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WO1991005529A1 - Systemes d'apport de medicaments et matrice prevue a cet effet - Google Patents

Systemes d'apport de medicaments et matrice prevue a cet effet Download PDF

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Publication number
WO1991005529A1
WO1991005529A1 PCT/US1990/005839 US9005839W WO9105529A1 WO 1991005529 A1 WO1991005529 A1 WO 1991005529A1 US 9005839 W US9005839 W US 9005839W WO 9105529 A1 WO9105529 A1 WO 9105529A1
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WO
WIPO (PCT)
Prior art keywords
accordance
drug
drug delivery
delivery system
pressure
Prior art date
Application number
PCT/US1990/005839
Other languages
English (en)
Inventor
Dilip R. Sanvordeker
Ramchander Malhotra
Wattanaporn T. Abramowitz
Original Assignee
Watson Laboratories, Inc.
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 Watson Laboratories, Inc. filed Critical Watson Laboratories, Inc.
Publication of WO1991005529A1 publication Critical patent/WO1991005529A1/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
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • 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
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F2013/00361—Plasters
    • A61F2013/00902—Plasters containing means
    • A61F2013/00906—Plasters containing means for transcutaneous or transdermal drugs application

Definitions

  • This invention relates to a pressure-sensitive adhesive drug delivery system with restricted moisture vapor permeability for the transdermal and transcutaneous administration of therapeutic agents.
  • Background of the Invention The delivery of drugs by transdermal or transcutaneous routes of administration have been described in U.S. Patents Nos. 3,598,122, 3,598,123, 3,731,683, 3,742,951, and 3,797,494 to Zaffaroni; Nos. 3,946,106, 3,992,518, and 4,053,580 to Chien et al.; Nos. 4,201,211 and 4,286,592 to Chandrasekaran; and Nos. 4,289,749, 4,470,962, 4,466,953, 4,292,301, 4,294,820, and 4,321,252 to Keith.
  • the adhesive polymers utilized in these devices are pressure- sensitive and include copolymers of acrylic acid, acrylamide, isobutylene, vinyl acetate and esters of acrylic acid.
  • Particular commercialized transdermal drug delivery systems are well known, such as Transderm Scop ® for scopolamine (CIBA-Geigy, Ardsley, New York) , Nitro- Disc* for nitroglycerin (G.D. Searle, Skokie, IL) , Catapress ® TTS for clonidine (Boehringer-Ingelheim, Ingelheim am Rhein, Fed. Rep.
  • Moisture vapor-permeable polymeric sheet materials have been used for medical purposes as illustrated in Great Britain Patent No. 1,280,631 to Smith et al.
  • U.S. Patent No. 4,340,043 to Smith et al. an adhesive-coated polyetherurethane sheet material is disclosed for incorporating antibacterial substances in the adhesive matrix.
  • These adhesive-coated films are used as surgical, medical or wound dressings.
  • Japanese Patent No. JP 63-21647, assigned to Fuji Photo Film KK fluoropolymer film is disclosed in a transdermal tape which is permeable to moisture released from the skin.
  • the transdermal tape is utilized to incorporate antibiotics, antihistamines, topical corticosteriods, coronary vasodilators and the like in an adhesive which is laminated on the fluoropolymer film, and this tape is used for topical therapy.
  • transdermal flux is improved by the use of penetrant aids or absorption promoters such as ethanol.
  • penetrant aids or absorption promoters such as ethanol.
  • U.S. Patent No. 4,379,454 to Campbell et al. the use of ethanol in the transdermal delivery of 17-beta-estradiol is disclosed.
  • ethanol increases the transepidermal loss of water from the skin and cannot be used in non-reservoir devices, such as solvent- or emulsion-based pressure-sensitive adhesives that require oven drying procedures for device fabrication.
  • alkanols as penetrant enhancers is that these compounds extract intercellular lipids from the stratum corneum.
  • the present invention contemplates a transdermal and transcutaneous drug delivery system which contains a backing layer coextensive with an adhesive matrix that contains a non- aromatic terpene alcohol.
  • the present invention contemplates an anhydrous, hydratable pressure-sensitive adhesive matrix that contains a terpene alcohol. This matrix is supported by a backing layer which is coextensive with the adhesive matrix.
  • the adhesive matrix of the present invention contains a pressure-sensitive adhesive, a non-aromatic terpene alcohol, an absorption promoter and a drug which is capable of transdermal or transcutaneous administration.
  • the adhesive matrix is a monolithic mono- or multi- laminated matrix.
  • the non-aromatic terpene alcohol is a high boiling non-aromatic and relatively hydrophobic terpene alcohol, such as alpha-terpineol, that is present in sufficient amount to promote drug release from the matrix.
  • the terpene alcohol is present in combination with a hydrophilic absorption promoter, such as propylene glycol, in suitable proportions to provide a balanced binary combination of a lipophilic vehicle and a hydrophilic vehicle which together impart desirable adhesion characteristics to the adhesive matrix.
  • a hydrophilic absorption promoter such as propylene glycol
  • This binary combination provides improved absorption of relatively lipophilic drugs such as estrogens, androgens, progestins, and the like.
  • the adhesive matrix is coextensive with a backing layer having restricted moisture vapor permeability, such as a polyetherurethane film or ethylene vinyl acetate film.
  • the backing layer is reinforced with a nylon scrim which improves the physical strength and performance of the backing layer.
  • the backing layer can allow variable gas permeability and moisture vapor transmission, depending upon whether local or systemic drug delivery is preferred, through the drug delivery system.
  • a dosage form for the administration of drugs to a mammal is also contemplated by the present invention.
  • This dosage form is attached to the skin of the mammal by means of a pressure-sensitive adhesive, and the drug is administered to the mammal through the adhesive layer.
  • This dosage form includes an adhesive matrix which is capable of attachment to the skin of the mammal through the pressure-sensitive adhesive as well as a backing layer.
  • the adhesive matrix comprises a medical-grade pressure-sensitive adhesive, a non- aromatic terpene alcohol such as alpha-terpineol, an absorption promoter such as propylene glycol or polyethylene glycol 400, and a drug to be administered.
  • the present invention further contemplates a method for the long-term administration of a drug to a mammal.
  • a pressure-sensitive adhesive drug delivery system (dosage form) is attached to the skin of a mammal by contact with the adhesive and the desired drug, present in the drug delivery system (dosage form) , is absorbed by the mammal through the adhesive attachment site during the period of attachment.
  • the pressure-sensitive adhesive drug delivery system of this invention is capable of extended wear without the detrimental moisture build-up and irritation which is encountered with the current systems.
  • the present system permits a longer wear time- with comfort, convenience and maximum therapeutic benefit, all without the need for removal and replacement of the system every few days.
  • FIGURE 1 is a graph of the transdermal flux of 17-beta-estradiol across excized Yucatan pig skin where either an Estraderm ® 0.05 patch (+) or a 17.5 cm 2 patch of the present invention containing 0.6 meg/cm 2 of 17- beta-estradiol (X) was applied.
  • FIGURE 2 is a bar plot illustrating the comparative serum levels of estradiol in the pig following the application of one of the following treatments: an Estraderm ® 0.05 patch for 3 days (Q) , a single estradiol dosage form of the present invention (4 mg of 17-beta-estradiol/dosage form) for 6 days (0) / °r two estradiol dosage forms of the present invention (4 mg/dosage form for 6 days __ ) .
  • FIGURE 3 is a bar plot illustrating comparative serum levels of estrone in the pig following application of one of the following treatments: an Estraderm ® 0.05 patch for 3 days (__ ) , a single estradiol dosage form of the present invention
  • estradiol/dosage form 4 mg estradiol/dosage form) for 6 days (0) or two estradiol dosage forms of the present invention (4 mg/dosage form) for 6 days (__) .
  • FIGURE 4 is an illustrative transdermal patch embodying the present invention.
  • FIGURE 5 is a graph of the in vitro penetration of estradiol from transdermal patches having different backing films: reinforced polyether urethane (£S0, polyether-polyethylene ( ⁇ ) , occlusive tetra- laminate (A) and Estraderm ® 0.05 (A).
  • FIGURE 6 is a graph of the plasma concentration of estradiol ( Q ) and estrone (#) over a period of 7 days in subjects following application of a patch of the present invention for 7 days (Panel A) and following application of an Estraderm ® 0.1 patch for 3 days (Panel B) .
  • the present invention contemplates an anhydrous, but hydratable monolithic mono- or multi- laminated pressure-sensitive adhesive matrix.
  • the matrix includes, among other things, a high boiling non- aromatic and relatively hydrophobic terpene alcohol that is present in sufficient amount to promote drug release from the monolithic matrix.
  • alpha-terpineol a non-aromatic terpene alcohol, which also has antiseptic properties, to reduce the likelihood of bacterial growth and infection, in combination with other inert ingredients in the monolithic matrix
  • alpha-terpineol a non-aromatic terpene alcohol
  • drugs particularly those which exhibit absorption and irritation problems by the gastro ⁇ intestinal route due to solubility limitations, pH or enzymatic degradation and/or extensive first pass metabolism by the liver, are particularly well suited for use in combination with the present therapeutic carrier system.
  • These drugs can be hydrophilic, hydrophobic or amphiphilic in nature, and can belong to specific therapeutic classes.
  • Illustrative of such drugs are compounds that are useful in wound therapy, cardiovascular treatment, bronchodilation, growth stimulation, memory maintenance, memory retention or enhancement, immunomodulation and appetite modulation.
  • exemplary drugs include estrogens, androgens, antidepressants, anticonvulsants, antimicrobials, nutritional supplements, vitamins, and drugs useful in the treatment of specific disorders such as anxiety, diabetes, gastrointestinal problems and parkinsonism, as well as biotechnology-derived drugs and hormones.
  • Particularly preferred hydrophilic drugs include nitroglycerin, phenylephrine and the like.
  • hydrophobic, or lipophilic, drugs include 17-beta-estradiol, dehydroepiandrosterone (DHEA) , nifedipine, diltiazem, ti olol, bupranolol, fentanyl, testosterone, progesterone, norethindrone, norethisterone, norgestrel, levonorgesterel, oxandrolone, piroxicam, ketoprofen, flurbiprofen, mestranol, cromoglycolic acid, ethinyl estradiol, triamcinolone, beclomethasone, corticosteroids, prostaglandins and the like.
  • DHEA dehydroepiandrosterone
  • nifedipine diltiazem
  • ti olol bupranolol
  • fentanyl testosterone
  • progesterone norethindron
  • amphiphilic drugs include fentanyl and the like.
  • the terpene alcohol or ester thereof in combination with a hydrophilic excipient or absorption promoter, such as propylene glycol, in suitable proportions, also provides a balanced binary combination of a lipophilic and a hydrophilic vehicle which imparts desirable adhesion and drug penetration characteristics to the adhesive matrix.
  • This binary combination is particularly well suited for the transdermal delivery of relatively lipophilic drugs such as estrogens, androgens, progestins, contraceptives, cardiovascular agents, and the like, at controlled rates.
  • the mono- or multi-laminated monolithic matrix in a preferred embodiment, is affixed onto a thin non-occlusive backing.
  • the non-occlusive backing such as a thin polyetherurethane film, can be reinforced with a nylon scrim which improves its physical strength.
  • a "backing layer” is a film which has variable permeability to moisture vapor and gases such as oxygen and carbon dioxide, and includes semi-occlusive material such as a polyetherurethane or polyesterurethane film, and a polyester/polyethylene copolymer film, and occlusive material such as a tri- laminate film of polyethylene/aluminum/polyester.
  • Semi- occlusive backing layers have a relatively high moisture vapor transmission rate (MVTR) of the order of about 0.3 to about 12 grams/centimeters 2 /24 hr. (g/cm 2 /24 hr.), a relatively high liquid barrier property and mechanical flexibility, as well as stability.
  • An occlusive backing film has an MVTR of less than 0.3 g/cm 2 /24 hr.
  • transdermal administration means that the drug permeates the skin, enters the blood and combines with drug receptor sites that are at organs remote from the application site. The drug thus remains in equilibrium with the blood that carries the drug from the skin at the absorption site.
  • transcutaneous administration means that the drug permeates through the skin and perfuses the subdermal tissue that needs it for a beneficial pharmacological response in the vicinity of the site of application.
  • the backing layer which is attached to the pressure-sensitive adhesive matrix of the drug delivery system of the present invention is preferably a semi- occlusive film with a nylon scrim reinforcement.
  • This semi-occlusive film with nylon scrim provides a barrier for external aqueous washes as well as a barrier for internal liquid components of the composition. It also provides conformance, flexibility and ease of lamination for the dosage form of the present invention. This enables die cutting of pressure-sensitive adhesive dosage forms in a wide variety of self-supporting sizes, shapes or forms to provide a therapeutic unit which is suitable for comfort and convenience, adhesion and prolonged application for periods of one week or more.
  • a semi-occlusive backing of the present invention is preferably a polyetherurethane film, about 1.0 mil thick, reinforced with about 3 to about 4 mils of nylon scrim.
  • the moisture vapor transmission rate of the film is in the range of about 0.3 to about 8.0 g/cm 2 /24 hr. , as tested by Mocon Analyzer at 38 degrees C. and 90% relative humidity.
  • the nylon scrim provides self-supporting strength to the polyetherurethane backing film and serves as a semi- occlusive backing for a mono- or bi-laminate monolithic pressure-sensitive adhesive matrix.
  • An occlusive backing is preferably a tri- laminate film of polyethylene/aluminum/polyester such as Scotchpak ® 1009 available commercially from 3M Co. about 2-4 mils thick.
  • the MVTR of the film is less than about 0.3 g/cm 2 /24 hr.
  • the backing layer of the dosage form of the present invention has an MVTR less than that of human skin and preferably of about zero to about 100 g/cm 2 /24 hr.
  • a dosage of the present invention has a backing layer with an MVTR equivalent to or greater than that of human skin and preferably of about 500 to 600 g/cm 2 /24 hr.
  • Exemplary pressure-sensitive adhesives which are useful in the adhesive matrix of the present invention are 2-ethylhexylacrylate, acrylate-acrylic acid copolymer, acrylic acid-acrylamide copolymer, dimethylsiloxanes, vinyl acetate-acrylate copolymers, polyisobutylenes and the like.
  • Several of these adhesives are commercially available as solutions in organic solvents or as emulsions in aqueous-based emulsion systems with biocompatible surfactants.
  • the emulsions systems are suitable for short-term adhesive application. The use of emulsion systems is limited for long-term application on the skin.
  • Solvent-based adhesives without surfactants such as vinyl acetate- acrylate copolymers with a solid content in a range of about 30 to about 50 percent are preferred.
  • an absorption promoter such as a hydrophilic excipient is present in a range of about 10 to about 50 weight percent of the adhesive matrix together with a non-aromatic terpene alcohol or ester thereof.
  • terpene alcohols include alpha-terpineol, citronellol, geraniol, and linalool.
  • Hydrolyzable esters of the terpene alcohols preferably include the C 2 -C 8 monocarboxylic acid esters.
  • Terpene alcohols such as alpha-terpineol have antiseptic properties that reduce the likelihood of bacterial growth and infection during administration.
  • Absorption promoters useful in the present invention are the hydrophilic polyhydroxy alcohols, fatty acid esters of aliphatic alcohols, monoesterified fatty acids, and partially esterified glycols.
  • Preferred absorption promoters include propylene glycol, ethylene glycol monoethyl ether (Transcutol ® ) , isopropyl palmitate, 1,2,6-hexanetriol, propylene glycol monolaurate, diisopropyl adipate, polyethylene glycol, and polyethylene glycol 400 acetate.
  • an “absorption promoter” is a compound as described above that facilitates the uptake of a drug from the adhesive matrix through a mammalian body surface such as skin and thus enables a therapeutically effective dosage of the drug to be administered to the mammal.
  • an absorption promoter in a dosage form of the present invention is able to increase the permeability of the drug into the body of the mammal to a rate that is at least comparable to the rate of release of the drug from the adhesive matrix.
  • Absorption promoters are selected for use in a dosage form of the present invention to provide either paracellular drug transport or intracellular drug transport.
  • Paracellular transport maintains drugs in the aqueous extracellular fluid, while intracellular transport dissolves drugs into the lipid containing cellular membranes.
  • the weight ratio of terpene alcohol to absorption promoter present in the present invention is about 3 to 1 to about 1:3, and preferably 1:1.
  • alpha-terpineol is combined with propylene glycol at approximately a 1:1 weight ratio.
  • This mixture is combined with a hydratable microparticulate solid material, such as fine-fumed silicon dioxide, and this mix is sheared with a mechanical stirrer to solvate and suspend uniformly the silicon dioxide particles in the admixture.
  • the solvated silicon dioxide serves the purpose of improving the physical holding capacity of the liquid components in the adhesive, as well as improving cohesiveness and tortuosity of the adhesive matrix.
  • insoluble hydratable microparticulate material useful in the present invention are microcrystalline cellulose and microcrystalline alginic acid.
  • a portion of this mixture is combined with an active ingredient, i.e., a drug, and added to a predetermined quantity of acrylic resin solution.
  • the final mixture is blended to obtain a viscous composition of the wet adhesive matrix.
  • the wet adhesive matrix composition is then coated, preferably at a thickness of about 0.2 to about 0.7 millimeters, on a silicone-coated paper release liner and air-dried for about fifteen minutes to produce a first layer, followed by application of a second coating layer of the same drug-adhesive composition on top of the first layer, followed by oven drying at 60 degrees C. for about 30 minutes.
  • a backing layer preferably polyetherurethane
  • release liners include silicone- or fluoro ⁇ polymer coated polyester or polyethylene-paper- polyethylene-laminate films of suitable thickness for ease of release in die cutting during processing by a converting process.
  • Preferred lipophilic drugs utilized in the present invention are steroids, particularly estrogens.
  • the present invention utilizes a high boiling non-aromatic terpene alcohol or a hydrolyzable ester thereof, in a range of about 10 to about 50 weight percent of the adhesive matrix, that has acceptable skin tolerance, improved drug solubilization capacity either alone or in combination with another solubilizer that is preferably hydrophilic in nature, functions as a suitable vehicle for pressure-sensitive adhesive matrices and promotes the transdermal/ transcutaneous flux of a drug.
  • a high boiling non- aromatic terpene alcohol, such as alpha-terpineol also acts as a metabolic inhibitor of beta-hvdroxy dehydrogenases in the skin.
  • Alpha-Terpineol is a preferred terpene alcohol for application as a suitable drug carrier and penetrant aid in the pressure-sensitive adhesive matrix of the present invention.
  • alpha-terpineol has a relatively high melting point (18-20 degrees C), boiling point (206-207 degrees C.) and very low vapor pressure. It is relatively stable to oxidation, and has a pleasant piney to floral odor.
  • a mixture of a relatively hydrophobic and a relatively hydrophilic solvent is contemplated.
  • a non-aromatic terpene alcohol or a hydrolyzable ester thereof, together with a hydrophilic excipient is utilized in the adhesive compositions of the present invention.
  • FIGURE 4 A transdermal patch utilizing the pressure- sensitive adhesive matrix of the present invention is illustrated in FIGURE 4 where hydratable pressure- sensitive adhesive layers 12 and 14 of patch 10 are juxtaposed and contiguous with one another.
  • a backing sheet 16 covers the exposed or outer face 22 of layer 12, while release sheet 18 covers the outer face 24 of layer 14.
  • a cut or a line of severance 20 can be optionally provided in release sheet 18 for facilitating its removal from face 24 when patch 10 is readied for use.
  • the concentration of the therapeutically active ingredient or drug in adhesive layers 12 and 14 can be the same or different, depending upon the desired transdermal flux of the active ingredient as layers 12 and 14 are hydrated when in place.
  • the weight ratio of the active ingredient to the terpene alcohol present can be the same in both adhesive layers or different, again depending upon the desired modulation of the transdermal flux of the active ingredient over the time period when the patch is in place.
  • the drug dosage form of the present invention contains about 30 to about 50 weight percent of a combination of a non- aromatic terpene alcohol and hydrophilic polyol absorption promoters or esters thereof, about 3 to about 10 weight percent of active ingredient (drug) , about 40 to about 60 weight percent of a medical-grade pressure- sensitive adhesive and up to about 1 weight percent of an insoluble hydratable microcrystalline material such as fumed silica.
  • the weight ratio individually of non- aromatic terpene and hydrophilic polyol is about 7.5 to about 37.5 weight percent each.
  • Excized Yucatan pig skin was used in a skin penetration study.
  • the dermal side of the skin was processed with a scalpel to remove excessive fat.
  • Excessive hair on the epidermal side was lightly clipped and circular pieces (4 cm in diameter) were cut and placed over the donor compartment of a Franz cell assembly, as described by Franz J., Invest. Dermatol.
  • the donor compartment was fitted onto the epidermal side of the skin and a sufficient amount of a saturated solution of 17-beta-estradiol in a given vehicle was added to cover the entire surface of the skin. Care was exercised to assure that the epidermal side of the skin was relatively dry in order to maximize surface contact and skin absorption of the drug in the vehicle combination. Seven hundred microliters (700 mcl) of the receptor solution were sampled intermittently and replaced with a blank vehicle.
  • Citronellol iisopropyl
  • estradiol Solubility mg/ l
  • Semi-occlusive transdermal and transcutaneous patch compositions for estradiol, ketoprofen and piroxicam were prepared. The process of fabrication of these patches was as follows. For each composition, required amounts of materials were weighed according to the proportions listed in TABLE III. The drug was dissolved in the penetrant aid vehicle before the addition of the adhesive in a suitable size glass bottle with an airtight cap. The adhesive composition was blended for approximately two hours. It was then coated on a #1361 paper release liner (3M Company, St. Paul, MN) using an SV-l Coater (Werner-Mathis Company, Concord, NC) and a Doctor Knife with 0.6 mm slit for wet coating.
  • SV-l Coater Wide-Mathis Company, Concord, NC
  • the coated adhesive was air-dried in a forced- air exhaust hood for 15 minutes followed by convective air-drying for two hours in an oven at 60 degrees C.
  • the dried adhesive was laminated on a 1 mil polyetherurethane film reinforced with a 4 mil Nylon ® scrim (supplied by Gila River Products, Inc., Chandler, AZ) . Circular patches (6.4 cm 2 and 9.5 cm 2 ) of the sheet were die cut to obtain the semi-occlusive transdermal/transcutaneous drug delivery systems of each drug.
  • PX-4 a-G737 Gelva ® Multi-polymer 737 solution a commercially available acrylate medical adhesive from Monsanto Company, St. Louis. MO.
  • Citronellol commercially available terpene alcohol from Berje, Inc., Bloomfield, NJ.
  • d-TCT Transcutol ® a commercially available diethylene glycol monomethyl ether from Gateffose Co., Elmsford, NY.
  • e-ED 17-beta-estradiol in micronized form available commercially from Biosyth, Inc., Chicago, IL.
  • h-DIPA Diisopropyl Adipate commercially available from Scher Chemicals, Inc., Clifton, NJ, under the trade name Schercemol DIA.
  • composition for Transcutaneous Drug Delivery Composition for Transcutaneous Drug Delivery
  • ketoprofen for transcutaneous delivery was prepared and tested in vitro for drug release and skin penetration using excized Yucatan pig skin.
  • composition Ingredient Amt/Batch.g % (on dry wt)
  • circular patches (6.413 cm ) were die cut and used as follows.
  • circular patches (17.81 cm 2 ) were die cut to suit the size of the skin samples used for in vitro penetration studies.
  • the assay of samples was performed using HPLC.
  • the C-18 reverse phase Bond-a-Pak ® (Beckman) column (as described in EXAMPLE 1) was used for ketoprofen separation.
  • the mobile phase used was acetonitrile: water: phosphoric acid (50:49.6:0.4) and the detector was set at an AUF of 0.01.
  • the flow rate was set at 1.0 ml/min and detection was done at 254 nm.
  • The.dosage form had a ketoprofen content of 2.0 mg/cm 2 .
  • Drug release studies were conducted using USP apparatus I (paddle method) .
  • an assembly composed of a covered vessel made of glass or other transparent material, a motor, a paddle formed from a blade and metallic drive shaft, and a cylindrical basket is utilized.
  • the vessel is partially immersed in a suitable water bath that permits holding the temperature inside the vessel at 37+0.5 degrees C. during the procedure and keeping the bath fluid in constant, smooth motion. There is no significant motion, agitation or vibration of the assembly beyond that due to the smoothly rotating stirring element.
  • the vessel is cylindrical, with a hemispherical bottom; it is 160 mm to 175 mm high, has an inside diameter of 98 mm to 106 mm and a nominal capacity of about 1000 ml.
  • the sides of the vessel are flanged at the top and a fitted cover, with openings for thermometer insertion and sample withdrawal, is preferably used.
  • the shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel, and rotates smoothly without significant wobble.
  • the blade passes through the diameter of the shaft so that the bottom of the paddle blade is flush with the bottom of the shaft.
  • the distance between the blade and the inside bottom of the vessel is maintained at 25+2mm.
  • the blade and shaft comprise a single entity that can be coated with a suitable inert coating.
  • the dosage form (patch) is allowed to sink to the bottom of the vessel before rotation of the blade is started. If the patch would otherwise float, it is attached to a metal/glass plate with an adhesive tape to prevent flotation.
  • a speed-regulating device is used that allows the shaft rotation speed to be selected and maintained at a specified rate within 4%.
  • the shaft and basket components of the stirring element are fabricated from stainless steel, and the basket can have a gold coating 2.5 urn thick.
  • a stock solution of 40% PEG 400 was used as the dissolution (drug release) medium.
  • a patch (6.413 cm 2 ) was affixed onto a glass plate and it was exposed to 9004 ml of dissolution medium maintained at 37 degrees C. Samples were collected at 1.3, 2.0, 3.0, 6.0, 9.0, 12.0, 17.0, 22.0, 25.0, 26.0, 27.0, 30.0, 33.0 and 46.0 hours. The mean triplicate runs were 27.89%, 40.53%, 51.45%, 69.97%, and 87.52% drug released at 2 hours, 6 hours, 12 hours, 25 hours, and 30 hours, respectively. This is indicative of the controlled release of the drug from the monolithic matrix under sink conditions.
  • Approximately 700 microliters (mcls) of receptor fluid was removed at predetermined intervals ranging from 0 to 72 hours after initiation of the study. The samples were replaced with blank receptor fluid after each sampling time. Samples were assayed by the above-described HPLC procedure.
  • composition Ingredient Amount/Batch
  • compositions were processed for coating by the procedure described in EXAMPLE 2.
  • a mono-laminate dosage form was prepared.
  • In vitro skin penetration studies in triplicate were conducted for each composition, and the flux was estimated by the procedure described in EXAMPLE 2. The results are illustrated below in TABLE IV.
  • compositions were prepared:
  • Alpha-Terpineol (2.2 g) and propylene glycol (2.0 g) were weighed and mixed in a sealed container. Then, to this mixture was added micronized 17-beta- estradiol (0.5g) and fumed silicon dioxide (0.5g). The mixture was allowed to mix well for about three hours. To this mixture was added Gelva ® 788 adhesive (17.Og) and this wet adhesive composition was mixed for an additional two hours. A suitable size (approximately
  • Irritation and product acceptance testing of placebo patches prepared in EXAMPLE 6 were tested on three female subjects. Test studies were performed as follows. Each subject was provided with an adhesive patch and an Adhesive Patch Evaluation Form. The subjects were instructed to apply the patch on the abdomen for a period of one week. The patch was evaluated for visual irritation, comfort, duration of adhesion to skin and edge curling problems.
  • the patch can provide the necessary platform for long-term transdermal or transcutaneous delivery of drugs for systemic and topical therapy.
  • bi-laminate composition (DHEA-1) was prepared and tested for skin irritation and duration of adhesion for one week:
  • DHEA-1-Part A In a suitable sized container with a screw cap labeled as DHEA-1-Part A, were weighed 2.4 g of alpha- terpineol and 2.2 g of propylene glycol. These components were mixed for approximately 15 minutes. To this mixture was added 0.3 g of dehydroepiandrosterone and this mixture was shaken for 1 hour on a rotating mixer. To this mixture was added 0.3 g of fumed silicon dioxide, and the mix was again blended for 2 hours. Finally, 17.0 g of Gelva ® 788 multi-polymer solution was added and the final blend was mixed for two hours to obtain a lightly translucent composition for coating.
  • Part B portion of the composition was prepared with higher drug loading.
  • Part A composition was then coated on a Scotchpak ® product 1361 release liner fitted on a SV-1 Coater, using a Doctor Knife with a 0.6 mm setting for wet coating thickness. It was air-dried in a forced-air exhaust hood for one hour, followed by coating of Part B, with the same knife setting, on top of it.
  • the bi-laminate composition was air-dried for 15 minutes followed by oven drying for 30 minutes in a convective air-drying oven at 60 degrees C.
  • the dried bi-laminate adhesive was laminated under pressure onto a Type II reinforced 1 mil polyetherurethane backing.
  • the tetra-laminate sheet prepared, as above, was composed of the semi-occlusive reinforced polyetherurethane backing, an adhesive laminate with a low drug loading onto which was affixed a second adhesive laminate with a higher drug loading and a release liner.
  • the release liner of Part B dried composition is held in position as the final laminate of the semi-occlusive dosage system for long-term therapy. Circular patches (6.418 cm 2 ) were die cut to obtain dosage units.
  • the dosage systems were tested for product acceptance and skin tolerance on two healthy male subjects. After removing the release liner, one system was applied on the upper chest area devoid of excessive hair. Both subjects were supplied with a product evaluation form to fill out as illustrated in EXAMPLE 7. After one week, the patches were removed. Despite routine showers and normal daily activities, the patches remained in place without any edge curling, lack of adhesion or redness, itching or burning. This was suggestive of excellent tolerance of the semi-occlusive dosage system.
  • DHEA was chosen as an acceptable substitute for 17-beta-estradiol in a semi-occlusive dosage form for long-term steroidal replacement therapy.
  • DHEA is produced abundantly by the adrenal glands as a sulfate conjugate as well as in its free form. It has been demonstrated that elevated serum DHEA (free and sulfate form) levels tend to prolong longevity through reduction of cardiovascular risk factors in male adults in the proximity of 50 years of age (Barrett-Conners, et al. New Engl. J. Med.. 315. 1519 (1986)).
  • the transdermal administration of DHEA can be therapeutically beneficial for such a purpose.
  • composition (ED-1) of 17-beta- estradiol was prepared and tested for in vitro skin flux using excized Yucatan pig skin:
  • Circular patches (6.413 cm 2 and 17.81 cm 2 ) were die cut from the tetra-laminate sheets. The larger patches were tested for in vitro skin penetration by the procedure, described in EXAMPLE 4.
  • the dose per 6.413 cm 2 patch was determined to be 0.64 meg/cm 2 .
  • the skin flux data for 10 cm 2 Estraderm 0.05 patch (CIBA Geigy) and the above- described 17.5 cm 2 patch containing 0.6 meg/cm 2 dose is illustrated in FIGURE 1.
  • the lag time for Estraderm 0.05 and the ED-1 patch are quite similar and approximate at about 15 hours post application.
  • the Estraderm patch shows two linear phases of steady state flux of estradiol. The first phase lasts about 65 hours with a mean flux of 0.06 mcg/cm 2 /hr. The second phase has a flux of about 0.2 mcg/cm 2 /hr.
  • the semi-occluded pharmaceutical dosage form of 17-beta-estradiol (ED-1) shows a steady single phase of skin flux of 0.05 meg/cm /hr.
  • Composition ED-1 was tested in a comparative bioavailability study with the Estraderm ® 0.05 therapeutic system.
  • the test animals were nine ovariectomized pigs weighing 90-120 pounds each. The animals were maintained under standard veterinary care. Three groups of three animals per group were used in the study. One group was used to apply Estraderm ® 0.05 patch per pig for 3 days on a lightly shaved area of the animal's back. The second group was used to apply one ED-1 (4 mg) patch per pig for 6 days. The third group received two ED-1 patches per pig for 6 days. Twenty- two hours prior to patch application, blood samples were withdrawn and serum estradiol and estrone levels in each pig were determined to establish a baseline.
  • FIGURES 2 and 3 are bar plots for serum estradiol and estrone levels before and after application of one and two semi-occlusive transdermal estradiol dosage forms (Composition ED-1) .
  • composition of 17-beta-estradiol was prepared and tested for both in vitro skin penetration and in vivo tolerance on menopausal women:
  • Estraderm ® 0.05 was used as a control each time to determine the relative performance of the system of the present invention.
  • the skin flux of Estraderm ® 0.05 was estimated to be 0.23 mcg/cm 2 /hr. as against 0.14 mcg/cm 2 /hr. estimated for this composition.
  • three female subjects with estradiol levels in the range of 5-20 pg/ml
  • the subjects were asked to wear the patch on the abdomen for a period of one week and perform daily routines after which the patch was removed.
  • the results of the skin tolerance study are illustrated in TABLE VI, below.
  • Circular patch samples (6.413 cm 2 ), prepared as described in EXAMPLES 7 and 8, of the bi-laminate composition of EXAMPLE 10 were packaged in aluminum laminated foil pouches and monitored at 60 degrees C. for 2 weeks, 40 degrees C. and 70% relative humidity, room temperature and 4 degrees-7 degrees C. for a period of four weeks.
  • the samples were assayed for drug content and an initial drug release profile was determined using the USP dissolution method I.
  • the patch sample was affixed on a 3" x 3" steel plate paddle with Scotch ® tape.
  • the sample was placed in 1000 ml of 40% PEG 400 in normal saline, as the drug release medium, maintained at 37 degrees C.
  • the paddle was rotated at 75 RPM.
  • TABLE VII Circular patch samples
  • compositions of piroxicam in solvent-based acidic acrylate adhesive MSP 93188 (3M Company) in combination with adhesive compatible vehicles were prepared and tested for potency, and drug flux across excized Yucatan pig skin:
  • Piroxicam 1.0 1.0 1.0 1.0 1.0 1.0 1.0
  • compositions For preparation of these compositions, a pre- mix of 100 g of propylene glycol and 15 g of fumed silicon dioxide was homogenized using a laboratory high speed stirrer. A required amount of this suspension was weighed in a suitable container and a required amount of piroxicam (for each part) was added along with a required amount of ethyl acetate and 12.1 g of Transcutol ® . The mixture was blended on a rotating mixer for 30 minutes. Acrylate adhesive (85.0 g) was then added and the mixture was blended overnight to obtain the final composition of Part A and Part B for coating. Each composition was coated on a #1361 release liner fitted on a SV-1 coating apparatus with a Doctor Knife setting at 0.6 mm.
  • Part A composition was laminated under pressure onto a reinforced Type II polyetherurethane non-occlusive backing. The release liner was removed and Part B adhesive was laminated onto the Part A to obtain tetra- laminate sheets of each composition. Large (17.8 cm ) and small (6.413 cm 2 ) circular patches were die cut from the sheets for penetration and drug content.
  • composition of 17-beta-estradiol in solvent-based aerylate-vinyl acetate copolymer adhesive (Gelva ® 788, Monsanto Company, St. Louis, MO) was prepared and tested using backings with varying degrees of occlusivity and moisture vapor transmission rates (MVTR) .
  • a premix of alpha-terpineol, propylene glycol and fumed silicon dioxide was homogenized using a high ⁇ speed stirrer.
  • To 14.1 g of the pre-mix was added 0.9 g of micromized estradiol and the mix was agitated for about 1.5 hours to disperse and solubilize the drug.
  • 34.0 g of the Gelva ® 788 adhesive was added and the mixture was agitated gently for about 2 hours to obtain the coating solution as Part A and Part B.
  • the setting of the slit was set at 0.2 mm with a Doctor Knife for the first coat with Part A.
  • the Part B coat was applied with a knife setting at 0.3 mm.
  • the adhesive matrix composition was oven-dried at 60 degrees C. for 30 minutes.
  • Three different backing materials were laminated respectively onto the adhesive to form three groups of patches, each of which had a different backing material, and die cut 17.81 cm 2 patches were prepared for skin penetration testing.
  • the three backing materials used were Type II reinforced polyether urethane film (Gila River Corporation, Chandler, AZ) , Polyester-polyethylene laminate film (Scotchpak ® 1220, 3M Health Care, 3M Company, St. Paul, MN) and an occlusive tetra-laminate film (Scotchpak ® 1009) .
  • Semi-occlusive patches were prepared with a tetra-laminate film (Scotchpak ® 1009, 3M Health Care, 3M Company, St. Paul, MN) backing layer and were assayed by extraction in 30 ml of ethanol to determine its content by an HPLC procedure similar to that described in EXAMPLE 1.
  • the dose per 17.81 cm 2 size circular patch was determined to be 9.0 mg.
  • Skin tolerance and estradiol bioavailability studies were performed with four postmenopausal subjects. This was established by predetermination of estradiol levels which ranged between 10-25 pg/ml for the test subjects. After a pre- study sampling of plasma estradiol and estrone levels for at least one day, one patch per subject was applied securely on the abdomen. Blood samples were withdrawn on a predetermined schedule during the entire period of patch application for one week.
  • TABLE XI and TABLE XII illustrate pharmacokinetic parameters derived based on the bioavailability results of these two products.
  • the present estradiol batch composition was applied for a one-week period; whereas the Estraderm ® 0.1 patch was applied for a period of 3 days in order to complement the recommended twice-a-week schedule for administration of the product.
  • the mean AUC (area under the plasma concentration - time curve) for estradiol, a measure of relative bioavailability of the patch of the present invention with reference to Estraderm ® 0.1 was about twofold. Since the patch was applied for 7 days compared to 3 days 1 application of the Estraderm ® patch, it is reasonable to expect these results.
  • the T ma ⁇ (time to achieve maximum plasma concentration in hours) for estradiol was substantially different for the patch of the present invention as compared to the Estraderm ® 0.1 patch.

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Abstract

Système d'apport de médicaments contenant une matrice adhésive renfermant des ingrédients actifs, de même étendue qu'une couche de support. Ladite matrice adhésive contient un adhésif anhydre autocollant hydratable, un alcool terpénique non aromatique ou un ester de celui-ci, un promoteur d'absorbtion ainsi qu'un médi ament, tel qu'un stéroïde pouvant être administré par voie transdermique ou transcutanée. L'alcool terpénique non aromatique est, de préférence, de l'alpha-terpinéol. Une forme posologique telle qu'un pansement transdermique est décrite, ainsi qu'un procédé d'administration à long terme d'un médicament à un mammifère.
PCT/US1990/005839 1989-10-13 1990-10-11 Systemes d'apport de medicaments et matrice prevue a cet effet WO1991005529A1 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993002669A1 (fr) * 1991-07-30 1993-02-18 Schering Aktiengesellschaft Berlin Und Bergkamen Systemes therapeutiques transdermiques
WO1993008795A1 (fr) * 1991-10-31 1993-05-13 Schering Aktiengesellschaft Systemes transdermiques therapeutiques contenant des inhibiteurs de cristallisation
WO1994010984A1 (fr) * 1992-11-06 1994-05-26 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg SYSTEME THERAPEUTIQUE TRANSDERMIQUE POUR L'APPLICATION DE 17-β-×STRADIOL ET SON PROCEDE DE FABRICATION
WO1996003119A1 (fr) * 1994-07-26 1996-02-08 Lavipharm S.A. Dispositif d'administration transdermique contenant un ×strogene
DE4429663A1 (de) * 1994-08-20 1996-02-22 Lohmann Therapie Syst Lts Transdermales therapeutisches System mit Hydrolyseschutz
DE4429664A1 (de) * 1994-08-20 1996-02-22 Lohmann Therapie Syst Lts Estradiol-TTS mit wasserbindenden Zusätzen
US5656286A (en) * 1988-03-04 1997-08-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5676968A (en) * 1991-10-31 1997-10-14 Schering Aktiengesellschaft Transdermal therapeutic systems with crystallization inhibitors
US5686098A (en) * 1993-03-26 1997-11-11 Lts Lohmann Therapie-Systeme Gmbh Active substance patch for the release of estradiol to the skin
EP0858805A3 (fr) * 1997-02-13 1998-09-02 National Research Institute of Chinese Medicine Préparations de'oxicames transdermales
WO1998037871A1 (fr) * 1997-02-28 1998-09-03 Minnesota Mining And Manufacturing Company Dispositif transdermique d'administration de testosterone
DE10033853A1 (de) * 2000-07-12 2002-01-31 Hexal Ag Transdermales therapeutisches System mit hochdispersem Siliziumdioxid
US8911742B2 (en) 1996-11-14 2014-12-16 The United States Of America As Represented By The Secretary Of The Army Transcutaneous immunization without heterologous adjuvant

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4808414A (en) * 1986-09-29 1989-02-28 Nelson Research & Development Co. Amide penetration enhancers for transdermal delivery of systemic agents
US4842864A (en) * 1987-03-25 1989-06-27 Laboratories D'hygiene Et De Dietetique Self-adhesive device for the percutaneous administration of an active ingredient

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4808414A (en) * 1986-09-29 1989-02-28 Nelson Research & Development Co. Amide penetration enhancers for transdermal delivery of systemic agents
US4842864A (en) * 1987-03-25 1989-06-27 Laboratories D'hygiene Et De Dietetique Self-adhesive device for the percutaneous administration of an active ingredient

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6024976A (en) * 1988-03-04 2000-02-15 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5656286A (en) * 1988-03-04 1997-08-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
WO1993002669A1 (fr) * 1991-07-30 1993-02-18 Schering Aktiengesellschaft Berlin Und Bergkamen Systemes therapeutiques transdermiques
AU676826B2 (en) * 1991-07-30 1997-03-27 Schering Aktiengesellschaft Berlin Und Bergkamen Transdermal therapeutic systems
WO1993008795A1 (fr) * 1991-10-31 1993-05-13 Schering Aktiengesellschaft Systemes transdermiques therapeutiques contenant des inhibiteurs de cristallisation
US5676968A (en) * 1991-10-31 1997-10-14 Schering Aktiengesellschaft Transdermal therapeutic systems with crystallization inhibitors
US5912008A (en) * 1992-11-06 1999-06-15 Lts Lohmann Therapie-Systeme Gmbh Transdermal therapeutic system for the release of 17-β-estradiol and process for its production
WO1994010984A1 (fr) * 1992-11-06 1994-05-26 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg SYSTEME THERAPEUTIQUE TRANSDERMIQUE POUR L'APPLICATION DE 17-β-×STRADIOL ET SON PROCEDE DE FABRICATION
HRP931360A2 (en) * 1992-11-06 1995-02-28 Lohmann Therapie Syst Lts Transdermal therapeutic system for the release of estradiol n active substance
US5686098A (en) * 1993-03-26 1997-11-11 Lts Lohmann Therapie-Systeme Gmbh Active substance patch for the release of estradiol to the skin
US6221383B1 (en) 1994-01-07 2001-04-24 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5925373A (en) * 1994-07-26 1999-07-20 Lavipharm S.A. Transdermal delivery device containing an estrogen
AU703074B2 (en) * 1994-07-26 1999-03-11 Lavipharm S.A. Transdermal delivery device containing an estrogen
WO1996003119A1 (fr) * 1994-07-26 1996-02-08 Lavipharm S.A. Dispositif d'administration transdermique contenant un ×strogene
DE4429664A1 (de) * 1994-08-20 1996-02-22 Lohmann Therapie Syst Lts Estradiol-TTS mit wasserbindenden Zusätzen
DE4429663A1 (de) * 1994-08-20 1996-02-22 Lohmann Therapie Syst Lts Transdermales therapeutisches System mit Hydrolyseschutz
US8911742B2 (en) 1996-11-14 2014-12-16 The United States Of America As Represented By The Secretary Of The Army Transcutaneous immunization without heterologous adjuvant
EP0858805A3 (fr) * 1997-02-13 1998-09-02 National Research Institute of Chinese Medicine Préparations de'oxicames transdermales
WO1998037871A1 (fr) * 1997-02-28 1998-09-03 Minnesota Mining And Manufacturing Company Dispositif transdermique d'administration de testosterone
US6132760A (en) * 1997-02-28 2000-10-17 3M Innovative Properties Company Transdermal device for the delivery of testosterone
AU735944B2 (en) * 1997-02-28 2001-07-19 Minnesota Mining And Manufacturing Company Transdermal device for the delivery of testosterone
DE10033853A1 (de) * 2000-07-12 2002-01-31 Hexal Ag Transdermales therapeutisches System mit hochdispersem Siliziumdioxid

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