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(12) United States Patent (10) Patent No.: US 6,716,437 B1 Pelle Et Al

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(12) United States Patent (10) Patent No.: US 6,716,437 B1 Pelle Et Al USOO6716437B1 (12) United States Patent (10) Patent No.: US 6,716,437 B1 Pelle et al. (45) Date of Patent: *Apr. 6, 2004 (54) TOPCAL COMPOSITION AND METHOD (56) References Cited FOR ENHANCING LIPID BARRIER SYNTHESIS U.S. PATENT DOCUMENTS 4,793.990 A 12/1988 Grollier et al. ............... 424/59 (75) Inventors: Edward Pelle, Valley Stream, NY (US); 5,855,897 A 1/1999 Pelle .......................... 424/401 Jon Anderson, Galesburg, MI (US) FOREIGN PATENT DOCUMENTS (73) Assignee: E-L Management Corporation, New RU 1770352 A1 10/1992 York, NY (US) RU 177O352 * 10/1992 WO WO 98/10739 3/1998 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 0 days. Miller et al., Kahweol and Cafestol: Inhibitors of Hamster Buccal Pouch Carcinogenesis, Nutrition and Cancer 15: This patent is Subject to a terminal dis 41–46, 1991. claimer. Hugget et al., Chemoprotective Effects of Coffee and its Components Cafestol and Kahweol: Effects Xenobiotic (21) Appl. No.: 09/806,667 Metabolizing Enzymes, Colloq. Sci. Int. Cafe (C.R.) 16(1): (22) PCT Fed: Sep. 11, 1997 65–72, 1995. Urgert et al., Effects of Cafestol and Kahweol from Coffee (86) PCT No.: PCT/US97/16364 Grounds on Serum Lipids and Serum Liver Enzymes in S371 (c)(1), Humans, Am. J. Clin. Nutr. 61: 149-154, 1995. (2), (4) Date: Apr. 2, 2001 Melnick et al., J. Invest. Dermoatol. 92:231–2234, 1989. (87) PCT Pub. No.: WO98/10739 * cited by examiner PCT Pub. Date: Mar. 19, 1998 Primary Examiner Neil S Levy (74) Attorney, Agent, or Firm-Jones Day Related U.S. Application Data (57) ABSTRACT (63) Continuation-in-part of application No. 08/712.988, filed on The present invention relates to topical compositions useful Sep. 13, 1993, now Pat. No. 5,855,897. in enhancing lipid synthesis in Skin comprising an effective (51) Int. Cl................................................... A61K 9/10 amount of cafestol or kahweol, or derivative thereof, in (52) U.S. Cl. ....................... 424/401; 514/169; 514/170; combination with a pharmaceutically or cosmetically 514/171; 514/172; 514/174; 514/182; 514/461; acceptable carrier. Such compositions are useful in treatment 514/469 or prevention of dry skin and conditions in which the skin's (58) Field of Search ................................. 424/400, 401, lipid barrier is defective or damaged. 424/59, 63; 514/169-172, 174, 182, 461, 469 8 Claims, 6 Drawing Sheets O 1 2 3 5 7 O.O1 (.5 AYS mg/ml 0.5 mgmi U.S. Patent Apr. 6, 2004 Sheet 1 of 6 US 6,716,437 B1 0.5 mg/ml U.S. Paten Apr. 6, 2004 Sheet 2 of 6 US 6,716,437 B1 CAFESTO. ACETAE U.S. Patent Apr. 6, 2004 Sheet 3 of 6 US 6,716,437 B1 2 ZY,||2 2 Nd up ZY 22 2 3 2 s 2 3 s 3. s s U.S. Patent Apr. 6, 2004 Sheet 4 of 6 US 6,716,437 B1 L H st s CD -5. U LO Lad, O O O O O O O w S. Nd No CN CN au an H9NGS W9 NI SW30N U.S. Patent Apr. 6, 2004 Sheet 5 of 6 ŽLLŽ T% 3 g s 3 O.2 S.O. O.3 &O. 9O. O.- C.2 N9W Dep U.S. Patent Apr.pr. 6, 2004 t E N on E d US 6,716,437 B1 1 2 TOPCAL COMPOSITION AND METHOD the individual being treated, while ultimately resulting in no FOR ENHANCING LIPID BARRIER actual repair of the lipid barrier. SYNTHESIS The present invention now provides a useful substitute for RELATED APPLICATIONS the daily application of Skin conditioning agents, or harsh topical active agents. It has now been discovered that it is This application claims priority under 35 U.S.C. S 120 to possible to actually amplify the production of the skin's International Application No. PCT/US97/16364, filed Sep. natural lipid barrier. Specifically, it has been found that 11, 1997, which is a continuation in part of U.S. Ser. No. cafestol, when applied topically to the skin, is capable of 08/712,988, filed Sep. 13, 1996, now U.S. Pat. No. 5,855, Stimulating the production of one or more of the naturally 897, both of which are incorporated by reference herein in occurring Stratum corneum lipid components, as well as their entireties. increasing the Stratum corneum per se. There is thus pro FIELD OF THE INVENTION Vided a new type of cosmetic or pharmaceutical composition which functions by enhancing the Skin's own functions, The present invention relates to topically applied compo 15 resulting in a more natural means of preventing dry skin and Sitions which increase lipid Synthesis in skin. More other undesirable results of a deficient lipid barrier. Specifically, the invention relates to compositions compris ing cafestol as a lipid barrier enhancer. BRIEF DESCRIPTION OF THE FIGURES BACKGROUND OF THE INVENTION FIG. 1 is photograph of a TLC plate showing the results Skin is typically characterized as consisting of three of dose-variable(left) and time-variable(right) application of distinct layers, namely the Stratum corneum, the epidermis cafestol acetate to living skin models. Each shows an and the dermis. The Stratum corneum, the Outermost layer, increase in ceramide production with increasing dosage and is made up of keratinized cells, Surrounded by intercellular time. Space filled with lipids. The Stratum corneum provides a 25 Substantial physical barrier to penetration of most Substances FIG. 2 is a photograph of a TLC plate showing the results to the lower layers of the skin. In addition to preventing of a comparison between application of cafestol acetate and transport of Substances to the other skin layers, however, this coffee bean oil to living skin models, with respect to barrier also aids in prevention of water loSS from the skin. dose-dependent increase in ceramide production. Both functions are primarily attributable to the presence of FIG. 3 is a graphic representation of densitometric analy the lipids in the Stratum corneum. sis of the TLC plate shown in FIG. 2, showing the effect of There are two Sources of the skin Surface lipids making up each treatment on ceramide content of Skin relative to this important barrier: Sebaceous glands and the epidermis. dosage. The lipids are a diverse group of compounds, comprising 35 triglycerides, diglycerides, ceramides, free fatty acids, wax FIG. 4 is a graphic representation of the effect of cafestol esters, cholesterol and cholesterol esters, and Squalene. The acetate and cafestol palmitate on barrier Strength measured quantity and composition of the skin Surface lipids differ via tape stripping and TEWL. from place to place on the body, and may to Some extent be FIG. 5 is a graphic representation of the effect of cafestol related to the number of Sebaceous glands in a given area of 40 the skin. The condition of the skin Surface lipids may also be on ceramide production in Skin over time. affected by an essential fatty acid deficiency. Additionally, FIG. 6 is a graphic representation of a dose-dependent the lipid barrier is easily diminished by exposure to harsh effect of cafestol on ceramide production in Skin detergents or Soaps. It is apparent, then, that the quality of the skin lipid barrier can vary widely, depending on a 45 SUMMARY OF THE INVENTION number of different factors, and therefore, may not always be adequate to perform its protective function optimally. The present invention relates to topical compositions AS an attempt to compensate for what may be a less than comprising as an active component an effective amount of adequate lipid barrier, cosmetic compositions frequently cafestol, kahweol, or derivatives thereof, in combination incorporate components which compensate for water loSS. 50 with a cosmetically or pharmaceutically acceptable carrier. Examples of Such materials are hygroscopic humectants, The invention also relates to a method for increasing lipid e.g., urea or propylene glycol, or emollients, e.g., oleyl Synthesis in the skin which comprises applying to the Skin an alcohol or caprylic/capric triglycerides. Certain cosmetic effective amount of cafestol or kahweol, or derivatives components may be occlusive skin conditioners, which are thereof. AS the lipid barrier is a key factor in maintaining the used to provide an “artificial” barrier, Such compounds are 55 frequently lipids which remain on the Skin Surface, and quality and moisture of Skin, the topical application of include various hydrogenated oils, waxes and butters. cafestol or its derivatives is thus also useful in improving Although many of these products provide an effective means overall skin condition, and in the prevention or treatment of of Stemming water loSS from the Skin, they do have to be a variety of dry skin generally, and Specific skin conditions reapplied frequently to maintain the effect, and do not 60 in which the natural lipid barrier is compromised or absent. generally constitute a natural-occurring component of the Stratum corneum, potentially giving rise to an unnatural, DETAILED DESCRIPTION OF THE greasy feel to the skin. In addition, various pharmaceutical INVENTION or cosmetic active agents are also frequently used to treat the Symptoms of dry skin-associated conditions; however, in 65 Cafestol and kahweol, and/or their esters, are the principle many cases, particularly with pharmaceutical agents, the components of the diterpene ester fraction of coffee bean oil. treatments themselves may cause undesirable Side effects in Cafestol has the following chemical formula: US 6,716,437 B1 4 least one lipid barrier component by at least 1% when compared with untreated Skin in the same location.
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