Background of the Invention The invention relates to compositions comprising erythromycin that are useful for treatment of dermatological disorders, particularly disorders involving the sebaceous glands and follicles in humans.

Such compositions may be used for the topical treatment of acne. The invention also includes a process for preparing such compositions and a method of treatment of humans with the topical compositions to treat dermatological disorders such as acne.

Acne is a common inflammatory disease in skin areas where sebaceous glands are the largest, most numerous and most active. In the more inflammatory types of acne, bacterial invasion of or about the pilosebaceous follicles occurs and pustules, infected cysts and, in extreme cases, canalizing inflamed and infected sacs appear. These lesions may become extensive and leave permanent, disfiguring scars.

To reduce the severity of acne, various forms of medication have been used. For example, topical compositions of erythromycin alone and in combination with other active drugs have been used for the treatment of acne. One presently available composition, Benzamycin (D, supplied by Dermik Laboratories, Inc., is a topical gel composition containing micronized benzoyl peroxide and erythromycin. This benzoyl peroxide/erythromycin composition is described in US Patent No.

4,692,329, issued September 8,1987, which patent is hereby incorporated in its entirety herein by reference. BenzamycinX is supplied to the pharmacist as a vial of erythromycin powder and a jar of benzoyl peroxide gel. The pharmacist taps the vial until the erythromycin flows freely, then adds a specified amount of ethyl alcohol (70%) to the vial and shakes to dissolve the erythromycin. The erythromycin solution is added to the peroxide gel and stirred until homogenous in appearance. The resulting composition is given to the patient with directions to apply it topically to infected or inflamed areas of the skin.

Compositions containing erythromycin have the disadvantage that they sometimes appear as non-homogenous compositions. When 90% ethyl alcohol is used to dissolve erythromycin, for example, if the resulting mixture is allowed to sit unagitated for relatively short periods (one or two minutes), a glassy surface complex forms that cannot be solubilized with vigorous agitation and mixing. Other problems are noticed in combination products of erythromycin and other active ingredients, such as peroxides. For example, graininess and lump formation has occurred in some compositions of benzoyl peroxide and erythromycin. This problem has been addressed in the past by specifying the specific grade and type of alcohol to be used to dissolve the erythromycin before adding it to the benzoyl peroxide gel. However, this has not always solved the problem. Even compositions formulated with the preferred grade of alcohol have shown a lumpy consistency. The graininess problem has also been addressed by using alcohols of 95% or greater purity. Although this has been shown to produce a product of smooth consistency, it is not a solution that is easily implemented in pharmacies. Pharmacies usually do not stock alcohols of 95% or greater purity. Therefore, a special supply of alcohol would need to be maintained to implement the solution. Another approach used was to modify the benzoyl peroxide gel to include a mixture of gelling agents, such as a mixture of different carboxyvinyl polymers and a mixture of acrylic polymers, particularly those sold by B. F. Goodrich Co. under the CarbopolX trademark. Such experiments, however, have resulted in unstable compositions with undesirable viscosities.

Non-homogenous compositions are not visually appealing to the patient and disadvantageously give the appearance of an unacceptable product that may have questionable activity. Some doctors have refused to prescribe combination erythromycin products for which they received reports of a lumpy consistency. A nonhomogenous product may have some differences in efficacy on the skin because of the nonuniform distribution of active ingredients. Also, a nonhomogenous product may be cosmetically unacceptable for application to the face.

Summary of the Invention Applicants'invention solves these problems. In accordance with the present invention, it has been discovered that a homogenous erythromycin composition can be prepared. In particular, a homogenous and smooth composition of erythromycin and benzoyl peroxide can be prepared in accordance with the present invention. Applicants made the surprising and unexpected discovery that when one form of erythromycin, erythromycin B, is present as not less than about 2% of the total erythromycin used in the composition, then the resulting composition has improved uniformity with great consistency between different batches of the composition. Preferably, the percentage of erythromycin B is between about 3 and about 12% by weight of the total erythromycin, and, more preferably, between about 3 and about 7%. Preferable ranges of erythromycin B also include about 3% to about 5% and also more than about 3%.

Detailed Description of the Invention Erythromycin is a mixture of antibiotic substances produced by a strain of Streptomyces erythreus. The main components are three erythromycins: erythromycins A, B and C. These three major components (also called cofactors) differ from each other slightly in the identity of side chains on the erythromycin molecule. Erythromycin A represents a major portion of the erythromycin mixture, frequently higher than 80%.

Although erythromycin A is the most pharmaceutically active of the three cofactors, it has been discovered that erythromycin B has the highest solubility in ethyl alcohol. Applicants believe that erythromycin B interferes with the formulation of erythromycin self assemblies and thereby aids in its dissolution.

Very little of the erythromycin dissociates in alcoholic solution. For example, even in excess 70% ethyl alcohol, less than 0.01 % of the erythromycin dissociates. In alcohol, erythromycin forms self assemblies comprised of more than one erythromycin molecule. It is believed that erythromycin B molecules prevent the formation of large erythromycin self assemblies by disturbing the extensive stacking of erythromycin A molecules. Thus, increasing the percentage of erythromycin B is believed to decrease the size of self assemblies and lead to better dissolution properties, such as increased stability of solution. Smaller self assemblies are also believed to result in homogenous and smooth combination products, such as peroxide and erythromycin combination compositions. The smaller erythromycin self assemblies are believed to allow more ready diffusion into the peroxide gel matrix and thereby produce less interaction with the peroxide gel constituents and less graininess.

The topical compositions and methods of the present invention utilize an effective amount of erythromycin to treat skin disorders such as acne. The erythromycin compositions of the present invention may also comprise part of a combination product having one or more peroxides effective for the treatment of dermatological disorders. For example, hydrogen peroxide, various alkyl peroxides, benzoyl peroxide and other peroxides may be used in the invention in amounts appropriate for therapeutic use.

In one preferred embodiment, an effective amount of a mixture of benzoyl peroxide and erythromycin is prepared. In Applicants'preferred embodiment, benzoyl peroxide is present in the composition in the amount of about 1% to about 30 weight percent and preferably about 2.5% to about 15 weight percent based on the total weight of the composition. A most preferred amount of benzoyl peroxide is about 5% to about 10 weight percent. The preferred benzoyl peroxide should be of high purity, and, most preferably be in the form of micronized particles having a mean average particle size of less than about 35 microns. The erythromycin antibiotic is present preferably in the form of erythromycin, its sterate and/or its glucoheptonate derivatives, and most preferably as erythromycin.

Erythromycin is present in the preferred embodiment in the amount of about 0.5% to about 5 weight percent of the total composition, and more preferably from about 2.0% to about 4 weight percent. In addition, optimally a suitable pharmaceutical carrier is employed. Suitable topically acceptable pharmaceutical carriers are those which are typically used in a topical application of pharmaceuticals and cosmetics. Samples of such carriers include solutions, lotions, creams, ointments and gels. In the preferred embodiment, the erythromycin is initially dissolved in an alcohol, preferably a low-molecular weight alcohol such as propyl alcohol, ethyl alcohol or isopropyl alcohol. Preferably the alcohol is ethyl alcohol and, more preferably, ethyl alcohol 70%.

In the preferred embodiment, the erythromycin is first analyzed to determine that it contains at least about 2% by weight of the erythromycin in form B. The erythromycin is then filled into vials and packaged with the jar of benzoyl peroxide. At the pharmacy, the erythromycin is then tapped to insure that the powder is free flowing. A sufficient amount of alcohol is added by the pharmacist to dissolve the erythromycin. Preferred amounts of alcohol to dissolve the erythromycin are indicated in the table below.

Erythromycin Powder Ethyl Alcohol (70%) 0.4 grams 1.5 ml 0.8 grams 3 ml 1. 6 grams 6 ml After the solution is sufficiently shaken to dissolve the erythromycin, the solution is added to a gel of benzoyl peroxide and stirred until homogenous in appearance.

In a preferred composition, the composition contained erythromycin, benzoyl peroxide, water, Carbomer 940, alcohol, sodium hydroxide, dioctyl sodium sulfosuccinate and fragrance.

A preferred composition of erythromycin and benzoyl peroxide is a hydro-alcoholic gel. The gelling agent used in the preferred composition of the invention may be selected as to type and quantity to give products of various viscosities. A variety of gelling agents may be used. Preferred gelling agents are pure micro-crystalline cellulose, colloidal magnesium silicate, hydroxy-propyl methyl cellulose and the so-called hydroxylated vinylic polymers, particularly those described in U. S. Patent Number 2,798,053. Those hydroxylated vinylic polymers of special interest herein can be described generally as interpolymers prepared from a monomeric mixture comprising a mono-olefinic acrylic acid and from about 0.1% to about 10 % by weight based on the total monomer of a monomeric polyether of an oligosaccharide having hydroxyl groups which are etherified with allyl groups, said oligosaccharide containing at least two allyl groups per oligosaccharide molecule. Commercially available interpolymers of this type or similar to it are marketed under the trademark Carbopol). These are described as polymers of acrylic acid cross-linked with about 1 % of an allyl sucrose or allyl pentaerythritol. These polymers have molecular weight in the order of magnitude of about 500,000 to 1,000,000. Such polymers are available from the B. F. Goodrich Chemical Company and are sold under such trademarks as Carbopol) 941, Carbopol 940, Carbopol 934 and Carbopol 980. Closely related copolymers, such as Carbopol@ 1342, may also be acceptable.

The amount of gelling agent included in the present preferred gel composition can range from about 0.1 to about 15 percent by weight and preferably from about 0.5 to about 3% by weight based on the total weight of the composition.

The composition of the present invention may include a surface active agent or dispersing agent to disperse uniformly the active ingredients. The preferred composition of the present invention includes a stabilizing agent which acts as an effective barrier to the possible degradation of the peroxide and the erythromycin when the two interact. The preferred stabilizing agent is dioctyl sodium sulfosuccinate.

The invention also includes a process for preparing a homogenous erythromycin composition comprising assaying the erythromycin to ascertain that it comprises not less than about 2% by weight erythromycin B and combining the erythromycin with an organic solvent, preferably an alcohol, and most preferably ethyl alcohol. Furthermore, the invention includes a method of treatment of dermatological disorders in humans comprising topical application of the homogenous erythromycin compositions of the invention. Such treatment may be applied at least once a day, preferably twice a day. The duration of treatment varies but preferably is at least two weeks. The treatment may provided in combination with other therapy.

The invention also is directed to a process for preparing an erythromycin composition comprising assaying the erythromycin to ascertain that it comprises not less than about 2% by weight of erythromycin B.

The following examples will serve to further typify the nature of the invention but should not be construed as a limitation on the scope thereof.

Example 1 Container #1 <BR> <BR> <BR> Ingredientw/w%<BR> <BR> PurifiedWater............................................... .....................74.1%<BR> <BR> Carbomer 940......................................................... ............1.5%<BR> <BR> SodiumHydroxide............................................. ................0.4%<BR> <BR> SD Alcohol #40/190..................................................... ......15.0%<BR> <BR> Fragrances.................................................. ........................0.1% Benzoyl Peroxide (70%).................................................... 8. 7% Dioctyl Sodium Sulfosuccinate (75%)............................... 0. 2% Container #2 Erythromycin................................................ .................... 4% of the contents of Container #I The erythromycin contains cofactor B in a range of 3%-12%.

Method of Manufacture Container # 1 In the main mixing kettle add purified water and carbomer 940 and mix. Prepare a sodium hydroxide solution and add to the main kettle. Fragrances are mixed with alcohol and added to the main kettle. Benzoyl peroxide and dioctyl sodium sulfosuccinate are added to the main kettle and mixed. Entire contents are mixed and milled. Product is filled into suitable containers. Containers are capped.

Container #2 Erythromycin powder is added to a vial. The vial is capped.

Product Compounding The erythromycin vial is tapped to loosen the powder. Three milliliters (3ml) of 70% alcohol for each 800mg active erythromycin are added to the erythromycin vial and shaken until the erythromycin is dissolved. The erythromycin solution is added to the benzoyl peroxide gel in container #l and mixed.

The resultant product is of uniform consistency and of smooth appearance.

Example 2 The same procedure and materials were used as in Example 1 except the erythromycin had a cofactor B content of a relatively low level, namely, about 1 % or less. The resulting product was lumpy and nonhomogenous.

Example 3 Procedure The same procedure and materials were used as in Example 1 except various erythromycin samples having various levels of cofactor B were used. Each erythromycin sample was prepared the same way. The powder was placed into a plastic vial. Alcohol was added. The vial immediately was capped and shaken by hand for 1.5 minutes. After shaking, each sample appeared to be clear.

Erythromycin suspensions were prepared by dissolving about 800 mg of active erythromycin in 3.0 ml of 70% ethyl alcohol (denatured) in a plastic vial. Each erythromycin sample was added to the benzoyl peroxide gel and mixed with a plastic spatula for about 1.5 minutes. Compositions of the final mixtures were 5% benzoyl peroxide and 3% erythromycin.

A sample was also made of benzoyl peroxide gel alone, without any erythromycin. See Figure 1.

The following erythromycin samples were used and the resulting benzoyl peroxide/erythromycin compositions were photographed as described below.

A. Erythromycin, cofactor B 2.0%. See Figure 2.

B. Erythromycin, cofactor B 2.5%. See Figure 3.

C. Erythromycin, cofactor B 3.0%. See Figure 4.

D. Erythromycin, cofactor B 3.7%. See Figure 5.

E. Erythromycin, cofactor B 8.8%. See Figure 6.

Results Visual evaluation of the mixtures showed various appearances, ranging from very smooth using erythromycin containing cofactor B at 8.8% to somewhat lumpy obtained by using erythromycin containing cofactor B at 2.0%. Although all mixtures showed acceptable spreadability on the skin, mixtures having higher cofactor B content correlated to a smoother composition and easier spreadability. Mixtures with a lower cofactor B content took more time to spread out evenly on the skin.

In addition to visual inspection, the samples were examined under an optical microscope. The photographs are attached as Figures 1-6. A Ziess Axiophot microscope with transmitted light was used for optical microscopy and photography. Actual magnification is reported on the Figures. The photomicrographs support the visual findings. The photomicrographs show that the degrees of graininess on the microscopic level correspond to the lumpiness observed visually and inversely correlate to the erythromycin B content of the composition. The photomicrograph of benzoyl peroxide gel before mixing is presented for comparison and shows no graininess.