MXPA97007238A - Butixoc aerosol formulations - Google Patents

Abstract

Aerosol formulations of pharmaceutical solution comprising butyroxocort propionate and a propellant selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, and a mixture of the same

Description

BUTIXOCORT AEROSOL FORMULATIONS FIELD OF THE INVENTION This invention relates to pharmaceutical aerosol formulations. In another aspect this invention relates to aerosol formulations of pharmaceutical solution, wherein the propellant comprises a hydrofluoroalkane propellant such as 1,1,1,2-tetrafluoroethane or 1, 1, 2, 3, 3, 3- heptafluoropropane. In another aspect this invention relates to pharmaceutical aerosol formulations containing butyrocort propionate.

BACKGROUND OF THE INVENTION The (1-beta-hydroxy-3-en-3, 20-dion-21-thiopropionate-17-butyrate of butyxocort propionate is an anti-inflammatory steroid described in US Patent No. 4,933,331 (Aubard et al). Common, propellant-based pharmaceutical aerosols use a mixture of liquid chlorofluorocarbons as the propellant.

Fluorotrichloromethane, dichlorodifluoromethane and dichlorotetrafluoroethane are the used propellants of REP: 25630 most common way in aerosol formulations for administration by inhalation. However, such chlorofluorocarbons (CFCs) have been implicated in the destruction of the ozone layer and its production is phased out. Hydrofluorocarbon 134a (HFC 134a, 1,1,1,2-tetrafluoroethane) and hydrofluorocarbon 227 (HFC 227, 1, 1, 1, 2, 3, 3, 3-heptafluoropropane) are cited as being less harmful to ozone than many chlorofluorocarbon propellants. Pharmaceutical aerosol formulations for inhalation more commonly contain a drug in the form of solid particles of respirable size suspended in the propellant system. Formulations involving the dissolved drug are also known but have generally been less preferred because of the tendency of the compounds (which include drug substances or medicinal substances) to be much more chemically reactive (and therefore unstable) in solution than in the solid state.

BRIEF DESCRIPTION OF THE INVENTION It has been found that butixocort propionate has appreciable solubility in HFA 134a and HFA 227 (at 20 ° C, HFA 134a dissolved at about 0.02% by weight of butixocort propionate and HFA 227 dissolved at about 0.03% by weight of butixocort propionate ). This level of solubility can lead to increasing the particle size of the drug in a suspension formulation. It is well known that particles having a diameter greater than about 10 mm are not suitable for lung inhalation. Therefore, the increased particle size may threaten the usefulness of a pharmaceutical aerosol formulation for inhalation. The present invention provides a solution aerosol formulation comprising a propellant system comprising a hydrofluoroalkane selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3 heptafluoropropane, and a mixture thereof, and a therapeutically effective amount of butyxocort propionate, wherein the butyclocort propionate is dissolved in the formulation. The present invention also provides a method of treating bronchial asthma, comprising administering via inhalation an amount of a formulation as described above, effective to control the inflammation associated with bronchial asthma.

The formulation of the solution of the invention exhibits adequate stability yet eliminates problems associated with increased particle size. This invention also eliminates other problems encountered with suspension aerosols such as rapid flocculation, irreversible particle aggregation and volumetric separation of the drug from the propellant (cremation or sedimentation), all this affecting the uniformity of the dose.

DETAILED DESCRIPTION OF THE INVENTION All weight percentages quoted herein are based on the total weight of the formulation unless otherwise indicated. The butixocort propionate of the drug is known and described, for example, in U.S. Patent No. 4,933,331 (Aubard et al., incorporated herein by reference). Butixocort propionate is generally presented in a formulation of the invention in a therapeutically effective amount, ie, an amount such that one or more dosed volumes of the formulation (eg, dosed volumes of approximately 50μL) when supplied to the lung by Oral or nasal inhalation contains an amount of effective medication to exert the intended therapeutic action (eg, controlled inflammation associated with bronchial asthma). The amount that constitutes a therapeutically effective amount will depend on the particular formulation, the indication being treated and the intended therapeutic effect, and the actuator or actuator that is used to disperse the formulation. Generally and preferably, butyxocort propionate constitutes about 0.1 to about 0.9 weight percent, more preferably about 0.4 to about 0.6 weight percent of the total weight of the formulation. The formulation of the invention is a solution formulation, that is, the butoxicity propionate is dissolved in the formulation and the formulation is substantially free of particulate butyrocort propionate (not dissolved). Certain steroids are known to exist in various crystalline forms (polymorphs). A formulation of the invention, however, contains butyxocort propionate but not a particular crystalline or polymorph form thereof, when the crystalline identity of the drug is lost by dissolution. Therefore, this invention avoids complications that may occur in certain suspension steroid formulations due to changes in itself in the crystal form (eg, a crystal polymorphism). Any properly soluble form of butixocort propionate can be used in the preparation of a formulation of the invention. As noted above, it has been found that butixocort propionate has appreciable solubility in HFA-134a and in HFA-227. In more cases, however, the solubility of butyxocort propionate in these propellants will not be sufficient to produce a formulation containing a therapeutically effective amount of dissolved butyrocort propionate. Therefore, it is often necessary or desirable to use a solubilizer to further solubilize butyxocort propionate (ie, to provide a system in which butycocort propionate is more soluble than in the hydrofluoroalkane propellant alone). The butycocort propionate can be further solubilized in any suitable manner. Well-known methods of solubilization include the use of cosolvents for the drug (for example, alcohols such as ethanol or propylene glycol, dimethyl ether) to aid in the dissolution of the drug, and micellar solubilization of the drug using a surfactant, for example , a glycerol phosphatide such as lecithin or other materials listed for this purpose in PCT publication No. WO93 / 04671 (Oliver et al). Sometimes it is necessary to use a cosolvent for the surfactant in order to dissolve enough surfactant to effect the micellar solubilization of a drug. The solubilizer or substance to solubilize, preferred for use in a formulation of the invention is ethanol. Ethanol, however, has been found to decrease the respirable fraction of a drug if it is used in an excessive amount. A formulation of the invention preferably contains ethanol in an amount effective to additionally solubilize butyrocort propionate in the formulation but less than that amount which causes a decrease in the respirable fraction. Preferably the ethanol constitutes about 3 to about 30 percent by weight of the total weight of the formulation. Most preferably, ethanol constitutes about 8 to about 16 percent by weight of the aerosol formulation.

A formulation of the invention contains a propellant system that functions to impel or propel the other components of the formulation through the valve of a metered dose inhaler filter or container in a manner such that the drug is presented for inhalation by a patient. patient. The propellant system comprises a hydrofluoroalkane propellant. Preferred propellants include 1,1,1,2-tetrafluoroethane, 1, 1, 2, 3, 3, 3-heptafluoropropane, and mixtures thereof in any proportion. The propellant is present in an amount sufficient to drive a plurality of doses from a container provided with a device for letting out the aerosol such as a metered dose inhaler. Preferably the propellant constitutes from about 60 to about 98 weight percent, and most preferably from about 75 to about 90 weight percent of the total weight of the aerosol formulation. The formulations of the invention are preferably free of chlorofluorocarbons such as fluorotrichloromethane, dichlorodifluoromethane, and dichlorotetrafluoroethane. More preferably, the hydrofluorocarbon propellant is the only propellant present in the formulations of the invention.

A formulation of the invention may contain suitable excipients (for example, those described in US Patent No. 5,225,183, to Purewal et al., Incorporated herein by reference) in amounts readily determined by those skilled in the art. Certain excipients, for example, certain surfactants (to optimize the function of the valve), flavoring agents, and / or water, are beneficial for some embodiments of the invention. For example, it has been found that in some cases the chemical stability of certain formulations of the invention (i.e., stability of the formulation for the degradation of butyclocort propionate) is improved by the presence of water. When the water is included in a formulation of the invention it will generally be present in an amount from about 0.005 percent to about 1 percent by weight of the total weight of the formulation. Strong inorganic acids (for example hydrochloric, nitric, phosphoric, or sulfuric acid) or organic acids (for example, ascorbic acid, citric acid) can also be incorporated into the formulation of the invention in the manner described in 094/13262 and W094 / 13263 (Jager et al., Incorporated herein by reference).

The formulations of the invention optionally further comprise a flavoring agent, for example, menthol, in an amount effective to mask the taste of butixocort propionate when an aerosol dose of the formulation is orally inhaled, for example, about 0.3 weight percent. of the total weight of the formulation. Notwithstanding the fact that the drug dissolves, the preferred formulations of the invention remain stable for a prolonged period of time for drug degradation. Preferably, a formulation of the invention when stored for ten months in a small aluminum aerosol flask as described above (Examples 11-50) exhibits a recovery of the percentage drug of at least about 93 percent, more preferably at least approximately 95 percent. The formulations of the invention can be prepared by either pressure filling or cold filling techniques, which are well known to those skilled in the art. Ethanol and the excipient or excipients, if any, are combined with the propellant. This solution is filled under pressure or filled cold in small aerosol flasks containing butyrocort propionate.

Alternatively, butycocort propionate and any non-volatile excipients are dissolved in ethanol in a small aerosol canister. Then the small aerosol canister is fixed with a valve and filled under pressure with the propellant. Filters or aerosol containers equipped with conventional valves, preferably metered dose valves, may be used to supply the formulations of the invention. A suitable valve rubber is a nitrile rubber ("DB-218") available from American Gasket and Rubber, Schiller Park, Illinois. Conventional aerosol filters or containers may be used to contain a formulation of the invention. It has been found, however, that certain containers improve the chemical stability of certain formulations of the invention and / or minimize the absorption of butixocort propionate on the walls of the container or container.; for this, it is preferred to contain a formulation of the invention within a small aluminum aerosol canister. A formulation of the invention can be administered to the lung by oral or nasal inhalation. Oral inhalation is preferred, and conventional actuators or actuators for oral inhalation may be used in connection with a formulation of the invention. The particle size or droplet size of the inhaled dose is important for an inhaled or breathable dosage form proposed to be administered to the lung. The particle size or droplet size and respirable fraction of an aerosol formulation of propellant-based solution can be affected by the size of the orifice through which the formulation passes. It is preferred to administer a formulation of the invention through an actuator or actuator having an orifice diameter of about 0.25 mm (0.010 inches) or less. An example of such an actuator or actuator is the model actuator M3756, 3M Company. The examples described below are proposed to illustrate the invention.

Breathable Fraction In this test the breathable fraction (the weight percent of particles having an aerodynamic particle size of less than 4.7 mm) of the aerosol formulation is determined using an Anderson Cascade Impactor (available from Anderson Sapler Inc., Atlanta , GA). The small aerosol bottle containing the formulation to be tested is primed or prepared 5 times. The valve and the valve stem are then cleaned with ethanol and dried with compressed air or nitrogen. The small aerosol canister and clean, dry actuator or actuator (unless otherwise indicated on Model M3756 that has an orifice diameter of approximately 0.25 mm (0.010 inches), 3M) are attached to the glass hole or throat fixed to the top of the impactor using an appropriate trigger or ignition adapter. The calibrated vacuum pump (28.3 L / min) fixed to the impactor is admitted or ignited. The small bottle is activated. After the aerosol cloud has disappeared (approximately 4 seconds), the small vial and the actuator are disconnected, shaken for approximately 10 seconds, then reconnected to the throat or neck and again actuated. This procedure is repeated until the small bottle has been operated a total of 10 times. The cascade impactor is disassembled and each component is rinsed with diluent. Each solution is analyzed by the content of butixocort propionate using high performance liquid chromatography or ultraviolet light spectroscopy (238 nm). The respirable fraction is calculated as follows: Butixocort propionate% Breathable = recovered from the plates 3-7 X 100 butixocort propionate recovered from the neck, jet 0 stage and 0-7 plates Impurities of Percentage Degradation and Recovery of the Percentage Drug In these assays the percentage of degradation impurities and the recovery rate of the drug is determined using high resolution liquid chromatography.

Preparation of the Sample Solution The small aerosol bottle containing the formulation to be analyzed is refrigerated in dry ice for 20 minutes. The lid is removed and the contents of the flask are poured into a pre-cooled gauze flask. The propeller is allowed to evaporate. The cap and the vial are rinsed with acetonitrile in the volumetric flask. The flask is induced to a volume with the indicated diluent. An aliquot of this solution is pipetted or pipetted into a volumetric flask and the flask is brought to a volume with the indicated diluent.

Preparation of the Standard Solution An accurately weighed quantity of butixocort propionate is placed in a volumetric flask then dissolved in ethanol or acetonitrile. The flask is brought to a volume with the indicated diluent. An aliquot of this solution is introduced with the pipette into a volumetric flask and the flask is brought to a volume with the indicated diluent.

Procedure A portion of the standard solution is injected into the CLAR using the parameters indicated below in connection with either the Percent Degradation Impurities or the Percent Drug Recovery, as appropriate, and the sensitivity of the recorder is adjusted to produce peaks of 70%. -90% of the total scale. The chromatogram is obtained and the peak areas are measured. This chromatogram provides a correlation between the peak area and the weight of the butyclocort propionate. The peak areas of impurities present in the pure drug (butixocort propionate) are also provided prior to the formulation. A portion of the sample solution is injected into the HPLC under the same conditions as the standard. The chromatogram is obtained and the peak areas are measured.

Percent of Degradation Impurities The percentage of impurities in the virgin or pure drug is determined using the peak areas of 1-HPAR chromatogram (diluent: acetonitrile; column: 15 cm x 4.6 mm, Supersil LC-18 5 micrometer Supelco mobile phase: 30:35:35 methanol: acetonitrile: water containing 0.1 mg of perchloric acid per 100 mL of solution, speed or magnitude of flow 1 mL / min, detection: 240 nm UV) of the standard solution and the equation later. % of impurities Sum of the areas of in the drug = the impurities peaks X 100 pure Sum of the areas of the impurities peaks and the peak of propionate of butixocort The percentage of impurities in the sample is obtained by performing the same calculation in the peak areas of the sample chromatogram. The percentage of impurities of degradation is then determined using the following equation:% of impurities =% of impurities in -% of impurities of degradation the sample in the pure drug Percent of Drug Recovery This is based on the amount of propionate of Butixocort in the small vial of the sample before and after storage. The amount of butixocort propionate that was in the small aerosol bottle after storage is determined by CLAR (diluent: a 55 percent volume solution of acetonitrile and 45 volume percent water containing 0.05 mg of ascorbic acid per 100 L of solution, column: 15 cm x 4.6 mm Supersil LC-18 5 micrometres of Supelco, mobile phase: 55:45 acetonitrile / water v / v, flow rate 1: 5 mL / min, detection: 240 nm UV) using the peak area of butixocort propionate from the sample chromatogram and the correlation between the peak area and the weight of butixocort propionate that is obtained from the standard chromatogram. The amount of butixocort propionate that was in the small aerosol canister is known when it was first prepared. The percentage recovery of the drug is then determined using the equation given below: Amount of butyxocort propionate% recovery = after storage X 100 of the drug initial amount of butixocort propionate Solubility Studies The solubility of butycocort propionate in P134a, P227, and mixtures thereof with ethanol, is determined as follows: The drug and the selected propulsion system was combined and stirred for a period of seven days at a selected temperature to produce a saturated solution. The solid was removed by filtration and the supernatant was weighed. The propellant was removed by evaporation and the drug was reconstituted quantitatively. The concentration of the drug in the reconstituted solution was determined and from this the amount and concentration of the drug dissolved in the propulsion system was calculated. TABLES 1 and 2 show the average of three independent determinations.

Example 1 Butixocort propionate (50 mg) and ethanol (1 g) were placed in a 10 mL aluminum aerosol flask. The flask was cooled to about -78 ° C in a dry ice / trichloromethane bath then filled with cold Pl34a (1,1,1,2-tetrafluoroethane, 8.95 g). The resulting formulations contain 0.5% by weight of butyclocort propionate, 10% by weight of ethanol, and 89.5% by weight of P134a. The small vial was sealed with a 50 μL metered dose valve having a nitrile rubber diaphragm of DB-218 (American Gasket and Rubber, Schiller Park, Illinois). The respirable fraction was found to be 42% using the test method described above and an actuator or actuator having a generally elliptical orifice of 0.422 mm (0.0166 inches) x 0.478 mm (0.0188 inches). This formulation was tested by respirable fraction using an actuator or actuator having a generally elliptical orifice of 0.22 mm (0.0086 inches) x 0.25 mm (0.0098 inches) (Model M3756-, 3M). It was found that the respirable fraction is 69%.

Example 2 Butixocort propionate (50 mg) and ethanol (1 g) were placed in a small vial with 10 mL aluminum aerosol device. The vial was sealed with a continuous valve then filled under pressure with P227 (1, 1, 1, 2, 3, 3, 3-heptafluoropropane, 8.95 g). The resulting formulation contains 0.5% by weight of butyxocort propionate, 10% by weight of ethanol, and 89.5% by weight of P227. The bottle was then cooled and the continuous valve was replaced with a 50 μL metered-dose valve having a diaphragm of nitrile rubber DB-218 (American Gasket and Rubber, Schiller Park, Illinois). The respirable fraction was determined using the method described above and found to be 45%.

Examples 3 - 10 Solution formulations containing weight percent ethanol, 0.5 weight percent butixocort propionate, and either P134a or P227 (as indicated in Table 3 below) were prepared and placed in small aerosol flasks of the various types shown in the Table 3 later. The bottles were sealed with blind splints. The bottles were stored at 40 ° C for one month then analyzed according to the test method described above for the percentage of degradation impurities and drug content. The results are shown in Table 3 below where each value is the average of 3 separate small bottles. x Glass Type-III (from soda and lime) and available from Wheaton Coated Products 2Available from 3M Company 3Vials or epoxy / phenol-formaldehyde resin-coated aluminum flasks, coated by Cebal Made of polyethylene terephthalate and available from Precise Plástic Ltd., United Kingdom.

Examples 11-50 The solution formulations described in Table 4 were prepared, placed in small aerosol flasks having diaphragms and nitrile rubber seals (DB-218, American Gasket and Rubber, Schiller Park, Illinois), stored at 40 ° C, and tested for percent drug recovery in accordance with the method described above. Each entry represents the average of 3 independent determinations. The designation "% by weight / weight" indicates the percent by weight of the indicated component based on the total weight of the formulation. The types of small bottles are those described in TABLE 3 above.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property

Claims (16)

1. A solution aerosol formulation comprising: a propellant system comprising a hydrofluorocarbon selected from the group consisting of 1,1,2,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, and a mixture thereof, and a therapeutically effective amount of butixocort propionate, characterized in that the butyclocort propionate is dissolved in the formulation.

2. An aerosol formulation according to claim 1, characterized in that the propellant comprises 1, 1, 1, 2-tetrafluoroethane.

3. An aerosol formulation according to claim 1, characterized in that the propellant comprises 1, 1, 1, 2, 3, 3, 3-heptafluoropropane.

4. An aerosol formulation according to claim 1, characterized in that the propellant comprises a mixture of 1,1,1,2-tetrafluoroethane and 1, 1, 2, 3, 3, 3-heptafluoropropane.

5. An aerosol formulation according to claim 1, characterized in that the butyrocort propionate is present in an amount of about 0.1 percent to about 0.9 percent by weight.

6. An aerosol formulation according to claim 1, characterized in that it is free of chlorofluorocarbons.

7. An aerosol formulation according to claim 1, characterized in that it also comprises ethanol.

8. An aerosol formulation according to claim 7, characterized in that the ethanol is present in an amount of about 3 percent to about 30 weight percent.

9. An aerosol formulation according to claim 8, characterized in that the ethanol is present in an amount of about 8 percent to about 16 weight percent.

10. An aerosol formulation according to claim 1, characterized in that it also comprises about 0.005 percent to about 1 weight percent water.

11. An aerosol formulation according to claim 1, characterized in that it also comprises an agent that provides flavor or aroma.

12. An aerosol formulation according to claim 1, characterized in that it comprises from about 0.1 percent to about 0.9 weight percent butyrocort propionate, from about 8 to about 16 weight percent ethanol, and 1 , 1,1,2,3,3,3-heptafluoropropane.

13. An aerosol formulation according to claim 1, characterized in that it comprises from about 0.1 percent to about 0.9 weight percent butyrocort propionate, from about 8 to about 16 weight percent ethanol, and 1 , 1, 1, 2-tetrafluoroethane.

14. An aerosol formulation according to claim 1, characterized in that the formulation exhibits at least 93 percent recovery of the drug after storage for six months at 40 ° C in an aluminum container with device for letting out the aerosol.

15. A method of treating bronchial asthma characterized in that it comprises administering via inhalation an amount of a formulation according to claim 1, sufficient to control the inflammation associated with bronchial asthma.

16. A regulated dose inhaler comprising: (i) an aerosol container defining a formulation or composition chamber; and (ii) a formulation according to claim 1, characterized in that the formulation is contained within the formulation chamber or composition.