MXPA97007868A - Triacetin as an incrementer of penetrationtransderm - Google Patents

Abstract

The present invention relates to a composition and method for increasing the transdermal penetration of a basic drug. The composition comprises a matrix patch consisting of an effective amount of a basic drug, preferably having a pKa of about 8.0 or more, an effective amount of a penetration enhancer consisting essentially of triacetin, and a polymer layer that it preferably comprises a pressure sensitive adhesive. A preferred basic drug is oxybutynin and acid addition salts thereof. The method to increase the transdermal penetration comprises the application of the matrix patch on a selected area of the pi

Description

TRIACETI A AS AN INCREMENTER FOR TRANSDERMAL PENETRATION FIELD OF THE INVENTION The present invention generally relates to a composition and method for increasing the supply of bioactive agents through biological membranes including the skin or mucosa. More particularly, the invention relates to the use of triacetin (glyceryl triacetate) to increase the transdermal or transmucosal delivery of a basic drug having a pH of about 8.0 or more, such as oxybutynin. BACKGROUND OF THE INVENTION The oral administration of drugs as currently used is unsatisfactory for numerous reasons. First, drugs with short half-lives require frequent dosing (2 to 4 times a day), which causes inadequate compliance on the part of the patient. Second, the short plasma half-life of the drug and the frequent dosing regimen result in "peaks" and "valleys" in terms of the plasma concentration profile which increases the likelihood of side effects associated with the peak concentration as well as a decrease in therapeutic effectiveness towards the end of the dosing interval. Third, the potential effect of the hepatic first-pass metabolism associated with oral administration may result in an unsatisfactory biodispani bility of the drug. Therefore, an effective and consistent drug delivery system that overcomes these disadvantages would be far superior to the oral oral regime. Transdermal drug administration provides many advantages compared to conventional oral administration. The advantages of transdermal systems include comfort, uninterrupted therapy, better compliance on the part of the patient, reversibility of treatment (by removing the skin system), elimination of the "first pass hepatic" effect, high degree of control over the blood concentration of the drug, and an improved overall therapy. Although transdermal systems have numerous advantages, most drugs can not be delivered by this form of administration due to the well-known skin barrier properties. Molecules that move from the environment to and through intact skin must first penetrate the stratum corneum, the outer cornea of the skin, and any material that is on its surface. The molecule must then penetrate through the viable epidermis and papillary dermis before passing through the capillary walls and into the systemic circulation. Along this route, each of the aforementioned tissues presents a different resistance to penetration by the same molecule. However, it is the stratum corneum, a complex structure of compact keratin cell residues separated by lipid domains and tracers that present the greatest barrier to the absorption of topical compositions or transdermally administered drugs. In comparison with the oral or gastric mucosa, the stratum corneum is much less permeable to external molecules. The flow of a drug through the skin can be increased by changing either < a) the resistance (the diffusion coefficient), or (b) the driving force (the solubility of the drug in the stratum corneum and therefore the diffusion gradient). Many incrementist compositions have been developed to change one of these factors to both. The North American Patents Number 4,006,218; 3,551,154? and 3,472,931, for example, respectively describe the use of di-ethylsulfoxide (DMSO), dimethylformamide (DMF), and N, N-dimethylacetamide < DMA) to increase the absorption of drugs applied topically through the stratum corneum. Combinations of enhancers consisting of diethylmaglyol monoethyl or onomethyl ether with propylene glycol onolaurate and methyl laurate are presented in North American Patent No. 4,973,468 with transdermal steroid supply enhancers such as progestogens and estrogens.

A double enhancer consisting of glycerol monolaurate and ethanol for transdermal drug delivery is known from U.S. Patent No. 4,820,720. The North American Patent No. 5,006,342, presents a list of numerous increments for the transdermal administration of drugs consisting of fatty acid esters or fatty alcohol esters of C2 to C4 alkanoles, where each fatty acid / alcohol portion of the ester / ether is suitably 8 to 22 carbon atoms. U.S. Patent No. 4,863,970 shows compositions that increase penetration for topical application comprising an active agent contained in a vehicle that increases penetration containing specific amounts of one or more compounds that disorder the cellular envelope such as oleic acid, oleyl alcohol, and glycerol esters of oleic acid? a C2 or C3 alkanol; and an inert diluent such as water. It is known that triacetin is a solvent for solubilizing a drug and / or other components of drug delivery systems. For example, Mahjour et al., U.S. Patent No. 4,879,297, presents triacetin as a solvent in a system of polyethylene glycol and linoleic acid enhancers. The increase in the amounts of triacetin and the corresponding decrease in the amounts of linoleic acid in the enhancer formulations correlate with a decrease in the flow and an increase in the delay of the penetration of the O !; I orphan drug, which suggests that triacetin is relatively? not important in the formulation of increments. In another example, Ebert et al, document Q932516B-A1, presents triacetin as a solvent, in a list of many other solvents, which may be used in conjunction with a cellular envelope disorder compound for the supply of clonidine, progesterone, testosterone, and other drugs. Other Patent documents that describe triacetin co or solvent include U.S. Patent No. 4,908,389; U.S. Patent No. 5,019,395; U.S. Patent No. 4,666,926; U.S. Patent No. 4,857,313; U.S. Patent No. 4,789,547; U.S. Patent No. 4,814,173? U.S. Patent No. 4,783,450; EP-387647-A; JP63255227-A? JP62240628-A; and JP62215537-A. Triacetin is also known as a plasticizer. For example, Edgren et al., US Patent No. 5,160,743, teaches the use of triacetin as a conventional plasticizer for its use as an agent and ulsifier in tablets, capsules, powders and the like for the gastrointestinal release of drugs. Other patent documents and publications that disclose the use of triacetin as a plasticizer include Lin et al., 8 Phar. Res. 1137 (1991); WO 9313753; EP 509335-A1? and JP3083917-A. Triacetin has been discarded as also functioning as an antimicrobial agent. Alien, U.S. Patent No. 4,895,727, indicates that triacetin has an activity as an antifungal agent. It has further been established that triacetin contains a co-activity or absorption accelerator. I eda et al., W09309783-A1, shows a plaster containing piroxicam par * to achieve an anti-inflammatory and analgesic effect due to the absorption of piroxicam through the skin and establishes that triacetin increases the percutaneous absorption of piroxicam. Gypsum is composed of water soluble polymer adhesive; a glycol compound such as, for example, glycerin or propylene glycol; a crosslinking agent; water an inorganic powder; and a surfactant, such as, for example, polyoxyethylene sorbitol monooleates, polyoxyethylene bleach hydroxide, sorbitol monooleate, or polyoxyethylene glycol castor oil. It is further stated that, if necessary, penetration enhancers, preservatives, antioxidants, flavoring agents and colorants can also be added to the formulation. Glucosols and surfactants are classic solvents and compounds that disrupt the cell envelope known in the technique of increased penetration, for example North American Patent No. 4,855,294, therefore the observed effects appear to result from the combination of glycol, surfactant, and tr i acet J na. Japanese Patent Document JP0 148141-A discloses a two-layer percutaneous absorption preparation containing an adhesive, isosorbide dinitrate, and an absorption accelerator. Absorption accelerators are described as glyceryl triesters where the fatty acid esters have chain lengths of 1 to 4 carbon atoms, with triacetin being preferred. It should be recognized that isosorbide dinitrate has solubilizing properties per se, that is, it is a neutral "drug with solvent action", Sablotsky et al., US Patent No. 5,186,938. Other vasodilators, such as, for example, nitrate esters (-C-0-N02) characterized by a carbon-oxygen-nitrogen sequence and nitrite esters characterized by a sequence (-C-0-NO), are among these drugs that act as a solvent, including glyceryl trinitrate (erroneously called nitroglice ina according to its generalized and official designation), mannitol hexanitrate, erythritol tetranitrate, and pentaerythritol tetranitrate. Accordingly, the effect of increased penetration of triacetin reported in JP05148141-A appears only in combination with a neutral drug, which acts as a solvent.

What has not been previously taught is that triacetin per se is an effective penetration enhancer to promote the transdermal supply of drugs that do not act as solvents, particularly drugs that are approximately a drug. 8.0 or more and its acid addition salts. In view of the foregoing, it will be noted that compositions and methods for increasing the penetration of such a basic drug and its acid addition salts would be a significant progress in the art. OBJECTS AND COMPENDIUM OF THE INVENTION It is an object of the present invention to provide a composition and method for increasing the percutaneous delivery of a basic drug through the skin or mucosa. It is also an object of the present invention to provide a composition and method for increasing the transdermal delivery of the basic oxibuin drug or an acid addition salt thereof through the skin or mucus a. It is another object of the present invention to provide a composition and method for increasing the transdermal delivery of a basic drug having a pH of 8.0 or more, such as for example γ-ibutinin or an acid addition salt thereof, using triacetin as Penetration enhancer to permeate the skin or mucosa with the drug. These and other objects are achieved by providing a matrix patch to increase the rate of transdermal penetration of a basic drug having a pKa of about 8. or m-1, comprising (a.) A patchable polymeric rape; (b) an effective amount of a percutaneously absorbable basic drug having a pKa of approximately 8.0 or more; and < c > an effective amount of a permeation enhancer consisting essentially of triacetin. Preferred basic drugs having a pKa of 8.0 or more include oxybutynin, scopalamine, fluoxetine, epinephrine, morphine, hydromorphone, atropine, cocaine, buprenorphine, clarpromazin, imipramine, desipramine, methy1-phenylate, meta-fetamin, lidocaine, procaine, pindolol , nadolol, carisoprodol, and acid addition salts thereof. Oxybutynin and acid addition salts thereof are especially preferred. Preferably, the matrix patch comprises approximately 0.1% to approximately 50% by weight of triacetin, with a higher degree of preference of approximately 1% to approximately 40% by weight of triacetin, and more preferably from approximately 2% to approximately 20% by weight of triacetin. The polymer layer is preferably an adhesive layer, but it can also be laminated on an adhesive layer or used with an adhesive coating. Suitable polymers include acrylics, vinyl acetates, natural and synthetic rubbers, copolymers of et i lenvini lacetate, polyoxynes, polyurethanes, polyurethanes, opalmers of polyether block amides of μlasti fi c weight , copal ies of plastics block, and mixtures thereof. Acrylic copolymer adhesives are preferred. The matrix part may also contain diluents, excipients, emollients, plasticizers, agents that reduce skin irritation, vehicles, and mixtures thereof provided that such additives do not alter the basic and novel features of the matrix patch.

The method for increasing the transdermal penetration of a base drug comprises the application of the matrix step described above to a selected application site. DETAILED DESCRIPTION OF THE INVENTION Before presenting and describing the present composition and method for increasing the transdermal delivery of a basic drug, such as oxybutynin, and acid addition salts thereof, it is understood that this invention is not limited to process steps and particular materials contained herein and that such process steps and materials may vary to some extent. It is also understood that the terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to limit the invention since the scope of the present invention will be limited only by the appended claims and equivalents thereto. It should be noted that, as used in this specific ion and in the ane ions, the singular forms "a", "an" and "the" include plural referents unless the context clearly indicates otherwise. Accordingly, for example, the reference to a drug delivery device containing "a drug" includes a mixture of two or more drugs, the reference to "an adhesive" includes reference to one or more such adhesives, and the reference to "an excipient" includes reference to a mixture of two or more such excipients. In the description and claim of the present invention, the following terminology will be employed in accordance with the definitions set forth below. As stated herein, the terms "increase", "increase in penetration" or "increase in permeability" refer to an increase in the permeability of a biological membrane (for example skin or mucosa) in relation to a drug, to increase the speed with which the drug permeates through the membrane. "Increase permeation enhancer", "increaser", "penetration enhancer" or similar terms refer to a material that achieves such an increase in permeation, and an "effective amount" of an increment refers to an effective amount to increase Penetration through the skin or mucosa of a selected agent to a selected degree. The increased permeability in accordance with what has been achieved through the use of such increters can be observed, for example, by measuring the rate of diffusion of the drug through the skin of a human or animal using an apparatus of diffusion cell. Such a diffusion cell is described, in Merritt et al., "Di ffusión Apparatus for Skin Penetration," (Diffusion Apparatus for Cutaneous Penetration), 1 J. of Control led Reléase 61 (1984), which is incorporated herein by reference. As used herein, a "transdermal" or "percutaneous" delivery means refers to a delivery of a drug through its passage in and through the cutaneous or mucosal tissue. Accordingly, the terms "transdermal" and "transmucosal1" are used interchangeably unless specifically stated otherwise. In the same manner, the terms "skin", "dermis", "epidermis", "mucosa", and the like will also be used interchangeably unless specifically stated otherwise. By the term "permeant" or "drug" we refer to any material or chemical compound suitable for transdermal or transmucosal administration, which exists in the form of a free base or an appropriate acid addition salt and which induces a biological effect or pharmacological desired by transdermal delivery. Such substances include the broad classes of compounds normally supplied through body systems such as skin. In general, this includes therapeutic agents in all major therapeutic areas including, but not limited to, anti-infective agents or for example antibiotics and antiviral agents, analgesics and combinations of analgesics, anorexics, antidiarrheals, anti-histamines, anti-inflammatory agents. , anti-migraine preparations, anti-movement disease agents, antineuant agents, antineoplastic agents, anti-Parkinson's disease drugs, antipruritics, antipsychotics, antipyretics, iodic anisers including gastrointestinal and urinary, anticholinergic, sympathomimetic, derivatives of anticancer drugs, cardiovascular preparations including calcium channel blockers, beta-blockers, apharyngotics, antihypertensives, diuretics, vasodilators including general coronary, peripheral and cerebral, stimulators of the central nervous system including cough and cold preparations, decongestants, day Gnostics, hormones, suppressors, muscle relaxants, parasympathetics, parasympathomimetics, psychostimulants, sedatives and tranquilizers. The term "per eante" or "drug" also means mixtures. By mixtures are meant combinations of permeants of different categories, ezcl s of permeants of the same category, and mixtures of the form of S ?! and free base of the same permeants or different permeants coming from the same categories or from different categories. By "basic drug" is meant a drug or per edant which is a free base or an acid addition salt thereof. Preferred basic drugs contain an amino group that provides the drug with a basic character. With greater degree of preference, they are strongly basic drugs with a pKa of about 8.0 or more. Preferred examples of basic drugs that can be delivered by means of the penetration enhancement system of the present invention include o? Ibutinin, scopola ina, fluoxetine, epinephrine, morphine, hydromorphone, atropine, cocaine, buprenorphine, chlorpromazine, imipramine, desipramine, methylphenidate , meta fetamine, lidocaine, procaine, pindolol, nadolol, carisoprodol, and acid addition salts thereof. Oxybutynin and acid addition salts thereof are especially preferred. By "effective amount" of a drug or permeant is meant a non-toxic but sufficient amount of a compound to provide the desired local or systemic effect. An "effective amount" of permeation enhancer, as used herein, refers to an amount selected to provide the desired increase in membrane permeability and consequently, the desired depth of penetration, rate of administration, and amount of drug. By "drug delivery system", "drug composition / enhancer", or any similar terminology, is meant a formulated composition containing the drug to be delivered transdermally in combination with a penetration enhancer. Other pharmaceutically acceptable materials or additives may also be contained in the drug / enhancer composition, such as, for example, diluent, skin irritation reduction agent, carrier or vehicle, excipient, plasticizer, emollient, or other additive and mixtures. thereof provided that such additives do not materially affect the basic and novel characteristics of the matrix part. By the term "matrix", "matrix system", or "matrix patch", we mean a permeant or active drug dissolved or suspended in a biocompatible polymer phase, preferably a pressure sensitive adhesive, which it may also contain other ingredients or in which the enhancer is dissolved or suspended as well. This definition is intended to include embodiments in which such a polymer phase is laminated onto a pressure sensitive adhesive or used with a coating adhesive. A matrix system usually and preferably comprises an adhesive layer having an impermeable film reinforcement laminated on the distal surface thereof and, prior to transdermal application, a release coating on the near surface of the adhesive. The film support protects the phase of the matrix patch and prevents the release of the drug and / or enhancer into the environment. The release liner functions in a manner similar to the waterproof support, but is removed from the matrix patch prior to the application of the patch on an application site. Matrix patches are known in the art of transdermal drug delivery which typically contain such liner and release liner components, and matrix patches in accordance with the present invention should be considered as comprising such liner and release liners or linings. functional equivalents. U.S. Patent No. 5,122,383 describes such reinforcements and is incorporated herein by reference. Accordingly, a matrix system is a unit dosage form of a pharmaceutical composition in a polymer vehicle, which also contains the enhancer and other components formulated to maintain the pharmaceutical composition in the polymeric layer in a ratio of drug transfer to the dermis, i.e., the skin or mucosa. A matrix patch is distinguished from a "liquid reserve patch", to the extent that a permeant or active drug is dissolved in a gel-like liquid contained in an occlusive device that has an impermeable reinforcing surface and a surface oppositely configured with a permeable and adhesive membrane for transdermal application. See, for example, U.S. Patent No. 4,983,395. As used herein, the term "application site" refers to a site suitable for topical application with or without the intermediary of a mechanical prolonged release device, patch or bandage, eg, behind the ear, in the arm, back, chest, abdomen, leg, upper part of the foot, etc. As described above, the present invention comprises a matrix patch for increasing the transdermal delivery of a basic drug having a pKa of about 8.0 or more, comprising (a) a biocompatible polymeric layer; (b) an effective amount of a percutaneously absorbable basic drug having a pKa of about 8.0 or more; and < c > an effective amount of a permeation enhancer consisting essentially of triacetin.

It is surprising and unexpected that triacetin is effective in increasing the transdermal penetration of basic drugs, particularly those with a pH of approximately 0.0 or more, but not of neutral to acidic drugs. Among these basic drugs for which permeation is increased by means of triacetin, an oxybutynin-free base and the acid addition salts thereof are preferred. It is also surprising that, even though triacetin is effective as a penetration enhancer for basic drugs, such as oxybutynin-free base, in matrix patch formulations, no increase in the penetration of basic drugs (including oxybutynin) has been observed. or other drugs with liquid reservoir patches containing pharmaceutical formulations in gel form. Suitable polymers that can be employed in the biocompatible polymeric layer of the matrix patch include pressure sensitive adhesives suitable for long-term contact with the skin. Such adhesives must be physically and chemically compatible with the drug and enhancer, and with any carrier and / or carrier or other additives incorporated in the drug / enhancer composition. Suitable additives for use in the matrix patch include acrylic adhesives that include copal crosslinked and non-crosslinked acrylic monomers; vinyl acetate adhesives; natural and synthetic rubbers which include polyisobutyl logs, neoprene, polybutadienes, and polyesters; copolymers of et i lertvi ni lacetai or? pal i si la: anos; pol ucp latos; polyurethanes; Polyamide block amide groups of plasticized weight, and plastic-rubber block copolymers plastified. Preferred contact adhesives for use in the matrix patch of the present invention are acrylic adhesives, such as TSR (Sekisui Chemical Co., Osaka, Japan), and Durotaf * (r) adhesives (National Starch Z > Co., Bridgewater, NJ), as well as polybutylene glycol adhesives such as ARc re (mr) MA-24 (Adhesives Research, Glen Fact < Pennsyl vania). In use, the matrix patch contains a distal laminated backing on the polymer layer. The distal backrest defines the side of the matrix patch that faces the environment, i.e., distal in relation to the skin or mucosa. The backup layer functions to protect the matrix polymer layer and the drug / enhancer composition and to provide an impenetrable layer that prevents drug loss to the environment. Therefore, the material chosen for the backing must be compatible with the polymer, drug, and enhancer layer and must be minimally permeable to matrix patch components. Preferably, the backing must be opaque to protect the components of the matrix patch against degradation due to exposure to ultraviolet light. In addition, the backing must be able to support the polymer layer, and yet be sufficiently faithful to allow the movements of a person using the matrix patch. Suitable materials for the backing include metal sheets, metallized polyhoyabs, sheets or composite films containing polyester such as polyester terephthalate, polyester or aluminized polyester, polyfluoroethane, polyether block amide copolymers, methacrylate block copolymers of methyl polyethylene, polyurethanes, polyvinyl chloride idens, naylon, silicone elastomers, rubber and rubber-based isobutyl, styrene, styrene / butadiene and styrene / isoprene copolymers, polyethylene and polypropylene. A thickness of approximately 0.0127 to 0.254 millimeters is preferred. The release liner may be made from the same materials as the backing, or other suitable films coated with an appropriate release surface. The matrix patch can also comprise several additives in addition to the polymer layer, basic drug, and penetration enhancer that contains triacetin, which are the fundamental components of the transdermal drug delivery system. These additives are generally the pharmaceutically acceptable ingredients that are known in the art of drug delivery and, more particularly, in the transdermal drug delivery technique provided that such additive ingredients do not pre-emanate the basic and novel therapeutic properties. For example, suitable diluents may include mineral oil, low molecular weight polymers, plasticizers and the like Many formulations of transdermal drug delivery tend to cause skin irritation after prolonged exposure to the skin, therefore the addition of a skin irritation reducing agent helps achieve a composition better tolerated by the skin.A preferred skin irritant reducing agent is glycerin, US Patent No. 4,855,294.However it is noteworthy that other acceleration promoters or components of Percentage increase as per e Example solvents and cell envelope messy compounds are not necessary, not even desired, in the present invention. To deliver the basic drug according to the present invention, the matrix patch device containing a polymer layer, a basic drug with or for example oxybutynin, and a penetration enhancer containing triacetin comes into contact with the skin or mucosa. at a selected site of application and held in place by means of a suitable pressure sensitive additive. Preferably, the polymer layer of the matrix patch is an adhesive, but the polymer layer can also be laminated on an adhesive layer or used with a coating adhesive. It is understood that while the present invention has been described in relation to the preferred embodiments thereof, the following is intended to illustrate and not i. limit the scope of the present invention. Other aspects of the invention will be apparent to those skilled in the art of this invention. EXPERIMENTAL SKIN FLOW STUDIES In vitro human cadaver skin flux studies are carried out using modified non-patched Franz permeation cells. The temperature of the cells was maintained at 32 ° C by placing the cells in a circulating water bath positioned on an application module. The hemidermal membrane was separated from the entire skin of the human cadaver by means of the ligman &; Christopher, 88 Arch. Der atol. 702 (1963), which is incorporated herein by reference, and includes the treatment of the total thickness of the skin at a temperature of 60 ° C for 60 seconds, after which the stratum corneum and the epidermis (epidermal membrane) were gently removed from the skin. dermis. For skin flow studies of matrix devices, the epidermal membrane was cut into rectangular bands, and the matrix device was cut into circular disks of 0.96 C? TI ?. The release liner was removed from the disc, and the disc was laminated on the surface of the stratum corneum of the epidermal membrane to form a skin-matrix laminate. The skin-matrix laminate was then loaded between the donor and recipient compartments of a diffusion cell with the epidermal side facing the receptor compartment. The laminate was fixed in place, and the receptor compartment was then filled with an appropriate reception solution for a selected drug. The reception solution was selected in such a way that the drug presented stability in the solution, the subsequent assay of the drug did not present interference, and the solubility of the drug was adequate to ensure penetration conditions during the experiment. The diffusion cell was then placed in a circulating water bath calibrated to maintain the surface temperature of the skin at 32 +/- lßC. At predetermined sampling intervals, all the content of the receptor compartment was collected for drug quantification, and the receiving compartment was filled with a fresh receiving solution, taking care to eliminate air bubbles in the skin / solution interface. For cutaneous flow studies of gel formulations (ie, for liquid reservoir patch design), the epidermal membrane was cut and placed between two halves of the permeation cell with the stratum corneum facing the donor compartment. The skin is hydrated at a temperature of 32 < * C overnight with a 0.02% sodium azide solution (weight / volume) in the receiving compartment. The next morning, 75 μl of a gel formulation was placed in a cavity created by placing a polyfluorset and log washer on the surface of the stratum corneum. The cavity was then closed by fixing an occlusion backing on the washer and gel. A suitable receptor solution for a selected drug was placed in the receptor compartment in contact with the dermal side of the epidermis. The solution in the receptor compartment was selected in such a way that the drug was stable in the solution, the subsequent assay of the drug did not present interferences, and the solubility of the drug was adequate to ensure penetration conditions throughout the experiment. At predetermined sampling intervals, the total content of the receiving compartment was collected to quantify the drug and the receiving compartment was filled with a fresh receiving solution, taking care to eliminate bubbles at the skin / solution interface. The cumulative amount of drug penetrating through the epidermal membrane, t (ug / cm2), at any time t was determined from the following formula: Qt *? (Cp * V) / A n «0 where Cn is the concentration (ug / ml) of the drug in the receptor sample for the corresponding sampling time, V is the volume of fluid in the receptor chamber (approximately 6.3 cm3), and A is the diffusion area of the cell (0.64 cm2). The slope of the line of best correspondence with the graph of Qt versus t provides the equilibrium state flow (Jss, μg / cm2 / hr); the intercept of this line with the time axis provides the delay (tL, h). EXAMPLE 1 The oxybutynin-free base, pKa = 10.3, is a strongly basic drug administered transdermally for anisic therapy and inertgic therapy. Matrix patch containing various amounts of oxybutynin-free base and increased penetration were prepared and tested in accordance with what was described above. The matrix systems consisted of 5 to 20% by weight of sibutibin-free base and 0 to 20% by weight of this enhancer contained in a medical grade acrylic copolymer adhesive. The matrix formulations were prepared in the following manner. First, the solids content of the adhesive was determined by weighing a small amount of the adhesive solution in a preweighed luminance dish. The solvent was evaporated overnight by drying in a convection oven at a temperature of 80 ° C, and the weight of the residue (dry adhesive) and the percentage content of solid adhesive of the solution were determined. Once the solids content was determined, a known weight of copal acrylic number was weighed in a glass bottle. From the weight of the adhesive solution and the percentage solid adhesive content, the amount of adhesive in the solution was calculated. The axibutinin free base and increaser were added to the bottle in proportions to offer the final composition selected. The bottle was then sealed, sealed with a laboratory film, and rotated overnight until all the ingredients were completely dissolved and until the resulting solution was visually clear. About 8 ml of the solution was then placed in a silanized palisates release liner and applied with an application knife of 0.254 millimeters of clearance. The application was then dried in a convection oven at a temperature of 70 ° C for 15 minutes to evaporate the solvent and to provide a dry film of approximately 0.0508 millimeters in thickness. A 0.0762 millimeter thick polyethylene backing film was laminated onto the adhesive film with a rubber roller. These matrix laminates were then used to carry out cutaneous flow studies as described above. The results of the skin-flow experiments are shown in Table 1-3.

Table 1 Formulation (a) Qt (t = 24 hours) Jss A / D / E (% weight / weight) (μg / cm2 / t) (b) (μg / cm2 / hr) (b) 80/20/0 47.05 +/- 21.01 2.03 +/- 0.95 75/20/5 63.90 +/- 23.45 3.07 +/- 1.06 70/20/10 125.75 +/- 56.00 6.08 +/- 2.62 60/20/20 152.08 +/- 74.55 7.46 +/- 3.44 (a) A = adhesive = TSR; D = drug = oxybutynin? E = Increasedar = triacetin (b) Mean +/- standard deviation Table 2 Formulation) Qt (t = 24 hours) Jss A / D / E (% weight / weight) < μg / cm2 / t) (b) (μg / cm2 / hr) (b) 80/20/0 28.12 +/- 13.74 1.13 +/- 0.52 70/20/10 84.41 +/- 30.72 3.64 +/- 1.23 60/20/20 132.31 - * - / - 42.61 5.92 +/- 1.85 (a) A = adhesive = DuroTa 87-2196; D = drug = oxygen-free base i nin; E = Incrementor = triacetin (b) Mean +/- standard deviation Table 3 Formulation (a) Qt (t = 24 hours) Jss A / D / E (% weight / weight) (ug / cm2 / t> (b) (μg / cm2 / hr) (b) 85/15 / 0 61.57 +/- 33.19 2.58 +/- 1.39 75/15/10 135.36 +/- 23.85 5.80 +/- 0.90 (a) A = adhesive = ARcare MA-24; D = drug = oxybutynin-free base; E = Incretador = triacetin (b) Mean +/- standard deviation These results show that triacetin significantly increases the cutaneous flow of the sibutibin-free base compared to oxybutynin-free adhesive / base controls that do not have triacetin . These increase effects by triacetin were observed with the three adhesives tested in these matrix formulations. With TSR adhesive with a 20% drug load, the increase is approximately 50% with 5% triacetin (weight / weight), 3 times with 10% triacetin (weight / weight), and almost 4 times with 20% triacetin (weight / weight), compared to the controls. With the DuraTak adhesive (mr) 87-2196 with a drug load of 20%, the increase in skin flow is approximately 3 times with 10% triacetin (weight / weight) and 5 times with 20% triacetin (weight / weight) compared to controls. With the ARcare (r) MA-24 adhesive with a 15% drug load, a two-fold increase in cutaneous flow was observed, observed with 10% triacetin (weight / weight), compared to the controls. EXAMPLE 2 The activity of several well-known enhancers to increase the transdermal flow of the oxybutynin-free base was evaluated according to the procedure of Example 1, with the exception that these incrementers were replaced by triacetin. The results of the cutaneous flow tests in vi tro appear in Table 4.

Table 4 Incrementor Incretador Formulation Qt (t = 24 hours) Jes (a) A / D / E ug / cm2 / t (/ b) (ug / cm2 / hr) (b) (% weight / weight) none 80 / 20/0 47.05 +/- 21.01 2.03 +/- 0.95 monooleata 70/20/10 42.47 +/- 21.63 1.92 +/- 0.98 sorbitan N-methyl pyrro- 60/20/20 54.36 +/- 1.98 2.42 +/- 0.97 1 idona Alcohol lauri- 70/20/10 24.29 +/- 8.73 1.25 +/- 0.41 1 ico Miristato 70/20/10 48.26 +/- 13.08 2.05 +/- 0.54 isopropy lo monoaliate of 70/20/10 52.78 - »• / - B.25 2.25 +/- 0.32 gl icerol (a) A = adhesive = TSR; D = drug = oxybutynin-free base; E = Incrementor (b) Mean • +/- standard deviation These results show that none of the proven well-known penetration enhancers, sorbitan monooleate (ARLACEL 80, ICI Americas, Wilmington, Delaware), N-meti Ipirrol idona (Phar asolve (mr), International Specialty Chemicals, Wayne NJ), lauryl alcohol, issprspyl myristate, or glycerol monooleate, exhibited the ability to increase the transdermal skin flux of the basic drug, oxybutynin-free base, in a matrix system. EXAMPLE 3 Piroxicam is a weak basic anti-inflammatory, analgesic and antipyretic agent with a pKa of 6.3. The activity of triacetin to increase the transdermal flow of pirsxicam was evaluated according to the procedure of example 1, with the exception that the pyridine was replaced by oxibu inine. These results appear in Table 5.

Table 5 Expt. No. Formulation (a) Qt (t = 24 hours) A / D / E (% weight / weight) (μg / cm2 / t) < b) 99.75 / 0.25 / 0. 0.56 +/- 0.30 1 99.25 / 0.25 / 0.5 0.58 +/- 0.07 97.75 / 0.25 / 2.0 0.32 +/- 0.08 95.75 / 0.25 / 4.0 0.45 +/- 0.17 99.75 / 0.25 / 0. 0.55 +/- 0.31 2 99.25 / 0.25 / 0.5 0.27 +/- 0.15 97.75 / 0.25 / 2.0 0.03 +/- 0.02 95.75 / 0.25 / 4.0 0.18 +/- 0.04 99.75 / 0.25 / 0. 0.60 • + • / - 0.20 3 99.25 / 0.25 / 0.5 0.36 • * • / - 0. 14 97.75 / 0.25 / 2.0 0.42 +/- 0.09 95 .75 / 0.25 / 4.0 0.31 +/- 0. 14 (a) A = adhesive = TSR; D = drug = pyro? Icam free base? E = Incrementor = triacetin (b) Mean +/- standard deviation These results show that triacetin decreases cutaneous flow of piroxicam. These results suggest, however, that the increase in the flow of piroxicam in gels, mentioned in Ikeda et al., WO 9309783-A1, is not due to triacetin alone, if it does not appear to be the result of a combination of glycerol and surfactants. EXAMPLE 4 Gel formulations in liquid reserve containing free base of oxybutynin and triacetin were tested as described above. Such gel formulations in liquid reserve were prepared in amounts of 10 ml. Ethanol, water, glycerin and triacetin were mixed in selected proportions in a stoppered flask. Then, 400 mg of oxybutynin-free base was added to the bottle, and the bottle was capped and ul-treated to completely dissolve the drug. Then, 0.3 g of modified hydroxyethylcellulose (NATR0S0L PLUS 330CS, Aqualsn, Wilmington, Delaware) was added as a gel-forming agent to the mixture and the contents were thoroughly mixed and subjected to gentle rotation overnight to completely dissolve the gel forming agent. The resulting gel was then used in the cutaneous flow studies, the results of which are presented in Table 6.

Table 6 Expt. No. Formulation (a) Qt (t = 24 hours) Jss Et / / G / E (μg / cm2 / t) (b) (μg / cm2 / hr) (b) (% weight / weight> (a) 30/60/10/0 178.41 +/- 24.04 7.40 +/- 0.98 1 30/58/10/2 191.54 +/- 35.48 7.91 +/- 1.48 30/50/10/10 110.58 +/- 20.06 4.49 +/- 0.83 30/60/10/0 172.41 +/- 45.51 7.16 + / - 1.89 2 30/58/10/2 144.05 +/- 40.63 5.94 +/- 1.68 30/50/10/10 155.74 +/- 61.53 6.43 +/- 2.60 30/60/10/0 118.23 +/- 52.30 4.86 + / - 2.15 3 30/58/10/2 65.27 +/- 10.81 2.65 +/- 0.44 30/50/10/10 54.75 +/- 12.91 2.22 +/- 0.52 (a) Et = ethanol? W = water; G = glycerin; E = Incrementor = triacetype (b) Mean +/- standard deviation These results show that triacetin does not increase the flow of o? Ibutinin from a gel formulation as it could be used in a liquid reserve device. The flow actually decreases with systems containing triacetin, which is consistent with the findings of Mahjsur et al., US Patent No. 4,879,297. Accordingly, even when triacetin very effectively increases the penetration of oxybutynin from matrix formulations, triacetin does not increase the penetration of the same drug from reserve formulations.

EXAMPLE 5 The following formulations are exemplary and other compositions within the scope of this invention with triacetin and other highly basic active terminators in matrix patches. Such matrix patches can be made according to the procedure of Example 1. Various different types of doctor-grade, skin-contact, pressure sensitive adhesives can be used, such as for example acrylic copolymer adhesives or "acrylic adhesive" ( for example DuroTak 80-1196, National Starch? Gelva 737, Monsanto Co., St. Louis, Missouri), adhesives based on rubber or "rubber adhesive" such as for example polystyrene or "PIB adhesive". (for example, Adhesive Research MA-24), and adhesives based on silicone or "silicone adhesive" such as Dwo Bio-PSA. All compositions are given in ranges expressed in percent by weight. Formulation 5-A Morphine 0.1-2.5% Acrylic adhesive 82.5-94.9% Triacetin ",. 5.0-15.0% Formulation 5-B Hydro orfona 30.0-40.0% Adhesive of PIB 55.0-68.0% Triacetin 2.0-20.0% Formulation 5-C Escapola ina 2.0-10.0% Adhe ivo de PIB 75.0-93.0% Triacet ina 5.0-15. % Formulation 5-D Atropine 1.0-10.0% Silicone adhesive 85.0-98.0% Triacetin 1. -5.0% Formulation 5-E Cocaine 0.5-5.0% Acrylic adhesive 80.0-94.5% Triacet ina 5.0-15.0% Formulation 5-F Buprenorf ina 0.5-5.0% Adhesive of PIB 85.0-97.0% Triacetin 2.5-10.0% Formulation 5-G Escopola í na 0.1-5.0% Acrylic adhesive 90.0-96.4% Triacet ina 1.0-5.0% Formulation 5-H C1orpromacin 0.5-7.5% Acrylic adhesive 78.5-94.5% Triacetin 1.0-5.0% Formulation 5-1 Imipramine 0.5-5.0% Acrylic adhesive 85.0-97.0% Triacet ina 2.5-10.0% Formulation 5-J Desipramine 0.5-5.0% Acrylic adhesive 87.5-94.0% Triacetin 2.5-7.5% Formulation 5- Meti lphenidate 0.1-1.0% Silicana adhesive 94.0-97.4% Triacetin 2.5-5.0% Formulation 5-L Metamfetamine 2.5-10.0% Acrylic adhesive 82.5-95.0% Triacetin 2.5-7.5% Formulation 5-M Lidoca Ina 0.1-5.0% Acrylic adhesive 90.0-98.9% Triacetin 1.0-5.0% Formulation 5-N Proca lna 0.1-5.0% Adhesive of GDP 80.0-97.4% Triacetin 2.5-15.0% Formulation 5-0 Pindolol 0.1-10.0% Acrylic adhesive 65.0-94.9% Triacetin 5.0-25.0% Formulation 5-P Nadolol 0.1-10.5% Acrylic adhesive 74.5-94.9% Triacetin 5.0-15.0% Formulation 5-Q Fluoetin 5.0-40.0% Adhesive acrylic 35.0-84.9% Triacetin 5.0-25.0% Formulation 5-R Fluoxetine 5.0-40.5% Adhesive of PIB 55.5-90.0% Triacetin 5.0-15.0% Formulation 5-S Fluoetin 5.0-40.5% Silicone adhesive 55.5-89.5% Triacetin 5.0-15.0% Formulation 5-T Fluoxetine 5.0-40.5% Copal EVA number 55.5-89.5% Triacetin 5.0-15.0% Formulation 5-U Fluoxetine 5.0-40.5% Block copolymer of rubber and rubber 55.5-89.5% 58 Triacetin 5.0-15.0% Formulation 5-V C r i op odo1 5.0-40.5% Adhesive of PIB 55.5-89.5% Triacetin 5.0-15.0%

Claims (24)

1. CLAIMS 1. A method for increasing the rate of trapsdermic penetration of a basic drug having a pKa of approximately BO or greater, comprising the application to an application site selected from a matrix patch comprising (a) a layer of biocompatible polymer, wherein said biocompatible polymer is a selected adhesive within the group consisting of acrylics, vinyl acetates, natural and synthetic rubbers, copolymers of eti lepvini lacetato, polysiloxanes, paliacrites, polyurethanes, block amide copolymers of plasticized polyethers, plastics-reinforced plastic block copolymers, and mixtures of the isms; (b) an effective amount of a percutaneously absorbable basic drug having a pKa of about 8.0 or more? and (c) an effective amount of a permeation enhancer consisting essentially of triacetin.
2. 2. The method of rei indication 1, wherein said basic drug is a member selected from the group consisting of oxybutynin, scopola ina, flusxetine, epinephrine, morphine, hydromarphone, atropine, cocaine, buprenorphine, chlorpromazine, imipramine, desipramine, methylphenidate, methamphetamine, lidocaine, procaine, pindolol, nadolol, carisoprodal, and acid addition salts of the same.
3. 3. The method of rei indicates ion 2 wherein said effective amount of increasing permeation comprises from about 0.1% to about 50% by weight of triacetin.
4. 4. The method of claim 3 wherein said basic drug is a member selected from the group consisting of oxybutynin and acid addition salts thereof.
5. The method of claim 4 wherein said effective amount of permeation enhancer comprises from about 1% to about 40% by weight of triacetin.
6. The method of claim 5 wherein the matrix patch further comprises a member selected from the group consisting of diluents, excipients, emollients, plasticizers, cutaneous irritation reducing agents, vehicles and mixtures thereof.
7. The method of claim 6 wherein said basic drug is oxybutynin.
8. 8. The method of claim 7 wherein said adhesive is an acrylic copal copal.
9. The method of claim 8 wherein the permeation enhancer comprises from about 2% to about 20% by weight of triacetin.
10. The method of claim 9 wherein said matrix patch comprises a skin irritation reducing agent, wherein said skin irritation reducing agent is glycerin.
11. 11. The method of claim 3 wherein said polymer layer is laminated onto an adhesive.
12. The method of claim 3 wherein said polymer layer is coated with an adhesive.
13. 13. A matrix patch for the transdermal administration of a basic drug having a pKa of about 8.0 or more, comprising (a) a biocampatable polymer layer, wherein said biocampatable polymer is an adhesive selected from the group consisting of of acrylics, vinyl acetates, natural and synthetic rubbers, co-polymers of et i lenvini lacetata, polysiloxanes, polyacids, polyurethanes, plasticized polyether block amide copolymers, copal lmerss of plastics reinforced plastic blocks, and mixtures thereof; (b) an effective amount of a percutaneously absorbable basic drug having a pKa of about 8.0 or more; and (c) an effective amount of a permeation enhancer consisting essentially of a triacetin.
14. 14. The matrix patch of claim 13, wherein said basic drug is a member selected from the group consisting of: oxybutynin, escspslamine, fluoxetine, epinephrine, morphine, hydromorphone, atropine, cocaine, buprenorphin, chlorpromazine, imipramine, desipramine, lpnidata, metamfetamine, lidocaine, procaine, pindolol, nadolol, carisoprodal, and acid addition salts thereof.
15. 15. The matrix patch of the rei indication 14 wherein said effective amount of permeation enhancer comprises from about 0.1% to about 50% by weight of triacetin.
16. 16. The matrix patch of claim 15 wherein said basic drug is a member selected from the group consisting of oxybutynin and acid addition salts thereof.
17. 17. The matrix patch of the rei indication 16 wherein said effective amount of permeation enhancer comprises from about 1% to about 40% by weight of triacetin.
18. 18. The matrix patch of claim 17 wherein the matrix patch additionally comprises a member selected from the group consisting of diluents, excipients, emollients, plasticizers, cutaneous irritation reducing agents, vehicles and mixtures thereof.
19. 19. The matrix patch of the rei indication 18 wherein said basic drug is or: - butyne inine.
20. 20. The matrix patch of the resin 19 wherein said adhesive is an acrylic co-polymer.
21. 21. The matrix patch of claim 20 wherein the permeation enhancer comprises from about 2% to about 20% by weight of triacetin.
22. 22. The matrix patch of claim 21 wherein said matrix portion comprises a skin irritation reducing agent, wherein said cutaneous irritation reducing agent is glycerin.
23. 23. The matrix patch of claim 15 wherein said polymer layer is laminated onto an adhesive.
24. 24. The matrix patch of claim 15 wherein said polymer layer is coated with an adhesive.