ether, steadilyincreasing(2) ether, lauryldimethylamine(4) ether, block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylenglycol, tetrahydrofurfurylamine, etiloleat, isopropylmyristate, glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, cetyl alcohol, stearyl alcohol, polyethylene glycol 400, cetylpyridinium, benzylaniline, olive oil, glycerylmonostearate, corn oil, cottonseed oil and sunflower oil.

If necessary, a surfactant can be included in the aerosol composition in the form of a coating on the particles monohydrate, beclometasone the substances, have reasonable solubility in non-polar solvents, because it contributes to the coating on the particles of medication, using solutions of surfactants in non-polar solvents in which the drug has limited or minimal solubility.

Thus, according to another aspect of the invention the aerosol composition can be obtained by rubbing a paste of crushed on the micron mill monohydrate beclomethasone with a solution of a surfactant, such as lecithin, in essentially non-polar solvent (e.g. a lower alkane, such as isopentane, or harperperennial connection, such as Trichlorofluoromethane), optional homogenizing pasta, for example, by ultrasonic treatment, removing the solvent with simultaneous and/or sequential crushing of the solid residue, if necessary, dispersive thus obtained is covered with a surface-active compound particles medicine in the selected propellant in an appropriate aerosol container, for example, by means of ultrasound. Preferred may be additive to any joint of the solvent after the unification of pokrytogo that the stability of the dispersion.

For coating particles of a medication, you must use the amount of surfactant is from 0.1 to 10% (weight/weight), preferably from 1 to 10 wt%. the weight of the drug. If surfactant is present in the form of external coatings, mainly choose the amount that it is formed mainly of monomolecular coating.

However, it is preferable that the composition of the invention basically had no surface-active substances.

Particularly preferred variant of the invention provides a pharmaceutical aerosol composition consisting mainly of monohydrate beclomethasone at least 0,015% weight. water and one or more fluorocarbon compounds or containing hydrogen of chlorofluorocarbons.

Specialists will be clear that the aerosol composition according to the invention can, if desired, contain one or more additional active ingredients. Known, for example, aerosol compositions containing two active ingredients (in the conventional system with a propellant, for the treatment of respiratory diseases such as asthma). According to the present invention also stated aerosol sustained fashion drugs can be selected from any other suitable drugs, useful in inhalation therapy, which may be present in the form, practically insoluble in the selected propellant. Thus, appropriate medications, for example, be selected from analgesics (eg, codeine dihydromorphine, ergotamine, fentanyl or morphine); anginal drugs (eg, diltiazem); antiallergenic (for example, cromoglycate, ketotifen or nedocromil); anti-infective drugs (e.g., cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines and pentamidine); antihistamines (e.g., methapyrilene); anti-inflammatory drugs (eg, fluticasone, flunisolide, budesonide, tipredane or triamcinolone acetonide); of cough medicines (e.g., noscapine); bronchodilators (for example, salmeterol.html, ephedrine, adrenaline, fenoterol, formoterol, izoprenalin, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol reproterol, rimiterol, terbutaline, isoetharine, tulobuterol, orciprenaline or (-)-4-amino-3,5-dichloro-L-[[[6-[2-(2-pyridinyl)-ethoxy] hexyl]-amino] methyl] besmear; diuretics (eg, anticholinergics (e.g., protropin, atropine or oxitropium); hormones (e.g., cor is Zina of theophyllinate or theophylline); and therapeutic proteins and peptides (e.g., insulin or glucagon). Specialists will be clear that to optimize the activity and/or stability of drugs or minimize the solubility of the drug in the propellant perhaps the use of medicines in the form of salts (e.g. alkali metal salts or amines or salts accession acids), or esters (e.g. esters of lower Akilov), or solvate (e.g. hydrate).

Particularly preferred aerosol compositions contain Salbutamol (e.g. as free base or sulphate) or Salmeterol (e.g. as xinafoate) in combination with monohydrate beclomethasone. Preferred are combinations of xinafoate salmeterola and monohydrate beclomethasone.

Combinations of the invention can be obtained, dispersive drug and added water in the selected propellant in an appropriate container, for example, by treatment with ultrasound.

Compositions according to the invention form during storage weakly flocculated suspensions, but it is surprisingly found that these suspensions can again easily atomized with mild stirring, receiving suspensions with neighbourhood, with some what more storage. Minimal use of or avoiding the use of excipients such as surfactants, co solvents and so on, in aerosol compositions according to the invention is also an advantage, since these compositions are able to have almost no taste and smell, to cause less irritation and to be less toxic than conventional compositions.

Chemical and physical stability and pharmaceutical suitability of aerosol compositions according to the invention can be determined by methods well known in the art. Thus, for example, the chemical stability of the components after prolonged storage of the product may be determined by the method of high performance liquid chromatography (HFLC). Data on physical stability can be obtained by other well-known analytical methods, for example, using a leak detector, exploring the valve (mean change of weight in a single injection) investigated the reproducibility of the dose (amount of active ingredient in a single injection) and examining the distribution of the sprayed material.

The particle size distributions of aerosol compositions according to the invention is Naib or analytical way of double collisions "Twin Impinger". Used in this way "Twin Impinger" means "determination of the deposition of the selected dose when inhaled under pressure using a device, as defined in British Pharmacopalia 1983, page A-207, Annex XVII C. Such methods allow to calculate the "respirable fraction" of aerosol compositions. Used here, the expression "respirable fraction" refers to the amount of active ingredient that is collected in the lower pressure chamber, with one-time injection, expressed as a percentage of the total amount of the active ingredient, selected with a single injection using the above described method of double collisions. Found that compositions according to the invention have a respirable fraction of $ 20 or more percent by weight of the medicinal product, preferably from 25 to 70%, for example, from 30% to 60%.

The compositions according to the invention can be filled cartridges, suitable for filing a pharmaceutical aerosol compositions. Cartridges typically include a container capable of withstanding the vapor pressure of the medium used, such as plastic or plastic-coated glass bottle or preferably a metal container, for example, aluminum, which at the same. syrovatskii valves are designed for dosing the quantity of the composition in a single action and include a gasket to prevent leakage of the medium through the valve. The gasket may include any suitable elastomeric material, such as, for example, low density polyethylene, butyl chloride, black and white butadiene-Acrylonitrile resin, synthetic butyl rubber and neoprene. In aerosol production are well known commercially available suitable industrial valves, for example, Valois, France (e.g., DF10, DF30, DF60), Bespak plc, UK (e.g., VC, VK) and 3M-Nootechnic Ltd, UK (e.g., SpraymiserTM).

To obtain large quantities for commercial production of filled containers is possible to apply the usual methods of industrial production and equipment well known in the art for the production of pharmaceutical aerosols. Thus, for example, in the manufacturing method of receiving empty containers dosing valve is fixed on the aluminum container.

Medication in the form of particles and water is added to the charging vessel and introducing the liquefied propellant through a charging vessel in the target vessel. Suspension by lecastlevania suspension medication. In an alternative method for industrial preparation of water dissolved in condensed media before receiving suspensions of drugs in water-containing media. Then in the usual way under pressure fill an empty spray suspension medication. Usually in batches obtained for pharmaceutical applications, each filled canister is subjected to control inflation, indicate the batch number and placed on the storage tray to check the leak.

Each filled canister before using supply device with a system of channels, receiving the dosing inhaler on a specific dose of drug injected into the lungs or nasal cavity of the patient. A suitable device with a system of channels include, for example, valve actuator and a cylindrical or conical channel through which medication can be obtained from a filled container through a metering valve in the nose or mouth of a patient, for example, actuator type mouthpiece. Inhalers at certain doses are designed to emit a fixed dose of medication in a single action, for example, from 10 to 5000 micrograms of the drug.

The purpose of the medication could be the imeneniya. It is clear that the exact input dose depends on the age and condition of the patient, characteristics of aerosol medicine and the frequency of application and, ultimately, the decision of the attending physician. When using a combination of medications, the dose of each component of the combination is basically the same as using each component separately. Usually applied one or more times a day, for example from 1 to 8 times, enter, for example, 1, 2, 3 or 4 strings each time.

A suitable daily dose may, for example, be from 100 to 2000 micrograms of beclomethasone, depending on the severity of the disease.

Thus, for example, every action of the valve can emit 50, 100, 200 or 250 micrograms of beclomethasone. Usually each filled container for use with a dosage inhaler contains 100, 160 or 240 of certain doses of medication.

Described here are filled containers and dosing inhalers are additional aspects of the present invention.

Another aspect of the present invention is a method of treating respiratory diseases, such as asthma, which includes an introduction by inhalation efficiency is at to illustrate the invention.

Example 1. Crushed on the micron mill monohydrate beclomethasone (68 mg) is weighed and placed in a clean, dry, plastic-coated glass bottle together with water (6,1 mg). Vacuum flask add dry (approximately 17 part/million on H2O) 1,1,1,2-Tetrafluoroethane (to 18.2 g). The bottle quickly seal the dosing valve. The resulting aerosol (330 frequent/million H2O) gives 250 micrograms of beclomethasone (as monohydrate) at a single dose of 75.8 mg

Example 2. Crushed on the micron mill monohydrate beclomethasone (52,2 g), water (44 ml) and 1,1,1,2-Tetrafluoroethane (to 72.8 kg) is added to the autoclave and mix thoroughly efficient mixer. An aliquot of the suspension (18.2 g) fill the aluminium container, closed-plunger valve, by filling under pressure through the valve, using conventional equipment for filling. Received inhalers contain 604 million shares added water and 13,04 mg monohydrate beclomethasone. Each spray gives 50 micrograms of beclomethasone at a single dose of 75.8 mg

Example 3. Crushed on the micron mill monohydrate beclomethasone (260,7 g), water (44 ml) and what Voth suspension (18.2 g) fill the aluminium container, closed metering valves by filling under pressure through the valve, using conventional equipment for filling. Received inhalers contain 605 frequent/million added water and to 65.2 mg monohydrate beclomethasone. Each spray gives 250 micrograms of beclomethasone. Each spray gives 250 micrograms of beclomethasone at a single dose of 75.8 mg

Example 4. Crushed on the micron mill monohydrate beclomethasone (62 mg) is weighed directly into an open aluminum tank with 6 Microlitre water. Then install the proportioning valve under pressure through a valve is added to the container 1,1,1,2,3,3,3-freon (to 21.4 g). The resulting aerosol contains 280 frequent/million added water and 258,3 micrograms monohydrate beclomethasone on single dose of 89.2 mg

1. Pharmaceutical aerosol composition for the treatment of respiratory diseases, including beclomethasone in the form of particles and a fluorocarbon or hydrogen-containing chloro-fluoro-carbon propellant, wherein beclomethasone in the form of a monohydrate beclomethasone with a particle size monohydrate mostly less than 20 composition is present in addition to the water of crystallization, associated with the specified monohydrate.

2. The composition according to p. 1, characterized in that it consists of 0.015 - 0.1 wt.% added water.

3. Composition according to any one of paragraphs. 1 and 2, characterized in that it includes at least 0,026% wt. added water.

4. Composition according to any one of paragraphs. 1 -3, characterized in that it includes 0,026 - 0.8 wt.% added water.

5. Composition according to any one of paragraphs. 1 to 4, characterized in that the carrier consists of C1-4the fluorocarbon containing hydrogen.

6. The composition according to p. 5, wherein the carrier includes 1,1,1,2,3,3,3-heptathlon-n-propane.

7. The composition according to p. 5, wherein the propellant comprises 1,1,1,2-Tetrafluoroethane.

8. The composition according to p. 1, characterized in that it comprises 0.03 to 0.08 wt.% added water and 1,1,1,2-Tetrafluoroethane as propellant.

9. The composition according to p. 1, characterized in that it comprises 0.02 to 0.05 wt.% added water and 1,1,1,2,3,3,3-heptathlon-n-propane as a propellant.

10. Composition according to any one of paragraphs. 1 -9, characterized in that it contains one or more additional active ingredients.

11. The composition according to p. 10, characterized in that it comprises salmeterol or salbutamol or their pharmaceutically prasa fact, that includes the salbutamol and the monohydrate beclomethasone.

13. The composition according to p. 10, characterized in that it includes xinafoate salmeterola and monohydrate beclomethasone.

14. Composition according to any one of paragraphs. 1 - 13, characterized in that the respirable fraction is 20% or more medicines.

15. Composition according to any one of paragraphs. 1 to 14, characterized in that it contains beclomethasone with a particle size of almost all of the monohydrate of less than 20 microns and a fluorocarbon or hydrogen-containing harperperennial propellant, the composition has a respirable fraction of 20% or more by weight of the drug.

16. A canister for storing and delivering pharmaceutical aerosol composition for the treatment of respiratory diseases, including container that can withstand the vapor pressure of the propellant used, covered with a metering valve and containing a pharmaceutical aerosol composition comprising beclomethasone in the form of particles and a fluorocarbon or hydrogen-containing harperperennial propellant, wherein beclomethasone present in the form of monohydrate beclomethasone with a particle size of m by weight of the composition of water is present in addition to the water of crystallization, related monohydrate.

17. Spray on p. 17, characterized in that it is provided with a device with a system of channels with the possibility of forming a metering pump for introducing drugs into the lungs or nasal cavity of the patient.

18. A method for the treatment of respiratory disorders associated with inflammatory diseases involving the introduction of an effective amount of a pharmaceutical aerosol composition containing beclomethasone in the form of particles and a fluorocarbon or hydrogen-containing harperperennial propellant, characterized in that the pharmaceutical composition is administered a composition containing monohydrate beclomethasone with a particle size of almost all of the monohydrate of less than 20 microns, in the amount of 0.005 - 10 wt.%/the weight of the total weight of the composition and at least 0,015% water by weight of the composition is present in addition to the water of crystallization associated in the specified monohydrate.

19. A method of obtaining a pharmaceutical aerosol composition according to any one of paragraphs. 1 - 15, characterized in that the monohydrate beclomethasone in the form of particles with a particle size almost the entire monohydrate less than 20 μm, is dispersed with additionally the

 

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