`
`
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`PCT
`lntemauonal Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`
`
`(11) International Publication Number:
`WO 96/14822
`(51) International Patent Classification 6 :
`
`(43) International Publication Date:
`23 May 1996 (23.05.96)
`
` (21) International Application Number:
`
`(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,
`
`
`L
`KG, KP, KR, KZ, LK, LR,
`, LU, LV, MD, MG, MK,
`
`
`(22) International Filing Date:
`13 November 1995 (13.11.95)
`
`MN, MW, MX, NO, NZ, P , PT, RO, RU, SD, SE, 56, SI,
`
`SK, 1'], TM, T'I‘, UA, U0, U2, VN, European patent (AT,
`
`
`BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL,
`
`
`(30) Priority Data:
`
`PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN,
`
`08/339,553
`15 November 1994 (15.11.94)
`US
`
`ML, MR, NE, SN, TD, TG), ARIPO patent (KE, LS, MW,
`
`08/414,345
`31 March 1995 (31.03.95)
`US
`
`
`SD, 52. U6).
`
`
`
`(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.
`p
`
`
`
`A61K 7/00, 7/48
`
`PCT/US95/l4682
`
`(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.v, 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 appearance of skin affected by
`aging, photodamage and/or oxidative stress. Specifi-
`
`cally, adhesive materials containing cosmetically ac-
`tive ingredients, e.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.
`
`
`
`1012-1
`
`L'OREAL USA, INC. EX. 1012
`
`L'OREAL USA, INC. EX. 1012
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`1012-1
`
`

`

`Viet Nam
`
`Republic of Korea
`Kanklman
`Liechtenstein
`Sri Lanka
`lanembomx
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`Senegal
`
`Togo
`Tajikinan
`Midad and Tobago
`Ukraine
`United Slates of America
`U l
`l .
`
`1012-2
`
`Austria
`Amalia
`Barbados
`Belgium
`Burk‘ma Filo
`Bulgaria
`Benin
`Brazil
`Belama
`Canada
`
`Central African Republic
`Conao
`Switzerland
`Cu: d'Ivoixe
`
`AT
`AU
`BB
`BE
`
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CS
`CZ
`DE
`DK
`L9
`Fl
`FR
`GA
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`1012-2
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`

`

`W0 96/14822
`
`PCT/US95I14682
`
`SKIN CARE COMPOSITIONS AND METHODS
`
`Field of the Invention
`
`This invention relates to skin care compositions and methods for the improvement of the
`
`to the improvement of wrinkling skin in target areas
`in particular,
`appearance of aging skin,
`including but not limited to the areas'outside and under the 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
`
`damage to 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, may be reflected in tangled, thickened, abnormal elastic fibers, decreased collagen and
`increased glycosaminoglycan content (Tanaka et al. (1993) Arch. Dermatol. Res. g§§:352-355).
`The aging process results 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 B-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 obtained in the diet and/or in nutritional supplements.
`Other cosmetically beneficial components can be applied to. Ically for improving skin appearance
`and quality; such components include 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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`PCT/US95114682
`
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`
`component of so-called oxidative stress. Oxidative stress leads to damage to 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
`
`Ascorbic acid (Vitamin C) is known to 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
`
`described (see, e.g., U.S. Patent No. 4,983,382, issued Jan. 8, 1991; Avon Products, lnc.). U.S.
`Patent No. "4,999,348, issued March 12, 1994, Estee Lauder,
`lnc., 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
`
`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
`
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`PCT[11895]14682
`
`3
`
`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 what fraction 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.
`
`B-carotene within physiologically advantageous levels is also essential for skin development.
`
`10
`
`An excess of B—carotene inhibits the keratinization of epithelial tissue, and a deficiency results in
`
`lit-carotene also acts to improve the skin's water barrier properties, and
`acne-like blackheads.
`therefore lS-carotene can be usefulrin treating seasonal and/or environmental problems (heat,
`
`dryness, air pollution). Provision of B-carotene to the skin will increase the amount of Vitamin A
`within the skin, and thereby impart beneficial effects on appearance of skin.
`
`15
`
`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, amino acids, 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
`
`20
`
`(as disclosed in W0 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.
`Transdermai 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 appearance of aging, photodamaged or oxidatively stressed skin, especially for
`
`the improvement of the appearance of wrinkled skin.
`
`Brief Descrigtion 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, upper lip, the area from the outside bottom edges of the nose
`
`to the outside corners of the mouth (the nasolablal fold areal 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 human face with a pair of the transdermal delivery devices for application
`
`of cosmetically active compositions in place in the nasolabial fold area.
`
`25
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`
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`
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`
`1012-5
`
`

`

`WO 96114822
`
`PCT/US95/l4682
`
`10
`
`15
`
`20
`
`25
`
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`
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`
`the appearance of aging skin or skin damaged by overexposure to oxidative stress, sunlight or
`ultraviolet light and the like. 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, dryness or leatheriness can also be lessened or slowed. The
`method of this invention is the percutaneous (or intradermal) delivery to the skin of cosmetically
`active compositions including antioxidants, for example, ascorbic acid, vitamin A, vitamin E, B-
`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 le.g. hyaluronic acid) and marine extracts from
`kelp and/or algae, essential fatty acids, collagen and lipids.
`Preferably, the antioxidant is Vitamin C, from 50 to 1000 mg per square inch in an adhesive
`matrix. More preferably ascorbic acid is formulated with a cosmetically acceptable salt of ascorbic
`acid in proportions such that the pH of the combination in 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.
`
`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
`a permeation enhancer and/or an anti-irritant, and a release liner.
`
`1012-6
`
`1012-6
`
`

`

`
`
`WO 96/14822
`
`PCT/US95/l4682
`
`5
`
`in most transdermal delivery systems, thin, flexible occlusive films serve as protective
`
`backing substrate and release liner. For the present skin care applications, an occlusive protective
`
`backing substrate is preferred over a non-occlusive backing substrate. The materials used for liner
`
`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 shear force is about 14 kg/6.25cm2. Preferably, the adhesive is a medical grade
`
`silicone adhesive. The peel force required to remove the release liner from the patch should be
`
`10
`
`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.
`
`Where an acrylic adhesive is used, that adhesive is medical grade and rated between 0 and
`
`2, preferably between 0 and 1 on the Draize Code Scale. On this scale a score of 0 means no
`
`erythema (reddening) and no edema (swelling when a test patch is applied to the skin and removed.
`
`15
`
`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
`
`20
`
`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 ingredientls) and other formulation ingredients
`are not fully in contact with the adhesive.
`In the preferred embodiment, the entire patch is 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.
`Where desired,
`
`the skin care patches of
`
`the present
`
`invention optionally comprise
`
`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, lactose gelatin,
`sucrose, sodium alginate, carboxymethyl cellulose, 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 decreased by the addition of
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`PCT/US95/l4682
`
`6
`
`compounds including such fillers as kaolin, Sephadex G-25 (high pressure liquid chromatography
`gel filtration resin) and silica.
`
`The skin care patches of the present invention can optionally further include an irritant
`buffer such as sodium bicarbonate, which is 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 patch is
`advantageously applied to the lower forehead area, an example of which is illustrated in Fig. 2. For
`application beneath and at the outer corners of the eye a generally kidney-shaped patch is used, and
`the shapes for the right and left sides are mirror images of one another. For the nasolabial fold area,
`the patch is shaped substantially like a boomerang, generally kidney-shaped. Skin care patches are
`also provided which fit the back of the hand, optionally with extensions down the fingers. Figures
`
`patches in place.
`
`Detailed Description of the lnventign
`
`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
`photodamaged skin 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), fl-carotene, Vitamin A and Vitamin C (and/or cosmetically
`acceptable salts thereof), and are generically termed cosmetically active ingredients herein.
`‘ A
`preferred tocopherol compound is 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.
`Because of 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 but not limited 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 ointment in that with a patch, application is 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
`
`1012-8
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`WO 96/14822
`
`PCTIUS95I14682
`
`7
`
`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 can also 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 Wu and Van Scott), which is incorporated by
`reference herein, can be incorporated into the adhesive matrices of skin care patches to ameliorate
`
`the unattractive effects of aging, photodamage or oxidative stress.
`in a
`The active antioxidant
`ingredients for cosmetic patch compositions are present
`cosmetically effective amount, preferably from about 1-1000 mg per patch. Ascorbic acid (and/or
`a cosmetically acceptable salt thereof),
`tocopherol, Vitamin A and B-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 beneficial in
`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 not limited to, collagen
`
`synthesis and reactions associated with oxidative stress.
`The permeability enhancer is 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 and its sticking properties.
`Preferred penetration enhancing compounds (also called permeability enhancers) are those
`which are not toxic, not irritating to the skin and not allergenic. Exemplary penetration enhancing
`
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`W0 96/14822
`
`PCT/US95/l4682
`
`8
`
`compounds include 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) J. Controlled Release 2:243),
`
`, ~dialkyl-substituted amino acetates (Wong et
`,
`al. (1989) Pharm. Res. 6:286), detergents and surfactants (Bettley et al. (1965) Br. J. Dermatol.
`flz98),
`lecithins (Mahjour et al.
`(1990) J. Control/ed Release 1_4:243),
`monolaurates (lyer et al. (1985) Abstract 132nd Annual Meeting,
`APHA Acad. Phar. Sci. fl :81)
`glyceryl monolaurates (Cheng et al.,
`U.S. Patent No. 4,746,515,
`issued 1988), pyrrolidone
`derivatives (Sasaki et al. (1991) J. Pharm Sci. @533) and terpenes (
`'
`'
`
`polyethylene glycol
`
`: System Design Considerations,"
`0, respectively.
`A preferred matrix
`y effective amount of an
`-type skin care patch contains a cosmeticall
`antioxidant (Vitamin C or E or B—carotene),
`preferably Vitamin C (and/or a cosmetically acceptable
`salt), and preferably at a concentration of about 2-50% (about 75 mg per square inch), optionally
`with a penetration enhancer present at a concentration of about 1-10% by weight. The preferred
`adhesive is a medical grade silicon polymer adhesive,
`The patch itself is preferably made of silicon,
`acrylate or polyisobutylene type polymeric
`material.
`Preferably the patch is made of a polymeric material which is chemicall
`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
`
`y and biologically
`
`and the matrix should rapidly mold itself 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
`
`1012-10
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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 above this
`
`level, then the adhesive is too aggressive to the skin.
`
`If the adhesion is below this level, then the
`
`patch may fall 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 impermeable film is not permeable to the active ingredientls), but it may
`
`1O
`
`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 ingredientls).
`
`Adhesives, e.g., acrylic adhesives and pressure sensitive adhesives can be rated according
`
`to the Draize Dermal Scoring Code. A score of 0 means there is no erythema or edema after test
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`15
`
`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 > 1mm
`
`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 used in
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`20
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`the skin care patches of the present invention without injuring 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
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`25
`
`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 some loss
`
`of adhesiveness.
`
`The surface of the transdermal or intradermal delivery device which is away from the skin
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`30
`
`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 product of a silicone resin and a silicone fluid and an acrylic polyisobutylene
`lPlB); the pressure sensitive adhesive exhibiting suitable tackiness and adhesiveness for delivery of
`
`35
`
`cosmetically active ingredients to sensitive or delicate skin.
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`1012-11
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`1012-11
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`

`

`W0 96/14822
`
`PCT/US95/l4682
`
`10
`
`The silicone resin may be further described as being a soluble, hydroxyl-functional
`organopolysiloxane resin comprising FlaSiO"2 siloxane units and SiOm, wherein R is selected from
`a monovalent
`radical selected from the group consisting of hydrocarbon and halogenated
`hydrocarbon radicals having 1 to 20 carbon atoms.
`In the RssiO1,2 and Slow nomenclature the 1/2
`and 4/2 represent the number of half bonds on the molecule sho
`wn. For example, in RgSiO”2 there
`is one (1) 1/2 bond which is on the oxygen. The other half of that ban
`other atom. Another way of describing this group is by nasio- or by
`
`d being bonded to some
`
`R l
`
`a-sr-o-
`
`lR
`
`completely, in either a hydrocarbon liquid such as benzene, toluene, xylene, heptane and the like
`or in a silicone liquid such as cyclic or linear polydiorganosiloxanes. Preferably the resin is soluble
`
`in the silicone fluid.
`
`in the formula for the silicone resin, R denotes a monovalent radical selected from the group
`consisting of hydrocarbon and halogenated hydrocarbon radicals, preferably having less than 20
`carbon atoms, and most preferably having from 1
`to 10 carbon atoms. Examples of suitable Fl
`radicals include alkyl radicals, such as methyl, ethyl, propyl, pentyl, octyl, undecyl, octadecyl and
`others; cycloaliphatic radicals, such as cyclohexyl; aryl radicals such as phenyl, tolyl, xylyl, benzyl,
`alpha-methyl styryl, 2-phenylethyl and others; alkenyl radicals such as vinyl;
`hydrocarbon radicals such as 3-chloropropyl, dichlorophenyl and others.
`
`and chlorinated
`
`Preferably, at least one-third, and more preferably substantially all, R radicals in the formula for the
`silicone resin are methyl radicals. Examples of preferred R3Si0 1,2 siloxane units include Measio
`and PhMeZSiOU2 and thMeSiO
`1,, where Me denotes methyl and Ph denotes phenyl.
`It is preferred that the ratio of Basic": siloxane units to srom units has a molar ratio of 0.5
`to 1.2, respectively.
`It is further preferred that the mole ratio of the total Rasio 1/2 siloxane units to
`SiO..,,2 units be between 0.6 and 0.8.
`
`1/2
`
`It is preferably prepared by the
`The silicone resin can be prepared by well known methods.
`silica hydrosol capping process of U.S. Patent No. 2,67,182 (Daudt et al.) as modified by U.S.
`Patent No. 3,627,851 (Brady) and U.S. Patent No. 3,772,247 (Flannigan); each patent being
`
`1012-12
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`1012-12
`
`

`

`W0 96/14822
`
`PCT[0895/14682
`
`11
`
`incorporated herein by reference to teach how to prepare soluble organopolysiloxanes which are
`
`useful in transdermal delivery devices. The resulting resin can be used in the pressure sensitive
`
`adhesive composition without further modification or it can be capped with trialkylsilyl groups to
`
`reduce the silanol content. This can be accomplished by well known methods, such as reacting the
`
`resin with a compound such as trimethylchlorosilane or hexamethyldisilazane.
`
`The silicone fluid is preferably a hydroxyl-terminated diorganopolysiloxane polymer. The
`
`repeat units of the silicone fluid are R,Si02,2 siloxy units wherein R is independently selected from
`the same hydrocarbon and halogenated radicals as defined above for the silicone resin. The silicone
`fluid can be comprised of a single polymer or copolymer or it can be a mixture of two or more such
`polymers. The silicone fluid can be a liquid or gum at 25°C. ItIs preferred that at least 50%, and
`preferably at least 85%, of the organic radicals along the chain of the silicone fluid are methyl
`radicals, which can be distributed in any manner in the silicone fluid. Further, the silicone fluid can
`comprise up to about 10 mole percent of siloxane branching sites, provided it meets the above
`
`10
`
`viscosity requirements.
`
`15
`
`The silicone resin is employed in amount from about 40 to 70 parts by weight in the silicone
`
`pressure sensitive adhesive, and the silicone fluid is employed from about 30 to about 60 parts by
`weight, wherein the total parts of the silicone resin and the silicone fluid are 100 parts.
`It is usually
`preferred that
`the silicone resin be employed from about 50 to 60 parts by weight, and
`correspondingly, the silicone fluid be employed from about 40 to 50 parts by weight, wherein the
`
`total parts by weight equals 100.
`The silicone resin and silicone fluid may be blended together to produce the pressure
`
`sensitive adhesive, or they may be condensed together to produce the pressure sensitive adhesive.
`
`Methods of condensing together the silicone resin and silicone fluid are well known in the art