SI9400222A - Non-chlorofluorocarbon aerosol formulations - Google Patents

Abstract

Aerosol formulations are described in full free of chlorofluorocarbons for oral and / or nasal administration. The formulations contain 1,1,1,2, tetrafluoroethane, drug, any excipient and any surfactant. Treatment methods are also described where formulations used.

Description

Presentation of the invention

The present invention is directed to formulations which are completely chlorofluorocarbons (CFC) aerosols. More specifically, the present invention is directed to formulations that are CFC-free and have particular utility in medical devices, especially in metered dose inhalers (MDI).

Dosing pressure inhalers have been shown to be an effective method of administering drugs orally and nasally. They are widely used in the administration of bronchodilator and steroid compounds to asthmatics and may also be useful for the administration of other compounds such as pentamidine and anti-inflammatory drugs other than bronchodilators. The rapid increase in the activity of the compounds administered in this manner and the absence of any side effects produced a large number of compounds formulated for administration by this route. Typically, the drug is administered to patients with a propellant system, which generally contains one or more propellants that have adequate vapor pressure and are suitable for oral and nasal administration. Most preferred propellant systems include propellant 11, propellant 12, propellant 114, or a mixture thereof. We often regulate the vapor pressure of the system with the propellant by mixing the liquid excipient with the propellant.

However, propellants 11, 12 and 114 belong to the class of compounds known as chlorofluorocarbons, which are associated with the release of ozone from the atmosphere. Ozone has been found to retain certain harmful UV rays and that a decrease in the ozone content of the atmosphere will lead to an increased incidence of skin cancer. In 1970, certain steps were taken to reduce CFC emissions from aerosols. They used other propellants, such as hydrocarbons, or otherwise marketed the product. Because the use of CFC in medical devices is relatively low, i.e. less than 1% of total emissions, and because of the health benefits associated with metered dose inhalers, did not limit the use of CFC propellants in metered dose inhalers at that time.

However, further and more sophisticated measurements of ozone indicated that previous restrictions on CFC use were insufficient and that significant further reductions in CFC emissions were required. It was recently recommended that by the end of the century, the production of CFCs should actually be stopped. Therefore, it will not be possible to continue using CFC propellants in the long term. Although considerable effort has been made to use non-pressure metered dose inhalers, many of these agents have not been completely successful. Many do not deliver fixed doses and are mechanically complex, do not allow 100-200 doses per unit of current aerosol reservoirs, are difficult for individuals to use and are bulky and / or awkward to use, especially when patients have an acute need for medication.

As a result, there is a need for formulations that are completely CFC free. Non-CFC propellants must satisfy several criteria for metered dose inhalers. They must be non-toxic, stable and non-reactive with the drug and other major components in the valve / trigger. The propellant that has proven to be suitable is CF3-CH2F, also known as Freon 134a, HFA 134a, HFC 134a or 1,1,1,2 tetrafluoroethane. However, the physical properties of HFC 134a, ie vapor pressure, polarity, density, viscosity and solubility, are different from the properties of CFC propellants commonly used. The HFC 134a propellant has a vapor pressure of 5.84x10 ⁵ N / m ² absolute (84.7 psia), which is too much to use in metered dose inhalers. In addition, the surfactants commonly used may be insoluble in HFC 134a. Moreover, where the drug is to be administered in solution, the drug may be less soluble in this propellant. The difference in polarity and density between HFC 134a and previously used CFC propellants may result in a different drug delivery if CFCs are replaced by HFC 134a propellants. In a non-CFC propellant, the drug may be stratified, possessed or agglomerated even if it did not appear in the CFC propellant.

The use of HFA 134a has been previously disclosed for use in medical inhalers. European Patent Publication 0 372 777 is directed to a medical aerosol formulation comprising Freon 134a and an adjuvant having a higher polarity than the propellant. This publication lists several possible adjuvants and surfactants for use in combination with a propellant and a drug.

International Patent Application No. WO 91/04011 discloses a combination of 1,1,1,2 tetrafluoroethane and a powdered drug which is pre-coated with a non-perfluorinated surfactant prior to dispersion into the propellant. Pages 6-7 list suitable surfactants for use with a propellant. Perfluorinated adjuvant may be added optionally. However, prior overlapping of the drug may be advantageous because it adds an additional complex rate to the production process.

Research Disclosure No. 30161, May 1989 discloses that non-CFC propellants, such as fluorohydrocarbons, can be used in pressurized drugs that are fed directly into the lungs, i.e. bronchodilators.

U.S. Pat. 4 174 295 discloses the combination of HFC 134a with various chlorofluorocarbons and optionally with saturated hydrocarbons.

U.S. Pat. 2 885 427 discloses the use of HFC 134a for propellant for aerosols.

U.S. Pat. 3 261 748 discloses the use of HFC 134a for anesthesia.

U.S. Pat. 4 129 603, 4 311 863, 4 851 595 in European Publication No. 3 379 793 also disclose the use of HFC 134a as a propellant for aerosols.

However, the specific combinations mentioned above may not provide the desired solubility, stability, low toxicity, precise dosing, correct particle size (in the case of suspension) and / or compatibility with the valve assembly methods commonly used in inhaler inhalers metered dose.

SUMMARY OF THE INVENTION

The present invention is directed to non-toxic, CFC-free formulations that have improved stability and compatibility with the drug and valve components and are relatively easy to manufacture.

The present invention is also directed to formulations that could be used in existing aerosol dispensing equipment with only relatively minor modifications and no overlapping of the drug.

The invention includes an aerosol formulation comprising:

A. The effective amount of drug; and

B. 1,1,1,2 Tetrafluoroethane

The formulation may further optionally contain an excipient, preferably selected from the group consisting of:

propylene glycol medium-chain fatty acid diesters; medium chain fatty acid ester triglyceride; perfluorodimethylcyclobutane;

pertluorocyclobutane; polyethylene glycol; menthol; luroglycol;

diethylene glycol monoethyl ether;

medium chain polyglycolated fatty acid glycerides;

alcohols;

eucalyptus oil;

short-chain fatty acids;

and combinations thereof.

The formulation may optionally contain a surfactant. The surfactant is preferably selected from the group consisting of:

oleic acids; sorbitan trioleate; cetyl pyridine chloride; soya lecithin;

polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (10) stearyl ether; polyoxyethylene (2) oleyl ether; polyoxypropylene-polyoxyethylene-ethylene diamine block copolymers;

polyoxyethylene (20) sorbitan monostearates; polyoxyethylene (20) sorbitan monooleates; polyoxypropylene-polyoxyethylene block copolymers; castor oil ethoxylate; and combinations thereof.

Desirable liquid excipients are: diethylene glycol monoethyl ether, propylene glycol mid-chain fatty acid diesters, perfluorodimethylcyclobutane and polyethylene glycol.

Desirable surfactants are: oleic acid, sorbitan trioleate cetylpyridine chloride, polyoxyethylene (20) sorbitan monolaurate, polyoxypropylene-polyoxyethylene block copolymers, soya lecithin and polyoxypropylene-ethyleneimine ethylene ether ethylene ether

The invention is particularly useful where the medicament is albuterol, monomethasone furoate or beclomethasone dipropionate and their salts and clathrates.

The formulation framework comprises:

A. 1,1,1,2 Tetrafluoroethane

B. medicine

C. excipient

E.surfactant (if present) wt% indicates mass percentages.

25-99.9 wt% 0.01-1.0 wt% 0-75 wt%

0-3 wt%

The present invention is also directed to a method of treating asthma in a mammal comprising administering to the mammal in need of such treatment an effective amount of an aerosol formulation comprising:

A. a medicine selected from the group consisting of albuterol, monomethasone furoate, beclomethasone dipropionate and their salts and clathrates;

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

C. any excipient, preferably selected from the group consisting of:

propylene glycolol medium chain fatty acid diesters;

medium chain fatty acid ester triglyceride;

perfluorodimethylcyclobutane;

perfluorocyclobutane;

polyethylene glycol;

menthol;

luroglycol;

diethylene glycol monoethyl ether;

medium chain polyglycolated fatty acid glycerides;

alcohols;

eucalyptus oil;

short-chain fatty acids;

and combinations thereof.

The surfactant is present arbitrarily. It is desirable that the surfactant is selected from the group consisting of:

oleic acids; sorbitan trioleate; cetyl pyridine chloride: soya lecithin;

polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (10) stearyl ether; polyoxyethylene (2) oleyl ether; polyoxypropylene-polyoxyethylene-ethylene diamine block copolymers;

polyoxyethylene (20) sorbitan monostearates; polyoxypropylene-polyoxyethylene block copolymers: castor oil ethoxylate; and combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION

In all the formulations of the present invention, propellant 134a is used in combination with a drug, optionally with a liquid excipient, and optionally with a surfactant. The excipient allows the drug to be compatible with the propellant and also lowers the trigger pressure to an acceptable level ie around 2.76-5.52x105 N / _m 2 absolute (40 to 80 psia), preferably 3.45-4.83x105 N / m ² absolute (50 to 70 psia). The selected excipient should be non-reactive with the drug, relatively non-toxic and should have a vapor pressure below about 4.35x10 ⁵ N / m ² absolute (50 psia). As used herein, the term 'medium chain fatty acids' refers to alkyl groups ending with a -COOH group having 6-12 carbon atoms, preferably 8-10 carbon atoms. The term 'short chain fatty acids' refers to chains of alkyl groups ending with a -COOH group having 4-8 carbon atoms. The term alcohol contains C-1-O3 alcohols such as methanol, ethanol and isopropanol. Desirable excipients include:

propylene glycol mid-chain fatty acid diesters, commercially available under the trade name Miglyol 840 (from Hills America, Inc. Piscataway, N.J.);

medium chain fatty acid triglyceride esters, available under the trade name Miglyol 812 (from Hills);

perfluorodimethylcyclobutane, commercially available under the trade name Vertrel 245 (from E.l DuPont de Nemours and Co. Inc. Wilmington, Delaware);

commercially available octafluorocyclobutane (from POR Gainsville, Florida);

polyethylene glycol, commercially available under the trade name PEG 400 (from BASF Parsippany, N.J.);

menthol (from Pluess-Stauffer International Stanford, Connecticut); propylene glycol monolaurate, commercially available under the trade name lauroglycol (from Gattefosse Elmsford, N.J.);

diethylene glycol monoethyl ether available by commercial name

Transcutol (from Gattefosse);

medium-chain polyglycolated fatty acid glycerides, available under the trade name Labrafac Hydro WL 1219 (from Gattefosse);

alcohols such as ethanol, methanol and isopropanol; eucalyptus oil (from Pluess-Stauffer International); and mixtures thereof.

Surfactant can be optionally added to reduce the surface and internal stresses between the drug and the propellant. Where the excipient and the vehicle must form a suspension, surfactant may or may not be used. Where the excipient and the propellant must form a solution, the surfactant may or may not be necessary depending on the solubility of the particular drug and excipient. The surfactant may be any suitable, non-toxic compound that is non-reactive with the drug and substantially reduces surface tension between the drug, excipient and propellant and / or acts as a valve lubricant. Desirable surfactants are;

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

cetylpyridine chloride (from Arrow Chemical, Inc. Westwood, N.J.); soybean lecithin available commercially under the name Epikuron

200 (from Lucas Meyer Decatur, Illinois);

polyoxyethylene (20) sorbitan monolaurate, commercially available under the trade name Tween 20 (from ICI Specialty Chemicals. Wilmington, Delaware);

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

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

polyoxyethylene (10) stearyl ether, available under the commercial name Brij 76 (from ICI);

polyoxyethien (2) oleyl ether, available under the commercial name Brij 92 (from ICI);

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

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

castor oil ethoxylate, commercially available under the trade name Alkasurf CO-40 (from Rhone-Poulenc Mississauga Ontario, Canada);

and mixtures thereof.

The medicaments of the present invention may include any pharmaceutically active compounds to be administered by oral inhalation or nasal. Typical classes of compounds include bronchodilators, anti-inflammatory compounds, antihistamines, anti-allergens, analgesics, cough drugs, anti-angina drugs, steroids, corticosteroids, vasoconstrictors and antibiotics. The specific compounds in these classes of compounds are albuterol, mometasone furoate, belkometazone dipropionate, isoproterenol, heparin, terbutaline, rimiterol, perbuterol, disodium chromoglycate, isoprenaline, adrenaline, pentamidine and ipratopium bromide. These compounds can be used as free bases or as salts or as clathrates, depending on the stability and solubility of the active compound in a specific formulation. When using clathrates, P-11 and hexane clathrates are especially desirable.

Where the active compound forms a suspension, the particle size should be relatively uniform, preferably with all particles within the range of 0.1-25 pm, preferably 0.5-10 pm, preferably 1-5 pm. Lumps greater than 25 pm may be retained in the pharynx, while particles smaller than about 0.5 pm may not be used because they are more likely to be exhaled and thus not reach the lungs of the patient.

The formulations of the present invention can be filled into aerosol tanks using conventional filling equipment. As propellant 134a may be incompatible with all the elastomeric compounds currently used in existing valve assembly, it may be necessary to replace it with other materials, such as white synthetic rubber, or to use excipients and optional surfactants that mitigate or counteract the effects of propellant means 134a to valve components. We can optionally use a device with an interface that reduces the power of spray from MDI.

In order to ensure uniform dispersion of the active ingredient, the formulations will typically contain components as follows:

Box wt% Desired box wt% The most desirable framework wt% Medication 0.01-1 0.03-0.7 0.05-0.5 Propellant 25-99.99 50-99.97 50-99.95 Excipient (s) 0-75 0-50 0-50 Surfactant (s) The scoreboard is now 0-3 The scoreboard is now 0-2 The scoreboard is now 0-1

Depending on the particular application, the tank may be filled with a predetermined amount of single or multiple dosage formulation. Typically, the reservoir is designed for multiple dosing, so it is very important that the formulation administered is exactly the same at each dosage. For example, where the formulation is for bronchodilation, the reservoir is typically filled with sufficient formulation for 200 administrations.

Suitable suspensions can be selected by observing some of the physical properties of the formulation, i.e. the particle agglomeration rates, the size of the agglomerates, and the stratification / settling rate, and comparing them with accepted standards. Suitable solutions can be selected by observing the solubility of the drug Over the entire recommended storage and temperature framework.

The suspensions of the present invention are preferably prepared by both pressurized, pressurized, or cold-fill processes well known to those skilled in the art.

For metered dose inhalers, suspensions are most preferred because of their high efficiency and stability.

Experts may opt for one or more preservatives, buffer, antioxidant, sweetener and / or flavors or other agents that mask (mask) the taste depending on the characteristics of the formulation.

Examples 1 to 32 below further describe representative formulations of the present invention, some examples show alternative formulations designated A and B.

EXAMPLE 1

Component wt% Albuterol 0.1 Vertrel 245 9.9 HFC-134a 90.0 EXAMPLE 2 Component wt% Albuterol 0.5 Vertrel 245 49.9 HFC-134a 49.6 EXAMPLE 3 Component wt% Albuterol 0.1 Oleic acid 0.01 Miglyol 840 9.0 HFC-134a 90.89

EXAMPLE 4

Component wt% Albuterol 0.1 Tetronic 150 R1 0.1 Miglyol 840 9.8 HFC-134a 90.0 EXAMPLE 5 Component wt% Albuterol 0.1 Pluronic L-121 0.1 Miglyol 840 9.8 HFC-134a 90.0 EXAMPLE 6 Component wt% Albuterol 0.1 Oleic acid 0.2 Transcutol 18.0 HFC-134a 81.7

EXAMPLE 7 wt%

Component A B Albuterol 0.10 0.10 Oleic acid 0.01 0.01 Ethanol 30.0 15.0 HFC-227 69.89 84.89

EXAMPLE 8 wt%

Component A B Albuterol sulfate 0.10 0.10 Oleic acid 0.01 0.01 Ethanol 30.0 15.0 HFC-227 69.89 84.89

EXAMPLE 9

Component wt% Albuterol 0.1 Vertrel 245 17.0 Miglyol 840 9.0 HFC-134a 73.9 EXAMPLE 10 Component wt% Albuterol 0.10 Oleic acid 0.01 Ethanol 10.0 Vertrel 245 9.90 HFC-134a 79.99

EXAMPLE

Component wt% Albuterol 0.10 Pluronic L-121 0.4 Vertrel 245 9.90 Miglyol 840 9 HFC-134a 73.9

EXAMPLE 12

Component wt% Albuterol 0.10 Pluronic L-121 0.90 Oleic acid 0.01 Miglyol 840 9.00 HFC-134a 89.99 EXAMPLE 13 Component wt% Albuterol 0.10 Tetronic 150 R1 0.10 Oleic acid 0.01 Miglyol 840 9.80 HFC-134a 89.99

EXAMPLE wt%

Component A B Mometasone turoate 0.10 0.10 Oleic acid 0.01 0.01 Ethanol 30.0 15.0 HFC-227 69.89 84.89

EXAMPLE 15

Component wt% Mometasone furoate 0.10 Oleic acid 0.2 Transcutol 18.0 HFC-134a 81.7

EXAMPLE 16

Component wt% Mometasone furoate 0.10 Tween 20 0.1 Miglyol 840 9.8 HFC-134a 90.0

EXAMPLE 17

Component wt% Mometasone furoate 0.10 Pluronic L-121 0.4 Miglyol 840 9.0 HFC-134a 90.5

EXAMPLE 18

Component wt% Mometasone furoate 0.10 Tetronic 150 R1 0.1 Miglyol 840 9.8 HFC-134a 90.0

EXAMPLE 19

Component wt% Beclomethasone dipropionate 0.10 Oleic acid 0.01 Ethanol 5 HFC-134a 94.89

EXAMPLE 20

Component wt% Beclomethasone ktatrat P-11 dipropionate 0.10 Oleic acid 0.01 Miglyol 840 1.5 HFC-134a 98.39 EXAMPLE 21 Component wt% Beclomethasone dipropionate 0.10 hexane clathrate Pluronic L121 0.01 Miglyol 840 1.5 HFC-134a 98.3 EXAMPLE 22 Component wt% Mometasone furoate 0.10 HFC-134a 99.9 EXAMPLE 23 Component wt% Beclomethasone dipropionate 0.10 clathrate P-11 HFC-134a 99.9

EXAMPLE 24

Component wt% Mometasone furoate 0.10 Tween 20 0.01 HFC-134a 99.89

EXAMPLE 25

Component wt% Beclomethasone dipropionate clathrate P-11 0.10 Tween 20 0.01 HFC-134a 99.89 EXAMPLE 26 Component wt% Mometasone turoate 0.10 Tween 20 0.01 Oleic acid 0.0005 HFC-134a 99.8895 EXAMPLE 27 Component wt% Mometasone turoate 0.10 Tetronic 150 R1 0.01 Oleic acid 0.005 Miglyol 840 9 HFC-134a 90.885 EXAMPLE 28 Component wt% Beclomethasone dipropionate clathrate P-11 0.10 Miglyol 840 3 Oleic acid 0.005 Pluronic L121 0.01 HFC-134a 96.885

EXAMPLE 29

Component wt% Beclomethasone dipropionate 0.10 Oleic acid 0.2 Transcutol 5 HFC-134a 94.7 EXAMPLE 30 Component wt% Beclomethasone dipropionate clathrate P-11 0.10 Miglyol 840 1.5 Pluronic L121 0.1 HFC-134a 98.7 EXAMPLE 31 Component wt% Beclomethasone dipropionate 0.10 PEG 400 5 HFC-134a 94.9 EXAMPLE 32 Component wt% Beclomethasone dipropionate clathrate P-11 0.10 Miglyol 840 1.5 HFC-134a 94.9

Although the examples above are directed to albuterol, albuterol sulfate, mometasone furoate, beclomethasone dipropionate, and clathrates beclomethasone dipropionate, we believe that other medicines administered orally or nasally may also be used. Similarly, we think that other excipients and surfactants can be used in addition to the above.

Descriptions of the aforementioned embodiments of the invention are presented for illustration and outline. They are not intended to be exhausted or to limit the invention to the precise forms disclosed, it is evident that, with the above knowledge, many modifications and variations are possible. Embodiments have been selected and described in order to best explain the principles of the invention and their practical application with this skilled other person skilled in the art in order to best use the invention in different embodiments and with various modifications corresponding to the intended particular use. We want the scope of the invention to be defined by the claims appended thereto.

Claims (8)

PATENT APPLICATIONS 1. Aerosol formulation, characterized in that it necessarily consists of: A. effective quantities of the medicinal product: B. 1,1,1,2, tetrafluoroethane; and C. an optional excipient selected from the group consisting of propylene glycol diester of medium chain fatty acid and medium chain triglyceride ester of fatty acid; a surfactant arbitrarily present together with the excipient; D. any one or more components selected from one or more of the following: preservatives; buffers; antioxidants; sweeteners; and taste masking / masking agents. A formulation according to claim 1, characterized in that the drug is selected from the group consisting of: albuterol, mometasone furoate, beclomethasone dipropionate, isoproterenol, heparin, terbutaline, rimiterol, perbuterol, disodium cromoglycate, isoprenaline, adrenaline, adrenaline , ipratropium bromide and their salts and clathrates. The formulation of claim 1, wherein the medicament is selected from the group consisting of: albuterol, albuterol sulfate, beclomethasone dipropionate, clathrates beclomethasone dipropionate and mometasone furoate. The formulation according to claim 1, characterized in that it contains 0.01 to 1 weight percent of the drug. The formulation according to claim 1, characterized in that it contains from 0.03 to 0.7% by weight of the drug. 6. A formulation according to claim 1, comprising 0.05 to 0.5% by weight of the drug. The formulation of claim 1, wherein the medicament is a powder having a mean particle size of about 1 to 5 gm. 8. Aerosol formulation, characterized in that it necessarily contains: A. a medicament selected from the group consisting of albuterol, mometasone furoate, beclomethasone dipropionate and their salts and kiatrates; B. 1,1,1,2, tetrafluoroethane; C. an optional excipient selected from the group consisting of propylene glycol diester of medium chain fatty acid and medium chain triglyceride ester of fatty acid; a surfactant arbitrarily present together with the excipient; D. any one or more components selected from one or more of the following: preservatives; buffers; antioxidants; sweeteners; and taste masking / masking agents. SCHERING CORPORATION, New