MXPA00002931A - Inhibition of crystallization in transdermal devices - Google Patents

Abstract

A steroid is used as an additive in manufacture of a transdermal drug delivery device, to act as a crystallization inhibitor inhibiting crystallization, during storage of the device, of an active drug in the form of a hormone which has a pharmaceutical or physiological effect in use of the device. The crystallization-inhibiting steroid is present in the device in an amount insufficient to provide significant pharmaceutical or physiological effect in use of the device.

Description

INHIBITION OF CRYSTALLIZATION IN TRANSDERMAL DEVICES FIELD OF THE INVENTION This invention relates to transdermal drug delivery devices and methods for constructing them. More particularly, this invention relates to the inhibition of crystal formation in a transdermal device such as the transdermal monolithic matrix system that releases a hormone at therapeutically effective rates.

BACKGROUND OF THE INVENTION The transdermal route for parenteral administration of drugs provides many advantages compared to other routes of administration, such as: slow and controlled release, avoiding first-pass liver metabolism (Stevenson et al., The Lancet, vol 336, ( 1990) pp. 265). Several patent publications describe transdermal administration devices for estradiol that are useful for the treatment of gynecological disorders such as climacteric discomfort and menstrual abnormalities.

REF. : 33093 For example, patent application US-A-5518734 discloses a device for the transdermal administration of estradiol or oestradiol and norethindrone acetate which includes an inhibitor of the enzymatic degradation of estradiol to estrone in the skin. Patent application EP-A-0328806 discloses an adhesive device containing a drug as a transdermal estrogen delivery system that does not contain any discrete polymeric permeable membrane that controls diffusion. International publication WO 90/06120 discloses the transdermal administration of estradiol using a solvent system comprising oleic acid, linear alcohol, lactate and, also, dipropylene glycol or N-methyl-2-pyrrolidone. This solvent system can be used to prepare a transdermal matrix adhesive device or a transdermal reservoir device. Patent application US-A-4814168 discloses a dermal composition suitable for use in the transdermal administration of drugs that allows a high drug loading. The dermal composition comprises a drug, a multi-polymer containing vinyl acetate and ethylene monomers, a natural or synthetic gum and a tackifying agent. International publication WO 89/07951 discloses a pressure sensitive adhesive material in the form of a sheet for the administration of estradiol through the skin comprising a pressure sensitive adhesive polymer, two or more ingredients that increase the permeation and estradiol. Patent application US-A-5352457 discloses a method of preparing a device for transdermal administration in which all or part of the active ingredient is present in a saturated or supersaturated solution. The protection of the endometrium from the unopposed effects of estradiol can be achieved through sequential treatment with norethisterone for two weeks of each 28-day cycle (Ettinger B. Obstetrics and Gynaecology vol 72, No 5 (supplement) 1988 pp. 12S , 31S, Whitehead et al., The Lancet, vol 335, 1990 pp. 310). Therefore, a transdermal patch of combination with estradiol / norethisterone is a very desirable article. There are several documents related to the monolithic transdermal systems of estradiol / norethindrone. For example, the aforementioned patent application US-A-5518734 discloses a monolithic device for the administration of estradiol by the transdermal route and the manufacturing process of said device, it also discloses that the system is sufficiently versatile to allow the incorporation of a progestin such as norethindrone acetate. US-A-5023084 patent application discloses a multi-compartment transdermal drug delivery system for the administration of norethindrone and estradiol. The system comprises a film layer of support, an adhesive layer in which an estrogen is dissolved or microdispersed and adhered to this layer, an adhesive layer in which a progestin is also dissolved or microdispersed. In monolithic transdermal systems, the hormones are dissolved in a pressure sensitive adhesive matrix. In order to deliver the desired therapeutic dose to the body, it is often necessary that the drug be in a supersaturated concentration. However, in this condition, the system is thermodynamically unstable and the supersaturated drug has a tendency to precipitate or crystallize (Ma et al., Poceed., Intern Symp. Control Reí. Bioact. Mater., 22 (1995)). Consequently, the control of the crystallization of drugs is of particular interest in transdermal systems. For example, Campbell et al. resorted to the method of heating above the melting point of a crystalline hydrate to prevent crystallization (US-A-4832953). Ma et al (Int. J. of Pharm. 142 (1996) pp. 115-119) found that the PVP added to the matrix acts as an effective inhibitor of crystallization for transdermal systems of norethindrone acetate. Also, DE-A-42107111 claims that cholesterol and SiO2 are crystallization inhibitors for the transdermal delivery system of 17-β-estradiol. Another document describing a crystal formation inhibitor is the international publication WO 95/18603 which holds that soluble PVP increases the solubility of a drug without adversely affecting the adhesiveness or the rate of drug release from the adhesive composition sensitive to the Pressure. Considerable development efforts have been made to design the process and equipment for the manufacture of a 7-day transdermal delivery patch that meets the daily therapeutic delivery rates required for 17-ß-estradiol and norethindrone acetate and for also demonstrate long-term satisfactory chemical and physical stability. In the development of transdermal administration systems, size is an important variable to consider. To release a therapeutically adequate dose having a suitable size, high concentrations of hormone are generally required. The concentration of drug in monolithic transdermal delivery systems can vary widely depending on the drug and the polymer used. To increase the flow of the active ingredient through the skin, high concentrations of dissolved active ingredient can be used, as shown in several patent publications. Failure to control the size and distribution of crystals can result in products whose appearance suggests that the manufacturing process through which they were prepared is not under control. In addition, the presence of crystals can lead to loss of adhesion and can cause skin irritation. In various coating matrices we have studied, the crystallization in the adhesive depends on the concentration of the hormone. As an example, we show in table 1 the results obtained after manufacturing the transdermal units with different hormone concentrations. Similar results have been obtained by Ma. Et al. (Proceed, Intern Symp. Control Relay Bioact Mater. 22 (1995) 712-713). The total concentration of drug significantly affects the growth of crystals. As the total drug concentration was increased, more crystal formation was observed.

TABLE 1 ND = Not Detected + = Less than 10 crystals in 16 cm2 ++ = Between 10 and 20 crystals in 16 cm2 +++ = More than 20 crystals in 16 cm2 Formulation of the matrix: Acrylic adhesive, tackifier, oleic acid, propylene glycol, antioxidants and hormones. The hormones in this table are norethindrone acetate (ANE) and 17-ß-Estradiol (E2). The total percentage of hormone is that of ANE plus E2, and is given here as % by weight in the liquid solution before coating. The manufacture of transdermal administration patches containing less than 3% of active drug has been carried out for approximately seven years without evidence of crystal formation, performing the process of drying the coating in both an infrared tunnel and an air tunnel Usually the original laminated film dried in a conventional air tunnel exhibited no crystals or, in some batches, showed a low degree of crystallization. However, when the laminate was introduced through a die-cutting machine for the formation of the individual transdermal delivery patches, crystallization began to occur around the edges of the cut with "pen-like" growth. In the attempt to develop patches of transdermal administration that involve higher concentrations of the drugs, we observe that the crystallization is different around the edges of the cut with respect to the center of the patch. In the first, the crystals are generally "feather-like" in shape and vary in size between 2 and 50 mm. However, in the center of the matrix, the crystals are less frequent, have a "cumulus" shape and their size does not exceed 100 μm. In our previous work we found that for the combination patches the crystallization did not depend only on the total hormone concentration but, particularly, on the estradiol concentration. (Stefano et al., Proc. Intern Symp. Control Reí. Bioact. Mater. 24 (1997), 703-704). Needham et al. reported (Journal of Pharm.Sci. 81, 10, (1992)) that during the development of a silicone rubber implant for the administration of 17-β-Estradiol, some batches thereof, prepared with certain batches of commercial estradiol , they inexplicably developed crystals on their surface after a few days of storage. The mentioned aus concluded that one or more unidentified impurities could have been related to the spontaneous growth of crystals on the surface of the implants.

BRIEF DESCRIPTION OF THE INVENTION It is an object of the present invention to prevent or reduce crystal formation in monolithic systems of transdermal administration while achieving the desired performance of the patch. It is another object of the present invention to prevent or reduce the formation of hormone crystals in transdermal administration systems of norethindrone-estradiol acetate combination. In contrast to the background described above, when the process developed by the present inventors was tested and found successful, obtaining transdermal devices without any crystal was totally unexpected. According to the invention, in one aspect, a method of preparing a transdermal delivery device is provided including the steps of preparing a mixture of an active drug component in a suitable amount to obtain a pharmaceutical or physiological effect when using the device and a material forming a matrix and, arranging said mixture on or on a support to then form a matrix containing said active drug component, said active drug component being an active hormone or a plurality of active hormones, the method by the step of mixing with at least one of said materials constituting the matrix and the aforementioned active drug component, a measured amount of a steroid, said measured amount having an effect of inhibiting the crystallization of said component of active drug when storing the finished device and being in an insufficient quantity to cause r a pharmacological or physiological effect when the device is used. According to the invention, in another aspect, a transdermal delivery device having a body of material and a support for it is provided, the body of the material containing an active drug component in an amount sufficient to cause a pharmaceutical effect or physiological when the device is used, said active drug component being an active hormone or a plurality of active drugs, said body of material further containing, as inhibitor of the crystallization of said active drug component, a steroid which is not a compound normally found as an impurity with said hormone or active hormones or which, in the case where this is a compound found as an impurity with said hormone or active hormones, is added in an amount greater than that normally found as impurity, said steroid being present in an insufficient amount to provide a pharmacological or physiological effect if when the device is used. The invention, more broadly, can be considered to consist of the use of a steroid as an additive in a manufacturing or storage process of a transdermal device in which the steroid acts as an inhibitor of crystallization by inhibiting crystallization, during the storage of the device, of a hormone that is present in the device to produce a pharmaceutical, physiological or therapeutic effect when using the device, said crystallization inhibiting steroid being present in the device in an amount insufficient to cause pharmacological or physiological effect when the device is used. The invention is generally applicable to transdermal delivery devices having an active drug in the form of a hormone to be released for its therapeutic effect (which will generally be referred to as the active drug hereafter), and is especially applicable in anti-cancer devices. adhesive matrix (monolithic) in which the active drug is distributed in a body of material which is an adhesive matrix that in use holds the device on the skin. This is also applicable to other transdermal delivery devices, such as those in which the active drug is sustained in a body of material acting as a reservoir which is not in contact with the skin and in which the active drug has a tendency to crystallization. The added steroid that was used in the present invention to inhibit crystallization may be one that is possibly present as an impurity in the active drug due to the process of manufacturing the drug or for any other reason. Presumably in the past, this impurity, when present, may have had an undetected effect of inhibiting the crystallization of the active drug. In this case the concentration of the steroid is increased by its addition according to the invention. Alternatively, the added impurity is one not found as an impurity with the active drug, being, for example, not chemically related. As a general rule, impurities in a drug used in a transdermal delivery device are at a low level, that is, at a concentration of less than 3% by weight of the drug. Generally, each impurity is in a concentration of less than 1% by weight of the drug and, frequently, it is much lower. In the present invention a steroid, which is an impurity possibly present in the active drug, is used as an inhibitor of crystallization, being present at a level higher than the level of impurity, preferably at a concentration of at least 1% in weight of the active drug, more preferably with a concentration of at least 3% by weight of the active drug. Considering the specific steroids added that were used in the examples of the invention given below, it is noteworthy that estriol, estrone and estradiol benzoate are not found as impurities in either testosterone or norethindrone acetate. Estriol, and estradiol benzoate are not normally identified as impurities in estradiol, while estrone is always at a level of less than 0.1% by weight in estradiol. The amount of the steroid inhibitor of the aggregated crystallization must be such that, in general, the steroid in the device has no physiological or pharmacological effect whatsoever or significant in the use of the device. This may be because its amount is so small, or because its effect, if any, is substantially nullified by that of the active drug, or because it is itself a compound that is degraded during the passage through the skin, or it is a degradation product of the active drug, for example, during the passage through the skin. It is desirable that the added steroid as an inhibitor of crystallization be selected in such a way that it has no pharmacological or physiological effect on the concentration used for one or more of the following reasons: its low intrinsic permeability through the skin in the system, its low permeation with a permeation enhancer, which is present in the device, its low permeation rate due to its low concentration in the device. Although intrinsically the steroid can, if it were to penetrate the skin in sufficient quantity, have a physiological or pharmaceutical action, in the devices of the present invention, due to factors such as its low intrinsic efficiency, its low concentration and the characteristics of the device; the level at which it can reach blood, if a quantity of it permeate, is not enough to provoke any response or any detectable or significant response in the organism. The amount of the added steroid must be chosen according to the particular transdermal system, and the amount of inhibition of crystallization can be found experimentally. The preferred range in our invention is between 0.05 and 1% by weight in the matrix containing the active drug (excluding the adhesive solvents), more preferably between 0.05 and 0.5%. In relation to the weight of the active drug or total weight of the active drugs in the device, the added steroid is preferably present in an amount in the range between 1 to 10% by weight, more preferably 3 to 10% by weight, as an example 4 to 10% by weight. The minimum amount of added steroid is the minimum that has any significant inhibition of crystallization and should be as low as 1/200 of the total amount of active drug but, as indicated, an amount greater than 1/100 is preferable.

Within the invention, the plurality of the aggregated steroids can be used together as inhibitors of crystallization. The ranges of the aggregated amounts of the crystallization inhibitor steroid are applied to a specific compound, or when more than one of these compounds is added, to each of the compounds. In more detail, we found that by adding a low amount of a steroid to the adhesive polymer matrix, we can control and prevent the formation of crystals of the active hormone (s). The addition of this type of compounds in a concentration still 100 times lower than that of the active drug can, in some cases, prevent the formation of crystals. The addition of these compounds can prevent crystal formation without adversely affecting transdermal permeation rates and, in a matrix device, can allow the adhesive matrix containing the drug to retain the necessary adhesiveness. The addition of a steroid to the adhesive polymer matrix can also allow a higher drug loading in the pressure sensitive adhesive composition. A small amount of the steroid hormone different from the saturated or supersaturated hormone is sufficient to prevent or control crystallization without affecting the overall performance of the patch. The exact amount of steroid to be added will depend on the system and can be determined experimentally by the skilled technicians. The maximum amount of crystallization inhibitor to be added is the amount that inhibits crystallization but has no or low biological activity and good toxicological safety behavior. In particularly preferred devices, the active drug to be administered transdermally is a hormone, such as an estrogen, a progestogen agent (progestin) or a combination thereof. Although this invention will be described with respect to specific examples related to the manture of the transdermal hormone delivery devices, it should be noted that the present invention is applicable to the manture of any transdermal delivery device in which the active drug is in a concentration of saturation or supersaturation. The addition of a small amount of a compound of similar structure but not the same as the structure of the drug prevents or controls the crystallization of the active drugs in the transdermal matrix delivery devices. As used herein, the term "hormone" and its equivalents "active drug" and "steroid hormone" are intended to have the broadest meaning including any therapeutic and / or pharmacological or physiological hormone, or mixture thereof, which is released to a living organism to produce the desired effect, usually beneficial. Examples of drugs that can be administered through the novel transdermal system of this invention include, but are not limited to: Estrogens including: Non-steroidal estrogens such as benzoestrol, broparaestrol, chlorotrianisine, dienestrol, diethylstilbestrol, diethylstilbestrol dipropionate, dimestrol, fosfestrol, hexoestrol, metalenestrile, and metestrol, steroid estrogens such as colpormon, conjugated estrogenic hormones, equilenin, equilin, estradiol, estriol, estrone, ethinylestradiol, estradiol benzoate, mestranol, moxestrol, mitatriendiol, quinestradiol, quinestrol. Progestins such as allystrenol, algestone, anagestone, chlormadinone acetate, delmadinone acetate, demegestone, desogestrel, dimetisterone, drospirenone, dydrogesterone, ethisterone, ethinodiol, flugestone acetate, gestodene, gestonorone caproate, 17-hydroxy-16-methylene- d-progesterone, 17-a-hydroprogesterone, linestrenol, medrogestone, medroxyprogesterone, megestrol acetate, melengestrol, norethindrone, norethindrone acetate, norethynodrel, norgesterone, norgestimate, norgestrel, norgestrienone, norvinisterone, pentagestrone, progesterone, promegestone, trengestone. Androgens such as boldenone, cloxotestosterona, fluoxymesterone, mestanolone, mesteronolona, 17-methyltestosterone, 17-a-methyltestosterone 3-cyclopentyl enol ether, norethandrolone, normetandrona, oxandrolone, oxymesterone, oxymetholone, prasterone, estanolona, stanozolol, testosterone, tiomesterona. Glucocorticoids such as 21-acetoxipregnenolone, aclometasone, amcinonid, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazole, deflazacort, desonide, deoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort , flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, butyl fluorocortin, fluocortolone, fluorometholone, fluperolone acetate, flupredinone acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocorthal, halcinonide, halobetasol propionate, halometasone, halopredone acetate , hydrocortisone, hydrocortisone, loteprednol etabonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, parametasone, prednicarbate, prednisolone, prednisolone-25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednilidene, rimexolone, tixocortol, triamc inolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide. The adhesive material can be selected from a wide variety of pressure sensitive adhesive materials such as silicones, gums, polyisobutylene and acrylic adhesives. Examples of acrylic adhesive can be used by this novel transdermal system of the present invention include but are not limited to: Acrylic adhesives polyacrylates type adhesives sold under the brand Duro-Tak 80-1194, 80-1196, 80-1197 , 2287, 2516, 2852, 387-2051, 387-2052, 387-2054, 387-2287, 387-2353, 387-2510, 387-2516, 387-2620, 387-2825, 387-2070, 87-2074 , 87-2097, 87-2100, 87-2154, 87-2194, 87-2196, 87-2852, and 87-2979 by National Starch and Chemical Corporation, Bridgewater, New Jersey, United States of America. Other suitable acrylic adhesives are those sold under the trademark Gelva - Multipolymer Solution GMS 737, 788, 263, 1151, 1159, 1430, 1753, 2450, 2465, 2480, 2495, 2497 and 2539 by Monsanto, St. Louis, MO United of America. Crosslinkers such as those sold under the name Resimene (Monsanto Chemical Co., ST Louis Mo.), titanium butoxide and aluminum acetyl acetonate can be added to the adhesive matrix. A permeation enhancer or a combination of permeation enhancers can be included in the adhesive matrix. These enhancers can be, but are not limited to: oleic acid, propylene glycol, ethyl oleate, oleyl alcohol, oleyl amide, Miglyol, myristate, isopropyl palmitate, isopropyl N, N-diethyl-m-toluamide. A reinforcing component (solid) may be employed and should be selected from polyterpene resins, rosins and modified as Pentalyn A and Pehtalyn H (Hercules Inc.) (a resin esterified with pentaerythritol rosin). They can also be used mixtures of materials suitable for the flexible substrate (film cellulose xanthate), Saran (film polyvinylidene chloride), polyvinyl chloride, polyethylene, polypropylene, polyurethane, polyesters such as polyethylene terephthalate including binary structures such as aluminum-polyethylene coatings, etc. For the take-off protective layer, any of the aforementioned coatings for the substrate can be used, preferably a polyester, such as polyethylene terphthalate, etc. coated with a silicone to prevent sticking to the adhesive. The packaging can be made either of the bubble or blister type, or of the envelope type. The packaging material must be impermeable to moisture. To add protection to moisture, a desiccant can be added to the container.

EXAMPLES The following specific examples are shown as examples of the invention but are not limiting.

General experimental details A) Preparation of the adhesive mixture A solid tackifying resin component is added with stirring to a multi-polymeric vinyl-acrylic adhesive solution diluted with ethanol, toluene, 31-34% by weight of ethyl acetate, at room temperature, by the period of time necessary to obtain a homogeneous mixture.

B) Preparation of the formula containing the active drug To the material prepared in step A) is added, with agitation, the active drug or the combination of active drugs, antioxidants, oleic acid and propylene glycol. When appropriate, the crystallization inhibitor is added. A clear solution is obtained and kept in a closed container to avoid evaporation of the solvent medium.

C) Preparation of the transdermal delivery system The solution prepared as described above is applied in the form of a conventional coating device on a take-off sheet (a polyester film with a layer of a silica gel). The solution is applied on the silicone surface. Then it is dried by infrared lamps or hot air circulation to obtain a final thickness layer of 80-110 μm. Then, this coated silicone polyester is laminated onto a second flexible sheet that forms the backing sheet in the finished device. The process ends with the cut to the final size, for example, by means of the punching of the multilaminate to give it the shape with the geometry and the appropriate size. When the packaging takes place, the final product is packed in a thermoformed PVC-aluminum bubble or blister system or in an aluminum envelope, which is heat sealed with a lacquered aluminum sheet. The container can contain a desiccant for water inside.

D) Supporting power / internal cohesiveness test The supporting power / internal cohesiveness test is the ability of pressure sensitive adhesive tapes to remain adhered when a load is applied parallel to the surface of the tape. This is a measure of the combined adhesive and cohesive strength of an adhesive (Council of pressure sensitive tapes "Test methods for pressure sensitive adhesive tapes", 1996). It is expressed as the time required for a given area of adhesive to peel off a vertical panel when a given weight is applied. In this work, 0.45 kg. of weight are applied to a strip of adhesive matrix attached to a steel panel. Since this "holding power" test is highly dependent on the area of adhesive that is in contact with the test panel, a strip of 3 cm2 of surface was used in all cases. A support holds the panel at 0o from the vertical, with the tape applied at an angle of 0o with the vertical, so that when the weight acts on the test object, no detachment forces are exerted on the tape. The internal cohesiveness test was carried out under ambient conditions (25 ± 2 ° C, 75% relative humidity). In all the following examples, the composition of the formula is expressed as a percentage by weight of the total content of the adhesive coating, i.e., excluding the solvents of the adhesive, but including materials such as propylene glycol and oleic acid.

EXAMPLE 1 Transdermal administration system of norethindrone acetate and estradiol In this example the quantities used were: Formula a Adhesive polymer 45.35% Taquificante 20% Norethindrone acetate 7.5% Estradiol. 1.5% Propylene glycol 15% Oleic acid 10% Antioxidants 0.55Í Estriol 0.1% Formula b Adhesive polymer 45.45% Taquificante 20% Norethindrone acetate 7.5% Estradiol 1.5% Propylene glycol 15% Oleic acid 10% Antioxidants 0.55% Results Observation of crystals of stored patches without container at 40 ° C, 75% relative humidity 30 days after the day of manufacture.

The above data clearly show that crystal formation in the transdermal patch of ANE-E2 can be prevented by the addition of a small amount of an estrogen (0.1% estriol in this example).

EXAMPLE 2 Transdermal administration system of norethindrone acetate and estradiol The composition is similar to that of Example 1, as follows: Formula a Adhesive polymer 45.35% Taquificante 20% Acetate of norethindrone 7.5% Estradiol 1.5% Propilenglicol 15% Oleic acid 10% Antioxidants 0.55% Estrone 0.1% Formula b Adhesive polymer 45.45% Taquificante 20% Norethindrone acetate 7.5% Estradiol 1.5% Propylene glycol 15% Oleic acid 10% Antioxidants 0.55% Results Observation of crystals of the stored patches without container at 40 ° C, 75% relative humidity 120 days after the day of manufacture.

The above data clearly show that the formation of crystals in the transdermal patch of ANE-E2 can be prevented by the addition of a small amount of an estrogen (estrone at 0.1% in this example).

EXAMPLE 3 Transdermal administration system of norethindrone acetate and estradiol In this example the quantities used were: Formula a Adhesive polymer 45.9% Taquificante 20% Norethindrone acetate 6.9% Estradiol 1.5% Propylene glycol 15% Oleic acid 10% Antioxidants 0.1% Norethindrone 0.6% Formula b Adhesive polymer 45.9% Taquificante 20% Norethindrone acetate 7.5% Estradiol 1.5% Propylene glycol 15% Oleic acid 10% Antioxidants 0.1% Results Observation of crystals of the patches stored in bubble or PVC-aluminum blisters without desiccant, at 40 ° C, 75% relative humidity one year after the day of manufacture.

Observation of crystals Formula a No crystals are detected Formula b Crystals grown in the form of a feather of approx. 15 mm The above data clearly show that crystal formation in the transdermal patch of ANE-E2 can be prevented by the addition of a small amount of a progestin (0.6% norethindrone in this example). It can be assumed that norethindrone has no pharmacological or physiological effect at this level, due to its low concentration and inherently low permeation compared to that of norethindrone acetate in this device.

EXAMPLE 4 Transdermal administration system of norethindrone acetate and estradiol In this example the quantities used were: Formula a Adhesive polymer 45.35% Taquificante 20% Acetate of norethindrone 7.5% Estradiol 1.5% Propilenglicol 15% Oleic acid 10% Antioxidants 0.55% Estradiol benzoate 0.1% Formula b Adhesive polymer 42.95% Taquificante 20% Norethindrone acetate 7.5% Estradiol. 1.5% Propylene glycol 15% Oleic acid 10% Antioxidants 0.55% PVP K30 2.5% Formula c Adhesive polymer 45.45% Taquificante 20% Norethindrone acetate 7.5% Estradiol 1.5% Propylene glycol 15% Oleic acid 10% Antioxidants 0.55% Si02 0.7% MgO 0.3% Results Observation of crystals of the patches stored in aluminum envelope with a desiccant for water, at 25 ° C, 60% relative humidity 60 days after the day of manufacture.

Observation of crystals Formula a No crystals are detected Formula b Crystals grown in the form of a feather of approx. 2 mm Formula c Crystals grown in the form of a feather of approx. 4 mm The above data clearly show that crystal formation in the transdermal patch of ANE-E2 can be prevented by the addition of a small amount of an estrogen (0.1% estradiol benzoate in this example). Under these experimental conditions, this estrogen proves to be a better crystallization inhibitor than PVP (a well-known crystallization inhibitor for pharmaceutical use) and that Si02 (as proposed in the patent application DE-A-4210711).

EXAMPLE 5 Transdermal estradiol administration system Two different concentrations of estradiol and their respective controls were evaluated in an acrylic adhesive.

Formula a Formula b Results Observation of crystals of the patches stored without packaging, at 40 ° C, 75% relative humidity.

Formula a (90 days after the day of manufacture) Formula b (45 days after the day of manufacture) The above data show that the formation of crystals in the transdermal patch containing only estradiol as an active hormone can be prevented by the addition of a small amount of an estrogen (estrone at 0.1% in this example). In addition, as was seen by Ma. Et al.

(Proceed, Intern Symp. Control Relay Bioact, Mater. 22 (1995) 712-713), the crystallization rate of the drug increased with increasing drug concentration by comparing the controls of formula a with the controls of the drug. formula b. However, the addition of 0.1% of estrone inhibited the crystallization of estradiol in both formulations.

EXAMPLE 6 Transdermal testosterone administration system In this example the quantities used were: Formula a Adhesive polymer 84.9% Testosterone 7.5% Permeation enhancer 7.5% Estrone 0.1% Formula b Adhesive polymer 85% Testosterone 7.5% Permeation intensifier 7.5% Results Observation of crystals of the patches stored unpacked, at 40 ° C, 75% relative humidity 15 days after the day of manufacture.

The above data clearly show that the formation of crystals in the transdermal testosterone patch can be prevented by the addition of a small amount of an estrogen (estrone at 0.1% in this example).

EXAMPLE 7 Transdermal administration system of norethindrone acetate and estradiol The composition is similar to that of Example 1: Formula a Adhesive polymer 60.35 Taquificante 20% Norethindrone acetate 7.5% Estradiol 1.5% Oleic acid 10% Antioxidants 0.55% Estrone 0.1% Formula b Adhesive polymer 60.45% Taquificante 20% Norethindrone acetate 7.5% Estradiol 1.5% Oleic acid 10% Antioxidants 0.55% Results Observation of crystals of the stored patches without container at 40 ° C, 75% relative humidity 90 days after the day of manufacture.

The above data clearly show that the formation of crystals in the transdermal patch of ANE-E2 can be prevented by the addition of a small amount of an estrogen (estrone at 0.1% in this example).

EXAMPLE 8 Effect of drug concentration Drug concentrations between 8.25% and 12% (weight by weight) of the total were evaluated. The size of the crystals was measured. The hormone contents were Formula at 8.25% total: ANE 7%, estradiol 1.25% Formula b 9% total: ANE 7.5%, estradiol 1.5% Formula c 10.5% total: ANE 8.75%, estradiol 1.75Í Formula d 12% total: ANE 10%, estradiol 2% Formula a Formula b Formula c Formula d As also shown in example 5, the crystallization rate of the drug increases as the total drug concentration increases. Figure 1 shows that estrone at 0.1% by weight was effective to totally inhibit crystallization to a total hormone concentration of 10.5%. Up to a total drug concentration value of 10.5%, with 0.1% estrone, no drug crystals were detected microscopically during one month of storage without a container and under accelerated crystallization conditions (40 ° C, 75% relative humidity). At a concentration of 12% total drug, with 0.1% estrone, the growth rate and the number of crystals was significantly lower than for controls without estrone.

EXAMPLE 9 This example shows that the patches to which the crystallization inhibitor has been added show similar results in the internal cohesiveness test. The devices contain 7.5% ANE and 1.5% estradiol as active drugs. The formulations were EXAMPLE 10 Transdermal administration system of norethindrone acetate and estradiol The composition is again similar to that of Example 1 Formula a Adhesive polymer 45.35% Taquificante 20% Norethindrone acetate 7.5% Estradiol 1.5% Propylene glycol 15% Oleic acid 10% Antioxidants 0.55% Hydrocortisone acetate 0.1% Formula b Adhesive polymer 45.45% Taquificante 20% Norethindrone acetate 7.5% Estradiol 1.5% Propylene glycol 15% Oleic acid 10% Antioxidants 0.55% Results Observation of crystals of stored patches without container at 40 ° C, 75% relative humidity 30 days after the day of manufacture.

The above data clearly show that crystal formation in the transdermal patch of ANE-E2 can be prevented by the addition of a small amount of a hormone (0.1% cortisone acetate in this example).

EXAMPLE 11 Transdermal administration system of norethindrone acetate and estradiol (prepared with purified estradiol) The composition is as follows: In the formula the estradiol used corresponds to a commercial lot of Schering AG without further purification. In formula b the same estradiol was purified by recrystallization.

Formula a Adhesive polymer 45.45 'Taquificante 20% Norethindrone acetate 7.5% Propilenglicol 15% Estradiol 1.5% Oleic acid 10% Antioxidants 0.55% Shering AG reported that the main impurities in the estradiol it provides are: 9-estradiol: n.d. (not detectable) - 0.05% Estrona: n.d. - 0.05% 4-methyl estradiol: 0.24 - 0.48% Formula b Adhesive polymer 45.45% Taquificante 20% Norethindrone acetate 7.5% Propylene glycol 15% Estradiol 1.5% Oleic acid 10% Antioxidants 0.55% Results Figure 2 shows that the growth of crystals in the transdermal patch of ANE-E2 made with recrystallized estradiol was higher than that in which the non-recrystallized estradiol was used, or stored under ambient conditions without packaging. Since this commercial lot contained small amounts of other steroids as impurities, it can be concluded that the small amounts of these impurities present in the starting material have some retarding effect on crystal growth. The addition of more steroids, as proposed in the previous examples, more broadly stabilizes the matrix patch.

EXAMPLE 12 Effect of different adhesive polymers The use of four different commercial adhesive polymers was evaluated in a matrix containing estradiol as the active drug and estrone as an inhibitor of crystal growth. For each adhesive, two different storage conditions were evaluated.

General Formula Adhesive polymer 84.6% Taquificante 10% Antioxidants 1.6% Estradiol 3.5% Estrone 0.3% The characteristics of the different pressure sensitive adhesives (PSA) are: Results Observations of matrix crystals stored at 25 ° C, - 60% relative humidity with and without a moisture protector 180 days after the day of manufacture. For protection against moisture, the matrices were ensobradas in sealed aluminum envelopes and with a desiccant.

The above data show that none of the matrices observed, all of them formulated with a small amount of estrone, grew crystals larger than 1 mm or pen shaped. However, the use of different adhesives shows a different degree of inhibition of crystallization, the most effective being that which possesses -COOH / -OH as functional groups. The protection against humidity exalts the effect of the crystallization inhibitor used.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (29)

1. A method of preparing a transdermal delivery device, characterized in that it includes the steps of preparing the mixture of an active drug component in an amount sufficient to cause a pharmaceutical or physiological effect in the use of the device and the materials constituting the matrix, and arranging said mixture in or on a support to form a matrix containing said active drug component, said active drug component being an active hormone or a set of active hormones wherein the or each active hormone is in a state of saturation or supersaturation in said matrix on said support, the method being characterized by the mixing step of at least one of said materials constituting the matrix and said active principle with a measured amount of a steroid hormone, said measured amount having an inhibitory effect of the crystallization of said active drug component to the store the finished device and being in an insufficient amount to cause a significant pharmacological or physiological effect when the device is used.

2. A method according to claim 1, characterized in that said material constituting the matrix is an adhesive.

3. A method according to claim 1 or 2, characterized in that it includes the steps of forming a solution of said active drug component and said material forming the matrix in at least one solvent, adding said measured amount of said steroid to said solution , applying said solution to a support sheet and at least partially removing said solvent or solvents.

4. A method according to any of claims 1 to 3, characterized in that the or each of said active drugs is an estrogen, a progestin, an androgen or a glucocorticoid.

5. A method according to any of claims 1 to 4, characterized in that a set of said active hormones is included in said active drug component.

6. A method according to any of claims 1 to 5, characterized in that said steroid hormone that acts as an inhibitor of crystallization is an estrogen, a progestogen, an androgen or a glucocorticoid.

7. A method according to claim 6, characterized in that the steroid hormone that acts as an inhibitor of crystallization is estrone, estriol, estradiol benzoate, norethisterone or hydrocortisone acetate.

8. A method according to claim 7, characterized in that said active principle is estradiol and the steroid hormone that acts as an inhibitor of crystallization is estrone.

9. A method according to claim 7, characterized in that said active drug component comprises norethindrone acetate and 17-β-estradiol and the steroid hormone that acts as an inhibitor of crystallization is estrone.

10. A method according to claim 7, characterized in that said active drug component is testosterone and the steroid hormone that acts as an inhibitor of crystallization is estrone.

11. A method according to any of claims 1 to 10, characterized in that said measured amount of said steroid hormone is such that, in said device, when ready to use, the amount of said steroid in said matrix is between 0.05 and 1% by weight of the total content excluding the solvents of the adhesive.

12. A method according to claim 11, characterized in that said quantity of said steroid hormone in said matrix is between 0.05 and 0.5% by weight of the total content excluding the solvents of the adhesive.

13. A method according to any of claims 1 to 12, characterized in that said measured amount of said steroid is such that when the device is ready for use, the amount present there is between 1 and 10% by weight relative to the total amount of said active hormone or said active hormones.

14. A method according to any of the preceding claims, characterized in that it includes the subsequent packing step of the delivery device in an air-tight package also containing a desiccant.

15. A transdermal delivery device characterized in that it is constituted by a body of material and a support therefor, the body of the material containing an active drug component in an amount sufficient to cause a pharmaceutical or physiological effect when the device is used, said active drug component an active hormone or a set of active hormones wherein the or each active hormone is in a state of saturation or supersaturation in said body of material, further containing this body of material, as an inhibitor of the crystallization of said component of active drug, a steroid hormone which is not a compound normally found as an impurity with said active hormone or active hormones, or which, in the case in which it is a compound found as impurity with said active hormone or active hormones, is present in an amount greater than that which normally exists as an impurity, or said steroid hormone present in an amount insufficient to cause any significant pharmacological or physiological effect when the device is used.

16. A transdermal delivery device according to claim 15, characterized in that it is contained in an air-tight package that also contains a desiccant.

17. A transdermal delivery device according to claim 15 or 16, characterized in that said body of material is a coated layer capable of being in contact with the skin when using the device.

18. A transdermal delivery device according to claim 17, characterized in that said body of matrix material comprises an adhesive.

19. A transdermal delivery device according to claims 15 to 18, characterized in that the or each active hormone is an estrogen, a progestin, an androgen or a glucocorticoid.

20. A transdermal administration device according to claims 15 to 19, characterized in that a set of active hormones is included in the body of material.

21. A transdermal delivery device according to any of claims 15 to 20, characterized in that said steroid hormone that acts as an inhibitor of crystallization is an estrogen, a progestogen, an androgen or a glucocorticoid.

22. A transdermal delivery device according to claim 21, characterized in that said steroid hormone, which acts as inhibitor of crystallization is estrone, estriol, estradiol benzoate, norethisterone or hydrocortisone acetate.

23. A transdermal delivery device according to claim 22, characterized in that said active ingredient- is estradiol and said steroid hormone that acts as an inhibitor of crystallization is estrone.

24. A transdermal delivery device according to claim 22, characterized in that the active drug component comprises norethindrone acetate and 17-β-estradiol and the steroid hormone that acts as an inhibitor of crystallization is estrone.

25. A transdermal delivery device according to claim 22, characterized in that said active drug component is testosterone and the steroid hormone that acts as an inhibitor of crystallization is estrone.

26. A transdermal administration device according to any of claims 15 to 25, characterized in that the amount of said steroid hormone in said device is between 0.05 and 1% by weight of the total content of said body of material excluding the solvents of the adhesive.

27. A transdermal delivery device according to claim 26, characterized in that said quantity of said steroid hormone in said device is between 0.05 and 0.5% by weight of the total content of said body of material excluding the solvents of the adhesive.

28. A transdermal delivery device according to any of claims 15 to 27, characterized in that the amount of said steroid hormone in said body of material is between 1 and 10% by weight relative to the total amount of said active hormone or said active hormones .

29. The use of a steroid hormone as an additive in the manufacturing or storage process of a transdermal device that acts as an inhibitor of crystallization by inhibiting the crystallization, during storage of the device, of an active hormone that is present in the device for the purpose of of having a pharmaceutical or physiological effect in the use of the device, wherein the active drug is in a state of saturation or supersaturation in said device, said steroid hormone being inhibitor of crystallization present in the device in an insufficient amount to cause a Pharmacological or physiological effect when using the device. : INHIBITION OF CRYSTALLIZATION IN TRANSDERMAL DEVICES SUMMARY OF THE INVENTION A steroid is used as an additive in the manufacture of a transdermal delivery device 5 drug, to act as an inhibitor of crystallization by inhibiting the crystallization, during storage of the device, of an active drug in the form of a hormone having a pharmaceutical or physiological effect when using the device. The steroid inhibitor of The crystallization is present in the device in an insufficient amount to cause a significant pharmacological or physiological effect when using the device.