Title:  Compositions and methods for decreasing sebum production

United States Patent:  6,271,268

Assignee:  Pfizer Inc (New York, NY)

Filed:  March 27, 2000

A method of treating diseases caused by sebaceous gland disorders, in humans and animals, which comprises administering to said humans and animals a composition comprising a sebaceous gland secretion inhibiting amount of an active compound comprising an acyl coA cholesterol acyl transferase (ACAT) inhibitor or prodrug therefor. A composition for use in treating diseases caused by sebaceous gland disorders such as acne in humans and animals which comprises a sebaceous gland secretion inhibiting amount of an acyl coA cholesterol acyl tanferase (ACAT) inhibitor or prodrug therefor and, optionally, a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a method for treating diseases caused by sebaceous gland disorders, especially acne, in humans and animals by inhibiting the secretions of such glands by administering to said humans and animals a sebaceous gland secretion inhibiting amount of an acyl coA cholesterol acyl transferase (hereafter `ACAT`) inhibitors or prodrugs therefor. The ACAT inhibitors and their prodrugs will hereafter be referred to as "active compounds".

ACAT inhibitors useful in the practice of the invention, and their preparation are disclosed, inter alia, in co-pending U.S. patent application Ser. Nos. 08/251075 and 08/133,206 and International Patent Application Numbers PCT/US92/10886 and PCT/US93/03539 (all of which are assigned to the assignee of this application and incorporated herein by reference). Other ACAT inhibitors, useful in the practice of the invention, are referred to in, e.g., U.S. Pat. Nos. 4,994,465, 4,716,175 (the '175 patent) and 4,743,605 (a divisional of the '175 patent) and in the European Patent Applications having publication numbers 0 242 610, 0 245 687, 0 252 524, 0 293 880, 0 297 610, 0 335 374, 0 335 375, 0 386 487, 0 399 422, 0 415 123, 0 421 456 and 0 439 059. Additional ACAT inhibitors are described in PCT publications WO 90/15048 and WO 91/04027.

Most preferred ACAT inhibitors for use in the invention are selected from

(2S) N-(2,4-bis(methylthio)-6-pyrid-3-yl)-(2-hexylthio)decanoamide, (Compound I) the preparation of which is described in co-pending U.S. patent application Ser. No. 08/251,075, incorporated herein by reference;

N-(2,6-Diisopropylphenyl)-N'-[2-(naphth-2-yl)-6,6,6-trifluorohexyl]urea (Compound II);

N-[(2,4-bis(ethylthio)-6-methylpyridin-3-yl]-N'-heptyl-N'-(4-isopropylbenzy l)urea (Compound III; and

N-[(2,4-bis(ethylthio)-6-methylpyridin-3-yl]-N'-heptyl-N'-(4-propylbenzyl)u rea (Compound IV); and

N-[(2,4-bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)-6-p henylhexyl]urea (Compound V) the preparations of which are described in co-pending International Patent Application Number PCT/US93/03539, incorporated herein by reference.

Inhibition of acyl-CoA cholesterol acyl transferase (ACAT) blocks the esterification of free cholesterol to cholesteryl esters. Cholesterol esters are the primary transportation and storage forms of cholesterol in animals. In the intestines, ACAT inhibitors have been shown to inhibit the absorption of cholesterol from the gut. In the liver, inhibition of ACAT has been shown to decrease the formation and secretion of cholesterol-containing lipoproteins by decreasing the cholesteryl ester mass of the lipoprotein core. For these reasons, ACAT inhibitors have previously been explored as potential therapy for hypercholesterolemia.

Dermal sebaceous glands are holocrine glands that secrete a mixture of lipids known as sebum. Sebum is composed of triglycerides, wax, sterol esters and squalene. There is considerable variation in the composition of human sebum based on individual variables such as age, sex, diet, and disease. Sebum is produced in the acinar cells of sebaceous glands, accumulates as those cells age and migrates towards the center of the gland. At maturation, the acinar cells lyse and release sebum into the lumenal duct, from which the sebum is secreted.

Formation of sebum is regulated by a variety of hormones that act primarily to regulate the rate of lipid metabolism. Although the exact biochemistry is poorly understood, it is believed that waxes and sterols are converted, within acinar cells, to a stable ester form for storage via the activity of a variety of acyl and fatty acid transferases. These esters are then stored in lipid droplets within the acinar cells prior to release. It is, therefore, reasonable to propose that an inhibitor of ACAT or other transferases, which block esterification, within the acinar cells of sebaceous glands would have the ability to decrease ester formation and thereby decrease overall sebum production. Decreased sebum production has therapeutic benefits in diseases caused by sebaceous gland disorders, such as acnes, characterized by over-production of sebaceous glands. Decreased sebum production as a result of retinoid therapy is a major factor in the successful use of these agents to treat various types of acne.

Although a theory has been proposed for the mechanism of the effect of the ACAT inhibitors on the production of sebum and, therefore, on the treatment of diseases caused by sebaceous gland disorders, the present invention is not dependent upon the validity of that theory.

The active compounds in the compositions of the invention may be administered to a subject, in need of treatment, by a variety of conventional routes of administration, including oral, parenteral and topical. In general, the active compound will be administered orally or parenterally at dosages between about 0.5 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 1.0 to 10 mg/kg. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, therefore, determine the appropriate dose for the individual subject.

The active compound may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the active compound and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, topical and injectable solutions, gels, creams lotions and the like.

These pharmaceutical compositions can, if desired, contain additional excipients such as flavorings, binders, and the like. Thus, for purposes of oral administration, tablets containing ingredients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatine and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred fillers include lactose, or milk sugar, and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active ingredient therein may be combined with sweetening or flavoring agents, coloring matter and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerine and combinations thereof.

For parenteral administration, solutions of the active compound in sesame or peanut oil, aqueous propylene glycol, or sterile aqueous solution may be employed. Such aqueous solutions should be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed are all readily available by standard techniques.

For topical administration a gel-forming composition, such as a carboxyvinyl polymers, or mixtures of gel-forming compositions are used in combination with the active compounds of the invention. Commercially available carboxyvinyl polymers are include Carbopol (trademark) 934, 940 and 941 (from Goodrich Chemicals, U.S.A.).

An aqueous solution containing the carboxyvinyl polymer is acidic, since the polymer has free carboxylic acid residues. Neutralization of the aqueous solution with an appropriate base furnishes a viscous gel with desired viscosity. The appropriate bases which can be used are alkanolamines, such as monoalkanolamines having from one to four carbon atoms including methanolamine, ethanolamine, propanolamine and butanolamine; dialkanolamines having from two to eight carbon atoms, e.g., dimethanolamine, diethanolamine, dipropanolamine and dibutanolamine; and trialkanolamines, having from three to twelve carbon atoms, for instance, trimethanolamine, triethanolamine, tripropanolamine and tributanolamine. Other bases, useful in the practice of the invention, include inorganic bases such as sodium hydroxide, potassium hydroxide and potassium carbonate and organic bases such as alkylamine, dialkylamine and trialkylamine. A preferred amount of the gel-forming agent is from about 0.2% to about 2.0% by weight of the total.

A gel ointment formulation containing carboxyvinyl polymer is generally stable. It has a constant viscosity with very little variation due to temperature or time. However, several problems may arise when the compositions of this invention containing carboxyvinyl polymers are applied to the skin. It may sometimes happen that the polymer is salted out by the salt contained in sweat and forms soft agglomerates which disintegrate easily. In such a case, the active ingredient may be lost before it is absorbed through skin and the formulation affords an unpleasant feeling on administration.

Accordingly, the formulation must be administered after the area of application is freed of sweat and cleaned. It has been discovered that if certain hydrophilic polymers are incorporated in the formulation, the ointment can be administered topically even on the sweating skin to form a suitable film without the above problems. Hydrophilic polymers useful in connection with this invention include poly(vinylpyrrolidinone), carboxymethyl cellulose, hydoxyethyl cellulose and mixtures thereof. A preferred amount of the film-forming agents is from about 0.2% to about 2.0% by weight of the total formulation.

In addition to the above-mentioned film-forming agents, various other ingredients can be incorporated into the compositions of this invention to improve their therapeutic efficacy and stability. These include antiseptics such as benzyl alcohol, corneous tissue-dissolving agents such as urea and suitable skin-permeation enhancing adjuvants, like diethyl sebecate, etc., which are well-known to those skilled in the art.

The compositions of this invention have a pH range of from about 6.5 to about 9.0, and preferably from 6.5 to 8.0. In general, it is believed that the percutaneous absorption or skin-penetration of a given drug is dependent upon the ratio of lipophilicity to water solubility (partition coefficient) and that a high ratio is preferred, but too high a ratio adversely decreases the absorption and skin-penetration. A preferred pH range for the compositions of this invention is from about 6.5 to about 8.0.

The following excipients may be used in preparing gels for use in accordance with the invention; lower alkanols, for example, methanol, ethanol, isopropanol and butanol; and lower alkylene glycols having from two to six carbons which can be used includes ethylene glycol, propylene glycol and butylene glycol. Glycerine or polyethylene glycol having an average molecular weight of from 200 to 2000 can also be used in place of glycol. It is possible to use only one kind of such polyhydric alcohol, but more than one kind may also be used. A preferred amount of the lower alkanol comprises from about 10% to about 50%, water from about 30% to about 60% and the polyhydric alcohol from about 5% to about 40% by weight of the total composition.

Claim 1 of 21 Claims

What is claimed is:

1. A method of treating a sebaceous gland disorder in a human or animal in need of said treatment, which comprises administering to said human or animal a composition comprising a sebaceous gland secretion inhibiting amount of an acyl coA cholesterol acyl transferase (ACAT) inhibitor or prodrug therefor.

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