Classifications

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  • 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
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  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
  • A61K35/37—Digestive system
  • A61K35/38—Stomach; Intestine; Goblet cells; Oral mucosa; Saliva
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  • 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
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  • 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
• • A—HUMAN NECESSITIES
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  • 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
  • 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
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  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
• • A—HUMAN NECESSITIES
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  • 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
  • A61L27/14—Macromolecular materials
  • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
• • A—HUMAN NECESSITIES
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  • 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
  • A61L27/14—Macromolecular materials
  • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• • 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
  • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
  • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
  • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
• • 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
  • A61L27/54—Biologically active materials, e.g. therapeutic substances
• • 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
  • A61L27/58—Materials at least partially resorbable by the body
• • 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
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/04—Macromolecular materials
• • 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
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L31/145—Hydrogels or hydrocolloids
• • A—HUMAN NECESSITIES
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  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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• • A—HUMAN NECESSITIES
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  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • 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
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
  • A61L2300/426—Immunomodulating agents, i.e. cytokines, interleukins, interferons
• • A—HUMAN NECESSITIES
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  • 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
  • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

• the present invention relates to a therapeutic agent useful for the treatment of urethral stricture.
• the invention also relates to a method of treating urethral stricture.
• Urethral stricture is caused by various factors such as prostatic hypertrophy and sequelae of urethral surgery for bladder cancer, trauma from traffic accidents and accidents during work, and congenital urethral disorders such as hypospadias. It occurs. It is a disease in which the urethral mucosa is injured due to injury or inflammation, and scarring occurs in the urethra cavernosum surrounding the urethral mucosa or the urethral mucosa as the filtration is performed to repair the wound, and the urethra narrows.
• An object of the present invention is to provide an agent for treating urethral stricture and a method for treating urethral stricture which can prevent restenosis by a minimally invasive transurethral endoscopic procedure in urethral stricture treatment.
• the present inventors promote the epithelialization of the incision treatment site by placing a hydrogel with specific physical properties on the inner surface of the urethral surface which has been treated with transurethral endoscopic technique as a treatment for urethral stricture. And found that the site effectively prevents recurrence of urethral stricture due to scar organization, and completed the present invention.
• the present inventors have found that inclusion of animal cells in the hydrogel is effective for solving the above-mentioned problems.
• the animal cells are the patient's own oral mucosal cells.
• the object of the present invention is solved by a therapeutic agent for urethral stricture characterized by containing at least a hydrogel-forming polymer, having a storage modulus of 50 Pa or less at 10 ° C. and a storage modulus of 100 Pa or more at 37 ° C. Be done.
• the object of the present invention is solved by the urethral stricture treating agent, wherein the urethral stricture treating agent comprises animal cells.
• the object of the present invention is also solved by a urethral stricture treating agent characterized in that the animal cell is a patient's own oral mucosal cell.
• a further object of the present invention is to provide at least a hydrogel-forming polymer on the inner surface of the urethra cut and treated by transurethral endoscopic procedure, and the storage elastic modulus at 10 ° C. is 50 Pa or less and the storage elastic modulus at 37 ° C. is 100 Pa
• a method for treating urethral stricture which comprises at least an operation of cooling and injecting a therapeutic agent for urethral stricture characterized by the above to a temperature of 10 ° C. or lower and indwelling on the inner surface of the urethra at a temperature above room temperature. Resolved.
• a hydrogel having specific physical properties on the inner surface of the urethra cut by the transurethral endoscopic technique, it promotes the epithelialization of the incision treatment site, The site can effectively prevent recurrence of urethral stricture by scar organization.
• animal cells in particular, the patient's own oral mucosa cells
• the hydrogel further promotes the epithelialization of the incision treatment site on the inner urethral surface.
• the “hydrogel-forming polymer” of the present invention is a thermoreversible formation of a crosslinking structure or a network structure, and based on the structure, a hydrogel that holds a dispersion liquid such as water inside is thermally treated. It refers to a polymer having reversibly formable properties. Also, “hydrogel” refers to a gel containing a crosslinked or network structure made of a polymer and water supported or held in the structure.
• the storage elastic modulus of the hydrogel can be measured by the method described in the literature (H. Yoshioka et al., Journal of Macromolecular Science, A31 (1), 113 (1994)). That is, the dynamic elastic modulus of the sample at an observation frequency of 1 Hz is measured at a predetermined temperature (10 ° C., 25 ° C. or 37 ° C.) to determine the storage elastic modulus (G ′, elastic term) of the sample. In the measurement, the following measurement conditions can be suitably used.
• the agent for treating urethral stricture of the present invention has a storage elastic modulus of 50 Pa or less at 10 ° C., preferably 30 Pa or less (particularly 10 Pa or less), and a storage elastic modulus of 100 Pa or more at 37 ° C., preferably 200 Pa or more In particular, the pressure is preferably 300 Pa or more.
• the urethral stricture treatment of the present invention is injected at a low temperature of 10 ° C. or less to the urethral stricture treatment site, and the urethral stricture treatment agent is indwelled at the urethral stricture treatment site at the temperature.
• the storage elastic modulus at 10 ° C. of the urethral stricture treatment exceeds 50 Pa, its hardness is too large, and injection through a catheter becomes difficult.
• the storage elastic modulus at 37 ° C. of the therapeutic agent for urethral stricture of the present invention is less than 100 Pa, the strength is insufficient and it becomes difficult to indwell in the urethral stricture treatment site for a long time.
• the urethral stricture treatment site is often located at the penis and is susceptible to the outside temperature because it is exposed outside the body.
• the storage elastic modulus at room temperature (25 ° C.) of the “hydrogel-forming polymer” aqueous solution of the present invention is less than 100 Pa
• the animal cells can be placed in the urethral stricture treatment site because Is incomplete.
• the storage elastic modulus of the urethral stricture treating agent of the present invention is preferably 100 Pa or more at 25 ° C., preferably 200 Pa or more (particularly 300 Pa or more).
• the “hydrogel-forming polymer”, which imparts a suitable storage elastic modulus as described above to the urethral stricture treating agent of the present invention, is a screening method (storage elastic modulus as described above among specific compounds as described later) It can be easily selected according to the measurement method).
• polyalkylene oxide block copolymers represented by block copolymers of polypropylene oxide and polyethylene oxide
• Etherified celluloses such as hydroxypropyl cellulose
• chitosan derivatives K, R, Holme, et al. Macromolecules, 24, 3828 (1991)
• hydrogel-forming polymers In the hydrogel-forming polymer that can be suitably used as the "hydrogel-forming polymer" of the present invention and that utilizes a hydrophobic bond for crosslinking, a plurality of blocks having a cloud point and a hydrophilic block are combined. It is preferable that
• the hydrophilic block is preferably present for the hydrogel to be water soluble at lower temperatures, and multiple blocks with cloud points cause the hydrogel to change to the gel state at higher temperatures. Is preferably present.
• the block having the cloud point dissolves in water below the cloud point and becomes insoluble in water above the cloud point, so that the block is gelled above the cloud point. It serves as a crosslinking point consisting of hydrophobic bonds to form.
• the hydrogel used in the present invention utilizes the property that the hydrophobic bond not only becomes strong with the increase of temperature but also that the change is reversible with respect to temperature.
• the "hydrogel-forming polymer” may have a plurality of "blocks having a cloud point” preferable.
• the hydrophilic block in the above-mentioned “hydrogel-forming polymer” has a function of changing the “hydrogel-forming polymer” to water solubility at a lower temperature, and It has a function of forming a state of a water-containing gel while preventing the above-mentioned hydrogel from coagulating and precipitating due to an increase in hydrophobic bond strength at a temperature higher than the transition temperature.
• the "hydrogel-forming polymer” used in the present invention be one that is decomposed and absorbed in vivo. That is, it is preferable that the “hydrogel-forming polymer” of the present invention is decomposed in the living body by a hydrolysis reaction or an enzyme reaction to be absorbed and excreted as a low molecular weight substance harmless to the living body.
• hydrogel-forming polymer of the present invention is formed by combining a plurality of blocks having a cloud point and a hydrophilic block, at least one of the block having a cloud point and the hydrophilic block It is preferred that both be decomposed and absorbed in vivo.
• the block having a cloud point is preferably a polymer block exhibiting a negative water solubility-temperature coefficient, and more specifically, a copolymer of polypropylene oxide, propylene oxide and another alkylene oxide, Polymer selected from the group consisting of poly N-substituted acrylamide derivatives, poly N-substituted methacrylamide derivatives, copolymers of N-substituted acrylamide derivatives and N-substituted methacrylamide derivatives, polyvinyl methyl ether, polyvinyl alcohol partial acetates Is preferably usable.
• polyester type biodegradable polymers such as polylactic acid and polyglycolic acid can be used as a block having a cloud point which is decomposed and absorbed in vivo.
• the measurement of the cloud point is carried out, for example, by cooling an aqueous solution of about 1% by mass of the above-mentioned polymer (block having a cloud point) to a transparent uniform solution and gradually raising the temperature (heating rate about 1 It can be carried out by setting the point at which the solution becomes cloudy for the first time to a cloud point.
• poly N-substituted acrylamide derivatives and poly N-substituted methacrylamide derivatives that can be used in the present invention are listed below.
• Poly-N-acryloyl piperidine poly-N-n-propyl methacrylamide; poly-N-isopropyl acrylamide; poly-N, N-diethyl acrylamide; poly-N-isopropyl methacrylamide; poly-N-cyclopropyl acrylamide
• Poly-N-acryloyl pyrrolidine poly-N, N-ethyl methyl acrylamide; poly-N-cyclopropyl methacrylamide; poly-N-ethyl acrylamide.
• the above-mentioned polymer may be a homopolymer (homopolymer) or a copolymer of a monomer constituting the polymer and another monomer.
• a monomer which comprises such a copolymer any of a hydrophilic monomer and a hydrophobic monomer can be used.
• the copolymerization of the hydrophilic monomer raises the cloud point of the product, and the copolymerization of the hydrophobic monomer lowers the cloud point of the product. Therefore, a polymer having a desired cloud point (for example, a cloud point higher than 4 ° C. and 40 ° C. or less) can also be obtained by selecting these monomers to be copolymerized.
• hydrophilic monomer N-vinyl pyrrolidone, vinyl pyridine, acrylamide, methacrylamide, N-methyl acrylamide, hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxymethyl methacrylate, hydroxymethyl acrylate, acrylic having an acidic group Acid, methacrylic acid and salts thereof, vinyl sulfonic acid, styrene sulfonic acid, etc., and N, N-dimethylaminoethyl methacrylate having a basic group, N, N-diethylaminoethyl methacrylate, N, N-dimethylaminobromo methacrylate Examples include, but are not limited to, pill acrylamide and salts thereof.
• hydrophobic monomer acrylate derivatives such as ethyl acrylate, methyl methacrylate, glycidyl methacrylate and the like, methacrylate derivatives, N-substituted alkyl methacrylamide derivatives such as N-n-butyl methacrylamide, vinyl chloride, acrylonitrile, Styrene, vinyl acetate and the like can be mentioned, but it is not limited thereto.
• hydrophilic block On the other hand, specific examples of the hydrophilic block to be bonded to the above-described block having a cloud point include methylcellulose, dextran, polyethylene oxide, polyvinyl alcohol, poly N-vinyl pyrrolidone, polyvinyl pyridine, polyacrylamide, polymethacrylamide , Poly N-methyl acrylamide, poly hydroxy methyl acrylate, poly acrylic acid, poly methacrylic acid, polyvinyl sulfonic acid, polystyrene sulfonic acid and salts thereof; poly N, N-dimethylaminoethyl methacrylate, poly N, N- diethyl aminoethyl methacrylate And poly N, N-dimethylaminopropyl acrylamide and salts thereof.
• the hydrophilic block is desirably degraded, metabolized and excreted in vivo, and hydrophilic biopolymers such as albumin, proteins such as gelatin, hyaluronic acid, polysaccharides such as heparin, chitin and chitosan are preferably used .
• the method for combining the block having a cloud point and the above-mentioned hydrophilic block is not particularly limited, but, for example, a polymerizable functional group (for example, an acryloyl group) is introduced into any of the above blocks to give the other block It can be carried out by copolymerizing the monomers.
• a combination of a block having the highest point and the above-mentioned hydrophilic block may be obtained by block copolymerization of a monomer giving a block having a cloud point and a monomer giving a hydrophilic block. It is possible.
• the bond between the block having a cloud point and the hydrophilic block previously introduces reactive functional groups (for example, a hydroxyl group, an amino group, a hydroxyl group, an isocyanate group, etc.) to both, and bonds both by a chemical reaction It can also be done by At this time, a plurality of reactive functional groups are usually introduced into the hydrophilic block.
• reactive functional groups for example, a hydroxyl group, an amino group, a hydroxyl group, an isocyanate group, etc.
• the bond between the polypropylene oxide having a cloud point and the hydrophilic block is, for example, an anionic polymerization or a cationic polymerization, repeating propylene oxide and a monomer (for example, ethylene oxide) constituting "another hydrophilic block" sequentially
• a block copolymer in which polypropylene oxide and a "hydrophilic block” (for example, polyethylene oxide) are bonded.
• Such a block copolymer can also be obtained by copolymerizing a monomer constituting a hydrophilic block after introducing a polymerizable group (for example, acryloyl group) at the end of polypropylene oxide.
• a polymer to be used in the present invention can be obtained by introducing a functional group capable of causing a bonding reaction with a functional group (for example, hydroxyl group) at the end of polypropylene oxide in a hydrophilic block and reacting both of them.
• a “hydrogel-forming polymer” used in the present invention can also be used by connecting materials such as Bluronic F-127 (trade name, manufactured by Asahi Denka Kogyo Co., Ltd.) or the like in which polyethylene glycol is bonded to both ends of polypropylene glycol. Can be obtained.
• the polymer of the present invention in the embodiment containing a block having a cloud point is soluble in water at a temperature lower than the cloud point because the above-mentioned "block having a cloud point" present in the molecule is hydrophilic together with the hydrophilic block. It completely dissolves in water and shows a sol state. However, when the temperature of the aqueous solution of this polymer is heated to a temperature higher than the above cloud point, the "cloud point block" present in the molecule becomes hydrophobic, and hydrophobic interactions cause association between separate molecules. Do.
• the polymer of the present invention is a hydrophobic association part between the blocks having the cloud point in water.
• the cloud point block becomes water soluble and the crosslinking point is released by hydrophobic association.
• the hydrogel structure disappears, the "hydrogel-forming polymer" of the present invention becomes a complete aqueous solution again.
• the change in the physical properties of the polymer of the present invention in a preferred embodiment is based on the change in hydrophilicity and hydrophobicity at the cloud point of the block having the cloud point present in the molecule. It has complete reversibility in response to temperature changes.
• the delicate hydrophilic-hydrophobic balance in water of the above-mentioned "hydrogel-forming polymer” contributes to the stability of cells in culturing the cells. It is considered to be a thing.
• the hydrogel-forming polymer of the present invention is substantially water-insoluble at body temperature (37 ° C.) and reversibly water-soluble under ice-cooling.
• substantially water-insoluble it is preferable that the amount of the polymer dissolved in 100 mL of water at 37 ° C. is 5.0 g or less (more preferably 0.5 g or less, particularly 0.1 g or less) .
• the amount of the above-mentioned polymer dissolved in 100 mL of water at 10 ° C. is 0.5 g or more (more preferably 1.0 g or more) as “water soluble” under ice cooling.
• “reversibly water-soluble” means that even after the aqueous solution of the above “hydrogel-forming polymer” once becomes a "substantially water-insoluble” gel state at 37 ° C, it is at 10 ° C. Refers to exhibiting the water solubility described above.
• the polymer preferably has a viscosity of 10 to 3,000 centipoise (more preferably 50 to 1.000 centipoise) at 5 ° C. in a 10% aqueous solution. Such viscosity is preferably measured, for example, under the following measurement conditions. Viscometer: Stress-controlled rheometer (model name: AR500, manufactured by TA Instruments) Rotor diameter: 60 mm Rotor shape: parallel plate
• the aqueous solution of the "hydrogel-forming polymer” of the present invention does not substantially dissolve the gel even when it is immersed in a large amount of water at 37 ° C.
• the above-described properties of the hydrogel formed by the above-mentioned “hydrogel-forming polymer” can be confirmed, for example, as follows. That is, 0.15 g of “hydrogel-forming polymer” is dissolved in 1.35 g of distilled water under ice cooling to prepare an aqueous solution of 10 wt%, and the aqueous solution is injected into a plastic petri dish having a diameter of 35 mm.
• the weight (f gram) of the whole petri dish containing the gel is measured. Then, after the whole petri dish containing the gel is allowed to stand in water in 250 ml at 37 ° C. for 10 hours, the weight (g gram) of the whole petri dish containing the gel is measured to dissolve the gel from the gel surface Evaluate the presence or absence.
• the weight loss ratio of the gel that is, (f-g) / f is preferably 5.0% or less, more preferably 1.0%. It is preferable that it is the following (especially 0.1% or less).
• the aqueous solution of the “hydrogel-forming polymer” of the present invention is gelled at 37 ° C. and then immersed in a large amount (about 0.1 to 100 times the volume of the gel) of water, The gel does not dissolve over time.
• Such properties of the polymer used in the present invention are achieved, for example, by the presence of two or more (plural) blocks having a cloud point in the polymer.
• the concentration to water that is, ⁇ (polymer) / (polymer + water) ⁇ ⁇ 100 (%), 20% or less (15 more) It is preferable to use a "hydrogel-forming polymer" which can be gelled at a concentration of at most 10%, particularly at most 10%.
• the molecular weight of the “hydrogel-forming polymer” used in the present invention is preferably 30,000 to 30,000, more preferably 100,000 to 1,000, and still more preferably 500,000 to 5,000,000. is there.
• the storage elastic modulus of the urethral stricture treatment of the present invention In order to adjust the storage elastic modulus of the urethral stricture treatment of the present invention to a preferable range, as described above, it is preferable to select “hydrogel-forming polymer” type together with “hydrohydrogen in the urethral stricture treatment”. It can also be carried out by adjusting the concentration of the “gel-forming polymer”. Generally, the storage elastic modulus of the urethral stricture treating agent of the present invention increases as the concentration of the “hydrogel-forming polymer” increases, and decreases as the concentration decreases.
• the agent for treating urethral stricture according to the present invention at least contains the above-mentioned "hydrogel-forming polymer", but the pH buffer solution, physiological saline, etc. can be used to give a pH or an osmotic pressure close to that of body fluid of a living body. It is desirable to add salts.
• the urethral stricture treatment of the present invention can be used by dispersing animal cells.
• animal cells urethral mucosal epithelial cells are most preferred.
• Self-oral mucosal cells are preferably used to facilitate collection and to avoid immune rejection.
• undifferentiated cells can also be used from the viewpoint of high tolerance as animal cells.
• undifferentiated cells include ES cells, pluripotent stem cells such as iPS cells, and mesenchymal stem cells.
• the therapeutic agent for urethral stricture of the present invention can be mixed immediately before using animal cells as a therapeutic agent for urethral stricture, the cells are preliminarily dispersed in the therapeutic agent for urethral stricture and cells are proliferated before the urethral stricture site. It can also be applied to
• the cells When the cells are undifferentiated cells, they can be proliferated undifferentiated and then induced to differentiate into a lineage to mucosal epithelial cells.
• the agent for treating urethral stricture of the present invention may contain various cytokines in order to promote mucosal cell epithelialization at the urethral stricture site.
• Cytokines are soluble in water, so they can be easily diffused even as they are injected into the urethral stricture site, but the therapeutic agent for urethral stricture of the present invention uses a hydrogel-forming polymer to form a dense polymer network. Since it forms, it suppresses the spread of cytokines. Therefore, since the cytokine can be maintained at a high concentration around the urethral stricture site, the effect of the cytokine can be maintained for a long time.
• the cytokine suitably used in the present invention can be used without particular limitation as long as it promotes mucosal cell epithelialization at the urethral stricture site, but as its action, maintenance of cell undifferentiation, growth promotion, urethral mucosal epithelial cell Those having an action such as differentiation induction to genealogy are preferably used.
• the agent for treating urethral stricture according to the present invention promotes epithelialization of the incision site by placing it on the inner surface of the urethral section which has been opened by transurethral endoscopic technique, and urethral stricture is relapsed by scar organization of the site. To effectively prevent.
• the urethral stricture treatment according to the present invention according to the present invention, the incision of the urethral stricture site is made by normal transurethral endoscopic dissection to the patient, and after inserting the urethral catheter, ice-cold between the urethral catheter circumference and the urethral internal dissection site
• the agent is injected through a catheter separate from the urethral catheter.
• the therapeutic agent for urethral stricture of the present invention is warmed by body temperature and immediately placed in a gelled state so as to cover the entire urethral internal incision site.
• the urethral stricture treatment of the present invention has the property of dissolving in ice-cold water, so if it is desired to remove the urethral stricture-treatment agent of the present invention after surgery for some reason, it can be easily washed away with ice cold water.
• Production Example 1 Dissolve 10 g of polypropylene oxide-polyethylene oxide copolymer (propylene oxide / ethylene oxide average polymerization degree about 60/180, Asahi Denka Kogyo Co., Ltd .: Bluronic F-127) in 30 ml of dry chloroform, and coexist with phosphorus pentoxide 0.13 g of methylene diisocyanate was added and reacted for 6 hours under reflux of boiling point. The solvent was distilled off under reduced pressure, the residue was dissolved in distilled water, and ultrafiltration was performed using an ultrafiltration membrane with a molecular weight cut off of 500,000 to fractionate a high molecular weight polymer and a low molecular weight polymer. The resulting aqueous solution was frozen to obtain F-127 high polymer and F-127 low polymer.
• Production Example 2 160 mol of ethylene oxide was added by cationic polymerization to 1 mol of trimethylolpropane to obtain polyethylene oxide triol having an average molecular weight of about 7000. After dissolving 100 g of the polyethylene oxide triol obtained above in 1000 ml of distilled water, 12 g of filtered potassium manganate was gradually added at room temperature, and the oxidation reaction was carried out for about 1 hour as it was. The solid matter was removed by filtration, the product was extracted with chloroform, and the solvent (chloroform) was evaporated under reduced pressure to obtain 90 g of polyethylene oxide tricarboxylate.
• hydrogel forming polymer (hydrogel forming polymer" -2) was obtained. 1 g of this polymer was dissolved in 19 g of distilled water under ice cooling to obtain a 5 wt% aqueous solution.
• the storage elastic modulus of this aqueous solution was measured at an applied frequency of 1 Hz using a stress control type rheometer (AR 500, manufactured by TA Instruments), and was 1 Pa at 10 ° C., 550 Pa at 25 ° C., and 3360 Pa at 37 ° C. . This temperature dependent storage modulus change was reversibly observed repeatedly.
• Production Example 3 Dissolve N-isopropylacrylamide (manufactured by Eastman Kodak Co., Ltd.) 96 g, N-acryloxysuccinimide (manufactured by Kokusan Chemical Co., Ltd.) 17 g, and n-peptyl methacrylate (manufactured by Kanto Chemical Co., Ltd.) 7 g in chloroform 4000 ml and replace with nitrogen Then, 1.5 g of N, N ⁇ -azobisisobutyro nitrile was added and polymerized at 60 ° C. for 6 hours. The reaction solution was concentrated and then reprecipitated (reprecipitated) in diethyl ether.
• hydrogel a hydrogel-forming polymer
• a forming polymer "-3) was obtained. 1 g of this polymer was dissolved in 9 g of distilled water under ice-cooling to obtain an aqueous solution of 10 wt%.
• the storage elastic modulus of this aqueous solution is measured at an applied frequency of 1 Hz using a stress control type rheometer (AR 500, manufactured by TA Instruments), and it is 1 Pa or less at 10 ° C., 30 Pa at 25 ° C., and 250 Pa at 37 ° C. The This temperature dependent storage modulus change was reversibly observed repeatedly.
• AR 500 stress control type rheometer
• Production Example 5 71.0 g of N-isopropylacrylamide and 4,4 g of n-butyl methacrylate were dissolved in 1117 g of ethanol. An aqueous solution of 22.6 g of polyethylene glycol dimethacrylate (PDE6000, manufactured by Nippon Oil and Fats Co., Ltd.) dissolved in 773 g of water was added to this, and humidified at 70 ° C. under a nitrogen stream. While maintaining the temperature at 70 ° C.
• PDE6000 polyethylene glycol dimethacrylate
• TEMED N, N, N, N, ⁇ ⁇ ⁇ -tetramethylethylenediamine
• APS 10% filtered ammonium sulfate
• the polymerization reaction was completed by adding 8 ml and 8 ml of a 10% aqueous solution of APS four times at intervals of 30 minutes.
• the reaction solution was cooled to 10 ° C. or less, 5 L of cold distilled water at 10 ° C. was added for dilution, and the solution was concentrated to 2 L at 10 ° C. using an ultrafiltration membrane with a fractional molecular weight of 100,000.
• the concentrated solution was diluted by adding 4 L of cold distilled water, and the above ultrafiltration concentration operation was performed again.
• the above dilution and ultrafiltration concentration operations were repeated five more times to remove those having a molecular weight of 100,000 or less. What was not filtered by this ultrafiltration (the one remaining in the ultrafiltration membrane) is recovered and lyophilized, and the hydrogel-forming polymer of the present invention having a molecular weight of 100,000 or more ("hydrogel-forming polymer Polymer "-5" 72g was obtained.
• hydrogel-forming polymer (“hydrogel-forming polymer” -5) of the present invention obtained as described above was dissolved in 9 g of distilled water under ice-cooling to obtain a 10 wt% aqueous solution.
• the storage elastic modulus of this aqueous solution is measured at an applied frequency of 1 Hz using a stress control type rheometer (AR 500, manufactured by TA Instruments), and it is 1 Pa or less at 10 ° C., 80 Pa at 25 ° C., and 460 Pa at 37 ° C. The This temperature dependent storage modulus change was reversibly observed repeatedly.
• the concentrated solution was diluted by adding 4 L of cold distilled water, and the above-described extraocular filtration concentration operation was performed again.
• the above dilution and ultrafiltration concentration operations were repeated five more times to remove those having a molecular weight of 100,000 or less. What was not filtered by this ultrafiltration (the one remaining in the ultrafiltration membrane) is recovered and lyophilized, and the hydrogel-forming polymer of the present invention having a molecular weight of 100,000 or more ("hydrogel-forming polymer Polymer "-6) 40g was obtained.
• hydrogel-forming polymer (“hydrogel-forming polymer” -6) of the present invention obtained as described above was dissolved in 9 g of distilled water under ice-cooling to obtain a 10 wt% aqueous solution.
• the storage elastic modulus of this aqueous solution was measured at an applied frequency of 1 Hz using a stress control type rheometer (AR 500, manufactured by TA Instruments), and was 43 Pa at 10 ° C., 680 Pa at 25 ° C., and 1310 Pa at 37 ° C. . This temperature dependent storage modulus change was reversibly observed repeatedly.
• Production Example 7 45, 5 g of N-isopropylacrylamide and 0.56 g of n-butyl methacrylate were dissolved in 592 g of ethanol. An aqueous solution prepared by dissolving 1.5 g of polyethylene glycol dimethacrylate (PDE6000, manufactured by Nippon Oil and Fats Co., Ltd.) I in 65.1 g of water was added thereto, and the mixture was heated to 70 ° C. under a nitrogen stream. While maintaining the temperature at 70 ° C.
• PDE6000 polyethylene glycol dimethacrylate
• the concentrated solution was diluted by adding 4 L of cold distilled water, and the above ultrafiltration concentration operation was performed again. The above dilution and ultrafiltration concentration operations were repeated five more times to remove those having a molecular weight of 100,000 or less. What was not filtered by this ultrafiltration (the one remaining in the ultrafiltration membrane) is recovered and lyophilized, and the hydrogel-forming polymer of the present invention having a molecular weight of 100,000 or more ("hydrogel-forming polymer Polymer "-7" 22g was obtained. 1 g of the hydrogel-forming polymer (“hydrogel-forming polymer” -7) obtained above was dissolved in 9 g of distilled water under ice-cooling to obtain an aqueous solution of 10 wt%.
• the storage elastic modulus of this aqueous solution is measured at an applied frequency of 1 Hz using a stress control type rheometer (AR 500, manufactured by TA Instruments). LPa or less at 10 ° C, lPa or less at 25 ° C, 90Pa at 37 ° C there were. This temperature dependent storage modulus change was reversibly observed repeatedly.
• Example 1 The freeze-dried hydrogel-forming polymer 6 obtained in Production Example 6 was subjected to EOG sterilization in the same manner as in Production Example 4.
• the hydrogel-forming polymer-6 after EOG sterilization was dissolved in a phosphate buffer at a concentration of 10 wt% under ice-cooling.
• Oral mucosal tissue (2 cm ⁇ 1 cm) of male ureteral stenosis patients was collected, and the patient's own serum (equivalent to the cells) was added to collagenase-treated cells, and phosphate buffer of the above-mentioned hydrogel-forming polymer-6
• the solution was dispersed under ice cooling.
• the cell dispersion was heated at 37 ° C.
• the urethral stricture site is dissected by transurethral endoscopic dissection for the patient, and after inserting the urethral catheter, the above-mentioned cell culture after ice-cooling between the urethral catheter circumference and the urethral internal incision site according to the present invention
• the urethral stricture treatment was infused.
• the therapeutic agent for urethral stricture of the present invention was warmed by body temperature and immediately indwelled so as to cover the entire internal urethral incision site by gelation.
• the urethral catheter was removed 3 weeks after the operation.
• the narrowed incision site was covered with mucosal epithelial cells without scarring, and good urine flow was secured. Ten patients were treated similarly and no restenosis was observed in all patients.
• Example 2 As a result of giving the same treatment as Example 1 to 10 patients except not adding the oral mucous cells and serum of male ureteral stenosis patients, restenosis was not recognized in all patients, but in 2 patients We confirmed the formation of scarring at the incision site.
• Example 3 The same treatment as Example 2 was repeated except using freeze-dried hydrogel-forming polymer 5 obtained in Production example 5 instead of freeze-dried hydrogel-forming polymer 6 obtained in production example 6 In 2 patients, restenosis was observed.
• Comparative Example 1 The same treatment as in Example 1 was repeated except that the freeze-dried hydrogel-forming polymer 7 obtained in Production example 7 was used instead of the freeze-dried hydrogel-forming polymer 6 obtained in production example 6 As a result of having been performed to the patient, scarring of the stenosis incision site was recognized in all patients. Since the storage elastic modulus at 37 ° C. of the hydrogel-forming polymer 7 is as low as less than 100 Pa, it is considered that it did not function as the urethral stricture treating agent of the present invention.
• Comparative example 2 In Example 1, lyophilized hydrogel-forming polymer-6 after EOG sterilization was dissolved in a phosphate buffer at a concentration of 11 wt% under ice-cooling. The storage elastic modulus of this aqueous solution was measured at an applied frequency of 1 Hz using a stress control type rheometer (AR 500, manufactured by TA Instruments), and was 75 Pa at 10 ° C. This solution had low fluidity even under ice-cooling, and could not be injected into the urethral stricture site through a catheter, and did not function as the urethral stricture treatment of the present invention.
• AR 500 stress control type rheometer

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