KR960013236B1 - Transdermal estrogen / progestin delivering device and a kit having the same - Google Patents

Abstract

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Description

[Name of invention]

Estrogen / progestin transdermal delivery device and kit comprising same

[Brief Description of Drawings]

FIG. 1 is a series of curve graphs showing the transdermal absorption cumulative value (Q) of ethynyl estradiol from the AD TYPE TDDS (adhesive type transdermal drug delivery system) through the skin of alopecia mice using seven different formulations.

2 is a series of curve graphs showing the percutaneous absorbed cumulative value (Q) of noethine drone from an adhesive drug transdermal delivery system through hair loss mouse skin using seven different formulations.

3 is a graph showing the transdermal absorption rate of ethynyl estradiol through anatomical human skin according to the skin absorption enhancer concentration.

4 is a graph showing the transdermal absorption rate of noethine drone through anatomical human skin according to the skin absorption enhancer concentration.

5 is a graph showing the transdermal absorption rate of ethynyl estradiol through anatomical human skin from a delivery device of the invention, wherein both the polymer layer and the adhesive layer are made from an adhesive polymer.

Detailed description of the invention

[Technical Field]

The present invention relates to novel estrogen / progestin transdermal delivery devices and kits for fertility control comprising the same. The kit includes an estrogen / progestin transdermal delivery device suitable for adhering to women who want fertility control or want to prevent unwanted pregnancy. In addition, the present invention relates to a series of estrogens containing a polymer layer adhered to a support layer and an adhesive layer adhered to the polymer layer, wherein the effective amount of estrogen and progestin are dissolved and / or microdispersed in the polymer and adhesive layer, respectively. A method of regulating fertility by using a transdermal absorbent system applying a progestin transdermal delivery device. It is preferable to use β-estradiol or ethynyl estradiol as estrogen, and noethyne drone or norgestimade as progenstine. The delivery device may also be used for estrogen replacement therapy.

Background Technology

Estrogen therapy includes two main areas: fertility control and estrogen replacement.

Fertility has been controlled by the use of a number of oral administration hormone products. This product is typically a combination of estrogen and progestin. Since oral administration of natural estrogen 17-β-estradiol normally destroys almost 90% or more, synthetic estrogens are used as conventional estrogen components. It is somewhat destroyed in the digestive tract before being absorbed, but the destructive metabolism of 17-β estradiol occurs primarily in the first metabolism of the liver. As such masses are destroyed, the oral administration of an effective amount must be administered in spite of secondary effects and undesired mass metabolites. Therefore, synthetic estrogens, such as ethynyl estradiol, usually have results that fall short of the desired results when administered orally.

The progestin component, as generally intended, inhibits ovulation. In addition, in the case of administered progestins, it is necessary to take an overdose for the desired firm fertility control.

A number of major side effects have been reported in relation to oral administration of fertility control agents, for example, thrombophlebitis and thrombosis, pulmonary arteriosclerosis, coronary artery thrombosis, myocardial infarction, thrombosis, cerebral edema and hypertension. These side effects are due to the estrogen component of the oral formulation. It has been found that the use of progestin alone (mini-pills) can reduce side effects due to estrogen. However, fertility control is weaker than fertility control by combination formulations, and the menstrual cycle becomes more irregular. Irregular menstrual cycles have been reported to occur less frequently when progestins are administered at more constant delivery rates. In addition to these side effects, oral fertility control formulations also have the disadvantage that the fertility control effect is highly dependent on the degree of patient's coagulation. It is known that the risk of pregnancy increases with every pill dose.

Ideally, the patient's acceptable fertility control system should provide the advantages of minimizing side effects, increasing ease of administration, and in some cases prompting the end of treatment and increasing patient acceptance. In recent years, considerable attention has been focused on the development of an endogenous intrauterine, intraoral or intravaginal fertility control delivery system for prolonging and controlling the administration of steroid hormones to the body for fertility control. However, none of these developed delivery systems could be considered ideal and without side effects.

Other fertility control means have been used, for example, topical creams and intravaginal devices that deliver a combination of one or more estrogens and one or more progestins, including 17-β-estradiol, a natural estrogen. However, such fertility control systems represent an undesirable form.

Therefore, (1) in some cases, the use of natural estrogen 17-β-estradiol may be allowed, and (2) minimal delivery devices may be used per menstrual cycle, for example three consecutive delivery devices per week. (3) transdermal to allow adhesion to the skin of subjects receiving high concentrations of estrogen and progestin hormones sufficient to provide reliable fertility control without generating large amounts of undesirable metabolic or chemical degradation products It is highly desirable to provide a system. The development of a rate-controlled transdermal drug delivery system that can minimize any individual variables and regional differences in skin permeability is necessary to obtain predictable blood amounts of the drug. Transdermal rate-controlling drug administration (i) avoids the risks and discomforts of intravenous therapy, and variability in absorption and metabolism associated with oral therapy, and (ii) drug administration to use pharmacologically active agents with short biological half-lives. (I) efficacy can be achieved by lowering the total daily dose of the drug due to reduced first pass metabolism and subsequent dosing of the liver, and (i) prolonging and planning the drug at the desired rate of treatment. As a result of delivery, the opportunity to administer excess or underdose is reduced, (i) provide simplified dosing, and (v) optionally terminate the drug infusion by removing the drug delivery system from the skin surface. It is known to provide some potential advantages for systemic dosing that can be achieved. Therefore, a transdermal contraceptive delivery system that can provide fast and effective dual-delivery of estrogens and progestins at a controlled duration at a controlled rate would be an ideal system to achieve female fertility control.

The second major field of estrogen therapy is due to the desire for estradiol replacement therapy. This is required due to menopause (stopping of ovarian function), ovarian reconstruction (surgery, one or both ovaries), or pituitary decline. Estrogen replacement therapy is an important requirement. In addition to being desired to reduce menopausal symptoms caused by estrogen steroid deficiency, there is further a need for such estrogen replacement therapies associated with osteoporosis (loss of skeletal mass) and atherosclerosis. It has also been found advantageous to administer a certain amount of progestin as part of the estrogen replacement therapy. The benefits and methods of estrogen steroid therapy need to be reliably improved. Although estradiol itself or estradiol in the form of certain derivatives (e.g., mono- or diesters such as acetate esters) has been found to be absorbed over time, improved transdermal estradiol and other estrogenic properties It is desirable to develop steroid absorption delivery devices and methods of transdermal administration.

The present invention provides a fertility transdermal absorption system capable of regulating fertility by using three adhesive transdermal delivery devices in succession, which can be easily applied to selected skin sites.

Typically, the first patch is applied on the fifth day of the menstrual cycle. The delivery device is replaced with a second delivery device after 7 days and the second delivery device is replaced with a third delivery device after 7 days again. Then, at the beginning of the next menstrual cycle, three fertility control patches are used again as another successive route, which repeats as long as desired.

The estrogen / progestin transdermal delivery device of the present invention is (a) a substantially impermeable to the estrogen and progestin hormones to be delivered transdermally, and optionally a breathable support layer, especially when the delivery device is based on prolonged periods of several days, (b A polymer layer adhered to the support layer described above, wherein an effective amount of estrogen, preferably 17-β-estradiol, ethynyl estradiol, or a combination thereof, is dissolved and / or microsprayed therein, wherein the polymer layer is an effective amount of Allows estrogens to be delivered transdermally) and (c) adheres the delivery device in close contact with the skin of the subject to be treated for transdermal absorption, adhered to the polymer layer, and an effective amount of progestin, Preferably noethyne drone, norgestimate or a combination thereof To and / or has been finely dispersed, can be a biologically acceptable, sikimyeo transfer them to the above-progestin and the estrogen may be dermal absorption, and includes an adhesive layer which contains a skin absorption enhancer in an effective amount.

Another layer may optionally be included in the delivery device between the polymer layer (b) in which estrogen is present and the adhesive layer (c) in which progestin is present. In this separation layer, it is preferred that there is little or no estrogen or progestin. The separation layer may be made of an adhesive polymer as used to make the adhesive layer (c), with a biologically acceptable polyisobutylene which allows transdermal absorption of the estrogens of the polymer layer (b). Do. In addition, the separation layer preferably does not contain a skin absorption enhancer substantially.

Estrogens dissolved or finely dispersed in the polymer layer include 17-β-estradiol or ethynyl estradiol in an amount effective to provide the role of estrogen in regulating fertility or replacing estrogens, and dissolved or microdispersed in the adhesive layer. Noethine drone or norgestimate is included in an amount that provides the role of progestin in the desired fertility control system or estrogen replacement. The delivery device preferably provides the estrogen and progestin components at the desired transdermal absorption rate for several days, preferably one week. The use of weekly transdermal delivery devices can minimize the possibility of overlooking dose administration in controlling fertility.

The backing layer consists of a material that is substantially impermeable to the hormones of the transdermal delivery device. It consists of polymers such as polyethylene, polypropylene, polyurethane, polyvinyl chloride, polyesters [e.g. poly (ethylene phthalate)] and thin films (e.g. laminates of polymer films and metal foils such as aluminum foils). Can be. When the delivery device is used on a long term (eg several days) basis, the support layer preferably has a microporous material that can pass through sweat and air to minimize skin hydration.

The polymer disc layer is suitably made from a biologically acceptable lipophilic or hydrophilic polymer, which allows the estrogen to be transdermally absorbed and provides miscibility and stability to the estrogen. The polymer layer in which the estrogen is dispersed may preferably be made of a suitable polymerizable adhesive, for example a suitable polyacrylic adhesive or silicone adhesive, in which the estrogen is stable and finely dispersed or dissolved. The polymer layer can also be used to make discs with microdispersion of estrogen. The polymer-estrogen mixture is then produced in layers of appropriate thickness and appropriate surface area and optionally cured. The polymer disc layer is then adhered to the support layer. Care should be taken to ensure that the selected polymer is miscible with the drug, is released upon transdermal absorption, and that there are no or in fact no biologically acceptable components.

Other estrogenic steroid hormones can be used as partial or complete replacements for 17-β-estradiol, for example 17-β-estra, which is biologically miscible and can be effectively absorbed percutaneously at a rate corresponding to the absorption rate of progestin. Esters of diols. It is also preferred that the esters can be biologically converted to 17-β-estradiol, typically by components of the skin or other body parts (eg hydrolytic enzymes such as estase). When the derivative is an ester, estradiol has hydroxyl groups at the 3- and 17-positions, 3-mono and 17-mono-esters and 3, 17 di-esters can be prepared by known ester preparation methods Therefore, the derivative can be selected from mono- or di-esters. Some ester derivatives can be absorbed more quickly than the basic 17-β-estradiol. In the selection of ester derivatives, the desired amount of estrogen on a daily basis in a system in which the main estrogen hormone used simultaneously affects the transdermal absorption of progestin hormone in a daily dosage effective amount over several days, preferably over a week. It is desirable to be absorbed at a rate to provide the hormone component.

For a daily dose of progestin, about 100 to about 1500 mcg, preferably about 125 to about 250 mcg / l days, if the progestin used is norgestimate, and the progestin used is noethine drone In general, about 1000 mcg / day is satisfactory. For estrogens, about 25 to about 50 mcg / l day based on 17-β-estradiol is the preferred daily dosage for humans.

Finally, the adhesive layer of the delivery device combines with other layer elements to form the delivery device. The adhesive layer chosen may depend on many factors, including economic factors such as the type of manufacturing equipment that can be most rapidly purchased, the speed of absorption desired or other factors. For example, the adhesive layer can be applied directly to the polymer layer. The skin absorption enhancer compound may be thoroughly mixed with an adhesive polymer suitable for adhering to the skin area where the transdermal delivery device is to be acted upon. The progestins used are also dissolved or microdispersed in the adhesive layer. The adhesive layer can be applied to the polymer layer by spraying or solvent injection or lamination. When used, the concentration of the skin absorption enhancer compound may be reduced at the adhesive layer specific site resulting from contact with the subject to be treated, in particular by applying it separately to the adhesive layer surface area when less adhesion than the desired adhesion is realized on the adhesive layer. Wherein the adhesive composition has a lower concentration of the skin absorption enhancer compound or both. The adhesive layer is thin with a thickness in μ-units, suitably between 5 and 200 microns, preferably between about 10 and 180 microns, more preferably between about 20 and 150 microns. Also, if desired, additional adhesives may be used in the form of rings adhered to the support layer that extend beyond the polymer layer area.

If used, any separation layer is applied to the polymer layer prior to bonding the adhesive layer (c) containing progestin. In addition, the separation layer may be applied to the surface of the adhesive layer prior to bonding to the delivery device. The separation layer suitably consists of polyisobutylene.

The rate of absorption of one or both hormones of the hormone transdermal delivery device of the present invention can be increased by, for example, having an enhancer of at least 1.2, preferably at least 1.3, more preferably at least about 1.5 to 2.0. The enhancing factor is defined as the ratio of the standard absorption rate (mcg / cm 2 / hour) of the delivery device of the present invention using the skin absorption enhancer / standard absorption rate (mcg / cm 2 / hour) of the corresponding delivery device without using the enhancer.

The present invention also provides a hormone-containing delivery having an effective amount of estrogen dissolved or finely dispersed and having a polymer layer bonded to the support layer, which is combined with these layers to deliver estrogen and progestin and contains a progestin and skin absorption enhancer. To form a device; Such a delivery device is in intimate contact with the skin of the subject to be treated; The present invention relates to a method of transdermally administering a hormone by percutaneously delivering the hormone to a subject to perform fertility control or estrogen replacement therapy.

[Detailed Description and Preferred Embodiments of the Invention]

The support layer can be made of a suitable material that is impermeable to the hormones of the polymer layer. The support layer serves as a protective film for the polymer layer and also serves as a support. The support layer may be made of a layer essentially the same size as the hormone-containing polymer layer, may extend beyond the side of the disk layer, or may cover the side (s) of the hormone-containing disk layer to extend the surface of the support layer. It can be in a larger dimension such that it can extend outward in a way that can be the base for this contact means. For long term (eg 7 days) applications, it is desirable to use microporous and / or breathable support laminates to minimize hydration or cooling of the skin. The adhesive secures the delivery device in intimate contact with the skin of the subject to be treated. Examples of materials suitable for preparing the support layer include films of high density and low density polyethylene, polypropylene, polyurethane, polyvinyl chloride, polyesters (eg poly (ethylene phthalate)), metal thin films, metal thin film laminates of the above suitable polymer films There are lights. Preferably, the material used as the support layer is a laminate of the above-described polymer film containing a metal thin film (eg aluminum foil). In such laminates, the polymer film of the laminate will typically be in contact with the polymer layer. The support layer may be present in a suitable thickness to provide the desired protective and support functions. Suitable thickness is about 10 to about 200 microns. The thickness is about 20 to about 150 microns, more preferably about 30 to about 100 microns.

In addition, the polymer layer can be prepared from a polymer adhesive (eg polyacrylsilicon) or other polymer adhesive. In addition, the polymer layer can be prepared from silicone elastomers having a common polydimericsiloxane structure, such as, for example, silicone polymers of the general formula:

Wherein R is alkyl or alkoxy, vinyl or phenyl having 1 to 7 carbon atoms and n is about 100 to about 5000.

Preferably selected silicone polymers can be crosslinked at a suitable temperature (eg room temperature) using a crosslinking catalyst which is biologically acceptable in the final polymer layer and can be miscible with the hormonal component to be used to prepare the polymer delivery form. have. If the silicone polymer contains free hydroxy groups, such as terminal hydroxy groups, various suitable crosslinkers [eg, tetrapropoxy silane [Si (OCH ₂ CH ₂ CH ₃ ) ₄ ] may be used to crosslink the polymers described above. Can be. Tin catalyst can be used for the above-mentioned crosslinking reaction. If the silicone polymer component contains vinyl groups, the silicone polymer can be crosslinked with the dimethyl-silicone polymer using a catalyst (eg platinum catalyst). Some suitable silicone polymers include crosslinkable copolymers having dimethyl and methylvinyl siloxane units, as can be crosslinked by using suitable peroxide catalysts. Other crosslinking sites may be present in the polysiloxane elastomer used. Suitable silocon-medical grade polymers are commercially available under the trade names Silastic 382, Q7-4635, Q7-4650, Q7-4665, Q7-4750, Q7-4765 and MDX-4-4210.

The selected silicone polymer may also have a block or graft structure or both. The block structure may have a fraction or block of polymer chain structure of the polymer in which the polymer may have one form of repeating unit (eg dimethylsiloxane), and another form of repeating unit (eg methylvinylsiloxane, Meaning diphenylsiloxane or diisopropyl siloxane units, or other siloxane, or silane units, as well as monomer units that can be miscible with non-siloxane or non-silane forms). The length of the blocks can vary and can be repeated as desired. For example, where the blocks are denoted by A and B, respectively, the block copolymer may be A-B, A-B-A or A-B-A-B and the like. Graft structure simply means that one or more polymer chains are bonded to the polymer backbone. Such graft chains may also have polymer units, which may be the same as or different from the polymer units of the main chain, such as the block copolymers described above. In addition, by introducing the copolymerizable monomers together into the polymerization reactor, the main chain of the polymer used may contain each monomer unit in a certain range.

Examples of block copolymers of the type usable in the present invention include copolymers of the general formula:

Wherein x, y and z represent sufficient number of repeat units to give the polymer the desired properties, for example from about 10 to about 5000.

Generally, the above-described polymers used to form a biologically acceptable polymer layer are those capable of forming thin layers or coatings by passing hormones at a controlled rate. Suitable polymers can be biologically and pharmaceutically compatible and can be compatible with the body fluids or body tissues that the device will come into contact with, and are non-allergic and insoluble. When soluble polymers are used, they should be avoided because dissolution or erosion of the matrix can affect the release rate of hormones as well as the capacity of the delivery device to remain in a location that is likely to be removed.

Examples of materials for preparing the biologically acceptable polymer layer include polyethylene, polypropylene, polyurethane, ethylene / propylene copolymers, ethylene / ethylacrylate copolymers, ethylene / vinyl acetate copolymers, silicone elastomers, in particular medical Grades polydimethylsiloxane, neopreon rubber, polyisobutylene, polyacrylate, chlorinated polyethylene, polyvinyl chloride, vinyl chloride-vinyl acetate copolymer, polymethacrylate polymer (hydrogel), polyvinylidene chloride, Vinyl chloride, poly (ethylene terephthalate), butyl rubber, epichlorohydrin rubber, ethylene-vinyl alcohol copolymer, ethylene-vinyl oxyethanol copolymer; Silicone copolymers [e.g. polysiloxane-polycarbonate copolymers, polysiloxane-polyethylene oxide copolymers, polysiloxane-polymethacrylate copolymers, polysiloxane-alkylene copolymers (e.g. polysiloxane-ethylene copolymers), polysiloxane-alkylenesilanes Copolymers such as polysiloxane-ethylenesilane copolymers; Cellulose polymers such as methyl or ethyl cellulose, hydroxypropyl methyl cellulose and cellulose and cellulose esters; Polycarbonate; Polytetrafluoroethylene and the like. To obtain the best results, a biologically acceptable polymer layer should be selected from polymers with glass transition temperatures below room temperature. The polymer is not necessarily required, but may have crystallinity at room temperature. Crosslinkable monomer units or fractions may be incorporated into these polymers. For example, the crosslinkable monomer may be incorporated into a polyacrylate polymer that provides a fraction for crosslinking the polymer layer after microdispersing the hormone into the polymer. Known crosslinkable monomers for polyacrylate polymers include polymethacrylic esters such as butylene diacrylate, dimethacrylate, trimethylol propane trimethacrylate, and the like. Other monomers providing such fractions include allyl acrylate, aryl methacrylate, diallyl maleate and the like.

The adhesive and polymer layer are suitably prepared using a silicone adhesive, such as a (polydimethylsiloxane-silicate resin) copolymer adhesive of the general formula:

Wherein Me is methyl, R is Si- (CH ₃ ) 3 and x and y are independently the number of repeat units sufficient to provide the desired properties for the adhesive polymer and other polymer layers.

For example, adhesive polymer products or amine-resistant adhesive products (available from Dow Corning; marketed under the DC-355 and X7-2920 medical adhesive trademarks) are suitable for use in preparing adhesive layers. Adhesive polymers, when used in conjunction with hormones and skin absorption enhancers, may be miscible with and should be biologically acceptable. Certain polyacrylic adhesive polymers (in the form of alkyl esters, amides, free acids, etc.) or polyisobutylene adhesive polymers may also be used with several hormones. Examples of suitable adhesive polymers for use in preparing the polymer layer are represented by the following general formula:

Wherein x represents the number of repeat units sufficient to provide the adhesive polymer with the desired properties, and R is H; Or lower alkyl including ethyl, butyl and 2-ethylhexyl.

Other suitable hyperallergic pressure sensitive contact adhesive compositions may also be used. Preferred adhesive layers are pressure sensitive.

However, depending on the pharmaceutical compatibility and optionally other factors, the method of adhesion may be in the form of a ring attached to an extended area of the support layer, for example, such that the adhesive layer is adjacent to the side of the hormone-containing disk layer. The width of these adjacent adhesive rings must be suitable for the delivery device to remain secure to the subject to be treated. Typically, suitable widths of such adhesive rings may be about 0.2 to 1.2 cm, preferably about 0.3 to about 1.0 cm.

The adhesive layer is then finally covered with a layer of release protective film made from a material that is substantially impermeable to hormones, skin absorption enhancers, and other components of the delivery device, if used. It can be used to make the polymer material and metal thin film laminates used for the support layer, provided that the layer is peelable or releaseable by conventional siliconization or Teflon coating. Emissive materials suitable for use with silicone polymer adhesives DC-355 and X7-2970 include Scotchpack 1022 material (3M Company) or Bio-Release Material; Dow Corning).

In preparing hormone-containing polymer layers, silicone elastomers, such as (polydimethylsiloxane-silicate resins) copolymers, polyacrylic adhesives of the above formula (commercially available under the tradename Duro-Tak), and a stable environment against hormones It is suitable to use other biologically acceptable adhesive polymers which can provide and release them. In preparing hormone-dispersed delivery devices, it has been found to be suitable to use dispersants such as lactose and silica. Other suitable dispersants available may also be used. Other suitable dispersants known in the formulation art can also be used. Depending on the hormone and the desired drug load, a suitable amount of dispersant may vary from 0 to about 20 weight percent based on the weight of the polymer layer. Typically, a dispersant is added with the hormone into the polymer used to prepare the layer. Depending on the desired rate of penetration, the specific hormone used, the interval and other factors, determine the amount of dispersant added. The amount of hormone applied depends on the amount of hormone delivery and the amount of treatment desired in each delivery device and incorporation into the polymer layer to provide the appropriate structure, diffusion and other properties to the final polymer layer. For example, it has been found to be satisfactory to add hormones to 50 parts of a polymer (such as a polyacrylic adhesive polymer) used to prepare a polymer layer. It has been found desirable to add and disperse the estrogens used in the selected amount of adhesive polymer. The mixture of polymer and hormone is then thoroughly mixed using a high torque mixer to form a homogeneous solution or microdispersion in the hormone's polymer. After performing the mixing step, the composition is left under vacuum to remove the air present.

The degassed mixture is then applied to a suitable substrate, similar support laminate or release liner by solvent casting techniques and heated to a suitable elevated temperature to remove the solvent. Under the temperature used, no hormonal breakdown will actually occur. The thickness of the polymer sheet is preferably about 10 to 400 microns, preferably about 20 to about 300 microns. The resulting drug added polymer sheet can be taken out of the casting machine and further coated on the first drug added union layer formed by direct casting or laminating another layer of drug added polymer containing the same or different hormones. have.

Any separation layer may be made of the adhesive or other material described for use in making the adhesive layer with progestin. In preparing the separation layer, it has been found to be suitable to use biologically acceptable polyisobutylene having a suitable molecular weight. For example, the relative molecular mass Mv (viscosity average) of polyisobutylene that can be suitably used is from about 800,000 to about 900,000, for example polyisobutyl sold under the trade name Oppanol B80 by BASF. The relative molecular mass Mv (viscosity average) value of rene is 850,000. Viscosity average relative molecular mass is obtained from equation J ₀ = 3.06 × 10 ⁻² × M × 0.65. The viscosity or molecular weight should generally be chosen so that it is large enough to provide a dimensionally stable separation layer but not excessively large to make a molded part of the separation layer unnecessarily difficult to provide a functional and pharmaceutically good delivery device.

The thickness of the separation layer can be varied as desired. However, it has been found that it is suitable that the layer thickness after all solvent removal is about 50 to about 150 mu, and preferably about 75 to 125 mu. The separation layer, which is about 100 microns thick, can be made of polyisobutylene with a viscosity and molecular weight of Oppanol B80 to work well when the estrogen in the polymer layer is 17-β-estradiol or ethynyl estradiol. Turned out.

The separation layer must have a thickness sufficient to minimize any migration, especially under elevated temperature conditions (eg 37 ° C. or 45 ° C. or higher). In addition, the separation layer must be made of a suitable material and estrogen delivery in the polymer layer, as needed to suitably provide a delivery ratio of transdermal absorption from 10 to 30/1, preferably from 12 to 20 It must have a thickness sufficient to slow down the speed.

The separation layer is made by dissolving about 10 parts of a suitable polyisobutylene (e.g. Oppanol B80 polyisobutylene) in a suitable solvent (e.g. a mixture of cyclohexane, hexane and heptane, e.g. 1: 1 mixture). Turned out to be. The mixture is gently stirred using a suitable stirrer.

When the dissolution is nearly complete to provide a clean polyisobutylene solution, the solution is used to prepare a low-adhesive film (e.g. polyester film) with a fluoropolymer-coated surface (e.g. Scotch-Pak by 3M Company). Material sold under the trade name 1022). R. D. Cordless sheath bars (eg # 12) may be used for sheathing. The resulting coating is dried and repeated as necessary to obtain a layer of the desired thickness (eg 100 μ). The separation layer thus formed can be assembled into a delivery device by laminating against a polymer layer. Alternatively, it may be applied to the top surface of the adhesive layer with progestin prior to assembly by lamination to the low surface of the polymer layer with estrogen. The actuated multilayered polymer layer may then be cut to obtain a disc having the desired shape and size. The area of the polymer layer disc should generally not exceed about 100 cm 2, suitably about 5 to 100 cm 2, preferably about 8 to 80 cm 2, more preferably about 10 to 60 cm 2. The layer discs can vary in shape, which can be round, square, rectangular or other desired shapes.

The hormone-containing polymer layer, generally speaking, may contain slightly more dispersing hormone than the desired dosage to be absorbed into the skin of the subject to be treated. Typically, depending on the physicochemical properties of the hormone, and on the properties of the polymer in the polymer layer disc and other factors, this excess is small, for example, an amount exceeding less than twice the dose that is lightly introduced.

If the adhesion means contain a skin absorption enhancer, it is prepared by dissolving the enhancer and progestin directly in an adhesive polymer solution or solvent that is miscible with the adhesive polymer solution used to prepare the adhesive layer containing the skin absorption enhancer. A suitable amount of solvent may be used as necessary to mix with the adhesive polymer solution in which a certain amount of enhancer and progestin are dissolved. For example, 3 to 10 parts of solvent may be used to dissolve 1 part of the skin absorption enhancer depending on the solubility of the enhancer. If a polydimethylsiloxane adhesive solution is used, use 2-20 parts of a skin absorption enhancer in 20-50 parts of a solvent (e.g. acetone, methyl ethyl ketone, trifluorotrichloroethane, or other suitable solvent) and the solution is used as adhesive solution 100 It was found appropriate to add wealth. The promoter-adhesive solution mixture is thoroughly mixed and prior to laminating its coating onto the polymer layer or on the polymer layer as described above using a film coating machine (e.g., a machine mentioned in the art as a K-bar coater). It is applied to a peelable release liner. Suitable release liners are poly (ethylenephthalate) or Teflon-coated polyester films laminated with aluminum foil, such as Scotchpak 1022 or the commercially available film under the trade name X7-2741 or X7-2752. The poly (ethylenephthalate) side with the adhesive-enhancer-progestin coating applied makes it peelable by conventional siliconization or other suitable method. Typically, the thickness of the adhesive-enhancer-progestin layer is suitably between about 20 and about 200 microns, preferably between about 30 and about 150 microns.

The amount of enhancer in the adhesive layer depends in part on the desired rate at which the hormone is absorbed. Generally speaking, about 1 to about 3% of skin absorption enhancer is suitable based on the weight of the adhesive, depending on the enhancer, the adhesive polymer, the desired degree of adhesion and other factors. Preferably, according to the factors described above, about 5% to about 20% of a skin absorption enhancer is used. The adhesive layer containing progestin and skin absorption enhancer is transferred to the polymer layer disc surface by applying a lamination technique under constant pressure. In order to properly adhere the adhesive layer to the skin of the treated subject, additional adhesive polymer coatings having a relatively low concentration of promoter, such as 1 to 5% by weight of the adhesive polymer, may be used as the progestin-enhancer-polymer. It can be further applied to the surface of the layer. The thickness of such coatings is typically a small proportion of the final adhesive layer thickness, for example 20-40% of the total adhesive polymer layer. In the progestin-containing adhesive layer, suitable high concentration enhancers are used. Suitable high concentration enhancers are typically 10-30% based on the adhesive polymer weight, solubility of the skin absorption enhancer and the desired final amount and other factors. The solvent in each coating is removed by evaporation. Each of the coatings can be combined to apply a lamination technique or continuous solvent casting technique under constant pressure to produce a final multilayer fertility-controlled transdermal delivery device.

A multi-layered transdermal hormone delivery device is excised. In some cases, when support layer protection is required, the lateral attention of the delivery device, including the polymer layer, may be molded into the support layer. The resulting hormonal polymer delivery device forms are suitably packaged for storage until they are used for transdermal therapy.

At least one estrogen and at least one progestin as described above are dissolved and / or microdispersed in the polymer and adhesive layers, respectively. When controlling hormone release at a relatively constant rate over a long period of time, typically several days and preferably one week, the advantage is that the hormone is constantly infused into the subject over a long period of time.

One of the presently preferred estrogens is 17-β-estradiol. It is a natural hormone and is typically transdermally delivered by a suitable system of the present invention in the preferred daily dosage. 17-β-estradiol is miscible and can be dissolved or microdispersed in the polymer. Transdermal delivery devices designed for week-therapies may contain at least about 100 to about 500 mcg (preferably about 125 to about 250 mcg) / day of norgestimate or about 1000 mcg / day of noethine drone and 17-β-estradiol 20 to 50 mcg / 20 cm 2 / day (or ethynyl estradiol or other effective amount of estrogen equivalent). In regulating fertility, the amount of progestin is necessary to suppress ovulation and the amount of estrogen is thought to be necessary to maintain normal women's physiology and properties. If the amount of absorption meets the daily requirement of the estrogen component and the hormone component is miscible, 17-β-estradiol which can be biologically miscible and percutaneously absorbed and preferably bioconverted to 17-β-estradiol Derivatives of can also be used. Derivatives of such estradiol may be selected from mono- or di-esters. The mono-esters can be 3- or 17-esters. Examples of estradiol esters include estradiol-3, 17-diacetate; Estradiol-3-acetate; Estradiol-17-acetate; Estradiol-3, 17-divalerate; Estradiol-3-valerate; Estradiol-17-valerate; 3-mono, 17-dipivalate ester; 3-mono, 17-mono and 3, 17-dipropionate esters; Esters of the corresponding cypionate, heptanoate, benzoate; Ethynyl estradiol; Estrone; Estrone; And other estrogenic steroids and derivatives thereof that can be transdermally absorbed, including benzestrol, chlorotrianicene, diensrol, mestranol and the like.

The progestin may now be preferably noethine drone or norgestimate or a combination thereof. However, other suitable progestins may be used instead or in mixtures thereof. For example, progestins can be levonorgestrel, noethinodrel, dydrogesterone, ethinodiol acetate, hydroxy processosterone caproate, hydroxy progesterone diacetate, noethine drone acetate, norgestrel, progesterone You can choose from among them.

In shaping the delivery device of the present invention, the use of other estrogens or progestins is suggested to those skilled in the art. The use of such other estrogens and progestins is contemplated as being within the scope of the present invention so long as it satisfactorily provides a delivery device within the scope of the present invention.

Skin absorption enhancers that can be used to carry out the invention can vary. Providing the desired results for the type of polymer delivery device containing a particular hormone can vary. In some instances, the use of skin absorption enhancers in the manufacture of delivery devices may result in good or very good absorption for one hormone and may result in no or little improvement when another hormone is used. . Mixing two or more skin absorption enhancer compounds can yield excellent results such as easy skin absorption.

Certain skin absorption enhancers that can be used to prepare the polymer delivery forms of the invention include saturated and unsaturated fatty acids and their esters, alcohols, monoglycerides, acetates, diethanol amides and N, N-dimethylamides such as oleic acid. , Propyl oleate, oleyl acetate, propyl myristate, isopropyl myristate, myristyl alcohol, myristyl N, N-dimethyl amide, stearic acid and stearyl alcohol, stearyl propyl ester, monostearine and for example 1-dodecyl azacycloheptan-2-one and mixtures thereof sold under the trade name Azon by Nelson Research and Development; Decyl methyl sulfoxide, dimethyl sulfoxide, salicylic acid and derivatives, N, N-diethyl-m-toluamide, crotamiton, 1-substituted azacycloalkyl-2- as described in US Pat. No. 4,316,893. There are a variety of other compounds that have a warm (wherein the 1-substituent has 0 to 17 carbon atoms, preferably 1 to 11 carbon atoms) and a salologically acceptable skin absorption enhancing activity. N-decyl alcohol has been found to be a preferred enhancer. In addition, capric acid has been found to be an enhancer. For chemicals represented by N-decyl alcohol or capric acid, modifications are proposed to those skilled in the art that hardly impair their function as preferred enhancers. About 10-40% (w / w) N-decyl alcohol or capric acid are typically found to be suitable amounts. About 20 to about 35% (w / w) of the adhesive layers of these enhancers have been found to provide highly satisfactory skin absorption enhancement and satisfactory adhesion. An amount greater than 35 or 40% (w / w) reduces skin absorption enhancement and can interfere with satisfactory adhesion to the treated patient.

Ethyl alcohol, and other short-chain alkanols (1 to 4 carbon atoms) having almost the same properties and activities as ethyl alcohol, are not included in the definition of skin absorption enhancers as used herein.

The following examples are intended to illustrate the invention in more detail and are not intended to be limiting.

Example 1

Using the following components, an estrogen-containing polymer layer is prepared: 5 parts of ethynyl estradiol; 100 parts of polyacrylic adhesive sold by National Starch and Chemical Corp. as Duro-Tak 80-1054.

Ethynyl estradiol is added to the polyacrylic adhesive using a high torque mixer (commercially available from Cole-Parmer Company) at a rate of about 1000 RPM.

The hormonal mixture is applied to a support layer formed of a polyester / aluminum laminate sold by 3M Company as Scotch-Pak 1005 using a K-bar coater equipped with bar number 3. The resulting polymer layer is dried in a hood for 1 hour to remove solvent. The thickness of the polymer layer obtained is about 10 microns.

To the polymer layer, 5% (w / w) noethin drone in a polyacrylic adhesive solution is applied using a K-bar coater (equipped with 16 bar). In addition to noethine drone, the coating solution also contains 25% (w / w) of n-decyl alcohol as a skin absorption enhancer. The coating is dried at ambient room temperature for 24 hours. The dry thickness of the dried noethyne drone-storage adhesive layer is about 120μ.

The bilayer delivery device is then covered with a transparent low-adhesive release liner (Scotch-Park 1022 / 3M). The finished delivery layer is then cut into delivery devices of various shapes and sizes using specially designed cutting devices, such as 20 cm 2 rectangular shapes.

The transdermal absorption of hormones from the fertility inhibiting polymer delivery device of the present invention is described using Y. M. Chien, K. Valia and U. B. Doshi in Drug Develop. Ind. Pharm, 11 (7) 1195-1212 (1985).

In general, according to the method described above, a polymer transdermal delivery device is obtained and evaluated as shown in the following Tables 1-3.

1) Take 12 samples for 115 hours of study.

2) 7th week old female hair loss mouse repair skin

3) Load Capacity: 30.5 (± 1.3) mcg / ㎠

4) Load Capacity: 338.0 (± 10.1) mcg / ㎠

IPM (isopropyl myristate); DMSO (dimethyl sulfoxide); DeMS (decyl methyl sulfoxide); LA (lauric acid); OA (oleic acid);

1) 12 samples are taken during a 122-hour study.

2) The left front leg of a 17 year old black girl with an average thickness of 220 (± 26) μ

3) Load Capacity: 30.5 (± 1.3) mcg / ㎠

4) Load Capacity: 338.0 (± 10.1) mcg / ㎠

1) Take 12 samples for 168 hours of study.

2) Anterior body of a white male with an average thickness of 180 ± 20μ (n = 6) is used

3) Load Capacity: 97.5 (± 2.9) mcg / ㎠

4) Load Capacity: 1.26 (± 0.03) mcg / ㎠

Example 2

The formulations in the table above are repeated using the following method. The following components are used in preparing the estrocene-containing polymer layer: 5 parts of ethynyl estradiol; 100 parts of polyacrylic adhesives sold by National Starch & Chemical Corporation as Duro-Tack 80-1054.

Ethynyl estradiol is added to the poly acrylic adhesive using a co-talk mixer (commercially available from Cole-Pharm Co.) at a rate of about 1000 RPM.

Using a K-bar counter fitted with bar 3, the hormonal mixture is applied to a support layer formed of a polyester-aluminum laminate commercially available as Scotch-Park 1005 by 3M Company. The resulting polymer layer is dried in a hood for 1 hour to remove the solvent. The thickness of the polymer layer obtained is about 10 microns.

In the polymer layer, 5% (w / w) noethin drone in a polyacrylic adhesive solution is applied on a transparent low adhesion substrate using a K-bar coater (with # 16 bar). In addition to noethine drone, this coating solution also contains 25% (w / w) of n-decyl alcohol as a skin absorption enhancer. The coating is dried in a hood at room temperature for 24 hours. The dried noethyne drone-storage adhesive layer has a thickness of about 120μ.

Using the lamination technique, the noethine drone layer is carefully applied to the ethynyl estradiol layer. Using a specially designed device cutter, such as a 20 μm square, the finished transfer layer is cut into delivery devices of various shapes and sizes.

Example 3

Example 1 is repeated except that the ethynyl estradiol loaded on the polymer layer changes from 200 mcg / 20 cm 2 to 1600 mcg / cm 2. Formulation 13 above is used. The data indicate that the loading of ethynyl estradiol penetrates into human skin as the load concentration increases to about 1600 mcg / cm 2 (in this respect, the increased load according to experimental data does not provide increased absorbency). Shows an increase in speed. This is shown in the diagram of FIG.

Example 4

Examples 1 and 2 are repeated except using the same amount of biologically active 17-β-estradiol in place of ethynyl estradiol.

Example 5

Examples 1 and 2 are repeated except that the same amount of biologically active norgestimate is used in place of noethine drone.

Example 6

Examples 1 and 2 are repeated except that instead of ethynyl estradiol and noredrones, biologically active equivalent amounts of 17-β-estradiol and norgestimate are used respectively.

Example 7

Examples 1, 2, 4, 5 and 6 are repeated using polydimethylsiloxane adhesive instead of polyacrylic adhesive.

Example 8

The following components are used to prepare a three layer estrogen / progestin transdermal delivery device:

(I) 1 part of ethynyl estradiol; 99 parts of polyacrylic adhesives (National Starch & Chemical Corporation, marketed as Duro-Tack 80-1054). Ethyl estradiol is dissolved in the polyacrylic adhesive by slowly rotating the vessel at low speed (10 rpm) using a rotator (Col-Pharmer Company) to form a clear solution. egg. D. The polyester was coated by coating this hormone / adhesive mixture on a sheet of polyester / aluminum laminate (commercially available as Scotch-Pack 1109 by 3M Company), using an RD wireless-coating bar (# 8). Apply on the surface. The resulting polymer layer is dried in a hood for 1 hour to remove the solvent fraction. The thickness of the dry estrogen storage polymer adhesive layer obtained is about 40μ).

10 parts of (II) polyisobutylene polymer (BASF marketed as Oppanol B80); 90 parts of a cyclohexane / hexane / heptane 1: 1: 1 mixture as solvent system for Oppanol B80. By rotating the vessel slowly at low speed (10 rpm) using a rotator (Col-Famo Company), the polyisobutylene polymer is dissolved in the solvent system in a closed vessel until all the polymer is dissolved to form a clear solution. egg. D. Using a wireless covering bar (# 12), this polymer solution is applied to the low adhesion side of the substrate (polyester film with a fluoropolymer-coated surface, commercially available as 3M Company Scotch-Pack 1022). This polymer coating is dried in the hood for 2 hours. The resulting dry polymer film has a thickness of about 100 μ.

(III) noethine drone 5 parts; 35 parts of n-decyl alcohol; 60 parts of polyacrylic adhesive (National Starch and Chemical Corporation, commercially available as Duro-Tack 80-1054). The noethyne drone is dispersed in n-decyl alcohol by slowly rotating the vessel at low speed (10 rpm) using a rotator (Col-Pharmer Company) to obtain a drug suspension. The polyacrylic adhesive is added to the suspension and the mixture is slowly rotated at a speed of 10 rpm until a homogeneous mixture is obtained using the same rotor again. egg. D. The cord is applied to the low adhesion surface of the substrate (polyester with a fluoropolymer-coated surface, commercially available as 3M Company Scotch-Pack 1022) using a wireless sheath bar (# 28). This coating layer is dried in a hood for 24 hours. The obtained dry noethyne drone / n-decyl alcohol storage layer has a thickness of about 250 µ.

The polyisobutylene product of (II) is laminated on the product of (I) containing ethynyl estradiol. The layer of (III) containing noethyne drone is laminated on the layered surfaces of (II) in the combined laminates (I) and (II) to form the final product. A steel die cutter is used to cut the final laminate product to a specific size to form a three layer estrogen / progestin transdermal delivery device.

10 cm 2 units are individually filled into paper / metal thin film / polyester pouches and then thermally bonded using a thermal adhesive. These thermal contact sealed pouches were subjected to 26 weeks at three different temperatures of room temperature, 37 ° C. and 45 ° C. in a stability test cabinet (Gravity Convection Incubator, available from GCA Corp.). Save it. During storage, according to the sampling schedule in Table 4, the porches are randomly sampled at specific intervals. Units sealed in pouches are evaluated for drug content and skin absorption rate.

The drug content is quantified in each unit by the solvent extraction method followed by high performance liquid chromatography (HPLC) for the drug. The skin penetration rate of the drug released from the device is quantified by a hydrodynamically corrected in vitro skin infiltration cell system. As skin swatches, freshly cut skin surfaces from 5-7 week old female hair loss are used. Skin penetration studies are performed at 37 ° C. using 40% v / v PEG 400 saline solution as the receptor solution. From the slope of the Q versus time plot, where Q is the cumulative amount of drug penetrating through the skin at specific sampling time intervals, the steady state skin penetration rate of noethynedrone and ethynyl estradiol is determined. This is calculated by quantifying drug concentration in the receptor solution by HPLC analysis.

The drug content or skin penetration rate of the drug quantified from the stability sample is plotted as storage time versus storage temperature. A 95% confidence interval is set based on the mean value obtained from the 0 week sample for statistical determination of the physical and chemical stability of the device tested. Data points allocated outside the 95% confidence interval are considered to be unstable chemically (from drug recovery studies) or physically (from skin penetration studies).

1) Mean ± standard error (N = 3)

2) Triplex the sample delivery solvent solvent extracted under the indicated storage time and temperature and measure the ethynyl estradiol and noethine drone contents using high performance liquid chromatography (HPLC).

1) Mean ± standard error (N = 3)

2) The penetration rate of the sample delivery device tripled using 5-7 week old female alopecia mouse skin for 146 hours by Chien et al. Was measured, and the penetration rate was measured by the slope of the Q versus penetration time plot.

a. Eleven samples are taken for each triplicate experiment (n = 3) for the duration of the study of 146 hours.

b. 40% PEG 400 / saline is used as the receptor solution.

c. Anatomical front body skin of young Caucasian woman.

d. Samples are taken at 0, 2, 4, 8, 12, 24, 48, 72, 96, 120 and 146 hour intervals using Chien et al., And the penetration rate is measured by the slope of the Q versus penetration time plot.

1) 11 samples are taken for each triplicate experiment (n = 3) during the 146 hour study period.

2) Samples are taken at 0, 2, 4, 8, 12, 24, 48, 72, 96, 120 and 146 hour intervals using the method of Chien et al., And the penetration rate is measured by the slope of the Q versus penetration time plot.

1) 11 samples are taken for each triplicate experiment (n = 3) during the 146 hour study period.

2) Samples are taken at 0, 2, 4, 8, 12, 24, 48, 72, 96, 120 and 146 hour intervals using the method of Chien et al., And the penetration rate is measured by the slope of the Q versus penetration time plot.

1) 11 samples are taken for each triplicate experiment (n = 3) during the 146 hour study period.

2) Samples are taken at 0, 2, 4, 8, 12, 24, 48, 72, 96, 120 and 146 hour intervals using the method of Chien et al., And the penetration rate is measured by the slope of the Q versus penetration time plot.

Tables 14 and 15 below show data for delivery devices without separation layers compared to the data shown in Tables 5 and 6 for delivery devices with separation layers.

1) Mean ± standard error (N = 3)

2) Triplex the sample delivery solvent solvent extracted under the indicated storage time and temperature and measure the ethynyl estradiol and noethine drone contents using high performance liquid chromatography (HPLC).

1) Mean ± standard error (N = 3)

2) 2) Samples are taken at 0, 2, 4, 8, 12, 24, 48, 72, 96, 120 and 146 hour intervals using Chien et al., And the penetration rate is measured by the slope of the Q versus penetration time plot. do.

Example 9

The method of Example 8 is carried out to provide other transdermal delivery devices of the invention: in amounts necessary to provide the desired fertility control or estradiol replacement, 1) in combination with noethine drone or norgestimate, 17-β-estradiol, 2) ethynyl estradiol-norgestimate formulations, and other combinations with progestins and estrogens selected from those listed above, as well as other adhesives and polymers listed above Repeat the delivery device of Example 8.

Claims (24)

(a) a support layer that is substantially impermeable to the estrogens and progestin hormones to be delivered transdermally, (b) an effective dosage of one or more effective estrogens connected to the support layer and transdermally absorbable is dissolved and / or microinjected therein; A pharmaceutically acceptable polymer layer, wherein the polymer layer is biologically acceptable and provides a suitable environment for one or more estrogens and delivers one or more estrogens for percutaneous absorption) and ( c) an effective dosage of one or more effective progestins that are in intimate contact with the polymer layer, transdermally absorbable, dissolved and / or microdispersed therein, and a pharmaceutically acceptable adhesive layer wherein the adhesive layer is biologically May be tolerated, and for one or more progestins Provides an environment, delivers one or more progestins and one or more estrogens for transdermal absorption, and contains an effective amount of a skin absorption enhancer), wherein the hormones are stable in the polymer layer and the adhesive layer and at the same time An estrogen / progestin transdermal delivery device characterized in that it is transdermally absorbed and provided at a daily minimum or more effective dose to control fertility or to be used for estrogen replacement therapy. The transdermal delivery device according to claim 1, which contains ethynyl estradiol or 17-β-estradiol or a combination thereof as one or more estrogens. The transdermal delivery device of claim 1, wherein the transdermal delivery device contains noethine drone or a combination thereof as one or more progestins. The transdermal delivery device according to claim 1, which contains ethynyl estradiol as estrogen and noethin drone or norgestimate as progestin. The transdermal delivery device according to claim 1, which contains 17-β-estradiol as estrogen and noethine drone or norgestinmate as progestin. The transdermal delivery device of claim 1, wherein the adhesive layer or polymer layer, or both layers, are made from an adhesive polyacrylic polymer. 7. The transdermal delivery device according to claim 6, wherein the adhesive polyacrylic polymer has the following general formula.

Wherein x represents the number of repeat units sufficient to provide the mentioned properties of the adhesive layer or the polymer layer or both layers, and R is hydrogen or lower alkyl. The transdermal delivery device of claim 1, wherein the support layer is microporous and breathable. The transdermal delivery device of claim 1, wherein the adhesive layer or polymer layer or both layers are made from an adhesive silicone polymer or an adhesive polyisobutylene polymer. The transdermal delivery device of claim 1, wherein the factor for progestin is at least 1.2, 1.3, 1.5, or 2.0. The transdermal delivery device of claim 1, wherein the skin absorption enhancer is n-decyl alcohol. The method according to claim 1, which contains a skin absorption enhancer in an amount that effectively provides at least a daily minimum dose of estrogen and progestin for about 1 week, and provides about 1.5 or more enhancement factors for progestin, Transdermal delivery device applied from about 5 days of the menstrual cycle. The method of claim 1, wherein the polymer layer providing one or more estrogens and the adhesive layer providing one or more progestins are separated by a biologically acceptable adhesive or polymer separation layer, wherein the layers and the separation layers are each closely related. Wherein one or more estrogens are delivered through the separation layer for desired transdermal absorption, wherein the separation layer is prepared using an adhesive or polymer that is free or substantially free of estrogens, progestins and enhancers. Device. The transdermal delivery device according to claim 13, which contains ethynyl estradiol or 17-β-estradiol or a combination thereof as one or more estrogens, and contains noethine drone or norgestimate or a combination thereof as one or more progestins. The transdermal delivery of claim 13, wherein the separation layer is made from a biologically acceptable adhesive or polymer having a viscosity or molecular weight large enough to provide a dimensionally stable separation layer and to significantly reduce the rate of delivery of one or more estrogens. Device. The transdermal delivery device of claim 15, wherein the separation layer is made from a polyisobutylene adhesive. The transdermal delivery device of claim 15, wherein the ratio of progestin hormone to estrogen hormone, which is transdermally absorbed, is in the range of about 10/1 to about 30/1. The transdermal delivery device of claim 17, wherein the ratio of progestin hormone to estrogen hormone, which is transdermally absorbed, is in the range of about 12/1 to about 20/1. 18. The transdermal delivery device according to claim 17, wherein the separation layer is made from polyisobutylene. The transdermal delivery device of claim 18, wherein the separation layer is made from polyisobutylene having a relative molecular mass Mv (viscosity average) of about 800,000 to about 900,000. 18. The transdermal delivery device according to claim 17, wherein the transdermal delivery device contains ethynyl estradiol or 17-β-estradiol or a combination thereof as one or more estrogens, and noethin drone or norgestimate or a combination thereof as one or more progestins. The transdermal delivery device of claim 21, wherein the adhesive or polymer is a biologically acceptable polyisobutylene. The transdermal delivery device of claim 22, wherein the separation layer has a thickness of about 75 to about 125 μ, and the polyisobutylene has a relative molecular mass Mv (viscosity average) of at least about 800,000. (a) a first delivery device that can be used for about one week starting from about five days of the menstrual cycle; (b) a second delivery device that can then be used for a further week; And (c) a third delivery device that can be used for about one week following use of the second delivery device, wherein the first, second and third delivery devices are each defined as defined in claim 1, wherein A fertility control kit comprising two estrogen / progestin transdermal delivery devices.

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