Topical Medicament Preparations

This invention relates to an improved method and compositions for the topical treatment of animal (including human) tissues. More particularly, the invention relates to penetration aids which, when incorporated into topical therapeutic compositions, enhance the penetration of various therapeutic agents into and/or through the skin of animals.

The skin is designed by nature to provide an effective barrier against the penetration of foreign substances into the body. Although generally beneficial, the barrier properties of the skin often interfere with the effective delivery of topically-applied medicaments to their intended site of action. To overcome this problem, a number of chemical penetration aids have been developed. For example, U.S. Pat. No. 3,326,768 discloses that the presence of a phosphine oxide surfactant in antiperspirant compositions containing anticholinergic compounds provides more efficient absorption of the active compounds at the site of application. U.S. Pat. No. 3,472,931 discloses that percutaneous absorption of certain therapeutic agents is enhanced by incorporating the agent into a vehicle containing a lower alkyl amide. Compositions for enhancing the penetration of pharmacologically active agents through the skin comprising a sugar ester in combination with a sulfoxide or phosphine oxide are disclosed in U.S. Pat. No. 3,896,238.

Dimethylsulfoxide (DMSO) is regarded as one of the most effective penetration enhancers discovered to date. However, it has been shown that DMSO has some undesirable side effects that preclude wide spread applications for human (as well as most animal) uses. Accordingly, prior to the present invention there existed a need for a penetration aid for topical therapeutic compositions which would be effective for a broad spectrum of therapeutic agents and cause a minimum of undesirable side effects.

According to the present invention, it has been discovered that certain water-soluble amine oxide compounds are extremely effective in enhancing penetration of certain therapeutic agents into and through the skin with minimal toxic side effects. Amine oxides have been used heretofore in compositions which contact the skin, most notably as solubilizers or emulsifying agents in certain cosmetic formulations and shampoos. U.K. Pat. Application No. GB2,004,185A discloses cosmetic preparations such as facial lotions and shampoos containing certain alkyl amine oxides as solubilizing agents. U.S. Pat. No. 4,048,338 discloses cosmetic compositions containing certain novel morpholine oxides. The compounds are described as having many desirable attributes of particular value in emulsification, cleansing and detergency. They are further described as having a non-irritating and even anti-irritating effect on the skin. Other amine oxides suggested for use in hair-treating compositions are disclosed in U.S. Pat. Nos. 3,098,794, 3,499,930 and 4,166,845. However, prior to the present invention, it was unappreciated that water-soluble amine oxides could be used to enhance penetration of therapeutic agents into and/or through the skin.

According to the present invention there are provided compositions for application to animal skin comprising: (1) an effective amount of a therapeutic agent selected from the group consisting of erythromycin, benzoyl peroxide, hydrocortisone, tetracycline, 5-fluorouracil and propranolol; (2) about 0.1 to 70 percent by weight of at least one water-soluble amine oxide; and (3) at least 1 molecule of water for every molecule of amine oxide. Other ingredients conventionally used in topical preparations such as water-soluble alcohols, glycols, surfactants, perfumes, preservatives, hydrophilic polymers, emulsifiers, natural and synthetic oils, lanolin, fatty alcohols, etc. may be added to the compositions. Hydrophilic polymers may be added to increase the viscosity or gel the composition and include such materials as hydrophilic acrylic polymers, polyvinyl alcohol, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, gum tragacanth, gum karaya, gum arabic and other thickening agents known to those skilled in pharmaceutical formulations.

Compositions of the invention exhibit enhanced penetration of the therapeutic agent through animal skin when compared to similar compositions containing no amine oxide. The amine oxides, when used in the concentration range specified, exhibit minimal toxic side effects.

The term "water-soluble" as used to characterize the amine oxide compounds means at least one percent solubility in water, i.e., one gram of amine oxide completely dissolves in 99 grams of water. It is believed that the polarity of the nitrogen-oxygen configuration of the amine oxides is the most important feature of this invention. The hydrocarbon moiety appended thereto is important only to the extent that it does not appreciably alter the electronic configuration of the --N.fwdarw.O and that its (the hydrocarbon portion) segment weight remains small enough to insure that the entire molecule maintains its water solubility.

In general, amine oxide compounds useful in the practice of the present invention may be characterized as water-soluble tertiary amine oxides of the group consisting of: ##STR1## wherein R.sub.1, R.sub.2 and R.sub.3 are saturated or unsaturated aliphatic radicals optionally containing ether or amide linkages and/or pendent hydroxyl groups and the total number of carbon atoms in R.sub.1 +R.sub.2 +R.sub.3 does not exceed 28; and ##STR2## wherein X is --O-- or ##STR3## R.sup.4 and R.sup.5 are saturated or unsaturated aliphatic radicals each containing 1 to 18 carbon atoms optionally containing ether linkages or pendent hydroxyl groups, p is 0 or 1, n=2 or 3, and m is 2, 3 or 4.

The preferred amine oxides of Formula 1 are those wherein the number of carbon atoms in the hydrocarbon portion (R.sub.1 +R.sub.2 +R.sub.3) does not exceed 18. Examples of preferred compounds of Formula 1 include:

trimethylamine oxide

tributylamine oxide

diheptylmethylamine oxide

dimethylheptylamine oxide

dimethyloctylamine oxide

dimethyldecylamine oxide

dimethyldodecylamine oxide

dimethylcocoamidopropylamine oxide

dipropyl-6-hydroxyhexylamine oxide

dicylohexylmethylamine oxide

Preferred amine oxides of Formula 2 are:

N-cocomorpholine-N-oxide

N-methylpyrrolidine-N-oxide

N-methylmorpholine-N-oxide

N-methylpiperidine-N-oxide

The amine oxides useful in the practice of the invention are either commercially available or readily prepared by known methods such as those described in U.S. Pat. Nos. 3,223,647 and 3,447,939 and Great Britain Pat. No. 437,566.

The amount of amine oxide incorporated into the topical preparations can range from about 0.1 to 70 percent by weight of the composition and can include mixtures of two or more amine oxides. The optimum concentration of any particular combination of amine oxide and a therapeutic agent will depend upon a number of factors such as potency of the therapeutic agent and the degree and speed of penetration, and can be readily determined empirically using the standard penetration test defined hereinbelow. In many cases, maximum penetration of the therapeutic agent does not occur at the highest concentration of amine oxide. The preferred concentration of amine oxide is generally between 2 and 10 percent by weight of the composition. The therapeutic agent will generally be present at a concentration of about 1 to 5 percent.

The compositions of the invention preferably contain from about 1 to 99 percent by weight of water. Water is the preferred common vehicle for the combination of amine oxide and therapeutic agent. In some instances, as indicated previously, a cosolvent may be added including, for example, isopropanol or propylene glycol.

The specific therapeutic agents incorporated into compositions of the invention include benzoyl peroxide used in the treatment of acne, tetracyline and erythromycin used in the treatment of microbial infections, hydrocortisone used in the treatment of inflammation, 5-fluorouracil used in the treatment of actinic keratosis and propanolol used as an antihypertensive drug.

Compositions of the invention for use on skin may be formulated in the conventional manner using pharmaceutically acceptable extending media such as gels, lotions and creams.

A typical gel composition may contain, for example, 1 percent hydroxyethyl cellulose. Typical lotion and cream vehicles are illustrated as follows.

To evaluate the ability of amine oxides to enhance penetration of therapeutic agents into or through animal skin, a standard assay using hairless mouse skin was used. (See T. J. Franz, Journal of Investigative Dermatology 64, 190 (1975) and T. J. Franz, Current Problems in Dermatology 7, 55 (1978)). A two square centimeter piece of hairless mouse skin (2-3 month old male-HRS/J) was placed over a reservoir in contact with 10 milliliters of 0.9% saline. A 0.05 milliliter solution or suspension of the therapeutic agent and amine oxide in water was applied to the top of the mouse skin. The diffusion cell was placed in a chamber with the temperature maintained at 32.degree. C. with 50% relative humidity. Five milliliter aliquots of saline were withdrawn (and replaced with fresh saline solution) from the reservoir at 2, 4, 8, and 24 hours after the therapeutic agent was applied and assayed for the total amount of therapeutic agent which had penetrated. The results obtained are the percent of the total amount of drug which penetrated the skin within 24 hours. These results were compared to a control solution or suspension of the drug without amine oxide. In some cases, i.e., where the drug had very low water solubility, the control vehicle was a mixture of ethanol and water. The presence of ethanol did not have a significant effect on drug penetration. In some cases, positive controls were also tested for purposes of comparisons. Each test value and control value obtained was the average of two duplicate penetration assays performed on separate halves of the same mouse skin. Compositions according to the invention showed at least 50 percent more drug penetration after 24 hours than their corresponding control.

Further understanding of the invention will be facilitated by reference to the following non-limiting examples. Where penetration data is reported as the average of two or more tests, this is intended to mean two or more tests on different mouse skins, i.e., four or more individual runs, since each skin provides enough surface area for two runs.

Twenty-five ml 30% hydrogen peroxide was slowly added to 8.5 g N-methyl pyrrolidine using an ice bath to maintain the reaction temperature below 40.degree. C. After the addition of the hydrogen peroxide was complete, the reaction was stirred overnight at room temperature. The excess hydrogen peroxide was decomposed by stirring the reaction mixture with 1 mg platinum black for 2 hours. The reaction mixture was filtered through Hyflo.RTM. filter-aid. Most of the water was removed in vacuo, leaving 12.0 g of a light brown liquid. Analysis by NMR showed that the amine oxide solution contained 24% water (mole basis). This corresonds to 1.8 moles water per mole of N-methyl pyrrolidine-N-oxide.

Following the procedure from Example 1, 9.9 g of N-methyl piperidine was treated with 30 ml of 30% hydrogen peroxide to give 16.0 g of light yellow liquid. NMR analysis showed 31/2 moles water per mole of amine oxide (34% water).

To a solution of 75 g of 85% m-chloroperoxybenzoic acid in 300 ml ether was added 58.2 g tributyl amine. After stirring the reaction mixture for 1 hour at room temperature, the ether was removed in vacuo. After adding 300 ml chloroform, the solution was extracted several times with 25% sodium hydroxide solution to remove m-chlorobenzoic and unreacted m-chloroperoxybenzoic acids. The chloroform was removed in vacuo to give 45 g of colorless liquid. The resulting liquid was dissolved in petroleum ether and cooled in an ice bath to give a semi-solid material which, when recrystallized from petroleum ether, gave 9.0 g of white crystalline needles (m.p. 57.degree.-58.degree. C.) NMR analysis showed 1 mole of water per mole of tributyl amine oxide.

To 35 g of dimethyloctyl amine was added slowly 150 ml of 30% hydrogen peroxide. After stirring overnight at room temperature, the excess hydrogen peroxide was destroyed by adding 1 mg platinum black. The reaction mixture was filtered through Hyflo.RTM. filter-aid and then extracted with ether to remove any unreacted amine. Most of the water was evaporated in vacuo leaving 40 g of a semisolid material which could not be made to crystallize. NMR analysis showed 41/2 moles water per mole of amine oxide (32% water).

To 28.6 g of dimethylheptyl amine was added slowly 100 ml 30% H.sub.2 O.sub.2 as in Example 4 to give the dimethylheptyl amine oxide. NMR showed the resulting semisolid material to contain 29% water and 71% of the amine oxide.

To a solution of 6.6 g of diheptylmethyl amine in 25 ml tetrahydrofuran (THF) was added 12 ml 30% hydrogen peroxide. The reaction mixture was refluxed for 24 hours, cooled to room temperature and then stirred with 0.2 mg platinum black overnight. After filtering the reaction mixture through Hyflo.RTM. filter-aid, the THF was removed in vacuo. The aqueous solution was extracted with 100 ml ether. The aqueous portion of the extraction was allowed to stand for several days to allow most of the water to evaporate. The resulting solution was found to be 40% water and 60% diheptylmethyl amine oxide by NMR analysis.

To 44 g of dipropyl-6-hydroxyhexyl amine was added slowly 11.0 g of 30% hydrogen peroxide. After stirring overnight at room temperature, the reaction mixture was stirred with 0.2 platinum black for several hours followed by filtration through Hyflo.RTM. filter-aid. After extraction with 50 ml ether, the aqueous phase was evaporated in vacuo to remove most of the water, leaving 2.0 g of dipropyl-6-hydroxyhexyl amine oxide. NMR analysis showed that there was 30% water present.

To a solution of 8.0 g of dicyclohexylmethylamine in 50 ml of tetrahydrofuran (THF) was added slowly 15 ml 30% hydrogen peroxide. The reaction mixture was refluxed overnight. The THF was removed in vacuo followed by stirring with 0.2 mg platinum black to destroy any remaining hydrogen peroxide. After filtering through Hyflo.RTM. filter-aid, the aqueous solution was allowed to stand for several days to allow most of the water to evaporate leaving 7.9 grams of the corresponding amine oxide solution. NMR analysis showed that it also contained 25% water and 75% dicyclohexylmethylamine oxide.

Using the hairless mouse skin penetration test described herein above, the results in Table I indicate that aqueous amine oxides significantly enhanced erythromycin penetration in comparison to an ethanol-water control.

It was noted that there is not a linear relationship between the concentration of the amine oxide and the percent erythromycin penetrated.

Considerable enhancement of benzoyl peroxide penetration through skin by aqueous amine oxides is illustrated in the following Table II.

The following Table VI sets forth penetration data for various vehicles containing 1 percent hydrocortisone. The ingredients in the lotion and cream vehicles are provided hereinabove.