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WO2006006799A1 - Systeme d'apport transdermique de ketoprofene avec element auto chauffant - Google Patents

Systeme d'apport transdermique de ketoprofene avec element auto chauffant Download PDF

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Publication number
WO2006006799A1
WO2006006799A1 PCT/KR2005/002196 KR2005002196W WO2006006799A1 WO 2006006799 A1 WO2006006799 A1 WO 2006006799A1 KR 2005002196 W KR2005002196 W KR 2005002196W WO 2006006799 A1 WO2006006799 A1 WO 2006006799A1
Authority
WO
WIPO (PCT)
Prior art keywords
transdermal delivery
ketoprofen
self
delivery system
heating element
Prior art date
Application number
PCT/KR2005/002196
Other languages
English (en)
Inventor
Yong Youn Hwang
Key An Um
Jeong Tae Kim
Joon Gyo Oh
Original Assignee
Sk Chemicals Co., Ltd.
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 Sk Chemicals Co., Ltd. filed Critical Sk Chemicals Co., Ltd.
Publication of WO2006006799A1 publication Critical patent/WO2006006799A1/fr

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Classifications

    • 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
    • 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
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F7/02—Compresses or poultices for effecting heating or cooling
    • A61F7/03—Compresses or poultices for effecting heating or cooling thermophore, i.e. self-heating, e.g. using a chemical reaction
    • A61F7/032—Compresses or poultices for effecting heating or cooling thermophore, i.e. self-heating, e.g. using a chemical reaction using oxygen from the air, e.g. pocket-stoves
    • A61F7/034—Flameless
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • 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
    • 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
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F2007/009—Heating or cooling appliances for medical or therapeutic treatment of the human body with a varying magnetic field acting upon the human body, e.g. an implant therein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents

Definitions

  • the present invention relates to a transdermal delivery system . of ketoprofen, which uses a self-heating element to enhance the skin permeation of ketoprofen.
  • the inventive transdermal delivery system of ketoprofen comprises a transdermal delivery composition applied to the lower surface of the self-heating element.
  • Methods of enhancing the transdermal absorption of drugs generally include physical, biochemical and chemical methods.
  • the physical methods mainly utilize heat, electricity, ultrasonic energy and the like.
  • the biochemical methods mainly use prodrugs, in which case the prodrugs show effects by conversion to their active parent drugs during or after their skin absorption, whereby the modification of the chemical structure is mainly applied for proteinaceous drugs.
  • the chemical methods which are most widely used, involve the formation of complexes and utilize various kinds of substances, surfactants, solvents and fatty acids.
  • a mechanism to enhance the transdermal absorption of drugs is attributable to changes in the thermodynamic properties of drugs or changes in the properties of the skin, particularly a change in the fluidity of lipids in the skin, the interaction between sugar and protein in the skin cells, and the promotion of the delivery of drug to the stratum corneum.
  • various methods are used to enhance the transdermal absorption of drugs, and among them, methods of using absorption enhancers to increase the transdermal absorption of drugs have been most commonly used.
  • the absorption enhancers are excessively used to increase the transdermal absorption of drugs, or patients have chronic diseases and are repeatedly administered with drugs, side effects, such as itching, erythema and skin rash, will frequently occur.
  • Thermal energy used in the present invention has been used for a long time, and recently, its sources are generally in the forms of UV lamps, hydrocolloidal packs, rubber heating cases, electrical heating pads and chemical packs. Also, the thermal energy is used as a means of physical therapy because it has the effects of pain relief, blood circulation improvement, muscle relaxation, fomentation and the like.
  • a mechanism of enhancing transdermal drug delivery using heat increases the skin absorption of a drug not only by increasing the internal energy of particles through a temperature increase in a transdermal drug delivery system so as to increase the diffusion coefficient of the drug and influence the concentration gradient of the drug in the system, but also by enhancing the migration of the drug from the skin to the blood by vasodilation and blood circulation improvement in the skin.
  • the self-heating element according to the present invention which is a kind of chemical pack among the above-described methods of using thermal energy, has oxidizable metal powder contained in an air-permeable sheet, and when brought into contact with air, it will generate heat and maintain a temperature of about 40-80 °C for several hours depending on its application site and use purpose. Accordingly, it will be attached to the skin or clothing so that it will be used either for the purpose of keeping a part of the body warm or for therapeutic purposes, such as pain relief, blood circulation improvement, muscle relaxation and fomentation.
  • FIG. 1 shows the general structure of the self-heating element.
  • the self-heating element has a structure in which an exothermic composition 2 is inserted and sealed in a sheet 3 having pores allowing the passage of air therethrough, and the sheet is inserted in an air-tight packing envelope (not shown), followed by vacuum- sealing.
  • an adhesive composition layer 4 is formed on one side of the sheet 3 so as to allow the self-heating element to adhere to the body or clothing, and a release layer 5 is formed on the adhesive composition layer 4 so as to maintain the adhesion of the adhesive composition layer 4.
  • the packing envelope when the packing envelope is opened, from which the sheet having the exothermic composition 3 included therein is then taken out, air passed through the pores formed in the sheet will be brought into contact with the exothermic composition 2, thus generating heat.
  • the self-heating element be applied directly to the skin for therapeutic purposes, the application of most self-heating products is limited to clothing. This is because when the self-heating element is applied to the skin, the temperature of the application site will increase, so that sweat will be generated and the exothermic composition will harden over the passage of time. Also, even self-heating elements applicable to the skin have a disadvantage in that they will not adhere to the skin for a long time, but will become detached from the skin.
  • adhesive agents for application to the skin are designed to have optimum adhesion at a general skin temperature of about 32 0 C 5 and their adhesion is reduced in inverse proportion to temperature.
  • self-heating elements those which are applied directly to a pain site for therapeutic purposes, such as pain relief, blood circulation improvement, muscle relaxation and fomentation, generally generate heat while maintaining a temperature of 40-45 °C to mitigate the risk of a low- temperature skin burn. Accordingly, if the self-heating element having a skin adhesive applied to the lower surface thereof is attached to the skin, it will not adhere well to the skin but will readily be detached from the skin for the following two reasons.
  • the temperature of the self-heating element will increase to 40-45 0 C 5 resulting in a reduction in the adhesion of the adhesive itself.
  • the heat generation from the self-heating element will cause sweat on the skin.
  • the self-heating element will show too strong adhesion at a skin temperature of about 32 °C after completion of the heat generation, so that upon its removal from the skin, it is liable to cause side effects, such as the removal of epidermal tissue and erythema.
  • Korean patent laid-open publication Nos. 1999-0044351 and 1991-0010137, and US patent Nos. 6146732, 5984995, 5975074, 5879378 and 5366492, disclose various methods for manufacturing self-heating elements.
  • these patents put technical emphasis only on the manufacturing of the self-heating elements, and even if they disclose a self- heating element for direct application to a pain site, which has an adhesive applied to one side thereof, there is no consideration for a change in adhesion as a function of temperature.
  • these patents do not propose a solution to problems occurring when the self-heating elements are actually applied to the skin.
  • Korean patent registration No. 382347 there is an attempt to improve the adhesion of a self-heating element to the skin by improving the structure of the self- heating element.
  • the self-heating element is manufactured by forming a plurality of cells in a sheet, filling and sealing an exothermic composition in the cells, and applying a pressure-sensitive tape to the lower surface of the sheet.
  • Korean patent application No. 2004-11051 discloses a skin adhesive composition suitable for a self-heating element, in which the composition contains a polymethacrylate having an amine functional group.
  • Ketoprofen an anti-inflammatory drug belonging to the propionic acid class, has a shorter half-life in serum than that of other non-steroidal anti-inflammatory drugs and shows excellent effects even at low doses. Also, it shows a relatively high transdermal absorption rate because of its low molecular weight and excellent physical properties, and thus, many kinds of transdermal delivery products containing ketoprofen are now developed. Particularly, many studies on the use of ketoprofen in adhesive matrix-type transdermal patches have been performed, and some of them were successfully commercialized and are now marketed.
  • adhesive matrix-type transdermal patches must show a high skin absorption rate of the drugs at an initial stage and maintain the high skin absorption rate of the drugs over a long period of time.
  • adhesive matrix-type transdermal patch that satisfies such requirements.
  • US patent No. 5,505,956 and Korean patent registration No. 188,180 disclose adhesive matrix-type transdermal patches containing ketoprofen.
  • the transdermal patches disclosed in these patents comprise a multilayer matrix consisting of 2-5 layers having different water absorption capabilities so as to absorb the water generated by the skin, thus inhibiting the induction of skin irritation and the reduction of adhesion.
  • these patents disclose a method of using hexylene glycol as a permeation enhancer.
  • 194,968 discloses a matrix-type patch comprising a water- permeable adhesive layer, a ketoprofen-containing drug layer and a skin adhesive and drug control layer with a drug control structure, in which the patch has a complex laminate structure where the drug layer and the adhesive layer are separated from each other.
  • the patches disclosed in these patents can be manufactured only using a complicated process because they have a multilayer structure consisting of at least two layers. Also, there is still a great need for a method of markedly improving the skin permeation of drugs.
  • the suggested transdermal patches of ketoprofen are all of a simple matrix-type and are disadvantageous in that, when applied to the skin, the skin absorption lag time of the drug at an initial stage will be long and it will be difficult to realize the skin absorption of the drag over a long time.
  • the present inventors have conducted studies to solve the above- described problems occurring in the prior art, and as a result, found that, when a self- heating element having a transdermal delivery composition applied to the lower surface thereof, the composition containing ketoprofen and a polymethacrylate having an amine functional group, is applied to the skin of a human or animal, the self-heating element will show synergistic effects of heat generated from the self-heating element and the suitability of the transdermal delivery composition, so as to increase the initial skin permeation rate of ketoprofen and maintain the skin absorption of the drug over a long period of time, thus showing excellent therapeutic effects, such as pain relief, and it will not show a reduction in its adhesion even due to the sweat generated at its application site, so that it can adhere to the skin for a long time.
  • the present invention has been made.
  • ketoprofen with a self-heating element, which can maintain its adhesion at a constant level for a long time when applied directly to the skin of a human or animal body, thus improving the therapeutic effect of ketoprofen for pain relief.
  • the present invention provides a transdermal delivery system of ketoprofen for application to the skin of a human or animal body, comprising: a self-heating element which will generate heat when exposed to air, the self-heating element being made of a moisture-permeable film or sheet having oxidizable metal powder filled and sealed therein; and a transdermal delivery composition applied to the lower surface of the self-heating element, the transdermal delivery composition comprising a ketoprofen, an adhesive polymer, and a polymethacrylate having an amine functional group.
  • the transdermal delivery system of ketoprofen with the self-heating element comprises the transdermal delivery composition comprising the amine functional group-containing polymethacrylate suitable for the self- heating element.
  • the transdermal delivery system according to the present invention will show synergistic effects resulting from the thermal effect of the self-heating element so as to obtain very rapid skin permeation of ketoprofen at an initial stage and obtain the maximum pharmacological effect of the drug.
  • it can maintain its adhesion at a constant level even during heat generation from the self-heating element and will not show a reduction in its adhesion even due to the sweat generated by the skin as a result of the heat generation, so that it can adhere to the skin for a long time.
  • the inventive transdermal delivery system can overcome the limitations or shortcomings of the prior ketoprofen-containing cataplasma or self-heating element alone.
  • FIG. 1 is a cross-sectional view showing one embodiment of a self-heating element applicable for a transdermal delivery system of ketoprofen according to the present invention.
  • FIG. 2 is a cross-sectional view showing another embodiment of a self-heating element applicable for a transdermal delivery system of ketoprofen according to the present invention.
  • FIG. 3 is a perspective view of the self-heating element shown hi FIG. 2.
  • FIG. 4 shows pharmacokinetic graphs of the inventive transdermal delivery system of ketoprofen in animal tests.
  • FIG. 5 shows pharmacokinetic graphs of the inventive transdermal delivery system of ketoprofen in human tests. * Description of the elements in the drawings
  • FIGS. 1 and 2 are cross-sectional views showing self-heating elements applicable for the transdermal delivery system of ketoprofen according to the present invention
  • the transdermal delivery system 1 according to the present invention comprises a self-heating element having the exothermic composition 2 filled and sealed therein, and the skin adhesive composition 4 applied to the lower surface of the self- heating element.
  • the skin adhesive composition 4 is a transdermal delivery composition containing ketoprofen.
  • the transdermal delivery composition containing ketoprofen comprises ketoprofen as a pharmacologically active ingredient, an adhesive polymer, and a polymethacrylate having an amine functional group, and optionally, a transdermal absorption enhancer and conventional additives.
  • Ketoprofen as a pharmacologically active ingredient is preferably contained in the transdermal delivery composition in an amount of 0.1-30% by weight. If too little ketoprofen is used, it will have no therapeutic effect, and if it is used in excessive amounts, a further increase in its therapeutic effect cannot be expected because it will remain in a crystalline state in the transdermal delivery composition and result in side effects, such as a reduction in a permeation effect, a reduction in adhesion, and skin irritation.
  • the adhesive polymer in the transdermal delivery composition according to the present invention is a medical pressure-sensitive adhesive (PSA) which can be made of water-based or organic solvent-based substances, and preferably, one or two or more selected from acrylic adhesives, such as acrylate polymer and vinylacetate-acrylate copolymer, polyisobutylene, polystyrene and polybutadiene, and copolymers thereof, such as synthetic rubbers, natural rubbers and silicon-based adhesives.
  • PSA medical pressure-sensitive adhesive
  • acrylic adhesives such as acrylate polymer and vinylacetate-acrylate copolymer, polyisobutylene, polystyrene and polybutadiene, and copolymers thereof, such as synthetic rubbers, natural rubbers and silicon-based adhesives.
  • the adhesive polymer is preferably contained in the transdermal delivery composition in an amount of 30-90% by weight.
  • the polymethacrylate having an amine functional group is a fully polymerized copolymer of methacrylic acid and acrylic ester or methacrylic ester (USPNF), which has an amine functional group. It is preferable to use a polymethacrylate which is pharmaceutically acceptable and is selected depending on the kind of general adhesive polymer and the preparation method of the transdermal delivery composition.
  • the polymethacrylate is preferably contained in the transdermal composition in an amount of 0.5-20% by weight. If too little polymethacrylate is used, the transdermal delivery system will not maintain constant adhesion at a temperature of 30-45 °C and cannot resist sweat. If the polymethacrylate is used in excessive amounts, the transdermal delivery system will show a reduction in adhesion to the skin, a reduction in the release rate of ketoprofen, leading to a reduction in the skin absorption of the drug, and the viscosity of the transdermal delivery composition will be excessively increased, thus making the preparation of the composition difficult.
  • the transdermal absorption enhancer is an optional component for enhancing the skin permeation of ketoprofen, and examples thereof include those conventionally used in the art, such as fatty acids, for example, oleic acid, linoleic acid, laurylic acid, palmitic acid, stearic acid, capric acid and myristic acid, fatty alcohols, for example, oleyl alcohol and lauryl alcohol, and fatty esters, for example, isopropyl myristate, propylene glycol monolaurate, polyethylene glycol laurate, and propylene glycol oleate.
  • fatty acids for example, oleic acid, linoleic acid, laurylic acid, palmitic acid, stearic acid, capric acid and myristic acid
  • fatty alcohols for example, oleyl alcohol and lauryl alcohol
  • fatty esters for example, isopropyl myristate, propylene glycol monolaurate, polyethylene glycol la
  • the transdermal absorption enhancer is contained in the transdermal delivery composition in an amount of 0.01-20% by weight. If the transdermal absorption enhancer is used in an amount of less than 0.01% by weight, it will have little or no effect, and if it is used in an amount of more than 20% by weight, it will cause skin side effects and reduce adhesion to the skin.
  • the self-heating element according to the present invention is provided in a form where an envelope having a structure made to allow air to pass through a single or both sides thereof has been filled with an exothermic composition containing oxidizable metal powder and has been sealed at the opening.
  • the envelope, having a structure made to allow the passage of air is in the form of a moisture-permeable film or sheet which can be made of one or more selected from the group consisting of paper, woven fabric, non-woven fabric, natural or synthetic rubber, PET, PP, PVC, PU, PS, PC, PETG, EVOH, PE and nylon.
  • the moisture-permeable film or sheet has a unit weight of 20-200 g/m , and preferably 30-150 g/m , and a moisture permeability of 100-2,000 g/m 2 -24hr, and preferably 300-1,000 g/m 2 -24hr, in order to prevent a low-temperature burn of the skin upon application to the skin.
  • Methods of imparting air-permeability to the moisture-permeable film or sheet include a method of forming air-permeable pores by drawing air upon the forming of the film or sheet, a method of forming air-permeable holes by extracting specific components from the film or sheet, and a method of mechanically forming air-permeable pores by punching or perforation with fine needles after the formation of the film.
  • the moisture- permeable film or sheet thus formed is filled with an exothermic composition containing oxidizable metal powder, followed by sealing, thus preparing a self-heating element.
  • the components of the exothermic composition containing oxidizable metal powder the components of all compositions used in the prior art can be used.
  • the exothermic composition may comprise, for example, 5-20 parts by weight, based on 100 parts by weight of oxidizable metal powder, of activated carbon, 1.5-10 parts by weight of inorganic electrolyte, and 25-60 parts by weight of water.
  • the oxidizable metal powder include iron powder, zinc powder and aluminum powder. Iron powder is generally used, and preferred examples thereof include reduced iron powder, ground iron powder and electrolytic iron powder.
  • the powders in the exothermic composition generally have a particle size of less than 60 meshes, and preferably, more than 50% of the powders have a particle size of less than 100 meshes.
  • the exothermic composition may comprise water retention agents, such as perlite powder, vermiculite and aqueous resin, hydrogen generation inhibitors, anticaking agents and the like.
  • a manufacturing method of the transdermal delivery system according to the present invention will be described by way of an example.
  • ketoprofen, a transdermal absorption enhancer, polymethacrylate, etc are uniformly mixed with an adhesive polymer solution.
  • the mixture is applied on release paper, and if necessary, dried, thus preparing the transdermal delivery composition 4 containing ketoprofen.
  • the exothermic composition 2 containing oxidizable metal powder, activated carbon, inorganic electrolyte, a water retention agent and water is filled and sealed in an envelope made of the moisture-permeable film or sheet 3, thus preparing the self-heating element 1.
  • the prepared transdermal delivery composition containing ketoprofen is transferred to the lower surface of the self-heating element and cut into a suitable size, thus manufacturing a transdermal delivery system attachable to the skin.
  • the time taken for the blood concentration of ketoprofen to reach 50 ng/ml is less than 3 hours. This indicates that the transdermal delivery system of ketoprofen comprising the self-heating element allows very rapid initial skin permeation of ketoprofen as a result of synergistic effects of heat generated from the self-heating element and the suitability of the transdermal delivery composition.
  • the transdermal delivery system can ensure the maximum pharmacological effect of the drug by a synergistic effect resulting from the thermal effect of the self-heating element, hi addition, the transdermal delivery system can maintain its skin adhesion at a constant level even during the heat generation from the self-heating element, and will not show a reduction in skin adhesion even due to the sweat generated from its application site, so that it can adhere to the skin for a long time.
  • Example 2 50% by weight of iron powder, 10% by weight of activated carbon, 8% by weight of diatomaceous earth, 5% by weight of wood flour and 2% by weight of sodium chloride were weighed and mixed well with each other. To the mixture, 25% by weight of water was added, thus preparing an exothermic composition. Then, an air-permeable sheet (Korea Vilene Co., Ltd.; air permeability: 450 ⁇ 50 g/m 2 -24h), which has been compressed into the structure described in Example 2 of Korean patent registration No. 382347, was filled with the prepared exothermic composition and sealed on four sides. This yielded a self-heating element which, when brought into contact with air, will generate heat.
  • Example 1 50% by weight of iron powder, 10% by weight of activated carbon, 8% by weight of diatomaceous earth, 5% by weight of wood flour and 2% by weight of sodium chloride were weighed and mixed well with each other. To the mixture, 25% by weight of water was added, thus preparing an exothermic composition. The
  • Example 2 10.0% (dry weight) of polymethacrylate (Eudragit ElOO) powder was mixed with an acrylic adhesive polymer solution (Monsanto Co., Gelva 1753). To the mixture, a solution of 10.0% (dry weight) of ketoprofen dissolved in ethyl acetate was added and mixed uniformly. The mixture solution was applied on release paper to a thickness of 350 ⁇ m and dried at 90 °C for 5 minutes, thus preparing a skin adhesive composition. The prepared composition was transferred to the lower surface of the self-heating element prepared in Preparation Example 1. The resulting structure was cut into a suitable size, vacuum- packaged, and stored.
  • Example 3 10.0% (dry weight) of polymethacrylate (Eudragit ElOO) powder was mixed with an acrylic adhesive polymer solution (Monsanto Co., Gelva 1753). To the mixture, a solution of 20.0% (dry weight) of ketoprofen dissolved in ethyl acetate and 7% by weight of oleic acid were added and mixed uniformly. The mixture solution was applied on release paper to a thickness of 350 ⁇ m and dried at 90 °C for 5 minutes, thus preparing a transdermal delivery composition. The prepared composition was transferred to the lower surface of the self-heating element prepared in Preparation Example 1. The resulting structure was cut into a suitable size, vacuum-packaged, and stored.
  • Example 4 Example 4
  • Example 5 13.0% (dry weight) of polymethacrylate (Eudragit ElOO) powder was mixed with an acrylic adhesive polymer solution (Monsanto Co., Gelva 1753). To the mixture, a solution of 20.0% (dry weight) of ketoprofen dissolved in ethyl acetate and 7% by weight of oleyl alcohol were added and mixed uniformly. The mixture solution was applied on release paper to a thickness of 350 ⁇ m and dried at 90 0 C for 5 minutes, thus preparing a transdermal delivery composition. The prepared composition was transferred to the lower surface of the self-heating element prepared in Preparation Example 2. The resulting structure was cut into a suitable size, vacuum-packaged, and stored.
  • Example 6 5.0% (dry weight) of polymethacrylate (Eudragit EPO) powder was mixed with an acrylic adhesive polymer solution (Monsanto Co., Gelva 1753). To the mixture, a solution of 20.0% (dry weight) of ketoprofen dissolved in ethyl acetate, and 3% by weight of propylene glycol dilaurate, were added and mixed uniformly. The mixture solution was applied on release paper to a thickness of 350 ⁇ m and dried at 90 °C for 5 minutes, thus preparing a transdermal delivery composition. The prepared composition was transferred to the lower surface of the self-heating element prepared in Example 2. The resulting structure was cut into a suitable size, vacuum-packaged, and stored.
  • Example 7 Example 7
  • Comparative Example 1 A solution of 20% (dry weight) of ketoprofen dissolved in ethyl acetate, and 3% by weight of propylene glycol dilaurate, were added and mixed uniformly with an acrylic adhesive polymer solution (Monsanto Co., Gelva 1753). The mixture solution was applied on release paper to a thickness of 350 ⁇ m and dried at 90 °C for 5 minutes, thus preparing a transdermal delivery composition. The prepared composition was transferred to the lower surface of the self-heating element prepared in Preparation Example 1. The resulting structure was cut into a suitable size, vacuum-packaged, and stored.
  • Example 2-6 Each of the transdermal delivery system of ketoprofen prepared in Example 2-6 and Comparative Example 1 was applied to the skin of the abdominal region, and the time taken for each of 25% and 50% of the application area to be detached from the skin was measured. The results are shown in Table 1 below. As can be seen in Table 1, the systems of Examples 2-6 comprising the skin adhesive composition containing polymethacrylate bound to the self-heating element could adhere to the skin for a longer time than the system of Comparative Example 1. (Table 1)
  • Comparative Example 1 in such a manner that each of them contains 30 mg of ketoprofen.
  • the manufactured transdermal delivery systems were applied to rabbits (NZW; male; 2.6 kg + 0.14 kg), and the blood concentration of ketoprofen in the rabbits was measured.
  • each of the transdermal delivery systems was applied to the back region of a rabbit, and a blood sample was collected from each of the animals for 8 hours.
  • Each of the test groups consisted of 5 rabbits.
  • the collected blood sample was centrifuged to isolate plasma.
  • the analysis of the plasma sample was performed by high performance liquid chromatography (HPLC), and the results are shown in Table 2 below and in FIG. 4. As can be seen in Table 2 and FIG.
  • Example 6 which has a self-heating element, was much higher in the initial transdermal absorption rate of ketoprofen than the transdermal delivery system of Comparative Example 1, which has no self-heating element. Also, Example 6 was at least two times higher in the AUC 0->8hr (absorption up to 8 hours) and Cmax (maximum plasma concentration) of ketoprofen than was Comparative Example 1. (Table 2)
  • Transdermal delivery systems were manufactured according to Example 6 and Comparative Example 1 in such a manner that each of them contains 30 mg of ketoprofen.
  • the manufactured transdermal delivery systems were applied to persons with arthritis pain or muscular pain, and the blood concentration of ketoprofen and the time required to reduce pain were measured.
  • one sheet of each of the transdermal delivery systems was applied to the upper arm of each person, and blood was collected from each person for 12 hours. The time to notice a reduction in pain as compared to an initial stage was recorded as the time required to reduce pain.
  • Each of the test groups consisted of 12 persons, and the collected blood sample was centrifuged to isolate plasma. The analysis of the collected plasma sample was performed by high performance liquid chromatography (HPLC), and the results are shown in Table 3 below and in FIG.
  • the transdermal delivery system of Example 6 was much higher in the transdermal absorption rate of ketoprofen at an initial stage than the transdermal delivery system of Comparative Example 1. Also, the transdermal delivery system of Example 6 was at least two times higher in the AUCo ->8hr (absorption up to 8 hours) and C max (maximum plasma concentration) of ketoprofen than those for Comparative Example 1. Also, as can be seen from the results of the pain reduction time measured in this test, a reduction in arthritis pain or muscular pain was felt at a blood ketoprofen concentration of about 50 ng/ml. In addition, the transdermal delivery system of Example 6 showed pain relief in a much shorter time than that of Comparative Example 1. (Table 3)

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Abstract

La présente invention concerne un système d'apport transdermique de kétoprofène avec un élément auto chauffant. Plus particulièrement, ce système d'apport transdermique comprend une composition d'apport transdermique contenant un kétoprofène appliqué à l'élément auto chauffant. Lorsque ce système d'apport transdermique est appliqué sur la peau, il présentera un effet synergique que résultant de l'effet thermique de l'élément auto chauffant de façon à permettre la perméation de la peau du kétoprofène d'être effectuée très rapidement à une étape initiale et à permettre d'obtenir un effet pharmacologique maximum du kétoprofène. Par ailleurs, il peut maintenir son adhérence à un niveau constant même lors de la génération de chaleur de l'élément auto chauffant et ne montrera pas de réduction de son adhérence même à cause de la sueur générée sur la peau résultant de la chaleur, de sorte qu'il peut adhérer à la peau pendant longtemps
PCT/KR2005/002196 2004-07-09 2005-07-08 Systeme d'apport transdermique de ketoprofene avec element auto chauffant WO2006006799A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2545912A4 (fr) * 2010-03-12 2013-10-16 Teikoku Seiyaku Kk Timbre transdermique adhésif aqueux contenant du kétoprofène

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993007842A1 (fr) * 1991-10-15 1993-04-29 Cygnus Therapeutic Systems Amelioration par voie thermique de l'administration percutanee de medicaments
WO1997036968A1 (fr) * 1996-03-29 1997-10-09 The Procter & Gamble Company Cellules chauffantes
WO2002064151A1 (fr) * 2001-02-09 2002-08-22 Physician's Choice Of Arizona, Inc. Traitement des acrochordons

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993007842A1 (fr) * 1991-10-15 1993-04-29 Cygnus Therapeutic Systems Amelioration par voie thermique de l'administration percutanee de medicaments
WO1997036968A1 (fr) * 1996-03-29 1997-10-09 The Procter & Gamble Company Cellules chauffantes
WO2002064151A1 (fr) * 2001-02-09 2002-08-22 Physician's Choice Of Arizona, Inc. Traitement des acrochordons

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2545912A4 (fr) * 2010-03-12 2013-10-16 Teikoku Seiyaku Kk Timbre transdermique adhésif aqueux contenant du kétoprofène

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