This invention relates to a medicinal aerosol suspension formulation and more particularly, to a medicinal aerosol formulation containing a particulate drug or a combination of at least two particulate drugs, a propellant and a stabilizing agent comprising a water addition.

SUMMARY OF THE INVENTION

It has surprisingly been found that novel medicinal aerosol formulations can be obtained without the use of either cosolvents, such as ethanol, or surfactants, such as sorbitan trioleate which are added to a binary aerosol formulation. Stable medicinal aerosol suspension formulations are obtained by the use of a water addition.

DETAILED DESCRIPTION OF THE INVENTION

This invention involves a stable suspension aerosol formulation suitable for pressurized delivery which comprises (1) a particulate medicament or drug or combination of at least two medicaments or drugs, (2) a suitable propellant, and (3) a stabilizer comprising a water addition.

A suitable medicament or drug is one which is suitable for administration by inhalation, the inhalation being used for oral and nasal inhalation therapy. Therapeutic categories of drugs or medicaments include cardiovascular drugs, antiallergics, analgesics, brochodilators, antihistamines, antitussives, antifungals, antivirals, antibiotics, pain medicaments, anti-inflammatories, peptides, proteins and steroids. Of course, not included within the medicaments of the subject invention are the solvates of a beclomethasone compound.

Particularly suitable medicaments or drugs include albuterol (also known as salbutamol), atropine, budesonide, cromolyn, epinephrine, ephedrine, fentanyl, flunisolide, formoterol, ipratropium bromide, isoproterenol, pirbuterol, prednisolone, mometasone, triamcinolone acetonide, salmeterol, amiloride, fluticasone, fluticasone esters, such as phosphate, monohydrate and furoate, (-)4-amino-3,5-dichloro-.alpha.-[[[6(2-pyridinyl)ethoxy]hexyl]amino]methy- l]benzene-methanol. Also included are the suitable acid addition salts of the foregoing drugs, their hydrates and their other solvates. In this regard, suitable acid addition salts include the salts obtained from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids. Suitable pharmaceutically acceptable solvates include solvates with ethylactate, alkanes, ethers, alcohols and water.

A preferred embodiment of this invention are aerosol formulations which provide for a combination of at least two and most preferably not more than four different medicaments such as cardiovascular drugs, antiallergenics, analgesics, bronchodilators, antihistamines, antitussives, antifungal, antiviral, antibiotics, pain medicaments, anti-inflammatories, peptides, proteins and steroids and of the use of these aerosol formulations to treat the disease states associated with these medicaments. These medicaments and their use to treat a particular disease state are well known to a practitioner of the art.

Especially preferred, are formulation which comprise combinations comprising at least two different medicants, such as .beta.2-adrenergic agonists, corticosteroids, anticholinergics and leucotriene modulators. Especially preferred are .beta.2-adrenergic agonists, such as albuterol and formoterol and corticosteroids, such as mometasone, hydrocortisone, fludrocortisone, dexamethasone, prednisone, cortisone, aldosterone hemi-acetal, betamethasone, beclomethasone dipropionate, triamcinolone acetonide, budesonide dipropionate, fluticasone propionate and flunisolide, anticholinergics, such as ipratropium bromide, histamine antagonists (mast cell modulators), such as cromolyn and non-steroidal antiinflamatory agents, such as acetaminophen or ibuprofen.

This invention includes the derivatives of the foregoing medicaments. These derivatives include all the salt, ester, solvate and hydrate forms of the foregoing drugs as well as their geometric and optical isomers, including their chiral forms. Such derivatives are well known to a practitioner in this art.

The leucotrienes contemplated in this invention are those which are implicated as mediators of allergic and inflammatory responses associated with bronchial asthma and rheumatoid arthritis. This medicaments are known in the art to constrict dramatically the pulmonary airways and small blood vessels. Thus, inhibitors or antagonists of leucotrienes are effective mediators of the allergic responses typified by asthma and maybe used to treat bronchial asthma and other diseases states associated with inflammation of the airways.

The leucotriene modulators contemplated in this application include, but not limited to the following: 1. Inhibitors or antagonists of lecotriene, including the PAF receptor antagonists and 5-lipoxynase inhibitors, for example 2,5-diaryl tetrahydrofurans, 2,5-diaryl tetrahydrothiophenes, 2,4-diaryl tetrahydrofurans, 2,4-diaryl tetrahydrothiophenes, 1,3-diaryl cyclopentanes, 2,4-diaryl pyrrolidines, and 2,5-diaryl pyrrolidines, triazolo(4,3-A)(1,4)benzodiazepines and thieno (3,2F)(1,2,4)triazolo(4,3-A)(1,4)diazepine compounds, 6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines (see, U.S. Pat. Nos. 5,856,323; 5,358,938; 4,959,361; and 3,987,052), including, both optically pure and racemates (U.S. Pat. No. 5,629,337). An example of this group of compounds is Zileuton.RTM. (Abbott Laboratories) and Acolate.RTM. (Merck). 2. Chromone-2-carboxylic acid derivatives as antagonists of SRS-A (slow reacting substance of anaphylaxis (see, Samuelsson et al., Department of Chemistry, Karolinska Institutet, Stockholm, Sweden, TIPS, 227, May, 1980; J. Med. Chem. 20 371 (1977)), such as 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo- -8-propyl-4H-1-benzopyran-2-carboxylate (FPL 55712), which is a specific antagonist of SRS-A as well as a standard for evaluating other inhibitors; 3. Aryloxyalkyloxy-and aralkyloxy-4-hydroxy-3-nitrocoumarins as antagonists of SRS-A and inhibitors of histamine release, (see. e.g. Buckle et al., J. Med. Chem. 22 158 (1979); U.S. Pat. No. 4,296,237; European Patent No. 0036663; U.S. Pat. No. 4,296,120; and U.S. Pat. No. 4,296,129), as well as other compounds which act as inhibitors of SRS-A including oxiranbutyric acid esters, 3-hydroxy-4-substituted-3-pyrroline-2,5-diones or carboxy-oxo-pyrrolidino)phenyl alkenamides and esters or (carboxyacylamino)phenyl alkenamides and esters, or the substituted derivatives of these before mentioned compounds, including, but not limited, to alkyl, hydroxy amino, dialkylamino, hydroxymethyl, aminomethyl, alkylaminomethyl or alkanoylaminomethyl of 1 to 12 carbon atoms; --CN, --CONH.sub.2 or --CO.sub.2M in which M is hydrogen, aryl, phenyl, or naphthyl, cyclohexyl, cyclopentyl, or fluoromethoxy; or 4. Antagonists and inhibitors of leukotriene including N-o-tolylsulfonylbenzamide compounds. All of the aforementional prior literature is expressly incorporated by reference. These medicaments are known in the art to treat inflammatory diseases and include medicaments that block the release, production, secretion, or any other biochemical action arachidonic acid, prostaglandins and thromboxanes, or other leukotrienes that participate in inflammatory reactions, exhibit chemotactic activities, stimulate lysosomal enzyme release and act as important factors in the immediate hypersensitivity reaction.

Especially preferred medicaments include groups comprising [1-formyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-- N-o-tolylsulfonylbenzamide, [1-(hydroxycarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl- ]-3-methoxy-N-o-tolylsulfonylbenzamide, [1-((2-carboxyethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3- -ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide, [1-((2-tetrazolylethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indo- l-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide, [1-(methylphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylm- ethyl]-3-methoxy-N-o-tolylsulfonylbenzamide, [1-(diphenylcarbamoyl)-5(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl- ]-3-methoxy-N-o-tolylsulfonylbenzamide; [1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-metho- xy-N-o-tolylsulfonylbenzamide, and [1-(pyrrolidine-carbonyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylme- thyl]-3-methoxy-N-o-tolylsulfonylbenzamide. Also, pharmaceutically acceptable salts of these agents, including addition salts derived from organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, nitric, p-toluene sulfonic, acetic, citric, maleic, succinic acid and the like. In addition, the compounds in their free carboxylic acid form may be converted by standard techniques well-known to the practioner to their corresponding alkali metal (e.g. sodium or potassium), alkaline earth metal (e.g. calcium or magnesium), ammonium or primary, secondary and tertiary alkylamine salts, the latter containing from 1 to 6 carbon atoms in their alkyl moieties or a pharmaceutically acceptable salt thereof. These components are known in the literature and are described, for example in Brown et al., J. Med. Chem., vol. 35(13), pp. 2419 to 2439 (1992) Jacobs et al., J. Med. Chem., vol. 37(9), pp. 1282 to 1297 (1994); AU 646 587 Australia March 1993; McFadden, E. R., Jr., Am Rev. Resp. Dis., vol. 147 pp. 1306 1310 (1993); Greenberger, P. A., Chest, vol. 101 pp. 418S 421S (1992); Lipworth, B. J. Pharmacol. Ther., vol. 58 pp. 173 209 (1993); Busse, W. W., Chest, vol. 104 pp. 1565 1571 (1993); Anonymous, Executive Summary: Guidelines for the Diagnosis and Management of Asthma, Public Health Service, Publication 91-3042A, NIH, Bethesda, Md., pp. 1 44 (1991); Israel, E., and Drazen, J. M., N. Engl. J. Med., vol., 331 pp. 737 739 (1994); or Barnes, P. J., N. Engl. Med., vol. 332 pp. 868 875 (1995). All these prior publications are expressly incorporated by reference.

For purposes of the formulations of this invention, which are intended for inhalation into the lungs, the medicament or drug is preferably micronized whereby a therapeutically effective amount or fraction (e.g., ninety percent or more) of the drug is particulate. Typically, the particles have a diameter of less than about 10 microns, and preferably less than about 5 microns, in order that the particles can be inhaled into the respiratory tract and/or lungs.

The particulate medicament or drug is present in the inventive formulations in a therapeutically effective amount, that is, an amount such that the drug can be administered as an aerosol, such as topically, or via oral or nasal inhalation, and cause its desired therapeutic effect, typically preferred with one dose, or through several doses. The particulate drug is administered as an aerosol from a conventional valve, e.g., a metered dose valve.

The term "amount" as used herein refers to quantity or to concentration as appropriate to the context. The amount of a drug that constitutes a therapeutically effective amount varies according to factors such as the potency of the particular drug, the route of administration of the formulation, and the mechanical system used to administer the formulation. A therapeutically effective amount of a particular drug can be selected by those of ordinary skill in the art with due consideration of such factors. Generally a therapeutically effective amount will be from about 0.001 parts by weight to about 2 parts by weight based on 100 parts by weight of the propellant.

A suitable propellant is selected. A suitable propellant is any fluorocarbon, e.g. a 1 4 hydrogen containing flurocarbon(, such as CHF.sub.2CHF.sub.2, CF.sub.3CH.sub.2F, CH.sub.2F.sub.2CH.sub.3 and CF.sub.3CHFCF.sub.3)), a perfluorocarbon, e.g. a 1 4 carbon perfluorocarbon, (such as CF.sub.3CF.sub.3, CF.sub.3CF.sub.2CF.sub.3); or any mixture of the foregoing, having a sufficient vapor pressure to render them effective as propellants. Some typical suitable propellants include conventional chlorofluorocarbon (CFC) propellants such as mixtures of propellants 11, 12 and 114. Non-CFC propellants such as 1,1,1,2-tetrafluoroethane (Propellant 134a), 1,1,1,2,3,3,3-heptafluoropropane (Propellant 227) or mixtures thereof are preferred. The propellant is preferably present in an amount sufficient to propel a plurality of the selected doses of drug from an aerosol canister.

A suitable stabilizer is selected. A suitable stabilizer is a "water addition". As used herein a "water addition" is an amount of water which (1) is added, either initially with other components of the aerosol formulation, e.g. medicament and propellant, or after the other components, e.g. medicament, propellant, are combined and processed, (2) is in addition to the water which is always present and which develops during processing and/or storage of the aerosol formulation, i.e. "developed" or "nascent" formulation water, and (3) is present in an amount which stabilizes the ordinarily unstable medicinal aerosol dispersion formulation having nascent formulation water.

An aerosol formulation preferably comprises the water addition in an amount effective to stabilize the formulation relative to an identical formulation not containing the water addition, i.e. containing only nascent formulation water, such that the drug does not settle, cream or flocculate after agitation so quickly as to prevent reproducible dosing of the drug. Reproducible dosing can be achieved if the formulation retains a substantially uniform drug concentration for about two or three seconds after agitation.

The particular amount of the water addition that constitutes an effective amount is dependent upon the particular propellant and on the particular drug used in the formulation. It is therefore not practical to enumerate specific effective amounts for use with specific formulations of the invention, but such amounts can readily be determined by those skilled in the art with due consideration of the factors set forth above. Generally, however, the water addition must be present in a formulation in an amount in excess of the concentration of the nascent formulation water. Such concentration of nascent formulation water typically ranges up to 300 parts by weight per one million parts by weight of the total weight of the aerosol formulation. Accordingly, the water addition in excess of this nascent water concentration typically ranges from about 300 parts by weight to 2000 parts by weight per one million parts by weight of the total aerosol formulation weight. Preferred is an amount ranging from about 500 parts by weight to about 2000 parts weight based on 1 million parts by total weight of the formulation. Most preferred is that the concentration of the water addition is from 500 parts by weight to 700 parts by weight per one million parts by weight of the total weight of the medicinal aerosol formulation.

It is to be emphasized that this is an amount which exceeds the amount of nascent or developed formulation water. It is also to be stressed that this amount of water addition can be added and initially combined with the other components of the formulation, e.g. medicament, such as triamcinolone acetonide, and propellant, e.g. 1,1,1,2-tetrahydrofluoroethane, or added to the resultant formulation after these other components have been processed, e.g. prior to or subsequent to storage.

It has surprisingly been found that the formulation of the invention is stable without the necessity of employing a cosolvent, such as ethanol, or surfactants. However, further components, such as conventional lubricants or surfactants, cosolvents, ethanol, etc., can also be present in an aerosol formulation of the invention in suitable amounts readily determined by those skilled in the art. In this regard, reference is made to U.S. Pat. No. 5,225,183, which is incorporated by reference hereinto in its entirety.

A most preferred formulation comprises the medicament, the propellant, the ethanol cosolvent and the water addition, for example, triamcinolone acetonide, budesonide, fluticasone, or mometasone, 1,1,1,2-tetrafluoroethane, ethanol and the water addition.

Generally the formulations of the invention can be prepared by combining (i) the drug in an amount sufficient to provide a plurality of therapeutically effective doses; (ii) the water addition in an amount effective to stabilize each of the formulations; (iii) the propellant in an amount sufficient to propel a plurality of doses from an aerosol canister; and (iv) any further optional components e.g. ethanol as a cosolvent; and dispersing the components. The components can be dispersed using a conventional mixer or homogenizer, by shaking, or by ultrasonic energy. Bulk formulation can be transferred to smaller individual aerosol vials by using valve to valve transfer methods, pressure filling or by using conventional cold-fill methods. It is not required that a stabilizer used in a suspension aerosol formulation be soluble in the propellant. Those that are not sufficiently soluble can be coated onto the drug particles in an appropriate amount and the coated particles can then be incorporated in a formulation as described above.

Aerosol canisters equipped with conventional valves, preferably metered dose valves, can be used to deliver the formulations of the invention. It has been found, however, that selection of appropriate valve assemblies for use with aerosol formulations is dependent upon the particular stabilizer and other adjuvants used (if any), on the propellant, and on the particular drug being used. Conventional neoprene and buna valve rubbers used in metered dose valves for delivering conventional CFC formulations often have less than optimal valve delivery characteristics and ease of operation when used with formulations containing HFC-134a or HFC-227. Therefore certain formulations of the invention are preferably dispensed via a valve assembly wherein the diaphragm is made of a nitrile rubber such as DB-218 (American Gasket and Rubber, Schiller Park, Ill.) or an EPDM rubber such as Vistalon.TM. (Exxon), Royalene.TM. (UniRoyal), bunaEP (Bayer). Also suitable are diaphragms fashioned by extrusion, injection molding or compression molding from a thermoplastic elastomeric material such as FLEXOMER.TM. GERS 1085 NT polyolefin (Union Carbide).

Conventional aerosol canisters, coated or uncoated, anodized or unanodized, e.g., those of aluminum, glass, stainless steel, polyethylene terephthalate, and coated canisters or cans with epon, epoxy, etc., can be used to contain a formulation of the invention.

The formulation of the invention can be delivered to the respiratory tract and/or lung by oral inhalation in order to effect bronchodilation or in order to treat a condition susceptible of treatment by inhalation, e.g., asthma, chronic obstructive pulmonary disease. The formulations of the invention can also be delivered by nasal inhalation in order to treat, e.g., allergic rhinitis, rhinitis, (local) or diabetes (systemic), or they can be delivered via topical (e.g., buccal) administration in order to treat, e.g., angina or local infection.

 

Claim 1 of 25 Claims

1. A medicinal aerosol formulation comprising: (a) a therapeutically effective amount of at least one particulate medicament which does not include a solvate of a beclomethasone compound; (b) a propellant; and (c) a stabilizer consisting of water, in addition to nascent water present in the formulation, in an amount ranging from about 300 parts by weight to about 2000 parts by weight to one million parts by total weight of the formulation.

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