MXPA00010742A - Adhesive microsphere drug delivery composition - Google Patents

Abstract

Transdermal drug delivery compositions comprising pressure sensitive adhesive microspheres that contain a softening agent and/or a drug. Typically the microspheres contain at least 10 wt.%of a softening agent. The drug and/or softening agent can be incorporated into the microspheres during or after their formation.

Description

COMPOSITION OF ADHESIVE MICROSPHERE DRUG SUPPLY DESCRIPTION OF THE INVENTION This invention relates to transdermal drug delivery compositions containing pressure sensitive adhesive microspheres containing a softening agent and / or a therapeutic agent. The invention additionally relates to an in-situ method of preparing pressure-sensitive adhesive microspheres containing a softening agent and / or a therapeutic agent. Inherently sticky pressure-sensitive adhesive microspheres are known in the art to be useful in reclosable pressure sensitive adhesive applications and there are numerous references that discuss the preparation and / or use of inherently tacky elastomeric polymer microspheres. The pressure sensitive adhesive microspheres may be solid or hollow and are generally crosslinked to such an extent that the nature of the particulate of the adhesive is maintained through processing and use. Typically, the pressure sensitive adhesive microspheres are prepared by suspension polymerization of one or more radically free polymerizable monomers in the presence of surfactants and / or suspension stabilizers. The choice of surfactants and / or suspension stabilizers and their specific combinations with the specific monomers can determine the determined suspension capacity, desired particle morphology, performance characteristics and the like. Various monomeric copolymerizable components have been added to the radically free polymerizable monomers, suspension stabilizers and / or surfactants to modify the adhesive properties of those polymerized suspension microspheres. For example, polar monomers containing nitrogen have been added to acid-free acrylic suspension polymerization blends to form adhesive microspheres containing multiple internal voids. Polar comonomers that do not have dissociable protons or low levels of dissociable protons, when used in conjunction with particular surfactants and combinations of polymeric stabilizers, can be added to the polymerizable suspension formulations to give adhesive microspheres that have enriched adhesive properties while maintaining their qualities repositionable and self-cleaning against a variety of surfaces. Polymeric and oligomeric additives copolymerizable or otherwise incorporated have been employed in suspension polymerization adhesive microspheres to alter the adhesive properties of the microsphere and other performance features. Hydrofolic oligomers and polymers have been included in suspension polymerizable adhesive microsphere formulations to provide improved microsphere stability and, in some formulations, water dispersibility. The water-insoluble psi-mers components have also been incorporated into the adhesive microspheres by the suspension polymerization of alkyl (meth) acrylate and other comonomers in the presence of such polymer components. This method of incorporation allows for the inclusion of the water insoluble polymer components in adhesive microspheres that can not typically be incorporated under standard free radical suspension polymerization conditions. Another advantage of this incorporation of water-insoluble polymer is to modify the physical and adhesive properties of the microspheres. Finally, crystalline polymers or crystallizable monomers have also been added during suspension polymerization to provide adhesive microspheres having thermally controllable shape memory. Drugs and other therapeutically active agents have been administered transdermally or percutaneously using a variety of methods and devices. A known method is incorporated into the drug in a continuous adhesive matrix, either alone or in combination with one or more excipients that enhance the delivery of the drug through the skin. Examples of such systems are found, for example, in Nelson et al., U.S. Patent 5,223,261 and U.S. Patent 5,494,680, Peterson. There have been some attempts in the prior art to develop transdermal drug delivery systems that utilize pressure sensitive adhesive particles instead of a continuous adhesive matrix. For example, JP 58-12255 discloses an adhesive tape or sheet made of acrylic polymer particles containing a drug such as a steroid. EP 793,972 discloses a transdermal drug delivery device containing finely powdered acrylic adhesive particles in combination with a drug. The transdermal drug delivery composition of the present invention comprises pressure sensitive adhesive microspheres comprising (a) at least 10% by weight of a softening agent incorporated within the microspheres and optionally comprising (b) a therapeutically effective amount of a drug The use of polymeric microspheres as described herein provides a high degree of flexibility in transdermal delivery drug delivery compositions. In particular, the transdermal drug delivery compositions of the invention can tolerate the inclusion of a relatively broad amount of a softening agent without undue loss of cohesive strength. This tolerance for softening agents or excipients allows one to achieve excellent drug delivery through the skin without immobilizing adhesive properties. The invention also provides a transdermal drug delivery device comprising a transdermal drug delivery composition comprised of pressure sensitive adhesive microspheres comprising (a) at least 10% by weight of a softening agent incorporated within the microspheres. and optionally comprises (b) a therapeutically effective amount of a drug disposed on a support. Another aspect of the invention provides a method of preparing a transdermal drug delivery composition comprising the steps of: a) forming an oil phase comprising one or more acrylic acid ester, methacrylic acid ester, or vinyl ester monomer alone or in any combination; an oil-soluble, non-reactive and / or drug softening agent; and an oil-soluble free radical initiator in an aqueous phase cosing an aqueous medium cosing at least one suspension stabilizer or surfactant and b) initiating the polymerization of the oil phase in the aqueous phase, thereby forming a composition of Adhesive microsphere transdermal drug supply. Unless indicated otherwise, all percentages by weight are based on the total weight of the transdermal drug delivery composition. The transdermal drug delivery composition of the invention can be formed by a "post-addition" method, wherein the polymerized microsphere component is mixed with the softening agent and / or drug under such conditions insofar as it causes the softening agent and / or drug are incorporated into the microsphere. This post-addition method of the preparation of the transdermal drug delivery composition of the invention coses the steps of: (a) providing a polymeric microsphere component; (b) mixing the polymeric microsphere component with a softening agent and / or a drug and, optionally, a solvent capable of dissolving the softening and / or druging agent and / or dilateing the polymeric microsphere component; and (c) remove the solvent. The polymeric microsphere component of the inventive compositions can be prepared by suspension, dispersion, direct emulsion and modified emulsion techniques. Preferably, the polymeric microsphere component is prepared according to the suspension polymerization methods described in, for example, U.S. Patent Nos. 3,691,140; 4,166,152; 4,495,318; 4,786,696; 4,988,467; 5,045,569; 5,508,313; and 5,571,617 and PCT Patent Applications. WO 96/01280; WO 97/46633; and WO 97/46634, the descriptions of which are incorporated herein by reference. The preferred polymeric microsphere components are cosed of acrylate or vinylester microspheres. In the preferred suspension polymerization methods, the acrylate or vinylester microspheres can typically be prepared by forming an oil phase cosed of (meth) acrylic acid ester and / or vinylester monomers, optionally also containing radically polymerizable polar comonomers free, and an oil-soluble free radical initiator in a water phase cosing an aqueous medium having at least one suspension or surfactant stabilizer. Depending on the types and amounts of monomers, comonomers, crosslinking agents, oligomeric or polymeric additives, stabilizers, surfactants, reaction conditions, and other composition and alternative process employed, these microspheres may be hollow (i.e. having at least one vacuum or internal cavity) or solid (that is, they do not have internal voids or cavities); water or dispersible solvent; light or highly reticulated; and processes in a range of diameters (from about 0.5 to about 300 microns) and polymeric morphologies. The (meth) acrylic acid ester monomers used in the acrylic microspheres are monofunctional unsaturated (meth) acrylate esters of non-tertiary alkyl alcohols. The alkyl groups of these alcohols preferably contain from 4 to 14 (more preferably 4 to 10) carbon atoms. Examples of the useful monomers include sec-butyl acrylate, n-butyl acrylate, isoamyl acrylate, 2-methylbutyl acrylate, 4-methyl-2-pentyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, acrylate. of isononyl, isodecyl methacrylate, isodecyl acrylate, dodecyl acrylate, tetradecyl acrylate, and mixtures thereof. Particularly preferred are n-butyl acrylate, sec-butyl acrylate, isoamyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, isononyl acrylate., isodecyl acrylate, and mixtures thereof. Of these, isooctyl acrylate and 2-ethylhexyl acrylate are most preferred. Vinylester monomers useful in providing the vinyl ester microspheres are unsaturated vinyl esters derived from linear or branched carboxylic acids having 1 to 14, preferably 7 to 12, carbon atoms (not counting the carbon atom of the carboxyl). Suitable vinyl ester monomers include vinylpropionate, vinylpelargonate, vinylhexanoate, vinylcaprate, vinyl 2-ethylhexanoate, vinyl octanoate, vinyl decacanoate, vinylurate, and mixtures thereof. Particularly preferred is vinylcaprate, vinyl 2-ethylhexanoate, vinillaurate; and mixtures thereof. Ester (meth) acrylate or other vinyl monomers which, like homopolymers, have higher vitreous transition temperatures of about -20 to 0 ° C, for example, ethyl acrylate, tert-butyl acrylate, isobornyl acrylate, methacrylate of butyl, vinyl acetate, acrylonitrile, mixtures thereof, and the like, may be used in conjunction with one or more of the (meth) acrylate and vinyl ester monomers provided that the glass transition temperature of the resulting microspheres is less than about -0 ° C. The acrylate or vinylester microspheres used in the present invention may further comprise a radically polymerizable polar comonomer, copolymerizable with the ester of (meth) acrylic acid or vinyl ester monomer. The radically polymerizable free polar comonomers can be added to improve or modify the cohesive strength, storage stability, and glass transition temperature of the microspheres. Preferably the polar monomer is present in an amount of not more than about 1 to about 20 parts by weight based on the total weight of the monomers. In addition to their copolymerizability with the ester of (meth) acrylic acid or vinylester monomer, the radically polymerizable free polar comonomers are monomers that are soluble in oil and water and include one of the following polar substituents: amide, nitrile, hydroxyl and acid groups carboxylic (including acid salts). Suitable classes of the polar monomers include monoolefinic monocarboxylic acids, monoolefinic dicarboxylic acids, salts thereof, acrylamides, N-substituted acrylamides, N-vinyl lactam, and mixtures thereof. Representative examples of these classes of useful polar monomers include acrylic acid, methacrylic acid, itaconic acid, crotonic acid, maleic acid, fumaric acid, sulfoethyl methacrylate, N-vinyl pyrrolidone, N-vinyl caprolactam, acrylamide, t-acrylamide. -butyl, dimethylamino ethyl acrylamide, N-octyl acryl amide, hydroxyethyl acrylate, and hydroxyethyl methacrylate. Ionic monomers such as sodium methacrylate, ammonium acrylate, sodium acrylate, trimethylamine p-vinyl benzimide, propionate betaine of N, N-dimethyl-N- (beta-methoxy-ethyl) ammonium, methacrylamide trimethylamine, methacrylamide 1,1-dimethyl-1- (2,3-dihydroxypropyl) amine, and mixtures thereof are also useful. Particularly preferred polar comonomers are acrylic acid, sodium acrylate, N-vinyl pyrrolidone, and mixtures thereof. The polymeric microspheres useful in the invention may also contain a multifunctional free radical polymerizable crosslinking agent. The crosslinking agents can achieve cohesive strength and solvent insolubility of the individual microspheres by crosslinking them internally. "Multifunctional" refers to crosslinking agents that possess two or more olefinically unsaturated polymerizable free radicals. Useful multifunctional crosslinking agents include esters of (meth) acrylic diols (eg, butanediol), triols (e.g., glycerol), and tetroles (e.g., pentaerythritol); Polymeric multifunctional (meth) acrylates (e.g., poly (ethylene oxide) diacrylate and poly (ethylene oxide) dimethacrylate); polyvinyl compounds (eg, substituted and unsubstituted divinylbenzene) difunctional urethane acrylates, and mixtures thereof When a crosslinking agent is employed, it is typically used at a level above about 0.15 weight percent equivalent. of about 0.15 weight percent equivalent, the microspheres tend to lose their pressure sensitive adhesive quality and eventually become non-sticky upon contact at room temperature.The sticky non-tacky microspheres are useful in this invention. The level of crosslinking affects particle dilatability, the high degree of crosslinking, the lower, the particle dilation.To ensure high particle expansion and achieve the desired rheological properties, low levels of crosslinking agents are desired. equivalent weight percent "of a given compound is defined as the number of equivalents of that compound divided by the total number of equivalent radically free polymerizable monomers in the total polymerizable composition. An equivalent is the number of grams divided by the equivalent weight. The equivalent weight is defined as the molecular weight divided by the number of polymerizable groups in the monomer. In the case of those monomers with only one polymerizable group, the equivalent weight is equal to the molecular weight. The cross-linking of the microspheres can also be controlled with the use of chain transfer agents. Useful chain transfer agents are those which are normally suitable for the free radical polymerization of acrylates. Chain transfer agents useful in the practice of the invention include, but are not limited to, carbon tetrabromide, n-dodecyl mercaptan, isooctyl thiol glycolate, and mixtures thereof. If used, the chain transfer agents are present in amounts of about 0.01 to about 1 weight percent of the total polymerizable composition. Useful oil-soluble free radical initiators are those which are normally suitable for the free radical polymerization of acrylate or vinylester monomers and which are oil soluble and have very low solubility in water, typically less than lg / lOOg of water at 20 ° C. Examples of such initiators include azo compounds, hydroperoxides, peroxides, and the like, and photoinitiators such as benzophenone, benzoin ethyl ether, 2, 2-dimethoxy-2-phenyl acetophenone. The initiator is generally used in an average amount from about 0.01 percent to about 10 percent by weight of the total polymerizable composition, preferably up to about 5 percent. The use of a substantially water-soluble polymerization initiator, such as those generally used in emulsion polymerizations, causes the formation of substantial amounts of latex. During the suspension polymerization, any significant formation of latex is undesirable due to the extremely small particle size. The surfactants will typically be present in the reaction mixture, preferably in an amount of not more than about 10 parts by weight per 100 parts by weight of the polymerizable monomer, more preferably not more than about 5 parts by weight, and more preferably in the range of 0.5 to 3 parts by weight per 100 parts by weight of the polymerizable monomer. Useful surfactants (also known as emulsifiers) include anionic, cationic, or non-ionic surfactants and include but are not limited to anionic surfactants, such as alkylaryl ether sulphates and sulfonates such as sodium alkylaryl ether sulfate, for example, Triton ™ X200, available from Rohm and Haas, alkylaryl polyether sulfates and sulfonates such as alkylaryl oxide (ethylene oxide) sulfates and sulfonates, preferably those having up to about four repeating units of ethyleneoxy, and alkyl sulfates and sulfonates such as sodium lauryl sulfate, ammonium lauryl sulfate, triethanolamine lauryl sulfate, and sodium hexadecyl sulfate, alkyl ether sulfates and sulfonates such as ammonium lauryl ether sulfate , and alkylpolyether sulfate and sulfonates such as poly (ethylene oxide) alkyl sulfates and sulfonates, preferably those having up to about four ethyleneoxy units. Alkyl sulfates, alkyl ether sulphates, and alkylaryl ether sulphates are preferred. Additional anionic surfactants may include, for example, alkylaryl sulfates and sulfonates, for example, sodium dodecylbenzene sulfate and sodium dodecylbenzene sulfonate, sodium and ammonium salts of alkyl sulfates, for example sodium lauryl sulfate, and lauryl sulfate. ammonium; nonionic surfactants, such as ethoxylated oleoyl alcohol and polyoxyethylene octylphenyl ether; and cationic surfactants, such as a mixture of alkyl dimethylbenzyl ammonium hydrochlorides wherein the alkyl chain contains from 10 to 18 carbon atoms. Amphoteric surfactants are also useful in the present invention and include for example sulfobetaines, N-alkylaminopropionic acid, and N-alkylbetaines. Optionally, a polymeric stabilizer can be used and if used is present in an amount of about 0.05 to about 3 parts by weight per 100 parts by weight of the microspheres, preferably about 0.1 to about 1.5 parts by weight per 100 parts by weight. weight of the microspheres. Advantageously, the presence of the stabilizer allows the use of relatively low amounts of surfactant while still obtaining the microspheres. Any polymeric stabilizer that effectively provides sufficient stabilization of the polymerized final droplets and prevents agglomeration within a suspension polymerization process useful in the present invention. And, polymeric stabilizers include polyacrylic acid salts greater than 5000 weight average molecular weight (e.g., ammonium, sodium, lithium and potassium salts), polyvinyl alcohol, modified carboxy polyacrylamides (e.g., Cyanamer ™ A- 370 of American Cyanamid), copolymers of acrylic acid and dimethylaminoethyl methacrylate and the like, the polymeric quaternary amines (eg, General Analine and Film's Gafquat ™ 755, a quaternized polyvinyl pyrrolidone copolymer, or "JR400" by Union Carbide, a quaternized cellulose amine substituted), cellulosics, and carbixo-modified cellulosics (e.g., Hercules' Natrosol CMC Type 7L, sodium carboxy methylcellulose). The microspheres tend to be spherical or pearl-shaped, although they can be more spheroidal. Typically, they have an average volume diameter of from about 0.5 to about 300 microns (more preferably, about 1 to about 100 microns) before dilation. The microspheres may be solid, hollow or a mixture thereof and are preferably elastomeric. As used herein, "elastomeric" materials mean amorphous or non-crystalline materials that can be shrunk and will rapidly retract to substantially their original dimensions in the release of force. The hollow microspheres contain one or more hollow spaces; that is, one or more spaces completely within the walls of a polymerized microsphere. Typically, the hollow portion is less than 100 microns in average diameter. The microsphere components comprise hollow microspheres that are preferably in some applications, such as the hollow spaces within the microspheres and the crosslinked microsphere matrix can be charged into the softening agent and / or drug. If the hollow microspheres are desired, they can be obtained, for example, by the "two-step" process as described in US Patent No. 4,968,562 or the "one step" process as described in US Patent No. 5,053,436, whose description is incorporated herein by reference. The solid microspheres can be prepared by suspension polymerization techniques using ionic or nonionic emulsifiers in an amount that is sufficient to generate the necessary particle and which is generally close to the critical micelle concentration. Each suspension polymerization method (if it produces hollow or solid microspheres) can be modified by the retention of the addition of all or some of the free radically polymerizable polar comonomers or other reactive components until after the polymerization of the oil phase (the ester of (meth) acrylic acid or vinyl ester monomer has been started., however, these components must be added to the polymerization mixture before 100% conversion of the (meth) acrylic acid ester or vinyl ester monomer. Similarly, a multifunctional free radical polymerizable crosslinking agent (if used) can be added at any time before 100% conversion to the polymer of the monomers of the microsphere composition. Preferably, the crosslinking agent is added before initiation occurs. Following the polymerization, a stable aqueous suspension of microspheres at room temperature is obtained. The suspension can have non-volatile solid contents from about 10 to about 60 percent by weight. The prolonged residence, the suspension is typically separated into two phases, a phase which is aqueous and essentially free of polymer and the other phase being an aqueous suspension of the polymeric microspheres, i.e., the phase rich in microspheres. The separation of the microsphere-rich phase provides an aqueous suspension having a non-volatile solid content. Alternatively, the microspheres can be isolated in the organic solvent to form a solvent dispersion if desired before mixing with the softening agent and / or drug. Once prepared, the microsphere component, either net, as an aqueous or co-suspension or a solvent dispersion, is mixed with a softening agent and / or drug. As used herein, the term "Therapeutically effective amount" means an amount effective to host the sufficient drug delivery composition to a subject that achieves a desired therapeutic result in the treatment of a condition.This amount will vary according to the type of drug used, the condition to be treated, the amount of time of the composition is allowed to remain in contact with the skin of the subject, and other factors known to those skilled in the art.However, the amount of the drug present in the transdermal drug delivery composition of the The invention will generally be from about 0.01 to 40% by weight, preferably about 0.5 to 10% by weight, based on the total weight of the composition.Any drug that is suitable for the transdermal delivery can be used in the delivery composition of the composition. transdermal drug of the invention Examples of useful drugs include, but are not limited to, anti-inflammatory, steroidal (eg, hydrocortisone, prednisolone, triamcinolone) and non-spheroidal drugs (eg, naproxen, piroxicam); bacteriostatic agents (for example, chlorhexidine, hexylresorcinol); antibacterials (for example, penicillins such as penicillin V, cephalosporins such as cephalexin, erythromycin, tetracycline, gentamicin, sulfathiazole, nitrofurantoin, and quinolones such as norfloxacin, flumequine, and ibafloxacin); of a single cell (e.g., metronidazole); antifungals (e.g., nystatin); coronary vasodilators (eg, nitroglycerin); calcium channel blockers (e.g., nifedipine, diltiazem); bronchodilators (eg, theophylline, pirbuterol, salmeterol, isoproterenol); enzyme inhibitors such as collagenase inhibitors, protease inhibitors, elastase inhibitors, lipoxygenase inhibitors (e.g., zileuton), and enzyme inhibitors that induce angiotensin (e.g., captopril, lisinopril); other antihypertensive agents (for example, propranolol); leukotriene antagonists; anti-ulcerative agents such as H2 antagonists; steroidal hormones (eg, progesterone, testosterone, estradiol); antivirals and / or immunomodulators (for example, 1-isobutyl-1H-imidazo [4, 5-c] quinolin-4-amine, 1- (2-hydroxy-2-methylpropyl) -lH-imidazo [4, 5-c] ] quinoline-4-amine, and other compounds described in U.S. Patent No. 4,689,338, incorporated herein by reference, acyclovir); local anesthetics (for example, benzocaine, propofol); cardiotonic (for example, digital, digoxin); antitussives (eg, codeine, dextromethorphan); antihistamines (for example, diphenhydramine, chlorpheniramine, terfenadine); narcotic analgesic (eg, morphine, fentanyl); peptide hormones (e.g., animal or human growth hormones, LHRH); sex hormones (eg, estrogens, testosterone, progestins such as levonorgestrol, norethindrone, gestodene); cardioactive products such as atriopeptides; protein products (eg, insulin); enzymes (e.g., anti-platelet enzymes, lysozyme, dextranase); a'ntinauseante (for example, scopolomina); anticonvulsants (eg, carbamazine); immunosuppressants (e.g., cyclosporin); psychotherapeutic (for example, diazepa); sedatives (e.g., phenobarbital); anticoagulants (eg, heparin); analgesic (for example, acetaminophen); antimigraine agents (e.g., ergotamine, melatonin, sumatripan); antiarrhythmic agents (e.g., flecainide); antimimetics (for example, metaclopromide, ondansetron); anticancer agents (e.g., methotrexate); neurological agents such as anxiolytic drugs; hemostats; anti-obesity agents; and the like, as well as pharmaceutically acceptable salts and esters thereof. Preferred drugs include testosterone, levonorgestrel, estradiol, and gestodene. Suitable softening agents (softeners) include certain pharmaceutically acceptable materials that have been used as skin penetration enhancers or solubilizers in transdermal drug delivery systems. Exemplary materials include C? -C3g fatty acids such as isostearic acid, octanoic acid, and oleic acid; the fatty alcohols of Cs-C36 such as oleyl alcohol and lauryl alcohol; lower alkyl esters of Cg-C36 fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate; di (lower) alkyl esters of Cβ-Ca diacid such as diisopropyl adipate; monoglycerides of C8-C36 fatty acids such as glyceryl monolaurate; polyethylene glycol ether tetrahydrofurfuryl alcohol; C6-C36 alkyl pyrrolidone carboxylates; polyethylene glycol; propylene glycol; 2- (2-ethoxyethoxy) ethanol; diethylene glycol onomethyl ether; N, -dimethyldodecylamine-N-oxide and combinations of the above. Alkylaryl polyethylene oxide ethers, polyethylene oxide monomethyl esters, and polyethylene oxide dimethyl ethers are also suitable, as are solubilizers such as glycerol and N-methylpyrrolidone. Terpenes are another useful class of softeners, including pinene, d-limonene, carene, terpineol, terpinen-4-ol, carveol, carvone, pulegone, piperitone, mentone, menthol, neomentol, thymol, camphor, borneol, citral, ionone, and cineole, alone or in any combination, of terpenes, terpineol, particularly α-terpineol, is preferred. Certain drug substances function as softeners and make it unnecessary to have the drug separated and the softening components. Softening drugs include nicotine, nitroglycerin, chlorpheniramine, nicotonic acid benzyl ester, orphenadrine, scopolamine, and valproic acid. If the softening drug is the only softening agent present, then it is present in an amount of at least 10% by weight based on the total weight of the transdermal drug delivery composition. If other softening agents are present in addition to the softening drug, then the total amount of the softener is at least 10% by weight. It is understood that any desired combination of softening agents and / or softening drugs can be used. Preferred softeners include glyceryl monolaurate, terpineol, lauryl alcohol, diisopropyl adipate, propylene glycol, isopropyl myristate, ethyl oleate, methyl laurate, 2- (2-ethoxyethoxy) ethanol, and oleyl alcohol. While many of the softeners listed in the foregoing are known to affect the penetration ratio of the skin, certain softeners affect the aspects of the different embodiment in addition to the penetration ratio of the skin. For example, they are useful in smoothing or increasing the tempering value and / or less than the otherwise not achieved vitreous transition temperature (and therefore no pressure-sensitive adhesive) polymers, which supply in a form suitable for the use as skin adhesives sensitive to pressure. While such softeners have been known to adversely affect the performance of a transdermal matrix, for example, softening it to the point of cohesive failure (where the substantial polymer residue is left on the skin after removing from a device containing the polymer from the skin) or by separating the continuous phase from the composition, the use of the microspheres according to the invention allows for the inclusion of relatively long amounts of softeners without giving rise to these adverse effects. The desired properties in a transdermal drug delivery composition are well known to those skilled in the art. For example, if it is necessary for the composition to remain in intimate contact with the skin to deliver the drug in a stable ratio. If it is desired for a composition to have cold flow small enough that it is stable to flow in storage and it is also preferred that it adhere to the skin and free of the skin cleanly. To achieve skin contact, cleanliness ratio, preferred levels of adhesion, and cold flow resistance, the amount and structure of the monomers in the polymeric microspheres, and the amount and structure of the softener are selected such that the composition has a tempering value (measured according to these methods set forth in detail in the foregoing) in the range of about 3 x 10 ~ 6 cm2 / dynes to about 1 x 10 ~ 3cm2 / dynes, preferably in the range of about 5 x 10 ~ 5cm2 / dynes to about 5 x 10 ~ cm2 / dynes, more preferably about 1 x 10_5cm2 / dynes to about 5 x 10_5cm2 / dynes. Contemplation values outside the broad range quoted before are sometimes obtained from compositions that are suitable for use as transdermal pressure sensitive adhesive drug delivery compositions. However, those compositions that have substantially lower temporization values will generally be relatively stiff and will have less optimal skin contact and skin adhesion. Those compositions have substantially high tempering values which will generally have less optimum cold flow and the strength of the residue decreases substantially when it is removed from the skin. The softener is present in less than % by weight, based on the total weight of the transdermal drug delivery composition, to provide improved drug delivery and maintain acceptable adhesive properties. Preferably, the softener is present in an amount of about 15 to about 50% by weight, and more preferably about 25 to about 50% by weight. The optional softener and drug are typically combined with a solvent and incorporated into the microsphere component of the composition in the manner described above. However, in suitable compositions they should also be prepared by separately incorporating the drug and the softener into microspheres, and then combining the drug mixtures and microspheres and softener / microspheres to obtain the final composition. Alternatively, the softener containing microspheres can be mixed with a drug and a conventional adhesive (ie without microspheres) to obtain the final composition. In another aspect of the invention, the transdermal drug delivery composition can be prepared by a modification of previously described suspension polymerization processes through the addition of all or any portion of the softening agent and / or drug to the suspension mixture. radically polymerizable free. To be useful in this method, the softening agent and drug, if one is used, must be sufficiently soluble in oil to be miscible in the oil phase of the suspension polymerization mixture and also not be reactive under free radical polymerization and other reactive conditions. By "non-reactive" it is meant that the softening agent or drug contains non-ethylenic unsaturation or other functionalities that may be co-reacted or otherwise interfere with the polymerization of the radically free reagent slurry mixture and / or that is not significantly degraded. the effectiveness of the softening agent or drug agent under the conditions of the reaction. The in-situ method of preparing the transdermal drug delivery composition of the present invention comprises the steps of: (a) forming an oil phase comprising acid (meth) acrylic and / or vinyl ester monomers and a non-reactive, oil and / or drug-soluble softening agent and an oil-soluble free radical initiator in an aqueous phase comprising an aqueous medium having at least one suspension stabilizer or surfactant; (b) initiating the polymerization of the oil phase in the aqueous phase; (c) optionally, adding the additional oil-soluble, non-reactive softening agent and / or drugs in the polymerizable transdermal adhesive microsphere drug delivery composition itself. The reinforcements used as substrates for the transdermal drug delivery device coated with the transdermal drug delivery composition of the present invention can be materials that are conventionally used as a backing band or can be of another flexible material that is substantially inert to the ingredients of the transdermal drug delivery composition. Such backings include, but are not limited to, those made from the materials selected from the group consisting of poly (propylene), poly (ethylene), poly (vinyl) chloride, polyester (e.g., poly (ethylene) terephthalate), such as those available under the designation mark of "Scotch" 3M 8050 film), polyamide films such as those available from DuPont Co., Wilmington, DE, under the trade designation "KAPTON", cellulose acetate, and ethyl cellulose. The backs can also be woven fabric formed from strands of synthetic or nature materials such as cotton, nylon, rayon, glass, or ceramic material, or they can also be non-woven fabric such as air-exposed fabrics of natural fibers or synthetic or mixtures of these. further, the backing can be formed of materials selected from the group consisting of, metallized polymeric film, metal and ceramic sheet material. Preferred materials include, but are not limited to, plastics such as polyethylene, polypropylene, polyesters, cellulose acetate, polyvinyl chloride, and poly (vinylidino) fluoride, as well as paper or other substrates covered or laminated with such plastics These papers covered with thermoplastic films are sometimes siliconized or otherwise treated to impart improved release characteristics. One or both sides of the backs or linings should have release characteristics. The devices of the invention may have a variety of configurations. The composition may be present as a single layer wherein the composition is made of microspheres containing softener and / or drug; a softener mixture containing microspheres and drug-containing microspheres; or softener containing microspheres mixed with a conventional drug and adhesive. It is also possible to use the compositions according to the invention in multiple layers. For example, a layer of softener containing microspheres can be laminated to a drug layer in a conventional adhesive or to the layer of the drug-containing microsphere. Such layers may be of uniform thickness or may have one or more gradients disposed. Other layers may be present, such as scrims, membranes and the like. All references to softener containing microspheres also include microspheres containing softener and drug. Typical coating methods that can be used to prepare adhesive articles according to the present invention include solvent coating and waterborne coatings and techniques commonly known to those skilled in the art. The objects and advantages of this invention are further illustrated by the following examples. The particular materials and amounts thereof cited in these examples as well as other conditions and details, should not be constructed to unduly limit this invention. All materials are commercially available except when established or otherwise made apparent. All parts and percentages used herein are by weight unless otherwise specified.

Contemplation Test Method The temporization values given in the following examples are obtained using a modified version of the Creep Compliance Procedure described in US Patent No. 4,737,559 (Keller). The release coating is removed from a sample of the material to be treated. The exposed surface is folded back on itself in the longitudinal direction to produce a "sandwich" configuration, ie, backing / adhesive / backing. The "sandwich" sample 1 is passed through a laminator, then two sample tests of the same area are cut using a rectangular side. A test sample focuses on the stationary plate of the deflection advance rehometer centered on the first sample on the stationary plate such that the hook faces and faces the front of the rehometer. The secondary test sample is centered on the top of the non-stationary, small plate attached to the axial orientation of at least the first sample. The long non-stationary plate is placed on the sample of the second test and the complete assembly is held in place. The end of the small non-stationary plate that is opposite the end with the hook is connected to a register chart. A rope is connected to the hook of the small non-stationary plate and extends over the front pulley of the rehometer. A weight (for example 500 g) is attached to the free end of the spring. The chart recorder starts and then at the same time the weight is released quickly so they hang freely. The weight is removed after exactly 3 minutes have elapsed. The placement is read from the chart recorder. The embodiment is then calculated using the equation: AX J = 2 hf where A is the area of a face of the test sample, h is the thickness of the adhesive mass (i.e., twice the thickness of the adhesive layer on the test sample), X is the placement and f is the life force to the mass attached to the cord. When A is expressed in cm2, h in cm, X in cm and / in dynes, the value of temporization is given in cm2 / dyne. In Vitro Skin Test Penetration Method The skin penetration data given in the following examples are observed using the following test method. A function cell is used with the mouse skin without hair. When a transdermal delivery device is evaluated, the released liner is removed from a patch of 2. 0 cm2 that is applied to the skin and pressed to cause uniform contact with the skin. The resulting skin sheet / patch is placed over the patch through the hole side of the lower portion of the diffusion cell. The diffusion cell is assembled and the lower portion is filled within 10 L of (32 ° C) hot so the receiving fluid is in contact with the skin. The receptor fluid is stirred using a magnetic stirrer. The sample port is covered except when used. The cell is then placed at a constant temperature (32 ± 2 ° C) and humidity (50 ± 10% relative humidity) chamber. The receptor fluid is agitated by means of a magnetic stirrer through the experiment to ensure a uniform sample and a reduced diffusion barrier on the dermal side of the skin. The entire volume of the receiving fluid is withdrawn at specific time intervals and immediately filled with fresh fluid. The extracted fluid is filtered through a 0.45 μM filter, then the drug content is analyzed using a high performance liquid chromatography. The cumulative amount of the drug penetrating the skin and the flow ratio are calculated. Drug Release Test Method The drug release data given in the following examples is obtained using the following test method. The drug-loaded microspheres are coated in a 2 mil (51 μM) polyester mixer, then the oven dries at 85 ° C (185 ° F) for 20 minutes and at 99 ° C (210 ° F) for 20 minutes. A patch (5 cm2) is cut from the dehumidified network. The patch is attached to the steel plate using a side adhesive tape such that the drug microsphere adhesive layer is exposed to the release medium. The steel plate is immersed in 30% aqueous release medium of ethyl alcohol. The medium is maintained at 32 ° C and is agitated by means of a magnetic stirrer at moderate speed (75 rpm) through the experiment. At specific time points, a 2 mL portion of the released medium is removed and immediately replaced with 2 mL of fresh medium. The extracted medium is filtered through a 0.22 μM filter to remove any particles then analyzed for drug content using high performance liquid chromatography. The cumulative amount of the drug released is calculated. Address Test Method The address values reported in the following examples were obtained using a Polyken Probe Tack Tester, Model 80-02-01 (Testing Machines, Inc., Amityville, NY). The established machine was as follows: speed: 0.5 c / second, dwell: 2 seconds; mode: peak. A stainless steel test tube was used. The result of the test is the reinforcement required to break the junction between the probe and the surface of the test sample. The force was measured in "address grams" EXAMPLE 1 A one liter reaction decrease bottle equipped with mechanical stirrer, condenser, and inlet-outlet lines for vacuum and argon was charged with 450 gs of deionized water and 6.0 gs of lauryl ammonium sulfate (Standpol, ™ A, available from Henkel AG). The reactor was then degassed filled with argon. The stirring was set at 400 rpm and the reactor was heated to 68 ° C. A mixture containing 141 g of isooctyl acrylate, 9 g of acrylic acid and 0.71 g of benzoyl peroxide (Lucidol-70, available from Elf Atochem) was prepared in a bottle. After the initiator was dissolved, the mixture was charged to the reactor at 68 ° C. The reactor temperature was then restored to 65 ° C for 22 hours. An argon purge was maintained during the polymerization. After 22 hours, the suspension was cooled to room temperature. The reactor was then emptied, the suspension was coagulated with cetyltrimethylammonium chloride and then collected. The resulting microspheres (94: 6 acrylic acid: isooctyl acrylate) had a hollow morphology and particle size of 45.5 μm. The microspheres were washed with isopropanol and redispersed in isopropanol before use. These microspheres were used to prepare an adhesive microsphere delivery system containing levonorgestrel and isopropyl myristate as follows. A solution of levonorgestrel in methanol was prepared by dissolving 0.0252 g of levonorgestrel in 1.0 g in methanol of isopropyl myristate (0.5549 g), SO g of microspheres (14.75 g of a dispersion in isopropanol to 33.9% solids) and 35.0 g were combined. of ethyl acetate and mixed on a shaking table for a minimum of 16 hours. About 25.15 g divided into the resulting mixture was combined with the levonorgestrel solution and mixed on a shaking table for a minimum of 16 hours. The resulting formulation was a blade coated with 27 mil (686 μm) of silicone release coating matrix space, the oven dried at 110 ° F (43 ° C) for 20 minutes. The resulting adhesive coating contained 1 percent levonorgestrel, 10 percent isopropyl myristate and 89 percent adhesive. The coating was uniform and microscopic examination showed that it was substantially free of drug crystals. The coated coating was laminated to a polyester backing. Examples 2-5 Using the general method of Example 1 and the same microsphere adhesive, a series of delivery systems was prepared in which the amount of isopropyl myristate varied. In all cases the adhesive coating contained 1 weight percent of levonorgestrel and the adhesive was hollow microspheres of 94: 6 IOA: AA. The weight percent of isopropyl myristate is shown in Tables 1 and 2 below. The address and temporization were determined by the delivery systems of Example 1-5 using the test methods described above. The results are shown in Table 1 below where each direction value is the average of 5 independent determinations and each value of temporization is the average of 3 independent determinations.

Penetration of levonorgestrel through the hairless mouse skin of the delivery systems of Examples 1-5 was determined using the test method described above. The receptor solution was 30% by weight of m-pyrol in water. Samples were refrigerated before containing the analysis with storage times of no more than two days. The results are shown in Table 2 below where each flow value is the average of 3 independent determinations. The value 0-24 hours is the average over the full 24 hours of the time period.

Example 6 A one-liter reaction decrease bottle equipped with a mechanical stirrer, condenser, and inlet-outlet lines for vacuum and argon was charged with 450 gs of deionized water and 6.0 gs of laurylammonium sulfate.

(Standpol, ™ A). The reactor was then degassed filled with argon. The stirring was set at 400 rpm and the reactor was heated to 68 ° C. A mixture containing 141 g of isooctyl acrylate, 9 g of acrylic acid and 0.71 g of benzoyl peroxide (Lucidol-70) was prepared in a flask. After the initiator was dissolved, the mixture was charged to the reactor at 68 ° C. The reactor temperature was then restored to 65 ° C for 22 hours. An argon purge was maintained during the polymerization. After 22 hours, the suspension was cooled to room temperature. The reactor was then emptied, the suspension was coagulated with cetyltrimethylammonium chloride and then collected. The resulting microspheres (94: 6 acrylic acid: isooctyl acrylate) had a hollow multi-space morphology and particle size of 64.4 μm. The microspheres were washed with isopropanol and redispersed in isopropanol before use. These microspheres were used to prepare an adhesive microsphere delivery system containing testosterone as follows. A solution of 4% testosterone was prepared by dissolving 0.977 g of testosterone with 23,445 g of microspheres (85.63 g of a dispersion in isopropanol at 27.38% solids) and Combine with 15.0 g of ethyl acetate. The resulting formulation was a blade coated with 27 mil (686 μm) of matrix space in a silicone release coating, the oven dried at 110 ° F (43 ° C) for 20 minutes. The resulting adhesive coating contained 4 percent levonorgestrel, 10 percent testosterone and 96 percent adhesive. The coating was uniform and microscopic examination showed that it was substantially free of drug crystals. The coated coating was laminated to a polyester backing. Example 7 A microsphere delivery system of adhesive containing testosterone and terpineol was prepared as follows. A solution in the presence of 15.2 p / p percent of testosterone in terpineol was prepared by dissolving 8.0261 g of testosterone in 44.9667 g of terpineol. A portion (0.598 g) of this solution was combined with 7.497 g of 4 p / p percent of a mixture of testosterone microsphere adhesive prepared in Example 6 and 21.6 g of ethyl acetate and then mixed on a shaking table for a minimum of 16 hours. The resulting formulation was a blade coated with 27 mil (686 μm) of silicone release coating matrix space then over a oven dried at 110 ° F (43 ° C) for 20 minutes. The resulting adhesive coating contained 6.45 percent by weight of testosterone, 20 percent by weight of terpineol and 73.55 percent by weight of adhesive. The coating was uniform and microscopic examination showed that it was substantially free of drug crystals. The coated coating was laminated to a polyester backing.

Examples 8-10 Using the general method of Example 7, a series of delivery systems in which the amount of testosterone and the amount of terpineol was prepared was varied. In all cases the microsphere adhesive prepared in Example 6 was used. The weight percent of testosterone and terpineol is shown in Table 3 below. The penetration of testosterone through the skin of the hairless mouse of the delivery systems of Examples 6-10 was determined using the test method described above. The receptor solution was 30% by weight of m-pyrol in water. The samples were refrigerated before containing the analysis with storage times of no more than two days. The results are shown in Table 3 below where each flow value is the average of 3 independent determinations. The value 0-24 hours is the average over the full 24 hours of the time period.

Example 11 A system for supplying microspheres of adhesive containing terpineol was prepared as follows. Terpineol microspheres of 10.0 g of 94:52 I0A: AA (2.50 g) i (36.52 g of a dispersion in isopropanol in 27. 38% solids, Example 6) and 26.52 g of ethyl acetate, then mixed on a shaking table for a minimum of 16 hours. The resulting formulation was a blade coated with 27 mil (686 μm) of silicone release coating matrix space then over a oven dried at 110 ° F (43 ° C) for 20 minutes. The resulting adhesive coating contained 20 percent by weight of terpineol and 80 percent by weight of adhesive. The coating was uniform. The coated coating was laminated to a polyester backing. Examples 12-14 Using the general method of Example 11, a series of delivery systems were prepared in which the amount of terpineol was varied. In all cases adhesive microspheres prepared in Example 6 were used. The weight percent of terpineol is shown in Table 4 below. The direction and temporization were determined by the delivery systems of Example 11-14 using the test methods described above. The results are shown in Table 4 in the following, where each direction value is the average of 5 independent determinations and each value of temporization is the average of 3 independent determinations.

Example 15 A one liter reaction decrease bottle equipped with a mechanical stirrer, condenser, and inlet-outlet lines for vacuum and argon was charged with 390 g of deionized water and 8.4 grams of lauplammonium sulfate (Standpol, ™ A). The reactor was then degassed filled with argon. The stirring was set at 425 rpm and the reactor was heated to 68 ° C. A mixture containing 210 g of isooctyl acrylate and 0.69 g of 2,2'-azobis (2-methylbutanonitrile) was prepared in a flask. After the initiator was dissolved, the mixture was charged to the reactor at 68 ° C. The reactor temperature was then restored to 60 ° C for 22 hours. An argon purge was maintained during the polymerization. After 22 hours, the suspension was cooled to room temperature. The reactor was then emptied, the suspension was coagulated with isopropanol and collected. The resulting microspheres had a hollow morphology and particle size of up to 50 μm. The microspheres were redispersed in 11/89 isopropanol / ethyl acetate before use. The microspheres were used to prepare an adhesive microsphere delivery system containing testosterone as follows. A solution of 4% w / w of testosterone in adhesive microspheres was prepared by combining 0.8358 g of testosterone with 20.0 g of the microspheres (181.88 g of a dispersion in isopropanol / ethyl acetate 11/89 p / w at 11% solids) after mixing on a fast-paced table for a minimum of 16 hours. A portion of the resulting formulation was a blade coated with 26 mil (660 μm) of matrix space in a flouropolymer release coating, over the oven dried at 110 ° F (43 ° C) for 20 minutes. The resulting adhesive coating contained 4 percent testosterone and 96 percent adhesive. The coating was uniform and microscopic examination showed that it was substantially free of drug crystals. The coated coating was laminated to a polyester support. The samples were stored in sealed laminated sheet polyester sachets. After a week of storage, microscopic examination showed that numerous crystals have formed. Example 16 A microsphere delivery system of adhesive containing testosterone and terpineol was prepared as follows. A stock solution of 14.02 w / w percent of testosterone in terpineol was prepared by combining 7,347.0261 g of testosterone with 41.64 g of terpineol, mixing. On a trepidating table for three days then it was filtered to remove the undissolved testosterone. The solutions prepared by this method have been tested by high performance liquid chromatography as a 1: 100 dilution in methanol and shown to contain 14.0 weight percent testosterone. A portion (0.35 g) of this solution was added with a portion (29.05 g) of the formulation prepared in Example 15. It was then mixed on a shaking table for a minimum of 16 hours. The resulting formulation of coating adhesive contained 4.8% by weight of testosterone, 8.2 percent by weight of terpineol and 87.0% by weight of adhesive. The coating was uniform and microscopic examination showed that it was substantially free of drug crystals. The coated coating was laminated to a polyester backing. Samples were stored in sealed laminated sheet polyester sachets. After a week of storage, microscopic examination showed that the numerous crystals had formed. Examples 17-19 Using the general method of Example 16 a series of delivery systems were prepared in which the amount of testosterone and the amount of terpineol was varied. In all cases the adhesive was hollow IOA microspheres. The weight percent of testosterone and terpineol is shown in Table 5 below. In all three examples the coating was uniform and microscopic examination showed that it was initially free of drug crystals.; but, after a week of storage, the microscopic examination showed that all the numerous crystals had been formed in the three examples. Example 20 Using the general method of Example 16, a delivery system containing 8.8 percent of testosterone, 42.3 of terpineol percent and 48.9 percent of IOA microspheres of adhesive was prepared. The coating was uniform and microscopic examination showed that the coating was substantially free of drug crystals initially and after storage for 5 weeks. The penetration of testosterone through the hairless mouse skin of the delivery systems of Examples 16-20 were used determining the test method described above. The penetration test was run in initial samples. The receptor solution was 30% by weight of m-pyrol in water. The samples were refrigerated before containing the analysis with storage time of no more than two days. The results are shown in Table 3 below, where each flow value is the average of 3 independent determinations. The value 0-24 hours is the average over the full 24 hours of the time period.

Example 21 A half-liter reaction decrease flask equipped with mechanical stirrer, condenser, and outlet-inlet lines for vacuum and argon was charged with 112.5 g of deionized water and 1.5 g of lauryl ammonium sulfate (Standpol ™ A). The reactor was then degassed filled with argon. The stirring was set at 300 rpm and the reactor was heated to 68 ° C. Isooctyl acrylate (36.75 g) and 0.75 g of β-estradiol-3-benzoate were then combined in a heated flask (approximately 50 ° C) until the drug completely dissolved in the monomer. Benzoyl peroxide (0.18 g of Lucidol-70) was added to the bottle. After the initiator was dissolved, the mixture was charged to the reactor at 68 ° C. The reactor temperature was then restored to 65 ° C for 22 hours. An argon purge was maintained during the polymerization. After 22 hours, the suspension was cooled to room temperature. The microspheres were stable in the aqueous phase. The reactor was then emptied and the suspension was filtered through cotton cloth to remove the agglomerates. Under optical microscopy, the resulting microspheres were found to be a mixture of several morphologies: multiple discrete space, hollow solid, and multiple chain space. The particle size was determined using Particle Image Analysis and was found to be 24.90 μm. A sample was cooled on a 2 mil (51 μM) polyester backing then dried in an oven at 85 ° C (185 ° F) for 20 minutes and at 99 ° C (210 ° F) for 20 minutes. The temporization was measured using the test method described above and was found to be 0.1 X 10 ~ 5 cm2 / dyne. Example 22 A half-liter reaction decrease bottle equipped with mechanical stirrer, condenser, and outlet-inlet lines for vacuum and argon was charged with 112.5 g of deionized water and 1.5 g of lauryl ammonium sulfate (Standpol ™ A). The reactor was then degassed filled with argon. The stirring was set at 300 rpm and the reactor was heated to 68 ° C. Isooctyl acrylate (34.9 g), 1.85 g of N-vinylpyrrolidone, 0.094 g of 1,6-hexanediol diacrylate and 0.75 g of β-estradiol-3-benzoate in a heated flask (approximately 50 ° C) were then combined. that the drug completely dissolved in the monomer mixture. Benzoyl peroxide (0.36 g of Lucidol-70) was added to the bottle. After the initiator was dissolved, the mixture was charged to the reactor at 68 ° C. The reactor temperature was then restored to 65 ° C for 22 hours. An argon purge was maintained during the polymerization. After 22 hours, the suspension was cooled to room temperature. The microspheres were stable in the aqueous phase. The reactor was then emptied and the suspension was filtered through cotton cloth to remove the agglomerates. Under optical microscopy, the resulting microspheres were found to be a mixture of several solid and hollow microspheres. The particle size was determined using Particle Image Analysis and was found to be 29.1 μM. A sample was cooled on a 2 mil (51 μM) polyester backing then dried in an oven at 85 ° C (185 ° F) for 20 minutes and at 99 ° C (210 ° F) for 20 minutes. Contemplation was measured using the test method described in the above and was found to be > 6.0 X 10 ~ 5 cm2 / dyne. Example 23 An aqueous phase was prepared by neutralizing a mixture of 0.75 g of acrylic acid in 56.25 g of deionized water at about pH 7 with ammonium hydroxide. A 40 g portion of the aqueous phase and 0.25 g laurylammonium sulfate (Standpol ™ A) were added to a one liter reaction decrease bottle with mechanical stirrer, condenser, and exit-inlet lines for vacuum and argon. The mixture was stirred at 350 rpm while purged with argon and heated to 68 ° C. An oil phase was prepared by dissolving 0.12 g of benzoyl peroxide (Lucidol 70) and 0.56 g of β-estradiol-3-benzoate in 18 g of isooctyl acrylate. The remaining portion of the aqueous phase was combined with 0.38 g of sorbitan monooleate, HLB = 4.3 (Arlacel 80 from ICI Specialties); The resulting mixture was homogenized to produce a foam. The oil phase was added with the mixture to the foam to form a petticoat emulsion. The emulsion was then charged to the reactor to form a water-in-oil-in-water emulsion for polymerization. The reactor was then degassed and the temperature was maintained at 65 ° C for 22 hours. An argon purge was maintained during the polymerization. After 22 hours the reactor was allowed to cool to room temperature. The microspheres were stable in the aqueous phase. The reactor was then emptied and the suspension filtered through cotton cloth to remove the agglomerates. Under optical microscopy the resulting microspheres were found to have a multiple vacuum morphology. The particle size was determined using Particle Image Analysis and was found to be 55 μM. A sample was covered in a 2 mil (51 μM) polyester backing then dried in an oven at 85 ° C (185 ° F) for 20 minutes and at 99 ° C (210 ° F) for 20 minutes. The temporization was measured using the test method described above and was found to be 0.3 X 10 ~ 5 cm2 dyne. Example 24 The procedure of Example 23 was repeated using β-estradiol diacetate in place of β-estradiol-3-benzoate. The microspheres were found to have a multiple space morphology and a particle size of 70 μM. Contemplation was found to be > 6.0 X 10 ~ 5 cm2 / dyne. The ability of the compositions of Examples 21-24 to release drug was measured using the test method described above. The values are given in Table 6 below where each value is the average of three independent determinations and the number in parentheses is the standard error of the mean.

Example 25 A one liter reaction decrease bottle with mechanical stirrer, condenser, and inlet-outlet lines for vacuum and argon was charged with 180 g of deionized water and 4.8 g of laurylammonium sulfate (Standpol ™ A). The mixture was then degassed, then filled with argon. The mixture was set at 550 rpm and heated to 68 ° C. Isooctyl acrylate (117.6 g), 2.4 g of polyacrylate ester (ethylene oxide) (AM-90G, available from Shin-Nakamura), 24 g of isopropyl myristate, 0.03 g of 1,6-hexanediol diacrylate were combined. and 0.57 g of benzoyl peroxide (Lucidol-70) in a bottle. After the initiator was dissolved, the mixture was charged to the reactor at 68 ° C. The reactor temperature was then restored to 65 ° C for 22 hours. An argon purge was maintained during the polymerization. After 22 hours, the suspension was cooled to room temperature. The reactor was then emptied, the suspension was filtered through a cotton bolt to remove the agglomerates. The resulting microspheres were found to have a fine multiple-space morphology and an average volume size of 28.4 μM. One sample was thickened with acrylic latex (1 pph of UCAR® polifobe-104 of Union Carbide), coated in a chemically treated polyester liner, then dried in an oven to provide a dry coating with a thickness of 4.4 mil. (112 μM). The temporization was found to be 7.87 X 10 ~ 5 cm2 / dyne. Example 26 The procedure of Example 25 was repeated except that the stirring was set at 450 rpm. The resulting microspheres were found to have a fine multiple-space morphology and an average volume size of 45.4 μM. One sample was swollen with acrylic latex (1 pph of Union Carbide's UCAR® polifobe-104), coated in a chemically treated polyester liner, then dried in a dry oven to provide a thickness of 3.8 mil to a dry layer (96.5 μM). Contemplation was found to be 1.21 X 10"5 cm2 / dyne The present invention has been described with reference to various embodiments thereof The above detailed description and examples have been provided only for clarity of understanding, and no unnecessary limitation It will be understood by those skilled in the art that many changes can be made to the described embodiments without departing from the spirit and scope of the invention, Thus, the scope of the invention should not be limited to the exact details of the invention. the compositions and structures described herein, but rather by the language of the claims that follow.

Claims (22)

1. REVTNDICTIONS 1. A transdermal drug delivery composition characterized in that it comprises at least 10% by weight of a softening agent incorporated within the microspheres and optionally a therapeutically effective amount of a drug.
2. 2. The composition according to claim 1, characterized in that the microspheres are hollow.
3. 3. The composition according to claim 1, characterized in that the microspheres are solid.
4. 4. The composition according to claim 1, characterized in that the composition has a tempering value of about 3 x 10 ~ 6 cm2 / dyne to 1 x 10 ~ 3 cm2 / dyne.
5. 5. The composition according to claim 1, characterized in that the microspheres are comprised of an acrylate polymer.
6. 6. The composition according to claim 5, characterized in that the acrylate polymer comprises a copolymer of at least one ester of acrylic or methacrylic acid and at least one radically free polymerizable comonomer.
7. The composition according to claim 6, characterized in that at least one ester of acrylic or methacrylic acid comprises a monofunctional unsaturated acrylic or methacrylic acid ester of a non-tertiary alkyl alcohol wherein the alkyl group of the alcohol contains 4 to 10 carbon atoms.
8. The composition according to claim 6, characterized in that at least one ester of acrylic or methacrylic acid comprises sec-butyl acrylate, n-butyl acrylate, tert-butyl acrylate, butyl methacrylate, isoamyl acrylate, 2-methylbutyl acrylate, 4-methyl-2-pentyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, isononyl acrylate, isodecyl methacrylate, isodecyl acrylate, dodecyl acrylate, tetradecyl acrylate, ethyl acrylate, isobornyl acrylate, or any mixture thereof.
9. 9. The composition according to claim 6, characterized in that at least one ester of acrylic or methacrylic acid comprises isooctyl acrylate or 2-ethylhexyl acrylate.
10. The composition according to claim 6, characterized in that the free radically polymerizable polar comonomer comprises a mono-olefinic monocarboxylic acid or a salt thereof; an acrylamide; an N-substituted acrylamide; a N-vinyl lactam or any mixture thereof.
11. 11. The composition according to claim 6, characterized in that the free radically polymerizable polar comonomer comprises acrylic acid, methacrylic acid, itaconic acid, crotonic acid, maleic acid, fumaric acid, vinyl acetate, sulfoethyl methacrylate, N-vinyl pyrrolidone, caprolactam of N-vinyl, acrylamide, t-butyl acrylamide, dimethylaminoethyl acrylamide, N-octyl acrylamide, hydroxyethyl acrylate, hydroxyethyl methacrylate, sodium methacrylate, ammonium acrylate, sodium acrylate, trimethylamine of p-vinylbenzimide, N, N-dimethyl-N- (beta-methoxy-ethyl) betaine of ammonium propionate, methacrylamide of trimethylamine, methacrylamide of 1,1-dimethyl-1- (2,3-dihydroxypropyl) amine or any mixture thereof.
12. 12. The composition of claim 6 wherein the free radically polymerizable polar comonomer comprises acrylic acid.
13. The composition according to claim 5, characterized in that the acrylate polymer comprises a copolymer of isooctyl acrylate and acrylic acid.
14. The composition according to claim 7, characterized in that the softening agent comprises a terpene; an alcohol containing from 8 to 36 carbon atoms; a fatty acid, fatty acid ester or fatty acid amide having from 8 to 36 carbon atoms; a glyceride of a fatty acid having from 8 to 36 carbon atoms; an alkylpyrrolidone carboxylate wherein the alkyl group contains from 6 to 36 carbon atoms or any mixture thereof.
15. 15. The composition according to claim 1, characterized in that the softening agent comprises terpineol, isopropyl myristate, or a mixture thereof.
16. 16. The composition according to claim 1, characterized in that the drug is incorporated into the microspheres
17. 17. The composition according to claim 1, characterized in that the drug comprises a steroid.
18. 18. The composition according to claim 17, characterized in that the drug comprises a combination of steroids.
19. 19. The composition according to claim 18, characterized in that the drug comprises a combination of an estrogen and a progestin.
20. 20. The composition according to claim 1, characterized in that the drug comprises testosterone or levonorgestrel.
21. 21. The transdermal drug delivery device characterized in that it comprises the transdermal drug delivery composition according to claim 1, disposed on a support.
22. 22. A method for preparing a transdermal drug delivery composition characterized in that it comprises the steps of: a) forming an oil phase comprising one or more of the ester of acrylic acid, methacrylic acid ester, or vinyl ester monomers alone or in any combination; a non-reactive, soluble oil softening agent and / or drug; and free radical initiator soluble in oil in an aqueous phase comprising an aqueous medium comprising at least one stabilizer or suspension surfactant and b) initiating the polymerization of the oil phase in the aqueous phase, thereby forming a supply composition of transdermal drug of adhesive microspheres.