Transdermal patch for the introduction of the 17 - diacetylmorphine alone or in combination with estrogen

 

(57) Abstract:

The invention relates to medicine, namely to transdermal devices for the introduction of inhibiting ovulation 17-diacetylmorphine. Transdermal patch to prevent ovulation in women, including: a) a substrate and b) a matrix layer underlying the backing, and the matrix layer contains a mixture of 17-diacetylmorphine and glue, effective under pressure, containing at least one of silicones and polyisobutylene and adapted for diffusional communication with the skin of the woman and for the introduction of inhibiting ovulation in the number of 17-diacetylmorphine. Transdermal patch allows hormonal therapy. This matrix provides an introduction of an effective amount of 17 - diacetylmorphine alone or in combination with estrogen. 11 C.p. f-crystals, 5 PL.

The technical field

The invention relates to transdermal delivery of drugs. More specifically, it relates to patches and methods of transdermal injection of 17 - diacetylmorphine or separately, or in combination with estrogen, in particular ethinyl estradiol.

Background of the invention

The combination of norgestimate /col. (1992) 166: 1969-77. McGuire, Am. J. Obstet. Gynecol. (1990) 163: 2127-2131 argue that oral introduced Because it is metabolized to 17-diacetylmorphine /17-d-NGM/, 3-katanagatari and levonorgestrel /LNG/ and that these metabolites may be involved in the pharmacological response to orally introduced drug.

Chien et. al. , U.S. patent N 4906169 describe transdermal patches for the joint delivery of estrogens and progestins women for contraception. EE is mentioned as one of the estrogens, which can be entered from the patch and NGM and LNG mentioned as a possible progestins that can be entered.

Applicants are not known prior art describing the introduction of 17-d-NGM alone or in combination with any estrogen transdermal or other routes of administration.

Disclosure of the invention

This invention provides a composition and method for preventing ovulation or carrying out of hormonal replacement therapy by introducing the woman an effective amount of 17-deaktiveret. On the one hand, 17 deaktiveret introduced the woman together with inhibiting ovulation the amount of estrogen. The composition preferably introduced transdermal.

On the other hand, the invention is a transdermal therapeutic system for the introduction of a woman 17-d-NGM and estrogen, and therapeutic system includes a backing layer and a matrix layer underlying the backing layer and a matrix layer contains a mixture of 17-d-NGM, estrogen and glue, effective under pressure and selected for entry into the diffusional communication with the skin of the woman and for the co-introduction of the woman inhibiting ovulation number 17-d-NGM and estrogen through the skin. These patches can also be used for hormone replacement therapy.

Ways of carrying out the invention

This invention is compositions and methods prevent ovulation in women, including the introduction of a vast ovulation number 17-deaktiveret. The effective amount may be from about 150 to problemata. On the one hand, 17 deaktiveret is introduced together with the overwhelming ovulation the amount of estrogen, such as ethinyl estradiol. The effective amount is from about 150 to about 350 μg/day and preferably from about 175 to about 300 μg/day of 17-deaktiveret and from 10 to 35 μg/day of ethinyl estradiol.

Claimed transdermal patches provide contraception to women. They are suitable for hormonal substitution therapy.

Transdermal patches are designed for continuous delivery of 17-d-NGM and, optionally, of estrogen to the skin for a long period of time, usually within 1-7 days and preferably for 7 days.

When the patches are for contraception, the patch is usually placed on the skin on the fifth day of the menstrual cycle and if necessary replace before the expiration of 21 days of wearing. For example, when using 7-day patch for delivery of the drug /drugs/ over the 21-day period will require three patch. Optionally, you can then wear the patch with placebo up to the fifth day of the next menstrual cycle. This scheme is repeated each time menst is no release of luteinizing hormone /LH/, while the dominant effect of estrogen is inhibiting the secretion of follicle-stimulating hormone /FSH/. Thus, when in accordance with the invention introduces the combination of 17-d-NGM and estrogen, ovulation is prevented by suppressing the ovulatory stimulus and/or by suppressing the growth of follicles. It is believed that the introduction of 17-d-NGM has the advantage relative to the parent compounds /NGM/ or other metabolites that 17-d-NGM little or no suppresses androgen activity.

The effective dose of 17-d-NGM to suppress ovulation is usually in the range from about 150 to about 350 μg/day and preferably from about 175 to about 300 μg/day and more preferably from about 175 to about 250 μg/day. The plasters according to the invention will typically have an area of the main surface /i.e., the area located in diffusion contact with skin/ from 10 to 50 cm2. Effective dose of estrogen to suppress ovulation will depend on the specific conjunction of the input estrogen. For example, when estrogen is a levonorgestrel, the dose will be usually at least 10 μg/day, preferably from 10 to 35 m is esta 17-d-NGM and in the case of the presence of estrogen to provide such daily doses for the anticipated duration of patch use. Typically, these doses are from about 20 μg/day to about 200 μg/day and preferably from about 30 μg/day to about 150 μg/day of ethinyl estradiol.

The patches according to this invention are layered structure matrix or monolithic type. Such adhesives are well known from the prior art. They contain a matrix layer of a drug /drugs/ mixed with glue, effective under pressure, and a backing layer. The matrix serves as a reservoir for the drug and the means by which the patch is fixed on the skin. Before using the patch will also include a layer of impermeable lining.

The substrate layer impermeable to the drug and other components of the matrix and defines the upper outer surface of the patch. It can be made of a single layer or film of polymer or consist of one or more layers of polymer and metal foil. Examples of polymers suitable for use in the manufacture of films of the substrate is shown, polypropylene, polyurethane, and polyesters such as polyethylene terephthalate.

Glue, effective under pressure matrix will usually be a solution of polyacrylate, silicone or polyisobutylene /PIB/. Such adhesives are well known in the art manufacturing transdermal patches. See, for example, "The Handbook of Pressure Sensitive Adhesive Technology, 2ndEdition (1989) Van Nostrand, Reinhold".

Adhesives from a solution of polyacrylate, effective under pressure, are produced by copolymerization of one or more acrylate monomers /the term "acrylate" includes acrylates and methacrylates/, one or more of the modifying monomers and one or more monomers containing functional group in an organic solvent. Acrylate monomers used for the manufacture of these polymers, are usually alkylacrylate from 4 to 17 carbon atoms with 2-hexyl acrylate, butyl acrylate and which is the preferred itachinaruto. Modifying monomers are typically included to change the Tg temperature of the glass/ polymer interface. For this purpose, can be used such monomers as vinyl acetate, acrylate and methacrylate and methyl methacrylate. The monomer containing the functional group, baseline carboxyl, hydroxyl group or a combination thereof. Examples of monomers which provide such groups are acrylic acid, methacrylic acid and monomers containing hydroxyl group such as hydroxyethylated. Polyacrylate adhesives are preferably transversely stitched using Poperechnaya substances to improve their physical properties (for example, creep resistance and shear/. The density of cross-linkage should be low, since a high degree of cross-linkage can adversely affect the adhesive properties of the copolymer. Poperechnaya agents are disclosed in U.S. patent N 5393529. Adhesives from a solution of polyacrylate, effective under pressure, available commercially under trade names such as GELVA TM u DUROTAK TM from ZM.

Polyisobutylene adhesives are mixtures of high molecular weight /VM/ and low molecular weight PIB /NM/ BIP. Such mixtures are described in the prior art technique, for example in PCT/US91/02516. The molecular mass of the VMS p & b will typically range from approximately 700000 to 2000000, then Yes as molecular weight NM PIB is usually in the range from 35000 to 60000. Mentioned here molecular weight are about average molecular enable the substance to increase stickiness, such as polybutene oil and high Tg, low molecular weight aliphatic resin, such as resin ESCOREZ TM, available from Exxon Chemical. Polyisobutylene polymers are commercially available under the trade name VISTANEX TM from Exxon Chemical.

Silicone adhesives that can be used in the manufacture of a matrix, usually a high molecular weight polydimethylsiloxane or polymethylphenylsiloxane. Formulations of silicone adhesives that can be used in transdermal patches are described in U.S. patents NN 5232702, 4906169 and 4951622.

Estrogens, which can be combined with 17-d-NMG in the matrix include 17-J-estradiol and its esters, such as estradiol valerate, estradiol cypionate, estradiol acetate, estradiol benzoate and EE. EE is a preferred estrogen for use in combination with 17-d-NGM. The combination of EE/7-d-NGM may favorably influence metabolic parameters, such as elevation of high density lipoprotein in serum and decrease of the ratio of low density lipoprotein to high density lipoprotein in the serum.

In addition to the glue, effective under pressure, 17-d-NGM and optional estrogen, the matrix usually bude is and through the skin and provide flows in the above-described intervals.

Amplifiers permeability of the skin, which can be included in the matrix are described in U.S. patents NN 5059426, 4973468, 4906463 and 4906169 and include, but are not limited to, ether lactic acid C12-C18aliphatic alcohol, laurinlactam, oleic acid or PGML. The amount included in the matrix amplifiers permeability will depend on the specific amplifier /amplifiers/. In most cases, the amplifier will be from 1 to 20 wt.% matrix.

Depending on the specific adhesive matrix may contain other additives. For example, can include materials such as polyvinylpyrrolidone /PVP/, which suppresses crystallization of the drug, hygroscopic agents, which improve the duration of wearing, or supplements that improve physical /for example, fluidity at cold/ or adhesive /for example, tack, cohesive strength/ properties of the matrix.

The above-described therapeutic system can also be used for hormone replacement therapy. When used for carrying out hormonal replacement therapy the matrix is made in such a way as to ensure effective kolichestvennie from about 150 to about 350 μg/day and preferably from about 175 to about 300 μg/day of 17-d-NGM, added together with from about 5 to about 45 μg/day and preferably from about 10 to about 35 μg/day of ethinyl estradiol. Alternatively, using the patch will be introducing from about 200 to about 350 μg/day and preferably from about 175 to about 300 μg/day of 17-d-NGM, added together with from about 20 to about 175 mcg/day and preferably from about 30 to about 150 μg/day of 17-estradiol. The patch is applied for 7 days and replaced with a new patch /7 days/ during the course of treatment.

The plasters according to the invention can be made using procedures known in the prior art for the manufacture of adhesives. The whole procedure will typically include the preparation of the composition of the matrix /ie mixing glue, drug /medicines/ amplifier permeability and additives /if they are included/ fill matrix on a substrate or a release backing layer, removing the solvent from the matrix and the deposition substrate/ releasing lining layer at a possible procedure. As obvious to the experts in this field, Compucase in various transdermal design, and therefore, applicants are not limited to, options, examples of which are given below.

The following additional examples illustrate the invention. These examples are in no way intended to limit the invention. If not indicated otherwise, values are presented in wt. %.

EXAMPLES

Example 1

Duro-Tak 87-2287 is a solution of polyacrylate adhesives, National Starch and Chemical Co. It has the following monomer composition: vinyl acetate, 2-ethyl hexyl acrylate, hydroxyethylacrylate and glycidylmethacrylate. It does not contain poperechnikami agent. It is presented in the form of a 50% solution of granular materials in ethyl acetate.

Prepare a mixture of Duro-Tak 87-2287, 0,26% Poperechnaya agent aluminiumalloy, 6% of 17-d-NGM, 1% EE and different amplifiers permeability. This mixture is subjected to curing and pour in a layer thickness of 100 microns /wet/ protective layer of polyester SM 1022 and dried. Test flows through the skin is performed on the resulting structures in accordance with the methodology described in the post.7 of U.S. patent 5252334. For the quantitative determination of 17-d-NGM and EE using HPLC. For the detection of 17-d-NGM and EE using, respectively, Sistemi flow rate 1.0 ml/min The retention time of 4.5 min and 3.0 min for 17-d-NGM and EE, respectively. Compositions and test results of the flow shown in table 1.

Example 2

Silicone 4202 is polydimethylsiloxane adhesive from Dow Corning. It is mixed with 17-d-NGM, EE, 7% PVP /CSO from BASF; dissolved in n-propanol/ and various amplifiers. This mixture is poured in a layer thickness of 100 microns /wet/ on a thin substrate layer of polyester SM 1022 and dried. Test flows through the skin is performed on the resulting constructions, as in example 1. Compositions and results of the flow are presented in table 2.

Example 3

Conduct comparative studies patches of silicone glue-17-d-NGM/EE using two types of PVP: soluble low molecular weight PVP, denoted PVP-K30 from BASF, and insoluble Poperechnaya micronized PVP, denoted PVP-CLM from BASF.

PVP-K30 dissolved in absolute ethanol. Prepare a mixture of 17-d-NGM, EE and PVP-K30 and after that add the silicone 4202 and meilleures. The mixture is stirred over night. The mixture is poured on the lining of the SM 1022 at a thickness of 100 mm /wet/ and dried at 700oC for 40 minutes

the rat, Uh, 17-d-NGM and ethanol. The mixture is stirred overnight, poured on the lining of the SM 1022 and dried as above.

Test flows through the skin is performed on the above-described constructions, as in example 1. Compositions and results of the research flows through the skin are presented in table 3.

Example 4

Solutions BEERS prepared by dissolving VISTANEX L100, Vistanex LM-MS-LC and polybutene /lndopol N/ hexane. Prepare suspension PVP-CLM, 17-d-NGM, EE and different amplifiers in ethanol/ethyl acetate. A solution of PIB added to suspensions of drugs and the resulting mixture is thoroughly mixed. The mixture is poured in a layer thickness of 10 mm /wet/release liner and dried at 70oC for 40 minutes To Assembly design make the substrate layer of the Saranex 2015. Test flows through the skin spend on these constructions, as in example 1. The details of these constructions and results flows through the skin are presented below in table 4.

Example 5

Composition and matrix suitable for hormone replacement therapy, is prepared as follows. 2% of 17-estradiol, 2% of 17-deacetylation, 20% PVP-CLM and 76% BEERS glue /1:5:2,5:1,5 Vistanex L-100:Vistanex LM-MS-LS: Polybut the lining and dried at 70oC for 45 minutes. Polyester substrate is applied before the test flow. The study flow is conducted as described in example 1.

Steroid - Flux (ág/cm2/h)

17-d-NGM - 0,10

17-estradiol - 0,20

Example 6

Transdermal patches having a matrix composed of PIB adhesive, PVP-CLM, lauryl and myristoleate, 17-d-NGM and EE, are made as follows:

17-d-NGM and EE was dissolved in ethyl acetate and PVP-CLM and laurolactam or myristoleate /received from ISP VanDYK of Belleville, New Jersey/ and add to this solution. The solution BEERS glue /1:5:4 Vistanex L-100:Vistanex LM-MS-LC:lndopol N/ in hexane is added to the solutions of steroids with vigorous stirring. In the final mixture is added slowly n-propanol in an amount of 10% by weight of PVP-CLM. The mixture is poured on releasing the lining and dried in an oven at 70oC for 40 minutes. The weight of the dried matrix is 7.5 mg/cm2. Design matrix-releasing lining layer on polyester /Scotchpak 1012/ layer substrate. Another design layer on non-woven polyester layer /Remay 2250/. Releasing the lining is removed from the substrate and applied to the design of the non-woven layer to obtain a 5-layer composite material, soloerotica through the skin was carried out, as described in example 1. Patches and research results flow through the skin is presented below in table 5.

It is assumed that modifications of the above described methods of carrying out the invention that are obvious to experts in the field of transdermal patches, are within the scope of the following claims claims.

1. Transdermal patch to prevent ovulation in women, including: a) a substrate and b) not containing acrylate matrix layer deposited on a substrate, and a matrix layer contains a mixture of 17-diacetylmorphine and glue, sensitive to pressure containing at least one of silicones and polyisobutylene, and matrix adapted for diffusion connection with the woman's skin and transdermal injection inhibiting ovulation number 17-diacetylmorphine.

2. The patch p. 1, wherein the specified number is 175 to 300 mcg/day.

3. The patch p. 1, characterized in that the matrix layer contains the amplifier permeability of the skin.

4. The patch p. 3, characterized in that the amplifier is the permeability of the skin selected from the group consisting essentially of the ester of lactic acid C

6. The patch p. 1, characterized in that the matrix layer further comprises an estrogen.

7. The patch p. 6, wherein the estrogen is a estradiol.

8. The patch p. 7, characterized in that estradiol is a ethinyl estradiol or 17-estradiol.

9. The patch p. 8, characterized in that estradiol is a levonorgestrel.

10. The patch p. 9, characterized in that the number of 17-diacetylmorphine ranges from 175 to 300 μg/day and the number of ethinyl estradiol is from 10 to 35 μg/day.

11. The patch p. 8, characterized in that estradiol is a 17--estradiol.

12. The patch p. 11, characterized in that the number of 17-diacetylmorphine ranges from 175 to 300 μg/day and the number 17--estradiol ranges from 30 to 150 mcg/day.

All items meet the priority 07.06.1995,

 

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