MXPA99001786A - Chlorofluorocarbon-free mometasone furoate aerosol formulations - Google Patents

Abstract

The invention relates to suspension aerosol formulations which exhibit stable particle sizes, containing mometasone furoate, about 1 to about 10 weight percent ethanol and 1,1,1,2,3,3, 3-Heptafluoropropane as the propellant. A surfactant, such as oleic acid, can also be included. These formulations are suitable for use in metered dose inhalers.

Description

MOLETASONE FUROATE AEROSOL FORMULATIONS WITHOUT CLORQFLUOROCARaURQS. INTRODUCTION TO THE INVENTION The present invention relates to aerosol drug formulations, such as suitable formulations, for use in metered dose nebulizers in pressurized aerosol. More specifically, the invention relates to aerosol formulations of the drug mometasone furoate with the impellent 1, 1, 1, 2,3,3, 3-heptafluoropropapo (HI C-227). Aerosol drugs have been used for many years to treat disorders of the respiratory system, and - or convenient means - for the systemic introduction of various pharmaceutical agents in the body. The typical metered-dose aerosol spray formulation for the treatment of disorders such as asthma or rhinitis is a suspension of one or more pharmacological substances in an impeller consisting of a fully halogenated lower alkyl compound (with chlorine and fluorine), which also contains small amounts of surfactants and / or excipients! which are usually soluble in the impeller. Pharmaceutical agents administered by means of metered dose nebulizers are generally bronchodilators or corticosteroids. Steroid drugs that are currently available in this form for therapeutic nebulization purposes in the United States include beciometasone dipropionate (for both nasal and lower respiratory), budesonide (for nasal and lower respiratory), dexamethasone (for Nasai administration and lower respiratory tract), flunisolide (for nasal administration), and thamcinolone acetonide (for nasative administration and infedorea). Lately, fluttcasone propionate has also been approved for sale as a lower respiratory tract drug. Typical formulations contain chlorofluorocarbon impellants, the drug substance and etapol, which is soluble in the impellent, and sometimes also contains a surfactant. such as oleic acid to maintain a stable suspension, the lubrication of the measuring valve and other functions. However, certain steroids have considerable solubility in ethanol When there is not a sufficient amount of ethanol present to maintain a solution of these drugs in an aerosol can, the normal temperature fluctuations encountered during storage and use can cause repeated increases and decreases in the solubility of a saturated solution. pharmacological becomes less soluble, such as in a period of decrease in ambient temperature, it tends to crystallize and, due to the slow progress of typical temperature changes, it is transformed into crystals much greater than those that can be adequately dispensed, especially when the drug is intended to be administered to the bronchi or lungs. In general, particle sizes of the drug of about 1 to about 5 microns are preferred for administration to the lower airway frequently expelling particles less than about 0.5 micrometers without obtaining the full deposition in the weaves os, while particles larger than 10 micrometers may exhibit considerable deposition in the mouth and / or pharynx and, therefore, not reach the lower airway. Very large particles can not pass through a valve meter (step buffer) and can not be reliably dispensed In the case of beclomethasone diproptonate, which in itself is quite soluble in ethanol, can be formed from this compound and chlorofluorocarbons or a fluorohydrocarbon other compound another compound (sometimes referred to as "solvate" or "clathrate"), when this clathrate is formulated with an impellent, no particle size growth is observed With the implication of fully halogenated chlorofluorocarbon impellers in the environmentally harmful destruction of ozone in the upper layer of the atmosphere, the availability of these impellants has become quite limited. This has encouraged the development work of formulations containing impellants that have less reactivity in the upper atmosphere, with each work focusing especially on the 1, 1, 1, 2-trafluoroethane impellants ( HFC-134a) and HFC-227, these compounds having approximately the same physical properties as those of chlorofluorocarbons previously used for medicinal aerosols. Recent studies have attributed to HFC-134a a potentially harmful potential for surface acidification of water, since seems to form the tpfluoroacetic acid, environmentally very stable in the atmosphere It has been proposed, in the European Patent 0 553 298 B1, the formulation of an aerosol with HFC-134a simply including enough ethanol to keep beclomethasone dipropionate in solution at least in the estimated range of room temperature However, the presence of ethanol is not supported by Many countries, due to the prevalence of alcoholism and the ease with which ethanol is absorbed systemically from the tissues of the lower airways. Products intended for children should generally have an ethanol content as low as possible. International WO 93/1 1745 discloses aerosol formulations in suspension of a stable particle size containing pharmacological substances, a chlorofluorocarbon impeller with a fluorocarbon or hydrogen content, and a polar cosolvent such as an alcohol. The need for surfactants is not expressed. International Patent Application WO 94/03153 reports that beclomethasone and HFC-134a solvates can be used to produce stable suspensions in a chlorofluorocarbon impeller containing fluorocarbon or hydrogen content, substantially in the absence of dissolution species such as alcohol. The drug fomeate from mometasone would offer advantages over the corticosteroids currently available to treat disorders of the respiratory tract. According to what is disclosed in the International Patent Application WO 95/20393, the drug has a very rapid onset of action and generally does not appear in the blood at detectable concentrations, after nasal administration or to the airways. Unfortunately, this drug has some degree of. solubility in ethanol and exhibits increases in particle size during storage of suspension aerosol formulations prepared with large amounts of ethanol. International Patent Applications WO 92/22287 and WO 92/22288 describe aerosol formulations of mometasone furoate in the HFC-134a and HFC-227 propellants, but do not face the problem of adverse particle size increases. Intent synthesis In accordance with the present invention, a suspension aerosol formulation of pressurized mometasone furoate with stable particle size comprising the HFC-227 impellent, from about 1 to about 10 weight percent ethanol is presented and mometasone furoate in concentrations of at least 1 percent of the ethanol concentration. The formulation may also contain a surfactant.

It has been found that the formulation of the present invention does not exhibit significant changes in particle size in the drug in suspension. In addition, the densities of the solid and liquid phases are similar, thus giving a suspension having a lower tendency to deposition of the particles; this results in a highly facilitated redispersion in uniform suspension, once the formulation has remained in a resting condition for prolonged periods. Detailed Description of the Invention The invention features pressurized aerosol formulations of the corticosteroid drug mometasone furoate, especially formulations suitable for use in metered dose nebulizers. Mometasone furoate is also known by the chemical designation 17- (2-furoate) of 9a, 21-dichloro-11β, 17-dihydroxy-16a-methylpregna-1,4-d-ene-3,20-dione. it has the empirical formula C? jHsoC Os, and has a molecular weight of 521, 44. The drug is currently marketed in preparations in cream, ointment and lotion, for the treatment of various dermatological disorders. In the formulations of the present invention which are suitable for treating disorders of the lower respiratory system such as asthma, at least a substantial portion of the drug is in the form of suspended particles with respirable sizes, for example, from about 0.5 to approximately 10 micrometers in its maximum dimension. In the formulations of the invention which are suitable for treating disorders of the upper respiratory system such as rhinitis, somewhat larger drug particle sizes can be admitted, although the size range discussed above is still preferred. As with other drugs with solubility Considerable in ethanol, there is a tendency for mometasone furoate to exhibit crystal growth in formulations containing ethanol. However, the inventors have discovered formulation parameters that do not promote the increase in size of the drug particles. These parameters also offer the advantage of minimizing the required concentrations of ethanol, to reduce the possibility of unpleasant taste sensations and to make the compositions more suitable for children and by others with low tolerance to alcohol. it needs a certain minimum level of ethanol to produce a consistent and predictable administration of the drug by a medwda dose dispenser. This minimum level of about 1 percent by weight of the total formulation, which results in a marginally acceptable administration of the drug. Increasing amounts of ethanol generally improve the drug's delivery characteristics. However, for the reasons discussed above, and to prevent the increase in size of the drug crystals in the formulation, it is necessary to limit the ethanol concentration. Experimental data indicate that the proportion by weight of furoate of mometasone to etapol is important to prevent increases in particle size; In general, when the drug is present in 0.6 percent of the ethanol concentration, immediate and adverse changes in the morphology and. size of the crystals. This effect is not observed when mometasone furoate is present in 1.3 percent of the ethanol concentration, which leads us to conclude that the drug must be present in concentrations of at least 1 percent of the Damage concentration The limitations of the volumes of administration by the available regulating valves (for example, 25 to 100 microliters per actuation) and the amounts of pharmacological substance needed in a dose to treat a certain condition (generally approximately 10 to approximately 500 micrograms per actuation). of the valve) dictate the points within the parameters of ethanol exposed for a specific formulation. The determination of such amounts is within the capabilities of the workers of this medium. A surfactant is often included in the aerosol formulations., for purposes such as contributing to maintaining a stable suspension of the drug and initiating the regulating valve. The formulation of the present invention does not require a surfactant to maintain easy dispersibility (such as by moderate agitation immediately prior to use), since the drug forms flocculated loose in the impeller and does not exhibit a tendency to settle or compact After storage at rest, the drug particles simply remain in their flocculated state However, surfactaptes have been incorporated in small amounts, as is usual in other suspensions in aerosol, to guarantee the correct functioning of the measuring valve. Ocetic acid commonly used is adequate, at levels that dispense up to approximately 50 micrograms of oleic acid per valve actuation. Naturally, it is always desired to minimize the amounts of chemical substances in a medicated dose, because the lowest concentrations must be used. Other desired substances include, but are not limited to, sorbitan tepoate, cetyl and pindinium chloride, soy lecithipa, polyoxyethylene (20) sorbitan monolaurate, oxyethylene stearyl ester (20), polyoxyethylene oleyl ether (2), block copolymers of polyoxyethylene-polyoxypropylene-ethylenediamine, polyoxyethylene (20) sorbitan monostearate, pol + oxyethylene-polyoxypropylene block copolymers, castor oil ethoxylate, and mixtures of any of the surfactants. It is generally preferred that the surfactant be soluble, aerosolized-employees, in the alcohol-impelept solution For any desired surfactant, simple experiments can be employed to measure the reproducibility of drug administration in order to identify the optimum amount of surfactant for any given formulation and administration form. The formulations of the present invention are prepared according to customary techniques for other aerosol compositions. Typically, all the components except the impelepte are mixed and introduced into the aerosol containers. The containers can then be cooled to temperatures below the boiling point of the impeller, and the required amount of the cooled impeller can be added before adjusting the regulating (metering) valve in the package. On the other hand, the regulating valve can be placed in the packages before the introduction of the impelepte, and introducing the necessary quantity thereof through the valve. In the following examples some additional aspects of the invention are described In the examples, 'percentage , or percent "indicates the percentage will weigh less than the context clearly indicates otherwise." Example 1 The following are examples of useful aerosol formulations, according to the present invention. The amounts of the ingredients are given as a percentage of metasopafuroate ( "FM"), oleic acid ("Oleteo"), ethanol ("EtOH") and HFC-227 ("Impeller") Formulation FM Oleico EtOH Impelepte A 0,112 0.001 2,497 97,389 B 0,028 0 1, 750 98,222 C 0,112 0,011 2,497 97,379 ° D 0,448 0,011 2,489 '97,052 E 0, 112 0 2,497 97,390 F 0,448 0,011 4,977 94,564 G 0,224 0,011 2,494 9-7,270 H 0,028 0,001 2,499 97,471 l 0,028 0.011 2,499 97,462 Example 2 Experiments are carried out to determine the effects on the administration characteristics of the aerosolized drug with varying low concentrations of ethanol In these experiments, micronized mometasopa furoate is incorporated into a suspension "concentrated" with ethanol and, optionally, , oleteo acid A required quantity of the intimately mixed concentrate is weighed for the administration of 120 doses in metallic aerosol containers, a regulating valve dispensing 63 microliters per actuation is fitted on the container (a volume containing 100 micrograms of mometasone furoate) and a quantity of liquid impellent HFC-227 is weighed to enter the container through the valve Mometasone furoate ion in the final formulation is 0, 112% To test the drug administration of the containers, the weight of the pharmacological substance dispensed by two drives of the regulating valve is measured, and divided by two to calculate the quantity dispensed in a single drive After a number of "preliminary" drives, this is done for the first two doses dispensed by the container, two doses at a midpoint of dosts- to be administered and two doses at the end of the expected capacity of the container The tables shown below show the average quantities recovered from multiple packages of each formulation, identifying this information on the formulation the amount of oleic acid dispensed with each valve drive 1% Ftanpt, 2.5 LUÍ Acid: OteiaxíS packaging) Start 75.2 μg Half 83.4 μg End 92.6- μg 1 75% Ethanol, 10 uq Oleic Acid (6 packs), Start 94 , 3 μg Half 96.4 μg Final 1 10 μg 2.5% Etarrpf. 1H ?? adE: Áctds O teraxttQ, packaging) Start 04 μg Half 102 μg End 106 μg 2 5% Ethanol without Oleic Acid (10 packs) Start 93 3 μg Half 968 μg End 99,0 μg The ~ adm? P? straetóf > of the drug in those containers with 1 percent ethanol would be marginally acceptable for a commercial product, while the ad- ministrations of all the containers- with formulations that present a higher level of alcohol would be acceptable. The general rules of drug administration for inhalation products that are intended to treat asthma are established by government agencies, such as the Untied States Food and Drug Admixture Example 3 Experiments are performed to determine the effects on the particle size stability of the drug of varying weight proportions of the drug to ethanol in the aerosol formulations The formulations are pfeparan in glass containers, equipped with aerosol valves, with the following components, where the quantities are expressed in percentages Formulation A HFC-227 94,969 Ethanol 4,985 Mometasone Furoate 0.034 Oleic acid 0,012 Mometasone Furoate / E tanol = 0.00674 Formulation B HFC-227 97,457 Ethanol 2,499 Mometasone Furoate 0.032 Alate QVQ.11 Mometasone Furoate / Ethanol = 0.0130 Formulation C HFC-227-97,366 • Ethanol 2,497 Mometasone Ftronate 0, 127 Oleic acid 0.011 Mometasone Furoate / Etapol = 0.0508 Formulation D HFC-227 97, 188 Ethanol 2,492 Mometasone Furoate 0.308 Oleic acid 0.011 Mometasone Furoate / Ethanol = 0.124 Each formulation is examined to detect evidence of increased size of the crystals after the preparation, visually inspecting the contents of the container and spraying a dose of the formulation onto a microscope glass slide, allowing the impeller to evaporate and visually inspecting the particles on the slide with polarized light at 100X magnification. A exhibits a large change in crystal morphology, producing elongated and acicular shapes, of which many have a maximum dimension that appears to be greater than about 30 μm, the changes are visually evident in the package without any enlargement. The particles in each of the other formulations appear to be similar to those of the Micronized mometasone furoate original, both in form and particle size Formulation A is not suitable for administration by inhalation of mometasone furoate The containers containing Formulations B, C and D are subjected to a program of freezing / thawing temperatures , as follows -20 ° C for 3 days, then room temperature for one day, then 50 ° C for 2 days, then -20 ° C for 4 days, then 50 ° C for, 3 days, then -20 ° C for 3 days, then 50 ° C for 3 days, and finally room temperature for 1 day When repeating the microscopic examination, no changes in shape or size are observed. The above descriptions of various embodiments of the present invention are representative of various aspects of the same, and are not intended to be exclusive or limited to precise precise forms. Those skilled in the art will be able to devise, undoubtedly, numerous modifications and variations It is intended that the scope of the definition be solely defined in its entirety by the appended claims

Claims (1)

1. CLAIMS 1 A suspension aerosol formulation comprising 1, 1, 1, 2,3,3,3-heptafluoropropane, from about 1 to about 10 percent by weight of ethanol, and micronized mometasone furoate in concentrations of at least about 1 percent of the ethanol concentration, formulation optionally further containing a surfactant 2 The aerosol suspension formulation according to claim 1, comprising from about 1 to about 5 weight percent ethanol 3 The aerosol suspension formulation according to claim 1, which comprises from about 2 to about 5 percent by weight of ethanol 4 The suspension aerosol formulation according to claim 1, which contains a surfactate 5 The aerosol suspension formulation according to claim 4 in which the surfactant consists of in oleic acid 6 The suspension aerosol formulation according to claim 1, which is contained in a container Metered Dose 7 The aerosol suspension formulation according to claim 1, which is contained in an apparatus that dispenses a regulated amount of about 10 to about 500 micrograms of mometasone furoate with a single driving operation 8 A method for treating allergic reactions in the respiratory tract, which comprises administering by inhalation, a suspension aerosol formulation comprising 1, 1, 1, 2,3,3,3-heptafluoro-linen, from about 1 to about 10 percent by weight of ethanol, and micronized mometasone furoate in concentrations of at least about 1 percent of the ethanol concentration, which formulation optionally further contains a surfactant. The method according to claim 8, wherein the suspension comprises from about about 5 percent by weight of ethanol. The method according to claim 8, wherein the The method according to claim 8, wherein the suspension contains a surfactant. The method according to claim 11, wherein the surfactant comprises acid. oleic 13 The method according to claim 8, wherein the suspension is contained in a metered dose pack 14"The method according to claim 8, wherein the suspension is contained in an apparatus that dispenses an amount regulated from about 10 to about 500 micrograms of mometasone furoate with a single driving operation 15 - A metered dose nebulizer containing a suspension aerosol formulation comprising 1, 1, 1.2.3.3.3-heptafluoropropane, of about 1 to about 10 weight percent ethanol, and micronized mometasone furoate in concentrations of at least about 1 per cent. of the ethanol concentration, formulation that optionally also contains a surfactant. 16. The metered dose nebulizer according to claim 15, wherein from about 10 to about 500 micrograms of mometasone furoate is dispensed with a single actuation operation.