WO2011000210A1

WO2011000210A1 - Composition of permeation enhancer and use thereof in transdermal drug delivery system

Info

Publication number: WO2011000210A1
Application number: PCT/CN2010/000935
Authority: WO
Inventors: 杨明京; 郑会义
Original assignee: 润和生物医药科技(汕头)有限公司
Priority date: 2009-07-01
Filing date: 2010-06-24
Publication date: 2011-01-06
Also published as: CN101940790A; CN101940790B

Abstract

A permeation enhancer and its use in the transdermal drug delivery system. The permeation enhancer comprises ethers and alcohols which are not C6-C18 fatty alcohols. It may further contains C6-C18 fatty acids or C6-C18 fatty alcohols. The ether compound is selected from dimethyl isosorbide, diethylene glycol monoethyl ether or diethylene glycol monomethyl ether. The alcohol compound is selected from propylene glycol, polyethylene glycol or benzyl alcohol. The permeation enhancer does not comprise DMSO.

Description

Permeation enhancer composition and application thereof in transdermal drug delivery system

The present invention relates to the field of pharmacy, and in particular to a novel penetration enhancer composition and its use in a transdermal delivery system.

Background technique

Synthetic compositions of estrogen and progestin are often used for contraception. If natural estrogen (17-beta estradiol) and progesterone (progesterone) compositions are used in the form of oral contraceptive pills, these two hormones undergo a large amount of initial metabolism in the liver and require a large dose. The resulting metabolites often cause undesirable side effects. Therefore, a combination of synthetic progesterone and estrogen is now mainly used as an oral contraceptive to overcome these drawbacks. Among them, one of the most representative combinations of oral contraceptives is a combination of levonorgestrel and ethinylestradiol.

Although synthetic progesterone and estrogen compositions are very effective in inhibiting ovulation, the use of this type of oral contraceptive still has certain side effects: in women who use oral contraceptives, thrombosis and strokes including myocardial infarction The incidence of related vascular disorders is high; the use of birth control pills is also associated with increased symptoms of benign liver tumors and a higher risk of gallbladder disease; if women continue to take pills after pregnancy may cause fetal abnormalities; oral contraceptives will also Stimulation of the human gastrointestinal digestive system, some women use oral contraceptives can cause discomfort; the possible complications of using oral contraceptives include breast cancer, uterine cancer, cervical cancer and vaginal cancer.

In recent years, fertility control drug delivery devices have been developed that can be implanted into the uterus, the cervix or the vagina, and subcutaneously implanted. These devices can provide sufficient steroid hormones to the human body for long-term and controlled control. purpose. Levonorgestrel is the most commonly used drug component in these devices, but the use and removal of these devices is very inconvenient, and the use of these drug delivery devices often causes discomfort and pain to the disease.

Transdermal drug delivery system (TDDS) is a new transdermal drug delivery preparation for the application of adhesives. It is applied on the surface of the skin and the drug passes through the skin at a constant speed (or near constant speed). Each layer enters the systemic circulation and produces a systemic or local therapeutic effect. Since the launch of Transderm Scop, the first transdermal absorption preparation in 1981, a variety of transdermal drug delivery formulations have been available. Drug absorption through the skin can reduce many side effects. Transdermal administration preparations have the following advantages: Avoiding the risks and inconveniences of intravenous injection and the variability of absorption and metabolism associated with oral treatment: Continuous administration, drugs with short biological half-life can also be used: because it is reduced in the digestive system The degradation can be effective even if the daily dose is lowered; the formulation is convenient to use, and if necessary, the treatment can be quickly terminated by removal from the surface of the skin.

Based on the above advantages, in recent years, domestic and foreign scholars have conducted extensive research on the transdermal drug delivery system. However, the skin that acts as a natural barrier to the body prevents the drug from entering the body. Most drugs, even those with low doses and high efficacy, have a transdermal rate that is difficult to meet. Overcoming the skin barrier and promoting the transdermal penetration of the drug to a therapeutic amount within a certain period of time is one of the key issues in the study of transdermal drug delivery systems such as body hormones. In recent years, the development and application of some penetration enhancers have greatly promoted the development of transdermal drug delivery systems.

U. The framework material used was ethylene-vinyl acetate copolymer (EVA 40) and the tackifier triethylene glycol hydrogenated rosinate, and the penetration enhancer was glycerol monooleate. US Patent Nos. 4,973,468 and 5,059,426 disclose a binary permeation combination of Diethylene glycol monoethyl ether and Methyl laurate, which can be used to increase the left block. Progesterone transdermal speed booth. However, this patent does not teach a reservoir or skeleton system that is compatible with this combination.

U.S. Patent No. 5,296,230 describes a system and method for the transdermal administration of levonorgestrel and estradiol compositions in the form of a matrix-type patch. The system skeleton material is medical silicone rubber, and the penetration enhancer is respectively made of polyethylene glycol aqueous solution (40% V/V) and Isoprop i myristate.

A system and method for transdermal administration of a novel levonorgestrel and estradiol composition is disclosed in U.S. Patent No. 5,560,922. Patch matrix material may be used in addition to medical silicone rubber, polyisoprene application also extends to a diene rubber and polyacrylate pressure-sensitive adhesive, the penetration enhancers are fatty alcohol series using n-decanol _(n - Decyl alcohol).

International Patent No. W09608255 to DUAN et al. discloses the polymerization of various kinds of monomers and different proportions of monomers to form various polyacrylic acid copolymers as pressure sensitive adhesive substrates for levonorgestrel-based transdermal delivery. In the case of medicine, the patent discloses Glyceryl monolaurate, N, N-dimethyldodecylamine-N-oxide, Tetrahydrofurfuryl alcohol, polyethylene glycol ether ( Polyethylene glycol ether ) , propylene glycol, dii sopropyl adipate and methyl ethyl laurate and combinations thereof can be used as a penetration enhancer for transdermal administration of levonorgestrel in the system. .

U.S. Patent No. 5,985,311, the disclosure of which is incorporated herein by reference to U.S. Pat. Skeletal transdermal delivery system.

US Patent No. 6,231,885 to CARRARA et al. discloses oleic acid and lauric acid (Laurie ac id) binary penetration system as a transdermal delivery system for levonorgestrel and estradiol compositions. Medium penetration enhancer.

U.S. Patent No. 6,312,715 to the entire disclosure of U.S. Pat. The system uses methanol, isopropanol, ethyl acetate as a co-solvent for levonorgestrel, and isopropyl myristate as a levonorgestrel penetration enhancer.

U.S. Patent No. 5,762,956 describes a levonorgestrel transdermal delivery device and a method of using the device for contraception. This system uses dimethylene sulfone (DMS0), lactic acid laurate ethyl lactate and citric acid as penetration enhancers.

In addition to the above-mentioned penetration enhancers involved in the transdermal administration of levonorgestrel, there are many patent documents reporting transdermal administration of other steroid hormones, particularly estradiol.

U.S. Patent No. 5,223,261 discloses the use of Isopropyi myristate, ethyl oleate, and Glyceryl monolaurate as penetration enhancers for the transdermal administration of estradiol. medicine. This patent forms the basis for BERLEX's development of CLIMARA and the Levonorgestrel CLIMARA PRO series of therapeutic osteoporosis patches for women.

Chinese patent CN1067875A discloses the use of azone, lauric acid and propylene glycol as penetration enhancers for transdermal administration of estradiol.

TO9832465 describes diethylene glycol monoethyl ether with sorbitan monolaurate (SPAN-20), diethylene glycol monoethyl ether and sorbitan monooleate (SPAN-80) binary penetration system for females Transdermal administration of diol.

The ideal steroid hormone penetration enhancer must meet the following requirements: (1) The penetration enhancer used has a certain solubility in steroid hormones; (2) The penetration enhancer used should have a good effect on promoting the penetration of body hormones, and the action time is predictable; (3) the penetration enhancer used is non-toxic, non-irritating and non-allergic to the skin and human body. No pharmacological effects; compatibility of drugs and other additives, including no physicochemical effects, no influence on drug activity and matching with drug properties; application can quickly work, but does not affect the normal physiological function of the skin after removal Does not cause loss of nutrients and moisture in the body: colorless, odorless: However, to date, no accelerator has been able to fully satisfy the conditions, and the permeation enhancers currently used have their own advantages and disadvantages.

Since levonorgestrel and estrogen are substances that represent very low solubility in steroid hormones, levonorgestrel and estrogen in an undissolved state are extremely difficult to penetrate the skin, therefore, in the production of levonorol When progesterone and estrogen transdermal delivery devices are selected, it is critical and important to select an appropriate solution to promote penetration. In order to solve the problem of levonorgestrel and estrogen dissolution, some dissolution-promoting systems use dimethylene sulfone (DMS0) to increase levonorgestrel dissolution and increase levonorgestrel penetration. The publication number is CN1399533. The Chinese patent discloses a transdermal contraceptive delivery system which uses dimethyl sulfoxide (DMS0), which has a good transdermal rate to human skin, but The potential toxicity of dimethyl sulfoxide to humans remains controversial. For safety reasons, dimethyl sulfoxide (DMS0) should be avoided in penetration enhancer compositions. There are also many fatty ester penetration enhancers that have been shown to have good penetration enhancing effects on levonorgestrel, for example, Methyl laurate, Polyethylene glycol monolaurate, Polypropylene glycol monolaurate

(Polypropylene glycol monolaurate) However, these penetration enhancers have a severe destructive effect on the viscosity or cohesion of the acrylic matrix system as a plasticizer, and the dissolution of levonorgestrel is very limited. In order to ensure the penetration-promoting effect, it is often required that high concentrations of levonorgestrel and estrogen are in a supersaturated state of dissolution in the viscous matrix of the transdermal delivery device, requiring the use of a high ratio of solubilizing penetration enhancers, When the above-mentioned high ratio fatty ester type penetration enhancer is used in the progesterone and estrogen transdermal delivery device, it often causes severe cold flow or loss of viscosity, and is not practically applicable.

In addition, the prior art transdermal drug delivery technical solutions use the mouse skin as an experimental object to achieve a certain transdermal amount of the drug to be transmitted through the mouse skin, in view of the great structure of the human skin and the mouse skin. Differently, the permeability of the mouse skin is much higher than that of the human skin. The transdermal rate given is very high, but it is not practical. The patch prepared on this basis can not really achieve the application on the human body. Achieve the amount of treatment required for medicine.

The inventors have unexpectedly discovered an ideal penetration enhancer composition that overcomes the problems of the prior art. The skin penetration enhancer composition of the present invention can not only effectively improve the solubility of body hormones, but also obtain better skin permeability and no damage to the adhesiveness of the patch. The penetration enhancer provided by the invention has a high transdermal rate on human skin in the absence of dimethyl sulfoxide (DMS0), and can provide the transdermal dose expected for steroid hormone treatment, thereby avoiding long-term use. Potential hazards associated with potential toxicity of dimethyl sulfoxide. Moreover, the transdermal drug delivery system is easy to manufacture by simple means, avoiding complicated manufacturing processes such as multilayer composite.

Summary of the invention

It is an object of the present invention to provide a penetration enhancer composition which does not contain dimethyl sulfoxide (DMS0) which is controversial for potential toxicity to humans. The penetration enhancer provided by the invention is applied to prepare a transdermal drug delivery system (patch), and the obtained product has good adhesion, no toxic side effects to the human body, safety and comfort, and the preparation process is simple and easy.

The penetration enhancer provided by the present invention contains an ether compound and an alcohol compound, or is composed of an ether compound and an alcohol compound. It should be particularly noted that: The term alcohol compound as used in the present invention refers to an alcohol compound which does not include 0 (:, ₈ fatty alcohol, that is, the alcohol of the present invention. The compound means an alcohol compound other than a c ₆ -c ₁₈ fatty alcohol.

In the penetration enhancer composed of the ether compound and the alcohol compound provided by the present invention, the ether compound and the alcohol compound are used in an amount of 1 to 30 parts by weight of the ether compound and 1 to 30 parts by weight of the alcohol compound. Preferably, the ether compound accounts for 1-20 parts, the alcohol compound accounts for 1-20 parts; more preferably: the ether compound accounts for 1-10 parts, and the alcohol compound accounts for 1-10 parts; most preferably The ether compound accounts for 1-4 parts, and the alcohol compound accounts for 1-4 parts. In the penetration enhancer of the present invention, the ether compound is preferably selected from the group consisting of isosorbide dimethyl ether, diethylene glycol monoethyl ether or diethylene glycol monomethyl ether.

In the penetration enhancer of the present invention, the alcohol compound is preferably selected from the group consisting of propylene glycol, polyethylene glycol (PEG400, PEG600, PEG1000 or PEG2000) or benzyl alcohol.

In a preferred embodiment of the invention, the penetration enhancer of the invention also contains (: ₆ - (: ₁₈ fatty acid or C ₆ - C ₁₈ fatty alcohol).

In the penetration enhancer comprising the ether compound, the alcohol compound and the C ₆ - C ₁₈ fatty acid or the C ₆ - fatty alcohol provided by the present invention, the three substances are used in parts by weight:

The ether compound accounts for 1-30 parts, the alcohol compound accounts for 1-30 parts, and the 0: ₁₈ fatty acid or C ₆ - C ₁₈ fatty alcohol accounts for 1-30 parts;

Preferably, the ether compound is 1 to 20 parts, the alcohol compound is 1 to 20 parts, the C ₆ -C _1S fatty acid or ( ₆ - (:, ₈ fatty alcohol is 1 to 20 parts; more preferably: The ether compound accounts for 10 parts, the alcohol compound accounts for 1-10 parts, the - ( ₁₈ fatty acid or the C ₆ - C ₁₈ fatty alcohol accounts for 1-10 parts. Most preferably: the ether compound accounts for 1-4 parts, The alcohol compound accounts for 1-4 parts, 0 (: ₁₈ fatty acid or GC ₁₈ fatty alcohol accounts for 1-4 parts. In the penetration enhancer of the present invention, the GrC ₁₈ fatty acid is preferably selected from the group consisting of citric acid, lauric acid or oleic acid. The C ₆ -C ₁₈ fatty alcohol is preferably selected from the group consisting of decyl alcohol, lauryl alcohol or oleyl alcohol.

In the penetration enhancer composition of the present invention, the most preferred embodiment is: the penetration enhancer is a combination of diethylene glycol monoethyl ether, propylene glycol and lauric acid; or a combination of isosorbide dimethyl ether, propylene glycol and lauric acid a composition of diethylene glycol monoethyl ether, propylene glycol and lauryl alcohol; or a combination of diethylene glycol monoethyl ether, benzyl alcohol and lauryl alcohol; or a combination of diethylene glycol monoethyl ether, propylene glycol and oleyl alcohol; A combination of sorbitol dimethyl ether, propylene glycol and oleyl alcohol: or a combination of diethylene glycol monoethyl ether, propylene glycol and decyl alcohol; or a combination of isosorbide dimethyl ether, propylene glycol and decyl alcohol. Among them, the ether compound in the above composition accounts for 1-4 parts by weight, the alcohol compound accounts for 1-4 parts by weight, and ( _6- (:, ₈ fatty acid or fatty alcohol accounts for 1-4 parts).

Another object of the present invention is to provide the use of the above penetration enhancers in the preparation of transdermal delivery systems.

The penetration enhancers of the present invention are particularly useful for the preparation of transdermal delivery systems (transdermal patches) for application to human skin. It is particularly suitable for the preparation of transdermal delivery systems for steroid hormones and compound steroid hormones which allow both progestogen and estrogen to penetrate the skin at the same time. The prepared transdermal delivery system for steroid hormones is applied to the skin of a woman and can be used to control fertility or treat osteoporosis in women, women's menopausal syndrome and the like. The steroid hormone transdermal delivery system of the present invention is particularly suitable for use in female contraception.

In one embodiment, the body hormone transdermal delivery system provided by the present invention comprises a protective layer 1, a reservoir layer 2 and a backing layer 3;

The drug storage layer 2 is attached between the peelable protective layer 1 and the backing layer 3, and is prepared from a viscous polymer matrix solution; the viscous polymer matrix solution components for preparing the drug storage layer 2 include: body hormones, viscous polymerization The above-mentioned penetration enhancer and viscosity modifier of the present invention.

The viscosities of the viscosities of the viscosities of the present invention are from 0 to 50 parts by weight, the viscous polymer is from 20 to 90 parts by weight, and the viscosity modifier is from 0.1 to 20 parts by weight. The steroid hormone accounts for 0. 1-5 parts by weight; more preferably: the penetration enhancer of the present invention accounts for 10-40 1-3重量份; Most preferably: The penetration enhancer of the present invention accounts for 10 parts by weight, the viscous polymer is 50-90 parts by weight, the viscosity modifier is 0.5 to 5 parts by weight, the steroid hormone is 0.1 to 1-3 parts by weight; 1-1重量份。 The -20 parts by weight, viscous polymer occupies 70-90 parts by weight, the viscosity modifier accounted for 0.5- 3 parts by weight, body hormones accounted for 0. 1-1 parts by weight.

The viscous polymer in the present invention may be selected from biologically acceptable viscous polymers such as crosslinked or uncrosslinked polyacrylate viscous polymers, silicone viscous polymers or polyisobutylene viscous polymers and the like. Preference is given to crosslinked or uncrosslinked polyacrylate viscous polymers.

Further details and examples of polyacrylate viscous polymers suitable for practicing the present invention have been described in Satas "Acryl ic Adhesives," Handbook of Pressure Sensitive- Adhesive Technology. 2 ^nd ed. pp 396- 456 (D. Satas, Ed. ) Ban Nostrand Reinhole, New York (1989). The polyacrylate viscous polymer may preferably be a compound having the following general formula (I):

- (C "CH_C00R) n

(I)

Wherein n represents the number of repeating units of the polymer monomer, and R is hydrogen or lower ((:, -(:,.))alkyl, and the lower fluorenyl group may be selected from ethyl, butyl, ethylhexyl and the like. In a preferred embodiment of the invention, the polyacrylate viscous polymer is preferably poly(2-ethylhexyl acrylate/acrylic acid copolymer), poly(2-hydroxyhexyl acrylate/acrylic acid/methyl acrylate copolymer) ), poly (2-ethylhexyl acrylate / acrylic acid / methyl acrylate copolymer) or poly (2-ethylhexyl acrylate / acrylic acid / butyl acrylate / vinyl acetate copolymer). Such as Cytec Surface Specialties Inc GMS 737, 788, 1753; DUROTAK 87-4098, 87-2287, 87-4297, 87_900A, 87-2677 of National Starch Chemical Company; R0DERM 607 or 610 of Rohm Haas company, and the like.

The silicone viscous polymer may be: A suitable silicone plant comprises a silicone pressure sensitive adhesive based on two main components, a polymer and an elastomer or a tackifying resin. The preparation of the silicone siloxane rubber is generally carried out in a suitable organic solvent, and the elastomer (typically a high molecular weight polydiorganosiloxane) is cross-linked with a resin by a condensation reaction to produce Three-dimensional polysiloxane structure. The ratio of the resin to the elastomer is an important factor that can be adjusted to modify the physical properties of the polysiloxane. Sobieski, et al., "Silocone Pressure Sensitive Adhesives, "Handbok of Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989). Suitable silicone siloxane pressure sensitive adhesives include the trade names BIO-PSA X7-3027, Χ7-4203, Q7-4503, Χ7-4603, Χ7-4301, Χ7-4303, Χ7-4919, available from Dow Coring Corporation. Χ7-2685 and Χ7-3122 polysiloxane pressure sensitive adhesive. ΒΙ0—PSA X7-4203, X7-4301 and X7-4303.

The polyisobutylene viscous polymer may be: a hydrocarbon polymer such as natural or synthetic poly-2-methylbutadiene, polybutene and polyisobutylene, styrene/butadiene polymer, styrene 2-A Butadiene-styrene block copolymer, hydrocarbon-based polymer (such as butyl rubber), polypropylene eye, halogen-containing polymer (such as polytetrafluoroethylene, polyvinyl chloride, poly(1-dichloroethylene) And polychloroprene) and their other copolymers.

The viscous polymer matrix of the present invention also includes a viscosity modifier dispersed in the matrix. A medicinal polymer material commonly used in the pharmaceutical industry can be used as a viscosity modifier. Viscosity modifiers are used to control the viscosity of the polymer matrix. Adding a viscosity modifier to the viscous polymer matrix can increase the comfort of the transdermal contraceptive delivery system (patch), reduce skin inflammation, and prevent long-term use of transdermal Fall off when the patch is applied. Wherein the viscosity modifier is polyvinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone, polybutyl methacrylate/methyl methacrylate copolymer or ethyl cellulose. The polyvinylpyrrolidone used in the practice of the present invention is selected from K12, Κ17, Κ25, 00 manufactured by BASF Corporation. The polybutyl methacrylate/methyl methacrylate used in the practice of the present invention is selected from Degusset (Plastoid B manufactured by DEGUSSA Co., Ltd.) The ethyl cellulose used in the practice of the present invention is selected from the group consisting of Dow Chemical Company. Produced Ethocel 7, 10, 14, 20. The viscosity modifier is preferably polyvinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone or ethylcellulose. The viscosity modifier is most preferably a polyvinylpyrrolidone having a molecular weight of 50,000/ Vinyl acetate, and the weight ratio of polyvinylpyrrolidone to vinyl acetate is 6: 4. For example, polyvinylpyrrolidone/vinyl acetate copolymer S-630 produced by American International Special Products Co., Ltd.; polyethylene produced by BASF of Germany Pyrrolidone/vinyl acetate copolymer VA64.

The steroid hormone is selected from one or more of a progestogen and an estrogen. The steroid hormone is preferably composed of 1 to 30 parts by weight of progestin and 1 to 10 parts by weight of estrogen; more preferably 1 to 20 parts by weight of progestogen and 1 to 5 parts of estrogen.

The progestogen in the steroid hormone may be selected from the group consisting of: levonorgestrel, norgestrel, norgestrel variant, formazin, norethisterone, acetyl unison, hydroprogesterone, Gestodene, diacetol diacetate, hydroxyprogesterone acetate, progesterone, other biocompatible progesterone that can be absorbed through the skin; absorbed through the skin and converted after absorption A biocompatible progestogen derivative such as a progestogen.

The estrogen in the steroid hormone may be selected from the group consisting of ethinyl estradiol, 170-estradiol, and biocompatible derivatives thereof. If the amount of absorption meets the daily dose of the estrogen component and if the hormone component is compatible, 17 beta-estradiol biocompatibility can also be used for transdermal absorption and preferably biotransformation to 17 beta - female a derivative of a diol. Such estradiol derivatives include esters, monoesters or diesters. The monoester may be a 3- or 17-ester. The estradiol ester can be, for example, estradiol-3,17-diacetate; estradiol-3-acetate; estradiol. 17-acetate; estradiol-3, 17 -divalerate; estradiol-3-valerate: estradiol-17-valerate; 3-mono-, 17-mono and 3, 17-dipivi lateesters; 3-mono-, 17-single -and 3,17-dipropionate; 3-mono-, 17-mono- and 3,17-dicyclopentyl-propionate: corresponding cypionate, heptanoate, benzoate and similar esters Thinyl estradiol: estrone; and other transdermally absorbable estrogen steroids and their derivatives.

Progesterone in steroid hormones is most preferably levonorgestrel, and estrogen is most preferably ethinyl estradiol.

For the steroid hormone transdermal delivery system provided by the present invention, a particularly preferred technical solution is as follows:

In a preferred embodiment, in the viscous polymer matrix solution for preparing the reservoir layer 2, the components are used in parts by weight: 10-20 parts by weight of the penetration enhancer of the present invention, viscous polymer 70- 90重量份, viscosity adjusting agent 0. 5-3 parts by weight, body hormone 0. 1-1 parts by weight; the body hormone is composed of 1-20 parts by weight of progestogen and 1-5 parts by weight of estrogen; The penetration enhancer is composed of 1-4 parts by weight of an ether compound, 1-4 parts by weight of an alcohol compound, and 1-4 parts by weight of (: ₆ - (:, ₈ fatty acid or C ₆ - C ₁₈ fatty alcohol) Composition; the ether compound is selected from diethylene glycol monoethyl ether or isosorbide dimethyl ether; the alcohol compound is propylene glycol, benzyl alcohol, PEG400, PEG600 or PEG1000; the 0 C ₁₈ fatty acid is selected from lauric acid Oleic acid or citric acid: The Or" _C18 fatty alcohol is selected from the group consisting of decyl alcohol, lauryl alcohol or oleyl alcohol.

The transdermal delivery system for body hormones prepared by the penetration enhancer of the present invention is preferably made into a round, square or rectangular patch having an area of 10 to 30 square centimeters; more preferably, the area is 15 to 25 square centimeters. Round, square or rectangular patch.

In the transdermal delivery system of steroid hormone prepared by the penetration enhancer of the present invention, the thickness of the reservoir layer 2 may be between 50 and 200 microns; Between 80-150 microns.

In the transdermal delivery system of the body hormone prepared by the penetration enhancer of the present invention, the backing layer is not particularly limited, and a backing layer which is substantially impermeable to a drug or the like is preferable; in other words, such a backing layer, which passes A drug, an additive or the like which is an active ingredient in the matrix layer is prevented from passing through it and is lost from the back side, so that the content of the drug, the additive or the like is not lowered. The laminate of the backing layer 3 may be a laminate of a polymer film with or without a metal foil such as aluminum foil. Materials suitable for use in the liner of the present invention include: polyethylene, polypropylene, polyurethane, polyvinyl chloride, poly(ethylene phthalate), metal foil, and the like. Scotchpakl l09 or C _O tran9720 produced by 3M Company is preferred as the backing material in the present invention. The thickness of the backing layer 3 may be between 10 and 300 microns; preferably between 20 and 100 microns, more preferably between 30 and 50 microns.

In the transdermal administration system of the steroid hormone prepared by the penetration enhancer of the present invention, the protective layer 1 is not particularly limited as long as the release characteristics of the transdermal administration system are sufficiently ensured. The material of the protective layer 1 may be a polyester film, a polyvinyl chloride film, a polyvinylidene chloride film, a poly(ethylene terephthalate) film, a high quality paper, a cellophane, etc., a polyolefin and a paper. Such as a laminate film of high-quality paper, cellophane or the like, the side which is in contact with the substrate layer is subjected to a release treatment by applying a silicone resin, a fluororesin or a corona. The invention is preferably produced by 3M Company

Scotchpakl022 is used as a protective layer material. The protective layer 1 may have a thickness of between 10 and 300 microns; preferably a thickness of between 30 and 200 microns, more preferably between 50 and 100 microns.

In order to increase the solubility of the active ingredient (steroidal hormone) during the preparation of the steroid hormone transdermal delivery system, an optional co-solvent may be added. These co-solvents may be selected from the group consisting of acetone, methanol, ethanol, isopropanol, ethyl formate, ethyl acetate, tetrahydrofuran, and any mixtures thereof. When necessary, physical means such as heating or ultrasonic vibration can be used to promote drug dissolution. The cosolvent can be removed during the subsequent preparation.

The invention also provides a preparation method for preparing a steroid hormone transdermal drug delivery system by using the penetration enhancer of the invention, comprising the following steps: (a) weighing a body hormone (active component), adding a viscosity modifier, a penetration enhancer , cosolvent, stir to dissolve; add viscous polymer, stir, mix thoroughly; stand, to obtain a viscous polymer matrix;

(b) the viscous polymer matrix obtained in step (a) is coated (sprayed, solution cast) on the protective layer 1 and dried to obtain a reservoir layer 2 attached to the protective layer 1;

(c) placing the material as the backing layer 3 on the reservoir layer 2 and laminating together;

(d) After lamination, the patch is transdermally applied according to the desired shape and area; it can be cut into a circular, square, rectangular or other desired shape.

(e) The resulting transdermal delivery system is placed in a package for storage and stored for transdermal treatment. In the prepared patch, the amount of the body hormone (active ingredient) dispersed in the viscous polymer matrix can be made larger than the desired delivery dose, for example, 10-50 times more than the total dose desired to be delivered: An excess of 20-30 times.

The reservoir layer 2 can be processed using any acceptable method known in the art, such as coating, spraying, solution casting, and the like. The permeation rate and adhesion of the desired transdermal delivery system can be obtained by adjusting the concentration or dry concentration of the penetration enhancer in a portion of the reservoir layer.

The transdermal drug delivery system provided by the invention is applied to the skin of a woman, can effectively control fertility, and achieve the purpose of contraception.

One skilled in the art can determine the composition of the steroid hormone selected for the purpose of treatment. For example, estradiol can be used to prevent osteoporosis, women's menopausal syndrome. The active ingredients determined by those skilled in the art based on the therapeutic purpose are all included in the present invention. In the present invention, "C ₆ -C _1S fatty acid" means an acid having a carbon chain of 6 to 18 carbon atoms: "C ₆ -C, ₈ fatty alcohol" means a carbon chain having 6 to 18 carbon atoms "A viscous polymer" means that when it is applied to a surface as a solution and dried, the polymer forms a film which, as understood by those skilled in the art, will have adhesion and cohesive strength; "Modulator" means a substance capable of changing viscosity; "steroidal hormone" means a hormone of a steroidal compound such as estrogen or progestin. In the present invention, "permeabilizing agent" means an agent capable of accelerating or promoting penetration of a drug into, for example, the skin, and may also be referred to as "permeation enhancer" in the art.

In this document, unless otherwise specified, the content or amount is in parts by weight; if not specified, the equipment, equipment, materials, materials, dosage, method, time, temperature and other conditions are all used. The art is well known or can be obtained by those skilled in the art in light of the prior art in accordance with the description of the present application.

The skin penetration enhancer composition of the present invention can not only effectively improve the solubility of steroid hormones in a transdermal administration system such as the transdermal drug delivery system of the present invention, but also obtain better skin permeability and adhesion. The adhesion of the agent was not destroyed. Moreover, since the penetration enhancer composition of the present invention is capable of producing a very good synergistic absorption promoting effect, it has an efficient penetration promoting effect, and can significantly increase the transdermal rate of the drug (active ingredient), without dimethyl groups. Under the condition of sulfoxide (DMS0), the expected dose of drugs (such as levonorgestrel and estrogen transdermal contraception) in transdermal drug delivery systems can also be provided, thus avoiding the long-term use of dimethyl sulfoxide (DMS0). The potential danger of osmosis. In addition, the penetration enhancers of the present invention are compatible with a number of acrylic pressure sensitive adhesive matrix systems and have less cohesive, viscous and rheological properties inherent to the matrix system. In addition, the transdermal drug delivery system provided by the present invention has a simple preparation method and avoids complicated processes such as multilayer composite. The initial tack and holding strength, thermal stability, oxidation resistance, release rate, safety and the like of the products obtained by the invention are superior to the prior art. The transdermal drug delivery system prepared by using the penetration enhancer composition of the invention has good therapeutic effect and is safe and convenient to use.

DRAWINGS

Figure 1 is a schematic cross-sectional view of a transdermal drug delivery system of the present invention

1. Protective layer 2. Storage layer 3. Backing layer

detailed description

The following "preparation method" is a general preparation method of the steroid hormone transdermal delivery system of the present invention, and the "in vitro skin permeation test" is a measurement of the permeation rate of the drug through the skin in the transdermal delivery system of each of the examples. experimental method.

Preparation

According to the amounts given in the examples, the active ingredient (body hormone) was weighed, placed in a glass bottle, and added with a viscosity modifier, a solubilizer, a penetration enhancer, and stirred until the active ingredient was dissolved. Viscous polymer solution was added to speed 200r _P m under stirring for 6 hours to form a uniform solution. Allow to stand for 3 hours. A viscous polymer matrix solution is obtained.

The resulting viscous polymer matrix solution was applied to a protective layer material (e.g., Scotch Pak 1022 manufactured by 3M Co., St. Paul Minn.), coated to a thickness of about 600 μm, and then dried in an oven at 65 ° C for 30 minutes. . After drying, the thickness of the viscous polymer matrix layer (storage layer) is about 120 μm. A piece of release liner (backing layer) of the same size (such as Scotch Pak 1109 or Cotran by 3M Co., St. Paul Minn.)

9720) was placed on a layer of viscous polymer matrix and laminated together to provide a patch for a transdermal delivery system. The patch was cut into a 20 square centimeter round patch. Place the patch in the appropriate packaging for storage (such as paper bags and/or foil pouches) and store it for later use. In vitro male penetration test:

The fresh human skin is cut into a certain size and the skin is tightly stretched between the two chambers of the VALIA-CHIEN permeation cell. The dermis layer faces the receiving chamber, and the horny layer is covered with a transdermal protective patch after removing the protective layer. The two chambers are fixed in a double port, and 40% (v/v) ?£&400 physiological saline solution 3.41111 is added in the receiving chamber to control the water temperature in the permeation pool interlayer at 32 ±0. 5° (:, electromagnetic stirring speed 500 r /min, according to the prescribed 4, 8, 24, 32, 48 hour interval, remove the ΙΟΟμΙ permeate from the receiving chamber, and add an equal amount of 40% (v/v) PEG400 physiological saline solution blank, determined by HPLC Transdermal cumulative release of LNG and EE in permeate. The cumulative amount of drug was analyzed linearly over time to calculate the rate of penetration of the drug through the skin for 48 hours.

Example 1

Steroid hormone: levonorgestrel 0. 05g, ethinyl estradiol 0. 05g;

Viscosity modifier: PVP / VA copolymer (VA64) 0. lg _;

5克 ; _2g; propylene glycol 2. 5g; diethylene glycol monoethyl ether 2. 5g _;

Viscous polymer: GMS737 20 g

The transdermal rate of levonorgestrel is 0.14 g/cm ² /h, and the transdermal rate of ethinyl estradiol is: 0.1 g/cm ² /h.

Example 2

The steroidal hormone: levonorgestrel 0. 2g, ethinyl estradiol 0. lg _;

Viscosity modifier: PVP / VA copolymer (VA64) 1. 5g;

6g of penetration enhancer: 2g of propylene glycol and 4g of diethylene glycol monoethyl ether _;

Viscous polymer: GMS737 30 g ;

The transdermal rate of levonorgestrel is 0.16 /cm7h, and the transdermal rate of ethinyl estradiol is: 0.1 _g / cm ² /h.

Example 3

Steroid hormone: levonorgestrel 0. 3g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 3g;

Penetration enhancer 8g: Propylene glycol 2g, isosorbide dimethyl ether 6g:

Viscous polymer: GMS737 40 g;

The transdermal rate of levonorgestrel is 0.2 (g/cm ² /h, and the transdermal rate of ethinyl estradiol is: 0.1 g/cm ² /h.

Example 4

Steroid hormone: levonorgestrel 0. 4g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP/VA copolymer (S-630) 0. 4g : .

Promoting agent 10g: propylene glycol 2g, diethylene glycol monoethyl ether 8g _;

Viscous polymer: GMS737 50 g:

The transdermal rate of levonorgestrel was measured to be 184 g/cra ² /h, and the transdermal rate of ethinyl estradiol was: 0.254 _g /cm ² /h.

Example 5 The steroidal hormone: levonorgestrel 0. 6g, ethinyl estradiol 0. lg _;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 5g;

Promoting agent 18g: propylene glycol 3g, diethylene glycol monoethyl ether 15g _;

Viscous polymer: GMS737 60 g;

The transdermal rate of levonorgestrel was 0. 18 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 124 g/cm ² /h. Example 6

Steroid hormone: levonorgestrel 0. 5g, ethinyl estradiol O. lg;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 6g;

Promoting agent 21g: propylene glycol 3g, diethylene glycol monoethyl ether _18g;

Viscous polymer: GMS737 70 g _;

The transdermal rate of levonorgestrel was 0.18 g/cm ² /h, and the transdermal rate of block estradiol was: 0.1 g/cm ² /h. Example 7

Steroid hormone: levonorgestrel 0. 7g, ethinyl estradiol O. lg;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 7g;

Penetration enhancer 24 _g: propylene glycol 3 g, isosorbide dimethyl ether 21 g;

Viscous polymer: GMS737 80 g;

The transdermal rate of levonorgestrel was 0. 20 g / _Cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.24 g / _Cni ² /h. Example 8

The steroidal hormone: levonorgestrel 0. 8g, ethinyl estradiol 0. 2g _;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 8g;

Penetration enhancer 20g: propylene glycol 10g, diethylene glycol monoethyl ether 10g;

Viscous polymer: DUR0TAK 87-4098 80 g;

The transdermal rate of levonorgestrel is 0. 20μ _Β /αη ² /1ι, and the transdermal rate of ethinyl estradiol is: 0.15 g/cm ² /h. Example 9

Steroid hormone: levonorgestrel 0. 9g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 9g;

Promoting agent 30g: propylene glycol 3g, diethylene glycol monomethyl ether 27g;

Viscous polymer: GMS 1753 80 g;

The transdermal rate of levonorgestrel was measured to be 0. . Example 10

Steroid hormone: levonorgestrel 0. 10g, ethinyl estradiol O. Olg:

Viscosity modifier: PVP/VA copolymer (S-630) l. Og;

Promoting agent 33g: propylene glycol 3g, isosorbide dimethyl ether 30g _; Viscous polymer: GMS737 75 g _;

The transdermal rate of levonorgestrel was measured to be 0.12 g/cm ² /h, and the transdermal rate of ethinyl estradiol was 0.08 g/cm ² /h. Example 11

Steroid hormone: levonorgestrel 0.15g, ethinyl estradiol O.Olg;

Viscosity modifier: PVP / VA copolymer (S-630) 1. lg;

Promoting agent 36g: Propylene glycol 3g, diethylene glycol monoethyl ether 33g:

Viscous polymer: GMS 788 60 g;

The transdermal rate of levonorgestrel was measured to be 0.16 g/cni ² /h, and the transdermal rate of ethinyl estradiol was 0.08 g/cm ² /h. Example 12

Steroid hormone: levonorgestrel 0.2g, ethinyl estradiol O.Olg;

Viscosity modifier: PVP / VA copolymer (S-630) 1.2g;

Promoting agent 39g: propylene glycol 3g, diethylene glycol monomethyl ether 36g;

Viscous polymer: GMS737 65 g;

The transdermal rate of levonorgestrel was measured to be 0.12 g/cra ² /h, and the transdermal rate of ethinyl estradiol was 0.08 g/cm ² /h. Example 13

Steroid hormone: levonorgestrel 0.3 _g , ethinyl estradiol O.Olg;

Viscosity modifier: PVP/VA copolymer (S-630) 1.3g;

Promoting agent 45g: propylene glycol 3g, diethylene glycol monoethyl ether 42g _;

Viscous polymer: GMS 788 80g _;

The transdermal rate of levonorgestrel was measured to be 0.12 g/cm ² /h, and the transdermal rate of ethinyl estradiol was 0.04 _g /cm ² /h. Example 14

Steroid hormone: levonorgestrel 0.1g, ethinyl estradiol 0.2g _;

Viscosity modifier: PVP / VA copolymer (S-630) 1.4g _;

Promoting agent 42g: propylene glycol 3g, isosorbide dimethyl ether 39g _;

Viscous polymer: GMS737 80 g;

The transdermal rate of levonorgestrel was measured to be 0.12 g/cra ² /h, and the transdermal rate of ethinyl estradiol was 0.18 _g /cm ² /h. Example 15

Steroid hormone: levonorgestrel 0.1g, ethinyl estradiol 0.02 _g;

Viscosity modifier: PVP / VA copolymer (S-630) 1.5g _;

Viscous polymer: GMS737 80 g;

The transdermal rate of levonorgestrel was measured to be 0.12 g/cm ² /h, and the transdermal rate of ethinyl estradiol was 0.06 g/cm ² /h. Example 16 The steroidal hormone: levonorgestrel 0. lg, ethinyl estradiol 0. 04g _;

Viscosity modifier: PVP / VA copolymer (S-630) 1. 6g;

Penetration enhancer 48g: propylene glycol 3g, isosorbide dimethyl ether 45g;

Viscous polymer: GMS737 80 g;

The transdermal rate of levonorgestrel was 0.16 g/cm7h, and the transdermal rate of ethinyl estradiol was: 0. Example 17

Steroid hormone: levonorgestrel 2g, ethinyl estradiol lg _;

Viscosity modifier: PVP / VA copolymer (S-630) 1. 7g;

Promoting agent 17g: propylene glycol lg, diethylene glycol monoethyl ether 16g;

Viscous polymer: GMS737 70 g;

The transdermal rate of levonorgestrel was 0. 20μ ₈ / η ² /1ι, and the transdermal rate of ethinyl estradiol was: 0.1 g/cm ² /h. Example 18

Steroid hormone: levonorgestrel lg, ethinyl estradiol lg:

Viscosity modifier: PVP/VA copolymer (S- 630) 1. 8g ·'

Promoting agent 19g: propylene glycol lg, isosorbide dimethyl ether 18g _;

Viscous polymer: GMS737 75 g;

The transdermal rate of levonorgestrel was measured to be 0.2 (g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.2 g/cm ² /h.

The steroidal hormone: levonorgestrel 1. 5g, ethinyl estradiol 1. 0g _;

Viscosity modifier: PVP / VA copolymer (S-630) 1. 9g;

Penetration inhibitor 20 _g: propylene glycol lg, isosorbide dimethyl ether 19 g;

Viscous polymer: GMS737 80 g;

The transdermal rate of levonorgestrel is 0. 2Wg/cm ² /h, and the transdermal rate of ethinyl estradiol is: 0.17 g / _Cm ² /h. Example 20

Steroid hormone: levonorgestrel 0. lg, acetylene female 0. 08g _;

Viscosity modifier: PVP / VA copolymer (S-630) 2. 0g;

Penetration enhancer 21g: propylene glycol lg, diethylene glycol monoethyl ether 20g;

Viscous polymer: GMS737 80 g;

The transdermal rate of levonorgestrel is 0. 12 g / cra ² / h, and the transdermal rate of ethinyl estradiol is: 0. l (^g / cm ² / h. Example 21

Steroid hormone: levonorgestrel 0. lg, ethinyl estradiol 0. 09g;

Viscosity modifier: PVP/VA copolymer (S-630) 2. lg :

Penetration inhibitor 22 _g: propylene glycol lg, diethylene glycol monoethyl ether 21g; Viscous polymer: GMS737 80 g;

Levonorgestrel permeation rate was measured as ^{0. 12 g / cm 2 / h} , ethinyl estradiol transdermal _{rate: 0. 12 g / c m h} . Example 22

Steroid hormone: levonorgestrel 0. 1g, ethinyl estradiol O. Olg:

Viscosity modifier: PVP / VA copolymer (S-630) 2. 2g;

Promoting agent 23g: propylene glycol lg, diethylene glycol monoethyl ether 22 _g:

Viscous polymer: DUROTAK87-2287 80 g;

The transdermal rate of levonorgestrel was 0.12 g/cm h, and the transdermal rate of ethinyl estradiol was: 0. 044 g/cm ² /h. Example 23

Steroid hormone: levonorgestrel O. Olg, ethinyl estradiol 0. 10g;

Viscosity modifier: PVP/VA copolymer (S-630) 2. 3g :

Promoting agent 25 _g: propylene glycol lg, isosorbide dimethyl ether 24g _;

Viscous polymer: DUR0TAK87- 4297 80 g _:

The transdermal rate of levonorgestrel is 0. 064g/cni ² /h, and the transdermal rate of ethinyl estradiol is: 0.17 g/cm ² /h. Example 24

Steroid hormone: levonorgestrel 0. lg, ethinyl estradiol 0. 20g;

Viscosity modifier: PVP / VA copolymer (S-630) 2. 4g;

Penetration enhancer 26g: propylene glycol lg, diethylene glycol monoethyl ether 25g;

Viscous polymer: DUROTAK87-900A 80 g;

The transdermal rate of ethinyl estradiol is 0. 14 g/cm ² /h, and the transdermal rate of ethinyl estradiol is: 0.2 Wg/cm ² /h. Example 25

The steroidal hormone: levonorgestrel 0. 05 _g , ethinyl estradiol 0. 25g;

Viscosity modifier: PVP / VA copolymer (S-630) 2. 5g;

Promoting agent 27g: propylene glycol lg, diethylene glycol monoethyl ether 26g;

Viscous polymer: GMS737 90 g;

The transdermal rate of levonorgestrel was 0. 044 g/cni ² /h, and the transdermal rate of ethinyl estradiol was: 184 g/cm ² /h. Example 26

Steroid hormone: levonorgestrel lg, ethinyl estradiol 3 _g;

Viscosity modifier: PVP / VA copolymer (S-630) 2. 6g;

Promoting agent 25g: propylene glycol lg, diethylene glycol monoethyl ether 28 _g;

Viscous polymer: DUR0TAK87-2677 80 g;

The transdermal rate of levonorgestrel was determined to be 0.2 (^g/cm ² /h, and the transdermal rate of estrone was: 254 g/cm ² /h. Example 27 Body hormone: levonorgestrel lg, ethinyl estradiol 0. lg _;

Viscosity modifier: PVP / VA copolymer (S-630) lg;

Penetration enhancer 20g: propylene glycol 10g, isosorbide dimethyl ether 10g;

Viscous polymer: GMS737 80 g;

The transdermal rate of levonorgestrel was 0. 254 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 154 g/cm ² /h. Example 28

Steroid hormone: levonorgestrel 0. 02g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP / VA copolymer (S-630) 2. 8g;

Promoting agent 31g: propylene glycol lg, diethylene glycol monoethyl ether 30g;

Viscous polymer: GMS737 80 g;

The transdermal rate of levonorgestrel is 0. 064g/cm ² /h, and the transdermal rate of ethinyl estradiol is: 144g/cm ² /h. Example 29

Steroid hormone: levonorgestrel 0. lg, ethinyl estradiol O. Olg;

Viscosity modifier: PVP/VA copolymer (S-630) 2. 9g;

Promoting agent 31g: propylene glycol 30g, diethylene glycol monoethyl ether l _g;

Viscous polymer: GMS737 80 g;

Levonorgestrel permeation rate was measured to ^{0. 14 ^ / cm 2 / h} , ethinyl estradiol transdermal ^{rate: 0. 03 g / cm 2 /} h. Example 30

Steroid hormone: levonorgestrel 0. lg, ethinyl estradiol O. Olg:

Viscosity modifier: PVP/VA copolymer (S-630) 3. 0g:

Penetration enhancer 26 _g: propylene glycol 25 _g , isosorbide dimethyl ether lg;

Viscous polymer: GMS737 80 g;

The transdermal rate of ethinyl estradiol was 0.3 g/cra ² /h, and the transdermal rate of ethinyl estradiol was 0.03 g/cm ² /h. Example 31

Steroid hormone: levonorgestrel 0. lg, ethinyl estradiol O. Olg:

Viscosity modifier: PVP/VA copolymer (S-630) 3. lg;

Promoting agent 21g: propylene glycol 20g, diethylene glycol monoethyl ether l _g;

Viscous polymer: GMS737 80 g;

The transdermal rate of norgestrel was 0. 144 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0. 034 g/cm ² /h. Example 32

The steroidal hormone: levonorgestrel 0. 01g, ethinyl estradiol 0. l _g;

Viscosity modifier: PVP/VA copolymer (S-630) 3. 2g;

Promoting agent 16g: propylene glycol 15g, diethylene glycol monoethyl ether l _g; Viscous polymer: GMS737 90 g;

The transdermal rate of levonorgestrel is 0. 044g/cm7h, and the transdermal rate of ethinyl estradiol is: 0.15 g/cm ² /h. Example 33

Steroid hormone: levonorgestrel 0. 1g, ethinyl estradiol O. Olg;

Viscosity modifier: PVP / VA copolymer (S-630) 3. 3g;

Penetration enhancer 22 _g: propylene glycol 20 g, diethylene glycol monoethyl ether 2 g _:

Viscous polymer: GMS737 80 g _;

The transdermal rate of levonorgestrel was 0.13 g/cni7h, and the transdermal rate of ethinyl estradiol was: 0.03 g/cm ² /h. Example 34

Steroid hormone: levonorgestrel 0. 2g, ethinyl estradiol O. Olg;

Viscosity modifier: PVP / VA copolymer (S-630) 3. 4g;

Promoting agent 18 _g: propylene glycol 15g, isosorbide dimethyl ether 3g _;

Viscous polymer: GMS737 80 g;

The transdermal rate of levonorgestrel was measured to be 0. The transdermal rate of ethinyl estradiol is: 0.05 g/cm ² /h. Example 35

The steroidal hormone: levonorgestrel 0. 1g, ethinyl estradiol 0. 3g _;

Viscosity modifier: PVP / VA copolymer (S-630) 3. 5g;

Promoting agent 15g: benzyl alcohol 12g, diethylene glycol monoethyl ether _3g;

Viscous polymer: GMS737 80 g _;

The transdermal rate of levonorgestrel is 0. 164 g / cin ² / h, and the transdermal rate of ethinyl estradiol is: 0. 25 g / cm ² / h. Example 36

The steroidal hormone: levonorgestrel 0. lg, ethinyl estradiol 0. 4g _;

Viscosity modifier: PVP/VA copolymer (S-630) 3. 6g;

Penetration enhancer 20g: PEG400 15g, diethylene glycol monoethyl ether 5g;

Viscous polymer: R0DERM 607 80 g:

The transdermal rate of levonorgestrel is 0. 124 g / cra ² / h, and the transdermal rate of ethinyl estradiol is: 0. 25 g / cm ² / h. Example 37

The steroidal hormone: levonorgestrel 0. lg, ethinyl estradiol 0. 5g _;

Viscosity modifier: PVP / VA copolymer (S-630) 3. 7g;

15g of penetration enhancer: propylene glycol 10g, diethylene glycol monoethyl ether 5g _;

Viscous polymer: R0DER 610 80 g;

The transdermal rate of levonorgestrel was 0.12 g/cra ² /h, and the transdermal rate of ethinyl estradiol was: 274 g/cm ² /h. Example 38 The steroidal hormone: levonorgestrel 0. 1g, ethinyl estradiol 0. 6g _;

Viscosity modifier: PVP / VA copolymer (S-630) 3. 8g;

Promoting agent 41 _g: propylene glycol 5 g, isosorbide dimethyl ether 36 g;

Viscous polymer: GMS737 80 g _:

The transdermal rate of levonorgestrel was 0.124 g/cra ² /h, and the transdermal rate of ethinyl estradiol was: 284 g/cm ² /h. Example 39

The steroidal hormone: levonorgestrel 0. lg, ethinyl estradiol 0. 7g _;

Viscosity modifier: PVP / VA copolymer (S-630) 4. lg;

Promoting agent 42 _g: propylene glycol 10 g, diethylene glycol monoethyl ether 32 g;

Viscous polymer: GMS737 80 g;

The transdermal rate of levonorgestrel is 0. 124g/cra ² /h, and the transdermal rate of ethinyl estradiol is: 0.3 (^g/cm ² /h. Example 40

The steroidal hormone: levonorgestrel 0. lg, ethinyl estradiol 0. 8g _;

Viscosity modifier: PVP / VA copolymer (S-630) 4. 2g;

Promoting agent 43g: propylene glycol 13g, diethylene glycol monoethyl ether 20g;

Viscous polymer: GMS737 80 g _;

The transdermal rate of levonorgestrel is 0.14 g/cra ² /h, and the transdermal rate of ethinyl estradiol is: 0.3 (^g/cm ² /h. Example 1

The steroidal hormone: levonorgestrel 0. lg, ethinyl estradiol 0. 9g _;

Viscosity modifier: PVP/VA copolymer (S-630) 4. 3g;

Promoting agent 44g: propylene glycol 10g, diethylene glycol monoethyl ether 44g;

Viscous polymer: GMS737 90 g _;

The transdermal rate of levonorgestrel was 0.14 g/cin ² /h, and the transdermal rate of ethinyl estradiol was: 0.29 Mg/cm ² /h. Example 2

Steroid hormone: levonorgestrel 0. lg, ethinyl estradiol 1. 0g;

Viscosity modifier: PVP/VA copolymer (S-630) 4. 5g ; ~"

Penetration enhancer 45g: propylene glycol 5g, isosorbide dimethyl ether 40g;

Viscous polymer: GMS737 80 g _;

The transdermal rate of levonorgestrel was 0. 084g/cm7h, and the transdermal rate of ethinyl estradiol was: 0.2 (g/cra ² /h. Example 43

Steroid hormone: levonorgestrel 3. 0g, ethinyl estradiol l. Og;

Viscosity modifier: PVP / VA copolymer (S-630) 5. 0g;

50g of penetration enhancer: propylene glycol 20g, diethylene glycol monoacetic acid 30g; Viscous polymer: GMS737 80 g;

The transdermal rate of levonorgestrel was 0.14 g/cni ² /h, and the transdermal rate of ethinyl estradiol was: 0. 25 g/cni ² /h. Example 44

5g _; ethinyl estradiol 1. 5g _;

Viscosity modifier: PVP / VA copolymer (S-630) 5. 0g;

Promoting agent 40g: propylene glycol 10g, diethylene glycol monoethyl ether _30g;

Viscous polymer: GMS737 80 g;

The transdermal rate of levonorgestrel was 0. 254 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 154 g/cm ² /h. Example 5

Steroid hormone: levonorgestrel 0. 05g, ethinyl estradiol 0. 05g;

Viscosity modifier: PVP / VA copolymer (S-630) 0. lg;

6g of penetration enhancer: 2g of propylene glycol, 2g of diethylene glycol monoethyl ether, 2g of lauric acid _;

Viscous polymer: GMS737 20g _:

The transdermal rate of levonorgestrel is 0.17^/cm ² /h, and the transdermal rate of ethinyl estradiol is: 174 _g /cni ² /h. Example 46

Steroid hormone: levonorgestrel 0. 07g, ethinyl estradiol 0. 13g;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 2g;

Penetration enhancer 10g: propylene glycol 8. 0g, diethylene glycol monoethyl ether 1. 0g, lauric acid lg;

Viscous polymer: GMS737 30g _;

The transdermal rate of levonorgestrel was measured to be 144 g/cm ² /h, and the transdermal rate of ethinyl estradiol was 0.2 (^g/cm ² /h. Example 47

Steroid hormone: levonorgestrel 0. 2g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 3g;

Promoting agent 7g: benzyl alcohol 5g, diethylene glycol monoethyl ether lg, lauric acid lg;

Viscous polymer: GMS737 40g _:

The transdermal rate of levonorgestrel was 0. 224 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.24 g/cm ² /h. Example 8

Steroid hormone: levonorgestrel 0. 3g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 4g;

Promoting agent 12 _g: propylene glycol 10g, diethylene glycol monoethyl ether lg, lauric acid lg;

Viscous polymer: GMS737 50g _;

The transdermal rate of ergoestrol was 0. 284 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0. l (^g/cm ² /h. Example 49 The steroidal hormone: levonorgestrel 0. 4g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 5g;

Promoting agent 17 _g: propylene glycol 15g, diethylene glycol monoethyl ether lg, lauric acid lg;

Viscous polymer: GMS737 60g:

The transdermal rate of levonorgestrel was 0.3 ( _g / cm ² /h, and the transdermal rate of ethinyl estradiol was: 0. 10 g / cm ² / h. Example 50

Steroid hormone: levonorgestrel 0. 5g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP/VA copolymer (S-630) 0. 6g

Penetration enhancer 22g: propylene glycol 20g, isosorbide dimethyl ether lg, lauric acid lg;

Viscous polymer: GMS737 70g;

The transdermal rate of levonorgestrel is 0.32 g/cm ² /h, and the transdermal rate of ethinyl estradiol is: 0. l (^g/cra ² /h. Example 51

Steroid hormone: levonorgestrel 0. 6g, ethinyl estradiol 0. lg:

Viscosity modifier: PVP / VA copolymer (S-630) 0. 7g;

Penetration inhibitor 32 _g: propylene glycol 30 g, diethylene glycol monoethyl ether lg, lauric acid lg;

Viscous polymer: GMS737 80g _;

The transdermal rate of levonorgestrel is 0. 34^/cra ² /h, and the transdermal rate of ethinyl estradiol is: 0. 10μ _δ /αη ² Α. Example 52

Steroid hormone: levonorgestrel 0. 7g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 8g;

Promoting agent 40g: propylene glycol 10g, isosorbide dimethyl ether 20g, lauric acid 10g;

Viscous polymer: GMS 788 80g _;

The transdermal rate of levonorgestrel is 0. 35 g / cm ² /h The transdermal rate of ethinyl estradiol is: 0. lO g / cmVho Example 53

Body hormone: levonorgestrel 0. 8g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 9g;

Promoting agent 16 _g: propylene glycol 6g, diethylene glycol monoethyl ether 6g, lauric acid 4g _:

Viscous polymer: GMS 1753 78g _;

The transdermal rate of levonorgestrel was determined to be 0. 354 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.44 g/cm ² /h. Example 54

Steroid hormone: levonorgestrel 0. 9g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP/VA copolymer (S-630) l. Og;

Promoting agent 35g: propylene glycol 5g, diethylene glycol monoethyl ether 25g, lauric acid 5g _; Viscous polymer: GMS 788 80g _;

The transdermal rate of levonorgestrel is 0. 24 g / cinVh, the transdermal rate of ethinyl estradiol is: 0. l (^g / cm ² / h. Example 55

The steroidal hormone: levonorgestrel 1. 0g, ethinyl estradiol 0. l _g;

Viscosity modifier: PVP / VA copolymer (S-630) 1. lg;

Promoting agent 40g: propylene glycol 5g, diethylene glycol monoethyl ether 30g, lauric acid 5g _;

Viscous polymer: GMS 1753 90g:

The transdermal rate of levonorgestrel was 0.25 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.1 _g (cm / cm ² /h. Example 56

Steroid hormone: levonorgestrel 1. lg, ethinyl estradiol 0. lg;

Viscosity modifier: PVP/VA copolymer (S-630) 1. 2g;

Promoting agent 39g: propylene glycol 3g, isosorbide dimethyl ether 30g, lauric acid 3 _g;

Viscous polymer: GMS 1753 80g _;

The transdermal rate of levonorgestrel was 0. 26 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.1 g (cm/cm ² /h. Example 57

Steroid hormone: levonorgestrel 1. 2g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP/VA copolymer (S-630) 1. 3g;

Promoting agent 34 _g: 2 _{g of} propylene glycol, 30 g of diethylene glycol monomethyl ether, 2 g of lauric acid _;

Viscous polymer: GMS 1753 80g _;

The transdermal rate of levonorgestrel was measured to be 264 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.1 _g (cm / cm ² /h. Example 58

Steroid hormone: levonorgestrel 1. 3g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP / VA copolymer (S-630) 1. 4g;

Promoting agent 41⁄2: propylene glycol 2g, diethylene glycol monoethyl ether 40g, lauric acid 2g;

Viscous polymer: GMS 1753 80g;

The transdermal rate of levonorgestrel was 0. 27 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.1 g/cm ² /h. Example 59

The steroidal hormone: levonorgestrel 1. 4g, ethinyl estradiol 0. lg _;

Viscosity modifier: PVP/VA copolymer (S-630) 1. 5g;

Promoting agent 32g: propylene glycol lg, diethylene glycol monomethyl ether 30g, oleic acid 1 _g;

Viscous polymer: DUR0TAK 87-4098 80g;

The transdermal rate of levonorgestrel was 0. 284 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.1 g (cm/cm ² /h. Example 60 The steroidal hormone: levonorgestrel 1. 5g, ethinyl estradiol 0. lg _;

Viscosity modifier: PVP / VA copolymer (S-630) 1. 6g;

15g of penetration enhancer: propylene glycol 3g, isosorbide dimethyl ether 6g, lauric acid 6g _;

Viscous polymer: DUR0TAK 87-4098 70g _;

The transdermal rate of levonorgestrel was 0. 35 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.1 g (cm/cm ² /h. Example 61

The steroidal hormone: levonorgestrel 1. 6g, ethinyl estradiol 0. lg _;

Viscosity modifier: PVP / VA copolymer (S-630) 1. 7g;

21g of penetration enhancer: propylene glycol 3g, diethylene glycol monoethyl ether 9g, oleic acid 9g _;

Viscous polymer: DUR0TAK 87-4098 80g;

The transdermal rate of levonorgestrel is 0. 354g/cmVh, and the transdermal rate of ethinyl estradiol is: 0.1 (^g/cm ² /h. Example 62

Steroid hormone: levonorgestrel 1. 7g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP/VA copolymer (S-630) 1. 8g;

Promoting agent 27g: propylene glycol 3g, diethylene glycol monoethyl ether 12g, oleic acid 12g _;

Viscous polymer: DUR0TAK 87-2287 80g;

The transdermal rate of levonorgestrel is 0. 254 g/cm ² /h, and the transdermal rate of ethinyl estradiol is: 0. 104 g/cm ² /h. Example 63

The steroidal hormone: levonorgestrel 1. 8g, ethinyl estradiol 0. l _g;

Viscosity modifier: PVP/VA copolymer (S-630) 1. 9g;

Promoting agent 33g: propylene glycol 3g, isosorbide dimethyl ether 15g, oleic acid 15g;

Viscous polymer: DUR0TAK 87-2287 80g;

The transdermal rate of levonorgestrel is 0. 294g/cra ² /h, and the transdermal rate of ethinyl estradiol is: 0. lC^ _g /cm ² /h. Example 64

Steroid hormone: levonorgestrel 1. 9g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP/VA copolymer (S-630) 2. 0g;

Promoting agent 26g: propylene glycol 2g, diethylene glycol monoethyl ether 12g, oleic acid 12g;

Viscous polymer: DUR0TAK 87-2287 80g _;

The transdermal rate of levonorgestrel was 0. 294 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0. 104 g/cmVh. Example 65

Steroid hormone: levonorgestrel 2. 0g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP/VA copolymer (S-630) 2. lg:

Promoting agent 28g: 2g of propylene glycol, 12g of diethylene glycol monoethyl ether, 14g of citric acid; Viscous polymer: DUROTAK 87-2287 80g;

The transdermal rate of levonorgestrel is 0. 294g/ciii ² /h, and the transdermal rate of ethinyl estradiol is: 0. Example 66

Steroid hormone: levonorgestrel 2. lg, ethinyl estradiol 0. lg _;

Viscosity modifier: PVP / VA copolymer (S-630) 2. 2 _g;

Promoting agent 34g: propylene glycol 2g, diethylene glycol monomethyl ether 12g, citric acid 20g;

Viscous polymer: DUROTAK 87-4297 _80g;

The transdermal rate of levonorgestrel was 0. 30 tig/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.1 g (cm/cm ² /h. Example 67

Steroid hormone: levonorgestrel 2. 3⁄4, ethinyl estradiol 0. lg;

Viscosity modifier: PVP/VA copolymer (S-630) 2. 3g :

Promoting agent 23g: propylene glycol lg, diethylene glycol monoethyl ether 6g, citric acid 15g;

Viscous polymer: DUROTAK 87-4297 80g _;

The transdermal rate of levonorgestrel is 0. 354g / _C ra7h, and the transdermal rate of ethinyl estradiol is: 0. l (^g / _C m ² / h. Example 68

Steroid hormone: levonorgestrel 2. 3g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP / VA copolymer (S-630) 2. 4g;

Promoting agent 27 _g: propylene glycol lg, isosorbide dimethyl ether 6 g, lauric acid 20 g;

Viscous polymer: DUROTAK 87-4297 80g;

The transdermal rate of levonorgestrel was 0. 354 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.1 g (cm/cm ² /h. Example 69

Steroid hormone: levonorgestrel 2. 4g, ethinyl estradiol 0. lg;

Viscosity modifier: PVP / VA copolymer (S 630) 2. 5g;

Promoting agent 36g: propylene glycol lg, diethylene glycol monomethyl ether 10g, lauric acid 25 _g;

Viscous polymer: DUROTAK 887-2677 80g;

The transdermal rate of levonorgestrel is 0. 354g/cm ² /h, and the transdermal rate of ethinyl estradiol is: 0. l (^g/cm ² /h.

Steroid hormone: levonorgestrel 2. 5g, ethinyl estradiol O. lg;

Viscosity modifier: PVP/VA copolymer (S-630) 2. 6g;

Promoting agent 46g: propylene glycol lg, diethylene glycol monoethyl ether 15g, lauric acid 30g;

Viscous polymer: DUROTAK 87-900A 80g _;

The transdermal rate of levonorgestrel is 0. 254g/cra ² /h, and the transdermal rate of ethinyl estradiol is: 0. Example 71 The steroidal hormone: levonorgestrel 2. 6g, ethinyl estradiol 0. lg _;

Viscosity modifier: PVP/VA copolymer (S-630) 2. 7g :

Promoting agent 41 _g: propylene glycol lg, diethylene glycol monoethyl ether 10 g, citric acid 30 g;

Viscous polymer: DUR0TM 87-2677 80g _;

The transdermal rate of levonorgestrel was measured to be 0.35 g/cra ² /h, and the transdermal rate of ethinyl estradiol was: 094 g/cni ² /h. Example 72

The steroid hormone: levonorgestrel 2. 7g, ethinyl estradiol 0. lg _;

Viscosity modifier: PVP / VA copolymer (S-630) 2. 8g;

Promoting agent 40g: 15 _{g of} propylene glycol, 15 _g of diethylene glycol monoethyl ether, 10 g of lauric acid;

Viscous polymer: DUR0TA 87-2677 80g _;

The transdermal rate of olynyl estradiol was 0. 354 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0. 09 g/cra h. Example 73

The steroidal hormone: levonorgestrel 2. 8g, ethinyl estradiol 0. lg _;

Viscosity modifier: PVP/VA copolymer (S-630) 2. 9g:

30 _{g of} penetration enhancer _: propylene glycol 10 g, isosorbide dimethyl ether 10 g, lauric acid 10 g;

Viscous polymer: DUROTAK 87-900A 80g;

The transdermal rate of olynyl estrone was 0. 35 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0. 09 g / _Cra ² /h. Example 74

The steroidal hormone: levonorgestrel 2. 9g, ethinyl estradiol 0. lg _;

Viscosity modifier: PVP / VA copolymer (S-630) 3. 0g;

Promoting agent 50g: propylene glycol 20g, diethylene glycol monoethyl ether 20g, lauric acid 10g;

Viscous polymer: DUROTAK 87-900A 80g;

The transdermal rate of levonorgestrel was 0. 304 g / cni ² / h, and the transdermal rate of ethinyl estradiol was: 0. 09 g / cin ² / h. Example 75

The steroid hormone: levonorgestrel 3. 0g, ethinyl estradiol 0. lg _;

Viscosity modifier: PVP/VA copolymer (S-630) 3. lg :

Promoting agent 40g: propylene glycol 10g, diethylene glycol monoethyl ether 30g, citric acid 10g;

Viscous polymer: DUROTAK 87-900A 80g;

The transdermal rate of levonorgestrel was 0.3 (g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 094 g/cm ² /h. Example 76

Steroid hormone: levonorgestrel 4. 0g, ethinyl estradiol 0. lg:

The viscosity modifier: PVP/VA copolymer (S-630) 0. 5g;

Promoting agent 34g: propylene glycol 12g, diethylene glycol monoethyl ether 12g, lauric acid _10g; Viscous polymer: GMS 737 80g _;

The transdermal rate of levonorgestrel is 0. 354g/cm7h, and the transdermal rate of ethinyl estradiol is: 0.05 g/cm ² /h. Example 77

Steroid hormone: levonorgestrel 0. 50g, ethinyl estradiol 0. 05g;

The viscosity modifier: PVP / VA copolymer (S-630) 0. 5g;

Promoting agent 34g: propylene glycol 12g, isosorbide dimethyl ether 12g, lauric acid 10g;

Viscous polymer: GMS 737 80g _;

The levonorgestrel permeability was measured to be 0. Permeation rate of ethinyl ^{estradiol: 0. 054g / cm 2 / h} . Example 78

Steroid hormone: levonorgestrel 2g, ethinyl estradiol lg;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 5g;

Promoting agent 34g: propylene glycol 12g, isosorbide dimethyl ether 12g, oleyl alcohol 10 _g;

Viscous polymer: 0DE M 607 80g;

The transdermal rate of levonorgestrel was 0. 334 g/cm ² /h, and the transdermal rate of ethinyl estradiol was 0.2 (^g/cm ² /h. Example 79

Steroid hormone: estradiol 0. 2 _g;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 5g;

Promoting agent 31⁄2: propylene glycol 12g, isosorbide dimethyl ether 12g, oleic acid 10g;

Viscous polymer: R0DERM 610 80g;

The transdermal rate of estradiol was measured to be 0.23 _g / cm ² /h.

Example 80

Steroid hormone: estradiol 8g _;

The viscosity modifier: PVP / VA copolymer (S-630) 0. 5g _;

Promoting agent 34g: propylene glycol 12g, diethylene glycol monoethyl ether 12g, lauryl alcohol 10g;

Viscous polymer: R0DE M 610 80g;

The transdermal rate of estradiol was measured to be 0.35 _g /cni ² /h.

Example 81

Steroid hormone: estradiol 5g,

The viscosity modifier: PVP / VA copolymer (S-630) 0. 5g;

Promoting agent 34g _: propylene glycol 12g, isosorbide dimethyl ether 12g, lauric acid 10g;

Viscous polymer: R0DERM 610 _80g;

354克/cni ² /h。 The estradiol transdermal rate was measured to be 0. 354g / cni ² / h.

Example 82 0克。 Ogmental steroids: 0. 2g estradiol 0. 04g;

Viscosity modifier: PVP / VA copolymer (S-630) 0. 5g;

Promoting agent 12g: propylene glycol 4g, isosorbide dimethyl ether 4g, lauric acid 4g _;

Viscous polymer: GMS 737 72g _:

The transdermal rate of levonorgestrel is 0. 25 g/cm ² /h, and the transdermal rate of ethinyl estradiol is: 0.05 g/cm ⁷ h. Example 83

The steroidal hormone: levonorgestrel 0. 2g estradiol 0. l _g;

Viscosity modifier: PVP / VA copolymer (S-630) lg;

Penetration inhibitor 20g: propylene glycol 12g, diethylene glycol monoethyl ether 12g, lauric acid 10g;

Viscous polymer: GMS 737 90g _;

The transdermal rate of levonorgestrel is 0. 224 g / _Cm ² /h, and the transdermal rate of block estradiol is: 0.1 g / cm ² / h. Example 84

Steroid hormone: levonorgestrel 0. lg estradiol 0. lg;

Viscosity modifier: PVP / VA copolymer (S-630) lg;

Promoting agent 14g _: propylene glycol 5g, diethylene glycol monoethyl ether 5g, oleic acid 4g _;

Viscous polymer: GMS 737 75g _;

The transdermal rate of levonorgestrel is 0. 24 g/cm ² /h, and the transdermal rate of ethinyl estradiol is: 254 g/cm ² /h. Example 85

Steroid hormone: levonorgestrel 0. 02 estradiol 0. lg;

Viscosity modifier: PVP / VA copolymer (S-630) lg;

15g of penetration enhancer: propylene glycol 6g, diethylene glycol monoethyl ether 6g, oleic acid 3g _;

Viscous polymer: GMS 737 75g _;

The transdermal rate of levonorgestrel is 0. 124g / _Cra ² / h, and the transdermal rate of ethinyl estradiol is: 254g / cm ² / h. Example 86

Steroid hormone: levonorgestrel 0. lg estradiol lg;

Viscosity modifier: PVP/VA copolymer (S-630) lg;

Promoting agent 13g: propylene glycol 5g, diethylene glycol monoethyl ether 5g, oleic acid 3g _:

Viscous polymer: GMS 737 75g _;

The transdermal rate of levonorgestrel is 0. 124g/cm ² /h, and the transdermal rate of ethinyl estradiol is: 254g/cni ² /h. Example 87

The steroid hormone: levonorgestrel 0. 5g estradiol 0. 2g;

Viscosity modifier: PVP / VA copolymer (S-630) lg;

20 _{g of} penetration enhancer _: 7 _{g of} propylene glycol, 7 g of diethylene glycol monoethyl ether, 6 g of lauric acid _; Viscous polymer: GMS 737 90g _;

The transdermal rate of levonorgestrel is 0. 254g/cm ² /h, and the transdermal rate of ethinyl estradiol is: 0. l (^g/cm ² /h.

Steroid hormone: levonorgestrel 4g estradiol lg _;

Viscosity modifier: PVP/VA copolymer (S-630) lg :

20g of penetration enhancer: 7 _{g of} propylene glycol, 7 _g of diethylene glycol monoethyl ether, 6 _{g of} lauric acid _:

Viscous polymer: GMS 737 90g;

The transdermal rate of levonorgestrel was 0. 354 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 254 g/cni ² /h. Example 89

Retaining hormone: levonorgestrel 3g estradiol lg;

Viscosity modifier: PVP / VA copolymer (S-630) lg;

10g of penetration enhancer: propylene glycol, diethylene glycol monoethyl ether 4g, lauric acid _2g;

Viscous _polymer: GMS 737 80g:

The transdermal rate of levonorgestrel was 0. 354 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 184 g/cra ² /h. Really turn 90

The steroidal hormone: levonorgestrel 0. 8g estradiol 0. 2 _g;

Viscosity modifier: PVP/VA copolymer (S-630) lg;

Promoting agent 14g _: propylene glycol 5g, diethylene glycol monoethyl ether 5g, lauryl alcohol 4g _;

Viscous polymer: GMS 737 86g _;

The transdermal rate of levonorgestrel was 0. 354 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 154 g/cm ² /h. Example 91

Steroid hormone: levonorgestrel 2 _g estradiol lg;

Viscosity modifier: PVP/VA copolymer (S-630) lg;

Penetration enhancers 14g: PEG1000 5g, diethylene glycol monoethyl ether 5 _g, oleic _4G;

Viscous polymer: GMS 737 86g:

The transdermal rate of levonorgestrel was 0. 354 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.3 g/cni ² /h. Example 92

Steroid hormone: levonorgestrel lg estradiol 2g _;

Viscosity modifier: PVP / VA copolymer (S-630) lg;

Promoting agent 14g: propylene glycol 5g, isosorbide dimethyl ether 5g, citric acid 4g _;

Viscous polymer: GMS 737 _86g;

The transdermal rate of levonorgestrel was 0. 354 g/cm7h, and the transdermal rate of ethinyl estradiol was: 404 g/cm ² /h. Example 93 Steroid hormone: levonorgestrel lg estradiol 3g _;

Viscosity modifier: PVP / VA copolymer (S-630) lg;

Promoting agent 14g: propylene glycol 5g, isosorbide dimethyl ether 5g, sterol 4g;

Viscous polymer: GS 737 86g _;

The transdermal rate of levonorgestrel was measured to be 0.35 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.44 gig/cni ² /h. Example 94

Steroid hormone: left block of progesterone lg estradiol 2 _g;

Viscosity modifier: PVP / VA copolymer (S-630) lg;

Promoting agent 14g: benzyl alcohol 5g, isosorbide dimethyl ether 5g, citric acid 4 _g;

Viscous polymer: GMS 737 86g _;

The transdermal rate of levonorgestrel was measured to be 354 g/cm ² /h, and the transdermal rate of ethinyl estradiol was: 0.4 (^g/cm ² /h. Example 95

Steroid hormone: levonorgestrel 4g estradiol lg;

Viscosity modifier: PVP / VA copolymer (S-630) lg;

20g of penetration enhancer: 7g of propylene glycol, 7g of diethylene glycol monoethyl ether, 6g of lauryl alcohol _;

Viscous polymer: GMS 737 90g _;

The transdermal rate of ethinyl estradiol was 0. 254 g/cm ² /h, and the transdermal rate of ethinyl estradiol was 0. 254 g/cm ² /h. Example 96

Steroid hormone: levonorgestrel 4g estradiol lg;

Viscosity modifier: PVP/VA copolymer (S-630) lg;

20g of penetration enhancer: 7g of propylene glycol, 7g of diethylene glycol monoethyl ether, 6g of oleyl alcohol _;

Viscous polymer: GMS 737 90g _;

The transdermal rate of levonorgestrel is 0. 35 g / _C m ² /h, and the transdermal rate of ethinyl estradiol is: 0. 25 g / cm ² / h. Example 97

Steroid hormone: levonorgestrel 4g estradiol lg;

Viscosity modifier: PVP / VA copolymer (S-630) lg;

Penetration enhancer 20g: propylene glycol 7g, isosorbide dimethyl ether 7g, oleyl alcohol 6g:

Viscous polymer: GMS 737 90g _;

The transdermal rate of levonorgestrel was 0.35 g/cni ² /h, and the transdermal rate of ethinyl estradiol was: 254 g/cni ² /h. Example 98

The steroid hormone: levonorgestrel 3. 0 _g , ethinyl estradiol 0. lg;

Viscosity modifier: PVP/VA copolymer (S-630) 3. lg;

Promoting agent 40g: propylene glycol 10 _g , diethylene glycol monoethyl ether 30 g, sterol 10 _g; Viscous polymer: DUROTAK 87-900A 80g _;

The transdermal rate of levonorgestrel is 0. 3C^g/cm ² /h, and the transdermal rate of ethinyl estradiol is: 094g/cm ² /h. Applying the obtained transdermal delivery system to the skin of a woman can achieve the desired effect of contraception or prevention of osteoporosis. Tests such as dermal toxicity, sensitivity, etc., prove that the patch of the present invention is greatly superior to the state of the art.

The above embodiments are for illustrative purposes only and are not intended to limit the scope of the invention in any way. A person skilled in the art can make various modifications or changes to the embodiments of the present invention without departing from the spirit and scope of the invention, which are included in the scope of the present invention.

Claims

Claim

A penetration enhancer characterized in that it contains an ether compound and an alcohol compound, and the alcohol compound does not include a C ₆ - C ₁₈ fatty alcohol.

The penetration enhancer according to claim 1, wherein the content of the ether compound and the alcohol compound is in parts by weight: the ether compound is 1 to 30 parts, and the alcohol compound is 1 to 30 parts.

The penetration enhancer according to claim 2, wherein the content of the ether compound and the alcohol compound is in parts by weight: the ether compound is 1 to 20 parts, and the alcohol compound is 1 to 20 parts.

The penetration enhancer according to claim 3, wherein the content of the ether compound and the alcohol compound is in parts by weight: the ether compound accounts for 1-10 parts, and the alcohol compound accounts for 1-10 parts.

The penetration enhancer according to claim 4, wherein the content of the ether compound and the alcohol compound is in parts by weight: the ether compound accounts for 1-4 parts, and the alcohol compound accounts for 1-4 parts.

The penetration enhancer according to any one of claims 1 to 5, wherein the ether compound is selected from the group consisting of isosorbide dimethyl ether, diethylene glycol monoethyl ether or diethylene glycol monomethyl ether.

The penetration enhancer according to any one of claims 1 to 5, wherein the alcohol compound is selected from the group consisting of propylene glycol, polyethylene glycol or benzyl alcohol.

The penetration enhancer according to claim 1, which further comprises a C ₆ -C ₁₈ fatty acid or ( ₆ - (:, ₈ fatty alcohol).

9, penetration enhancers according to claim 8, characterized in that the content of the ether compound, an alcohol compound, and C ₆ _C ₁₈ fatty acids or C ₆ ~ C ₁₈ aliphatic alcohol to parts by weight:

The ether compound accounts for 1 to 30 parts, the alcohol compound accounts for 1 to 30 parts, the C ₃ - C ₁₈ fatty acid or the 0 (:, ₈ fatty alcohol accounts for 1 to 30 parts.

The penetration enhancer according to claim 9, wherein the content of the ether compound, the alcohol compound and the 3⁄4-(: ₁₈ fatty acid or C ₆ - C ₁₈ fatty alcohol is in parts by weight:

The ether compound accounts for 1-20 parts, the alcohol compound accounts for 1-20 parts, the 0 (: ₁₈ fatty acid or the 0 ( ₁₈ fatty alcohol) accounts for 1-20 parts.

11, the penetration enhancers according to claim 10, wherein the ether compound, an alcohol compound, and c ₆ -c ₁₈ fatty acids or - (: fatty alcohol content to ₁₈ parts by weight:

Ether-based compound comprises 1-10 parts, parts of 1% to 10 alcohols, -C _l8 fatty acids or Ce-C, _e fatty alcohols 1-10 parts accounted for.

12, penetration enhancers according to claim 11, characterized in that the content of ₆ -C _l8 fatty alcohol ethers, alcohols and fatty acids or C GrC ₁₈ parts by weight in terms of:

The ether compound accounts for 1-4 parts, the alcohol compound accounts for 1-4 parts, the C ₆ -C ₁₈ fatty acid or the C ₆ -C ₁₈ fatty alcohol accounts for 1-4 parts.

The penetration enhancer according to any one of claims 8 to 12, wherein the ether compound is selected from the group consisting of isosorbide dimethyl ether, diethylene glycol monoethyl ether or diethylene glycol monomethyl ether; The alcohol compound is selected from the group consisting of propylene glycol, polyethylene glycol or benzyl alcohol; the GC _1S fatty acid is selected from the group consisting of citric acid, lauric acid or oleic acid; and the C ₆ -C ₁₈ fatty alcohol is selected from the group consisting of decyl alcohol, lauryl alcohol or oleyl alcohol.

The penetration enhancer according to claim 13, wherein the penetration enhancer is a composition of diethylene glycol monoethyl ether, propylene glycol and lauric acid.

15. A penetration enhancer according to claim 13 wherein the penetration enhancer is a combination of isosorbide dimethyl ether, propylene glycol and lauric acid.

The penetration enhancer according to claim 13, wherein the penetration enhancer is a composition of diethylene glycol monoethyl ether, propylene glycol and lauryl alcohol.

The penetration enhancer according to claim 13, wherein the penetration enhancer is a composition of diethylene glycol monoethyl ether, benzyl alcohol and lauryl alcohol.

18. A penetration enhancer according to claim 13 wherein the penetration enhancer is a combination of diethylene glycol monoethyl ether, propylene glycol and oleyl alcohol.

The penetration enhancer according to claim 13, wherein the penetration enhancer is a combination of isosorbide dimethyl ether, propylene glycol and oleyl alcohol.

20. A penetration enhancer according to claim 13 wherein the penetration enhancer is a combination of diethylene glycol monoethyl ether, propylene glycol and decyl alcohol.

The penetration enhancer according to claim 13, wherein the penetration enhancer is a combination of isosorbide dimethyl ether, propylene glycol and decyl alcohol.

22. Use of a penetration enhancer according to any one of claims 1 to 21 in the manufacture of a transdermal delivery system.

23. Use of a penetration enhancer according to any one of claims 1 to 21 for the preparation of a steroid hormone transdermal delivery system.

24. The use of a transdermal delivery system for a steroid hormone according to claim 23 in contraception.

25. A transdermal delivery system for body hormones, comprising: a protective layer (1), a reservoir layer (2) and a backing layer (3); a reservoir layer (2) attached to a peelable protection The layer (1) and the backing layer (3) are prepared from a viscous polymer matrix solution; the viscous polymer matrix solution components for preparing the reservoir layer (2) include: body hormones, viscous polymers, claims The penetration enhancer and viscosity modifier of any of 1-21.

26. The transdermal delivery system for body hormone according to claim 25, wherein the amount of the component in the viscous polymer matrix solution is in parts by weight: the penetration enhancer is 5-50 parts by weight, 1-5重量份。 The viscous polymer occupies 0. 1-5 parts by weight.

The steroid hormone transdermal drug delivery system according to claim 26, wherein the amount of the component in the viscous polymer matrix solution is in parts by weight: the penetration enhancer accounts for 10 to 40 parts by weight. 1-3重量份。 The viscous polymer occupies 50-90 parts by weight, the viscosity modifier accounted for 0. 5-5 parts by weight, steroid hormones 0. 1-3 parts by weight.

The transdermal delivery system for body hormone according to claim 27, wherein the amount of the component in the viscous polymer matrix solution is in parts by weight: the penetration enhancer accounts for 10-20 parts by weight, 1-1重量份。 The viscous polymer occupies 0. 1-1 parts by weight.

The steroid hormone transdermal drug delivery system according to any one of claims 25 to 28, wherein the viscous polymer is selected from the group consisting of crosslinked or uncrosslinked polyacrylate, polyguilonone or polyisobutylene.

30. The steroid hormone transdermal delivery system of claim 29, wherein the viscous polymer is a crosslinked or uncrosslinked polyacrylate.

The transdermal delivery system for body hormone according to claim 29, wherein the polyacrylate is selected from the group consisting of poly(2-ethyl acrylate) Ester/acrylic acid copolymer), poly(2-hydroxyhexyl acrylate/acrylic acid/methyl acrylate copolymer), poly(2-ethylhexyl acrylate/acrylic acid/methyl acrylate copolymer) or poly(2-ethyl acrylate) Hexyl hexyl ester / acrylic acid / butyl acrylate / vinyl acetate copolymer >.

The steroid hormone transdermal delivery system according to any one of claims 25 to 28, wherein the viscosity modifier is polyvinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone, polybutyl methacrylate/ Methyl methacrylate copolymer or ethyl cellulose.

The transdermal delivery system for body hormone according to claim 32, wherein the viscosity modifier is polyvinylpyrrolidone/vinyl acetate having a molecular weight of 50,000, and the weight of polyvinylpyrrolidone and ethyl acetate The ratio is 6: 4.

The transdermal delivery system for a body hormone according to any one of claims 25 to 33, wherein the body hormone is one or more of a progestogen and an estrogen.

The steroid hormone transdermal delivery system according to claim 34, wherein the steroid hormone is composed of 1 to 30 parts by weight of a progestogen and 1 to 10 parts by weight of estrogen.

The steroid hormone transdermal delivery system according to claim 35, wherein the steroid hormone is composed of 12 parts by weight of a progestogen and 1-5 parts of estrogen.

The steroid hormone transdermal delivery system according to any one of claims 34 to 36, wherein the progestin in the steroid hormone is selected from the group consisting of: left block progesterone, norgestrel, alkyne Nodecyl ester variant, megestrol, norethisterone, alkanoyl ketone, hydroprogesterone, gestodene, norethenol diacetate, hydroxyprogesterone acetate, progesterone, other A probiotic that is biocompatible and absorbable through the skin; a biocompatible progestogen derivative that can be absorbed through the skin and that can be converted to the original progestogen after absorption by the skin.

The transdermal delivery system for a body hormone according to any one of claims 34 to 36, wherein the estrogen in the body hormone is selected from the group consisting of ethinyl estradiol, 17 estradiol, and a biocompatible derivative thereof. .

The transdermal delivery system for body hormones according to any one of claims 34 to 36, wherein the progestin in the steroid hormone is levonorgestrel and the estrogen is ethinyl estradiol.

40. The steroid hormone transdermal delivery system according to claim 25, wherein the content of the component in the viscous polymer matrix is in parts by weight: the penetration enhancer is 10-20 parts by weight, 1-1重量份; The viscous occupant occupies 0. 1-1 parts by weight;

Wherein the body hormone is composed of 1-20 parts by weight of levonorgestrel and 1-5 parts of ethinyl estradiol; the penetration enhancer is composed of 1-4 parts by weight of an ether compound, 1- 4 Parts by weight of a non-Ce-C, ₈ fatty alcohol compound, 1-4 parts by weight of a C ₃ -C, ₈ fatty acid or a C ₆ ~ & ₈ fatty alcohol; the ether compound is selected from diethylene glycol Monoethyl ether or isosorbide dimethyl ether; the alcohol compound is propylene glycol, benzyl alcohol, PEG400, PEG600 or PEG1000; the C ₆ -C ₁₈ fatty acid is selected from lauric acid, oleic acid or citric acid; _{The 6-} _C18 fatty alcohol is selected from the group consisting of decyl alcohol, lauryl alcohol or oleyl alcohol.

41. Use of a steroid hormone transdermal delivery system according to claims 25-40 for the control of fertility or treatment of osteoporosis in women, and menopausal syndrome in women.