WO2004026953A1 - Compositions aqueuses transparentes et a thermogelification reversible - Google Patents

Compositions aqueuses transparentes et a thermogelification reversible Download PDF

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Publication number
WO2004026953A1
WO2004026953A1 PCT/JP2003/011928 JP0311928W WO2004026953A1 WO 2004026953 A1 WO2004026953 A1 WO 2004026953A1 JP 0311928 W JP0311928 W JP 0311928W WO 2004026953 A1 WO2004026953 A1 WO 2004026953A1
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WO
WIPO (PCT)
Prior art keywords
aqueous composition
pharmaceutically acceptable
composition according
reversible thermogelling
acid
Prior art date
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PCT/JP2003/011928
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English (en)
Japanese (ja)
Inventor
Hidekazu Suzuki
Yuichiro Nakano
Kuniko Ochiai
Masahiko Usui
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Wakamoto Pharmaceutical Co.,Ltd.
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Application filed by Wakamoto Pharmaceutical Co.,Ltd. filed Critical Wakamoto Pharmaceutical Co.,Ltd.
Priority to JP2004568913A priority Critical patent/JPWO2004026953A1/ja
Priority to AU2003264498A priority patent/AU2003264498A1/en
Publication of WO2004026953A1 publication Critical patent/WO2004026953A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
    • C08L1/08—Cellulose derivatives
    • C08L1/26—Cellulose ethers
    • C08L1/28—Alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02—Polyalkylene oxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea

Definitions

  • the present invention relates to a transparent reversible thermogelling aqueous composition and an artificial vitreous body using the composition. More specifically, the present invention relates to a reversible thermogelling aqueous composition which, when injected into the vitreous body, gels due to body temperature to produce the evening-ponade effect on the retina, and an artificial solid body using the same.
  • Background art
  • Vitreous surgery has been common since around 1970 and has been performed for vitreous opacity and retinal detachment.
  • surgical techniques and associated instruments have been improved year by year, and various types of vitreous and retinal lesions are being treated.
  • intractable retinal detachment in order to obtain sufficient retinochoroidal adhesion after vitreous surgery, it is necessary to inject a tamponade substance in place of the vitreous body into the vitreous cavity, and bring about a tamponade effect on the retina. is necessary.
  • Such a substance is called an artificial vitreous.
  • hydrophobic substances include silicone oil, fluorosilicone oil, and liquid perfluorocarbon, all of which are concerned about retina damage or toxicity.
  • hydrophilic substance sodium hyaluronate, a mixture of sodium hyaluronate and collagen, polyvinyl alcohol gel, polyvinylpyrrolidone, physiological saline, and the like have been attempted, but handling at the time of injection is difficult, and surgery is also difficult. The danger of inducing glaucoma due to increased intraocular pressure has also been pointed out.
  • perfluoropropane gas and 6-fluoropolygas are widely used in clinical practice, but it is difficult to see through the fundus after surgery, causing increased intraocular pressure and toxicity to eye tissues. There is concern.
  • the ideal artificial vitreous is transparent and easy to observe the fundus, stable in the eye, resistant to increased intraocular pressure, proliferative retinopathy and inflammatory response, and not toxic to ocular tissues It is sterile and easy to inject and withdraw.
  • an artificial vitreous that satisfies these conditions has not yet been developed.
  • the present inventors have proposed a reversible thermogelling aqueous pharmaceutical composition (patent no.
  • Rizmon TG (registered trademark), which is a commercial preparation using the present invention, is placed in a 1 cm square plastic cell for a spectrophotometer, stored at 10 ° C; for 24 hours, and then placed in a 37 ° C water bath for 1 hour. Held.
  • This formulation was low toxic to ocular tissues, sterile, easy to inject and withdraw, and met many of the requirements for an ideal artificial vitreous body as described above.
  • This formulation gels at body temperature, so when injected into the eye, it gels in the shape of the eyeball due to body temperature in the eye, and it is clear that a strong evening Bonnade effect can be expected to maintain that shape for a long time.
  • an object of the present invention is to provide a transparent irreversible thermogelling aqueous composition having high transparency when gelled at body temperature, and an artificial vitreous body using the same. Things.
  • the present inventors have intensively studied to develop a reversible thermogelling aqueous composition that gives an artificial vitreous body having a high transparency when gelled at body temperature.
  • the composition is transparent enough to be used as an artificial vitreous, and methylcellulose is used.
  • the reversible thermogelling aqueous composition contains such a transparent feeling even after gelling at body temperature. And found that the present invention was completed.
  • the present invention provides the following reversible thermogelling aqueous composition and an artificial vitreous body using the same.
  • thermogelling aqueous composition containing methylcellulose 1.
  • thermogelling aqueous composition according to 1 above which gels at body temperature and has a light transmittance of 70% or more of a water transmittance after gelling.
  • thermogelling aqueous composition according to the above item 1, wherein the aqueous gel composition is gelled at body temperature and has a light transmittance of at least 80% of a water transmittance after the gelation.
  • thermogelling aqueous composition containing at least one selected from the group consisting of hydroxypropylmethylcellulose, polyethylene glycol, oxyacid and pharmaceutically acceptable salts thereof, amino acids and pharmaceutically acceptable salts thereof, and urea:
  • thermogelling aqueous composition according to the above item 4, wherein the oxyacid and a pharmaceutically acceptable salt thereof are cunic acid, tartaric acid, malic acid, lactic acid, and a pharmaceutically acceptable salt thereof.
  • thermogelling aqueous composition according to any one of the above 1 to 6, further comprising a drug.
  • thermogelling aqueous composition according to any one of the above items 4 to 8, comprising hydroxypropyl methylcellulose, the concentration of which is 0.5 to 6 w / v%. 10.
  • Polyethylene glycol is contained at a concentration of 0.1 to 13 w / v. /.
  • thermogelling aqueous composition according to any one of the above items 4 to 8, comprising oxyacid or a pharmaceutically acceptable salt thereof, and having a concentration of 0.01 to 2.0 w / v%.
  • thermogelling aqueous composition according to any one of the above 4 to 8, which comprises an amino acid or a pharmaceutically acceptable salt thereof, and has a concentration of 0.01 to 2.0 w / v%.
  • thermogelling aqueous composition according to any one of the above items 4 to 8, comprising urea and having a concentration of 0.01 to 2.0 w / v%.
  • a reversible thermogelling aqueous composition comprising at least one selected from the group consisting of:
  • the present invention is a transparent reversible thermogelling aqueous composition containing methylcellulose, is low toxic to ocular tissues, is sterile, is easy to inject or remove, gels at body temperature, and is transparent. It is a reversible thermogelling aqueous fiber containing methylcellulose that is easy to observe the fundus and is expected to have a strong evening effect.
  • reversible containing at least one selected from the group consisting of hydroxypropyl methylcellulose, polyethylene glycol, oxyacid and pharmaceutically acceptable salts thereof, amino acids and pharmaceutically acceptable salts thereof, and urea
  • An aqueous thermogelling aqueous composition is also included in the present invention.
  • a reversible thermogelling aqueous composition containing a drug is also included in the present invention.
  • the reversible thermogelling aqueous composition of the present invention is preferably methylcellulose, preferably further hydroxypropylmethylcellulose, polyethylene glycol, oxyacid and pharmaceutically acceptable salts thereof, amino acid and pharmaceutically acceptable salts thereof.
  • a reversible thermogelling aqueous composition comprising at least one selected from the group consisting of a salt and urea.
  • Methylcellulose (hereinafter sometimes abbreviated as MC) used in the composition of the present invention is 20% of a 2% w / v aqueous solution.
  • MC can be used alone or as a mixture as long as the viscosity at C is 3 to: L2000 millipascal's.
  • 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.For example, for commercial varieties, the indicated viscosity is 4, 15, 25, 100, 400, 1500, 8000 (the figures are millipascals at 20 ° C viscosity of 2w / v% aqueous solution). ⁇ Seconds) and are readily available.
  • MC having a display viscosity of 4 to 400 is preferable because it is easy to handle when injected into the eye.
  • the outline, standards, uses, amounts used, and trade names of MC are described in detail in the Pharmaceutical Excipients Dictionary (edited by the Japan Pharmaceutical Excipients Association, published by Yakuji Nippo).
  • HPMC Hydroxypropyl methylcellulose
  • the HPMC used in the present invention preferably has a display viscosity of 10,000 or less from the viewpoint of handling.
  • the outline, standards, uses, amounts used, and trade names of HPMC are described in detail in the Pharmaceutical Excipients Dictionary (edited by the Japan Pharmaceutical Excipients Association, published by Yakuji Nippo).
  • the polyethylene glycol (hereinafter sometimes abbreviated as PEG) used in the present invention is PEG-200, -300, -600, -1000, -1540, -2000, -4000, -6000, -20000, From Wako Pure Chemical Industries, Ltd. with trade names of -50000, -500000, -2000000 and -400000 also Macrogol -200, -300, -400, -600, -1000, -1540, -4000, -6000, It is sold by NOF Corporation under the trade name of -20,000.
  • the weight average molecular weight of PEG used in the base of the present invention is preferably from 300 to 50,000, particularly preferably from 1,000 to 20,000.
  • Examples of the oxyacid used in the present invention include cunic acid, tartaric acid, malic acid and lactic acid.
  • Examples of pharmaceutically acceptable salts of oxyacid include sodium salts and potassium salts.
  • amino acids used in the present invention include glycine, aspartic acid, histidine, glutamic acid, lysine, arginine, alanine, serine, proline, methionine, taurine, threonine, cystine, aminoaminoacetic acid, norin, tryptophan, phenylalanine. , Leucine, isoleucine and the like.
  • pharmaceutically acceptable salt include hydrochloride, sulfate, sodium salt, potassium salt and the like.
  • a commercially available intravenous nutritional supplement, amino acid infusion can be used.
  • the composition of the present invention has low toxicity to ocular tissues, gels at body temperature, and has a light transmittance after gelation that is not too low as compared with that of water, for example, 70% or more.
  • concentration range of each component of the composition there is no particular limitation on the concentration range of each component of the composition, but the group consisting of MC and HPMC, PEGs oxyacid and its pharmaceutically acceptable salts, amino acids and its pharmaceutically acceptable salts, and urea.
  • the concentration range is preferable for the following reason.
  • the concentration of MC used is preferably 0.2 to 7 w / v%.
  • MC concentration of 0.2w / v% If it is lower than the temperature, the composition hardly gels at the body temperature, and if the MC concentration exceeds 7 w / v%, the gel does not become transparent even if the composition gels at the body temperature.
  • the use concentration of HPMC is preferably 0.5 to 6 w / v%. If the concentration of HPMC is less than 0.5 w / v%, the composition does not easily gel at body temperature, and if the concentration of HPMC exceeds 6 w / v%, the gel does not easily become transparent even if the composition gels at body temperature.
  • the working concentration of PEG is usually 0.1 to 13 w / v%. If the PEG concentration is less than 0.1 w / v%, the composition will not easily gel at body temperature, and if the PEG concentration exceeds 13 w / v%, the viscosity of the composition will be too high to make it difficult to handle.
  • the working concentration of carboxylic acid and / or its pharmaceutically acceptable salt is usually 0.01 to 2.0 w / v%, preferably 0.05 to 1.0 w / v%. If the concentration of carboxylic acid and / or its pharmaceutically acceptable salt is less than 0.01 w / v%, the composition will not easily gel at body temperature, and if it exceeds 2.0 w / v%, the composition will gel at body temperature. The gel is difficult to become transparent even after the gelation.
  • the working concentration of the amino acid and / or its pharmaceutically acceptable salt is usually 0.01 to 2.0 w / v%, preferably 0.05 to: L.0 w / v%.
  • the concentration of amino acid and Z or a pharmaceutically acceptable salt thereof is less than 0.01 w / v%, the composition will not easily gel at body temperature, and if it exceeds 2.0 w / v%, the composition will not be gelled at body temperature. Even when gelled, the gel is hardly transparent.
  • the use concentration of urea is usually 0.01 to 2.0 w / v%, preferably 0.05 to 1.0 w / v%. If the urea concentration is less than 0.01 w / v%, the composition will not easily gel at body temperature, and if it exceeds 2.0 w / v%, the gel will not be transparent even if the composition gels at body temperature.
  • a preferred embodiment of the present invention is a transparent aqueous reversible thermogelling composition comprising at least one member selected from the group consisting of 0.01 to 2.0 w / v% urea and an artificial vitreous body using the same.
  • the reversible thermogelling aqueous composition of the present invention is liquid at room temperature or lower, is desired to gel at the body temperature of mammals, especially humans, and has an evening Bonade effect. In order to obtain, it is preferable to gel within 2 hours after exposure to body temperature.
  • the transmittance of light after gelation (660 nm) is preferably 70% or more, more preferably 80% or more, as compared with the transmittance of water.
  • the reversible thermogelling aqueous composition of the present invention may contain a drug.
  • drugs include antifungal agents such as amphotericin B, fluconazole, and miconazole nitrate; colistin sodium methanesulfonate, carbenicillin sodium; genyumycin sulfate, erythromycin, tobramycin, and kanamycin.
  • Antibiotics such as sodium chromoglyxate, tranilast, betamethasone phosphate, dexamethasone, hydrocortisone, diclofenac sodium, planobrophene, indomethacin, bromefenac sodium
  • Anti-inflammatory drugs such as meloxicam, lornoxicam, flavin adenine dinucleotide, vitamin drugs such as pyridoxal phosphate, cyanocobalamin, cyclosporine, evening chlorim ,
  • Immunosuppressive drugs such as mycophenolic acid, diabetic drugs such as aminoguanidine, epallesate, amino acids such as chondroitin sulfate and taurine, surgical aids such as sodium hyaluronate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride
  • Synthetic antibacterial agents such as ofloxacin, levofloxacin, pazufloxacin
  • the reversible thermogelling aqueous composition used in the present invention takes advantage of its properties to be used not only for artificial vitreous but also for injections, oral preparations, ear drops, nasal drops, eye drops, coatings, etc. Can be used.
  • the reversible thermogelling aqueous composition of the present invention is usually adjusted to pH 4 to 10, particularly preferably adjusted to pH 6 to 8.
  • various pH adjusters usually added are used. Examples of the acids include ascorbic acid, hydrochloric acid, gluconic acid, acetic acid, lactic acid, boric acid, phosphoric acid, sulfuric acid, and citric acid.
  • bases examples include potassium hydroxide, calcium hydroxide, sodium tauoxide, magnesium hydroxide, monoethanolamine, jetanolamine, and triethanolamine.
  • pH adjusters include glycine, histidine, amino acids such as epsilon aminocaproic acid, and the like.
  • a pharmaceutically acceptable isotonic agent, solubilizing agent, preservative, preservative, and the like may be used, if necessary, to impair the effects of the present invention. It can be added to the reversible thermogelling aqueous composition of the present invention within a range not present.
  • the tonicity agent include sugars such as xylitol, mannitol, and pudose, propylene glycol, glycerin, sodium chloride, and potassium chloride.
  • Solubilizing agents include polysorbate 80, polyoxetylene hardened castor oil and cyclodextrin.
  • reversible stones such as penzalkonium chloride, benzethonium chloride and chlorhexidine gluconate, parabens such as methyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate; Alcohols such as ethanol, phenylethyl alcohol and benzyl alcohol, organic acids such as sodium dehydroacetate, sorbic acid and potassium sorbate and salts thereof can be used.
  • additives include thickeners such as hydroxyethylcellulose, polyvinylpyrrolidone, polyvinylalcohol, propyleneglycol, ethylene glycol or sodium polyacrylate, EDTA (ethylenediaminetetraacetic acid) and Stability of their pharmaceutically acceptable salts, tocopherol and its derivatives, sodium sulfite, etc. Agents.
  • the reversible thermogelling aqueous composition of the present invention can be produced, for example, as follows. Disperse MC and, if necessary, HPMC and PEG in hot water at 70 ° C or higher, and cool on ice. If necessary, add amino acids, drugs, additives, etc., dissolve and mix well. The pH is adjusted, and the volume is adjusted with sterile purified water to prepare the reversible thermogelling aqueous composition of the present invention. The prepared reversible thermogelling aqueous composition of the present invention is sterilized by filtration through a membrane filter, and then filled into a glass ampule.
  • Example 1 the present invention will be described in more detail with reference to Examples, but these Examples do not limit the scope of the present invention.
  • methylcellulose manufactured by Shin-Etsu Chemical Co., Ltd., Metrolz (registered trademark) SM-4
  • PEG4000 Microgol 4000, manufactured by NOF Corporation
  • test example 1 After adjusting the pH to 7.8 with 1N NaOH or IN HC1, the volume is adjusted to a predetermined volume with sterilized purified water, and the reversible thermogelling aqueous composition of the present invention and the comparative reversible thermogelling aqueous composition are compared. Prepared. Test example 1
  • thermogelling state of the prepared reversible thermogelling aqueous composition, the transmittance after gelation, and the visibility when the object was seen through the gel were examined.
  • 3 mL of the reversible thermogelling aqueous composition of the present invention or for comparison, or RISMON TG (registered trademark) is placed in a plastic cell of lcm ⁇ 1cm for spectrophotometer and stored at 10 ° C for 24 hours. Thereafter, the mixture was heated for 1 hour in a water tank maintained at 37 ° C. Immediately, the cell was placed in a spectrophotometer and the transmittance of light at 660 nm was measured.
  • the transmittance of water and the transmittance of the artificial vitreous obtained by the same method were compared, and the transmittance of the artificial vitreous relative to the transmittance of water was determined as the transmittance. After measuring the transmittance, the cell was tilted, and it was observed whether a gel was formed by heating at 37 ° C for 1 hour.
  • thermogelling aqueous composition was similarly placed in a cell and heated at 37 ° C for 1 hour to prepare a gelled sample.
  • white paper with a red dot with a diameter of 3 mm was prepared.
  • Two gelled cells were stacked, and a red dot was seen across the stacked cells. The appearance of this red dot was evaluated according to the following score. Readability score: Invisible 0
  • Table 1 shows the evaluation results of the thermal gelation state, the transmittance after gelation, and the visibility of the reversible thermogelling aqueous composition subjected to the test. All the compositions gelled by heating at 37 C for 1 hour, and the gel did not flow out of the cell even when inverted.
  • Lismon TG registered trademark
  • a comparative composition is difficult to see If the comparative composition gels, it is difficult to see the object through the gel, and it may be difficult to use it as an artificial vitreous. Indicated.
  • the visibility of the composition of the present invention is slightly hazy to hard to see, or slightly hazy to clear, it is easy to see the object through the gel, the transparency is high, and it can be used as an artificial vitreous body. It was shown that there is.
  • a predetermined amount of SM-4, HPMC (TC-5RW, manufactured by Shin-Etsu Chemical Co., Ltd.) and PEG4000 were mixed, sterile purified water heated to 85 ° C was added thereto, and the mixture was dispersed by stirring. After confirming uniform dispersion, the mixture was cooled with ice while stirring. After confirming that the whole was clear, a predetermined amount of oxyacid, amino acid or urea was gradually added, and the mixture was uniformly mixed or dissolved. Furthermore, after adjusting the pH to a predetermined value with 1N NaOH or IN HC1, it was confirmed that the entire liquid was clear. Put this in sterile purified water to the specified volume.
  • Aminolevan (registered trademark) Note: (Analytic injection for hepatic encephalopathy, manufactured by Otsuka Pharmaceutical Co., Ltd.)
  • SM-4 HPMC manufactured by Shin-Etsu Chemical Co., Ltd., TC-5RW
  • PEG4000 sterile purified water heated to 85 ° C was added thereto, and the mixture was dispersed by stirring. After confirming uniform dispersion, the mixture was cooled with ice while stirring. After confirming that the whole had become clear, glycine and ofloxacin or diclofenacnadium were gradually added in predetermined amounts, and mixed uniformly. Furthermore, after adjusting the pH to a predetermined value with 1N NaOH or IN HC1, it was confirmed that the entire solution was clear.
  • Vitreous surgery was performed on a white rabbit, and after liquid-air replacement, about 2 mL of the formulation 30 prepared in Example 4 was injected into the vitreous cavity. From the day after the operation to one month, follow-up observation was performed with a slit lamp microscope and an inversion fundus, and intraocular pressure and electroretinogram were measured over time. As a result, no corneal J3 opacity, corneal edema, fibrin deposition in the anterior chamber, lens opacity, vitreous opacity, or increased intraocular pressure were observed throughout the entire process. In addition, the electroretinogram showed no change in amplitude and prolonged latency compared to the companion eye.
  • the reversible thermogelling aqueous composition of the present invention has excellent transparency of the fundus even after gelation due to body temperature and does not show any invasion to the eye tissue, so it is clear that it is an excellent artificial vitreous body. became.
  • Test example 3
  • a predetermined amount of the drug described below was dissolved or suspended in 100 mL of the reversible thermogelling aqueous composition of the present invention prepared in Example 4 (No. 28). 5 mL of this was placed in a glass cylindrical tube having an inner diameter of 14.5 mm, and heated at 50 ° C for 15 minutes to gel. Immediately after heating, separately: A glass tube containing the gelled artificial vitreous body of the present invention was placed in a 26 mm inner diameter glass cylindrical tube containing 25 mL of PBS, capped, and kept at 40 ° C. . .
  • PBS was sampled over time, and the concentration of the drug released into the PBS from the artificial vitreous body of the present invention was measured. All drug concentrations were determined using the HPLC method.
  • the 100% release concentration was determined from the amount of drug added to the artificial vitreous body of the present invention.
  • clofenac sodium 100% release concentration 10 / g / mL Tammetari phosphate, sodium (BSP) 100% release concentration 100 / g / mL reholokinin (LVFX) 100% release concentration 16 Zg / mL ⁇ Suho.
  • Phosphorus A 100% release concentration 167 Z g / mL Taxolimus 100% release concentration 16 g / mL
  • the LVFX-WTG or LFV comparative solution prepared in Example 5 was injected into the vitreous cavity of a Japanese white rabbit (male, body weight 2.5 to 3.0 kg), and the vitreous body and anterior aqueous humor 3 days after the operation were injected.
  • the LVFX concentration was measured.
  • LVFX-WTG was injected as follows. Vitrectomy was performed on one eye of a white rabbit. First, after anesthesia was given under general anesthesia, mydriasis was sufficiently applied by instilling a mydriatic agent. After conjunctival detachment, create two scleral wounds, sew an infusion tube on one side, and Luyu Zion Eye Perfusion • A lavage solution (BSS PLUS®, Santen Pharmaceutical Co., Ltd.) was perfused.
  • BSS PLUS® Santen Pharmaceutical Co., Ltd.
  • vitreous strength was introduced and a core vitrectom was performed.
  • 0.5 mL of LVFX-WTG 500 ⁇ g of LVFX content
  • 0.5 mL of LVFX-WTG 500 ⁇ g of LVFX content
  • the LVFX comparative solution was injected as follows. One eye of a white rabbit is anesthetized with an eye, an injection needle is inserted through the corneal limbus to aspirate and collect about 0.2 mL of aqueous humor, and the injection needle is inserted directly from above the bulbar conjunctiva into the center of the vitreous body. Then, 0.1 mL of the comparative solution (LVFX content 500 ⁇ g) was injected at one time (one shot). Control eyes were untreated.
  • the LVFX concentration in the vitreous was determined as follows. After homogenizing the collected vitreous, LVFX was extracted with an organic solvent and measured by HPLC.
  • the LVFX concentration in the aqueous humor was determined by filtering the aqueous filtrate by HPLC after filtering the aqueous humor overnight.
  • the reversible thermogelling aqueous composition of the present invention has the above-mentioned constitution, it is low toxic to eye tissue, is sterile, is easy to inject and remove, gels at body temperature, is transparent and has a fundus. It is possible to provide an ideal artificial vitreous body that is easy to observe and that is expected to have a strong tambonade effect.

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Abstract

Cette invention se rapporte à une composition aqueuse à thermogélification réversible, contenant de la méthyle cellulose associée de préférence à au moins un élément choisi dans le groupe constitué par de l'hydroxypropylméthylcellulose, du polyéthylèneglycol, des oxyacides et des sels pharmaceutiquement acceptables de ceux-ci, des acides aminés et des sels pharmaceutiquement acceptables de ceux-ci et de l'urée, et à un corps vitreux artificiel utilisant une telle composition. Cette composition permet de produire un corps vitreux artificiel idéal qui est peu toxique pour les tissus oculaires et qui est aseptique, qui peut être facilement injecté et retiré, qui gélifie à température ambiante, qui facilite l'observation du fond de l'oeil, grâce à sa transparence, et qui est supposé exercer l'effet de tamponade.
PCT/JP2003/011928 2002-09-18 2003-09-18 Compositions aqueuses transparentes et a thermogelification reversible WO2004026953A1 (fr)

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JP2004568913A JPWO2004026953A1 (ja) 2002-09-18 2003-09-18 透明な可逆性熱ゲル化水性組成物
AU2003264498A AU2003264498A1 (en) 2002-09-18 2003-09-18 Transparent and reversibly heat-gelling aqueous compositions

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JP2002/271284 2002-09-18
JP2002271284 2002-09-18
JP2002340903 2002-11-25
JP2002/340903 2002-11-25
JP2003/15468 2003-01-24
JP2003015468 2003-01-24

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006036660A (ja) * 2004-07-23 2006-02-09 Wakamoto Pharmaceut Co Ltd 難溶性薬物含有水性懸濁熱ゲル製剤
WO2010050215A1 (fr) 2008-10-31 2010-05-06 Hoya株式会社 Composition ophtalmique pouvant former un gel
WO2010150875A1 (fr) * 2009-06-26 2010-12-29 住友精化株式会社 Composition de résine à capacité lubrifiante conservée en conditions humides

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4969774A (fr) * 1972-10-18 1974-07-05
WO1986000079A1 (fr) * 1984-06-08 1986-01-03 Pharmacia Ab GEL D'ACIDE HYALURONIQUE RETICULE A UTILISER COMME SUBSTITUT DE l'HUMEUR VITREUSE
EP0386960A2 (fr) * 1989-03-07 1990-09-12 American Cyanamid Company Compositions pharmaceutiques utilisables comme véhicules de délivrance d'un médicament et/ou comme pansements pour blessures
WO1992000105A1 (fr) * 1990-06-25 1992-01-09 Genzyme Corporation Derives d'acide hyaluronique insolubles dans l'eau
WO1992009307A1 (fr) * 1990-11-22 1992-06-11 Kabi Pharmacia Ab Composition pour un support liquide formant un gel
JPH05184663A (ja) * 1991-02-27 1993-07-27 Shiseido Co Ltd 硝子体注入物
JPH05194603A (ja) * 1992-01-23 1993-08-03 Asahi Chem Ind Co Ltd 透明なコンニャクマンナンゲル
WO1994023750A1 (fr) * 1993-04-16 1994-10-27 Wakamoto Pharmaceutical Co., Ltd. Composition medicamenteuse se tranformant en gel thermiquement de façon reversible
JPH0959303A (ja) * 1995-08-22 1997-03-04 Shiseido Co Ltd 生体適合性ヒアルロン酸ゲル及びその用途
JPH10290830A (ja) * 1997-04-18 1998-11-04 Ofutekusu:Kk 眼手術用補助剤
WO2002011734A1 (fr) * 2000-08-08 2002-02-14 Wakamoto Pharmaceutical Co., Ltd. Compositions pharmaceutiques aqueuses
JP2002051758A (ja) * 2000-08-10 2002-02-19 Shin Etsu Chem Co Ltd 凍結冷凍保存食品用安定剤及び凍結冷凍保存食品
JP2003267892A (ja) * 2002-03-18 2003-09-25 Wakamoto Pharmaceut Co Ltd 熱ゲル化人工涙液
JP2003342197A (ja) * 2002-03-18 2003-12-03 Wakamoto Pharmaceut Co Ltd ヒアルロン酸含有熱ゲル化製剤

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05237142A (ja) * 1992-02-27 1993-09-17 Asahi Chem Ind Co Ltd 眼科用治療具
JP2729859B2 (ja) * 1993-04-16 1998-03-18 わかもと製薬株式会社 可逆性熱ゲル化水性医薬組成物

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4969774A (fr) * 1972-10-18 1974-07-05
WO1986000079A1 (fr) * 1984-06-08 1986-01-03 Pharmacia Ab GEL D'ACIDE HYALURONIQUE RETICULE A UTILISER COMME SUBSTITUT DE l'HUMEUR VITREUSE
EP0386960A2 (fr) * 1989-03-07 1990-09-12 American Cyanamid Company Compositions pharmaceutiques utilisables comme véhicules de délivrance d'un médicament et/ou comme pansements pour blessures
WO1992000105A1 (fr) * 1990-06-25 1992-01-09 Genzyme Corporation Derives d'acide hyaluronique insolubles dans l'eau
WO1992009307A1 (fr) * 1990-11-22 1992-06-11 Kabi Pharmacia Ab Composition pour un support liquide formant un gel
JPH05184663A (ja) * 1991-02-27 1993-07-27 Shiseido Co Ltd 硝子体注入物
JPH05194603A (ja) * 1992-01-23 1993-08-03 Asahi Chem Ind Co Ltd 透明なコンニャクマンナンゲル
WO1994023750A1 (fr) * 1993-04-16 1994-10-27 Wakamoto Pharmaceutical Co., Ltd. Composition medicamenteuse se tranformant en gel thermiquement de façon reversible
JPH0959303A (ja) * 1995-08-22 1997-03-04 Shiseido Co Ltd 生体適合性ヒアルロン酸ゲル及びその用途
JPH10290830A (ja) * 1997-04-18 1998-11-04 Ofutekusu:Kk 眼手術用補助剤
WO2002011734A1 (fr) * 2000-08-08 2002-02-14 Wakamoto Pharmaceutical Co., Ltd. Compositions pharmaceutiques aqueuses
JP2002051758A (ja) * 2000-08-10 2002-02-19 Shin Etsu Chem Co Ltd 凍結冷凍保存食品用安定剤及び凍結冷凍保存食品
JP2003267892A (ja) * 2002-03-18 2003-09-25 Wakamoto Pharmaceut Co Ltd 熱ゲル化人工涙液
JP2003342197A (ja) * 2002-03-18 2003-12-03 Wakamoto Pharmaceut Co Ltd ヒアルロン酸含有熱ゲル化製剤

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006036660A (ja) * 2004-07-23 2006-02-09 Wakamoto Pharmaceut Co Ltd 難溶性薬物含有水性懸濁熱ゲル製剤
WO2010050215A1 (fr) 2008-10-31 2010-05-06 Hoya株式会社 Composition ophtalmique pouvant former un gel
JP2010104632A (ja) * 2008-10-31 2010-05-13 Hoya Corp ゲル化能を有する眼科用組成物
WO2010150875A1 (fr) * 2009-06-26 2010-12-29 住友精化株式会社 Composition de résine à capacité lubrifiante conservée en conditions humides
US10000629B2 (en) 2009-06-26 2018-06-19 Sumitomo Seika Chemicals Co., Ltd. Resin composition whose lubricity under wet conditions is maintained

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