`
`
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`PCT
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`
`(11) International Publication Number:
`WO 96/14822
`(51) International Patent Classification 6;
`
`
`
`
`A61K 7/00, 7/48
`23 May 1996 (23.05.96)
`(43) International Publication Date:
`
`
`
`
` (21) International Application Number:
`PCT/US95/14682|(81) Designated States: AM, AT, AU, BB, BG, BR, BY, CA, CH,
`CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU,IS, JP, KE,
`
`KG, KP, KR, KZ, LK, LR, LT, LU, LV, MD, MG, MK,
`
`
`(22) International Filing Date:
`13 November 1995 (13.11.95)
`
`MN, MW,MX,NO,NZ,PL, PT, RO, RU, SD, SE, SG,SI,
`
`SK, TJ, TM, TT, UA,
`UG, UZ, VN, European patent (AT,
`BE, CH, DE, DK, ES, FR, GB,GR,IE,IT, LU, MC, NL,
`
`
`
`
`PT, SE), OAPIpatent (BF, BJ, CF, CG, CI, CM, GA, GN,
`(30) Priority Data:
`08/339,553
`15 November 1994 (15.11.94)
`US
`
`ML, MR, NE, SN, TD, TG), ARIPO patent (KE, LS, MW,
`
`
`
`31 March 1995 (31.03.95)08/414,345 US
`
`
`SD, SZ, UG).
`
`
`(71) Applicant: OSMOTICS CORPORATION [US/US]; Suite 610,
`
`
`Published
`
`1860 Blake Street, Denver, CO 80202 (US).
`With international search report.
`
`Before the expiration of the time limit for amending the
`
`
`
`claims and to be republished in the event of the receipt of
`
`amendments.
`/
`
`
`
`
`
`
`
`(72) Inventors: PORTER,Steven, Scott; 1860 Blake Street #610,
`Denver, CO 80202 (US). PORTER, Francine, Edmund;
`Suite 610, 1860 Blake Street, Denver, CO 80202 (US).
`
`(74) Agents: GREENLEE,Lorance,L.et al.; Greenlee and Winner,
`P.C., Suite 201, 5370 Manhattan Circle, Boulder, CO 80303
`(US).
`
`
`(54) Title: SKIN CARE COMPOSITIONS AND METHODS
`(57) Abstract
`
`Skin care compositions and methods are pro-
`vided for improving the appearanceof skin affected by
`
`aging, photodamage and/or oxidative stress. Specifi-
`cally, adhesive materials containing cosmetically ac-
`tive ingredients, ¢.g., one or more antioxidants such
`as Vitamins A, C and/or E, or moisturizers are ap-
`plied to target areas including the frowline area of the
`forehead,
`the front of the neck, the crows-feet area
`near the eyes, the upper lip and the nasolabial area.
`
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`SYfo
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`L'OREAL USA,INC. EX. 1012
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`L'OREAL USA, INC. EX. 1012
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`GA 1012-2
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`FOR THE PURPOSES OF INFORMATION ONLY
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing intemational
`Austria
`GB
`MR
`Australia
`GE
`MW
`Barbados
`GN
`NE
`Belgium
`GR
`NL
`Burkina Faso
`Hu
`NO
`Bulgaria
`IE
`NZ
`Benin
`PL
`Brazil
`PT
`Belarus
`RO
`Canada
`RU
`Central African Republic
`SD
`Congo
`SE
`Switzerland
`SI
`Céte d'Ivoire
`SK
`Cameroon
`SN
`China
`TD
`Czechoslovakia
`TG
`Czech Republic
`TJ
`Germany
`TT
`Denmark
`UA
`Spain
`us
`Finland
`UZ
`France
`VN
`Gabon
`
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`applications under the PCT.
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`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`cl
`CM
`CN
`cs
`cz
`DE
`DK
`ES
`FI
`FR
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`WO 96/14822
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`PCT/US95/14682
`
`SKIN CARE COMPOSITIONS AND METHODS
`
`Field of the Invention
`This invention relates to skin care compositions and methods for the improvementof the
`appearance of aging skin,
`in particular,
`to the improvement of wrinkling skin in target areas
`including but not limited to the areasoutside and underthe eyes,in the nasolabial area, the upper
`lip, the forehead, the neck and the hands.
`
`Background of the Invention
`People in general are very concerned with maintaining youthful and attractive appearances.
`As populations age,it is anticipated there will be increasing markets for skin care products which
`can improve the appearance of aging skin and/or maintain attractive skin qualities. Treatments
`designed to prolong or promote youthful appearance include topical applications of cosmetic
`preparations,lotions and moisturizer, electrical stimulation, collagen injections and cosmetic surgery.
`With aging, prolonged or repeated exposure to ultraviolet radiation and/or oxidative stress,
`the skin of the face often shows signs of damage resulting from such exposure. Aging or other
`damagetu skin may be recognized by effects including wrinkling, yellowing, laxing, lines, spots,
`mottling and a leathery or dry appearance. At the histological level, skin damage, e.g., from
`photoaging, maybereflected in tangled, thickened, abnormal elastic fibers, decreased collagen and
`increased glycosaminoglycan content (Tanaka etal. (1993) Arch. Dermatol. Res. 285:352-355).
`The aging processresults in thinning and deterioration of the skin. There is a reduction in cells and
`in blood supply, and a flattening in the junction between the dermis and epidermis.
`Ascorbic acid (Vitamin C), Vitamin A, tocopherol (Vitamin E) and &-carotene, which can at
`least in part be functionally characterized as antioxidants, are essential to the maintenance of a
`healthy and attractive skin appearance in humans. Vitamin K is also beneficial to maintaining
`attractive skin. Generally, these nutrients are obtainedin the diet and/or in nutritional supplements.
`Other cosmetically beneficial components can be applied to: ‘cally for improving skin appearance
`and quality; such componentsinclude moisturizers, including but not limited to polysaccharides and
`
`marine extracts.
`The aforementioned antioxidants help to prevent damage to skin and/or body organs
`resulting from poor nutrition, physiological processes and exposure to environmental pollutants,
`certain drugs, alcohol,and ultraviolet (UV) radiation. Normal physiological processes,
`including
`aging, and exposure to deleterious agents can lead to the generation of free oxygen radicals, a
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`componentof so-called oxidative stress. Oxidative stress leads to damageto cellular membranes,
`the genetic material and other cellular targets including connective tissue and collagen. Other
`Sources of oxidative stress include heat,
`trauma,
`infection, hyperoxia,
`toxins and excessive
`exercise. Antioxidants can donate electrons without generating potentially harmful chain reactions
`and oxidation ofcellular components, and thus provide Protection from oxidative damage. A further
`problem, especially with aging skin is a decrease in blood circulation.
`Ascorbic acid (Vitamin C) is knownto stimulate and/or regulate collagen synthesis in human
`tissue. When collagen synthesis is stimulated in skin, a healthier and younger skin appearance
`results. Ascorbic acid can also help to prevent or minimize UV-induce lipid oxidation, thus providing
`further benefits in maintaining or promoting attractive skin appearance. Further, ascorbic acid acts
`to inhibit melanin synthesis, which leads to skin discoloration during the aging Process, and to
`inhibit histamine release from cellular membranes, which is associated with allergenic reactions,
`Particularly amongindividuals with so-called "sensitive skin."
`Ascorbic acid-containing compositions for topical application to the skin have been
`described (see, e.g., U.S. Patent No. 4,983,382, issued Jan. 8, 1991; Avon Products,inc.). U.S.
`Patent No. 4,999,348, issued March 12, 1994, Estee Lauder, Inc., refers to cholesteric liquid
`crystal compositions for controlled release and enhanced penetration of biologically active materials
`such as Vitamin A to the skin. Vitamin A is said to make wrinkling in the Skin less noticeable. U.S.
`Patent No. 5,238,965, issued August 24, 1993, Procter & Gamble Company,refers to regulating
`wrinkling using topical applications of lipophosphatidic acid compositions. WO 94/00109 and Wo
`94/00098(Lancaster Group AG), both incorporated by reference, refer to dermatological agents for
`increasing oxygen transport in the skin; these agents comprise phospholipids and oxygen-loaded
`fluorocarbons. U.S. Patent No. 5,296,500 (issued March 22, 1994, Proctor & Gamble Co.) claims
`methods for regulating wrinkles or atrophy of the skin using compositions comprising N-acetyl
`cysteine,
`including compositions where one or more additional components
`(sunscreen,
`antioxidants, anti-inflammatory agents) are added. The present invention has the advantage over
`these conventional preparations in that absorption of Vitamin C or other cosmetically active
`ingredient into the skin can continue over an extended period of time without the extra effort or
`inconvenience of needingto actively apply anothercoat of a lotion, cream orthelike.
`Tocopherol (Vitamin E, with a-tocopherol being the most potent) has effects in the skin
`including antioxidant activity, improved membrane Stability, protection against UV radiation and
`nitrosamine formation, moisturizing action on dry skin and anti-inflammatory action.
`{t
`is the
`antioxidant effect which is believed most
`important
`in protection from oxidative damage.
`Tocopherol has also been shownto play a role in maintaining the structural integrity of cell
`membranes and connective tissue. Firmness, texture and/or tone are maintained by theintegrity
`of the elastic fiber in the dermis and collagen in connective tissue. Vitamin E is also believed to
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`improve the hydration of the skin, and insufficiently hydrated skin is characterized by lines at
`relatively closer distance than in normal skin, irregular texture and a "scruffy" appearance.
`It has been reported that only about 20-40% of oral vitamin E is absorbed, and it is not
`known whatfraction of the absorbed vitamin E is available to the skin. Topically applied vitamin
`E, either in the alcohol or the acetate form, can be absorbed through the skin. When combined with
`ascorbyl palmitate which acts as an oxygen scavenger, tocopherol is particularly effective as an
`antioxidant to extend the shelf-life of natural products formulations such as perfumes, vitamins and
`
`herbal extracts.
`&-carotene within physiologically advantageouslevels is also essential for skin development.
`An excess of &-carotene inhibits the keratinization of epithelial tissue, and a deficiency results in
`acne-like blackheads. &-carotene also acts to improve the skin’s water barrier properties, and
`therefore &-carotene can be usefulin treating seasonal and/or environmental problems (heat,
`dryness,air pollution). Provision of &-carotene to the skin will increase the amount of Vitamin A
`within the skin, and thereby impart beneficial effects on appearance of skin.
`Other cosmetically active compositions, when topically applied to the skin, include marine
`extracts and moisturizers, for example, hyaluronic acid. Marine extracts, for example, those
`prepared from seaweed,are rich in minerals, aminoacids, vitamins, and polysaccharides which are
`believed to function as moisturizing agents. Additional embodiments of a skin care patch can
`increase the oxygen supply to the skin, for example, using oxygen-loaded fluorocarbon compounds
`(as disclosed in WO 94/00109, WO 94/00098,for example) within the patch. Further embodiments
`include patches comprising cosmetically effective amounts of an active ingredient such as
`lysophosphatidic acid, an a-hydroxyacid and N-acetyl cysteine.
`Transdermal delivery of pharmaceutical compositions is well known. Such well-known
`pharmaceutical compositions include scopolamine for treatment of motion sickness, estrogen
`replacement therapy and nicotine for assistance in breaking tobacco habits. The present invention
`is believed to be the first application of transdermal delivery systems for skin care and the
`improvement of the appearanceof aging, photodamagedor oxidatively stressed skin, especially for
`the improvement of the appearance of wrinkled skin.
`Brief Description of the Drawings
`Fig. 1
`is a sketch of a typical aging human face with wrinkles under and in the outside
`corners of the eyes, the forehead, upperlip, the area from the outside bottom edges of the nose
`to the outside corners of the mouth (the nasolabial fold area) and the neck.
`Fig. 2 illustrates a human face with the transdermal delivery device for application of
`cosmetically active compositions in place on the forehead.
`Fig. 3 illustrates a humanface with a pair of the transdermal delivery devices for application
`of cosmetically active compositions in place in the nasolabial fold area.
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`Fig. 4 illustrates a human face with the transdermal delivery device for application of
`cosmetically active compositionsin place on the nasolabial fold area upperlip.
`Fig. 5 illustrates a humanface with a pair of the transdermal delivery devices for application
`of cosmetically active compositions in place at the outer corners of the eyes.
`Fig. 6 illustrates a humanwith the transdermal delivery device for application of cosmetically
`active compositions in place on the neck.
`Fig. 7A-7B illustrates a human hand with the transdermal delivery device (cross-hatched)
`for application of cosmetically active compositions in place on the backof the hand, with extensions
`on the backs of the fingers and thumbin Figure 7A and without finger extensions in Figure 7B.
`Summary of the Invention
`It is an object of this invention to provide cosmetic compositions and methodsfor improving
`the appearanceof aging skin or skin damaged by overexposure to oxidative stress, sunlight or
`ultravioletlight and thelike. With treatment, the appearance of the wrinkling of the skin becomes
`less apparent. Other outward indications of aging, photodamage or oxidative Stress to the skin
`such as mottling, laxness, spots, drynessor leatheriness can also be lessened or slowed. The
`method ofthis invention is the Percutaneous(or intradermal) delivery to the skin of cosmetically
`active compositions including antioxidants, for example, ascorbic acid, vitamin A, vitamin E, &-
`carotene or a combination thereof, via a transdermal delivery device. Other cosmetically active
`ingredients which can be incorporated into a transdermal
`(or intradermal) delivery device for
`Sustained application to the skin include moisturizers (e.g. hyaluronic acid) and marine extracts from
`kelp and/or algae, essential fatty acids, collagen andlipids.
`Preferably, the antioxidantis Vitamin C, from 50 to 1000 mg per squareinch in an adhesive
`matrix. More Preferably ascorbic acid is formulated with a cosmetically acceptable salt of ascorbic
`acid in proportions suchthat the pH of the combinationin solution is about 4 to about 7, preferably,
`about 5 to about 6, most preferably about 5.5. Those salts include, but are not limited to, sodium
`ascorbate, potassium ascorbate and calcium ascorbate, preferably sodium ascorbate. Where sodium
`ascorbate is combined with ascorbic acid in the matrix, the preferred ratio is from about 1:20 to
`about 1:25 acid: salt, preferably about 1:22.
`Preferably, the delivery device is adhered to the skin using a silicone Pressure sensitive
`adhesive, but other adhesives are knownto theart, including but notlimited to, natural, isobuty!
`and buty! rubber compositions and acrylate-based adhesives and pressure sensitive adhesives. The
`configuration of the delivery device for the sustained delivery of cosmetically active ingredients to
`the skin can be adhesive matrix, liquid or solid state reservoir or polymer matrix; the preferred
`delivery device is the adhesive matrix type.
`In an adhesive matrix type patch,
`there is an
`impermeable backing, a matrix comprising the cosmetically active ingredient, optionally comprising
`@ permeation enhancer and/or an anti-irritant, and a release liner.
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`In most transdermal delivery systems, thin, flexible occlusive films serve as protective
`backing substrate and releaseliner. For the present skin care applications, an occlusive protective
`backing substrate is preferred over a non-occlusive backing substrate. The materials used forliner
`and backing provide storage stability by keeping the active ingredients from migrating into or
`through the backing material and liner before use. The patches of the present invention desirably
`have the following tape properties: release or peel force < 50 g/cm; tack value > 50 g/cm;
`adhesion force 100-1200 g/cm; release force < 1 g/cm; preferably the adhesion force is about 50-
`300 g/cm and the shearforce is about 14 kg/6.25cm?. Preferably, the adhesive is a medical grade
`silicone adhesive. The peel force required to removethe releaseliner from the patch should be
`sufficient to prevent inadvertent separation of the liner from the patch before use and low enough
`so that it can be readily removed by the intended user.
`Whereanacrylic adhesive is used, that adhesiveis medical grade and rated between O and
`2, preferably between O and 1 on the Draize Code Scale. On this scale a score of O means no
`erythema (reddening) and no edema (swelling when a test patch is applied to the skin and removed.
`The acrylic adhesive can optionally include a cross-linking agent.
`Liquid and solid state reservoir transdermal delivery devices are configured so that the
`reservoir comprising the cosmetically active ingredients, enhancers and any other formulation
`ingredients is located between the backing material and the adhesive, and during use, formulation
`ingredients pass through the adhesive and then into the skin. Compatibility of various excipients
`and penetration enhancers with adhesives are well known to the art, and the skilled artisan can
`readily choose suitable concentrations and combinations of ingredients and adhesives.
`A typical non-silicone polymer matrix transdermal delivery device has a rim of adhesive so
`that the penetration enhancer, cosmetically active ingredients) and other formulation ingredients
`are notfully in contact with the adhesive.
`In the preferred embodiment, the entire patchis adhesive
`and contains at least one cosmetically active ingredient. One surface is applied to the intended
`position on the face with gentle pressure to promote adhesion, after removal of a release liner. The
`other surface (away from the skin) is covered with a protective backing during storage, before use
`
`and during use.
`invention optionally comprise
`the present
`the skin care patches of
`Where desired,
`formulation ingredients which either increase or decrease the release rates and/or absorption rates
`of the cosmetically active ingredients. Water soluble additives which increase release rate include
`ethylene glycol, glycerine, polyethylene glycols 200, 400, 600; polysorbate 80, lactoss gelatin,
`sucrose, sodium alginate, carboxymethylcellulose, ammonium chloride, and polyvinylpyrollidone.
`Lipid soluble additives which tend to increase release rate include cholesterol. Certain surfactants
`also have the effect of increasing release rate; these surfactants include sodium lauryl sulfate,
`dodecyltrimethylammonium chloride and azone. Release rates can be decreasedby the addition of
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`compoundsincluding suchfillers as kaolin, Sephadex G-25 (high pressureliquid chromatography
`gelfiltration resin) andsilica.
`The skin care patches of the present invention can optionally further include an irritant
`buffer such as sodium bicarbonate, whichis incorporated at 1-10% by weight when Present, or a
`stabilizing agent, such as propylgallate or sodium bisulfite.
`Preferably, the skin care transdermal or intradermal delivery devices (patches) are shaped
`specifically for the target skin area to be treated. A generally rectangular with chevron patchis
`advantageously applied to the lower forehead area, an example of whichisillustrated in Fig. 2. For
`application beneath and at the outer cornersof the eye a generally kidney-shaped Patch is used, and
`the shapesfor the right andleft sides are mirror imagesof one another. For the nasolabialfold area,
`the patch is shaped substantially like a boomerang, generally kidney-shaped. Skin care patches are
`also provided whichfit the back of the hand, optionally with extensions down the fingers. Figures
`2-7 illustrate human faces and hands with the aforementioned anatomically designed skin care
`
`Patchesin place.
`Detailed Description of the Invention
`A transdermal or intradermal delivery device, known colloquially as a patch,is a unit which
`adheresto the skin of an individual, and allows for sustained release of an active ingredient into the
`Skin, from whichthe active ingredient usually enters systemic circulation. Typesof patchesinclude
`liquid reservoir, solid state reservoir, polymer matrix, adhesive matrix and wet wick patches,
`depending on the configuration of the active ingredients and the patch materials. The active
`ingredients
`in an intradermal delivery device for
`improving the appearance of aging or
`photodamagedskin can include one or more of the following: alpha hydroxyacids, alpha ketoacids
`and polymeric hydroxyacids, moisturizers, collagen, marine extract and anti-oxidants including one
`or more of a tocopherol (Vitamin E), &-carotene, Vitamin A and Vitamin C (and/or cosmetically
`acceptable salts thereof), and are generically termed cosmetically active ingredients herein. A
`preferred tocopherol compoundis a-tocopherol. Additionally or alternatively, cosmetic benefits may
`be obtained by the use of skin care patches comprising molecules (e.g., fluorocarbons) capable of
`improving oxygen supply in skin tissue, as described, e.g., in WO 94/00098 and WO 94/00109.
`Becauseof the beneficial effects of various cosmetically active ingredients, it has been a
`longstanding objective of skin care products to deliver effective concentrations of the active
`ingredients to the skin’s tissue matrix (the dermal layers) via the most effective method possible to
`achieve maximal skin appearance benefits. Topical application of cosmetically active ingredients
`including butnotlimited to antioxidants, moisturizers and marine extracts via a transdermal delivery
`device has several advantages over topical application of a conventional formulation such as a
`lotion, creme or ointmentin that with a patch, applicationis passive and continuous delivery of the
`active ingredient can be achieved for up to 24 hrs, or longer. Conventional topical application is
`limited by the amount of lotion, etc. which is administered, the amount of the active ingredient
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`which penetrates and the depth to which it penetrates, oxidation of the active ingredients before
`or during penetration and evaporative loss of solvents and/or active ingredients from lotions and the
`like. With a patch, evaporation is minimal, even when a non-occlusive patch is used.
`Skin care patches canalso include cosmetically active ingredients other than antioxidants;
`for example, one or more of marine extracts, moisturizers and collagen, with or without a
`penetration enhancer, can be loaded in the reservoir, matrix or wet wick transdermal patch.
`Moisturizers can be one or more of hyaluronic acid, marine extract (of kelp and/or algae), fatty
`acids,lipids, and glycerides. Alpha hydroxyacids, alpha keto acids and polymeric hydroxyacids, for
`example, as described in U.S. Patent No. 5,091,171 (Yu and Van Scott), whichis incorporated by
`reference herein, can be incorporated into the adhesive matrices of skin care patches to ameliorate
`the unattractive effects of aging, photodamageor oxidative stress.
`in a
`The active antioxidant
`ingredients for cosmetic patch compositions are present
`cosmetically effective amount, preferably from about 1-1 000 mg per patch. Ascorbic acid (and/or
`a cosmetically acceptable salt thereof),
`tocopherol, Vitamin A and &-carotene are preferred
`antioxidants. Taurine can also be used. Preferably, each active ingredient is present at about 75
`mg per square inch.
`In combination with one or more antioxidants (or other cosmetically active ingredients),
`there are advantageously combined skin penetration-enhancing agents,i.e., agents which increase
`the penetration of the active ingredients into the skin which lead to improved skin appearance and
`at locations within the skin where the antioxidant effects of the active ingredients are beneficialin
`preventing or minimizing damage due to such agents as UV radiation, oxidative stress and aging
`in general. Generally, percutaneous absorption enhancers act by reducing the permeability or
`diffusion resistance of the stratum corneum, for example, by changing the hydration or by
`influencing the packing structure of the ordered lipids in the intercellular channels. Permeability
`enhancers tend to be small polar molecules with outstanding solvent and hydrogen-bonding
`properties. Penetration is generally better where the stratum corneum is well hydrated. The skilled
`artisan knows how to choose a permeability enhancer with properties compatible with those of the
`adhesive and the active ingredients whose permeability into the skin is desired.
`Examples of processes within the dermal layer affected by the application of antioxidants,
`moisturizers and other cosmetically active ingredients can include, but are notlimited to, collagen
`synthesis and reactions associated with oxidative stress.
`The permeability enhanceris selected using parameters understood in the art including the
`appropriate solubility characteristic of the active ingredient in the enhancer, maximizing of the
`partitioning of the active ingredient into the skin, and enhanced percutaneous absorption, while not
`interfering with the requirements for the adhesive andits sticking properties.
`Preferred penetration enhancing compounds(alsocalled permeability enhancers) are those
`which are not toxic, not irritating to the skin and notallergenic. Exemplary penetration enhancing
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`compoundsinclude but are not limited to vegetable oils such as soybean, sesame, palm, almond,
`peanut, olive and castor oils as described in WO 93/12744. Other permeability enhancing
`compounds include palmitate, alkanols (Friend et al.
`(1988) Y. Controlled Release 7:243),
`dimethylsulfoxides (Scheuplein et al. (1971) Physiol. Rev. 51:702), urea (Feldman et al. (1974)
`Arch. Dermatol]. 109:58), azone (laurocapram, Nelson Research Corp., Stockton, CA) {Stoughton
`(1982) Arch. Dermatol. 118:474),fatty acids (Cooper (1984) J. Pharm. Sei. 73:1153), alkyl esters
`(Friend et al. (1984) y. ControlledRelease 9:33), N,N-dialkyl-substituted amino acetates (Wonget
`al. (1989) Pharm. Res. §:286), detergents and surfactants (Bettley et al. (1965) Br. Dermatol.
`27:98),
`lecithins (Mahjour et al.
`(1990) V. Controlled Release 14:243), polyethylene glycol
`monolaurates(lyer et al.
`{1985) Abstract 132nd Annual Meeting, APHA Acad. Phar. Sci. 15:81)
`glycery! monolaurates (Cheng et al., U.S. Patent No. 4,746,515,
`issued 1988), pyrrolidone
`derivatives (Sasaki et al. (1991) J. Pharm Sci. 80:533) and terpenes (Williams et al. (1991) Pharm.
`res. 8:17). Only a limited numberof these compoundsare used in transdermal Products, among
`them Miglyol 849 (propylene glycol diesters of caprylic and capric acids, Mahjouret al. (1993) int.
`J. Pharmaceutics 95:161).
`Preferably,
`the permeability enhancing ingredient is present at a
`concentration of about 1-50% by weight, more preferably from about 1-20% by weight in an
`adhesive-active ingredient mixture. The Penetration enhancer must be compatible with the active
`ingredients and with the Polymeric material of the patch,as will readily be understood bytheskilled
`artisan. For a discussion of permeation enhancers compatible with patch technology, see Pfister
`and Hsieh (1990) "Permeation Enhancers Compatible with Transdermal Drug Delivery Systems: Part
`I:
`Selection and Formulation Considerations and "Part
`It: System Design Considerations,"
`Pharmaceutical Technology, September 1990 and October 1990, respectively.
`A preferred matrix-type skin care patch contains a cosmetically effective amount of an
`antioxidant (Vitamin C or E or &-carotene), preferably Vitamin C (and/or a cosmetically acceptable
`Salt), and preferably at a concentration of about 2-50% (about 75 mg per squareinch), optionally
`with a penetration enhancer present at 4 concentration of about 1-10% by weight. The preferred
`adhesive is a medical gradesilicon polymer adhesive.
`The patchitself is Preferably made of silicon, acrylate or polyisobutyiene type polymeric
`material. Preferably the patch is made of a polymeric material whichis chemically and biologically
`inert, non-toxic, non-irritating, non-sensitizing, non-allergenic and has adhesive properties which are
`easily manipulated. The Patch material should further be flexible, with good cohesive strength
`(shear strength of >5 kg/6.25 cm), suitable and easily controlled tack Properties, low release force
`So that it can be readily removed from theliner backing and easily manipulated skin adhesion. The
`Patch should have tack and adhesive properties which allow rapid adherence to the skin after
`minimal application of gentile hand pressure, and the matrix should rapidly molditself closely with
`the contours of the target skin for best transfer of active ingredients. Adhesion properties can be
`determined using techniques well known to the art, for example using a digital probe tack tester
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`(e.g., Polyken, Testing Machines, Amityville, NY) and as described in Pfister et al., Pharmaceutical
`Technology, January 1992, pp. 42, 46. The desired adhesion of the silicone pressure sensitive
`adhesive is between about 50 and 300 g/cm, preferably 80-300 g/cm. If the adhesion is abovethis
`level, then the adhesive is too aggressive to the skin.
`!f the adhesion is below this level, then the
`patch mayfall off. One way of controlling the adhesion is by the amount of resin in the pressure
`sensitive adhesive. More resin may result in a higher adhesion. An impermeable film is bound to
`the surface of the patch destined to be away from the skin during use; a release liner is bound to
`the surface of the patch destined to be applied to the skin during use, and the release liner is
`removed prior to use. The impermeablefilm is not permeable to the active ingredient(s), but it may
`be occlusive; or more preferably, nonocclusive. The skilled artisan understands how to manipulate
`the adhesive composition in combination with the active ingredients so as to maintain desirable
`adhesive properties and effective delivery of the cosmetically active ingredient(s).
`Adhesives,e.g., acrylic adhesives and pressure sensitive adhesives can be rated according
`to the Draize Dermal Scoring Code. A score of 0 meansthere is no erythema or edemaafter test
`application; 1 means barely perceptible reddening or swelling; 2 means well defined erythema or
`slight edema; 3 means moderate to severe erythema or moderate edema (raised 1mm); and 4
`reflects severe erythema (beet redness)to slight eschar formation and severe edema (raised > Imm
`and extending beyond the area of exposure). Nontoxic adhesives with Draize Code Scores of 0-1
`are deemed suitable for use on premature infants, and such medical adhesives can also be usedin
`the skin care patches of the present invention withoutinjuring or irritating the relatively delicate
`facial and neck target skin areas. Medical acrylate adhesives and/or medical acrylic pressure
`sensitive adhesives with Draize scores of 0-1 are well known and commercially available.
`The acrylate-based matrix preferably contains medical acrylate adhesive, preferably
`pressure-sensitive adhesive, and active ingredient in a ratio of from about 40:60 to about 60:40,
`preferably about 50:50 by weight.
`It is understood that the incorporation of the cosmetically active
`ingredient into the adhesive may change the adhesion of the matrix composition relative to adhesive
`alone. Adjusting (increasing) the thickness of the matrix composition can compensate for someloss
`of adhesiveness.
`The surface of the transdermal or intradermal delivery device which is away from the skin
`may be non-occlusive, i.e., permeable to air and/or water, or it may be occlusive,
`i.e., non-
`
`permeable to water vapor.
`Pressure sensitive adhesives useful in transdermal and intradermal delivery devices include
`those silicone pressure sensitive adhesives comprising a mixture of a silicone resin and a silicone
`fluid or a condensed productof a silicone resin and a silicone fluid and an acrylic polyisobutylene
`(PIB); the pressure sensitive adhesive exhibiting suitable tackiness and adhesivenessfor delivery of
`cosmetically active ingredients to sensitive or delicate skin.
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`1012-11
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`The silicone resin may be further described as being a soluble, hydroxyl-functional
`organopolysiloxaneresin