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US20010002396A1 - Compositions and methods of treating skin conditions - Google Patents

Compositions and methods of treating skin conditions Download PDF

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Publication number
US20010002396A1
US20010002396A1 US09/116,632 US11663298A US2001002396A1 US 20010002396 A1 US20010002396 A1 US 20010002396A1 US 11663298 A US11663298 A US 11663298A US 2001002396 A1 US2001002396 A1 US 2001002396A1
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United States
Prior art keywords
skin
composition
vitamin
retinyl
retinol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US09/116,632
Inventor
Charles Achkar
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Gentrix LLC
Original Assignee
Gentrix LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gentrix LLC filed Critical Gentrix LLC
Priority to US09/116,632 priority Critical patent/US20010002396A1/en
Priority to US09/351,020 priority patent/US6242435B1/en
Priority to EP99933947A priority patent/EP1104294B8/en
Priority to MXPA01000492A priority patent/MXPA01000492A/en
Priority to PCT/US1999/015769 priority patent/WO2000003700A1/en
Priority to DK99933947T priority patent/DK1104294T3/en
Priority to AU49889/99A priority patent/AU4988999A/en
Priority to AT99933947T priority patent/ATE305296T1/en
Priority to ES99933947T priority patent/ES2249900T3/en
Priority to CA002337138A priority patent/CA2337138A1/en
Priority to PT99933947T priority patent/PT1104294E/en
Priority to DE69927507T priority patent/DE69927507T2/en
Priority to JP2000559835A priority patent/JP2002527356A/en
Assigned to GENTRIX LLC reassignment GENTRIX LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ACHKAR, CHARLES C.
Publication of US20010002396A1 publication Critical patent/US20010002396A1/en
Priority to US09/872,662 priority patent/US6552009B2/en
Priority to US10/420,106 priority patent/US20030207848A1/en
Abandoned legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/007—Preparations for dry skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/06—Preparations for styling the hair, e.g. by temporary shaping or colouring
    • A61Q5/065—Preparations for temporary colouring the hair, e.g. direct dyes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • the present invention relates to compositions comprising certain retinoids and vitamin D analogs useful in inducing differentiation and inhibiting undesirable proliferation of cells, such as cancer cells and skin cells.
  • the present invention also relates to methods of using the above compositions in the treatment of diseases and conditions characterized by abnormal cell differentiation and/or cell proliferation.
  • Abnormal cell differentiation and/or cell differentiation is associated with many conditions and diseases. For instance, hyperproliferation of epithelial cells is associated with psoriasis causes the skin to shed itself too rapidly, every three to four days. The goal in treating psoriasis is to reduce inflammation and to slow down rapid skin cell division.
  • U.S. Pat. No. 4,866,048 discloses that certain vitamin D derivatives, in particular calcitriol (1 alpha,25-dihydroxy-vitamin D 3 or) and calcipotriol are able to stimulate the differentiation of cells and inhibit excessive cell proliferation, and it has been suggested that these compounds are useful in the treatment of diseases characterized by abnormal cell differentiation and/or cell differentiation such as leukemia, myelofibrosis, psoriasis and acne.
  • retinoids are also known for their antiproliferative and differentiation activity.
  • retinol vitamin A
  • Retinoic acid is believed to be an active derivative of retinol.
  • retinoic acid is believed to be more effective than retinol and retinyl esters at providing skin benefits.
  • Natural and synthetic vitamin A derivatives have been used extensively in the treatment of a variety of skin and hyperproliferation disorders.
  • retinoic acid has been employed to treat certain types of leukemia like acute apromyelocytic leukemia as well as a variety of skin conditions such as acne, wrinkles, psoriasis, age spots and discoloration (Vahlquist, A. et al., J. Invest. Dermatol., Vol. 94, Holland D. B. and Cunliffe, W. J. (1990), pp. 496-498; Ellis C. N.
  • Vitamin D for instance, the synthetic Vitamin D, calcipotriol, or retinoic acid which are available in prescription form are somewhat useful for individuals with localized psoriasis. However, these compound are not very effective on most patients.
  • Therapeutic regimens for acne involve local and systemic therapies, although the former is indicated in the vast majority of cases.
  • Topical application of a variety of chemical application which include mainly sulfur, resorcinol, salicylic acid, benzoyl peroxide, and retinoic acid are frequently used to treat acne. All the foregoing agents are known as “peeling” or “drying” agents which are believed to exert their therapeutical effect by causing erythema, irritation, and desquamination of the skin to expel comedones.
  • the therapeutic efficacy of these agents is rather variable, and their utility is limited partially because of the irritation caused by their application (see U.S. Pat. No. 3,932,665).
  • Oral formulations of retinoic acid are also used but serious side effects are associated with the oral use of this compound including severe fetal malformation in pregnant women.
  • compositions comprising certain vitamin D and retinoid compounds at particular concentrations which are useful for the treatment of disorders characterized by abnormal cell-proliferation and/or cell-differentiation.
  • the present invention provides a composition comprising a vitamin D analog and a retinoid, wherein:
  • the vitamin D analog is capable of binding a vitamin D receptor or being converted in vivo into a compound capable of binding a vitamin D receptor;
  • the retinoid is selected from the group consisting of a compound capable of binding a retinoic acid receptor, retinol in a concentration of at least about 0.1% and a compound in a concentration of at least about 0.1% capable of being converted in vivo into retinol.
  • the present invention provides a composition comprising retinol in a concentration of at least about 1.5% or a compound in a concentration of at least about 1.5% capable of being converted in vivo into retinol.
  • a composition comprising (i) a vitamin D analog; and (ii) a retinoid selected from the group consisting of a compound capable of binding a retinoic acid receptor, retinol in a concentration of at least about 0.1% and a compound in a concentration of at least about 0.1% capable of being converted in vivo into retinol, is useful in treating a subject suffering from a disorder characterized by abnormal cell-proliferation and/or cell-differentiation more effectively than either a composition comprising a vitamin D analog without the above defined retinoid or a composition comprising the above retinoid without a vitamin D analog.
  • the abnormal cell proliferation is associated with cancer cells and more preferably with skin cancer such as melanoma.
  • the abnormal cell proliferation is associated with cancer cells that can at least partially respond to hormone or retinoid treatment.
  • the present invention also provides a method of treating a subject suffering from a disorder selected from the group consisting of psoriasis, acne, eczema, rosacea, actinic keratosis, seborrheic dermatitis, and congenital keratinization disorders, in which any composition of the present invention is administered to the subject in need of such treatment.
  • a disorder selected from the group consisting of psoriasis, acne, eczema, rosacea, actinic keratosis, seborrheic dermatitis, and congenital keratinization disorders
  • the disorder is psoriasis, eczema, or acne.
  • the present invention further provides a method of treating one or more conditions of the skin selected from the group consisting of dry skin, photodamaged skin, age spots, aged skin, increasing stratum corneum flexibility, wrinkles, fine lines, actinic blemishes, skin dyschromias, and ichthyosis, comprising applying to the skin having said one or more condition any composition of the present invention.
  • the skin condition is actinic blemishes or fine wrinkles.
  • 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).
  • vitamin D analog includes but is not limited to vitamin D 2 and virtaminD 3 derivatives such as cholecalciferol, calcifediol, calcitriol, calcipotriol, ergosterol, ergocalciferol, dihydrotachysterol, 1, 25- dihydroxyergocalciferol, 25-hydroxydihydrotachysterol, and the vitamin D analogs disclosed in U.S. Pat. No. 4,866,048.
  • Preferred analogs are cholecalciferol, calcifediol, calcitriol, calcipotriol and the vitamin D analogs disclosed in U.S. Pat. No. 4,866,048. More preferred analogs are cholecalciferol, calcifediol, calcitriol and calcipotriol. Most preferred analogs are calcitriol and calcipotriol.
  • the concentration of the vitamin D analog may vary from about 0.0001% to about 10% by weight of the total composition of the invention.
  • concentrations employed of vitamin D analogs that can directly bind to the vitamin D receptors range from about 0.0001% to about 1%, more preferably from about 0.0005% to about 0.05%, still more preferably from about 0.009% to about 0.5%, yet still more preferably from about 0.001 to about 0.008%, and most preferably at about 0.005%.
  • the concentration employed of vitamin D analogs that can be converted in vivo to a compound capable of binding a vitamin D receptor is from about 0.001% to about 10%, more preferably from about 0.01% to about 8%, still more preferably from about 1% to about 6%, and most preferably from about 2% to about 5%.
  • the retinoids that are capable of binding to a retinoic acid receptor include but are not limited to many synthetic retinoids such as etretineate, all-trans-retinoic acid, 9-cis-retinoic acid, 4-oxo-retinoic acid, 4-oxo-retinol, and 4-oxo-retinal.
  • the preferred retinoid that is capable of binding to retinoic acid receptors is all-trans-retinoic acid and 4-oxo-retinol. Most preferably, 4-oxo-retinol.
  • the concentration of these retinoids in the compositions of the invention ranges from about 0.001% to about 1%, more preferably from about 0.025% to about 0.1%, most preferably about 0.05%.
  • retinol includes but is not limited to the following: 4-oxo-retinol, all-trans-retinol, 13-cis-retinol, 11-cis-retinol, 9-cis-retinol, 3,4-didehydro-retinol. Preferred isomers are all-trans-retinol, 13-cis-retinol, 3,4-didehydro-retinol, and 9-cis-retinol. Most preferred is all-trans-retinol due to its wide commercial availability.
  • the concentration employed of retinol is at least about 0.1%, preferably at least 0.3% by weight of the total weight of the composition.
  • the concentration such retinoid is from about at 0.3% to about 20%, more preferably from about 0.5% to about 15%, still more preferably from about 0.5% to about 10%, still more preferably from about 1% to about 10%, still more preferably from about 2% to about 10%, and most preferably about 5%.
  • the retinoids that can be converted in vivo to a compound capable of binding a retinoic acid receptor include but are not limited to retinyl esters, 4-oxo-retinyl esters, retinyl-glucoronides, retinoicacid-glucoronides, retinal, 3,4-didehydro-retinol, 13-cis-retinoic acid, 9-cis-retinoic acid.
  • Some retinoids bind a retinoic acid receptor and can also be converted in vivo to a compound capable of binding a retinoic acid receptor such as 13-cis-retinoic acid, 9-cis-retinoic acid, and 4-oxo-retinol.
  • a retinoic acid receptor such as 13-cis-retinoic acid, 9-cis-retinoic acid, and 4-oxo-retinol.
  • Compounds that are converted spontaneously by isomerization are also included in the compounds of the invention.
  • Retinyl ester is an ester of retinol and is capable of being converted in vivo into retinol.
  • Retinyl esters suitable for use in the present invention include but are not limited to C 1 -C 30 esters of retinol, preferably C 2 -C 20 esters, and most preferably C 2 , C 3 , and C 6 esters because they are commonly available.
  • retinyl,esters include but are not limited to: retinyl palmitate, retinyl formate, retinyl acetate, retinyl propionate, retinyl butyrate, retinyl valerate, retinyl isovalerate, retinyl hexanoate, retinyl heptanoate, retinyl octanoate, retinyl nonanoate, retinyl decanoate, retinyl undecandate, retinyl laurate, retinyl tridecanoate, retinyl myristate, retinyl pentadecanoate, retinyl heptadecanoate, retinyl stearate, retinyl isostearate, retinyl nonadecanoate, retinyl arachidonate, retinyl behenate, retin
  • the preferred retinyl esters for use in the present invention are retinyl palmitate, retinyl acetate, retinyl propionate and retinyl linoleate. More preferred retinyl esters are retinyl palmitate and retinyl acetate. The most preferred retinyl ester is retinyl palmitate.
  • the concentration employed of the retinoid that can be converted in vivo to a compound capable of binding a retinoic acid receptor is at least about 0.1%, preferably at least 0.3% by weight of the total weight of the composition. More preferably, the concentration such retinoid is from about at 0.3% to about 20%, more preferably from about 0.5% to about 15%, still more preferably from about 0.5% to about 10%, still more preferably from about 1% to about 10%, still more preferably from about 2% to about 10%, and most preferably about 5%.
  • a composition comprising retinol in a concentration of at least about 1.5% or a compound in a concentration of at least about 1.5% capable of being converted in vivo into retinol is as effective as retinoic acid in treating one or more conditions of the skin selected from the group consisting of dry skin, photodamaged skin, age spots, aged skin, increasing stratum corneum flexibility, wrinkles, fine lines, actinic blemishes, skin dyschromias, ichthyosis and acne.
  • retinol and the compounds capable of being converted into retinol has been defined above.
  • the concentration employed of retinol or of the compound capable of being converted in vivo into retinol is at least about 1.8%, more preferably at least about 2% by weight of the total weight of the composition. More preferably, the concentration such retinoid is from about at 2% to about 20%, more preferably from about 2% to about 15%, still more preferably from about 2% to about 10%, and most preferably about 5%.
  • compositions of the present invention are preferably topical and/or pharmaceutical. They may be in the form of a cream, ointment, and gel. They may also comprise a cosmetically acceptable vehicle to act as a diluent, dispersant or carrier for the active components in the composition, so as to facilitate their distribution when the composition is applied to the skin.
  • Vehicles other than water can include liquid or solid emollients, solvents, humectants, thickeners and powders.
  • An especially preferred nonaqueous carrier is a polydimethyl siloxane and/or a polydimethyl phenyl siloxane.
  • Silicones of this invention may be those with viscosities ranging anywhere from about 10 to 10,000,000 centistokes at 25° C. Especially desirable are mixtures of low and high viscosity silicones. These silicones are available from the General Electric Company under trademarks Vicasil, SE and SF and from the Dow Corning Company under the 200 and 550 Series. Amounts of silicone which can be utilized in the compositions of this invention range anywhere from 5% to 95%, preferably from 25% to 90% by weight of the composition.
  • the cosmetically acceptable vehicle will usually form from 5% to 99.9%, preferably from 25% to 80% by weight of the emulsion, and can, in the absence of other cosmetic adjuncts, form the balance of the composition.
  • An oil or oily material may be present in the claimed compositions, together with an emulsifier to provide either a water-in-oil emulsion or an oil-in-water emulsion, depending largely on the average hydrophilic-lipophilic balance (HLB) of the emulsifier employed.
  • HLB hydrophilic-lipophilic balance
  • Various types of active ingredients may be present in cosmetic compositions of the present invention.
  • Various types of active ingredients may be present in cosmetic compositions of the present invention.
  • Actives are defined as skin benefit agents other than emollients and other than ingredients that merely improve the physical characteristics of the composition. Although not limited to this category, general examples include sunscreens and tanning agents.
  • Sunscreens include those materials commonly employed to block ultraviolet light.
  • Illustrative compounds are the derivatives of PABA, cinnamate and salicylate.
  • octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone also known as oxybenzone
  • Octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone are commercially available under the trademarks, Parsol MCX and Benzophenone-3, respectively.
  • the exact amount of sunscreen employed in the emulsions can vary depending upon the degree of protection desired from the sun's UV radiation.
  • Another preferred optional ingredient is selected from essential fatty acids (EFAs), i.e., those fatty acids which are essential for the plasma membrane formation of all cells (in keratinocytes, EFA deficiency makes cells hyperproliferative). Supplementation of EFA corrects this. EFAs also enhance lipid biosynthesis of epidermis and provide lipids for the barrier formation of the epidermis.
  • EFAs essential fatty acids
  • the essential fatty acids are preferably chosen from linoleic acid, gamma -linolenic acid, homo- gamma -linolenic-acid, columbinic-acid, eicosa-(n-6,9,13)-trienoic acid, arachidonic acid, gamma -linolenic acid, timnodonic acid, hexaenoic acid and mixtures thereof.
  • Emollients are often incorporated into cosmetic compositions of the present invention. Levels of such emollients may range from about 0.5% to about 50%, preferably between about 5% and 30% by weight of the total composition. Emollients may be classified under such general chemical categories as esters, fatty acids and alcohols, polyols and hydrocarbons.
  • Esters may be mono- or di-esters.
  • Acceptable examples of fatty di-esters include dibutyl adipate, diethyl sebacate, diisopropyl dimerate, and dioctyl succinate.
  • Acceptable branched chain fatty esters include 2-ethyl-hexyl myristate, isopropyl stearate and isostearyl palmitate.
  • Acceptable tribasic acid esters include triisopropyl trilinoleate and trilauryl citrate.
  • Acceptable straight chain fatty esters include lauryl palmitate, myristyl lactate, oleyl eurcate and stearyl oleate.
  • Preferred esters include coco-caprylate/caprate (a blend of coco-caprylate and coco-caprate), propylene glycol myristyl ether acetate, diisopropyl adipate and cetyl octanoate.
  • Suitable fatty alcohols and acids include those compounds having from 10 to 20 carbon atoms. Especially preferred are compounds such as cetyl, myristyl, palmitic and stearyl alcohols and acids.
  • polyols which may serve as emollients are linear and branched chain alkyl polyhydroxyl compounds.
  • propylene glycol, sorbitol and glycerin are preferred.
  • polymeric polyols such as polypropylene glycol and polyethylene glycol.
  • Butylene and propylene glycol are also especially preferred as penetration enhancers.
  • Exemplary hydrocarbons which may serve as emollients are those having hydrocarbon chains anywhere from 12 to 30 carbon atoms. Specific examples include mineral oil, petroleum jelly, squalene and isoparaffins.
  • a thickener will usually be present in amounts anywhere from 0.1 to 20% by weight, preferably from about 0.5% to 10% by weight of the composition.
  • Exemplary thickeners are cross-linked polyacrylate materials available under the trademark Carbopol from the B. F. Goodrich Company. Gums may be employed such as xanthan, carrageenan, gelatin, karaya, pectin and locust beans gum. Under certain circumstances the thickening function may be accomplished by a material also serving as a silicone or emollient. For instance, silicone gums in excess of 10 centistokes and esters such as glycerol stearate have dual functionality.
  • Powders may be incorporated into the cosmetic composition of the invention. These powders include chalk, talc, Fullers earth, kaolin, starch, smectite clays, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, aluminum starch octenyl succinate and mixtures thereof.
  • adjunct minor components may also be incorporated into the cosmetic compositions.
  • These ingredients may include coloring agents, opacifiers, perfumes and preservatives (e.g., imidazolidinyl urea, dimethyl imidazolidinone and diazolidinyl urea). Amounts of these materials may range anywhere from 0.001% up to 20% by weight of the composition.
  • composition according to the invention is intended primarily but not exclusively as a product for topical application to human skin are as a product to modulate cell differentiation.
  • a small quantity of the composition for example from 1 to 5 ml, is applied to exposed areas of the skin, from a suitable container or applicator and, if necessary, it is then spread over and/or rubbed into the skin using the hand or fingers or a suitable device.
  • the topical skin treatment composition of the invention can be formulated as a lotion having a viscosity of from 4,000 to 10,000 mPas, a fluid cream having a viscosity of from 10,000 to 20,000 mPas or a cream or a gel having a viscosity of from 20,000 to 100,000 mPas or above.
  • the composition can be packaged in a suitable container to suit its viscosity and intended use by the consumer.
  • a lotion or fluid cream can be packaged in a bottle or a roll-ball applicator, or a capsule, or a propellant-driven aerosol device or a container fitted with a pump suitable for finger operation.
  • the composition When the composition is a cream, it can simply be stored in a non-deformable bottle or squeeze container, such as a tube or a lidded jar.
  • the invention accordingly also provides a closed container containing a cosmetically acceptable composition as herein defined.
  • This example compares therapeutically applied retinyl palmitate, retinoic acid, calcitriol, and combinations thereof in a cream at different concentrations with the effectiveness of the cream without any of the above compounds present in treating acne.
  • the cream used is the commercially available LUBRIDERM cream.
  • the different compounds at different concentrations were added to the cream and mixed very well.
  • Sixty six volunteers were recruited and were randomly assigned to each of the groups. The subjects were selected on the basis of their having moderate to severe papular-pustular acne. Each group consisted of 3 males and 3 females. No other acne treatment was permitted during the period. Preparations were applied to the face in the morning and evening after washing the face with ordinary soap.
  • Table 1 illustrates that retinyl palmitate in concentrations at about 1.5% and more shows a remarkable improvement over lower concentrations in treating acne.
  • the combination of retinoic acid and calcitriol shows a synergistic effect when compared with either retinoic acid and calcitriol.
  • a synergistic effect is also seen when calcitriol is combined with retinyl palmitate particularly at concentrations of 0.5% of retinyl palmitate.
  • This example compares therapeutically applied retinyl palmitate, retinoic acid, calcitriol, and combinations thereof in a cream at different concentrations with the effectiveness of the cream without any of the above compounds present in treating psoriasis.
  • the cream used is the commercially available LUBRIDERM cream. The different compounds at different concentrations were added to the cream and mixed very well.
  • commercially available 0.005% calcipotriol (DOVONEX) and commercially available 0.005% calcipotriol supplemented with 5% retinyl palmitate were employed in treating psoriasis.
  • Two different and distant psoriatic spots were selected on the skin of patients diagnosed with psoriasis for different treatment. Each patient used two type of creams twice a day, one cream on each selected spot.
  • Group I consisting of five patients applied on one selected spot (spot A) control LUBRIDERM cream and on the other selected spot (spot B) cream containing 0.1% retinoic acid. None of the patients showed any improvement in either spots even after 12 weeks of treatment.
  • Group II consisting of five patients applied on one selected spot (spot A) control LUBRIDERM cream and on the other selected spot (spot B) cream containing 0.1% retinyl palmitate. Three out of five patients showed mild improvement in itching after 3 days in spot B but no improvement in stopping scaling which results from cellular hperproliferation. The rest of the spots showed no improvement.
  • Group III consisting of five patients applied on one selected spot (spot A) control LUBRIDERM cream and on the other selected spot (spot B) cream containing 1% retinyl palmitate.
  • spot A control LUBRIDERM cream
  • spot B selected spot containing 1% retinyl palmitate.
  • Four out of five patients showed good improvement in itching after 3 days in spot B but no improvement in stopping scaling which results from cellular hperproliferation. The rest of the spots showed no improvement.
  • Group III consisting of five patients applied on one selected spot (spot A) control LUBRIDERM cream and on the other selected spot (spot B) cream containing 5% retinyl palmitate. Five out of five patients showed good improvement in itching after 3 days in spot B but no improvement in stopping scaling which results from cellular hperproliferation. The rest of the spots showed no improvement.
  • Group IV consisting of five patients applied on one selected spot (spot A) control LUBRIDERM cream and on the other selected spot (spot B) cream containing 0.005% calcipotriol.
  • spot A control LUBRIDERM cream
  • spot B selected spot
  • calcipotriol a selected spot
  • Group V consisting of five patients applied on one selected spot (spot A) a cream containing 0.0025% calcipotriol and on the other selected spot (spot B) cream containing 0.0025% calcipotriol and 0.1% retinyl palmitate.
  • spot A a cream containing 0.0025% calcipotriol
  • spot B cream containing 0.0025% calcipotriol and 0.1% retinyl palmitate.
  • One out of five patients showed partial clearance (about 20% of spot area) in spot A after 4 weeks of treatment. However, even in spot A that is showing improvement and partial clearance, a certain amount of scaling is still occurring.
  • Two out of Five patients showed considerable amount of clearance (about 40% of spot area) in spot B and with little scaling and itching. The rest of the spots showed no improvement.
  • Group VI consisting of five patients applied on one selected spot (spot A) a cream containing 0.0025% calcipotriol and on the other selected spot (spot B) cream containing 0.0025% calcipotriol and 0.5% retinyl palmitate.
  • spot A a cream containing 0.0025% calcipotriol
  • spot B cream containing 0.0025% calcipotriol and 0.5% retinyl palmitate.
  • Two out of five patients showed partial clearance (about 25% of spot area) in spot A after 4 weeks of treatment. However, even in spots A that are showing improvement and partial clearance, a certain amount of scaling is still occurring.
  • Three out of Five patients showed considerable amount of clearance (about 50% of spot area) in spot B and with barely noticeable scaling and no itching. The rest of the spots showed no improvement.
  • Group VII consisting of five patients applied on one selected spot (spot A) a cream containing 0.0025% calcipotriol and on the other selected spot (spot B) cream containing 0.0025% calcipotriol and 1% retinyl palmitate.
  • spot A a cream containing 0.0025% calcipotriol
  • spot B cream containing 0.0025% calcipotriol and 1% retinyl palmitate.
  • Two out of five patients showed partial clearance (about 20% of spot area) in spot A after 4 weeks of treatment. However, even in spots A that are showing improvement and partial clearance, a certain amount of scaling is still occurring.
  • Four out of Five patients showed considerable amount of clearance (about 50% of spot area) in spot B and with barely noticeable scaling and no itching. The rest of the spots showed no improvement.
  • Group VIII consisting of five patients applied on one selected spot (spot A) a cream containing 0.0025% calcipotriol and on the other selected spot (spot B) cream containing 0.0025% calcipotriol and 5% retinyl palmitate.
  • spot A a cream containing 0.0025% calcipotriol
  • spot B cream containing 0.0025% calcipotriol and 5% retinyl palmitate.
  • One out of five patients showed partial clearance (about 30% of spot area) in spot A after 4 weeks of treatment. However, even in spot A that is showing improvement and partial clearance, a certain amount of scaling is still occurring.
  • Five out of Five patients showed considerable amount of clearance (average about 85% of spot area and one complete clearance) in spot B and with no scaling and itching. The rest of the spots showed no improvement.
  • Group IX consisting of five patients applied on one selected spot (spot A) a cream containing 0.0025% calcipotriol and on the other selected spot (spot B) cream containing 0.0025% calcipotriol and 10% retinyl palmitate.
  • spot A a cream containing 0.0025% calcipotriol
  • spot B cream containing 0.0025% calcipotriol and 10% retinyl palmitate.
  • One out of five patients showed partial clearance (about 15% of spot area) in spot A after 4 weeks of treatment. However, even in spot A that is showing improvement and partial clearance, a certain amount of scaling is still occurring.
  • Five out of Five patients showed considerable amount of clearance (average about 90% of spot area and two complete clearance) in spot B and with no scaling and itching. The rest of the spots showed no improvement.
  • Group X consisting of five patients applied on one selected spot (spot A) a cream containing 0.005% calcipotriol and on the other selected spot (spot B) cream containing 5% Cholecalciferol and 5% retinyl palmitate.
  • spot A a cream containing 0.005% calcipotriol
  • spot B cream containing 5% Cholecalciferol and 5% retinyl palmitate.
  • Two out of five patients showed partial clearance (about 15% of spot area) in spot A after 4 weeks of treatment. However, even in spots A that are showing improvement and partial clearance, a certain amount of scaling is still occurring.
  • Five out of Five patients showed considerable amount of clearance (average about 75% of spot area and one complete clearance) in spot B and with no scaling and itching. The rest of the spots showed no improvement.
  • Various types of human melanoma, breast cancer and prostate cancer cells will be cultured according to standardized procedures. These cells will be incubated with in the presence of various concentrations of retinol, retinoic acid, retinyl esters, calcitriol or a combination thereof. Cell growth of at least some of these cells will be shown to be significantly inhibited in the presence of calcitriol and high concentrations of retinol (about 10 ⁇ 5 M) as compared with cells incubated in the absence of the above compounds or in the presence of each of the above compounds alone.
  • Various types of human melanoma, breast cancer and prostate cancer cells will be cultured according to standardized procedures. These cells will be incubated with in the presence of various concentrations of retinol, retinoic acid, retinyl esters, calcitriol or a combination thereof. Some cells will also be incubated in media collected from F9 mouse teratocarcinoma cells after these F9 cells were incubated in the presence of 10 ⁇ 5 M retinal for 12-48 hours ⁇ calcitriol.
  • Cell growth of at least some of these cell lines will be shown to be significantly inhibited in the presence of calcitriol and high concentrations of retinal (about 10 ⁇ 5 M) or in the presence F9 cultured media containing calcitriol prior to incubation with F9 cells or after.

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Abstract

A composition is described comprising a vitamin D analog and a retinoid, wherein: (a) the vitamin D analog is capable of binding a vitamin 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 a compound capable of binding a retinoic acid receptor, retinol in a concentration of at least about 0.1% and a compound in a concentration of at least about 0.% capable of being converted in vivo into retinol. Further, methods of treating disorders characterized by abnormal cell-proliferation and/or cell-differentiation are also described.

Description

    FIELD OF THE INVENTION
  • The present invention relates to compositions comprising certain retinoids and vitamin D analogs useful in inducing differentiation and inhibiting undesirable proliferation of cells, such as cancer cells and skin cells. The present invention also relates to methods of using the above compositions in the treatment of diseases and conditions characterized by abnormal cell differentiation and/or cell proliferation. [0001]
    • DESCRIPTION OF THE RELATED ART
  • Abnormal cell differentiation and/or cell differentiation is associated with many conditions and diseases. For instance, hyperproliferation of epithelial cells is associated with psoriasis causes the skin to shed itself too rapidly, every three to four days. The goal in treating psoriasis is to reduce inflammation and to slow down rapid skin cell division. [0002]
  • U.S. Pat. No. 4,866,048 discloses that certain vitamin D derivatives, in particular calcitriol (1 alpha,25-dihydroxy-vitamin D[0003] 3 or) and calcipotriol are able to stimulate the differentiation of cells and inhibit excessive cell proliferation, and it has been suggested that these compounds are useful in the treatment of diseases characterized by abnormal cell differentiation and/or cell differentiation such as leukemia, myelofibrosis, psoriasis and acne.
  • Certain retinoids are also known for their antiproliferative and differentiation activity. For instance, retinol (vitamin A) is an endogenous compound which occurs naturally in the human body and is essential for normal cell differentiation of certain cell types such as epithelial cells. Retinoic acid is believed to be an active derivative of retinol. Thus, retinoic acid is believed to be more effective than retinol and retinyl esters at providing skin benefits. [0004]
  • Natural and synthetic vitamin A derivatives (including retinoic acid) have been used extensively in the treatment of a variety of skin and hyperproliferation disorders. For example, retinoic acid has been employed to treat certain types of leukemia like acute apromyelocytic leukemia as well as a variety of skin conditions such as acne, wrinkles, psoriasis, age spots and discoloration (Vahlquist, A. et al., [0005] J. Invest. Dermatol., Vol. 94, Holland D. B. and Cunliffe, W. J. (1990), pp. 496-498; Ellis C. N. et al., “Pharmacology of Retinols in Skin”, Vasel, Karger, Vol. 3, (1989), pp.249-252; Lowe, N. J. et al., Vol. 3, (1989), pp. 240-248; PCT Patent Application No. WO 93/19743). Although retinoids have been viewed classically as cancer prevention agents, considerable laboratory evidence supports their testing as antitumor drugs as well (Cancer Treat Rep 1987; 71: 493-515 May, 1987).
  • It is important to note that while clinical experience with either retinoids or vitamin D derivatives against conditions associated with abnormal cell differentiation and/or cell differentiation has met with certain amount of success in some instances, these compounds have frequently been unable to provide the desired clinical results. [0006]
  • For instance, the synthetic Vitamin D, calcipotriol, or retinoic acid which are available in prescription form are somewhat useful for individuals with localized psoriasis. However, these compound are not very effective on most patients. [0007]
  • Therapeutic regimens for acne involve local and systemic therapies, although the former is indicated in the vast majority of cases. Topical application of a variety of chemical application which include mainly sulfur, resorcinol, salicylic acid, benzoyl peroxide, and retinoic acid are frequently used to treat acne. All the foregoing agents are known as “peeling” or “drying” agents which are believed to exert their therapeutical effect by causing erythema, irritation, and desquamination of the skin to expel comedones. The therapeutic efficacy of these agents, however, is rather variable, and their utility is limited partially because of the irritation caused by their application (see U.S. Pat. No. 3,932,665). Oral formulations of retinoic acid are also used but serious side effects are associated with the oral use of this compound including severe fetal malformation in pregnant women. [0008]
    • SUMMARY OF THE INVENTION
  • It is an object of the present invention to provide compositions comprising certain vitamin D and retinoid compounds at particular concentrations which are useful for the treatment of disorders characterized by abnormal cell-proliferation and/or cell-differentiation. [0009]
  • In one embodiment, the present invention provides a composition comprising a vitamin D analog and a retinoid, wherein: [0010]
  • (a) the vitamin D analog is capable of binding a vitamin D receptor or being converted in vivo into a compound capable of binding a vitamin D receptor; and [0011]
  • (b) the retinoid is selected from the group consisting of a compound capable of binding a retinoic acid receptor, retinol in a concentration of at least about 0.1% and a compound in a concentration of at least about 0.1% capable of being converted in vivo into retinol. [0012]
  • In yet another embodiment, the present invention provides a composition comprising retinol in a concentration of at least about 1.5% or a compound in a concentration of at least about 1.5% capable of being converted in vivo into retinol. [0013]
    • DETAILED DESCRIPTION OF THE INVENTION
  • In accordance with the invention, It has been surprisingly discovered that a composition comprising (i) a vitamin D analog; and (ii) a retinoid selected from the group consisting of a compound capable of binding a retinoic acid receptor, retinol in a concentration of at least about 0.1% and a compound in a concentration of at least about 0.1% capable of being converted in vivo into retinol, is useful in treating a subject suffering from a disorder characterized by abnormal cell-proliferation and/or cell-differentiation more effectively than either a composition comprising a vitamin D analog without the above defined retinoid or a composition comprising the above retinoid without a vitamin D analog. Preferably, the abnormal cell proliferation is associated with cancer cells and more preferably with skin cancer such as melanoma. Also more preferably, the abnormal cell proliferation is associated with cancer cells that can at least partially respond to hormone or retinoid treatment. [0014]
  • The present invention also provides a method of treating a subject suffering from a disorder selected from the group consisting of psoriasis, acne, eczema, rosacea, actinic keratosis, seborrheic dermatitis, and congenital 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. [0015]
  • The present invention further provides a method of treating one or more conditions of the skin selected from the group consisting of dry skin, photodamaged skin, age spots, aged skin, increasing stratum corneum flexibility, wrinkles, fine lines, actinic blemishes, skin dyschromias, and ichthyosis, comprising applying to the skin having said one or more condition any composition of the present invention. Preferably, the skin condition is actinic blemishes or fine wrinkles. [0016]
  • 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” includes but is not limited to vitamin D[0017] 2 and virtaminD3 derivatives such as cholecalciferol, calcifediol, calcitriol, calcipotriol, ergosterol, ergocalciferol, dihydrotachysterol, 1, 25- dihydroxyergocalciferol, 25-hydroxydihydrotachysterol, and the vitamin D analogs disclosed in U.S. Pat. No. 4,866,048. Preferred analogs are cholecalciferol, calcifediol, calcitriol, calcipotriol and the vitamin D analogs disclosed in U.S. Pat. No. 4,866,048. More preferred analogs are cholecalciferol, calcifediol, calcitriol and calcipotriol. Most preferred analogs are calcitriol and calcipotriol.
  • The concentration of the vitamin D analog may vary from about 0.0001% to about 10% by weight of the total composition of the invention. Preferably, the concentrations employed of vitamin D analogs that can directly bind to the vitamin D receptors, range from about 0.0001% to about 1%, more preferably from about 0.0005% to about 0.05%, still more preferably from about 0.009% to about 0.5%, yet still more preferably from about 0.001 to about 0.008%, and most preferably at about 0.005%. [0018]
  • Preferably, the concentration employed of vitamin D analogs that can be converted in vivo to a compound capable of binding a vitamin D receptor is from about 0.001% to about 10%, more preferably from about 0.01% to about 8%, still more preferably from about 1% to about 6%, and most preferably from about 2% to about 5%. [0019]
  • The retinoids that are capable of binding to a retinoic acid receptor (not necessarily all) include but are not limited to many synthetic retinoids such as etretineate, all-trans-retinoic acid, 9-cis-retinoic acid, 4-oxo-retinoic acid, 4-oxo-retinol, and 4-oxo-retinal. The preferred retinoid that is capable of binding to retinoic acid receptors is all-trans-retinoic acid and 4-oxo-retinol. Most preferably, 4-oxo-retinol. Preferably, the concentration of these retinoids in the compositions of the invention ranges from about 0.001% to about 1%, more preferably from about 0.025% to about 0.1%, most preferably about 0.05%. [0020]
  • Also, for the purpose of this invention, the term “retinol” includes but is not limited to the following: 4-oxo-retinol, all-trans-retinol, 13-cis-retinol, 11-cis-retinol, 9-cis-retinol, 3,4-didehydro-retinol. Preferred isomers are all-trans-retinol, 13-cis-retinol, 3,4-didehydro-retinol, and 9-cis-retinol. Most preferred is all-trans-retinol due to its wide commercial availability. The concentration employed of retinol is at least about 0.1%, preferably at least 0.3% by weight of the total weight of the composition. More preferably, the concentration such retinoid is from about at 0.3% to about 20%, more preferably from about 0.5% to about 15%, still more preferably from about 0.5% to about 10%, still more preferably from about 1% to about 10%, still more preferably from about 2% to about 10%, and most preferably about 5%. [0021]
  • The retinoids that can be converted in vivo to a compound capable of binding a retinoic acid receptor (not necessarily all) include but are not limited to retinyl esters, 4-oxo-retinyl esters, retinyl-glucoronides, retinoicacid-glucoronides, retinal, 3,4-didehydro-retinol, 13-cis-retinoic acid, 9-cis-retinoic acid. Some retinoids bind a retinoic acid receptor and can also be converted in vivo to a compound capable of binding a retinoic acid receptor such as 13-cis-retinoic acid, 9-cis-retinoic acid, and 4-oxo-retinol. Compounds that are converted spontaneously by isomerization are also included in the compounds of the invention. [0022]
  • Retinyl ester is an ester of retinol and is capable of being converted in vivo into retinol. Retinyl esters suitable for use in the present invention include but are not limited to C[0023] 1-C30 esters of retinol, preferably C2-C20 esters, and most preferably C2, C3, and C6 esters because they are commonly available. Examples of retinyl,esters include but are not limited to: retinyl palmitate, retinyl formate, retinyl acetate, retinyl propionate, retinyl butyrate, retinyl valerate, retinyl isovalerate, retinyl hexanoate, retinyl heptanoate, retinyl octanoate, retinyl nonanoate, retinyl decanoate, retinyl undecandate, retinyl laurate, retinyl tridecanoate, retinyl myristate, retinyl pentadecanoate, retinyl heptadecanoate, retinyl stearate, retinyl isostearate, retinyl nonadecanoate, retinyl arachidonate, retinyl behenate, retinyl linoleate, and retinyl oleate.
  • The preferred retinyl esters for use in the present invention are retinyl palmitate, retinyl acetate, retinyl propionate and retinyl linoleate. More preferred retinyl esters are retinyl palmitate and retinyl acetate. The most preferred retinyl ester is retinyl palmitate. [0024]
  • The concentration employed of the retinoid that can be converted in vivo to a compound capable of binding a retinoic acid receptor is at least about 0.1%, preferably at least 0.3% by weight of the total weight of the composition. More preferably, the concentration such retinoid is from about at 0.3% to about 20%, more preferably from about 0.5% to about 15%, still more preferably from about 0.5% to about 10%, still more preferably from about 1% to about 10%, still more preferably from about 2% to about 10%, and most preferably about 5%. [0025]
  • It has also been surprisingly discovered that a composition comprising retinol in a concentration of at least about 1.5% or a compound in a concentration of at least about 1.5% capable of being converted in vivo into retinol is as effective as retinoic acid in treating one or more conditions of the skin selected from the group consisting of dry skin, photodamaged skin, age spots, aged skin, increasing stratum corneum flexibility, wrinkles, fine lines, actinic blemishes, skin dyschromias, ichthyosis and acne. The term “retinol” and the compounds capable of being converted into retinol has been defined above. Preferably, for this composition, the concentration employed of retinol or of the compound capable of being converted in vivo into retinol is at least about 1.8%, more preferably at least about 2% by weight of the total weight of the composition. More preferably, the concentration such retinoid is from about at 2% to about 20%, more preferably from about 2% to about 15%, still more preferably from about 2% to about 10%, and most preferably about 5%. [0026]
  • The compositions of the present invention are preferably topical and/or pharmaceutical. They may be in the form of a cream, ointment, and gel. They may also comprise a cosmetically acceptable vehicle to act as a diluent, dispersant or carrier for the active components in the composition, so as to facilitate their distribution when the composition is applied to the skin. [0027]
  • Vehicles other than water can include liquid or solid emollients, solvents, humectants, thickeners and powders. An especially preferred nonaqueous carrier is a polydimethyl siloxane and/or a polydimethyl phenyl siloxane. Silicones of this invention may be those with viscosities ranging anywhere from about 10 to 10,000,000 centistokes at 25° C. Especially desirable are mixtures of low and high viscosity silicones. These silicones are available from the General Electric Company under trademarks Vicasil, SE and SF and from the Dow Corning Company under the 200 and 550 Series. Amounts of silicone which can be utilized in the compositions of this invention range anywhere from 5% to 95%, preferably from 25% to 90% by weight of the composition. [0028]
  • The cosmetically acceptable vehicle will usually form from 5% to 99.9%, preferably from 25% to 80% by weight of the emulsion, and can, in the absence of other cosmetic adjuncts, form the balance of the composition. [0029]
  • An oil or oily material may be present in the claimed compositions, together with an emulsifier to provide either a water-in-oil emulsion or an oil-in-water emulsion, depending largely on the average hydrophilic-lipophilic balance (HLB) of the emulsifier employed. [0030]
  • Various types of active ingredients may be present in cosmetic compositions of the present invention. Various types of active ingredients may be present in cosmetic compositions of the present invention. Actives are defined as skin benefit agents other than emollients and other than ingredients that merely improve the physical characteristics of the composition. Although not limited to this category, general examples include sunscreens and tanning agents. [0031]
  • Sunscreens include those materials commonly employed to block ultraviolet light. Illustrative compounds are the derivatives of PABA, cinnamate and salicylate. For example, octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone (also known as oxybenzone) can be used. Octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone are commercially available under the trademarks, Parsol MCX and Benzophenone-3, respectively. The exact amount of sunscreen employed in the emulsions can vary depending upon the degree of protection desired from the sun's UV radiation. [0032]
  • Another preferred optional ingredient is selected from essential fatty acids (EFAs), i.e., those fatty acids which are essential for the plasma membrane formation of all cells (in keratinocytes, EFA deficiency makes cells hyperproliferative). Supplementation of EFA corrects this. EFAs also enhance lipid biosynthesis of epidermis and provide lipids for the barrier formation of the epidermis. The essential fatty acids are preferably chosen from linoleic acid, gamma -linolenic acid, homo- gamma -linolenic-acid, columbinic-acid, eicosa-(n-6,9,13)-trienoic acid, arachidonic acid, gamma -linolenic acid, timnodonic acid, hexaenoic acid and mixtures thereof. [0033]
  • Emollients are often incorporated into cosmetic compositions of the present invention. Levels of such emollients may range from about 0.5% to about 50%, preferably between about 5% and 30% by weight of the total composition. Emollients may be classified under such general chemical categories as esters, fatty acids and alcohols, polyols and hydrocarbons. [0034]
  • Esters may be mono- or di-esters. Acceptable examples of fatty di-esters include dibutyl adipate, diethyl sebacate, diisopropyl dimerate, and dioctyl succinate. Acceptable branched chain fatty esters include 2-ethyl-hexyl myristate, isopropyl stearate and isostearyl palmitate. Acceptable tribasic acid esters include triisopropyl trilinoleate and trilauryl citrate. Acceptable straight chain fatty esters include lauryl palmitate, myristyl lactate, oleyl eurcate and stearyl oleate. Preferred esters include coco-caprylate/caprate (a blend of coco-caprylate and coco-caprate), propylene glycol myristyl ether acetate, diisopropyl adipate and cetyl octanoate. [0035]
  • Suitable fatty alcohols and acids include those compounds having from 10 to 20 carbon atoms. Especially preferred are compounds such as cetyl, myristyl, palmitic and stearyl alcohols and acids. [0036]
  • Among the polyols which may serve as emollients are linear and branched chain alkyl polyhydroxyl compounds. For example, propylene glycol, sorbitol and glycerin are preferred. Also useful may be polymeric polyols such as polypropylene glycol and polyethylene glycol. Butylene and propylene glycol are also especially preferred as penetration enhancers. [0037]
  • Exemplary hydrocarbons which may serve as emollients are those having hydrocarbon chains anywhere from 12 to 30 carbon atoms. Specific examples include mineral oil, petroleum jelly, squalene and isoparaffins. [0038]
  • Another category of functional ingredients within the cosmetic compositions of the present invention are thickeners. A thickener will usually be present in amounts anywhere from 0.1 to 20% by weight, preferably from about 0.5% to 10% by weight of the composition. Exemplary thickeners are cross-linked polyacrylate materials available under the trademark Carbopol from the B. F. Goodrich Company. Gums may be employed such as xanthan, carrageenan, gelatin, karaya, pectin and locust beans gum. Under certain circumstances the thickening function may be accomplished by a material also serving as a silicone or emollient. For instance, silicone gums in excess of 10 centistokes and esters such as glycerol stearate have dual functionality. [0039]
  • Powders may be incorporated into the cosmetic composition of the invention. These powders include chalk, talc, Fullers earth, kaolin, starch, smectite clays, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, aluminum starch octenyl succinate and mixtures thereof. [0040]
  • Other adjunct minor components may also be incorporated into the cosmetic compositions. These ingredients may include coloring agents, opacifiers, perfumes and preservatives (e.g., imidazolidinyl urea, dimethyl imidazolidinone and diazolidinyl urea). Amounts of these materials may range anywhere from 0.001% up to 20% by weight of the composition. [0041]
  • The composition according to the invention is intended primarily but not exclusively as a product for topical application to human skin are as a product to modulate cell differentiation. In use, a small quantity of the composition, for example from 1 to 5 ml, is applied to exposed areas of the skin, from a suitable container or applicator and, if necessary, it is then spread over and/or rubbed into the skin using the hand or fingers or a suitable device. [0042]
  • The topical skin treatment composition of the invention can be formulated as a lotion having a viscosity of from 4,000 to 10,000 mPas, a fluid cream having a viscosity of from 10,000 to 20,000 mPas or a cream or a gel having a viscosity of from 20,000 to 100,000 mPas or above. The composition can be packaged in a suitable container to suit its viscosity and intended use by the consumer. For example, a lotion or fluid cream can be packaged in a bottle or a roll-ball applicator, or a capsule, or a propellant-driven aerosol device or a container fitted with a pump suitable for finger operation. When the composition is a cream, it can simply be stored in a non-deformable bottle or squeeze container, such as a tube or a lidded jar. [0043]
  • The invention accordingly also provides a closed container containing a cosmetically acceptable composition as herein defined. [0044]
  • The following specific examples further illustrate the invention, but the invention is not limited thereto. [0045]
    • EXAMPLE 1
  • This example compares therapeutically applied retinyl palmitate, retinoic acid, calcitriol, and combinations thereof in a cream at different concentrations with the effectiveness of the cream without any of the above compounds present in treating acne. The cream used is the commercially available LUBRIDERM cream. The different compounds at different concentrations were added to the cream and mixed very well. Sixty six volunteers were recruited and were randomly assigned to each of the groups. The subjects were selected on the basis of their having moderate to severe papular-pustular acne. Each group consisted of 3 males and 3 females. No other acne treatment was permitted during the period. Preparations were applied to the face in the morning and evening after washing the face with ordinary soap. Observations were made at time 0, 1, 4, and 8 weeks to assure that treatment was carried out according to direction. Judgments of “worse”, “no change”, “mild”, and “good” were made after 8 weeks of treatment. Table 1 illustrates the results. [0046]
    TABLE 1
    Results of treatment with various compounds on acne
    no
    Treatment worse change mild good
    Control 2 4 0 0
    0.1% retinoic acid 0 2 3 1
    0.1% retinyl 2 3 1 0
    palmitate
    1% retinyl palmitate 0 4 2 0
    1.5% retinyl 0 1 3 2
    palmitate
    5% retinol 0 1 2 3
    10% retinol 0 0 3 3
    0.0025% calcitriol 2 3 1
    0.1% retinoic acid 0 1 3 2
    and 0.0025%
    calcitriol
    0.1% retinyl 1 2 2 1
    palmitate and
    0.0025% calcitriol
    0.5% retinyl 0 1 3 2
    palmitate and
    0.0025% calcitriol
    5% retinyl palmitate 0 0 1 5
    and 0.0025%
    calcitriol
  • Table 1 illustrates that retinyl palmitate in concentrations at about 1.5% and more shows a remarkable improvement over lower concentrations in treating acne. In addition, the combination of retinoic acid and calcitriol shows a synergistic effect when compared with either retinoic acid and calcitriol. A synergistic effect is also seen when calcitriol is combined with retinyl palmitate particularly at concentrations of 0.5% of retinyl palmitate. [0047]
  • The use of each of retinoic acid and calcitriol caused skin irritation while the use of retinyl palmitate did not. [0048]
    • EXAMPLE 2
  • This example compares therapeutically applied retinyl palmitate, retinoic acid, calcitriol, and combinations thereof in a cream at different concentrations with the effectiveness of the cream without any of the above compounds present in treating psoriasis. The cream used is the commercially available LUBRIDERM cream. The different compounds at different concentrations were added to the cream and mixed very well. Also, commercially available 0.005% calcipotriol (DOVONEX) and commercially available 0.005% calcipotriol supplemented with 5% retinyl palmitate were employed in treating psoriasis. Two different and distant psoriatic spots were selected on the skin of patients diagnosed with psoriasis for different treatment. Each patient used two type of creams twice a day, one cream on each selected spot. [0049]
  • Group I consisting of five patients applied on one selected spot (spot A) control LUBRIDERM cream and on the other selected spot (spot B) cream containing 0.1% retinoic acid. None of the patients showed any improvement in either spots even after 12 weeks of treatment. [0050]
  • Group II consisting of five patients applied on one selected spot (spot A) control LUBRIDERM cream and on the other selected spot (spot B) cream containing 0.1% retinyl palmitate. Three out of five patients showed mild improvement in itching after 3 days in spot B but no improvement in stopping scaling which results from cellular hperproliferation. The rest of the spots showed no improvement. [0051]
  • Group III consisting of five patients applied on one selected spot (spot A) control LUBRIDERM cream and on the other selected spot (spot B) cream containing 1% retinyl palmitate. Four out of five patients showed good improvement in itching after 3 days in spot B but no improvement in stopping scaling which results from cellular hperproliferation. The rest of the spots showed no improvement. [0052]
  • Group III consisting of five patients applied on one selected spot (spot A) control LUBRIDERM cream and on the other selected spot (spot B) cream containing 5% retinyl palmitate. Five out of five patients showed good improvement in itching after 3 days in spot B but no improvement in stopping scaling which results from cellular hperproliferation. The rest of the spots showed no improvement. [0053]
  • Group IV consisting of five patients applied on one selected spot (spot A) control LUBRIDERM cream and on the other selected spot (spot B) cream containing 0.005% calcipotriol. Two out of five patients showed partial clearance (average of 35% of spot area) in spot B after 4 weeks of treatment. However, even in the spots showing improvement and partial clearance, a certain amount of scaling is still occurring. The rest of the spots showed no improvement. [0054]
  • Group V consisting of five patients applied on one selected spot (spot A) a cream containing 0.0025% calcipotriol and on the other selected spot (spot B) cream containing 0.0025% calcipotriol and 0.1% retinyl palmitate. One out of five patients showed partial clearance (about 20% of spot area) in spot A after 4 weeks of treatment. However, even in spot A that is showing improvement and partial clearance, a certain amount of scaling is still occurring. Two out of Five patients showed considerable amount of clearance (about 40% of spot area) in spot B and with little scaling and itching. The rest of the spots showed no improvement. [0055]
  • Group VI consisting of five patients applied on one selected spot (spot A) a cream containing 0.0025% calcipotriol and on the other selected spot (spot B) cream containing 0.0025% calcipotriol and 0.5% retinyl palmitate. Two out of five patients showed partial clearance (about 25% of spot area) in spot A after 4 weeks of treatment. However, even in spots A that are showing improvement and partial clearance, a certain amount of scaling is still occurring. Three out of Five patients showed considerable amount of clearance (about 50% of spot area) in spot B and with barely noticeable scaling and no itching. The rest of the spots showed no improvement. [0056]
  • Group VII consisting of five patients applied on one selected spot (spot A) a cream containing 0.0025% calcipotriol and on the other selected spot (spot B) cream containing 0.0025% calcipotriol and 1% retinyl palmitate. Two out of five patients showed partial clearance (about 20% of spot area) in spot A after 4 weeks of treatment. However, even in spots A that are showing improvement and partial clearance, a certain amount of scaling is still occurring. Four out of Five patients showed considerable amount of clearance (about 50% of spot area) in spot B and with barely noticeable scaling and no itching. The rest of the spots showed no improvement. [0057]
  • Group VIII consisting of five patients applied on one selected spot (spot A) a cream containing 0.0025% calcipotriol and on the other selected spot (spot B) cream containing 0.0025% calcipotriol and 5% retinyl palmitate. One out of five patients showed partial clearance (about 30% of spot area) in spot A after 4 weeks of treatment. However, even in spot A that is showing improvement and partial clearance, a certain amount of scaling is still occurring. Five out of Five patients showed considerable amount of clearance (average about 85% of spot area and one complete clearance) in spot B and with no scaling and itching. The rest of the spots showed no improvement. [0058]
  • Group IX consisting of five patients applied on one selected spot (spot A) a cream containing 0.0025% calcipotriol and on the other selected spot (spot B) cream containing 0.0025% calcipotriol and 10% retinyl palmitate. One out of five patients showed partial clearance (about 15% of spot area) in spot A after 4 weeks of treatment. However, even in spot A that is showing improvement and partial clearance, a certain amount of scaling is still occurring. Five out of Five patients showed considerable amount of clearance (average about 90% of spot area and two complete clearance) in spot B and with no scaling and itching. The rest of the spots showed no improvement. [0059]
  • Group X consisting of five patients applied on one selected spot (spot A) a cream containing 0.005% calcipotriol and on the other selected spot (spot B) cream containing 5% Cholecalciferol and 5% retinyl palmitate. Two out of five patients showed partial clearance (about 15% of spot area) in spot A after 4 weeks of treatment. However, even in spots A that are showing improvement and partial clearance, a certain amount of scaling is still occurring. Five out of Five patients showed considerable amount of clearance (average about 75% of spot area and one complete clearance) in spot B and with no scaling and itching. The rest of the spots showed no improvement. [0060]
  • This data clearly indicates the synergistic effect of using retinoic acid or retinyl esters above 0.1% particularly at higher concentrations in treating psoriasis. Similar experiments were carried out using retinol rather than retinyl palmitate with similar results. [0061]
    • EXAMPLE 3
  • Three patients diagnosed with eczema were treated with cream containing 0.0025% calcipotriol and 5% retinyl palmitate. A significant improvement was noticed in all three patients within 5 days and two had normal-looking skin after two weeks. [0062]
    • EXAMPLE 4
  • Various types of human melanoma, breast cancer and prostate cancer cells will be cultured according to standardized procedures. These cells will be incubated with in the presence of various concentrations of retinol, retinoic acid, retinyl esters, calcitriol or a combination thereof. Cell growth of at least some of these cells will be shown to be significantly inhibited in the presence of calcitriol and high concentrations of retinol (about 10[0063] −5M) as compared with cells incubated in the absence of the above compounds or in the presence of each of the above compounds alone.
    • EXAMPLE 4
  • Various types of human melanoma, breast cancer and prostate cancer cells will be cultured according to standardized procedures. These cells will be incubated with in the presence of various concentrations of retinol, retinoic acid, retinyl esters, calcitriol or a combination thereof. Some cells will also be incubated in media collected from F9 mouse teratocarcinoma cells after these F9 cells were incubated in the presence of 10[0064] −5M retinal for 12-48 hours ± calcitriol. Cell growth of at least some of these cell lines will be shown to be significantly inhibited in the presence of calcitriol and high concentrations of retinal (about 10−5M) or in the presence F9 cultured media containing calcitriol prior to incubation with F9 cells or after.
  • The invention has been described in terms of preferred embodiments thereof, but is more broadly applicable as will be understood by those skilled in the art. The scope of the invention is therefore limited only by the following claims. [0065]

Claims (21)

What is claimed is:
1. A composition comprising a vitamin D analog and a retinoid, wherein:
(a) the vitamin D analog is capable of binding a vitamin 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 a compound capable of binding a retinoic acid receptor, retinol in a concentration of at least about 0.1% and a compound in a concentration of at least about 0.1% capable of being converted in vivo into retinal.
2. A topical composition according to
claim 1
.
3. The composition of
claim 1
, wherein the vitamin D analog is selected from the group consisting of cholecalciferol, calcifediol, calcitriol, calcipotriol, ergocalciferol, dihydrotachysterol, 1,25-dihydroxyergocalciferol, and 25-hydroxydihydrotachysterol.
3. The composition of
claim 1
, wherein the vitamin D analog is calcitriol.
4. The composition of
claim 1
, wherein the vitamin D analog is calcipotriol.
5. The composition of
claim 1
, wherein the retinoid is retinal.
6. The composition of
claim 1
, wherein the retinoid is a retinyl ester.
7. The composition of
claim 1
, wherein the vitamin D analog is calcitriol or calcipotriol at a concentration of about 0.005% and the retinoid is a retinyl ester at a concentration of about 5%.
8. The composition of
claim 6
, wherein the retinyl ester is retinyl palmitate.
9. The composition of
claim 1
, wherein the retinoid is retinal.
10. A method of treating a subject suffering from a disorder characterized by abnormal cell-proliferation and/or cell-differentiation, in which a composition according to
claim 1
 is administered to the subject in need of such treatment.
11. A method of treating a subject suffering from a disorder selected from the group consisting of psoriasis, acne, eczema, rosacea, actinic keratosis, seborrheic dermatitis, and congenital keratinization disorders, in which a composition according to
claim 1
 is administered to the subject in need of such treatment.
12. The method of
claim 11
, wherein the disorder is psoriasis.
13. The method of
claim 11
, wherein the disorder is eczema.
14. The method of
claim 11
, wherein the disorder is acne.
15. A method of treating one or more conditions of the skin selected from the group consisting of dry skin, photodamaged skin, age spots, aged skin, increasing stratum corneum flexibility, wrinkles, fine lines, actinic blemishes, skin dyschromias, and ichthyosis, comprising applying to the skin having said one or more condition the composition of
claim 1
.
16. A composition comprising retinol in a concentration of at least about 1.5% or a compound in a concentration of at least about 1.5% capable of being converted in vivo into retinol.
17. A method of treating one or more conditions of the skin selected from the group consisting of dry skin, photodamaged skin, age spots, aged skin, increasing stratum corneum flexibility, wrinkles, fine lines, actinic blemishes, skin dyschromias, ichthyosis and acne, comprising applying to the skin having said one or more condition the composition of
claim 16
.
18. The method of
claim 17
, wherein the skin condition is acne.
19. The method of
claim 17
, wherein the skin condition is actinic blemishes.
20. The method of
claim 16
, wherein the skin condition is fine wrinkles.
US09/116,632 1998-07-16 1998-07-16 Compositions and methods of treating skin conditions Abandoned US20010002396A1 (en)

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US09/116,632 US20010002396A1 (en) 1998-07-16 1998-07-16 Compositions and methods of treating skin conditions
US09/351,020 US6242435B1 (en) 1998-07-16 1999-07-12 Compositions and methods of treating abnormal cell proliferation
AT99933947T ATE305296T1 (en) 1998-07-16 1999-07-13 COMPOSITIONS AND METHODS FOR TREATING ABNORMAL CELL PRODUCTION
CA002337138A CA2337138A1 (en) 1998-07-16 1999-07-13 Compositions and methods of treating abnormal cell proliferation
PCT/US1999/015769 WO2000003700A1 (en) 1998-07-16 1999-07-13 Compositions and methods of treating abnormal cell proliferation
DK99933947T DK1104294T3 (en) 1998-07-16 1999-07-13 Compositions and Methods for Treating Abnormal Cell Proliferation
AU49889/99A AU4988999A (en) 1998-07-16 1999-07-13 Compositions and methods of treating abnormal cell proliferation
EP99933947A EP1104294B8 (en) 1998-07-16 1999-07-13 Compositions and methods of treating abnormal cell proliferation
ES99933947T ES2249900T3 (en) 1998-07-16 1999-07-13 COMPOSITIONS AND PROCEDURES TO TREAT ANOMAL CELL PROLIFERATION.
MXPA01000492A MXPA01000492A (en) 1998-07-16 1999-07-13 Compositions and methods of treating abnormal cell proliferation.
PT99933947T PT1104294E (en) 1998-07-16 1999-07-13 COMPOSITIONS AND METHODS OF TREATMENT OF ABNORMAL CELLULAR PROLIFERATION
DE69927507T DE69927507T2 (en) 1998-07-16 1999-07-13 COMPOSITIONS AND METHOD FOR THE TREATMENT OF ABNORMAL CELL REPRODUCTION
JP2000559835A JP2002527356A (en) 1998-07-16 1999-07-13 Compositions and methods for treating abnormal cell proliferation
US09/872,662 US6552009B2 (en) 1998-07-16 2001-06-01 Compositions and methods of treating abnormal cell proliferation
US10/420,106 US20030207848A1 (en) 1998-07-16 2003-04-17 Compositions and methods of treating abnormal cell proliferation

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JP2002527356A (en) 2002-08-27
DE69927507T2 (en) 2006-03-23
ES2249900T3 (en) 2006-04-01
ATE305296T1 (en) 2005-10-15
MXPA01000492A (en) 2002-11-29
EP1104294B1 (en) 2005-09-28
CA2337138A1 (en) 2000-01-27
US6242435B1 (en) 2001-06-05

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