US3106511A - Amyl nitrite inhalant composition - Google Patents

Description

United States Patent 6 3,106,511 AMYL NITRETE INHALANT CGMPGSITIQN Harry A. 'Cuttler, Gien Cove, and Herman E. Jass, Hartsdaie, Nfifl, assignors to Revlon, Inc, New York, N311, a corporation of Deiaware No Drawing. Filed Dec. 14, 1961, Ser. No. 159,462

9 Claims. (Q1. 167-54) This invention relates to medicament compositions containing amyl nitrite, and to their preparation and use. In particular, this invention relates to self-propelling medicament compositions containing amyl nitrite and adaptable to dispersion in aerosol form, and to their preparation and use.

The use of amyl nitrite as a vasodilator in the treatment of angina pectoris is well known in the art. Treatment using this drug is commonly by inhalation, and the drug is usually marketed in sealed breakable ampoules or pearls. When chest pain occurs, a patient employing the drug breaks the ampoule wrapped in a handkerchief and inhales the fumes of the drug.

This method of treatment suffers from a number of disadvantages. First, it is almost imposible properly to dose a patient with the drug by this technique, since the amount of drug inhaled will vary greatly with the manner of inhalation, such as the depth of breathing and the distance at which the source of the drug is held from the nose and mouth. Also, to insure that an adequate dosage of the drug is delivered to the patient, the ampoules must containwastefully large amounts of the drug, usually 200300 mg., which amount far exceeds the required dose. Further, the drug has a characteristic and offensive odor which may make its use in public inconvenient and embarrassing. Also, the inconvenience of packaging, merchandising, and carrying breakable ampoules is selfevident. Further, amyl nitrite vapors are inflammable, and inhalation of the vapors involves some risk.

However, the most important impediments to the medicinal use of amyl nitrite are its characteristic unpleasant taste and odor, which commonly cause nausea, vomiting, and headaches in many patients who ingest the drug. These side effects of the drug have heretofore hindered its use, even though the problems of inconvenient administration ofthe drug can be overcome by dispensing it in aerosol form, for example.

According to the present invention, it has been discovered that the disagreeable'taste and odor of amyl nitrite can be eilectively masked to reduce or eliminate the disagreeable side eflects often caused by the drug.

Although the masking agent may be combined with amyl nitrite for administration by conventional inhalation or other means, the greatest significance of the discovery is that it makes possible the practical administration of amyl nitrite by aerosol inhalation.

The masking agent of the invention is a critical combination of performing and flavoring agents. In particular, the disagreeable taste and odor of amyl nitrite are effectively masked with ionones. Many ionone isomers, including the alpha, beta-, gamma-, and deltaetc. isomers, are known to the art and can be employed either alone or in mixtures containing two or more components in all proportions. Similarly, the isomeric methyl and allyl ionones can be employed, either alone, in admixture in all proportions with one another, or in admixture in all proportions with any and all of the unsubstituted ionone isomers.

These ionones have been used in the prior art in perfumery, and, in combination with sweetening agents, in small amounts as flavoring agents in hard candies, cough syrups and other artificially flavored materials. The ionones, undiluted, have a bitter and disagreeable taste,

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however, and because of this property the prior art has not heretofore employed them in the relatively large amounts in which they are used in the present invention, where they are not combined with sweeteners.

In the masking agent of the invention, these ionone materials are critically employed in combination with the so-called Cl4, C16, and Cl8 aldehydes, also known in the perfuming art. As known in the art, these various aldehydes are compounds, not necessarily aldehydes, which have common characteristic properties useful in flavoring and perfuming. The Cl4 or peach aldehydes, for example, include gamma-undecalactone, delta-undecalactone, gamma-decalactone, and alpha-substituted gamma butyrolactones in which the substituents may be aliphatic, such as allyl, propyl, heptyl, and octyl, or aromatic, such as phenyl, benzyl, and citronellyl. Those skilled in the art recognize that these Cl4 mate rials may contain more or fewer than 14 carbon atoms.

' Similarly, the C16 or strawberry aldehydes include materials such as ethyl-phenyl-glycidate and ethyl-methylphenl-glycidate.

The C18 or coconut aldehydes include octalactone,

.gamma-nonyllactone, gamma-substituted gamma-butyrolactones such as gammacaprylolactone, gamma-n-amyl butyrolactone, and 8-methyl-l,4-octanolide.

These perfuming agents, together with other optional perfuming agents of a wide variety, are critically combined with a flavoring agent aiding the masking of the taste and odor of amyl nitrite and additionally masking the often disagreeable taste of the perfuming agents principally employed to mask the drug. As flavoring agents, agents from the so-called mint series are critically present, but can be used in combination with numerous other flavoring agents, preferably those from the so-called spice series, but also including fruit flavors, anise flavors (lic 'orice, anethol, etc), root extracts, and/or Wintergreen,

critically contains between about 7.5 and about 22.5 percent by weight, based on the total masking agent composition, preferably about 10-20 percent by weight, of ionone and/or methyl ionone and/or allyl ionone isorners. These materials are critically combined with between about 0.5 and about 2.5 percent by weight, preferably about 1 to about 2 percent by weight, of the socalled Cl4 to (3-18 aldehydes, alone or in combination. The composition also critically contains between about 45 and about 70 percent by weight of a flavoring agent from the mint series, preferably about 50 to percent by weight of such a flavoring agent. In addition, other perfumi-ng agents, well known to those skilled in the art, may be present in amounts of up to 8 percent by weight, suitably from about 6 to about 8 percent by weight, or 6.5 to 7.5 percent by weight of the composition. Also, other flavoring agents well known to those skilled in the art may be present in amounts of up to 30 percent by weight, suitably from 10 to 30 percent by weight, or 12 to 25 percent by weight of the composition. 1

Many flavoring agents in the so-called =rnint series are known to the flavoring chemist. This series includes spearmint oil, USP, peppermint oil, USP, terpeneless peppermint, terpeneless spearrnint, menthol, synthetic menthols, and others.

As additional flavoring agents may be mentioned substances in the so-c alled spice series suchas cassia, USP, clove bud oil, USP, eugenol, nutmeg oil, cinnamic aldehyde, methyl cinnamic aldehyde, as well as other flavoring agents such as vanillin, ethyl vanillin, heliotropin, methyl salicylate, sweet birch oil, and various esters of aromatic alcohols *and/ or acids such as methyl'anthranilate, or other esters of anthranilic, benzoic, salicylic, and

cinnamic acids, or benzyl, and cinnarnyl alcohols, and the like. Additional flavoring agents may be found in the fruit flavors, such as orange, lemon, lime, the anise flavors, the root extracts, Wintergreen, and others.

As additional perfuming agents useful in the compositions of the invention may be mentioned materials such as iso-eugenol, benzyl acetate, linalool, geranyl acetate, rose oil, and the like.

The above listing of perfuming and flavoring agents, including materials in the mint series, spice series, and others, is not intended to be exhaustive. Numerous other flavoring and perfuming agents are known to those skilled in the art and are comprised within the scope of the present invention. Specific reference is made to Synthetic Food Adju-ncts, by Morris B. Jacobs, D. Van Nest-rand, New York (1947), and Perfume and Flavor Materials of Natural Origin, by Steflan Arctander, published by the author, Elizabeth, New Jersey (1960), where numerous materials known to the art and suitable for use in the invention are discussed.

To prepare a masked amyl nitrite composition, the pre-cornpounded masking agent, prepared by thorough mixing of the flavoring and perfuming ingredients, is suitably combined with amyl nitrite in amounts of from about 0.5 to about 4 percent by Weight of amyl nitrite, preferably in amounts of from 1 to 3 percent by weight of amyl nitrite. The final composition, with an aerosol propellant, suitably contains a minimum of about 0.1 perent by weight of masking agent.

In preparing an aerosol composition, the masking agent and amyl nitrite are dissolved in a non-toxic volatile liquefied propellant. Suitable non-toxic volatile propellants are known in the art, and are discussed in Patent 2,868,691 for example. These materials are generally fluorinated or fluorochlorinated lower saturated aliphatic hydrocarbons, suitably halogenated alka-nes containing one to four carbon atoms, preferably one or two carbon atoms, and at least one fluorine atom. In general, any of the materials disclosed in the earlier mentioned patent can be employed according to the present invention, including propellants such as dichlorodifluoromethane (Freon 12), dichlorotetrafluoroethane (Freon 114), trichloromonofluoromethane (Freon 11), and octafluorocyclobutane (Freon C-3l8). These propellants, or suitable mixtures thereof, will produce a propellant vapor pressure between about 25 and about 60 pounds per square inch at room temperatures (20-25 C.). Suitable mixtures of the propellants can be employed to give a preferred vapor pressure between about 35 and about 40 pounds per square inch at these temperatures. The best propellant compositions contain about 60 percent by weight of Freon 12, blended with Freon 114. However, this mixture or other specific mixtures are not critical to the invention and any non-toxic liquid volatile propellant, such as those earlier described herein, may be employed.

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 material, such as glass, plastic, or metal, adequate to contain the pressures generated by the volatile propellant materials therein. Conventionally, these metered containers have an internal well of predetermined volume which is filled with the self-propelling composition. On activation of the aerosol valve, only this predetermined volume of self-propelling composition is dispersed as an aerosol, and the internal well is refilled.

When used in such a metered valve container, the relative proportion of amyl nitrite (and masking agent) to volatile propellant may vary with the dose of pure amyl nitrite to be dispensed and the size of the metered dose delivered by the valve. Dosage rates of pure amyl nitrite will vary between about 1 milligram and about 25 milligrams, generally between about 5-10 milligrams, and the quantity of propellant combined therewith will be chosen to deliver this amount of pure amyl nitrite on activation of a metered valve of chosen size. For example, in metered aerosol dispensers having a so-called 50 milligram valve, that is, a valve which will dispense 50 milligrams of a liquid of unit density each time it is activated, amyl nitrite is usually combined with a propellant in amounts of between about 5 and about 20 percent, suitably about 10 percent by weight, based on the total composition. In such a combination containing 10 percent by weight of amyl nitrite, about 0.5 to 0.4 percent by weight of masking agent, usually between about 0.1 and 0.3 percent by weight, is present, the balance being the volatile propellant mixture.

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

Example The following masking agents were prepared by mixing the enumerated ingredients in the amounts indicated.

Parts by weight A. Ionones: 11-13 methyl ionone 2000 B. Mint flavors:

Spearmint oil, USP 2000 Peppermint oil, USP 5000 Menthol 2000 C. C-14--C-18 aldehydes: C-14 aldehyde 150 D. Other flavoring agents:

Cassia, USP 1000 -Eugeno1 500 Vanillin 500 Heliotropin 500 Methyl anthranilate E. Other perfuming agents:

Benzyl acetate 500 Rose oil 500 A. Ionones:

a-flionone 1000 11-13 methyl ionone 1500 B. C-l4-C18 aldehydes:

C-l4 aldehyde 100 C-l8 aldehyde 50 C. Mint flavors:

Spearmint oil, USP 3000 Peppermint oil, USP 2000 Terpeneless Spearmint 1000 Menthol 3000 D. Other flavoring agents:

Cassia, USP 500 Clovebud oil, USP 500 Nutmeg oil 500 Vanillin 200 Ethyl vanillin 200 Heliotropin 400 E. Other perfuming agents:

Benzyl acetate 400 Lin-alool 100 Geranyl acetate 100 Rose oil 400 A. Ionones:

a-fi ionone 600 a-fi methyl ionone 1500 B. C14- Cl8 aldehydes: C-l4 aldehyde C. Mint flavors:

Peppermint oil, USP 3000 Terpeneless peppermint 1000 Menthol 2000 D. Other flavoring agents:

Cassia, USP 500 Cinnamic aldehyde 300 Vanillin 500 Heliotropin 400 Methyl salicylate 500 Sweet birch oil 100 Methyl anthranilate 50 E. Other perfurning agents:

Benzyl acetate 400 Rose oil 400 These masking agents were used to compound aerosol compositions with amyl nitrite as follows.

Ingredients: Parts by weight Masking agent 0.25 Amyl nitrite 9.75 Freon 12 54 Freon 114 36 Ingredients: Parts by weight Masking agent 0.30 Amyl nitrite 14.70 Freon 12 60 Freon 114 15 Freon 11 Ingredients: Parts by Weight Masking agent 0.20 Amyl nitrite 6.80 Freon 12 53 Freon 114 30 Freon C-318 10 Although specific embodiments have been shown and described, it is to be understood that they are illustrative, and are not to be construed as limiting on the scope and spirit of the invention.

What is claimed is:

1. A composition suitable for inhalation therapy consisting of amyl nitrite and a masking agent comprising a blend of (A) a member selected from the group consisting of ionone, methyl ionone, and allyl ionone isomers, (B) a perfuming agent selected from the group consisting of the C-14, C-l6, and C18 aldehydes, and (C) a flavoring agent of the mint series.

2. A composition as in claim 1 wherein said masking agent is present in an amount of at least 0.5 percent by weight of amyl nitrite.

3. A composition as in claim 1 in a non-toxic liquefied propellant.

4. A composition as in claim 1 wherein additional flavoring and perfuming agents are present. 1

5. A composition as in claim 4 wherein said propellan comprises 60 percent by Weight of dichlorodifiuoromethane, the balance being dichlorotetrafluoroethane.

6. In a composition adaptable to use in inhalation therapy in aerosol form and comprising amyl nitrite in a non-toxic liquefied propellant, a masking agent combined in said composition and consisting essentially of a blend of:

(A) between about 7.5 and 22.5 percent by weight of a member selected from the group consisting of ionone, methyl ionone, and allyl ionone isomers;

(B) between about 0.5 percent to about 2.5 percent by weight of a perfuming agent selected from the group consisting of the C-14, C-16, and C-18 aldehydes;

(C) between about 45 percent and about 75 percent of a flavoring agent of the mint series;

(D) up to about 8 percent by weight of other optional perfuming agents; and

(E) up to about percent by Weight of other optional flavoring agents, all percentages being based on the weight of the blend.

7. A composition as in claim 6 wherein said masking agent is present in an amount of at least 0.5 percent I by weight of amyl nitrite.

8. The method of masking the disagreeable taste and odor of amyl nitrite which comprises combining therewith from about 0.5 to about 4 percent, by weight of amyl nitrite, of a masking agent comprising a blend of (A) a member selected from the group consisting of ionone, methyl ionone, and allyl ionone isomers, (B) a perfuming agent selected from the group consisting of the C-14, C-16, and C-18 aldehydes, and C a flavoring agent of the mint series.

9. The method as in claim 8 wherein said amyl nitrite and masking agent are dispersed in a non-toxic liquefied propellant.

References Cited in the file of this patent FOREIGN PATENTS 461,813 Canada Dec. 20, 1949 OTHER REFERENCES U.S. Dispensatory, 25th edition, 1955, pages 89 and 90 Lippincott Co., Phila., Pa.

Pharmaceutical Formulas, vol. 1, 12th edition, 1953, The Chemist and Druggist, London, England, pages 648- 650.

Shepherd: Aerosols: Science and Technology, 1961, Interscience Publishers, Inc., N.Y., N.Y., pages 293, 294, 298, and 311.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N00 3 106,511 October 8 1963 Harry A. Cutt ler et a1.

he above numbered pat- It is hereby certified that error appears in 1:

Patent should read as ent requiring correction and that the said Letters corrected below.

Column 6, line 3. for the claim reference numeral "4" read 6 same column '6, lines 35 and 36 ing agent read (C) e filBVOIiflQ agent Signed and sealed this IZth day of May 1964;

(SEAL) Attest:

ERNEST Wo SWIDER EDWARD J BRENNER Attesting Officer Commissioner of Patents for "C a flavor"-

Claims (1)

1. A COMPOSITION SUITABLE FOR INHALATION THERAPY CONSISTING OF AMYL NITRITE AND A MASKING AGENT COMPRISING A BLEND OF (A) A MEMBER SELECTED FROM THE GROUP CONSISTING OF IONONE, METHYL IONONE, AND ALLYL IONONE ISOMERS, (B) A PERFUMING AGENT SELECTED FROM THE GROP CONSISTING OF THE C-14, C-16, AND C-18 ALDEHYDES, AND (C) A FLAVORING AGENT OF THE MINT SERIES.