HRP920362A2 - Non-chlorofluorocarbon aerosol formulations - Google Patents

Description

Introduction

The present invention relates to aerosol formulations substantially free of chlorofluorocarbon (CFC) compounds. Aerosol formulations according to the invention have a wide range of applications, and one of the areas is application in medicine, especially in pressurized metered dose inhalers (MDIs).

Metered dose inhalers have proven to be an efficient way to administer drugs orally and nasally. They are widely used to administer bronchodilator and steroid compounds to asthmatics, and can also be used to administer other compounds such as pentamidine and anti-inflammatory drugs that do not have a bronchodilator effect. The quick onset of action and the absence of any significant side effects led to the formulation of a large number of drugs for this method of administration. The drug is typically administered to the patient using a carrier system that, in principle, contains one or more carriers with appropriate vapor pressure, suitable for oral or nasal administration. More preferred carrier systems typically include carrier 11, carrier 12, carrier 114, or mixtures thereof. Often the vapor pressure of the carrier system is adjusted by adding some liquid excipient to the carrier.

Carriers 11, 12 and 114, however, belong to a class of compounds known as chlorofluorocarbon compounds, which are linked to the depletion of ozone in the atmosphere. Ozone is thought to block certain harmful ultraviolet radiations, so a decrease in the amount of ozone in the atmosphere will lead to an increased number of skin cancer cases. In the 1970s, certain steps were taken to reduce the release of CFC compounds originating from aerosols. Other carriers, such as hydrocarbons, were used, or the product was administered in another way. Given that the use of CFC compounds in medical applications is relatively small, i.e. representing less than 1% of the total release of CFC compounds, and given the health benefits achieved by using metered dose inhalers, no steps were taken at that time to limit the use of CFCs compounds in metered dose inhalers. However, the continuous and increasingly precise measurement of ozone has shown that the previous restrictions on the use of CFCs are not sufficient, so additional significant measures should be taken to drastically reduce the release of CFCs. Recommendations have recently been made that CFC production should virtually cease by the end of this century. The result is that in the medium and long term it will not be possible to continue using CFCs. Although some efforts have been made to use non-pressurized metered dose inhalers, most such devices have not been entirely successful. Many of them do not give uniform doses, are mechanically complicated, do not provide 100-200 doses per aerosol bottle, are difficult for an individual to use, are bulky and/or inconvenient to use, especially when the patient has an acute need for medicine.

As a result, there is a need for aerosol formulations that are substantially CFC-free. Carriers that do not contain CFCs should meet several criteria set for pressurized metered dose inhalers. They should be non-toxic, stable and non-reactive with the drug or other major components in the valve/actuator. One of the carriers that proved to be more suitable is CF3-CH2F, also known as Freon 134a, HFA 134a, HFC 134a, or 1,1,1,2-tetrafluoroethane. However, the physical properties, i.e. vapor pressure, polarity, solubility, density and viscosity of HFC 134a differ from those of commonly used carriers. The HFC 134a carrier has a vapor pressure of 5.84 x 105 N/m2 absolute, which is too high for use in metered dose inhalers. In addition, commonly used surfactants may be insoluble in HFC 134a. Furthermore, when the drug is to be administered in solution, the drug need not be readily soluble in this carrier. Differences in density and polarity between HFC 134a and previously used CFC carriers may cause different drug delivery when the CFC carrier is replaced with HFC 134a. Medicines can turn into a paste, settle or agglomerate in a carrier other than CFC, even if such phenomena did not occur in a CPC carrier.

The use of HFA 134a in medical inhalers has already been described in science. European patent No. 0 372 777 relates to medical aerosol formulations containing Freon 134a and an adjuvant having a higher polarity than the carrier. This publication lists several possible adjuvants and surfactants that can be used in combination with the carrier and drug.

International patent application No. WO 91/04011 describes a combination of 1,1,1,2-tetrafluoroethane and a powdered drug which is coated with a non-perfluorinated surfactant before the powdered drug is dispersed in a carrier. On p. 6-7 of this publication list surfactants suitable for use with a carrier. If necessary, a perfluorinated adjuvant can be added. Pre-coating the drug, however, does not necessarily have advantages, as it represents an additional, complicated step in the production process.

Test report No. 30161 of May 1989 states that carriers other than CFCs, such as fluorocarbons, can be used for pressurized drugs that are delivered directly to the lungs, for example bronchodilators. US Patent No. 4,174,295 describes the combination of HFC 134a with various chlorinated hydrocarbons and, if necessary, with a saturated hydrocarbon.

US Patent No. 2,885,427 describes the use of HFC-134a as an aerosol carrier. US Patent No. 3,261,748 describes the use of HFC-134a for anesthesia.

US Patent No. 4,129,603, 4,311,863, 4,851,595 and European Patent No. 379,793 also describes the use of HFC-134a as an aerosol carrier.

The particular combinations described above may not, however, provide the desired solubility, stability, low toxicity, accurate dosing, appropriate particle size (if a suspension) and/or compatibility with conventional valve assemblies used for metered dose inhalers.

Description of the invention

The present invention relates to non-toxic formulations which are substantially free of CFC compounds, which exhibit improved stability and compatibility with drugs and valve assemblies, and which are relatively easy to manufacture.

The present invention also relates to formulations that can be used in existing aerosol filling devices, with only relatively minor modifications and without the need for prior drug coating.

The invention includes an aerosol formulation containing:

A. effective amount of medicine; and

B. 1,1,1,2-tetrafluoroethane.

The formulation can, if necessary, also contain an excipient which is preferably chosen from the group that includes: propylene glycol diesters of fatty acids with a medium chain length; triglyceride esters of fatty acids with a medium chain length; perfluorodimethylcyclobutane; perfluorocyclobutane; polyethylene glycol; menthol; lauroglycol; diethylene glycol monoethyl ether; polyglycolized glycerides of medium-chain fatty acids; alcohols; eucalyptus oil; short chain fatty acids; and their combinations.

The formulation can, if necessary, further contain a surfactant. Surfactants are preferably selected from the group comprising: oleic acid; sorbitan trioleate; cetyl pyridinium chloride; soy lecithin; polyoxyethylene(20) sorbitan monolaurate; polyoxyethylene(20) sorbitan monostearate; polyoxyethylene(20) sorbitan monooleate; polyoxy-propylene-polyoxyethylene block copolymers; polyoxyethylene(10) stearyl ether; polyoxyethylene(2) oleyl ether; polyoxypropylene-polyoxyethylene-ethylenediamine block copolymers; castor oil ethoxylate; and their mixtures.

Preferred liquid excipients are diethylene glycol monoethyl ether, propylene glycol diesters of medium chain fatty acids, perfluorodimethylcyclobutane, and polyethylene glycol.

Preferred surfactants are oleic acid, sorbitan trioleate, cetylpyridinium chloride, polyoxyethylene(20) sorbitan monolaurate, polyoxypropylene-polyoxyethylene block copolymers, soy lecithin and polyoxypropylene-polyoxyethylene-ethylenediamine block copolymers, with oleic acid being particularly preferred.

The invention is particularly useful when used for drugs such as albuterol, mometasone furoate or beclomethasone dipropionate, as well as their salts and clathrates.

The composition of the formulation is in the following scope:

A. 1,1,1,2-tetrafluoroethane 25 - 99.99 wt.%

B. drug 0.01 - 1 wt.%

C. excipient 0 - 75 wt.%

D. surfactant 0-3 wt.%

The present invention also relates to a method for treating asthma in mammals, which consists in administering to a mammal in need of such treatment an effective amount of an aerosol formulation containing:

A. a drug selected from the group comprising albuterol, mometasone furoate, beclomethasone dipropionate, as well as their salts and clathrates;

B. 1,1,1,2-tetrafluoroethane; and

C. if necessary, an excipient, preferably selected from the group comprising propylene glycol diesters of fatty acids with a medium chain length; triglyceride esters of fatty acids with a medium chain length; perfluorodimethylcyclobutane; perfluorocyclobutane; polyethylene glycol; menthol; lauroglycol; diethylene glycol monoethyl ether; polyglycolized glycerides of medium-chain fatty acids; alcohols; eucalyptus oil; short chain fatty acids; and their combinations.

Surfactant is present as needed. It is preferably selected from the group comprising oleic acid; sorbitan trioleate; cetyl pyridinium chloride; soy lecithin; polyoxyethylene(20) sorbitan monolaurate; polyoxyethylene(20) sorbitan monostearate; polyoxyethylene(20) sorbitan monooleate; polyoxy-propylene-polyoxyethylene block copolymers; polyoxyethylene(10) stearyl ether; polyoxyethylene(2) oleyl ether; polyoxypropylene-polyoxyethylene-ethylenediamine block copolymers; castor oil ethoxylate; and their mixtures.

All formulations of the present invention utilize carrier 134a in combination with a drug, optionally with a liquid excipient, and optionally with a surfactant. The excipient aids the compatibility of the drug with the carrier and also lowers the pressure under which the formulation is administered to a tolerable range, ie to about 2.76 - 5.52 x 105 N/m2 absolute, preferably 3.45 - 4.83 x 105 N/m2. The selected excipient should not be reactive with the drug, should be relatively non-toxic and have a vapor pressure below about 3.45 x 105 N/m2 absolute. The term "medium chain fatty acids", as used herein, refers to chains of alkyl groups ending in -COOH and having 6-12 carbon atoms, preferably 8-10 carbon atoms. The term "short-chain fatty acids" refers to chains of alkyl groups ending in -COOH and having 4-8 carbon atoms. The term "alcohol" includes C1-3 alcohols such as methanol, ethanol and isopropanol. Among the preferred excipients are the following:

propylene glycol diesters of medium chain fatty acids, available under the trade name Miglyol 840 (Hüls America, Inc., Piscataway, N.J);

triglyceride esters of fatty acids with a medium chain length, which are available under the trade name Miglyol 812 (Hüls);

perfluorodimethylcyclobutane, which is available under the trade name Vertrel 245 (E.I. DuPont de Nemours & Co. Inc., Wilmington, Delaware);

perfluorocyclobutane, which is available under the trade name octafluorocyclobutane (PCR Gainsville, Florida); polyethylene glycol, available under the trade name PEG 40 (BASF, Parsippany, N.J.);

menthol (Pluess-Stauffer International Stanford, Connecticut);

propylene glycol monolaurate, which is available under the trade name lauroglycol (Gattefossé Elmsford, N.Y.);

diethylene glycol monoethylether, which is available under the trade name Transcutol (Gattefossé);

polyglycolized glycerides of medium-chain fatty acids, which are available under the trade name Labrafac Hydro WL 1219 (Gattefossé);

alcohols, such as ethanol, methanol or isopropanol;

eucalyptus oil (Pluess-Stauffer International); and their mixtures.

In order to lower the surface and interfacial tensions between the drug and the carrier, a surface-active agent can be added if necessary. When the drug, carrier and excipient need to form a suspension, a surfactant may or may not be necessary. When the drug, carrier and excipient need to form a solution, a surfactant may or may not be necessary, depending in part on the solubility of the particular drug and excipient. The surfactant can be any suitable, non-toxic compound that is not reactive with the drug and that significantly lowers the surface tension between the drug, excipient and carrier and/or acts as a valve lubricant. Among the preferred surfactants are:

oleic acid, which is available under the trade name oleic acid NF6321 (Henkel Corp. Emery Group, Cincinnati, Ohio);

cetylpyridinium chloride (Arrow Chemical, Inc. Westwood, N.J.);

soy lecithin, available under the trade name Epikuron 200 (Lucas Meyer Decatur, Illinois);

polyoxyethylene(10) stearyl ether, which is purchased under the trade name Briji 76 (Imperial Chemical Industries - ICI);

polyoxyethylene(2) oleyl ether, which is available under the trade name Briji 92 (ICI);

polyoxypropylene-polyoxyethylene-ethylenediamine block copolymer, which is available under the trade name Tetronic 150 R1 (BASF);

polyoxyethylene(20) sorbitan monolaurate, which is available under the trade name Tween 20 (ICI Specialty Chemicals, Wilmington, Delaware);

polyoxyethylene(20) sorbitan monostearate, which is available under the trade name Tween 60 (ICI);

polyoxyethylene(20) sorbitan monooleate, which is available under the trade name Tween 80 (ICI);

polyoxypropylene-polyoxyethylene block copolymers, which are available under the trade names Pluronic L-92, Pluronic L-121 and Pluronic F 68 (BASF);

castor oil ethoxylate, which is available under the trade name Alkasurf CO-40 (Rhone-Poulenc Mississauga Ontario, Canada); and their mixtures.

The medicaments used according to the present invention include any pharmaceutically active compound to be administered by oral inhalation or nasal administration. Typical classes of compounds include bronchodilators, anti-inflammatory compounds, antihistamines, antiallergens, analgesics, antitussives, anti-anginal drugs, steroids, corticosteroids, vasoconstrictors, and antibiotics. Specific compounds within these classes are albuterol, mometasone furoate, beclomethasone dipropionate, isoproterenol, heparin, terbutaline, rimiterol, perbuterol, disodium cromoglycate, isoprenaline, adrenaline, pentamidine, and ipratropium bromide. These compounds can be used either as free bases, as salts or as clathrates, depending on the stability and solubility of the active compound in the particular formulation. When clathrates are used, P-11 and hexane clathrates are particularly preferred.

When the active compound forms a suspension, the particle size should be relatively uniform, whereby all particles will essentially be in the range of about 0.1 to 25 μm, preferably from 0.5 to 10 μm and preferably from 1 to 5 μm. Particles larger than 25 μm can be retained in the oropharyngeal cavity, while particles smaller than about 0.5 μm should not be used because they will probably be exhaled and will not reach the patient's lungs.

The formulations of the present invention can be filled into aerosol containers using conventional filling equipment. Since carrier 134a may not be compatible with all elastomeric compounds currently used in aerosol valve assemblies, it may be necessary to use other materials, such as white butadiene gum, or to use excipients and, if necessary, surfactants that mitigate the harmful effect of the carrier 134a on the valve components. If necessary, an excitation mechanism with a spacer can be used, in order to reduce the force of the sprayed jet from the MDI.

To ensure even dispersion of the active ingredient, formulations typically contain the following ingredients:

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Depending on the specific application, the container can be filled with a predetermined amount of the formulation for one or more administrations. Typically, the container is intended for multiple administration, so it is very important that the formulation is administered equally in each dose. For example, when the formulation is for bronchodilation, the container is typically filled with an amount sufficient for 200 doses.

Suitable suspensions can be partially determined by observing several physical properties, i.e. particle agglomeration rate, agglomerate size and rate of paste formation and particle settling, after which these parameters will be compared with some acceptable standard. Suitable solutions can be determined by observing the solubility of the drug throughout the temperature range recommended for storage.

The suspensions of the present invention may preferably be obtained by either pressure filling or low temperature filling, both of which are well known in the art.

Suspensions can prove to be particularly desirable for use in metered dose inhalers, as they meet the conditions of efficiency and stability.

Experts may decide to add one or more agents such as preservatives, buffers, antioxidants, sweeteners and/or flavoring agents and other agents for masking the taste, depending on the characteristics of the specific formulation.

Examples I - XXXII describe examples of formulations according to the present invention, whereby in some of them alternative formulations are also given, designated as "A" and "B".

Examples

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Example II

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Example III

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Example IV

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Example V

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Example VI

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Example VII

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Example VIII

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Example IX

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Example X

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Example XI

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Example XII

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Example XIII

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Example XIV

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Example XV

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Example XVI

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Example XVII

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Example XVIII

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Example XIX

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Example XX

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Example XXI

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Example XXII

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Example XXIII

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Example XXIV

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Example XXV

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Example XXVI

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Example XXVII

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Example XXVIII

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Example XXIX

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Example XXX

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Example XXXI

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Example XXXII

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Although examples have been given of albuterol, albuterol sulfate, mometasone furoate, beclomethasone dipropionate, and beclomethasone dipropionate clathrate, other drugs intended for oral or nasal administration may be used. Similarly, it is also possible to use excipients and surfactants that are not given in the examples.

The description of the mentioned embodiments of the invention is given only as an illustration. It is not intended to exhaust or limit the invention only to the specifically given forms, as it is obvious that many modifications and variations can be made within the scope of the description. The realizations have been chosen for description so as to explain the principles of the invention and its practical application in the best way, thus enabling other experts to use the invention in different realizations and with different modifications that will adapt it to the specific purpose. The scope of the present invention is defined in the appended patent claims.

Claims (16)

1. Aerosol formulation, characterized by essentially consisting of: A. effective amounts of medicine; B. 1,1,1,2-tetrafluoroethane; C. if necessary, an excipient selected from the group consisting of propylene glycol diester of a medium chain fatty acid and triglyceride ester of a medium chain fatty acid, a surface active agent which is present together with the excipient if necessary; and D. as appropriate, one or more components selected from one or more of the following, as follows: condoms; buffers; antioxidants; sweeteners; and taste masking agents. 2. Formulation according to claim 1, characterized in that the drug is selected from the group comprising: albuterol; mometasone furoate; beclomethasone dipropionate; isoproterenol; heparin; terbutaline; rimiterol; perbuterol; disodium cromoglycate; isoprenaline; adrenaline; pentamidine; ipratropium bromide; and their salts and clathrates. 3. The formulation according to claim 1, characterized in that the drug is selected from the group comprising albuterol, albuterol sulfate, beclometasone dipropionate, beclometasone dipropionate clathrates and mometasone furoate. 4. The formulation according to claim 1, characterized in that it contains 0.01 to 1 wt. % of the drug. 5. Formulation according to claim 1, characterized in that it contains 0.03 to 0.7 wt. % of the drug. 6. The formulation according to claim 1, characterized in that it contains 0.05 to 0.5 wt. % of the drug. 7. Formulation according to claim 1, characterized in that the medicine is used in the form of a powder with an average particle size of about 1 to 5 microns. 8. Aerosol formulation according to claim 1, characterized in that it essentially consists of the following: A. a drug selected from the group consisting of albuterol, mometasone furoate, beclomethasone dipropionate, and their salts and clathrates; B. 1,1,1,2-tetrafluoroethane; C. as needed, an excipient selected from the group consisting of propylene glycol diester of a medium chain fatty acid and triglyceride ester of a medium chain fatty acid, where a surfactant is present as needed, together with the excipient; and D. as appropriate, one or more components selected from one or more of the following, as follows: condoms; buffers; antioxidants; sweeteners; and taste masking agents. 9. Aerosol formulation, characterized by the fact that it includes: A. an effective amount of mometasone fuorate; B. 1,1,1,2-tetrafluoroethane; and C. if necessary, one or more components selected from at least one of the following: excipients; surface active substances; and supplements which are: condoms; buffers; antioxidants; sweeteners; and taste masking agents. 10. Formulation from claim 9, characterized in that it contains the following: [image] 11. Formulation from claim 9, characterized in that it contains the following: [image] 12. Formulation from claim 9, characterized by the fact that it contains the following: [image] 13. Formulation from claim 9, characterized in that chlorofluorocarbon is actually released. 14. Use of mometasone fuorate, characterized in that it is combined with 1,1,1,2-tetrafluoroethane to form an aerosol pharmaceutical compound for oral and/or nasal administration to patients suffering from asthma. 15. Application of claim 14, characterized in that the aerosol pharmaceutical compound further includes a surfactant. 16. Use of claim 14, characterized in that the aerosol pharmaceutical compound further includes an excipient.