WO1994021262A1

WO1994021262A1 - Device for the transdermal administration of alprazolam

Info

Publication number: WO1994021262A1
Application number: PCT/US1994/002880
Authority: WO
Inventors: Lina Tormen Taskovich; Su Il Yum; Tyler Watanabe; Nieves Marzan Crisologo
Original assignee: Alza Corporation
Priority date: 1993-03-17
Filing date: 1994-03-17
Publication date: 1994-09-29
Also published as: AU6410494A

Abstract

The present invention is directed to the transdermal administration of alprazolam together with a therapeutically acceptable permeation enhancer. The invention includes a transdermal drug delivery device comprising a matrix adapted to be placed in alprazolam- and permeation enhancer-transmitting relation with the skin site. The matrix contains sufficient amounts of permeation enhancer and of alprazolam to continuously administer alprazolam to the skin for an extended period of time to provide an effective therapeutic result. The invention is also directed to a method for the transdermal administration of a therapeutically effective amount of alprazolam together with a skin permeation-enhancing amount of a therapeutically acceptable permeation enhancer. The invention further includes methods for treating anxiety disorders, alcoholism, sexual dysfunction, panic disorders, major depression and various psychiatric disorders.

Description

Device for the transdermal admini stration of alprazolam

FIELD OF THE INVENTION This invention relates to the efficacious and safe, controlled transdermal administration of alprazolam and related compounds for the treatment of anxiety disorders, panic disorders, negative symptoms of schizophrenia, withdrawal symptoms due to smoking cessation, fertility, Crohn's disease, anxiety associated with depression and various psychiatric disorders, and more particularly, to methods and devices for administering alprazolam to a human through intact skin over an extended period of time.

BACKGROUND OF THE INVENTION Alprazolam is an effective anxiolytic drug and is indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. The efficacy of alprazolam has been demonstrated in controlled clinical trials of patients whose diagnosis roughly corresponds to Generalized Anxiety Disorder (300.02) of the American Psychiatric Association's Diagnostic and Statistical Manual lll-R and for panic disorders.

The synthesis of the compound and disclosure of its psychotropic properties are described in the following patents and publications, which patents are incorporated herein by reference. U.S. Patent No. 3,987,052, U.S. Patent No. 4,1 16,956, U.S. Patent No. 4,508,726

(treatment of panic disorders), U.S. Patent No. 4,588,721 (treatment of the negative symptoms of schizophrenia), U.S. Patent Nos. 4,588,739 and 4,683,231 (treatment of withdrawal symptoms associated with the cessation or reduction of tobacco smoking), U.S. Patent No. 4,879,285 (method for the control of fertility in mammals),

U.S. Patent No. 4,925,844 (antagonizing the pharmacoiogical effects of a benzodiazepine receptor agonist), U.S. Patent No. 5,017,575 (treatment of Crohn's disease), J. B. Hester et al., Tetrahedron Letters, 1971 , 1609; A. Waiser, G. Zenchoff, J. Med. Chem.. 20, 1694 (1977); R. Nakajima et al., Japan J. Pharmacol.. 21, 497 (1971 ), V. H. Sethy, Arch. Pharmacol.. 301 , 157 (1978); L. F. Fabre. Curr. Ther. Res., 19, 661 (1976); J. B. Cohn, J. Clin. Psvchiat.. 42, 347 (1981 ); D. R. Abernethyl et al., J. Clin.

Psvchiat., 44, 45 (1983); and J. A. Fawcett, H. M. Kravitz, Pharmacotherapy. 2, 242 (1982). As used herein, the term "psychiatric dysfunctions" refers to those disease conditions for which alprazolam is effective, such as anxiety disorders, panic disorders, negative symptoms of schizophrenia, withdrawal symptoms due to smoking cessation, fertility, Crohn's disease, anxiety associated with depression and the like. In U.S. Patent No. 4,933,184, alprazolam is listed as a tranquilizer that may be transdermally administered with menthol.

In U.S. Patent No. 4,863,970, alprazolam is listed as a sedative that may be transdermally delivered with an enhancer comprising 1 ) oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate or mixtures thereof, 2) ethanol, isopropanol, propanoi or mixtures thereof, and 3) an inert diluent.

In U.S. Patent No. 4,801 ,458, alprazolam is listed as a central nervous system agent that may be delivered with a sustained release pharmaceutical plaster.

In U.S. Patent No. 4,994,278, alprazolam is listed as a tranquilizer that may be transdermally administered with a device having a backing with a high water vapor transmission rate. In U.S. Patents Nos. 4,752,612 and 4,590,190, alprazolam is listed as a drug that may be transdermally administered with a higher monoalcohol or a mixture thereof in combination with a thioglycerol, lactic acid, and esters thereof, a cyclic urea, a pyrrolidone-type compound, an amide, a lactone or a mixture thereof. In U.S. Patent No. 4,710,497, alprazolam is listed as a drug that can be transdermally administered with a aliphatic hydrocarbon, a halogen substituted aliphatic hydrocarbon, an alcohol ester of aliphatic carboxylic acid, mono- or di-ethers, ketones or mixtures thereof in combination with a thioglycerols, lactic acid, and esters thereof, a cyclic urea, a pyrrolidone-type compound, an amide, a lactone or a mixture thereof. In U.S. Patent No. 5,030,629, alprazolam is listed as a drug that can be transdermally administered with a 2-imidazoline derivative. None of the above mentioned patents contain any in vitro or in vivo data concerning the transdermal delivery of alprazolam.

Alprazolam has been administered to human beings orally. Although alprazolam has a mean plasma elimination half-life of

1 1 .2 hours (range 6.3-26.9 hours) in healthy adults, alprazolam is rapidly absorbed in man and peak concentrations in plasma occur in one to two hours following administration. This rapid absorption requires that a patient take a pill three times daily. Additionally, even with only brief therapy with alprazolam, withdrawal symptoms (including seizures) can occur when the patient stops taking alprazolam. Thus, the oral route of administration is inefficient, inconvenient for the patient, and can have severe withdrawal effects.

When first investigated in depth in the late 1960s, the transdermal route of administration appeared to offer many advantages, particularly with respect to agents that had short half-lives and a high degree of first-pass metabolism by the liver when orally administered. Presentation of the agent through the skin directly into the blood stream would eliminate "first-pass" metabolism of orally administered agents, which excludes the oral portal for some agents or requires extremely large oral doses for others.

In spite of intensive research and development activities by most of the major pharmaceutical companies on the potential candidates for transdermal administration, only six drugs are presently commercially available in the United States in the form of transdermal drug delivery devices: nitroglycerin, scopolamine, clonidine, estradiol, fentanyl and nicotine. This set is small because of difficulties inherent in the barrier properties of skin (see "Transdermal Drug Delivery: Problems and Possibilities", V. M. Knepp et al., CRC Critical Reviews and Therapeutic Drug Carrier Systems, Vol. 4, Issue 1 , 1987). Just as certain drugs can irritate, sensitize or be otherwise toxic, so can permeation enhancers. The use of permeation enhancers for transdermal administration is described in numerous technical publications and patents, such as U.S. Patents Nos. 5,122,383; 4,940,586; 4,863,738; 4,820,720; 4,783,450; 4,746,515; 4,568,343; 4,557,934; 4,552,872; 4,537,776; 4,440,777; 4,405,616;

4,379,454; 4,343,798; 4,335,1 15; 4,299,826; 4,130,667; 4, 130,643; 4,046,886; 4,006,218; 3,551 ,554; 3,472,931 ; British Patent No. 1 ,001 ,949, EP Publication No. 261429, and Idson, Percutaneous Absorption, J. Phar. Sci., Vol. 64, No. 66, June 1975, pp. 901-924. The disclosures of the above patents are incorporated herein by reference.

Permeation enhancers that are not normally toxic at the concentrations employed in cosmetic or medical compositions may exhibit toxic effects at the higher concentrations required to produce adequate permeation enhancement. No "universal" permeation enhancer has been identified. Instead, the behavior of permeation enhancers is highly idiosyncratic; a permeation enhancer or combination of permeation enhancers effective for one drug may not be effective with other drugs, including closely related drugs. Often, a permeation enhancer will exacerbate irritation and sensitization problems by allowing high transdermal permeation rates of the drug or permeation enhancer or permitting otherwise impermeable components of the transdermal device to enter the skin. Many potential permeation enhancers interact adversely with other components of transdermal devices. One major problem is that many potential permeation enhancers are not compatible with medically acceptable contact adhesives and other components of the device. Enhancers may improve the transdermal permeation rate adequately, but not adequately reduce the lag time.

The use of a permeation enhancer in any transdermal drug delivery device necessarily complicates the design and development of the device.

Permeation enhancers cause compatibility problems throughout the delivery system. Instead of having to characterize the properties of the reservoir compositions, adhesives, and release-controlling materials with respect to just the drug, these materials must now have the proper characteristics with respect to both the drug and the permeation enhancer. Typically, drugs and permeation enhancers have very different physical and chemical properties, and, in most cases, the properties of mixtures of the drug with the permeation enhancer are unknown. For example, permeation enhancers can cause, among other problems, cohesive failure of adhesives and can partition into other components in the system.

The above summarizes the primary characteristics recognized to date that affect suitability of alprazolam and a permeation enhancer for transdermal administration. In order for alprazolam and a permeation enhancer to be suitable for transdermal administration they must possess this rare and unpredictable combination of characteristics. Moreover, the use of a transdermal device permits controlled, slow withdrawal from alprazolam, thereby making withdrawal from the drug easier and safer for the patient.

SUMMARY OF THE INVENTION

According to the present invention, it has been discovered that alprazolam may be safely and efficaciously administered transdermally, together with a therapeutically acceptable permeation enhancer. The invention includes a transdermal drug delivery device containing sufficient amounts of a permeation enhancer and of alprazolam to provide an effective therapeutic result by administration through the skin.

The invention is also directed to a method for the transdermal administration of a therapeutically effective amount of alprazolam together with a skin permeation-enhancing amount of a therapeutically acceptable permeation enhancer, as well as to a method for the transdermal administration of a therapeutically effective amount of alprazolam, together with a therapeutically acceptable permeation enhancer, at a controlled, preferably substantially constant rate for the treatment of psychiatric dysfunctions.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a cross-section through a schematic perspective view of one embodiment of transdermal therapeutic devices according to this invention. FIG. 2 is a cross-section through another embodiment of a transdermal therapeutic device according to this invention.

FIG. 3 is a cross-section through yet another embodiment of a transdermal therapeutic device according to this invention.

FIG. 4 is a cross-section through yet another embodiment of a transdermal therapeutic device according to this invention.

FIG. 5 is a graph of the flux of alprazolam through human epidermis at 35 °C, in vitro, with glycerol monolaurate and lauryl lactate.

FIG. 6 is a graph of the flux of alprazolam through human epidermis at 35°C, in vitro, with glycerol monolaurate and lauryl lactate. FIG. 7 is a graph of the flux of alprazolam through human epidermis at 35°C, in vitro, with glycerol monolaurate and lauryl lactate.

FIG. 8 is a graph of the flux of alprazolam through human epidermis at 35 °C, in vitro, with glycerol monolaurate and lauryl lactate. FIG. 9 is a graph of the flux of alprazolam through human epidermis at 35°C, in vitro, with glycerol monolaurate, lauryl lactate, myristyl lactate, cetyl lactate and ethyl lactate.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

According to the present invention, it has been found that alprazolam may be administered to the human body in a therapeutically effective amount via the transdermal route when it is co-administered with a therapeutically acceptable permeation enhancer. Therapeutic blood levels from 1.0 to 50 ng/ml can be obtained from administration rates in the range of 2 μg/hr to 100 g/hr.

The range of desired and achievable administration rates of alprazolam, arriving through the skin from a limited area, are 0.5-5 mg over a period of 24 hours. Representative fluxes of alprazolam through living human skin are in the range of

0.1 /vg/cm²/hr to 15 y-vg/cm²/hr, depending on the permeation enhancer used. The term "flux" refers to the rate of transfer of alprazolam across skin as measured. The units of flux are preferably μg/cm²/hr. The plasma terminal half-life of alprazolam administered transdermally is in the range of 4 to 6 hours. Therapeutic blood levels can be achieved within approximately 2 hours, and peak blood concentrations are achieved at about 4-6 hours when the system is worn for 24 hours. Typically, the system is applied for 16 hours to 7 days. The system application is easily adapted for various duration treatments, but generally 24 to 72 hours is the nominal duration for treatment of a single dose.

Typical transdermal delivery devices are described in U.S. Patents Nos. 3,598,122; 3,598,123; 3,731 ,683; 3,797,494; 4,031 ,894; 4,201 ,21 1 ; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,559,222; 4,573,995; 4,588,580; 4,645,502; 4,704,282; 4,788,062; 4,816,258; 4,849,226; 4,908,027; 4,943,435; and 5,004,610, for example. The disclosures of the above patents are incorporated herein by reference. The co-administration of alprazolam and a permeation enhancer as disclosed herein can be accomplished by using transdermal devices of these kinds.

Because of the wide variation in skin permeability from individual and from site to site on the same body, it may be preferable that alprazolam and the permeation enhancer be administered from a rate-controlled transdermal delivery device. Rate control can be obtained either through a rate-controlling membrane or adhesive or through the other means disclosed in the patents noted above.

A certain amount of alprazolam will bind to the skin, and it is accordingly preferred that the skin-contacting layer of the device include this amount of the agent as a loading dose. Examples of suitable transdermal delivery devices are illustrated in

FIGS. 1 , 2, 3 and 4. In the drawings, the same reference numbers are used throughout the different figures to designate the same or similar components. The figures are not drawn to scale.

In FIG. 1 , the presently preferred embodiment of this invention, transdermal delivery device 10 comprises a reservoir 12 containing both alprazolam and a therapeutically acceptable permeation enhancer. Reservoir 12 is preferably in the form of a matrix containing alprazolam and the permeation enhancer dispersed therein.

Reservoir 12 is sandwiched between a backing layer 14 and an in- line contact adhesive layer 16. Preferably, the backing is permeable to water vapor. The backing layer 14 serves the purpose of preventing passage of alprazolam through the surface of the reservoir distant the skin, and also for providing support for the system, where needed. The backing layer can be flexible or nonflexible. Suitable materials include, without limitation, polyethylene terephthalate, some types of nylons, polypropylene, metallized polyester films, polyvinylidene chloride, multi- laminate films and aluminum foil. Preferably, the backing is a multi- laminate film layer, such as Saranex^® Type 52, Dow Corning or Medpar^®, 3M.

The device 10 adheres to the surface of the skin 18 by means of the adhesive layer 16. The adhesive layer 16 may optionally contain enhancer and/or alprazolam. The composition and thickness of adhesive layer 16 is selected such that the adhesive does not constitute a significant permeation barrier to the passage of alprazolam and is compatible with alprazolam at the activity chosen for the device. Preferably, the adhesive is an acrylic adhesive, such as MSP041991 P,

3M; No. 16, Adhesive Research; or No. 2, Adhesive Research. A strippable release liner (not shown in FIG. 1 ) is normally provided along the exposed surface of adhesive layer 16 and is removed prior to application of device 10 to the skin 18. Preferably, the strippable liner is a siliconized polyester film.

Optionally, a rate-controlling membrane (not shown) may be present between the reservoir 12 and the adhesive layer 16. The rate- controlling membrane may be fabricated from permeable, semipermeable or microporous materials which are known in the art to control the rate of agents into and out of delivery devices. Suitable materials include, but are not limited to, polyethylene, polyvinyl acetate, polypropylene and ethylene vinyl acetate copolymers. Preferably, the rate controlling membrane is microporous high density polyethylene, the pores of which are impregnated with reservoir fluid. Alternatively, as shown in FIG. 2, transdermal therapeutic device 20 may be attached to the skin or mucosa of a patient by means of an adhesive overlay 22. Device 20 is comprised of a alprazolam- and permeation enhancer-containing reservoir 1 2 which is preferably in the form of a matrix containing alprazolam and the enhancer dispersed therein. A backing layer 14 is provided adjacent one surface of reservoir 12. Adhesive overlay 22 maintains the device on the skin and may be fabricated together with, or provided separately from, the remaining elements of the device. With certain formulations, the adhesive overlay 22 may be preferable to the in-line contact adhesive 16 as shown in FIG. 1. This is true, for example, where the alprazolam/enhancer reservoir contains a material (such as, for example, an oily surfactant permeation enhancer) which adversely affects the adhesive properties of the in-line contact adhesive layer 16. Backing layer 14 is preferably slightly larger than reservoir 12, and in this manner prevents the materials in reservoir 12 from adversely interacting with the adhesive in overlay 22. Optionally, a rate-controlling membrane (not shown in FIG. 2) may be provided on the skin-proximal side of reservoir 12. A strippable release liner 24 is also provided with device 20 and is removed just prior to application of device 20 to the skin.

In FIG. 3, transdermal delivery device 30 comprises an alprazolam- and permeation enhancer-containing reservoir ("drug reservoir") 12 substantially as described with respect to FIG. 1 . Permeation enhancer reservoir ("enhancer reservoir") 26 comprises a permeation enhancer dispersed throughout and is substantially free of any undissolved alprazolam. Enhancer reservoir 26 is preferably made from substantially the same matrix as is used to form drug reservoir 12. A rate-controlling membrane 28 for controlling the release rate of the permeation enhancer from enhancer reservoir 26 to drug reservoir 12 is placed between the two reservoirs. A rate-controlling membrane (not shown in FIG. 3) for controlling the release rate of the enhancer from drug reservoir 12 to the skin may also optionally be utilized and would be present between adhesive layer 16 and reservoir 12.

Superimposed over the permeation enhancer reservoir 26 of device 30 is a backing 14. On the skin-proximal side of reservoir 12 are an adhesive layer 16 and a strippable liner 24 which would be removed prior to application of the device 30 to the skin. In the embodiments of FIGS. 1 , 2 and 3, the carrier or matrix material of the reservoirs has sufficient viscosity to maintain its shape without oozing or flowing. If, however, the matrix or carrier is a low viscosity flowable material such as a liquid or a gel, the composition can be fully enclosed in a pouch or pocket, as known to the art from U.S.

Pat. No. 4,379,454 (noted above), for example, and as illustrated in FIG. 4. Device 40 shown in FIG. 4 comprises a backing member 14 which serves as a protective cover for the device, imparts structural support, and substantially keeps components in device 40 from escaping the device. Device 40 also includes reservoir 12 which contains the alprazolam and the permeation enhancer and bears on its surface distant from backing member 14, a rate-controlling membrane 28 for controlling the release of alprazolam and permeation enhancers.

The outer edges of backing member 14 overlay the edges of reservoir 12 and are joined along the perimeter with the outer edges of the rate-controlling membrane 28 in a fluid-tight arrangement. This sealed reservoir may be effected by pressure, fusion, heat, adhesion, an adhesive applied to the edges, or other methods known in the art. In this manner, reservoir 12 is contained wholly between backing member 14 and rate-controlling membrane 28. On the skin-proximal side of rate- controlling membrane 28 are an adhesive layer 1 6 and a strippable liner 24 which would be removed prior to application of the device 40 to the skin.

In an alternative embodiment of device 40 of FIG. 4, reservoir 12 contains the permeation enhancer only and is substantially free of alprazolam. The alprazolam and an additional amount of permeation enhancer are present in adhesive layer 1 6 which acts as a separate reservoir.

The alprazolam and the permeation enhancer can be co-extensively administered to human skin or mucosa by direct application to the skin or mucosa in the form of an ointment, gel, cream or lotion, for example, but are preferably administered from a skin patch or other known transdermal delivery device which contains a saturated or unsaturated formulation of alprazolam and the enhancer(s).

The formulation may be aqueous or non-aqueous based. The formulation should be designed to deliver the alprazolam and the permeation enhancer at the necessary fluxes. Aqueous formulations typically comprise water, water/ethanol or water/isopropanol and about 1-2 wt% of a gelling agent, an example being a hydrophilic polymer such as hydroxyethylcellulose or hydroxypropylcellulose. Typical non-aqueous gels are comprised of silicone fluid or mineral oil. Mineral oil-based gels also typically contain 1 -2 wt% of a gelling agent such as colloidal silicone dioxide. The suitability of a particular gel depends upon the compatibility of its constituents with both the alprazolam and the permeation enhancer and any other components in the formulation.

The reservoir matrix should be compatible with alprazolam, the permeation enhancer and any carrier therefor. The term "matrix" as used herein refers to a well-mixed composite of ingredients fixed into shape. When using an aqueous-based formulation, the reservoir matrix is preferably a hydrophilic polymer, e.g., a hydrogel. When using a non- aqueous-based formulation, the reservoir matrix is preferably composed of a hydrophobic polymer. Suitable polymeric matrices are well known in the transdermal drug delivery art, and examples are listed in the above- named patents previously incorporated herein by reference. A typical laminated system would comprise a polymeric membrane and/or matrix such as ethylene vinyl acetate (EVA) copolymers, such as those described in U.S. Pat. No. 4, 144,31 7, preferably having a vinyl acetate (VA) content in the range of from about 9% up to about 60% and more preferably about 28% to 50% VA. Polyisobutylene/oil polymers containing from 4-25% high molecular weight polyisobutylene and 20-80% low molecular weight polyisobutylene with the balance being an oil such as mineral oil or polybutylenes may also be used as the matrix material.

The aforementioned patents describe a wide variety of materials which can be used for fabricating the various layers or components of the transdermal alprazolam delivery devices according to this invention. This invention therefore contemplates the use of materials other than those specifically disclosed herein, including those which may hereafter become known to the art to be capable of performing the necessary functions.

As used herein, the term "therapeutically effective" amount or rate refers to the amount or rate of alprazolam needed to effect the desired therapeutic result. The amount of alprazolam present in the therapeutic device and required to achieve a therapeutically effective result depends on many factors, such as the minimum necessary dosage of alprazolam for the particular indication being treated; the solubility in the matrix and permeability through the matrix, of the adhesive layer and of the rate- controlling membrane, if present; and the period of time for which the device will be fixed to the skin. The minimum amount of alprazolam is determined by the requirement 'that sufficient quantities of alprazolam must be present in the device to maintain the desired rate of release over the given period of application. The maximum amount for safety purposes is determined by the requirement that the quantity of alprazolam present cannot exceed a rate of release that reaches toxic levels. The oral LD₅₀ of alprazolam discovered for mice is 1020 mg/kg and rats is > 2000 mg/kg. When a constant drug delivery rate is desired, the alprazolam is normally present in the matrix or carrier at a concentration in excess of saturation, the amount of excess being a function of the desired length of the drug delivery period of the system. The alprazolam may, however, be present at a level below saturation without departing from this invention as long as alprazolam is continuously administered to the same skin or mucosa site in an amount and for a period of time sufficient to provide the desired therapeutic rate and delivery profile of alprazolam delivery.

The permeation enhancer is dispersed through the matrix or carrier, preferably at a concentration sufficient to provide permeation-enhancing 5 amounts of enhancer in the reservoir throughout the anticipated administration period. Where there is an additional, separate permeation enhancer matrix layer as well, as in FIG. 3, the permeation enhancer normally is present in the separate reservoir in excess of saturation. As used herein the term "therapeutically acceptable permeation o enhancer" means a diethanolamide of a fatty acid; a monoglyceride or a mixture thereof; a dimethyl alkylamide; a sucrose ester or a mixture thereof; a lactic ester of an alcohol or a mixture thereof; a polyethylene glycol ester of a fatty acid; a benzoic acid of a fatty acid ester; an alkyl laurate; and the like, and combinations thereof. Preferably, the 5 therapeutically acceptable permeation enhancer means a combination of two or more of the above permeation enhancers. More preferably, the therapeutically acceptable permeation enhancer comprises a permeation enhancer that is solid at room temperature and a permeation enhancer that is liquid at room temperature. o The presently preferred permeation enhancers of the present invention are 1 ) lauryl lactate in combination with glycerol monolaurate, 2) lauryl lactate in combination with lauramide diethanolamide, 3) ethyl laurate in combination with glycerol monolaurate, 4) ethyl laurate in combination with lauramide diethanolamide, 5) isoestearyl benzoate in 5 combination with glycerol monolaurate, 6) isoestearyl benzoate in combination with lauramide diethanolamide, 7) lauryl lactate, 8) glycerol monolaurate and 9) ethyl lactate and lauryl lactate in combination with gylcerol monolaurate.

In addition to alprazolam and a therapeutically acceptable o permeation enhancer, the matrix or carrier may also contain dyes, pigments, inert fillers, diluents, antioxidants, antibacterials, stabilizers, vehicles, anesthetics, rubefacients, antipruritics, gelling agents, excipients and other conventional components of pharmaceutical products or transdermal devices known to the art. One such additive the matrix or carrier may contain is polyvinyl pyrrolidone. In an embodiment of the invention, the reservoir 12 comprises 0.1 to 90 weight percent cross- linked polyvinyl pyrrolidone, more preferably 1 to 50 weight percent. The cross-linked polyvinyl pyrrolidone has a molecular weight of 10,000 to 5,000,000 daltons and a particle size from 0.1 to 1000 μ .

Optionally, the device can contain one or more antagonists for alprazolam such that the device is resistant to misuse and abuse. Such devices are described in U.S. Patents 4,806,341 , 4,626,539, 4,935,428, 4,464,378, 4,573,995, 4,588580, 5, 149,538, WO 90/04965 and EP Publication No. 0368409, which are incorporated by reference.

In a preferred embodiment of the invention, reservoir 12 comprises about 1 to about 40 weight percent alprazolam, about 10 to about 70 weight percent water, about 10 to about 50 weight percent C₂.₄ alcohol, preferably isopropanol, about 0.1 to about 10 weight percent gelling agent, preferably hydroxypropylcellulose, about 0.1 to 20 weight percent monoglyceride or mixture of monoglyceride of a fatty acid, preferably glycerol monolaurate, and about 1.0 to 30 weight percent diethylene glycol monoalkyl ether, preferably diethylene glycol monoethyl ether.

In another preferred embodiment of this invention, reservoir 12 comprises 30 to 70 weight percent ethylene vinyl acetate copolymer having a 9 to 60 percent vinyl acetate content, 1 to 40 weight percent alprazolam, 5 to 40 percent benzoic acid of a fatty acid ester, preferably isoestearyl benzoate, and 1 to 40 weight percent diethanolamide of a fatty acid, preferably lauramide diethanolamide.

In another preferred embodiment of this invention, reservoir 12 comprises 30 to 70 weight percent ethylene vinyl acetate copolymer having a 9 to 60 percent vinyl acetate content, 1 to 40 weight percent alprazolam, 5 to 40 percent benzoic acid of a fatty acid ester, preferably isoestearyl benzoate, and 1 to 40 weight percent monoglycerides or mixture of monoglycerides of a fatty acid, preferably glycerol monolaurate. In yet another preferred embodiment of this invention, reservoir 12 comprises 30 to 70 weight percent ethylene vinyl acetate copolymer having a 9 to 60 percent vinyl acetate content, 1 to 40 weight percent alprazolam, 5 to 40 percent alkyl laurate, preferably ethyl laurate, and 1 to 40 weight percent diethanolamide of a fatty acid, preferably lauramide diethanolamide.

In another preferred embodiment of this invention, reservoir 12 comprises 30 to 70 weight percent ethylene vinyl acetate copolymer having a 9 to 60 percent vinyl acetate content, 1 to 40 weight percent alprazolam, 5 to 40 percent alkyl laurate, preferably ethyl laurate, and 1 to 40 weight percent monoglyceride or mixture of monoglycerides of a fatty acid, preferably glycerol monolaurate.

In a more preferred embodiment of this invention, reservoir 12 comprises 30 to 70 weight percent ethylene vinyl acetate copolymer having a 9 to 60 percent vinyl acetate content, 1 to 40 weight percent alprazolam, and 5 to 50 percent lactic ester of an alcohol or a mixture thereof, preferably lauryl lactate and ethyl lactate.

In a more preferred embodiment of this invention, reservoir 1 2 comprises 30 to 70 weight percent ethylene vinyl acetate copolymer having a 9 to 60 percent vinyl acetate content, 1 to 40 weight percent alprazolam, 5 to 40 percent lactic ester of an alcohol or a mixture thereof, preferably lauryl lactate, and 1 to 40 weight percent diethanolamide of a fatty acid, preferably lauramide diethanolamide.

In another more preferred embodiment of this invention, reservoir 1 2 comprises 30 to 70 weight percent ethylene vinyl acetate copolymer having a 9 to 60 percent vinyl acetate content, 1 to 40 weight percent alprazolam (preferably 5 to 25 weight percent), 5 to 40 percent lactic ester of an alcohol or a mixture thereof (preferably 10 to 35 weight percent), preferably lauryl lactate and ethyl lactate, 5 to 40 weight percent monoglyceride or mixture of monoglycerides of a fatty acid (preferably 5 to 25 weight percent), preferably glycerol monolaurate. Most preferably, the device for the transdermal administration of alprazolam, at a therapeutically effective rate, comprises a first reservoir comprising: (i) 5 to 40% by weight alprazolam (preferably 10 to 25%), (ii) 5 to 40% by weight glycerol monolaurate (preferably 5 to 20%), (iii) 5 to 40% by weight a lactic ester of an alcohol or mixture thereof (preferably 15 to 35%), and (iv) 20 to 70% by weight ethylene vinyl acetate

(preferably 30 to 60%); (b) a second reservoir comprising: (i) 5 to 40% by weight glycerol monolaurate (preferably 5 to 20%), (ii) 5 to 40% by weight lactic ester of an alcohol or a mixture thereof (preferably 15 to 35%), and (iii) 20 to 80% by weight ethylene vinyl acetate (preferably 30 to 80%); (c) a membrane between the first reservoir and the second reservoir that is impermeable to alprazolam; (d) a backing on the skin- distal surface of the second reservoir; and (e) means for maintaining the first and second reservoirs in alprazolam- and lactic ester of an alcohol and glycerol monolaurate-transmitting relation with the skin. Preferably, the backing is an occluded backing, such as Medpar^®.

Preferably the means for maintaining the first and second reservoirs in alprazolam- and lactic ester of an alcohol and glycerol monolaurate- transmitting relation with the skin is a acrylic adhesive, such as MSP 041991 p, 3M. Preferably, the membrane between the first and second reservoir is ethylene vinyl acetate with a 9% acetate content.

Another preferred embodiment of the present invention comprises a method of treating psychiatric dysfunctions by administering a therapeutically effective amount of alprazolam and a therapeutically acceptable permeation enhancing amount of permeation enhancer through intact skin to a patient suffering from such a disorder. Another preferred embodiment of the present invention comprises a method of treating anxiety in which it is therapeutic to administer a therapeutically effective amount of alprazolam and a therapeutically acceptable permeation enhancing amount of permeation enhancer through intact skin over an extended period of time to a patient suffering from such disorder. Preferably, the method of treating psychiatric dysfunctions comprises using a device for the transdermal administration of alprazolam, at a therapeutically effective rate, comprising the preferred devices described above. To be useful in treating anxiety, alprazolam should be present in plasma at levels above about 4.0 ng/ml, preferably at levels above about 8.0 ng/ml and most preferably at levels of about 15.0 ng/ml. To achieve this result, alprazolam is delivered at a therapeutic rate of at least about 0.5 /tg/cm²-hour, but typically of at least 2.0 μg/cm²-hr, and more typically at 3.0 //g/cm²-hr or greater, for the treatment period, usually about 24 hours to 7 days.

The devices of this invention can be designed to effectively deliver alprazolam for an extended time period of from several hours up to 7 days or longer. Seven days is generally the maximum time limit for application of a single device because the skin site is adversely affected when occluded for a period greater than 7 days.

The administration rate through the skin should be sufficient to minimize the size of the device. The size of the device of this invention can vary from 1 cm² to greater than 200 cm². A typical device, however, will have a size within the range of 5-50 cm². The delivery device containing the alprazolam is placed on a user such that the device is delivering alprazolam in a therapeutically effective amount to the user to effectively treat an anxiety disorder.

The length of time of alprazolam's presence and the total amount of alprazolam in the plasma can be changed following the teachings of this invention to provide different treatment regimens. Thus, they can be controlled by the amount of time during which alprazolam is delivered transdermally to an individual or animal.

The transdermal therapeutic devices of the present invention are prepared in a manner known in the art, such as by those procedures, for example, described in the transdermal device patents listed previously herein.

As used herein, the term "alprazolam" is used to designate the compound 8-chloro-1-methyl-6-phenyl-4H-[1 ,2,4]triazolo[4,3- a][1 ,4]benzodiazepine. As used herein, the term "transdermal" delivery or application refers to the delivery or application of alprazolam by passage through skin, mucosa and/or other body surfaces by topical application.

As used herein, the term "substantial portion of the time period" means at least about 60% of the time period, preferably at least about 90% of the time period. Correlatively, the term "substantially constant" means a variation of less than .±20%, preferably less than ±10%, over a substantial portion of the time period.

As used herein, the term "about" means a variation from the number indicated that still achieves the desired therapeutic result. As used herein, the term "extended period of time" or "extended time period" means at least 1 6 hours.

As used herein, the term "C₂.₄ alcohol" refers to an alcohol having two to four carbon atoms, such as ethanol and isopropanol.

As used herein, the term "a monoglyceride or mixture of monoglycerides of fatty acids" has a total monoesters content of at least

51 %, where the monoesters are those with from six to twenty carbon atoms, such as glycerol monooleate, glycerol monolaurate and glycerol monolinoleate.

As used herein, the term "fatty acids" refers to fatty acids that are saturated or unsaturated and straight or chained, and include, for example, lauric acid, myristic acid, stearic acid, oleic acid, Unoleic acid and palmitic acid.

As used herein, the term "dimethyl alkylamide" refers to an alkyl having 1 to 18 carbon atoms, preferably eight to sixteen carbon atoms, such as dimethyl lauramide.

As used herein, the term "sucrose ester or a mixture of sucrose esters of a fatty acid" refers to a fatty acid having six to twenty carbon atoms, such as sucrose monococoate.

As used herein, the term "lactic ester of an alcohol" refers to an alcohol having two to eighteen carbon atoms, such as lauryl lactate, ethyl lactate, cetyl lactate and myristyl lactate, or a mixture thereof.

As used herein, the term "polyethylene glycol ester of a fatty acid" refers to a polyethylene glycol having an average molecular weight of 50 to 1000 and a fatty acid having from six to twenty carbon atoms, such as polyethylene glycol-200 monolaurate and polyethylene glycol-400 monolaurate.

As used herein, the term "benzoic acid of a fatty acid ester" refers to a fatty acid having from eight to eighteen carbon atoms, such as isoestearyl benzoate. As used herein, the term "alkyl laurate" refers to an alkyl having from two to eight carbon atoms, such as ethyl laurate.

As used herein, the term "diethanolamide of a fatty acid" refers to an amide, such as lauramide diethanolamide or cocamide diethanolamide, formed by a condensation reaction between a fatty acid having eight to eighteen carbon atoms, preferably ten to sixteen carbon atoms, and diethanolamine.

As used herein, the term "glycerol monooleate" refers to glycerol monooleate itself or a mixture of glycerides wherein glycerol monooleate is present in the greatest amount. As used herein, the term "glycerol monolaurate" refers to glycerol monolaurate itself or a mixture of glycerides wherein glycerol monolaurate is present in the greatest amount.

As used herein, the term "glycerol monolinoleate" refers to glycerol monolinoleate itself or a mixture of glycerides wherein glycerol monolinoleate is present in the greatest amount.

As used herein, the term "administration rates" refers to the average amount of alprazolam per hour that passes from a transdermal device through the epidermis at 35°C into a receptor solution. As used herein, the term "alkyl" refers to straight or branched saturated aliphatic hydrocarbon radical having a single available bond.

Having thus generally described the invention, the following specific examples describe preferred embodiments thereof.

EXAMPLE 1 The drug/permeation enhancer reservoir was prepared by mixing ethylene vinyl acetate having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, Illinois) and polyvinyl pyrrolidone, if present, in an internal mixer (Bra Bender type mixer) until the EVA 40 pellets fused. Alprazolam, glycerol monolaurate and lauryl lactate were then added. The mixture was blended for approximate 20 minutes at 54°-56°C and

30 rpm. After blending, the mixture was quickly cooled to 40°-45°C, and calendered to a 5 mil thick film.

This film was then laminated to an acrylic contact adhesive (MSP041991 P, 3M) on one side and Medpar^® backing (3M) on the opposite side. The laminate was then cut into 2.54 cm² circles using a stainless steel punch.

Circular pieces of human-epidermis were mounted on horizontal permeation cells with the stratum corneum facing the donor compartment of the cell. The release liner of the system was then removed and the system was centered over the stratum corneum side of the epidermis. A known volume of the receptor solution (0.01 M potassium phosphate at pH 6 containing 2% isopropanol) that had been equilibrated at 35 °C was placed in the receptor compartment. Air bubbles were removed; the cell was capped and placed in a water bath-shaker at 35 °C.

At given time intervals, the entire receptor solution was removed from the cells and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35°C. The receptor solutions were stored in capped vials at 4°C until assayed for alprazolam content by HPLC. From the drug concentration and the volume of the receptor solutions, the area of permeation and the time interval, the flux of the drug through the epidermis was calculated as follows: (drug concentration x volume of receptor)/(area x time) = flux (/;g/cm²-hr). The fluxes achieved for the different systems are shown in Table 1.

Table 1

Drug/Permeation Enhancer Reservoir Composition Average Flux (weight percent) ( yg/cm²-hr) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 8.07 ( 10/20/20/50) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 1 .92 (10/10/30/50) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 0.99 (10/20/10/60) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 3.41 (1 5/10/30/45) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 3.53 (25/10/30/35) alprazolam/glycerol monolaurate/lauryl 2.61 lactate/EVA 40/polyvinyl pyrrolidone (1 5/10/30/35/10) alprazolam/EVA 40 0.08 (10/90) EXAMPLE 2

The drug/permeation enhancer reservoir was prepared by mixing ethylene vinyl acetate having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, Illinois) and polyvinyl pyrrolidone, if present, in an internal mixer (Bra Bender type mixer) until the EVA 40 pellets fused.

Alprazolam and the permeation enhancers were then added. The mixture was blended for approximate 20 minutes at

54°-56°C and 30 rpm. After blending, the mixture was quickly cooled to 40°-45°C, and calendered to a 5 mil thick film. This film was then laminated to an acrylic contact adhesive

(MSP041991 P, 3M) on one side and Medpar^® backing (3M) on the opposite side. The laminate was then cut into 2.54 cm² circles using a stainless steel punch.

A given time intervals, the entire receptor solution was removed from the cells and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35 °C. The receptor solutions were stored in capped vials at 4°C until assayed for alprazolam content by

HPLC. The fluxes achieved for the different systems are shown in Table 2. Table 2

Drug/Permeation Enhancer Reservoir Composition Average Flux (weight percent) ( /g/cm²-hr) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 1 .52 (10/10/30/50) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 5.29 (10/20/20/50) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 1.72 (10/10/20/60) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 2.67 (15/10/30/45) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 2.74 (25/10/30/35) alprazolam/glycerol monolaurate/lauryl 2.73 lactate/EVA 40/polyvinyl pyrrolidone (15/10/30/35/10) alprazolam/glycerol monolaurate/lauryl 2.13 lactate/EVA 40/polyvinyl pyrrolidone (15/10/30/40/5) alprazolam/EVA 40 0.07 (10/90)

EXAMPLE 3

The drug/permeation enhancer reservoir was prepared by mixing ethylene vinyl acetate having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, Illinois) and polyvinyl pyrrolidone, if present, in an internal mixer (Bra Bender type mixer) until the EVA 40 pellets fused. Alprazolam and the permeation enhancers were then added . The mixture was blended for approximate 20 minutes at

54°-56°C and 30 rpm. After blending, the mixture was quickly cooled to 40°-45 °C, and calendered to a 5 mil thick film. This film was then laminated to an acrylic contact adhesive (MSP041991 P, 3M) on one side and Medpar^® backing (3M) on the opposite side. The laminate was then cut into 1.63 cm² circles using a stainless steel punch. Circular pieces of human-epidermis were mounted on horizontal permeation cells with the stratum corneum facing the donor compartment of the cell. The release liner of the system was then removed and the system was centered over the stratum corneum side of the epidermis. A known volume of the receptor solution (0.01 M potassium phosphate at pH 6 containing 2% isopropanol) that had been equilibrated at 35°C was placed in the receptor compartment. Air bubbles were removed; the cell was capped and placed in a water bath-shaker at 35 °C.

At given time intervals, the entire receptor solution was removed from the cells and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35°C. The receptor solutions were stored in capped vials at 4°C until assayed for alprazolam content by HPLC. The fluxes achieved for the different systems are shown in Table 3.

Table 3

Drug/Permeation Enhancer Reservoir Composition Average Flux (weight percent) (/yg/cm²-hr) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 3.92 (15/10/30/45) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 6.99 (10/20/20/50) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 10.20 (15/20/20/45) alprazolam/glycerol monolaurate/lauryl 1 1 .05 lactate/EVA 40/polyvinyl pyrrolidone (15/20/20/40/5) alprazolam/glycerol monolaurate/ethyl laurate/EVA 40 3.81 (15/10/30/45) alprazolam/glycerol monolaurate/isoestearyl 3.06 benzoate/EVA 40 (15/10/30/45) alprazolam/lauryl lactate/lauramide 4.90 diethanolamide/EVA 40 (15/30/10/45) alprazolam/ethyl laurate/lauramide diethanol/EVA 40 3.36 (15/30/10/45) alprazolam/isoestearyl benzoate/lauramide diethanol/EVA 1 .69 40 (15/30/10/45) alprazolam/lauryl lactate/EVA 40 (15/30/55) 2.01 alprazolam/lauryl lactate/EVA 40 (15/30/55) - monolith 3.23 thickness of 13 mils alprazolam/EVA 40 0.14 (10/90) EXAMPLE 4A

A formulation was prepared by mixing the weight percent shown in Table 4A of ethylene vinyl acetate with a 40% vinyl acetate content and a permeation enhancer in chloroform. The amount of chloroform used was approximately 85 weight percent ("wt %") of the combined weight of the EVA 40 and the permeation enhancer.

The solution was poured onto a glass plate lined with sheet of siliconized polyester release liner to dry. The chloroform was evaporated off until the film was dried. The amount of drug indicated in Table 4A was then dry-blended in the weighed amount of permeation enhancer/ethylene vinyl acetate monolith in a rubber mill until the mixture was homogenous. The resulting material was then passed through a calender at a 12-14 mil thickness between two sheets of siliconized polyester release liner at 75 °C. One of the release liners was then removed and replaced with a Medpar^® backing. The finished laminates were cut into 2.54 cm² discs with a stainless steel punch. The weight of the monolith was 39 mg/cm².

The in vitro transdermal alprazolam fluxes through the epidermis of 3 human skin donors from horizontal diffusion cells were determined. For each device tested, the release liner was removed and the alprazolam- releasing surface was placed against the stratum corneum side of a disc of human epidermis which had been blotted dry just prior to use. The excess epidermis was wrapped around the device so that none of the device edge was exposed to the receptor solution. The device covered with epidermis was attached to the flat side of the Teflon^® holder of a release rate rod using nylon mesh and metal string. The rods were reciprocated in a fixed volume of receptor solution of 0.01 M phosphate buffer, pH 6 with 2% isopropanol. The entire receptor solution was changed at 10 hours, 22 hours, 34 hours, 50 hours and 70 hours. The temperature of the receptor solution in the water bath was maintained at 35°C. The receptor solutions were assayed for alprazolam content by HPLC. Results are summarized in Table 4A.

Table 4A

Drug/Permeation Enhancer Reservoir Composition Average Flux (weight percent) (μg/cm²-hr) alprazolam/dimethyl lauramide/EVA 40 0.61 (5/20/75) alprazolam/dimethyl lauramide/EVA 40 0.98 (10/20/70) alprazolam/dimethyl lauramide/EVA 40 0.72 (15/20/65) alprazolam/dimethyl lauramide/EVA 40 0.20 (15/10/75) alprazolam/dimethyl lauramide/EVA 40 1 .10 (15/30/55) alprazolam/diisopropyl sebacate/EVA 40 0.09 (15/30/55) alprazolam/lauryl lactate/EVA 40 1.13 (15/30/55) alprazolam/PEG-200 monolaurate/EVA 40 0.62 (15/30/55) alprazolam/PEG-250 monolaurate/EVA 40 0.54 (15/30/55) alprazolam/EVA 40 0.06 (15/85)

EXAMPLE 4B

A formulation was prepared by mixing the weight percent shown in Table 4B of ethylene vinyl acetate with a 40% vinyl acetate content ("EVA 40", U.S.I. Chemicals, Illinois) and one permeation enhancer in chloroform. The amount of chloroform used was approximately 85 weight percent ("wt %") of the combined weight of the EVA 40 and the permeation enhancer.

Table 4B

Drug/Permeation Enhancer Reservoir Composition Average Flux (weight percent) ( g/cm²-hr) alprazolam/diethylene glycol monoethyl ether/EVA 40 0.09 (15/30/55) alprazolam/diethylene glycol monoethyl ether/lauramide 0.34 diethanolamide/EVA 40

(15/30/10/45) alprazolam/diethylene glycol monoethyl ether/glycerol 0.90 monolaurate/EVA 40

(15/30/10/45) alprazolam/dimethyl lauramide/EVA 40 1.29 (10/20/70) alprazolam/lauryl lactate/EVA 40 2.36 (15/30/55) alprazolam/lauryl lactate/lauramide diethanolamide/EVA 2.55

40

(15/30/10/45) alprazolam/lauryl lactate/glycerol monolaurate/EVA 40 3.40 (15/30/10/45) alprazolam/EVA 40 0.10 (15/85)

The solution was poured onto a glass plate lined with sheet of siliconized polyester release liner to dry. The chloroform was evaporated off until the film was dried. The amount of alprazolam and second permeation enhancer indicated in Table 4B was then dry-blended in the weighed amount of permeation enhancer/ethylene vinyl acetate monolith in a rubber mill until the mixture was homogenous. The resulting material was then passed through a calender at a 12-14 mil thickness between two sheets of siliconized polyester release liner at 75 °C. One of the release liners was then removed and replaced with a Medpar^® backing. The finished laminates were cut into 2.54 cm² discs with a stainless steel punch. The monoliths weighed 26 mg/cm².

The in vitro transdermal alprazolam fluxes through the epidermis of 3 human skin donors from horizontal diffusion cells were determined. For each device tested, the release liner was removed and the alprazolam- releasing surface was placed against the stratum corneum side of a disc of human epidermis which had been blotted dry just prior to use. The excess epidermis was wrapped around the device so that none of the device edge was exposed to the receptor solution. The device covered with epidermis was attached to the flat side of the Teflon^® holder of a release rate rod using nylon mesh and metal string. The rods were reciprocated in a fixed volume of receptor solution of 0.01 M phosphate buffer, pH 6 with 2% ethanol. The entire receptor solution was changed at 1 1 hrs, 24 hours, 36 hours, 54 hours and 72 hours. The temperature of the receptor solution in the water bath was maintained at 35 °C. The receptor solutions were assayed for alprazolam content by HPLC. Results are summarized in Table 4B.

EXAMPLE 4C

The devices that were prepared in Example 4B of ethylene vinyl acetate/permeation enhancer(s)/alprazolam were laminated to an acrylic adhesive (3M, MSP041991 P) to form a bilaminate composition.

The in vitro transdermal alprazolam fluxes through the epidermis of 3 human skin donors from horizontal diffusion cells were determined. For each device tested, the adhesive was placed against the stratum corneum side of a disc of human epidermis which had been blotted dry just prior to use. The excess epidermis was wrapped around the device so that none of the device edge was exposed to the receptor solution. The device covered with epidermis was attached to the flat side of the Teflon^® holder of a release rate rod using nylon mesh and metal string. The rods were reciprocated in a fixed volume of receptor solution of 0.01 M phosphate buffer, pH 6 with 2% ethanol. The entire receptor solution was changed at 10 hrs, 22 hours, 34 hours, 52 hours and 70 hours. The temperature of the receptor solution in the water bath was maintained at 35 °C. The receptor solutions were assayed for alprazolam content by HPLC. Results are summarized in Table 4C.

Table 4C

Drug/Permeation Enhancer Reservoir Composition Average Flux (weight percent) (μg/cm²-hr) alprazolam/diethylene glycol monoethyl ether/glycerol 1.11 monolaurate/EVA 40

(15/30/10/45) alprazolam/lauryl lactate/EVA 40 1.99 (15/30/55) alprazolam/lauryl lactate/lauramide diethanolamide/EVA 6.21

40

(15/30/10/45) alprazolam/lauryl lactate/glycerol monolaurate/EVA 40 9.58 (15/30/10/45) alprazolam/EVA 40 0.1 1 (15/85)

EXAMPLE 5

Alprazolam and the corresponding vehicle/permeation enhancer mixture were placed in a vial according to the weight percents shown in Table 5; a mini teflon-coated magnetic stirring bar was placed in each vial. The mouth of the vial was covered with a piece of teflon film, capped and stirred at 35 °C for 48 hours. Hydroxypropylcellulose was then added to the saturated solutions and the mixture was equilibrated in a Roto-Torque Rotator overnight. The different compositions of the drug reservoirs are shown in Table 5. Table 5

Drug/Permeation Enhancer Reservoir Composition Average Flux (weight percent) (//g/cm²-hr) alprazolam/dimethyl lauramide/sucrose 2.1 monococoate/isopropanol/water/hydroxypropylcellulose

(10.0/3.5/5.3/26.4/52.8/2.0) alprazolam/glycerol monolaurate/diethylene glycol 1.65 monoethyl ether/isopropanol/water/ hydroxypropylcellulose (10.0/4.9/9.8/26.4/61.6/2.0) alprazolam/lauramide diethanolamide/ 1 .4 isopropanol/water/hydroxypropylcellulose

(10.0/10.0/26.4/52.8/2.0) alprazolam/isopropanol/water/hydroxypropylcellulose 0.5 (10.0/26.4/61.6/2.0)

Circular pieces of epidermis were mounted in horizontal permeation cells with the stratum corneum facing the donor compartment of the cells. "O" rings were pressed in place, and the cavity formed within the "O" ring was filled with the gelled drug donor formulation. The drug donor volume was 200 /yg/cm². The gel was covered with a piece of teflon film before completing the assembly of the cell. The receptor solution was filled with a known volume of solution that had been equilibrated at 35 °C. Air bubbles were removed; the cell was capped and placed in a water bath-shaker at 35°C. At given time intervals, the entire receptor solution was removed from the cells and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35°C. The receptor solutions were stored in capped vials at 4°C until assayed for alprazolam content by HPLC. The fluxes achieved for the different compositions are shown in Table 5. EXAMPLE 6

A formulation for the drug reservoir was prepared by mixing alprazolam, isopropanol USP, glycerol monolaurate, diethylene glycol monoethyl ether, purified water USP and hydroxypropylcellulose (Klucel^® HF) in the weight percents shown in Table 6. The reservoir was prepared using a Glas-Col^® non-aerating stirrer, which mixed the formulation without introducing air bubbles, producing a gel in 30 minutes.

The drug reservoir gel was then heat sealed with an Ivers-Lee Form-Fill-Seal machine using an Ivek pump between a backing membrane (Saranex^® 52, Dow Corning) and a rate controlling membrane

(microporous high density polyethylene, Cotran^®, 3M)/contact adhesive (an acrylic adhesive, MSP 041991 p, 3M)/release liner (siliconized polyester) laminate. Excess membrane was trimmed from the 20 cm² systems and packaged in Surlyn pouches. Before testing, each system was equilibrated for six days to allow the alprazolam to partition into the contact adhesive.

Table 6

Drug/Permeation Enhancer Reservoir Composition Average (weight percent) Flux

Reservoir Loading (mg/cm²) 25 50 alprazolam/glycerol monolaurate/diethylene glycol monoethyl ether/isopropanol/ 1.3 1 .7 water/hydroxypropylcellulose (3.0/4.8/9.5/28.5/52.2/2.0) alprazolam/glycerol monolaurate/diethylene glycol monoethyl ether/isopropanol/ 1.2 2.0 water/hydroxypropylcellulose (10.0/4.4/8.8/26.4/48.4/2.0) alprazolam/isopropanol/ water/hydroxypropylcellulose 0.2 0.4

(3.0/28.5/66.5/2.0) alprazolam/isopropanol/ water/hydroxypropylcellulose 0.2 0.3

(10.0/26.4/61.6/2.0)

At given time intervals, the entire receptor solution was removed from the cells and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35 °C. The receptor solutions were stored in capped vials at 4°C until assayed for alprazolam content by HPLC. The fluxes achieved for different systems are shown in Table 6.

EXAMPLE 7

A formulation for the drug reservoir was prepared by mixing alprazolam, isopropanol USP, permeation enhancer, purified water USP and hydroxypropylcellulose (Klucel^® HF) in the weight percents shown in Table 7. The reservoir was prepared using a Glas-Col^® non-aerating stirrer, which mixed the formulation without introducing air bubbles, producing a gel in 30 minutes. The drug reservoir gel (50 mg/cm²) was then heat sealed with an

Ivers-Lee Form-Fill-Seal machine using an Ivek pump between a backing membrane (Saranex^® 52, Dow Corning) and a rate controlling membrane (microporous high density polyethylene, Cotran^®, 3M)/contact adhesive (an acrylic adhesive, MSP 041991 p, 3M)/release liner (siliconized polyester) laminate. In test number one, the adhesive contained no alprazolam and in test number two, the contact adhesive contained 2.5 weight percent alprazolam. Excess membrane was trimmed from the 20 cm² systems and packaged in Surlyn pouches. Before testing, each system was equilibrated for six days to allow the alprazolam to partition into the contact adhesive.

Table 7

Average Flux

Drug/Permeation Enhancer Reservoir Composition (weight percent) Test Test No. 1 No. 2

alprazolam/sucrose monococoate/isopropanol/ water/hydroxypropylcellulose 1 .0 0.8

(10.0/8.7/26.1 /52.2/3.0) alprazolam/lauryl lactate/tween-20/ isopropanol/water/hydroxypropylcellulose 1 .7 1.5

(10.0/4.35/4.35/26.1 /52.2/3.0) alprazolam/diethylene glycol monoethyl ether/isopropanol/water/hydroxypropylcellulose 0.5 0.4

(10.0/8.7/26.1 /52.2/3.0) alprazolam/glycerol monolaurate/diethylene glycol monoethyl ether/isopropanol/ 1 .8 1.7 water/hydroxypropylcellulose (10.0/4.35/8.7/26.1 /47.85/3.0) alprazolam/dimethyl lauramide/sucrose monococoate/isopropanol/water/ 1.6 1.4 hydroxypropylcellulose (10.0/3.48/5.22/26.1 /52.2/3.0) alprazolam/isopropanol/water/ hydroxypropylcellulose 0.3 0.3

(10.0/26.1 /60.9/3.0)

Circular pieces of human-epidermis were mounted on horizontal permeation cells with the stratum corneum facing the donor compartment of the cell. The release liner of the system was then removed and the system was centered over the stratum corneum side of the epidermis. A known volume of the receptor solution (0.01 M potassium phosphate at pH 6 containing 2% isopropanol) that had been equilibrated at 35 °C was placed in the receptor compartment. Air bubbles were removed; the cell was capped and placed in a water bath-shaker at 35 °C. At given time intervals, the entire receptor solution was removed from the cells and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35 °C. The receptor solutions were stored in capped vials at 4°C until assayed for alprazolam content by HPLC. The fluxes achieved for different systems are shown in Table 7.

EXAMPLE 8

Alprazolam and the corresponding vehicle/permeation enhancer mixture were placed in a vial according to the weight percents shown in Table 8; a mini teflon-coated magnetic stirring bar was place in each vial. The mouth of the vial was covered with a piece of teflon film, capped and stirred at 35 °C for 48 hours. The different compositions of the drug reservoirs are shown in Table 8.

Table 8

Average Flux (μg/cm²-hr)

Drug Donor Solution Composition (weight Test Test Test Test Dercent) No. 1 No. 2 No. 3 No. 4 sucrose monococoate/ isopropanol/water 1 1.9 2.0 1.9 5.6

(10/20/70) polyethylene glycol-400 monolaurate/isopropanol/ 6.5 1.0 0.4 water (10/20/70) dimethyl lauramide/ sucrose monococoate/ 33.3 8.9 1 .6 17.8 isopropanol/water (4/6/20/70) glycerol monolaurate/ tween-20/isopropanol/ 3.1 0.7 water (5/10/20/65) isopropanol/water (20/80) 2.3 0.3 0.3 1 .1 Average Flux (μg/cm²-hr)

Drug Donor Solution Composition (weight Test Test Test Test percent) No. 1 No. 2 No. 3 No. 4 dimethyl lauramide/ olive oil (20/80) 0.3 polyethylene glycol-200 monolaurate/olive oil 2.4 (20/80) glycerol monolaurate/ tween-20/olive oil 0.1 (5/20/75) olive oil (100) 0.08 polyethylene glycol-

400/sucrose 0.9 monococoate/ isopropanol/water

(4/6/20/70) polyethylene glycol-5 oleate/tween-20/ 6.6 isopropanol/water (10/10/20/60) glycerol monolaurate/ diethylene glycol 5.6 monoethyl ether/ isopropanol/water (5/10/20/65)

Circular pieces of epidermis were mounted in horizontal permeation cells with the stratum corneum facing the donor compartment of the cells. "O" rings were pressed in place. The drug donor volume per unit area was 2.0 ml/cm². The concentration of alprazolam in the drug donor solution was 20-30% in excess of saturation. The receptor compartment was filled with a known volume of 0.01 M KH₂PO₄ at pH 6 with 2% isopropanol that had been equilibrated at 35 °C. Air bubbles were removed; the cell was capped and placed in a water bath-shaker at 35°C.

At given time intervals, the entire receptor solution was removed from the cells and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35 °C. The receptor solutions were stored in capped vials at 4°C until assayed for alprazolam content by HPLC. The fluxes achieved for the different compositions are shown in Table 8.

EXAMPLE 9 The drug/permeation enhancer reservoir was prepared by mixing ethylene vinyl acetate having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, Illinois) in an internal mixer (Bra Bender type mixer) until the EVA 40 pellets fused. Alprazolam (GYMA Labs of America, Garden City, NJ), glycerol monolaurate (Grindsted ML 90, Grindsted Products A/S, Brabrand, Denmark) and lauryl lactate (Van Dyk, Inc.,

Belleview, NJ) were then added. The mixture was blended for approximately 20 minutes at 54°-56°C and 30 rpm. After blending, the mixture was quickly cooled to 40°-45 °C, and calendered to a 1 3 mil thick film. The film was then laminated to a Medpar^® backing (3M, St. Paul, Minn.) and cut into circles using a stainless steel punch.

Table 9

Drug/Permeation Enhancer Reservoir Composition (weight percent) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 (15/10/30/45) alprazolam/lauryl lactate/EVA 40 (15/30/55)

Circular pieces of human-epidermis were mounted on horizontal permeation cells with the stratum corneum facing the donor compartment of the cell. The release liner of the system was then removed and the system was centered over the stratum corneum side of the epidermis. A known volume of the receptor solution (0.01 M potassium phosphate at pH 6 containing 2% isopropanol) that had been equilibrated at 35 °C was placed in the receptor compartment. Air bubbles were removed from the receptor compartment; the cell was capped and placed in a water bath- shaker at 35°C.

HPLC. The fluxes achieved for the different systems are shown in Figure 5. As can be seen in Figure 5, the fluxes obtained from the systems containing glycerol monolaurate and lauryl lactate were significantly higher than the fluxes obtained from the systems containing lauryl lactate alone. EXAMPLE 10

The drug/permeation enhancer reservoir was prepared by mixing ethylene vinyl acetate having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, Illinois) in an internal mixer (Bra Bender type mixer) until the EVA 40 pellets fused. Alprazolam, glycerol monolaurate and lauryl lactate were then added. The mixture was blended for approximately 20 minutes at 54°-56°C and 30 rpm. After blending, the mixture was quickly cooled to 40°-45°C, and calendered to a 5 mil thick film.

Table 10

Drug/Permeation Enhancer Reservo ir Composition (weight percent)

Figure 6 alprazolam/glycerol monolaurate/lai jryl lactate/EVA 40 (15/20/20/45) alprazolam/glycerol monolaurate/lai jryl lactate/EVA 40 (15/10/30/45) alprazolam/lauryl lactate/EVA 40 (15/30/55)

Figure 7 alprazolam/glycerol monolaurate/lai jryl lactate/EVA 40 (15/20/20/45) alprazolam/glycerol monolaurate/EVA 40 (15/20/65)

Figure 8 alprazolam/glycerol monolaurate/lai jryl lactate/EVA 40 (15/10/30/45) alprazolam/lauryl lactate/EVA 40 (15/30/55) This film was then laminated to an acrylic contact adhesive (MSP041991 P, 3M) on one side and Medpar^® or NRU-100-C^® backing (Flexcon, Spencer, MA) on the opposite side. The laminate was then cut into circles using a stainless steel punch. Circular pieces of human-epidermis were mounted on horizontal permeation cells with the stratum corneum facing the donor compartment of the cell. The release liner of the system was then removed and the system was centered over the stratum corneum side of the epidermis. A known volume of the receptor solution (0.01 M potassium phosphate at pH 6 containing 2% isopropanol) that had been equilibrated at 35 °C was placed in the receptor compartment. Air bubbles were removed; the cell was capped and placed in a water bath-shaker at 35 °C.

At given time intervals, the entire receptor solution was removed from the cells and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35°C. The receptor solutions were stored in capped vials at 4°C until assayed for alprazolam content by HPLC. The fluxes achieved for the different systems are shown in Figures 6, 7 and 8.

EXAMPLE 11 The drug/permeation enhancer reservoir was prepared by mixing ethylene vinyl acetate having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, Illinois) in an internal mixer (Bra Bender type mixer) until the EVA 40 pellets fused. Alprazolam, glycerol monolaurate and lauryl lactate were then added. The mixture was blended for approximately 20 minutes at 54°-56°C and 30 rpm. After blending, the mixture was quickly cooled to 40°-45°C, and calendered to a 5 mil thick film. The compositions of reservoirs are shown in Table 1 1 . Table 1 1

Composition of Reservoir Plasma Levels of Alprazolam (ng/ml)

24 hrs 48 hrs alprazolam/glycerol monolaurate/EVA 40 0.2 0.2 (15%/20%/65%) alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 0.7 1.2 (15%/20%/20%/45%)

This film was then laminated to an acrylic contact adhesive (MSP041 991 P, 3M) on one side and Medpar^® backing (3M) on the opposite side. The laminate was then cut into 5 cm² square. As can be seen in Table 3, the plasma levels for the combination of glycerol monolaurate and lauryl lactate was significantly higher than the plasma level for glycerol monolaurate alone.

EXAMPLE 12

The drug/permeation enhancer reservoir was prepared by mixing ethylene vinyl acetate having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, Illinois) in an internal mixer (Bra Bender type mixer) until the EVA 40 pellets fused. Alprazolam, glycerol monolaurate and a lactate ester were then added (lauryl lactate, myristyl lactate and cetyl lactate: Van Dyk, Belleville, NJ; ethyl lactate: Aldrich Chemical Co., Milwaukee, WI.) The mixture was blended for approximately 20 minutes at 54°-56°C and 30 rpm. After blending, the mixture was quickly cooled to 40°-45 °C, and calendered to a 5 mil thick film. The film was then cut into circles using a stainless steel punch. Table 12

Drug/Permeation Enhancer Reservoir Composition (weight percent) alprazolam/glycerol monolaurate/ myristyl lactate/EVA 40 (1 5/13/27/45) alprazolam/glycerol monolaurate/ lauryl lactate/EVA 40 (1 5/13/27/45) alprazolam/glycerol monolaurate/ ethyl lactate/EVA 40 (1 5/13/27/45) alprazolam/glycerol monolaurate/ cetyl lactate/EVA 40 (1 5/13/27/45)

This film was then laminated to an acrylic contact adhesive (MSP041 991 P, 3M) on one side and Medpar^® backing (3M) on the opposite side. The laminate was then cut into 2.54 cm² circles using a stainless steel punch. Circular pieces of human-epidermis were mounted on horizontal permeation cells with the stratum corneum facing the donor compartment of the cell. The release liner of the system was then removed and the system was centered over the stratum corneum side of the epidermis. A known volume of the receptor solution (0.01 M potassium phosphate at pH 6 containing 2% isopropanol) that had been equilibrated at 35 °C was placed in the receptor compartment. Air bubbles were removed; the cell was capped and placed in a water bath-shaker at 35°C.

A given time intervals, the entire receptor solution was removed from the cells and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35 °C. The receptor solutions were stored in capped vials at 4°C until assayed for alprazolam content by HPLC. The fluxes achieved for the different systems are shown in Figure 9.

Having thus generally described the present invention and described certain specific embodiments thereof including the embodiments that the applicants consider the best mode of practicing their invention, it will be readily apparent that various modifications to the invention may be made by workers skilled in the art without departing from the scope of this invention which is limited only by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A device for the transdermal administration, at a therapeutically effective rate, of alprazolam, which device comprises:

(a) a reservoir comprising a therapeutically effective amount of alprazolam and a skin permeation-enhancing amount of a therapeutically acceptable permeation enhancer;

(b) a backing on the skin-distal surface of the reservoir; and

(c) means for maintaining the reservoir in alprazolam- and permeation enhancer-transmitting relation with the skin.

2. A device according to claim 1 wherein the alprazolam is administered through the skin at a rate of at least 0.5 /g/cm²-hour for an extended period of time.

3. A device according to claim 1 wherein the therapeutically acceptable permeation enhancer is a diethanolamide of a fatty acid; a monoglyceride or a mixture thereof; a dimethyl alkylamide; a sucrose ester or a mixture thereof; a lactic ester of an alcohol or a mixture thereof; a polyethylene glycol ester of a fatty acid; a benzoic acid of a fatty acid ester; and an alkyl laurate; or combinations thereof.

4. A device according to claim 1 , wherein the reservoir comprises about 1 to about 40 weight percent alprazolam, about 10 to about 70 weight percent water, about 10 to about 50 weight percent a C₂.₄ alcohol, about 0.1 to about 10 weight percent gelling agent, about 0.1 to 20 weight percent a monoglyceride or mixture of monoglycerides of a fatty acid, and about 1.0 to 30 weight percent a diethylene glycol monoalkyl ether.

5. A device according to claim 4, wherein the C₂-₄ alcohol is isopropanol, the gelling agent is hydroxypropylcellulose, the monoglyceride or mixture of monoglycerides of a fatty acid is glycerol monolaurate, and the diethylene glycol monoalkyl ether is diethylene glycol monoethyl ether.

6. A device according to claim 1 wherein the reservoir comprises 30 to 70 weight percent ethylene vinyl acetate copolymer having from about 9% to about 60% vinyl acetate and 1 to 40 weight percent alprazolam.

7. A device according to claim 3, wherein the permeation enhancer comprises a benzoic acid of a fatty acid ester and a diethanolamide of a fatty acid; a benzoic acid of a fatty acid ester and a monoglyceride or mixture of monoglycerides of a fatty acid; an alkyl laurate and a diethanolamide of a fatty acid; an alkyl laurate and a monoglyceride or mixture of monoglycerides of a fatty acid; a lactic ester of an alcohol or a mixture thereof; a lactic ester of an alcohol or a mixture thereof and a diethanolamide of a fatty acid; or a lactic ester of an alcohol or a mixture thereof and a monoglyceride or mixture of monoglycerides of a fatty acid.

8. A device according to claim 7, wherein the benzoic acid of a fatty acid ester is isoestearyl benzoate, the diethanolamide of a fatty acid is lauramide diethanolamide, the monoglyceride or mixture of monoglycerides of a fatty acid is glycerol monolaurate, the alkyl laurate is ethyl laurate and the lactic ester of an alcohol is lauryl lactate or ethyl lactate or a mixture thereof.

9. A device according to claim 1 wherein the means for maintaining the reservoir in relation with the skin comprises an in-line adhesive layer on the skin-proximal surface of the reservoir.

10. A device for the transdermal administration, at a therapeutically effective rate, of alprazolam, which device comprises:

(a) a first reservoir comprising a therapeutically effective amount of alprazolam and a skin permeation-enhancing amount of a therapeutically acceptable permeation enhancer;

(b) a second reservoir comprising an excess of the permeation enhancer and substantially free of alprazolam;

(c) a rate-controlling membrane between the first reservoir and the second reservoir;

(d) a backing on the skin-distal surface of the second reservoir; and (e) means for maintaining the first and second reservoirs in alprazolam- and permeation enhancer-transmitting relation with the skin.

1 1 . A device according to claim 10 wherein the alprazolam is administered through the skin at a rate of at least 0.5 μg/cm²-hour for an extended period of time.

12. A device according to claim 10 wherein the means for maintaining the reservoirs in relation with the skin comprises an in-line adhesive layer on the skin-proximal surface of the first reservoir.

13. A device according to claim 10 wherein the first reservoir also is an adhesive layer which functions as the means for maintaining the reservoirs in relation with the skin.

14. A device according to claim 10 wherein the permeation enhancer is a diethanolamide of a fatty acid, a monoglyceride or mixture of monoglycerides of a fatty acid, a dimethyl alkylamide, a sucrose ester or a mixture of sucrose esters of a fatty acid, a lactic ester of an alcohol or mixture thereof, a polyethylene glycol ester of a fatty acid, a benzoic acid of a fatty acid ester, and an alkyl laurate, or combinations thereof.

15. A device according to claim 14 wherein the reservoir comprises ethylene vinyl acetate copolymer having from about 9% to about 60% vinyl acetate.

16. A device according to claim 10 wherein the permeation enhancer is lauryl lactate in combination with glycerol monolaurate, lauryl lactate and ethyl lactate in combination with glycerol monolaurate, ethyl lactate and myristyl lactate in combination with glycerol monolaurate, lauryl lactate in combination with lauramide diethanolamide, ethyl laurate in combination with glycerol monolaurate, ethyl laurate in combination with lauramide diethanolamide, isoestearyl benzoate in combination with glycerol monolaurate, isoestearyl benzoate in combination with lauramide diethanolamide, or lauryl lactate.

17. A device for the transdermal administration, at a therapeutically effective rate, of alprazolam, which device comprises:

(a) a first reservoir comprising:

(i) 5 to 40% by weight alprazolam, (ii) 5 to 40% by weight glycerol monolaurate, (iii) 5 to 40% by weight lactic ester of an alcohol selected from the group consisting of lauryl lactate, ethyl lactate or myristyl lactate, or a combination thereof, and (iv) 20 to 70% by weight ethylene vinyl acetate; (b) a second reservoir comprising:

(i) 5 to 40% by weight glycerol monolaurate, (ii) 5 to 40% by weight lactic ester of an alcohol selected from the group consisting of lauryl lactate, ethyl lactate or myristyl lactate, or a combination thereof, and (iii) 20 to 80% by weight ethylene vinyl acetate;

(c) a membrane between the first reservoir and the second reservoir that is impermeable to alprazolam; (d) a backing on the skin-distal surface of the second reservoir; and (e) means for maintaining the first and second reservoirs in alprazolam- and glycerol monolaurate and lactic ester of an alcohol-transmitting relation with the skin.

18. A device for the transdermal administration, at a therapeutically effective rate, of alprazolam, which device comprises: (a) a first reservoir comprising:

(i) 10 to 25% by weight alprazolam, (ii) 5 to 20% by weight glycerol monolaurate, (iii) 1 5 to 35% by weight lactic ester of an alcohol selected from the group consisting of lauryl lactate, ethyl lactate or myristyl lactate, or a combination thereof, and (iv) 30 to 60% by weight ethylene vinyl acetate; (b) a second reservoir comprising:

(i) 5 to 20% by weight glycerol monolaurate, (ii) 1 5 to 35% by weight lactic ester of an alcohol selected from the group consisting of lauryl lactate, ethyl lactate or myristyl lactate, or a combination thereof, and (iii) 30 to 80% by weight ethylene vinyl acetate;

(c) a membrane between the first reservoir and the second reservoir that is impermeable to alprazolam;

(d) a backing on the skin-distal surface of the second reservoir; and

(e) means for maintaining the first and second reservoirs in alprazolam- and glycerol monolaurate and lactic ester of an alcohol-transmitting relation with the skin.

19. A method for the transdermal administration of alprazolam, which method comprises:

(a) administering alprazolam at a therapeutically effective rate to an area of skin; and

(b) simultaneously administering a therapeutically acceptable permeation enhancer to the area of skin at a rate which is sufficient to substantially increase the permeability of the area to the alprazolam.

20. A method according to claim 19 wherein the permeation enhancer is a diethanolamide of a fatty acid; a monoglyceride or mixture of monoglycerides of a fatty acid; a dimethyl alkylamide; a sucrose ester or a mixture of sucrose esters of a fatty acid; a lactic ester of an alcohol or mixture thereof; a polyethylene glycol ester of a fatty acid; a benzoic acid of a fatty acid ester; and an alkyl laurate; or combinations thereof.

21 . A method according to claim 19 wherein the permeation enhancer is lauryl lactate in combination with glycerol monolaurate, lauryl lactate in combination with lauramide diethanolamide, ethyl laurate in combination with glycerol monolaurate, ethyl laurate in combination with lauramide diethanolamide, isoestearyl benzoate in combination with glycerol monolaurate, isoestearyl benzoate in combination with lauramide diethanolamide, or lauryl lactate.

22. A method according to claim 21 wherein the reservoir comprises ethylene vinyl acetate copolymer having from about 9% to about 60% vinyl acetate.

23. A method according to claim 19 wherein the alprazolam is administered through the skin at a rate of at least 0.5 μg/cm²-hour for an extended period of time.

24. A method for treating psychiatric dysfunctions, the method comprising the step of placing an alprazolam transdermal delivery device onto the skin of a person, the alprazolam transdermal delivery device comprising:

(a) a reservoir comprising alprazolam in an amount sufficient to provide a therapeutic effect for an extended period of time and a therapeutically acceptable permeation enhancer in a skin permeation-enhancing amount;

(b) a backing on the skin-distal surface of the reservoir; and

25. A method according to claim 24 wherein the permeation enhancer is a diethanolamide of a fatty acid; a monoglyceride or mixture of monoglycerides of a fatty acid; a dimethyl alkylamide; a sucrose ester or a mixture of sucrose esters of a fatty acid; a lactic ester of an alcohol; a polyethylene glycol ester of a fatty acid; a benzoic acid of a fatty acid ester; and an alkyl laurate; or combinations thereof.

26. A method according to claim 24 wherein the permeation enhancer is lauryl lactate in combination with glycerol monolaurate, lauryl lactate in combination with lauramide diethanolamide, ethyl laurate in combination with glycerol monolaurate, ethyl laurate in combination with lauramide diethanolamide, isoestearyl benzoate in combination with glycerol monolaurate, isoestearyl benzoate in combination with lauramide diethanolamide, or lauryl lactate.

27. A method according to claim 26 wherein the reservoir comprises ethylene vinyl acetate copolymer having from about 9% to about 60% vinyl acetate.

28. A method according to claim 24 wherein the alprazolam is administered through the skin at a rate of at least 0.5 /g/cm²-hour for an extended period of time.

29. A method according to claim 24 wherein the means for maintaining the reservoir in relation with the skin comprises an in-line adhesive layer on the skin-proximal surface of the reservoir.

30. A method according to claim 24 for treating psychiatric dysfunctions, which further comprises continuously administering alprazolam transdermally at an administration rate sufficient to maintain the blood concentrations of alprazolam at therapeutically effective levels in the range of 4.0 ng/ml to 50 ng/ml for an extended period of time.

31 . A method for treating psychiatric dysfunctions, the method comprising the step of placing an alprazolam transdermal delivery device onto the skin of a person, the alprazolam transdermal delivery device comprising:

(a) a first reservoir comprising: (i) 5 to 40% by weight alprazolam, (ii) 5 to 40% by weight glycerol monolaurate, (iii) 5 to 40% by weight lauryl lactate, and (iv) 20 to 70% by weight ethylene vinyl acetate; 5 (b) a second reservoir comprising:

(i) 5 to 40% by weight glycerol monolaurate,

(ii) 5 to 40% by weight lauryl lactate, and

(iii) 20 to 80% by weight ethylene vinyl acetate;

(c) a membrane between the first reservoir and the ιo second reservoir that is impermeable to alprazolam;

(d) a backing on the skin-distal surface of the second reservoir; and

(e) means for maintaining the first and second reservoirs in alprazolam- and lauryl lactate and glycerol

15 monolaurate-transmitting relation with the skin.

/

32. A method for treating psychiatric dysfunctions, the method comprising the step of placing an alprazolam transdermal delivery device onto the skin of a person, the alprazolam transdermal delivery device comprising: 20 (a) a first reservoir comprising:

(i) 10 to 25% by weight alprazolam, (ii) 5 to 20% by weight glycerol monolaurate, (iii) 1 5 to 35% by weight lauryl lactate, and (iv) 30 to 60% by weight ethylene vinyl acetate; 25 (b) a second reservoir comprising:

(i) 5 to 20% by weight glycerol monolaurate, (ii) 1 5 to 35% by weight lauryl lactate, and (iii) 30 to 80% by weight ethylene vinyl acetate; (c) a membrane between the first reservoir and the 30 second reservoir that is impermeable to alprazolam; (d) a backing on the skin-distal surface of the second reservoir; and

(e) means for maintaining the first and second reservoirs in alprazolam- and lauryl lactate and glycerol monolaurate-transmitting relation with the skin.

33. A method for the transdermal administration of alprazolam, the method comprising the step of placing a transdermal drug delivery device onto the skin of a person, the transdermal delivery device comprising: (a) a first reservoir comprising:

(i) 5 to 40% by weight alprazolam, (ii) 5 to 40% by weight glycerol monolaurate, (iii) 5 to 40% by weight lauryl lactate, and (iv) 20 to 70% by weight ethylene vinyl acetate; (b) a second reservoir comprising:

(i) 5 to 40% by weight glycerol monolaurate,

(ii) 5 to 40% by weight lauryl lactate, and

(iii) 20 to 80% by weight ethylene vinyl acetate;

(c) a rate-controlling membrane between the first reservoir and the second reservoir that is impermeable to alprazolam;

(d) a backing on the skin-distal surface of the second reservoir; and