WO2005046600A2 - Systeme d'application de tulobuterol transdermique, procede et composition correspondants - Google Patents

Systeme d'application de tulobuterol transdermique, procede et composition correspondants Download PDF

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Publication number
WO2005046600A2
WO2005046600A2 PCT/US2004/037305 US2004037305W WO2005046600A2 WO 2005046600 A2 WO2005046600 A2 WO 2005046600A2 US 2004037305 W US2004037305 W US 2004037305W WO 2005046600 A2 WO2005046600 A2 WO 2005046600A2
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WO
WIPO (PCT)
Prior art keywords
adhesive
tulobuterol
skin
composition
transdermal
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PCT/US2004/037305
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English (en)
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WO2005046600A3 (fr
Inventor
David B. Lebo
Juny Lee
Vincent Luisi
Je Phil Ryoo
Oliver J. Toigo, Iii
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Nexmed Holdings, Inc.
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Publication of WO2005046600A2 publication Critical patent/WO2005046600A2/fr
Publication of WO2005046600A3 publication Critical patent/WO2005046600A3/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
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof

Definitions

  • Tulobuterol is a ⁇ 2 -adrenergic receptor agonist widely used in the treatment of acute bronchitis, chronic bronchitis, bronchial asthma, pulmonary emphysema, and like respiratory conditions to relieve dyspnea of patients suffering from bronchoconstriction.
  • Tulobuterol is a recognized bronchodilator that acts selectively at a ⁇ 2 -receptor of the sympathetic nervous system to relax the bronchial smooth muscles.
  • Tulobuterol is generally administered through oral routes, in the form of tablets, syrups, lozenges, and the like, or through the airway delivered in aerosolized form, typically with a metered-dose inhaler. Oral dosages, however, are difficult to administer to infants, feeble or elderly persons, and are associated with side effects caused by steep increases of the drug concentration in the blood, a brief period of therapeutic efficacy, and the like. Aerosolized forms present misuse problems, such as incorrect or excessive inhalation, and in some cases are associated with a higher risk of death.
  • Topically applied dosage forms such as ointments, creams, and the like, can avoid the undesirable temporary increases of tulobuterol blood levels associated with oral administration, but such externally applied dosage forms are easily removed by clothing, making it difficult to control effecting the therapeutic dosage.
  • Transdermal drug delivery systems in the form of patches or tapes containing medicaments have been developed and are rapidly gaining in popularity and increasing usage.
  • a general discussion of transdermal drug delivery patch systems, measurement of skin permeation, and methods of manufacturing conventional transdermal patch devices is found in Cleary, Chapter 11, entitled "Transdermal
  • a transdermal composition for example, a pressure-sensitive adhesive containing a drug, as a means of controlling drug delivery through the skin at essentially a constant rate, is well known.
  • a transdermal composition for example, a pressure-sensitive adhesive containing a drug, as a means of controlling drug delivery through the skin at essentially a constant rate.
  • Such known delivery systems generally incorporate the medicament into a carrier such as a polymeric matrix and/or a pressure-sensitive adhesive formulation.
  • the pressure-sensitive adhesive must adhere effectively to the skin and permit migration of the medicament from the carrier through the skin and into the bloodstream of the patient.
  • U.S. Patent No. 5,571,530 describes a percutaneous preparation of tulobuterol dissolved or dispersed in a pressure-sensitive adhesive base layer composed of polyisobutylene rubber mixtures with no percutaneous penetration enhancers, carriers, or the like, to minimize interaction between the base layer and tulobuterol and thereby improve drug stability.
  • 5,639,472 discloses tape preparations containing tulobuterol in a plaster layer in which tulobuterol is present in a concentration of not lower than the solubility of the drug in the adhesive, and the ratio of dissolved tulobuterol to crystalline tulobuterol is from 0.1 to 10.
  • increasing the tulobuterol content dissolved in a plaster layer is considered to lead to a higher percutaneous abso ⁇ tion rate of the drug, and to lead to a longer duration of drug release.
  • tulobuterol in a dissolved state at a high concentration and stable in the polymeric adhesive medium used to form a plaster layer is generally difficult to achieve.
  • the total drug content is generally contained in a plaster layer at a concentration of not less than the solubility of the drug in the adhesive, and part of the drug load is intentionally present in a crystalline state in the plaster layer, as taught in, for example, U.S. Patent No. 5,639,472.
  • U.S. Patent No. 6,117,447 discloses a percutaneous abso ⁇ tion preparation comprising a support and plaster layer laminate comprising not less than 5 weight %, based on the weight of the plaster tulobuterol dissolved in an adhesive composition.
  • a commercially available transdermal therapeutic system for bronchial asthma that embodies a reservoir of crystalline tulobuterol and percutaneous abso ⁇ tion preparations described in one or more of U.S. Patents No. 5,639,472 and No. 6,117,447, is sold under the trademark HOKUNALIN ® Tapes by Hokuriku Seiyaku Co., Ltd., Japan.
  • These commercial tapes are available as patches for dosages amounts of 0.5 mg, 1 mg, and 2 mg tulobuterol to use, respectively, for children from 6 months to less than 3 years of age, children from 3 to less than 9 years of age, and children of 9 years of age and older.
  • the crystal reservoir of the commercial tape is intended to have a long lag-time, so the patches are attached to the skin of the chest, back or upper arm once a day at bedtime to provide peak drug levels in the morning.
  • the commercial tape is intended to treat "morning-dip" bronchial asthma attacks, especially in children, that occur as a result of low cortisol levels and low inhaled bronchodilator drug levels.
  • Preparations containing solid drug crystals in the plaster layer are susceptible to precipitation of the drug crystals on the surface of the plaster layer where it comes into contact with the skin, thus undesirably degrading the adhesive property to the skin.
  • the present invention provides a transdermal tulobuterol delivery system comprising a composition containing less than 5 weight percent tulobuterol dissolved in an adhesive medium, and a method for transdermal delivery of a bronchodilating effective amount of tulobuterol upon application of the transdermal system to the surface of human skin.
  • a preferred transdermal tulobuterol delivery system is a single-layer, drug-in-adhesive matrix patch system.
  • a preferred transdermal skin adhesive composition comprises a therapeutically effective amount of less than 5 weight percent total tulobuterol, on a total composition weight basis, dissolved in at least one physiologically tolerable adhesive, and preferably at least one skin penetration enhancer.
  • a preferred transdermal tulobuterol delivery patch comprises an inert impermeable backing film having a therapeutically effective amount of skin adhesive composition of the invention coated thereon.
  • the patch includes a protective release liner laminated to the skin contacting surface of the skin adhesive composition and through which the tulobuterol is not permeable.
  • the release liner is removed and the skin adhesive face of the patch is placed in contact with a skin surface, such as the skin of the chest, back or upper arm.
  • a particularly preferred transdermal tulobuterol composition comprises, on a total drug-in-adhesive matrix composition weight basis, tulobuterol base in the range of about 1 to about 4.9 weight percent, at least one skin penetration enhancer in a total amount in the range of about 0.1 to about 40 weight percent, preferably in the range of about 5 to about 20 weight percent, and the remainder comprising an effective skin adhesive amount of at least one polymeric pressure-sensitive adhesive.
  • Preferred adhesives can be acrylic acid based, rubber based, silicone based or combinations thereof.
  • a preferred transdermal tulobuterol patch has an active surface area size in the range of about 2.5 to about 10 square centimeters, a drug loading of not more than about 0.2 milligrams per square centimeters, and a drug delivery rate of about 7.5 micrograms per square centimeters per hour.
  • patch embodiments of tulobuterol containing skin adhesive compositions of this invention maintain a relatively low (i.e., less than 5%) content of tulobuterol in a dissolved state (i.e., no apparent crystalline tulobuterol in the adhesive matrix), and were judged substantially equivalent, in % drug release and in rate of permeation through skin, to conventional transdermal preparations having a relatively high (i.e., not less than 5%) content of tulobuterol.
  • FIG. 1 is a schematic illustration of a transdermal tulobuterol delivery patch of the present invention represented as a single-layer drug-in adhesive delivery system; and FIG. 2 is a graphical representation of % release of tulobuterol from two transdermal tulobuterol delivery systems of the invention compared to that of a commercial product over a period of about 24 hours.
  • transdermal patch or "patch” as used herein includes structures in the form of tapes, strips, sheets, dressings or any other like form known to those skilled in the art, without limitation as to dimensional size or construction, except where specifically indicated, that can be applied to the skin of a mammal.
  • a preferred transdermal tulobuterol system embodiment without being limited thereto, has a single-layer, drug-in-adhesive (DIA) patch anatomy, characterized by the inclusion of the drug directly within the skin-contacting adhesive medium rather than as a separate layer.
  • DIA drug-in-adhesive
  • the adhesive medium serves to both affix the bronchodilator system device to the skin and as the formulation foundation containing the drug and all excipients, and is applied as a substantially coterminous coating on a backing support film or layer.
  • skin adhesive composition drug-in-adhesive matrix
  • DIA matrix drug-in-adhesive matrix
  • Tulobuterol is a beta-2 agonist used as a bronchodilator for the treatment of bronchial asthma, acute bronchitis, chronic bronchitis, and pulmonary emphysema.
  • Tulobuterol is designated chemically as 2-chloro- ⁇ -[[(l,l-dimethylethyl)amino]methyl]benzenemethanol, has a molecular weight of 221.13, and the molecular formula: C 12 H 18 ClNO. Crystals of tulobuterol have a reported melting point in the range of about 89 to about 93 °C. Tulobuterol is available in the free base form or as a hydrochloride salt. Crystalline tulobuterol hydrochloride powders have a reported melting point in the range of about 161 to about 163 °C.
  • the term "tulobuterol", as used herein, includes the free base form of this compound, as well as chemotherapeutically acceptable acid addition salts thereof. Without limitation thereto, tulobuterol base is preferred for use in practicing the present invention and will be referred to for convenience as
  • Transdermal tulobuterol delivery system embodiments of this invention provide tulobuterol dissolved in a physiologically tolerable adhesive and maintained in dissolved (i.e. , non-crystalline) form therein.
  • the amount of tulobuterol inco ⁇ orated into the adhesive medium of the skin adhesive composition varies with the desired therapeutic dosage effect and the time period over which the drug delivery system patch is to provide therapy.
  • the amount of tulobuterol base content in the skin adhesive composition, on a drug-in-adhesive matrix composition weight basis is less than 5%, and preferably may be in the range of about 1 to about 4.9% , more preferably in the range of about 2 to about 4.5 % .
  • the transdermal tulobuterol delivery system of this invention having a tulobuterol content of less than 5% in the skin adhesive composition provided skin permeation equivalent to or greater than that provided by conventional transdermal delivery systems having a tulobuterol content of not less than 5% in the adhesive layer.
  • a preferred composition of the drag delivery system also contains at least one skin penetration enhancer, and more preferably at least two skin penetration enhancers.
  • a preferred transdermal tulobuterol patch embodiment for daily dosage intervals has an active drag area size in the range of about 2.5 to about 10 square centimeters (cm 2 ), a drag load of about 0.2 milligrams (mg)/cm 2 , a drug content of less than 5 weight percent, based on the weight of the drag-in-adhesive matrix, a drag flux rate of about 7.5 micrograms/cm 2 /hour, and is substantially free of tulobuterol crystals in the adhesive matrix.
  • a particularly preferred transdermal tulobuterol patch has an active drag release area size in the range of about 10 cm 2 , a drag concentration of about 4.5 weight %, a drag assay in the range of about 1.8 to about 2.2 mg of tulobuterol per patch, and has a translucent appearance with no discoloration or signs of crystallization.
  • a general discussion of transdermal patch drag delivery systems, measurement of skin permeation, and methods of manufacturing conventional transdermal patch devices is found in Cleary, Chapter 11, entitled “Transdermal Drug Delivery,” and general discussion of various skin penetration enhancers is in Rieger, Chapter 2, entitled “Factors Affecting So ⁇ tion of Topically Applied
  • the penetration enhancer is present in an amount sufficient to enhance the penetration of the tulobuterol.
  • the specific amount of skin penetration enhancer varies necessarily according to the desired release rate.
  • the amount of total skin permeation enhancer in the skin adhesive composition, on a total composition weight basis may be in the range of about 0.1 to about 40%, more preferably in the range of about 5 to about 20%, most preferably in the range of about 1 to about 15%.
  • Particularly preferred were combinations of at least two skin permeation enhancers.
  • each skin permeation enhancer may be in the range of about 0.05 to about 5%, more preferably in the range of about 0.5 to about 20%, based on the total weight of the skin adhesive composition.
  • suitable penetration enhancers can be chosen from alcohols, carboxylic acids, carboxylic esters, polyols, amides, surfactants, te ⁇ enes, alkanones, organic acids, solvents, and mixtures thereof. See generally Chattaraj, et ah, "Penetration Enhancer Classification", pp. 5-20 in Maibach, et al. (eds.), Percutaneous Penetration Enhancers, CRC Press, Inc., Boca Raton, FL (1995),
  • Suitable aliphatic alcohols include, without limitation thereto, ethanol, propanol, butanol, pentanol, hexanol, octanol, nonanol, decanol, 2-butanol, 2-pentanol, benzyl alcohol, caprylic alcohol, decyl alcohol, lauryl alcohol, 2-lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, linolyl alcohol, linolenyl alcohol and mixtures thereof. Lauryl alcohol is preferred. Suitable aromatic alcohol is benzyl alcohol and the like.
  • Non-limiting examples of suitable carboxylic acids include fatty acids, such as caproic, capric, caprylic, lauric, myristic, palmitic, stearic, isostearic acid, oleic, linoleic, linolenic, and the like; and other straight-chain or branched organic acids, such as valeric, heptanoic, pelargonic, isovaleric, neopentanoic, neoheptanoic, neononanoic, trimethyl hexanoic, neodecanoic and mixtures thereof.
  • fatty acids such as caproic, capric, caprylic, lauric, myristic, palmitic, stearic, isostearic acid, oleic, linoleic, linolenic, and the like
  • other straight-chain or branched organic acids such as valeric, heptanoic, pelargonic, isovale
  • Non-limiting examples of suitable carboxylic esters include sorbitan derivatives, such as sorbitan laurate (SPAN ® 20), sorbitan oleate (SPAN ® 80), and the like; esters of C 6 -C 22 carboxylic acid, such as isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, ethyl oleate, ethyl laurate, isopropyl n-hexanoate, isopropyl n-decanoate, isopropyl n-butyrate, methylvalerate, methylpropionate, diethyl sebacate, and the like; and acetates, such as ethyl acetate, butyl acetate, methyl acetate, and the like, and mixtures thereof. Ethyl acetate is preferred.
  • suitable polyols include propylene glycol sulft
  • TEG dipropylene glycol
  • glycerol propanediol
  • sorbitol isosorbitol
  • dextrans butanediol
  • pentanediol pentanediol
  • hexanetriol hexanetriol
  • Suitable surfactants include, without limitation thereto, anionic surfactants, cationic surfactants, nonionic surfactants, amphoteric surfactants, bile salts and lecithin.
  • Example anionic surfactants include sodium laurate, sodium lauryl sulfate, and mixtures thereof.
  • Example cationic surfactants include cetyltrimethylammonium bromide, tetradecyltrimethylammomum bromide, benzalkonium chloride, octadecyltrimethylammonium chloride, cetylpyridinium chloride, dodecyltrimethylammonium chloride, hexadecyltrimethylammonium chloride, and mixtures thereof.
  • Example nonionic surfactants include ⁇ -hydro- ⁇ -hydroxypoly(oxyethylene)poly(oxypropyl) poly(oxyethylene) block copolymers, polyoxyethylene ethers, polyoxyethylene sorbitan esters, polyethylene glycol esters of fatty alcohols, and mixtures thereof.
  • Exemplary ⁇ -hydro- ⁇ -hydroxy-poly(oxyethylene) poly(oxypropyl) poly(oxyethylene) block copolymers include Poloxamers 182, 184, 231, and mixtures thereof.
  • Exemplary polyoxyethylene ethers include PEG-4 lauryl ether (BRIJ ® 30), PEG-2 oleyl ether (BRIJ ® 93), PEG-10 oleyl ether (BRIJ ® 96), PEG-20 oleyl ether (BRIJ ® 99), and mixtures thereof.
  • Example polyoxyethylene sorbitan esters include the monolaurate (TWEEN ® 20) the monopalmitate (TWEEN ® 40), the monostearate (TWEEN ® 60), the monooleate (TWEEN ® 80), and mixtures thereof.
  • Example polyethylene glycol esters of fatty acids include polyoxyethylene (8) monostearate (MYRJ ® 45), polyoxyethylene (30) monostearate (MYRJ ® 51), the polyoxyethylene (40) monostearate (MYRJ ® 52), and mixtures thereof.
  • Suitable amphoteric surfactants include, without limitation thereto, lauramidopropyl betaine, cocamidopropyl betaine, lauryl betaine, cocobetaine, cocamidopropylhydroxysultaine, aminopropyl laurylglutamide, sodium cocoamphoacetate, sodium lauroamphoacetate, disodium lauroamphodiacetate, disodium cocoamphodiacetate, sodium cocoamphopropionate, disodium lauroamphodipropionate, disodium cocoamphodipropionate, sodium lauriminodipropionate, disodium cocoamphocarboxymethylhydroxypropylsulfate, and the like.
  • the skin penetration enhancer is an alkyl-2-(N-substituted amino)-alkanoate, an (N-substituted arnino)-alkanol alkanoate, or a mixture of these.
  • alkyl-2-(N-substituted amino)-alkanoates and (N-substituted amino)-alkanol alkanoates can be grouped together under the designation alkyl-(N-substituted amino) esters.
  • a preferred penetration enhancer comprises an N,N-di(C r C 8 ) alkylamino substituted, (C 4 -C Ig ) alkyl (C 2 -C lg ) carboxylic ester or pharmaceutically acceptable acid addition salt thereof.
  • (C 4 -C 1S ) alkyl (C 2 -C ⁇ 8 ) carboxylic ester means an ester of a (C 4 -C 18 ) alcohol and a (C 2 -C 18 ) carboxylic acid.
  • N,N-di(C r C 8 ) alkylamino substituted in reference to a (C 4 -C 18 ) alkyl (C 2 -C ⁇ 8 ) carboxylic ester means that either the alcohol portion or the carboxylic acid portion from which the ester is prepared bears an amino substituent NR x R y , wherein R x and R y are each independently a (C r C 8 ) alkyl group. Preferably R x and R y are both methyl groups.
  • DDAIP dodecyl-2-(N,N-dimethylamino)-propionate
  • DDAA dodecyl-2-(N,N-dimethylamino)-acetate
  • DDAA dodecyl-2-(N,N-dimethylamino)-acetate
  • DAIPD dodecyl-2-(N,N-dimethylamino)-2-propyl dodecanoate
  • DAIPM l-(N,N-dimethylamino)-2-propyl myristate
  • DAIPO l-(N,N-dimethylamino)-2-propyl oleate
  • DDAIP is available from Steroids, Ltd. (Chicago, IL).
  • Non-limiting examples of solvents include aliphatic esters such as triethylcitrate (TEC), aromatic esters, such as diethylphthalate (DEP), dipolar aprotic solvents, N-methyl-2-pyrrolidone (NMP), diethylene glycol monoethyl ether (DGME), dimethyldecylphosphoxide, methyloctylsulfoxide, dimethyllaurylamide, dodecylpyrrolidone, dimethylacetamide, dimethylsulfoxide, decylmethylsulfoxide, dimethylformamide, oils such as squalane, and the like which affect keratin permeability.
  • aliphatic esters such as triethylcitrate (TEC)
  • aromatic esters such as diethylphthalate (DEP)
  • dipolar aprotic solvents such as N-methyl-2-pyrrolidone (NMP), diethylene glycol monoethyl ether (DGME), dimethyldecy
  • PSAs Pressure-sensitive adhesives
  • the major classes of PSAs are composed of polymers, such as acrylics, silicones, and isobutylenes.
  • the PSA component provides for intimate contact of the drag-containing skin adhesive and the skin surface for maintaining controlled and sustained transdermal release of the drug.
  • the adhesive component is not limited as long as it is physiologically tolerable to human skin and can dissolve and maintain tulobuterol dissolved therein in a crystal-free form, i.e., no crystals are visually or microscopically observable in the adhesive formulation.
  • the adhesive may constitute an amount in the range of about 1% to about 99% of the total weight of the total skin adhesive composition, preferably about 2% to about 90%, and more preferably about 50% to about 85%; the amount of adhesive being dependent on the amount of drug and other formulation components.
  • a preferred adhesive is an acrylic-based polymer, such as any of the homopolymers, copolymers, te ⁇ olymers, and the like of various acrylic acids known in the pressure-sensitive adhesive arts.
  • Exemplary acrylate polymers include, but are not limited to, polymers of one or more monomers of acrylic acids and other copolymerizable monomers.
  • the acrylate polymers also include copolymers of alkyl acrylates and/or methacrylates and/or copolymerizable secondary monomers or monomers with functional groups. By varying the amount of each type of monomer added, the cohesive properties of the resulting acrylate polymer can be changed as is known in the art.
  • Acrylate monomers which are generally used include acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecyl methacrylate.
  • Functional monomers copolymerizable with the above alkyl acrylates or methacrylates, which are generally used include acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate and methoxyethyl methacrylate.
  • acrylic adhesives suitable in the practice of the invention are described in Satas (ed.), "Acrylic acid"
  • Adhesives Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456, Van Nostrand Reinhold, New York (1989).
  • Other suitable adhesive materials for the skin adhesive layer may include, polysiloxanes, polyisobutylenes, polyurethanes, plasticized ethylenevinyl acetate copolymers, low molecular weight polyether amide block polymers (e.g.,
  • tacky rabbers such as polyisobutene, polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and mixtures thereof.
  • Preferred adhesive materials for use in the skin adhesive layer are polyacrylates, polystyrene-isoprene block copolymers, polyisobutylenes, amine-compatible and standard silicones, and polyurethane, with polyacrylates and tacky rabbers particularly preferred.
  • acrylic adhesives are commercially available and include a series of polyacrylate adhesives sold under the trademarks GELVA ® Multipolymer Solution as GMS grades 2873, 3067, 3083, and 3235 by UCB Group, and pressure sensitive adhesives sold under the trademarks DURO- TAK ® 80-1194, DURO-TAK ® 80-1196, DURO-TAK ® 80-1197, DURO-TAK ®
  • Example silicone pressure-sensitive adhesives include the amine-compatible BIO-PSA ® 4200 Series and the standard BIO-PSA ® 4500 Series sold by Dow Corning Co ⁇ oration.
  • a suitable rubber adhesive is styrene-isoprene- styrene (SIS) block copolymer, available under the trademarks QULNTAC ® 3433 from Nippon Zeon (Japan) and CARLFLEXTMTR-1107 from Shell Kogaku K.K.
  • GELVA ® Multipolymer Solution GMS grade 3083, an acrylic resin solution which, according to the manufacturer, is a copolymer of 2-ethylhexylacrylate and methacrylate designed with no functional monomers for pressure sensitive adhesives.
  • GELVA ® 3083 solution is available at a total solids content of about 37.5% in ethyl acetate, having a Brookfield viscosity of about 4800 milli-Pascal seconds (mPa»s), a shear rate of about 37.8 minutes, and reportedly typically provides a 180° peel strength of about 2.5 pounds/inch width at a 20 minute bond time for polyester film to stainless steel (1 mil (25.4 ⁇ m) dry adhesive on 1 mil film).
  • GELVA ® 3067 solution is available at a total solids content of about
  • GELVA ® 3235 solution is available at a total solids content of about 37.6% in ethyl acetate, having a Brookfield viscosity of about 11,140 (mPa's), a peel strength of about 0.4 pounds/inch, and a shear rate in the range of about 50 to about 90 hours.
  • GELVA ® 3067 has a higher tack adhesion and a lower shear and GELVA ® 3235 has a lower adhesion and higher shear than GELVA ® 3083.
  • GELVA ® 2873 reportedly has acid functionality.
  • DURO-TAK ® 87-2516 an acrylate-vinyl acetate, self curing pressure sensitive adhesive supplied at a total solids content in the range of about 40 to about 43%) in an organic solvent solution which according to the manufacturer is typically composed of about 63% ethyl acetate, about 21% ethanol, about 8%> heptane, and about 2% methanol, and reportedly typically provides a 180° peel strength in the range of about 25 oz/inch (10 N/25mm) at a 20 minute bond time and about 80 oz/inch (22 N/25mm) at a one week bond time. Also preferred is
  • DURO-TAK ® 87-9301 an acrylic, non-curing pressure sensitive adhesive, containing no vinyl acetate or functional monomers, supplied at a total solids content of about 40% in an organic solvent solution which according to the manufacturer is composed of 100% ethyl acetate, and reportedly typically provides a 180° peel strength in the range of about 52 oz/inch (14 N/25mm) at a 20 minute bond time, and a tack (Loop) of 45 oz/in 2 (12 N/25mm 2 ).
  • DURO- TAK ® pressure-sensitive adhesives are DURO-TAK ® 87-2194, an acrylate-vinyl acetate self-curing PSA supplied at a solids content of about 45% in an organic solution, which according to the manufacturer contains about 46% heptane, about 21%) xylene, about 15% ethylacetate, about 10% isopropanol, about 7% toluene and about 1%) 2,4-pentanedione, and DURO-TAK ® 87-2353 an all-acrylic non-curing PSA supplied at a solids content of about 36.5% in an organic solution which according to the manufacturer contains about 87% ethylacetate and about 13%) hexane.
  • each of the foregoing PSAs reportedly typically provides a 180° peel strength in the range of about 55 oz/in (15 N/25mm) at a 20-minute bond time and about 75 oz/in (21 N/25mm) at a one- week bond time.
  • a preferred amine-compatible, medium tack, silicone pressure-sensitive adhesive is a methylated trimethylated silica sold under the trade name, BIO-PSA ® 7-4202 Silicone Adhesive by Dow Corning Co ⁇ oration supplied at a solids content of about 60% in ethyl acetate, reportedly having a peel adhesion of about 900 g/cm.
  • the skin adhesive composition may include a plasticizer or tackifying agent in the formulation to improve the adhesive characteristics of the composition.
  • Suitable tackifying agents are known in the art and generally include aliphatic hydrocarbons; mixed aliphatic and aromatic hydrocarbons; aromatic hydrocarbons; substituted aromatic hydrocarbons; hydrogenated esters; polyte ⁇ enes; rosin esters, hydrogenated wood rosins, and the like.
  • the tackifying agent employed is preferably compatible with the adhesive.
  • An exemplary tackifying agent is silicone fluid (e.g., 360 Medical Fluid, available from Dow Corning Co ⁇ oration, Midland, Mich.), mineral oil, or rosin ester (e.g., KE-311 available from Arakawa Chemical Co., Osaka, Japan).
  • Patches prepared with a transdermal tulobuterol skin adhesive composition of this invention can be prepared to provide any desired active dimensional surface area.
  • a useful area may be in the range of about 1 to about 15 square centimeters (cm 2 ), preferably in the range of about 2 to about 12 cm 2 .
  • the transdermal patches have a drag load in the range of about 0.01 to about 2 mg cm 2 , more preferably in the range of about 0.1 to about 0.4 mg/cm 2 .
  • the transdermal tulobuterol skin adhesive compositions of this invention can be produced by a variety of methods known in the preparation of drug-containing adhesive preparations, including the mixing of a polymeric adhesive, drag, and additional excipient ingredients in solution, followed by removal of the processing solvents.
  • the drug-in-adhesive delivery system of this invention permits inclusion of therapeutically effective amounts of the tulobuterol drag directly within the skin-contacting adhesive formulation of a patch, while maintaining acceptable transdermal delivery of the tulobuterol, and acceptable tack, and peel adhesive properties of the delivery device.
  • the skin adhesive composition can comprise a single layer, drag-inadhesive monolithic device or can comprise an adhesive portion of any other type of transdermal drug delivery device (e.g., a reservoir device).
  • a single layer, drag-in-adhesive monolithic device embodiment is preferred.
  • a patch, or individual dosage unit, of the present invention can be produced in any manner known to those of skill in the art. After the skin adhesive composition is formed, it may be brought into contact with the backing layer in any manner known to those of skill in the art. Such techniques include calender coating, hot melt coating, solution coating, etc.
  • FIG. 1 is a schematic illustration of an single-layer drag-in-adhesive patch embodiment of the invention.
  • the delivery system comprises a monolithic body 10 of a defined geometric shape with a protective release liner 14 on one side of the monolithic body 10 and a backing layer 16 on the other side. Removal of the release liner 14 exposes the pressure-sensitive drag-in-adhesive matrix 12 which functions both as the drag carrier matrix and as the means of applying the drag delivery system to the skin of the patient.
  • the backing 16 is substantially coterminous with the drug-in-adhesive matrix 12.
  • the liner 14 is substantially coterminous with the drag-in-adhesive matrix 12 and may be configured or adapted to include a finger hold for grasping and aiding in removal of the liner therefrom.
  • the backing functions as the primary structural element of the device and provides the patch with flexibility, drape and, preferably, controlled occlusivity.
  • the material used for the backing layer is inert and incapable of absorbing drug, enhancer or other components of the pharmaceutical composition contained within the device.
  • the backing may be made of one or more sheets or films of a flexible material that serves as a protective covering to prevent loss of drug or vehicle or both by transmission through the upper surface of the device, and imparts a desired degree of occlusivity to the device, such that the area of the skin covered on application becomes hydrated.
  • the material used for the backing layer may permit the device to follow the contours of the skin and be worn comfortably on areas of the skin, such as at joints or other points of flexure, that are normally subjected to mechanical strain with little or no likelihood of the patch disengaging from the skin due to differences in the flexibility or resiliency of the skin and the device.
  • the backing is sufficiently flexible to conform to the skin area on which the patch is applied and be worn comfortably with little or no likelihood of the patch disengaging from the skin due to differences in the flexibility or resiliency of the skin and the device.
  • the backing material should be substantially inert, i.e., non-reactive with the ingredients of the formulations.
  • the backing can be occlusive, semi-occlusive, or non-occlusive (breathable), depending on the amount of moisture vapor transmission rate (MVTR) desired.
  • MVTR moisture vapor transmission rate
  • a presently preferred occlusive backing has a MVTR value of not more than about 200 g/m 2 /24 hours; more preferably of not more than about 75 g/m /24 hrs, and most preferably of not more than about 50 g/m 2 /24 hrs.
  • a presently preferred substantially semi-occlusive backing has a MVTR value in the range of about 400 g/m 2 /24 hrs to not more than about 1 ,000 g/m 2 /24 hrs.
  • a presently preferred substantially non-occlusive backing has a MVTR value in the range of about 1,000 g/m 2 /24 hrs. to not more than about 1,500 g/m 2 /24 hrs.
  • Backing materials are well known in the art and can comprise films or sheets of polyesters; such as polyethylene terephthalate (PET); polyolefins, such as polyethylene, polypropylene and copolymers thereof; vinyl acetate resins, such as ethylene/vinyl acetate copolymers (EVA), ethylene-ethylacrylate copolymer (EEA), vinyl acetate-vinyl chloride copolymers, vinylon, and the like; polyamides, polyvinyl chlorides, polyvinylidene chlorides, polyurethanes, such as spandex (SPDX); celluloses, such as cellulose acetate, ethyl cellulose, cotton, rayon, and the like; metal foils, such as aluminum; and laminate combinations thereof.
  • PET polyethylene terephthalate
  • EVA ethylene/vinyl acetate copolymers
  • EAA ethylene-ethylacrylate copolymer
  • SPDX spandex
  • celluloses
  • Backing materials can be woven fabric, non-woven fabric, elastomeric fabric, knitted fabric, spun-bonded fabric, and combinations thereof.
  • Exemplary backing materials include polyester film laminates sold by , 3M under the trade names SCOTCHPAKTM 9732 (polyester laminate with a (9%) ethylene vinyl acetate heat seal layer having a nominal caliper thickness of 2 mils.
  • SCOTCHPAKTM 9733 polyethylene with (12%) ethylene vinyl acetate having a nominal caliper thickness of 2 mils (50.8 ⁇ m) and a reported MVTR of 17 g/m 2 /24 hrs
  • SCOTCHPAKTM 9735 polyyester with (12%) ethylene vinyl acetate heat-seal layer), having a nominal caliper thickness of 2 mil (50.8 ⁇ m) and a reported MVTR of 7 g/m 2 /24 hrs
  • SCOTCHPAKTM 9723 polyethylene and polyester laminate heat-seal layer having a nominal caliper thickness of 1.7 mil (43.2 ⁇ m) and a reported MVTR of 12 g/m 2 /24 hrs
  • SCOTCHPAKTM 1109 pigmentmented polyethylene and aluminum vapor coated polyester having a nominal caliper thickness of 1.3 mils
  • Another exemplary occlusive backing is a non- woven cotton and PET laminate fabric having a MVTR of about 200 g/m 2 /24 hrs. sold by Nichiban KK.
  • Other exemplary occlusive backing materials are a non- woven material sold by 3M under the tradename COTRANTM, such as COTRANTM 9720 polyethylene monolayer film having a reported MVTR of 9.4 g/m 2 /24 hrs; COTRANTM 9722 polyolefm monolayer film having a reported MVTR of 7.9 g/m 2 /24 hrs; COTRANTM 9726 ethylene vinyl acetate (EVA) having a reported MVTR of 18.1 g/m 2 /24 hrs, and the like.
  • COTRANTM 9720 polyethylene monolayer film having a reported MVTR of 9.4 g/m 2 /24 hrs
  • COTRANTM 9722 polyolefm monolayer film having a reported MVTR of 7.9 g
  • Exemplary semi-occlusive backings are a polyurethane film sold by Nichiban KK having a MVTR value of about 405 g/m 2 /24 hrs, and a polyurethane film sold by 3M under the tradename COTRANTM 9701 having a reported MVTR value of 709 g/m 2 /24 hrs.
  • An exemplary non-occlusive, non- woven backing material is a cotton fabric, sold by Nichiban KK, having a MVTR value of about 1205 g/m 2 /24 hrs.
  • Another exemplary backing sold by 3M under the tradename COTRANTM 9700 is a melt-blown polyurethane having a reported MVTR value of 8408 g/m 2 /24 hrs.
  • Other non-woven backings can be a biaxially oriented polypropylene (BOPP) or polypropylene having multidirectional stretch, such as the backing sold by 3M under the tradenames COTRANTM 9725 and COTRANTM 9729 and elastomeric fabrics, such as spandex (SPDX).
  • An exemplary elastomeric fabric is Lycra spandex having a MVTR value of about 1352 g/m 2 /24 hrs.
  • Other suppliers of suitable polyurethane and non- woven backing materials are known in the art.
  • a preferred occlusive backing material is a polyester/EVA laminate (3MTM SCOTCHPAKTM 9732).
  • a preferred substantially semi-occlusive, backing may be rayon, vinylon, or a PET-lined non-woven fabric.
  • Preferred substantially non-occlusive backing materials include polyurethane and non- woven fabrics.
  • Backing materials are well known in the art and can comprise films of polyesters, polyethylene, polypropylene, polyamides, vinyl acetate resins, ethylene/vinyl acetate copolymers, polyvinyl chloride, polyurethane, and the like, and combinations thereof, metal foils, non-woven fabric, cloth and commercially available laminates.
  • a useful backing material generally has a thickness in the range of 2 micrometers to 1,000 micrometers, preferably in the range of about 15 micrometers to about 70 micrometers, more preferably in the range of about 30 micrometers to about 60 micrometers.
  • the release liner is a disposable element which protects the device prior to application. Typically, the release liner is formed form a material impermeable to the drug, vehicle and adhesive, and which is easily stripped from the contact adhesive. The release liner is occlusive and functions to protect the surface of the drag-in-adhesive layer during production, storage, and transport. Suitable release liners are well known in the art and are commercially available.
  • Release liner materials are generally occlusive sheet materials, such as webs or films of polyester, poly(vinyl chloride), poly(vinylidene chloride), polyethylene, polyethylene terephthalate (PET), ethylene/vinyl acetate copolymers (EVA) polystyrene and the like, paper (e.g. wood-free paper and glassine paper), and laminate films of paper and polyolefin, metal foils, and the like.
  • Release liners are preferably subjected to a release treatment, such as silicone or fiuoropolymer treatment, on the surface of the liner that comes in direct contact with the skin adhesive matrix of the transdermal patch.
  • Silicone-coated polyester, fluoropolymer-coated polyester, and silicone-coated aluminum are typically preferred. Where a polysiloxane is part of the adhesive system, the release liner must be compatible with the silicone adhesive.
  • Exemplary liners include, without limitation, fiuoropolymer coated polyester film sold by 3M under the trade names SCOTCHPAKTM 1022 Release
  • Liner reportedly having a caliper nominal thickness of 3 mils (76.2 ⁇ m) and a liner release force of ⁇ 100g in ( ⁇ 1.0 Newtons/25.4 millimeters (mm)); SCOTCHPAKTM 9742 having a nominal thickness of 5 mils (127 ⁇ m); and SCOTCHPAKTM 9744 reportedly having a nominal caliper thickness of 3 mils (76.2 ⁇ m) and a liner release force of ⁇ 100g/in ( ⁇ 1.0 Newtons/25.4 millimeters (mm)).
  • exemplary liners include a silicone-coated PET liner sold under the trade name MEDIRELEASE ® by Mylan Technologies Inc., silicone-coated polyester film sold in various liner grades by Loparex Inc, and liner films sold under trade names BIO-RELEASE ® and SYL-OFF ® 7610 by Dow Corning Co ⁇ oration.
  • a preferred release liner film is a silicone-coated PET, such as MEDIRELEASE ® 2249 available from Mylan Technologies Inc., reportedly having a nominal caliper thickness of 3 mils (76.2 ⁇ m) and a nominal liner release force value of 14 g/in (14 g/2.54 cm).
  • a useful release liner generally has a thickness in the range of about 12 to about 500 micrometers, preferably about 50 to about 400 micrometers, more preferably about 60 to about 150 micrometers.
  • the configuration of the transdermal delivery system of the present invention can be in any shape or size as is necessary, desirable, or practical.
  • a single dosage unit may have a surface area in the range of 1 to 100 cm 2 .
  • Preferred active dosage surface areas sizes are in the range of about 1 to about 30 cm 2 , more preferably in the range of about 2 to about 15 cm 2 .
  • a transdermal patch, or individual dosage unit, of the present invention can be produced in any manner known to those of skill in the art.
  • the skin adhesive composition is first formulated as a water-insoluble, liquid solution, referred to herein as a "wet-base” solution.
  • a water-insoluble, liquid solution referred to herein as a "wet-base” solution.
  • the wet-base solution may be cast on a support, such as a release liner, substantially dried to remove unwanted volatile processing solvent and provide a drug-in-adhesive (DIA) matrix, which is then brought into contact with a second support, such as the backing layer, in any manner known to those of skill in the art.
  • DIA drug-in-adhesive
  • Such techniques include calender coating, hot melt coating, solution coating, etc.
  • An exemplary general method of preparation of single layer, drug-in-adhesive transdermal patches is as follows: 1.
  • pressure-sensitive adhesive such as acrylic acid-based or rubber-based, or silicone-based adhesive, dissolved in an appropriate solvent
  • a mixing vessel 2.
  • the drug is then added to the adhesive mixture and mixing agitation is carried out until the drag is uniformly inco ⁇ orated therein to provide a DIA mixture.
  • Penetration enhancer, and any optional co-solvent and excipients, is then added to the drug-adhesive mixture, and thoroughly mixed to provide a wet-base formulation. 4.
  • the wet-base formulation is permitted to de-aerate, as necessary, and is then transferred to a coating operation where it is uniformly cast or coated onto a release liner at a controlled specified thickness by any conventional technique, such as pouring, brushing, spraying, and the like to provide a DIA coating.
  • the DIA coated product is then substantially dried, such as by passing through an oven, preferably at a temperature of not more than about 80 °C, to drive off all unwanted volatile processing solvents to provide a substantially dried DIA matrix.
  • the substantially dried DIA matrix on the release liner is then laminated to the backing material by any conventional laminating technique, such as rolling under uniform pressure, and wound into rolls or folded into sheets for storage or further manufacture of patches. 7.
  • Appropriately sized and shaped dosage units may be die-cut from the roll or sheet material and then packaged, such as in a heat sealed pouch or packet.
  • the drag is preferably solubilized in ethyl acetate before adding the drug to the adhesive mixture.
  • the thickness of the cast wet-base formulation is preferably in the range of about 100 to about 400 micrometers on the release liner.
  • drying is preferably carried out at a temperature of not more than about 70 °C, the dried DIA matrix preferably has a thickness in the range of about 12 to about 250 micrometers.
  • steps 1-3 may be performed concurrently or sequentially, or, in step 4, the formulation may be cast onto the backing material in which case, in step 6, the dried product may be laminated onto the release liner.
  • steps 1-3 may be performed concurrently or sequentially, or, in step 4, the formulation may be cast onto the backing material in which case, in step 6, the dried product may be laminated onto the release liner.
  • the process factors can be readily adjusted by those of skill in the art as required to provide a uniform product which has acceptable pressure-sensitive adhesive characteristics without sacrificing acceptable drug delivery efficacy.
  • Skin permeation may be determined using in vitro methods well known in the art using human cadaver skin mounted on either a Franz cell equipped with an auto sampling system or in side-by-side permeation cells.
  • a therapeutic dose of tulobuterol can be delivered to a mammal, preferably a human, by removing the liner from a dosage unit of the transdermal tulobuterol delivery system, contacting the skin surface with the skin adhesive DIA matrix and maintaining the contact for a period sufficient to maintain effective bronchodilation therapy.
  • the transdermal tulobuterol delivery system may be provided for bronchio respiratory tulobuterol therapy in packaged kit form with instructional indicia included therein for use.
  • Instructional indicia includes, without limitation, printed media, aural media, visual aids, electronic media or a combination thereof which inform and instruct the user.
  • Printed media includes, but is not limited to, labels, pamphlets, books, flyers and the like.
  • Aural media includes, but is not limited to, tape recordings, audio compact disks, records, and the like.
  • Visual aids include, but are not limited, to photographs, slides, movies, videos, DVDs, and the like.
  • Electronic media includes all forms of electronic data storage media, such as, but not limited to, diskettes, interactive CD-ROMs, interactive DVDs, and the like. The following examples further illustrate the preparation and use of preferred embodiments but are not intended to be limiting.
  • Examples 1-13 illustrate the formulation of transdermal tulobuterol skin adhesive compositions and transdermal patches containing, in the drug-in-adhesive matrix, varying amounts of the drag, varying amounts of penetration enhancers and adhesive, in the amounts indicated in Table 1.
  • the transdermal tulobuterol delivery patches of this invention were formulated to vary both the drag load and skin permeation enhancer content in the skin adhesive composition. Tulobuterol base was used, and the total tulobuterol content, based on the weight of the skin adhesive composition, was varied in the range of about 2.5 to about 4.5 weight %. The total amount of penetration enhancer in the skin adhesive composition was varied from zero to about 20 weight %.
  • the remainder of the skin adhesive composition was made up of commercial polyacrylate adhesive (GELVA ® 3083, about 37.5% total solids in ethyl acetate). TABLE 1
  • PAC Polyacrylate adhesive, (GELVA ® 3083).
  • NMP N-Methyl-2-pyrrolidone
  • DGME Diethylene glycol monoethyl ether
  • DDAIP Dodecyl-2-N,N-dimethylaminopropionate
  • QS Quantity sufficient.
  • the compositions were prepared by mixing the drag, penetration enhancer(s) and adhesive solution together, stirring slowly until all ingredients dissolved, for a period of several hours or until homogeneous, to provide a wet-base solution. The wet-base solution was allowed to de-aerate on standing.
  • Patches were prepared with each of the composition of Examples 1 - 13, by pouring the wet-base solution onto a release liner (SCOTCHPAKTM 1022, 3M) to provide a wet-base film thickness of about 100 to about 400 micrometers ( ⁇ m).
  • the cast film was then substantially dried in a laboratory dryer unit at a temperature of not more than about 70 °C for a period sufficient to volatilize the ethyl acetate solvent.
  • the % tulobuterol load of the dried adhesive coating is shown in Table 1 above, along with the estimated % amount of total penetration enhancer.
  • a backing film (SCOTCHPAKTM 9732, 3M, polyester/EVA laminate) was then laminated onto the substantially dried drag-containing, skin-adhesive coated surface.
  • Example 14 This example illustrates the effective tack and peel adhesion of the transdermal patches prepared with the skin adhesive compositions of Examples
  • % skin permeation of tulobuterol through human cadaver skin, in vitro relative to that of a commercial transdermal patch, HOKUNALIN ® Tape (2 mg dosage) having a dimensional size of about 10 cm 2 .
  • the commercial transdermal HOKUNALIN ® patch reportedly controls the release of tulobuterol by utilizing a crystal reservoir of tulobuterol. This technology is described by Yosbihisa, in "Transdermal Patch for Asthma Therapy," Nitto Technical Report, V38, No. 2, pp 61-63, published by Nitto Denko, Japan (Dec. 2000).
  • the commercial HOKUNALIN ® patch reportedly has a drag content of not less than 5% in the adhesive layer and utilizes isopropyl myristate as the skin permeation enhancer.
  • Tack adhesion was determined using the Standard Test Method for Pressure-Sensitive Tack of Adhesives using an Inverted Probe Machine, ASTM D2979-01. The release liner was removed from the patch, the patch was mounted on the tester, (Model PT-500, Chemlnstraments Probe Tack Tester) and peak removal force was measured in Newton (N) units using a probe having a diameter of 0.5 cm and a probe end area of 0.196 cm 2 . Tack adhesion values of at least about 0.5 N, and more preferably greater than about 2 N, are judged acceptable.
  • the skin permeation data showed that the permeation rate of tulobuterol through human cadaver skin from the commercial tape was in the range of 5 to 12 ⁇ g/cm 2 /min.
  • the permeation rate from the transdermal patches of Examples 12 and 13 was judged substantially equivalent to that of the commercial transdermal patch.
  • Table 3 compares the relatively low content of tulobuterol in the skin adhesive layer of the patches of Examples 12 and 13, providing an overall drag load ( ⁇ g/cm 2 ) that is judged as substantially similar to that of the 2 mg size commercial HOKUNALIN ® Tape, which has a relatively high tulobuterol (not less than 5%) content in the adhesive layer.
  • Patch weight includes backing and release liner 2.
  • Coating weight Dry patch weight - (release liner weight and backing weight). 3. Calculated dry base concentration from assayed drug amount and coating weight. The % drug release over a period of about 24 hours from the patches of
  • Example 12 and 13 was also determined using the USP rotating paddle over disk Apparatus-5 technique disclosed in United States Pharmacopeia XXIII, (USP), Drag Release Physical Tests, Chapter 724, Apparatus 5, p. 2018, using water as the test medium. The results are graphically depicted relative to that of the commercial tape in FIG. 2.
  • Example 13 was examined by X-ray Diffraction technique and under a polarizing microscope. No crystals of tulobuterol were found. In contrast, crystals were detected in the transdermal layers of HOKUNALIN ® Tapes of 0.5mg, lmg, and
  • transdermal delivery system of this invention permits the inclusion of relatively low amounts (less than 5%») of dissolved tulobuterol (free of crystalline tulobuterol) in the skin adhesive formulation of a transdermal patch without sacrificing tack and peel adhesive properties of the device.
  • Example 15 The solubility of tulobuterol base in various penetration enhancers was determined by incrementally adding small amounts of the drug to 100 ml of penetration enhancer until the drag no longer dissolved or the amount dissolved exceeded about 30 g/100 ml. The results are shown in Table 4. Solubility was judged as optimal in NMP, DGME, oleic acid, and DDAIP. A particular preferred combination of skin permeation enhancers was DDAIP and DGME. This combination provides increased skin permeation and maintains the drag in dissolved, non-crystalline, form in the adhesive medium.
  • NMP N-methyl-2-pyrrolidone
  • DGME Diethylene glycol monoethyl ether
  • DDAIP Dodecyl-2-N,N-dimemylaminopropionate
  • Examples 16-21 illustrate tulobuterol patches of this invention prepared with a (styrene-isoprene-styrene) SIS rabber-based adhesive (A) system having the composition shown in Table 5. TABLE 5 SIS Rubber-Based Adhesive A Wt.
  • the dry load content of the tulobuterol in the adhesive was about 4.5%> as shown in Table 6 below, along with the % penetration enhancer and %> rabber adhesive (A) indicated. Weight % values are based on the weight of the coating composition after drying. Also shown in Table 6 is the skin permeation rate and lag time, as well as the relative % permeation rate and relative % lag time compared to that of commercial HOKUNALIN ® 2 mg tape.
  • the approximate dry drag load provided at a 400 ⁇ m thickness was about 250 mg/cm 2 , at a 300 ⁇ m thickness was about 180 mg/cm 2 , and at a 200 ⁇ m thickness was about 80 mg/cm 2 .
  • the results in a skin permeation test over a period of 24 hours compared to HOKUNALIN ® 2 mg tape showed the skin permeation rate increased as the thickness of the poured film, and hence, the drag load increased.
  • a series of patches were prepared with the wet-base skin adhesive compositions of Examples 16-21, in which the thickness of the poured coating was varied as shown in Table 7 below. Probe tack adhesion was measured in Newtons (N) as described in Example 14 and is also shown in Table 7 along with the thickness of the adhesive layer (coating thickness) after drying.
  • Coating values are average of 5 patches/Example; coating thickness is calculated as the thickness of the patch less the thickness of the backing and the release liner. Patch thickness is the total thickness of the patch, including the backing and release liner.
  • Examples 22-27 patches of this invention were prepared with various penetration enhancers, N-methyl-2-pyrrolidone (NMP), triethylcitrate (TEC), triethylene glycol (TEG) and diethylphthalate (DEP) employed in the concentrations shown in Table 8.
  • NMP N-methyl-2-pyrrolidone
  • TEC triethylcitrate
  • TOG triethylene glycol
  • DEP diethylphthalate
  • the SIS rabber based adhesive (A) described in Examples 16-21 was employed in the amount shown in Table 8 and the tulobuterol content was about 4.5% in the adhesive layer. Weight percent values are based on the coating of the skin adhesive composition after drying.
  • Examples 28-51 illustrate the formulation of transdermal tulobuterol skin adhesive compositions and transdermal patches containing varying amounts of tulobuterol base, varying amounts of penetration enhancers and adhesive, as indicated in Table 10, based on the weight of the substantially dried drug-in-adhesive (DIA) matrix.
  • DIA substantially dried drug-in-adhesive
  • compositions were prepared generally as described in Examples 1-13, except that the tulobuterol base was solubilized in ethyl acetate (about 5 to about 10 weight % based on the weight of the wet-base formulation) before being added to the adhesive composition; and, as shown in Table 10, the concentration of drug was varied in the range of about 1 to about 4.5 weight % and the concentration of penetration enhancer was varied from zero to about 20 weight % based on the dry weight of the DIA matrix.
  • the penetration enhancers were diethylene glycol monoethyl ether (DGME);dodecyl-2-N,N-dimethylaminopropionate (DDAIP); triethylene glycol (TEG), N-methyl-2-pyrrolidone (NMP); propylene glycol (PG), lauryl alcohol (LA); and oleic acid as indicated.
  • DGME diethylene glycol monoethyl ether
  • DDAIP diethylene glycol monoethyl ether
  • DDAIP diethylene glycol
  • TAG triethylene glycol
  • NMP N-methyl-2-pyrrolidone
  • PG propylene glycol
  • LA lauryl alcohol
  • oleic acid oleic acid as indicated.
  • Three pressure-sensitive acrylic adhesives were studied: GELVA ® 3083
  • the release liner used for the patches of Examples 28-36 and 42-50 was a fiuoropolymer coated polyester film (SCOTCHPAKTM 1022).
  • the release liner used for patch Examples 37-41 was a silicone coated PET liner (MEDIRELEASE ® 2249).
  • the backing material used for all patch examples 28-50 was SCOTCHPAKTM 9732, poly ester /EVA laminate.
  • the skin permeation rate ( ⁇ g/cm 2 /hr) was determined by in vitro method as described in Example 14; and skin permeation rate relative to that of the commercial HOKUNALIN ® Tape (2 mg. dosage) and lag-time (hrs.) was determined for patch Examples 28, 30-39, 42-44, and 47-50. The results are shown in Table 11. The data for patch Example 29 was not determined. The patch of Example 45 was not tested because the propylene glycol was judged incompatible with Adhesive F. Patch Examples 40, 41, 46, and 51 also were not tested.
  • ND Not Determined. * Franz diffusion cell using pH 7.4 phosphate buffered saline medium. ** Relative to that of HOKUNALIN ® Tape 2 mg. at 100% .
  • the patch of Example 39 was judged substantially equivalent to the commercial tape in skin permeation rate but some incompatibility between the drug and Adhesive E in the drug-in-adhesive wet-base formulation was noted resulting in a decrease in available drug activity, suggesting an interaction.
  • the data illustrate that the skin permeation rate and lag-time can be varied and optimized, as desired, by the appropriate selection of penetration enhancer(s) and adhesives.
  • the lag-time data of Examples 44 and 47 show that the amine-compatible pressure-sensitive silicone adhesive, Adhesive F, provided a rapid release of tulobuterol, which can be mediated by adding penetration enhancer, without the reducing skin penetration rate.
  • Adhesive F the amine-compatible pressure-sensitive silicone adhesive
  • the tack adhesion of patches of Examples 28, 32, 33 and 43 was determined in Newtons by probe tack tester technique as described in Example 14. The results are shown in Table 12.

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Abstract

Cette invention se rapporte à un système d'application de tulobutérol transdermique, se présentant sous la forme d'un timbre en une seule couche à matrice de médicament incorporé dans l'adhésif, comprenant une concentration relativement faible (moins de 5 % en poids) d'une base de tulobutérol dissoute dans une composition adhésive pour la peau, contenant au moins un agent améliorant la perméation de la peau. Ce système d'application transdermique assure la libération régulée du principe actif, il contient une concentration relativement faible de tulobutérol dans la formulation adhésive en contact avec la peau d'un timbre transdermique et il assure une application transdermique soutenue acceptable du tulobutérol dissout, ainsi que des propriétés de pégosité et de pélliculage acceptables pour le dispositif d'application.
PCT/US2004/037305 2003-11-07 2004-11-05 Systeme d'application de tulobuterol transdermique, procede et composition correspondants WO2005046600A2 (fr)

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WO2006044206A2 (fr) 2004-10-08 2006-04-27 Noven Pharmaceuticals, Inc. Dispositif d'administration transdermique de medicaments avec couche support occlusive
EP1685830A1 (fr) * 2003-11-21 2006-08-02 Sekisui Chemical Co., Ltd. Pansement adhesif
EP2172194A1 (fr) * 2008-10-02 2010-04-07 Amarin Technologies S.A. Système d'administration transdermique de médicaments pour ingrédients actifs liquides
WO2012103015A2 (fr) * 2011-01-27 2012-08-02 Csi Gmbh Patchs transdermiques à libération prolongée associant un bêta-agoniste et un stéroïde et leurs procédés d'utilisation
WO2012103016A3 (fr) * 2011-01-26 2012-09-20 Csi Gmbh Patchs transdermiques à libération prolongée associant un bêta-agoniste et un anticholinergique et leurs procédés d'utilisation
US9775908B2 (en) 2007-07-10 2017-10-03 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Pharmaceutical preparations containing highly volatile silicones
US10045935B2 (en) 2012-07-31 2018-08-14 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
CN110433146A (zh) * 2018-05-03 2019-11-12 中国医学科学院药物研究所 一种妥洛特罗晶体贮库型透皮贴剂及其制备方法
WO2020264032A1 (fr) * 2019-06-28 2020-12-30 Passport Technologies, Inc. Timbre d'administration de médicament transdermique, système d'administration de médicament et procédé d'administration de médicament
CN112826809A (zh) * 2019-11-22 2021-05-25 北京泰德制药股份有限公司 一种稳定的妥洛特罗经皮吸收制剂
US11154535B2 (en) 2012-07-31 2021-10-26 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1685830A4 (fr) * 2003-11-21 2010-04-28 Sekisui Chemical Co Ltd Pansement adhesif
EP1685830A1 (fr) * 2003-11-21 2006-08-02 Sekisui Chemical Co., Ltd. Pansement adhesif
US8815281B2 (en) 2004-10-08 2014-08-26 Noven Pharmaceuticals, Inc. Transdermal drug delivery device including an occlusive backing
US9155712B2 (en) 2004-10-08 2015-10-13 Noven Pharmaceuticals, Inc. Transdermal drug delivery device including an occlusive backing
EP1807033A2 (fr) * 2004-10-08 2007-07-18 Noven Pharmaceuticals, Inc. Dispositif d'administration transdermique de medicaments avec couche support occlusive
US10231938B2 (en) 2004-10-08 2019-03-19 Noven Pharmaceuticals, Inc. Transdermal drug delivery device including an occlusive backing
EP1807033A4 (fr) * 2004-10-08 2009-12-30 Noven Pharma Dispositif d'administration transdermique de medicaments avec couche support occlusive
US8591941B2 (en) 2004-10-08 2013-11-26 Noven Pharmaceuticals, Inc. Transdermal drug delivery device including an occlusive backing
WO2006044206A2 (fr) 2004-10-08 2006-04-27 Noven Pharmaceuticals, Inc. Dispositif d'administration transdermique de medicaments avec couche support occlusive
US9775908B2 (en) 2007-07-10 2017-10-03 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Pharmaceutical preparations containing highly volatile silicones
EP2172194A1 (fr) * 2008-10-02 2010-04-07 Amarin Technologies S.A. Système d'administration transdermique de médicaments pour ingrédients actifs liquides
WO2012103016A3 (fr) * 2011-01-26 2012-09-20 Csi Gmbh Patchs transdermiques à libération prolongée associant un bêta-agoniste et un anticholinergique et leurs procédés d'utilisation
WO2012103015A3 (fr) * 2011-01-27 2012-09-20 Csi Gmbh Patchs transdermiques à libération prolongée associant un bêta-agoniste et un stéroïde et leurs procédés d'utilisation
WO2012103015A2 (fr) * 2011-01-27 2012-08-02 Csi Gmbh Patchs transdermiques à libération prolongée associant un bêta-agoniste et un stéroïde et leurs procédés d'utilisation
US10045935B2 (en) 2012-07-31 2018-08-14 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
US11154535B2 (en) 2012-07-31 2021-10-26 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
CN110433146A (zh) * 2018-05-03 2019-11-12 中国医学科学院药物研究所 一种妥洛特罗晶体贮库型透皮贴剂及其制备方法
CN110433146B (zh) * 2018-05-03 2022-03-15 中国医学科学院药物研究所 一种妥洛特罗晶体贮库型透皮贴剂及其制备方法
WO2020264032A1 (fr) * 2019-06-28 2020-12-30 Passport Technologies, Inc. Timbre d'administration de médicament transdermique, système d'administration de médicament et procédé d'administration de médicament
CN112826809A (zh) * 2019-11-22 2021-05-25 北京泰德制药股份有限公司 一种稳定的妥洛特罗经皮吸收制剂
CN112826809B (zh) * 2019-11-22 2023-01-10 北京泰德制药股份有限公司 一种稳定的妥洛特罗经皮吸收制剂

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