US3155574A - Aerosol composition - Google Patents

Description

United States Patent 3,155,574 AEROSOL COMPOSITION John E. Siison, Pleasantville, and John Frangos, Brooklyn,

N.Y., assignors to Revlon, Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed May 24, 1962, Ser. No. 197,284 11 Claims. (Cl. 167-54) This invention relates to aerosol compositions, and to methods for making and using the same. In particular, this invention relates to aerosol compositions containing nitroglycerin, to methods of making the same, and to the use of such aerosol compositions in inhalation therapy.

The beneficial effects of nitroglycerin in relieving the pain associated with angina pectoris has long been known in the art. Although numerous other medicaments have been prescribed for the treatment of anginal pain, nitroglycerin remains the most effective and medically safest -therapeutic agent in this field.

The clinical role, administration, and effects of nitroglycerin and other anti-anginal drugs are extensively discussed in recent articles by Modell in Clinical Pharmacology and Therapeutics, pp. 97-198 (1962), and by Russek et al. in Postgraduate Medicine, pp. l50155 (February 1962). As emphasized in these articles, the only clinically useful means of administering nitroglycerin heretofore have been sublingually and parenterally. Nitroglycerin is relatively involatile, and not suitable to administration by direct inhalation of its fumes. Further, of course, the explosive properties of nitroglycerin have heretofore required that it be combined with a solid desensitizing agent (e.g., a therapeutically inert substance such as mannitol) in the form of tablets.

As pointed out in the article by Modell, the oral administration of nitroglycerin is of little value because the time required for the drug to be absorbed into the blood stream and carried to the coronary arterioles usually far exceeds the duration of the paroxysm of anginal pain which the drug is intended to relieve, and the drug is rapidly destroyed in the gastro-intestinal tract or is removed by the liver.

Sublingual administration suffers from similar limitations. The speed of action of sublingual administration may be as long as 2 to 3 minutes. Further, sublingual administration is erratic, since there is no control over the amount of nitroglycerin eiiectively absorbed by the mucous membranes of the mouth. Further, the nitroglycerin present in the uncoated tablets of the prior art is gradually decomposed on exposure to air and the efiicacy of the tablets is reduced with time. This lack of stability of the tablets is not only undesirable from a marketing standpoint, but also contributes to the problem of erratic dosing.

The present invention concerns methods for treating anginal pain associated with constriction of the coronary arteries with nitroglycerin by inhalation therapy, specifically by inhalation of a nitroglycerin-containing aerosol composition. According to the methods of the invention, safe, controlled, and speedy administration of nitroglycerin can be effected. Inhalation therapy, with pulmonary absorption of nitroglycerin into the bloodstream, is comparable in speed to intravenous administration, and insures prompt delivery of the nitroglycerin to the coronary arterioles in about 30 seconds or so. The use of metered valves with aerosol packages of the compositions of the invention insures that a controlled dose of the drug is administred. Since, in the aerosol package, the nitroglycerin is not exposed to the deleterious influences of air, the compositions retain their potency and efiicacy at original levels, making the product not only more accurate for dosing purposes, but more desirable from a marketing viewpoint.

The compositions of the present invention comprise 3,155,574 Patented Nov. 3, 1964 from about 30 to about percent by weight of a nontoxic volatile liquefied and/or liquid propellant, preferably from about 65 to about 95 percent, in admixture with about 5 to about 50 percent, preferably about 5 to about 25 percent, by Weight of a non-toxic substance solubilizing a desensitized nitroglycerin component in the propellant, the balance being a stabilized nitroglycerin component in which component about 1 to about 10 percent by weight, preferably about 5 to 10 percent, is the therapeutically active nitroglycerin and the balance is a nontoxic non-volatile liquid desensitizing agent for the nitroglycerin.

Suitable non-toxic volatile liquid or liquefied propellants are Well known in the aerosol art. These materials are generally fluorinated, chlorinated, or fiuorochlorinated saturated lower aliphatic hydrocarbons, or liquefied petroleurn gases. Suitably halogenated lower alkanes containing 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms, and at least 1 fluorine atom, are often generically referred to as fiuorohydrocarbon propellants, and are commercially available under the trade names Freons, Genetrons, Ucons, etc. These materials include such particularly useful propellants as dichlorodifluoromethane (Freon 12), dichlorotetrafiuoroethane (Freon 114),

trichloromonofluoromethane (Freon l1), and octafluo-' rocyclobutane (Freon C3 18). Other examples of suitable propellants are ethyl chloride, 1,1,l-trichloroethane, butane, isobutane, propane, etc.

The propellants, or suitable mixtures thereof (which mixtures are also referred to herein simply as propellants) are such as produce a desirable vapor pressure for the composition between about 15 and about 60 pounds per square inch at room temperatures (20-25 0.), preferably between about 35 and about 40 pounds per square inch at these temperatures. A combination of propellants particularly suitable for use in the present invention comprises a mixture of about 60 parts by Weight of Freon 12 with 40 parts by weight of Freon 11. However, it is to be understood that individual Freons or mixtures of Freons can be employed in the invention in various amounts with the other ingredients mentioned before so that the resulting mixtures show a pressure within the limits recited.

As the non-toxic agent solubilizing the stabilized nitroglycerin component, in the propellants just mentioned, ethyl alcohol has proved to be particularly suitable. This substance promotes the formation of uniform, homogeneous mixtures of the nitroglycerin-containing component with the propellants, and is unobjectionable from a clinical standpoint. The alcohol is suitably employed in amounts sufiicient to prevent separation of the nitroglycerin from the propellant but insufficient to reduce the volatility of the final composition below the pressure limits mentioned earlier as desirable in areosol packages.

The nitroglycerin-containing component, which is a mixture of nitroglycerin with one or more non-toxic nonvolatile liquid desensitizing agents, is compounded to contain from 5 to 10 percent by weight of nitroglycerin. If the amount of nitroglycerin is much in excess of the latter figure, the sensitivity of the composition may increase to a point at which the highly safe properties of the present compositions are lost. On the other hand, decreasing the amount of nitroglycerin in the composition merely increases the amount of therapeutically inactive desensitizing agent administered.

The desensitizing agents are preferably those non-toxic non-volatile liquid compounds having at least 3 carbon atoms and characterized by the structural formula XO(RO),,Y, in which R is alkylene, ketoalkylene or hydroxyalkylene having from 2 to 6 carbon atoms, X and Y may be different and are alkyl, ketoalkyl, hydroxyalkyl,

acyl, oxy-substituted acyl, and hydrogen, and n is an integer from 1 to 10. Exemplary of desensitizing substances of this class are the following: propanediol-1,2; diethylene glycol; polypropylene glycol (M.W. 400); diethylene glycol diacetate; polyethylene glycol (M.W. 200); diethyleneglycol butyl ether; glycol monoethyl ether; diethyleneglycol diethyl ether; diacetone alcohol; triethylene glycol; polyethylene glycol (M.W. 300); hydroxyethyl acetate; diethyleneglycol ethyl ether; dimethoxytetraglycol; trimethylene glycol; glycol diethyl ether; ethoxyethyl acetoxyethyl ether; diethyleneglycol methyl ether; methoxyethyl acetoxyethyl ether; glycol monomethyl ether; bis- (methoxyethyl) formal; bis(methoxyethyl) acetal; 2- methoxymethyl-2,4-dimethylpentane diol-1,5; butanedioi- 1,3; Z-methyl-pentanediol-2,4, and the like.

Of these materials, propanediol-1,2 has proved particularly suitable for use in the compositions of the invention, not only because of its excellent desensitizing properties, but also because of its extremely low toxicity. The glycol is compatible with the propellants commonly used in aerosol compositions, and blends well with the remaining components of the aerosol compositions of the invention with the formation of a homogeneous solution.

However, other of the sensitizing agents described above, particularly other glycols, can be used in compounding the compositions of the invention. Because of the extremely small amounts of sensitizing agent dispensed in practicing the inhalation therapy of nitroglycerin according to certain methods of the present invention, toxicity problems are minimized, and many materials otherwise considered unsuitable for inhalation can be employed. Thus, in administration of a dose of nitroglycerin of between about 0.05 to about 1.0 milligram, preferably 0.1 to 0.4 milligram, as contemplated by the present invention, as little as about 0.45 milligram of the desensitizing agent is inhaled.

In referring to the desensitizing agents, the term nonvolatile, as used herein, is defined as having vapor pressure characteristics such that evaporation of a mixture of nitroglycerin and the desensitizer in the proportions contemplated herein will not leave a nitroglycerin residue, e.g., the desensitizer has vapor pressure characteristics similar to those of nitroglycerin. The use of such a desensitizing agent insures that if, by accident, an aerosol container containing the compositions of the invention is punctured, with loss of the propellants, and, perhaps, the alcohol component, any residue will still be a desensitized nitroglycerin mixture, the desensitizer being the least fugitive ingredient of the composition, persisting even in the preference to the nitroglycerin under volatilizing conditions.

The compositions of the invention are conveniently prepared by dissolving a pharmaceutical grade of nitroglycerin in a suitable liquid desensitizer. This combination is then mixed with a solubilizing agent such as absolute ethyl alcohol. This mixture may then be combined with the propellants and put into containers, or the mixture and propellants may be separately put into containers by conventional cold fill or pressure methods.

The products of the invention are conveniently used in aerosol containers having a metered valve which dispenses a controlled quantity of the self-propelling aerosol composition as a single dose. These containers are Well known in the art, and may be made of any materials, such as glass, plastic, or metal adequate to contain the pressures generated by the volatile propellant materials therein. Conventionally, these metered containers operate by filling a well of predetermined volume with the self-propelling composition which is dispersed as an areosol.

When used in such a metered valve container, the amounts of propellant and active ingredients in the aerosol composition and the quantity of composition delivered by the valve are, relatively, such that a desired predetermined dose of active ingredient is delivered.

Administration is suitably effected by directing the orifice of the aerosol unit into the mouth and simultaneously inhaling and activating the metered valve.

A better understanding of the invention and of its many advantages will be had by referring to the following examples, given by way of illustration.

Example 1 An aerosol composition suitable for inhalation therapy and having a pressure of 53 p.s.i.g. at 70 F. was prepared by combining 4 weight percent of a combination of propanediol-l,2 and nitroglycerin containing 10 weight percent of nitroglycerin with 10 parts by weight of anhydrous ethyl alcohol, 51.6 parts by weight of dichlorodifluoromethane (Propellant 12), and 34.4 parts of dichloromonofluoromethane (Propellant 11).

Butanediol-LZ, propanediol-L3 or polypropylene glycol (MFN. about 300) can be substituted for propanediol-1,2 as desensitizers.

Example 2 A composition having a vapor pressure of 45 p.s.i.g. was prepared from 1.43 parts by Weight of a mixture containing 10 percent nitroglycerin (N6) in propanediol- 1,2 (PG), 10 parts of anhydrous ethanol, 53.13 parts of ropellant 12, and 35.44 parts of Propellant 11.

Example3 10% NG/PG 10.0 Anhydrous ethanol 25.0 Propellant 12 26.0 Propellant 11 39.0

Pressure: 36 p.s.i.g.

Example4 5% NG/PG 10.0 Anhydrous ethanol 25.0 Propellant l2 39.0 Propellant 11 26.0

Pressure: 43 p.s.i.g.

ExampleS 10% NG/PG 20.0 Anhydrous ethanol 25.0 Propellant 12 33.0 Propellant 11 22.0

Pressure: 45 p.s.i.g.

Example6 10% NG/PG 10.0 Anhydrous ethanol 35.0 Propellant 12 20.0 Ethyl chloride 35.0

Pressure: 25 p.s.i.g.

Example7 10% NG/PG 10.0 Anhydrous ethanol 40.0 Propellant 11 30.0 Isobutane 20.0

Pressure: 21 p.s.i.g.

Example8 10% NG/PG 10.0 Anhydrous ethanol 50.0 Propellant 12 30.0 1,1,1-trichloroethane 10.0

Pressure: 36 p.s.i.g.

Example9 10% NG/PG 10.0 Anhydrous ethanol 25.0 Propellant l2 8.0 Propellant 11 32.0 Dichlorotctrafluoroethane (Propellant 114) 25.0

Pressure: 22 p.s.i.g.

Example 10% NG/PG 10.0 Anhydrous ethanol 25.0 Propellant 12 50.7 Propellant 114 14.3

Pressure: 55 p.s.i.g.

Example 11 10% NG/PG 10.0 Anhydrous ethanol 25.0 1,1-difluoroethane 65.0

Pressure: 60 p.s.i.g.

Example 12 10% NG/PG 10.0 Anhydrous ethanol 25.0 l-chloro-l,l-difluoroethane 65.0

Pressure: p.s.i.g.

Atlhough specific embodiments have been described in the examples, and although various preferences, recommendations, and alternatives have been given, it is to be understood that these are not exhaustive or limiting of the invention, but are illustrative and for the purpose of instructing others in the principles of the invention and how to modify it so that they may be able to use it in a variety of embodiments as best suited to the conditions and requirements of a particular use.

What is claimed is:

1. An aerosol composition comprising a liquefied propellant, nitroglycerin and a non-volatile liquid desensitizing agent therefor, and an agent solubiiizing said nitroglycerin in said propellant.

2. An aerosol composition comprising a liquefied propellant, ethyl alcohol, nitroglycerin and a non-volatile liquid desensitizing agent therefor of the formula in which R is selected from the group consisting of alkylene, ketoalkylene, and hydroxyalkylene having 2-6 carbon atoms, X and Y are individually selected from the group consisting of alkyl, ketoalkyl, hydroxyalkyl, acyl, oxy-substitutcd acyl, and hydrogen, and n is an integer from 1 to 10.

3. A composition as in claim 2 wherein said desensitizing agent is a glycol.

4. A desensitized nitroglycerin-containing areosol composition comprising about 30-95 percent by weight of a volatile non-toxic liquefied propellant, about 5-50 percent by weight of ethyl alcohol, the balance being a mixture containing about 1-10 percent by weight of nitroglycerin with a non-toxic non-volatile liquid glycol.

5. A composition as in claim 4 wherein said glycol is propanediol-LZ.

6. The method of treating anginal pain by inhalation therapy which comprises inhaling between about 0.05-1.0 milligram of nitroglycerin in an aerosol composition containing the same, said composition comprising a volatile non-toxic liquefied propellant, ethyl alcohol, and nitroglycerin, and a non-toxic non-volatile liquid desensitizing agent therefor.

7. The method as in claim 6 wherein said non-toxic liquefied propellant is selected from the group consisting of fluorinated and fluorochlorinated saturated lower aliphatic hydrocarbons and said desensitizing agent is a glycol.

8. The method of treating anginal pain which comprises inhaling between 0.05-1.0 milligram of nitroglycerin in an aerosol composition containing the same, said composition comprising about 30-95 percent by weight of a volatile non-toxic liquefied propellant selected from the group consisting of liquefied petroleum gases, chlorinated, fluorinated and fluorochlorinated saturated lower aliphatic hydrocarbons, about 5-50 percent by weight of ethyl alcohol, the balance being a mixture containing about 1-10 percent by weight of nitroglycerin with a non-toxic non-volatile glycol.

9. The method as in claim 8 wherein said glycol is propanediol-1,2.

10. The method as in claim 8 wherein said composition has a vapor pressure of about 15-60 pounds per square inch at room temperatures and said propellant is at least one fluorochlorinated saturated lower aliphatic hydrocarbon.

11. The method as in claim 10 wherein said glycol is propanediol-1,2.

References Cited in the tile of this patent UNITED STATES PATENTS 2,648,698 Preckel Aug. 11, 1953 2,868,691 Porush et al. Jan. 13, 1959 3,014,844 Thiel et al. Dec. 26, 1961 OTHER REFERENCES Russek et al.: Paradoxical Action of Glyceryl Trinitrate (Nitroglycerin) in Coronary Patents, J. Am. Med. Assoc., volume 158, No. 12, pages 1017-1021, July 23, 1955.

Riseman: Current Concepts in Therapy, the Treatment of Angina Pectoris (HI); I. New England 1. Medicine, volume 261, No. 20, pages 1017-1020, November 12, 1959; II. Ibid., volume 261, No. 22, pages 1126-1129, November 26, 1959.

Claims (1)

1. AN AEROSOL COMPOSITION COMPRISING A LIQUEFIED PROPELLANT NITROGLYCERIN AND A NON-VOLATILE LIQUID DESENSITZING AGENT THEREFOR, AND AN AGENT SOLUBILZING SAID NITROGLYCERIN IN SAID PROPELLANT.