Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1993-12-09
2003-01-07
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S045000
Reexamination Certificate
active
06503482
ABSTRACT:
INTRODUCTION TO THE INVENTION
The present invention is directed at aerosol formulations which are substantially free of chlorofluorocarbons (CFC's). More specifically, the present invention is directed at formulations substantially free of CFC's and having particular utility in medicinal applications, especially in metered dose pressurized inhalators (MDI's).
Metered dose inhalators have proven to be an effective method for delivering medicaments orally and nasally. They have been used extensively for delivering bronchodilating and steroidal compounds to asthmatics and may also be useful for delivering other compounds such as pentamidine and non-bronchodilator anti-inflammatory drugs. The rapid onset of activity of compounds administered in this manner and the absence of any significant side effects have resulted in a large number of compounds being formulated for administration via this route. Typically, the drug Is delivered to the patient by a propellant system generally comprising one or more propellants which have the appropriate vapor pressure and which are suitable for oral or nasal administration. The more preferred propellant systems typically comprise propellant 11, propellant 12, propellant 114 or mixtures thereof. Often the vapor pressure of the propellant systems is adjusted by admixing a liquid excipient with the propellant.
However, propellants 11, 12 and 114 belong to a class of compounds known as chlorofluorocarbons, which have been linked to the depletion of ozone in the atmosphere. It has been postulated that ozone blocks certain harmful UV rays and that a decrease in the atmospheric ozone content will result in an increase in the incidence of skin cancer. In the 1970's certain steps were taken to reduce the CFC emissions from aerosols. Other propellants, such as hydrocarbons, were used, or the product was delivered in a different manner. Because CFC usage in medicinal applications is relatively low i.e. less than 1% of total CFC emissions, and because of the health benefits associated with metered dose inhalators, steps were not taken at that time to restrict the use of CFC propellants in metered dose inhalators.
However, continuing and more sophisticated ozone measurements have indicated that the earlier restrictions in CFC usage were insufficient and that additional, significant steps should be taken to drastically reduce CFC emissions. Recently, recommendations have been made that CFC production be virtually discontinued by the end of this century. As a result, it may not be possible to continue to use CFC propellants in the intermediate and long term. While some efforts have been made to use non-pressurized metered dose inhalators, many of these devices have not been completely successful. Many do not deliver uniform doses, are mechanically complex, do not provide the 100-200 doses per unit of current aerosol containers, are difficult for individuals to utilize, are bulky and/or cumbersome for the patients to use, particularly when they have an acute need for the medication.
As a result, there is a need for aerosol formulations substantially free of CFC's. Non-CFC propellants must meet several criteria for pressurized metered dose inhalators. They must be non-toxic, stable and non-reactive with the medicament and the other major components in the valve/actuator. One propellant which has been found to be suitable is CF
3
—CH
2
F, 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 propellants. Propellant HFC 134a has a vapor pressure of 5.84×10
5
newton/meter
2
absolute (84.7 psia), which is too high for use in metered dose inhalators. In addition, commonly used surfactants may be insoluble in HFC 134a. Moreover, where the medicament is to be delivered as a solution, the medicament may not be readily soluble in this propellant. The density and polarity difference between HFC 134a and the previously used CFC propellant may result in a different delivery of the medicament when HFC 134a replaces a CFC propellant. The medicament may cream, settle or agglomerate in the non-CFC propellant even though this did not occur in the CFC propellant.
The use of HFA 134a previously has been disclosed for use in medicinal inhalators. European Patent Publication No. 0 372 777 is directed at medicinal aerosol formulations incorporating 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 the propellant and the medicament.
International patent application No. WO 91/04011 discloses the combination of 1,1,1,2 tetrafluoroethane and a powdered medicament pre-coated with a non-perfluorinated surfactant prior to dispersing the powdered medicament in the propellant. Pages 6-7 of the publication list suitable surfactants for use with the propellant. A perfluorinated adjuvant optionally could be added. However, the pre-coating of the medicament may not be advantageous, since it adds an additional, complex step to the manufacturing process.
Research Disclosure
No. 30161, May 1989 discloses that non-CFC propellants such as fluorohydrocarbons may be used in pressurized medicaments delivered directly to the lungs e.g. bronchodilators.
U.S. Pat. No. 4,174,295 discloses the combination of HFC 134a with various chlorofluorocarbons and optionally a saturated hydrocarbon.
U.S. Pat. No. 2,885,427 discloses the use of HFC-134a as an aerosol propellant.
U.S. Pat. No. 3,261,748 discloses the use of HFC-134a for anesthesia.
U.S. Pat. Nos. 4,129,603, 4,311,863, 4.851,595 and European Publication No. 379,793 also disclose the use of HFC-134a as an aerosol propellant.
However, the specific combinations noted above may not provide the desired solubility, stability, low toxicity, exact dosage, correct particle size (if suspension) and/or compatibility with commonly used valves assemblies of metered dose inhalers.
SUMMARY OF THE INVENTION
The present invention is directed at non-toxic formulations substantially free of CFC's, having improved stability and compatibility with the medicament and valve components and which are relatively easily manufactured.
The present invention also is directed at formulations which may be utilized in present aerosol filling equipment with only relatively minor modifications and without pre-coating the medicament.
The invention includes an aerosol formulation comprising:
A. an effective amount of medicament; and
B. 1,1,1,2 tetrafluoroethane.
The formulation optionally may further comprise an excipient preferably selected from the group consisting of:
propylene glycol diesters of medium chain fatty acids;
triglyceride esters of medium chain fatty acids;
perfluorodimethylcyclobutane;
perfluorocyclobutane;
polyethylene glycol;
menthol;
lauroglycol;
diethylene glycol monoethylether;
polyglycolized glycerides of medium chain fatty acids;
alcohols;
eucalyptus oil;
short chain fatty acids;
and combinations thereof.
The formulation optionally may further comprise a surfactant. The surfactant preferably is selected from the group consisting of:
oleic acid;
sorbitan trioleate;
cetyl pyridinium chloride;
soya lecithin;
polyoxyethylene(20) sorbitan monolaurate;
polyoxyethylene(20) sorbitan monostearate;
polyoxyethylene(20) sorbitan monooleate;
polyoxypropylene-polyoxyethylene block copolymers;
polyoxyethylene (10) stearyl ether;
polyoxyethylene (2) oleyl ether;
polyoxypropylene-polyoxyethylene-ethylenediamine block copolymers;
castor oil ethoxylate; and combinations thereof.
The preferred liquid excipients are diethylene glycol monethyether, propylene glycol diesters of medium chain fatty acids, perfluorodimethylcyclobutane and polyethylene glycol.
The preferred surfactants are oleic acid; sorbitan trioleate, cetylpyridinium chloride; polyoxyethylene (20) sorbitan monolaurate; polyoxypropylene-polyoxyethylene block copolymers; soya lecthin; and polyoxypropylene-poly
Chaudry Imtiaz A.
Fassberg Julianne
Kopcha Michael
Sequeira Joel A.
Dees Jose′ G.
Franks Robert A.
Mazer Edward H.
Schering Corporation
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