CN101940790A

CN101940790A - Novel penetration-promoting agent composition and application thereof to transdermal administration system

Info

Publication number: CN101940790A
Application number: CN2010102082582A
Authority: CN
Inventors: 杨明京; 郑会义; 夏敏; 吴树明
Original assignee: RUNBIO BIOTECH CO Ltd
Current assignee: Guangdong Iconas Biomedical Technology Co ltd; Yang Mingjing
Priority date: 2009-07-01
Filing date: 2010-06-24
Publication date: 2011-01-12
Anticipated expiration: 2030-06-24
Also published as: CN101940790B; WO2011000210A1

Abstract

The invention provides a novel penetration-promoting agent composition and the application thereof to a transdermal administration system. The penetration-promoting agent provided by the invention contains an etheric compound and an alcohol compound and more preferably contains fatty acid having 6 to 18 carbon atoms or fatty alcohol having 6 to 18 carbon atoms. In the penetration-promoting agent of the invention, dimethylsulfoxide (DMSO) with controversial potential toxicity to a human body is not used; and an obtained product has the advantages of high transdermal rate, high adhesion, no potential toxic or side effect to the human body and safe and comfortable use. The transdermal administration system provided by the invention is applied by being stuck to the skin of a woman so as to fulfill the aims of effectively controlling birth and realizing conception control. The novel penetration-promoting agent composition can also be used for preventing and treating osteoporosis, climacteric metancholia of women and the like.

Description

A kind of novel penetrating agent compositions and the application in transdermal drug delivery system thereof

Technical field

The present invention relates to pharmaceutical field, particularly a kind of novel penetrating agent compositions and the application in transdermal drug delivery system thereof.

Background technology

The estrogen of synthetic and the compositions of progestogen often are used to contraception.If the form with oral contraceptive pills is used natural estrogen (17-β estradiol) and progesterone (Progesterone) compositions, these two kinds of hormones can carry out a large amount of first metabolism and need to use very big dosage in liver.The gained metabolite causes undesirable side effect through regular meeting.Therefore, main now artificial synthetic progesterone of use and estrogenic compositions overcome these defectives as oral contraceptive.Wherein, one of the most representative combination is levonorgestrel and ethinylestradiol combination in the oral contraceptive.

Although the progesterone of synthetic and estrogenic compositions are very effective to suppressing ovulation, but use the oral contraceptive of this type still can produce certain side effect: in the women who uses oral contraceptive, thrombosis is higher with the sickness rate of the related artery disease that comprises apoplexy and myocardial infarction; Use contraceptive also relevant with the increase of optimum liver tumor symptom and higher gallbladder disease risk; If continuing pills after pregnancy, the women may cause fetal abnormality; Oral contraceptive also can produce human body the intestines and stomach digestive system to stimulate, and some women uses oral contraceptive can produce malaise symptoms; Use the possible complication of oral contraceptive also to comprise breast carcinoma, uterus carcinoma, cervical cancer and cancer of vagina etc.

In the last few years, develop the fertility restraining doser of implantable intrauterine, cervix uteri or intravaginal and subdermal implantation successively, thereby these devices can also controllably provide enough steroid hormone doses to reach the purpose of contraception for a long time to human body.Levonorgestrel is the drug components of normal use of these devices, but these devices use and take out very inconveniently, uses in these doser processes, often brings uncomfortable and painful to sufferer.

Transdermal drug delivery system (transdermal drug delivery system, TDDS) be the transdermal administration novel formulation of using the skin patch type of binding agent, be in the skin surface administration, medicine passes through each layer of skin with constant speed (or near constant speed), enter the body circulation, produce whole body or local therapeutic effects.Since first transdermal absorption formulation Transderm Scop listing in 1981, existing multiple at present drug transdermal drug-delivery preparation listing.Medicine can reduce many side effect by skin absorbs.Percutaneously administrable preparation has following advantage: avoid intravenous risk and inconvenience and absorption and the metabolic polytropy relevant with oral medication; Successive administration also can use the short medicine of biological half-life; Because reduced the degraded in digestive system, also can play effect even reduced the every day dosage; Preparation is easy to use, if desired, and can be by remove stopped treatment apace from skin surface.

Based on above-mentioned advantage, in recent years, Chinese scholars has been carried out big quantity research to the steroid hormone transdermal drug delivery system.Yet, as the skin of the human body natural cover for defense, hindered medicine and entered in the body, most drug, even some medicines that dosage is low, curative effect is high, percutaneous rate also is difficult to satisfy the treatment needs.Overcome the skin barrier effect, promote medicine within a certain period of time transdermal penetration reach therapeutic dose, be one of key issue of transdermal drug delivery system research such as steroid hormone.The exploitation of some penetrating agents and application in recent years promoted the development of transdermal drug delivery system greatly.

U.S. Pat 4,816,258 discloses the system and method that carries out levonorgestrel and estradiol compositions transdermal administration with the form of matrix type patch.What this system framework material used is ethylene-vinyl acetate copolymer (EVA 40) and viscosifier 2,2'-ethylenedioxybis(ethanol). hydrogenated rosins acid esters, and penetrating agent then adopts glycerin mono-fatty acid ester.

U.S. Pat 4,973,468 and 5,059,426 disclose a diethylene glycol monoethyl ether (Diethyleneglycol monoethyl ether) oozes combination with methyl laurate (Methyl laurate) binary is short, and this combination can be used to improve the levonorgestrel percutaneous rate.But this patent does not provide bank or shell system with this combination and compatibility.

U.S. Pat 5,296,230 have described the system and method that levonorgestrel and estradiol compositions is carried out transdermal administration with the form of matrix type patch.What this system framework material used is medical grade silicon rubber, and penetrating agent then adopts Polyethylene Glycol aqueous solution (40%V/V) and isopropyl myristate (Isopropylmyristate) respectively.

U.S. Pat 5,560,922 disclose the system and method for new levonorgestrel and estradiol compositions transdermal administration.The patch framework material also expands to and uses poly-isoolefine rubber and polyacrylic acid pressure sensitive adhesive except using medical grade silicon rubber, and penetrating agent then adopts the Decanol (n-Decyl alcohol) in the aliphatic alcohol series.

The international monopoly WO9608255 that authorizes people such as DUAN has put down in writing by various variety classes monomers, the monomer institute polymerization of different proportionings generates various acrylic copolymers and is used for levonorgestrel matrix-type transdermal administration situation as pressure sensitive adhesive matrix, patent disclosure glyceryl monolaurate (G1yceryl monolaurate), dimethyl dodecyl amine oxide (N, N-dimethyldodecylamine-N-oxide), tetrahydrofurfuryl carbinol (Tetrahydrofurfuryl alcohol), polyglycol ether (Polyethylene glycol ether), propylene glycol, diisopropyl adipate (Diisopropyl adipate) and methyl laurate (Methyl laurate) and their compositions can be used as the penetrating agent of levonorgestrel transdermal administration in the system.

Authorize people's such as CORDES U.S. Pat 5,985,311 disclose diethylene glycol monoethyl ether (Diethylene glycol monoethyl ether) oozes system with oleic acid (Oleic acid) binary is short, can be used to contain levonorgestrel polyacrylic acid matrix-type transdermal drug delivery system.

The U.S. Pat 6,231,885 of authorizing people such as CARRARA discloses oleic acid (Oleic acid) and lauric acid (Lauric acid) binary is short oozes system as penetrating agent in levonorgestrel and the estradiol compositions transdermal drug delivery system.

The U.S. Pat 6,312,715 of authorizing people such as CANTOR is described a kind of synthetic especially polyacrylic binder and be can be used for the levonorgestrel transdermal delivery device, and binding agent is the hollow microsphere form.System adopts methanol, isopropyl alcohol, and ethyl acetate is as the levonorgestrel cosolvent, and isopropyl myristate is then as the levonorgestrel penetrating agent.

U.S. Pat 5,762,956 have described levonorgestrel percutaneous contraceptive drugs transporter, and use this device to carry out method of contraception.This system uses two methylene sulfones (DMSO), lactic acid laurate ethyl lactate and capric acid as penetrating agent.

Except the related penetrating agent of above-mentioned relevant levonorgestrel transdermal administration, also have many patent documentation reports to relate to the particularly estradiol transdermal administration of other steroid hormone.

The transdermal administration that is used for estradiol with isopropyl myristate (Isopropyl myristate), ethyl oleate (ethyl oleate), glyceryl monolaurate (Glyceryl monolaurate) as penetrating agent is disclosed in the U.S. Pat 5223261.This patent becomes BERLEX development CLIMARA and contains the basis of levonorgestrel CLIMARA PRO serial therapy women osteoporosis patch product.

The transdermal administration that is used for estradiol with azone, lauric acid, propylene glycol as penetrating agent is disclosed among the Chinese patent CN1067875A.

WO9832465 has described diethylene glycol monoethyl ether and Arlacel-20 (SPAN-20), diethylene glycol monoethyl ether and Arlacel-80 (SPAN-80) binary are urged the transdermal administration that the system of oozing is used for estradiol.

Ideal steroid hormone penetrating agent must satisfy following requirement: (1) employed penetrating agent has certain dissolubility to steroid hormone; (2) employed penetrating agent has the good short effect of oozing should have rapid-actionly to steroid hormone, and action time is measurable; (3) employed penetrating agent, nonirritant nontoxic, the irritated reaction of nothing and do not have pharmacological action to skin and human body; The compatibility of medicine and other additives comprises not producing physics chemical action, not influencing pharmaceutically active and be complementary with pharmaceutical properties; Can work very soon during application, but not cutaneous normal physiological function after removing; Do not cause the loss of endotrophic material and moisture; Colourless, odorless; Yet up to now, also do not have a kind of promoter to satisfy condition completely, the penetration enhancer of using all has pluses and minuses separately at present.

Because levonorgestrel and estrogen are that the representative steroid hormone all is the extremely low material of dissolubility, and be in the levonorgestrel and the extremely difficult skin that sees through of estrogen of dissolved state not, therefore, when making levonorgestrel and estrogen transdermal delivery device, it is very crucial and important selecting the short system of oozing of appropriate hydrotropy.For solving levonorgestrel and estrogen problems of dissolution, the short system of oozing of some hydrotropy has adopted two methylene sulfones (DMSO) to urge to ooze to increase the levonorgestrel dissolving and to increase levonorgestrel, publication number is the Chinese patent of CN1399533, a kind of percutaneous contraceptive drugs delivery system is disclosed, this system enhancer of cutaneous penetration compositions has been used dimethyl sulfoxide (DMSO), this system has percutaneous rate preferably to human body skin, but because at present still there is bigger dispute in dimethyl sulfoxide to the genotoxic potential of human body, for safety, the penetrating agent compositions should avoid using dimethyl sulfoxide (DMSO).Also have many fatty esters penetrating agents to be proved to be levonorgestrel is had the good short effect of oozing, for example, methyl laurate (Methyl laurate), polyethylene glycol monolaurate (Polyethyleneglycol monolaurate), polypropylene glycol monolaurate (Polypropylene glycolmonolaurate) but these penetrating agents have serious destruction as plasticiser to the viscosity or the cohesiveness of acrylic matrix system, and very limited to the levonorgestrel dissolving.In order to guarantee the short effect of oozing, often need high concentration levonorgestrel and estrogen to be in the adhesive matrix of transdermal delivery device with the over-saturation dissolved state, need to use the hydrotropy penetrating agent of height ratio, when the above-mentioned height ratio fat of use in making levonorgestrel and estrogen transdermal delivery device esters penetrating agent, often cause serious cold flow or lose viscosity, can't practical application.

In addition, existing disclosed transdermal administration technical scheme all is as experimental subject with Corium Mus, realize that institute's medicine of giving can and reach certain transdermal amount through Corium Mus, in view of people's skin and Corium Mus structure has a great difference, the permeability of Corium Mus is higher than the skin of human body far away, given percutaneous rate is very high, but and impracticable, prepared based on this patch often can't really be realized using on human body and reach medically needed therapeutic dose.

The inventor has unexpectedly found to overcome in-problem desirable penetrating agent compositions in the prior art.Enhancer of cutaneous penetration compositions of the present invention not only can improve the dissolubility of steroid hormone effectively, and obtains better percutaneous permeability, the cohesiveness of patch is not destroyed.Penetrating agent provided by the invention, do not having under dimethyl sulfoxide (DMSO) condition, fell equally also there is very high percutaneous rate, the steroid hormone transdermal dosage compositions that treatment is expected can be provided, thereby avoid life-time service genotoxic potential to be had the short potential danger that to bring that is impregnated with of dimethyl sulfoxide of dispute.And transdermal drug delivery system is easy to easy means manufacturing, avoids complicated processing technology such as MULTILAYER COMPOSITE.

Summary of the invention

One object of the present invention is to provide a kind of penetrating agent compositions, and it does not comprise the dimethyl sulfoxide (DMSO) that the human body genotoxic potential is had dispute.Penetrating agent provided by the invention is applied to prepare transdermal drug delivery system (patch), and resulting product cohesiveness is good, human body is not had potential toxic and side effects, safety and comfort, and preparation is simple.

Penetrating agent provided by the invention contains ether compound and alcohol compound, perhaps is made up of ether compound and alcohol compound.Of particular note: used term alcohol compound all is meant and does not comprise C among the present invention ₆-C ₁₈The alcohol compound of aliphatic alcohol, alcohol compound promptly of the present invention is meant non-C ₆-C ₁₈The alcohol compound of aliphatic alcohol.

In the penetrating agent of ether compound provided by the invention and alcohol compound composition, the consumption of ether compound and alcohol compound is counted with weight portion: ether compound accounts for 1-30 part, and alcohol compound accounts for 1-30 part; Be preferably: ether compound accounts for 1-20 part, and alcohol compound accounts for 1-20 part; More preferably be: ether compound accounts for 1-10 part, and alcohol compound accounts for 1-10 part; Be most preferably: ether compound accounts for 1-4 part, and alcohol compound accounts for 1-4 part.In penetrating agent of the present invention, described ether compound preferably is selected from isosorbide dimethyl ether, diethylene glycol monoethyl ether or diethylene glycol monomethyl ether.

In penetrating agent of the present invention, described alcohol compound preferably is selected from propylene glycol, Polyethylene Glycol (PEG400, PEG600, PEG1000 or PEG2000) or benzyl alcohol.

In embodiment preferred of the present invention, penetrating agent of the present invention also contains C simultaneously ₆-C ₁₈Fatty acid or C ₆-C ₁₈Aliphatic alcohol.

At ether compound, alcohol compound and the C of comprising provided by the invention ₆-C ₁₈Fatty acid or C ₆-C ₁₈The penetrating agent of aliphatic alcohol in, the consumption of these three kinds of materials is counted with weight portion:

Ether compound accounts for 1-30 part, alcohol compound accounts for 1-30 part, C ₆-C ₁₈Fatty acid or C ₆-C ₁₈Aliphatic alcohol accounts for 1-30 part;

Be preferably: ether compound accounts for 1-20 part, alcohol compound accounts for 1-20 part, C ₆-C ₁₈Fatty acid or C ₆-C ₁₈Aliphatic alcohol accounts for 1-20 part;

More preferably be: ether compound accounts for 1-10 part, alcohol compound accounts for 1-10 part, C ₆-C ₁₈Fatty acid or C ₆-C ₁₈Aliphatic alcohol accounts for 1-10 part.

Be most preferably: ether compound accounts for 1-4 part, alcohol compound accounts for 1-4 part, C ₆-C ₁₈Fatty acid or C ₆-C ₁₈Aliphatic alcohol accounts for 1-4 part.

In penetrating agent of the present invention, C ₆-C ₁₈Fatty acid preferably is selected from capric acid, lauric acid or oleic acid.C ₆-C ₁₈Aliphatic alcohol preferably is selected from decanol, lauryl alcohol or oleyl alcohol.

In penetrating agent compositions of the present invention, most preferred scheme is: penetrating agent is diethylene glycol monoethyl ether, propylene glycol and lauric compositions; Or isosorbide dimethyl ether, propylene glycol and lauric compositions; Or the compositions of diethylene glycol monoethyl ether, propylene glycol and lauryl alcohol; Or the compositions of diethylene glycol monoethyl ether, benzyl alcohol and lauryl alcohol; Or the compositions of diethylene glycol monoethyl ether, propylene glycol and oleyl alcohol; Or the compositions of isosorbide dimethyl ether, propylene glycol and oleyl alcohol; Or the compositions of diethylene glycol monoethyl ether, propylene glycol and decanol; Or the compositions of isosorbide dimethyl ether, propylene glycol and decanol.Wherein in weight portion, the ether compound in the above-mentioned composition accounts for 1-4 part, alcohol compound accounts for 1-4 part, C ₆-C ₁₈Fatty acid or aliphatic alcohol account for 1-4 part.

Another object of the present invention has been to provide the application of above-mentioned penetrating agent in the preparation transdermal drug delivery system.

Penetrating agent of the present invention is particularly useful for making the transdermal drug delivery system (transdermal patch) that pastes usefulness on human body skin.Be particularly useful for making steroid hormone and compound recipe steroid hormone transdermal drug delivery system, it can make progestogen and estrogen bi-component well penetrate skin simultaneously.Preparation-obtained steroid hormone transdermal drug delivery system is applied on the female skin, can be used for birth control or treatment female osteoporosis, associated conditions such as climacteric syndrome.Steroid hormone transdermal drug delivery system of the present invention is specially adapted to female contraception.

In one embodiment, steroid hormone transdermal drug delivery system provided by the invention comprises protective layer 1, drug storing layer 2 and backing layer 3;

Drug storing layer 2 is attached between strippable protective layer 1 and the backing layer 3, is to be prepared from by the sticky polymers matrix solution; The sticky polymers matrix solution composition of preparation drug storing layer 2 comprises: steroid hormone, sticky polymers, aforementioned penetrating agent of the present invention and viscosity modifier.

Components contents is counted with weight portion in the sticky polymers matrix solution: penetrating agent of the present invention accounts for 5-50 weight portion, sticky polymers and accounts for that 20-90 weight portion, viscosity modifier account for the 0.1-20 weight portion, steroid hormone accounts for the 0.1-5 weight portion; More preferably be: penetrating agent of the present invention accounts for 10-40 weight portion, sticky polymers and accounts for that 50-90 weight portion, viscosity modifier account for the 0.5-5 weight portion, steroid hormone accounts for the 0.1-3 weight portion; Be most preferably: penetrating agent of the present invention accounts for 10-20 weight portion, sticky polymers and accounts for that 70-90 weight portion, viscosity modifier account for the 0.5-3 weight portion, steroid hormone accounts for the 0.1-1 weight portion.

Sticky polymers among the present invention can be selected biological acceptable sticky polymers, for example crosslinked or uncrosslinked polyacrylate sticky polymers, silicone sticky polymers or the polyisobutylene sticky polymers etc. for use.Preferred crosslinked or uncrosslinked polyacrylate sticky polymers.

Be appropriate to implement further describing of polyacrylate sticky polymers of the present invention and be described in Satas " Acrylic Adhesives, " Handbook of Pressure Sensitive-Adhesive Technology.2 with example ^NdEd.pp 396 1 456 (D.Satas, ed.) Ban NostrandReinhole, New York (1989).The polyacrylate sticky polymers preferably can be for having the chemical compound of following general formula (I):

-(CH ₂-CH-COOR)n-

(I)

Wherein n represents the number of repeat unit of polymer monomer, and R is hydrogen or rudimentary (C ₁-C ₁₀) alkyl, described rudimentary (C ₁-C ₁₀) alkyl can be selected from ethyl, butyl and ethylhexyl etc. 1 in a preferred embodiment of the invention, described polyacrylate sticky polymers is preferably poly-(2-EHA/acrylic copolymer), poly-(the own ester/acrylic acid of acrylic acid 2-hydroxyl/methyl acrylate copolymer), poly-(2-EHA/acrylic acid/methyl acrylate copolymer) or poly-(2-EHA/acrylic acid/butyl acrylate/vinyl acetate copolymer).GMS 737,788,1753 as Cytec Surface Specialties Inc company; DUROTAK 87-4098,87-2287,87-4297,87-900A, the 87-2677 of National Starch Chemical Company; The RODERM 607 of Rohm Haas company or 610 etc.

Described silicone sticky polymers can for: suitable polysiloxanes comprises the siloxanes pressure sensitive adhesive, and it is based on two kinds of main components, polymer and elastomer or and tacky resin.The preparation of this silicone gums generally ties up in the appropriate organic solvent, utilizes condensation reaction with this elastomer (typically being a high-molecular weight polydiorganosiloxanepolyurea) and a resin interlinkage bond, to produce three-dimensional polysiloxane structure.This resin is one can controlled important factor to elastomeric ratio, to modify the physical characteristic of this polysiloxanes.Sobieski, et al., " Silocone Pressure SensitiveAdhesives; " Handbok ofPressure-Sensitive AdhesiveTechnology, 2nd ed., pp.508 one 517 (D.Satas, ed.), Van Nostrand Reinhold, New York (1989).Suitable polysiloxanes pressure sensitive adhesive comprises that the brand name that Dow Coring Corporation company sells is BIO-PSA X7-3027, X7-4203, Q7-4503, the polysiloxanes pressure sensitive adhesive of X7-4603, X7-4301, X7-4303, X7-4919, X7-2685 and X7-3122.BI0 one PSA X7-4203, X7-4301 and X7-4303.

Described polyisobutylene sticky polymers can be hydrocarbon polymer, the for example natural or synthetic polymer that gathers 2 monomethyl butadiene, polybutene and polyisobutylene, phenylethylene/butadiene polymer, styrene one 2 monomethyl butadiene one styrene block copolymer, hydrocarbyl polymers (for example butyl rubber), polyacrylonitrile, contains halogen (for example politef, polrvinyl chloride, poly-vinylidene chloride and polychlorobutadiene) and their other copolymer.

Sticky polymers substrate of the present invention also comprises the viscosity modifier that is dispersed in the substrate.Can use pharmaceutical polymers commonly used in pharmaceuticals industry as viscosity modifier.The use viscosity modifier is the viscosity for controlling polymers substrate.Adding viscosity modifier in sticky polymers substrate can increase the comfort of percutaneous contraceptive drugs delivery system (patch) when wearing, and helps reducing scytitis, and comes off when preventing the life-time service transdermal patch.Wherein said viscosity modifier is polyvinylpyrrolidone//vinyl acetate copolymers, polyvinylpyrrolidone, polybutyl methacrylate/methylmethacrylate copolymer or ethyl cellulose.Implement polyvinylpyrrolidone used in the present invention and be selected from K12, K17, K25, the K30 that BASF (BASF) company produces.Implement polybutyl methacrylate/methyl methacrylate used in the present invention and be selected from the Plastoid B that moral is filled in the production of (DEGUSSA) company admittedly.Implement ethyl cellulose used in the present invention and be selected from the Ethocel 7,10,14,20 that Dow Chemical (DOW CHEMICAL) company produces.Viscosity modifier preferably polyethylene ketopyrrolidine/vinyl acetate copolymer, polyvinylpyrrolidone or ethyl cellulose.Viscosity modifier is most preferably the polyvinylpyrrolidone/vinyl acetate of molecular weight 50,000, and the weight ratio of polyvinylpyrrolidone and vinyl acetate is 6: 4.Polyvinylpyrrolidone//vinyl acetate copolymers S-630 as the production of the U.S. international special product company; The polyvinylpyrrolidone//vinyl acetate copolymers VA64 that BASF Aktiengesellschaft produces.

Described steroid hormone is selected from one or more in progestogen and the estrogen.In weight portion, steroid hormone preferably is made up of the estrogen of 1-30 weight portion progestogen and 1-10 weight portion; More preferably form by the progestogen of 1-20 weight portion and the estrogen of 1-5 part.

Progestogen in the described steroid hormone can be selected from: the diacetate esters of levonorgestrel, methylnorethindron, norgestimate variant, gestodene, norethindrone, norethynodrel, hydrogen progesterone, gestodene, etynodiol, hydroxyprogesterone acetas, gestogen, other is biocompatible and can be by the progestogen of skin absorbs; Can pass through skin absorbs, and skin absorbs can change into the biocompatible progestogen derivant of original progestogen etc. afterwards.

Estrogen in the described steroid hormone can be selected from ethinylestradiol, 17 beta estradiols and biocompatible derivant thereof etc.If if absorbtivity meets the requirement and the hormone component of estrogenic component daily dose is compatible, what also can use 17 beta estradiol biocompatibility can be the derivant of 17 beta estradiols by Transdermal absorption and preferred biotransformation.Such derivatives of estradiol comprises ester, monoesters or diester.Monoesters can be 3-or 17-ester.Estradiol ester can be, for example, and estradiol-3,17-diacetate esters; Estradiol-3-acetas; Estradiol 17-acetas; Estradiol-3,17-two valerates; Estradiol-3-valerate; Estradiol l7-valerate; 3-is single-, 17-is single and 3,17-dipivilateesters; The 3-list-, the 17-list-and 3, the 17-dipropionate; The 3-list-, the 17-list-and 3,17 1 two cyclopenta-propionic esters; Corresponding cypionate, heptanoate, benzoate and similar ester; The thinyl estradiol; Estrone; But estrogens sterin and derivant thereof with other Transdermal absorption.

Progestogen in the steroid hormone are levonorgestrel most preferably, and estrogen is ethinylestradiol most preferably.

For steroid hormone transdermal drug delivery system provided by the invention, particularly preferred technical scheme is as follows: in a preferred embodiment, be used for preparing the sticky polymers matrix solution of drug storing layer 2, the consumption of component is counted with weight portion: penetrating agent 10-20 weight portion of the present invention, sticky polymers 70-90 weight portion, viscosity modifier 0.5-3 weight portion, steroid hormone 0.1-1 weight portion; Described steroid hormone is made up of the progestogen of 1-20 weight portion and the estrogen of 1-5 weight portion; Described penetrating agent is by the alcohol compound of the ether compound of 1-4 weight portion, 1-4 weight portion, the C of 1-4 weight portion ₆-C ₁₈Fatty acid or C ₆-C ₁₈Aliphatic alcohol is formed; Described ether compound is selected from diethylene glycol monoethyl ether or isosorbide dimethyl ether; Described alcohol compound is propylene glycol, benzyl alcohol, PEG400, PEG600 or PEG1000; Described C ₆-C ₁₈Fatty acid is selected from lauric acid, oleic acid or capric acid; Described C ₆-C ₁₈Aliphatic alcohol is selected from decanol, lauryl alcohol or oleyl alcohol.

Adopt the steroid hormone transdermal drug delivery system of penetrating agent preparation of the present invention, preferably making area is the circle of 10-30 square centimeter, the patch of square or rectangular; More preferably make area and be the patch of round, the square or rectangular of 15-25 square centimeter.

Adopt in the steroid hormone transdermal drug delivery system of penetrating agent preparation of the present invention, the thickness of drug storing layer 2 can be between the 50-200 micron; Preferably between the 80-150 micron.

Adopt in the steroid hormone transdermal drug delivery system of penetrating agent preparation of the present invention, do not limit backing layer is concrete, preferably to impermeable basically backing layer such as medicines; In other words be such backing layer, it loses from the back side by stoping medicine as the active component in the hypothallus, additive etc. to pass it, does not allow the content of medicine, additive etc. reduce.The material of backing layer 3 can be selected the laminated product of the polymeric film that contains or do not contain metal formings such as aluminium foil for use.Being suitable for the present invention is comprised by the material of lining: polyethylene, polypropylene, poly-ammonia phenol, polrvinyl chloride, poly-(O-phthalic vinyl acetate), tinsel etc.Scotchpak1109 that the preferred 3M of the present invention company produces or Cotran9720 are as back lining materials.The thickness of backing layer 3 can be between 10 to 300 microns; Preferred thickness is between 20 to 100 microns, and more preferably thickness is between 30 to 50 microns.

Adopt in the steroid hormone transdermal drug delivery system of penetrating agent preparation of the present invention, do not limit protective layer 1 is concrete, as long as fully guarantee the release characteristics of transdermal drug delivery system.The material of described protective layer 1 can be selected poly-vinegar film for use; polychloroethylene film; the polyvinylidene chloride film; poly-(ethylene glycol terephthalate) film etc.; high quality paper; cellophane etc., laminated film of polyolefin and paper such as high quality paper, cellophane etc. or the like, the side that they contact with hypothallus is carried out release treatment by applying silicone resin, fluororesin or corona etc.The Scotchpak1022 that the preferred 3M of the present invention company produces is as protective layer material.The thickness of protective layer 1 can be between 10 to 300 microns; Preferred thickness is between 30 to 200 microns, and more preferably thickness is between 50 to 100 microns.

In preparation steroid hormone transdermal drug delivery system process,, can add optional cosolvent for increasing the dissolubility of active constituent (steroid hormone).These cosolvents can be selected from: acetone, methanol, ethanol, isopropyl alcohol, formic acid second fat, ethyl acetate, oxolane and any mixture thereof.In case of necessity, can promote medicine dissolution by physical means such as heating or sonic oscillations.Cosolvent can remove in preparation process subsequently.

The present invention also provides the preparation method that adopts penetrating agent of the present invention to prepare the steroid hormone transdermal drug delivery system, comprises the steps:

(a) take by weighing steroid hormone (active component), add viscosity modifier, penetrating agent, cosolvent, stir and make dissolving; Add sticky polymers again, stir, make abundant mixing; Leave standstill, promptly get sticky polymers substrate;

(b) on protective layer 1, drying must be attached to the drug storing layer 2 on the protective layer 1 with the sticky polymers substrate of step (a) gained coating (spraying, solution casting);

(c) will be placed on as the material of backing layer 3 on the drug storing layer 2, together lamination;

(d) behind the lamination, according to required form and area, cutting gets the transdermal administration patch; Can cut into circle, square, rectangle or other desirable shape.

(e) the gained transdermal drug delivery system is put into the packing that is used for storing, be saved in skin-penetrating therapeutic.

In prepared patch, in the sticky polymers substrate the amount of dispersive steroid hormone (active component), can make it greater than the desired dosage of sending, for example doubly than the excessive 10-50 of desired accumulated dose of sending; Preferred excessive 20-30 doubly.

Drug storing layer 2 can use any acceptable method processing in the prior art, as coating, and spraying, solution casting etc.Can obtain the infiltration rate and the adhesive force of desirable transdermal drug delivery system by the concentration or the dry concentration of the penetrating agent in the subregion of adjusting drug storing layer.

Transdermal drug delivery system provided by the invention is bonded on the female skin to be used, and can effectively control birth, and realizes the purpose of contraception.

Those skilled in the art can determine the composition of selected steroid hormone according to therapeutic purposes.Prevent and treat osteoporosis, climacteric syndrome as selecting estradiol for use.Those skilled in the art all are included within the present invention according to the determined active ingredient of therapeutic purposes.

In the present invention, " C ₆-C ₁₈Fatty acid " be meant to have 6 acid to 18 carbon atom carbochains; " C ₆-C ₁₈Aliphatic alcohol " be meant to have 6 alcohol to 18 carbon atom carbochains; " sticky polymers " is meant when it is applied to surface and drying with the solution form, the polymer formation film, and as skilled in the art to understand, this film will have bonding and cohesive strength; " viscosity modifier " refers to change the material of viscosity; " steroid hormone " is meant the hormone of steroidal compounds class, for example estrogen, progestogen etc.In the present invention, " penetrating agent " is meant and can quickens or promote drug osmotic to enter for example reagent of skin, and this area also can be called " penetration enhancer " etc.

In this article, if not explanation especially, content or consumption are all in weight portion; If not special explanation, the device that is adopted, instrument, raw material, material, consumption, method, time, temperature and other condition etc. all are well-known in the art, or those skilled in the art can obtain in conjunction with prior art according to the application's description.

Enhancer of cutaneous penetration compositions of the present invention not only can improve the dissolubility of steroid hormone in the transdermal drug delivery system (such as steroid hormone transdermal drug delivery system of the present invention) effectively, and obtains better percutaneous permeability, the cohesiveness of patch is not destroyed.And, because penetrating agent compositions of the present invention can produce extraordinary collaborative promotion Absorption, has the short efficiently effect of oozing, can improve the percutaneous rate of institute's transdermal thing (active constituent) significantly, do not having under dimethyl sulfoxide (DMSO) condition, the transdermal drug delivery system Chinese medicine dosage that (such as levonorgestrel and the contraception of estrogen transdermal) expected can be provided equally, thereby avoid the short potential danger of bringing of oozing of life-time service dimethyl sulfoxide (DMSO).In addition, penetrating agent of the present invention is compatible with many acrylic compounds pressure sensitive adhesive matrixs system, and to the inherent cohesiveness of matrix system, viscosity and rheological property destroy less.In addition, transdermal drug delivery system preparation method provided by the invention is simple, has avoided complicated technologies such as MULTILAYER COMPOSITE.The resulting product initial bonding strength of the present invention and hold viscous force, heat stability, non-oxidizability, rate of release, safety etc. all are better than the prior art level.The transdermal drug delivery system that adopts penetrating agent preparation of compositions of the present invention to obtain, therapeutic effect is good, and is safe and convenient to use.

Description of drawings

Fig. 1: transdermal drug delivery system schematic cross-section of the present invention

1, protective layer 2, drug storing layer 3, backing layer

The specific embodiment

The general preparation method of the steroid hormone transdermal drug delivery system that following " preparation method " is the embodiment of the invention, " vitro skin permeability test " are to measure the experimental technique of the transdermal infiltration rate of transdermal drug delivery system Chinese medicine of each embodiment.

Preparation method:

By the consumption that each embodiment provides, take by weighing active component (steroid hormone), put into vial, add viscosity modifier, cosolvent, penetrating agent, be stirred to solubilization of active ingredient.Add viscous polymer solution,, form homogeneous solution to stir 6 hours under the 200rpm speed.Left standstill 3 hours.Get the sticky polymers matrix solution.

The sticky polymers matrix solution that obtains is coated on the protective layer material (as 3M Co., the Scotch Pak 1022 that St.Paul Minn. produces), and applied thickness is about 600 microns, subsequently 65 ℃ of oven dryings 30 minutes.After the drying, about 120 microns of the thickness of sticky polymers hypothallus (drug storing layer).(as 3M Co., Scotch Pak 1109 or Cotran 9720 that St.Paul Minn. produces) is placed on the sticky polymers hypothallus with the release liner (backing layer) of a slice same size, and lamination together obtains the patch of transdermal drug delivery system.Patch cut into 20 square centimeters round patch.Patch is put into the appropriate packaging (as paper bag and/or metallic foil bag) that is used for storing to be preserved standby.

The vitro skin permeability test:

The skin that fresh human body skin is cut into a certain size is tight respectively between two Room of VALIA-CHIEN osmotic cell; skin corium is towards receiving chamber; stratum corneum side is sticked the transdermal contraception patch behind the removal protective layer; with alligator clamp the twoport of two Room is fixed; in receiving chamber, add 40% (v/v) PEG400 normal saline solution 3.4ml; water temperature in the control osmotic cell interlayer is at 32 ± 0.5 ℃; electromagnetic agitation rotating speed 500r/min; in accordance with regulations 4; 8; 24; 32; 48 hour blanking time; take out the penetrating fluid of 100 μ l respectively from receiving chamber; replenish equivalent 40% (v/v) PEG400 normal saline solution blank solution simultaneously, with LNG in the HPLC method mensuration penetrating fluid and the transdermal cumulative release amount of EE.The amount of linear regression analysis drug accumulation is over time calculated 48 hours transdermal infiltration rates of medicine thus.

Embodiment 1

Steroid hormone: levonorgestrel 0.05g, ethinylestradiol 0.05g;

Viscosity modifier: PVP/VA copolymer (VA64) 0.1g;

Penetrating agent 5g: propylene glycol 2.5g, diethylene glycol monoethyl ether 2.5g;

Sticky polymers: GMS737 20g

Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.14 μ g/cm ²/ h.

Embodiment 2

Steroid hormone: levonorgestrel 0.2g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (VA64) 1.5g;

Penetrating agent 6g: propylene glycol 2g, diethylene glycol monoethyl ether 4g;

Sticky polymers: GMS737 30g;

Recording the levonorgestrel percutaneous rate is 0.16 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm ²/ h.

Embodiment 3

Steroid hormone: levonorgestrel 0.3g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.3g;

Penetrating agent 8g: propylene glycol 2g, isosorbide dimethyl ether 6g;

Sticky polymers: GMS737 40g;

Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm ²/ h.

Embodiment 4

Steroid hormone: levonorgestrel 0.4g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.4g;

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

Sticky polymers: GMS737 50g;

Recording the levonorgestrel percutaneous rate is 0.18 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm ²/ h.

Embodiment 5

Steroid hormone: levonorgestrel 0.6g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;

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

Sticky polymers: GMS737 60g;

Embodiment 6

Steroid hormone: levonorgestrel 0.5g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.6g;

Penetrating agent 21g: propylene glycol 3g, diethylene glycol monoethyl ether 18g;

Sticky polymers: GMS737 70g;

Embodiment 7

Steroid hormone: levonorgestrel 0.7g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.7g;

Penetrating agent 24g: propylene glycol 3g, isosorbide dimethyl ether 21g;

Sticky polymers: GMS737 80g;

Embodiment 8

Steroid hormone: levonorgestrel 0.8g, ethinylestradiol 0.2g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.8g;

Penetrating agent 20g: propylene glycol 10g, diethylene glycol monoethyl ether 10g;

Sticky polymers: DUROTAK 87-4098 80g;

Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.15 μ g/cm ²/ h.

Embodiment 9

Steroid hormone: levonorgestrel 0.9g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.9g;

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

Sticky polymers: GMS 1753 80g;

Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm ²/ h.

Embodiment 10

Steroid hormone: levonorgestrel 0.10g, ethinylestradiol 0.01g;

Viscosity modifier: PVP/VA copolymer (S-630) 1.0g;

Penetrating agent 33g: propylene glycol 3g, isosorbide dimethyl ether 30g;

Sticky polymers: GMS737 75g;

Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.08 μ g/cm ²/ h.

Embodiment 11

Steroid hormone: levonorgestrel 0.15g, ethinylestradiol 0.01g;

Viscosity modifier: PVP/VA copolymer (S-630) 1.1g;

Penetrating agent 36g: propylene glycol 3g, diethylene glycol monoethyl ether 33g;

Sticky polymers: GMS 788 60g;

Recording the levonorgestrel percutaneous rate is 0.16 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.08 μ g/cm ²/ h.

Embodiment 12

Steroid hormone: levonorgestrel 0.2g, ethinylestradiol 0.01g;

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

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

Sticky polymers: GMS737 65g;

Embodiment 13

Steroid hormone: levonorgestrel 0.3g, ethinylestradiol 0.01g;

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

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

Sticky polymers: GMS 788 80g;

Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.04 μ g/cm ²/ h.

Embodiment 14

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.2g;

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

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

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.18 μ g/cm ²/ h.

Embodiment 15

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.02g;

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

Sticky polymers: 6MS737 80g;

Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.06 μ g/cm ²/ h.

Embodiment 16

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.04g;

Viscosity modifier: PVP/VA copolymer (S-630) 1.6g;

Penetrating agent 48g: propylene glycol 3g, isosorbide dimethyl ether 45g;

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.16 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm ²/ h.

Embodiment 17

Steroid hormone: levonorgestrel 2g, ethinylestradiol 1g;

Viscosity modifier: PVP/VA copolymer (S-630) 1.7g;

Penetrating agent 17g: propylene glycol 1g, diethylene glycol monoethyl ether 16g;

Sticky polymers: 6MS737 70g;

Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.14 μ g/cm ²/ h.

Embodiment 18

Steroid hormone: levonorgestrel 1g, ethinylestradiol 1g;

Viscosity modifier: PVP/VA copolymer (S-630) 1.8g;

Penetrating agent 19g: propylene glycol 1g, isosorbide dimethyl ether 18g;

Sticky polymers: GMS737 75g;

Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.21 μ g/cm ²/ h.

Embodiment 19

Steroid hormone: levonorgestrel 1.5g, ethinylestradiol 1.0g;

Viscosity modifier: PVP/VA copolymer (S-630) 1.9g;

Penetrating agent 20g: propylene glycol 1g, isosorbide dimethyl ether 19g;

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.21 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.17 μ g/cm ²/ h.

Embodiment 20

Steroid hormone: levonorgestrel 0.1g, the female 0.08g of alkynes;

Viscosity modifier: PVP/VA copolymer (S-630) 2.0g;

Penetrating agent 21g: propylene glycol 1g, diethylene glycol monoethyl ether 20g;

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm ²/ h.

Embodiment 21

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.09g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.1g;

Penetrating agent 22g: propylene glycol 1g, diethylene glycol monoethyl ether 21g;

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm ²/ h.

Embodiment 22

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.01g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.2g;

Penetrating agent 23g: propylene glycol 1g, diethylene glycol monoethyl ether 22g;

Sticky polymers: DUROTAK87-2287 80g;

Embodiment 23

Steroid hormone: levonorgestrel 0.01g, ethinylestradiol 0.10g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.3g;

Penetrating agent 25g: propylene glycol 1g, isosorbide dimethyl ether 24g;

Sticky polymers: DUROTAK87-4297 80g;

Recording the levonorgestrel percutaneous rate is 0.06 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.17 μ g/cm ²/ h.

Embodiment 24

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.20g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.4g;

Penetrating agent 26g: propylene glycol 1g, diethylene glycol monoethyl ether 25g;

Sticky polymers: DUROTAK87-900A 80g;

Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.21 μ g/cm ²/ h.

Embodiment 25

Steroid hormone: levonorgestrel 0.05g, ethinylestradiol 0.25g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.5g;

Penetrating agent 27g: propylene glycol 1g, diethylene glycol monoethyl ether 26g;

Sticky polymers: GMS737 90g;

Recording the levonorgestrel percutaneous rate is 0.04 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.18 μ g/cm ²/ h.

Embodiment 26

Steroid hormone: levonorgestrel 1g, ethinylestradiol 3g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.6g;

Penetrating agent 25g: propylene glycol 1g, diethylene glycol monoethyl ether 28g;

Sticky polymers: DUROTAK87-2677 80g;

Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm ²/ h.

Embodiment 27

Steroid hormone: levonorgestrel 1g, ethinylestradiol 0.1g;

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

Penetrating agent 20g: propylene glycol 10g, isosorbide dimethyl ether 10g;

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.25 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.15 μ g/cm ²/ h.

Embodiment 28

Steroid hormone: levonorgestrel 0.02g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.8g;

Penetrating agent 31g: propylene glycol 1g, diethylene glycol monoethyl ether 30g;

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.06 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.14 μ g/cm ²/ h.

Embodiment 29

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.01g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.9g;

Penetrating agent 31g: propylene glycol 30g, diethylene glycol monoethyl ether 1g;

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.03 μ g/cm ²/ h.

Embodiment 30

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.01g;

Viscosity modifier: PVP/VA copolymer (S-630) 3.0g;

Penetrating agent 26g: propylene glycol 25g, isosorbide dimethyl ether 1g;

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.13 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.03 μ g/cm ²/ h.

Embodiment 31

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.01g;

Viscosity modifier: PVP/VA copolymer (S-630) 3.1g;

Penetrating agent 21g: propylene glycol 20g, diethylene glycol monoethyl ether 1g;

Sticky polymers: GMS737 80g;

Embodiment 32

Steroid hormone: levonorgestrel 0.01g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 3.2g;

Penetrating agent 16g: propylene glycol 15g, diethylene glycol monoethyl ether 1g;

Sticky polymers: GMS737 90g;

Recording the levonorgestrel percutaneous rate is 0.04 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.15 μ g/cm ²/ h.

Embodiment 33

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.01g;

Viscosity modifier: PVP/VA copolymer (S-630) 3.3g;

Penetrating agent 22g: propylene glycol 20g, diethylene glycol monoethyl ether 2g;

Sticky polymers: GMS737 80g;

Embodiment 34

Steroid hormone: levonorgestrel 0.2g, ethinylestradiol 0.01g;

Viscosity modifier: PVP/VA copolymer (S-630) 3.4g;

Penetrating agent 18g: propylene glycol 15g, isosorbide dimethyl ether 3g;

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.05 μ g/cm ²/ h.

Embodiment 35

Steroid hormone: levonorgestrel O.1g, ethinylestradiol 0.3g;

Viscosity modifier: PVP/VA copolymer (S-630) 3.5g;

Penetrating agent 15g: benzyl alcohol 12g, diethylene glycol monoethyl ether 3g;

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.16 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm ²/ h.

Embodiment 36

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.4g;

Viscosity modifier: PVP/VA copolymer (S-630) 3.6g;

Penetrating agent 20g:PEG40015g, diethylene glycol monoethyl ether 5g;

Sticky polymers: RODERM 607 80g;

Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm ²/ h.

Embodiment 37

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.5g;

Viscosity modifier: PVP/VA copolymer (S-630) 3.7g;

Penetrating agent 15g: propylene glycol 10g, diethylene glycol monoethyl ether 5g;

Sticky polymers: RODERM 610 80g;

Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.27 μ g/cm ²/ h.

Embodiment 38

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.6g;

Viscosity modifier: PVP/VA copolymer (S-630) 3.8g;

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

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.28 μ g/cm ²/ h.

Embodiment 39

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.7g;

Viscosity modifier: PVP/VA copolymer (S-630) 4.1g;

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

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.30 μ g/cm ²/ h.

Embodiment 40

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.8g;

Viscosity modifier: PVP/VA copolymer (S-630) 4.2g;

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

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.30 μ g/cm ²/ h.

Embodiment 41

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.9g;

Viscosity modifier: PVP/VA copolymer (S-630) 4.3g;

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

Sticky polymers: 6MS737 90g;

Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.29 μ g/cm ²/ h.

Embodiment 42

Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 1.0g;

Viscosity modifier: PVP/VA copolymer (S-630) 4.5g;

Penetrating agent 45g: propylene glycol 5g, isosorbide dimethyl ether 40g;

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.08 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.20 μ g/cm ²/ h.

Embodiment 43

Steroid hormone: levonorgestrel 3.0g, ethinylestradiol 1.0g;

Viscosity modifier: PVP/VA copolymer (S-630) 5.0g;

Penetrating agent 50g: propylene glycol 20g, diethylene glycol monoethyl ether 30g;

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm ²/ h.

Embodiment 44

Steroid hormone: levonorgestrel 3.5g, ethinylestradiol 1.5g;

Viscosity modifier: PVP/VA copolymer (S-630) 5.0g;

Penetrating agent 40g: propylene glycol 10g, diethylene glycol monoethyl ether 30g;

Sticky polymers: GMS737 80g;

Embodiment 45

Steroid hormone: levonorgestrel 0.05g, ethinylestradiol 0.05g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.1g;

Penetrating agent 6g: propylene glycol 2g, diethylene glycol monoethyl ether 2g, lauric acid 2g;

Sticky polymers: GMS737 20g;

Recording the levonorgestrel percutaneous rate is 0.17 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.17 μ g/cm ²/ h.

Embodiment 46

Steroid hormone: levonorgestrel 0.07g, ethinylestradiol 0.13g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.2g;

Penetrating agent 10g: propylene glycol 8.0g, diethylene glycol monoethyl ether 1.0g, lauric acid 1g;

Sticky polymers: GMS737 30g;

Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.20 μ g/cm ²/ h.

Embodiment 47

Steroid hormone: levonorgestrel 0.2g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.3g;

Penetrating agent 7g: benzyl alcohol 5g, diethylene glycol monoethyl ether 1g, lauric acid 1g;

Sticky polymers: GMS737 40g;

Recording the levonorgestrel percutaneous rate is 0.22 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm ²/ h.

Embodiment 48

Steroid hormone: levonorgestrel 0.3g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.4g;

Penetrating agent 12g: propylene glycol 10g, diethylene glycol monoethyl ether 1g, lauric acid 1g;

Sticky polymers: GMS737 50g;

Recording the levonorgestrel percutaneous rate is 0.28 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm ²/ h.

Embodiment 49

Steroid hormone: levonorgestrel 0.4g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;

Penetrating agent 17g: propylene glycol 15g, diethylene glycol monoethyl ether 1g, lauric acid 1g;

Sticky polymers: GMS737 60g;

Recording the levonorgestrel percutaneous rate is 0.30 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm ²/ h.

Embodiment 50

Steroid hormone: levonorgestrel 0.5g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.6g;

Penetrating agent 22g: propylene glycol 20g, isosorbide dimethyl ether 1g, lauric acid 1g;

Sticky polymers: GMS737 70g;

Recording the levonorgestrel percutaneous rate is 0.32 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm ²/ h.

Embodiment 51

Steroid hormone: levonorgestrel 0.6g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.7g;

Penetrating agent 32g: propylene glycol 30g, diethylene glycol monoethyl ether 1g, lauric acid 1g;

Sticky polymers: GMS737 80g;

Recording the levonorgestrel percutaneous rate is 0.34 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm ²/ h.

Embodiment 52

Steroid hormone: levonorgestrel 0.7g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.8g;

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

Sticky polymers: GMS 788 80g;

Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm ²/ h.

Embodiment 53

Steroid hormone: levonorgestrel 0.8g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.9g;

Penetrating agent 16g: propylene glycol 6g, diethylene glycol monoethyl ether 6g, lauric acid 4g;

Sticky polymers: GMS 1753 78g;

Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm ²/ h.

Embodiment 54

Steroid hormone: levonorgestrel 0.9g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 1.0g;

Penetrating agent 35g: propylene glycol 5g, diethylene glycol monoethyl ether 25g, lauric acid 5g;

Sticky polymers: GMS 788 80g;

Recording the levonorgestrel percutaneous rate is 0.24 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm ²/ h.

Embodiment 55

Steroid hormone: levonorgestrel 1.0g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 1.1g;

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

Sticky polymers: GMS 1753 90g;

Recording the levonorgestrel percutaneous rate is 0.25 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm ²/ h.

Embodiment 56

Steroid hormone: levonorgestrel 1.1g, ethinylestradiol 0.1g;

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

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

Sticky polymers: GMS 1753 80g;

Recording the levonorgestrel percutaneous rate is 0.26 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm ²/ h.

Embodiment 57

Steroid hormone: levonorgestrel 1.2g, ethinylestradiol 0.1g;

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

Penetrating agent 34g: propylene glycol 2g, diethylene glycol monomethyl ether 30g, lauric acid 2g;

Sticky polymers: GMS 1753 80g;

Embodiment 58

Steroid hormone: levonorgestrel 1.3g, ethinylestradiol 0.1g;

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

Penetrating agent 44g: propylene glycol 2g, diethylene glycol monoethyl ether 40g, lauric acid 2g;

Sticky polymers: GMS 1753 80g;

Recording the levonorgestrel percutaneous rate is 0.27 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm ²/ h.

Embodiment 59

Steroid hormone: levonorgestrel 1.4g, ethinylestradiol 0.1g;

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

Penetrating agent 32g: propylene glycol 1g, diethylene glycol monomethyl ether 30g, oleic acid 1g;

Sticky polymers: DUROTAK 87-4098 80g;

Embodiment 60

Steroid hormone: levonorgestrel 1.5g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 1.6g;

Penetrating agent 15g: propylene glycol 3g, isosorbide dimethyl ether 6g, lauric acid 6g;

Sticky polymers: DUROTAK 87-4098 70g;

Embodiment 61

Steroid hormone: levonorgestrel 1.6g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 1.7g;

Penetrating agent 21g: propylene glycol 3g, diethylene glycol monoethyl ether 9g, oleic acid 9g;

Sticky polymers: DUROTAK 87-4098 80g;

Embodiment 62

Steroid hormone: levonorgestrel 1.7g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 1.8g;

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

Sticky polymers: DUROTAK 87-2287 80g;

Embodiment 63

Steroid hormone: levonorgestrel 1.8g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 1.9g;

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

Sticky polymers: DUROTAK 87-2287 80g;

Recording the levonorgestrel percutaneous rate is 0.29 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm ²/ h.

Embodiment 64

Steroid hormone: levonorgestrel 1.9g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.0g;

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

Sticky polymers: DUROTAK 87-2287 80g;

Embodiment 65

Steroid hormone: levonorgestrel 2.0g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.1g;

Penetrating agent 28g: propylene glycol 2g, diethylene glycol monoethyl ether 12g, capric acid 14g;

Sticky polymers: DUROTAK 87-2287 80g;

Embodiment 66

Steroid hormone: levonorgestrel 2.1g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.2g;

Penetrating agent 34g: propylene glycol 2g, diethylene glycol monomethyl ether 12g, capric acid 20g;

Sticky polymers: DUROTAK 87-4297 80g;

Embodiment 67

Steroid hormone: levonorgestrel 2.2g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.3g;

Penetrating agent 23g: propylene glycol 1g, diethylene glycol monoethyl ether 6g, capric acid 15g;

Sticky polymers: DUROTAK 87-4297 80g;

Embodiment 68

Steroid hormone: levonorgestrel 2.3g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.4g;

Penetrating agent 27g: propylene glycol 1g, isosorbide dimethyl ether 6g, lauric acid 20g;

Sticky polymers: DUROTAK 87-4297 80g;

Embodiment 69

Steroid hormone: levonorgestrel 2.4g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.5g;

Penetrating agent 36g: propylene glycol 1g, diethylene glycol monomethyl ether 10g, lauric acid 25g;

Sticky polymers: DUROTAK 887-2677 80g;

Embodiment 70

Steroid hormone: levonorgestrel 2.5g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.6g;

Penetrating agent 46g: propylene glycol 1g, diethylene glycol monoethyl ether 15g, lauric acid 30g;

Sticky polymers: DUROTAK 87-900A 80g;

Embodiment 71

Steroid hormone: levonorgestrel 2.6g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.7g;

Penetrating agent 41g: propylene glycol 1g, diethylene glycol monoethyl ether 10g, capric acid 30g;

Sticky polymers: DUROTAK 87-2677 80g;

Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.09 μ g/cm ²/ h.

Embodiment 72

Steroid hormone: levonorgestrel 2.7g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.8g;

Penetrating agent 40g: propylene glycol 15g, diethylene glycol monoethyl ether 15g, lauric acid 10g;

Sticky polymers: DUROTAK 87-2677 80g;

Recording left alkynes W norgesterone percutaneous rate is 0.35 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.09 μ g/cm ²/ h.

Embodiment 73

Steroid hormone: levonorgestrel 2.8g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 2.9g;

Penetrating agent 30g: propylene glycol 10g, isosorbide dimethyl ether 10g, lauric acid 10g;

Sticky polymers: DUROTAK 87-900A 80g;

Embodiment 74

Steroid hormone: levonorgestrel 2.9g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 3.0g;

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

Sticky polymers: DUROTAK 87-900A 80g;

Recording the levonorgestrel percutaneous rate is 0.30 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.09 μ g/cm ²/ h.

Embodiment 75

Steroid hormone: levonorgestrel 3.0g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 3.1g;

Penetrating agent 40g: propylene glycol 10g, diethylene glycol monoethyl ether 30g, capric acid 10g;

Sticky polymers: DUROTAK 87-900A 80g;

Embodiment 76

Steroid hormone: levonorgestrel 4.0g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;

Penetrating agent 34g: propylene glycol 12g, diethylene glycol monoethyl ether 12g, lauric acid 10g;

Sticky polymers: GMS 737 80g;

Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.05 μ g/cm ²/ h.

Embodiment 77

Steroid hormone: levonorgestrel 0.50g, ethinylestradiol 0.05g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;

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

Sticky polymers: GMS 737 80g;

Embodiment 78

Steroid hormone: levonorgestrel 2g, ethinylestradiol 1g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;

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

Sticky polymers: RODERM 607 80g;

Recording the levonorgestrel percutaneous rate is 0.33 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.20 μ g/cm ²/ h.

Embodiment 79

Steroid hormone: estradiol 0.2g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;

Penetrating agent 34g: propylene glycol 12g, isosorbide dimethyl ether 12g, oleic acid 10g;

Sticky polymers: RODERM 610 80g;

Recording estradiol transdermal speed is 0.23 μ g/cm ²/ h.

Embodiment 80

Steroid hormone: estradiol 8g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;

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

Sticky polymers: RODERM 610 80g;

Recording estradiol transdermal speed is 0.35 μ g/cm ²/ h.

Embodiment 81

Steroid hormone: estradiol 5g,

Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;

Sticky polymers: RODERM 610 80g;

Recording estradiol transdermal speed is 0.35 μ g/cm ²/ h.

Embodiment 82

Steroid hormone: levonorgestrel 0.2g estradiol 0.04g;

Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;

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

Sticky polymers: GMS 737 72g;

Recording the levonorgestrel percutaneous rate is 0.25 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.05 μ g/cm ²/ h.

Embodiment 83

Steroid hormone: levonorgestrel 0.2g estradiol 0.1g;

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

Penetrating agent 20g: propylene glycol 12g, diethylene glycol monoethyl ether 12g, lauric acid 10g;

Sticky polymers: GMS 737 90g;

Embodiment 84

Steroid hormone: levonorgestrel 0.1g estradiol 0.1g;

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

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

Sticky polymers: GMS 737 75g;

Recording the levonorgestrel percutaneous rate is 0.24 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm ²/ h.

Embodiment 85

Steroid hormone: levonorgestrel 0.02g estradiol 0.1g;

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

Penetrating agent 15g: propylene glycol 6g, diethylene glycol monoethyl ether 6g, oleic acid 3g;

Sticky polymers: GMS 737 75g;

Embodiment 86

Steroid hormone: levonorgestrel 0.1g estradiol 1g;

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

Penetrating agent 13g: propylene glycol 5g, diethylene glycol monoethyl ether 5g, oleic acid 3g;

Sticky polymers: GMS 737 75g;

Embodiment 87

Steroid hormone: levonorgestrel 0.5g estradiol 0.2g;

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

Penetrating agent 20g: propylene glycol 7g, diethylene glycol monoethyl ether 7g, lauric acid 6g;

Sticky polymers: GMS 737 90g;

Embodiment 88

Steroid hormone: levonorgestrel 4g estradiol 1g;

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

Sticky polymers: GMS 737 90g;

Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm ²/ h.

Embodiment 89

Steroid hormone: levonorgestrel 3g estradiol 1g;

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

Penetrating agent 10g: propylene glycol 4g, diethylene glycol monoethyl ether 4g, lauric acid 2g;

Sticky polymers: GMS 737 80g;

Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.18 μ g/cm ²/ h.

Embodiment 90

Steroid hormone: levonorgestrel 0.8g estradiol 0.2g;

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

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

Sticky polymers: GMS 737 86g;

Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.15 μ g/cm ²/ h.

Embodiment 91

Steroid hormone: levonorgestrel 2g estradiol 1g;

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

Penetrating agent 14g:PEG1000 5g, diethylene glycol monoethyl ether 5g, oleic acid 4g;

Sticky polymers: GMS 737 86g;

Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.35 μ g/cm ²/ h.

Embodiment 92

Steroid hormone: levonorgestrel 1g estradiol 2g;

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

Penetrating agent 14g: propylene glycol 5g, isosorbide dimethyl ether 5g, capric acid 4g;

Sticky polymers: GMS 737 86g;

Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm ²/ h, ethinyl estradiol gas permeable speed are: 0.40 μ g/cm ²/ h.

Embodiment 93

Steroid hormone: levonorgestrel 1g estradiol 3g;

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

Penetrating agent 14g: propylene glycol 5g, isosorbide dimethyl ether 5g, decanol 4g;

Sticky polymers: GMS 737 86g;

Embodiment 94

Steroid hormone: levonorgestrel 1g estradiol 2g;

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

Penetrating agent 14g: benzyl alcohol 5g, isosorbide dimethyl ether 5g, capric acid 4g;

Sticky polymers: GMS 737 86g;

Embodiment 95

Steroid hormone: levonorgestrel 4g estradiol 1g;

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

Penetrating agent 20g: propylene glycol 7g, diethylene glycol monoethyl ether 7g, lauryl alcohol 6g;

Sticky polymers: GMS 737 90g;

Embodiment 96

Steroid hormone: levonorgestrel 4g estradiol 1g;

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

Penetrating agent 20g: propylene glycol 7g, diethylene glycol monoethyl ether 7g, oleyl alcohol 6g;

Sticky polymers: GMS 737 90g;

Embodiment 97

Steroid hormone: levonorgestrel 4g estradiol 1g;

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

Penetrating agent 20g: propylene glycol 7g, isosorbide dimethyl ether 7g, oleyl alcohol 6g;

Sticky polymers: GMS 737 90g;

Embodiment 98

Steroid hormone: levonorgestrel 3.0g, ethinylestradiol 0.1g;

Viscosity modifier: PVP/VA copolymer (S-630) 3.1g;

Penetrating agent 40g: propylene glycol 10g, diethylene glycol monoethyl ether 30g, decanol 10g;

Sticky polymers: DUROTAK 87-900A 80g;

Resulting transdermal drug delivery system is bonded on the female skin uses, can reach contraception or prevent and treat osteoporotic ideal effect.Through tests such as skin toxicity, sensitivity, prove that patch of the present invention is better than the prior art level greatly.

The as above embodiment purpose that is only used for setting forth, and and limit protection scope of the present invention never in any form.Those skilled in the art can make multiple modification or change to embodiment of the present invention under spirit of the present invention and purport under the instruction of this description, these all will comprise within the scope of the invention.

Claims

1. a penetrating agent is characterized in that it contains ether compound and alcohol compound, and described alcohol compound does not comprise C ₆-C ₁₈Aliphatic alcohol.

2. penetrating agent according to claim 1, it is characterized in that the content of ether compound and alcohol compound is counted with weight portion: ether compound accounts for 1-30 part, and alcohol compound accounts for 1-30 part.

3. penetrating agent according to claim 2, it is characterized in that the content of ether compound and alcohol compound is counted with weight portion: ether compound accounts for 1-20 part, and alcohol compound accounts for 1-20 part.

4. penetrating agent according to claim 3, it is characterized in that the content of ether compound and alcohol compound is counted with weight portion: ether compound accounts for 1-10 part, and alcohol compound accounts for 1-10 part.

5. penetrating agent according to claim 4, it is characterized in that the content of ether compound and alcohol compound is counted with weight portion: ether compound accounts for 1-4 part, and alcohol compound accounts for 1-4 part.

6. according to each described penetrating agent among the claim 1-5, it is characterized in that described ether compound is selected from isosorbide dimethyl ether, diethylene glycol monoethyl ether or diethylene glycol monomethyl ether.

7. according to each described penetrating agent among the claim 1-5, it is characterized in that described alcohol compound is selected from propylene glycol, Polyethylene Glycol or benzyl alcohol.

8. penetrating agent according to claim 1 is characterized in that it also contains C ₆-C ₁₈Fatty acid or C ₆-C ₁₈Aliphatic alcohol.

9. penetrating agent according to claim 8 is characterized in that ether compound, alcohol compound and C ₆-C ₁₈Fatty acid or C ₆-C ₁₈The content of aliphatic alcohol is counted with weight portion:

Ether compound accounts for 1-30 part, alcohol compound accounts for 1-30 part, C ₆-C ₁₈Fatty acid or C ₆-C ₁₈Aliphatic alcohol accounts for 1-30 part.

10. penetrating agent according to claim 9 is characterized in that ether compound, alcohol compound and C ₆-C ₁₈Fatty acid or C ₆-C ₁₈The content of aliphatic alcohol is counted with weight portion:

Ether compound accounts for 1-20 part, alcohol compound accounts for 1-20 part, C ₆-C ₁₈Fatty acid or C ₆-C ₁₈Aliphatic alcohol accounts for 1-20 part.

11. penetrating agent according to claim 10 is characterized in that ether compound, alcohol compound and C ₆-C ₁₈Fatty acid or C ₆-C ₁₈The content of aliphatic alcohol count with weight portion:

Ether compound accounts for 1-10 part, alcohol compound accounts for 1-10 part, C ₆-C ₁₈Fatty acid or C ₆-C ₁₈Aliphatic alcohol account for 1-10 part.

12. penetrating agent according to claim 11 is characterized in that ether compound, alcohol compound and C ₆-C ₁₈Fatty acid or C ₆-C ₁₈The content of aliphatic alcohol count with weight portion:

Ether compound accounts for 1-4 part, alcohol compound accounts for 1-4 part, C ₆-C ₁₈Fatty acid or C ₆-C ₁₈Aliphatic alcohol account for 1-4 part.

13. each described penetrating agent according to Claim 8-12 is characterized in that ether compound wherein is selected from isosorbide dimethyl ether, diethylene glycol monoethyl ether or diethylene glycol monomethyl ether; Alcohol compound is selected from propylene glycol, Polyethylene Glycol or benzyl alcohol; C ₆-C ₁₈Fatty acid is selected from capric acid, lauric acid or oleic acid; C ₆-C ₁₈Aliphatic alcohol is selected from decanol, lauryl alcohol or oleyl alcohol.

14. penetrating agent according to claim 13 is characterized in that described penetrating agent is diethylene glycol monoethyl ether, propylene glycol and lauric compositions.

15. penetrating agent according to claim 13 is characterized in that described penetrating agent is isosorbide dimethyl ether, propylene glycol and lauric compositions.

16. penetrating agent according to claim 13 is characterized in that described penetrating agent is the compositions of diethylene glycol monoethyl ether, propylene glycol and lauryl alcohol.

17. penetrating agent according to claim 13 is characterized in that described penetrating agent is the compositions of diethylene glycol monoethyl ether, benzyl alcohol and lauryl alcohol.

18. penetrating agent according to claim 13 is characterized in that described penetrating agent is the compositions of diethylene glycol monoethyl ether, propylene glycol and oleyl alcohol.

19. penetrating agent according to claim 13 is characterized in that described penetrating agent is the compositions of isosorbide dimethyl ether, propylene glycol and oleyl alcohol.

20. penetrating agent according to claim 13 is characterized in that described penetrating agent is the compositions of diethylene glycol monoethyl ether, propylene glycol and decanol.

21. penetrating agent according to claim 13 is characterized in that described penetrating agent is the compositions of isosorbide dimethyl ether, propylene glycol and decanol.

22. the application of each described penetrating agent in the preparation transdermal drug delivery system among the claim 1-21.

23. the application of each described penetrating agent in preparation steroid hormone transdermal drug delivery system among the claim 1-21.

24. the application of the described steroid hormone transdermal drug delivery system of claim 23 in contraception.

25. a steroid hormone transdermal drug delivery system is characterized in that: it comprises protective layer (1), drug storing layer (2) and backing layer (3);

Drug storing layer (2) is attached between strippable protective layer (1) and the backing layer (3), is to be prepared from by the sticky polymers matrix solution; The sticky polymers matrix solution composition of preparation drug storing layer (2) comprising: each described penetrating agent and viscosity modifier among steroid hormone, sticky polymers, the claim 1-21.

26. want 25 described steroid hormone transdermal drug delivery systems according to right, it is characterized in that the consumption of component is counted with parts by weight in the described sticky polymers matrix solution: penetrating agent accounts for 5-50 weight portion, sticky polymers and accounts for that 20-90 weight portion, viscosity modifier account for the 0.1-20 weight portion, steroid hormone accounts for the 0.1-5 weight portion.

27. steroid hormone transdermal drug delivery system according to claim 26, it is characterized in that the consumption of component is counted with parts by weight in the described sticky polymers matrix solution: penetrating agent accounts for 10-40 weight portion, sticky polymers and accounts for that 50-90 weight portion, viscosity modifier account for the 0.5-5 weight portion, steroid hormone accounts for the 0.1-3 weight portion.

28. steroid hormone transdermal drug delivery system according to claim 27, it is characterized in that the consumption of component is counted with parts by weight in the described sticky polymers matrix solution: penetrating agent accounts for 10-20 weight portion, sticky polymers and accounts for that 70-90 weight portion, viscosity modifier account for the 0.5-3 weight portion, steroid hormone accounts for the 0.1-1 weight portion.

29. according to the arbitrary described steroid hormone transdermal drug delivery system of claim 25-28, wherein said sticky polymers is selected from crosslinked or uncrosslinked polyacrylate, silicone or polyisobutylene.

30. steroid hormone transdermal drug delivery system according to claim 29, wherein said sticky polymers are crosslinked or uncrosslinked polyacrylate.

31. steroid hormone transdermal drug delivery system according to claim 29, wherein said polyacrylate are selected from poly-(2-EHA/acrylic copolymer), poly-(the own ester/acrylic acid of acrylic acid 2-hydroxyl/methyl acrylate copolymer), poly-(2-EHA/acrylic acid/methyl acrylate copolymer) or poly-(2-EHA/acrylic acid/butyl acrylate/vinyl acetate copolymer).

32. according to the described steroid hormone transdermal drug delivery system of claim 25-28, wherein said viscosity modifier is polyvinylpyrrolidone//vinyl acetate copolymers, polyvinylpyrrolidone, polybutyl methacrylate/methylmethacrylate copolymer or ethyl cellulose.

33. steroid hormone transdermal drug delivery system according to claim 32, wherein said viscosity modifier are molecular weight is polyvinylpyrrolidone/vinyl acetate of 50,000, and the weight ratio of polyvinylpyrrolidone and vinyl acetate is 6: 4.

34. according to each described steroid hormone transdermal drug delivery system among the claim 25-33, wherein said steroid hormone is one or more in progestogen and the estrogen.

35. steroid hormone transdermal drug delivery system according to claim 34, wherein said steroid hormone is made up of the progestogen of 1-30 weight portion and the estrogen of 1-10 weight portion.

36. steroid hormone transdermal drug delivery system according to claim 35, wherein said steroid hormone is made up of the progestogen of 1-20 weight portion and the estrogen of 1-5 part.

37. according to each described steroid hormone transdermal drug delivery system among the claim 34-36, the progestogen in the wherein said steroid hormone are selected from: the diacetate esters of levonorgestrel, methylnorethindron, norgestimate variant, gestodene, norethindrone, norethynodrel, hydrogen progesterone, gestodene, etynodiol, hydroxyprogesterone acetas, gestogen, other is biocompatible and can be by the progestogen of skin absorbs; Skin absorbs can be passed through, and the biocompatible progestogen derivant of original progestogen can be changed into after the skin absorbs.

38. according to each described steroid hormone transdermal drug delivery system among the claim 34-36, the estrogen in the wherein said steroid hormone is selected from ethinylestradiol, 17 beta estradiols and biocompatible derivant thereof.

39. according to each described steroid hormone transdermal drug delivery system among the claim 34-36, the progestogen in the wherein said steroid hormone are that levonorgestrel, estrogen are ethinylestradiols.

40. steroid hormone transdermal drug delivery system according to claim 25, it is characterized in that components contents is counted with parts by weight in the described sticky polymers substrate: penetrating agent accounts for 10-20 weight portion, sticky polymers and accounts for that 70-90 weight portion, viscosity modifier account for the 0.5-3 weight portion, steroid hormone accounts for the 0.1-1 weight portion;

Wherein, described steroid hormone is made up of the levonorgestrel of 1-20 weight portion and the ethinylestradiol of 1-5 part; Described penetrating agent is the non-C by the ether compound of 1-4 weight portion, 1-4 weight portion ₆-C ₁₈The C of aliphatic alcohol alcohol compound, 1-4 weight portion ₆-C ₁₆Fatty acid or C ₆-C ₁₈Aliphatic alcohol form; Described ether compound is selected from diethylene glycol monoethyl ether or isosorbide dimethyl ether; Described alcohol compound is propylene glycol, benzyl alcohol, PEG400, PEG600 or PEG1000; Described C ₆-C ₁₈Fatty acid is selected from lauric acid, oleic acid or capric acid; Described C ₆-C ₁₈Aliphatic alcohol is selected from decanol, lauryl alcohol or oleyl alcohol.

41. the described steroid hormone transdermal drug delivery system of claim 25-40 is in birth control or treatment female osteoporosis, the application in the climacteric syndrome.