TWI298253B - Transdermal delivery of lasofoxifene - Google Patents

Description

1298253 Α7 Β7 V. INSTRUCTIONS (1) Cross-Reference of Related Applications This application is based on 3 5 U · S · C · § 1 1 9 ( e ) (please read the notes on the back and fill out this page) It is called the priority of the US Temporary Application No. 60/208,789 (application for the period of June 1, 2000). The contents of this application are hereby incorporated by reference in its entirety. FIELD OF THE INVENTION This invention relates to the transdermal delivery of a compound of lasofoxifene (5 - substituted 6-ring-5,6,7,8-tetrahydronaphthalen-2-ol). BACKGROUND OF THE INVENTION The Ministry of Economic Affairs, the Intellectual Property Office, the Staff Consumer Cooperative, which prints natural estrogens and exhibits "emotional hormone" activity, can be used for a variety of therapeutic purposes, such as oral contraception; soothing menopause symptoms; prevention of potential or habitual abortion; Dysmenorrhea; alleviate dysfunctional uterine bleeding; promote ovarian development; treat acne; reduce excessive growth of hair in women (hirdiness); prevent cardiovascular disease; treat osteoporosis; treat prostate cancer; and inhibit postpartum lactation [Goodman and Gilman, The Pharmacological Basis Of Therapeutics (Seventh Edition) Macmillan Publishing Company, 1985, pages 1 4 21-1423 ]. Therefore, research into new synthetic compositions and the development of new uses of compounds having estrogen stimulating properties (i.e., mimicking the action of estrogen in estrogen-reactive tissues) has continued. The most important point for pharmacists to develop new drugs for the treatment of human diseases and specific conditions is that the paper must be compliant with the Chinese National Standard (CNS) A4 specification (210X297 mm) ~ 1298253 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Print A7 _ B7 V. INSTRUCTIONS (2) Seeking compounds with some estrogen-like functions but no proliferative side effects. For example, the use of fully active estrogen can significantly improve osteoporosis (a disease that makes bones more fragile); however, patients with long-term use of active estrogen will increase the risk of uterine cancer, so clinically Long-term treatment of osteoporosis is not recommended for women with fully active estrogens. Estrogen is a selective agent for preventing osteoporosis in women or post-menopausal bone loss; it is the only treatment that can significantly reduce fractures. However, estrogen stimulates the uterus and increases the risk of endometrial cancer. Although the use of hormonal hormone at the same time reduces the risk of endometrial cancer, it may increase the risk of breast cancer. Estrogen and estrogen-like compounds also lower plasma L D L and increase the content of favorable high-density lipoprotein (H D L ). Black, et al. E P 0 upload 5 1 9 3 A 1. However, long-term treatment with estrogen can involve a variety of conditions, including increasing the potential risk of uterine cancer and breast cancer, causing many women to avoid this treatment. Recently, treatments designed to reduce the risk of cancer, such as the combination of progestogens and estrogens, have resulted in improper bleeding. In addition, the combination of progesterone and estrogen seems to inactivate the effect of estrogen in lowering blood cholesterol. Due to a series of adverse effects on the treatment of estrogen, it is necessary to develop a hypercholesterolemia treatment that has a considerable effect on blood stasis LDL but does not cause undue effects. Lasofoxifene (CP-3) 3 6,1 5 6 ) is a selective estrogen receptor modulator (agonist/antagonist). According to research, its treatment effect on bone and L D L content is similar to that of female (please read the notes on the back and fill out this page)

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丨 I I This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1298253 Μ __________ Β7 _ V. Illustrative (3) diol, but no uterine-stimulation effect related to estradiol therapy. Ke H. Z. (1998) Endocrinology 139(4): 2068-2076 and Roasti, R.L. (1 998) Med. Chem. 4 1 (1 6): 2928-293 1. The results of the study also showed that they could prevent bone loss in ovariectomized rats and postmenopausal women. Zhu Ke, Η. (2000) Endocrinology 1 41 (4): 1 338- 1 344. The latter study also pointed out that lasofoxHene can reduce the total blood cholesterol of women and males and rats, and does not affect the prostate of male rats. Thus, the therapeutic advantages of oral administration of lasofoxifene are established. However, in some cases, oral administration of the drug is not satisfactory. Due to the short half-life of the drug, frequent medications (2 to 4 times a day) result in inadequate patient compliance. Second, the short plasma half-life of the drug and the frequent course of medication can lead to a difference between the "peak period" and the "low tide period" in the plasma concentration distribution, which increases the difference between the absorption peak concentration and the therapeutic effect (end of the drug treatment interval). side effect. Third, metabolism through the liver after oral administration may result in poor bioavailability of the drug. Therefore, there is a need for an effective and consistent drug delivery system that overcomes such shortcomings. Transdermal delivery of drugs has many of the advantages of conventional oral administration. Advantages of the percutaneous system include: convenience, uninterrupted treatment, improved patient compliance, reversible treatment (removal from the skin), removal of "first through the liver" effect, tight control of blood drug concentrations, and improved overall efficacy . DISCLOSURE OF THE INVENTION The present invention provides a transdermal delivery of a 5-substituted-g-cyclo-5,6,7,8-tetrahydronaphthalen-2-ol compound ("Raxephine (this paper scale applies to China) National Standard (CNS) A4 Specification (210X297 mm) (Please read the note on the back and fill out this page) Order Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1292823 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Five , invention (4) lasofoxifene) '' or "CP-3 3 6 , 1 5 δ ′′) and methods, pharmaceutical formulations, and devices thereof for pharmaceutically acceptable salts. The invention also provides dissolution or dispersion A transdermal composition of C Ρ - 3 3 6 , 156 or a salt thereof in a suitable carrier vehicle (including a permeation aid and other excipients as needed). The carrier carrier can be pressure-sensitive adhesive. a carrier, a polymeric reservoir, or a fluid that controls the viscosity thereof. The carrier carrier can be incorporated into a device that allows the composition to adhere to the surface of the skin. The device can be a matrix patch (the drug is contained in a binder) or stored. Body patch (drug contained in a circle) The form of a shaped, built-in, or overlying pressure sensitive adhesive in a liquid or polymeric reservoir. The invention further provides a treatment associated with lasofoxifene and a human estrogen receptor-alpha A method of combining the conditions. For example, the preparation and apparatus of the present invention are applicable to the treatment or prevention of bone loss, obesity, breast cancer, endometrial tissue ectopic formation, cardiovascular disease, and diseases of the prostate. In the description and application of the present invention, the terms used will be defined below. Unless otherwise indicated herein, the singular forms "a", "a", "the" and "the" "A cell" as used herein includes a plurality of cells, including mixtures thereof. "Comprising" herein means that the compositions and methods include the recited elements, but do not exclude other elements. "composition" is used to define the composition and method, and should not exclude anything other than the essential components of the combination. Therefore, the composition is essentially composed of... (Please read the notes on the back and fill out this page.) This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1298253 A7 B7 Ministry of Economic Affairs Intellectual Property Office employees Printed by the Consumer Cooperatives. V. INSTRUCTIONS (5) Component composition, the definition of which will not exclude the separation and purification methods and pharmaceutically acceptable carriers, such as phosphate buffered physiological saline, preservatives, etc. The trace contaminants, which are composed of "..", should exclude other components and the trace elements in the substantial method steps of the compositions of the present invention. Specific embodiments defined by the respective tentative terms are within the scope of the present invention. In this paper, "lasofoxifene" and "CP-3 3 6 ,1 5 6" and "5 -substituted 6-ring-5,6,7,8,tetrahydronaphthalene 2" Alcohol" and its pharmaceutically acceptable salts are synonymous. The preparation of lasofoxifene and its pharmaceutically acceptable salts is disclosed in U.S. Patent No. 5,5,502, the entire disclosure of which is incorporated herein by reference. "Lasofohefene" as used herein means a compound and formulation disclosed in U.S. Patent No. 5,5 5 2, 4 1 . As used herein, "enhancement", "penetration enhancement" or "osmotic enhancement" means increasing the permeability of a biofilm (i.e., skin or mucosa) to a drug to increase the rate of penetration of the drug through the membrane. "Infiltration enhancer", "enhancing agent", "penetration enhancer" or similar term means a material that enhances the penetration, and an "effective amount" of a fortifier is sufficient to effectively enhance the selected agent via the skin or The total amount of fortifier that the mucosa penetrates to a selected degree. Permeation enhancement can be observed using the enhancer, for example using a diffusion chamber device to measure the rate of diffusion of the drug through the skin of the animal or human. The diffusion chamber is described in Memtt et al., Diffusion Apparatus for Skin Penetration, 11 of Controlled Release 61 (19.8), which is incorporated herein by reference in its entirety. (Please read the notes on the back and fill out this page)

, 1T This paper scale applies to China National Standard (CNS) Α4 specification (210X 297 mm) 1298253 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (6) "percutaneous" or "by" "Delivery of the skin refers to the delivery of the drug through and through the tissue of the skin or mucosa. Thus, "transdermal" and "transmucosal" herein may be used interchangeably unless otherwise specified. Similarly, "skin", "dermis", "skin", "mucosa" and the like herein may be used interchangeably unless otherwise specified. By "effective amount" of a drug or penetrant herein is meant a sufficient amount of a compound that is non-toxic but provides the desired local or systemic effect. By &quot;effective amount&quot; of the penetration enhancer herein is meant to provide the desired increased membrane permeation and (correspondingly) the desired penetration depth, rate of administration, and amount of drug selected. By "drug delivery system", "drug/enhancing agent composition" or any similar term herein is meant a modulating composition comprising a transdermally delivered drug and a penetration enhancer. The pharmaceutical/enhancing agent composition may also contain other pharmaceutically acceptable materials or additives, such as diluents, skin desensitizing agents, carriers or carriers, excipients, plasticizers, emollients, or other The additive and the above mixture are limited in that the additive does not substantially affect the basic and novel properties of the matrix patch. By "matrix", "matrix system" or "matrix patch" herein is meant an active penetrant or drug that is dissolved or suspended in a biocompatible polymeric phase, preferably a pressure sensitive adhesive, Other ingredients may be included or may be dissolved or suspended therein. This definition includes examples in which the polymeric phase layer is laminated to a pressure sensitive adhesive or covered with a binder. A typical and preferred matrix system comprises a layer of adhesive having a non-permeable film support layer pressed against the end surface of the adhesive and applied to the proximal end of the adhesive prior to transdermal use (please read the back of the back sheet and fill out this page) This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1298253 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (7) There are release liners on the surface. The film support layer protects the polymeric phase of the matrix patch and prevents the release of the drug and/or enhancer to the periphery. The release liner functions the same as the non-permeable membrane support layer, but can be removed from the matrix patch prior to use of the patch. The matrix patch typically comprises the support layer and release liner composition in a transdermal drug delivery technique, and the matrix patch in accordance with the present invention should comprise the support layer and release liner or equivalent functional composition thereof. The support layer and release liner are described in U.S. Patent No. 5,122,338, the entire disclosure of which is incorporated herein by reference. Thus the matrix system is a single dosage form of the pharmaceutical composition in a polymeric carrier which may also contain a fortifier and other ingredients to maintain the pharmaceutical composition in the polymeric layer in relation to the dermis (ie, the skin or mucosa) in drug transfer. . The matrix patch differs from the "liquid reservoir patch" in that the active penetrant or drug is dissolved in a gelling liquid of an occluding device having a non-permeable back surface and a permeable membrane and adhesive layer on the reverse side. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; By "application site" herein is meant a location suitable for topical application (with or without the use of devices, patches, or dressings), such as behind the ears, on the arms, on the back, on the chest, on the abdomen, on the legs, on the feet, on the feet. Superior. &quot;Composition&quot; as used herein refers to a combination of an active agent with another compound or composition, an inert (e.g., detectable agent or label), or an active compound (e.g., an adjuvant). By a combination of an active agent and an inert or active carrier, the composition is suitable for in vitro, in vivo or in vitro diagnostic or therapeutic use. This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇&gt;&lt;297 mm&quot;&quot;] ----- (please read the notes on the back and fill out this page)

1T 1298253 A7 B7 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed V. Description of the Invention (8) The "pharmaceutically acceptable carrier" herein contains any standard pharmaceutical carrier, such as a phosphate buffered physiological saline solution, Water, and emulsions, such as oil/water or water/oil emulsions, and various types of wetting agents. The composition may also include a stabilizer and a preservative. Carriers, stabilizers, and Zuzi! I can be found in REMINGTON' S PHARM. SCI, 15th Ed. (M ack P ub 1 · C ο ·, E aston (1 9 7 5) ” "Patient" It refers to a vertebrate, preferably a mammal, and more preferably a human. Mammals include, but are not limited to, murine animals, monkeys, humans, domestic animals, sport animals, and pets. A clinical manifestation that alleviates symptoms or modifies a disease or condition. "Prophylaxis" as used herein refers to delaying or reducing the signs or clinical manifestations of a disease or condition. For the purposes of the present invention, the present invention is suitable for the treatment of estrogen receptors. A disease or condition associated with its natural ligand, including but not limited to: obesity, breast cancer, osteoporosis, ectopic endometrial tissue formation, cardiovascular disease, prostate disease, ovulation, and blood cholesterol levels, In particular, the content of bloody LDL. In its most basic form, the present invention provides an effective amount of lasofohfene and/or a pharmaceutically acceptable salt thereof. The storage means is a transdermal formulation. In another embodiment, the formulation may optionally comprise an effective amount of a drug permeation enhancer and/or a compound that disrupts the cell envelope. Examples of cell envelope disrupting agents include (but not Limited to: isopropyl myristate, methyl laurate, oleic acid, oleic acid alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glyceryl monostearate, glycerol monolauric Acid ester, propylene glycol monolaurate or sorbitan ester. Reference (please read the back note first and then fill out this page) This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1298253 A7 B7 V. INSTRUCTIONS (9) (Please read the notes on the back and then fill out this page.) See U.S. Patent No. 5,6 2 6,8 6 6 and the full text is hereby incorporated by reference. Examples of perfuming agents that contain one or more skin permeation agents, such as triacetin, which may be used without limitation, include: saturated and unsaturated fatty acids and their esters, alcohols, monoglycerides Acetate, Ethanol decylamine and N,N-dimethyl decylamine, for example: oleic acid, propyl oleate, isopropyl myristate, glycerol monooleate, glycerol monolaurate, methyl laurate, lauryl Alcohol, laurylamine diethanolamine, and combinations thereof. Saturated and unsaturated sorbitan esters such as sorbitan monooleate and sorbitan monolaurate may also be used. In one of the printed characteristics of the property bureau employee consumption cooperative, the drug storage body is an aqueous or solvent-based adhesive matrix. The adhesive matrix can be pressure-sensitive for long-term contact with the skin. The physical properties of the adhesive must be It is compatible with lasofoxifene, a reinforcing agent added as needed, and any carrier and/or carrier or other additive added to the drug/enhancer composition. Adhesives suitable for matrix patches include: acrylic adhesives containing crosslinked and non-crosslinked acrylic copolymers; vinyl acetate adhesives; comprising polyisobutylene, neoprene, polybutadiene, and Natural and synthetic rubbers of polyisoprene; ethylene vinyl acetate copolymer; polyoxyalkylene; polyacrylate; polyurethane; plasticity weight polyether block phthalamide copolymer, and plasticized benzene Ethylene-rubber block copolymer. Suitable pressure sensitive adhesives include polyoxyalkylene oxides, polyacrylates, polyisobutylene, and the like. Such pressure sensitive adhesive polymers are very hydrophobic and are typically sold in the form of polymer solutions which are soluble in organic solvents. Drugs and selection -12- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1298253 A7 B7 V. Invention description (10) (Please read the note on the back and fill in this page) The agent (if present) can be directly added to the organic solvent-based pressure-sensitive adhesive solution, mixed and cast to form a film, and the solvent is evaporated to dryness to produce a dry adhesive matrix film containing the drug and the excipient. This is a known technique in which the drug must be a water-repellent drug incorporating an organic solvent-based, water-repellent binder. In general, a drug in the form of a hydrophilic salt is not compatible with the organic solvent-based pressure-sensitive adhesive, so it must be converted into a free-acid free acid or free-base form to break into an organic solvent-based, water-repellent bond. In the agent. Aqueous pressure sensitive adhesives are also commercially available. Such aqueous binders can be formulated into emulsions in which a water-repellent pressure-sensitive adhesive polymer is dispersed in water with the aid of a surfactant. Since the carrier is water rather than an organic solvent, the aqueous binder provides the safety advantage and environmental problems of the low solvent pressure sensitive adhesive. Water-based adhesives are widely used in the manufacture of medical tapes and bandages and provide excellent skin adhesion. US Patent No. 5,9 8 5,3 1 7 ; 5,783,208; 5,78 0,050; Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives 5,6 2 6,8 6 6 ; 5,4 6 0,8 2 0 and 4,9 8 3 ,3 9 5 describe various polymeric transdermal matrix formulations. The entire disclosure of such patents is hereby incorporated by reference in its entirety in its entirety in its entirety in its entirety in its entirety In addition, liquid drug reservoirs are described in U.S. Patent Nos. 5,662,925; 4,829,224 or 4,9, 3, 3, 5, the entire disclosure of which is incorporated herein by reference. Another specific embodiment known in the art is described in the US Patent Standard Paper Standard for China National Standard (CNS) A4 Specification (210X 297 mm) 1298253 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printing 5, Invention Description (11) 4,829,224; 4,849 '224 and 4,9 8 3,3 9 5, the entire disclosure of which is incorporated herein by reference. The matrix patch may further contain various additives in addition to the polymer layer which is a basic component of the transdermal drug system and which is added with a reinforcing agent as needed. In general, such additives are pharmaceutically acceptable ingredients known in the art of drug delivery, and more specifically, the limitations of the additive ingredients in transdermal delivery techniques are such that the material does not alter the matrix patch. Basic and novel features. For example, suitable diluents may include: mineral oils, low molecular weight polymers, plasticizers, and the like. Many transdermal drug delivery formulations cause skin irritation after prolonged contact with the skin, so the addition of a skin desensitizer helps to improve the skin's resistance to the composition. A preferred skin desensitizing agent is glycerin, U.S. Patent No. 4,85,5, 094, the entire disclosure of which is incorporated herein by reference. However, it is noted that the present invention does not require other so-called acceleration enhancers or penetration enhancer compositions such as solvents and compounds that destroy cell envelopes. Drug reservoirs containing lasofoxifene can be embedded in various types of configurations known in the art of transdermal drug delivery. For example, the drug reservoir (the most important component of the device) may be a simple matrix containing a saturated solution of lasofoxifene in the carrier, or may be impregnated with lasofohfene in the carrier. The fibrous form of the saturated solution. In addition to the reservoir, the device includes means for maintaining communication between the reservoir and the skin during drug delivery. The member includes a carrier (also a binder), a separate base adhesive layer under the storage body, and a sticky joint with the storage body (please read the back of the weeping matter first.) The paper size is applicable to the Chinese national standard (CNS) A4 size (21〇X 297 mm) 714 · 1298253 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (12) mixture ring, adhesive for covering the storage body, and belt. Preferably, the member is a binder carrier or a separate layer of adhesive underneath. Preferably, the device is in the form of a laminated composite. Such devices can be made using techniques known in the art of transdermal drug delivery devices. For example, drugs and carriers are available. The desired ratios are mixed to form a homogeneous mixture and cast or applied to the support layer, followed by lamination on the release liner layer. If a separate base adhesive layer is to be formed, it can be cast on the release liner prior to the lamination. On the layer, the polymer layer of the matrix patch may contain an end support layer when used. The end support layer serves as a matrix patch facing the outside (ie, non-skin or sticky) The side of the film. The support layer functions to protect the matrix polymer layer and the drug/enhancer composition and acts as a non-penetrating layer to prevent drug loss to the outside world. Therefore, the support layer material selected should be polymerized. The layer, the drug and the reinforcing agent are compatible, and the permeability of any composition on the substrate patch is allowed to be extremely small. Advantageously, the support layer is preferably an opaque layer to prevent degradation of the protective substrate patch composition by ultraviolet light. The support layer should be capable of bonding and supporting the polymer layer' but still be compatible with the activities of the substrate patch user. Suitable materials for the support layer include: metal foil, metallized poly foil, and polyester (eg, terephthalic acid) Composite foil or film of polyester), polyester or alumized polyester, polytetrafluoroethylene, polyether block decylamine copolymer, polyethylene methyl methacrylate block copolymer, polyfee, polyethylene fine base Chlorine, nylon, polyxide elastomer, rubbery polyisobutylene, styrene, styrene-butadiene and styrene isoprene copolymer, polyethylene, and polypropylene. Thickness about 〇· 0 〇〇 5 to 0 · 0 1 inch is better. The release liner can be made of the same material as the support layer (please read the note on the back side and fill out this page), 1Τ Ρ This paper size applies to the Chinese National Standard (CNS) Α4 specification (210χ;297 1298253 A7 B7 Ministry of Economic Affairs, Smart Finance-1 Bureau, Staff Consumer Cooperatives, Printing, Inventions (13) or other suitable film coated with a suitable release surface. The drug storage system is applied to the application site and The drug is spread through the dermis. The present invention also provides a drug reservoir (described herein) and a member for bonding the reservoir to the site of application. Examples of the device are as described above, including a drug-containing adhesive matrix, a support layer. And release liners. See also U.S. Patent Nos. 5,164,190 and 5,985,317. For example, the device includes a laminate composite support layer as the upper end portion of the storage body and extending to the periphery of a stripping sealing disk; the film for the active agent to penetrate extends to the periphery of the stripping sealing disk And the support layer, and under the support layer, the support layer and the film are here; the intervening between them is - the storage body containing the formulation of the invention; the film for the penetration of the active agent has a stripping seal circle The heat sealing ring is located on the periphery of the stripping sealing disc, the film for the active agent to penetrate and the support layer; the adhesive covering layer covers the support layer at the center, and the entire stripping type is covered by the peripheral part. Sealing the outer edge of the disc; a removable release liner at the periphery of the adhesive layer and under the stripping seal disc. The above pharmaceutical formulations, drug reservoirs and devices are suitable for use in contact with a patient's site of administration for the treatment or prevention of a patient associated with an estrogen disorder. The present invention further provides for the use of an effective amount of rasofefene (lasof〇5ufene) A transdermal agent is prepared to treat or prevent a condition associated with a disorder of estrogen. Experimental method (please read the note on the back and then fill out this page) This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm): 16- 1298253 A7 __B7_______ V. Description of invention (14) Adhesive matrix preparation (Please read the notes on the back and fill out this page.) The Ministry of Economic Affairs, Intellectual Property Office, and the Consumer Cooperatives Printed Pressure Sensitive Adhesive Matrix System is prepared according to the teachings of US Patent No. 5, 9 52,000. references. First, the solid content in the binder solution (aqueous or organic solvent) was measured by placing a known weight of the solution on a weighing aluminum pan' and evaporating the solvent overnight in a convection oven at 70 °C. When calculating the amount of solid binder in the solution, the solid weight of the binder after drying is divided by the initial total weight of the solution. A weighed binder solution is then added to the glass vial and the weighed drug substance, penetration enhancer & other excipients are added to the binder solution to achieve the desired dry matrix film composition. The solution containing the binder polymer, drug substance, and other excipients is then mixed overnight. After stirring, about 8 ml of the solution was poured onto the decadiated polyester release liner and cast into a film having a final dry thickness of about 〇 5 mm using a casting tool of appropriate pore size. The cast film was dried in a 70 ° C convection oven until all the solvent had evaporated to dryness to give a dry matrix (organic solvent adhesive for 15 minutes, water emulsion adhesive for 30 minutes). Finally, a 0. 08 mm thick occlusive polyethylene support film was laminated to a dry bonded substrate and the in vivo skin flux experiments described below were performed using such a system. Storage body or free-form hydroalcoholic gel preparation The following hydroalcoholic gel of 10 ml size was prepared. Mix the appropriate proportion of ethanol (190 °C ethanol), water, glycerin, fortifier, and drug for several hours. Adding gelling agent (hydroxypropyl cellulose) and applying Chinese National Standard (CNS) A4 specification (210X297 mm) on high shear paper scale -17 - 1298253 A7 Ministry of Economic Affairs Intellectual Property Bureau employee fee cooperative cooperative printing 5 DESCRIPTION OF THE INVENTION (15) A brief mixed solution under force is then mixed with low shear until the gel is formed. Skin flux studies In vitro skin flux studies were performed using a human cadaveric epithelial membrane in a modified Franz hoodless diffusion chamber. The epidermis (striatum and epidermis) was separated from the entire skin (epidermal and dermal) using Kligman and Christopher (Arch. Dermatol 88: 702 (1 963)). This method involves exposing the full thickness of the skin to 60 ° C for 60 seconds. After that, the epidermal membrane was gently peeled off from the dermis and stored in a box at 5 t for later use. Prior to the infiltration test of the matrix system, the matrix system was cut into round samples of 0 · 7 cm 2 and the sandalized release liner was removed. The adhesive is attached to the stratum corneum side of the thawed epidermis, then cut to size and sandwiched between the two halves of the diffusion chamber, with the stratum corneum facing the supply zone. Water or a suitable aqueous solution is placed in the receiving zone to maintain the drug in an immersion condition. All receiving solutions contained 0 · 〇 2 % (w / w) sodium azide. (, N a N 3 ) to inhibit bacterial growth. The diffusion chamber was placed in a temperature controlled circulating water bath to maintain a skin surface temperature of 32 °C. The receiving zone is continuously agitated with a stir bar (located in the receiving zone driven by a magnetic stirring assembly in a magnetic water bath). The hydroalcoholic gel permeation experiment was performed using a small occlusion dose. Such occlusive doses are suitable as an in vitro mode for administration of a transdermal patch delivery system containing a liquid or gel reservoir. The occlusion dose experiment was based on the following steps. In the skin penetration test (please read the note on the back and then fill in the page) This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1298253 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed five Prior to the invention (16), the epidermal membrane was first cut into an appropriate size and placed between the two semi-diffusion chambers so that the epidermis faced the receiving zone. Water or a suitable aqueous solution was placed in the receiving zone, and then the diffusion chamber was placed. The skin surface temperature was maintained at 32 ° C (corrected) in a temperature controlled circulating water bath and allowed to absorb water overnight. After water absorption, the gel sample (7 5 mu · 1 ) was moved to the surface of the stratum corneum. A cavity created by a polyethylene gasket. The cavity is covered with a occlusive support layer film and clamped. The aqueous solution penetration test uses a presaturated drug solution containing an excess (maximum dose) of solid drug. Before the skin penetration test, The epidermis was first allowed to absorb water overnight as described above. After the water was absorbed, the fully mixed aqueous sample solution (1 ml) was transferred to the surface of the stratum corneum by the cover glass. The supply area is formed. The coverslip is then sealed with a polypropylene cap lined with Teflon® RT®. The following sampling procedure is used for all dosage forms. All within the receiving area are collected at predetermined sampling time points. The contents are dosed for drug dosing, fresh solution is placed in the receiving zone, and any air at the skin/solution interface is carefully removed. The cumulative amount of osmotic drug in the unit area at any time is obtained. The following examples are intended to illustrate rather than limit the present Invention Example 1 A solvent-based acrylic pressure-sensitive adhesive (TSR 58; Sekisui Chemical Co., Sakamoto Osaka, Japan), glycerin triacetate (Eastman '), and CP - 336,156 were used. Prepare a percutaneous matrix formulation at /6% w /w. Use this matrix formulation (please read the back note first and then fill out this page) This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 PCT) 1298253 _ B7 V. INSTRUCTIONS (17) The results of the in vitro skin flux experiment are summarized in Table 1. Table 1 The number of skin-derived diffusion chambers average daily CP-336,156 flux during 7 days, ll g/cm 2/day skin 1 A 7 5.5±3.4 Skin 1B 4 5.7±0.8 Skin 1C 8 9.2±2.9 Skin 1D 4 13.4±7.8 Skin 1E 4 10·2±3·4 Skin 1F 4 5.1+1.1 Skin 1G 4 1 1.4 ± 2.4 All skin average 値: tSEM 8.6 ± 1.2 The results shown in Table 1 show that CP-3 3 6,1 5 6 can be added to the matrix patch containing triacetin as a skin penetration enhancer. Transdermal delivery of C P — 3 3 6,1 5 6 with this formulation can be maintained for at least 7 days. (Please read the precautions on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumers Co., Ltd. Printed Example 2 Using water-based acrylic acid with a concentration of 3% w/w CP - 3 3 6 , 1 5 6 tartrate Transdermal matrix formulations were prepared using a sensitive adhesive (Morstik 214, Morton, Greenville, SC). Use 3% w/w CP — 336,156 tartrate and 1.5 % w / w sodium lauryl glycolate in the same adhesive (RITA Corporation, this paper scale applies Chinese National Standard (CNS) A4 specification (210/: 297 mm) 1298253 A7 __ V. Description of the Invention (18) Woodtock, IL) Preparation of formulations for enhanced permeability. The results of in vitro skin flux experiments using such matrix agents are summarized in Table 2.

Table 2 The number of skin-derived diffusion chambers accumulates the permeation amount of CP-336,1 56 within 24 hours, microgram/cm 2/24 hour enhancement coefficient Q24 enhancement/Q24 unfortified unfortified enhancement 1.5% w/w NaLG skin 5 0.1310. 09 0.30±0.12 2.28 2A 5 2.70±1.08 3.5110.93 1.30 5 0.15±0.09 0·46±0·16 3.06 All skin average 値0.99±0.85 1.42±1·05 2.2110.51 Soil SEM The results of Table 2 show the bonding C. .P - . 3 3 6 , 156 salts may be added to the matrix patch. The average enhancement factor is 2 · 2, indicating that an effective amount of penetration enhancer can also be added to such matrix systems. (Please read the note on the back and then fill out this page.) Clothing · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Example 3 Use ratio is 5 0 / 1 5 / 3 0 / 2 · 5 / 2 · 5 of 113 ? Alcohol (£1〇, water (H2〇), glycerol (Gly), glycerol monooleate (G Μ〇), and methyl laurate (ML) solvent composition prepared into a percutaneous liquid storage The mixture is a solution of sputum. Add C Ρ - 3 3 6 , 165 tartrate, the concentration is --- This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1298253 A7 B7 V. Inventive Note (19) 2 mg/ml, formulated. Gelatinized with 30 mg/g hydroxypropylmethylcellulose (Methocel® E10M, Dow Chemical). Use this formulation for in vitro skin. The results of the flux experiments are summarized in Table 3. Table 3 Number of skin-derived diffusion chambers Average daily CP-336,1 56 flux during 7 days, micrograms/cm 2/day skin 3A 8 17417.7 Skin 3B 4 15.3±8.7 Skin 3C 8 23.9±11.0 Skin 3D 4 27.9±2.2 Skin 3E 4 21.2±9·9 Skin 3F 4 15·4±7·2 Skin Skin 3G 4 30·3±4·9 All skin average 値+SEM 21·6±2·3 (Please read the notes on the back and fill out this page)

1T The Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed on Table 3 shows that CP-3 3 6,1 5. 6 salt can be added to the liquid storage patch containing lower alkanol and skin penetration enhancer. class. Transdermal delivery of C P - 3 3 6,1 5 6 with this formulation can be maintained for at least 7 days. Example 4 USP Alcohol (E t 0 Η ), water (Η 2 〇), glycerol (G 1 y ), glycerol monooleic acid in a ratio of 3 0 / 3 8 / 3 0 / 1 / 1 % v / v Ester (G Μ 0 ), and lauryl alcohol (LA ) solvent This paper scale applies to China National Standard (CNS) Α 4 specifications (210X297 mm) 1298253 kl — ____B7 V. Description of invention (20) Composition preparation Transdermal liquid reservoir formulation. This mixture is a hazy two-phase dispersion. Add c P — 3 3 6 , 1 5 6 tartrate at a concentration of 6 mg/ml, and mix the formulation with 30 mg/g of water-repellent modified ethylcellulose (Natrosol® Plus 3 30CS, Aqualon) to make the gel The results of in vitro skin flux experiments using this liquid reservoir formulation are summarized in Table 4. (Please read the notes on the back and fill out this page.) Table 4 Number of skin source diffusion chambers average daily CP-336, 1 56 flux, micrograms/cm 2 / day - skin 4Α 5 42.4±15.5 skin during 6 days 4Β 5 3 6 · 3 ± 5.2 Skin 4C 5 36.2±14,9 All skin average 値±SEM 38·3±3·3 The results in Table 4 show that the liquid storage preparation of the two-phase dispersion can be used for transdermal delivery of CP- 336, 156. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Example 5 Using solvent composition USP alcohol (E t〇Η ), isopropanol (ΙΡΑ), water (Η2〇), glycerin (Gly) 26.25/ 8 · 7 5 / A percutaneous liquid reservoir preparation was prepared at 3 5 / 30% v / v. Glycerol monooleate was prepared using a concentration of 0.03 %, 〇.0 6 %, and 0 · 1 2 % v / v to form an osmotic strength-enhancing preparation, and the amount of water was reduced to make up the added enhancer. 0 %, 0 · 〇3 %, and 〇· 〇 6 % ^^ Long scale applies to China National Standard (CNS) A4 specification (210 X297^^ 1298253 A7 B7 V. Invention description (21) G Μ〇 preparation is Cheng Yu Solution, while 0 · 1 2 % G Μ ◦ formulation is a misty dispersion. Add C Ρ - 3 3 6,1 5 6 tartrate at a concentration of 6 mg / ml, preparation with 30 mg / gram of hydroxypropyl Methylcellulose (Methocel® EIOM, Dow Chemical) gelled. The results of in vitro skin flux experiments using these formulations are summarized in Table 5. (Please read the notes on the back and fill out this page) Intellectual Property Office Staff Consumer Cooperative Printed - 24 - This paper scale applies to China National Standard (CNS) A4 Specification (210X297 mm) 1298253 A7 B7 V. Invention Description ( 22 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print

S漱0.12%GMO 2.62 4.89 2.03 3.18±.36 ίΓ ^ q gff i|ifl Φ Step _ g Ning back i }K m ^ 5Γ 16.8±2.1 85.2 Soil 13.0 23.6+5.3 1 41.8 Soil 21·8 1 0.06% GMO m oq 4.30 fSl r—Η 2.62+0.43 I I ^ , h ^ ffl Φ ά ά π basket back to H&lt;Xiong I ordered 刼11.6±4.2 :-1 74.9 soil 12.8 20.3+5.4 1 35.6+19.8 丨一I 0.03% GM〇W csi τ H i—&lt; 3.99 &lt;r) Ο) τ—Η 2.34+0.37 11 . 1 fe §, step on the medicine plate. Wine cellar &lt; Μ ^ 5? 7.1±1.8 1 69.5 Soil 23.8 1 22.4+ 3.5 ! _=:_;_I 1 33.0+18.8 ! Unenhanced 0%GM〇ft *1 ϋ m 刼宁% m® csi wi* 霖~::i H&lt; Φ 5Γ .ί 句 If 6.4+2.3 17.4 Soil 26.4 11.6 Soil 4.4 11.8 Soil 3.2 Skin source skin 5A Skin 5B Skin 5C All skin _ Lai 0 job % ί ^ ^ 藤朝^缌张 \ ¥熙0谢驭降忉松区||^缌=镓筚^馔卩3 ·©嵌依逝\ _ 谥iiLOlcxl卩C (Please read the notes on the back and fill out this page)

, 1T This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1298253 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 _____B7 _ V. Invention description (23) The results of Table 5 show low content Even a very small amount of glycerol monooleate (0 · 0 3 % v / v ) can be added to the cartanol liquid storage vehicle carrier, which can substantially increase the transdermal rate of CP - 3 3 6,1 5 6 the amount. Such results also show an approximately proportional enhanced penetration at a concentration of glycerol monooleate from 0. 03% to 0.12%. Example 6 Solvent composition E t〇H / IPA / G 1 y / G Μ〇 26 · 2 5/ 8 · 7 5/ 34 · 94% / 30 . 00% / Ο · Ο 6 % % v / v A transdermal liquid reservoir preparation is prepared. 6 mg/ml of C P 3 3 6,1 5 6 tartrate was added, and the formulation was gelled with 30 mg/g hydroxypropylmethylcellulose (Methocel® ElOM, Dow Chenncal). The liquid reservoir patch (3. active area of 2 cm) was prepared as described above and the initial dermal hypersensitivity of the white rabbit was tested. Six rabbits were each affixed with an active patch (3 cm 2 active area). After 2-4 hours, the patch was removed, and after removing the patch for 1 and 72 hours, the erythema and the ice on the site were counted. The erythema and edema scores counted 1 and 72 hours after removal were then averaged to obtain a preliminary dermal hypersensitivity index (P D I ). P D I値 is 0 · 3, and this widely accepted animal model classifies this formulation as an unrecognizable irritant. The foregoing discussion and examples are merely illustrative of the subject art. A person skilled in the art can make various modifications without departing from the spirit and scope of the invention. - This paper size applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) (please read the notes on the back and fill out this page).

Claims (1)

1298253 ..................—^—一— Annex 2A: Patent Application No. 9 1 1 006 1 1 v. .., λ·- -.. .......•,..厂............. 丨&quot;I:彳^^文Application for replacement of patent scope - ·-........ .........- Amendment to the following day of March 1997. 1. A transdermal drug delivery device comprising: a drug reservoir; an effective amount of lasofoxifene or a pharmaceutically acceptable substance thereof An acceptable salt; and an effective amount of a drug penetration enhancer, wherein the drug penetration enhancer comprises an effective amount of a lower alkanol having from 1 to 6 carbon atoms and an effective amount of a glycerol monooleate. 2. The transdermal drug delivery device of claim 1, wherein the drug reservoir is a bonded drug matrix reservoir. 3. The transdermal drug delivery device of claim 2, wherein the adhesive matrix is a solvent-based pressure-sensitive adhesive matrix. 4. The transdermal drug delivery device of claim 2, wherein the adhesive matrix is an aqueous pressure sensitive adhesive matrix. 5. The transdermal drug delivery device of claim 1, wherein the drug reservoir is a liquid reservoir drug reservoir. 6. The transdermal drug delivery device of claim 1, wherein the effective amount of glycerol monooleate is greater than or equal to 0.01 °/〇 w/w. 7. The transdermal drug delivery device of claim 1, wherein the drug reservoir is a free form hydroalcoholic gel. 1298253 8 - A transdermal device comprising the transdermal drug delivery device of any one of claims 1 to 7 and a member for bonding the drug reservoir to the site of application. 9. A device for applying an active agent to an individual's skin or mucosa comprising a laminated composite material: a) a support layer 'which defines an upper portion of a reservoir and extends to a stripping type a periphery of the sealing disk; b) a film that is permeable to the active agent, extending to the periphery of the stripping sealing disk and the support layer, and below the support layer, the support layer and the film defining e) a storage body therebetween, comprising the drug delivery device of any one of claims 1 to 7; d) the stripping sealing disk, which is located below the membrane through which the active agent can penetrate; e) in the stripping sealing disc, the membrane permeable to the active agent, and a heating seal around the support layer; f) an adhesive covering layer having a central portion covering the support layer And a peripheral portion extending beyond the periphery of the stripping sealing disc; and g) a removable release liner positioned adjacent the peripheral portion of the adhesive cover layer and the stripping sealing disc . A transdermal drug delivery device according to any one of claims 1 to 7, which is a method for treating a human or an animal. -2- 1298253. The transdermal drug delivery device of any one of claims 1 to 7 for use in the treatment or prevention of a condition associated with a female # deficiency or disorder in a human or animal. 12. The use of an effective amount of lasofoxifene or a pharmaceutically acceptable salt thereof and an effective amount of a drug penetration enhancer, wherein the drug penetration enhancer comprises an effective amount of from 1 to 6 carbon atoms The lower alkanol is an effective amount of glycerol monooleate for use in the preparation of a transdermal drug for the treatment or prevention of a condition associated with estrogen deficiency. 13. The use of an effective amount of lasofoxifene or a pharmaceutically acceptable salt thereof and an effective amount of a drug penetration enhancer, wherein the drug penetration enhancer comprises an effective amount of from 1 to 6 carbon atoms The lower alkanol and an effective amount of glycerol monooleate are used in the preparation of a transdermal drug for treating or preventing a condition associated with estrogen deficiency at the dermal site. -3-