NON-YELLOWING TOPICAL PHARMACEUTICAL COMPOSITION

Abstract: Topical compositions, containing tetracycline, tetracy­ cline salts or tetracycline derivatives, which do not cause skin yellowing, are disclosed. These compositions are formulated such that, upon application to the skin, the tetracycline component recrystallizes in small, irregular crystals at the skin surface. Preferred compositions are buffered at a pH between about 2.0 and 4, such as by the addition of citric acid. The method of treating skin disorders such as acne, using these compositions is also disclosed.

Description: NON-YELOWING TOPICAL PHARMACEUTICAL COMPOSITION The invention described and claimed herein relates to pharmaceutical compositions formulated for topical. application, containing tetracycline, tetracycline salts or tetracycline derivatives, used in the treatment of a variety of skin disorders. The use of antibiotics, especially tetracycline, is a widely accepted mode of therapy for a variety of conditions, including skin disorders, such as acne. Especially in the case of skin disorders, the convenience and the fact that application of the active ingredient is made directly to the afflicted situs with only a minimal systemic exposure to the active component, makes topical application a preferred mode of administration. However, the topical use of tetracycline or tetracycline-derived compounds, can lead to a yellowing of the skin at the site of application, particularly in people with fair complexions.and pink skin tones. Although this skin yellowing is temporary and can be washed away by normal soap and water washing, it can be viewed by users of the topical tetracycline composition as a cosmetically undesirable characteristic and can even be perceived in efficacy terms since, as a result of the skin yellowing, the patient may decrease usage of the tetracycline composition, causing an exacerbation of the condition being treated. Thus, it would be very desirable from both cosmetic and treatment viewpoints, to be able to formulate a tetracycline-containing topical composition which does not exhibit this skin yellowing characteristic. The use of topical pharmaceutical compositions, some of which contain tetracycline, in the treatment of a wide variety of conditions, such as acne, is known in the art. See, for example, U.S. Patent 3,896,238, Smith, issued July 22, 1975, and U.S. Patent 3,527,864, MacMillan and Lyness, issued September 8, 1970, both of which are incorporated herein by reference. Citric acid is known for use as a component in a variety of therapeutic treatments such as in the preparation of effervescent granules, the enhancement of antioxidant effectiveness, as a disinfectant, and in a lotion for the neutralization of alkali materials in the eyes. See, Martindale, The Extra Pharmacopoeia, 26th Edition, The Pharmaceutical Press, 1972, pages 880881, incorporated herein by reference. In addition, citric acid has been used.at low levels (i.e., less than about 0.1%) as a stabilizer in various pharmaceutical products. It has now been found that by carefully controlling the size and configuration of tetracycline crystals as they recrystallize at the skin surface after application, it is possible to formulate topical tetracycline-containing compositions which do not yellow the skin upon use. A preferred way of accomplishing this is to buffer the compositions at a pH between about 2.0 and about 4, preferably using citric acid as the buffering acid. It is, therefore, an object of the present invention to provide topical pharmaceutical compositions, containing tetracycline or tetracycline-derived compounds, which do not yellow the skin upon use. It is a further object of the present invention to provide a method for topically treating skin disorders with tetracycline or tetracycline derivatives in a manner which does not cause yellowing of the skin area being treated. The present invention encompasses topical pharmaceutical compositions for use in the treatment of skin disorders, containing from about 0.005% to about 5% of a tetracycline compound selected from the group consisting of tetracycline, a tetracycline salt, or a tetracycline derivative in solution, said compositions formulated such that following application the tetracycline recrystallizes at the skin forming irregularly shaped crystals having an average size of no greater than about 30 microns. Preferred compositions are those which comprise: (1) from about 0.005% to about 5% of a tetracycline compound selected from the group consisting of tetracycline, a tetracycline salt or a tetracycline derivative, in solution; (2) from about 0.5% to about 10% of a pharmaceutically-acceptable acid which buffers the composition at a pH of from about 2.0 to about 4; and (3) a pharmaceutically-acceptable topical carrier. The preferred buffering acid for use in thes-e compositions is citric acid. The method of treating skin disorders with these compositions is also disclosed and claimed. DETAILED DESCRIPTION OF THE INVENTION The present invention encompasses pharmaceutical compositions, containing tetracycline, which may be used topically (as in the treatment of skin disorders, such as acne) without yellowing the skin of the user. The formulation of these compositions revolves wound the discovery that by controlling the size and shape sharacteristics of the tetracycline compound as it recrystallizes on the skin after application, the tendency to yellow the skin can be eliminated. Generally, when applied to the skin from a solution, tetracycline recrystallizes t the skin surface in relatively large, yellow rhombohedm-shaped crystals, having an average size of at least about 35-40 microns. The flat surfaces of these crystals reflect light, imparting a yellow coloration to the skin. By formulating the compositions such that the tetracycline compound recrystallizes at the skin surface in small crystals, i.e., having an average size of about 30 microns or less, preferably less than about 25 microns, of irregular shape, the perception of skin yellowing is eliminated. One way to achieve this result is to lower the pH of the skin prior to application of the tetracycline composition. This may be accomplished by washing the area to be treated with an acidic soap just prior to application of the tetracycline-containing composition. A far superior way to achieve this result, both in terms of convenience and elimination of yellow coloration, is by controlling the pH of the composition itself. Thus, preferred compositions of the present invention are those containing from about 0.5% to about 10%, preferably from about 0.75% to about 6%, most preferably from about 1% to about 3%, of an acid which buffers the compositions at a pH of from about 2.0 to about 4, preferably from about 2.5 to about 3.5. Examples of such acids include but are not limited to citric acid, lactic acid, ascorbic acid, glutaric acid, oxalic acid, hydrochloric acid, and mixtures' thereof, with citric acid being preferred. In addition to the crystal modification effect, the lowering of the pH of the composition may act to shift its light absorption characteristics, thereby eliminating skin yellowing. Excellent therapeutic and skin yellowing results are also obtained where acad is added to the composition, bringing the pH down to from about 2.0 to about 2.5, and then an alkaline compound, such as sodium hydroxide, is added to bring the composition pH to from about 3.0 to about 3.5. Similar results are obtained where the composition is formulated to include a weak acid (e.g., citric acid) and its basic salts (e.g., sodium citrate), such that the final composition has a pH between about 3.0 and about 3.5 and contains from about 0.75% to about 6%, preferably from about 1% to about 3t, of the acid/salt mixture. The compositions of the present invention contain from about 0.005% to about 5%, preferably from about 0.05% to about 2%, and most preferably about 0.5%, of tetracycline, a tetracycline salt or a tetracycline derivative. Mixtures of such tetracycline compounds may be used. The tetracycline compound contained in the composition must be present in solution; the skin yellowing effect is not present when the tetracycline compound is in a suspension, as in an ointment formulation. Tetracycline compounds useful in the present invention include tetracycline itself, as well as the salts thereof, for example, tetracycline hydrochloride and the tetracycline phosphate complex marketed under the trademarks "Tetrex" and "Panmycin Phosphate", and the like. Tetracycline analogues, for example, the oxytetracyclines or terramycins, such as terramycin hydrochloride, terramycin disodium salt dihydrate, and the like are also suitable herein. Preferred tetracycline compounds for use herein include tetracycline, tetracycline hydrochloride, and equilibrium mixtures of epi-tetracycline hydrochloride and tetracycline hydrochloride (formed on dissolution of tetracycline hydrochloride in water2. Especially preferred tetracycline compounds include tetracycline hydrochloride and the equilibrium mixture of tetracycline hydrochloride and epitetracycline hydrochloxide which forms spontaneously after aqueous solutions of tetracycline hydrochloride have been allowed to age at about 900F for about 7 days. In general, this equilibrium mixture comprises about 40-45% by weight tetracycline hydrochloride and 55-60% by weight epi-tetracycline hydrochloride. Other additives conventionally used in topical pharmaceutical compositions, such as perfumes, colorants, thickeners, preservatives, and penetration enhancers, may be included in the compositions of the present invention. Examples of such penetration enhancers include sugar esters, sulfoxides or phosphine oxides, and the combinations of these components described in U.S. Patent 3,896,238, Smith, issued July 22, 1975, and U.S. Patent 3,952,099, Smith, issued April 20, 1976, both incorporated herein by reference. Compositions of the present invention may contain up to about 10%, preferably about 0.1% to about 1% by weight of a sugar ester of the type hereinafter disclosed. The sugar esters suitable for use in this invention can be classified as hydrocarbyl and alkyl polyoxyalkylene esters of cyclic polyhydroxy saccharides wherein one or more of the hydroxyl groups on the saccharide moiety is substituted with an acyl or polyoxyalkylene group. Preferred sugar esters herein are those prepared by the esterification of sugars in a mole ratio of esterification agent:sugar of 1:1 and 2:1, i.e., the mono-acyl and di-acyl sugar esters. Especially preferred are the mono-acyl and di-acyl sugar esters wherein the acyl substituents contain from about 8 to about 2Q carbon atoms. Of the mono-acyl and di-acyl sugar esters, the respective esters of di-saccharide sugars, especially sucrose, wherein the acyl groups contain from about 8 to about 20 carbon atoms are especially preferred. Sucrose monooleate has been found to he particularly efficacious. The following is a list of typical sugar esters suitable for use in the instant invention but is not intended to be limiting of suck esters and is only mentioned by way of example: glucose monooctanoate, glucose mono-caprate, glucose monolaurate, glucose monomyristate, galactose monopalmitate, galactose monostearate, galactose monooleate, mannose dipalmitate, xylose diooleate, xylose di-eicosanate, sucrose monooctanoate, sucrose monocaprate, sucrose monolaurate, sucrose monomyristate, sucrose monopalmitate, sucrose monostearate, sucrose monooleate, sucrose di-octanoate, sucrose dilaurate, sucrose dimyristate, sucrose dioleate, sucrose trilaurate, sucrose tripalmitate, sucrose trioleate, maltose monooleate, maltose dilaurate, galactose monolaurate, galactose dir laurate, cellibiose trilaurate, raffinose monomyristate, gentianose dioctanoate, and gentianose trioleate. Preferred sugar esters include sucrose monooctanoate, sucrose monodecanoate, sucrose monolaurate, sucrose monomyristate, sucrose monopalmitate, sucrose monostearate, sucrose monooleate, and sucrose dioleate. Preferred compositions herein, having improved skin penetration properties, contain a compound selected from sulfoxides of the formula R1S(O), wherein R1 is a straight chain or branched chain alkyl, alkenyl, substituted alkyl, heteroalkyl or hydroxy-substituted alkyl substituent containing from 4 to 12 carbon atoms, and R2 is a low molecular weight (C1-C82 alkyl or low molecular weight (C1-C8) hydroxy-substituted alkyl substituent; and phosphine oxides of the formula R3R4RsP(O), wherein R3 is an alkyl, aralkyl, substituted alkyl, heteroalkyl, or hydroxy-substituted alkyl substitutent containing from 1 to 12 carbon atoms, or aryl Ce,g-, phenyl or toll) containing from 6 to 9 carbon atoms; and h and R5 are each low molecular weight alkyl tcl-c4l or low molecular weight hydroxy- substituted alkyl CCl-C41 substituents. Preferred herein are the alkyl sulfoxides wherein R1 is an alkyl or hydroxyalkyl substitutent containing about 8 to 12 carbon atoms and R2 is a low molecular weight alkyl or low molecular weight hydroxyalkyl group containing about 1 to 8 carbon atoms. Alkyl tertiary phosphine oxides wherein R3 is an alkyl or hydroxyalkyl substituent containing 8 to 12 carbon atoms and R4 and R5 are each lower alkyl or lower hydroxyalkyl substitutents are the preferred phosphine oxides herein. The concentration of sulfoxide or phosphine component oxide employed in the preferred compositions of the present invention is at least about 0.18 by weight of the composition and can range from about 0.1% to about 108 by weight. If concentrations less than about 0.1% are used, the degree of penetration enhancement attained, especially with the lower chain lengths is not appreciable. If concentrations greater than about 10% are employed, solubility problems may be encountered with the higher chain length materials. Preferably, the concentration of sulfoxide or phosphine oxide will range from about 0.18 to about 1% by weight of the total composition. The balance of the compositions of the present invention, generally from about 50% to about 99.5% of the compositions, comprises a conventional pharmaceutical carrier material, generally in liquid or semi-liquid state, especially adapated for topical application. It is desirable that the carrier selected be capable of codissolving the materials used in the composition. Carrier materials suitable for use in the instant compositions include those well-known for use in the cosmetic and medical arts as bases for ointments, lotions, salves, aerosols, suppositories and the like. Suitable carriers include, for example, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrosylates, liquid alkylated protein hydrosylates, liquid lanolin and lanolin derivatives, and like materials commonly employed in cosmetic and medicinal compositions. Exemplary carriers include alcohols, including both monohydric and polyhydric alcohols, for example, ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethylene glycol, ethylene glycol, hexylene glycol, mannitol, and propylene glycol; ethers, such as diethyl or dipropyl ether; polyethylene glycols and methoxypolyoxyethylenes (such as carbowaxes having molecular weights ranging from 200 to 20,000); polyoxyethylene glycerols, polyoxyethylene sorbitols, and stearoyl diacetin. Oil-in-water emulsions such as cold cream bases, can also be used. Preferably the carrier herein is a pharmaceuticallyacceptable liquid alcohol containing from about'2 to about 6 carbon atoms. Mixtures comprising from about 0 to 80% by weight of water and about 20 to 100% by weight of said C2-C6 alcohols are also suitable. Alcohols useful herein include ethanol, isopropanol, hexanol, and the like. Especially preferred carriers are water-ethanol mixtures at a weight ratio of about 1:20 to 5:1. Ethanol containing from about 5 to about 50% by weight of water, especially 40:60 by volume ethanol-water, is preferred as the carrier. Because of storage stability considerations relating to tetracycline hydrochloride and epi-tetracycline hydrochloride when formulated in solution, for particular formulations it may be preferable to package the compositions of the present invention in kit form. In such executions the tetracycline compound is packaged separately from any water-based carrier material, such as a mixture of ethyl alcohol, water, sucrose monooleate and decyl methyl sulfoxide, used in the composition. Accordingly, a preferred embodiment of the present invention encompasses a separately packaged portion of the tetracycline component, such as an equilibrium mixture of tetracycline hydrochloride and epi-tetracycline hydrochloride and a separately packaged portion of a penetration enhancing carrier. Such separately packaged portions are stable on prolonged storage and can be admixed by the user immediately before the course of treatment. It is convenient to package the two portions to provide a sufficient quantity of the composition to last for about 4 to 8 weeks of treatment. This, of course, is not critical to the present invention inasmuch as the clinical efficacy of the compositions herein is satisfactory even after storage. However, the use of separate packages for the tetracycline active and for the fluid ointment base insures that fresh material will be provided to the user. The buffering acid component of the present invention, preferably citric acid, may be included either with the tetracycline portion or the liquid carrier portion of such a kit. The size of the kits herein are of no consequence to the practice of the invention. For example, such kits can be provided which contain only a few grams of material and which are suitable for but a single application. Alternatively, kits can be provided which comprise a relatively large volume of the composition. The user can then measure aliquots of the carrier material and add thereto a premeasured packet of the tetracycline component. A preferred example of a composition of the present invention, used to provide an anti-acne benefit, contains a separately packaged, fluid ointment base comprising from about 0.1 to about 1% by weight of sucrose monooleate, from about 0.1 to about 8% by weight of decyl methyl sulfoxide, from about 30 to about 70% by weight of water, from about 30 to about 70% by weight of ethyl alcohol, and from about 1 to about 6% by weight of citric acid. The second component of the kit comprises a separately packaged, dry portion of an anti-acne agent comprising an equilibrium mixture of tetracycline hydrochloride and epi-tetracycline hydrochloride in an amount sufficient to provide a Q.1% to 1% by weight concentration of said equilibrium mixture when dissolved in the fluid ointment base composition. The equilibrium mixture of tetracycline hydrochloride and epi-tetracycline hydrochloride may also contain from about 0.05 to about 0.15% by weight (based on the total weight of all components) of a color stabilizer, especially sodium bisulfite. Alternatively, the second compqnent can be an equivalent amount of either tetracycline hydrochloride or epi-tetracycline hydrochloride, since these materials are stable in the dry state, and may contain the citric acid component rather than having it in the liquid portion of the kit. Topical treatment regimens according to the practice of this invention comprise applying the compositions herein directly to the skin, e.g., at the situs of a dermatosis, such as acne. The rate of application and duration of treatment will, of course, depend on the severity of the condition, the response of the particular patient, and related factors within the sound medical judgment of an attending physician. In general, for the compositions of the present invention, application rates of 2 to 25 ml/cm2 from about 0.01 ml/cm to about 25 ml/cm per day are used. Application can be made once, or preferably several times, daily for periods of a week or more, and do not result in a yellow coloration of the skin at the site of application. The following examples illustrate topical compositions prepared and used in the manner of this invention, but are not intended to be limiting thereof. EXAMPLE I The skin yellowing effect of the compositions of the present invention, as compared with control compositions, was tested as follows using a control composition having the following formulation. CONTROL Tetracycline hydrochloride 154 mg. 4-Epitetracycline hydrochloride k96 mg. n-Decyl methyl sulfoxide 87.5 mg. Sucrose monooleate 87.5 mg. Sodium bisulfite 7Q mg. Vehicle = 70 ml. of a 40% y volume) ethanol/water mixture. Compositions of the present invention were formulated by adding citric acid to the control composition in an amount such that the final composition contained 1%, by weight, of the citric acid (Composition A) and another composition was formed such that the final composition contained 2% citric acid (Composition B). Compositions A and B both have pH's between about 2.5 and about 3.5. These compositions were applied to skin once at 4 ml/cm2. The skin yellowing effect of these compositions was then graded on a O to 5 grading scale, with 0 indicating the yellow staining effect of the control compositions and 5 indicating no yellow skin coloration at all. The tests were repeated on 8 subjects and the skin staining was evaluated by two graders for each subject. The results were averaged and are summarized in the table below. Test Control ' Composition A -Composition B 1 0 4.25 4.75 2 0 - 4.4Q The benefit in terms of minimization of skin yellowing is dramatically demonstrated by the data contained in the above table. Substantially similar results are obtained where the citric acid component is replaced, in whole or in part, by lactic acid, ascorbic acid, hydrochloric acid, glutaric acid, oxalic acid, or mixtures of these components. Substantially similar results are also obtained where a composition similar to Composition A is formulated but with the amount of citric acid being 0.5%, 0.75%, 1.5%, 3%, 4%, 5%, 7%, or 8% of the final composition. Similar results are also obtained where the tetracycline components in the above compositions are replaced, in whole or in part, by tetracycline, tetracycline phosphate complexes, terramycin hydrochloride, terramycin disodium salt dihydrate, or mixtures of these components. A study of crystals formed on the skin surface in the above test indicates that the control composition resulted in the formation of crystals having a rhombohedral shape and an average size of greater than 30 microns, while the crystals formed from Composition B on the skin surface had an average crystal size of less than 28 microns and were irregular in shape. EXAMPLE II The control composition, described in Example I, and compositions of the present invention, formulated by adding amounts of citric acid ranging from 0.5% to 10%, by weight, of the final composition te the control were applied to white press-apply labels; the amount applied was approximately 3 ml/cm2. The color differences obtained from these compositions, as judged under white light, were found to be as follows: (1) Composition obtained by adding 0.5% citric acid to the control resulted in noticeably less yellow color than did the control composition. (2) Compositions formulated by adding 2 to 4% citric acid to the control composition resulted in noticeably less yellow coloration than that obtained using the control plus 0.5% citric acid and, when compared to the control, showed al most no yellow coloration. (3) Levels of citric acid above the range of 2-4% did not give any significant improvement over the 2 4% citric acid level, but were significantly better than the control composition. Substantially similar results are obtained where the citric acid is replaced, in whole or in part, by lactic acid, ascorbic acid, hydrochloric acid, glutaric acid, oxalic acid, and mixtures thereof. EXP3IPLE III A composition of the present invention, having the formulation given below, is formulated in a conventional manner. COMPONENT Weight % Tetracycline hydrochloride 0.22 4-Epitetracycline hydrochloride 0.28 Citric acid 2.0 Sodium bisulfite 0.1 Propylene glycol monoisostearate 1.5 40/60(approximately) ethanol/water Balance to 100 This composition when applied to the skin at an 2 application rate of about 10 mg/cm2 per day, provides effective therapy in the treatment of acne without causing the treated skin area to become yellow. EXAMPLE IT A composition of the present invention, having the formulation given below, is formulated in a conventional manner. COMPONENT Welght % Tetracycline hydrochloride 0.22 4-Epitetracycline hydrochloride 0.22 Citric acid 2.0 Sodium bisulfite 0.1 Myristyl alcohol 1-5 40/60(approximately2 ethanol/water Balance to 100 This composition, when applied in a daily dosage 2 of about 5 ml/cm2, provides an effective topical treat- ment for a variety of skin disorders, including acne, without causing the treated skin area to become yellow stained. EXAMPLE V A composition of the present invention, having the formulation given below, is formulated in a conventional manner. COMPONENT Tetracycline hydrochloride 2.2 mg/ml 4-Epitetracycline hydrochloride 3.25 mg/ml Decyl methyl sulfoxide 1.25 mg/ml Citric acid 18.95 mg/ml Sodium bisulfite 1 mg/ml Appropriate amounts of the above components are dissolved in 40/60 ethanol/water vehicle to form about 70 ml. of the desired composition. The composition has a pH between about 2.5 and 3.0. This composition, when 2 applied in a daily dosage of about 5 ml/cm , provides an effective topical treatment for a variety of skin disorders, including acne, without causing the treated area to become yellow stained. Excellent results are also obtained where sodium hydroxide is added to the above composition in an amount to raise the pH of the composition to 3.5. EXAMPLE VI l A composition, effective in the topical treatment of acne, sold in kit form, and having the formulation given below is made in a conventional manner. COMPONENT Weight % Component 1 Tetracycline hydrochloride/epi tetracycline hydrochloride 0.06 oz. mixture Sodium bisulfite 0.02 oz. Citric acid 0.25 oz. Component 2 Ethanol 4.0 oz. Sucrose monooleate 0.06 oz. Decyl methyl sulfoxide 0.06 oz. Water 2.5 oz. In the above composition, Component 1 is packaged in a dry, water-proof foil packet; Component 2 is packaged in a bottle having sufficient head space to allow mixing. Immediately prior to use, Component 1 is added to Component 2 and the mixture is shaken to mix. The user applies an effective amount of the composition to the acne lesions, ad lib, and alleviation of the acne is secured; such use does not cause the treated situs to take on a yellow coloration. In the above composition, the citric acid component may be included in Component 2 rather than in Component 1, while retaining its yellow stain reduction benefit. Further, in the above example, the mixture of tetracycline hydrochloride and epi-tetracycline hydrochloride mar be replaced by tetracycline hydrochloride and epi-tetracycline hydrochloride, respectively, and equivalent results are secured. Similar results are also obtained where the above composition is formulated without the sucrose monooleate and/or the sodium bisulfite components

Claims: CLAIMS 1. A topical pharmaceutical composition, containing from 0.005% to 5% of a tetracycline compound selected from the group consisting of tetracycline, a tetracycline salt or a tetracycline derivative in solution, characterized in that said composition is formulated such that following application the tetracycline compound recrystallizes at the skin forming irregularly shaped crystals having an average size of no greater than 30 microns. 2. A composition according to Claim 1 characterized in that said composition is buffered at a pH of from 2.0 to 4.0. 3. A topical composition, for use in the treatment of skin disorders, comprising from 0.005% to 5% of a tetracycline compound selected from the group consisting of tetracycline, a tetracycline salt or a tetracycline derivative in solution together with a pharmaceutically-acceptable topical carrier, characterized in that said composition contains from 0.5% to 108 of a pharmaceutically-acceptable acid which buffers the composition at a pH of from 2.0 to 4.0. 4. A composition according to Claim 3 characterized in that said pharmaceutically-acceptable acid is selected from the group consisting of citric acid, lactic acid, ascorbic acid, hydrochloric acid, glutaric acid, oxalic acid, and mixtures thereof. 5. A composition according to Claims 3 or 4 characterized in that said pharmaceutically-acceptable acid is citric acid. 6. A composition according to any one of Claims 3-5 characterized in that said composition contains from 1% to 3% of the pharmaceutically-acceptable acid. 7. A composition according to any one of Claims 3-6 characterized in that said composition is buffered at a pH of from 2.5 to 3.5. 8. A composition according to any one of Claims 3-7 characterized in that said composition additionally contains up to 10% of a sugar ester and from 0.1% to 108 of a sulfoxide having the formula R1S(O)R2 wherein R1 is a C8-C12 alkyl or hydroxyalkyl substituent and R2 is a substituent selected from the group consisting of C1-C4 alkyl and hydroxy-substituted alkyl substituents. 9. A composition according to any one of Claims 3-8 characterized in that said composition additionally contains an alkaline salt of the pharmaceuticallyacceptable acid in an amount such that the composition contains from 0.75% to 6% of the acid and salt together, and has a pH of from 3.0 to 3.5. 10. A method for topically applying a tetracycline compound-containing composition without causing skin yellowing characterized in that said composition is formulated to contain from 0.5% to 10% of a pharmaceutically-acceptable acid which buffers the composition at a pH of from 2.0 to 4.0.

Inventors: KOONSVITSKY, BURTON PHILLIP, MANRING, GARY LEE
Applicants: THE PROCTER & GAMBLE COMPANY
Application year: 1981
Main classification: A61K9
IPC codes: A61K47, A61K9, A61P17, A61K31