WO1993023019A1 - Dispositifs d'apport medicamenteux transcutane, compositions qui y sont associees et procedes d'utilisation - Google Patents

Dispositifs d'apport medicamenteux transcutane, compositions qui y sont associees et procedes d'utilisation Download PDF

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Publication number
WO1993023019A1
WO1993023019A1 PCT/US1993/004442 US9304442W WO9323019A1 WO 1993023019 A1 WO1993023019 A1 WO 1993023019A1 US 9304442 W US9304442 W US 9304442W WO 9323019 A1 WO9323019 A1 WO 9323019A1
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WO
WIPO (PCT)
Prior art keywords
captopril
skin
lower aliphatic
pharmacologically active
active agent
Prior art date
Application number
PCT/US1993/004442
Other languages
English (en)
Inventor
David R. Friend
Harold W. Nolen, Iii
Paul G. Catz
Original Assignee
Sri International
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Filing date
Publication date
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Publication of WO1993023019A1 publication Critical patent/WO1993023019A1/fr

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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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • the present invention relates generally to the transdermal administration of pharmacologically active agents, and more particularly relates to novel transdermal drug delivery systems and methods of administering drugs using such systems.
  • Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
  • Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum comeum and any material on its surface. The molecules must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels.
  • stratum comeum which present the primary barrier to absorption of topical compositions or transdermally administered drugs.
  • the stratum comeum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body.
  • the skin may be pretreated with a penetration enhancing agent (or "permeation enhancer," as sometimes referred to herein) prior to application of a drug.
  • a penetration enhancing agent or "permeation enhancer," as sometimes referred to herein
  • a drug and a permeation enhancer are delivered concurrently.
  • the present invention is directed to a novel composition for enhancing the penetration of pharmacologically active agents through skin, the composition based on (1) a lower aliphatic ester of a lower aliphatic carboxylic acid with (2) a lower alkanol.
  • the enhancer compositions of the invention have been found by the inventors herein to be particularly effective in enhancing the penetration of pharmaceutically active agents through skin, and surprisingly more effective than either component of the composition when used alone. While there are a number of patents and publications available which relate to the transdermal adiJ-t-nistration of drugs and to skin permeation enhancer compositions, applicants are unaware of any art which suggests that the combinations now disclosed herein provide a synergistic enhancing effect.
  • the present invention is directed to novel transdermal drug delivery systems in which the penetration of pharrnacologically active agents through skin is enhanced by c ⁇ -aclrr---r ⁇ istering drug with a permeation enhancing composition as described in copending, commonly assigned U.S.
  • the enhancer compositions described in the aforementioned application contain ( 1) a lower aliphatic ester of a lower aliphatic carboxylic acid, (2) a lower alkanol, and (3) optionally, additional permeation enhancing components such as a lower aliphatic ester of a higher carboxylic acid (e.g., isopropyl myristate).
  • additional permeation enhancing components such as a lower aliphatic ester of a higher carboxylic acid (e.g., isopropyl myristate).
  • Such enhancer compositions were found to be surprisingly more effective than either component of the composition used alone.
  • the drug delivery systems disclosed herein make use of such a permeation enhancer composition, in a device containing a release rate-controlling means which controls the flow of drug out of the device but not the flow of permeation enhancer. That is, the devices contain specifically formulated polymer membranes which do not limit the rate of enhancer delivery in any way— so that the delivery of solvent is skin rate-controlled— but which provide for a steady-state flux of drug out of the device, i.e., release rate of drug is "system-controlled.”
  • the present systems are particularly useful in the transdermal administration of the angiotensin converting enzyme (ACE) inhibitor drug captopril, the beta blocker timolol, and the narcotic analgesics buprenorphine and nalbuphine.
  • ACE angiotensin converting enzyme
  • Skin permeation enhancers generally: Various compounds for enhancing the permeability of skin are known in the art.
  • Other compounds which have been used to enhance skin permeability include: decylmethylsulfoxide (CJQMSO); diethylene glycol monoethyl ether, polyethylene glycol monolaurate (PEGML; see, e.g., U.S.
  • Patent No.4,568,343 to Leeper et al. glycerol monolaurate (U.S. Patent No.4,746,515 to Cheng etal.); propylene glycol monolaurate (e.g., U.S. Patent No.4,764,379 to Sanders et al.); ethanol (e.g., as in U.S. Patent No. 4,379,454 to Campbell et al.); eucalyptol (U.S. Patent No.4,440,777); lecithin (U.S. Patent No.
  • CA see U.S. Patent Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); "cell envelope disordering compounds” such as methyl laurate or oleic acid in combination with N- (hydroxyethyl) pyrrolidone (U.S. Patent No. 4,537,776 to Cooper) C3-C4 diols (U.S. Patent
  • Transdermal systems containing rate-controlling membranes U.S. Patent No. 4,615,699 to Gale etal. describes a transdermal therapeutic system for the administration of nitroglycerin, which contains a rate-controlling membrane of ethylene-vinyl acetate.
  • U.S. Patent Nos. 3,731,683, 3,854,480, and 3,996,934 to Zaffaroni describe a transdermal drug delivery device containing a wall member which is stated to meter the flow of drug.
  • U.S. Patent No. 4,262,003 to Urquhart et al. describes a transdermal therapeutic system for administering scopolamine base, wherein the system contains a membrane for controlling the rate at which drug is released from the drug reservoir.
  • U.S. Patent No. 4,834,979 to Gale describes a medical bandage for administering drug to the skin; the device contains a polymeric membrane apparently designed to control the rate of drug release from the drug reservoir.
  • the polymeric membrane is an ethylene-vinyl acetate based membrane. It is yet another object of the invention to provide such a device containing a skin permeation enhancer composition of a lower aliphatic ester of a lower aliphatic carboxylic acid in combination with a lower alkanol, and optionally additional permeation enhancing components such as a lower aliphatic ester of a higher carboxylic acid. It is a further object of the invention to provide such a device for the transdermal administration of captopril.
  • a transdermal drug delivery device for administering a pharmacologically active agent through a selected area of skin over a sustained time period, comprising a laminated composite of: (a) a backing layer which is substantially impermeable to the pharmacologically active agent and which defines the upper surface of the device during use;
  • a reservoir layer containing a therapeutically effective amount of the pharmacologically active agent and a permeation enhancer composition comprising (i) a lower aliphatic ester of a lower aliphatic carboxylic acid, and (ii) a lower alkanol; (c) a release rate-controlling means which controls the flow of pharmacologically active agent but not the flow of permeation enhancer composition from the device; and
  • (d) means for maintaining the device in agent-and enhancer-transmitting relationship to the skin.
  • a method for administering a pharmacologically active agent transdermally which comprises applying the above-defined laminated composite to a selected area of intact skin for a time period effective to produce the desired therapeutic effect.
  • Figure 1 is a sectional representation of a preferred transdermal patch which may be used in conjunction with the methods and compositions of the invention.
  • Figure 2 graphically illustrates the flux of captopril into an infinite reservoir permeating through human skin, as described in Example 1.
  • Figure 3 graphically illustrates the flux of propyiene glycol into an infinite reservoir from a trarisdermal patch (Figure 3A) and the cumulative delivery of propyiene glycol from the patch over a 24 hour period ( Figure 3B), as described in Example 2.
  • Figure 4 graphically illustrates the flux of ethyl acetate into an infinite reservoir from a transdermal patch and the cumulative delivery of ethyl acetate from the patch over a 24 hour period, as described in Example 2.
  • Figure 5 graphically illustrates the flux of ethyl acetate into an infinite reservoir from a transdermal patch, with and without skin, over a 24 hour period, as described in Example 3.
  • Figure 6 graphically illustrates the flux of captopril into an infinite reservoir from a transdermal patch over a 24 hour period, as described in Example 4.
  • Figure 7 graphically illustrates the flux of captopril into an infinite reservoir permeating through skin or from a transdermal patch permeating through skin over a 60 hour period, as described in Example 5.
  • Figures 8A and 8B graphically illustrate the flux of ethyl acetate and ethanol, respectively, into an infinite reservoir permeating from a transdermal patch loaded with variable permeation enhancer vehicle compositions and captopril through human cadaver abdominal skin over a 24 hour period, as described in Example 6.
  • Figures 9A and 9B graphically illustrate the flux of captopril into an infinite reservoir permeating from a transdermal patch loaded with variable permeation enhancer vehicle compositions and captopril through human cadaver abdomen and thigh skin, respectively, over a
  • Figure 10 graphically illustrates the flux of timolol maleate through skin, through an ethylene-vinyl acetate membrane, and through an ethylene-vinyl acetate membrane placed on skin, as described in Example 8.
  • Figures 11 A and 1 IB graphically illustrate solvent flux versus time for the experiment of
  • Poration enhancement or “permeation enhancement” as used herein relates to an increase in the permeability of skin to a pharmacologically active agent, i.e., so as to increase the rate at which the agent permeates into and through the skin.
  • a “permeation enhancer” is a material which achieves such permeation enhancement, and a “penetration enhancing amount” of an enhancer as used herein means an amount effective to enhance skin penetration of a selected agent to a desired degree, i.e., to effect the desired pharmacologic response.
  • transdermal drug delivery applicant is using the term in its conventional sense, i.e., to indicate delivery of a drug by passage through the skin and into the blood stream.
  • transmucosal drug delivery applicant intends delivery of a drug by passage of a drug through the mucosal tissue into the blood stream.
  • Topical drug delivery is used to mean local administration of a topical drug as in, for example, the treatment of various skin disorders. Aspects of the invention which are described in the context of "transdermal” drug delivery, unless otherwise specified, can apply to transmucosal or topical delivery as well. That is, the compositions, systems, and methods of the invention, unless explicitly stated otherwise, should be presumed to be equally applicable with any one of these three modes of drug delivery.
  • drug or "pharmacologically active agent” as used herein is intended to mean a compound or composition of matter which, when administered to an organism (human or animal) induces a desired pharmacologic and or physiologic effect by local and/or systemic action.
  • the terms include the therapeutic or prophylactic agents in all major therapeutic or prophylactic areas of medicine.
  • drugs useful in conjunction with the present invention include: anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; antihelrninthics; antia ⁇ hritics; antiasthmatic agents anticholinergic agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; ant-Wstamines; anti- inflammatory agents; antirnigraine preparations; anti-motion sickness drugs; antinauseants; antineoplastics; antiparkinsonisrn drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and antiarrhythmics; antihypertensives; diuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; cough,
  • drug as used herein also include locally administered topical medicaments such as antibacterial agents, antifungals, antimicrobials, cutaneous growth enhancers, antipsoriatics, anti-acne medicaments, and the like.
  • Carriers or “vehicles” as used herein refer to carrier materials without pharmacological activity which are suitable for administration in conjunction with the presently disclosed and claimed compositions, and include any such carrier or vehicle materials known in the art, e.g., any liquid, gel, solvent, liquid diluent, solubilizer, or the like.
  • the carriers and vehicles suitable herein are "pharmaceutically acceptable” in that they are nontoxic, do not interfere with drug delivery, and are not for any other reasons biologically or otherwise undesirable. Examples of specific suitable carriers and vehicles for use herein include water, mineral oil, silicone, inorganic gels, aqueous emulsions, liquid sugars, waxes, petroleum jelly, and a variety of other oils and polymeric materials.
  • a “therapeutically effective” amount of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired therapeutic effect.
  • the invention is thus, in one embodiment, a transdermal drug delivery device which comprises a laminated composite of a backing layer, a drug reservoir layer, a release rate- controlling means, and a means for maintaining the device in agent- and enhancer-transmitting relationship to the skin.
  • the device may also include one or more other layers, e.g., additional drug and/or enhancer reservoirs or the like.
  • the backing layer will function as the primary structural element of the device and provide the device with much of its flexibility.
  • This layer also serves as a protective covering to prevent loss of drug and enhancer via transmission through the upper surface of the device.
  • the backing layer may also be used to impart the device with a desirable or necessary degree of occlusivity which in turn causes the area of skin on which the device is placed to become hydrated.
  • the backing is preferably made of a sheet or film of a flexible elastomeric material, and may or may not be metallized.
  • Suitable flexible elastomeric materials include polyether block amide copolymers, polyurethanes, silicone elastomers, rubber-based polyisobutylene, styrene, polyethylene, polypropylene, polyesters, or the like.
  • the preferred polymer used for the backing will depend primarily on the particular pharmacologically active agent incorporated into the device.
  • the reservoir layer which contains the selected pharmacologically active agent in a therapeutically effective amount and the skin permeation enhancer composition may comprise either an adhesive polymer or a gelled system, which is preferably but not necessarily of a material in which the selected drug or vehicle has moderate solubility and diffusivity.
  • suitable adhesive materials which may be used to formulate the drug reservoir layer include polysiloxanes, polyacrylates, polyurethanes, polyisobutylene, and tacky rubbers. It is preferred, however, that the drag reservoir be a gelled system; either aqueous or nonaqueous gelled systems may be used.
  • An exemplary gelled formulation will include about 0.1 to 40 WL% drug and 1 to 10 WL% gelling agent, with the remainder of the formulation being enhancer, carriers, or the like. It will be appreciated by those skilled in the art, however, that the relative quantities of drug, enhancer, carrier (if any), and gelling agent will vary, depending on a number of factors, including the particular drug to be administered, desired dosage, and the like. Optimization of the drug/enhancer reservoir composition may be carried out readily using routine methods known to those working in the field of transdermal drug delivery. Suitable gelling agents include, for example, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, carbopol resins, and the like.
  • the release rate-controlling means of the invention will typically be a polymeric membrane placed in the flow path of drug from the reservoir layer to the skin, although the drug reservoir matrix itself may serve as a release rate-controlling element.
  • the membrane material will generally be selected from the group consisting of ethylene-vinyl acetate (ENAc), ethylene-vinyl acetate organic acid terpolymer, polyamide, polyester, and acrylic resins.
  • the release rate- controlling membrane has an vinyl acetate (NAc) content of at least about 15 wt.%, more preferably at least about 18 wt.%, most preferably at least about 25 wt.%.
  • the means is typically an adhesive means formulated from an adhesive material which is chemically and physically compatible with all components of the device and which is pharmacologically acceptable, i.e., it should be of a material suitable for placement on the skin.
  • adhesive materials will typically be selected from that class of materials which may be used for the drug reservoir layer; preferred materials include polysiloxanes, polyacrylics, and polyisobutylene.
  • the transdermal devices of the invention are formulated with an enhancer composition suitable for enhancing the rate of penetration of a selected drug through the skin, wherein the composition comprises a lower aliphatic ester of a lower aliphatic carboxylic acid and propyiene glycol.
  • the term "lower” is used to mean a chemical compound having six carbon atoms or less.
  • Preferred materials useful as the lower aliphatic esters have a total of from about three to about six carbon atoms in their esterifying groups plus their acid groups.
  • typical materials include methyl butrate, methyl proprionate, methyl acetate, ethyl butrate, ethyl propionate, ethyl acetate, propyl butrate, propyl propionate, and propyl acetate.
  • methyl butrate methyl proprionate
  • methyl acetate methyl acetate
  • ethyl butrate ethyl propionate
  • ethyl acetate ethyl acetate
  • propyl butrate propyl propionate
  • propyl propionate propyl acetate
  • the permeation enhancer compositions of the invention also contain a lower alkanol.
  • the lower alkanol can be amonoalkanol such as methanol, ethanol, 1-propanol, 2-propanol, or a butanol (a-, i- or t-butanol), or it may be a diol such as propyiene glycol. Propyiene glycol and ethanol are particularly preferred.
  • the enhancers of the invention preferably contain on the order of 25 wt.% to 90 wt.% lower aliphatic ester and approximately 10 wt.% to 75 wt.% lower alkanol.
  • the compositions may also include carriers or vehicles as described above, and/or various additional agents and ingredients such as fragrances, pacifiers, preservatives, antioxidants, gelling agents, perfumes, thickening agents, stabilizers, surfactants, emollients, coloring agents, and the like, so long as they are pharmaceutically acceptable and compatible with the selected pharmacologically active agent in the permeation enhancer composition as described above.
  • Particularly preferred additives include hydrophobic co-solvents such as squalene, decylme ⁇ ylsulfoxide, and isopropyl myristate, and surfactants, including anionic, cationic, nonionic, and amphoteric surfactants. If such co- solvents or surfactants are present, they will preferentially be included at less than about 15 wt.%, preferably less than about 10 wt.% of the total enhancer composition. Addition of a lower aliphatic ester of a higher carboxylic acid (i.e., containing seven carbon atoms or more), such as isopropyl myristate, is particularly preferred.
  • hydrophobic co-solvents such as squalene, decylme ⁇ ylsulfoxide, and isopropyl myristate
  • surfactants including anionic, cationic, nonionic, and amphoteric surfactants. If such co- solvents or surfactants are present, they
  • compositions of the present invention While a variety of pharmacologically active agents may be administered using the compositions of the present invention, particularly preferred active agents are selected from the group consisting captopril, timolol, nalbuphine, buprenorphine, and salts thereof. Captopril and timolol maleate are especially preferred.
  • a preferred enhancer formulation contains about 25 wt% to 90 wt.% lower aliphatic ester and about 10 wt.% to 75 wt.% lower alkanol.
  • Particularly preferred enhancer compositions for use with captopril contain about 50 WL% to 90 wt.% ethyl acetate, 25 wt.% to 45 wt.% propyiene glycol, and 0 wt.% to 15 wt.%, preferably 5 wt.% to 10 wt.%, isopropyl myristate.
  • enhancer compositions for use with captopril contain 25 wt% to 65 wt.% ethyl acetate and 35 wt.% to 75 wt.% ethanol.
  • an optimum enhancer formulation contains about 70 wt.% to 90 WL% lower aliphatic ester (preferably ethyl acetate) and about 10 wt.% to 30 wt.% lower alkanol (preferably propyiene glycol or ethanol).
  • the amount of drug contained within the composition will depend on a variety of factors, including the desired rate of delivery, the desired dosage, the disease to be treated, the nature and activity of the drug, the desired effect, possible adverse reactions, the ability and speed of the drug selected to reach its intended target, and other factors within the particular knowledge of the patient and physician.
  • the laminated composite Prior to use, the laminated composite also includes a release liner layer. Just prior to use, this layer is removed from the device to expose the basal surface of the device.
  • the release liner will normally be made from a drag/enhancer-impermeable material that is inherently “strippable” or rendered so by techniques such as silicone or fluorocarbon treatment.
  • An exemplary system is illustrated in cross-section in Figure 1.
  • the transdermal patch is shown generally at 10, with backing material 14 overlying drug reservoir 12.
  • Adjacent to and underlying the reservoir is a release rate-controlling membrane 16 which, as mentioned above, is preferably comprised of a vinyl acetate-containing material.
  • Underlying membrane 16 is a protective layer 18 which is typically comprised of a material similar to that selected for backing 14.
  • Release liner 20 forms the basal surface of the device prior to use, and may be peeled away to expose adhesive ring 22. Heat seals 24, 26, 28, and 30 ensure that the various components and layers of the device remain bonded
  • Preferred daily dosages obtained with the present methods and systems will, similarly, vary with the drug administered.
  • the targeted daily dosage will depend on the individual being treated, the indication addressed, the length of time the individual has been on the drug, and the like.
  • the human cadaver skin used in the experiments was excised from the abdomen, back or thigh area of 40- to 80-year-olds within 12 hours post-mortem at a thickness ranging from 150-600 ⁇ m.
  • the skin was stored frozen.
  • the skin was then thawed, cut to circular pieces of approximately 2.0-5.0 cm , and placed on the cells, epidermis side up, to equilibrate for one hour, with a glass cell cap clamped above.
  • the surface area exposed to the donor phase was 0.65 car or 2.0 cm .
  • the donor vehicles were prepared by saturating the drug to be tested in the different enhancer mixtures to ensure a constant driving force. In some experiments, donor vehicles were prepared using other concentrations of drugs. Captopril was saturated at 33 wt.%. Timolol maleate was saturated at 25 wt.%. The suspensions were stirred overnight In some experiments, donor vehicles were prepared using other concentrations of drugs. At the start of the experiment, 325 ⁇ l of the saturated rnixture was pipetted through the cell cap directly onto the skin, and the cap sealed with a glass stopper.
  • the donor vehicle was gelled by the addition of a combination of hydroxypropyl cellulose and Carbopol 1342 (obtained from B.F. Goodrich, Cleveland, Ohio) at a concentration of 1 to 2 wt.% (and added to the skin at a concentration of 150 ⁇ lJc ⁇ r).
  • entire transdermal devices were placed on the skin or in the cell without skin.
  • the receptor phase in contact with the underside of the skin, was phosphate-buffered (0.01
  • Receptor phase solution was pumped through the diffusion cells by means of a Manostat Cassette Pump drive unit.
  • a fraction collector was used to collect the cell effluent.
  • the flow rate was set so that drug concentration in the receptor phase remained well below saturation; a typical flow rate was 5 ml/hr.
  • Uniform mixing of the drug in the receptor phase was achieved by a small magnetic stirring bar driven by an external 600 rpm motor. Fractions were collected at regular intervals and analyzed for the selected drug using HPLC. Each donor vehicle/therapeutic agent formulation was tested in triplicate and the 24-hour cumulative drug deliveries averaged for the three cells.
  • Captopril concentration in the receptor phase was measured using HPLC. No sample pretreatment was required.
  • the HPLC analyses were performed on a Waters 840 system consisting of two Model 510 pumps, a Model 481 UV detector, a Model 710 B WISP (sample processor), and a Digital Computer Model 350 rmcroprocessor/programmer. The column used was a 4.6 mm x 25 cm Whatman ODS-3 Partisil C-18 at 40°C.
  • Captopril was measured using a mobile phase of 0.10 M phosphate buffer, pH 3.0: acetonitrile, at a flow rate of 1.0 ml/min. After an initial 2 rnin.
  • Transdermal patches were prepared as follows. A 300 ⁇ L reservoir was created in the backing material (Scotchpak #1009, Health Care Specialties Division, 3M) using a steel mold machined at SRI International, Menlo Park, CA. The steel mold consisted of three parts: 1/2"
  • the lower half of the mold had a depression that was used to shape the reservoir in the backing material.
  • the upper half of the mold had a 2.0 c ⁇ r hole drilled through it to accommodate the third part of the mold, the plunger.
  • the bottom of the plunger was machined to fit into the depression in the lower half of the mold.
  • the depression was defined by a 2.0 cm ⁇ circular area cut about 1 mm into the lower half of the mold. The edges of the depression were rounded, and there was a 6 mil clearance between the sides of the depression and the plunger, to prevent shearing of the backing material.
  • the reservoir was created by centering a 1.75" (4.45 cm) i.d. piece of backing material on the lower half of the mold, with the aluminized side up.
  • the upper half of the mold was secured to the lower half using alien screws, immobilizing the backing material.
  • the plunger was pushed through the hole in the upper half of the mold until it rested on the backing material.
  • the entire mold was then placed in a heat press at 185°F (85°C) for fifteen minutes.
  • the upper and lower plates of the heat press were then brought together until the backing layer was driven to the bottom of the depression in the lower half of the mold.
  • the pressure used was less than about 500 psi (3447 kPa).
  • the heat press plates were moved apart, and the mold was removed and placed in a second press that was at room temperature. The plates of this press were brought together as before and the mold allowed to cool with the plunger at the bottom of the depression. The backing material with reservoir was then rinsed in 70% isopropanol and allowed to dry.
  • a ring of transfer adhesive (3M Pharmaceutical Grade Transfer Adhesive No.9871) with a paperrelease liner (3M Silicone Treated Paper Release Liner No.9743) was added.
  • the adhesive ring was prepared as follows. First, the non-sticking layer was removed from a portion of the transfer adhesive and a piece of the paper release liner added. 1.25" (3.18 cm) i.d. circles were punched out of the transfer adhesive/paper release liner laminate. Then, 1.75" (4.45 cm) i.d. circles were punched out. The result was a ring with a 1.75" (4.45 cm) outer diameter and a 1.25" (3.18 cm) inner diameter.
  • the paperrelease liner was removed and the adhesive attached to the backing layer.
  • the outer layer of material was removed from the adhesive ring, exposing the adhesive.
  • the paper release liner (previously removed) was then placed on the adhesive. When the paper release liner is removed, the adhesive on the backing layer can be affixed to the skin.
  • a captopril patch was then prepared as follows: 300 ⁇ L donor solution (e.g., EtAc/PG/IPM, 65:30:5 with 25 wt.% captopril, gelled using 1 wt.% hydroxypropyl cellulose) was pipetted into the reservoir using an SMI pipet. A 7/8"(2.22 cm) circular piece of 3 mil 18% EVAc membrane (3M) was heat-sealed over the top of the reservoir using a 1.8 cm id. heat sealer for 6 seconds at 133°C. The release liner was attached to the backing material using a 2.6 cm i.d. heat sealer for two seconds at 125°C.
  • donor solution e.g., EtAc/PG/IPM, 65:30:5 with 25 wt.% captopril, gelled using 1 wt.% hydroxypropyl cellulose
  • enhancer vehicle with 33 wt.% captopril.
  • the captopril-containing vehicle was gelled with 1-2 wt.% hydroxypropyl cellulose and added to the skin at 150 ⁇ lJcm .
  • Flux of PG and EtAc from the loaded transdermal patches into the receptor solution were evaluated as in Example 1. EtAc and PG were measured using a Waters Fast Fruit Juice Column (7.8 mm x 15 cm).
  • the mobile phase was 0.05% H3PO4 in water (vol vol) at a flow rate of 1.5 ml/min.
  • Example 2 The procedures described in Example 2 were used to evaluate the flux of EtAc from transdermal patches, with and without human cadaver skin, and skin only. The experimental results are summarized in Figure 5. As in Example 2, the flux of EtAc from the patch reached a peak of about 9.3 mg/cm ⁇ hr at 4 hours. The flux of EtAc from the patch through skin reached a peak of about 3 mg/cm 2 at 6 hours and declined to a steady-state level thereafter. These results indicate that solvent delivery is controlled to a large extent by the skin.
  • Example 2 The procedures of Example 2 were used to evaluate the flux of captopril from transdermal patches into the receptor phase solution. The experimental results are summarized in Figure 6.
  • the captopril target flux was exceeded between 2 and 4 hours, and, unlike the permeability results observed using skin alone (see Example 1), a steady-state level of about 125 ⁇ g/cm ⁇ hr was reached by 6 hours. This level was maintained for the 24 hour duration of the experiment.
  • Example 2 The procedures described in Example 2 were used to evaluate the flux of captopril into the receptor phase solution from transdermal patches through human back skin. Patches were left in place for 24 hours and either removed or removed and a second patch placed on the same skin.
  • Example 1 The procedures described in Example 1 were used to evaluate the flux of captopril from a gelled enhancer vehicle through skin only. The experimental results of both these procedures are summarized in Figure 7.
  • Flux increased to a level of about 400 ⁇ g/cnAir by 32 hours and decreased thereafter until 50 hours when an apparently anomalous increase in flux was observed.
  • target flux was again exceeded between 12 and 16 hours.
  • a steady-state flux level of about 140 ⁇ g/cncrhr was achieved by 24 hours and was maintained for an additional 8 hours despite the removal of the patch.
  • the flux decreased thereafter until it dropped below the target level between 42 and 45 hours.
  • Example 6 The procedure described in Example 1 (b) was used to load transdermal patches made with
  • Example 1(b) The procedure described in Example 1(b) was used to load transdermal patches made with 28 wt% NAc-content ENAc copolymer membranes with various amounts of EtAc / ethanol (EtOH) (0.65:0.35, 0.50:0.50, 0.35:0.65, 0.25:0.75, 0.15:0.85) enhancer vehicle with 10% captopril.
  • EtAc / ethanol EtAc / ethanol
  • the captopril-containing vehicle was gelled and added to the skin as in Example 2.
  • the procedures described in Example 1(a) were used to evaluate the effect of enhancer vehicle composition on the flux of captopril from transdermal patches through human cadaver skin.
  • the experimental results are summarized in Figures 9A (abdominal skin) and 9B (thigh skin).
  • the captopril target flux was exceeded when the enhancer vehicle composition (EtAc / EtOH) was 0.25:0.75, 0.35:0.65, 0.50:0.50 or 0.65:0.35.
  • the longer lag time observed in the experiments depicted in Figure 9B is postulated to be due to the fact that the skin used was considerably thicker than in other experiments.
  • Example s The procedures of Example 1 were used to evaluate the flux of timolol maleate through human skin, through an ENAc membrane, and through an ENAc membrane placed on human skin.
  • sample/processor and a Digital Computer Model 350 microprocessor/programmer.
  • the column used wa a 4.6 mm x 25 cm Whatman ODS-3 Partisil C-l 8. Timolol was measured using a mobile phase of 0.05 M sodium acetate buffer, pH 3.5 90% acetonitrile (10% acetate buffer) (30/70) at a flow rate of 1.8 ml min. Absorbance monitoring was performed at 295 nm, and the retention time was found to be 5.3 minutes.
  • the goal of this experiment was to evaluate the flux of timolol maleate, ethyl acetate and propyiene glycol from a saturated drug solution in an ethyl acetate (EtAc) / propyiene glycol (PG) / isopropyl myristate (IPM) (0.55:0.40:0.05) donor vehicle through human skin, through a 2 mil (28% vinyl acetate) EVAc membrane (3M), and through the membrane placed on the skin. It was intended that the membrane be rate-controlling for the drug only, and yield a sustained flux for timolol at or near the minimum target flux of 5 ⁇ g/cncr, which was calculated based on theoretical delivery from a 30 cm 2 patch.
  • EtAc ethyl acetate
  • PG propyiene glycol
  • IPM isopropyl myristate
  • Ethyl acetate and propyiene glycol concentration in the receptor phase was also measured, using the method outlined in Example 2.
  • the experimental results for ethyl acetate and propyiene glycol are summarized in Figures 11 A and 1 IB, respectively. As can be seen, solvent flux was much higher through skin than through the membrane or membrane/skin composite, until the solvent neared depletion, at which point the solvent flux dropped toward zero.

Abstract

L'invention concerne des dispositifs d'apport médicamenteux transcutané dans lesquels un moyen de régulation de la vitesse de libération limite le flux médicamenteux qui sort du dispositif, sans limiter pour autant le flux de l'activateur de pénétration dans la peau. Les dispositifs comprennent une composition activatrice d'un ester aliphatique inférieur d'un acide carboxylique aliphatique inférieur, un alcanol inférieur et éventuellement, des constituants additionnels activant la pénétration. L'invention concerne en outre des dispositifs transcutanés permettant d'administrer des substances actives sur le plan pharmacologique.
PCT/US1993/004442 1992-05-11 1993-05-10 Dispositifs d'apport medicamenteux transcutane, compositions qui y sont associees et procedes d'utilisation WO1993023019A1 (fr)

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US08/014,922 1993-02-08

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WO1996019205A1 (fr) * 1994-12-21 1996-06-27 Theratech, Inc. Systeme de liberation transdermique avec opercule adhesif et rondelle pelable
DE19512181A1 (de) * 1995-03-31 1996-10-02 Hexal Pharma Gmbh Transdermal applizierbares Arzneimittel mit ACE-Hemmern
US6805878B2 (en) 2001-09-13 2004-10-19 Noven Pharmaceuticals, Inc. Transdermal administration of ACE inhibitors
WO2004091589A1 (fr) * 2003-04-14 2004-10-28 Mutzbauer Till S Agent calmant et sedatif administrable par voie transdermique
US8025898B2 (en) 2001-06-18 2011-09-27 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
US8124141B2 (en) 2003-03-12 2012-02-28 Mitsui Norin Co., Ltd. Rapidly absorbing lipophilic skin compositions and uses therefor
US9642850B2 (en) 1997-02-24 2017-05-09 Purdue Pharma L.P. Method of providing sustained analgesia with buprenorphine
US10010612B2 (en) 2007-05-25 2018-07-03 Indivior Uk Limited Sustained delivery formulations of risperidone compounds
US10022367B2 (en) 2014-03-10 2018-07-17 Indivior Uk Limited Sustained-release buprenorphine solutions
US10058554B2 (en) 2005-09-30 2018-08-28 Indivior Uk Limited Sustained release small molecule drug formulation
US10172849B2 (en) 2010-06-08 2019-01-08 Indivior Uk Limited Compositions comprising buprenorphine
US10198218B2 (en) 2010-06-08 2019-02-05 Indivior Uk Limited Injectable flowable composition comprising buprenorphine

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EP0399432A2 (fr) * 1989-05-25 1990-11-28 Takeda Chemical Industries, Ltd. Composition thérapeutique transdermique
EP0452837A2 (fr) * 1990-04-18 1991-10-23 Nitto Denko Corporation Dispositif adhésif d'administration d'un principe actif par voie transdermique
WO1992005811A1 (fr) * 1990-10-05 1992-04-16 Ethical Pharmaceuticals Limited Dispositif percutane
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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996019205A1 (fr) * 1994-12-21 1996-06-27 Theratech, Inc. Systeme de liberation transdermique avec opercule adhesif et rondelle pelable
US5662925A (en) * 1994-12-21 1997-09-02 Theratech, Inc. Transdermal delivery system with adhesive overlay and peel seal disc
DE19512181A1 (de) * 1995-03-31 1996-10-02 Hexal Pharma Gmbh Transdermal applizierbares Arzneimittel mit ACE-Hemmern
WO1996029999A1 (fr) * 1995-03-31 1996-10-03 Hexal Ag Medicament a administration transdermique, comportant des inhibiteurs de l'enzyme de conversion de l'angiotensine
US6303141B1 (en) 1995-03-31 2001-10-16 Hexal Ag Transdermally administrable medicament with ACE inhibitors
DE19512181C2 (de) * 1995-03-31 2003-11-06 Hexal Pharma Gmbh Transdermales System mit Ramipril und/oder Trandolapril als ACE-Hemmer
US9642850B2 (en) 1997-02-24 2017-05-09 Purdue Pharma L.P. Method of providing sustained analgesia with buprenorphine
US8025898B2 (en) 2001-06-18 2011-09-27 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
US6805878B2 (en) 2001-09-13 2004-10-19 Noven Pharmaceuticals, Inc. Transdermal administration of ACE inhibitors
US8124141B2 (en) 2003-03-12 2012-02-28 Mitsui Norin Co., Ltd. Rapidly absorbing lipophilic skin compositions and uses therefor
WO2004091589A1 (fr) * 2003-04-14 2004-10-28 Mutzbauer Till S Agent calmant et sedatif administrable par voie transdermique
US10058554B2 (en) 2005-09-30 2018-08-28 Indivior Uk Limited Sustained release small molecule drug formulation
US11110093B2 (en) 2005-09-30 2021-09-07 Indivior Uk Limited Sustained release small molecule drug formulation
US11013809B2 (en) 2007-05-25 2021-05-25 Indivior Uk Limited Sustained delivery formulations of risperidone compound
US10010612B2 (en) 2007-05-25 2018-07-03 Indivior Uk Limited Sustained delivery formulations of risperidone compounds
US11712475B2 (en) 2007-05-25 2023-08-01 Indivior Uk Limited Sustained delivery formulations of risperidone compound
US10376590B2 (en) 2007-05-25 2019-08-13 Indivior Uk Limited Sustained delivery formulations of risperidone compound
US10198218B2 (en) 2010-06-08 2019-02-05 Indivior Uk Limited Injectable flowable composition comprising buprenorphine
US10558394B2 (en) 2010-06-08 2020-02-11 Indivior Uk Limited Injectable flowable composition comprising buprenorphine
US10592168B1 (en) 2010-06-08 2020-03-17 Indivior Uk Limited Injectable flowable composition comprising buprenorphine
US10172849B2 (en) 2010-06-08 2019-01-08 Indivior Uk Limited Compositions comprising buprenorphine
US10517864B2 (en) 2014-03-10 2019-12-31 Indivior Uk Limited Sustained-release buprenorphine solutions
US10022367B2 (en) 2014-03-10 2018-07-17 Indivior Uk Limited Sustained-release buprenorphine solutions

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