TW316846B - A styrene-isoprene-styrene copolymer-based transdermal matrix system for the administration of an oestrogen and/or a progestogen - Google Patents

Abstract

This invention is concerned with a new transdermal matrix system for the percutaneous administration of a hormone, the matrix system, which has support and a self-adhesive matrix, comprising a matrix containing: (a) 20 to 42 parts by weight of a poly (styrene-isoprene-styrene) triblock copolymer, (b) 35 to 55 parts by weight of a tackifying resin, (c) 5 to 25 parts by weight of a plasticizing agent selected from the group consisting of oleic alcohol, peglicol 5-oleate, propyleneglycol laurate or a polypropoxyl ether of cetyl alcohol, (d) 5 to 15 parts by weight of at least one compound selected from the group consisting of: - crotamiton, and - N-substituted 2-pyrrolidones of formula I, (see figure I) in which R represents a (C1-C15)-alkyl, cyclohexyl or 2- hydroxyethyl group, (e) 0.01 to 1 part by weight of a stabilizing agent and, (f) 0.1 to 5 parts by weight of a hormone selected from the group consisting of oestrogen components, progestogen components and mixtures thereof. It also relates to a method for prepararing the system.

Description

316 S 46 A7 B7 Fifth, the description of the invention (1) No picture A general-purpose base based on styrene-isoprene-styrene co-polymer as a substrate for the administration of estrogen and / or progesterone Material field of invention: 5 The subject of this invention is a long-term release of estrogen and, or progesterone, a new element or pervasive substrate, the aforementioned element has a carrier of self-adhesive substrate, and This self-adhesive base material is composed of poly (styrene, isoprene, styrene) interpolymer copolymer (abbreviated as SIS), and the aforementioned estrogen and / or progestin components, together with The plasticizer / accelerator is dissolved together. 10 In this substrate, the invention also includes a method of manufacturing the aforementioned substrate. Prior art: A number of skin-permeable substrates for the release of estrogen and / or progesterone have been proposed, including the so-called " storage " system recently (it is to dissolve the active ingredient in a solvent, via Porous membrane moved to Pi Yong). The seed components are sold by Ciba Yijia 15 Ji Company (i) 1 7 — / 3 —estrogen (registrant name: ESTRADERM® TTS) and (ii) 1 7 — -estrogen combined with Nuoz Sterone acetate (registered trade name ESTRAGEST®TTS). The viscous substrate printed by the Peking Consumer Cooperative of the Ministry of Economic Affairs of the Ministry of Economic Affairs and dissolving or dispersing the active ingredients is made of ethylene-ethyl acetate copolymer and acrylic polymer, (styrene-one It is composed of high molecular materials such as 20-diamine-styrene) copolymer. In order to obtain the final product with therapeutic effect, the most important thing for the Soso system is that after a long period of time, the effective ingredient still maintains the degree of administration, so that the plasma maintains the degree required for curative effect. In addition, in order to make the patient acceptable, it needs to be reduced in size and has appropriate viscosity, so as to avoid the use of the base material due to deformation and damage 83. 3.10,000 (please read the precautions on the back before filling this page) This paper The standard is applicable to the Chinese National Standard (CNS) A4 specification (210X297mm) 316846 A7 B7 V. Description of the invention (2) Clothing. However, in known products of estrogen and / or progesterone (〇 There is only a slight solubility of the polymer constituting the susceptible substrate, and (ii) there is difficulty in penetrating the skin. 5 Therefore, with the original Compared with the suspension of the active ingredients of skin-penetrating components, the release amount to achieve the expected therapeutic effect is usually lower and the release rate is lower, so it is necessary to use a hormone that is much larger than the actual consumption. In this situation, it is difficult There is a compromise between the efficiency of transmissible administration and the physical properties of the system. 10 Although, there are many known formulas based on SIS copolymers, such as ΕΡ-A-0 439 180, ΕΡ-Α- 0 285 181 or ΕΡ-Α-0 483 370, but there has never been a report showing or suggesting a specific formulation like the present invention. Object of the invention: In the field of the translucent administration of estrogen and / or progestin, it will be Expectation 15 There is a new technology solution based on SIS copolymer as a base material, so that the above-mentioned shortcomings and good release rate can be a compromise solution. The first key point is to make SIS materials transparent Base material for the administration of estrogen and / or progesterone. The second main point is to propose a method for preparing such a system. 20 Subject of the invention: For the purposes mentioned above, M SIS materials and plasticizers can be used 、 Promoters made of new estrogen and / or progesterone base materials to achieve new technology methods. As with the same new industrial products, the present invention first provides a skin-transparent base material system with hormone therapy ， This base material consists of a set of 艚 and a 83.3.10,000 (please read the $ item on the back and then fill in this page) The paper size adopts the Chinese National Standard (CNS) A4 specification (210X297mm) (Gang) 316846 A7 A7 B7 V. Description of the invention (3) The self-adhesive base material is composed of the following specifications: (a) 20 ~ 42wt% poly (phenyl ethyl sulfide-isopentyl bis-diphenyl phenyl ethyl sulfide) inter-group Copolymer, (b) 35 ~ 55wt% viscous resin, 5 (c) 5 ~ 25wt; «Plasticizers, including oleaginous, 5-oleic acid monopigrel ester, dodecyl propionate or Hexadecanol polypropoxy ether, (d) 5 ~ 15wt ^ of the following substances (at least one): --Crotacetam, and N —Substituent 2 — Slightly burn the heir (as in formula I)

R 10 (I) where R represents Cl ~ C15 halide, o-hexyl, or 2-ethoxy group, (e) 0.01 ~ lwt: a stabilizer, and (f) 0.1 ~ 5wt5K of estrogen, pregnant Hormones are mixed with 15 hormones. Secondly mentioned is the method of preparing the aforementioned base material system, the process of which is as follows: Printed by the Ministry of Economic Affairs Central Bureau of Standards and Labor under the Consumer Cooperative («) At a temperature above 110t, mix SIS polymer, stabilizer and Stick β oligomeric resin to make it uniform. 20 (/ 3) Add plasticizer and accelerator at a temperature of 80 ~ 110TC, and mix evenly. (7) Add estrogen containing ingredients, pregnancy? &Amp;; Hormones of the elemental ingredients and the mixture of the two, and mix the sentence, (5) between 80 ~ 130 ", apply the above sentence sentence mixture to a temporary 83. 3.10,000 (please read the notes on the back first (Fill in this page again) This paper size is applicable to China National Standard (CNS) Α4 specification (210X297mm) f) Printed by the Ministry of Economic Affairs Central Bureau of Accreditation Consumer Cooperative A7 B7_ V. Invention description (4) Non-stick Form a 50 to 300g / m2 coating on a solid carrier, and (e) transfer the coating to the final carrier. Or («) mix SIS polymer, stabilizer and adhesive in SIS polymerization 5 solvents, at a temperature below the boiling point of the solvent, so that the mixing is uniform; (/ 3) Add plastic Agents and accelerators, and mix evenly, (〇0 add hormones selected from estrogen-like ingredients, progesterone-like ingredients and mixtures of the two, mix evenly, (S) at room temperature, apply this uniform mixture in Form a 50 to 300 s / m2 coating film on the non-sticky carrier 10 with a cut-off time, and (e) heat the above coating film to a temperature higher than the boiling point of the solvent to volatilize the solvent, and then transfer the coating film to the final carrier Legend: In the attached drawings, Figures 1 and 5 show the release amount Q (in units of ws / cm2) of the function 7 (in hours) of 1 7-point one-fermentation with respect to time 15. Figures 2 to 4 and 6 show the release rate R (in%) of 17 — / S—estrogen or Norstrom_acetate (abbreviated as NETA) with respect to time function 1: (M hours) The unit is more detailed explanation as follows: 20 circle 1, providing curve 4 (the product of Example 4 of the present invention) and curve A (comparison product, CP4)-comparison of the release amount of estrogen (Q / t Shitong); Circle 2 is curves 10, 11, 12 (relative to the products of Examples 10, 11, and 12 of the present invention) and E2 (sold by Ciba Yijiaji Company, registrar name) -ESTRAGEST% scoop skin-penetrating product), 17 — / 3—estrogen release rate is more suitable for this paper than the Chinese National Standard (CNS) Α4 specification (210X297mm) c 7) 83.3.10,000 --- ------- For installation ------ Subscribe I (please read the precautions on the back before filling in this page) _ Printed by Beigong Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs 〇β δ 4 6 Α7 Β7 5. Description of the invention (5) Comparison (R / t system); Figure 3 shows the comparison of the release rate of ΝΕΤΑ (R / t system) for curves 10, 11, 12 and E3 (ESTRAGEST® mentioned above): Garden 4 , For curve 5 (product of Example 5 of the present invention) and E4 (ESTRAGEST ^ 5 1 7 — / 3—estrogen release rate comparison (R / t)); Figure 5, for curves 8, 9 (relative to Examples 8 and 9 of the present invention) and E5 (ELTRAGEST®), 1 7-Comparison of the release amount of cold-estrogen (Q / t Shishu); Figure 6, curves 8, 9 and E6 (ELTRAGEST®) ), The release rate of ΝΕΤΑ is more than 10 (R / t system). Detailed description of the present invention: Poly (ABA) para-copolymer copolymer type poly (styrene-butadiene-isoprene-styrene) · Styrene accounts for 14 ~ 50Wt; K (relative to SIS) In particular, SIS contains 17 ~ 47Wt% of phenethylbenzene. 15 The knee-adhesive resin suitable for the present invention is a general artificial adhesive, such as polyolefin resin or modified olefin resin, gasified or polymerized rosin resin, rosin brewing resin and so on. In particular, carbon-nitrogen resins, such as Aishon Chemical Co., Ltd.'s registered trade name is ESC0REZ®-385, combining these resins with SIs can obtain proper adhesive properties. 20 This so-called "active ingredient or hormone" refers to any estrogen component, progesterone component, or a mixture of the two, which can be used through a transparent route. The estrogen components suitable for the present invention are derivatives of 1 7 _ > 9 _ estradiol and estradiol, especially monoesters or bislipids of estradiol, such as estradiol. This paper scale is suitable for China National Standard (CNS) A4 specification (210 X 297mm) (5) 83. 3.10,000 (please read the notes on the back before filling in this page) 316S46 A7 B7 Fifth, the description of the invention (6) One 1 7 — Acetic acid, female fermented _ 3,1 7 —Diacetic acid brewed · female two fermented — 3-benzoic acid brewed. Female two fermented 17 — +-acid brewed , Burnt-based derivatives of estradiol at the 17 position, such as estradiol estradiol, estradiol estradiol 3-isoamyl ift, methyl estradiol, 17 — «-ethynyl estradiol, 5 Maastricht and its proper mixture. Particular mention is made of progesterone ingredients suitable for the present invention such as: progesterone, Metsopristone and its derivatives (especially 17-hydroxypregnone acetate brew, medroxyprogesterone acetate brew) Sterone and its derivatives, especially 17-norsterone acetate. 10 The estrogen and progesterone components in the present invention are preferred by 1 7/3 _ estrogen and norestrone. The transformation of the ship is that the skin-penetrating system of the present invention can contain both estrogen and progestin components. The stabilizer used in the present invention is a widely used antioxidant, such as the registrar of Ciba 15 Jiaji Company, which is named IRGAN0X®565 or IRGAN0X® B215. The selected accelerators include: crotazone, 1 ^ -alkyl-2, and ketone compound, in which the alkyl group contains: C1 ~ C15, N- (2-ethyl) -2-Btt. Burning ketone, a mixture of N-mahexyl 2-miaoluo ketone and 20. The N— (Cl—C15) -alkyl-2-D used in the present invention is more preferred than ketone: N_methyl-2-—slightly burned. N—ethyl-2-—oh ketone, N —Octyl 1-2 —Batch 〇Yaki, N-h diyl-2—Oh yaki ketone, respectively, the registered names of Jiafu Company, NMP®, NEP®, this paper size is suitable for Chinese national rubbing Standard (CNS) A4 specification (210X297mm) (

(Please read the note ^^ on the back before filling in this page) rf-J 83. 3.10,000 5. Description of the invention (7) A7 B7 m Printed by SURFADONEWLPIOO and SURFADONEULPSOO and the SURFADONEULPSOO mixture. The plasticizer is a polypropoxy ether which is hexadecanoic acid, especially a compound with ten oxaloxypropyl hooves per hexadecanoic acid, such as PROCETYL® 10 〇5, which is a registrar of Croda Corporation. The carrier of the rudimentary base material can be any carrier, as long as it does not escape into the structure of the base material. The present invention prefers to use polyethylene, polypropylene or polycool film, polyethylene and ethylene-acetic acid Ethylene cool copolymer polymer, or this kind of foamed M〇 In fact, the surface of the substrate is not in contact with the load sa, but is covered with a protective film that can be torn off before use, and the entire element It is sealed and protected with polyethylene-ming compound. Due to the characteristics of the composition of the formulations that constitute the substrate, the substrate system of the present invention has the following countless advantages: It can be found that only the above composition contains (1) a pair of plasticizers / accelerators, and 15 (i ) The plasticizer includes oleaginous enzyme, and (ii) the accelerator includes at least an N-substituent and a 2-Btfc slightly burned_ and crotamine, and (2) s IS material, has a significant release rate and Desired adhesion properties. However, other types of copolymers, such as the copolymer of ethylene and vinyl acetate (E V A) combined with the plasticizers / accelerators mentioned above, cannot achieve the same results. Undoubtedly, it is due to (i) poly (phenylethylbenzene-isopentane-diphenylene-phenylene-ethylene) ginseng interpolymer copolymer has a tendency to repel hormones, resulting in a particularly synergistic effect, and Ui ) The specific plasticizer makes the SIS polymer stretch, so that it has a larger space for movement, and reduces the macromolecular network (please read the precautions on the back before filling this page). National Standards (CNS) Μ specifications (210X297 bumps) 83. 3.10,000 316846 A7 B7__ 5. Description of invention (8) Rigidity, and promote the circulation of hormones. However, these plasticizers are derived from oleaginous substances. If used too much, it will reduce the adhesion of the substrate, so it needs to be used with one or more accelerators with different permeability, such as crotasterone or formula (I) In the N-substituent 2-5 pyrrolidone, M achieves the desired rate of administration and release without losing its adhesion. The above-mentioned crostatin and N-substituent-2-pyrrolidine in formula (I) can increase the solubility of hormonal in the substrate. These specific formulations can make the self-adhesive translucent system have good adhesion and adhesion properties, and provide 10 to 84% of the release rate of estrogen components and progestins in 24 hours or 48 hours. The release rate of ingredients 3.5 ~ 32JK. The use of smaller estrogen components and / or progesterone components to obtain a greater possibility of drug suspension simplifies the development and production of base material formulations that constitute components 15. In this way, the problem of solubility of hormones in SI S co-polymers, as well as the physical incompatibility of other components in the substrate, can be reduced or eliminated. This also solves the problem of hormonal crystallization and device instability caused by time. This kind of phenomenon is not accepted by the approval and market of this kind of long-term curative effect products of this kind of skin type system. The last but not negligible The advantage is that, due to the use of the lowest and most expensive Pleiogen, its cost is significantly reduced compared to currently known components. The technology used in the manufacture of the universal substrate of the present invention is: either coating (in the solvent phase), or the ‘hot-melt’ technology (in the absence of solvent, this paper standard uses the Chinese National Standard (CNS)) Α4 specifications (210X297 mm) 〇 /) -------- ^-{installed ------ ordered (please read the note Ϋ on the back before filling in this page) Printed by employee consumer cooperatives 83. 3.10,000 Printed by the Ministry of Economic Affairs Central Bureau of Accreditation Zhengong Consumer Cooperatives A7 B7 V. Description of the invention (9)) For the purpose of industrial production, the unit area is effective relative to the time required at a specific time The hormone administration agent of the ingredient administration agent is coated on a large surface area, and then cut into a desired size. 5 For the solvent phase technique, a method for preparing a self-adhesive transparent substrate, the steps are as follows: (1) In a reactor with a solvent and a temperature control adjustment device, heat to a temperature below the solvent After the boiling point temperature (such as 60TC vs. ethyl acetate), add the SIS copolymer to the stabilizer, add stabilizer resin, and then add the viscose resin 10, and stir to mix evenly; (2) At the same temperature, continue to mix Under heating, add plasticizers and accelerators, and mix evenly; (3) Under continuous stirring and heating at the same temperature, directly add powdered estrogen and / or progesterone, or its solution of tetrahydrofuran ， And continue to mix after mixing with cocoa 15; (4) Coat the homogeneous mixture obtained in step (3) on a non-sticky temporary carrier, such as a ketone polybrown film, to obtain a 50 ~ 300g / m2 coating film; (5) Heat the coating film to 40 ~ 1101, the suitable temperature is 60 ~ 80 20 (depending on the boiling point of the solvent), to vaporize the solvent; ⑹ Transfer this dry substrate to the final carrier. For the "Hot Melt" technical process, the steps are as follows:

(la) At a temperature higher than nor: especially 130 * 0, the adhesive resin Μ 10%, 30%, 60¾ even proportion, add the SIS under the mixing of this paper standard to use the Chinese national standard ( CNS) A4 specification (210X297mm) C / 2 ·) 83. 3.10,000 (please read the precautions on the back before filling this page)

316846 A7 B7 Fifth, the description of the invention (10) In the polymer / stabilizer mixture, after adding M in such a ratio, a good and uniform mixture of U can be obtained; (please read the precautions on the back before filling this page ) (2a) At a temperature slightly lower than step (la) (depending on the thermal stability of the product), the liquid in the formula is gradually added, that is, the plasticizer and accelerator in the formula are Add at this temperature, and keep stirring to obtain a homophrase mixture; (3a) At a temperature of about 100 TC, add the active ingredients to the mixture of step (2a) and stir until a uniform sentence mixture is obtained; (4a ) Between 80 ~ 130TC, pour the uniform mixture of step (3a) on 10 a temporary non-sticky carrier, especially silicone polyester film, and get it! I a 50 ~ 300g / m2 coating film ;

(5a) Transfer the substrate obtained in step (4a) to the selected final carrier. P ί The translucent system of the present invention is quite effective for the symptoms such as menopausal symptoms, cardiac and vascular lesions, and osteoporosis treated with estrogen and / or progesterone. The best formula: The best formula of the transparent substrate in the present invention printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs is: The total weight is 100% and contains: (a) 37.3wt% of poly (styrene) (Isoprene-styrene) Ginseng Group 20 polymer, (b) 38wt $ viscose resin, (c) 15wt% propylene dodecanoate, (d) 7wtJK 1 ^ -octane Base one 2-slightly ketone, _ (e) 〇.2wta; white spoon stabilizer, __ > paper scales using the Chinese National Standard (CNS) A4 specifications (210X297 mm) (/ J) 83. 3.10, 000 A7 B7 printed by the Beigong Consumer Cooperative of the Central Ministry of Economic Affairs of the Ministry of Economic Affairs 5. Description of the invention (11) (f) 0.5wt * of 1 7-> 9-estrogen, and (g) 2% by weight Starkone acetate, other characteristics and advantages of the present invention can be fully understood from the following practical examples and description of comparative experiments. 5 These examples and experiments are for illustration only, not only for this. For practical needs, the following abbreviations are defined as follows: ΝΕΤΑ: Nostrone acetic acid brewing SIS: poly (stupid female-isoprene-styrene) ginseng group copolymer EVA: ethylene / Vinyl Acetate Copolymer 10 Example 1: Put 13.9 g of VECTOR® 4211D (Registrar of SIS Copolymer of Ai Song Chemical Company) in a 250 ml beaker, and 23 g of f ECR® 385 (Ai The registrar of Song Chemical Company's viscose resin), 9 grams of PR0CETYL® 10 (Kroda's hexadecanoic acid polypropylene ether), 3 15 grams of SURFAD0NE® LP100 (Jiafu company sells N —Octyl-2-Btfc slightly ketone), 0.1 grams of IRGAN0 # 565 (Steam B—an anti-gasification agent sold by Jiaji) and 19.65 grams of ethyl acetate. After heating to 60TC, the mixture is completely dissolved, and then add 1g of ΝΕΤΑ predissolved in 5g of the four raspberry solution, followed by ore and mix about 30 minutes, so that the mixture is 20 minutes, and set it to let it Cool and degas until bubbles completely disappear. Apply the mixture at room temperature (15 ~ 200 on the sand-swelling polyfilm to form a coating film of 110 ± 10 g / m2. Heat the coating film under 50 ° C for at least 10 minutes to complete. The film is transferred to a non-acetone polyethylene carrier, and then cut into a large size, and then packed into a spice bag. This paper size is suitable for Chinese national standard (CNS > A4 specification (210X297 mm) (/ Duo) 83 . 3. 10,000 (please read the precautions on the back before filling in this page). • 316646 A7 B7 The Ministry of Economic Affairs, Central Standards Bureau, Beigong Consumer Cooperative Institution V. Invention Instructions (12) Get a Νeta original amount of 231 Wg / cm2. Example 2: The procedure is the same as Example 1, but instead uses 13.4 grams of VECTOR ^ 4211D, 0.1 grams of IRGAN0X®565, 26.5 grams of ECFf® 385, 5 grams of oleaginate, and 5 4.5 grams of crotax. Ketone [N-ethyl-N (2-methylphenyl) -2-buteneamine, sold by Bollinger Ingelheim], 20 grams of ethyl acetate and 0.5 grams of 1 7 _ / 3 _The female ferment is dissolved in 2.5 g of tetrahydropyridine. After coating, a coating film of ill〇〇 ± l〇s / m2 is obtained. A 1 7 — / 3—female is obtained The original yeast is 94.5 Wg / cm2 of Shito system. Example 3: The procedure is the same as Example 1, but instead use 13.9 g of VECTOR® 421 ID, I 0.1 g of IRGAN0X® 565, 27.5 g of ECR®385, 5 g of oil Alcohol and 0.5 g of 1 7 — / 5 — estrogen are dissolved in 2.5 g of tetrahydrofuran. 15 After coating, a coating film of 100 soil and 10 g / m 2 is obtained. The original amount of 1 7 — / 3 — estrogen is obtained Qlyug / cm2. Example 4: The procedure is the same as example 1, but 7.25 grams of VECTOR0 4211D, 20 0.07 grams of IRGAN0X® 565, 11 grams of ECR® 385, 3.75 grams of LABRAFIL® 1944Cs (Gardfoss The sold 5-oleic acid peghe (1 ester), 2.5 grams of tetrahydrobicarbonate, coated to a coating film of U 90 ± 10s / m2. Obtained a 1 7-/ 3-estradiol original The volume is 181.7 wg / cm * (please read the precautions on the back before filling in this page). _ The size of the paper is applicable to the Chinese National Gradient (CNS) A4 specification (2l〇X297mm) (7 夂) 83 .3.1〇, 〇00 S16S46 A7 £ 7_ V. Description of the invention (13) System. Example 5: --------: --f Installed ------ ordered (please read the note on the back of the machine first $ ¾fill this page again) 4, but use 12.9 grams of VECTOR® 4211D, 0.1 grams of IRGAN0X® 565, 26 grams of ECR® 385, 8 grams of 5 LABRAFIL® 1944Cs, 2.5 grams of SURFAD0NE ^ LP300, 19.4 grams of ethyl acetate and 0.5 grams 1 7— /? — Estradiol was dissolved in 2.5 g of Sihanna, to obtain a coating film of 100 ± 10s / m2. Achievement 丨 "a 1 7-cold-female yeast with the original amount of 87 · 1 W s / cm2 system. 10 Example 6: The procedure is similar to Example 2, but instead uses 13.16 g of VECTOR® 4211D, 0.1 g of IRGAN0X® 565, 26.5 g of ECR® 385, 5.08 g f

I of oleyl alcohol, 4.53 g of crostatone, 19.8 g of ethyl acetate and 0.75 g of 1 7- / 3-estrogen are dissolved in 3.75 g of Sizhan to obtain 10015 ± 10g / m2 coating film. Obtain a 1 7-the original amount of female fermented yeast is 87.1 wg / cm2. It is printed by the Central Ministry of Economic Affairs Central Bureau of Labor and Consumer Cooperatives. Example 7: The procedure is similar to Example 3, but with 0.75 grams of 1 7-/? —Digestion 20 is dissolved in 3.75 grams of tetrahydrogen into B South, 13.64 grams of VECTOR® 4211D, 0.1 grams of IRGAN0X® 565, 27.51 grams of ECR® 385, 5 grams of oleyl alcohol, and 3 grams of SURFAD0NE® LP300 With 20.5 grams of ethyl acetate acetic acid, to get a coating film of 100 ± 10〇 / 1112 _Obtain a 1 7 — / 3 —Ester-fermentation raw quantity of 162.3 // g / cm2 of Shitomoto paper scale applicable to China National Standardization (CNS) A4 specification (210X297 mm) d / 6) 83.3.10,000 Ministry of Economic Affairs A7 B7 printed by the Central Bureau of Employment and Consumer Cooperatives V. Description of invention (14). Example 8: The procedure is similar to Example 1, but with 13.9 grams of VECTOR® 4211D, 0.1 grams of IRGAN0X® 565, 24 grams of ECR⑧ 385, 3.5 grams of 5 SURFADONE® LP300, and 7.5 grams of LAUR0GLYC0L® (sold by Jiadefusi The mixture of dodecanoic acid and malonate monoester and double brew) replaces PR0CETYL® 10, 19.9 g of ethyl acetate, 0.25 g of 17-> 3 — Estradiol and 0.75 g of NETA dissolved in 5 g Tetrahydrogen murmured to obtain a 100 ± 10g / m2 coating film. 10 Obtained a lineage of 1 7 — / 3 -estradiol with an original suspension of 48.6 a g / cm2 and NETA with an original amount of 145.3 At g / cm2. Example 9: The procedure is the same as Example 8, but instead uses 15.9 grams of VECTOR® 4211D, 0.1 grams of IRGAN0X®565, 21 grams of ECR®385, 7.5 grams of LAUR0GLYC0L® 15, 4.5 grams of crostatone (replaces SURFADONE ® LP300), 21.15 grams of ethyl acetate, 0.25 grams of 1 7-> 3-estrogen and 0.75 grams of NETA dissolved in 5 grams of tetrahydrofuran, resulting in a coating film of 10 g / m2 in J70 soil . You can get a 1 7 — / 3 — female yeast with a raw quantity of 33.1 w g / cm2 and a ΝΕΤΑ raw quantity of 99 * 4 ju g / cm2. 20 Example 1 Ο: The procedure is the same as Example 1, using 14.9 grams of VECTOR® 4211D, 0.11 grams of IRGAN0X® 565, 23.25 grams of EC # 385, 7 grams of PR0CETYL® 10, 3.56 grams of SURFADONE® LP100, 20.7 grams of Ethyl acetate brewing, 0.25 g of 1 7-estrogen and 1 g of ΝΕΤΑ dissolved in 6.25 g of ¥ paper size using the Chinese National Standard (CNS) Α4 specifications (210X297 mm) <: / 7) 83 . 3.10,000 (please read the precautions on the back before filling in this page), installed, 1Τ 316846 A7 B7 Printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs Beigong Consumer Cooperatives 5. Description of the invention (15) Tetrahydrogen, obtained 100 soil lOg / m2 coating film. The badger got a 1 7 — / 3 — female yeast with a raw Dong of 51 w g / cm2 and a NETA of 207.1iug / cm2. Example 1 1: 5 The procedure is the same as example 10, but SURFADONE® LP300 with 3.5 g replaces SURFADONE ^ LPIOO, and a coating of 120 ± 10g / m2 is obtained. The U-unit 1 7 — / 5 —the original amount of female yeast is 60.5 μ g / cm2 and the original amount of NETA is 242 / us / cm2. Example 1 2: 10 The procedure is the same as Example 10, but using 14.65 grams of VECT0R®4211D • 0.1 grams of IRGAN0X® 565, 21 * 75 grams of ECR® 385, 7 grams of PR0CETYL® 10, and 5 grams of crostatin Ketone, 20.1 g of ethyl acetate, 0.25 g of 1 7- > 3-estrogen and 1 g of NETA were dissolved in 6.25 g of tetrahydroshuran to obtain a 120 ± 10 g / m2 coating film. 15 Obtained a system of 1 7 — / 3 _ female yeast with a raw quantity of 60.5 w s / cm2 and a raw quantity of NETA of 235.4 / ug / cm2. Example 13: The procedure is similar to Example 8, but uses 18.65 grams of VECTOR® 4211D, 0.1 grams of IRGAN0X® 565, 19 grams of ECR® 385, 3.5 grams of SURFAD0NE® 20 LP100, 7.5 ^ fi < jLAUR0GLYC0L®, 23 grams of Acetic acid ethyl acetate, 0.25 g of 1 7-> S-estrogen and 0.75 g of NETA were dissolved in 5 g of tetrahydrofuran to obtain a coating film of 100 ± 10 g / m2. A set of 1 7-β-estradiol original Dong was 47.3 mg / cm2 and the original amount of NETA was 190 s / cm2. (Please read the precautions on the back before filling in this page) -β Γ This paper size is applicable to China National Standard (CNS) A4 (210X297mm) ί / g;) 83. 3.10,000 Central Ministry of Economic Affairs A7 B7_ Printed by the Negative Consumer Cooperative. V. Description of the invention (16) For the purpose of comparison, it is changed to B; N8—Ethyl Acetate Acetate Copolymer (E VA) as the base material. fcb product, C Ρ 1 In a 250-liter beaker, add 29 grams of LEVAPREi ^ 450P (EVA sold by Bayer), 15.5 grams of PR0CETYL · ® 10, 3.5 grams of 3111 ^ &00; 00 For @ 1 ^ 100 and 67.7 g of ethyl acetate, heat to 6010 and stir for five hours until the EVA dissolves. First dissolve 2 grams of NETA in 10 grams of tetrahydrofuran, and then add to the above mixture, followed by heating, stirring, and shoveling until completely homogenized. Leave 10 to cool and degas until bubbles are completely expelled. After cooling to room temperature, the substance was poured on the sand brewing I paper to form a coating of 120 ± 10 g / m2, and then heated to 70TC for at least 10 minutes to obtain the desired coating film. Finally, transfer to a non-silicone polyether, then cut to the appropriate size, and then packaged in a fragrance bag. 15 Obtained 丨 J NET with an original volume of 488ius / cm2. Comparing the product, the CP 2 procedure is similar to CP 1, but instead uses 29 grams of LEVAPREN® 450P, 16.5 grams of oleaginous acid, 3.5 grams of crostatone, 67.6 grams of ethyl acetate and 1 grams of 1 7-Lu Yi Estradiol was dissolved in 5 g of tetrahydrogen and coated with a coating film of 20 ± 80 g / m2. Get a 1 7 — / 3 _ female fermented yeast with a raw quantity of 157 ws / cm2. Comparative product, c P 3 _ procedure is similar to CP 2, but use 1 gram of 1 7 _ > 9 — female fermented solution Use Chinese National Standard Rate (CNS) A4 (210X297mm) C / 9) 83.3.10,000 ^ ϋ ·· ^^ 1 · I —Λ ^^^ 1 ^^^ 1 ^^^ 1 ^ — ^ Ϋ n (Please read the precautions on the back before filling in this page) Order Λ 〇1βδ46 Α7 ___ Β7_ V. Description of the invention (17) 5 grams of tetrahydro Aran, 29 grams of LEVAPREN® 450P, 16.25 grams of oil Alcohol, 67.6 grams of ethyl acetate and 3.75 grams of 3111 ^ 00 serving @ 1 ^:> 300, coated to form a coating of 80 ± 10s / m2. A set of 7-β-estrogen with a raw quantity of 157 μg / cm2 was obtained. The fcb is the same as the product, and the formulation of the E V A substrate used in CP 4 Xuan is the same as the formulation mentioned in the literature report F R — A — 2 6 1 2 7 8 3. In a 250 ml beaker, add 21.97 grams of 1 ^ 八? 1 ^ @ 450? 10 and 12.54 grams of EUTANOL® G (sold by 2-octyl-h-unitary hunger company), stir and heat After 130 1C, add 6.03 grams of £ 1 ^ (^^ 1 ^ 20 (ethyl cellulose, sold by Dow Chemical Company) and 6.46 | grams of EUTM0L® G, stirring until uniform and no particles Leave it to cool for 1 hour. Dissolve 1.5 grams of 1 7- / 3-estradiol in 12 grams of anhydrous alcohol at 701C. After heating the above mixture to 80¾, add it to the Central Bureau of Economic Affairs of the Ministry of Economic Affairs. Zhen Gong Consumer Cooperatives Indo (please read the precautions on the back and then fill out this page) 17 — / 3—estrogen fermentation solution, stirring for at least one hour until it is completely homogenized. The obtained substance is at 7. r: Transfer it to sand paper to obtain a coating film with a thickness of 150 ± 10g / m2. Dry it under 80¾ and vaporize the alcohol. The substrate is transferred to the final polyethylene carrier and then cut into suitable 20 When the size is packed into a spice bag. Get a 1 7 — β _ female two yeast original Dong is 463.6 wg / cm2. Test: __ from comparative test Some of the results obtained • Sorted and sorted in nursery 1 to 6. This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) i io) 83. 3.10,000 Printed by the Central Bureau of Economics and Trade of the Ministry of Economic Affairs of China. A7 B7 V. Description of the invention (18) The components obtained in the previous example are used to test the release of hormones in various skin models over 24 hours or 48 hours, and calculate the relative release rate. Compared with other known systems, the advantages of the components claimed in the present invention are clearly revealed. 5 According to the agreement under Μ, place the component on the abdomen skin of a male nude mouse, and test its penetration test. Place the skin-permeable component with a surface area of 2.54 cm2 in a 3.14 cm2 male nude mouse abdomen skin The disc-shaped tissue is susceptible to the release of hormones. With a temperature control device (temperature set at 37TC), 10 pieces of 11.5 liters of physiological food solution and PEG400 (75/25) Measured in the static glass chamber of the mixed liquid (used as the absorption phase).

After two, four, six, eight, twelve, sixteen, twenty and twenty-four hours, the sample obtained from the L absorber solution was analyzed by a liquid phase analyzer. In order to obtain the difference in the permeability between the Piru samples, at least 3 to 5 Piru samples are required for the permeability test of each element. Each component undergoes some tests and then averaged to get the results. After 24 hours, the ratio of the average amount of hormone released to the original amount of the device can be used to express the release rate of the skin-applicable system in the invention within 24 hours. 20 See Table I. Compared with known components released Dong in 24 hours. According to the same previous agreement, the invention contains various components of 17 * — /? —Estrogen and the same form of self-adhesive substrate system in FR-A-2 612 758. Comparison of skin penetration. The size of this paper is in accordance with the Chinese National Standard (CNS) 8.4 specifications (2 丨 0 297mm) 〇1) 83.3.10,000 (please read the precautions on the back before filling out this page) 装 · < ^ τ

Si 6646 Α7 Β7 5. Description of the invention (19) The release amount and release rate are shown in Table Π. Finally, it is compared with ESTRAGEST® (which contains both estrogen and progesterone) sold by Ciba-Jiaji Company, which is only known to the current system. This product is currently the only effective one on the market product. Under the same agreement as the previous 5, an abductance test was performed on the abdomen skin of male nude mice. Calculate the amount of release in 24 hours and calculate the release rate on the same principle. Regarding the ESTRAGEST® product, this element consists of two connected storages containing a total of 10 μg of 1 7 — / 3-estrogen and 30 μg of NETA, each storage tank containing 5 μg of 1 7 _ / 5-A mixture of estrogen and 15 mg of 10 META. Under the same agreement, through the measurement, only one of the two storage tanks was placed on the 3.14cm2 Piru sample. ^ 1 The original barrier of each hormone in the tank is converted into ^ the original amount per unit surface area, expressed in z / g / cm2. 15 In a storage eave, the average original amount of hormones per unit area is 1590 soil 30 At g / cm2 (17- — female fermented) and 4770 soil 30 ws / cm2 (ΝΕΤΑ). Central Bureau of Standards of the Ministry of Economic Affairs Printed by Beigong Consumer Cooperative (ϊ) 1 7 — / 3 — The average value of the release of female Eryouxiang or META in 24 hours and (ii) the original amount in the storage tank, which can be used to calculate 1 7 — / ? — 20 The release rate of estrogen and NETA in 24 hours. First, the base material system containing 17-> 9-estrogen and NETA is requested in the invention, compared with the previously mentioned translucent system ESTRAGEST®. The results are shown in Table III. Secondly, the penetration test of another skin type (pig ear mixed skin) · 83. 3.10,000 (please read the precautions on the back before filling this page) This paper size is applicable to China National Oak Standard (CNS) Α4 Specifications (210X297mm) 16846 Printed by the Ministry of Economic Affairs, Central Bureau of Standardization, ec, industrial and consumer cooperatives Α7 Β7 V. Description of the invention (20) Generally, the results of the penetration test of pig ear mixed skin are closer to human skin. The test procedure is similar to the test of the abdomen skin of naked mice, but this time it is changed to 3.14cm2 of pig ear mixed skin, the absorption phase is still the same as saline / P EG400 (the aspect ratio of the ship is 75/25) The time was changed to 48 hours and 5 hours. The test results for each component require an average of at least 3 to 5 Piru samples. The ratio of the average value of hormone release of component (i) at forty-eight hours to (i i) its original director is used to express the release rate of this translucent system at forty-eight hours. The relevant results are shown in Tables IV and V. Table I is the study of the release amount of 24 / J, for two substrate systems with the same plasticizer / accelerator but different copolymers. The examples II to 3 are the use of s IS, and the examples CP 1 ~ CP 3 use E VA. 15 The analysis in Table I shows that for the release rate comparison of NETA (EX 1 vs. CP 1), SIS is 2.5 times higher than EVA (both have the same plasticizer / accelerator, PROCETYL® 10 / SURFADONEi® LP100 ), And the release amount of EX1 ENTA is also higher. 17-estrogen (EX2 is compared with CP2fcb) has similar results, both of which contain oleyl alcohol / crotasterone plasticizers and accelerators, and the release rate of SIS is about 1.7 times higher. Similarly, when EX3 is compared with CP3 (with the same oleaginous / SURFADONE® LP300), the release rate of 1 7 —> 9 —estrogen is about 4 times higher than EVA (CP3) Times, and 1 7 — (please read the notes on the back before filling this page)

I This paper scale applies the Chinese Standard (CNS) A4 specification (210X297mm>) 83. 3.10,000 The A7 B7 printed by the Central Industry Bureau of the Ministry of Economic Affairs A5 B7. Invention description (21) / 3 — The release of female fermented yeast is about 2.2 times higher. From this, it can be seen that, with the same plasticizer / accelerator, the permeable substrate system of SIS has better release performance than EVA. All the results in Table I show that due to the special combination of the SI S material of the present invention and the plasticizer / 5 accelerator, the release rate is better, and the release rate is either the same or higher. Table IE compares the components of the present invention with the same components as F R A 2 6 1 2 7 8 5. The analysis of Table π shows that for the release amount of 17 — / 5-estrogen, all 10 components are higher than the component C Ρ 4 of FR — A-2 6 1 2 7 8 5 and this result is completely shown in the figure. 1 (It is the example 4, release comparison of EX 4 and CP4). Regarding the release rate, compared with the CP4 device, it was observed that: Example 2 (ΕΧ 2) is 7 times higher, 15 Example 3 (ΕΧ 3) is 13 times higher, Example 6 (ΕΧ 6) is 7 times higher, and Example 7 (ΕΧ 7 ) 1 Ο times higher, Example 4 (ΕΧ 4) is 6 times higher, the corollary is that in all cases, the use of plasticizers / accelerators is 20. Examples 2 and 6 use oleaginous enzymes / crotasterone, Examples 3 and 7 are oleaginous / SURFADONE® LP300, and example 4 is LABRAFIL® 1944 CS / Crotacetone, both of which have a higher release rate than CP 4 (about 6 to 13 times higher). The amount is about 2.5 times higher than that of EVA substrate. Table m is for the invention that contains 17- / 3-estradiol and this paper is also applicable to the Chinese National Standard (CNS) A4 specifications (210X297 mm) 83. 3.10,000 -----.- -h --- * install-- (please read the precautions on the back before filling in this page):? [Two-one order 316846 A7 _B7_ V. Invention description (22) The substrates of the two hormones ΝΕΤΑ and Comparison of ESTRAGEST® products. The results of all the cases in Table m are shown (i) at 24 hours 1 7 —the release of estradiol is about 2 to 3 times higher than that of ESTRAGEST® and (ii) the release of ΝΕΤΑ and ESTRAGEST at 24 hours Compared to ®, it is either quite or higher. 5 10 15 Printed by the Employee Consumer Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs 20 At the same time, the release rates of 1 7 — / 3—estrogen and NETA are higher than ESTRAGEST®, and more particularly, compared with ESTRAGEST®, 1 7 — The data obtained by Lengyihenyouyouxiang are: Example ΙΟ (ΕΧΙΟ) is about 90 times higher, Example 1 1 (EX 1 1) is about 72 times higher, Example 12 (EX 12) is about 47 times higher, For HETA, the release rate data are as follows: Example 1 is about 25 times higher, Example 11 is about 20 times higher, and Example 12 is about 19 times higher. These obvious differences provide the transparency in the present invention. Proof that the rugged system is superior to the only products currently on the market. This difference can be confirmed from Figure 2 and Garden 3, which respectively show the relationship between the release rate of 17-> 3-estrogen and time and the relationship between the release rate and time of NETA. In the Japanese case, it was also observed that the accelerator that is matched with the plasticizer (PR0CETYL® 10 in this case)-crostatone or Ν- 焼 基 -2-2-Π 比 焼 焼 晒 (SURFADONE® LP300 or SURFADONE® LP100) is quite conspicuous. (Please read the note $ item on the back and then fill out this page). Packing, ordering. This paper standard is applicable to the Chinese standard (CNS) Α4 specification (210X297 mm) OJT) 83. 3.10,000 3l6σ46 Α7 ___ Β7_ V. Invention Explanation (23) The comparative study of the elements of the present invention and ESTRAGEST® relative to the swine ear peel is shown in Table IV and Table V. Table IV is about the release amount and release rate of 17-valeryl estradiol, as shown in the table, Example 5 (EX 5) of the present invention releases the amount and release of 17-5 estradiol at forty-eight hours The rate is higher than ESTRAGEST®, and the release amount is about 3 times higher. Figure 4 represents the relationship between EX 5 and ESTRAGEST® 1 7-the release rate of female and female unitary time and time, and also shows the same results. The results in Table IV show that the release rate of EX 5 is 10 5 7 times higher than that of ESTRAGEST®. For this new type of pig-ear mixed skin horizontal type, there are similarly higher values, which further confirm the results of the test of the abdominal skin susceptibility of rats. This result further confirms the advantages of the combination of oleic acid-pagley brewing (LABRAF IL® 1944, C S) plasticizer with SURFADONE® LP300 accelerator and SI S 15. Printed by the Zhengong Consumer Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs (please read the precautions on the back and then fill in this page) Table V is a component that contains both 1 7 _ / 3 -estrogen and NETA 8, 9 and 13 products) compared with ESTRAGEST® on pig ears. With regard to this type of hordeum, the release rate of 1 7 _ / 3 -estrogen is much higher than that of ESTRAGEST®. Figure 5 also confirms that the release of 17- / S-estrogen forty-eight hours also has the same image. In particular, Table V shows that compared with ESTRAGEST®, the release rate of ΕΧ 9 is 1 38 times higher, the release rate of Ε 8 is 72 times higher, and the release rate of EX 1 3 is higher. The paper size is free to use the Chinese National Standard (CNS) Α4 specifications (2 丨 0〆297mm) <: to) 83. 3.10,000 S16846 Α7 Β7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy V. Invention Instructions (24) 1 Ο 7 times 〇 At the same time, for HETA Compared with ESTRAGEST®, it also has a higher release rate. From Figure 6 (the erythroid system showing the% release rate and time), it is also perfectly verified. Although it is not more significant than 17-cold-estrogen, it has been more difficult to pass through. The results in Table V show that the release rate of EX 8 is 21 times higher than that of ESTRAGEST®, the release rate of EX 9 is 35 times higher, and the release rate of Ε X 13 is 25 times higher. 10 Suppose, in a plasticizer / accelerator pair, the plasticizer is LAUR0GL-YC0L® and the accelerator is crostatone (Ex. 9) or N-alkyl-2-pharyngolone ( The combination of SURFADONE® LP300 in Example 8 and SURFADONE® LP100 in Example 1 3), together with SIS material, can obtain a remarkable result. 15 In conclusion, it is confirmed from the above results that, compared with the only products on the market that contain estrogen and progesterone and self-adhesive substrate components, the skin-permeable substrate system in the present invention is not Xing recognizes the advantages. In particular, the combination of the SIS copolymer of the present invention and a plasticizer / accelerator pair can achieve a higher release rate.

II (Please read the precautions on the back before filling in this page). The bound paper is also used in the Chinese National Standard (CNS> Α4 specification (210Χ297 mm) CZ7) 83.3.10,000 3l6〇46 A7 B7 5. Description of invention (25

Table I

Exl ΝΕΤΑ 231 5 Q24 10 15 CP1 ΝΕΤΑ

Ex 2 Es CP2 Es

Ex 3 Es CP3 Es 488 94,5 157 91 169,6 12.7 ± 3 10 ± 1,5 16.4 ± 1,8 15.8 ± 5 29 ± 3.2 13.4 ± 2

R 5.5 2.05 17.3 10 32 7.9 QO: 1 7 — / 3—the original quantity of estrogen or ΝΕΤΑ, expressed in MWg / cij6 ^. Q24: 1 7 — > 9-Female Eryou enjoy 24 hours? The amount of completion is expressed in w g / cm2. R: release rate, expressed as a percentage of M (%). (R = 10〇x Q24 / QO) Printed form of the Beigong Consumer Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs] I Ex 2 Ex 3 Ex 4 Ex 6 Ex 7 CP4 Qo 94.5 91 181.7 159 162.3 463.6 Q24 16.4 taxi 1,8 29 ± 3.2 26 · 1 soil 1,5 27 ± 1.3 42.2 soil 3.7 11.22 ± 1 R 17.3 32 14.4 17 26 2.42 Q.0: 1 7 — / 3—the original amount of estrogen, expressed as At g / cm2 Q24: 1 7-Call out one female and two females to enjoy 24 hours of release, M wg / cm2 This paper scale is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) (2J ·) 83. 3.10,000 A7 B7 316S46 V. Description of the invention (26) R: release rate, expressed as a percentage of M (%), that is, 100X Q24 XQO 〇 Printed by the Ministry of Economic Affairs Central Bureau of Standardization Beigong Consumer Cooperatives > 0 Table m L0 Ex 10 Ex 11 Ex 12 ESTRAGEST® Q〇51 60.5 60.5 l · 1565 h Es Q24 8.95 ± 0.9 8.74 ± 0.16 5.76 ± 0.6 · 3.13 ± 0_21; i R 17.56 14.4 9.52 0.2 Q〇207.1 242 235.4 4820 ΝΕΤΑ Q24 9.05 ± 1.4 10.11 ± 0.6 7.65 ± 0.4 8.2 ± 1 R 4.37 4.18 3.25 0-17 ΝΕΤΑ: norestrone acetate. Q0: the original amount of ES or NETA, expressed in MWg / cm2. Q24: The release amount of ES or ΝΕΤΑ 24 hours, M «g / cm2 table ES: means 17-/ 5-estradiol. ○ R: release rate, expressed as a percentage of M (%), that is, 100XQ24 Q0. This paper scale is suitable for China's sleepy family standard (CNS > Α4 specification (210Χ297mm > C2 present)) 83. 3.10,000 (please read the precautions on the back before filling in this page) 袈 · Order 316846 A7 B7 5. Description of the invention (27) 5 Table IV Ex 5 ESTRAGEST® Qo 87.1 1584 Q48 30.5 ± 7 9.66 soil 0.9 R 35 0.61 Q0: 17 — / 3—the original amount of estrogen, expressed in M / ug / cm2. Ίϊ ::! _K3) 10 Q48: 1 7 — / 3 —The release amount of female fermented forty-eight hours, M wg / cm2 R: Release rate, expressed as a percentage (%), that is, 100X Q24 / Q0 〇- .-- ^-一 装-(Please read the precautions on the back before filling out this page) Order :: Sf; 15 Printed by Beigong Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs 20 a Table V Es ΝΕΤΑ Ex 8 Ex 9 Ex 13 ESTRAGEST® Qo 48.6 33.4 47.3 1584 Q48 21.4 ± 2 27.8 ± 3 12 ± 2 9.66 ± 0.9 R 44. 84 65 0.61 Qo 145.3 99.4 190 4740 Q48 27.6 ± 7 31.7 ± 8 41.8 42.6 ± 7 R 19 31.9 22 0.9 ' Write_; Miscellaneous do: the original amount of ES or NETA, Mwg / cm2 said. Q48: Forty-eight hours of ES or ΝΕΤΑ release, Mwg / cm2 The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm). 83. 3.10,000 A7 B7 V. Description of the invention (28) Bu. R: Release rate, expressed as a percentage (%), that is, 100Χ Q48 / Q0 〇 (please read the precautions on the back and then fill out this page) 袈 · Set the size of the paper printed by the Beigong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs Applicable to China National Standardization (CNS) Α4 specifications (210X297 public daughter) door 〇83. 3.10,000

Claims (1)

5 10 15 Complement 7 1 ft Amendment to apply for patent scope 1. A self-adhesive and transparent substrate system for the hormonal administration of the translucent route, including a carrier and a self-adhesive substrate, this substrate contains: (a) 20 ~ 42wt% poly (styrene-isoprene-dipyridylbenzene) ginseng interpolymer copolymer, (b) 35 ~ 55wt% viscous resin, (c) 5 ~ 25wt% plasticizer , Which contains oleyl alcohol, 5-oleic acid mono-pegley vinegar, propylene glycol dodecanoate or polypropoxy ether of cetyl alcohol, (d) 5 ~ 15wt% of the following substances (at least one): He Mingshi, and --N —Substituent one 2 — each ketone (see formula I) R, Ν, I i. · ΙΜ ·-(please read the precautions on the back before filling this page) (I) The Ministry of Economic Affairs of the Central Bureau of Pre-employment Cooperative Labor Cooperatives printed 2 20 3 where R represents Cl ~ C 15 halide, bad hexyl or 2-hydroxyethyl group, (e) 0.01 ~ lwt% stabilizer, and (f ) 0.1 ~ 5wt% of estrogen, progesterone and mixed hormone of both. 1. The self-adhesive transmissive substrate system for the hormonal administration of the translucent route according to item 1 of the patent scope, where the plasticizer is oleaginous. 1. The self-adhesive transparent substrate system according to the hormonal administration method of the transmissible route according to item 1 of the patent application scope, wherein the plasticizer is 5-oleic acid Pegelli vinegar. 1. The self-adhesive transdermal substrate system for the hormonal administration of the skin-penetrating route according to item 1 of the patent application scope, where the plasticizer is propyl dodecanoate paper standard and is used by the Chinese National Standards (CNS) ) Α4 specification (210X297 mm); ®16S46 A8 B8 C8 D8 86. 7. 18 Amendment of the scope of patent application for printing and printing of the Central Bureau of Chess and Industrial and Consumer Cooperatives of the Ministry of Wood Economy-Unitary Purpose. 5. The self-adhesive diaphanous base material system for the hormonal administration of the transdermal route according to item 1 of the scope of the patent application, in which the plasticizer is cetyl alcohol polypropylene base, especially per mole The sixteen leaven contains ten moles of propylene oxide. The self-adhesive skin-permeable substrate system for the hormonal administration method for the translucent route according to item 1 of the patent scope, wherein the compound that promotes permeability is selected from the group consisting of crotasterone and Ν— The substituent is a 2-like slightly ketone, in which R represents a C1-C15 alkyl group, cyclohexyl group or 2-ethyl group. The self-adhesive transmissive substrate system for the method of hormonal administration for the translucent route according to item 1 of the patent application, in which the poly (stupene-isoprene-styrene) interpolymer group is copolymerized The material contains styrene 14 ~ 50Wt% relative to the copolymer, the preferred range is 17 ~ 47Wt%. 〇15 8, according to the first patent application of the hormonal administration method of self-adhesive permeability Skin base material system, in which the estrogen is 1 7 _ / 3-estradiol. 9. The self-adhesive translucent substrate system for the hormonal administration of the translucent route according to item 1 of the patent application scope, in which the progesterone is norstel 20 ketone acetate 0 1 Ο, according to the patent application Scope item 1 is a self-adhesive transdermal substrate system for hormonal administration of transdermal routes. The total weight of the substrate is: (a) 37.3wt% poly (styrene-isoprene) Ene-stupene) Lijian 5 10 6 T The paper size is applicable to the national standard (CNS) A4 specifications (2 丨 X297mm) (please read the notes on the back before writing this page) 3ί6δ4β Α8 Β8 C8 D8 86. 7 "Amendment_printed by the Ministry of Economic Affairs, Central Bureau of Economic Development, Beigong Consumer Cooperative Co., patent-applicable circle copolymer, (b) 33Wt% viscose resin, (c) 15Wt% 12 Propylene glycolate, (d) 7 Wt% of 1 ^ -octyl-2-pyrrolidone, 5 (e) 0.2Wt% stabilizer, (f) 0.5 duty 1 7 — > 3 —female Two enzymes, and (s) 2 Wt% of norestrone acetate. 1 1. The self-adhesive transmissible base material system according to item 1 of the patent application scope for the hormonal administration of the skin-penetrating route, wherein the adhesive resin is selected from poly10 resin, modified vanene resin, Hydrogenated or polymerized rosin resin, or rosin resin. 1 2. A method for preparing a self-adhesive transmissive substrate system such as the hormonal administration method of any one of the patent application ranges from 1 to 1 1 that includes the following steps: 15 (〇〇 一At a temperature higher than nor: mix s I s polymer, stabilizer and viscose resin, and mix them evenly, (厶) Add accelerator and plasticizer between 80 ~ 100 ° C and mix evenly , (0〇 Add hormones selected from estrogen, progesterone and a mixture of the two, and mix evenly, 20 (s) apply this mixed mixture to a non-sticky temporary carrier to form 50 ~ 300g / m2 coating film, (e) Transfer the above coating film to the final carrier. 1 3. A self-adhesive property of a hormonal administration method for preparing a translucent route according to any one of patent applications 1 to 11 For the method of translucent base material, the paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210X297mm) (please read the note f on the back before filling this page) 316846 A8 B8 C8 D8 Re. 7 6. The scope of the patent application includes the following steps: («) Mix the SIS polymer, stabilizer and adhesive resin into the SIS solvent, and mix at a temperature below the boiling point of the solvent Sentence mixture, 5 (/ 3) Add accelerator and plasticizer, and mix them together * (π) Add hormones selected from estrogen, progestin, and both * and mix them, (5) in the room At a low temperature, apply the mixture of the above sentence to a non-adhesive Zhe Shi carrier to form a coating film of 50 ~ 300g / m2, and 10 (e) heat the coating film to a temperature above the boiling point of the solvent, so that After the solvent evaporates, the coating film is transferred to the final carrier. (Please read the notes on the back before filling this page) Printed by the Ministry of Economic Affairs, Central Bureau of Precision Industry and Consumer Cooperatives, 11 copies of this paper are suitable for the Chinese National Standard (CNS > A4 specification (2 丨 0X297mm)