WO2005042026A1 - 可逆性熱ゲル化水性組成物 - Google Patents
可逆性熱ゲル化水性組成物 Download PDFInfo
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- WO2005042026A1 WO2005042026A1 PCT/JP2004/016500 JP2004016500W WO2005042026A1 WO 2005042026 A1 WO2005042026 A1 WO 2005042026A1 JP 2004016500 W JP2004016500 W JP 2004016500W WO 2005042026 A1 WO2005042026 A1 WO 2005042026A1
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- aqueous composition
- reversible thermogelling
- reversible
- thermogelling aqueous
- composition according
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- 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
- A61K9/0043—Nose
-
- 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
- A61K9/0046—Ear
-
- 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
- A61K9/0048—Eye, e.g. artificial tears
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- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic 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
-
- 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
- A61P37/08—Antiallergic agents
Definitions
- the present invention relates to a reversible thermogelling aqueous composition having a large thixotropic property.
- Japanese Patent No. 2722959 discloses a reversible thermogelling aqueous pharmaceutical composition using methylcellulose which gels at body temperature.
- This composition is easy to administer in liquid form before administration, and gels and increases viscosity at body temperature after administration, improving drug retention at the administration site and improving drug bioavailability (BA).
- BA drug bioavailability
- JP-A-2003-0959924 describes that this reversible thermogelling aqueous pharmaceutical composition is used as an artificial tear.
- This reversible thermogelling aqueous pharmaceutical composition can increase the amount of tears and protect the tear oil layer as compared with conventional artificial tears, and is very effective as artificial tears. It is said that there is.
- the reversible thermogelling aqueous pharmaceutical compositions disclosed in these patent documents are usually assumed to be stored at a low temperature (for example, 1 to 10 ° C.). This is because, when the reversible thermogelling aqueous pharmaceutical composition is stored at room temperature, especially in the summer, the composition gradually gels due to the heat in the room and is easy to administer as a liquid before administration. This is because
- An object of the present invention is to solve the problem of a conventional reversible thermogelling aqueous composition that gels and solidifies at room temperature, making administration difficult, and a reversible thermogelling aqueous composition that can be carried around at room temperature. It is to provide things.
- ⁇ ——.- ⁇ The present invention has been completed based on the finding that the above object can be achieved by adding a substance that increases denaturation to the reversible thermogelling aqueous composition.
- the present invention provides a reversible thermogelling aqueous composition shown below.
- the substance according to the above 1, wherein the substance that increases thixotropic properties is at least one selected from the group consisting of sugar alcohol, lactose, carmellose or a pharmaceutically acceptable salt thereof, and cyclodextrin. Reversible thermogelling aqueous composition.
- thermogelling aqueous composition according to the above 2, wherein the sugar alcohol is mannitol, xylitol or sorbitol.
- thermogelling aqueous composition according to the above item 2, wherein the cyclodextrin is para-cyclodextrin, cyclodextrin, or cyclodextrin.
- thermogelling aqueous composition according to any one of the above 1 to 6, comprising a drug.
- the drug is an antifungal, antibiotic, antiallergic, antiinflammatory, glaucoma, vitamin, immunosuppressant, antidiabetic, amino acid, corneal protectant, corneal epithelial disorder, synthetic antibacterial 8.
- the drug is amphotericin B, fluconazole, miconazole nitrate, colistin .. Sodium methanesulfonate, carpenicillin sodium, genyumycin sulfate, erythromycin, azithromycin, tobramycin, kanamycin, ashizananolast, levocabastine hydrochloride, Ketotipun fumarate, sodium cromoglycate, tranilast, betamethasone phosphate, dexamethasone, hydrocortisone, diclofenac sodium, planoprofen, indomethacin, promufenac sodium, meloxicam, lornoxicam, timololol maleate, punazocine hydrochloride , Layunoprost, Niptidelol, Carteolol hydrochloride, Isopro doluunoprostone, Dorzolamide hydrochloride, Flavin adenine di Creotide, pyridoxal
- thermogelling aqueous composition according to any one of the above items 7 to 9, which is in the form of an injection, an oral preparation, an eardrop, a nasal drop, an eye drop or a liniment.
- the reversible thermogelling aqueous composition according to the above item 10 in the form of eye drops.
- thermogelling aqueous composition according to any one of the above items 1 to 11, which is an artificial tear.
- Thixotropic also called thixotropic
- Thixotropic is a type of abnormal viscosity.
- the gel replaces the fluid sol and returns to the gel when left alone.
- the reversible thermogelling aqueous composition of the present invention gels by heat, it has thixotropy even after gelation, so that shaking gently increases the fluidity of the gel, making it easy to administer to a living body. Will be possible.
- the reversible thermogelling aqueous composition of the present invention administered to a living body easily gels again at its body temperature.
- Examples of the substance that increases the thixotropic property of the reversible thermogelling aqueous composition of the present invention include sugar Alcohol, lactose, carmellose or a pharmaceutically acceptable salt thereof, or cyclodextrin.
- the amount of the substance that increases the thixotropic property of the present invention is not particularly limited as long as the effects of the present invention can be obtained.
- Sugar alcohols preferably include mannitol, 'xylitol or sol' bitol.
- examples of the cyclodextrin include para-cyclodextrin,? -Cyclodextrin, and ⁇ -cyclodextrin.
- Pharmaceutically acceptable salts of carmellose include sodium and potassium salts.
- Particularly preferred substances for increasing denaturation used in the present invention are D-mannitol, D-sorbitol, xylitol and lactose. These substances not only increase the denaturation of the reversible thermogelling aqueous composition, but also have a function of lowering the gelation temperature of the thermogelling aqueous composition.
- the reversible thermogelling aqueous composition of the present invention is liquid in a cold place (for example, 15 ° C or lower) and is desirably gelled at the body temperature of a mammal. Is from about 20 ° C to about 40 ° C; more preferably from 24 to 37 ° C.
- the viscosity of methylcellulose (hereinafter abbreviated as MC) used in the present invention is not particularly limited, but the viscosity of the w / v% aqueous solution at 20 ° C. is preferably in the range of 3 to 12000 millipascal seconds. Is desirable. Any MC within this range can be used alone or as a mixture.
- the content of the methoxyl group is preferably in the range of 26 to 33% from the viewpoint of solubility in water.
- MC is distinguished by the viscosity of its aqueous solution.
- the viscosity of the commercially available product is 4, 15, 25, 100, 400, 1500, or 8000 (the figures indicate the viscosity at 20 ° C of 2 w / v% aqueous solution). MilliPascal's) and are readily available.
- MC having a display viscosity of 4 to 400 is preferable because it is easy to handle.
- MC concentration range of MC used in the composition of the present invention is as follows: If the effect of the present invention is obtained, there is no particular limitation, but preferably 0.2 to 7 w / v. %, More preferably '1-4 w / v%.
- the viscosity of the composition is preferably in a range where it can be easily handled, and when the MC concentration is 0.2 w / v% or more, it is preferable because gelation at body temperature is easy.
- Polyethylene glycol (hereinafter abbreviated as PEG) used as a gelling aid in the composition of the present invention includes PEG-200, -300, -600, -1000, -1540, -2000, -4000, -6000, -2000, -300, -400, -600, -1000 from Wako Pure Chemical Industries, Ltd.
- the weight average molecular weight of PEG used as a gelling aid in the composition of the present invention is not particularly limited, but is preferably from 300 to 50,000, and more preferably from 1,000 to 6,000.
- the weight average molecular weight is 300 or more, a liquid-gel phase transition occurs due to body temperature, and when the weight average molecular weight is 50,000 or less, the viscosity in a liquid state is not excessively high, which is preferable. It is also possible to adjust the weight average molecular weight within the above-mentioned optimal range by mixing two or more PEGs.
- the outline, specifications, uses, amounts used, and trade names of PEG are described in detail in the Pharmaceutical Excipients Dictionary (edited by the Japan Pharmaceutical Excipients Association, published by Yakuji Nippo).
- the content of PEG used as a gelling aid in the composition of the present invention is preferably usually 0.1 to: I3 w / v%, more preferably 1 to 9 w / v. /. It is.
- the composition of the present invention preferably contains oxyacid or a pharmaceutically acceptable salt thereof as another gelling aid.
- the oxalic acid include cunic acid, tartaric acid, malic acid, and lactic acid.
- Examples of the pharmaceutically acceptable salts of oxyacids include sodium salts and potassium salts.
- the content of oxalic acid or a pharmaceutically acceptable salt thereof is usually 0.01 to 7 w / v%, preferably '0.05 to 4 w / v ° / 0 .
- the composition of the present invention preferably contains an amino acid or a pharmaceutically acceptable salt thereof as a gelling aid.
- amino acid used in the present invention include aspartic acid, glutamic acid, histidine, lysine, arginine, glycine, alanine, serine, proline, and methionine.
- pharmaceutically acceptable salt include a hydrochloride, a sulfate, a sodium salt, a potassium salt and the like.
- the content of the amino acid or a pharmaceutically acceptable salt thereof is usually 0.01 to 7 w / v%, preferably 0.05 to 4 w / v. /. It is.
- a preferred embodiment of the present invention comprises: 0.1 to: 10% w / v% increase denaturing agent, 0.2 to 7 w / v% MC, 0.1 to: 13 w / v% PEG and 0.01 to 7 w / v%. It is a reversible thermogelling aqueous composition consisting of 1% oxyacids or amino acids.
- Another preferred embodiment of the present invention is a substance which increases denaturation of 0.1-5 w / v%, 0.2-7% of] ⁇ 1 €! , 0.;! It is a reversible thermogelling aqueous composition comprising 1313 w / v% PEG and 0.05-4 w / v% oxyacid or amino acid.
- Yet another preferred embodiment of the present invention is 0.1-5 w /.
- Reversible thermogelling aqueous solution consisting of 1.0-4.0 w / v% MC, 1-9.0 w / v% PEG and 0.054 w / v% oxyacid or amino acid A composition.
- the reversible thermogelling aqueous composition of the present invention can contain a drug.
- drugs include, for example, antifungal agents such as amphotericin 8, fluconazole, miconazole nitrate, colistin sodium methanesulfonate, carbenicillin sodium, genyumycin sulfate, and ellis mouth.
- Antibiotics such as a, dythromycin, hbramycin, and kanamycin, ash zanolast, repocabastine hydrochloride, ketotifen fumarate, nadolium cromoglycate, and tiger.
- Anti-allergic drugs such as Last, methasone phosphate, methasone, dexamethasone, hydrocortisone, diclofenac sodium, pranoprofen, indomethacin, bromfenac sodium, meloxicam, lornoxicam, and other anti-inflammatory agents, zimolol maleate, bunazosin hydrochloride , Latanoprost, Neptidilol, Carteo mouth hydrochloride, glaucoma treatment drugs such as isopropyl unoprostone, dorzolamide hydrochloride, vitamin drugs such as flavin adenine dinucleotide, pyridoxal phosphate, cyanocobalamin, cyclosporine, evening chlorimus Immunosuppressants such as mycophenolic acid, diabetic drugs such as aminoguanidine, epalles sunset, aminoethyl sulfonate, amino acids, sodium chondroitin sulfate, etc.
- Film protection agents hyaluronan Synthetic antibacterial agents such as sodium lonate for treating corneal epithelial disorders, ciprofloxacin hydrochloride, mefloxacin hydrochloride, ofloxacin, levofloxacin, pazfloxacin tosylate, gatifloxacin, moxifloxacin hydrochloride, mitomycin C
- anti-neoplastic agents such as 5-fluorouracil and adriamycin
- anti-viral agents such as acyclovir, ganciclovir, cidofovir, sorivudine, and trifluoromethyl.
- the amount of these drugs is not particularly limited as long as the concentration is such that the expected drug effect can be obtained.
- the reversible thermogelling aqueous composition of the present invention is usually adjusted to pH 4 to: 10, preferably adjusted to pH 6 to 8.
- various pH adjusting agents Normally added is used.
- the acids include ascorbic acid, hydrochloric acid, gluconic acid, acetic acid, lactic acid, boric acid, phosphoric acid, sulfuric acid, and citric acid.
- the bases include potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, mono'ethanolamine, dienoamine, and triethanolamine.
- the regulator include amino acids such as glycine, histidine, and epsin-amino-cabronic acid.
- a pharmaceutically acceptable isotonic agent such as pudose sugar, propylene glycol, glycerin, sodium chloride, potassium potassium and the like.
- a solubilizing agent such as sodium chloride, potassium potassium and the like.
- a preservative such as sodium chloride, potassium potassium and the like.
- the solubilizer include polysorbate 80 and polyoxyethylene castor oil.
- reversible stones such as Shiridani benzalkonium, benzethonium chloride and chlorhexidine gluconate, methyl parahydroxybenzoate, and parahydroxybenzoate Pills such as pills and butyl para-hydroxybenzoate, alcohols such as chlorobutanol, phenylethyl alcohol and pendyl alcohol, organic acids such as sodium dehydroacetate, sorbic acid and sorbic acid potassium and their salts are used. it can.
- Other additives include hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, propylene glycol, and
- thermogelling aqueous composition of the present invention will be exemplified.
- 'With MC Disperse PEG in more than 70 liters of hot water and cool on ice.
- a substance that increases thixotropicity such as'. Oxyacid or amino acid, a drug, and additives are added and dissolved, and mixed well.
- the pH is adjusted and the solution is added with sterile purified water to prepare the reversible thermogelling aqueous composition of the present invention.
- the reversible thermogelling aqueous composition of the present invention comprises: Since it has large thixotropic properties, it can be liquefied by shaking lightly even at gelation at room temperature, and can be easily administered. However, since the reversible thermogelling aqueous composition of the present invention can be stored at room temperature, there is an advantage that it can be always carried.
- the reversible thermogelling aqueous composition of the present invention can be used as an artificial tear in the form of injections, oral preparations, ear drops, nasal drops, eye drops, coatings, etc. can do.
- the present invention will be described more specifically with reference to Examples.
- Methyl cellulose manufactured by Shin-Etsu Chemical Co., Ltd., Metrolose (registered trademark) SM-4
- Polyethylene glycol manufactured by Nippon Oil & Fats Co., Ltd.
- sodium citrate and substances that increase the thixotropic properties of the present invention were gradually added, and after dissolution, they were mixed uniformly. Further, the pH was adjusted to 7.0 with 1N NaOH or 1N HC1, and then adjusted to a predetermined volume (iOOmL) with sterilized purified water to prepare a reversible thermogelling aqueous composition of the present invention.
- thermogelling aqueous composition for comparison without addition of a substance that increases thixotropic properties was prepared in the same manner.
- Table 1 shows the formulation of the prepared reversible thermogelling aqueous composition, its gelation temperature, and ⁇ denaturation. '
- methylcellulose SM-4
- polyethylene glycol Micro'Gol 4000
- sodium citrate, glycine, D-mannitol, aminoethylsulfonic acid, sodium chondroitin sulfate, and benzalkonium chloride were gradually added in predetermined amounts, and after mixing, they were mixed uniformly.
- the pH was adjusted to 7.4 with 1N HC1, and then adjusted to a predetermined volume (100 mL) with sterile purified water to prepare a reversible thermogelling aqueous composition of the present invention.
- Table 1 shows the formulation of the reversible thermogelling aqueous composition prepared, its gelling temperature, and thixotropic properties.
- Table 2 Gelation temperature and thixotropic properties of the reversible thermogelling aqueous composition of the present invention.
- Methylcellulose (SM-4) and D-man as a substance for increasing the denaturation of the present invention
- comparative reversible thermogelling aqueous compositions without D-mannitol (a substance that promotes thixotropic) were prepared in the same manner.
- the gelling temperature and thixotropic properties of the prepared reversible thermogelling aqueous composition were evaluated.
- Table 3 shows the formulation and gelling temperature of the prepared reversible thermogelling aqueous composition, and ⁇ Degeneration was indicated.
- Table 1 Gelation temperature and ⁇ denaturation of the reversible thermogelling aqueous composition of the present invention
- Example 4 injection), methylcellulose LLG (SM-4), polyethylene glycol (macrogol one Le 4000) of 20g and 15g of D- mannitol were mixed, sterilized purified 800mL heated here to 85 q C Water was added and dispersed by stirring. After confirming uniform dispersion, the mixture was cooled with ice while stirring. After confirming that the whole had become clear, 20 g of sodium citrate and 1 g of levofloxacin were gradually added and, after dissolution, mixed uniformly. Further, the pH was adjusted to 7.4 with 1N HCl, and then adjusted to 100 mL with sterile purified water to prepare a reversible thermogelling aqueous composition of the present invention. ''
- Example 8 oral formulation
- Example 4 The reversible thermogelling aqueous composition of the present invention obtained in Example 4 was
- Example 9 eye drops
- Example 10 artificial tear
- Example 1 (artificial tear)
- thermogelling aqueous composition of the present invention Since the reversible thermogelling aqueous composition of the present invention has a large thixotropic property, even if it is gelled at room temperature, it can easily flow by shaking, so that it is portable at room temperature and makes use of its characteristics. It can be used as artificial tears and in the form of injections, oral preparations, ear drops, nasal drops, eye drops, liniments and the like.
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Abstract
Description
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2005515218A JP4947977B2 (ja) | 2003-10-31 | 2004-11-01 | 可逆性熱ゲル化水性組成物 |
KR1020067008092A KR101144647B1 (ko) | 2003-10-31 | 2004-11-01 | 가역성 열 겔화 수성 조성물 |
EP04799523A EP1681065A4 (en) | 2003-10-31 | 2004-11-01 | WATER-BASED COMPOSITION SUBJECTED TO REVERSIBLE THERMOREGULATION |
US11/414,498 US20060211599A1 (en) | 2003-10-31 | 2006-05-01 | Reversibly heat-gelable aqueous composition |
US13/175,394 US20110263587A1 (en) | 2003-10-31 | 2011-07-01 | Reversibly heat-gelable aqueous composition |
Applications Claiming Priority (2)
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JP2003371572 | 2003-10-31 | ||
JP2003-371572 | 2003-10-31 |
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US11/414,498 Continuation US20060211599A1 (en) | 2003-10-31 | 2006-05-01 | Reversibly heat-gelable aqueous composition |
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WO2005042026A1 true WO2005042026A1 (ja) | 2005-05-12 |
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PCT/JP2004/016500 WO2005042026A1 (ja) | 2003-10-31 | 2004-11-01 | 可逆性熱ゲル化水性組成物 |
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US (2) | US20060211599A1 (ja) |
EP (1) | EP1681065A4 (ja) |
JP (1) | JP4947977B2 (ja) |
KR (1) | KR101144647B1 (ja) |
WO (1) | WO2005042026A1 (ja) |
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JP2008120795A (ja) * | 2006-10-18 | 2008-05-29 | Taisho Pharmaceutical Co Ltd | 粘膜適用液剤 |
WO2008100032A1 (en) * | 2007-02-15 | 2008-08-21 | Choongwae Pharma Corporation | Thixotropic pharmaceutical compositions |
WO2009001899A1 (ja) | 2007-06-26 | 2008-12-31 | Wakamoto Pharmaceutical Co., Ltd. | 水性組成物 |
JP2009515921A (ja) * | 2005-11-17 | 2009-04-16 | ウーアザファルマ アールツナイミッテル ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント カンパニー カーゲー | デクスパンテノール、カルシウムイオン、およびリン酸塩を含まない薬学的組成物、ならびにカルシウムキレート剤および眼科的に適合性の粘性調節剤の使用 |
JP2009263340A (ja) * | 2008-03-31 | 2009-11-12 | Taisho Pharmaceutical Co Ltd | 粘膜適用液剤 |
JP2010143868A (ja) * | 2008-12-19 | 2010-07-01 | Wakamoto Pharmaceut Co Ltd | 化粧料 |
JP2014512387A (ja) * | 2011-04-22 | 2014-05-22 | アルコン リサーチ, リミテッド | 二つの異なる粘性増強剤を有する粘性増強システムを備えた眼科用組成物 |
JP2016525115A (ja) * | 2013-07-17 | 2016-08-22 | ダウ グローバル テクノロジーズ エルエルシー | メチルセルロースを含む粘膜適用組成物 |
US9456980B2 (en) | 2007-08-29 | 2016-10-04 | Wakamoto Pharmaceutical Co., Ltd. | Latanoprost-containing aqueous pharmaceutical composition |
WO2018199180A1 (ja) | 2017-04-25 | 2018-11-01 | わかもと製薬株式会社 | 熱ゲル化人工涙液 |
WO2022065404A1 (ja) * | 2020-09-25 | 2022-03-31 | アステラス製薬株式会社 | 耳内投与用の医薬組成物 |
JP2022163118A (ja) * | 2017-09-14 | 2022-10-25 | 協同乳業株式会社 | 涙液分泌能・涙液安定性を改善するための飲食品または製剤 |
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- 2004-11-01 WO PCT/JP2004/016500 patent/WO2005042026A1/ja active Application Filing
- 2004-11-01 EP EP04799523A patent/EP1681065A4/en not_active Withdrawn
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Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2006004086A1 (ja) * | 2004-07-02 | 2006-01-12 | Wakamoto Pharmaceutical Co., Ltd. | アジスロマイシン含有可逆性熱ゲル化水性組成物 |
JP2009515921A (ja) * | 2005-11-17 | 2009-04-16 | ウーアザファルマ アールツナイミッテル ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント カンパニー カーゲー | デクスパンテノール、カルシウムイオン、およびリン酸塩を含まない薬学的組成物、ならびにカルシウムキレート剤および眼科的に適合性の粘性調節剤の使用 |
JP2008120795A (ja) * | 2006-10-18 | 2008-05-29 | Taisho Pharmaceutical Co Ltd | 粘膜適用液剤 |
WO2008100032A1 (en) * | 2007-02-15 | 2008-08-21 | Choongwae Pharma Corporation | Thixotropic pharmaceutical compositions |
WO2009001899A1 (ja) | 2007-06-26 | 2008-12-31 | Wakamoto Pharmaceutical Co., Ltd. | 水性組成物 |
JP5340149B2 (ja) * | 2007-06-26 | 2013-11-13 | わかもと製薬株式会社 | 水性組成物 |
US9456980B2 (en) | 2007-08-29 | 2016-10-04 | Wakamoto Pharmaceutical Co., Ltd. | Latanoprost-containing aqueous pharmaceutical composition |
JP2009263340A (ja) * | 2008-03-31 | 2009-11-12 | Taisho Pharmaceutical Co Ltd | 粘膜適用液剤 |
JP2010143868A (ja) * | 2008-12-19 | 2010-07-01 | Wakamoto Pharmaceut Co Ltd | 化粧料 |
JP2014512387A (ja) * | 2011-04-22 | 2014-05-22 | アルコン リサーチ, リミテッド | 二つの異なる粘性増強剤を有する粘性増強システムを備えた眼科用組成物 |
JP2016525115A (ja) * | 2013-07-17 | 2016-08-22 | ダウ グローバル テクノロジーズ エルエルシー | メチルセルロースを含む粘膜適用組成物 |
WO2018199180A1 (ja) | 2017-04-25 | 2018-11-01 | わかもと製薬株式会社 | 熱ゲル化人工涙液 |
KR20190110624A (ko) | 2017-04-25 | 2019-09-30 | 와카모토 세이야꾸 가부시끼가이샤 | 열겔화 인공 누액 |
US10532026B2 (en) | 2017-04-25 | 2020-01-14 | Wakamoto Pharmaceutical Co., Ltd. | Thermo-responsive gelling artificial lacrima |
KR20200020999A (ko) | 2017-04-25 | 2020-02-26 | 와카모토 세이야꾸 가부시끼가이샤 | 열겔화 인공 누액 |
US11096889B2 (en) | 2017-04-25 | 2021-08-24 | Wakamoto Pharmaceutical Co., Ltd. | Thermo-responsive gelling artificial lacrima |
JP2022163118A (ja) * | 2017-09-14 | 2022-10-25 | 協同乳業株式会社 | 涙液分泌能・涙液安定性を改善するための飲食品または製剤 |
JP7336105B2 (ja) | 2017-09-14 | 2023-08-31 | 協同乳業株式会社 | 涙液分泌能・涙液安定性を改善するための飲食品または製剤 |
WO2022065404A1 (ja) * | 2020-09-25 | 2022-03-31 | アステラス製薬株式会社 | 耳内投与用の医薬組成物 |
Also Published As
Publication number | Publication date |
---|---|
JPWO2005042026A1 (ja) | 2007-04-26 |
KR20060108628A (ko) | 2006-10-18 |
EP1681065A1 (en) | 2006-07-19 |
US20110263587A1 (en) | 2011-10-27 |
US20060211599A1 (en) | 2006-09-21 |
KR101144647B1 (ko) | 2012-05-08 |
JP4947977B2 (ja) | 2012-06-06 |
EP1681065A4 (en) | 2011-12-28 |
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