[go: up one dir, main page]

EP0695179A1 - Composition transdermique anti-inflammatoire - Google Patents

Composition transdermique anti-inflammatoire

Info

Publication number
EP0695179A1
EP0695179A1 EP94914184A EP94914184A EP0695179A1 EP 0695179 A1 EP0695179 A1 EP 0695179A1 EP 94914184 A EP94914184 A EP 94914184A EP 94914184 A EP94914184 A EP 94914184A EP 0695179 A1 EP0695179 A1 EP 0695179A1
Authority
EP
European Patent Office
Prior art keywords
formulation
excipient
formulation according
nonsteroidal antiinflammatory
drug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94914184A
Other languages
German (de)
English (en)
Inventor
Christiane Grun
Eberhard Gruhlke
Hanns Wendel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
3M Co
Original Assignee
Minnesota Mining and Manufacturing Co
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 Minnesota Mining and Manufacturing Co filed Critical Minnesota Mining and Manufacturing Co
Publication of EP0695179A1 publication Critical patent/EP0695179A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to topical and transdermal drug formulations. In another aspect this invention relates to formulations containing nonsteroidal antiinflammatory drugs.
  • Topical and transdermal drug formulations are designed to deliver a therapeutically effective amount of drug to or across the skin of a patient.
  • Devices known to the art include reservoir type devices involving membranes that control the rate of drug release to the skin, gels and creams, and devices involving a dispersion of the drug in a matrix such as a pressure sensitive adhesive.
  • a matrix such as a pressure sensitive adhesive.
  • the transdermal flux rate that is suitable, and suitable formulation components are dependent upon the particular drug to be delivered.
  • Nonsteroidal antiinflammatory drugs are commonly used as analgesic, antipyretic, and antiinflammatory treatments. Oral dosage forms are most common. However, sustained use of oral NSAIDS is known to cause peptic ulcers. Accordingly it is sometimes desirable to administer such drugs in a manner that avoids the gastrointestinal tract.
  • Transdermal administration is one such route.
  • a transdermal formulation in order for a transdermal formulation to be effective - 2 - and suitable for general use by patients it is desirable that the formulation have a high transdermal flux rate, allowing a therapeutically effective blood level of the drug to be achieved or maintained when the formulation is applied to a relatively small area of the skin.
  • This invention provides a substantially non- aqueous topical and/or transdermal drug delivery formulation, comprising:
  • a therapeutically effective amount of a nonsteroidal antiinflammatory drug selected from the group consisting of phenylpropionic acid derivatives and phenylacetic acid derivatives;
  • a lipophilic excipient selected from the group consisting of fatty acid alkyl esters and fatty acid monoglycerides
  • a hydrophilic excipient selected from the group consisting of polyethylene glycols, polyethylene glycol esters, isosorbide ethers, and diethylene glycol ethers, wherein the lipophilic excipient and the hydrophilic excipient are miscible with one another in the amounts employed, and wherein the nonsteroidal antiinflammatory drug is substantially fully dissolved in the formulation.
  • This invention also provides a topical and/or transdermal formulation as described above, wherein the formulation further comprises a pressure sensitive adhesive and wherein the drug, the lipophilic excipient, and the hydrophilic excipient are substantially uniformly dispersed or preferably dissolved in the pressure sensitive adhesive.
  • This invention also provides a topical and/or transdermal drug delivery formulation, comprising: (i) a therapeutically effective amount of a nonsteroidal antiinflammatory drug selected from the group consisting of phenylpropionic acid derivatives and phenylacetic acid derivatives; (ii) a lipophilic excipient selected from the group consisting of ethyl oleate, isopropyl myristate, and a mixture thereof; and
  • This invention also provides a topical and/or transdermal drug delivery formulation, comprising: (i) a therapeutically effective amount of a nonsteroidal antiinflammatory drug selected from the group consisting of phenylpropionic acid derivatives and phenylacetic acid derivatives; (ii) a lipophilic excipient selected from the group consisting of fatty acid alkyl esters and fatty acid monoglycerides;
  • hydrophilic excipient selected from the group consisting of polyethylene glycols, polyethylene glycol esters, isosorbide ethers, and diethylene glycol ethers;
  • a pressure sensitive adhesive wherein the drug, the lipophilic excipient, and the hydrophilic excipient are substantially uniformly dispersed or preferably dissolved in the pressure sensitive adhesive.
  • This invention also provides an adhesive coated sheet material comprising a flexible backing bearing on one surface thereof a formulation comprising a homogeneous mixture of
  • a therapeutically effective amount of a nonsteroidal antiinflammatory drug selected from the group consisting of phenylpropionic acid derivatives and phenylacetic acid derivatives
  • a lipophilic excipient selected from the group consisting of fatty acid alkyl esters and fatty acid monoglycerides
  • a hydrophilic excipient selected from the group consisting of polyethylene glycols, polyethylene glycol esters, isosorbide ethers, and diethylene glycol ethers.
  • This invention also provides a method of treating in an animal a condition capable of treatment by a nonsteroidal antiinflammatory drug, comprising the steps of:
  • the drawing shows a perspective view of a diffusion cell used to determine transdermal flux of a formulation of the invention.
  • the formulations of the invention contain a nonsteroidal antiinflammatory drug.
  • This class of drugs is well known to those skilled in the art and includes phenylpropionic acid derivatives (e.g., fenoprofen, ibuprofen, flurbiprofen, ketoprofen, and - 5 - naproxen) and phenylacetic acid derivatives (e.g., 4- biphenylacetic acid, ibufenac) .
  • Preferred NSAIDs for use in this invention include phenylpropionic acid derivatives.
  • the most preferred propionic acid derivative is flurbiprofen, especially S(+) flurbiprofen.
  • the nonsteroidal antiinflammatory drug is present in a formulation of the invention in a therapeutically effective amount.
  • the amount that constitutes a therapeutically effective amount varies according to the particular drug to be delivered, the indication to be treated, the surface area of the skin over which the formulation is to be placed, and on the other components of the formulation. Accordingly it is not practical to enumerate particular preferred amounts but such can be readily determined by those skilled in the art with due consideration of these factors.
  • the nonsteroidal antiinflammatory drug is preferably present in an amount of about 1 to about 25 percent, preferably about 5 to about 15 percent, by weight based on the total weight of the formulation.
  • hydrophilic and lipophilic refer to relative hydrophilicity/lipophilicity as measured on the hydrophile-lipophile balance (HLB) scale (see, e.g., pages 304-306, Remington's Pharmaceutical Sciences, 18th Edition, 1990, A. R. Gennaro, Ed. , Mack Publishing Company, Easton, Pennsylvania, Griffin, . C. , J. Soc. Cos. Chem. 1949, 1 , 311, and Griffin, W. C. , J. Soc. Cos. Chem. 1954, 5 , 249) .
  • hydrophilic ex ⁇ ipients have an HLB of at least about 10
  • lipophilic excipients have an HLB of less than about 10.
  • the formulations of the invention contain a lipophilic excipient.
  • Suitable lipophilic excipients include fatty acid alkyl esters, preferably alkyl esters of C 8 -C 22 fatty acids, more preferably alkyl - 6 - esters of C ⁇ 2 -C, g fatty acids.
  • Lower alkyl esters (lower alkyl as used herein means straight chain or branched chain alkyl containing one to four carbon atoms) such as ethyl oleate, isopropyl pal itate, and isopropyl myristate are preferred.
  • Fatty acid monoglycerides e.g., glycerol monolaurate are also suitable.
  • the formulations of the invention also contain a hydrophilic excipient.
  • the drug used in the formulation has a solubility in this excipient of at least about 200 mg/g, more preferably at least about 300 mg/g, most preferably at least about 350 mg/g.
  • Suitable hydrophilic excipients include polyethylene glycols (e.g. , PEG 400) and esters thereof such as PEG 400 monolaurate, isosorbide ethers such as isosorbide dimethyl ether, and diethylene glycol ethers such as diglyme, diethylene glycol diethyl ether, and diethylene glycol dibutyl ether.
  • the formulations of the invention can contain one or more excipients from each of the above described classes.
  • the hydrophilic excipient can be present in any ratio relative to the lipophilic excipient. It is preferred that the hydrophilic excipient be present in an amount of about 10 to about 1000, parts by weight, preferably about 100 parts by weight, based on 100 parts by weight of the lipophilic excipient.
  • the total excipient (hydrophilic and lipophilic combined) is preferably present in an amount of about 25 to about 5000, more preferably about 50 to about 1000, parts by weight based on 100 parts by weight of the drug. It is generally preferred that a formulation of the invention exhibit a relatively high flux rate, and certain combinations of excipients will be found to be preferable when used in connection with certain drugs.
  • a particularly preferred formulation of the invention involves flurbiprofen as the nonsteroidal antiinflammatory drug and a lipophilic excipient including isopropyl myristate, ethyl oleate, or both, and including dimethyl isosorbide as the hydrophilic excipient.
  • the lipophilic excipient can contain a combination of isopropyl myristate and ethyl oleate in any ratio, preferably in a ratio of about 2:1 to 1:2.
  • the hydrophilic excipient dimethyl isosorbide is preferably present in an amount of about 10 to about 1000 parts by weight, preferably about 100 parts by weight, based on 100 parts by weight of the weight of the lipophilic excipient.
  • the formulations of the invention can be used as solutions containing essentially only the drug, the lipophilic excipient, and the hydrophilic excipient. Preferably they contain further components, such as those that form a matrix for the drug, the lipophilic excipient, and the hydrophilic excipient.
  • a preferred matrix for use in a formulation of the invention is a pressure sensitive adhesive.
  • the pressure sensitive adhesive preferably constitutes from about 60 to about 80 percent by weight based on the total weight of the formulation;
  • the hydrophilic excipient preferably constitutes from 5 to 15 percent by weight based on the total weight of the formulation, the lipophilic excipient preferably constitutes about 5 to 15 percent by weight based on the total weight of the formulation, and the drug preferably constitutes 1 to about 25 percent by weight based on the total weight of the formulation.
  • Suitable pressure sensitive adhesives include acrylic polymers and polyisobutylene pressure sensitive adhesives.
  • Particularly preferred acrylic polymers include acrylic adhesives that contain, as a major constituent (i.e., at least about 80 percent by weight of all monomers in the polymer) , a hydrophobic monomeric acrylic or methacrylic acid ester of an alkyl alcohol, the alkyl alcohol containing 4 to 10 carbon atoms. Examples of suitable monomers are those discussed below in connection with the "A Monomer". - 8 -
  • These adhesives can further contain minor amounts of other monomers such as the "B Monomers” listed below.
  • Preferred adhesives include acrylic pressure sensitive adhesive copolymers containing A and B Monomers as follows: Monomer A is a hydrophobic monomeric acrylic or methacrylic acid ester of an alkyl alcohol, the alkyl alcohol containing 4 to 10 carbon atoms, preferably 6 to 10 carbon atoms, more preferably 6 to 8 carbon atoms, and most preferably 8 carbon atoms. Examples of suitable A Monomers are n-butyl, n- pentyl, n-hexyl, isoheptyl, n-nonyl, n-decyl, isohexyl, 2-ethyloctyl, isooctyl and 2-ethylhexyl acrylates. The most preferred A Monomer is isooctyl aerylate.
  • Monomer B is a reinforcing monomer selected from the group consisting of acrylic acid; methacrylic acid; alkyl acrylates and methacrylates containing 1 to 3 carbon atoms in the alkyl group; acrylamide; methacrylamide; lower alkyl-substituted acrylamides (i.e., the alkyl group containing 1 to 4 carbon atoms) such as tertiary-butyl acrylamide; diacetone acrylamide; n-vinyl-2-pyrrolidone; vinyl ethers such as vinyl tertiary-butyl ether; substituted ethylenes such as derivatives of maleic anhydride, dimethyl itaconate and monoethyl formate and vinyl perfluoro-n-butyrate.
  • acrylic acid methacrylic acid
  • acrylamide methacrylamide
  • the preferred B Monomers are acrylic acid, methacrylic acid, the above described alkyl acrylates and methacrylates, acrylamide, methacrylamide, and the above described lower alkyl substituted acrylamides.
  • the most preferred B Monomer is acrylamide.
  • the pressure sensitive adhesive copolymer containing A and B Monomers as set forth above preferably contains the A Monomer in an amount by weight of about 80 percent to about 98 percent of the total weight of all monomers in the copolymer.
  • the A Monomer is more preferably present in an amount by weight of about 88 percent to about 98 - 9 - percent, and is most preferably present in an amount by weight of about 91 percent to about 98 percent.
  • the B Monomer in such a copolymer is preferably present in the pressure sensitive adhesive copolymer in an amount by weight of about 2 percent to about 20 percent, more preferably about 2 percent to about 12 percent, and most preferably 2 to 9 percent of the total weight of the monomers in the copolymer.
  • the adhesive copolymer comprises about 60 to about 80 percent by weight (and preferably about 70 to about 80 percent by weight) of the above-mentioned hydrophobic monomeric acrylic or methacrylic acid ester of an alkyl alcohol (i.e., Monomer A described above) based on the total weight of all monomers in the copolymer; about 4 to about 9 percent by weight based on the total weight of all monomers in the copolymer of a reinforcing monomer selected from the group consisting of acrylic acid, methacrylic acid, an alkyl aerylate or methacrylate containing 1 to 3 carbon atoms in the alkyl group, acrylamide, methacrylamide, a lower alkyl-substituted acrylamide, diacetone acrylamide and N-vinyl-2- pyrrolidone; and about 15 to about 35 percent by weight (and preferably about 15 to about 25 percent by weight) of vinyl acetate based on the total weight of all monomers in the copoly
  • the preferred acrylic or methacrylic acid ester is isooctyl acrylate and the preferred reinforcing monomer is acrylamide.
  • the above described adhesive copolymers are known, and methods of preparation therefor are well known to those skilled in the art, having been described for example, in U.S. Patent RE 24,906 (Ulrich) , the disclosure of which is incorporated herein by reference.
  • the polymerization reaction can be carried out using a free radical initiator such as an organic peroxide (e.g., benzoylperoxide) or an organic azo compound (e.g., 2,2 '-azobis(2,4-dimethylpentane- nitrile) , available under the trade designation "Vazo 52" from DuPont) .
  • a free radical initiator such as an organic peroxide (e.g., benzoylperoxide) or an organic azo compound (e.g., 2,2 '-azobis(2,4-dimethylpentane- nitrile) , available under the trade designation "Vazo 52" from DuPont) .
  • pressure sensitive adhesives such as those described above are inherently rubbery and tacky and are suitably heat and light stable, there is no need to add tackifiers or stabilizers. However, such can be added if desired.
  • creams, gels, and ointment formulations are suitable.
  • a cream formulation can contain conventional components including emollients (such as long chain alcohols, petrolatum, light mineral oil, or acetylated lanolin) , emulsifiers (e.g., nonionic surfactants such as polysorbate 60 and sorbitan monostearate, aluminum stearate) , thickeners (gums, long chain alcohols such as stearyl alcohol) , and preservatives.
  • emollients such as long chain alcohols, petrolatum, light mineral oil, or acetylated lanolin
  • emulsifiers e.g., nonionic surfactants such as polysorbate 60 and sorbitan monostearate, aluminum stearate
  • thickeners gums, long chain alcohols such as stearyl alcohol
  • An ointment formulation can contain a pharmaceutically acceptable ointment base such as petrolatum, and emollients, emulsifiers, and thickeners. Suitable amounts of the components of such matrices are readily selected by those skilled in the art.
  • a gel, cream, ointment, or solution formulation of the invention can be prepared using conventional methods, combining the drug, the lipophilic excipient, the hydrophilic excipient, and any other components in suitable amounts readily selected by those skilled in the art. It is preferred that the drug remain dissolved in the formulation in order that it is readily released from the formulation to the skin.
  • Adhesive coated sheet materials of the invention can be prepared by combining dry adhesive, drug, and the excipients with a suitable organic solvent (e.g., hexane, heptane, ethyl acetate, ethanol, or methanol, depending upon the particular adhesive used) to afford a coating solution.
  • a suitable organic solvent e.g., hexane, heptane, ethyl acetate, ethanol, or methanol, depending upon the particular adhesive used
  • the total solids content of the solution is preferably in the range of about 15 percent to about 40 percent, and more preferably in the range of about 20 to about 35 percent by weight, based on the total weight of the coating solution.
  • the coating solutions described above are preferably coated onto one surface of a suitable backing of sheet material, such as a film, to form a pressure sensitive adhesive coated sheet material.
  • a pressure sensitive adhesive coated sheet material of the invention can be prepared by knife coating a suitable release liner to a predetermined uniform thickness with a wet adhesive formulation. This adhesive coated release liner is then dried and laminated onto a backing using conventional methods.
  • Suitable release liners include conventional release liners comprising a known sheet material, such as a polyester web, a polyethylene web, or a polystyrene web, or polyethylene-coated paper, coated with a suitable silicone-type coating such as that available under the trade designation Daubert 164Z, from Daubert Co.
  • the backing can be occlusive, non-occlusive or a breathable film as desired.
  • the backing can be any of the conventional materials for pressure sensitive adhesive tapes, such as polyethylene, particularly low density polyethylene, linear low density polyethylene, high density polyethylene, randomly-oriented nylon fibers, polypropylene, ethylene-vinylacetate copolymer, polyurethane, rayon and the like.
  • Backings that are layered, such as polyethylene-aluminum-polyethylene composites are also suitable.
  • the backing should be substantially non-reactive with the ingredients of the formulation.
  • the adhesive coated sheet material of the invention can be made in the form of an article such as a tape, a patch, a sheet, a dressing or any other form known to those skilled in the art. - 12 -
  • a formulation of the invention can be used to treat any condition capable of treatment with a nonsteroidal antiinflammatory drug, e.g., pain and inflammation associated with arthritis and soft tissue injury.
  • the formulation can be incorporated in an appropriate device if necessary or desirable (e.g., in the case of a solution formulation it might be necessary or desirable to use a suitable reservoir device to contain the formulation) .
  • the formulation can then be placed on the skin and allowed to remain for a time sufficient to achieve or maintain the intended therapeutic effect.
  • Drug delivery can be topical such that the drug has a local therapeutic effect or transdermal such that the drug has a systemic effect.
  • mouse skin 20 was mounted epidermal side up between upper portion 21 and lower portion 22 of the cell, which are held together by means of ball joint clamp 23.
  • the portion of the cell below the mounted skin was completely filled with receptor fluid (40% PEG 400 modified Ringer solution) such that the receptor fluid contacted the skin.
  • the receptor fluid was stirred using magnetic stir bar 24 and a magnetic stirrer (not illustrated) .
  • the sampling port 25 was covered except when in use.
  • the formulation was applied to the epidermal (upper) side of the skin to cover in an even layer only the area of the skin that would be in contact with the receptor fluid when the skin is mounted in the diffusion cell.
  • the skin was mounted on the diffusion cell and a 1.77 cm ** patch was applied to the skin and pressed to cause uniform contact to the skin.
  • the formulation was applied to the skin prior to the time the receptor fluid was added to the cell below the skin.
  • the cell was then placed in a constant temperature (32 ⁇ 2°C) chamber. To maintain constant temperature, the chamber utilized a heat exchanger coupled to a constant temperature bath, with a fan to circulate air.
  • the receptor fluid was stirred by means of a magnetic stirring bar throughout the experiment to assure a uniform sample and a reduced diffusion barrier layer on the dermal side of the skin.
  • the receptor fluid was - 14 - replaced at 3, 6, 9, 12, 19, and 24 hours.
  • the withdrawn receptor fluid was analyzed for drug content by conventional high pressure liquid chromatography. This in vitro method is referred to as the hairless mouse skin model.
  • the values stated for skin penetration are the average of 3 independent determinations using a different mouse skin for each determination.
  • Solubility of a representative nonsteroidal antiinflammatory drug, flurbiprofen, in representative hydrophilic excipients was determined by a sequence of quantitative additions of drug to the respective excipient followed by stirring in a test tube for 24 h at 20°C. The data below show the drug content of a saturated solution.
  • a solution formulation of the invention was prepared by saturating a 1:1 mixture of dimethyl isosorbide (a hydrophilic excipient) and isopropyl myristate (a lipophilic excipient) with flurbiprofen.
  • the solution was used in the Hairless Mouse Skin model described above. Three independent determinations gave cumulative drug release amounts of 12.18, 9.66, and 14.53 mg/24h/cm 2 .
  • a solution formulation of the invention was prepared by saturating a 1:1 mixture of dimethyl isosorbide (a hydrophilic excipient) and ethyl oleate (a lipophilic excipient) with flurbiprofen.
  • the solution was used in the Hairless Mouse Skin model - 15 - described above.
  • Three independent determinations gave cumulative drug release amounts of 11.66, 4.77, and 10.43 mg/24h/cm 2 .
  • a formulation of the invention involving an acrylate based pressure sensitive adhesive matrix was prepared by dissolving the excipients (isopropyl myristate, 5.50 g, dimethyl isosorbide, 4.50 g) , the drug [S(+) flurbiprofen, 4.00 g] , and an adhesive [a 93:7 isooctylacrylate:acrylamide polymer (19.33 g) , prepared according to the method set forth in Example 6 of U.S. Pat. No. 4,751,087 (Wick)] in an appropriate solvent (ethyl acetate, 61.68 g, and methanol, 6.85 g) to form a coating solution.
  • an appropriate solvent ethyl acetate, 61.68 g, and methanol, 6.85 g
  • the coating solution was coated out onto a transparent release liner (SCOTCHPAK" * 1022 liner, 3M) at a wet film thickness of 560 ⁇ m.
  • the coating was dried for 2 min at 20°C and then at 45 min at 60°C.
  • the coated release liner was laminated onto a polyethylene foam backing.
  • the resulting device had a drug loading of 1.2 mg/cm 2 .
  • a 1.77 cm 2 sample of the device was tested according to the Hairless Mouse Skin model set forth above.
  • An identical sized sample of a commercially available flurbiprofen device (ADOFEED, Mikasa) having a drug loading of 0.3 mg/cm 2 was also tested.
  • the device of the invention afforded a transdermal flux of 26.4 ⁇ g/cm/h, while the commercial device afforded a transdermal flux rate of 3.3 ⁇ g/cm 2 /h.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Formulations médicamenteuses transdermiques contenant un médicament anti-inflammatoire non stéroïdien, un excipient lipophile et un excipient hydrophile. Le médicament est presque entièrement dissous dans la formulation, les excipients étant miscibles entre eux aux doses utilisées.
EP94914184A 1993-04-22 1994-04-15 Composition transdermique anti-inflammatoire Withdrawn EP0695179A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US5206993A 1993-04-22 1993-04-22
US52069 1993-04-22
PCT/US1994/004156 WO1994023713A1 (fr) 1993-04-22 1994-04-15 Composition transdermique anti-inflammatoire

Publications (1)

Publication Number Publication Date
EP0695179A1 true EP0695179A1 (fr) 1996-02-07

Family

ID=21975248

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94914184A Withdrawn EP0695179A1 (fr) 1993-04-22 1994-04-15 Composition transdermique anti-inflammatoire

Country Status (4)

Country Link
EP (1) EP0695179A1 (fr)
JP (1) JPH08509222A (fr)
AU (1) AU6635294A (fr)
WO (1) WO1994023713A1 (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5702720A (en) * 1995-12-22 1997-12-30 Minnesota Mining And Manufacturing Company Transdermal device for the delivery of flurbiprofen
KR100294084B1 (ko) * 1998-06-02 2001-09-22 성재갑 비-스테로이드성소염진통제의경피흡수투여용조성물및이를포함하는경피흡수투여용제형
DE19834496B4 (de) 1998-07-31 2004-02-26 Beiersdorf Ag Verbesserte Freisetzung von Ibuprofen aus Heißschmelzklebemassen in wirkstoffhaltigen Pflastern durch Zusatz von pharmazeutischen Hilfsstoffen und Verwendung von Hilfsstoffen zur Verbesserung der Freisetzung von Ibuprofen
AU2816700A (en) * 1999-03-01 2000-09-21 Amarin Technologies S.A. Transdermal device comprising non-steroidal anti-inflammatory drugs incorporatedin acrylic adhesive polymer matrix
US6455067B1 (en) * 2000-05-24 2002-09-24 Sang-A Pharmaceutical Co., Ltd. Transdermal patch for nonsteroidal antiinflammatory drug(s)
DE10032537A1 (de) * 2000-07-05 2002-01-31 Labtec Gmbh Dermales System, enthaltend 2-(3-Benzophenyl)Propionsäure
DE10049225A1 (de) * 2000-09-28 2002-04-11 Labtec Gmbh Dermales System, enthaltend Diclofenac
BR0215068A (pt) 2001-12-21 2004-11-09 Coloplast As Dispositivo para cuidar de feridas
DE10212864B4 (de) 2002-03-22 2005-12-22 Beiersdorf Ag Polymermatrizes umfassend ein Mischsystem zur Löslichkeitsvermittlung von pharmazeutischen Wirkstoffen, Verfahren zu deren Herstellung und deren Verwendung
CA2526751A1 (fr) 2003-06-19 2004-12-23 Coloplast A/S Dispositif de soin des plaies
US8563031B2 (en) * 2010-05-27 2013-10-22 Absize, Inc. Piroxicam-containing matrix patches and methods for the topical treatment of acute and chronic pain and inflammation therewith
GB201010954D0 (en) * 2010-06-29 2010-08-11 Edko Pazarlama Tanitim Ticaret Compositions
JP5723823B2 (ja) * 2012-05-02 2015-05-27 帝國製薬株式会社 非ステロイド系消炎鎮痛貼付剤
AU2013370290A1 (en) * 2012-12-28 2015-07-16 Noven Pharmaceuticals, Inc. Compositions and methods for transdermal delivery of non-steroidal anti-inflammatory agents
JP6104222B2 (ja) * 2014-10-28 2017-03-29 帝國製薬株式会社 非ステロイド系消炎鎮痛貼付剤
WO2016135038A1 (fr) * 2015-02-23 2016-09-01 Nitto Denko Corporation Pansement pour plaies

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5855411A (ja) * 1981-09-28 1983-04-01 Nitto Electric Ind Co Ltd 基剤組成物および外用医薬組成物
DE3522550A1 (de) * 1985-06-24 1987-01-02 Klinge Co Chem Pharm Fab Aufspruehbare pharmazeutische zubereitung fuer die topische anwendung
GB8701392D0 (en) * 1987-01-22 1987-02-25 Boots Co Plc Therapeutic agents
US5380927A (en) * 1989-05-16 1995-01-10 Medice Chem.-Pharm. Fabrik Putter Gmbh & Co. Kg Process for preparing optically active 2-aryl-alkanoic acids, in particular 2-aryl-propionic acids

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9423713A1 *

Also Published As

Publication number Publication date
WO1994023713A1 (fr) 1994-10-27
JPH08509222A (ja) 1996-10-01
AU6635294A (en) 1994-11-08

Similar Documents

Publication Publication Date Title
US5223261A (en) Transdermal estradiol delivery system
EP0402407B1 (fr) Systeme d'administration transcutanee d'estradiol
JP2588180B2 (ja) 皮膚浸透ニトログリセリン投薬系
US5380760A (en) Transdermal prostaglandin composition
US4789547A (en) Transdermal matrix system
WO1994023713A1 (fr) Composition transdermique anti-inflammatoire
JP2604097B2 (ja) 皮膚浸透増強剤としてソルビタンエステルを用いた経皮的に薬物を投与するための方法およびシステム
CA2667477C (fr) Administration transdermique de derives polaires de ketoprofene
JP2002510617A (ja) ジクロフェナクの経皮送達用デバイス
KR20090049597A (ko) 첩부제
KR900009084A (ko) 1-이소부틸-1H-이미다조[4,5-c] 퀴놀린-4-아민을 함유하는 국소제제 및 경피 투여시스템
CA2041330C (fr) Preparation d'eperisone ou de tolperisone a absorption percutanee
WO1999062557A1 (fr) Composition destinee a une administration transdermique de medicaments anti-inflammatoires non steroidiens
US5385736A (en) Transdermal melatonin delivery system
JPH01233213A (ja) 貼付剤
JPH01233212A (ja) 貼付剤
JPH0533929B2 (fr)
JPH0753671B2 (ja) 経皮・経粘膜製剤
NZ228533A (en) Adhesive-coated sheet material for transdermal estradiol delivery
KR20070059758A (ko) 비스테로이드성 항염증제와 국소마취제를 포함하는 경피투여 조성물
JPH0344326A (ja) 経皮吸収製剤
EP1043979B1 (fr) Compositions destinees a l'administration transcutanee et cutanee d'agents biologiquement actifs
JPH0344327A (ja) 経皮吸収製剤
HK1006545B (en) Transdermal estradiol delivery system
HK1006545A1 (en) Transdermal estradiol delivery system

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19951117

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): BE CH DE ES FR GB IE IT LI NL SE

17Q First examination report despatched

Effective date: 19980226

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19980709