US2788308A - Topical non-aqueous acetic compositions - Google Patents

Description

United States Irving L. Ochs, Annapolis, and Preston L. Veltman, Severna Park, Md.

No Drawing. Application July 7, 1953, Serial No. 366,631

7 Claims. (Cl. 167-58) This invention relates to substantially non-aqueous compositions substantially insoluble in water and capable of providing therapeutically useful concentrations of ace tic acid for treating a variety of infections and potentially infected wounds of epithelial and other tissues.

Among the objects to the present invention are nonaqueous compositions which provide a therapeutic concentration of aqueous acetic acid at the interface of topical application.

Further objects include such compositions containing normally highly toxic or caustic materials under control to produce therapeutically beneficial materials.

Still further objects and advantages of the present invention will appear from the more detailed description set forth below, it being understood that such more detailed description is given by way of illustration and explanation only, and not by way of limitation since various changes therein may be made by those skilled in the art without departing from the scope and spirit of the present invention.

In accordance with the present invention, the necessary control of aqueous acetic acid concentration is obtained at the tissue interface by compositions for topical application containing a substance capable of producing acetic acid in topically effective concentrations by reaction at the aqueous interface where topical application is effected. The compositions are thus suitable for therapeutic use where healing and epithelial growth is the desired objective. Methods of employing what are normally considered to be dangerous materials, known to be lethal to even healthy tissue, in a way that results in new and useful therapeutic compositions is within the scope of the present invention. It has been found that substantially non-aqueous systems can be prepared containing substantial quantities of, for instance, acetic anhydride. The acetic anhydride is capable of dilfusing thru the mass and at the aqueous interface provides a source of aqueous acetic acid. In certain instances it has been found desirable to assist the solution of acetic anhydride (or other active ingredient) by first dissolving the acetic anhydride in a solvent, e. g. a sweet oil (for instance, medicinal olive oil) and, then, compounding this base material with for example petrolatum to obtain a desired composition. A homogeneous, single phase, composition may thus be obtained. The same general procedure may be employed using glacial acetic acid or other active component.

The concentration of acetic acid at the'point of use is a function of the concentration of acetic ingredient (i. e., acetic anhydride, glacial acetic acid, or other material) in the non-aqueous medium and it is proportional to the rate of diffusion thru the holding medium to the interface. The rate of dilution at the interface, rate of diffusion within the medium, and mechanical mixing action of the body on the vehicle are also factors to be considered.

An optimum system can be compounded wherein a maximum concentration of acetic acid producing material atent O 2,788,308 Patented Apr. 9, 1957 ice may be contained in the non-aqueous mass and the diffusion factors regulated to provide a desired rate of production of aqueous acetic acid for therapeutic purposes. The diflusion rate may be controlled by the addition of selected agents that may, by their interreaction with the active ingredient, either, as desired, increase, or decrease, the diffusion rate and thereby influence the aqueous acetic acid concentration at the interface between the substantially non-aqueous medium and the tissue surface. The fundamental physical characteristics of the substantially non-aqueous vehicle may also be selected or altered to provide a desired physical effect or a. beneficial additional therapeutic action.

The active component e. g. one capable of generating acetic acid as by hydrolysis and or dilution at the interface of topical application, is desirably acetic anhydride or glacial acetic acid or mixtures thereof. These active agents will be utilized to illustrate the invention. But one may obtain the desired result of providing a therapeutic level of acetic acid solution at an interface by utilizing molecular compositions capable of producing acetic acid by reaction at the aqueous interface. For instance, a complex acetate molecule such as cellulose triacetate may be hydrolyzed in the vicinity of the interface to produce acetic acid. As indicated previously, a molecule of acetic anhydride may react with a molecule of water to produce two molecules of acetic acid. The acetic acid produced would then be diluted by the body fluids to provide the desired suitable therapeutic concentration. Likewise, if glacial acetic acid is used as the active ingredient, it is diluted at the interface by body fluids to form a therapeutically useful concentration of aqueous acetic acid. Such active components capable of producing acetic acid of therapeutic utility are called herein pro-acetic components.

Acetic anhydride and glacial acetic acid are preferred materials to be used in substantially non-aqueous mediums. Acetic acid in aqueous solution in the form of concentrated acetic acid solutions e. g. acetic acid may be used provided they are dispersed or dissolved in a substantially non-aqueous medium so that :a therapeutically useful concentration -of acetic acid may be produced at the tissue interface. As the amount of water increases in a substantially non-aqueous system, the physical stability of the system generally decreases. Dispersing agents such as soaps, detergents, and the like may be added to aid in dispersing an aqueous material through a substantially non-aqueous medium. Also, if a substance such as lanolin is part of the composition, more water in admixture with the acid can be tolerated. But as indicated above, the preferred embodiment of the invention minimizes the amount of water present in the substantially nonaqueous composition containing a pro-acetic component.

The pro-acetic component is used in a substantially non-aqueous topical medium, e. g. a medium suitable for topical application as to the human epithelium. Such medium serves to control the rate of delivery of the active component to the aqueous interface. The media should serve as a reservoir for the pro-acetic component and permit its slow diffusion to the aqueous interface. For instance, various grades of petrolatum may be employed. If one desires a fluid or semi-fluid mass, a relatively low viscosity, oily, material may be used, whereas, if a more solid mass is desired, a highly viscous medium may be employed. Petrolatum is used to describe a refined petroleum material having the general formula CnH2n-l-2. These materials have melting points in the range of 38 to 54 C. and they are sometimes called paraffin jellies. Specific fractions may be more suitable for a desired application than others. For instance, if a less fluid composition is desired, a higher melting petrolatum is used. Substantially anhydrous lanolin may also be used in for pro-acetic components.

compounding materials'of the kind here described. Lanolin has the property of promoting interreaction with an aqueous phase.

Thus, it is not meant to limit the main vehicle material to petrolatum types or to be limited in the ways of incorporating aqueous acetic acid producing materials in the substantially non-aqueous medium. Glyceride oils have been used particularly olive, corn and peanut. Of these, medicinal olive oil has been most extensively used because of its purity and known quality. The vegetable oils are theglycerides of palmitic, stearic, oleic, arachidic, hypogalic, lignoceric, linolic, and the like and these areparticularly suited for use desirably with other substantially anhydrous Oils to hold acetic anhydride to form compositions which are therapeutically useful. Tallow is also available in many degrees of refinement and such materials can be used advantageously. Tallow has an ability toxhold: substantial quantities of .both' acetic anhydride and glacialacetic acid in apparentsolution and permits slow diifusion of. the pro-acetic component to an aqueousinterface where therapeutically useful concentrationsof acetic acid are formed.

The polyethylene glycols e. g. Carbowaxes, and such other non-aqueous materials, therapeutically suitable, may be used, as components of the substantially water insoluble composition. The term Carbowax is used to .describe compounds of the dihydroxy-ether typehaving the, general formula HOCH2(CH2OCH)7LCH2OH. They vary in degree of solidness and hygroscopicity. Individual commercially available compounds identified in terms of molecular weight and melting point ranges include:

IVI. W. M. P., C.

acetic components. Thus, glacial acetic acid can be contained in glycol containing compositions without reaction. Acetic anhydride, on the other hand, tends to react with glycol and similar types to form esters. This tendency increases with temperature, concentration and is influenced by certain catalysts. Propylene glycol may be used as a solvent aid in acetic anhydride and/or glacial aceticpetrolatumpropylene glycol compositions without apparent reaction to form esters. Both .acetic anhydride and glacial acetic acid are unreactive towards the petrolatum type media. Esters, if formed, can be present as a source of acetic acid by hydrolysis at the interface. Other glycols and their esters such as acetic esters which have a solvent action on pro-acetic compounds and are substantially water insoluble also may be used in compositions of thisinvention as vehicles Propylene glycol diacetate maybe used as a cooperative solvent agent in substantially water insoluble compositions and also it may, on slow, partial, hydrolysis, at the aqueous interface,

.serve as a pro-acetic component.

fter insoluble and capable of holding a supply of the acetic is I acid producing agent and permit diitusion of this agent to the interface where an aqueous acetic acid solution of the proper concentration can be formed by reaction and/or dilution.

The non-aqueous topical medium may desirably be a solvent tor the pro-acetic component or a more active topically suitable solvent, desirably liquid, may be used as illustrated above to enhance solution of the proacetic component in the topical medium. The ultimate composition employed may be of any desired consistency as liquid, unctuous, solid, etc. and the application may also be made in aerosol types of compositions and other compositions for application in body cavities by vapor or spray transfer or" active ingredients to the tissue surface. Various mediums and adjuvants may be mixed to adjust the properties of the composition. One or more of the pro-acetic components may be utilized with any combination of mediums so that two or more of any of the :sp'ecific components'set forth may be'mixed to produce a variety of physical 'propertiesas desired.

The ranges of proportions of components even of the pro-acetic component depend'on the nature of the composition, the solvent and other components, their ratios, and the conditions under which the composition is used. Various considerations bearing onthe question of proportions are givenlbelow. One of themprincipal objects of the present invention is the employment of what-are normally considered lethal:materials, for. therapeutic purposes. In our copending application, Serial No. 164,028,

now U. S. Patent No. 2,726,982, filed May 24, 1950, entitled Hydrous Gels, under the conditions there set forth, an upper limit of approximately 4% aqueous acetic acid is claimed to be the maximum that can be tolerated in contact with a wound to inhibit bacterial growth while still permitting epithelial growth. Compositions containing 10% acetic anhydride in a petrolatum, parawax, olive .oil composition have been successfully employed. -If

the composition contain suflicient diffusion inhibiting material, such as parawax, the rate of deliverance of pro-acetic component can be controlled to obtain a desired therapeutic concentration of aqueous acetic acid at the tissue interface while still permitting the use of a relatively high concentration of pro-acetic component in the substantially non-aqueous phase. Even 20% may not be unreasonable in a relatively slow diffusing system. One such highly concentrated composition, was made by blending 30 grams of Esso parawax, 30 grams of yellow petrolatum, 48 grams of olive oil, and 12 grams of acetic anhydride. The olive oil and petrolatum were melted together and the acetic anhydride added thereto with efficient stirring. This was then blended with the melted parawax and the resulting mass allowed to cool. In use, this relatively solid composition was melted and used to impregnate gauze bandage in which form it handles nicely.

The oil, wax, etc., proportions are not critical but the The following examples will illustrate the invention, parts being by weight unless otherwise indicated.

5 0.1 parts "acetic anhydride 290.8 parts medicinal olive oil 2,265.0 parts petrolatum (Vaseline) Any method of compounding the components may be used. The following is exemplary. The acetic anhydride is first dissolved .in theolive oil and this solution added with stirring to the meltedpetrolatum. A homogeneous preparation of good consistency results. This has been usedv in various ways, generally, with. gauzeas is done with ordinary Vaseline or petrolatum.

avsasos Percent Percent Petrolatum Esso parawnx A 100 B- 95 C 90 D. 85

Base compositions A, B, C, and D are progressively less mobile and when used as part of the non-aqueous carrier for active ingredient, offer progressively greater resistance to diffusion and thus this permits one to exercise a degree of control of rate of deliverance of active ingredient to the aqueous interface.

Four compositions were prepared using base stock A (pure yellow petrolatum).

Percent grams A grams R acetic anhydride net Likewise, four compositions were prepared using base stock B (95% petrolatum and 5% Esso parawax).

Percent grams B grams R acetic anhydride net In the same way preparations have been made with base stocks C and D.

Also, selected preparations have been made wherein glacial acetic acid was substituted for acetic anhydride in the preparation of an active ingredient containing base solution.

III

Lanolin containing compositions are illustrated by the following consisting of a blend of petrolatum (85 grams), anhydrous lanolin (15 grams), and 3.5 grams of the olive oil base stock containing 14.9% acetic anhydride. The resulting composition contained 0.50% acetic anhydride and has a desirable physical nature for therapeutic use.

Peanut oil may be used in place of medicinal olive oil in the compositions given above with encouraging results as a primary solvent for acetic anhydride.

Compositions consisting solely of an oil such as olive oil and acetic anhydride have been used with demonstrated utility. Five percent acetic anhydride in olive oil has been used to treat scalp infections. The pro-acetic component diffuses out of the oil and slowly hydrolyzes to form aqueous acetic acid. Compositions can vary widely and perfumes and other agents commonly used in such mixtures may be included. Spefific examples are:

To 95 grams olive oil add 5 grams acetic anhydride and affect solution by effective agitation.

To 50 grams olive oil add 5 grams acetic anhydride and affect solution. To this add 45 grams of liquid petroleum jelly normally liquid at room temperature.

This type of composition by its anti-bacterial action may also be used to improve the function of scalp cosmetics by addition thereto. The other glyceride oils may be used in such compositions in lieu of olive oil.

The Carbowax type compounds are particularly suited to be a part of a substantially non-aqueous substantially water insoluble medium carrying the pro-acetic component. Carbowax compounds are unctuous wax-like solids having excellent physical and physicalchemical characteristics for the purpose here described.

The following compositions illustrate methods of using Carbowaxes:

VII

10 grams of Esso parawax and grams of Carbowax 1540 were melted together and thoroughly mixed. To this blend was added 5 grams of glacial acetic acid and on cooling a composition of this invention is obtained. The parawax tends to make the composition less fluid at body temperature and also slows down the rate of diffusion of pro-acetic component to the aqueous interface.

As a second example of Carbowax containing compositions, the following is cited:

VIII

10 grams olive oil or other glyceride oil and 80 grams of Carbowax 4000 were melted together and 10 grams of glacial acetic acid added with stirring. The mass on cooling provides therapeutic concentrations of aqueous acetic acid at an aqueous interface by the slow diffusion of the pro-acetic component to the point of use.

Substantially non-aqueous compositions substantially insoluble in water carrying a pro-acetic component can be formed into a fine mist and as such can be used to disinfect air and thereby control air borne infectious agents. This discovery makes it possible to use compositions of this invention for a variety of purposes.

In animal husbandry one often seeks to control the spread of infection from one animal to another. Disinfection of the air in the confining area is possible by fine spray application. Also, breathing the pro-acetic spray may tend to assist recovery of the animal. A spray suited to disinfect flocks confined in close quarters may for example be made using peanut oil for carrying the pro-acetic component as follows:

95 parts of peanut oil and 5 parts of glacial acetic acid were blended and used directly.

Pine oil and other perfumants may be used to disguise the odor and possibly improve over-all utility. For instance:

parts peanut oil, 5 parts pine oil, and 5 parts glacial acetic acid were mixed to form a spray which is highly effective as an air disinfecting agent.

Similar compositions may be made using a pro-acetic component with any of the usual vehicles employed in fine spray applied type compositions particularly those which are inert to the particular pro-acetic component employed. Poppy seed and other vegetable oils may be used as a vehicle for the proacetic component. Glycols hours.

.may be added as adjuvants for specific effects and/or solventing action.

Compositions of the type described are particularly effective against gram negative bacillae, pyocaneus, proteus, and E. coli. Hemolytic Streptococcus and Staphylococcus aurcus are other typical organisms controlled by compositions of this invention. Both skin and mucosa lesions have been treated by these preparations. Infected infantile eczema with severe multiple ulceration have been cleared and epithelialized with this material. Foul infected severe second degree burns have been cleared and healed rapidly with these compositions. Severe trauma to extremities with avulsion of the skin remained free of infection and have healed with this material. This material has been usedas a packing in the maxillary sinus for 5 days without inhibiting epithelial growth and remainingfree of the foul odor usually resulting when-inert materials are used. it has also been .usedin many'noses as a packing for nose bleed andas a .splint to hold nasal fracture in place, without becoming infected.

stratetheeifectiveness of compounds described to inhibit bacterial growth. The pro-acetic component diffuses out of the substantially non aqueous composition to form therapeutically useful concentrations of acetic acid.

A mixture of yellow petrolatum with olive oil was used as a control and results compared with an identical mixture containing 2% added acetic ranhydride as the pro-acetic component. Filter paper discs were impregnated with one cc. each of the control blank and the pro-acetic containing composition. These impregnated discs were applied to the surface of heavily streaked cultures of several organisms and incubated for 48 Examination of the cultures clearly showed a ring of clear media around the disc containing the proacetic component. The control composition impregnated discs show heavy growth of organisms up to and even under the disc itself.

The following series of experiments are presented to demonstrate the facts in regard to the actual diffusion of .platesdemonstrate this-action. However, to further establish the facts a seriesof diffusion experiments whereby the production of acetic acid at the interface was measured as a function of time by the movement of a pH front through a-column of a 2% C. M. C. gel containing chlorphenol red as an indicator. Chlorphenol red changes color between 5.8 and l'5.2'pH. A second set of identical experiments-were carried out using bromthymol blue which changes at a pH of 6.0.

10 cc. portions of the C.- M. C. gel containing an indicator were placed in 10 mm. tubes and 5 cc. of proacetic (2% acetic anhydride) containing substantially non aqueous composition placed on top. The tubes were maintained at 70 F. and the pH front observed as a 1 Carboxyinethylcellulose.

solvent-vehicle is petrolaturn.

function of time. Two types of petrolatum were used and the experiments run in quadruplicate. For convenience, the information is tabulated.

Penetration mm. 5.2 Penetration-mm.-6.0

The-above data, when plotted indicate that the 6.0 pH front moved 40 mm. in 50 hours and the 5.2 pH front moved 26 mm. in 50 hours. The relative slopes of the curves between 10 and 50 hours indicate that the 6.0 pH front moves 1.57 times faster than the 5.2 pH front. These data prove beyond reasonable doubt that the pro-acetic component moved out-of the substantially non-aqueous mediumand diflused through an adjacent aqueous medium. Likewise when such substantiallynon aqueous compositions containing a pro-acetic agentare used for therapeutic purposes, a useful concentration of acetic acid is produced at the interface. Within experimental error, there was no difference in the rate of diffusion caused by substituting yellow petrolatum for-the more highly refined white variety. For some applications the yellow is preferred in that it has more fibre and is less fluid at body temperature.

Having thus set forth our invention, we claim:

1. A substantially anhydrous topical composition for the promotion of epithelialization by the control of antia bacterial action consisting of an acetic component selected from the group consisting of glacial acetic acid and acetic anhydride in a non-aqueous solvent-vehicle selected from the group consisting of glyceride oils, propylene glycols, polyethylene glycols, and petrolatum, and mixtures thereof, the acetic component being present in proportions from 0.5% to 20% by weight, so as to produce therapeutic action at tissue interface.

2. The topical composition of claim 1 acetic component is glacial acetic acid.

3. The topical composition of claim 1 acetic component is acetic anhydride.

4. The topical composition of claim 1 solvent-vehicle is a glyceride oil.

5. The topical composition of claim 1 solvent-vehicle is a propylene glycol.

6. The topical composition of claim 1 solvent-vehicle is a polyethylene glycol.

7. The topical composition of claim 1 in which the in which the in which the in which the inwh'ich' the in" which" the References tCited inthe file of this patent UNITED STATES PATENTS Knaggs Nov.-8, 21887 OTHER REFERENCES Lesser: Drug-and Cosmetic Ind 'January i949; v61 64, No. l, p. 44-.

Am. Iour. of Pharm., vol. 119, pp. 393 and 394.

Pharmaceutical Formulas, The Chemist and Driiggist,

4 London. 1944, page 660.

7 Hopkins: Tour. of Investigative -Derinatology,"'Augiist 1946,pp. 171-173.

Claims (1)

1. A SUBSTANTIALLY ANHYDROUS TOPICAL COMPOSITION FOR THE PROMOTION OF EPITHELIALIZATION BY THE CONTROL OF ANITBACTERIAL ACTION CONSISTING OF AN ACETIC COMPONENT SELECTED FROM THE GROUP CONSISTING OF GLACIAL ACETIC ACID AND ACETIC ANHYDRIDE IN A NON-AQUEOUS SOLVENT-VEHICLE SELECTED FROM THE GROUP CONSISTING OF GLYCERIDE OILS, PROPYLENE GLYCOLS, POLYETHYLENE GLYCOLS, AND PETROLATUM, AND MIXTURES THEREOF, THE ACETIC COMPONENT BEING PRESENT IN PROPORTIONS FROM 0.5% TO 20% BY WEIGHT, SO AS TO PRODUCE THERAPEUTIC ACTION AT TISSUE INTERFACE.