NO880356L - DOSAGE UNIT FOR ABSORPTION OF OESTRADIOL AND OTHER OESTROGEN STEREOIDS THROUGH THE SKIN, AND PROCEDURE FOR ADMINISTRATING THE STEREOIDS. - Google Patents

Description

Technical area

The present invention relates to a new skin-absorbing dosage unit comprising a substrate, an adjacent layer of solid polymer mass in which there is microdispersed estradiol or other steroid pharmaceuticals that have estrogenic activity, and a biologically compatible adhesive that is used to adhere the dosage unit to the skin of the being that has having been administered the said estradiol or another steroid pharmaceutical, and arranged to enable the estradiol or other steroid pharmaceutical to be absorbed through the skin. The invention also relates to an improved therapy for maintaining the concentration of estradiol or other estrogenic steroids.

Known technique

It has been shown that some pharmaceuticals are absorbed to a certain extent through the skin. This is referred to as transdermal absorption of pharmaceuticals. One method of performing transdermal absorption has been to distribute the pharmaceutical inside a polymeric plate or in a capsule with a gel which is then brought into contact with a skin area of the being to be treated with the drug. Ointments or lotions containing the desired pharmaceutical also have

has been applied to an area of skin on the being to be treated. During such treatment, however, problems arise since both the rate and duration of absorption through the skin are difficult to control, or the rate for certain dosage forms may be too low, particularly from dosage units in the form of pharmaceutical-containing plates, gel capsules or pads. It has been shown that the transdermal absorption rate of certain drugs can be increased by using absorption-promoting compounds

(also referred to as skin permeation enhancers) together with the pharmaceutical to be absorbed, during the composition of the polymeric sheet or the pharmaceutical-containing gel.

It is desirable to improve the design of the dosage units or the design of the agents used to absorb pharmaceuticals through the skin, particularly in light of the importance these agents have during the administration of pharmaceuticals. The desired absorption of pharmaceuticals through the skin will lead to avoiding stomach and intestinal compatibility with the pharmaceuticals and an unwanted breakdown of the pharmaceuticals by metabolism in the stomach and intestinal channels and by first pass hepatic metabolism. The absorption through the skin minimizes the variations from patient to patient and for the individual patient as regards such incompatibility and metabolism. By absorption through the skin, it becomes possible to obtain a more constant pharmaceutical concentration in the body and to achieve a greater pharmaceutical effect. It is possible to reduce the effective dosage frequency by a suitable absorption through the skin. Transdermal administration provides most of the advantages of intravenous dosing without the need for hospitalization and the accompanying discomfort and inconvenience.

As regards the individual pharmaceuticals to which the present invention relates, the estrogen-steroid estradiol can illustrate a pharmaceutical where a large loss occurs with orally administered estrogen during the first passage through the liver, since it is almost completely metabolised. Consequently, the normal estradiol levels cannot be reliably replaced by oral administration. It has been shown that when administered through the skin, with only a fraction of the amount needed for oral dosing, sufficient levels of estradiol that the body does not produce naturally for one or more reasons can be achieved, thereby achieving sufficient levels in women to prevent body conditions and symptoms caused by such insufficient concentration levels. Furthermore, e.g. the unwanted estradiol metabolites formed by first pass hepatic metabolism, strongly when estradiol is administered through the skin. A further advantage of transdermal administration is that more uniform concentration levels of estradiol and other estrogenic steroids are achieved.

The need for replacement therapy for estradiol is due to the cessation of menstruation (stoppage of ovarian functions), ovarian inflammation (loss of one or both ovaries during surgical interventions) or failure of mucus secretion. Estrogen replacement therapy represents an important need. In addition to the need to alleviate menopausal symptoms caused by the lack of estrogen steroids, such estrogen replacement therapy also contributes to osteoporosis (loss of bone tissue) and atherosclerosis. There is clearly a need for improvements in agents and methods for estrogen steroid therapy. Although it has been shown that estradiol itself or estradiol in the form of certain derivatives such as mono- or diesters (e.g. acetate esters) can be absorbed through the skin, it is desirable to develop improved absorption dosage units for transdermal estradiols and other estrogenic steroids as well as methods for administration through the skin. This will bring a number of advantages.

Summary of the Invention

The present invention relates to an improved transdermal pharmaceutical-containing dosage unit comprising: a) a substrate layer which is largely impermeable to the pharmaceuticals to be delivered through the skin, b) a plate layer of polymer mass which is in contact with said substrate layer and where a quantity of estradiol is microdispersed or other oestrogen-steroids capable of transdermal absorption or pharmacologically acceptable derivatives thereof which can be absorbed through the skin, the plate layer producing a dosage amount of the pharmaceutical to be delivered through the skin, and c) an adhesive agent which adheres the dosage unit in intimate contact with the skin on the being to be treated, so that the pharmaceutical can be absorbed through the skin.

The backing layer can be made from materials that are largely impermeable to the pharmaceuticals in the transdermal dosage unit. It can be produced from polymers such as polyethylene, polypropylene, polyvinyl chloride, polyesters such as poly(ethylene phthalate), and in the form of foils such as laminates of polymer films with metallic foils such as aluminum foil.

The plate layer of the polymer mass is suitably produced from biologically acceptable lipophilic polymers. The plate layer of polymer mass in which the pharmaceutical is distributed can conveniently be produced from a silicone polymer of medical grade such as a polydimethylsiloxane polymer. The silicone polymer can also be a block or graft or of another type of copolymer. The pharmaceutical is appropriately dispersed in the silicone polymer, a curing agent being suitably added to the mixture. The polymer-pharmaceutical mixture is then formed into a layer of suitable thickness and surface area and cured if necessary. The mass layer is then glued to the base layer. Other suitable polymers that can be used during the formulation of the plate layer's polymer mass are elastomers and thermoplastics. It must be taken into account that the selected polymer is compatible with the drug, that the drug can be triggered for absorption through the skin, and that it is free from or sufficiently free from biologically unacceptable components.

A suitable derivative of estradiol or other estrogenic steroids used during formulation of the plate layer's polymer mass is suitably an ester which is biologically compatible and can be effectively absorbed through the skin. It is also generally preferred that such esters are bioconvertible with components in the skin or in other body parts such as hydrolytic enzymes (eg estarase) to estradiol or other preferred estrogenic steroids. If the derivative is an ester, the derivative can be a mono- or diester if the estrogenic steroid has two esterifiable groups. In the case of estradiol, this has hydroxy groups at the 3- and 17-positions and therefore 3-mono and 17-mono as well as 3,17-diesters can be prepared by well-known esterification methods. Some ester derivatives are absorbed more easily than basic estradiol or other estrogenic steroids that are the basic compound. When selecting the ester derivatives, it is usually preferred that the ester derivative is absorbed more effectively than the basic compound and is effectively bioconverted to estradiol or other basic estrogen steroids used after absorption. Valerianate mono- and diesters of estradiol are currently considered to be the preferred esters. During the formulation of the polymeric plate layer, it is sometimes preferred to use two or more drugs, such as an estradiol ester, e.g.

estradiol-valerianate, combined with a quantity of estradiol. An estrogen-steroid in the form of the basic compound or derivative thereof such as a bioconvertible ester, or combinations thereof, may be combined with another steroid having a different action, such as a progestin, in an appropriate amount to produce the appropriate estrogen -therapy.

Finally, the dosing unit's adhesive device is combined with the other layer components so that a dosing unit is formed. The preferred adhesive may vary depending on many factors including economic factors such as which production equipment is most readily available, and how fast absorption is preferred, or other factors. E.g. the adhesive layer can be applied directly to the plate layer's polymer mass. A skin penetration enhancing compound can be carefully mixed with the adhesive polymer suitable for adhesion to the skin area where the dosage unit skin penetrating mass is to be applied. The adhesive layer of polymer agent for promoting polymer penetration can be applied to the plate layer's polymer mass by spraying or by solvent casting or lamination. If a compound that promotes skin penetration is used, the concentration of this can be reduced in the adhesive layer part, if it leads to a weaker adhesion from the adhesive layer, by separately applying the adhesive layer to the surface part whereby the adhesive mixture has a lower concentration of the compound that promotes skin penetration. The adhesive layer preferably has a small micro-sized thickness, suitably a thickness of 10-200 µm, preferably 20-180 µm and preferably a thickness of 30-150 µm. An effective amount of a compound to promote skin penetration may also be incorporated in the drug-containing plate layer. The adhesive device can also, if desired, be in the form of a ring glued to the substrate layer that extends outside the periphery of the plate layer. When such a concentric ring-shaped adhesive device is used, the exposed surface of the drug-containing plate layer is kept in intimate contact with the skin of the being treated.

The absorption rate of the transdermal pharmaceutical absorption dosage unit according to the invention can be increased so that an increase factor of at least 1.2, preferably at least 1.3 and more preferably at least approx. 1.5. The enhancement factor is defined as the ratio between a normalized penetration rate (in mg/cm<2>/hour) for a dosage unit including an agent for promoting skin penetration according to the invention, and the normalized penetration rate for a corresponding dosage unit without this agent.

The invention also includes a method for administering the aforementioned drug through the skin by designing a pharmaceutical-containing dosage unit of a polymer mass plate comprising a plate layer polymer mass in which the pharmaceutical dose is dispersed, and where a substrate layer is adhered to the plate mass, by cooperating the dosage unit with a adhesive to keep the dosage unit in intimate contact with the skin of the subject to be treated so that the pharmaceutical can be absorbed through the skin, and by applying the dosage unit by means of an adhesive to the skin of the subject to be treated so that the pharmaceutical is administered through the skin of the being so that systemic effects are achieved.

Detailed description of the invention and the preferred embodiment

The base layer can be made of any suitable material which cannot be penetrated by the drug in the polymer mass layer. The base layer serves as a protective cover for the mass layer and also performs a support function. The sub-layer can be designed so that it has roughly the same layer thickness as the plate layer of the pharmaceutical-containing mass or it can have larger dimensions so that it can extend beyond the sides of the plate layer of the mass or overlap the side or sides of the 1-eigenagent-containing plate layer, and it can thus projecting outwards in such a way that the extent of the underlayer's surface can form the basis for an adhesive. The adhesive keeps the dosage unit in close contact with the skin of the being being treated. Examples of materials that are suitable for the production of the underlayment are films of polyethylene, polypropylene, polyvinyl chloride, polyesters with high and low density such as poly(ethylene phthalate), and metal foils, metal foil laminates of such suitable polymer films, and the like . The materials used in the substrate layer are preferably laminates of such polymer films with a metal foil such as aluminum foil. In such laminates, the laminate's polymer film is usually in contact with the polymer pulp layer. The base layer can have an arbitrarily suitable thickness that provides the desired protection and support functions. A suitable thickness can be 10-200 µm. If desired, the thickness can be 20-185 µm, and preferably 30-100 µm.

The polymeric pulp layer can be made from silicone elastomers with the general polydimethylsiloxane structure, such as silicone polymers with the following general formula:

where R is alkyl or alkoxy containing 1-7 carbon atoms, vinyl or phenyl and where n is 100-5000.

The selected silicone polymers are preferably crosslinked at moderate temperatures such as room temperature, using crosslinking catalysts which are biologically acceptable in the final polymer mass and which are compatible with the pharmaceutical preparation used in the preparation of the dosage forms of the polymeric mass. Various suitable crosslinking agents can be used during crosslinking of the above-mentioned polymer such as tetrapropoxysilane [si(OCH2CH3)4] if the silicone polymer comprises free hydroxy groups such as hydroxy groups on the ends. A tin catalyst can be used in such crosslinking reactions. If a silicone polymer component comprises vinyl groups, it can be crosslinked with a dimethyl silicone polymer using a catalyst such as a platinum catalyst. Certain suitable silicone polymers are crosslinked copolymers having dimethyl and methylvinylsiloxane units, which can be crosslinked by using a suitable peroxide catalyst. In the polysiloxane elastomer used, there may be other crosslinking points present. Suitable medical grade silicone polymers are commercially available under the designation Silastic 382, Q7-4635, Q7-4650, Q7-4665, Q7-4735, Q7-4750, Q7-4765 and MDX-4-4210.

The selected silicone polymers can also have a block and/or a grafted structure. By a block structure it is meant that the polymer may comprise a section or a block of the polymeric chain structure of the polymer which may have a repeating unit of one type such as dimethylsiloxane, and further comprise a subsequent block made up of repeating units of another type, such as methyl-vinylsiloxane, diphenylsiloxane, diisopropylsiloxane units or other siloxane or silane units or even of monomer units of a compatible non-siloxane or non-silane type. The blocks can vary in length and be repeated as desired. If the blocks e.g. are represented as "A" and "B" respectively, the block copolymer may be A-B or A-B-A or A-B-A-B, etc. The graft structure simply means that one or more polymer chains are attached to the main polymer chain. These grafted chains may have the same polymer units as in the main chain or they may be different, as described above in connection with block copolymers. The polymer used can also be of a different type in that copolymerizable monomers are brought together in a polymerization reactor so that the main chain can comprise a certain population of each of the monomer units

The following are examples of block copolymers of the type that can be utilized in this invention.

where y and z are the number of repeating units necessary to achieve the desired properties in the polymer, such as 10-5000.

The polymers that are generally used to form the biologically acceptable polymer mass are those that can form thin walls or coatings through which drugs can pass at a controlled rate. Suitable polymers are biologically and pharmaceutically compatible, non-allergenic and insoluble in and compatible with body fluids or tissues with which the device comes into contact. The use of soluble polymers should be avoided since dissolution or erosion of the mass may affect the release rate of the drug as well as the ability of the dosage unit to remain in place for easier removal.

Examples of materials for manufacturing the biologically acceptable polymer mass include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone elastomers, especially medical grade polydimethylsiloxanes, neoprene rubber, polyisobutylene, chlorinated polyethylene, polyvinyl chloride, vinyl chloride-vinyl acetate copolymer, polymethacrylate polymer (hydrogel), polyvinylidene chloride, poly(ethylene terephthalate), butyl rubber, epichlorohydrin rubber, ethylene-vinyl alcohol copolymer, ethylene-vinyloxyethanol copolymer, silicone copolymers, e.g. polysiloxane-polycarbonate copolymers, polysiloxane-polyethylene oxide copolymers, polysiloxane-polymethacrylate copolymers, polysiloxane-alkylene copolymers (e.g. polysiloxane-ethylene copolymers), polysiloxane-alkylene-silane copolymers (e.g. polysiloxane-ethylenesilane -copolymers), and the like, cellulose polymers, e.g. methyl or ethyl cellulose, hydroxypropyl methyl cellulose, and cellulose esters, polycarbonates, polytetrafluoroethylene, and the like. To achieve the best possible results, the biologically acceptable polymer mass should be selected from polymers with glass transition temperatures lower than room temperature. The polymer may, but not necessarily, to a certain extent have a crystalline state at room temperature. Cross-linking monomer units or sites can be incorporated into such polymers. E.g. crosslinking monomers can be incorporated into polyacrylate polymers, where there are places for crosslinking of the mass after the drug has been microdispersed in the polymer. Known crosslinking monomers for polyacrylate polymers include polymethacrylic esters of polyols such as butylene diacrylate and dimethacrylate, trimethylolpropane trimethacrylate and the like. Other monomers that form such sites include allyl acrylate, allyl methacrylate, diallyl maleate and the like.

The adhesive is conveniently produced in the form of a layer covering the pharmaceutical-containing plate and it is used by a silicone adhesive such as a polydimethylsiloxane derived from the following formula:

where Me is methyl and R is SKCH^)^.

E.g. adhesives or amine-resistant adhesive products sold by Dow Corning, such as that sold under the designation DC-355, can be used to produce an adhesive layer. The adhesive polymer must be biologically acceptable and compatible with the drug and the compound that increases penetration through the skin if such is used. Certain polyacrylic adhesive polymers (in the form of an alkyl ester, amide,

free acid or similar) or polyisobutylene adhesive polymers can also be used together with certain medicines. Other suitable hypoallergenic pressure sensitive contact adhesive compositions may be used. A preferred adhesive layer is pressure sensitive.

However, if desired and depending on economic or other factors, the adhesive device can be in the form of a ring such as is attached to an extended portion of the backing layer so that the adhesive layer is next to the side wall of the drug-containing plate layer. The width of such an adjacent adhesive ring must be sufficient to keep the dosage unit fixed on the being being treated. Usually, such an adhesive ring can conveniently be approx. 0.2-1.2 cm preferably 0.3-1.0 cm.

Finally, the adhesive is covered with a removable protective film layer in accordance with common therapeutic practice, as this is made from a material that is largely impermeable to the drug, the compound that promotes skin penetration if this is used, and possibly other components in the polymer mass of the dosage unit. The polymeric materials and metal foil laminates used in the underlay can

also used to produce the protective layer, provided that the layer can be torn off or detached as in

to use conventional siliconization. A suitable releasable material that can be used with the silicone polymer adhesive DC-355 is Scotchpak 1022 material sold by the 3M Company.

During the production of the drug-containing plate layer's polymer mass, silicone elastomers such as polydimethylsiloxane with the above-mentioned formula can be suitably used. During the production of dosage units with an estradiol-dispersed polymer mass, it has proven appropriate to use a dispersant in the form of a polyol such as a polyethylene glycol. Other suitable dispersants may be used instead when they are effective. In general, water-soluble polyols can be used. E.g. polyethylene glycols can be used, such as those having a molecular weight of approx. 400, as the molecular weight may vary from this, such as suitably between 300 and 500. Other suitable dispersants which are known for such formulation techniques may also be used. Depending on the steroid drug and the desired drug loading, a suitable amount of dispersant can vary from 0-50% (by weight) based on the weight of the polymeric sheeting. Usually the polyol is added as an aqueous solution, the polyol content varying from 10-50% based on the weight of the final polymer mass. Aqueous solutions with approx. 40% polyol is usually suitable, with some variation depending on the rate of penetration desired for the steroid drug used, and occasionally on other factors. The drug is then added to the polymer that is used to produce the plate-layer mass. The amount of pharmaceutical added depends on the amount of the desired drug dose in each dosage unit as well as the amount that can be incorporated into the plate polymer mass to maintain a suitable structure, diffusion and other properties in the final plate mass. It has e.g. it has been shown that the drug can be added with good results to 70 parts of the polymer used in the production of the sheet material, such as silicone elastomers. It has been found to be preferred to dissolve and disperse the steroid pharmaceutical used in a given quantity of a selected aqueous polyol solution, such as PEG 400. The mixture of polymer and drug or the drug-dispersed aqueous polyol solution is then carefully mixed using a high-torque stirrer as that a homogeneous microdispersion of the drug is formed in the polymer. With continuous stirring, a crosslinking catalyst is preferably added together with a polymer with a relatively low molecular weight and which has a compatible chemical structure. When, for example, polydimethylsiloxane-based polymer is used as polymer, a relatively low molecular weight polydimethylsiloxane and a crosslinking catalyst (such as 10 parts by weight of low molecular weight polydimethylsiloxane and 30 drops of tin octanoate per 100 g of final mixture of polydimethylsiloxane pharmaceuticals) are added to the above mixture of 20 parts pharmaceutical dispersion and 70 parts polydimethylsiloxane polymer. Again, the mixture is stirred with a high-torque stirrer so that a uniform mixture is formed. After each mixing step, the mixture is subjected to vacuum to remove trapped air.

The deaerated mixture is then placed in a device (device maker) and heated to a suitable higher temperature to promote crosslinking. A suitable crosslinking temperature is 10-200°C and preferably 20-100°C when the polymer used is polydimethylsiloxane with the above formula and the crosslinking catalyst and tin octanoate. The temperature used should not result in significant degradation of the medicine. The polymer mass flake preferably has a thickness of 0.05-5 mm, preferably 0.1-3 mm. The resulting cross-linked polymer mass flake is removed from the device and can be cut into sheets of desired shapes and sizes. The plates are then fixed to the base layer, as described above, using an adhesive. Optionally, the plate can be designed directly on the base sheet used. The plate should generally not exceed an area of 100 cm<2>, preferably 5-100 cm<2>, preferably 8-80 cm2, and usually 10-60 cm<2> is more preferred. The design of the plates can vary as they can be circular, square, rectangular or have other desired shapes.

The plate layer containing the drug in the polymer mass should generally contain a certain excess of the dispersed drug over and above the dosage amount to be absorbed through the skin of the treated being. Usually this excess is small, such as less than a two-fold excess. In general, an amount of the pharmaceutical used sufficiently is less than 2-10 times the desired dosage to approx. less than 2-5 times the desired sufficient dose to be absorbed through the skin, depending on the physiochemical properties of the pharmaceutical as well as the properties of the polymer in the plate pulp layer and other factors.

If the adhesive contains an agent for promoting skin penetration, it is prepared by dissolving the enhancing agent in a suitable solvent that is compatible with the adhesive polymer solution used to prepare the adhesive layer containing the agent that increases skin penetration. Any suitable amount of solvent can be used if necessary to dissolve the amount of extender to be mixed with the adhesive polymer solution used. E.g. 3-10 parts of solvent may be used to dissolve one part of the skin penetration enhancer, depending on the solubility of the enhancer. When using a dimethylsiloxane adhesive solution, it has been found appropriate to use 2-20 parts skin penetration agent in 20-50 parts solvent (such as acetone, methyl ethyl ketone, triflourtrichloroethane or other suitable solvents) and add the solution to 100 parts of the adhesive solution. The mixture of increasing agent and the adhesive is carefully mixed and a coating is applied, using

a film coating machine, directly on the polymer mass or on a tear-off release tape before the lamination on the polymer mass as described above. A suitable release tape comprises poly(ethylene phthalate) laminated with aluminum foil or a Teflon-coated polyester film sold under the designation Scotchpak 1022. The poly(ethylene phthalate) side to which the adhesive-enhanced coating is applied is made strippable by conventional silicone sealing or other suitable means. The thickness of the adhesive agent layer is suitably 10-200 µm, preferably 30-150 (im. The amount of agent in the adhesive layer depends partly on how quickly it is desired that the drug be absorbed. In general, 1-30% of the agent is sufficient increases skin penetration, based on the weight of adhesive, depending on the enhancer, the adhesive polymer, the desired adhesive effect and other factors. Preferably, 5-20% of the skin penetration enhancing agent is used depending on the above factors. The adhesive layer containing the agent which increases skin penetration, is transferred to the surfaces of the polymeric sheet mass using a lamination technique at constant pressure. In order to ensure a satisfactory absorption of the adhesive polymer layer to the skin of the subject being treated, preferably an enhancer-adhesive polymer solution is used which has

a relatively low concentration of enhancer, e.g. 1-2% based on the weight of adhesive polymer, to apply a coating to the release tape. The thickness of this coating is ordinarily a small percentage of the thickness of the final adhesive layer, such as 20-40% of the total adhesive polymer layer. The rest of the adhesive polymer layer, which has a suitable higher concentration of agent that increases skin penetration, is used to coat the plate layer of the mass. Suitable higher concentrations of the skin permeation enhancer are generally 10-30% based on the weight of the adhesive polymer, the solubility and the desired final amount of the skin permeation enhancer and other factors. The solvent in the respective coatings is removed by evaporation. The respective coatings are combined to form the final layer of the adhesive polymer enhancer using constant pressure.

The four-layer dosage unit of the transdermal pharmaceutical-containing polymer mass is subjected to testing. The base layer can

if desired, is designed around the sides of the dosing unit including the polymeric mass layer if such protection is desired. The

resulting designs of the pharmaceutical-containing polymer mass dosage unit are then placed in a suitable package for storage until they are to be used in transdermal treatment.

At least one drug is dispersed in the plate layer of the polymeric mass. The type of drug that can be dispersed in the polymeric sheet layer composition includes any pharmaceutical that can be administered transdermally or topically to the patient to be treated. With a controlled release of the drug at a relatively constant rate over an extended period of time, usually 24 hours or longer, the patient can benefit from a constant drug infusion over a long period of time. As examples of drugs that can be included in the plate layer's polymer mass according to the present invention, the following shall be mentioned: Estradiol and derivatives thereof, and which are biocompatible, can be absorbed through the skin and are preferably bioconvertible to estradiol. Such estradiol derivatives include esters, either mono- or di-esters. The monoesters can either be 3- or 17-esters. The estradiol esters can be, for example, estradiol-3,17-diacetate, estradiol-3-acetate, estradiol-17-acetate, estradiol-3,17-divalerianate, estradiol-3-valerianate, estradiol-17-valerianate, 3-mono, 17-mono and 3,17-dipivylate esters, 3-mono, 17-mono and 3,17-dipropionate esters, corresponding cypionate, heptaonate, benzoate and similar esters, ethinyl estradiol, estrone, and other estrogenic steroids and derivatives of these which can be absorbed through the skin.

Combinations of the above or other estradiol drugs include basic estradiol pharmaceuticals, e.g. a combination of estradiol and estradiol-17-valerianate or, furthermore, a combination of estradiol, estradiol-17-valerianate, and estradiol-3,17-divelerianate, can be used with favorable results. E.g. 15-80% of each compound can be used based on the total weight of estrogen-steroid component, to achieve the desired result. Other combinations can also be used to achieve the desired absorption and estradiol levels in the body of the patient being treated.

It is preferred that the drug can be added to the above-mentioned mixture not exclusively in the form of the pure chemical compound, but also in admixture with other drugs that can be administered through the skin, or with other ingredients that are not incompatible with the desired purpose of the transdermal drug sub-administration to a patient. Thus, simple pharmacologically acceptable derivatives of the drugs such as ethers, esters, amides, acetals, salts and the like can be used if appropriate. In some cases, such derivatives can really be preferred. In the present invention, biologically acceptable esters have been found to be suitable. If an ester of estradiol or other estrogenic steroids is used, the selected ester is preferably absorbed more easily through the skin and is effectively bioconverted back to the basic compound after absorption through the skin, such as by naturally occurring esterase enzymes in the skin.

It is often preferred in estrogen steroid therapy such as estradiol therapy to simultaneously administer a progestin amount. Occasionally this concomitant progestin administration is necessary to obtain the full benefit of the estradiol replacement therapy, e.g. in case of premenstrual tension, uterine dysfunction, bleeding or missing menstruation. Progesterone is a suitable progestin compound for such concomitant therapy. Other progestin compounds from which a suitable compound can be selected are norethindrone, ethynodiol diacetate, medroxyprogesterone acetate and the like. The amount of the progestin compound administered daily and the term of therapy depend on the compound, the particular patient and the conditions of treatment. A daily dose for an adult is often in the range of 1-30 mg.

(Remington's Pharmaceutical Sciences, 16th ed., 1980, Arthur Osol et al., Eds., Mack Publishing Company, pages 933-936).

The progestin compound and the estrogenic steroid can usually be mixed together during the manufacture of the pharmaceutical dosage layer plate according to the present invention.

The agent used to promote skin penetration during the practice of the present invention may vary. Which gives a preferred result with a design of the dosage unit's polymer mass with a specific drug, can vary. In some cases, the use of an agent that increases skin penetration during the preparation of a polymer mass dosage form can result in good or even excellent absorption for one drug, while it leads to no or a relatively low increase when another drug is used. The use of combinations of two or more compounds that increase skin penetration often leads to excellent results, such as a higher transdermal absorption.

In particular, compounds that increase skin penetration and that can be used during the production of the dosage forms of the polymer mass according to the present invention include saturated and unsaturated fatty acids and their esters, alcohols, monoglycerides, acetate, diethanolamides and N,N-dimethylamides, such as oleic acid, propyl oleate, oleyl acetate, propyl myristate, myristyl alcohol, myristyl N,N-dimethylamide, stearic acid and stearyl alcohol, stearyl propyl ester, monostearin, and combinations thereof with, for example, l-dodecyl azacycloheptan-2-one sold under the trade name Azone by Nelson Research and Development , decylmethylsulfoxide, dimethylsulfoxide, salicylic acid and derivatives, N,N-diethyl-m-tolu-amide, crotamiton, 1-substituted azacycloalkan-2-ones which are discussed in US patent 4,316,893 (wherein the 1-substituent has 0-17 carbon atoms, preferably 1-11 carbon atoms), and various other compounds which are biologically compatible and have a transdermal absorption action. Ethyl alcohol and other short chain alkanols (with 1-4 carbon atoms) which have largely the same properties and effects as ethyl alcohol do not fall within the definition of the compound that increases skin penetration as used herein.

The above description of estradiol is primarily aimed at estradiol-17-beta, which has estrogenic activity. Estradiol-17-alpha, which in contrast to this also has an estrogen antagonist effect, also falls within the scope of the present invention. The above formulation description, the description of the esters or other qualities also relate to estradiol-17-alpha. The dosage amount of estradiol-17-alpha or its derivatives depends on the patient's needs and the treatment conditions. The daily administered dose can often be chosen on the basis of estradiol-17-alpha in the range of 0.1-1 mg per day.

The following examples illustrate the invention and should not be considered limiting.

Example 1

The following ingredients are used during the manufacture of -the pharmaceutical-containing polymer mass sheets: 10 parts estradiol, 10 parts DC-360 polysiloxane medical fluid (20 eps), 80 parts silicone (medical grade) 382 elastomer, 20 drops per 100 g mixture of catalyst M.

The estradiol crystals are carefully dispersed in 80 parts of medical grade Silastic 382 elastomer using a high torque stirrer (sold by the Cole-Parmer Company) at approx. 1000 RPM

With continuous stirring, 20 parts of DC-360 (silicone medical fluid) and 20 drops (for every 100 g of the mixture) of a cross-linking agent, designated Catalyst M, which is tin octanoate, are added to the microdispersed estradiol elastomer mixture. After each addition of the mixture, the material is thoroughly stirred and the dispersed mixture is placed under vacuum to remove entrapped air.

The dispersion of estradiol-polydimethylsiloxane is placed in a device (device maker) and cross-linked at an elevated temperature (25-100°C) so that a cross-linked prepared polymer flake is formed which has a thickness of 0.2-3 mm.

The prepared polymer flake is removed from the device (device maker) and cut into circular slices of approx. 3-20 cm<2>. The discs are attached to a base layer of heat-sealed polyester film which is laminated to an aluminum foil. This laminate is sold by the 3M Company as Scotchpak 1006. The prepared discs are attached using an adhesive polymer solution, which is a silicone adhesive polymer sold by Dow Corning as DC-355. Optionally, the disks can be designed directly on the substrate layer, which is also done in practice.

The silicone adhesive is believed to have the following structure:

The skin penetration enhancing compound adhesive film is prepared using the following ingredients: 6.5 parts of the skin penetration enhancing compound, 30 parts of acetone and 100 parts of adhesive polymer solution. The skin penetration enhancing compound adhesive layer is prepared by dissolving 6.5 parts by weight of a skin penetration enhancing compound in 30 parts acetone. The acetone solution is then added to 100 parts of a silicone adhesive solution sold by Dow Corning under the designation DC 355.

The mixture is carefully stirred to form a homogeneous mixture of the skin penetration enhancing compound and the adhesive polymer, which is applied to a strip of release tape which is a siliconized or Teflon-coated polyester film that allows the release tape to be easily removed just prior to application of the finished polymer mass dosage unit - the plate for the patient to be treated transdermally. The adhesive mixture is applied with a controlled thickness. The designed layer has a thickness of approx. 50-200 µm. The layer is completely dried under vacuum to remove volatile material.

The polymer layer with the skin penetration enhancing compound, the adhesive polymer layer and the tear-off tape are applied to the drug-containing polymer mass disc with the adhesive backing under a constant pressure to form a firmly adhered strip of a four-layer structure comprising:

1. The base layer

2. Estradiol-containing polymer mass layer

3. the compound that increases skin penetration - the adhesive layer. 4. The layer with the tear-off film which can be easily removed for application to the skin of the patient to be treated with estradiol transdermally.

Using a suitable cutter, the strip can be cut to produce the dosage units of the transdermal 17-beta-estradiol polymer mass having a circular shape and an area of approx.

10 cmJ .

The above tabular polymer mass dosage unit is prepared using the following skin penetration enhancing compounds: 1-dodecylazacyclophtan-2-one, propyl myristate and propyl oleate.

The transdermal absorption of the drug from the drug-containing polymer mass dosage unit of the present invention is evaluated using a skin sample from a hairless mouse or a human cadaver following the procedures described by P.R. Keshary and Y.W. Chien, in Drug Develop. & Ind. Pharm., 10 (6) 883-913 (1984).

Transdermal polymer mass dosage units are obtained and evaluated as shown in Table I.

Example 2

Dosage units are prepared in accordance with Example 1 using the following esters of both 17-beta-estradiol and 17-alpha-estradiol: estradiol-3-acetate, estradiol-3-valerianate, estradiol-17-valerianate, estradiol-3-17 -divalerianate, estradiol-3-heptanoate, estradiol-17-propionate, estradiol-17-isopropionate, estradiol-3-propionate, estradiol-3,17-dipropionate, estradiol-3-butyrate, estradiol-17-butyrate, estradiol-3 ,17-dibutyrate, estradiol-17-caprate, estradiol-17-acetate, estradiol-3,17-diacetate, estradiol-17-heptanoate, estradiol-17-cypionate, estradiol-3-acetate-17-valerianate.

The dosage units are evaluated.

Example 3

The following procedures and materials are used in conjunction with the process equipment outlined below to prepare the transdermal polymer mass dosage plates listed in this example.

(1) In a disposable polyethylene beaker, quantities are mixed

drug carefully with an aqueous solution containing a given volume fraction of polyethylene glycol (PEG) 400, using a high-torque laboratory stirrer at a high stirring rate, to form a paste.

(2) The paste of drug/PEG is added to a medical grade silicone elastomer (Silastic 382 elastomer, Dow Corning Corporation) and thoroughly mixed again, using a high-torque laboratory stirrer, to form a homogeneous dispersion of drug / PEG/polymer. (3) An appropriate amount of silicone medical fluid (DC-360, Dow Corning Corporation) is added and mixed again thoroughly. (4) The solution is then deaerated under vacuum at 20 psi until trapped air is removed. (5) The catalyst M (tin noctonate) is added dropwise and mixed well. (6) Again deaerate the mixture under vacuum at 20 psi until entrained air is removed. (7) The mixture is poured into a specially constructed device (device maker) and spread out on a sheet of an underlay laminate, which is then covered with a sheet of equally sized tear-off tape. (8) The combination is placed between two pressure plates in a thermo-press held at 60°C and 1000 psi for 30 minutes. Spacers of different thicknesses are inserted between the plates to control the thickness of the flakes where the pharmaceutical component is microdispersed. (9) The plate layer containing the polymeric trandermal mass is removed and cut into slices of the desired size and shape for further use. The following plates are produced:

The above plate preparations are repeated, using estradiol-17-beta, the following derivatives of this and other listed steroids instead: estradiol-17-acetate, estradiol-3,17-diacetate, estradiol-17-valerianate, estradiol-17-heptanoate , estradiol-17-cypionate, estradiol-3-valerianate, estradiol-3,17-divalerianate, estradiol-3-acetate-17-valer ianoate, estradiol,17-benzoate, estradiol-17-alpha (and esters corresponding to the above-mentioned esters of estradiol-17-beta).

The following dosage units of those listed in the table

II, is evaluated using a hydrodynamic and well-calibrated skin permeation system with a freshly taken skin sample following the procedure described by Y.W. Chien and K.H. Valia, in Drug Develop. Ind. Pharm., 10(4) 575-599 (1984). The results are shown in Table II in which X+ S.D. means the mean of the permeation rates listed in column 2 with standard deviation:

Example 4

The following dosage units are prepared and evaluated by following the procedure of Example 3. The results are listed in Table IV:

The following references describe methods that can be used for the production of esters of hydroxy-substituted steroids such as estradiol and other estrogenic steroids. Chem. Pharm. Bull., 29(11), 3202-7 (1981), Tetrahedron Lett., (26), 2431-2

(1979), J. Org. Chem., 44(4), 654-6 (1979), Invest. Uroi., 17(6), 506-9 (1980), US Patent No. 3,478,070, issued Nov. 11, 1969 to Stein, Reinhardt Peter, et al., Yao Hsueh Hsueh Pao, (14(6), 343-8

(1978), Aust. J. Biol. Sei., 24(6), 1263-75, US Patent No. 3,496,272, issued February 17, 1980 by Kruger, Gunther, Farmaco, Ed. Sci., 28(3), 186-202 (1973), Am. J. Anim. Sei., 48(3), 449-53

(1968).

Example 5

The procedure of Example 3 is repeated to prepare transdermal polymer mass dosage units in which an effective amount of progestin is incorporated by microdispersion together with an effective amount of ethinyl-estradiol, estradiol-17-beta or one or more ester derivatives indicated above either with or without the basic compound estradiol-17-beta. The following combinations are illustrative of the drug combinations produced:

a) Ethynodiol diacetate/ethinyl estradiol, 1 mg/50 ug,

b) Ethynodiol diacetate/mestranol, 1 mg/100 ug,

c) Norethindrone/mestranol, 1/20, 1/50, 1/80, 1.5/30, 2/100, and 10/60 (mg/ug), d) Norethindrone acetate/ethinyl estradiol, 2.5/50, 1.5/30, 1/50 ug, and 1/20 (mg/ug), e) Norethynodremestranol, 2.5/100, 5/75, and 9.85/150 (mg/ug), d) Norgestrel /mestranol, 500/50 and 300/30 (ug/ug).

Hydroxyprogesterone caproate or another suitable ester,

medroxyprogesterone acetate or another suitable ester, dydrogesterone, or progesterone may also be used as the progestin in an appropriate amount.

Example 6

The above Example 3 is repeated except that an adhesive polyurethane foam disc is applied to the exposed surface of the backing layer which is then formed around the edge of the pharmaceutical containing polymer mass in the plate layer to protect this side. An adhesive layer can be applied to the surface of the drug-containing disc. The adhesive used is a silicone adhesive, polyacrylic adhesive or a polyisobutylene adhesive, which is biocompatible and enables the pharmaceutical component in the polymer sheet to be absorbed through the skin. If desired, one or more compounds which increase skin penetration can be incorporated into the adhesive layer in an effective amount. Optionally or in addition, one or more compounds that increase skin penetration can be incorporated into the drug-containing polymer mass plate layer.

Example 7

The procedure according to examples 3 and 6 is repeated using respectively polyisobutylene, polydimethylsiloxane-polyvinylmethyl-siloxane block and graft copolymers, polydimethylsiloxane-polymethyl-vinylsiloxane copolymers, polymethylsiloxane-polyethylenesilane block and graft copolymers, polydimethylsiloxane-polymethacrylate block and graft copolymers, polydimethylsiloxane-polyethylene oxide block and graft copolymers, polymethylpropylsiloxane-polydimethylsiloxane-polyvinyl acetate block and graft copolymers, polydimethylsiloxane-polyethylene copolymers, polydimethylsiloxane-polycarbonate and graft copolymers in the design of the transdermal drug-containing polymer mass sheets.

Claims (20)

1. Dosage unit for a transdermal pharmaceutical containing polymer mass comprising, a) a substrate layer that is largely impermeable to the pharmaceuticals to be delivered transdermally, b) a plate layer of a polymer mass which is glued to the said substrate layer and in which is microdispersed an amount of a pharmaceutical selected from an estradiol, another estrogenic steroid capable of being absorbed transdermally and which produces a dosage amount of the said pharmaceutical to be delivered through the skin, esters thereof which can be absorbed by the skin of the patient to be treated, and which after transdermal absorption are bioconvertible to estradiol or the aforementioned other estrogenic steroid, as well as pharmaceutically effective combinations thereof, c) an adhesive device for attaching the dosage unit to the patient being treated by transdermal absorption, and where an effective amount of one or more compounds that increase skin penetration is optionally distributed to produce a significant increase in the absorption of the pharmaceutical by the skin. 2. Transdermal pharmaceutical-containing polymer dosage unit in accordance with claim 1, characterized in that the plate layer of the polymer mass is made of a silicone polymer or copolymer. 3. Transdermal pharmaceutical-containing polymer dosage unit in accordance with claim 2, characterized in that the silicone polymer or copolymer is a methyl silicone polymer or copolymer. 4. Transdermal pharmaceutical-containing polymer mass dosage unit in accordance with claim 1, characterized in that the plate layer of the polymer mass is a cross-linked polysiloxane polymer with the following formula: in which R is alkyl or alkoxy with 1-7 carbon atoms, vinyl, phenyl or combinations thereof, and where n is approx. 100-5000. 5. Transdermal pharmaceutical-containing polymer mass dosage unit in accordance with claim 2, characterized in that the mass is made up of microdispersed sections that have a cross-sectional dimension of 10-200 µm. 6. Transdermal dosage unit in accordance with claim 1, characterized in that the pharmaceutical is selected from estradiol-17-beta, estradiol-17-alpha, transdermally absorbable, bioconvertible mono- or diesters thereof, or pharmaceutically effective combinations thereof. 7. Transdermal dosage unit in accordance with claim 2, characterized in that the pharmaceutical is selected from estradiol-17-beta, estradiol-17-alpha, transdermally absorbable, bioconvertible mono- or diesters thereof, or pharmaceutically effective combinations thereof. 8. Transdermal dosage unit in accordance with claim 3, vessel characterized by the pharmaceutical being selected from estradiol-17-beta, estradiol-17-alpha, transdermally absorbable bio convertible mono- or diesters thereof, or phamastically effective combinations thereof. r 9. Transdermal dosage unit in accordance with claim 4, characterized in that the pharmaceutical is selected from estradiol-17-beta, estradiol-17-alpha, transdermally absorbable, bioconvertible mono- or diesters thereof, or pharmaceutically effective combinations thereof. 10. Transdermal dosage unit in accordance with claim 6, characterized in that the mass comprises microdispersion of pharmaceutical sections that have a cross-sectional dimension of 10-200 (im. 11. Transdermal dosage unit in accordance with claim 10, characterized in that a polyethylene glycol dispersant is present in the microdispersed pharmaceutical sections. 12. Transdermal dosage unit in accordance with claim 6, characterized in that the pharmaceutical is estradiol-17-beta. 13. Transdermal dosage unit in accordance with claim 7, characterized in that the pharmaceutical is a combination of estradiol-17-beta and one or more of the aforementioned esters of estradiol-17-beta. 14. Transdermal dosage unit in accordance with claim 7, characterized in that the pharmaceutical is a combination of two or more esters of estradiol-17-beta. 15. Transdermal dosage unit in accordance with claim 7, characterized in that the pharmaceutical is a combination of two or more esters of estradiol-17-beta or a combination of estradiol-17-beta and one or more of the said esters of estradiol-17- beta, and at least one of said esters in each combination is estradiol valerianate. 16. Transdermal dosage unit in accordance with claim 6, characterized in that the pharmaceutical is estradiol-17-alpha. 17. Transdermal estrogen-pharmaceutical-containing polymer mass dose comprising a) a substrate layer which is largely impermeable to the pharmaceuticals to be delivered transdermally, b) a plate layer of polymer mass which is glued to the said substrate layer and in which is microdispersed an amount of a pharmaceutical selected from estradiol-17-beta, another estrogenic steroid capable of transdermal absorption and which will provide a dosage amount of the aforementioned pharmaceutical to be delivered transdermally, esters thereof which can be absorbed by the skin of the treated patient, and which after transdermal absorption are bioconvertible to estradiol or the aforementioned second estrogenic steroid, and combinations thereof, the said microdispersed pharmaceutical also comprising a pharmaceutically effective amount of a progestin, c) an adhesive for attaching the dosage unit to the patient who is treated by transdermal absorption and where an effective amount of one or more compounds that increase skin penetration is optionally distributed so that a significant increase in skin absorption of the said pharmaceutical is produced. 18. Transdermal dosage unit of oestrogen-pharmaceutical-containing polymer mass in accordance with claim 17, characterized in that the pharmaceutical is selected from estradiol-17-beta, esters of estradiol-17-beta, or combinations of two or more esters thereof or estradiol-17-beta and one or more esters thereof. 19. Method for estradiol-17-beta replacement therapy in that a dosage unit as described in claim 1 is placed on the skin of a patient in need of said therapy. 20. Method in accordance with claim 19, characterized in that the pharmaceutical is estradiol-17-beta, esters of estradiol-17-beta, or combinations of two or more esters thereof or estradiol-17-beta and one or more esters thereof.