United States Patent (10) Patent No.: US 6,552,009 B2 Achkar (45) Date of Patent: *Apr

USOO6552009B2 (12) United States Patent (10) Patent No.: US 6,552,009 B2 Achkar (45) Date of Patent: *Apr. 22, 2003

(54) COMPOSITIONS AND METHODS OF EP 704210 4/1996 TREATING ABNORMAL CELL FR 2714595 7/1995 PROLIFERATION JP 63.060910 3/1988 WO WO84O2845 8/1984 (75) Inventor: style C. Achkar, North Bergen, NJ WO WO964O1540512814 12/199611/1992 WO 9709987 2/1997 (73) Assignee: Gentrix LLC, North Bergen, NJ (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this Carlberg et al., “Vitamin D-Retinoid ASSociation: Molecular patent is extended or adjusted under 35 Basis and Clinical Applications”, J. Invest. Dermatol. Symp. U.S.C. 154(b) by 0 days. Proc.R. Ceovic 1(1), et82-86, al., “Calciprotiol-A 1996. Vitamin D3 Analogue This patent is Subject to a terminal dis- (MC903) in the Treatment of Psoriasis Vulgaris: A Review”, claimer. Acta Dermatovenerologica Alpina, Panonica et Adriatica, 7/2, 67–77, 1998 (abstract). S. Segaert et al., “Retinoic Acid Modulates the Anti (21) Appl. No.: 09/872,662 join Effect of 1,25-dihydroxyvitamain D3 in Cul (22) Filed: Jun. 1, 2001 tured Human Epidermal keratinocytes,” J. Invest. Dermatol., O O 109/1, 46-54, 1997. (65) Prior Publication Data M. Skopinska et al., “Calcitriol and Isotretinoin Combined US 2001/0049365 A1 Dec. 6, 2001 Therapy for Precancerous and Cancerous Skin Lesions,” J. Dermatol. Treatment, 8/1, 5-10, 1997. Related U.S. Application Data A. Bargagna et al., “TLC, HPTLC and HPLC Determination of Cis- and Trans-retinoic Acids, Retiniol and Retinyl (63) Continuation-in-part of application No. 09/351,020, filed on Acetate in Topically Applied Products,” Acta. Tachnol. Jul. 12, 1999, now Pat. No.6.242,435, which is a continu- Legis Med., 202), 75–86, 1991. agree Elisation No. 09/116,632, filed on Jul. 16, Van Der Vleuten et al., “In-Patient Treatment with Calci 2 potriol Versus Dithranol in Refractory Psoriasis”, Eur. J. (51) Int. Cl...... A61K31/07; A61K 31/592; Dermatol., 5(8), 676-679, 1995 (abstract). A61K 3 1/593 (52) U.S. Cl...... s14/168514,725 Primary Examiner-Phyllis G. Spivack (58) Field of Search ...... 514/168, 725 (57) ABSTRACT (56) References Cited A composition is described comprising a vitamin D analog and a retinoid wherein: (a) the vitamin D analog is capable U.S. PATENT DOCUMENTS of binding a vitamin D receptor or being converted in vivo 4.866,048 A 9/1989 Calverly et al...... s1467 into a compound capable of binding a vitamin D receptor; 5514,672 A 5/1996 Bazzano. ... s14/68 and (b) the retinoid is selected from the group consisting of 5,547,947 A 8/1996 Dore et al...... 514/167 retinol in a concentration of at least about 1.0% and a 5,786,391 A 7/1998 Gudas et al...... 514/690 retinoid characterized by having a Substitution at the 4-position. Further, methods of treating disorders character FOREIGN PATENT DOCUMENTS ized by abnormal cell-proliferation and/or cell CA 20961.96 5/1993 differentiation are also described. CA 20961.96 11/1993 EP O57991.5 1/1994 53 Claims, No Drawings US 6,552,009 B2 1 2 COMPOSITIONS AND METHODS OF associated with abnormal cell differentiation and/or cell TREATING ABNORMAL CELL differentiation has met with certain amount of Success in PROLIFERATION Some instances, these compounds have frequently been RELATED APPLICATIONS unable to provide the desired clinical results. This application is a continuation-in-part of U.S. Ser. No. For instance, the Synthetic Vitamin D, calcipotriol, or 09/351,020, filed Jul 12, 1999 now U.S. Pat. No. 6,242,435, retinoic acid which are available in prescription form are which is a continuation-in-part of U.S. Ser. No. 09/116,632, Somewhat useful for individuals with localized pSoriasis. filed Jul. 16, 1998 abandoned. However, these compound are not very effective on most Throughout this application, various references are patients. referred to within parentheses. Disclosures of these publi cations in their entireties are hereby incorporated by refer Therapeutic regimens for acne involve local and Systemic ence into this application to more fully describe the State of therapies, although the former is indicated in the vast the art to which this invention pertains. 15 majority of cases. Topical application of a variety of chemi FIELD OF THE INVENTION cal application which include mainly Sulfur, resorcinol, The present invention relates to compositions comprising Salicylic acid, benzoyl peroxide, and retinoic acid are fre certain retinoids and Vitamin D analogs useful in inducing quently used to treat acne. All the foregoing agents are differentiation and inhibiting undesirable proliferation of known as "peeling” or “drying agents which are believed to cells, Such as cancer cells and skin cells. The present exert their therapeutical effect by causing erythema, invention also relates to methods of using the above com irritation, and descquamination of the skin to expel come positions in the treatment of diseases and conditions char dones. The therapeutic efficacy of these agents, however, is acterized by abnormal cell differentiation and/or cell prolif rather variable, and their utility is limited partially because eration. 25 of the irritation caused by their application (see U.S. Pat. No. DESCRIPTION OF THE RELATED ART 3,932,665). Oral formulations of retinoic acid are also used but Serious Side effects are associated with the oral use of Abnormal cell differentiation and/or cell differentiation is this compound including Severe fetal malformation in preg asSociated with many conditions and diseases. For instance, hyperproliferation of epithelial cells is associated with pSo nant WOmen. riasis which causes the skin to shed itself too rapidly, every three to four days. The goal in treating psoriasis is to reduce SUMMARY OF THE INVENTION inflammation and to Slow down rapid skin cell division. U.S. Pat. No. 4.866,048 discloses that certain vitamin D The present invention provides compositions comprising derivatives, in particular calcitriol (1 alpha,25-dihydroxy Vitamin D or) and calcipotriol are able to Stimulate the 35 certain Vitamin D and retinoid compounds which are useful differentiation of cells and inhibit excessive cell for the treatment of disorders characterized by abnormal proliferation, and it has been Suggested that these com cell-proliferation and/or cell-differentiation. pounds are useful in the treatment of diseases characterized Specifically, the present invention provides a composition by abnormal cell differentiation and/or cell differentiation Such as leukemia, myelofibrosis, psoriasis and acne. 40 comprising a vitamin D analog and a retinoid, wherein: Certain retinoids are also known for their antiproliferative (a) the Vitamin D analog is capable of binding a vitamin and differentiation activity. For instance, retinol (vitamin A) D receptor or being converted in Vivo into a compound is an endogenous compound which occurs naturally in the capable of binding a Vitamin D receptor; and human body and is essential for normal cell differentiation 45 of certain cell types Such as epithelial cells. Retinoic acid is (b) the retinoid is selected from the group consisting of believed to be an active derivative of retinol. Thus, retinoic retinol in a concentration of at least about 1.0% by acid is believed to be more effective than retinol and retinyl weight, a compound in a concentration of at least about esters at providing skin benefits. 1.0% by weight capable of being converted in vivo into Natural and Synthetic Vitamin A derivatives (including 50 retinol, retinoid D with an alcohol CH-OH terminal retinoic acid) have been used extensively in the treatment of Side chain, retinoid D with an ester at the terminal Side a variety of skin and hyperproliferation disorders. For chain, retinoid D with an ether at the terminal side example, retinoic acid has been employed to treat certain chain, retinoid D with an aldehyde at the terminal side types of leukemia like acute apromyelocytic leukemia as chain, and retinoid D with a carboxylic acid at the well as a variety of Skin conditions Such as acne, wrinkles, 55 psoriasis, age spots and discoloration (Vahlquist, A. et al., J. terminal side chain, wherein retinoid D with the alcohol Invest. Dermatol, Vol. 94, Holland D. B. and Cunliffe, W.J. CH-OH terminal side chain has the structure: (1990), pp. 496-498; Ellis C. N. et al., “Pharmacology of

Retinols in Skin", Vasel, Karger, Vol. 3, (1989), pp.249-252; 9 11 13 Lowe, N.J. et al., Vol. 3, (1989), pp. 240–248; PCT Patent 60 CH2OH Application No. WO 93/19743). Although retinoids have N1 N. been viewed classically as cancer prevention agents, con siderable laboratory evidence Supports their testing as anti tumor drugs as well (Cancer Treat Rep 1987; 71: 493–515 May, 1987). 65 wherein the configuration at the 7-, 9-, 11- and 13-position It is important to note that while clinical experience with double bonds is independently Z or E and wherein R is either retinoids or Vitamin D derivatives against conditions Selected from the group consisting of US 6,552,009 B2

X, Y,

1O wherein X and Y are independently Selected from the wherein the keto group at the 4-position is free or protected, group consisting of hydrogens, C-alkyl, hydroxyl, or is replaced by a thioketone group which is free or alkoxyl, acyloxyl, halide, azide, Sulfhydryl, amine and C protected or is replaced by C-alkylidene group; alkyl Substituted amino So long as X and Y are not both 15 hydrogens. The present inventions also provides methods for treating various conditions associated with abnormal cell prolifera tion and/or abnormal cell differentiation.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the invention, It has been Surprisingly 25 discovered that a composition comprising a vitamin D wherein X is Selected from the group consisting of hydrogen analog and a certain retinoid is useful in treating a Subject and C-alkyl and Y is Selected from the group consisting Suffering from a disorder characterized by abnormal cell of C -alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, proliferation and/or cell-differentiation more effectively than Sulfhydryl, amine and C-alkyl Substituted amino and either a composition comprising a vitamin D or the above wherein the absolute configuration at the 4-position is inde retinoid or a composition comprising a vitamin D analog pendently R or S; with other types of retinoids.

The retinoid used in the composition of the present invention is Selected from the group consisting of retinol in 35 a concentration of at least about 1.0% by weight, a com pound in a concentration of at least about 1.0% by weight capable of being converted in vivo into retinol, retinoid D with an alcohol CH-OH terminal side chain, retinoid D with an ester at the terminal Side chain, retinoid D with an ether 40 at the terminal side chain, retinoid D with an aldehyde at the terminal Side chain, and retinoid D with a carboxylic acid at the terminal side chain, wherein retinoid D with the alcohol wherein X, Y are independently Selected from the group CH-OH terminal side chain has the structure: consisting of hydrogen, C-alkyl, hydroxyl, alkoxyl, 45 acyloxyl, halide, azide, Sulfhydryl, amine and C-alkyl 9 11 13 Substituted amino and Z is Selected from the group con N1 N. CH2OH Sisting of C-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, Sulfhydryl, amine and C-alkyl Substituted amino; 50 wherein the configuration at the 7-, 9-, 11- and 13-position double bonds is independently Z or E and wherein R is Selected from the group consisting of 55

60 wherein X is selected from the group consisting of hydrogen, C-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, Sulfhydryl, amine and C-alkyl Substituted amino and Z is Selected from the group consisting of C-alkyl, 65 wherein the keto group at the 4-position is free or protected, hydroxyl, alkoxyl, acyloxyl, halide, azide, Sulfhydryl, amine or is replaced by a thioketone group which is free or and C-alkyl Substituted amino; protected or is replaced by C-alkylidene group; US 6,552,009 B2 6 The present invention also provides a method of treating a Subject Suffering from a disorder Selected from the group consisting of psoriasis, acne, atopic dermatitis, eczema, rosacea, actinic keratosis, Seborrheic dermatitis, and con genital keratinization disorders, in which any composition of the present invention is administered to the Subject in need of Such treatment. Preferably, the disorder is psoriasis, eCZema, Or acne. The present invention further provides a method of treat wherein X is Selected from the group consisting of hydrogen 1O ing one or more conditions of the skin Selected from the and C-alkyl and Y is selected from the group consisting group consisting of dry skin, photodamaged skin, age spots, of C-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, aged skin, increasing Stratum corneum flexibility, wrinkles, Sulfhydryl, amine and C-alkyl Substituted amino and fine lines, actinic blemishes, skin dySchromias, and wherein the absolute configuration at the 4-position is inde ichthyosis, comprising applying to the Skin having Said one pendently R or S; 15 or more condition any composition of the present invention. Preferably, the skin condition is actinic blemishes or fine Wrinkles. The present invention also provides methods for prevent ing or treating individuals Suffering hair loSS Such as male pattern baldneSS or female pattern baldness comprising applying to the affected areas of the skin any composition of the present invention. The present invention further provides methods for restor ing the natural color of gray hair comprising applying to the 25 affected areas of the Skin any composition of the present wherein X, Y are independently Selected from the group invention. consisting of hydrogen, C-alkyl, hydroxyl, alkoxyl, For the purpose of this invention, treatment of a Subject acyloxyl, halide, azide, Sulfhydryl, amine and C-alkyl with the composition of the present invention means admin Substituted amino and Z is Selected from the group con istering or applying to Said Subject either together or Sepa sisting of C-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, rately both the vitamin D analog and the retinoid as defined azide, Sulfhydryl, amine and C-alkyl Substituted amino; in the composition of the present invention. Thus, the Vitamin D analog and the retinoid may be administered or applied together or Separately using either the Same or different forms of administration or application. 35 Also, for the purpose of this invention, the term “Vitamin D analog is defined as a compound capable of binding a Vitamin D receptor (not necessarily all) or being converted in Vivo into a compound capable of binding a vitamin D receptor (not necessarily all). The term "vitamin D analog 40 includes but is not limited to vitamin D and vitamin D. derivatives Such as cholecalciferol, calcifediol, calcitriol, wherein X is Selected from the group consisting of calcipotriol, ergosterol, ergocalciferol, dihydrotachysterol, hydrogen, C-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, 1,25-dihydroxy ergo calcife rol, azide, Sulfhydryl, amine and C-alkyl Substituted amino 25-hydroxydihydrotachysterol, and the vitamin D analogs and Z is Selected from the group consisting of C-alkyl, 45 disclosed in U.S. Pat. No. 4.866,048. Preferred analogs are hydroxyl, alkoxyl, acyloxyl, halide, azide, Sulfhydryl, amine cholecalciferol, calcifediol, calcitriol, calcipotriol and the and C-alkyl Substituted amino; vitamin D analogs disclosed in U.S. Pat. No. 4.866,048. More preferred analogs are cholecalciferol, calcifediol, cal citriol and calcipotriol. Most preferred analogs are calcitriol 50 and calcipotriol. The concentration of the Vitamin D analog may vary from about 0.0001% to about 10% by weight of the total com position of the invention. Preferably, the concentrations employed of Vitamin D analogs that can directly bind to the X, Y, 55 vitamin D receptors, range from about 0.0001% to about 1%, more preferably from about 0.0005% to about 0.05%, wherein X and Y are independently selected from the still more preferably from about 0.009% to about 0.5%, yet group consisting of hydrogens, C-alkyl, hydroxyl, still more preferably from about 0.001 to about 0.008%, and alkoxyl, acyloxyl, halide, azide, Sulfhydryl, amine and C most preferably at about 0.005%. alkyl Substituted amino So long as X and Y are not both 60 Preferably, the concentration employed of vitamin D hydrogens. analogs that can be converted in Vivo to a compound capable Preferably, the abnormal cell proliferation treated with the of binding a vitamin D receptor is from about 0.001% to composition of the present invention is associated with about 10%, more preferably from about 0.01% to about 8%, cancer cells and more preferably with skin cancer Such as still more preferably from about 1% to about 6%, and most melanoma. Also more preferably, the abnormal cell prolif 65 preferably from about 2% to about 5%. eration is associated with cancer cells that can at least Retinoid D is preferably 4-oxo-retinoic acid, 4-oxo partially respond to hormone or retinoid treatment. retinol, and 4-oxo-retinal, 4-hydroxy-retinol, 4-hydroxy US 6,552,009 B2 7 8 retinal, 4-OXO-retinyl ester, and 4-hydroxyretinyl ester. The about 1.8%, more preferably at least about 2% by weight of most preferred retinoid is 4-oxo-retinol. Preferably, the the total weight of the composition. More preferably, the concentration of retinoid D in the compositions of the concentration Such retinoid is from about at 2% to about invention ranges from about 0.001% to about 1%, more 20%, more preferably from about 2% to about 15%, still preferably from about 0.025% to about 0.1%, most prefer more preferably from about 2% to about 10%, and most ably about 0.05%. preferably about 5%. Also, for the purpose of this invention, the term “retinol” The compositions of the present invention are preferably includes but is not limited to the following: all-trans-retinol, topical and/or pharmaceutical. They may be in the form of 13-cis-retinol, 1-cis-retinol, 9-cis-retinol, 3,4-didehydro a cream, ointment, and gel. They may also comprise a retinol. Preferred isomers are all-trans-retinol, 13-cis cosmetically acceptable vehicle to act as a diluent, disperS retinol, 3,4-didehydro-retinol, and 9-cis-retinol. Most pre ant or carrier for the active components in the composition, ferred is all-trans-retinol due to its wide commercial So as to facilitate their distribution when the composition is availability. The concentration employed of retinol is at least applied to the skin. about 0.1%, preferably at least 0.3% by weight of the total Vehicles other than water can include liquid or solid weight of the composition. More preferably, the concentra 15 emollients, Solvents, humectants, thickeners and powders. tion Such retinoid is from about at 0.3% to about 20%, more An especially preferred nonaqueous carrier is a polydim preferably from about 0.5% to about 15%, still more pref ethyl Siloxane and/or a polydimethyl phenyl siloxane. Sili erably from about 0.5% to about 10%, still more preferably cones of this invention may be those with Viscosities ranging from about 1% to about 10%, still more preferably from anywhere from about 10 to 10,000,000 centistokes at 25°C. about 2% to about 10%, and most preferably about 5%. Especially desirable are mixtures of low and high Viscosity The retinoids that can be converted in vivo to retinol Silicones. These Silicones are available from the General include but are not limited to retinyl esters, retinyl Electric Company under trademarks Vicasil, SE and SF and glucoronides, retinal, 3,4-didehydro-retinol. Compounds from the Dow Corning Company under the 200 and 550 that are converted Spontaneously by isomerization are also Series. Amounts of silicone which can be utilized in the included in the compounds of the invention. 25 compositions of this invention range anywhere from 5% to Retinyl ester is an ester of retinol and is capable of being 95%, preferably from 25% to 90% by weight of the com converted in vivo into retinol. Retinyl esters suitable for use position. in the present invention include but are not limited to C-Co The cosmetically acceptable vehicle will usually form esters of retinol, preferably C-Co esters, and most prefer from 5% to 99.9%, preferably from 25% to 80% by weight ably C, C, and C. esters because they are commonly of the emulsion, and can, in the absence of other cosmetic available. Examples of retinyl, esters include but are not adjuncts, form the balance of the composition. limited to: retinyl palmitate, retinyl formate, retinyl acetate, An oil or oily material may be present in the claimed retinyl propionate, retinyl butyrate, retinyl Valerate, retinyl compositions, together with an emulsifier to provide either isovalerate, retinyl hexanoate, retinyl heptanoate, retinyl a water-in-oil emulsion or an oil-in-water emulsion, depend octanoate, retinyl nonanoate, retinyl decanoate, retinyl 35 ing largely on the average hydrophilic-lipophilic balance undecandate, retinyl laurate, retinyl tridecanoate, retinyl (HLB) of the emulsifier employed. myristate, retinyl pentadecanoate, retinyl heptadecanoate, Various types of active ingredients may be present in retinyl Stearate, retinyl isoStearate, retinyl nonadecanoate, cosmetic compositions of the present invention. Various retinyl arachidonate, retinyl behenate, retinyl linoleate, and types of active ingredients may be present in cosmetic retinyl oleate. 40 compositions of the present invention. Actives are defined as The preferred retinyl esters for use in the present inven skin benefit agents other than emollients and other than tion are retinyl palmitate, retinyl acetate, retinyl propionate ingredients that merely improve the physical characteristics and retinyl linoleate. More preferred retinyl esters are retinyl of the composition. Although not limited to this category, palmitate and retinyl acetate, the most preferred retinyl ester general examples include SunScreens and tanning agents. is retinyl palmitate. 45 Sunscreens include those materials commonly employed The concentration employed of the retinoid that can be to block ultraviolet light. Illustrative compounds are the converted in vivo to retinol is at least about 0.1%, preferably derivatives of PABA, cinnamate and salicylate. For at least 0.3% by weight of the total weight of the compo example, octyl methoxycinnamate and 2-hydroxy-4- Sition. More preferably, the concentration Such retinoid is methoxybenzophenone (also known as oxybenzone) can be from about at 0.3% to about 20%, more preferably from 50 used. Octyl methoxycinnamate and 2-hydroxy-4-methoxy about 0.5% to about 15%, still more preferably from about benzophenone are commercially available under the 0.5% to about 10%, still more preferably from about 1% to trademarks, Parsol MCX and Benzophenone-3, respectively. about 10%, still more preferably from about 2% to about The exact amount of Sunscreen employed in the emulsions 10%, and most preferably about 5%. can vary depending upon the degree of protection desired It has also been Surprisingly discovered that a composi 55 from the Sun's UV radiation. tion comprising retinol in a concentration of at least about Another preferred optional ingredient is Selected from 1.5% or a compound in a concentration of at least about essential fatty acids (EFAS), i.e., those fatty acids which are 1.5% capable of being converted in vivo into retinol is as essential for the plasma membrane formation of all cells (in effective as retinoic acid in treating one or more conditions keratino cyte S, EFA deficiency make S cells of the Skin Selected from the group consisting of dry skin, 60 hyperproliferative). Supplementation of EFA corrects this. photodamaged skin, age Spots, aged skin, increasing Stratum EFAS also enhance lipid biosynthesis of epidermis and corneum flexibility, wrinkles, fine lines, actinic blemishes, provide lipids for the barrier formation of the epidermis. The skin dySchromias, ichthyosis and acne. The term “retinol” essential fatty acids are preferably chosen from linoleic acid, and the compounds capable of being converted into retinol gamma-linolenic acid, homo-gamma-linolenic acid, colum has been defined above. Preferably, for this composition, the 65 binic acid, eicosa-(n-6,9,13)-trienoic acid, arachidonic acid, concentration employed of retinol or of the compound gamma-linolenic acid, timnodonic acid, hexaenoic acid and capable of being converted in Vivo into retinol is at least mixtures thereof. US 6,552,009 B2 10 Emollients are often incorporated into cosmetic compo The topical skin treatment composition of the invention Sitions of the present invention. Levels of Such emollients can be formulated as a lotion having a Viscosity of from may range from about 0.5% to about 50%, preferably 4,000 to 10,000 mPas, a fluid cream having a viscosity of between about 5% and 30% by weight of the total compo from 10,000 to 20,000 mPas or a cream or a gel having a Sition. Emollients may be classified under Such general viscosity of from 20,000 to 100,000 mPas or above. The chemical categories as esters, fatty acids and alcohols, composition can be packaged in a Suitable container to Suit polyols and hydrocarbons. its Viscosity and intended use by the consumer. For example, Esters may be mono- or di-esters. Acceptable examples of fatty di-esters include dibutyl adipate, diethyl Sebacate, a lotion or fluid cream can be packaged in a bottle or a diisopropyl dimerate, and dioctyl Succinate. Acceptable roll-ball applicator, or a capsule, or a propellant-driven branched chain fatty esters include 2-ethyl-hexyl myristate, aeroSol device or a container fitted with a pump Suitable for isopropyl Stearate and isoStearyl palmitate. Acceptable triba finger operation. When the composition is a cream, it can sic acid esters include triisopropyl trilinoleate and trilauryl Simply be stored in a non-deformable bottle or Squeeze citrate. Acceptable Straight chain fatty esters include lauryl container, Such as a tube or a lidded jar. palmitate, myristyl lactate, oleyl eurcate and Stearyl oleate. The invention accordingly also provides a closed con Preferred esters include coco-caprylate/caprate (a blend of 15 tainer containing a cosmetically acceptable composition as coco-caprylate and coco-caprate), propylene glycol myri herein defined. Styl ether acetate, diisopropyl adipate and cetyl octanoate. The following specific examples further illustrate the Suitable fatty alcohols and acids include those compounds invention, but the invention is not limited thereto. having from 10 to 20 carbon atoms. Especially preferred are compounds Such as cetyl, myristyl, palmitic and Stearyl EXAMPLE 1. alcohols and acids. Among the polyols which may serve as emollients are This example compares therapeutically applied retinyl linear and branched chain alkyl polyhydroxyl compounds. palmitate, retinoic acid, calcitriol, and combinations thereof For example, propylene glycol, Sorbitol and glycerin are in a cream at different concentrations with the effectiveness preferred. Also useful may be polymeric polyols Such as 25 of the cream without any of the above compounds present in polypropylene glycol and polyethylene glycol. Butylene and treating acne. The base cream used to prepare the experi propylene glycol are also especially preferred as penetration mental formulations is the commercially available LUBRI enhancers. DERM cream. The different compounds at different con Exemplary hydrocarbons which may serve as emollients centrations were added to the cream and mixed very well. are those having hydrocarbon chains anywhere from 12 to Sixty Six Volunteers were recruited and were randomly 30 carbon atoms. Specific examples include mineral oil, assigned to each of the groups. the Subjects were Selected on petroleum jelly, Squalene and isoparaffins. the basis of their having moderate to Severe papular-pustular Another category of functional ingredients within the acne. Each group consisted of 3 males and 3 females. No cosmetic compositions of the present invention are thicken other acne treatment was permitted during the period. Prepa ers. A thickener will usually be present in amounts anywhere 35 rations were applied to the face in the morning and evening from 0.1 to 20% by weight, preferably from about 0.5% to after washing the face with ordinary Soap. Observations 10% by weight of the composition. Exemplary thickeners were made at time 0, 1, 4, and 8 weeks to assure that are cross-linked polyacrylate materials available under the treatment was carried out according to direction. Judgments trademark Carbopol from the B. F. Goodrich Company. of “worse”, “no change”, “mild”, and “good” were made Gums may be employed Such as Xanthan, carrageenan, 40 after 8 weeks of treatment. Table 1 illustrates the results. gelatin, karaya, pectin and locust beans gum. Under certain circumstances the thickening function may be accomplished TABLE 1. by a material also Serving as a Silicone or emollient. For Results of treatment instance, Silicone gums in excess of 10 centistokes and esters with various compounds on acne Such as glycerol Stearate have dual functionality. 45 PowderS may be incorporated into the cosmetic compo O Sition of the invention. These powders include chalk, talc, Treatment WOSC change mild good Fullers earth, kaolin, Starch, Smectite clays, chemically Control 2 4 O O modified magnesium aluminum Silicate, organically modi 0.1% retinoic acid O 2 3 1. fied montmorillonite clay, hydrated aluminum Silicate, 50 0.1% retiny 2 3 1. O fumed Silica, aluminum Starch octenyl Succinate and mix palmitate tures thereof. 1% retinyl palmitate O 4 2 O 1.5% retiny O 1. 3 2 Other adjunct minor components may also be incorpo palmitate rated into the cosmetic compositions. These ingredients may 5% retinol O 1. 2 3 include coloring agents, opacifiers, perfumes and preserva 55 10% retinol O O 3 3 0.0025% calcitriol 2 3 1. tives (e.g., imidazolidinyl urea, dimethyl imidazolidinone 0.1% retinoic acid O 1. 3 2 and diazolidinyl urea). Amounts of these materials may and 0.0025% range anywhere from 0.001% up to 20% by weight of the calcitriol composition. 0.1% retiny 1. 2 2 1. palmitate and The composition according to the invention is intended 60 0.0025% calcitriol primarily but not exclusively as a product for topical appli 0.5% retiny O 1. 3 2 cation to human skin and as a product to modulate cell palmitate and differentiation. In use, a Small quantity of the composition, 0.0025% calcitriol 5% retinyl palmitate O O 1. 5 for example from 1 to 5 ml, is applied to exposed areas of and 0.0025% the skin, from a Suitable container or applicator and, if 65 calcitriol necessary, it is then Spread over and/or rubbed into the skin 0.1% 4-oxo-retinol O 1. 4 1. using the hand or fingers or a Suitable device. US 6,552,009 B2 11 12 of treatment. Five out of five patients showed good improve TABLE 1-continued ment in itching after 3 days in Spot B but no improvement in Stopping Scaling which results from cellular hyperprolif Results of treatment eration. with various compounds on acne Group V consisting of five patients applied on one O selected spot (spot A) control LUBRIDERM cream and on Treatment WOSC change mild good the other selected spot (spot B) cream containing 0.005% 0.1% 4-oxo-retinol O O 3 3 calcipotriol. No change in Spot A was observed after 4 weeks and 0.0025% of treatment. Two out of five patients showed partial clear calcitriol ance (average of 35% of spot area) in spot B after 4 weeks of treatment. However, even in the Spots showing improve Table 1 illustrates that retinyl palmitate in concentrations ment and partial clearance, a certain amount of Scaling is at about 1.5% and more shows a remarkable improvement Still occurring. over lower concentrations in treating acne. In addition, the Group VI consisting of five patients applied on one combination of 4-OXO-retinol and calcitriol shows a Syner 15 Selected Spot (spot A) a cream containing 0.0025% calcipo gistic effect when compared with either 4-oxo-retinol and triol and on the other Selected spot (spot B) cream containing calcitriol alone. A Synergistic effect is also seen when 0.0025% calcipotriol and 0.1% retinyl palmitate. One out of calcitriol is combined with retinyl palmitate particularly at five patients showed partial clearance (about 20% of spot concentrations of 0.5% of retinyl palmitate. area) in spot A after 4 weeks of treatment. However, even in The use of each of retinoic acid and calcitriol caused skin Spot A that is showing improvement and partial clearance, a certain amount of Scaling is still occurring. Two out of Five irritation while the use of retinyl palmitate or 4-oxo-retinol patients showed considerable amount of clearance (about did not. 40% of spot area) in spot B and with little scaling and EXAMPLE 2 itching. 25 Group VII consisting of five patients applied on one This example compares therapeutically applied retinyl Selected Spot (spot A) a cream containing 0.0025% calcipo palmitate, retinoic acid, calcitriol, and combinations thereof triol and on the other Selected spot (spot B) cream containing in a cream at different concentrations with the effectiveness 0.0025% calcipotriol and 0.5% retinyl palmitate. Two out of of the cream without any of the above compounds present in five patients showed partial clearance (about 25% of spot treating psoriasis. The base cream used to prepare the area) in spot A after 4 weeks of treatment. However, even in experimental formulations is the commercially available spots A that are showing improvement and partial clearance, LUBRIDERM cream. The different compounds at different a certain amount of Scaling is still occurring. Three out of concentrations were added to the cream and thoroughly Five patients showed considerable amount of clearance mixed. Also, commercially available 0.005% calcipotriol (about 50% of spot area) in spot B and with barely notice (DOVONEX) and commercially available 0.005% calcipo 35 able Scaling and no itching. triol was supplemented with 5% retinyl palmitate and Group VIII consisting of five patients applied on one employed in treating psoriasis. Two different and distant Selected Spot (spot A) a cream containing 0.0025% calcipo pSoriatic Spots were Selected on the skin of patients diag triol and on the other Selected spot (spot B) cream containing nosed with psoriasis for different treatment. Each patient 0.0025% calcipotriol and 1% retinyl palmitate. Two out of used two type of creams twice a day, one cream on each 40 five patients showed partial clearance (about 20% of spot Selected Spot. area) in spot A after 4 weeks of treatment. However, even in Group I consisting of five patients applied on one Selected spots A that are showing improvement and partial clearance, spot (spot A) control LUBRIDERM cream and on the other a certain amount of Scaling is Still occurring. Four out of Selected spot (spot B) cream containing 0.1% retinoic acid. 45 Five patients showed considerable amount of clearance None of the patients showed any improvement in either (about 50% of spot area) in spot B and with barely notice spots even after 12 weeks of treatment. able Scaling and no itching. Group II consisting of five patients applied on one Group IX consisting of five patients applied on one selected spot (spot A) control LUBRIDERM cream and on Selected Spot (spot A) a cream containing 0.0025% calcipo the other Selected Spot (spot B) cream containing 0.1% 50 triol and on the other Selected spot (spot B) cream containing retinyl palmitate. No change in Spot A was observed after 4 0.0025% calcipotriol and 5% retinyl palmitate. One out of weeks of treatment. Three out of five patients showed mild five patients showed partial clearance (about 30% of spot improvement in itching after 3 days in Spot B but no area) in spot A after 4 weeks of treatment. However, even in improvement in Stopping Scaling which results from cellular Spot A that is showing improvement and partial clearance, a hyperproliferation. 55 certain amount of Scaling is Still occurring. Five out of Five Group III consisting of five patients applied on one patients showed considerable amount of clearance (average selected spot (spot A) control LUBRIDERM cream and on about 85% of spot area and one complete clearance) in spot the other selected spot (spot B) cream containing 1% retinyl B and with no Scaling and itching. palmitate. No change in Spot A was observed after 4 weeks Group X consisting of five patients applied on one of treatment. Four out of five patients showed good improve 60 Selected Spot (spot A) a cream containing 0.0025% calcipo ment in itching after 3 days in Spot B but no improvement triol and on the other Selected spot (spot B) cream containing in Stopping Scaling which results from cellular hyperprolif 0.0025% calcipotriol and 10% retinyl palmitate. One out of eration. five patients showed partial clearance (about 15% of spot Group IV consisting of five patients applied on one area) in spot A after 4 weeks of treatment. However, even in selected spot (spot A) control LUBRIDERM cream and on 65 Spot A that is showing improvement and partial clearance, a the other selected spot (spot B) cream containing 5% retinyl certain amount of Scaling is Still occurring. Five out of Five palmitate. No change in Spot A was observed after 4 weeks patients showed considerable amount of clearance (average US 6,552,009 B2 13 14 about 90% of spot area and two complete clearance) in spot This data clearly indicates the Synergistic effect of Vitamin B and with no Scaling and itching. D analogs with retinyl esters above 0.1%, 4-oxo-retinol, or Group XI consisting of five patients applied on one 4-hydroxy-retinol in treating psoriasis. However, there were Selected Spot (spot A) a cream containing 0.0025% calcipo no synergistic effects with of Vitamin Danalogs with retinoic triol and on the other Selected spot (spot B) cream containing acid. Similar experiments were carried out using retinol 0.0025% calcipotriol and 0.1% 4-oxo-retinol. One out of rather than retinyl palmitate with Similar results. five patients showed partial clearance (about 20% of spot area) in spot A after 4 weeks of treatment. However, even in EXAMPLE 3 Spot A that is showing improvement and partial clearance, a certain amount of Scaling is Still occurring. Five out of Five Three patients diagnosed with eczema were treated with patients showed considerable amount of clearance (average 1O cream containing 0.0025% calcipotriol and 5% retinyl about 95% of spot area and four complete clearances) in spot palmitate. A significant improvement was noticed in all three B and with no Scaling and itching. patients within 5 days and two had normal-looking skin after Group XII consisting of five patients applied on one two weeks. A similar results was also observed with patients Selected spot (spot A) a cream containing 0.1% 4-oxo-retinol treated with 0.002% calcitriol and 0.1% 4-oxo-retinol. Treat and on the other Selected spot (spot B) cream containing 15 ment with 5% retinyl palmitate, with 0.1% 4-oxo-retinol 0.0025% calcipotriol and 0.1% 4-oxo-retinol. One out of without a Vitamin D analog, or with a vitamin D analog and five patients showed partial clearance (about 10% of spot 0.1% all-trans retinoic acid did not result in any significant area) in spot A after 4 weeks of treatment. However, even in improvements over the same period of time. Spot A that is showing improvement and partial clearance, a Significant amount of Scaling is Still occurring. Five out of EXAMPLE 4 Five patients showed complete clearances (100%) in spot B A patient diagnosed with atopic dermatitis was treated and with no Scaling and itching. with cream containing 0.05% calcipotriol and 0.1% 4-oxo Group XIII consisting of five patients applied on one retinol. A significant improvement was noticed in within 1 Selected spot (spot A) a cream containing 0.1% 4-oxo-retinol 25 week and the appearance of normal-looking skin after two and on the other Selected spot (spot B) cream containing weeks. 0.002% calcitriol and 0.1% 4-oxo-retinol. One out of five patients showed partial clearance (about 15% of Spot area) EXAMPLE 5 in Spot A after 4 weeks of treatment. However, even in Spot Various types of human melanoma, breast cancer and A that is showing improvement and partial clearance, a prostate cancer cells will be cultured according to Standard Significant amount of Scaling is Still occurring. Five out of ized procedures. These cells will be incubated with in the Five patients showed complete clearances (100%) in spot B presence of various concentrations of retinol, retinoic acid, and with no Scaling and itching. retinyl esters, calcitriol or a combination thereof. Cell Group XIV consisting of five patients applied on one growth of at least some of these cells will be shown to be Selected spot (spot A) a cream containing 0.1% 4-hydroxy 35 Significantly inhibited in the presence of calcitriol and either retinol and on the other Selected spot (spot B) cream 4-oxo-retinol or high concentrations of retinol (about 10 containing 0.002% calcitriol and 0.1% 4-hydroxy-retinol. M) as compared with cells incubated in the absence of the One out of five patients showed partial clearance (about 10% above compounds or in the presence of each of the above of spot area) in Spot A after 4 weeks of treatment. However, compounds alone. even in Spot A that is showing improvement and partial 40 clearance, a significant amount of Scaling is still occurring. EXAMPLE 6 Four out of Five patients showed complete clearances with an average clearance of 95% in Spot B and with no Scaling Patients with breast cancer, prostate cancer or leukemia, and itching. particularly acute promyelocytic leukemia treated with a combination of oral doses of 4-OXO-retinol or 4-hydroxy Group XV consists of five patients applied on one Selected 45 spot (spot A) a cream containing 0.0025% calcipotriol and retinol (100 mg/Square meter) and oral doses of calcitriol on the other Selected Spot (spot B) cream containing will have a reduced tumor burden, undergo prolonged remis 0.0025% calcipotriol and 0.1% all-trans retinoic acid. Two Sion or are permanently cured. out of five patients showed partial clearance (about 15% of EXAMPLE 7 spot area) in spot A after 4 weeks of treatment. However, 50 even in Spots A that are showing improvement and partial Current Systemic chemotherapy regimens are unable to clearance, a certain amount of Scaling is still occurring. prolong Survival of patients with advanced head and neck Similar results were obtained in spot B after 4 weeks of cancer. Patients treated with a combination of oral doses of treatment (about 20% partial clearance with persistence of 4-oxo-retinol or 4-hydroxy-retinol (100 mg/Square meter) Scaling). 55 and oral doses of calcitriol will survive beyond the median Group XVI consisting of five patients applied on one of 4-6 months, and/or have reduced tumor burden during the Selected spot (spot A) a cream containing 0.005% calcipo period during which this treatment is administered. triol and on the other Selected spot (spot B) cream containing 5% Cholecalciferol and 5% retinyl palmitate. Two out of EXAMPLE 8 five patients showed partial clearance (about 15% of spot 60 Patients with deep (cystic acne) treated with a combina area) in spot A after 4 weeks of treatment. However, even in tion of oral doses of 4-oxo-retinol or 4-hydroxy-retinol (100 spots A that are showing improvement and partial clearance, mg/Square meter) and oral doses of calcitriol will have a certain amount of Scaling is still occurring. Five out of Five greater than 50% mean reduction in lesion counts at the end patients showed considerable amount of clearance (average of 3 to 6 months treatment period and in Some cases about 75% of spot area and one complete clearance) in spot 65 complete treatment will occur after discontinuation of B and with no Scaling and itching. The rest of the Spots therapy. A very prolonged remission and permanent cure for showed no improvement. Some will be obtained. US 6,552,009 B2 15 EXAMPLE 9

Patients with psoriatic arthritis treated with a combination of oral doses of 4-oxo-retinol or 4-hydroxy-retinol (50-100 mg/Square meter) and oral doses of calcitriol exhibit fewer tender joints and a decreased duration of morning Stiffness. EXAMPLE 10 Individuals Suffering from male pattern baldness treated once or twice daily with a topical formulation of any of the compositions of the present invention, particularly with a wherein X is Selected from the group consisting of hydrogen topical formulation containing 0.002% calcitriol and 0.1% and C-alkyl and Y is Selected from the group consisting 4-oxo-retinol or 0.1% 4-hydroxy-retinol will regrow a cos of hydroxy and C-alkyoxyl and wherein the absolute metically significant amount of hair within 6–9 months of configuration at the 4-position is independently R or S. treatment. Similar results would be expected with oral 15 2. The composition of claim 1, wherein the retinoid is formulations. retinoid D with an alcohol CH-OH terminal side chain. EXAMPLE 11 3. The composition of claim 1, wherein the retinoid is Individuals with gray hair treated once or twice daily with Selected from the group consisting of 4-OXO-retinol, 4-OXO a topical formulation of any of the compositions of the retinal, and 4-OXO-retinyl ester. present invention, particularly with a topical formulation 4. A topical composition according to claim 1. containing 0.002% calcitriol and 0.1% 4-oxo-retinal or 0.1% 5. The composition of claim 1, wherein the vitamin D 4-hydroxy-retinol will grow hair having the natural color analog is Selected from the group consisting of within 6–9 months of treatment. Similar results would be cholecalciferol, calcifediol, calcitriol, calcipotriol, expected with oral formulations. 25 ergo calcife rol, dihydro tachy Ste rol, 1,25 The invention has been described in terms of preferred dihydroxy ergo calcife rol, and embodiments thereof, but is more broadly applicable as will 25-hydroxydihydrotachysterol. be understood by those skilled in the art. The scope of the invention is therefore limited only by the following claims. 6. The composition of claim 1, wherein the vitamin D What is claimed is: analog is calcitriol. 1. A composition comprising a vitamin D analog and a 7. The composition of claim 1, wherein the vitamin D retinoid, wherein: analog is calcipotriol. (a) the vitamin D analog is capable of binding a vitamin 8. The composition of claim 1, wherein the retinoid is D receptor or being converted in Vivo into a compound 4-oxo-retinol. capable of binding a Vitamin D receptor, and 35 9. The composition of claim 1, wherein the vitamin D (b) the retinoid is selected from the group consisting of analog is calcitriol or calcipotriol and the retinoid is a retinoid D with an alcohol CH-OH terminal side chain, 4-oxo-retinol. an ester of retinoid D having an ester bond, an ether of 10. The composition of claim 1, wherein the vitamin D retinoid D having an ether bond, and retinoid D where analog is a vitamin D3 analog. the alcohol CH-OH terminal side chain is replaced with 40 an aldehyde CHO terminal side chain, wherein each of 11. The composition of claim 1, wherein the retinoid is the ester bond and the ether bond is formed with the 4-oxo-retinal. oxygen at the terminal Side chain of Retinoid D and 12. The composition of claim 1, wherein the retinoid is wherein said retinoid D with the alcohol CH-OH 4-methoxy-retinol. terminal Side chain has the Structure: 45 13. A method of treating a Subject Suffering from a disorder characterized by abnormal cell-proliferation and/or cell-differentiation, comprising administering to the Subject 9 11 13 in need of Such treatment a vitamin D analog and a retinoid, N1 N. CH2OH 50 wherein the combination of the vitamin D analog and the R retinoid is an effective combination and the retinoid and the Vitamin D analog are administered simultaneously or at wherein the configuration at the 7-, 9-, 11- and 13-position different times and wherein: double bonds is independently Z or E and wherein R is (a) the Vitamin D analog is capable of binding a vitamin Selected from the group consisting of: 55 D receptor or being converted in Vivo into a compound capable of binding a Vitamin D receptor; and (b) the retinoid is selected from the group consisting of retinoid D with an alcohol CH-OH terminal side chain, 60 an ester of retinoid D having an ester bond, an ether of retinoid D having an ether bond, and retinoid D where the alcohol CH-OH terminal side chain is replaced with an aldehyde CHO terminal side chain, wherein each of the ester bond and the ether bond is formed with the 65 Oxygen at the terminal Side chain of Retinoid D and wherein the keto group at the 4-position is free or protected; wherein said retinoid D with the alcohol CH-OH and terminal Side chain has the Structure: US 6,552,009 B2 17 18 the combination of the Vitamin D analog and the retinoid is an effective combination and the retinoid and the vitamin D 9 11 13 analog are administered simultaneously or at different times N1 N. CH2OH and wherein: 5 (a) the Vitamin D analog is capable of binding a vitamin R D receptor or being converted in Vivo into a compound capable of binding a Vitamin D receptor; and wherein the configuration at the 7-, 9-, 11- and 13-position (b) the retinoid is selected from the group consisting of double bonds is independently Z or E and wherein R is retinoid D with an alcohol CH-OH terminal side chain, Selected from the group consisting of: an ester of retinoid D having an ester bond, an ether of retinoid D having an ether bond, and retinoid D where the alcohol CH-OH terminal side chain is replaced with an aldehyde CHO terminal side chain, wherein each of the ester bond and the ether bond is formed with the 15 Oxygen at the terminal Side chain of Retinoid D and wherein said retinoid D with the alcohol CH-OH terminal Side chain has the Structure: wherein the keto group at the 4-position is free or protected; 9 11 13 CH2OH and N1 N. R

25 wherein the configuration at the 7-, 9-, 11- and 13-position double bonds is independently Z or E and wherein R is Selected from the group consisting of:

wherein X is Selected from the group consisting of hydrogen and C6-alkyl and Y is Selected from the group consisting of hydroxy and C-alkyoxyl and wherein the absolute configuration at the 4-position is independently R or S. 35 14. The method of claim 13, wherein the retinoid is retinoid D with an alcohol CH-OH terminal side chain. 15. The method of claim 13, wherein the retinoid is wherein the keto group at the 4-position is free or protected; Selected from the group consisting of 4-oxo-retinol, 4-OXO and retinal, and 4-oxo-retinyl ester. 40 16. The method of claim 13, wherein the vitamin D analog is Selected from the group consisting of cholecalciferol, calcifediol, calcitriol, calcipotriol, ergocalciferol, dihydrotachysterol, 1,25-dihydroxyergocalciferol, and 25-hydroxydihydrotachysterol. 45 17. The method of claim 13, wherein the vitamin D analog is calcitriol. 18. The method of claim 13, wherein the vitamin D analog is calcipotriol. wherein X is Selected from the group consisting of hydrogen 19. The method of claim 13, wherein the vitamin D analog 50 and C-alkyl and Y is selected from the group consisting is a vitamin D3 analog. of hydroxy and C-alkyoxyl and wherein the absolute 20. The method of claim 13, wherein the retinoid is configuration at the 4-position is independently R or S. 4-oxo-retinol. 26. The method of claim 25, wherein the retinoid is 21. The method of claim 13, wherein the retinoid is retinoid D with an alcohol CH-OH terminal side chain. 4-hydroxy-retinol. 55 27. The method of claim 26, wherein the retinoid is 22. The method of claim 13, wherein the retinoid is 4-oxo-retinol. 4-methoxy-retinol. 28. The method of claim 26, wherein the retinoid is 23. The method of claim 13, wherein the vitamin D analog 4-hydroxy-retinol. is calcitriol or calcipotriol and the retinoid is a 4-OXO-retinol. 29. The method of claim 26, wherein the retinoid is 24. The method of claim 13, wherein the retinoid is 60 4-methoxy-retinol. administered topically. 30. The method of claim 26, wherein the vitamin Danalog 25. A method of treating a Subject Suffering from a is calcitriol or calcipotriol and the retinoid is a 4-OXO-retinol. disorder Selected from the group consisting of psoriasis, 31. The method of claim 25, wherein the retinoid is acne, atopic dermatitis, eczema, rosacea, actinic keratosis, Selected from the group consisting of 4-OXO-retinol, 4-OXO Seborrheic dermatitis, and congenital keratinization 65 retinal, and 4-OXO-retinyl ester. disorders, comprising administering to the Subject in need of 32. The method of claim 25, wherein the vitamin Danalog Such treatment a vitamin D analog and a retinoid, wherein is Selected from the group consisting of cholecalciferol, US 6,552,009 B2 19 20 calcifediol, calcitriol, calcipotriol, ergocalciferol, wherein the configuration at the 7-, 9-, 11- and 13-position dihydrotachysterol, 1,25-dihydroxyergocalciferol, and double bonds is independently Z or E and wherein R is 25-hydroxydihydrotachysterol. Selected from the group consisting of: 33. The method of claim 25, wherein the vitamin D analog is calcitriol. 34. The method of claim 33, wherein the disorder is pSoriasis. 35. The method of claim 33, wherein the disorder is CCZC. 36. The method of claim 25, wherein the vitamin D analog is calcipotriol. 37. The method of claim 25, wherein the vitamin D analog is a vitamin D3 analog. wherein the keto group at the 4-position is free or protected; 38. The method of claim 25, wherein the disorder is and pSoriasis. 15 39. The method of claim 25, wherein the retinoid is applied topically. 40. The method of claim 25, wherein the disorder is CCZC. 41. The method of claim 25, wherein the disorder is acne. 42. The method of claim 25, wherein the disorder is atopic dermatitis. 43. A method of treating one or more conditions of the skin Selected from the group consisting of dry skin, photo damaged skin, age spots, aged skin, inflexibility of Stratum 25 wherein X is Selected from the group consisting of hydrogen corneum, wrinkles, fine lines, actinic blemishes, skin and C-alkyl and Y is Selected from the group consisting dySchromias, and ichthyosis, comprising applying to the of hydroxy and C-alkyoxyl and wherein the absolute skin having Said one or more condition a vitamin D analog configuration at the 4-position is independently R or S. and a retinoid, wherein the combination of the vitamin D 44. The method of claim 43, where in the retinoid is retinoid D with an alcohol CH-OH terminal side chain. analog and the retinoid is an effective combination and the 45. The method of claim 43, wherein the retinoid is retinoid and the Vitamin D analog are administered Simul Selected from the group consisting of 4-OXO-retinol, 4-OXO taneously or at different times and, wherein: retinal, and 4-OXO-retinyl ester. (a) the vitamin D analog is capable of binding a vitamin 46. The method of claim 44, wherein the vitamin Danalog D receptor or being converted in Vivo into a compound is Selected from the group consisting of cholecalciferol, capable of binding a Vitamin D receptor, and 35 calcifediol, calcitriol, calcipotriol, ergocalciferol, (b) the retinoid is selected from the group consisting of dihydrotachysterol, 1,25-dihydroxyergocalciferol, and retinoid D with an alcohol CH-OH terminal side chain, 25-hydroxydihydrotachysterol. an ester of retinoid D having an ester bond, an ether of 47. The method of claim 44, wherein the vitamin Danalog retinoid D having an ether bond, and retinoid D where is calcitriol. the alcohol CH-OH terminal side chain is replaced with 40 48. The method of claim 44, wherein the vitamin Danalog an aldehyde CHO terminal side chain, wherein each of is calcipotriol. the ester bond and the ether bond is formed with the 49. The method of claim 44, wherein the retinoid is oxygen at the terminal Side chain of Retinoid D and 4-oxo-retinol. wherein said retinoid D with the alcohol CH-OH 50. The method of claim 44, wherein the retinoid is terminal Side chain has the Structure: 45 4-hydroxy-retinol. 51. The method of claim 44, wherein the retinoid is 4-methoxy-retinol. 52. The method of claim 44, wherein the vitamin Danalog 9 11 13 CH2OH is calcitriol or calcipotriol and the retinoid is a 4-OXO-retinol. 50 53. The method of claim 44, wherein the vitamin Danalog is a vitamin D3 analog.

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