Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers

Definitions

• the present invention relates to a hydrogel formulation for treating wounds comprising water; the active drug or salt thereof; one or more water soluble polymers selected from the group consisting of polyacrylate, polyvinylpyrrolidone, carboxymethyl cellulose, polyhexamethylene biguanide, carageenan, polyethylene oxide, polysaccharide, collagen, gelatin, hyaluronic acid, xanthan gum, acacia gum, guar gum, alginic acid, agar, arabic gum, tragant, karaya gum, pectin and starch, and a salt thereof; and polyols.
• water soluble polymers selected from the group consisting of polyacrylate, polyvinylpyrrolidone, carboxymethyl cellulose, polyhexamethylene biguanide, carageenan, polyethylene oxide, polysaccharide, collagen, gelatin, hyaluronic acid, xanthan gum, acacia gum, guar gum, alginic acid
• Hydrogels are a material used to keep the skin moist in the treatment of burns or regeneration of skin. In order to keep the skin moist, the hydrogels must contain more than 80% moisture.
• Serious burns are treated by autotransplantation or transplantation of tissue cultured in vivo of patient's fibroblast. There is the danger of lesions being infected due to the extended period of time needed for the treatment to be preformed. Infections of the lesions can be prevented by using the hydrogels, which are compatible with blood, body fluid, and living tissue, as a wound dressing to be used during pre-treatment to prevent infections of the lesions.
• the polymers which form the hydrogels should be selected first.
• the polymers must have a three- dimensional network structure so that proper amount of moisture can be contained.
• the polymers comprise a hydrophilic functional group, and therefore, the polymers are not soluble in water while they can absorb water.
• CA 180 622 discloses the formulation comprising gelatin, polyethylene oxide, and polyethylene amine
• DE 28 49 570 discloses the formulation comprising hydrophilic poly(meth-) in the presence of polysaccharide/protein
• DE 30 31 304 discloses the formulation comprising hydrophilic ethylenically unsaturated monomer cross-linked with bifunctional compounds as a base
• EP 0 099 758 discloses the formulation comprising synthesized collagen or alginate and other biopolymers.
• EP 0 262 405 discloses the formulation comprising sodium polyacrylate/polyacrylate/acryloyl amide and derivatives of acrylamide
• EP 0 27 074 discloses the formulation comprising a copolymer of a carboxy group-containing unsaturated oligomer and di- or oligosaccharide
• USP 3,249,109 discloses the formulation comprising gelatin, water, polyalchol and pectin
• USP 4,234,656 discloses the formulation comprising an absorbent, gelatin and water.
• USP 4,930,500 discloses the hydrogel formulation comprising the reaction product of an acrylamide compound, and a bis-functional cross- linking agent, mixed with water and a polyol.
• the traditional hydrogel formulations effect the treatment of the wound by absorbing exudation to provide moist condition, and therefore, there are limitations in directly treating the wound.
• active drugs such as anti-infections and antibiotics
• Representative drugs are fusidic acid and sodium salts thereof. Fusidic acid is a drug used in anti-infections and antibiotics as external preparation, oral medication, or intravenous injection, and is usually used to treat staphylococcus infections as external preparation applied to burns, acne, pyoderma and other trauma cutis.
• Fusidic acid is also used to treat osteomyelitis, sepsis, cystic fibrosis and bronchopneumonia as an antibiotic when taken orally, but oral administration in the form of syrups and tablets can cause hepatopathy, stomach disorders and jaundice. There is also a high possibility of thrombophlebitis from intravenous injections of fusidic acid.
• fusidic acid is used as an external preparation, such as an ointment, the treatment period is shorter compared to that of other topical agents (Rietchie IC, Clinical trials J.3, 529 (1996)).
• External preparations of fusidic acid have excellent effect in treating inflammations, such as furuncles, boils, scabies, etc.
• JP S55-49570 discloses the external dispersing agent comprising cellulose derivatives, an anti-inflammatory agent and anodyne
• KR 0483227, JP Hl-165521 and JP Hl-230514 disclose the external dispersing agent comprising polyvinyl acetate, an anti-inflammatory agent and anodyne.
• these external dispersing agents have problems, such as the ability to form a film, stability, and the properties of these external dispersing agents at forming the film are not specifically described.
• KR 0073354 discloses a controlled release composition in the form of a solution type-poultice
• KR 0104709 discloses the composition comprising water-soluble film forming agents, moisturizer, evaporation accelerator and water, but even though these inventions relate to the anti-inflammatory agent and anodyne, these inventions do not consider the skin stimulation of the compositions.
• the current hydrogels are known to have only the ability to absorb water from the wound, and studies of the function to release ingredients with in the hydrogels into the skin have not advanced. Thus, there are no examples in which the hydrogels are used as a carrier to release the active drugs into the skin.
• the inventors have researched to develop conventional hydrogel formulations or ointments that exhibit superior effect in healing wounds, bacteriocidal action, preventing or inhibiting scarring, wound recovery, etc. for burns, wounds, trauma, decubitus and skin disorders.
• the inventors have confirmed that when an active drug or salt thereof is included or dispersed into the hydrogel formulation prepared by combining water; one or more water soluble polymers selected from the group consisting of polyacrylate, polyvinylpyrrolidone, carboxymethyl cellulose, polyhexamethylene biguanide, carageenan, polyethylene oxide, polysaccharide, collagen, gelatin, hyaluronic acid, xanthan gum, acacia gum, guar gum, alginic acid, agar, arabic gum, tragant, karaya gum, pectin and starch, and a salt thereof; and polyols, the proper moisture condition can be preserved by absorbing exudation, and the ability of the hydrogel in treatment of the wound is improved by the continuous release of the active drug, completing this invention.
• water soluble polymers selected from the group consisting of polyacrylate, polyvinylpyrrolidone, carboxymethyl cellulose, polyhexamethylene biguanide, carageen
• the purpose of the present invention is to provide a hydrogel formulation comprising water; an active drug or salt thereof; one or more water soluble polymers selected from the group consisting of polyacrylate, polyvinylpyrrolidone, carboxymethyl cellulose, polyhexamethylene biguanide, carageenan, polyethylene oxide, polysaccharide, collagen, gelatin, hyaluronic acid, xanthan gum, acacia gum, guar gum, alginic acid, agar, arabic gum, tragant, karaya gum, pectin and starch, and a salt thereof; and polyols, which not only to protect the wound by absorbing exudation, but also maintain stability of the hydrogel formulation while the effect of the active drug is allowed to manifest as the active drug is continuously released directly onto the wound.
• water soluble polymers selected from the group consisting of polyacrylate, polyvinylpyrrolidone, carboxymethyl cellulose, polyhexamethylene biguanide, carageenan
• Fig. 1 is a photo of a solid media on which staphylococcus aureus has been smeared showing the antibacterial activity of the present hydrogel formulation.
• No. 1, 2, 3 and 4, marked on the back side of the plate, refer to the position attached to the hydrogel formulation of Comparative Example 1, Example 1-1, Example 1-3, and Example 1-5, respectively.
• Fig. 2 is a graph showing the change in the wound size in an excision wound rat model after the present hydrogel formulation was attached.
• the hydrogel formulation a, b and c refer to the hydrogel formulation of Example 1-1 , Example 1-3, and Example 1-5, respectively.
• Fig. 3 to 10 are photos showing the change in wound size over time in an excision wound rat model to which the hydrogel formulation of Example 1-5 is attached. More specifically, Fig. 3, 4, 5, 6, 7, 8, 9 and 10 refer to the photo showing the wound size after 0 day, 2 days, 4 days, 6 days, 8 days, 10 days, 12 days and 14 days, respectively.
• Fig. 1 1 to 17 are photos showing the change in wound size over time in an excision wound rat model to which the hydrogel formulation of the comparative Example which does not comprise of an unattached fusidic acid sodium salt. More specifically, Fig. 1 1, 12, 13, 14, 15, 16 and 17 refer to the photo showing the wound size after 0 day, 2 days, 4 days, 6 days, 8 days, 10 days, and 12 days, respectively.
• the present invention relates to a hydrogel formulation for treating wounds comprising i) water; ii) and active drug or salt thereof; iii) one or more water soluble polymers selected from the group consisting of polyacrylate, polyvinylpyrrolidone, carboxymethyl cellulose, polyhexamethylene biguanide, carageenan, polyethylene oxide, polysaccharide, collagen, gelatin, hyaluronic acid, xanthan gum, acacia gum, guar gum, alginic acid, agar, arabic gum, tragant, karaya gum, pectin and starch, and a salt thereof; and iv) polyols.
• the hydrogel formulation of the present invention may comprise the active drug selected from the group consisting of fusidic acid, centella asiatica extra, mupirocin, neomycin, bacitracin, gentamycin, lincomycin, erythromycin, heparin, extratum cepae and allantion, but preferably comprises fusidic acid.
• the active drug or salt thereof should preferably be in a form so that it can be included or dispersed in a water soluble polymer.
• the hydrogel formulation of the present invention may comprise one or more polyols selected from the group consisting of glycerin, prophylene glycol, sorbitol, ethylene glycol, diethylene glycol, polyethylene glycol, polypropylene glycol and 1,3- butylene glycol.
• the weight ratios of water to the active drug to the water soluble polymer to the polyols could be 10-80: 0.01-10: 1-50: 3-60, but preferably 20-70: 0.1-7: 3-30: 5-50, or more preferably 25-65: 0.3-3: 5-20: 10- 45.
• the hydrogel formulation of the present invention may further comprise one or more selected from the group consisting of an absorption enhancing agent, excipient, abirritant, juvantia and pH adjuster.
• the hydrogel formulation of the present invention can be used for healing wounds, bacteriocidal action, preventing or inhibiting scarring, wound recovery, etc. for pyoderma, burns, wounds, trauma, suture-wounds, graft-wounds, decubitus or skin disorders.
• the hydrogel formulation of the present invention can be used in the form of which the hydrogel is placed on sticking plaster or a bandage.
• the present invention provides a hydrogel formulation for treating wounds comprising water; an active drug or salt thereof; one or more water soluble polymers selected from the group consisting of polyacrylate, polyvinylpyrrolidone, carboxymethyl cellulose, polyhexamethylene biguanide, carageenan, polyethylene oxide, polysaccharide, collagen, gelatin, hyaluronic acid, xanthan gum, acacia gum, guar gum, alginic acid, agar, arabic gum, tragant, karaya gum, pectin and starch, and a salt thereof; and polyols.
• water soluble polymers selected from the group consisting of polyacrylate, polyvinylpyrrolidone, carboxymethyl cellulose, polyhexamethylene biguanide, carageenan, polyethylene oxide, polysaccharide, collagen, gelatin, hyaluronic acid, xanthan gum, acacia gum, guar gum, alginic acid,
• any drugs and salt thereof that are effective in the treatment of wounds can be used as the active drug, but preferably, fusidic acid, centella asiatica extra, mupirocin, neomycin, bacitracin, gentamycin, lincomycin, erythromycin, heparin, extratum cepae and allantion should be used. More preferably, fusidic acid salt, or most preferably fusidic acid sodium salt can be used as the active drug.
• the active drug or salt thereof should be in a form which it can be included or dispersed into the water soluble polymer.
• the active drug or salt thereof is released into the skin by absorbing the exudation from the wound.
• the active drug is comprised of the form of its salt, the active drug is released into the skin as a free-drug because the exudation is bound to the salt.
• the content of the active drug should be preferably 0.01 to 10 weight part based on the total amount of the hydrogel formulation, but more preferably 0.1 to 7 weight part, and most preferably 0.3 to 3 weight part. If the content of the active drug is less than 0.01 weight part, the active drug does not have sufficient effect in treatment, and if it exceeds 10 weight part, the active drug is released in a crystal form preventing the hydrogel from being formed.
• one or more of the water soluble polymer which is a base component is selected from the group consisting of polyacrylate, polyvinylpyrrolidone, carboxymethyl cellulose, polyhexamethylene biguanide, carageenan, polyethylene oxide, polysaccharide, collagen, gelatin, hyaluronic acid, xanthan gum, acacia gum, guar gum, alginic acid, agar, arabic gum, tragant, karaya gum, pectin and starch, and a salt thereof.
• the role of the water soluble polymer in the hydrogel is a carrier which allows continuous release of the active drug, and also the component which appropriately absorbs the exudation. Therefore, the bulk corrosion, initial release rate and release rate of the hydrogel formulation of the present invention can be easily controlled.
• polyacrylate or its salt such as polyacrylate sodium salt is preferably used as the water soluble polymer.
• the water soluble polymer can be used as a mixture with the following semi- synthetic polymer or synthetic polymer.
• the semi-synthetic polymer is selected from methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, soluble starch, carboxymethyl starch, dialdehyde starch, etc.
• the synthetic polymer is selected from polyvinyl alcohol, polyvinyl acrylate, copolymer of methyl vinyl ether and maleic anhydride, copolymer of isobutylene and maleic anhydride, copolymer of methacrylic acid and butyl acrylate, copolymer of methoxy ethylene and maleic anhydride, etc.
• the water soluble polymer includes polymers treated by the conventional cross-linking agent or polymerization agent.
• the content of the water soluble polymer should be preferably 1 to 50 weight part based on the total amount of the hydrogel formulation, but more preferably 3 to 30 weight part, and most preferably 5 to 20 weight part.
• Such content and ratio of the water soluble polymer preserves the content of the water in the hydrogel formulation, enhances its stability, and improves adhesion to the skin. Also, such content and ratio prevents the substrate from becoming sticky or stretching out, and reduces pain by preventing the substrate from sticking to the skin when the bandage (dressing) on which the hydrogel is applied is exfoliated.
• the polyols is used as a moisturizer.
• the moisturizer includes glycerin, prophylene glycol, sorbitol, ethylene glycol, diethylene glycol, polyethylene glycol, polypropylene glycol, 1,3-butylene glycol, etc. If necessary, the moisturizer can be a combination of one or more kinds of the moisturizer.
• the content of the moisturizer is preferably 3 to 60 weight part based on the total amount of the hydrogel formulation, but more preferably 5 to 50 weight part, and most preferably 10 to 45 weight part.
• the moisturizer in such content allows the hydrogel formulation to maintain proper moisture condition and continuous cooling condition, and improves the water-volatility of the hydrogel formulation.
• the content of the water which is an essential component of the hydrogel formulation, is preferably 10 to 80 weight part based on the total amount of the hydrogel formulation, but more preferably 20 to 70 weight part, and most preferably 25 to 65 weight part.
• the water in such content improves the stability of the hydrogel formulation.
• oils or surfactants are added to the hydrogel formulation.
• the oils or surfactants include glycerol esters of fatty acids, sorbitan fatty acid ester, propylene glycol esters of fatty acids, propylene glycol monolauryl ethers, monooleate, polyoxyethylene (20EO) sorbitan (trade name: polysorbate 80), polyoxyethylene ("POE"), hydrogenated castor oil, POE sorbitan monolaurate, POE nonylphenyl ether, POE lauryl ether, POE (40) stearate, POE (20) monostearate, lauric acid diethanolamide, sodium lauryl sulfate, lauromacrogol or monostearate polyethyleneglycol, glyceryl monooleate, glyceryl monolauryl
• the content of the surfactant is preferably 0.01 to 10 weight part based on the total amount of the hydrogel formulation, but more preferably 0.1 to 7 weight part, and most preferably 0.3 to 5 weight part.
• the surfactant in such content improves the prolonged effect of the active drug.
• the hydrogel formulation can further comprise an excipient, abirritant, juvantia, pH adjuster, etc.
• the excipient includes a filler such as kaolin, loess, charcoal, titan, talc, bentonite and hydrous aluminum silicate; an antiseptic such as a thymol, methylparaben, benzakonium chloride and ethylparaben; an antioxidant such as an ascorbic acid, stearic acid ester, sodium pyrosulfite, edetate disodium, dibutylhydroxytoluene, butylhydroxyanisole and gallic acid esters; an emulsifier, such as a sorbitan fatty acid ester, glycerin esters of fatty acids, polyethyleneglycol fatty acid ester, polyoxyethylenesorbitan fatty acid ester and polyoxyethylene alkyl ether; a UV absorber, such as a phenyl salicylate, glycol salicylate, para-aminobenzoic acid methyl, 2- hydroxyl-4-methoxy benzophenone, 2,2'-d
• the abirritant includes an antihistamine, such as a diphenhydramine hydrochloride, diphenhydramine tannate, dl- chlorophenylamine maleate, d-chlorophenylamine maleate, and chlorophenylamine maleate; an antiallergic agent or steroid agent such as an amlexanox, evcilast, azelastine, oxatomide, sodium cromoglicate, tazanolast, terfenadine, tolanilast, fumaric acid, ketotifen and lepilinasto; a compound derived from a glycyrrhetinic acid, ⁇ , ⁇ or ⁇ cyclodextrin or cyclodextrin.
• an antihistamine such as a diphenhydramine hydrochloride, diphenhydramine tannate, dl- chlorophenylamine maleate, d-chlorophenylamine maleate, and chlor
• the pH of the hydrogel formulation is adjusted by using an organic acid, such as citric acid, tartaric acid, malic acid and succinic acid, and a water-soluble organic amine, such as diisopropanol amine and diethanolamine as the pH adjuster from pH 4 to 8, but preferably 4.5 to 7, and more preferably 5 to 6.5.
• an organic acid such as citric acid, tartaric acid, malic acid and succinic acid
• a water-soluble organic amine such as diisopropanol amine and diethanolamine
• the content of the pH adjuster can be modified according to the concentration of pH.
• the hydrogel formulation can be prepared as a plaster by applying the hydrogel on materials, for example on a bandage or dressing.
• the materials allow for ventilation and are pliable.
• a porous material will have these properties.
• Porous materials are classified into non-fiber or fiber porous materials.
• the non-fiber porous materials include a membrane filter, foam (foamed polypropylene, foamed polyethylene, foamed polyurethane, etc.), conventional porous film, mesh, etc.
• the fiber porous materials include woven or knit fabric, non-woven fabric, paper, short fiber aggregate, etc.
• the hydrogel formulation can be used as an occlusive moist dressing comprising a wound contacting layer, absorption layer, protective layer and fixed layer which keeps the dressing in place.
• the layer which comes into contact with the wound absorbs the exudation and protects the wound, and the absorption layer stores the exudation absorbed through the wound contacting layer.
• the protective layer transpires the exudation stored in the absorbing layer as moisture, and defends against infiltration of bacteria and other external impurities.
• the fibers composed of non-fiber or fiber porous materials include a natural or chemical fiber, for example cellulosic fiber, cotton, linter, kapok, flax, hemp, ramie, cupra, acetate, vinylon, acrylic, polyethylene terephthalate (polyester) and polypropylene, polyurethane, and mixture thereof.
• a thickness of the fiber may differ depending on the type of the fiber, a thickness of about 0.1 to 5.0 denier is preferable.
• the plaster in which the hydrogel formulation is applied is preferably 5-140cm 2 in area and 0.5-1Og in weight. It is preferable to apply the plaster to the wounded area 1 ⁇ 2 times a day.
• the hydrogel formulation of the present invention is prepared by the following method.
• the water soluble polymer and active drug are uniformly dispersed into the polyols, and then, if necessary, the excipient and other additives are added to prepare a uniform mixture. If necessary, a blend of water (purified water) and the surfactant is added to the mixture.
• the mixture is applied to the base layer by conventional methods, and then, the release-coating material is attached over the base layer to complete the present invention.
• the active drug or salt thereof is in a form that it can be included or dispersed into the water soluble polymer.
• the dispersed form refers to the ingredient is distributed in a liquid as a molecular or ion, and the included form refers to when two molecules form a crystal under the appropriate condition, one molecule forms a steric-network structure, and the other molecule is inserted into the space of the steric-network structure.
• the combination order of the active drug and/or other components in the preparation method is only an example, and is not limited thereby.
• the water soluble polymer and active drug were uniformly dispersed into the polyols, and then, the excipient and other additives were added to prepare a uniform mixture.
• the blend of the excipient and other additives were mixed and the purified water was added to the mixture.
• the mixture was applied to the base layer (dressing or bandage) by conventional methods, and then, the release-coating material was attached over the base layer to complete the present invention.
• Examples 1-1 to 1-6 were prepared using the content and type of water, water soluble polymer, moisturizer, excipient and other additives provided in the following Table 1.
• the contacting layer of the hydrogel formulation prepared by Examples 1-1 to 1- 6 were attached to the mesh of the disk assembly, and then, the reverse side was closed with the beaten silver-tape to perform the dissolution test according to the Paddle Over
• Disk method 500ml of water was added to the vessel as the dissolution medium, and the temperature was set to 32 ⁇ 0.5 ° C , and the paddle was rotated at speed of 50 rpm.
• HPLC High- Performance Liquid Chromatography
• the dissolution rate was less than 1% at 6 hours for both the first and second time. In other words, dissolution almost did not occur.
• the dissolution rate at 24 hours when the hydrogel formulation absorbed the exudation was 20.0 to 30.0%.
• the hydrogel formulation of the present invention comprising fusidic acid sodium salt was attached to the skin, it absorbed the exudation and preserved the moist condition in the early stages and then, released the active drug to the effective concentration by acting as a carrier after the lapse of a certain period of time.
• the solid medium was prepared by mixing 1.5g of Agar bios and 3g of Tryptic Soy Broth with 100ml of water. Staphylococcus aureus was spread on three plates containing the solid medium.
• the hydrogel formulations prepared by Comparative Example 1 refer to the hydrogel formulation in which the components are identical with that of Example 1-1 with the exception of the fusidic acid sodium salt), Examples 1- 1, 1 -3 and 1 -5 were attached to a disk 0.8cm in diameter, and then the disks were attached to the solid medium.
• the solid medium was cultured at 37 ° C for 18-24 hours, and then the area of the inhibition zone in which Staphylococcus aureus did not grow was measured. The results are listed in the following Table 3.
• the hydrogel formulation of the present invention comprising fusidic acid sodium salt showed antibacterial activity against Staphylococcus aureus (Fig. 1).
• the hair on the back of a rat was removed, and the hairless-skin was pierced by using a skin punch 0.8 cm in diameter to prepare the excision wound rat model.
• hydrogel formulations prepared in Examples 1-1, 1-3 and 1-5 were attached to the wound of the rat model once every two days over a period of 14 days, and the Comparative Example 1 which does not comprise the fusidic acid sodium salt, was applied to the wound of the rat model, which is the Control (refers to the Control in Fig. 2).
• Six rat models were used in the individual groups. The effectiveness in treating the wound was measured by the percentage of the reduction of the wound size over 14 days
• the present invention has an improved effect in healing wounds compared to the conventional hydrogel formulations or ointments because the present invention comprises the active drug or salt thereof.
• the present invention can effectively treat a bacterial infection by continuously releasing the active drug, and can absorb the exudation by using the water soluble polymers, such as a polyacrylate.
• the present invention is convenient to use, does not stimulate the skin, and can be easily removed from the skin after use.

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• 2007
  • 2007-01-31 KR KR1020070010093A patent/KR20070080823A/ko not_active Application Discontinuation
• 2008
  • 2008-01-31 WO PCT/KR2008/000595 patent/WO2008094002A1/en active Application Filing

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