MXPA06004788A - Transdermal drug delivery device - Google Patents

Abstract

A transdermal delivery system is provided for the topical application of one or more active agents contained in one or more polymeric and/or adhesive carrier layers, proximate to a non-drug containing polymeric and/or adhesive coating that is applied to either the transdermal system's backing or release liner. The transdermal delivery device is manufactured to optimize drug loading while providing desirable adhesion to skin or mucosaas well as providing modulation of the drug delivery and profile.

Description

DEVICE FOR THE SUPPLY OF TRANSDERMAL DRUG TECHNICAL FIELD This invention relates generally to transdermal drug delivery systems, and more particularly to pharmaceutically acceptable adhesive matrix compositions. The invention further relates to transdermal drug delivery systems wherein the profiles and delivery rates, drug permeation can be modulated selectively within the transdermal drug delivery system. The present invention relates to transdermal delivery systems, their method of making and method of use. In particular, the present invention is directed to a transdermal drug delivery system for the topical application of one or more active agents contained in one or more adhesive and / or polymer carrier layers close to an adhesive and / or polymeric coating. It does not contain any drug that is applied to either the release liner or the transdermal system backing. The release liner or backing coated with adhesive is processed or manufactured separately from the adhesive and / or polymeric drug carrier layers to prevent or minimize the loss of drug or other components of the system, and to be combined before topical application. The profile and rate of delivery of the drug can also be controlled by adjusting certain characteristics of the polymers and / or adhesives themselves or of the method for making the system, relative to the properties of the active agent in this transdermal system.

BACKGROUND OF THE INVENTION The use of a transdermal drug delivery system as a means of administering therapeutically effective amounts of an active agent is well known in the art. Transdermal systems or devices can be categorized in many different ways, but those commonly referred to as transdermal patches, incorporate the active agent into a carrier, usually a pressure sensitive and / or polymeric adhesive formulation. Many factors influence the design and performance of such drug delivery devices, such as individual drugs themselves, the physical / chemical characteristics of the system components themselves and their performance / behavior in relation to other components of the system once combined, external / environmental conditions during manufacturing and subsequent storage, the properties of the topical site of application, the desired rate of drug delivery and initiation, the profile of drug delivery, and the duration of attempted delivery. Cost, appearance, size and ease of manufacture are also important considerations. The ability to deliver a therapeutically effective amount of the drug according to the therapy or treatment proposed is the goal. The simplest design is one, in which the drug is incorporated into a pressure-sensitive adhesive carrier layer, each surface of which is fixed to a film / polymeric layer - one serving as the backing (to hold the carrier layer and control the passage of environmental influences inward and system components outward during use) and the other serving as a removable liner (to protect the carrier layer before being used but removed in the topical application of the carrier layer). However, when all the performance and design factors and considerations are addressed to achieve the objective, this system alone can not always provide the best method. In this aspect, a rate of drug delivery is affected by its degree of saturation and solubility in the carrier composition. Depending on the active agent itself or the dosage necessary to be therapeutically effective, the amount of drug necessary to be incorporated into a single matrix composition or adhesive carrier (i.e., drug loading) may adversely affect or be adversely affected. by, such carrier or matrix. Drug carrier compositions typically require one or more processing solvents, usually organic solvents, in which the active agent is incorporated and / or the adhesive / polymeric carrier is allowed to be more easily covered in a envelope with a release liner or backing. The removal of such solvents is necessary to avoid the problems associated with residual solvent amounts, such as topical application site irritation, drug degradation, drug instability, adhesive loss or cohesive properties impacting the binding of the system to the user and loss of speed or quantity of supply desired. Removal of solvent requires that elevated temperatures be applied to the carrier composition to evaporate such solvents. But at the same time, the removal of solvents by use of elevated temperatures can also remove or evaporate other desirable components, such as the active agent and drug permeation enhancers. Their loss may still occur at temperatures below which such components may otherwise volatilize by virtue of their interaction with each other and with other carrier components (reactivity or relative volatility). This is particularly problematic for drugs that are controlled substances (for which the Food and Drug Administration requires strict consideration during the manufacturing process) and / or drugs that have relatively low melting or boiling points, such as low-weight drugs. molecular and drugs in their free base form. Another problem often encountered with low molecular weight drugs, particularly those that are liquid at or near room temperature, is the plasticizing effect such drugs have on the carrier polymers in the transdermal drug delivery system. Primarily, the composition becomes "long or sticky" resulting in sufficient loss of cohesive and / or adhesive properties and therefore is unsuitable for sticking to the user's skin or mucosa. Although low concentrations of drug are used the harmful effects to the cohesive or adhesive properties of the carrier can be reduced, low concentration can result in difficulties in achieving an acceptable delivery rate and the drug can still be lost during processing. Similarly, increasing polymer concentrations by increasing the thickness or surface area of the carrier composition provides little flexibility to effectively control the rate of release of a variety of drugs. It would therefore be valuable to provide a transdermal delivery system, which allows the adhesive characteristics to be maintained in the drug-containing layer while providing desired speed control and system delivery profile. Formulation with low molecular weight drugs that are liquid at or near ambient temperatures is particularly difficult in adhesive carrier layer compositions because such drugs more readily penetrate the skin or mucosa. Such systems often can not be adequately optimized to control the onset of supply (ie, decrease or delay) and / or maintain the supply for an extended duration of supply without compromising other performance and design factors and considerations. With respect to d-amphetamine in free base form, a particularly preferred low molecular weight drug which is liquid at or near ambient temperatures, multiple issues arise when manufactured with process solvents. The drug is volatile at room temperature. The drug degrades in the presence of certain solvents, particularly ethyl acetate. The drug is degraded in the carbonate form in the presence of carbon dioxide commonly found in atmospheric air. According to the above, the manufacture of a transdermal system using processing solvents and effectively delivering such a drug is even more problematic. Additionally, transdermal carrier compositions based on acrylic pressure sensitive adhesive polymers are often preferred for their ability to incorporate or solubilize many drugs. In order to provide suitable usage properties and drug release of the composition, acrylic-based pressure sensitive adhesives are typically polymerized with functional monomers to provide functional groups in the acrylic-based adhesive. A problem associated with the use of such acrylic-based polymers with functional groups is that due to the generally high solubility of the drug, a large amount of drug generally must be incorporated into the composition to saturate it and provide adequate drug release to the skin. of the user. In use with low molecular weight drugs or controlled substances, the loss of the drug in the manufacturing process again can be a significant problem. Attempts have been made to use membranes that control speed and / or multiple layers, and to dissolve or suspend certain drugs in thermoplastic carrier compositions without the use of solvents. These drug delivery devices generally do not allow a great deal of flexibility to control the rate of release of a variety of drugs, which in turn also severely limits their therapeutic application, and are costly or problematic to manufacture. In addition, multiple adhesive layers are often required to secure the other layers or membranes together, and / or to the topical application site. In this way, it would therefore be desirable to provide a system for use with many types of drugs, in which the profile and rate of permeation can be easily adjusted while providing a carrier composition containing active agent formulated in a cost-effective manner and simple. It would be advantageous to avoid the loss of drug found in manufacturing methods that require heating or drying at high temperature after the addition of a drug to the carrier composition.

BRIEF DESCRIPTION OF THE INVENTION Based on the foregoing, it is an object of the present invention to overcome the limitations of the above transdermal systems, and to provide a transdermal drug delivery system that allows the selective modulation of profiles and delivery and permeation rates of drug. Another object is to provide a transdermal system, which is simple and inexpensive to manufacture, while preventing or minimizing the loss of drug and / or other volatile components in the composition. The present invention provides a transdermal drug delivery system for the topical application of one or more active agents contained in one or more adhesive and / or polymeric carrier layers, close to an adhesive and / or polymeric coating that does not contain a drug that is applied to either the transdermal system backing or release liner, fabricated to optimize drug loading while providing desirable adhesion to the skin or mucosa as well as profile modulation and drug delivery is provided. The invention is further directed to a transdermal delivery system comprising a backup compound comprising an adhesive and / or polymer coating that does not contain drug, which may contain volatile or low boiling components such as permeation enhancers, fixed or applied to a drug-impermeable layer. A carrier layer of active agent comprising a pressure sensitive adhesive composition and a drug incorporated therein is attached to the backing compound. The polymeric coating is designed to provide control of permeation rate, initiation and profile of the active agent of the system. The agent-carrier composition may comprise one or more layers. The carrier-agent composition may comprise at least one layer formed of a mixture of at least one acrylic-based polymer and at least one silicone-based polymer, to serve as a pressure-sensitive adhesive composition for applying the system to the dermis, or a mixture of acrylic-based polymers. The non-drug-containing acrylic-based polymer coating is designed to interact with the drug composition layer (s). The invention is also directed to compositions and methods for manufacturing a transdermal delivery system prepared by controlling (a) the amounts of percentage solids of the adhesives, (b) the amounts of the processing solvents, and (c) the amounts and types of intensifiers, used in transdermal systems incorporating reactive or relatively volatile drugs or hydrophilic drugs when used with reactive or volatile intensifiers. The invention is also directed to compositions and methods for controlling rates of drug delivery, initiation and profiling of at least one active agent in a transdermal delivery system, comprising the use of an acrylic-based polymer not containing drug and / or coating adhesive, a surface of which is applied to either the release or backing liner of the transdermal system and the other surface is fixed to a layer of drug containing carrier composition, wherein the delivery rate, start of delivery (time lapse) and a drug delivery profile can be selectively modulated by one or more of (a) increasing or reducing the thickness or weight of the acrylic-based polymer coating and / or adhesive coating per cm2 as applied to the backing or release liner of the drug. system, (b) manipulating the portion or functionality of the acrylic based polymer and / or adhesive coating, and (c) manipulating the composition monomer and / or proportions of the acrylic based polymer and / or adhesive coating. Either the drug-free coating or the carrier composition should be a pressure-sensitive adhesive when used as a binding area to the user's skin or mucosa. The drug carrier composition can be comprised of (a) one or more acrylic-based polymers having one or more functionality or (b) one or more silicone-based polymers having one or more silanol contents (coverage) and / or proportions from resin to polymer, alone or in combination, and are present in proportions to provide a desired solubility for the drug. Additional manipulation of the supply drug, initiation and profiles can be achieved by varying the concentrations of the drug in the carrier loaded in the drug. For a better understanding of the present invention, together with other and additional objects, reference is made to the following description taken together with the accompanying drawings, and its scope will be pointed out in the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a schematic cross-sectional view of a transdermal delivery device according to an embodiment of the invention before being used. FIG. 2 shows a schematic cross-section of the carrier-carrier assembly and backup assembly according to the embodiment of the present invention as shown in FIG. 1 before lamination. FIG. 3 is a graphic representation of the effects on drug delivery, onset and profile of d-amphetamine with different proportions of acrylic-based adhesives, non-functional in the polymeric coating. FIG. 4 is a graphic representation of the effects of drug delivery, initiation and profile of d-amphetamine with varying concentrations of functional carboxy monomers in acrylic-based adhesives in the polymeric coating. FIG. 5 is a graphical representation of the effects on drug delivery, onset and profile of d-Amphenamine with varying coating weights of an acrylic-based adhesive coating.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES In the following description, the embodiments of the invention are established, and terms are used to describe such modalities, wherein: The term "topical", or "topically" is used herein in its conventional meaning as referring to direct contact with an anatomical site or surface area in a mammal including skin, teeth, nails and mucosa. The term "mucosa" as used herein means any anatomical membrane or surface in a mammal such as oral, buccal, rectal, nasal or ophthalmic surfaces. Similarly, "skin" is understood to include mucosa, which also includes oral, buccal, nasal, rectal and vaginal mucosa. The term "transdermal" refers to the delivery, administration or application of a drug by means of direct contact with tissue, such as skin or mucosa. Such delivery, administration or application is also known as percutaneous, dermal, transmucosal and buccal. As used herein, the terms "mixture" or "paste" are used herein to mean that there was, or substantially no, chemical reaction or degradation (other than simple H-bonding) between the different polymers in the polymer matrix. However, degradation between a single polymer component is fully contemplated to be within the scope of the present invention. The term "adhesive" means a substance, inorganic or organic, natural or synthetic that is capable of surface bonding at the site of topical application proposed by itself or functions as an adhesive by mixing with thickeners, plasticizers, degrading agents or other additives . In the most preferred embodiment, the carrier of the present invention is a "pressure sensitive adhesive" which refers to a viscoelastic material that adheres instantaneously to most substrates with the application of very light pressure and remains permanently tacky. A polymer or dermal composition is a pressure sensitive adhesive within the meaning of the term as used herein if it has the adhesive properties of a pressure sensitive adhesive per se or functions as a pressure sensitive adhesive by mixing with thickeners, plasticizers, degradation agents and other additives. As used herein, a "polymer composition of two or more polymers" is defined as a physical mixture of at least two polymers and may include 3 or more polymers. The two or more polymers may include the acrylic-based polymers described herein and may optionally include other polymers treated more fully below. The term "acrylic-based" polymer is defined as any polyacrylate, polyacrylic, acrylate or acrylic polymer. The acrylic-based polymers can be any of the homopolymers, copolymers, terpolymers, and the like of various acrylic acids or esters. The acrylic-based polymers useful for practicing the invention are polymers of one or more monomers of acrylic acids and other copolymerizable monomers. The acrylic-based polymers also include copolymers of alkyl acrylates and / or methacrylates and / or compolymerizable secondary monomers. The acrylic-based polymers with functional groups as described more fully below, are copolymerized with functional monomers. As used herein, "functionality" is broadly defined as a measure of the type and amount of functional groups that a particular acrylic-based polymer has. This definition also comprises acrylic-based polymers having no or substantially no functional groups. As used herein, "functional groups or monomers" are monomer units in acrylic-based polymers having reactive chemical groups that modify the acrylic-based polymers directly or provide sites for further reactions. Examples of functional groups include carboxyl, epoxy and hydroxy groups. As used herein, the "non-functional acrylic based polymer" is defined as an acrylic-based polymer that has substantially no reactive non-functional portions present in the acrylic. These are generally acrylic esters that can be copolymerized with other monomers that do not have functional groups, such as vinyl acetate. The term "carrier" as used herein refers to any non-aqueous material known in the art as suitable for administration of transdermal drug delivery, and includes any polymeric material in which an active agent can be solubilized in combination or mixture with other ingredients of the composition. The polymeric materials preferably comprise adhesives and, in particular, pressure sensitive adhesives. The carrier material is typically used in an amount of from about 40% to about 90%, and preferably from about 50% to about 80% by weight based on the dry weight of the total carrier composition. The term "carrier composition" may also refer to enhancers, solvents, co-solvents and other types of additives useful in facilitating transdermal drug delivery. The carrier compositions of the present invention may also contain one or more non-aqueous solvents and / or co-solvents. Such solvents and / or co-solvents are those known in the art, and are pharmaceutically acceptable non-toxic substances, preferably non-aqueous liquids, which do not adversely affect the adhesive properties or the solubility of the active agents in the concentrations used. The solvent and / or co-solvent may be for the active agent or for the carrier materials, or both. Suitable solvents include volatile processing liquids such as alcohols (e.g., methyl, ethyl, isopropyl alcohols and methylene chloride); ketones (for example, acetone); aromatic hydrocarbons such as benzene derivatives (for example, xylenes and toluenes); lower molecular weight cycloalkanes and alkanes (for example, hexanes, heptanes and cyclohexanes); and esters of alkanoic acid (eg, ethyl acetate, n-propyl acetate, isobutyl acetate, n-butyl isobutyrate, butyl butyl acetate, hexyl acetate, 2-ethylhexyl acetate or butyl acetate); and combinations and mixtures thereof. Other suitable co-solvents include polyhydric alcohols, which include glycols, triols and polyols such as ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, trimethylene glycol, butylene glycol, polyethylene glycol, hexylene glycol, polyoxyethylene, glycerin, trimethylpropane, sorbitol, polyvinylpyrrolidone and the like. Alternatively, the co-solvents may include glycol ethers such as ethylene glycol monoethyl ether, glycol esters, glycol ether esters such as ethylene glycol monoethyl ether acetate and ethylene glycol diacetate; saturated and unsaturated fatty acids, mineral oil, silicone fluid, lecithin, retinol derivatives and the like, and ethers, esters and fatty acid alcohols. As will be described in more detail below, the solvents or co-solvents used according to the invention are desirably a low volatile solvent that does not require excessive temperatures for evaporation thereof. The term "solubilized" is intended to mean that in the carrier composition there is an intimate dispersion or dissolution of the active agent at the crystalline, molecular or ionic level, so that crystals of the active agent can not be detected using a microscope having a magnification of 25X. . As such, the active agent is considered herein to be in "non-crystallized" form when it is in the compositions of the present invention. As used in the present "flow" is defined as the percutaneous absorption of drugs through the skin, and is described by the first law of diffusion Fick: J = -D (dCm / dx), where J is the flow in g / cm2 / sec, D is the diffusion coefficient of the drug through the skin in cm2 / sec and dCm / dx is the concentration gradient of the active agent through the skin or mucosa. As used herein, "therapeutically effective" means an amount of an active agent that is sufficient to achieve the desired systemic or local effect or effect, such as to prevent, cure, diagnose, mitigate or treat a disease or condition, when it is applied topically for the duration of the proposed use. The amounts required are known in the literature or can be determined by methods known in the art, but typically range from about 0.1 mg to about ,000 mg, and preferably from about 0.1 mg to about 1,000 mg, and more preferably from about 0.1 to about 500 mg per human or mammalian adult of approximately 75 kg of body weight per 24 hours. The term "approximately", and the use of ranges generally qualified or not by the term approximately, means that the number comprised is not limited to the exact number set forth herein, and it is proposed to refer to ranges substantially within the quoted range without departing of the scope of the invention. The term "user" or "subject" is intended to include all warm-blooded mammals, preferably humans. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although any method and material similar or equivalent to those described herein can be used in practice to test the present invention, preferred materials and methods are described herein. Referring to FIG. 1, the most preferred embodiment of the invention, transdermal drug delivery system 10 comprises a layer of carrier composition 12 incorporating the active agent. The surface 14 of the adhesive carrier layer 12 is fixed to release the liner 15 to protect the carrier layer before use but which is removed in the topical application of the carrier layer to the user's skin or mucosa. An adhesive and / or polymeric non-drug-containing coating 18 is fixed to the backing 20 on one surface, with the other surface being fixed to the carrier layer 12. The backing compound 16 comprises a coating 18 fixed to the backing 20, which as described below , is made or processed separately from the carrier layer 12 attached to the release liner 15. The carrier composition layer 12 may comprise any polymer or adhesive generally known in the art to formulate a drug carrier composition, and includes all synthetic polymers and natural non-toxic known or suitable for use in transdermal systems including solvent-based, heat-melted and grafted adhesives, and may be used alone or in combination, blends or pastes. Examples include based on acrylic, silicone-based, rubbers, gums, polyisobutylenes, polyvinyl ethers, polyurethanes, styrene block copolymers, styrene / butadiene polymers, polyether block amide copolymers, ethylene / vinyl acetate copolymers, and adhesives based on vinyl acetate, and bioadhesives as set forth in Pat. from the USA No. 6,562,363 which is expressly incorporated by reference in its entirety. The term "silicone-based" polymer is intended to be used interchangeably with the terms siloxane, polysiloxane, and silicones as used herein and as is known in the art. The silicone-based polymer can also be a pressure-sensitive adhesive, with a polysiloxane adhesive prepared by degrading an elastomer, typically a high molecular weight polydiorganosiloxane, with a resin, to produce a three-dimensional siloxane structure, through a condensation reaction in an appropriate organic solvent. The ratio of resin to elastomer is a critical factor that can be adjusted to modify the physical properties of polysiloxane adhesives. Sobieski, et al., "Silicone Pressure Sensitive Adhesives ", Handbook of Pressure-Sensitive Adhesive Technology, 2nd., Ed., Pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989) .Examples and additional details of pressure sensitive adhesives. of silicone which are useful in the practice of this invention are described in the following U.S. Patent Nos. 4,591, 622, 4,584,355, 4,585,836, and 4,655,767, all expressly incorporated herein in their entirety. Suitable silicone pressures are commercially available and include silicone adhesives sold under the BIO-PSA® trademarks by Dow Corning Corporation, Medical Products, Midland, Michigan (such as -2685, -3027, -3122, -4101, -4102, -4203, -4301, -4302, -4303, -4401, -4403, -4501, -4503, - 4602, -4603 and -4919). Silicones coated with high resin content are preferred. In the practice of the preferred embodiments of the invention, the acrylic-based polymer can be any of the homopolymers, copolymers, terpolymers and the like of various acrylic acids. In such preferred embodiments, the acrylic based polymer constitutes from about 2% to about 95% of the total dry weight of the carrier composition, and preferably from about 2% to about 90%, and more preferably from about 2% to about 85. %), wherein the amount of the acrylic-based polymer is dependent on the amount and type of drug used. The acrylic-based polymers usable in the invention are polymers of one or more monomers of acrylic acids and other copolymerizable monomers. The acrylate polymers also include copolymers of alkyl acrylates and / or methacrylates and / or copolymerizable secondary monomers or monomers with functional groups. By varying the amount of each type of monomer added, the cohesive properties of the resulting acrylate polymer can be changed as is known in the art. In general, the acrylate polymer is composed of at least 50% by weight of an acrylate or alkyl acrylate monomer, from 0 to 20% of a functional monomer copolymerizable with the acrylate, and from 0 to 40% of other monomers. Acrylate monomers that may be used include acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecyl methacrylate. Functional monomers, copolymerizable with the above alkyl methacrylates or acrylates, which may be used include acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, methacrylate dimethylaminoethyl, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate and methoxyethyl methacrylate. Suitable acrylic-based polymers can also be a pressure-sensitive adhesive which are commercially available and include acrylic-based adhesives sold under the Duro-Tak® trademarks by National Starch and Chemical Corporation, Bridgewater, N.J. (such as 87-2287, -4098, -2852, -21 96, -2296, -2194, -2516, -2070, -2353, -2154, -2510, -9085 and -9088). Other suitable acrylic-based adhesives include HRJ 4483, 1 0127 and 1 1588 sold by Schenectady International, Inc., Schenectady, N.Y. , and those sold by Monsanto; St. Louis, Mo., under the trademarks Gelva® Multipolymer Solution (such as 2480, 788, 737, 263, 1430, 1753, 1 151, 2450, 2495, 3067, 3071, 3087 and 3235). The carrier composition may comprise mixtures of acrylic-based polymers, silicone-based polymers and rubbers based on their different solubility parameters, alone or in combination with other polymers, for example polyvinylpyrrolidone, as described more fully in US Pat. from the USA Nos. 5,474,783; 5,656,286; 5,958,446; 6,024,976; 6,221, 383; and 6,235,306 which are incorporated herein in their entirety. The amount of each polymer is selected to adjust the saturation concentration of the drug in the multiple polymer system, and to result in the desired drug delivery rate of the system and through the skin or mucosa. Combinations of acrylic based polymers based on their functional groups is also contemplated. Acrylic-based polymers having functional groups are copolymers or terpolymers which contain in addition to non-functional monomer units, additional monomer units having free functional groups. The monomers can be monofunctional or polyfunctional. These functional groups include carboxyl groups, hydroxy groups, amino groups, amido groups, epoxy groups, etc. Preferred functional groups are carboxyl groups and hydroxy groups. Preferred carboxyl functional monomers include acrylic acid, methacrylic acid, itaconic acid, maleic acid, and crotonic acid. Preferred functional hydroxy monomers include 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, hydroxymethyl acrylate, hydroxymethyl methacrylate, hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate, hydroxybutyl acrylate, hydroxybutyl methacrylate. , hydroxyamyl acrylate, hydroxyamyl methacrylate, hydroxyhexyl acrylate, hydroxyhexyl methacrylate. The non-functional acrylic-based polymers can include any acrylic-based polymer having no or substantially no free functional groups. The acrylic based polymer may include homopolymers, copolymers and terpolymers. The monomers used to produce the polymers can include methacrylic or alkyl acrylic esters such as methyl acrylate, ethyl acrylate, propyl acrylate, amyl acrylate, butyl acrylate, 2-ethylbutyl acrylate, hexyl acrylate, heptyl acrylate. , octyl acrylate, nonyl acrylate, 2-ethylhexyl acrylate, decyl acrylate, dodecyl acrylate, tridecyl acrylate, glycidyl acrylate and the corresponding methacrylic esters.

Both the acrylic-based polymer having substantially non-functional groups and the aero-based polymers having functional groups may optionally include additional modifying monomers. These modifying monomers may include any conceivable monomer that is capable of undergoing vinyl polymerization. For example, the incorporation of styrene monomers can be used to increase the glass transition temperature and are used in some way to improve the cohesive strength. The copolymerization of vinyl acetate monomers with acrylic esters is also used to form acrylic-based polymers. Ethylene can also be copolymerized with acrylic esters and vinyl acetate to give suitable acrylic-based polymers. For example, a composition will require less than one functional acrylic containing 20% by weight of functional groups as opposed to one containing 0.5% by weight of functional groups to achieve the same effect required for solubility and flow. Broadly speaking, the amount of functional acrylic is generally within the range of about 1 to 99% by weight and preferably 5 to 95% by weight, more preferably 20 to 75% by weight, even more preferably 30 to 65% by weight, in based on the total polymer content of the transdermal composition. The amount of non-functional acrylic or acrylic with a functional group that does not have as much affinity for the drug is within the range of about 99 to 1% by weight, preferably 95 to 5% by weight, more preferably 75 to 20% by weight , and even more preferably 30 to 65% by weight, based on the total polymer content of the composition. Additional details and examples of acrylic based adhesives, functional monomers and polymers having non-functional groups and which are suitable in the practice of the invention as described in Satas, "Acrylic Adhesives", Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed. , pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, N.Y. (1989): "Acrylic and Methacrylic Ester Polymers", Polymer Science and Engineering, Vol. 1, 2nd ed. , pp. 234-268, John Wiley & Sons, (1984); Pat. from USA UU No. 4,390,520; and Pat. from the USA No. 4,994,267 all of which are expressly incorporated for reference in their totalities. The required proportions of acrylic-based or other polymers used are generally dependent on the specific drug, its desired delivery rate and the desired duration of drug delivery. In general, the proportions of acrylic-based polymers also depend on the content of the functional monomer units in the functional acrylic. When the drug carrier composition is intended to function as the face layer, i.e. the layer that comes in contact with the topical application site as depicted in FIG. 1, it is preferable that the carrier composition comprises a bioadhesive or a sensitive adhesive. under pressure. In transdermal systems according to the invention, the drug carrier composition is designed to minimize or prevent the loss of drug and / or other desirable volatile components, such as hydrophilic permeation enhancers, in compositions containing processing solvents, as well as to provide selectable modulation of drug delivery, initiation, and profiling rates when used in combination with an adhesive and / or polymeric drug-free coating that is applied to either the release or backing liner of the transdermal system. The minimization or prevention of drug loss is particularly desirable when it comes to supplying controlled substances. With drugs that have relatively low melting or boiling points, such as drugs that are liquid at or near room temperature, or readily volatilize and / or degrade during the manufacture of the transdermal delivery system one may experience drug loss during processing. . This is particularly relevant for controlled substances for which the regulatory agencies, such as FDA, require consideration of any loss of the controlled substance. Particular drugs that are usable in the present invention include low molecular weight drugs. Any drug that is liquid at or about room temperature can be used according to the present invention. As used herein, the term "low molecular weight" is defined as including any drug and its equivalent forms having a boiling point so that it exists as a liquid at or about room temperature. This term comprises low molecular weight drugs having a molecular weight of less than about 300 daltons. A drug that is low molecular weight and liquid at or about room temperature is generally in its free base or free acid form, and as such, is understood by this term. The drugs usable for practicing the invention include amphetamine, d-amphetamine, metafetam, prilocaine, benzocaine, butacaine, butamben, butanilicaine, corticaine, lidocaine, menannin, pilocarpine, cyclobenzaprine, paroxetine, fluoxetine, duloxetine, imipramine, decipramine, doxeprine, nortriptylene, protriptylene, bupropion, azelastine, chlorpheniramine, bisoprolol, pheniramine, alprazolam, captopril, clonidine, clonazepam, enalapril, ramipril, haloperidol, ketoprofen, loratadine, methimazole, (antihyperthyroid), methylphenidate, methyl testosterone, nicotine, nitroglycerin, pramipexole, ropinirola, hldromorphone, selegiline (deprenyl and L-deprenyl), scopolamine, testosterone, methamphetamine, and phentermine. For desired therapeutic effect, certain drugs, such as methylphenidate, d-amphetamine, methamphetamine and phentermine, may be desirable for use in their base form. The transdermal supply of d-amphetamine base is preferably used to treat Attention Deficit and hyperreactivity disorders, and suppression of appetite. The transdermal supply of a combination of d-amphetamine base and 1 -anfentamine base is preferably used to treat Attention Deficit and hyperreactivity disorders, and suppression of appetite. The transdermal delivery of a combination of d-amphetamine base and 1 -anfentamine base is preferably used to treat attention deficit and hyperreactivity disorders, and suppression of appetite wherein the ratio of da 1 to the amphetamine base is between approximately 1 to 1 to approximately 4 to 1. The transdermal delivery of a combination of d-amphetamine base and 1-amphetamine base is preferably used to treat attention deficit and hyperreactivity disorders, and appetite suppression wherein the ratio of da 1 to the amphetamine base is between approximately 3 to 1 to approximately 4 to 1. Any drug of molecular weight and its equivalent forms can be used in the present invention provided that such drugs would be substantially unstable or substantially evaporate or flush at temperatures generally known or used in the art to remove solvents during manufacturing processing, typically in the range from 72 ° C to 122 ° C, for its own properties or by virtue of its relative volatility or reactivity with the other carrier components. In certain other embodiments, the preferred drug is one that is hydrophilic and not relatively volatile or reactive with the other carrier components, but that is incorporated in a carrier composition with certain preferred co-solvents or enhancers for use with such drugs that would be, their own properties or by virtue of their relative volatility or reactivity with the other carrier components, substantially unstable or substantially evaporate or flush at temperatures generally known or used in the art to remove solvents during manufacturing processing. The drugs and mixtures thereof may be present in the composition in different forms, depending on which the optimum supply characteristics are produced. In this manner, the drug can be in its free base form or in the form of salts, esters, or any other pharmacologically acceptable derivative, or as prodrugs, molecular complex components or as combinations thereof. Any drug suitable for transdermal administration by methods previously known in the art and by the methods of the present invention can be used in the present invention, and further include such active agents that can then be established as drugs and are suitable for delivery by the present invention. These drugs include but are not limited to those categories and species for drugs set forth on page ter-1 to ter-28 of Merck Index, 12th Edition Merck and Co. Rahway, N.J. (1999). This reference is incorporated for reference in its entirety. Exemplary drugs that can be administered by the new dermal drug delivery system include, but are not limited to: 1. Central nervous system agents and stimulants such as Dextroamphetamine, Amphetamine, Methamphetamine, D-Amphetamine, L-amphetamine Phentermine, Methylphenidate, Nicotine combinations thereof and combinations thereof. 2. Analgesics and / or Anti-Migraine such as Acetaminophen, Acetylsalicylic acid, Buprenorphine, Codeine, Fentanyl, Lisurite, derivatives of Salicylic Acid and Sumatriptan. 3. Androgen agents such as Fluoxymesterone, Methyl Testosterone, Oxymesterone, Oxymetholone, Testosterone and Testosterone derivatives, ~ < "4. Anesthetic agents such as Benzocaine, Bupivicaine, Cocaine, Dibucaine, Diclone, Etidocaine, Lidocaine, Mepivacaine, Prilocaine, Procaine and Tetracaine. 5. Anorectic agents such as Fenfluramine, Mazindol and Phentermine. 6. Antibacterial agents (antibiotics) including Aminoglycosides, ß-Lactams, Cefamycins, Macrolides, Penicillins, Polypeptides and Tetracyclines 7. Anti-cancer agents such as aminolevulinic acid and Tamoxifen. 8. Anti-cholinergic agents such as Atropine, Eucatropin and Scopolamine. 9. Anti-diabetic agents such as Glipizide, Gliburide, Glipinamide and Insulins. 1 0. Anti-fungal agents such as Clortrimazole, Ketoconazole, Miconazole, Nystatin and Triacetin. eleven . Anti-inflammatory and / or corticoid agents such as Beclomethasone, Betamethasone, Betamethasone Dipropionate, Betamethasone Valerate, Corticosterone, Cortisone, Deoxychocosterone and Deoxychocosterone, Acetate, Diclofenac, Fenoprofen, Flucinolone, Fludrocortisone, Fluocinonide, Fluradrenolide, Flurbiprofen, Halcinonide, Hydrocortisone, Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Ketorolac, Naproxen, Oxametacin, Oxifenbutazone, Piroxicam, Prednisolone, Prednisone, Suprofen and Triamcinolone Acetonite. > '12. Anti-malarial agents such as pyrimethamine. 13. Anti-Parkinson and / or anti-Alzhiemer agents such as Bromocriptine, 1-Hydroxy-Tacrine, Levodopa, Pergolide of Lisaride, Pramipexole, Ropinirola, Fisostigimine, Selegiline (Deprenyl and L-Deprenyl), Tacrine Hydrochloride and Teruride. 14. Anti-anxiety and / or anti-psychotic agents such as Acetofenazine, Azapironeas, Bromperidol, Clorproetazine, Chlorpromazine, Fluoxetine, Flufenazine, Haloperidol, Loxapine, Mesoridazine, Molindone, Ondansetron, Perphenazine, Piperacetazine, Thiopropazate, Thioridazine, Thiotomyne, Trifluoperazine and Triflupromazine 15. Anti-ulcer agents such as Enprostil and Misoprostol. 16. Anti-viral agents such as Acyclovir, Rimantadine and Vidarabine. 17. Anxiolytic agents such as Buspirone, Benzodiazepines such as Alprazolan, Chlordiazepoxide, Clonazepam, Clorazepate, Diazepam, Flurazepan, Halazepan, Lorazepan, Oxazepan, Oxazolan, Prazepan and Triazolan. 1 8. β-adrenergic agonist agents such as Albuterol, Carbuterol, Fenoterol, Metaproterenol, Rimiterol, Quinterenol, Salmefamol, Soterenol, Tratoquinol, Terbutalina and Terbuterol. 1 9. Bronchodilators such as ephedrine derivatives including Epiniprine and Isoproterenol, and Theophylline. 20. Cardioactive agents such as Atenolol, Benzidroflumetiazide, Bendroflumethiazide, Calcitonin, Captopropyl, Clorothiazide, Clonidine, Dobutamine, Dopamine, Diltiazen, Enalapril, Enalaprilat, Galopamil, Indomethacin, Isosorbide Dinitrate and Mononitate, Nicardipine, Nifedipine, Nitroglycerin, Papaverine, Prazosin, Procainamide, Propanolol, Prostaglandin E1, Sulfate of Quinidina, Timolo, and Verapamil. twenty-one . A-adrenergic agonist agents such as Phenyl propanolamine. 22. Cholinergic agents such as Acetylcholine, Arecoline, Bethanechol, Carbachol, Choline, Methacholine, Muscarine and Pilocarpine. 23. Estrogens such as conjugated estrogenic hormones, Equilenin, Aquilin, Esterified Estrogens, 17β-Estradiol, Estradiol Benzoate, 17β-Estradiol Valerate, 17β-Estradiol Cypionate, Estriol, Estrone, Estropipate, 17β-Etinyl Stage and Mestranol. 24. Muscle relaxants such as Baclofen. 25. Narcotic antagonist agents such as Nalmfeno and Naloxone. 26. Progestational agents such as Chlormadinone and Chlormadinone Acetate, Demegestone, Desogestrel, Dimetisterone, Dydrogesterone, Ethinyl Ethrenol, Etisterone, Etinodiol, and Etinodiol Diacetate, Gestodene, 17a-Hydroxyprogesterone, Caproate Hydroxygesterone, Medroxyprogesterone and Medroxyprogesterone Acetate, Megestrol Acetate, Melengestrol, Norethindrone and Norethydrone Acetate, Norethinodrel, Norgesterone, Norgestrel, 19-Norprogesterone, Progesterone, Promegestone and esters thereof. Drug free base forms that have a higher affinity for the acid functional group (carboxyl) in a functional acrylic carboxyl based polymer are preferred in some applications. For most drugs, their passage through the skin or mucosa will be the stage that limits the speed of delivery. In this manner, the amount of drug and the rate of release is typically selected to provide delivery characterized by a time-dependent pseudo-zero order for a prolonged period of time. The minimum amount of drug in the system is selected based on the amount of drug that passes through the skin or mucosa in the time period for which the device is to provide a therapeutically effective amount.

Generally, the amount of drug in the transdermal system can vary from about 0.1 to 40% by weight, preferably 0.5 to 30% by weight, and optimally 1 -20% by weight percent, based on the total dry weight of the agent composition -carrier. In the preferred embodiments of the invention, the inventors have found that in preparing and processing the drug carrier composition and polymeric coating separately, greater flexibility is provided when manufacturing a transdermal device employing solvent-based adhesives or processing solvents. Such solvents are typically volatile, non-aqueous liquids, and are used to solubilize or dissolve the active agent and polymers together in a composition that can be processed more easily in a transdermal system, such as by coating or melting. Typical liquids are volatile polar and polar organic liquids such as low molecular weight alkanes (eg, isopropanol and ethanol), aromatics such as benzene derivatives (eg, xylene and toluene), low molecular weight alkanes and cycloalkanes ( for example, hexane, heptane and cyclohexane) and esters of alkanoic acid such as butyl acetate or ethyl acetate. Such solvents are added in some way to the carrier composition (also referred to as co-solvents) and are typically found in commercially available adhesives as is known in the art for preparing transdermal systems. The drug carrier composition should be substantially free of residual solvents after manufacture, preferably less than 0.5% and more preferably 0.2% or less. To minimize the loss of the desirable components while making a transdermal system according to the invention, the amount of processing solvents typically needed to solubilize the drug or polymer in a desirable composition (and achieve the other performance and design characteristics for a transdermal system) is minimized or substantially reduced. In this regard, the drug carrier composition can be prepared with a greater amount of solids against solvents, and still be manufactured in a cost-effective and simple manner. By increasing the solids content, a relatively low amount of volatile solvent, such as ethyl acetate, can be used. This will greatly reduce the drying times and the need to subject the carrier composition to elevated temperatures, and therefore minimizes the choice of loss of desired volatile components, such as the drug. This, in turn, results in a carrier composition wherein the amount of drug necessary to achieve the desired rate of permeation and profile can be significantly reduced from what would be otherwise needed, or be impossible to load properly, as the Loss of such drug is minimized. With respect to acrylics and silicones, this refers to their resin / polymer or monomer content, respectively. Typical carrier compositions limit their total solids content to about 40% to 50% as desirable or necessary to provide sufficient solvents to solubilize a sufficient amount of the active agent and / or solids therein, and still impart sufficient cohesive and adhesive properties. to form a transdermal delivery system. However, such compositions require a significant amount of solvent to be removed. The agent carrier according to the invention is therefore prepared with a solids content of about 50% to 98% of the total weight of the carrier composition, or more preferably in the range of about 65% to about 85%. In preferred embodiments using both silicone and acrylic adhesives, the solids content and amount of the base, silicone adhesive can be increased to about 70% to about 80%, and 60% to about 80% by weight, respectively, while the amount of acrylic adhesive can be reduced to about 1% to about 15% by weight based on the dry weight of the total carrier composition. The use of an acrylic adhesive as part of the carrier composition is preferred, particularly with silicone adhesives, due to its ability to solubilize and maintain drug and still impart adhesive properties for binding to other transdermal films / layers and skin or mucosa. Such acrylic adhesives should not exceed a percentage solids content of more than about 40% when used in the lower ranges described to retain their desired effect. When used alone or in mixtures, the percentage solids of such acrylic adhesives would need to be increased substantially. The amount of drug typically lost during processing to remove solvents from a carrier composition can be as high as 20%, and even 40% or more, depending on the functionality or coverage of the adhesive or by virtue of the reactivity or relative volatility of the drug with the other carrier components. Due to the relatively thick coating weights of carrier compositions necessary to provide the necessary amount of drug and adhesive / cohesive properties to achieve the desired final product when dried, the manufacturing process required relatively long exposure at elevated temperatures to substantially remove the solvents . An additional benefit of the invention is the ability to increase processing speeds during fabrication, since the coating weight of the carrier composition and / or the concentration of the drug can be reduced. For example, typical carrier compositions prepared with acrylic-based polymers or polymer blends for a transdermal delivery device require coating weights of approximately 10 mg / cm 2 to achieve the desired drug loading and adhesive characteristics. In the present invention, the coating weight of a carrier composition for delivering at least one drug to a similar flow can be reduced to about 5 mg / cm2, or about one-half the coating weight of prior systems.

The agent-carrier composition according to the invention, containing significantly higher solids contents and interior solvents, and capable of being coated to a release liner or liner at a lower coating weight, can be processed faster or with reduced exposure to elevated temperatures to minimize or prevent the loss of or other desirable components, such as hydrophilic enhancers, but can not yet achieve other design and performance characteristics necessary to be a transdermal delivery device. Increasing percentage solids increase the "stiffness" of the carrier which can adversely affect the adhesive and cohesive properties required to function as a pressure sensitive adhesive for topical application. Additionally, increasing percentage solids may decrease the ability of the carrier to adequately solubilize and maintain the which adversely affects pressure sensitive properties as well as a controlled delivery profile or rate. Accordingly, the carrier composition of the invention can not adequately provide a controlled delivery, initiation or profile for the , or the necessary cohesive and adhesive properties, to be used by itself as a transdermal device until combined with a adhesive and / or polymeric coating not loaded with that is applied to either the release liner or backing. The polymeric coating 18 may comprise one or more of the polymers or adhesives described with reference to the carrier composition, generally with higher percentage solids, but does not contain active agent during its exposure to elevated temperatures for solvent removal before being fixed to the carrier composition. Acrylic-based, non-functional adhesives are preferred. The polymeric coating is placed in either the backing or release liner and generally at a thickness ranging from about 2.5 mg / cm2 to about 15 mg / cm2. Once fixed to the carrier composition, it serves to absorb or attract and retain amounts of from the carrier composition, and subsequently release in the topical application of the transdermal system. This process also allows the potentially high loading of in the carrier composition, where desired or necessary, for example, to deliver therapeutically effective amounts during a longer delivery period, since the excess will be absorbed thereby allowing the carrier composition maintain its desired adhesive properties while still providing profile and desired permeation rate to be achieved. The polymeric coating can further be prepared to selectively control the desired delivery rate, start and profile for the by varying certain other physical characteristics. As demonstrated in the examples using an acrylic-based adhesive coating, the delivery rate, delivery start (time lapse) and amphetamine base supply profile of the transdermal system can be modulated selectively by one or more of (a) increase or decrease the coating thickness or weight per cm 2 (as applied to the backing or release liner of the system), (b) manipulate the portion or functionality, and (c) manipulate the monomer composition and / or proportions of the coating not loaded with acrylic-based . Although one or more acrylic based adhesives are preferred for use as the non- loaded coating, other polymers, alone or in combination, can be used stipulating that such polymers have the ability to (a) incorporate and hold of the carrier composition loaded with after manufacture, (b) maintain contact / adhesion to both the carrier composition and the film / backing layer or release liner, preferably without the use of additional adhesives, (c) without degrading or interfering with the stability of the drug, and (d) releasing or delivering the drug to the skin or mucosa after topical application of the transdermal system. In the most preferred embodiment according to the invention as depicted in Fig. 1, about 10% to about 30%, and more preferably from about 10% to about 20% of drug, and more particularly amphetamine or an enantiomer of the same, preferred d-amphetamine, or in a racemic mixture, 3: 1 d- to 1 preferred, is incorporated into a pressure-sensitive adhesive carrier composition comprising a mixture of (a) a solvent-based acrylic adhesive having a concentration of percent solids of about 30% to 50%, preferably polymerized with non-functional monomers, in an amount of about 60% to 80%, and more preferably about 70% to about 80%, and (b) a silicone-based adhesive having a concentration of percent solids of from about 60% to about 90%, and more preferably from about 60% to about 80%, which is fixed to an acrylic coating. Non-drugic lico which is an adhesive and has a percentage solids concentration of about 30% to about 50%, preferably polymerized with carboxy and / or non-functional functional monomers, in an amount of about 3% to about 15%, and more preferably from about 3% to about 10%, wherein the amounts described are based on the dry weight of the total carrier composition. The drug delivery is desired from such system at a rate of about 0.1 mg / cm2 to about 10 mg / cm2 and more preferably 0.1 mg / cm2 to about 0.6 mg / cm2, to deliver from about 2 to about 50 mg per 24 hours . In certain embodiments of the invention, an enhancer may be incorporated in either the carrier composition or the polymeric coating, or both. The term "enhancers" as used herein refers to substances used to increase the permeability and / or accelerate the delivery of an active agent through the skin or mucosa, and include monohydric alcohols such as ethyl, isopropyl, butyl and benzyl alcohols; or dihydric alcohols such as ethylene glycol, diethylene glycol, or propylene glycol, dipropylene glycol, and trimethylene glycol; or polyhydric alcohols such as glycerin, sorbitol and polyethylene glycol, which enhance the solubility of the drug; polyethylene glycol ethers of aliphatic alcohols (such as cetyl, lauryl, oleyl and stearyl) including polyoxyethylene lauryl ether (4), polyoxyethylene oleyl ether (2) and oleyl ether of commercially available poly (oxyethylene) available under the trademark BRIJ® 30, 93 and 97 of ICI Americas, Inc., and BRIJ® 35, 52, 56, 58, 72, 76, 78, 92, 96, 700 and 721; fish and animal and vegetable oils and fats such as cottonseed, corn, sunflower, olive and castor oils, squalene, and lanolin; fatty acid esters such as propyl oleate, decyl oleate, isopropyl palmitate, glycol palmitate, glycol laurate, dodecyl myristate, isopropyl myristate and glycol stearate that enhance the diffusion of the drug; fatty acid alcohols such as oleyl alcohol and its derivatives; fatty acid amides such as oleamide and its derivatives; urea and urea derivatives such as alontine that affect the ability of keratin to retain moisture; polar solvents such as dimethyldecylphosphoxide, methyloctylsulfoxide, dimethylarnurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide and dimethylformamide affecting the permeability of keratin; salicylic acid that softens keratin; amino acids that are penetration assistants; benzyl nicotinate which is a hair follicle opener; and higher molecular weight aliphatic surfactants such as lauryl sulfate salts that change the surface condition of the skin and drugs administered and sorbitol esters and sorbitol anhydride such as commercially available polysorbate 20 under the brand name Tween® 20 from ICI Americas, Inc., as well as other polysorbates such as 21, 40, 60, 61, 65, 80, 81 and 85. Other suitable enhancers include oleic and linoleic acids, triacetin, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, acetate of tocopherol, tocopheryl linoleate. If the enhancers are incorporated into the transdermal system, the amount typically varies up to about 30% or preferably from about 0.1% to about 15% > , by weight based on the dry weight of the total carrier composition. The preferred enhancers for use in the drug carrier composition and polymeric coating differ by virtue of their different processing conditions. Intensifiers suitable for use with the polymeric coating are those with sufficiently high boiling points or lower volatile reactivity within the coating to withstand prolonged exposure to high processing temperatures used to scavenge the solvents therein, and include saturated aliphatic and cycloaliphatic alcohols and unsaturated, monovalent having 6 to 12 carbon atoms such as cyclohexanol, lauryl alcohol and the like; the cycloaliphatic and aliphatic hydrocarbons such as mineral oils; aromatic and cycloaliphatic aldehydes and ketones such as cyclohexanone; N, N- di (lower alkyl) acetamides such as diethyl N-acetamide, dimethyl N-acetamide, N- (2-hydroxyethyl) acetamide, and the like; aliphatic and cycloaliphatic esters such as isopropyl myristate and lauricidin; N, N-di (lower alkyl) sulfoxides such as decylmethyl sulfoxide; essential oils; cycloaliphatic and nitrated aliphatic hydrocarbons such as N-methyl-2-pyrrolidone, Azona; salicylates, polyalkylene glycol silicates; aliphatic acids such as oleic acid and lauric acid, terpenes such as cineole, surfactants such as sodium lauryl sulfate, siloxanes such as hexamethyl siloxane; polyethylene glycols, polypropylene glycols, and polyether polyols, epoxidized flax seed oils, simple liquid esters and the like, alone or in combination. On the other hand, enhancers suitable for use with the drug carrier composition are those with lower boiling points or reactivity or higher relative volatility within the carrier composition since exposure to high processing temperatures is decreased, and therefore both its loss, similar to drug loss, is decreased. Such enhancers are well known in the art and examples include alcohols, propylene glycol, dipropylene glycol, butylene glycol, m-pyrol, oleates, and laurates, with propylene glycol being preferred.

In addition, the enhancers may also be incorporated in various pharmaceutically acceptable excipients and additives available to those skilled in the art. These additives include thickeners such as aliphatic hydrocarbons, mixed aromatic and aliphatic hydrocarbons, aromatic hydrocarbons, substituted aromatic hydrocarbons, hydrogenated esters, polyterpenes, silicone fluid, mineral oil and hydrogenated wood resins. Additional additives include binders such as lecithin which "bind" the other ingredients, or Theological agents (thickeners) containing silicone such as silica in smoke, reagent grade sand, precipitated silica, amorphous silica, colloidal silicon dioxide, fused silica, silica gel, particulate silica and quartz materials commercially available as Syloid®, Cabosil®, Aerosil® and Whitelite®, for purposes of increasing the uniform consistency or continuous phase of the composition or coating. Other additives and excipients include diluents, stabilizers, fillers, clays, regulating agents, biocides, humectants, anti-irritants, antioxidants, preservatives, plasticizing agents, degradation agents, flavoring agents, dyes, pigments, and the like. Such substances may be present in any amount sufficient to impart the desired properties to the composition or coating. Such additives or excipients are typically used in amounts up to 25%, and preferably from about 0.1% to about 10%, by weight based on the dry weight of the total carrier composition. The transdermal system 10 also employs release liners or removable / peelable covers and backs to protect and / or hold the system or its components during manufacture as described herein, or later, and to permit handling and transportation. The release liner is typically impermeable and occlusive, and must be compatible with the particular polymers or active agents so as not to interfere with the ultimate application of the composition and therapeutic effect. Some suitable materials that can be used, singularly, in combination, such as laminates, films or as coextrusions, to form the release liner are known in the art. When the release liner is composed of a material that is typically not easily released (i.e., it is not easily removed or separated from the coating or composition to which it is fixed), eg, paper, a releasable material such as a silicone, Teflon®, or the like, can be applied to the surface by any conventional means. Preferred release liners are commercially available films from DuPont, Wilmington, Del., Under the trademarks Mylar® and commercially available fluoropolymer (silicone) coated films available from Rexam Reeléase, Oak Brook, III, under the trademarks FL2000® and MRL2000 ®, and 3M Corporation, St. Paul, Minn, sold under the trademarks ScotchPak® such as 1022. The backing is typically moisture impermeable and flexible but must be compatible with the particular polymers or active agents used so as not to interfere with the Last application of the composition and therapeutic effect. Some suitable materials can be used, singularly, in combination, such as laminates, films or as coextrusions, to form the backing layer 20 are also known in the art and include films or sheets of polyethylene, polyester, polypropylene, polyurethane, polyolefin, alcohol polyvinyl, polyvinyl chloride, polyvinylidene, polyamide, vinyl acetate resins, BAREX®, ethylene / vinyl acetate copolymers, ethylene / ethylacrylate copolymers, sheets or films deposited from metal vapor thereof, films or sheets of rubber, films or sheets of expanded synthetic resin, non-woven fabrics, fabrics, woven fabrics, garments, sheets and papers. The backing layer 20 can generally have a thickness in the range of 2 to 1000 microns. The backing layer 20 can be pigmented, for example, coloring to either match or easily distinguish in a conversational manner the application site, and / or contain printing, labeling and other means of identification and / or tracing of the transdermal unit or system itself. The backing layer 20 can be made opaque or substantially opaque (ie, preventing light or certain energy wavelengths from penetrating or passing through it), such as by metallization, fillers, inks, dyes and the like, for purposes of protecting photosensitive active agents from degradation and / or preventing photoallergic reactions or irritations in the subject.

In the manufacture of a transdermal system 10 according to the present invention, the drug carrier composition 12 and the adhesive and / or polymeric coating not loaded with drug 1 8 are prepared separately and then combined. The drug carrier and polymeric coating comprising the present invention can be prepared in any manner known to those skilled in the art. An exemplary general method for preparing the transdermal system 10 is as follows: 1. Amounts - appropriate to the polymer (s), adhesive (s), solvent (s), co-solvent (s), enhancer (s), additive (s) and / or excipient (s) are combined and mixed completely and uniformly together in a container to form the polymeric coating not loaded with drug. 2. The polymeric coating is then transferred to a coating operation where it is melted in a backing layer / film to a specific controlled thickness and exposed to elevated temperatures, such as in an oven, to remove volatile processing solvents. 3. The polymeric coating is then laminated to a release liner applied to the surface opposite the backing / layer and rolled into rolls. 4. Appropriate quantities of drug (s), polymer (s), adhesive (s), solvent (s), co-solvent (s), enhancer (s), additive (s) and / or excipient (s) are combined and thoroughly and uniformly mixed together in a container to form the active agent carrier composition. 5. The composition is then transferred to a coating operation where it is melted in a release liner at a specific controlled thickness and exposed to elevated temperatures, such as in an oven, to remove solvents from volatile processing. 6. As shown in Fig. 2, the release liner 22 which is fixed to the polymeric coating 18 to form the backing compound 16 is then removed and fixed to the exposed surface of the drug carrier composition 12, and the assembly Laminate is rolled into rolls. 7. Then, the supply systems of desired size and shape 10 are prepared by die-cutting or the like, of the rolled laminate and then packaged. Alternatively, the release liner 22 may not be necessary if both the carrier-agent composition 12 and the back-up compound 16 are produced concomitantly, where attachment to each other could be made after processing each individually, such as in a online process, thus avoiding stage 3 above. As described above, either the drug carrier composition 12 or the polymeric coating 1 8 can be a pressure sensitive adhesive or adhesive, allowing pressure lamination to each other by other adhesive qualities. However, where a release liner 22 is employed in the manufacturing steps, it is preferable to attach it to the polymeric coating and not the drug carrier composition to prevent any additional drug loss that could occur from coiling the rolls and subsequent removal of such. release liner, or release liner failure 22 to adhere to the drug carrier composition. Additionally and alternatively, a separate adhesive can be used to (a) fix the backing compound 16 to the drug carrier composition 12 on the surface opposite the release liner 15 and / or (b) fix the polymeric coating or the carrier composition of the adhesive. drug, depending on what is used as the point of topical application to the skin or mucosa, to either the film / backing layer or release liner. In certain other preferred embodiments, a non-woven drug permeable film / layer, such as a polyester film, may be interposed, such as pressure lamination, for structural support or ease of fabrication (ie, has no effect on controlling the permeation of drug or supply) between the drug-laden coating and the carrier composition loaded with drug. When the manufacture of a transdermal system to deliver certain drugs, such as amphetamine base, which volatilize at or near room temperature and / or degrade by exposure to atmospheric air, or that employ the use of volatile intensifiers, particular care must be employed to avoid prolonged processing times or exposure to air . In this regard, the controlled manufacturing environments, for example, using lower temperatures or pressures, modifying the atmospheric gases present (such low carbon dioxide levels or using nitrogen instead of air), or modifying air or gas flow (such as during oven drying to remove solvents) at various stages during the process, it may also be necessary or desirable. The order of the processing steps, the amount of the ingredients, and the amount and time of agitation or mixing can be important process variables that will depend on the specific polymers, active agents, solvents or co-solvents, enhancers and additives and excipients used in the transdermal system. These factors can be adjusted by those skilled in the art, while keeping in mind the objects of achieving interaction between the drug carrier composition and the non-drug loaded coating. It is believed that a number of other methods, for example, other coating methods that are well known in the art, such as Mayer rod, gravure, knife on roller, extrusion, casting, calendering, and model, or changing the order of certain stages, it can be carried out and it will also give desirable results. EXAMPLES In the Examples as shown with respect to Figs. 3-5, the effect of variations in the coating not loaded with drug is determined, indicating effective control of the rate of permeation, initiation and profile as well. Referring to the most preferred embodiment shown in Fig. 1, although the Examples are directed to formulations using amphetamine base d, representative of a low molecular weight drug, and using acrylic based adhesive coating, it should be understood that the modulation of Similar drug can be achieved with other active agents, and through the use of other polymers and system configurations as it is treated. All studies were conducted in relation to a transdermal control delivery system, which is a transdermal methylphenidate base delivery system (MethyPatch® produced by the assignee of the present invention, Noven Pharmaceuticals, Inc.) having a permeation rate known, start and profile. All drug-laden carrier compositions containing d-amphetamine are prepared using a mixture of an acrylic-based, non-functional pressure sensitive adhesive having 75% solids in ethyl acetate and a silicone pressure sensitive adhesive (BIO-PSA 7-4302). The composition is coated on a fluoropolymer liner and dried in an oven at 76 ° C to produce a pressure sensitive adhesive composition by dry weight of 5% acrylic adhesive, 75% silicone adhesive, and 20% drug in a coating weight of approximately 5 mg / cm2. All acrylic-based adhesive coatings not loaded with medicament are prepared using the same acrylic adhesive used to prepare the drug-laden carrier composition, which is coated on a polyester backing and dried in a coating weight, for example 1 and 2, at about 7.5 mg / cm 2 (example 3 addressing variable coating weights as indicated below) before being laminated by pressure in the drug carrier composition. The drug flow determination of the described formulations is conducted in a modified Franz diffusion cell through a stratum corneum disk obtained from human cadaver skin. The formulations of the transdermal system are cut by die to be punched, mounted on the disc, and placed in the cell, which contains an isotonic saline solution. The cells are stored at 32 ° C for the duration of each flow study while having the solution stirred at a constant speed of about 300 rpm. Samples (n = 5) of the solution are taken at various time points for the duration of the study (9 hours), and drug concentrations are determined by high pressure liquid chromatography. EXAMPLE 1 In Example 1, two acrylic-based adhesive coatings are prepared, each containing two different non-functional monomers but in different proportions, 1: 1 and 8: 2. No effect has been observed based on the non-reactive properties of non-functional acrylic adhesives with drugs. As seen in Fig. 3, the effect of varying the monomer proportions significantly influences both the profile and the speed of supply, one being of a first-order type (rapid start and amount followed by elimination) and the other being close to the order of zero ("sustained"). EXAMPLE 2 In Example 2, three acrylic-based adhesive coatings are prepared, which had different functionality, one being non-functional and the other two being carboxy functional but with varying concentrations (4% and 8%) of the monomeric acrylic acid functional of carboxy. As indicated in Fig. 4, the non-functional acrylic coating imparted faster drug onset and drug removal higher than any functional carboxy coating. In addition, the use of functional carboxy monomers decreased the onset of drug and provided a zero order delivery profile. Accordingly, the addition of functional portion to the acrylic coating, in this case acid functionality, increasingly decreased both the drug flow and the start with increasing carboxy concentrations, but can provide a zero order delivery rate profile. EXAMPLE 3 In Example 3, three acrylic-based adhesive coatings are each prepared using the acrylic adhesive coating described in Example 2 containing 8% carboxy functionality but applied to the backing in three different thicknesses, approximately 2.5 mg / cm 2, approximately 5%. mg / cm2, and approximately 7.5 mg / cm2. As indicated in Fig. 5, the flow rate increases as the thickness of the acrylic adhesive coating decreases, while the supply profile approaches close to zero order as the thickness of the acrylic adhesive coating increases. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention described herein. The benefit of provisional application 60 / 515,306, filed on October 28, 2003, is claimed herein. The complete contents of this provisional application are incorporated in the present for reference. It is proposed that the specification be considered as exemplary only, with the scope and true spirit of the invention indicated by the following claims.

Claims (43)

1. CLAIMS 1. A transdermal drug delivery composition, said composition comprising. a backup layer; at least one adhesive coating layer, a first surface of said at least one layer of adhesive coating being fixed to a surface of said backing layer; at least one layer of carrier composition, a first surface of said at least one layer of carrier composition being fixed to a second surface of said at least one layer of adhesive coating; and a removable release liner affixed to a second surface of said at least one layer of carrier composition, wherein said at least one layer of carrier composition includes a therapeutically effective amount of one or more drugs incorporated into the at least one layer of composition. carrier 2. The transdermal drug delivery composition according to claim 1, characterized in that said adhesive coating layer comprises at least acrylic-based polymer. 3. The transdermal drug delivery composition according to claim 1, characterized in that said layer of carrier composition comprises at least one acrylic-based polymer. 4. The transdermal drug delivery composition according to claim 3, characterized in that said carrier composition is a mixture of at least one acrylic-based polymer and at least one second polymer selected from the group consisting of silicone-based polymers, rubbers, gums, polyisobutylenes, polyvinyl ethers, polyurethanes, styrene block copolymers, styrene / butadiene polymers, polyether block amide copolymers, ethylene / vinyl acetate copolymers, and vinyl acetate based adhesives, and bioadhesives. 5. The transdermal drug delivery composition according to claim 4, characterized in that said at least one second polymer includes a silicone-based polymer. 6. The transdermal drug delivery composition according to claim 4, characterized in that the acrylic based polymer is present from about 2% to about 95% of the total dry weight of the carrier composition. The transdermal drug delivery composition according to claim 1, characterized in that said layer of carrier composition includes an acrylic-based polymer that is present from about 2% to about 95% of the total dry weight of the carrier composition. 8. The transdermal drug delivery composition according to claim 7, characterized in that said acrylic based polymer is present from about 2% to about 85% of the total weight of the carrier composition layer. The transdermal drug delivery composition according to claim 1, characterized in that said layer of carrier composition includes: (i) a first acrylic-based polymer having a first functionality and a first solubility parameter; and (ii) a second acrylic-based polymer having a second functionality and solubility parameter, wherein the functionalities, first and second, differ in the amount and type of functional groups, to provide a combination of acrylic-based polymer having a net functionality proportional to the proportion of the acrylic, first and second base polymers used, and they are present in proportions to provide a net solubility parameter. The transdermal drug delivery composition according to claim 9, characterized in that the first acrylic-based polymer is present in an amount to provide a flow of one or more drugs in the dermal drug delivery composition that is greater than one. composition based only on the second acrylic-based polymer. eleven . The transdermal drug delivery composition according to claim 10, characterized in that the amount of the second acrylic-based polymer is in the range of 5-95% by weight and the amount of the first acrylic-based polymer is in the range of 95. to 5% by weight, all based on the total dry weight of the polymer. The transdermal drug delivery composition according to claim 1, characterized in that the amount of the second acrylic-based polymer is in the range of 20-75% by weight and the amount of the first acrylic-based polymer is in the range of 20-75% by weight. range of 75 to 20% by weight, all based on the total dry weight of the polymer. The transdermal drug delivery composition according to claim 9, characterized in that the first acrylic-based polymer has substantially non-functional groups and the second acrylic-based polymer has predetermined functional groups. 14. The transdermal drug delivery composition according to claim 13, characterized in that the second acrylic-based polymer has hydroxy and / or carboxyl functional groups. The transdermal drug delivery composition according to claim 13, characterized in that the second acrylic-based polymer is present in an amount to provide an increased saturation concentration in the dermal drug delivery composition that is greater than a composition based on only in the first acrylic-based polymer. 16. The transdermal drug delivery composition according to claim 9, characterized in that the functional groups are provided by monomer units containing functional groups that are incorporated in the second acrylic-based polymer in an amount of from 0.1 to 20% by weight, in based on the dry weight of the second acrylic-based polymer. 17. The transdermal drug delivery composition according to claim 16, characterized in that the functional monomers are incorporated in the second acrylic-based polymer in an amount of from 0.1 to 8% by weight, based on the dry weight of the second polymer. acrylic base. 18. The transdermal drug delivery composition according to claim 9, characterized in that the at least two polymers contain substantially only the first and second acrylic based polymers. 19. The transdermal drug delivery composition according to claim 9, characterized in that the second acrylic based polymer includes carboxyl functional groups. 20. The transdermal drug delivery composition according to claim 19, characterized in that the carboxyl-functional acrylic-based polymer includes 0.1 to 10% by weight of carboxyl functional monomer units. twenty-one . The transdermal drug delivery composition according to claim 20, characterized in that the carboxyl-functional acrylic-based polymer is an acrylic based polymer of degraded vinyl acetate. 22. The transdermal drug delivery composition according to claim 1, characterized in that said adhesive coating layer includes: (i) a first acrylic-based polymer having a first functionality; and (i) a second acrylic-based polymer having a second functionality, wherein the functionalities, first and second differ in the amount and -type of functional groups, to provide an acrylic-based polymer combination having a net functionality proportional to the proportion of the acrylic based, first and second, used polymers. The transdermal drug delivery composition according to claim 22, characterized in that the amount of the second acrylic based polymer is in the range of 5-95% by weight and the amount of the first acrylic-based polymer is in the range from 95 to 5% by weight, all based on the total dry weight of the polymer. 24. The transdermal drug delivery composition according to claim 22, characterized in that the amount of the second acrylic-based polymer is in the range of 20-75% > by weight and the amount of the first acrylic based polymer is in the range of 75 to 20% by weight, all based on the total dry weight of the polymer. 25. The transdermal drug delivery composition according to claim 22, characterized in that the first acrylic-based polymer has substantially non-functional groups and the second acrylic-based polymer has predetermined functional groups. 26. The transdermal drug delivery composition according to claim 25, characterized in that the second acrylic based polymer has hydroxy and / or carboxyl functional groups. 27. The composition of the transdermal drug delivery according to claim 22, characterized in that the functional groups are provided by monomer units containing functional groups that are incorporated in the second acrylic-based polymer in an amount of from 0.1 to 20% by weight, based on the dry weight of the second acrylic-based polymer. 28. The transdermal drug delivery composition according to claim 27, characterized in that the functional monomers are incorporated into the second acrylic-based polymer in an amount of from 0.1 to 8% by weight, based on the dry weight of the second polymer. acrylic base. 29. The transdermal drug delivery composition according to claim 22, characterized in that the at least two polymers contain substantially only the first and second acrylic based polymers. 30. The transdermal drug delivery composition according to claim 22, characterized in that the second acrylic based polymer includes carboxyl functional groups. 31 The transdermal drug delivery composition according to claim 30, characterized in that the carboxyl-functional acrylic-based polymer includes 0.1 to 10% by weight of carboxyl functional monomer units. 32. The transdermal drug delivery composition according to claim 31, characterized in that the carboxyl-functional acrylic-based polymer is an acrylic polymer of degraded vinyl acetate. 33. The transdermal drug delivery composition according to claim 1, characterized in that said adhesive coating layer includes a mixture of: (i) an acrylic-based polymer and (ii) at least one second polymer selected from the group consisting of polymers based on silicone, rubbers, gums, polyisobutylenes, polyvinyl ethers, polyurethanes, styrene block copolymers, styrene / butadiene polymers, polyether block amide copolymers, ethylene / vinyl acetate copolymers, and acetate-based adhesives came, and bioadhesives. 34. The transdermal drug delivery composition according to claim 33, characterized in that said second polymer includes a silicone-based polymer. 35. The transdermal drug delivery composition according to claim 1, characterized in that said adhesive coating layer has a coating weight of from about 2.5 to about 15 mg / cm2. 36. The transdermal drug delivery composition according to claim 35, characterized in that said adhesive coating layer has a coating weight of from about 2.5 to about 7.5 mg / cm2. 37. The transdermal drug delivery composition according to claim 1, characterized in that said adhesive coating layer has a coating weight. from about 5 mg / cm2. 38. The transdermal drug delivery composition according to claim 1, characterized in that said adhesive coating includes at least one acrylic-based polymer and wherein said acrylic-based polymer is composed of at least 50% by weight of an acrylate or alkyl acrylate monomer, from 0 to 20% of a functional monomer copolymerizable with the acrylate, and from 0 to 40% of other monomers. 39. The transdermal drug delivery composition according to claim 38, characterized in that said acrylate or alkyl acrylate monomer includes acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, acrylate -ethylbutyl, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecyl methacrylate. 40. The transdermal drug delivery device according to claim 39, characterized in that said functional monomer is a monomer selected from the group consisting of methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate and methoxyethyl methacrylate. 41 A method for producing the transdermal drug delivery composition according to claim 1, comprising the steps of: thoroughly and uniformly mixing together in a package appropriate amounts of the polymer (s), adhesive (s), solvent (s) , co-solvent (s), enhancer (s), additive (s) and / or excipient (s) to form said adhesive coating layer; melting said adhesive coating layer on a backing film and exposing said melted adhesive layer at elevated temperatures to remove the volatile processing solvents; laminating said adhesive coating on a first release liner that is applied to the surface opposite the backing film; thoroughly and uniformly mixing together appropriate amounts of drug (s), polymer (s), adhesive (s), solvent (s), co-solvent (s), enhancer (s), additive (s) and / or excipient (s) ) in a container to form the carrier composition layer; melting said carrier composition onto a second release liner; removing said first release liner and fixing said adhesive coating layer to said layer of carrier composition. 42. The method according to claim 41, characterized in that said carrier composition is exposed to elevated temperatures to remove the volatile processing solvents after melting in said second release liner. 43. A method for controlling the flow of a drug of a dermal drug delivery composition, comprising: (a) providing a composition comprising: (i) a backing layer; (ii) at least one adhesive coating layer, a first surface of said at least one adhesive coating layer being fixed to a surface of said backing layer; (iii) at least one layer of carrier composition, a first surface of said at least one layer of carrier composition being fixed to a second surface of said at least one layer of adhesive coating; and (iv) a release liner affixed to a second surface of said at least one layer of carrier composition, wherein said at least one layer of carrier composition includes a therapeutically effective amount of one or more drugs incorporated in the at least one layer of carrier composition. (b) selectively adjusting said adhesive coating layer by modifying the coating weight, monomeric processing or functionality of said adhesive coating layer.