WO2005123046A1 - Preparation percutanee et procede de production - Google Patents

Preparation percutanee et procede de production Download PDF

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Publication number
WO2005123046A1
WO2005123046A1 PCT/KR2005/001838 KR2005001838W WO2005123046A1 WO 2005123046 A1 WO2005123046 A1 WO 2005123046A1 KR 2005001838 W KR2005001838 W KR 2005001838W WO 2005123046 A1 WO2005123046 A1 WO 2005123046A1
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WIPO (PCT)
Prior art keywords
transdermal preparation
group
pressure
sensitive adhesive
preparation according
Prior art date
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PCT/KR2005/001838
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English (en)
Inventor
Young Chang Ah
Yang Gyu Choi
Jin Hyuk Choi
Jung Ju Kim
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Amorepacific Corporation
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Publication of WO2005123046A1 publication Critical patent/WO2005123046A1/fr

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    • 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
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids

Definitions

  • the present invention relates to a transdermal preparation comprising a hydrophobic polymeric pressure-sensitive adhesive matrix layer, and a method for producing the transdermal preparation.
  • Transdermal preparations are collectively termed "transdermal preparations". Transdermal preparations developed hitherto other than external preparations in the form of a lotion or cream are largely classified into two groups, i.e.
  • transdermal preparations operated by a passive transfer system and those operated by an active transfer system.
  • active ingredients are delivered depending only on the distribution and diffusion of the active ingredients as a function of concentration.
  • active ingredients are delivered by externally applied physical energies, such as electricity, ultrasonic waves, heat, magnetic field, etc.
  • Transdermal preparations for delivering active ingredients by the passive transfer system are further divided into reservoir type and matrix type in terms of their structure. The reservoir type transdermal preparations are easy to control the permeation rate of active ingredients and to modulate the content of the active ingredients in a broad range according to the compositions present in reservoirs.
  • the matrix type transdermal preparations have a form in which an active ingredient is dissolved or its particles are dispersed in a pressure-sensitive adhesive or a polymeric material.
  • the matrix type transdermal preparations suffer from the disadvantage in that since characteristics of materials constituting an active ingredient-containing matrix have a great influence on the matrix, the active ingredients cannot be contained in high concentrations in the matrix.
  • the matrix type transdermal preparations are advantageous in terms of simple production processes, a small thickness (100 ⁇ 1,000 ⁇ m), and a convenience of use due to their good flexibility. For these reasons, application of the matrix type transdermal preparations to joint sites is particularly advantageous.
  • the matrix type transdermal preparations are subdivided in terms of the following criteria: location of an active ingredient-containing layer, state of the active ingredient contained in the layer, and use of a semi-permeable membrane to modulate the delivery rate of the active ingredient.
  • the present invention provides a matrix type transdermal preparation which delivers an active ingredient through the skin.
  • the production of conventional matrix type transdermal preparations, which deliver active ingredients by the passive transfer system without physical damage to the horny layer (stratum corneum), which is the outermost layer of the skin includes the following techniques.
  • U.S. Patent No. 3,632,740 describes the simplest technique for producing a matrix type transdermal preparation by dissolving an active ingredient in an amount lower than the saturation concentration in an acrylic or rubber-based pressure-sensitive adhesive.
  • 6,211,425 and 5,948,433 disclose techniques for excessively containing an active ingredient scarcely soluble in a pressure-sensitive adhesive by dissolving the active ingredient in a solvent and uniformly mixing the solution with the adhesive. Further, techniques for modulating the delivery rate and content of an active ingredient by mixing polymers having different solubility parameters to the active ingredient are disclosed in U.S. Patent No. 6,235,306, Korean Patent Application No. 2002-7016273, and Korean Patent Nos. 194968 and 0336975. A technique associated with the use of a semi-permeable membrane in order to control the delivery rate of active ingredients is known in U.S. Patent No. 4,201,211. U.S. Patent Nos.
  • U.S. Patent No. 5,164,189 discloses a technique for controlling the diffusion rate of an active ingredient present in a matrix by the use of a diffusion accelerator.
  • Korean Patent Application No. 2001-0019869 suggests a technique for including an active ingredient in polymer nanoparticles and mixing the polymer nanoparticles with a pressure-sensitive adhesive.
  • Korean Patent No. 393478 reports a technique for dispersing liquid regions inside a matrix into the form of droplets.
  • 4,997,656 teaches a technique for forming a matrix capable of stabilizing an active ingredient unstable in water or oil using a heat-sensitive and water-sensitive amphiphilic polymer.
  • the techniques comprising dissolving an active ingredient in a solvent or skin absorption enhancer and mixing the solution with a polymeric material, including a pressure-sensitive adhesive, have disadvantages in that when the solvent or the skin absorption enhancer is used in an excessively large amount, adhesiveness of the transdermal preparations to the skin is greatly deteriorated.
  • the solvent or the skin absorption enhancer is required to be compatible with the polymeric material, an increase in the amount of the active ingredient is restricted and the kind of the pressure-sensitive adhesive used is limited depending on the particular solvent used.
  • a self-emulsifiable surfactant is mixed with an aqueous pressure-sensitive adhesive containing water so that the active ingredient is present in the liquid regions.
  • the technique cannot be applied to the formation of matrixes using organic solvents.
  • the techniques associated with the use of nanoparticles and a semi-permeable membrane for controlling the delivery rate of active ingredients are disadvantageous in terms of complex production processes and an economic burden of high costs.
  • methods for controlling the water content by forming several layers also have the disadvantage of complicated production procedure.
  • the present inventors have conducted extensive research to produce a matrix type transdermal preparation for delivering an active ingredient through the skin that can contain an active ingredient at a high concentration, irrespective of the solubility of the active ingredient, shows superior skin absorption, and can be produced in a simple manner.
  • the present invention relates to transdermal preparation comprising a hydrophobic polymeric pressure-sensitive adhesive matrix layer, and a method for producing transdermal preparation.
  • a transdermal preparation comprising a hydrophobic polymeric pressure-sensitive adhesive matrix layer wherein droplets containing an active ingredient and an alkanolamine are uniformly dispersed in the hydrophobic polymeric pressure-sensitive adhesive matrix layer, the alkanolamine being a liquid material represented by the following formula: R' R 1 — N ⁇ R ⁇ (wherein R , R and R are each independently a C 2 ⁇ 9 alkyl group substituted with one hydroxyl group, or a hydrogen, at least one of R , R and R being C 2 ⁇ 9 alkyl substituted with one hydroxyl group).
  • the matrix layer of the transdermal preparation according to the present invention preferably contains 40-90% by weight of the hydrophobic polymeric pressure-sensitive adhesive, 5-60% by weight of the alkanolamine, and 0.5-25% by weight of the active ingredient, based on the total weight of the matrix layer after formation. It is preferred that the thickness of the matrix layer is between 10 ⁇ m and 120 ⁇ m.
  • hydrophobic polymeric pressure-sensitive adhesive that can be applied to the formation of the matrix layer of the transdermal preparation according to the present invention include acrylic pressure-sensitive adhesives, rubber-based pressure-sensitive adhesives and silicone pressure-sensitive adhesives. These pressure-sensitive adhesives may be used alone or in combination.
  • the acrylic pressure-sensitive adhesive is preferably a polymer prepared from at least one monomer selected from the group consisting of: acrylic monomers having a C ⁇ ._ ⁇ 8 alkyl group, including methylmethacrylate, ethylmethacrylate, propylmethacrylate, butylmethacrylate, pentylmethacrylate, hexylmethacrylate, heptylmethacrylate, octylmethacrylate, nonylmethacrylate, decylmethacrylate, undecylmethacrylate, dodecylmethacrylate and tridecylmethacrylate; and acrylic monomers having an acrylic acid, methacrylic acid or hydroxyl group.
  • acrylic monomers having a C ⁇ ._ ⁇ 8 alkyl group including methylmethacrylate, ethylmethacrylate, propylmethacrylate, butylmethacrylate, pentylmethacrylate, hexylmethacryl
  • the rubber-based pressure-sensitive adhesive is preferably at least one adhesive selected from the group consisting of natural rubbers, styrene copolymers, polyisoprenes and polyisobutylenes.
  • the alkanolamines that can be contained in the matrix layer of the transdermal preparation according to the present invention preferably have a melting point of
  • alkanolamine examples include ethanolamine, diethanolamine, triethanolamine, isopropanolamine, diisopropanolamine and triisopropanolamine. These alkanolamines can be used individually or in combination.
  • Korean Patent No. 0332210 which is the prior art using a composition most similar to that used in the present invention, describes the use of tromethamine as an alkanolamine and dimethylsulfoxide as a dissolution assistant in order to improve the solubility and skin absorption of piroxicam.
  • tromethamine is not a liquid, it cannot be dispersed in the matrix layer of the transdermal preparation according to the present invention and thus droplets are not formed.
  • the active ingredient contained in the matrix layer of the transdermal preparation according to the present invention may be ionic, weakly ionic, or non-ionic.
  • the matrix layer of the transdermal preparation according to the present invention may further include at least one skin absorption enhancer.
  • the skin absorption enhancer is preferably present in an amount of from 0.5 to 15% by weight, based on the total weight of the matrix layer after formation.
  • skin absorption enhancers include, for example: fatty acids, including linoleic acid, oleic acid, palmitic acid, stearic acid, capric acid and myristic acid; polyhydric alcohols, including propyleneglycol, polyethyleneglycol, dipropyleneglycol, diethyleneglycol and glycerol; surfactants, including Tween 80, labrasol and cremophor; fatty acid alcohols, including oleyl alcohol and stearyl alcohol; fatty acid esters, including isopropyl myristate, propyleneglycol caprylate, propyleneglycol laurate and polyethyleneglycol laurate; and fatty acid alkanolamides
  • the matrix layer of the transdermal preparation according to the present invention may further include at least one thickener. It is preferred that the content of the thickener is between 0.5 and 15% by weight, based on the total weight of the matrix layer after formation.
  • thickeners that can be used in the present invention include polyvinylpyrrolidone, polyethyleneoxide, silicon oxides, aluminum oxides and titanium oxides.
  • the transdermal preparation of the present invention may further comprise a backing layer and a release paper, in addition to the matrix layer having self-adhesive force and containing droplets dispersed therein.
  • the transdermal preparation of the present invention may further comprise a tie-layer.
  • the transdermal preparation of the present invention may further comprise a skin-adhesive layer for improving the adhesion to the skin and increasing the attachment maintenance time
  • the backing layer is used to maintain the shape of the transdermal preparation according to the present invention, prevent the active ingredient from being lost, and increase the convenience of use.
  • the backing layer is composed of a water-permeable or water-impermeable film made of at least one material selected from the group consisting of polyolefmes (including polyethylene and polypropylene), polyesters, polyurethanes and aluminum; or a fabric or non- woven fabric made of one or more materials selected from the group consisting of polyolefmes, polyesters, nylons and cottons.
  • the release paper there can be used a paper or polymer film coated with silicone or fluorinated hydrocarbon resin.
  • the skin adhesive layer and the tie-layer that can be included individually and simultaneously in the transdermal preparation of the present invention preferably contain 70-99% by weight of a polymeric pressure-sensitive adhesive and 1—30% by weight of a pressure-sensitive adhesion improver, which is an additive for improving their pressure-sensitive adhesive properties, on a dry weight basis. It is preferred that both the skin adhesive layer and the tie-layer have a thickness of 10 ⁇ m to 100 ⁇ m.
  • polymeric pressure-sensitive adhesives that can be contained in the skin adhesive layer and the tie-layer include acrylic pressure-sensitive adhesives; rubber-based pressure-sensitive adhesives, including natural rubbers, styrene copolymers, polyisoprenes and polyisobutylenes; and silicone pressure-sensitive adhesives, which may be used alone or in combination.
  • Examples of pressure-sensitive adhesion improvers that can be contained in the skin adhesive layer and the tie-layer include fatty acid esters, including isopropyl myristate, propyleneglycol caprylate, propyleneglycol laurate, polyethyleneglycol laurate, propyleneglycol oleate and the like; polyethyleneglycol; polyethyleneglycol- polypropyleneglycol copolymers; polyvinylpyrrolidone; and inorganic fillers, including silicon oxides, aluminum oxides and titanium oxides. These adhesion improvers may be used alone or in combination.
  • a method for producing the transdermal preparation comprising a polymeric pressure- sensitive adhesive matrix layer wherein the matrix layer is formed by preparing a solution-phase mixture containing an active ingredient, a volatile organic solvent, a polymeric pressure-sensitive adhesive soluble in the volatile organic solvent, a polar aprotic organic solvent and an alkanolamine, and removing the volatile organic solvent from the solution-phase mixture to form droplets containing the active ingredient and uniformly dispersed in the matrix layer.
  • the solution-phase mixture contains 0.01—10% by weight of the active ingredient, 5-25% by weight of the polymeric pressure-sensitive adhesive, 20-60%) by weight of the volatile organic solvent, 6-55%) by weight of the polar aprotic organic solvent, and 1 ⁇ 15%> by weight of the alkanolamine.
  • volatile organic solvents examples include hydrocarbons, including hexane, heptane, etc.; alcohols, including methanol, ethanol, propanol, etc.; halogenated hydrocarbons, including methylene chloride, chloromethane, etc.; aromatic hydrocarbons, including benzene, toluene, xylene, etc.; and polar organic solvents, including ethylacetate, acetone, tetrahydrofuran, etc., which have a boiling point of 40-110°C under normal pressure. These organic solvents can be used alone or in combination as a mixture of two or more solvents.
  • Polymeric pressure-sensitive adhesives that can be used to form the matrix layer may be in a state wherein the volatile organic solvent is dissolved.
  • polar aprotic organic solvents that can be used in the present invention include dimethylsulfoxide, dimethylacetamide, dimethylformamide and dimethylisosorbide, which may be used alone or in combination. Of these, solvents having a boiling point higher than 150°C are preferred.
  • the polar aprotic organic solvent preferably has a boiling point exceeding 150°C, it is dried to a considerable extent during drying of the volatile organic solvent because it forms an azeotropic mixture with the polar aprotic organic solvent in the course of the formation of the matrix layer of the transdermal preparation according to the present invention.
  • a portion or none of the polar aprotic organic solvent may be contained in the transdermal preparation of the present invention.
  • the polar aprotic organic solvent contained in the solution-phase mixture for the formation of the matrix layer of the transdermal preparation according to the present invention serves to improve low compatibility between the alkanolamine and the volatile organic solvent as main components for the formation of droplets, thus preventing phase separation of the droplet-forming materials in the solution-phase mixture.
  • the use of the polar aprotic organic solvent allows the solution-phase mixture containing the droplet-forming materials to be uniform, thus facilitating spreading, i.e. coating, of the mixture on a release paper for the formation of the matrix layer.
  • the matrix layer in which droplets are dispersed is formed by mixing the polymeric pressure-sensitive adhesive dissolved in the volatile solvent, the polar aprotic organic solvent, the alkanolamine and the active ingredient (if necessary, a skin absorption enhancer and/or a thickener), coating the mixture on a film, e.g., a release paper, to a given thickness, and removing the volatile organic solvent by solvent evaporation.
  • the droplets dispersed in the matrix layer are formed because the polymeric pressure-sensitive adhesive constituting the matrix layer shows low compatibility with the active ingredient and the alkanolamine, which form droplets. Removal of the organic solvent from the solution-phase mixture for the formation of the matrix layer leaves the pressure-sensitive adhesive and the non-volatile materials.
  • the remaining polymeric pressure-sensitive adhesive causes phase separation because of low compatibility with the active ingredient and the alkanolamine constituting the droplets.
  • the polymeric material forms the shape of the matrix layer.
  • the liquid materials composed of active ingredient and the alkanolamine etc. are dispersed in the polymeric matrix layer while forming fine liquid spheres, i.e. droplets (Fig. 1).
  • the matrix layer in which droplets are dispersed can be easily formed by evaporating the volatile organic solvent, can contain large amounts of a variety of active ingredients, independent of the polarity and dissolution characteristics of the active ingredients, and shows superior skin absorption.
  • the matrix layer can inhibit the liquid materials from soaking, which is a common problem of matrix layers containing liquid materials in large amounts.
  • the matrix layer in which droplets are dispersed is formed, for example, in accordance with the following procedure. First, the active ingredient, the polymeric pressure-sensitive adhesive, the polar aprotic organic solvent, the alkanolamine, and if necessary, other additives are mixed in accordance with the given composition. Thereafter, the mixture is stirred until it becomes a transparent solution. At this time, the polymeric pressure-sensitive adhesive may be purchased as a solution in the volatile organic solvent.
  • the polymeric pressure-sensitive adhesive is purchased in a solid state, it is dissolved in the volatile organic solvent and then the resulting solution is used to form the matrix layer of the transdermal preparation according to the present invention. Air bubbles present in the solution composition are removed by stirring.
  • the degassed composition is coated on a polyethylene terephthalate release paper coated with a silicone polymer in such a manner that the thickness of the resulting structure is maintained constant after drying. After coating, the structure is heated in an oven at 60 ⁇ 90°C for 10-30 minutes to remove the organic solvents, thereby achieving the formation of the matrix layer in which droplets are dispersed.
  • the backing layer is laminated to the matrix layer thereby to complete the production of the transdermal preparation comprising the matrix layer in which droplets are dispersed.
  • the amount of the volatile organic solvent used is preferably in the range of from 20% to 60% by weight, based on the weight of the solution-phase mixture prior to removal of the volatile organic solvent.
  • the optimum content of the volatile organic solvent may vary depending on the composition of the solution-phase mixture.
  • the skin adhesive layer and the tie-layer are formed, for example, by the following procedure. First, the polymeric pressure-sensitive adhesive and additives to improve the adhesive properties are mixed in accordance with the particular composition. Thereafter, the resulting mixture is stirred until it becomes a transparent solution. Air bubbles present in the solution are removed by stirring.
  • the degassed solution is coated on a polyethylene terephthalate release paper coated with a silicone polymer in such a manner that the thickness of the resulting structure is maintained constant after drying. After coating, the structure is heated in an oven at 60 ⁇ 90°C for
  • the skin adhesive layer and the tie-layer can be laminated to the matrix layer in which droplets are dispersed.
  • Transdermal preparations comprising a polyurethane non-woven fabric as a backing layer were evaluated for adhesiveness. After each sample of the transdermal preparations was attached to the forearm and knee of a healthy man, the attachment maintenance force was identified, and at the same time, the attachment force was measured on the sample using an apparatus.
  • the skin absorption of active ingredients in the transdermal preparation was evaluated by measuring the permeation of the active ingredients by an in- vitro skin absorption test using a Franz diffusion cell. An optical microscope was used to observe the state of droplet dispersion.
  • Fig. 1 is an exemplary diagram schematically showing the formation procedure of a matrix layer in which droplets are dispersed: Specifically, 1 represents a state before a volatile solvent is evaporated, i.e. a stable single solution phase, 2 represents a state during drying of the volatile solvent, i.e. a state wherein a liquid phase is separated from a pressure-sensitive adhesive, and 3 represents a state after the volatile solvent is evaporated, i.e. droplets containing an active ingredient are dispersed in a matrix layer; Figs.
  • FIG. 2a to 2c are cross-sectional views of transdermal preparations comprising a matrix layer in which droplets are dispersed (1: backing layer, 2: matrix layer, 3: release paper, 4: tie-layer, and 5: skin adhesive layer): Specifically, Fig. 2a show a transdermal preparation comprising a matrix layer in which droplets are dispersed, Fig.
  • Figs. 2b show a transdermal preparation comprising a matrix layer in which droplets are dispersed and a tie-layer
  • Fig. 2c show a transdermal preparation comprising a matrix layer in which droplets are dispersed, a tie-layer, and a skin adhesive layer
  • Figs. 3a and 3b show an optical micrograph (x 200) of a transdermal preparation produced in Comparative Example 1 and that (x 1,000) of a transdermal preparation produced in Example 3, respectively.
  • Comparative Examples 1 ⁇ 6 An acrylic pressure-sensitive adhesive (87-2074, manufactured by National starch, U.S.A., solid content: 28%, crosslinked type, main solvent: ethylacetate), meloxicam and dimethylsulfoxide were mixed in accordance with the compositions indicated in Table 2, and stirred until the mixtures became uniform solutions. After the solutions were allowed to stand at room temperature, visual examination was conducted to observe crystallization of the active ingredient. Each of the samples in which no crystal was formed were coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not.
  • a polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce transdermal preparations.
  • the transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.
  • Comparative Example 7 28.6g (corresponding to 8g on a dry weight basis) of acrylic pressure-sensitive adhesive (87-2074), 0.5g of meloxicam and 1.5g of diethanolamine were mixed and stirred. Thereafter, it was observed whether or not a crystal of the drug was precipitated and whether or not the phase of the mixture was uniform.
  • Examples 1-4 and Comparative Examples 8 and 9 An acrylic pressure-sensitive adhesive (87-2074), meloxicam, and a solution of dimethylsulfoxide and dimethanolamine (4/1, (w/w)) were mixed in accordance with the compositions indicated in Table 2, and stirred until the mixtures became uniform solutions. After the solutions were allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. Each of the samples in which no crystal was formed was coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non- woven fabric as a backing layer was laminated to the dried coating layer to produce transdermal preparations. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.
  • Examples 5 ⁇ 8 and Comparative Examples 10 and 11 An acrylic pressure-sensitive adhesive (87-2074), meloxicam, and a solution of dimethylsulfoxide, dimethylisosorbide and diethanolamine (3/1/1 (w/w)) were mixed in accordance with the compositions indicated in Table 2, and stirred until the mixtures became uniform solutions. After the solutions were allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. Each of the samples in which no crystal was formed was coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at
  • transdermal preparations An optical microscope was used to observe whether droplets were formed or not.
  • a polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce transdermal preparations.
  • the transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.
  • Examples 12-14 and Comparative Examples 15-17 An acrylic pressure-sensitive adhesive (Gelva 2883, Solutia, U.S.A., non- crosslinked type, main solvent: ethylacetate), meloxicam, and a solution of dimethylsulfoxide, dimethylisosorbide and diethanolamine (2/2/1 (w/w)) were mixed in accordance with the compositions indicated in Table 3, and then ethylacetate was further added to the mixtures such that the total amount of ethylacetate was the same as that in the previous examples using 87-2074 as an pressure-sensitive adhesive. The resulting mixtures were stirred until they became uniform solutions. After the solutions were allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient.
  • an acrylic pressure-sensitive adhesive (Gelva 2883, Solutia, U.S.A., non- crosslinked type, main solvent: ethylacetate), meloxicam, and a solution of dimethylsulfoxide, dimethylisosorb
  • Each of the samples in which no crystal was formed was coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not.
  • a polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce transdermal preparations. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.
  • Example 15 6g of polyisobutylene (Oppanol-BlOO, BASF, U.S.A.) was dissolved in hexane to obtain a solution having a solid content of 10%, and then 0.7g of diethanolamine, 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide and 0.5g of meloxicam were added to the solution. The mixture was stirred until it became a uniform solution. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. Each samples in which no crystal was formed was coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes.
  • polyisobutylene Oppanol-BlOO, BASF, U.S.A.
  • Example 16 1 .1g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2196, National starch, U.S.A., solid content: 35%), non-crosslinked type, main solvent: ethylacetate), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of tulobuterol were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not.
  • an acrylic pressure-sensitive adhesive 87- 2196, National starch, U.S.A., solid content: 35%), non-crosslinked type, main solvent: ethylacetate
  • 1.4g of dimethylsulfoxide 1.4g of dimethyl
  • a polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation.
  • the transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.
  • Example 17 15.8g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2976, National starch, U.S.A., solid content: 38%, non-crosslinked type, main solvent: ethylacetate), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of water-soluble tulobuterol HCl were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes.
  • an acrylic pressure-sensitive adhesive 87- 2976, National starch, U.S.A., solid content: 38%, non-crosslinked type, main solvent: ethylacetate
  • 1.4g of dimethylsulfoxide 1.4g of dimethylisosorbide
  • a polyurethane non- woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation.
  • the transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.
  • Example 18 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87-
  • Example 19 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of tramadol HCl were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.
  • an acrylic pressure-sensitive adhesive 87- 2074
  • dimethylsulfoxide 1.4g of dimethylis
  • Example 20 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of cetirizine were mixed and stirred until the mixture became transparent.
  • the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient.
  • the solution was coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not.
  • a polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.
  • Example 21 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of cetirizine HCl were mixed and stirred until the mixture became transparent.
  • the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient.
  • the solution was coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not.
  • a polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.
  • Example 22 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of oxybutynin were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non- woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation.
  • an acrylic pressure-sensitive adhesive 87- 2074
  • dimethylsulfoxide 1.4g of dimethylisosorbide
  • 0.7g of diethanolamine 0.5g of oxybutynin
  • Example 23 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of lidocaine were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not.
  • a polyurethane non- woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation.
  • the transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.
  • Example 24 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of piroxicam were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non- woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.
  • an acrylic pressure-sensitive adhesive 87- 2074
  • dimethylsulfoxide 1.4g of dimethylisosorbide
  • Example 25 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of ketoprofen were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.
  • an acrylic pressure-sensitive adhesive 87- 2074
  • dimethylsulfoxide 1.4g of dimethylisosorbide
  • Example 26 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87-
  • the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient.
  • the solution was coated on a release paper so as to have a thickness of 60 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not.
  • a polyurethane non- woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation.
  • the transdermal preparation was tested for the content of the drug, in- vitro skin absorption, in-vivo retention, and adhesiveness.
  • Example 27 32 lg (9g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074) and lg of isopropyl myristate were mixed, stirred until the mixture became transparent, coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes to form a skin adhesive layer.
  • the release paper of the transdermal preparation produced in Example 26 was peeled off, and then the skin adhesive layer was laminated thereto to produce a transdermal preparation comprising the skin adhesive layer.
  • the transdermal preparation was tested for in-vitro skin absorption, in-vivo retention, and adhesiveness.
  • Example 28 32 lg (9g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074) and lg of isopropyl myristate were mixed, stirred until the mixture became transparent, coated on a release paper so as to have a thickness of 30 ⁇ m after drying, and dried at 80°C for 20 minutes to form a tie-layer. A polyurethane non-woven fabric as a backing layer was laminated to the tie-layer. After completion of the lamination, the release paper was peeled off. The resulting structure was laminated to a pressure- sensitive adhesive layer formed in the same manner as in Example 26 to produce a transdermal preparation comprising the tie layer. The transdermal preparation was tested for in-vitro skin absorption, in-vivo retention, and adhesiveness.
  • Example 29 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.2g of dimethylsulfoxide, 1.2g of dimethylisosorbide, 0.6g of diethanolamine and 1.5g of piroxicam were mixed and stirred until the mixture became transparent.
  • the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient.
  • the solution was coated on a release paper so as to have a thickness of 60 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not.
  • a polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was tested for the content of the drug, in-vitro skin absorption, in-vivo retention, and adhesiveness.
  • Example 30 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.2g of dimethylsulfoxide, 1.2g of dimethylisosorbide, 0.6g of diethanolamine and 0.5g of ketoprofen were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 60 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was tested for the content of the drug, in-vitro skin absorption, in-vivo retention, and adhesiveness.
  • an acrylic pressure-sensitive adhesive 87- 2074
  • 1.2g of dimethylsulfoxide 1.2g of dimethylisosorbide,
  • Example 31 23.6g (6.6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 5.6g of dimethylsulfoxide, 1.4g of diethanolamine, 0.5g of meloxicam and lg of propyleneglycolmonocaprylate were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 60 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was tested for the content of the drug, in-vitro skin absorption, in-vivo retention, and adhesiveness.
  • Example 32 23.6g (6.6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 5.6g of dimethylsulfoxide, 1.4g of diethanolamine, 0.5g of meloxicam, lg of propyleneglycolmonocaprylate and 0.5g of polyvinylpyrrolidone were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 60 ⁇ m after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not.
  • a polyurethane non- woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation.
  • the transdermal preparation was tested for the content of the drug, in-vitro skin absorption, in-vivo retention, and adhesiveness.
  • the experiment was performed in such a way that the phosphate buffer solution was completely changed with another fresh buffer solution with stirring at 600 rpm at 1, 3, 5, 7, 12 and 24 hours.
  • the content of the active ingredient in the phosphate buffer solution sampled from the receptor was quantitatively analyzed by high performance liquid chromatography (HPLC).
  • Experimental Example 2 Measurement of content of active ingredient The content of active ingredients in the matrix type transdermal preparations was determined by cutting each of the transdermal preparations to a size of 2 x 2 cm 2 , extracting the preparation with 100 ml of methanol, and quantitatively analyzing the extract by high performance liquid chromatography (HPLC).
  • Experimental Example 5 Observation by optical microscopy To confirm the shape and size of droplets dispersed in the matrix layers, the matrix layers were observed using an optical microscope. The shape and size were observed at a magnification of l,000x by an immersion method using cedar oil. The optical micrographs of the transdermal preparations produced in Comparative Example 1 and Example 3 are shown in Figs. 3a and 3b.
  • Experimental Example 6 Adhesiveness test 2 (measurement of 180° peel adhesion) To observe the adhesive force of the matrix type transdermal preparations, 180° peel adhesion was measured using a TA-XT2iHR (manufactured by Stable micro system Co.). A substrate used for the measurement was made of stainless steel (Cheminstrument Co.). The test was conducted under the following measurement conditions. Sample size: 10 cm x 2.5 cm Interval: 10-40 mm Velocity: 2.0 mm/s Temperature: 25°C
  • Experimental Example 7 Stability test Each of the transdermal preparations was cut to a size of 7 x 7 cm 2 , placed in a paper envelope internally coated with aluminum, and sealed. Tests shown in Experimental Examples 3 and 6 were conducted, crystal precipitation of the drugs was observed, and changes in appearance according to the changes in area were evaluated once every two months while the samples were stored at 40°C for 6 months. Table 6 shows the stability test results on the transdermal preparation produced in Example 32.
  • the matrix type transdermal preparation of the present invention can be applied to patches and plasters. Since the transdermal preparation of the present invention comprises a polymeric matrix layer in which droplets containing an active ingredient are uniformly dispersed, it shows superior skin abso ⁇ tion.
  • the transdermal preparation of the present invention can be produced in a simple manner, and can contain an active ingredient at a high concentration, irrespective of the solubility of the active ingredient. Accordingly, the transdermal preparation of the present invention can be applied to a variety of drugs.
  • the present invention provides a method for producing the transdermal preparation.

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Abstract

La présente invention concerne une préparation percutanée comportant une couche matrice auto-adhésive polymère hydrophobe. L'absorption par la peau est d'autant plus importante que le principe actif se présente sous forme de gouttelettes en dispersion uniforme dans une couche matrice polymère intégrée à la préparation percutanée. Cette préparation percutanée présente l'avantage d'être simple à produire et de convenir à des principes actifs très concentrés, quelle qu'en soit la solubilité. De ce fait, l'invention convient à de très nombreux médicaments. L'invention concerne également un procédé de production de cette préparation percutanée.
PCT/KR2005/001838 2004-06-15 2005-06-15 Preparation percutanee et procede de production WO2005123046A1 (fr)

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WO2007049892A1 (fr) 2005-10-24 2007-05-03 Amorepacific Corporation Préparations transdermiques contenant des médicaments anti-inflammatoires non stéroïdiens hydrophobes
WO2008038939A1 (fr) * 2006-09-27 2008-04-03 Industry-Academic Cooperation Foundation, Chosun University Élaboration et composition de système d'administration médicamenteuse transdermique de méloxicam
EP2042174A1 (fr) * 2006-07-14 2009-04-01 Hisamitsu Pharmaceutical Co., Inc. Préparation d'adhésif
WO2009106831A2 (fr) * 2008-02-28 2009-09-03 Syntropharma Limited Composition pharmaceutique
EP2143743A1 (fr) * 2008-07-08 2010-01-13 Akzo Nobel Coatings International B.V. Utilisation de dérivés de dianhydrohexitol dans la préparation de résines
EP2545912A1 (fr) * 2010-03-12 2013-01-16 Teikoku Seiyaku Co., Ltd. Timbre transdermique adhésif aqueux contenant du kétoprofène
US9731490B2 (en) 2008-10-02 2017-08-15 Mylan Inc. Method for making a multilayer adhesive laminate
US9931307B2 (en) 2014-01-22 2018-04-03 Daewoong Pharmaceutical Co., Ltd. Transdermal delivery system comprising donepezil or its salt
JP2018090538A (ja) * 2016-12-05 2018-06-14 王子ホールディングス株式会社 経皮吸収型製剤
US10166199B2 (en) 2013-10-07 2019-01-01 Buzzz Pharmaceuticals Limited Transdermal patch comprising a ropivacaine formulation
CN110441302A (zh) * 2018-05-03 2019-11-12 中国医学科学院药物研究所 一种妥洛特罗透皮贴剂无损质量控制方法
JP2020532558A (ja) * 2017-09-04 2020-11-12 エルテーエス ローマン テラピー−ジステーメ アーゲー 乳化剤を含む経皮送達システム
CN112206222A (zh) * 2018-11-09 2021-01-12 北京德默高科医药技术有限公司 含有布洛芬结构类似物的多层经皮给药系统
US20210251913A1 (en) * 2016-12-28 2021-08-19 Hisamitsu Pharmaceutical Co., Inc. Patch
CN113855651A (zh) * 2021-11-25 2021-12-31 上海健康医学院 一种纳米中草药缓释透皮贴片及其制备方法
US11510882B2 (en) * 2017-09-22 2022-11-29 Medrx Co., Ltd. Non-readherable adhesive patch

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KR100929560B1 (ko) * 2008-01-09 2009-12-03 에코 퍼시픽 엘티디 그라니세트론을 함유한 매트릭스 형태의 경피 흡수제
US20110182949A1 (en) * 2008-05-30 2011-07-28 Jiashang Tang Stabilized transdermal drug delivery system
KR101746204B1 (ko) * 2010-02-18 2017-06-13 에스케이케미칼주식회사 피부 투과가 개선된 톨테로딘의 경피 투여용 조성물
CN103930098B (zh) * 2011-09-22 2017-06-06 株式会社三养生物制药 含有芬太尼及其同族体的经皮吸收制剂

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EP1951211A4 (fr) * 2005-10-24 2010-10-06 Amorepacific Corp Préparations transdermiques contenant des médicaments anti-inflammatoires non stéroïdiens hydrophobes
WO2007049892A1 (fr) 2005-10-24 2007-05-03 Amorepacific Corporation Préparations transdermiques contenant des médicaments anti-inflammatoires non stéroïdiens hydrophobes
EP1951211A1 (fr) * 2005-10-24 2008-08-06 Amorepacific Corporation Préparations transdermiques contenant des médicaments anti-inflammatoires non stéroïdiens hydrophobes
US8728514B2 (en) 2005-10-24 2014-05-20 Pacific Pharmaceutical Co., Ltd. Transdermal preparations containing hydrophoic non-steroidal anti-inflammatory drugs
EP2042174A1 (fr) * 2006-07-14 2009-04-01 Hisamitsu Pharmaceutical Co., Inc. Préparation d'adhésif
US8647664B2 (en) 2006-07-14 2014-02-11 Hisamitsu Pharmaceutical Co., Inc. Adhesive preparation
EP2042174A4 (fr) * 2006-07-14 2012-10-10 Hisamitsu Pharmaceutical Co Préparation d'adhésif
US8968774B2 (en) 2006-09-27 2015-03-03 Industry-Academic Cooperation Foundation, Chosun University Preparation and composition of meloxicam transdermal drug delivery system
EP2068847A4 (fr) * 2006-09-27 2013-03-13 Univ Chosun Iacf Élaboration et composition de système d'administration médicamenteuse transdermique de méloxicam
JP2010504959A (ja) * 2006-09-27 2010-02-18 インダストリー−アカデミック コーポレーション ファンデーション， チョースン ユニバーシティー メロキシカムの経皮薬物送達システムの組成物及びその製造方法
WO2008038939A1 (fr) * 2006-09-27 2008-04-03 Industry-Academic Cooperation Foundation, Chosun University Élaboration et composition de système d'administration médicamenteuse transdermique de méloxicam
EP2068847A1 (fr) * 2006-09-27 2009-06-17 Industry-academic Cooperation Foundation, Chosun University Élaboration et composition de système d'administration médicamenteuse transdermique de méloxicam
US9700552B2 (en) 2008-02-28 2017-07-11 Syntropharma Limited Pharmaceutical compositions for treatment of addiction
WO2009106831A2 (fr) * 2008-02-28 2009-09-03 Syntropharma Limited Composition pharmaceutique
WO2009106831A3 (fr) * 2008-02-28 2009-10-29 Syntropharma Limited Composition pharmaceutique
US10729686B2 (en) 2008-02-28 2020-08-04 Libero Pharma Limited Pharmaceutical compositions
EP2143743A1 (fr) * 2008-07-08 2010-01-13 Akzo Nobel Coatings International B.V. Utilisation de dérivés de dianhydrohexitol dans la préparation de résines
US9731490B2 (en) 2008-10-02 2017-08-15 Mylan Inc. Method for making a multilayer adhesive laminate
US10272656B2 (en) 2008-10-02 2019-04-30 Mylan Inc. Method for making a multilayer adhesive laminate
EP2545912A4 (fr) * 2010-03-12 2013-10-16 Teikoku Seiyaku Kk Timbre transdermique adhésif aqueux contenant du kétoprofène
EP2545912A1 (fr) * 2010-03-12 2013-01-16 Teikoku Seiyaku Co., Ltd. Timbre transdermique adhésif aqueux contenant du kétoprofène
US10166199B2 (en) 2013-10-07 2019-01-01 Buzzz Pharmaceuticals Limited Transdermal patch comprising a ropivacaine formulation
US9931307B2 (en) 2014-01-22 2018-04-03 Daewoong Pharmaceutical Co., Ltd. Transdermal delivery system comprising donepezil or its salt
JP2018090538A (ja) * 2016-12-05 2018-06-14 王子ホールディングス株式会社 経皮吸収型製剤
US20210251913A1 (en) * 2016-12-28 2021-08-19 Hisamitsu Pharmaceutical Co., Inc. Patch
JP2020532558A (ja) * 2017-09-04 2020-11-12 エルテーエス ローマン テラピー−ジステーメ アーゲー 乳化剤を含む経皮送達システム
JP7212676B2 (ja) 2017-09-04 2023-01-25 エルテーエス ローマン テラピー－ジステーメ アーゲー 乳化剤を含む経皮送達システム
US11510882B2 (en) * 2017-09-22 2022-11-29 Medrx Co., Ltd. Non-readherable adhesive patch
CN110441302A (zh) * 2018-05-03 2019-11-12 中国医学科学院药物研究所 一种妥洛特罗透皮贴剂无损质量控制方法
CN112206222A (zh) * 2018-11-09 2021-01-12 北京德默高科医药技术有限公司 含有布洛芬结构类似物的多层经皮给药系统
JP2022507102A (ja) * 2018-11-09 2022-01-18 北京▲徳▼默高科医▲薬▼技▲術▼有限公司 イブプロフェンまたはその構造類似体を含む多層経皮薬物送達システム
EP3900710A4 (fr) * 2018-11-09 2022-10-12 Demotech. Inc. Système d'administration de médicament transdermique multicouche contenant de l'ibuprofène ou un analogue structural associé
JP7354242B2 (ja) 2018-11-09 2023-10-02 北京▲徳▼默高科医▲薬▼技▲術▼有限公司 イブプロフェンまたはその構造類似体を含む多層経皮薬物送達システム
CN113855651A (zh) * 2021-11-25 2021-12-31 上海健康医学院 一种纳米中草药缓释透皮贴片及其制备方法

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