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WO1994021262A1 - Dispositif d'administration transdermique d'alprazolam - Google Patents

Dispositif d'administration transdermique d'alprazolam Download PDF

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Publication number
WO1994021262A1
WO1994021262A1 PCT/US1994/002880 US9402880W WO9421262A1 WO 1994021262 A1 WO1994021262 A1 WO 1994021262A1 US 9402880 W US9402880 W US 9402880W WO 9421262 A1 WO9421262 A1 WO 9421262A1
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WO
WIPO (PCT)
Prior art keywords
alprazolam
reservoir
skin
weight
fatty acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1994/002880
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English (en)
Inventor
Lina Tormen Taskovich
Su Il Yum
Tyler Watanabe
Nieves Marzan Crisologo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alza Corp
Original Assignee
Alza Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alza Corp filed Critical Alza Corp
Priority to AU64104/94A priority Critical patent/AU6410494A/en
Publication of WO1994021262A1 publication Critical patent/WO1994021262A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • alprazolam is listed as a tranquilizer that may be transdermally administered with menthol.
  • 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.
  • 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.
  • alprazolam is listed as a central nervous system agent that may be delivered with a sustained release pharmaceutical plaster.
  • alprazolam is listed as a tranquilizer that may be transdermally administered with a device having a backing with a high water vapor transmission rate.
  • 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.
  • 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.
  • 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
  • alprazolam 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.
  • 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.
  • 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.
  • 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;
  • 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.
  • 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.
  • 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.
  • 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.
  • permeation enhancers can cause, among other problems, cohesive failure of adhesives and can partition into other components in the system.
  • 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.
  • 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.
  • 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 ⁇ g/hr to 100 g/hr.
  • alprazolam 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
  • the term "flux” refers to the rate of transfer of alprazolam across skin as measured.
  • the units of flux are preferably ⁇ g/cm 2 /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.
  • 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.
  • 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.
  • suitable transdermal delivery devices are illustrated in
  • the same reference numbers are used throughout the different figures to designate the same or similar components.
  • the figures are not drawn to scale.
  • 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.
  • 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.
  • 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.
  • the adhesive is an acrylic adhesive, such as MSP041991 P,
  • 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.
  • the strippable liner is a siliconized polyester film.
  • 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.
  • the rate controlling membrane is microporous high density polyethylene, the pores of which are impregnated with reservoir fluid.
  • 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.
  • a material such as, for example, an oily surfactant permeation enhancer
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • reservoir 12 is contained wholly between backing member 14 and rate-controlling membrane 28.
  • an adhesive layer 1 6 and a strippable liner 24 which would be removed prior to application of the device 40 to the skin.
  • 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.
  • matrix refers to a well-mixed composite of ingredients fixed into shape.
  • the reservoir matrix is preferably a hydrophilic polymer, e.g., a hydrogel.
  • 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.
  • EVA vinyl acetate
  • 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 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 LD 50 of alprazolam discovered for mice is 1020 mg/kg and rats is > 2000 mg/kg.
  • 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.
  • 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.
  • the 5 therapeutically acceptable permeation enhancer means a combination of two or more of the above permeation enhancers.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ .
  • the device can contain one or more antagonists for alprazolam such that the device is resistant to misuse and abuse.
  • 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.
  • 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 C 2 . 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the device for the transdermal administration of alprazolam 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
  • 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.
  • the backing is an occluded backing, such as Medpar ® .
  • 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.
  • 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.
  • 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.
  • 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.
  • alprazolam is delivered at a therapeutic rate of at least about 0.5 /tg/cm 2 -hour, but typically of at least 2.0 ⁇ g/cm 2 -hr, and more typically at 3.0 //g/cm 2 -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 cm 2 to greater than 200 cm 2 .
  • a typical device, however, will have a size within the range of 5-50 cm 2 .
  • 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.
  • 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.
  • alprazolam is used to designate the compound 8-chloro-1-methyl-6-phenyl-4H-[1 ,2,4]triazolo[4,3- a][1 ,4]benzodiazepine.
  • 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.
  • 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.
  • the term “substantially constant” means a variation of less than . ⁇ 20%, preferably less than ⁇ 10%, over a substantial portion of the time period.
  • C 2 . 4 alcohol refers to an alcohol having two to four carbon atoms, such as ethanol and isopropanol.
  • a monoglyceride or mixture of monoglycerides of fatty acids has a total monoesters content of at least
  • the monoesters are those with from six to twenty carbon atoms, such as glycerol monooleate, glycerol monolaurate and glycerol monolinoleate.
  • 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.
  • dimethyl alkylamide refers to an alkyl having 1 to 18 carbon atoms, preferably eight to sixteen carbon atoms, such as dimethyl lauramide.
  • 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.
  • 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.
  • 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.
  • benzoic acid of a fatty acid ester refers to a fatty acid having from eight to eighteen carbon atoms, such as isoestearyl benzoate.
  • alkyl laurate refers to an alkyl having from two to eight carbon atoms, such as ethyl laurate.
  • 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.
  • glycerol monooleate refers to glycerol monooleate itself or a mixture of glycerides wherein glycerol monooleate is present in the greatest amount.
  • glycerol monolaurate refers to glycerol monolaurate itself or a mixture of glycerides wherein glycerol monolaurate is present in the greatest amount.
  • glycerol monolinoleate refers to glycerol monolinoleate itself or a mixture of glycerides wherein glycerol monolinoleate is present in the greatest amount.
  • 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.
  • alkyl refers to straight or branched saturated aliphatic hydrocarbon radical having a single available bond.
  • 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
  • This film was then laminated to an acrylic contact adhesive (MSP041991 P, 3M) on one side and Medpar ® backing (3M) on the opposite side.
  • MSP041991 P, 3M acrylic contact adhesive
  • Medpar ® backing 3M
  • 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.
  • 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 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.
  • EVA 40 ethylene vinyl acetate having a vinyl acetate content of 40 percent
  • Polyvinyl pyrrolidone if present
  • Alprazolam and the permeation enhancers were then added. The mixture was blended for approximate 20 minutes at
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • 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 cm 2 discs with a stainless steel punch.
  • the weight of the monolith was 39 mg/cm 2 .
  • the in vitro transdermal alprazolam fluxes through the epidermis of 3 human skin donors from horizontal diffusion cells were determined.
  • 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.
  • 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.
  • 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
  • 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 cm 2 discs with a stainless steel punch.
  • the monoliths weighed 26 mg/cm 2 .
  • the in vitro transdermal alprazolam fluxes through the epidermis of 3 human skin donors from horizontal diffusion cells were determined.
  • 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 4B 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.
  • 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.
  • 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
  • alprazolam/glycerol monolaurate/diethylene glycol 1.65 monoethyl ether/isopropanol/water/ hydroxypropylcellulose
  • 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/cm 2 .
  • 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.
  • 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
  • contact adhesive an acrylic adhesive, MSP 041991 p, 3M
  • release liner siliconized polyester laminate. Excess membrane was trimmed from the 20 cm 2 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.
  • 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.
  • 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.
  • 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/cm 2 ) was then heat sealed with an
  • a rate controlling membrane microporous high density polyethylene, Cotran ® , 3M
  • contact adhesive an acrylic adhesive, MSP 041991 p, 3M
  • release liner siliconized polyester
  • 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.
  • 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.
  • Table 8 The different compositions of the drug reservoirs are shown in Table 8.
  • Drug Donor Solution Composition (weight 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
  • Drug Donor Solution Composition (weight 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-
  • 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/cm 2 .
  • 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 KH 2 PO 4 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.
  • 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.
  • EVA 40 ethylene vinyl acetate having a vinyl acetate content of 40 percent
  • Alprazolam GYMA Labs of America, Garden City, NJ
  • glycerol monolaurate Grindsted ML 90, Grindsted Products A/S, Brabrand, Denmark
  • lauryl lactate Van Dyk, Inc.
  • 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.
  • 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
  • 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.
  • EVA 40 ethylene vinyl acetate having a vinyl acetate content of 40 percent
  • 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.
  • 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
  • alprazolam/glycerol monolaurate/EVA 40 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%)
  • 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 cm 2 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.
  • 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.

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Abstract

L'invention concerne l'administration transdermique d'alprazolam avec un amplificateur de perméation acceptable thérapeutiquement. L'invention comprend un dispositif transdermique d'administration de médicament composé d'une matrice conçue pour effectuer la transmission de l'alprazolam et de l'amplificateur de perméation vers l'épiderme. La matrice contient des quantités suffisantes d'amplificateur de perméation et d'alprazolam pour administer l'alprazolam en continu dans l'épiderme pendant une durée prolongée, de façon à assurer un résultat thérapeutique efficace. L'invention concerne également un procédé d'administration transdermique d'une quantité thérapeutiquement efficace d'alprazolam avec une quantité d'amplification de la perméabilité épidermique d'un amplificateur thérapeutiquement acceptable. L'invention concerne, de plus, des procédés de traitement des troubles de l'anxiété, de l'alcoolisme, des disfonctionnements sexuels, de l'angoisse, de la dépression et de différents troubles psychiatriques.
PCT/US1994/002880 1993-03-17 1994-03-17 Dispositif d'administration transdermique d'alprazolam Ceased WO1994021262A1 (fr)

Priority Applications (1)

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AU64104/94A AU6410494A (en) 1993-03-17 1994-03-17 Device for the transdermal administration of alprazolam

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US3236393A 1993-03-17 1993-03-17
US032,363 1993-03-17
US12842093A 1993-09-29 1993-09-29
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WO2000007627A3 (fr) * 1998-08-04 2000-08-17 Johnson & Johnson Consumer Systemes de distribution topique d'agents actifs
US6203817B1 (en) 1997-02-19 2001-03-20 Alza Corporation Reduction of skin reactions caused by transdermal drug delivery
US6512010B1 (en) 1996-07-15 2003-01-28 Alza Corporation Formulations for the administration of fluoxetine
WO2006032624A1 (fr) * 2004-09-23 2006-03-30 Laboratorio Reig Jofré, S.A. Composition pharmaceutique a administration transdermique
EP1666026A2 (fr) 1999-02-08 2006-06-07 Alza Corporation Excipients visqueux à phase unique non aqueux stables et formulations utilisant ces excipients
CN100402036C (zh) * 2004-04-26 2008-07-16 袁重华 治疗失眠的涂敷剂
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US10159714B2 (en) 2011-02-16 2018-12-25 Intarcia Therapeutics, Inc. Compositions, devices and methods of use thereof for the treatment of cancers
US10231923B2 (en) 2009-09-28 2019-03-19 Intarcia Therapeutics, Inc. Rapid establishment and/or termination of substantial steady-state drug delivery
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US10501517B2 (en) 2016-05-16 2019-12-10 Intarcia Therapeutics, Inc. Glucagon-receptor selective polypeptides and methods of use thereof
US10527170B2 (en) 2006-08-09 2020-01-07 Intarcia Therapeutics, Inc. Osmotic delivery systems and piston assemblies for use therein
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US10925639B2 (en) 2015-06-03 2021-02-23 Intarcia Therapeutics, Inc. Implant placement and removal systems
USD933219S1 (en) 2018-07-13 2021-10-12 Intarcia Therapeutics, Inc. Implant removal tool and assembly
US11246913B2 (en) 2005-02-03 2022-02-15 Intarcia Therapeutics, Inc. Suspension formulation comprising an insulinotropic peptide

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2141025A (en) * 1983-05-20 1984-12-12 Nitto Electric Ind Co Compositions for percutaneous administration
GB2142237A (en) * 1983-07-01 1985-01-16 Nitto Electric Ind Co Pharmaceutical compositions for percutaneous administration
EP0267617A1 (fr) * 1986-11-14 1988-05-18 Theratech, Inc. Augmentation du pouvoir de pénétration au moyen d'un système binaire consistant en composées modifiant l'enveloppe cellulaire et en alcools à courte chaîne
WO1993003694A1 (fr) * 1991-08-27 1993-03-04 Cygnus Therapeutic Systems Administration transdermique de benzodiazepines de demi-vies courtes ou intermediaires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2141025A (en) * 1983-05-20 1984-12-12 Nitto Electric Ind Co Compositions for percutaneous administration
GB2142237A (en) * 1983-07-01 1985-01-16 Nitto Electric Ind Co Pharmaceutical compositions for percutaneous administration
EP0267617A1 (fr) * 1986-11-14 1988-05-18 Theratech, Inc. Augmentation du pouvoir de pénétration au moyen d'un système binaire consistant en composées modifiant l'enveloppe cellulaire et en alcools à courte chaîne
WO1993003694A1 (fr) * 1991-08-27 1993-03-04 Cygnus Therapeutic Systems Administration transdermique de benzodiazepines de demi-vies courtes ou intermediaires

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 118, no. 10, 8 March 1993, Columbus, Ohio, US; abstract no. 87506w *
V.CARELLI ET AL.: "ENHANCEMENT EFFECTS IN THE PERMEATION OF ALPRAZOLAM THROUGH HAIRLESS MOUSE SKIN", INT.J.PHARM., vol. 88, no. 1-3, 1992, pages 89 - 97 *

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WO1998002169A3 (fr) * 1996-07-15 1998-03-12 Alza Corp Nouvelles preparations pour l'administration de fluoxetine
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US6284234B1 (en) 1998-08-04 2001-09-04 Johnson & Johnson Consumer Companies, Inc. Topical delivery systems for active agents
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