MXPA01005716A - A medicinal aerosol formulation - Google Patents

Abstract

This invention relates to a medicinal aerosol formulation and more particularly, to a medicinal aerosol formulation containing a particulate drug, a propellant and a stabilizing agent comprising a water addition.

Description

ot d ^ ß MEDICINAL FORMULATION IN AEROSOL FIELD OF THE INVENTION Field of the Invention This invention relates to a medicinal aerosol formulation and, more specifically, to a medicinal aerosol formulation containing a stabilizer comprising an addition of water.

Description of the Related Art The delivery of drugs to the lung by inhalation is an important means of treating different states, which includes common local conditions such as bronchial asthma and chronic obstructive pulmonary disease and some systemic conditions, including hormone replacement, the management of pain, cystic fibrosis, etc. Steroids, β2 agonists, anticholinergic agents, proteins and polypeptides are among the drugs that are administered to the lung for such purposes. These medications are usually administered to the lung in the form of a respirable particle size aerosol (less than about 10 μ in diameter). The aerosol formulation can be presented as a liquid or an anhydrous powder. To guarantee the proper particle size in a liquid aerosol, such as a suspension, the particles can be prepared in respirable size and then incorporated in the suspension formulation containing a propellant. Otherwise, the formulations can be prepared in the form of a solution to avoid the appearance of a suitable particle size in the formulation. Solution formulations, however, must be dosed in a form that produces particles or droplets of respirable size. Once prepared, an aerosol formulation is filled into an aerosol container equipped with a metering valve. In the hands of the patient, the formulation is dosed by an actuator adapted to direct the dose from the valve to the patient. It is important that an aerosol formulation be stable so that the pressurized dose discharged from the metering valve is reproducible. The rapid formation of sedimentation cream or flocculation after agitation are common sources of dose irreproducibility in suspension formulations. This is especially true where a binary formulation for aerosol containing only medicament and propellant is employed, for example 1,1,1,2-tetrafluoroethane, or where such formulation contains small amounts of surfactant as well. The stickiness of the valve also It can cause dose irreproducibility. To solve these problems, aerosol formulations usually contain surfactants that serve as suspension aids to stabilize the suspension for a sufficient time in order to allow reproducible dosing. Some surfactants also function as lubricants to lubricate the valve and ensure smooth action. Multiple materials are known and described for use as dispersing aids in aerosol formulations. However, the suitability of the materials depends on the specific medication and the propellant or propellant class used in the formulation. It is sometimes difficult to dissolve sufficient amounts of traditional surfactants in hydrofluorocarbon (HFC) propellants such as HFC-134a and HFC-227. To solve this problem cosolvents such as ethanol have been used, as described in US Pat. No. 5,114,183. An alternative method that avoids cosolvents includes materials that are soluble in hydrofluorocarbon propellants and are said to be effective surfactants or dispersing aids in an aerosol formulation. Among such materials are certain fluorinated surfactants and certain polyethoxysurfactants. In the art it is known that the presence of water in Traditional aerosol formulations often lead to some potential problems, for example, stability of the formulation, erratic delivery of the dose and, in some cases, reactions of free radicals in the propellant. SoIn general, it has been accepted that these preparations should be kept practically without water. The rigorous exclusion of atmospheric moisture during the manufacture and storage of these formulations, known as "developed" or "nascent" formulation water, increases the difficulties in the satisfactory preparation of stable aerosols containing the drug and increases the total cost of the product final, especially when a moisture barrier is included, for example, 'metallized paper bags as a secondary container. An exception has been found for beclomethasone dipropionate monohydrate. It has been reported that a formulation of this specific medication combined with a quantity of water in addition to its water of hydration is stable. In this regard, reference is made to U.S. Patent No. 5,695,744. However, what was not observed is that despite all the efforts, a quantity of water develops in the medicinal formulations in aerosol during the processing of such formulations that can not be eliminated and is always present (formulation water "developed" or "nascent"). What is more surprising and unexpected is that such unstable formulations, containing water of nascent formulation, can be and are stabilized by the presence of a concentration of water added to the water of the nascent or developed formulation that stabilizes such drug formulations, and wherein such a concentration of water addition is much lower than that required by the beclomethasone dipropionate monohydrate formulations reported in U.S. Patent No. 5,696,744.

SUMMARY OF THE INVENTION It has surprisingly been found that medicinal aerosol formulations can be obtained without the use of cosolvents, such as ethanol, or surfactants such as sorbitan trioleate that are added to a binary formulation for aerosol. Such medicinal formulations for aerosol are obtained by the use of addition of water.

DETAILED DESCRIPTION OF THE INVENTION This invention includes a stable suspension formulation for aerosol suitable for pressurized delivery that contains: (1) a particulate medicament, (2) a suitable propellant and (3) a stabilizer consisting of the addition of water. A suitable medicament is one that is suitable for administration by inhalation, with inhalation being used for oral or nasal inhalation treatment. Therapeutic categories of medications include cardiovascular, antiallergic, analgesic, bronchodilator, antihistamine, antitussive, antifungal, antiviral, antibiotic, anti-pain, anti-inflammatory, peptide, protein and steroid medications. Particularly convenient medications or drugs include albuterol (also known as salbutamol), atropine, budesonide, cromolyn, epinephrine, ephedrine, fentanyl, flunisolide, formoterol, ipratropium bromide, isoproterenol, pirbuterol, prednisolone, triamcinolone acetonide, salmeterol, amiloride, fluticasone esters such as phosphate, monohydrate and furoate, (-) - 4-amino-3,5-dichloro-a- [[[6 (2-pyridin-J) -ethoxy] hexyl] amino] methyl] benzenemethanol. Also included are suitable acid addition salts for the aforementioned drugs, their hydrates and their other solvates. In this regard, suitable acid addition salts include the salts obtained from the inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric acids, phosphoric and perchloric as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids. Suitable pharmaceutically acceptable solvates include solvates with ethyl lactate, alkanes, ethers, alcohols and water. For the purposes of the formulations of this invention, which are proposed for inhalation to the lungs, the drug or drug is preferably micronized, whereby a therapeutically effective amount or fraction (eg, 90% or more) of the drug is particulate. . Commonly, the particles have a diameter of less than about 10 microns, and preferably less than about 5 microns, so that the particles can be entrained into the respiratory tract and / or the lungs.-The drug or particulate drug is present. in the inventive formulations in an amount effective for therapeutic use, i.e., an amount such that the drug can be administered as an aerosol, such as by topical route, or by oral or nasal inhalation, and cause its desired therapeutic effect , usually preferably with a dose, or by several doses. The particulate drug is administered as an aerosol from a traditional valve, for example, a metering valve.

The term "amount" when used herein refers to the amount or concentration as appropriate for the context. The amount of a drug that constitutes an effective amount for therapeutic use 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. An effective amount for therapeutic use of a specific drug can be selected by those skilled in the art with due consideration to such factors. In general, an effective amount for therapeutic use 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, for example, the fluorocarbon (such as CHF2CHF2, CF3CH2F, 'cH2F2CH3 and CF3CHFCF3) containing 1-4 hydrogens, a perfluorocarbon, for example a perfluorocarbon containing 1-4 carbons (such as CF3CF3, CF3CF2CF3); or any mixture of the above, having a sufficient vapor pressure to make them effective as propellants. Some common suitable propellants include traditional chlorofluorocarbon propellants (CFCs) such as propellant mixtures 11, 12 and 114. Propellants no CFCs such as 1,1,1,1-tetrafluoroethane (propellant 134a), 1,1,1,3,3,3-heptafluoropropane (propellant 227) or mixtures of these are preferred. The propellant is preferably present in an amount sufficient to propel a plurality of selected doses of the drug from the aerosol can. A suitable stabilizer is selected. A convenient stabilizer is a "water addition". When used herein a "water addition" is an amount of water that: (1) is initially added with the other components of the aerosol formulation, eg, the medicament and the propellant, or after the other components , for example the medicament, the propellant are combined and processed, (2) it is in addition to the water that is always present and that develops during the processing and / or storage of the aerosol formulation, that is, the formulation water "developed" "or" nascent ", and (3) is present in an amount that stabilizes the medicinal formulation for normally unstable aerosol having water of nascent formulation. An aerosol formulation preferably contains addition of water in an amount effective to stabilize the formulation relative to an identical formulation that does not contain water, ie, contains only the water of nascent formulation, so that the drug does not settle, acme or flocculate after agitation so quickly to prevent the reproducible dosage of the drug. The reproducible dosage can be achieved if the formulation retains a practically uniform drug concentration for about 2 to 3 seconds after shaking. The particular amount of the addition of water constituting an effective amount depends on the specific propellant and the particular medicament that is used in the formulation. Therefore, it is not practical to mention specific effective amounts for use with specific formulations of the invention, but these amounts can be readily determined by the person skilled in the art with due consideration of the factors set out above. In general, however, the addition of water must be present in a formulation in an amount in excess of the water concentration of the nascent formulation. Such a concentration of nascent formulation water is usually in the range of up to 300 parts by weight per one million parts by weight of the total weight of the aerosol formulation. Therefore, the addition of excess water to this nascent water concentration is usually in the range from about 300 parts by weight to 2000 parts by weight per one million parts by weight of the total weight of the aerosol formulation. It is more preferred that the concentration of the water addition be 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 should be noted that this is an amount that exceeds the amount of formulation water nascent or developed. It should also be emphasized that this amount of water addition can be added and initially combined with the other components of the formulation, for example, the drug such as triamcinolone acetonide, and the propellant, for example 1,1,1,2 -tetrahydrofluoroethane, or added to the resulting formulation after these other components have been processed, for example, before or after storage. It was surprisingly found that the formulation of the invention is stable without the need to employ a cosolvent, such as ethanol, or surfactants. However, other components such as traditional lubricants or surfactants, cosolvents, ethanol, etc., may also be present in an aerosol formulation of the invention in convenient amounts. easily determined by those skilled in the art. In this sense, reference is made to U.S. Patent No. 5,225,183, which is incorporated herein by reference in its entirety. A more preferred formulation contains the medicament, the propellant, the ethanol cosolvent and the addition of water, for example, triamcinolone acetonide, 1,1,1,2-tetrafluoroethane, ethanol and the addition of water. In general, the formulations of the invention can be prepared by combining: (i) the drug in an amount sufficient to provide a plurality of effective doses for therapeutic use; (ii) the addition of water 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 can; and (iv) any optional additional component, for example ethanol as a cosolvent; and dispersing the components. The components can be dispersed using a traditional mixer or homogenizer, by stirring, or by ultrasonic energy. Bulk formulation can be transferred to smaller, individual aerosol canisters using valve to valve transfer methods, pressure filling or using cold fill methods traditional The stabilizer used in an aerosol suspension formulation is not required to be soluble in the propellant. Those that are not sufficiently soluble can be coated onto the drug particles in a suitable amount and the coated particles can then be incorporated into a formulation as already described. Aerosol cans equipped with traditional valves, preferably metering valves, can be used to supply the formulations of the invention. However, it has been found that the selection of valve units suitable for use with the aerosol formulations depends on the particular stabilizer and other adjuvants used (if any), the propellant and the particular drug used. The traditional neoprene and buna valve rubbers that are used in the dumper valves for the supply of traditional CFC formulations have less than optimal valve delivery characteristics and easy operation when used in formulations containing HFC-134a or HFC -227. Therefore, certain formulations of the invention are preferably dosed through a valve unit, wherein the diaphragm is made of a nitrile rubber such as DB-218 (American Gasket and Rubber, Schiller Park, 111.) or an EPDM rubber like Vistalon ™ (Exxon), Royalene ™ (UniRoyal), bunaEP (Bayer). ^ p- Diaphragms made by extrusion, injection molding or molding are also suitable. compression from an elastomeric, thermoplastic material such as FLEXOMER ™ GERS 1085 NT poiyolefin (Union Carbide). Traditional aerosol cans, coated or uncoated, anodized or non-anodized, for example those of aluminum, glass, stainless steel, polyethylene terephthalate, and coated cans or cans with epon, epoxy, etc., may be used to contain a formulation of the invention. The formulation of the invention can be supplied to the respiratory tract and / or lung by oral inhalation to effect bronchodilation or to treat a condition susceptible to treatment by inhalation, for example asthma, chronic obstructive pulmonary disease. The formulations of the invention can also be supplied by nasal inhalation to treat, for example, allergic rhinitis, rhinitis, (local) or diabetes (systemic) [sic] or may be delivered by topical (eg buccal) administration to treat for example angina or local infection.

Claims (22)

1. A medicinal aerosol formulation containing: (a) an effective amount for therapeutic use of a particulate medicament (b) a propellant, and (c) a stabilizer comprising an addition of water present in an amount such that (a) is also of nascent formulation water, and (b) stabilize the formulation.

The formulation as defined in claim 1, wherein the medicament is selected from the group consisting of albuterol, atropine, budesonide, cromolyn, epinephrine, ephedrine, fentanyl, flunisolide, formoterol, ipratropium bromide, isoproterenol, pirbuterol, prednisone , acetonic triamcinolone, salmeterol, amiloride, fluticasone, fluticasone esters, (-) -4-amino-3,5-dichloro-a- [[[6- (2-pyridinyl) ethoxy] hexyl] amino] methyl] benzenemethanol and the salts, esters, hydrates and solvates acceptable for pharmaceutical use of the above.

3. The formulation as defined in claim 2, wherein the medicament consists of triamcinolone acetonide.

4. The formulation as defined in claim 1, wherein the propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1, 1, 1, 2, 3, 3, 3-heptafluoropropane or a mixture of these.

5. The formulation as defined in claim 1, which further includes a cosolvent.

6. The formulation as defined in claim 5, wherein the cosolvent consists of ethanol. The formulation as defined in claim 1, wherein the stabilizer is present in an amount effective to prevent sedimentation, scaling or flocculation of the formulation for a time sufficient to allow reproducible dosing of the medicament after the formulation is shaken. The formulation as defined in claim 7, wherein the stabilizer is present in an amount ranging from about 500 parts by weight to about 2000 parts by weight, based on one million parts by total weight of the formulation . 9. The formulation as defined in claim 8, wherein the stabilizer is present in an amount ranging from 500 parts by weight up to 700 parts by weight for one million parts by total weight of the formulation. A method for preparing an aerosol medicinal formulation according to claim 1, which comprises: (a) combining (i) the medicament in an amount sufficient to provide a plurality of therapeutically effective doses, (ii) the propellant in an amount sufficient to propel a plurality of therapeutically effective doses from an aerosol can; (iii) the stabilizer in an effective amount to stabilize the formulation, and (b) disperse the components (i), (ii) and (iii). The method as defined in claim 10, wherein the aerosol medicinal formulation further comprises combining in step (a) J a cosolvent and in step (b) dispersing the components (i), ( ii), (iii) with the cosolvent 12. A method of treatment in an animal of a state capable of oral or nasal inhalation treatment, which comprises administering a formulation according to claim 1 to the animal by oral inhalation. or nasal. 13. The formulation according to the claim 1 in an aerosol can equipped with a valve for metered doses. 14. A method of stabilizing a suspension formulation for aerosol contains a propellant and a particulate drug, which consists of: incorporating into the formulation a stabilizer comprising a convenient concentration of an addition of water where the concentration is present in an amount which is effective to prevent sedimentation, accretion or flocculation of the formulation for a sufficient time to allow reproducible dosing of the drug after agitation of the formulation. 15. An inhaler for medical doses containing a medicinal aerosol formulation, the formulation contains: (a) a drug in particulate form in an effective amount for therapeutic use (b) a propellant, and (c) a stabilizer comprising an addition of water that is present in an amount that: (1) is in excess of the nascent formulation water, and (2) is present in an amount to stabilize the formulation to prevent sedimentation. Accretion or flocculation for a sufficient time to allow reproducible dosing of the drug after agitation of the formulation. The medical dose inhaler as defined in claim 15, wherein the stabilizer is present in an amount of 300 parts by weight to about 2000 parts by weight, based on one million parts by weight of the total formulation medicinal spray. The inhaler for medical doses as defined in claim 16, wherein the drug is selected from the group consisting of albuterol, atropine, budesonide, cromolyn, epinephrine, ephedrine, fentanyl, flunisolide, formoterol, ipratropium bromide, isoproterenol, pirbuterol, prednisone, acetonic triamcinolone, salmeterol, amiloride, fluticasone, fluticasone esters, (-) -4-amino-3,5-dichloro-a- [[[6- (2-pyridinyl) ethoxy] hexyl] amino] methyl ] benzenemethanol and the hydrates, salts and solvates acceptable for pharmaceutical use of the above. 18. The metered dose inhaler as defined in claim 17, wherein the propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1, 1, 1, 2, 3, 3, 3 heptafluoropropane or a mixture of these. 19. The metered dose inhaler as defined in claim 18, wherein the medicament consists of in triamcinolone acetonide. 20. The metered dose inhaler as defined in claim 19, wherein the stabilizer is present in an amount ranging from 500 parts by weight to 700 parts by weight per one million parts by weight of the medicinal aerosol formulation. . 21. The metered dose inhaler as defined in claim 20, wherein the medicinal aerosol formulation further comprises a cosolvent. 22. The metered dose inhaler as defined in claim 21, wherein the cosolvent consists of ethanol.