MXPA99004581A - Transdermal administration of ment - Google Patents

Abstract

The present invention relates to transdermal dosage forms (10) for delivery of androgens.

Description

TRANSDERMAL ADMINISTRATION OF 7-a-METHYL-19- NORTESTOSTERONE (MENT) Technical Field The present invention relates to the fields of medicine and pharmacology and specifically to the production of transdermal devices for the administration of MENT and transdermal methods for the administration of MENT. Background Technique Due to the obvious drawbacks of physical barrier techniques, we can look for a chemical solution for male contraception. But the problems of developing a suitable contraceptive for men with a chemical basis are significant. Sterilants such as LHRH can be administered and will effectively reduce the sperm count of man. However, there may be an accompanying loss of sexual function in men. Therefore, several subcutaneous implantable systems have been proposed to administer both a sterilant and an androgen. See U.S. Patent No. 5,733,565 These systems are effective and can generally provide contraception in men without long-term maintenance. But these systems also have their drawbacks. Some people have an aversion to subcutaneous implants. The implant removal and reimplantation of devices requires inconvenient doctor visits and, while they are minimally invasive, all these are surgical procedures. As a result, some subjects do not carry them out. Others will reject this form of contraception as an alternative. There is always a risk of secondary infection. Of course, the dosage form itself is not the only problem.

The selection of an appropriate androgen is also often an important aspect. For example, testosterone is often used for androgen replacement therapy. However, the potency of testosterone is limited, requiring that large doses be administered. Testosterone is also reduced to a metabolite known as Dihydrotestosterone ("DHT"). DHT is very active on the prostate and can cause normal growth of the prostate Therefore, there is a need for convenient and effective non-surgical methods to administer potent, safe and effective androgens to subjects who need them. These objects are satisfied by the present invention. SUMMARY OF THE INVENTION It has now been discovered that, unlike the teachings of the art, it is possible and advantageous to administer transdermally androgens. While testosterone provides significant problems for transdermal applications, other androgens and in particular, 7α-methyl-19-nortestosterone ("MENT") can not only be administered transdermally, but can offer a great advantage. Therefore, the present invention relates to a transdermal dosage form. The transdermal dosage form may be an ointment, cream, gel, powder, transdermal patch, lotion, spray or the like. The dosage form is produced from an androgen that is not 5a-reducible provided in at least a therapeutically effective amount and is loaded into a pharmaceutically acceptable transdermal vehicle. The carrier may have an ointment base, gel base, cream base, lotion base, powder base. , spray base or a transdermal patch in which it is formulated in androgen In preferred aspects of the present invention, the androgen which is not 5a-reducible is an androgen 7a-mod? f? Particularly preferred embodiment of the present invention, a transdermal dosage form is provided which includes an amount of between about 0 to about 10 mg of MENT loaded in the transdermal vehicle. MENT is acceptable in an amount of from about 0-5 to about 90% by weight relative to the weight of the vehicle. In a particularly preferred embodiment the transdermal dosage form can include between about 0-5 and about 10mg of androgen., as previously discussed, for each day of application Therefore, if a patch is to be applied for a total of three days, for example it may contain between about 1 5 and about 30 mg of MENT The transdermal application of an androgen is ideal for, among other things, contraceptive and androgen replacement therapies. Transdermal systems are easy to use for the subject, increasing compliance. Transdermal systems can generally be produced inexpensively and in a number of different relevant formats, helping the attraction and level of access of these types of therapies. Although periodic monitoring by a doctor is still convenient, visits to the doctor are not necessary to ongoing therapy. As a non-invasive drug delivery technique, the risks of side effects are greatly reduced. In addition, the unprecedented control is given to the subject. However, it is not enough to propose only the transdermal application of androgens in general. It has been found that the transdermal administration of MENT provides significant advantages in terms of safety and efficacy in transdermal formats. It has been found that the flow, ie the amount of drug capable of penetrating a known surface area of the skin for a given time, for MENT can be as much as twice as much testosterone or depending more on the particular transdermal formulation. For a purely hypothetical example, if a transdermal patch is formulated to provide 1 mg of MENT to a subject per day and the patch outside of 2 5 cm by 2.5 cm, it could take as long as 48 hours, or even longer for the same amount of testosterone penetrate the same area of the skin. To obtain a comparable flow, two patches of 1 cm by 1 cm each containing 1 mg of testosterone may be necessary. Even ignoring the additional cost of the drug, it could cost at least twice as much to treat the subject with testosterone than if it were with MENT under these circumstances. In addition, the application of two patches or a larger patch is less convenient and less desirable, potentially reducing compliance. Only supplying the same amount of testosterone during the same time is not useful, given that testosterone is between 5 and 10 times less potent than MENT. Therefore, to obtain the same level of biological activity, that is to say to have the same bioavailability, it could take as much as 10 mg of testosterone to equal the therapeutic efficacy of 1 mg of MENT The provision of ten patches of 2 5 cm by 2 5 cm could therefore be necessary to provide the same potency as that obtained from a patch of 1 mg of MENT. Of course, due to the flow of testosterone, the ten patches will still require 48 hours to deliver their full dose. Therefore, to obtain the real bioequivalence, ie the same biologically effective dose at the same time would require 20 patches of 2 5 cm by 2 5 cm As a result, instead of a patch of 2 5 cm by 2 5 cm, a subject might have to cover an area of the skin of 2 7 cm by 10 16 cm Even this example is not completely representative The skin contains Several enzymes that can metabolize transdermally applied androgens The greater the area and time of administration, the greater the degree to which metabolic enzymes can work. Therefore, it could be more accurate to establish that at least about twenty patches of 2 5 cm by 2 5 cm would be necessary to provide comparable levels of testosterone for a comparable time. Furthermore, the situation could be worse. The use of Testosterone Patch may require a lot more time not only the use of testosterone patches would be inconvenient, but it would also be very difficult to apply a patch of 25 cm by 2.5 cm. In addition, since testosterone is 5a-reduced to DHT, if an attempt is made to equalize the efficacy of increased MENT, the administration of testosterone would only result in an increase in significant side effects such as, for example, over-stimulation of the prostate Testosterone, MENT and other androgens 7a-mod? f? They are also drugs based on powerful steroids and, to the extent possible, it is convenient to reduce the degree of exposure to such steroids. It has been found that MENT can be administered transdermally to provide resting blood levels that are sufficient for therapeutic purposes. that MENT allows the construction of supply vehicles that are cost effective, efficient and increase compliance Brief Description of the Drawings Figure 1 illustrates the "? n vivo" permeation of testosterone ("T") and MENT through the rat skin measured as a function of the concentration (microgram / mL) against the time for the gel described in Example 2 Figure 2 illustrates the steroid flow measured in mcrograms / cm / hours for MENT and T through the rat skin of the gel described in example 2 Figure 3 illustrates the permeation profile (flow) of MENT and T through the skin of rats for the gel formulation described in example 1 (A) (1) (KY jelly) Figure 4, illustrates the permeation profile (flow) of MENT and T through the rat skin of the gel described in example 1 (A) (2) (pharmaceutical value lubricant jelly) Figure 5 illustrates the permeation profile (flow) of MENT and T through the rat skin of a patch transdermal described in example 1 (B) Figure 6 illustrates the permeation profile (flow) of MENT and T through the rat skin of a cream formulation described in example 1 (C) (1) (base of cream A) Figure 7 illustrates the permeation profile (flow) of MENT and T through the rat skin of a cream formulation described in example 1 (C) (2) (cream base). B) Figure 8 illustrates the permeation profile (flow) of MENT and T of a cream formulation treated in Example 1 (C) (3). Figure 9 illustrates the permeation (flow) profile of MENT and T through the gel rat skin O described in example 1 (D). Figure 10 illustrates the permeation (flow) profile of MENT and T through the gel rat skin D described in example 1 (D). Figure 11 illustrates the permeation (flow) profile of MENT and T through the gel rat skin F described in example 1 (D). Figure 12 illustrates the permeation (flow) profile of MENT and T through the gel rat skin P described in example 1 (D). Figure 13 illustrates the permeation (flow) profile of MENT and T through the T-gel rat skin described in Example 1 (D). Figure 14 illustrates MENT blood levels after topical application to rabbit skin as a concentration function (ng / mL) versus time for gel formulation O at a dose of 0.4 mg MENT / 0.2 mL gel . Figure 15 illustrates MENT blood levels after topical application to rabbit skin as a concentration function (ng / mL) versus time for gel formulation O at a dose of 0.8 mg MENT / 0.4 mL gel Figure 16 illustrates MENT blood levels after topical application to rabbit skin measured as a concentration function in ng / mL versus time for gel formulation F at a dose of 0.4 mg / 02 mL gel Figure 17, illustrates MENT blood levels after topical application to rabbit skin measured as a concentration function in ng / mL versus time for gel formulation F at a dose of 0.8 mg / 0.4 mL gel. Figure 18 illustrates blood levels of MENT after topical application to rabbit skin measured at MENT concentration ng / mL versus time for formulation T at a dose of 0.4 mg / 02 mL gel Figure 19, illustrates levels MENT blood after topical application to rabbit skin measured at MENT concentration ng / mL versus time for formulation T at a dose of 08 mg / 04 mL gel Figure 20 illustrates the Brookfield viscosity of a formulation of MENT gel prepared according to examples 1 and 2 (Formulation T), using 3 different spindles. Figure 21 is a cross-sectional plan view of a transdermal patch according to the aspect of the present invention. Best Mode for Carrying Out the Invention A pharmaceutically acceptable transdermal vehicle is an ointment base, cream base, lotion base , balsam base, gel base, powder base or vehicle material used for the construction of a transdermal patch. The term may also include for example, physical materials such as gauze, cloth and the like. The term "dispersed" includes dissolved, distributed , emulsified, homogeneously mixed, suspended and the like The androgen used according to the present invention is an androgen that is not 5a-reducible. Testosterone is excluded by this definition since it is a androgen 5a-reducible and as such, can produce higher levels of adverse side effects than the equivalent potencies of other androgens as described Androgens that are not 5a-reducible include, without modified 7a androgen limitation Examples of these include 7a-alkyl androgens such as 7a-meth? L-14-dehydro-19-nor-testosterone (CDB-868B) 7a-met? l-17aß-prop? on? -lox? -D-homoestra-4,16-d? en-3-one (CBD 2322A) and 7a-met? l-19-nortestosterone (MENT) and their pharmaceutically acceptable salts. See Kumar et al., "The Biological Activity of 7a-Met? L-19-Nortest-osterone Is Not Amplified in Male Reproductive Tract as is That of Testosterone," Endocnnology, Vol 130 No. 6, pp. 3677-3683 (1992) Androgen more preferred is MENT its acetate, MENT Ac and related compounds. However it has been found that the MENT flux is generally higher than that of MENT Ac so that MENT is preferred for many transdermal techniques and transdermal devices described herein. androgens useful in the method of the invention are testosterone derivatives having a non-hydrogen substituent in the 6a or 7a position As used in The application for the term testosterone derivatives encompasses compounds that have the basic structure of four testosterone rings, optionally modified at positions 3, 5, 9, 11, 17 or 19 Examples of said compounds include 7-a-meth? testosterone, 7-a-met? l-11? -h id roxy testosterone, 7- a, 17-d? met? ltestosterone, 7-a-17-d? met? l-11? -h? drox? testosterone, 7-a, 17-d? met? l-19-nort these tea, 7 -a-17-d? met? l-11? -h? drox? -19-nortestosterone, 6-a-met? testosterone, 6-a-met? l-19-nort is tosté roña, 6-a- met? l-11? -h? drox? tes tost? ro? a, 6-a, 17-d? met? l? tes tost? roña, 6-a, 17-d? met? l-11? -hydroxy-testosterone, 6-a, 17-d? Met? L-19-nortestosterone, and 6-a, 17-d? Met? L-11? -h? Drox? -19-nortestosterone The 7a-methalo compounds for use in the invention can be prepared as described in the Patent of E U A No. 3,341,557 which is incorporated herein by reference. The synthesis of another compound identified herein has been described in the literature.

The transdermal dosage forms of the present invention will have application in a wide range of indications including, without limitation, androgen replacement therapy, contraception, primary hypogonadism, testicular failure, baldness, aging, loss of bone mass, muscle wasting and cachexia, BPH, and prostate cancer Therefore, the dose of androgen required can vary significantly. In addition, the potency, bioequivalence, and bioactivity of androgens useful for these indications can vary significantly. This can also have a dramatic effect on dosing. Other factors include the size, health and biochemistry of the subject also play a significant role in the dosage. The type of transdermal dosage form and the androgen used play an important role in the formulation, if not the actual dose that will be administered. It should be remembered that each microgram of drug formulated in the form The doses of the present invention are not necessarily made through the skin of a subject and in his circulatory system, therefore, in certain cases, it may be convenient to formulate with an excess of androgen to ensure that the amount is being supplied. correct drug through the skin in a bioavailable form Certain dosage forms are also limited in terms of size, solubility, flow, and drug capacity. These factors, plus the size of the dose you want and the time over which it will be administered. The dose may have an effect on the amount of androgen in the dosage form. Therefore it is necessary to distinguish between the dose, the amount that is actually bioavailable for a certain time and the amount used to formulate the dosage form. These amounts can be the same. However, the amount used to formulate the dosage form more often is in excess of the desired dose. In addition, unless otherwise indicated either specifically or by contexts, references of an amount of an androgen dose generally refer to the amount that is bioavailable for 24 hours. For example, a transdermal patch can be formulated with 2 milligrams of MENT. The flow of MENT coupled with the area of the patch can dictate that in 24 hours, only 1.25 milligrams are dispensed. And of those, only 1 milligram is bioavailable. That 1 milligram, is never present all at once. The total that is bioavailable during the course of 24 hours is 1 milligram. Therefore, this is the amount of MENT bioavailable. In this case, 1 milligram of MENT during 24 hours can provide blood levels by more than 1.0 nmol / L during the day. Generally, the amount of androgen that is bioavailable can be determined in vitro by the methods to determine the flow as described in the present or in vivo by the subject's actual blood tests using known methods. The amount of androgen administered transdermally can be adjusted on a subject-to-subject basis to provide optimal results. Using the above example, one might expect that a certain transdermal patch provides 1 milligram of MENT in bioavailable form to a subject for 24 hours. However, blood tests could indicate that a particular subject does not respond at this level. Alternatively, due to this subject's metabolic system, less than 1 milligram is actually bioavailable. Any situation could be directed to reformulate the patch to administer more androgen and / or expand the surface area of the patch to take up the need to supply a certain amount of androgen in the flow for that androgen from that dosage form. The amount of androgen delivered in bioavailable form will therefore generally vary from about 50 micrograms to as much as about 8 milligrams during the course of a 24-hour day. This may mean that significantly more androgen, ie 10 mg / day / dose, is formulated in a daily dosage form. Therefore, if a patch is to supply 1 mg of MENT in bioavailable form every day for 3 days before being replaced, but an excess of 1 mg / day in the patch will be necessary to obtain the desired amount in a bioavailable form, then the Patch could be formulated with 2 mg of MENT per day for each day of use for a total of 6 mg. More preferably, the amount of androgen that is bioavailable for 24 hours can vary from about 100 micrograms to about 2 milligrams and more preferably from about 400 to about 1600 micrograms. The term "therapeutically effective amount" is meant to mean the bioavailable amount of androgen that is sufficient to produce a desired response. Finally, while the dose and dosage will usually be treated in terms of administration for a time of 24 hours, this is not an Limitation A gel formulation may be able to provide a lot of androgen through the skin in a relatively few hours (1-4 hours). Peak serum levels could be achieved very quickly. While the dose is calculated to provide serum levels in above any minimum white amount, the therapeutic effect of the dose should be maintained. Similarly, a transdermal patch can be used for 2, 3 or 4 days, or even a week before being replaced. Transdermal dosage forms according to the present invention They can have any number of forms. These formulations can include powders, cosmetics, or Ointments, gels, creams lotions, balm and the like The androgen can be formulated in transdermal patches by mixing the androgen with a material that itself is adhesive or by adhering a non-adhesive drug containing deposit or vehicle to the skin of the subject using the backing material having adhesive on its surface facing the peripheral skin Hydrogen materials, which are adhesive or non-adhesive, can be used for this purpose. Drugs can also be formulated in adhesive or non-adhesive bandages. The topical dosage forms of the present invention are prepared with methods well known in the art and may contain other active ingredients (also referred to herein as the "androgen"). For example, androgen may be formulated into the preparation suitable for topical administration in a topical ointment, lotion, gel, cream, spray and / or powder. Ointments and creams, for example, can be formulated with an aqueous or oily base with the addition of suitable thickeners, gelling agents and / or emulsifiers. Therefore, said bases, for example, may include water and / or an oil such as petroleum, liquid paraffin or a vegetable oil such as peanut oil or castor oil. Thickening agents that can be used according to the nature of the base include mild paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols, wool grease, hydrogenated lanolin, beeswax, etc. The emulsifying agents may include, for example, PEG monostearate, lauryl sulfate, Tween 80, sodium deoxycholate, Brji 30, Myrj 45, etc. The lotions can be formulated with an aqueous and oily base and will generally also include one more of the following, namely, stabilizing agents, emulsifying agents, dispersing agents, suspending agents, thickening agents, coloring agents, perfumes and the like. Gels can be produce using well known techniques from conventional pharmaceutically acceptable gelling agents including, without limitation, modified celluloses such as methyl cellulose, hydroxy methyl cellulose, hydroxy propyl methyl cellulose, starch, modified starches, natural and synthetic gums including tragacanth, guar, acacia, carrageenan and the like, gelatin, sodium alginate, PVP, polyvinyl alcohol and CARBOPOL available from CRODA, Inc. of Edison, New Jersey Powders can be formed with the help of any suitable powder base, v gr, talc, lactose, starch, etc. The drops can be formulated with a water based or a non-aqueous base also comprising one or more dispersing agents, suspending agents, solubilizing agents, etc. The pharmaceutical compositions according to the invention may also include one or more preservatives or bactetastatic agents, v gr, methyl hydroxybenzoate, propyl hydroxybenzoate, colocresol , benzalkonium chloride, etc. The compositions according to the invention may also contain other active ingredients such as antimicrobial agents, particularly antibiotics. The proportion of androgen in the compositions according to this aspect of the invention, depends on the precise type of formulations that will be prepared but will vary from 05% to 90% by weight Rgo, for most types of preparations advantageously the proportion used will be within the range of 10 to 80% and more preferably 50 to 50% by weight The formulation of dosage forms according to the present invention can be as simple how to measure a suitable amount of a specific androgen and homogenously mix the androgen with a vehicle or base, such as a cream, lotion, gel, etc., as described above. In the context of a gel, the androgen can be introduced before gel formation or physically mixed with the gel uniformly. The androgen is also mixed with a known amount of, for example, a drug release adhesive before the adhesive is formulated into a patch and / or dried, entangled or the like, as discussed herein. However, androgen will often have to be solubilized in a solvent prior to formulation with the vehicle. The formulation of androgen in a solvent could allow the material to be mixed homogeneously with certain bases such as adhesive materials, creams and ointments. The use of a solvent may also assist emulsification and / or absorption in, for example, gauze patches used in an adhesive-style bandage. The solvents useful in formulating the transdermal dosage forms of the present invention are pharmaceutically acceptable non-toxic substances, preferably liquids. The solvent is preferably an alcohol including polyhydric alcohols or combination of polyhydric alcohols. The term "hydrophobic alcohol" means any organic polyalcohol and includes dipropylene glycol, propylene glycol, polyethylene glycol, ghuprene, 11-butylene glycol, hexylene glycerol, polyoxyethylene, polypropylene glycol, sorbitol, ethylene glycol, and the like. The polyhydric alcohols can include those having from 2 to 6 alcoholic hydroxyl groups. Other suitable solvents include fatty acids such as oleic acid, linoleic acid, capric acid and the like, as well as esters or fatty alcohols. Additional suitable solvents include other non-volatile, non-volatile solvents commonly used in dermal or transdermal compositions to dissolve similar compounds. Although the exact amount of the solvent used in these formulations depends on the nature of other components, and therefore can be stated in general terms, the ratio can vary from about 5 to about 70 weight percent based on total composition. Preferably the androgen is substantially dissolved in the solvent so that when mixed with the adhesive or other carrier materials, the androgen is dispersed and / or dissolved. The selection of the solvent for a single androgen or a combination of androgens in base form Free or in a salt or derivative form, depends in part on the androgen form. The solvents for the salt forms are usually polar organic solvents. The polar organic solvents are preferably polyhydric alcohols., as discussed earlier. Other different solvents include cyclic ketones such as 2-pyrrolidone; N- (2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1-dodecylazacycloheptan-2-one and other n-substituted alkyl-aza-cycloalkyl-2-ones (azones), dimethylformamide and dimethyl sulfoxide. Other suitable solvents for the free base form of the androgen are cell cover disorder compounds known to be useful in the topical pharmaceutical preparation, whose compounds are thought to aid in the penetration of the skin by the disorder of the lipid structure of the ciliary covers of the cornea extract. See Patent of E.U.A. No. 5,332,576, the text of which is incorporated herein by reference. Another form of transdermal doses particularly useful for administering androgens according to the present invention are transdermal patches. While there is an almost infinite variety of transdermal patches that can be used, there are many that share a number of common elements. For example, many useful patches in accordance with the present invention include an occlusive outer surface or reinforcement layer. The reinforcing layer is preferably a thin film or sheet. In many cases, because the area of the skin to which the device must be attached, the device and therefore the reinforcing layer has flesh color for cosmetic reasons. But this will not be the case. Preferably, there is a transparent polyester layer, which is occlusive with respect to the active agent or drug, which in this case includes at least one androgen, but may have various colors or include printed matter thereon. The reinforcing layer typically provides support and a protective covering for the patch device. The reinforcing layer is preferably made of a material or combination of materials that is substantially impermeable to the layer or layers containing the drug with which it may be in contact. , that is, the carrier layer of the drug and the androgen and possibly other active ingredients contained therein, the adhesives, etc. However, a main objective is to prevent infiltration of the active ingredient through the reinforcement layer of the device, if the reinforcement layer is coated on the surface in contact with the rest of the device with an adhesive layer which is impermeable to the active ingredient. This waterproof adhesive layer will realize this purpose even if the reinforcement layer is not totally impermeable to the active ingredient. Therefore, it is not necessary in all cases that the reinforcing layer is impermeable to the active ingredient, although in most cases it is normally and when it is not a layer that provides this barrier function, such as an adhesive layer. Impervious to the active ingredient will be located between the reinforcement layer and the vehicle layer. By substantially impervious, it is understood that the other components in contact with the reinforcing layer or components under consideration will not pass appreciably through said layer or component during the normal period of use and storage of the device. The actual material used for the reinforcement layer it will depend on the properties of the materials in contact with it. Some suitable materials include, for example, cellophane, cellulose acetate, ethyl cellulose, vinyl acetate-vinyl chloride copolymers plasticizers, ethylene-vinyl acetate copolymer, polyethylene terephthalate , nylon, polyethylene, polypropylene, polyvinyl chloride (v. g, SARAN), paper, cloth and aluminum foil. The material used is preferably impermeable to the active ingredient. The material forming this reinforcing layer may be flexible or non-flexible. Preferably, A flexible reinforcement layer is used to shape the shape of the body member to which it is attached. joins the device. Preferably, the material forming the reinforcing layer is a composite film or film. The mixed material can be a metallized (v gr, aluminized) film or a sheet material of two or more films or a combination thereof. For example, a polyethylene terephthalate sheet material or a polyethylene terephthalate / metallized polyethylene terephthalate / polyethylene sheet material can be used. Preferred polymers include polyethylene, polypropylene, polyethylene chloride, and polyethylene terephthalate. polyvinylidene (SARAN) The reinforcing layer can be attached to the vehicle layer containing androgen either directly, wherein the vehicle layer is adhesive to the skin and the reinforcing layer, or by an adhesive layer. When an adhesive layer is used, as previously treated, the adhesive layer may be impermeable to the active ingredient (androgen) to prevent androgen infiltration of the vehicle layer into the reinforcing layer, and shall be waterproof androgen when the layer Reinforcement is not. The adhesive layer and the reinforcing layer may extend peripherally beyond the vehicle layer around the entire periphery thereof so as to form an extended peripheral area of the reinforcing layer with the adhesive layer peripherally extending beyond the layer of the backing layer. vehicle coextensively with the extended peripheral area of the reinforcing layer. Therefore, another purpose of the adhesive layer may be to secure the device to the skin or mucosa. Any adhesive capable of providing adhesion to the reinforcement layer to the vehicle layer and / or the reinforcement layer to the skin will be suitable for use. Preferably, the adhesive layer is a pressure sensitive adhesive suitable for contact with the skin or mucosa, e.g., dermatologically acceptable. Waterproofing adhesives of active ingredient (androgen) are normally coated on the vehicle or reinforcement layer in liquid form. The liquid form of the adhesives is obtained either by dissolving or suspending the adhesive components in a liquid vehicle or emulsion or by heating a thermoplastic adhesive above its melting temperature. The adhesive layer is dried by evaporation of the liquid vehicle or emulsion or hardens by cooling the thermoplastic material below its melting temperature. The adhesives impermeable to the active ingredient are therefore defined to be impervious to the active ingredient when the adhesive layer is substantially dry or hardened Examples of suitable pressure sensitive adhesive materials for use in the present invention as the waterproof adhesive layer of active ingredient, include some natural rubber and synthetic rubber adhesives and interlaced laminated adhesives. Examples of suitable natural rubber adhesives include R-1072 from B. F. Grodich Co., No. 735 of C. L. Hathaway, and no. 5702 by Evans St. Clair. Examples of synthetic rubber adhesives include Jowatherem 270-00 and Jowatherem S-3202 from Jowat Corp. and 70-9416 from National Starch. Other suitable laminating adhesives include the Dow Corning laminating silicone adhesives and the 7900 series laminating adhesives from Lord Corporation Tycel. The most impervious adhesives to the most active ingredients are laminated laminate adhesives that are well known to those of ordinary skill in the art. When pressure-sensitive adhesives are used, as the thickness of the adhesive layer that binds the adhesive layer increases. reinforcement to the vehicle layer, the impermeability of the adhesive layer to the active ingredient is also increased. To provide impermeability of the active ingredient to the adhesive layer, the thickness of the adhesive layer impermeable to the active ingredient is the thickness that provides sufficient impermeability to the active ingredient (and if necessary, to the other components of the device with which it is in contact with the active ingredient). waterproof adhesive layer) so that the active ingredient is not separated from the device as explained above. Normally, to obtain the impermeability of the active ingredient, the impermeable adhesive layer that joins the layer of reinforcement to the vehicle layer will have a thickness between about 50.8 and about 127 μm and preferably will have a thickness of about 50.8 μM. The interlacing pressure sensitive adhesives provide even more impermeability to the adhesive layer to the active agents and improvers. By increasing the interlacing density to the adhesive layer, an even larger barrier is provided to activate the diffusion of the agent. The patches of the present invention may also include a permeable adhesive layer of active ingredient between the vehicle layer and the skin or mucosa of the subject., joining the device to it. Certain embodiments may use a plurality of said adhesive layer permeable to the active ingredient. For example, an adhesive layer permeable to the active ingredient can be used to fix a polymeric regime control layer to a support to a layer of androgen containing vehicle. The device is then fixed to the skin or mucosa of the subject by a second adhesive layer permeable to the active ingredient which is applied to the surface of the control polymer layer of regime opposite to the vehicle layer. At least the adhesive layer permeable to the active ingredient (androgen) attaching the device to the skin or mucosa of the subject is preferably dematologically acceptable. Each permeable adhesive layer of active ingredient is also preferably a pressure sensitive adhesive. Any of the well known dermatologically acceptable pressure sensitive adhesives, which allows the migration of the drug can then be used in the present invention. Some suitable permeates include acrylic or methacrylic resins such as polymers of alcohol esters of acrylic or methacrylic acids and alcohols such as n-butanol, isopentanol, 2-methanol, butanol. -met? l-butanol, 1-met? l-pentanol, 2-met? lpentanol, 3-met? lpentanol, 2-e t-l-butanol, isooctanol, n-decanol or n-dodecanol, alone or copolyaminated with ethylenically unsaturated monomers such as acrylic acid, methacrylic acid, acplamide, metacplamide, N-alkoxymethyl acplamide, N-alkoxymethyl metacplamide, Nt-butyl-acplamide , itaconic acid, vinyl acetate, maleric acid N-branched alkyl wherein the alkyl groups have 10-24 carbon atoms, glycol diacchates I or mixtures of these monomers, polyurethane elastomers, polymers of vi such as poly vindic alcohol, polyvinyl ethers, polyvinyl pyrrolidone and polyvinyl acetate, urea formaldehyde resins, phenol formaldehyde resins, resorcinol formaldehyde resins, cellulose derivatives such as ethyl cellulose methyl cellulose, nitrocellulose acetate butyrate cellulose and carboxymethylcellulose; and natural gums such as guar, acacia, pectin, starch, dextrin, gelatin, casein, etc. Other suitable pressure sensitive adhesives include polyisobutylene pressure sensitive adhesives, rubber pressure sensitive adhesives and silicone pressure sensitive adhesives. The adhesives can also form compounds with sticky and stabilizing agents as is well known in the art. The adhesives that are preferred for their active agent permeability include acrylic copolymer adhesives such as AS-351 HSX from Avery Chemical Company, preferably at a coating weight between 25 and 35 g / m2. This pressure sensitive adhesive is a crosslinkable polymer which provides a permanently tacky film having a total solids content of about 52%, Brookfield viscosity (LVT / Spindle No. 4/12 RPM @ 25 ° C) of about 15,000 to 25,000 cps a weight per gallon from approximately 3.78 liters to around 3.31 kg. It can also be diluted with hexane or toluene to a desired scale of solids and / or viscosity, particularly for use in conventional coating equipment. Other adhesives that may also be used for these purposes include an acrylic pressure sensitive adhesive sold by National Adhesives under the designation DUROTAK 80-1054. This adhesive has a solids content of 47.5%. a viscosity of 3,000 cps. and plasticity (Williams) of 2.9 mm. It is generally used with a solvent system that includes ethyl acetate, heptane, isopropyl alcohol and toluene. Another such adhesive is sold by Monsanto under the designation GELVA Multipolymer Emulsion 2484, and comprises a sensitive adhesive emulsion pressure aqueous acrylic stable having a content of 59% and a viscosity of 1.500 to 2.300 cps Examples of other adhesives acrylics include Gelva 788 and 733 from Monsanto, PS-41 CL -Hathaway, Vr-0833 from HB Fuller, Adcot 73A207A from Morton Chemical, Nos 80-2404, 80-1054, 72-9056 and 72-9399 from National Starch, We E-2015, E-2067 and E-1960 from Rohm & Haas, M-6112 from Uniroyal, Inc. and Daratak 74 L of WR Grace suitable rubber adhesives include Durotak of 36-6172 from National Starch and Morstik 118 from Morton Chemical An example of suitable adhesive is X7-4502 sihcón Dow Corning The layers of permeable adhesives of active ingredients preferably contain some of the active ingredients when the device is placed on the skin This provides a presence of initial active ingredient in the skin or mucosa and eliminates the absorption delay of the active ingredient or topical application, If so desired, the active ingredient is immediately available to the host. The presence of the initial active ingredient may be due to migration through the layer or layers of adhesive and, if present, to the regime control layer, or to an amount of the active ingredient mixed with the adhesive layer or layers permeable to the active ingredient or regime control layer during manufacture. thus while either or both of the androgen and / or permeation enhancer may be present in several laminated layers used, this may be the result of incorporating the ingredients into only one of the layers, followed by migration of the ingredients to other layers. It can also be observed that the materials that can be used for the creation of the permeable layers of the active ingredient. They can also be used as vehicle layers of adhesives for the androgen and any other drug or excipient that will be administered with the androgen. When used as a drug reservoir, the patch may also include one or more regimen control layers as discussed herein. The width (i.e., surface area) and thickness of the permeable adhesive layer for contact with the skin or mucosa is the width and thickness that provides sufficient permeability to the active agent or active agent enhancer and a suitable surface area to allow the regimen of desired dose to the skin or mucosa. These widths and thicknesses are conventional in the art and therefore need not be discussed in greater detail herein. The androgen carrier layers can be vehicle layers of monolithic polymeric active ingredients (androgen). Thus, in essence, these vehicle layers of monolithic active ingredients basically comprise a thermoplastic polymer matrix which is mixed with the androgen and another active agent, enhancer or excipient. The monolithic poremic vehicle carrier layers can be formed by mixing the androgen with a matrix polymer in a common solvent and then evaporating the solvent to form a plastic film. The vehicle layers of the present invention can also be formed by mixing a polymer of thermoplastic matrix with the active agent at an elevated temperature from which the polymer softens and melts, but below which in androgen it is negatively affected, at whose temperature the polymer melts and is a fluid. This has been termed as mixed by Fusion See, U.S. Patent No. 5,662,926 the text of which is incorporated herein by reference The androgen may also be included in both the vehicle layer and the regime control layer. Such modalities may include laminates that do not utilize an androgen enhancer. , as well as laminates that have an androgen enhancer in one or more of the vehicle layers, cap Regimen Control Polymer and Androgen Permeable Adhesive Layers The present invention also includes modalities in which androgen and orrogen aggregates are included in the layers in which they have not been melt blended, said layers may also be Non-polimepcas Instead said layers are prepared and assembled into the sheet material by conventional methods using prior art materials which are well known to those of ordinary skill in the art Laminates according to the present invention, however, at least they will include a vehicle layer of a thermoplastic matrix polymer mixed by fusion with an active agent, an active agent blocker, or both. In addition, the present invention further includes embodiments in which one or more vehicle layers or more than one regime control layer, or both, are present in any order, as long as a regime control polymer layer, if present, is present. present, it is placed between a layer of vehicle and the mucosal skin of the host. At least one vehicle layer is melt-blended with an active agent, active agent enhancer, or both, either the other layers may include an androgen, androgen enhancer, or both, or may be substantially free of an androgen or androgen enhancer The androgen or androgen enhancer can be mixed by fusion with the other layers or combined with the other layers by conventional methods the active agent and thermoplastic matrix polymer can be melt-mixed in an extruder and then formed into a layer of extrusion vehicle Coextrusion of several layers is also possible as is known in the art When the enhancer is to be mixed by fusion with the vehicle layer, the regime control polymer layer or the adhesive layer permeable to the active agent, The enhancer should be an active agent stabilizer stable to heat at the polymer's melting temperature. The polymer, the rate control polymer or the adhesive permeable to the active agent in which it is to be mixed by fusion. The thermoplastic matrix polymers suitable for the vehicle layer include the class of elastomeric resins which are polyether block amides commercially designed by the company. trademark PEBAX. Another class of suitable thermoplastic matrix polymers are thermoplastic polyurethanes. Of this class, polyether polyurethanes are preferred. These include such commercial polyurethane compositions as PELLETHANE from Dow Chemical Company, including their grade AE 2363-80 thereof, K. J. Quin'2 Q-THANE; ESTAÑE de B.F. Goodrich; TXIN dev Mobay Chemical Company; and others. Suitable thermoplastic matrix polymers also include various polyesters, such as copolymers of different cyclic polyesters including DuPont's HYTREL, including its grade 4056 thereof and LOMOD from General Electric, both of which are copolymers of polyether and polybutylene terephthalate prepolymers and poly-isobutylene terephthalate, respectively as well as PCCE from Eastman Chemical. Other suitable polymers include copolymers of methacrylic acid and ethylene acrylic, such as ethylene methacrylic acid having the trade designation NUCREL 699. Suitable adhesive carriers also include any of the non-toxic polymers, particularly those of the type used to carry drugs for transdermal delivery Including natural or synthetic elastomers, such as polyisobutene block copolymers, styrene, butadiene, styrene, isoprene, acrylics, urethanes, silicones, styrene butadiene copolymers, methyl acrylate copolymers, acrylic acid, polyacrylates and polysaccharides such as gum gum, tragacanth gum, pectin, guar gum, cellulose, and cellulose derivatives such as methyl cellulose, propyl cellulose, cellulose acetate and the like, together with other substances known for use in transdermal preparations capable of forming a solid colloid which can adhere to the skin om ucose, used alone or in combination with other suitable vehicles A particularly preferred vehicle is a bioadhesive for application to the dermis. The adhesive can be modified so that it adheres to the skin or mucosal tissue, depending on the intended application site. before, the preferred adhesives for application to the skin are bioadhesives. The term "adhesive" as used herein means a substance, inorganic or organic, natural or synthetic, which is capable of surface bonding to the intended application site. The term "bioadhesive" as used herein means an adhesive that binds preferably binds strongly to a living or freshly dead biological surface such as skin or mucosal tissue by hydration. In addition, to qualify as a bioadhesive, a substance may be capable of maintaining adhesion in humid or wet environments m vivo or vitro The adhesion strength can be measured by standard tests for measuring force, v gr, in dynes per square centimeter as described in U.S. Patent No. 4,615,697 Suitable bioadhesives include those prepared from optionally partially-polyacrylic acid polyacrylic acid polymers, including, but not limited to, polymers of polyacrylic acid lightly crosslinked with a polyalkenyl polyether such as those commercially available from BF Goodrich, Cmcinnati, Ohio, under the trademarks Carbopol 934, 934P, 940 and 941 Other suitable bioadhesives include natural or synthetic polysaccharides The term "pohsacápdo" as used in the present means a carbohydrate that is broken down by hydrolysis into two or more molecules of monosacapds or their derivatives. The pohsacapdos include cellulose derivatives such as methylcellulose, cellulose acetate, carboxymethyl cellulose, hydroxyethylcellulose and the like. Other suitable bioadhesives are pectin, a mixture of sulfated sucrose and hydro aluminum oxide, hydrophobic pohsacapdo gums such as natural plant exudates, including carayá gum, tragacanth coma In addition to the above ingredients, other additives selected from various pharmaceutically acceptable additives available to those skilled in the art will also be incorporated. These additives include binders, stabilizers, preservatives and pigments. The patch should be made of common adhesives in medicine and other common pharmacopoeial auxiliaries (without skin damage or potential skin damage properties). It should be possible for the patch to be loaded with ingredients. active at the highest possible level, without losing any of its adhesive strength in order to generate uniformly high blood levels for the longest possible time When using acrylic polymers, the acrylate polymer can be any desired homopolymer, copolymer or terpolymer comprising various acid derivatives acrylic. In said preferred embodiment, the acrylic acid polymer forms from about 2 to about 95% of the total weight in the total dermal composition and preferably from about 2 to about 90%. The amount of acrylic polymer depends on the amount and type of acrylic acid. drug used when incorporated into the medicament used The acrylic polymers of this invention are polymers of one or more monomers of acrylic acids and other copolymeable monomers. The acrylic polymers further comprise copolymers of alkyl acrylic and / or meta-platelets and / or copolymeable secondary monomers or monomers having functional groups. If the amount of each type added as a monomer is changed, the cohesive properties and the solution properties of the The resulting acrylic polymers can be changed In general, the acrylic polymer comprises at least 50% by weight of acrylic or monomer of alkyl acrylic, 0 to 20% of a functional monomer that can be copolymeated with acplate, and from 0 to 40% of another monomer Acrylic monomers that can be used with acrylic acid and methacrylic acid are listed below. Butyl metaplatter Hexyl acyl acetate, Hexyl metaplate Isooctyl acrylate, isooctyl metaplatode, 2-ethylhexyl acutate, metaplate of 2-ethylhexyl, decyl acyl, decyl metacplato, dodecyl acplate, dodecyl metaplat, tpdecyl acplate and tpdecyl metacplato The following monom Examples of functions which can be copolymeated with the abovementioned alkyl acplants or meta-plates can be used together with acrylic acid and methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acplamide, dimethylacplamide, acplon itplo, dimethylaminoethyl acrylate, dimethylaminoethyl meta-platelet, tert-butylaminoethyl acrylate, tert-butylaminoethyl metacrate, methoxyethyl acrylate and methoxyethyl metacrate See U.S. Patent No. 5,683,711, the text of which is incorporated herein by reference. Details and additional examples of adhesive acrylics which are suitable for the invention are described in Satas' Handbook of Pressure Sensitive Adhesive Technology "Acphc Adhesives", 2nd edition, pp. 396-456 (D Satas, Editor), Van Nostrand Reinhold, New York (1989) Adhesive acrylics are commercially available under the trade name Duro-Taki and include poly acp I ato adhesive Suitable pohsiloxanes include pressure sensitive silicone adhesives which are based on two main constituents, a polymer or adhesive and a tackifying resin. The polysiloxane adhesive is usually formulated by an interlacing agent for the adhesive normally a weight polydiorganosiloxane. high molecular weight and with the resin to provide a three-dimensional silicate structure via an appropriate organic solvent. The mixture of the resin to the polymer is the most important factor in modifying the physical properties of the polysiloxane adhesive. Sobieski et al., "Hcone Pressure Sensitive Adhesives," Handbook of Pressure Sensitive Adhesive Technology, 2nd edition, p. 508-517 (D. Satas, Editor), Van Nostrand Reinhold, New York (1989). While the purpose of the topical transdermal dosage forms of the present invention is the delivery of a selected group of androgens, other pharmaceutically active agents may also be administered. These may include psychoactive agents such as nicotine, caffeine, mesocarb, mefexamma, cannabinoles such as THC, and the like, sedatives such as diazepam, mepipdin, uldazepam, tibamate, metaclazepam, tetrabarbitol and the like, antidepressants such as amitriptyline, imipramine desipramine, nialamide, melitracen, tsocarboxazid and the like, anticonvulsants such as phenobarbitol, carbamazepine, methsuximide, 2-et? l-2-phenolmalonamide (PEMA), phenytoin and the like Analgesics, include narcotic analgesics such as codeine, morphine, analorphin, Demerol and the like, and analgesics such as acetaminophen, aspirin, alprazolam and the like antimicrobial agents such as sulconazoi, siccanin, silver sulfadiazine, benthiazide and the like tranquilizers such as meprobamate and the like, antineoplastic agents such as sulfosfamide, rufocromomycin and the like, and antibiotic agents such as tetracycline, penicillin, streptozine and the like The amount of these other non-androgenic active agents present in the transdermal patch and also in the creams, lotions, gels, ointments, powders, balsam and other transdermal formulations of the pre This invention is the amount sufficient to provide a pharmaceutically or physiologically effective dose regimen of the active agent to a subject in need thereof. This amount can be readily determined by those of ordinary skill in the art. The relative proportion of androgen and any other drug in the The dosage forms of the present invention will depend on a number of previously treated factors including the nature of the dosage form, the indication and duration of administration, the flow of androgen and the device, etc. However, generally at least about 0 5% by weight of the dosage form will be androgen according to the present invention More preferably, the amount of androgen will vary from about 10 to about 80% by weight, more preferably from about 50 to about 50% by weight. Weight The devices of the present invention will optionally include a polymetric layer of regime control What can be the adhesive layer permeable to the active ingredient? These flow regulation layers of adhesives or without adhesives can modify the rate at which the androgen is administered topically therefore the flow See, for example, US Patent Nos. 5,676,969 and 5,503,804 , the text of which is incorporated herein by reference. Polymers suitable for use as the regime control polymer layer are conventional in the art and need not be discussed in detail. Some preferred materials include, for example, polyethylene, polypropylene, ethylene vinyl acetate (EVA) copolymers, copoesters (v gr, HYTREL) and polyurethanes. The permeation rate of the active agent through the polymer layer of control regime it depends on factors such as androgen affinity for the polymer layer, androgen molecular size, polymeric structure of the carrier layer and the thickness of the layer. Therefore, the polymeric control material of appropriate regime and its thickness depends on the used androgen and the desired permeation regime The selection of the polymer layer and its thickness provides a means, if desired, to control the dose regimen to the skin or mucosa. An enhancer to promote the penetration of the androgen through the skin as well. It can be included in any of the vehicle layers, regimen control polymer layers or the adhesive layers to the active agent. e can be incorporated into these layers by solvent blends or by melt blending, that is, by the same processes used to incorporate the androgen into the vehicle layer or the regime control polymer layer. Suitable enhancers include those described in U.S. Patent No. 4,573,996, such as the following boosters with a sufficiently high boiling point, monovalent saturated and unsaturated, aliphatic and cycloaliphatic alcohols having from 6 to 12 carbon atoms such as cyclohexanol, lauryl alcohol and the like, aliphatic and cycloaliphatic hydrocarbons such as mineral oils, cycloaliphatic and aromatic aldehydes and cetanes such as cyclohexanone, N, N-di (lower alkyl) acetamides such as N, N-diethyl acetamide, N, N-dimethylacetamide, N- (2- h? drox? et? l) acetamido and the like, aliphatic and cycloaliphatic esters such as isopropyl mipstate and laupcidin, N, N-di (lower alkyl) sulfoxides such as decylmethyl sulfoxide, essential oils, aliphatic and cycloaliphatic nitrocarbons such as N-met? l-2-P? rrol? dona, Azona, Salicatos, polyalkylene glycol silicates, aliphatic acids such as oleteo acid and laupco acid, terpenes such as cineole, surface active agents such as I even I sulfate sodium, siloxanes such as hexamethylsiloxane, mixtures of the above materials and the like In a preferred embodiment, the device contains a protective liner attached to the device on the surfaces that will be adhered to the skin or The adhesive liner, namely, the permeable adhesive layer of the active agent if present, the peripheral adhesive layer. The protective liner can be formed of the same materials suitable for use in the reinforcing layer as discussed above. Such material preferably becomes removable or removable from the adhesive layers for example by conventional treatment with Teflon silicon or other suitable coating on the surface thereof Removal of the protective liner device can also be provided by mechanical treatment of the protective liner, e.g., by soaking the protective lining however , the protective liner, can comprise several layers, including paper or layers containing paper or laminates; thermoplastic apertures, such as extruded polyolefins, such as polyethylene; various polyester films; linings of metal sheets; other layers; including fabric layers, coated or laminated to various polymers, as well as extruded polyethylene, ethylene terephthalate, various polyamides and the like A particularly preferred embodiment of the protective liner of the present invention includes sheet material of an outer foil layer and a layer internal plastic, such as polyethylene or the like, which become releasable not only by means of a siliconized coating, but also includes a raised or rough surface The enhancement of this surface can be achieved by a number of conventional methods In general, the preparation of the relief surface formation can be achieved by the use of male-female tools, preferably increased by the application of heat. The main intention of this enhancement process is to roughen the surface or make it uneven so that less of all the surface is in physical contact with the corresponding adhesive layer The actual pattern of relief carried out may vary, and in some cases may involve the relief of vain contiguous areas of protective lining. Preferably, therefore, about 30% of the surface of the protective liner will be in relief. The particular design of the relief, such as the production of a granular texture or the like, is a choice within the parameters discussed above. The presence of the surface in relief on the inner surface of the protective lining, therefore, is extremely significant to prevent the protective liner from sticking or adheres to the adhesive layer or layers, which could cause the liner to not properly separate from the adhesive layer or layers when it is desired to use the device of the present invention. This ease of operation is an important element for marketing these devices. of a particular protective liner will also depend on the final requirements of the particulate device In question, including if desired for a transparent or opaque liner, etc. Therefore, it can be seen that although substantially all of the surface of the protective liner is in contact with the adhesive layer or layers, the seal provided to the layer or layers adhesives by the protective liner is "removable" or releasable, merely separating the edge of the protective liner At the same time, when this is done, the adhesive layer or layers for contact with the skin or mucosa remain in contact with the surface of the layer carrier and the peripherally extending reinforcement area, if present, because the adhesion coefficient between the adhesives and these layers face to face with the coefficient of adhesion between the adhesive layers and the coated surface of the protective liner. See generally US Patent No. 5,662,926 It is also possible to use a "bottom" layer which, if desired, should be flexible enough to generally follow the contour of the host area where the device will be applied. On the other hand, it should have sufficient strength and substance so as to serve as carrier of the active agent carrying members without wrinkling, etc. The actual material from which the lower layer can be produced can therefore include a variety of different materials. Some suitable materials for this layer include, for example, polyethylene, polypropylene, pohvinihdene cluride, polyethylene terephthalate, polyesters, polyamides and others, as well as laminates of two or more of these layers with any other or one or more of these layers with additional layers such as foil, paper, vain fabrics, etc., but in this case, preferably with the polymer layer on the inside, that is, in contact with and thus carrying the members carrying the active agent Therefore, in a preferred aspect of these embodiments of the invention, the lower layer is a laminar material of an outer metal layer and an inner layer of plastic, such as polyethylene or the like. The reinforcement layers of the members carrying the active agent are disposed on the lower layer by one of the sensitive adhesives. the acrylic, natural rubber or synthetic rubber pressure mentioned above The thickness of the adhesive layer is controlled in a conventional manner to ensure that the members carrying the active agent adhere preferentially to the skin or mucosa of the host on the lower layer. The different layers of the device of the present invention can be combined to form a sheet material by conventional methods in the art. However, the present invention includes a process of the invention for combining the active agent and a thermoplastic matrix polymer by melting of two components, as well as a process of the invention for combining the polymer layers together by extrusion, preferably coextrusion .

The active agent and thermoplastic matrix polymer can be melt blended using any method known in the art to mix polymers with additives. Essentially, the thermoplastic matrix polymer is melt-blended with the active agent at a temperature above the softening point of the polymer using any conventional melt mixing apparatus including extruders, satiners, kneaders, sigma spatula mixers such as mixers of type Brabender, Banbury type mixers and the like, preferably at a temperature between about 170 ° C and about 200 ° C. The active agent can also be melt-blended with the rate control polymer by the method described above. In addition, the active agent build-up can also be melt-blended with the thermoplastic matrix polymer or the rate control polymer by the method described above. The carrier layers for the devices of the present invention can be formed directly from the resulting mixture. or die cutting of the films formed therefrom. As such, the polymer blends of thermoplastic matrix and active agent of the present invention can be extruded, satined, compression molded, injection molded, thermally formed or otherwise Straight way, by conventional solvent-free methods well known to those of ordinary skill in the art Alternatively, the mixture of active agent and thermoplastic matrix polymer can first be formed by extrusion into pellets for storage, the pellets of which can subsequently be formed the carrier layer by any of the method The aforementioned forming structures The carrier layers of the present invention are preferably formed in extruders that are formed into compounds in which the active agent and the thermoplastic matrix polymer can be melt-blended and the resulting melt mixture extruded in the aforementioned pellets. before, or in a film from which the carrier layers can be formed, or within the current carrier layers. All the process is carried out without dissolving the polymer the active agent, or the active agent and the polymer mixture in a solvent for the polymer or active agent other than the optional compatible heat resistant liquid carrier The monolithic carrier layer, once formed, can be cut with die immediately and combined on a surface with the reinforcement layer Alternatively, the layers can be combined before cut into cubes The reinforcement layer is laminated to the carrier layer by an adhesive layer, or extruded Endo the reinforcement layer and the carrier layer together As will be readily understood by those skilled in the art, when the reinforcement layer and the carrier layer are extruded together without an adhesive layer impervious to the active agent, then it is critical that the reinforcement layer is formed from the impermeable material to the active agent The adhesive layer that provides a means for securing the device to the skin or mucosa for the host is applied to the carrier layer to the extruded peripheral area of the reinforcement layer, if present. If a layer of control polymer is set at the carrier layer, then any adhesive layer that will be attached to the carrier layer is applied to the regime control polymer layer in place. The adhesive layers can be applied either before or after the carrier layer and the reinforcement layer are applied. Laminate Joints Whenever mentioned herein, die cutting is carried out by processes well known in the laminate art. As noted above, certain embodiments include a polymembrane rate control layer attached to the carrier layer on the surface that will be applied to the skin or mucosa of the host This polymer layer adheres to the carrier layer by an adhesive layer permeable to the active agent, or this layer can also be extruded with the carrier layer alone or with the reinforcement layer. As will be well understood by those skilled in the art of forming polymers, layers of the same or different polymers are conventionally extruded together. Two or more of the carrier layer, reinforcement layer, regime control polymer layer, can be coextruded together in one step. When these layers are co-extruded, the only adhesive layer required will adhere to the regime control polymer layer and therefore the sheet material to the skin or mucosa of the host. Once the device is formed, it can be kept sealed in an airtight bag before use. The device of the present invention is used in the same way as devices that are conventional in the prior art. In most chaos, the releasable protective liner attached to the lateral surface of the skin of the adhesive layer or layers of the device by contact with the skin or mucosa of the host is removed and said surface of the adhesive layer or layers is applied. to the desired area of the skin or mucosa A transdermal patch can have a very simple construction As illustrated in Figure 21, a transdermal patch 10 can include a permeable, androgen-free reinforcing layer, occlusive 12 and a monolithic androgen permeable carrier 14 that contains the apdrogen 16. The carrier layer 14 can be fixed to the reinforcement layer 12 using a suitable adhesive layer 18. The adhesive layer 18 can also be used to releasably attach the patch 10 to the skin of a subject and in particular, a man. As described herein, other layers, not shown, may include regimen control layers, release release layers, and the like. The flow of a specific formulation can be determined using a modified Franz diffusion cell as discussed herein. First, the skin of female Sprague-Dawley rats (body weight 200-250g) can be obtained. The rats are anesthetized, the abdominal skin is shaved and then it is removed. Excess fat and connective tissues are removed. The skin (1.77cm2) is sandwiched between two chambers of a modified Franz diffusion cell, with the surface of the skin facing the upper chamber (donor) of the cell. A measured amount of an androgen-containing formulation is applied to the surface of the skin, so that the skin is completely covered. The lower chamber (recipient) is filled with sterile saline, which thoroughly bathes the lower surface of the rat's skin. The content of the receiving chamber is constantly stirred with a magnetic stirrer. The aliquots of the saline solution in the receiving chamber are removed at predetermined intervals and analyzed by HPLC. The saline remains in constant contact with the skin at all times. The Franz cell is kept at 37 ° C during the time of each test. EXAMPLES EXAMPLE 1 A system of Franz cells modified in vitro was used as described in Example 2 to study the permeability of testosterone and MENT of various forms of transdermal doses through rat skin. Several formulations of creams, gels and topical patches were tested. The concentration of testosterone and MENT in all gels and creams described herein was 2 mg per gram of gel or cream. The following formulations were tested: (A) Tested Commercial Gel Base Formulations (1) Jelly KY Lot: 28G787A Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ 08869 Tested Preparation: 10% Ethyl Alcohol added (Results are illustrated) in Figure 3) (2) Pharmaceutical Value Lubricant Jelly Distributors: Taro Pharmaceuticals, Hawthorne, NY 10532 Tested Preparation: 10% Ethyl Alcohol added (The results are illustrated in Figure 4) On each of these gel bases . 2 mg of MENT or testosterone were mixed per gram of base together with 10% ethyl alcohol by weight of the finished gel. These formulations were prepared by measuring an amount of the base material and mixing therein the appropriate amount of alcohol drugs until homogeneity was achieved.

(B) Transdermal patch. Transdermal patches containing either testosterone or MENT were formed from a silicone elastomer (NuSil R-2602, Nusil Silicone Technology, Carpentry, California 93013). The drug load was 25% (w / w). The drug was measured and mixed with an appropriate amount of the elastomer. Then a catalyst, stannous octoate was added, and the formulation was mixed. The material was then injected into three centimeter diameter molds and allowed to polymerize to form a monolithic carrier material. The discs adhered to a polyethylene impermeable reinforcement having an external metallic coating. Adhesion was provided using a medical grade silicone adhesive. The resulting patches contained no permeation enhancers or adhesives on the drug release surface. Said patches can be adhered to the skin of a subject by the use of a reinforcing layer having an extended flange which surrounds the vehicle containing the drug. The flange may have a suitable adhesive disposed on the contact surface of the skin, so that the resulting structure may resemble an adhesive bandage (The results are illustrated in Figure 5) (C) Cream Formulations Tested: (1) Cream Base A Commercial Lot 471. Medco Lab Inc, Sioux City, Iowa 51103 10% Ethyl Alcohol added (Results are illustrated in Figure 6) (2) Base B Commercial Acrylic Ointment B cream: 1305. Medco Lab. , Inc., Sioux City, Iowa 51103 10% Ethyl Alcohol added (The results are illustrated in Figure 7) (3) Formulation of CBR: Stearilic alcohol 24g White Petrolatum 20g Sodium Lauryl Sulfate 1g Mineral Oil 2g Propylene Glycol 12g Ethyl Acetate 4g Isopropyl Alcohol 5g Ethyl Alcohol 10g Water q.s. 100g (The results are illustrated in Figure 8) The cream base for the CBR Formulation was produced by mixing all the ingredients in a single reaction vessel using medium agitation. For the formulation of the therapeutic topical creams according to the present invention, each of the three cream bases were measured and the appropriate amount of drug was mixed therein for homogeneity.

(D) Formulations of Gel Formulation Component O D F P T (g) (g) (g) (g) (g) Methyl cellulose 1.0 1.0 0.2 0.2 Carbopol 0.3 0.3 0.8 1.0 0.8 Benzyl alcohol 0.9 0.9 0.9 0.9 0.9 Propylene glycol 35.0 25.0 25.0 23.0 23.0 Isopropyl alcohol 10.0 10.0 10.0 10.0 10.0 Ethanol 0 10.0 10.0 12.0 12.0 Water c.s. 100.0 100.0 100.0 100.0 100.0 Note: 1N Sodium Hydroxide was used to adjust the pH to 6.5-7.5. (The results of the gel formulation O are illustrated in Figure 9. For formulation D see Figure 10, for formulation F see Figure 11, for formulation P see Figure 12, for formulation T see Figure 13). These gels were produced as described according to Example 2 The results illustrated in Figures 3 to 13 indicate that in a cream base, MENT and testosterone were passed through the rat skin at similar regimens (Figure 8). Of course, a close examination of Figure 8 reveals that at most points of comparison, the MENT formulation provided a higher flow than the identical formulation including testosterone. In particular, the transdermal dosage forms according to the present invention preferably have, in general, a greater flow rate than the identical formulation using testosterone and this cream, as well as other formulations identified herein, demonstrate the same in the other formulations (1 patch, 2 creams and 7 gels) tested, MENT passed through the skin of the rat at considerably higher concentrations and flow regimes than those of testosterone (Figures 3 to 7 and 9 to 13) Also, in certain dosage forms , the flow of MENT was more than twice that of testosterone (See Figures 3, 4, 6, 7, 10, 11 and 12) Section II Studies m vivo The bioavailability of three transdermal MENT gel formulations (2 mg of MENT / g gel) (Formulations O, F and T) were studied in rabbits Three New Zealand white rabbits weighing 3 5-4 5 kg were used in each group Each animal was applied, 02g gel (04 mg MENT) or 04g gel (08 mg from MENT) to an area of 5x5cm or 10x10cm of shaved skin for three consecutive days On days 1 and 3 the blood samples were recovered at 0, 1, 2, 4 and 8 hours after the application of the gel. The serum levels of MENT were determined by radioimmunoassay TABLE 1 Bioavailability of MENT in Rabbits Formulation Dose Day Area under the curve (mg) (ng / hr / mL) O 0.4 1 3.4 3 3.8 0.8 1 12.5 3 10.4 0. 4 1 27.5 3 8.2 0.8 1 41.3 3 31.0 T 0.4 1 28.6 3 28.3 0.8 1 51.8 3 52.8 The results indicated that MENT in all formulations passed through the skin of the rabbit and gave measurable serum levels (Figures 14 to 19). The bioavailability of MENT also depended on the dose (Table 1). EXAMPLE 2 A topical gel containing MENT or testosterone ("T") was prepared. For each gram of prepared topical gel, the coition was as follows: 1. MENT (or T) 2 mg 2. Propylene glycol 230 mg 3. Ethyl alcohol 130 mg 4. Isopropyl alcohol 100 mg 5. Benzyl alcohol 9 mg 6. Carbopol 934 8 mg 7. Sodium Hydroxide IN 70 mg 8. Water 461 mg Total 1000 mg The gel (almost identical to the formulation T of Example 1) was produced by taking all the aqueous coents and mixing them under medium agitation in a vessel and all organic, non-aqueous materials and mixing them in a separate vessel. The organic mixture and the aqueous mixture were mixed using medium stirring provided by a spatula mixer. Of course, the electric discharge mixer or magnetic stirrer could also be used. The viscosity profile of the gel produced is illustrated in Figure 20. The spheroid permeation (in vitro) through the Rat Skin for each of these gel formulations was tested using two chambers of a modified Franz diffusion cell. as previously described The skin of female Sprague-Dawley rats (body weight of 200-250 g) that were used in these studies. The rats were anesthetized, the abdominal skin was shaved and excised. Excess fat and connective tissues were removed. The skin (1.77 cm2) was sandwiched between two chambers of a modified Franz diffusion cell, with the surface of the skin facing the upper chamber (donor) of the cell. Approximately 0.5 gm of gel (1 mg of steroid) was applied to the surface of the skin, so that the skin was completely covered with the gel. The lower chamber (recipient) was filled with 11.4 ml of sterile saline, which completely bathed the lower surface of the skin of the rat. The content of the receiving chamber was constantly stirred with a magnetic stirrer during the experiment. 200 μL aliquots of the saline were removed in the receiving chamber at 1 hour intervals for 4 hours; and it was analyzed by CLARA for MENT or T. The saline solution remained in constant contact with the skin at all times. The Franz cell was maintained at 37 ° C during the time of the test. Figure 1 illustrates the resulting penetration of MENT and T through the rat skin of these gel formulations. Figure 2 shows the steroid flow of the MENT and T gel formulations. Both Figures clearly show that MENT penetrates the skin at a faster rate than T, and that MENT flow was greater at each time studied. Industrial Applicability The present invention relates to medical and pharmaceutical industries and, in particular, to the preparation and use of various forms of transdermal doses, as well as dosage forms per se.

Claims (7)

1. CLAIMS 1. A transdermal dosage form comprising: an androgen that is not 5a-reducible in therapeutically effective amounts, dispersed within a pharmaceutically acceptable transdermal vehicle.
2. 2. The transdermal dosage form of claim 1, wherein the androgen which is not reducible is a modified androgen 7a modified.
3. 3. The transdermal dosage form of claim 2, wherein the modified androgen 7 is 7a-methyl-19-nortestosterone.
4. 4. The transdermal dosage form of claim 1, wherein the androgen is provided in an amount between about 0.5 to about 90% by weight of the dosage form.
5. 5. The transdermal dosage form of claim 4, wherein the androgen is provided in an amount between about 1.0 to about 80% by weight of the dosage form.
6. 6. The transdermal dosage form of claim 5, wherein the androgen is provided in an amount between about 5.0 to about 50% by weight of the dosage form.
7. 7. The transdermal dosage form of claim 1, wherein the dosage form has a flow greater than that exhibited by an equal amount of testosterone when administered through another form of identical transdermal dose. claim 1, wherein the transdermal pharmaceutically acceptable carrier is an ointment 9 The transdermal dosage form of claim 1, wherein the transdermal pharmaceutically acceptable carrier is a gel 10 The transdermal dosage form of claim 1, wherein the carrier The transdermal dosage form of claim 1, wherein the transdermal pharmaceutically acceptable carrier is a lotion, is a transdermal dosage form of claim 1, wherein the transdermal dose form of claim 1, wherein the transdermal pharmaceutically acceptable carrier is a powder. transdermal dosage form of claim 1, wherein The pharmaceutically acceptable transdermal vehicle is a spray 14 The transdermal dose form of claim 1, wherein the transdermal pharmaceutically acceptable carrier is a transdermal patch. A transdermal dose form comprising between about 0 5 and about 10 mg of 7a met L-19-nortestosterone per day of use dispersed in a pharmaceutically acceptable transdermal vehicle, said 7α-methyl-19-nortestosterone being present in an amount of about 0.5 to about 90% by weight relative to the weight of the transdermal vehicle pharmaceutically acceptable.