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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F13/00—Bandages or dressings; Absorbent pads
  • A61F2013/00361—Plasters
  • A61F2013/00544—Plasters form or structure
  • A61F2013/00646—Medication patches, e.g. transcutaneous
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F13/00—Bandages or dressings; Absorbent pads
  • A61F2013/00361—Plasters
  • A61F2013/00655—Plasters adhesive
  • A61F2013/00659—Plasters adhesive polymeric base
  • A61F2013/00663—Plasters adhesive polymeric base acrylic

Definitions

• Transdermal drug delivery systems also known as transdermal patches or skin patches, are medicated adhesive patches that are placed on the skin to deliver medication through the skin.
• Transdermal patches deliver medication by percutaneous absorption, which is the absorption of substances through unbroken skin.
• the transdermal patch After a transdermal patch is applied to the skin, the medication contained in the patch passes through, or permeates, the skin and can reach its site of action through a systemic blood flow.
• the transdermal patch may be placed on the desired treatment site such that the medication contained in the patch is delivered topically.
• Ketotifen (4,9-dihydro-4-(1 -methyl-4-piperidinylidene)- 10H- benzocyclohepta[1 ,2-b]thiopen-10-one) is an antihistamine and mast cell stabilizer that is used to treat allergic conjunctivitis, or itchy red eyes caused by allergies.
• ketotifen is provided as a solution of Ketotifen fumarate (brand name solutions include Zaditor from Novartis and Alaway from Bausch and Lomb). Inviduals use solution formulations of Ketotefin fumarate as eye drops to treat allergic symptoms.
• a ketotefin transdermal drug delivery system includes a support layer and a plaster layer provided on the support, wherein the plaster layer contains ketotifen freebase. Also provided are methods of using the transdermal drug delivery systems, e.g., for treatment of ophthalmic diseases. Also provided are kits containing the transdermal drug delivery system for use in the subject methods.
• Figure 1 shows a graph of permeation amount ( ⁇ g/cm 2 ) vs. time (hours) for rat in vitro permeation tests using Example formulations 1 and 2.
• Figure 2 shows a graph of permeation amount ( ⁇ g/cm 2 ) vs. time (hours) for rat in vitro permeation tests of Example formulation 1 of an embodiment of the invention and a comparative example formulation 3.
• plaster and "plaster layer” mean a solid or semi-solid preparation spread on the surface of a support, such as cloth, plastic, or other material, and applied to a skin surface of a subject.
• pressure-sensitive adhesive means an adhesive that forms a bond when pressure is applied to adhere the adhesive with a surface. Typically, no solvent, water, or heat is needed to activate the adhesive.
• degree of bond strength is proportional to the amount of pressure that is used to apply the adhesive to the surface.
• skin surface and “surface of skin” mean the outer surface of the skin, including the skin surfaces of the front surface of the eyelid, such as but not limited to, the skin surfaces of the front surfaces of the upper and lower eyelids, and the skin surfaces of the front surfaces of the upper and lower eyelids and in the vicinity thereof.
• the front surface of the eyelid is covered with the skin, while the rear surface thereof is covered with the conjunctiva.
• a ketotifen transdermal drug delivery system includes a support layer and a plaster layer provided on the support, wherein the plaster layer contains ketotifen freebase. Also provided are methods of using the transdermal drug delivery systems, e.g., for treatment of ophthalmic diseases. Also provided are kits containing the transdermal drug delivery system for use in the subject methods.
• transdermal drug delivery systems are reviewed first in greater detail, followed by a detailed description of embodiments of using the transdermal delivery systems and a review of kits that include the transdermal delivery systems.
• Transdermal delivery systems of the invention are formulations or compositions that are configured to deliver an active agent, specifically ketotefin, to a subject when topically applied to a skin surface of a subject.
• Transdermal drug delivery systems of the invention may have one or more layers.
• the transdermal drug delivery systems may have a support layer and a plaster layer, where the plaster layer is present on the support layer.
• the plaster layer may contain an active agent for ophthalmic diseases.
• the active agent for ophthalmic diseases includes, but is not limited to ketotifen freebase.
• Ketotifen free base has the formula: Ci 9 H 19 NOS and the IUPAC name 4,9-dihydro-4-(1 -methyl-4-piperidinylidene)-10/-/-benzo[4,5]cyclohepta[1 ,2- ⁇ >]thiophen-10-one. Ketotifen is described by the formula:
• compositions are storage stable.
• storage-stable is meant that the compositions may be stored for extended periods of time without significant degradation and/or significant reduction in activity of the ketotifen active agent.
• the subject compositions are stable for 3 years or longer, etc., when maintained at 25 0 C.
• the ratio of the amount of ketotifen freebase in the system to the initial amount of ketotifen freebase in the system after storage at about 60 0 C for at least one month is 92% or more, 93% or more, such as 94% or more, including 95% or more, or greater. In some embodiments, the ratio of the amount of ketotifen freebase in the system to the initial amount of ketotifen freebase in the system is 92% or greater after storage at about 60 0 C for at least one month as determined using the assay protocol reported in the experimental section, below.
• An aspect of the subject delivery systems is that they provide for effective transdermal delivery of ketotifen.
• the permeation amount of ketotifen freebase after about 12 hours is 1 ⁇ g/cm 2 or greater, 2 ⁇ g/cm 2 or greater, such as 3 ⁇ g/cm 2 or greater, including 4 ⁇ g/cm 2 or greater, e.g., 5 ⁇ g/cm 2 or greater, e.g., 10 ⁇ g/cm 2 or greater, etc.
• the permeation amount of ketotifen freebase is 1 ⁇ g/cm 2 or greater after about 12 hours as determined using the assay protocol reported in the experimental section, below.
• the transdermal drug delivery system may be provided in the form of an adhesive tape or an adhesive patch.
• the transdermal drug delivery system may be applied to a skin surface such that the pressure-sensitive adhesive is applied to a skin surface, including an eyelid, by the adhesion of the pressure-sensitive adhesive to the skin surface.
• the transdermal drug delivery system may have a support layer.
• the support layer may be flexible to an extent that it can be brought into close contact with a skin surface including a front surface of an eyelid.
• the support is such that it does not absorb the active agent, and does not allow the active agent to be released from the side of the support.
• the support may include, but is not limited to, non-woven fabrics, woven fabrics, films (including sheets), porous bodies, foamed bodies, paper, composite materials obtained by laminating a film on a non-woven fabric or fabric, and combinations thereof.
• Non-woven fabric may include, but is not limited to, the following: polyolefin resins such as polyethylene and polypropylene; polyester resins such as polyethylene terephthalate, polybutylene terephthalate and polyethylene naphthalate; and besides rayon, polyamide, poly(ester ether), polyurethane, polyacrylic resins, polyvinyl alcohol, styrene-isoprene-styrene copolymers, and styrene-ethylene-propylene-styrene copolymers; and combinations thereof.
• Fabric may include, but is not limited to cotton, rayon, polyacrylic resins, polyester resins, polyvinyl alcohol, and combinations thereof.
• the film may include, but is not limited to the following: polyolefin resins such as polyethylene and polypropylene; polyacrylic resins such as polymethyl methacrylate and polyethyl methacrylate; polyester resins such as polyethylene terephthalate, polybutylene terephthalate and polyethylene naphthalate; and besides cellophane, polyvinyl alcohol, ethylene-vinyl alcohol copolymers, polyvinyl chloride, polystyrene, polyurethane, polyacrylonitrile, fluororesins, styrene-isoprene-styrene copolymers, styrene-butadiene rubber, polybutadiene, ethylene-vinyl acetate copolymers, polyamide, and polysulfone; and combinations thereof.
• polyolefin resins such as polyethylene and polypropylene
• polyacrylic resins such as polymethyl methacrylate and polyethyl methacryl
• the paper may include, but is not limited to, impregnated paper, coated paper, wood free paper, Kraft paper, Japanese paper, glassine paper, synthetic paper, and combinations thereof.
• Composite materials may include, but are not limited to, composite materials obtained by laminating the above-described film on the above-described non-woven fabric or fabric.
• the transdermal drug delivery system that is employed herein may have a plaster layer provided on the support layer.
• the plaster layer includes ketotifen freebase, as described in more detail below.
• the plaster layer is an acrylic pressure-sensitive adhesive layer that includes ketotifen freebase.
• the acrylic pressure-sensitive adhesive is a random copolymer of 2-ethylhexyl acrylate and at least one other monomer, e.g., vinyl acetate, butyl acrylate, t-octyl acrylamide and methyl methacrylate.
• the acrylic pressure-sensitive adhesive is a random copolymer of 2-ethylhexyl acrylate and vinyl acetate.
• the adhesive may have a composition that is substantially the same as the composition of DuroTak ® 87-4098 (National Adhesives, Bridgewater, NJ).
• the term "substantially the same” as used herein refers to a composition that is a copolymer of 2-ethylhexyl acrylate and vinyl acetate and provides for the storage stable functionality as described above.
• the acrylic pressure-sensitive adhesive is DuroTak ® 87-4098.
• DuroTak ® 87-4098 is a random copolymer of 2-ethylhexyl acrylate and vinyl acetate pressure-sensitive adhesive.
• the acrylic pressure-sensitive adhesive is a random copolymer of 2-ethylhexyl acrylate, butyl acrylate, t-octyl acrylamide and methyl methacrylate.
• the adhesive may have a composition that is substantially the same as the composition of DuroTak ® 87-900A (National
• Adhesives Bridgewater, NJ.
• the term "substantially the same” as used herein refers to a composition that is a copolymer of 2-ethylhexyl acrylate, butyl acrylate, t- octyl acrylamide and methyl methacrylate and provides for the storage stable functionality as described above.
• the acrylic pressure- sensitive adhesive is DuroTak ® 87-900A.
• DuroTak ® 87-900A is a random copolymer of 2-ethylhexyl acrylate, butyl acrylate, t-octyl acrylamide and methyl methacrylate pressure-sensitive adhesive.
• the plaster layer may further include a plasticizer.
• the plasticizer may include, but is not limited to liquid paraffin.
• the adhesive layer of a subject transdermal delivery system will, in some embodiments, include in addition to the above-discussed components one or more additional components. Additional components of interest include, but are not limited to, a transdermal absorption enhancer, a preservative (e.g., paraben), an antioxidant, a stabilizing agent, a filling agent that contains a hydrophilic polymer; and a cross-linking agent.
• the plaster layer consists of either DuroTak ® 87-4098 or DuroTak ® 87-900A as the acrylic pressure-sensitive adhesive and ketotifen freebase as the active agent. In certain embodiments, the plaster layer consists of either DuroTak ® 87-4098 or DuroTak ® 87-900A as the acrylic pressure-sensitive adhesive, liquid paraffin as a plasticizer, and ketotifen freebase as the active agent.
• the amount of either DuroTak ® 87-4098 or DuroTak ® 87- 900A in the plaster layer may range from 60 % to 99 % (w/w), such as from 70 % to 98 % (w/w), and including 80 % to 97 % (w/w).
• the amount of liquid paraffin in the plaster layer may range from 0.1 % to 20 % (w/w), such as from 1 % to 8 % (w/w), and including 2 % to 6 % (w/w).
• the amount of ketotifen freebase in the plaster layer may range from 0.5 % to 20 % (w/w), such as from 1 % to 10 % (w/w), and including 2 % to 6 % (w/w).
• the plaster layer may have the following composition: DuroTak ® 87-4098 in an amount of 91 % (w/w); liquid paraffin in an amount of 5% (w/w); and ketotifen freebase in an amount of 4% (w/w).
• the plaster layer may have the following composition: DuroTak ® 87- 900A in an amount of 94% (w/w); and ketotifen freebase in an amount of 4% (w/w).
• the active agent of the subject compositions is ketotifen free base.
• the weight percentage of ketotifen freebase contained in the plaster layer may be in an amount ranging from 0.5 % to 20 % (w/w), such as an amount ranging from 1 % to 10 % (w/w), and including an amount ranging from 2 % to 6 % (w/w).
• the weight percentage of ketotifen freebase contained in the plaster layer is 4% (w/w).
• the ketotifen freebase is stable during storage and does not decompose significantly.
• the ratio of the amount of ketotifen freebase in the transdermal drug delivery system to the initial amount of ketotifen freebase in the system is greater than 93% after storage at about 60 0 C for at least one month.
• the ketotifen freebase for ophthalmic diseases permeates the skin such that an effective amount of ketotifen freebase is delivered.
• the permeation amount of ketotifen freebase is at least 1 ⁇ g/cm 2 after about 12 hours.
• the transdermal drug delivery system is prepared as an adhesive patch or an adhesive tape preparation.
• the transdermal drug delivery system includes a plaster layer, such as a pressure- sensitive adhesive layer, which contains the active agent for ophthalmic diseases.
• the plaster layer is provided on a support layer.
• a releasable liner is provided on the plaster layer. The releasable liner facilitates the protection of the plaster layer. Prior to application onto a skin surface, the releasable liner may be removed, thereby exposing the plaster layer.
• the releasable liner may be prepared by treating one side of polyethylene-coated wood free paper, polyolefin-coated glassine paper, a polyethylene terephthalate (polyester) film, a polypropylene film, or the like with a silicone treatment.
• the transdermal drug delivery system is an adhesive patch preparation that includes a pressure-sensitive adhesive. In these cases, the transdermal drug delivery system may be prepared in accordance with the solvent coating method, or the like.
• the transdermal drug delivery system may be prepared using a pressure-sensitive adhesive tape type preparation making use of an acrylic pressure-sensitive adhesive.
• the thickness of the plaster layer is about 20 to 300 ⁇ m for the pressure-sensitive adhesive type preparation.
• the transdermal drug delivery systems find use in any application where a subject would benefit from being administered ketotifen.
• the systems are employed in the treatment of a condition.
• treatment is meant that at least an amelioration of the symptoms associated with the condition afflicting the subject is achieved, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g., symptom, associated with the condition being treated.
• amelioration also includes situations where the pathological condition, or at least symptoms associated therewith, are completely inhibited, e.g., prevented from happening, or stopped, e.g., terminated, such that the subject no longer suffers from the condition, or at least the symptoms that characterize the condition.
• ketotifen can be used to treat diseases or conditions including, but not limited to allergic conjunctivitis, vernal conjunctivitis, chronic conjunctivitis, pollinosis, and the like.
• Conjunctivitis (commonly called “pink eye”) is an inflammation of the conjunctiva (e.g., the outermost layer of the eye and the inner surface of the eyelids), commonly due to an allergic reaction or an infection (usually bacterial, or viral).
• Pollinosis also known as "allergic rhinitis” and commonly called “hay fever” is an allergic reaction to pollen or other microscopic substances such as dust mites, mold, animal dander, feathers, and the like.
• the transdermal drug delivery system may be used for administering ketotifen to a subject.
• the method includes applying a transdermal drug delivery system, as described herein, to a skin surface of a subject.
• Subjects may include humans or animals, such as but not limited to mice, rats, dogs, rabbits, and the like.
• the method includes applying a transdermal drug delivery system, as described herein, to a skin surface including a front surface of an eyelid to administer the ketotifen freebase in the plaster layer to an ophthalmic topical tissue by percutaneous permeation.
• the transdermal drug delivery system may be used for treatment of ophthalmic diseases by applying the transdermal drug delivery system to a skin surface, including a front surface of an eyelid to transfer an active agent for ophthalmic diseases in a plaster layer to an ophthalmic topical tissue by percutaneous permeation.
• the pressure-sensitive adhesive layer of the transdermal drug delivery system can be directly applied to a skin surface, including an eyelid, by the adhesion of the pressure-sensitive adhesive layer to the skin surface.
• the transdermal drug delivery system is provided as an adhesive patch and is applied to the skin surface including the front surface of the eyelid, whereby the active agent in the plaster layer can be administered by percutaneous permeation to the ophthalmic topical tissue.
• the active agent permeates the skin in contact with the patch to reach an external ophthalmic tissue such as, but not limited to the conjunctiva, lacrimal tissue or cornea.
• the active agent in the plaster layer is administered by percutaneous permeation to the ophthalmic topical tissue without being substantially administered through a systemic blood flow.
• the active agent is administered in such a manner that it is transferred mainly by percutaneous permeation to the external ophthalmic tissue such as, but not limited to the conjunctiva, lacrimal tissue, or cornea from the skin surface, on which the transdermal drug delivery system has been affixed.
• the efficacy of the transdermal drug delivery system is developed through topical application of the active agent, before a part of the active agent reaches the ophthalmic topical tissue through the systemic blood flow. Accordingly, this does not intend to exclude the fact that a part of the active agent for ophthalmic diseases may be delivered to the ophthalmic topical tissue through the systemic blood flow.
• kits include a transdermal drug delivery system that includes a support layer and a plaster layer provided on the support layer, wherein the plaster layer contains ketotifen freebase, as described above.
• kits will further include instructions for practicing the subject methods or means for obtaining the same (e.g., a website URL directing the user to a webpage which provides the instructions), where these instructions may be printed on a substrate, where substrate may be one or more of: a package insert, the packaging, reagent containers and the like.
• substrate may be one or more of: a package insert, the packaging, reagent containers and the like.
• the one or more components are present in the same or different containers, as may be convenient or desirable.
• Ketotifen patch formulations as described in Table 1 below were prepared. For each formulation, a Ketotifen patch was cut to a 2 cm x 2 cm size. The patch was removed from release liner, then placed into a 50-mL volumetric flask. The polyacrylate adhesive was dissolved by adding 5-mL of tetrahydrofuran (THF) and sonicating for 30 minutes. Then, methanol was added and diluted to volume. The obtained solution was cloudy from the precipitated adhesive. An aliquot of the solution was filtered through a 0.45- ⁇ m PTFE filter, then filled into an HPLC vial. The ketotifen concentration in the filtrate was determined by using HPLC.
• THF tetrahydrofuran
• the mobile phase consisted of 0.01 M phosphate buffer (KH 2 PO 4 ) adjusted to pH 8.0 with triethylamine:methanol:acetonitrile (30:15:55, by volume).
• the mobile phase was delivered at a flow rate of 1.0 ml/min through a C-18 column (4.6 mm I.D. ⁇ 15 cm, 5 ⁇ m) at 40 0 C and the detection wavelength was 300 nm.
• Example Formulations 1 and 2 were compared (See FIG. 1 ), as well as Example Formulation 1 and Comparative Example Formulation 3 (See FIG. 2).
• Skin samples were obtained from male Wister rats aging 4 to 6 weeks. After hair was shaven using a mechanical hair clipper, without damaging skin, a patch of skin was excised from the dorsal region of each sacrificed rat. The excised rat skins were used as received. They were placed between the donor and receptor compartments of the cells, with the dermal side in direct contact with the receptor medium.
• Example Formulations 1 and 2 Approximately 10 ml_ of phosphate buffer (pH 7.4) with 20% ethanol was placed in the receptor compartment. Outside the receptor compartment was maintained at 37 0 C by the water jacket connected to the thermostatic water bath. The medium was stirred at 600 rpm throughout the experiment.
• the donor compartment contained 1 1 mg of the sample, i.e., the tape formulations of Example Formulations 1 and 2 reported above and as indicated in FIG. 1 ; or the tape formulations of Example Formulation 1 and Comparative Example Formulation 3 as reported above and indicated in FIG. 2.
• Aliquots (0.3 ml_) were withdrawn at predetermined time intervals and then the same amount of fresh buffer was added to the receptor compartment to replace what had been removed. The drug concentration was analyzed using HPLC. The results are shown in FIGS. 1 and 2. The results shown in these figures illustrate that Example Formulations 1 and 2 exhibited good permeation profiles while Comparative Example Formulation 3 did not.

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• Animal Behavior & Ethology (AREA)
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• 2008
  • 2008-09-23 US US12/236,392 patent/US20090297590A1/en not_active Abandoned
  • 2008-10-08 EP EP08824894.3A patent/EP2296748B1/en not_active Not-in-force
  • 2008-10-08 ES ES08824894.3T patent/ES2458627T3/es active Active
  • 2008-10-08 KR KR1020107029270A patent/KR20110019382A/ko not_active Ceased
  • 2008-10-08 WO PCT/US2008/079211 patent/WO2009145801A1/en not_active Ceased
  • 2008-10-08 CN CN2008801296458A patent/CN102083494B/zh not_active Expired - Fee Related
  • 2008-10-08 JP JP2011511584A patent/JP2011523650A/ja active Pending
  • 2008-10-29 AR ARP080104724A patent/AR070031A1/es unknown
  • 2008-10-30 TW TW097141712A patent/TW200948401A/zh unknown

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