WO2016114355A1 - Composition pour prévenir les adhésions - Google Patents

Composition pour prévenir les adhésions Download PDF

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WO2016114355A1
WO2016114355A1 PCT/JP2016/050998 JP2016050998W WO2016114355A1 WO 2016114355 A1 WO2016114355 A1 WO 2016114355A1 JP 2016050998 W JP2016050998 W JP 2016050998W WO 2016114355 A1 WO2016114355 A1 WO 2016114355A1
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Prior art keywords
adhesion
alginic acid
composition
metal salt
monovalent metal
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PCT/JP2016/050998
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English (en)
Japanese (ja)
Inventor
大知 伊藤
典宏 國土
西山　徹
篤志 清水
賢 清水
三津子 伊佐次
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国立大学法人東京大学
持田製薬株式会社
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Priority to JP2016569507A priority Critical patent/JPWO2016114355A1/ja
Publication of WO2016114355A1 publication Critical patent/WO2016114355A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K35/14—Blood; Artificial blood
    • A61K35/15—Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

Definitions

  • the present invention relates to an adhesion preventing composition.
  • Adhesion refers to a state where the surfaces of tissues that should be separated from each other are connected or fused with a fibrous tissue. Adhesion occurs when exudate containing fibrin is generated on the surface of the tissue due to trauma or inflammation, and the exudate is organized and the tissue surfaces are connected or fused. Injuries that occur on the surface of tissues during surgery, inflammation caused by the trauma, and inflammation caused by drying of the tissue surface during surgery cause adhesions.
  • Adhesion can sometimes cause infertility, bowel passage problems and chronic pelvic pain.
  • another surgical operation may be required in order to peel off the adhesion that has occurred after the surgical operation. For these reasons, it is necessary to prevent adhesion, and various measures have been taken to prevent adhesion.
  • Some such means for preventing adhesions are to place a physical barrier between the site of trauma or inflammation and its adjacent tissue to prevent tissue connection or fusion.
  • a physical barrier As such a physical barrier, a sheet form and a gel form are known.
  • the sheet-like material is a polytetrafluoroethylene (PTFE) film (Prelude (trade name) (WL Gore and Associates, Inc.)), a sheet (Seprafilm (product) containing hyaluronic acid (HA) and carboxymethyl cellulose (CMC). Name) (Genzyme GmbH)), regenerated oxidized cellulose sheet (Intraceded (trade name) (Johnson & Johnson)) and the like.
  • PTFE film Prelude (trade name) (WL Gore and Associates, Inc.)
  • a sheet Seprafilm (product) containing hyaluronic acid (HA) and carboxymethyl cellulose (CMC). Name) (Genzyme GmbH)
  • regenerated oxidized cellulose sheet (Intraceded (trade name) (Johnson & Johnson)) and the like.
  • the PTFE film is not biodegradable and has a problem of remaining in the body.
  • the sheet containing HA and CMC and the regenerated oxidized cellulose sheet are biodegradable, serious adhesion such as adhesion occurring after hepatectomy cannot be completely prevented, and the effect of preventing adhesion can be improved. There was room.
  • gels examples include iron ion cross-linked hyaluronic acid gel (Intergel (trade name) (Lifecore Biomedical, LLC)).
  • Intergel trade name
  • iron ion-crosslinked hyaluronic acid gels are not currently used in clinical practice because they cause severe inflammation mainly due to an increase in the concentration of iron ions in the peritoneal cavity and the long-term remaining of the hydrogel.
  • a gel containing alginic acid, HA, CMC or a mixture thereof as a physical barrier for preventing adhesions (Patent Documents 1 and 2, and Non-Patent Documents 1 to 3)
  • the optimum physical properties capable of sufficiently exerting the adhesion preventing effect were not clear.
  • the surface of the tissue associated with the surgery may be treated with a biocompatible and pharmacologically acceptable water-soluble polypeptide, It has been proposed to coat with an aqueous solution of a hydrophilic polymer material selected from the group consisting of sugars, synthetic polymers, salts and complexes thereof, and mixtures thereof to prevent tissue adhesion due to drying. (Patent Document 3).
  • the present inventors have found that (a) a monovalent metal salt of low endotoxin alginic acid, (b) carboxymethylcellulose or a pharmaceutically acceptable salt thereof, and (c) an adhesion using a combination of cells.
  • the inventors have found that the prevention composition has a high adhesion prevention effect and have completed the present invention.
  • An anti-adhesion composition comprising a combination of (a) a monovalent metal salt of low endotoxin alginic acid, (b) carboxymethylcellulose or a pharmaceutically acceptable salt thereof, and (c) a cell.
  • a monovalent metal salt of low endotoxin alginic acid comprising a combination of (a) a monovalent metal salt of low endotoxin alginic acid, (b) carboxymethylcellulose or a pharmaceutically acceptable salt thereof, and (c) a cell.
  • the cells are mesenchymal stem cells.
  • the endotoxin content of the monovalent metal salt of alginic acid is 500 EU / g or less.
  • the monovalent metal salt of alginic acid is sodium alginate or potassium alginate.
  • An anti-adhesion composition comprising a combination of (a) a monovalent metal salt of low endotoxin alginic acid and (b) carboxymethylcellulose and a pharmaceutically acceptable salt thereof, and (c) a cell not used.
  • composition according to [12] The composition according to [11] above, wherein the composition is in a liquid form having fluidity and has a viscosity of 5 mPa ⁇ s to 100,000 mPa ⁇ s.
  • a subject in need of anti-adhesion using a composition comprising (a) a monovalent metal salt of low endotoxin alginic acid, (b) carboxymethylcellulose or a pharmaceutically acceptable salt thereof, and (c) cells.
  • a method for preventing adhesions comprising applying to.
  • An anti-adhesion method comprising applying the composition to a subject in need of anti-adhesion.
  • An anti-adhesion composition comprising (b) carboxymethylcellulose or a pharmaceutically acceptable salt thereof, and (c) a monovalent metal salt of low endotoxin alginic acid used in combination with cells.
  • An anti-adhesion composition comprising (b) carboxymethylcellulose or a pharmaceutically acceptable salt thereof and (c) a cell-free (a) monovalent metal salt of low endotoxin alginic acid. object.
  • An anti-adhesion kit comprising (a) a monovalent metal salt of low endotoxin alginic acid, (b) carboxymethylcellulose or a pharmaceutically acceptable salt thereof, and a curing agent.
  • An anti-adhesion kit comprising (a) a monovalent metal salt of low endotoxin alginic acid, (b) carboxymethylcellulose or a pharmaceutically acceptable salt thereof, and a curing agent, used in combination with cells.
  • An anti-adhesion kit comprising (a) a monovalent metal salt of low endotoxin alginic acid and (b) carboxymethylcellulose containing a curing agent or a pharmaceutically acceptable salt thereof.
  • An anti-adhesion kit comprising (c) a monovalent metal salt of low endotoxin alginic acid used in combination with cells, and (b) carboxymethylcellulose containing a curing agent or a pharmaceutically acceptable salt thereof. .
  • an anti-adhesion composition having a high anti-adhesion effect can be provided.
  • Adhesion refers to a condition in which the surfaces of tissues that should be separated from each other are connected or fused with a fibrous tissue.
  • causes of adhesion include trauma that can occur on the surface of a tissue during surgery, inflammation caused by the trauma, inflammation due to dry tissue surface during surgery, and the like. With these trauma and inflammation, exudate containing fibrin is generated on the surface of the tissue, and this exudate becomes organized and the tissue surface is connected or fused to form an adhesion.
  • Anti-adhesion refers to reducing the formation of adhesions.
  • adhesion prevention may be rephrased as adhesion reduction. For example, it is sufficient that at least one selected from the frequency, range, and degree of adhesion is reduced. “Adhesion prevention” means that, for example, when the adhesion grade evaluation described in the Examples is performed, the average adhesion grade is higher than the average adhesion grade when the composition of the present invention is not applied. It only has to be low.
  • “adhesion prevention” means, for example, when the extent evaluation of adhesion described in the Examples is performed, compared to the extent of average adhesion when the composition of the present invention is not applied, the extent of average adhesion Should be lower.
  • “Anti-adhesion” is preferably prevention of adhesions resulting from surgery, more preferably peritoneal adhesions resulting from surgery. That is, “adhesion prevention” is preferably prevention of postoperative adhesion.
  • composition A of the present invention may be referred to as (a) a monovalent metal salt of low endotoxin alginic acid (hereinafter referred to as “component (a)”). ), (B) carboxymethylcellulose or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “(b) component”), and (c) a cell (herein referred to as “(c) component”)
  • component (a) a monovalent metal salt of low endotoxin alginic acid
  • component (b) component) carboxymethylcellulose or a pharmaceutically acceptable salt thereof
  • cell herein referred to as “(c) component”.
  • a composition according to another aspect of the present invention (sometimes referred to herein as “the composition B of the present invention”) is: (a) a monovalent metal salt of low endotoxin alginic acid, and (b) carboxymethylcellulose or its An anti-adhesion composition that uses a combination of pharmaceutically acceptable salts and does not use (c) cells.
  • a composition according to another aspect of the present invention (sometimes referred to herein as “composition C of the present invention”) comprises (b) carboxymethylcellulose or a pharmaceutically acceptable salt thereof, and (c) a cell. And (a) a composition for preventing adhesion containing a monovalent metal salt of low endotoxin alginic acid.
  • composition D of the present invention The composition according to another aspect of the present invention (hereinafter, sometimes referred to as “the composition D of the present invention”) is used in combination with (b) carboxymethylcellulose or a pharmaceutically acceptable salt thereof, And (c) a composition for preventing adhesion containing (a) a monovalent metal salt of low endotoxin alginic acid without using cells.
  • the composition A of the present invention, the composition B of the present invention, the composition C of the present invention and the composition D of the present invention may be collectively referred to as “the composition of the present invention”.
  • the present invention also relates to an adhesion prevention method comprising applying the composition of the present invention to a subject in need of adhesion prevention.
  • the method of certain aspects of the invention comprises (a) a monovalent metal salt of low endotoxin alginic acid, (b) carboxymethylcellulose or a pharmaceutically acceptable salt thereof, and (c) a cell.
  • An anti-adhesion method comprising applying a composition to be used to a subject in need of anti-adhesion.
  • the method of another aspect of the present invention uses a combination of (a) a monovalent metal salt of low endotoxin alginic acid and (b) a thickener selected from carboxymethylcellulose or a pharmaceutically acceptable salt thereof, and (C) An anti-adhesion method comprising applying a cell-free composition to a subject in need of anti-adhesion.
  • Another aspect of the present invention provides (a) a monovalent monovalent form of low endotoxin alginic acid for use in adhesion prevention in combination with (b) carboxymethylcellulose or a pharmaceutically acceptable salt thereof, and (c) cells. It is a metal salt.
  • Another aspect of the present invention provides (a) a low endotoxin alginic acid for use in the prevention of adhesion in combination with (c) a cell, and (b) carboxymethylcellulose or a pharmaceutically acceptable salt thereof. It is a monovalent metal salt.
  • “Use in combination” means to use in combination.
  • the component (a), the component (b), and the component (c) are used in combination, the component (a), the component (b), and the component (c) are included in the composition when the composition is applied to a target. It means that it should be.
  • the component (a) and the component (b) are used in combination, and the component (c) is not used, the component (a) and the component (b) are included in the composition when the composition is applied to the object.
  • the component (c) should not be contained in the composition. Therefore, the term “used in combination” does not particularly refer to the form in the distribution stage including sales.
  • (b) component may contain the hardening
  • component, (b) component and (c) component when used in combination, (1) (a) component, (b) component and (c) component are combined in advance, (2) (a A form in which component (b) and component (b) are pre-combined and component (c) are combined into a kit, or prepared separately without being combined, and used in a mixed form when applied (3) (a) Either of the two types of compositions obtained by separately preparing the component and the component (b) and the component (c) are combined into a kit, or prepared separately without being combined and used in combination when applied. But you can.
  • the component (b) may be provided in the form of a composition previously blended with the component (a), and two types of compositions obtained by separately preparing the component (a) and the component (b). You may provide as a kit which combined and packaged.
  • the component (b) may further contain a curing agent, and in addition to the components (a), (b), and (c), a combination of curing agents is used. Also good. The same applies to the following examples.
  • component and (b) component when (a) component and (b) component are used in combination and (c) component is not used, (1) a form in which (a) component and (b) component are combined in advance, (2) (a ) Component and (b) component may be prepared separately, and two types of compositions obtained may be combined into a kit, or may be prepared separately without combining and used in combination. That is, the component (b) may be provided in the form of a composition previously blended with the component (a), and two types of compositions obtained by separately preparing the component (a) and the component (b). You may provide as a kit which combined and packaged.
  • each of the component (a) and the component (b) or a mixture thereof may be provided in a solution state using a solvent, or may be provided as a solid material such as a lyophilized product (particularly a lyophilized powder). May be.
  • the composition of the present invention may be used in a state having fluidity such as a solution or a gel using a solvent at the time of administration.
  • the component (a) and the component (b) are each a solid or a mixture selected from the group consisting of a sheet, sponge, powder, or powder Semi-solid; or gel.
  • the solvent is not particularly limited as long as it is a solvent applicable to a living body.
  • water for injection purified water, distilled water, ion-exchanged water (or deionized water), milli-Q water, physiological saline, phosphate buffered physiological Examples include saline (PBS).
  • PBS saline
  • Preferred are water for injection, distilled water, physiological saline and the like that can be used for treatment of humans and animals.
  • the content of the monovalent metal salt of alginic acid in the composition is about 0.1 wt% to 10 wt%, and the content of carboxymethyl cellulose or a pharmaceutically acceptable salt thereof The amount is about 0.1 wt% to 10 wt%. More preferably, the content of the monovalent metal salt of alginic acid in the composition is about 1 wt% to 5 wt%, and the content of carboxymethyl cellulose or a pharmaceutically acceptable salt thereof is about 1 wt% to 5 wt%. .
  • the content of the monovalent metal salt of alginic acid in the composition is about 0.1 wt% to 99.9 wt%, and carboxymethylcellulose or a pharmaceutically acceptable salt thereof.
  • the acceptable salt content is about 0.1 wt% to 99.9 wt%. More preferably, the content of the monovalent metal salt of alginic acid in the composition is about 1 wt% to 99 wt%, and the content of carboxymethyl cellulose or a pharmaceutically acceptable salt thereof is about 1 wt% to 99 wt%. .
  • Subjects are human or non-human warm-blooded animals, such as birds, and non-human mammals such as cows, monkeys, cats, mice, rats, guinea pigs, hamsters, pigs, dogs, rabbits, sheep, horses.
  • the method of applying the composition of the present invention to a subject is not particularly limited, and for example, it may be directly injected onto the surface of a tissue related to surgery with a syringe, a gel pipette, a dedicated filler, or the like.
  • tissue associated with surgery is tissue that has been traumatically injured on the surface during surgery, or tissue that has become or may be inflamed due to dryness of the surface during surgery.
  • the tissues associated with the surgery are organs encased in the peritoneum, such as the stomach, jejunum, ileum, appendix, colon, liver, spleen, duodenum, and pancreas. is there.
  • Particularly preferred compositions of the present invention can effectively prevent serious adhesions such as adhesions that occur after hepatectomy.
  • the form of the composition of the present invention is, for example, a fluid liquid form (ie, a solution form); a solid form such as a sheet form, a sponge form, a powder (particularly freeze-dried powder) or a powder form; Solid; or gel.
  • “having fluidity” means having a property of changing its form into an indefinite form. For example, it is desirable to have fluidity so that the composition can be encapsulated in a syringe or the like and injected into the surface of tissue associated with the surgical procedure.
  • composition of the present invention that is in the form of a gel or solution can be easily applied to the surface of a tissue with a syringe, a pipette for gel, a dedicated syringe or the like.
  • the powder and the powdery composition can also be applied to the tissue surface with a spray device or the like.
  • Sheet-like, sponge-like, powder, powder-like, gel-like, and fluid liquid compositions are suitable for any surface shape and are applied to the entire surface of the tissue to which the composition of the present invention is applied. You can also touch.
  • the sheet form is a flat plate having a suitable thickness and flexibility, and the sponge form is processed into a porous state.
  • composition can also be made into a semi-solid state with a freezing or hardening
  • the gel can be prepared by covalently bonding the composition with a polyvalent cation or a cross-linking reagent as a curing agent (cross-linking agent).
  • Monovalent metal salt of alginic acid is a water-soluble substance formed by ion exchange of the hydrogen atom of the 6-position carboxylic acid of alginic acid with monovalent metal ions such as Na + and K + . It is salt.
  • Specific examples of the monovalent metal salt of alginic acid include sodium alginate and potassium alginate. In particular, sodium alginate that is commercially available is preferable.
  • a solution of a monovalent metal salt of alginic acid forms a gel when mixed with a crosslinking agent.
  • Alginic acid used in the present invention is a biodegradable polymer polysaccharide, a polymer in which two types of uronic acids, D-mannuronic acid (M) and L-guluronic acid (G), are polymerized in a straight chain. It is. More specifically, D-mannuronic acid homopolymer fraction (MM fraction), L-guluronic acid homopolymer fraction (GG fraction), and D-mannuronic acid and L-guluronic acid are randomly arranged. This is a block copolymer in which the fractions (MG fraction) are bound arbitrarily.
  • the composition ratio (M / G ratio) of D-mannuronic acid and L-guluronic acid of alginic acid varies depending on the type of organism mainly derived from seaweed, etc. It ranges from a high G type with an M / G ratio of about 0.4 to a high M type with an M / G ratio of about 5.
  • the monovalent metal salt of alginic acid is a high molecular weight polysaccharide, and it is difficult to accurately determine the molecular weight, but generally the weight average molecular weight is 10 to 10 million, preferably 10,000 to 10 million, more preferably 2 It ranges from 10,000 to 3,000,000.
  • a preferable range of the weight average molecular weight measured by gel permeation chromatography (GPC) method is 300,000 to 2,000,000.
  • GPC-MALS method is 1,000 to 300,000, and a more preferable range is 50,000 to 300,000.
  • a measurement error of 10 to 20% or more may occur.
  • the value may vary in the range of about 32 to 480,000 for 400,000, 400,000 to 600,000 for 500,000, and about 800 to 1,200,000 for 1,000,000. Therefore, a suitable weight average molecular weight range for the monovalent metal salt of alginic acid is at least 20,000, more preferably 50,000, and even more preferably 100,000. If the molecular weight is too high, it is difficult to produce and causes problems such as excessively high viscosity when used as an aqueous solution, poor solubility, and difficulty in maintaining physical properties during long-term storage. Is preferably 5 million or less, more preferably 3 million or less.
  • a polymer substance derived from a natural product does not have a single molecular weight but is an aggregate of molecules having various molecular weights, and thus is measured as a molecular weight distribution having a certain width.
  • a typical measurement technique is gel filtration chromatography. Representative information on the molecular weight distribution obtained by gel filtration chromatography includes weight average molecular weight (Mw), number average molecular weight (Mn), and dispersion ratio (Mw / Mn).
  • the weight average molecular weight places importance on the contribution to the average molecular weight of a polymer having a large molecular weight and is represented by the following formula.
  • the number average molecular weight is calculated by dividing the total weight of the polymer by the total number of polymers.
  • W is the total weight of the polymer
  • Wi is the weight of the i-th polymer
  • Mi is the molecular weight at the i-th elution time
  • Ni is the number of molecular weights Mi
  • Hi is the height at the i-th elution time.
  • the molecular weight of a high molecular weight substance derived from a natural product may vary depending on the measurement method (examples of hyaluronic acid: Chikako YOMOTA et.al., Bull. Natl. Health Sci., Vol. 117, pp 135-139 (1999), Chikako YOMOTA et.al., Bull. Natl. Inst. Health Sci., Vol. 121, pp 30-33 (2003)).
  • the molecular weight measurement of alginate there is a method of calculating from intrinsic viscosity (Intrinsic Viscosity), SEC-MALLS (Size Exclusion Chromatography with Multiple Laser Light Scattering, which is calculated by the Ft.
  • the molecular weight of the alginate is specified, it is a weight average molecular weight calculated by gel filtration chromatography unless otherwise specified.
  • Typical conditions for gel filtration chromatography include using a calibration curve with pullulan as a standard substance.
  • the molecular weight of pullulan used as the standard substance is preferably at least 1.6 million, 788,000, 404,000, 212,000 and 112,000 as the standard substance.
  • eluent 200 mM sodium nitrate solution
  • column conditions it is preferable to use a polymethacrylate resin filler and use at least one to three columns having an exclusion limit molecular weight of 10 million or more.
  • Typical columns are TSKgel GMPW x1 (diameter 7.8 mm ⁇ 300 mm) and G2500PW XL (diameter 7.8 mm ⁇ 300 mm) (manufactured by Tosoh Corporation).
  • the monovalent metal salt of alginic acid initially has a large molecular weight and a high viscosity when extracted from brown algae, but the molecular weight becomes small and the viscosity becomes low in the process of drying by heat, lyophilization and purification. Therefore, monovalent metal salts of alginic acid having different molecular weights can be produced by performing appropriate temperature control in each production process.
  • a monovalent metal salt of alginic acid having a large molecular weight can be obtained by controlling the temperature in each step of the production to be lower, and a monovalent metal salt of alginic acid having a smaller molecular weight can be obtained as the temperature is increased.
  • the monovalent metal salt of alginic acid from which molecular weight differs can also be manufactured by the method of selecting suitably the brown algae used as a raw material, or performing the fractionation by molecular weight in a manufacturing process. Furthermore, the molecular weight or viscosity of the monovalent metal salt of alginic acid produced by each method is measured, and then mixed with another lot of monovalent metal salt of alginic acid having a different molecular weight or viscosity to have the target molecular weight. It is also possible to use a monovalent metal salt of alginic acid.
  • the alginic acid used in the present invention may be naturally derived or synthetic, but is preferably naturally derived.
  • naturally occurring alginic acid include those extracted from brown algae.
  • brown alga containing alginic acid is nowadays in coastal areas around the world, seaweed that can actually be used as a raw material for alginic acid is limited, such as Lessonia in South America, Macrocystis in North America, Laminaria and Ascofilum in Europe, Typical examples are Daviglia.
  • brown algae used as a raw material for alginic acid include, for example, the genus Lesonia, the genus Macrocystis, the genus Laminaria (comb), the genus Ascophyllum, the genus Durvillea, Examples include the genus Eisenia and the genus Ecklonia.
  • Carboxymethylcellulose or a pharmaceutically acceptable salt thereof is carboxymethylcellulose or a pharmaceutically acceptable salt thereof.
  • the carboxymethyl cellulose or a pharmaceutically acceptable salt thereof used in the present invention is not particularly limited, but it is preferable to use a carboxymethyl cellulose having a weight average molecular weight of 10,000 to 1,500,000.
  • a carboxymethyl cellulose having a weight average molecular weight of 10,000 to 1,500,000 about the measuring method of the weight average molecular weight of such carboxymethylcellulose or its pharmaceutically acceptable salt, the measuring method similar to the weight average molecular weight of the said monovalent metal salt of alginic acid can be utilized.
  • Such carboxymethylcellulose or a pharmaceutically acceptable salt thereof can be produced by using various known methods, or a commercially available product can be purchased (for example, Sigma-Aldrich, Daiichi Kogyo Seiyaku Co., Ltd.).
  • Examples of pharmaceutically acceptable salts of carboxymethyl cellulose include alkali metal salts such as sodium salt, potassium salt and lithium salt, and alkaline earth metal salts such as calcium salt.
  • a particularly preferable salt is a sodium salt.
  • composition A of the present invention uses component (c), ie, cells.
  • composition B of the present invention does not use component (c), that is, cells.
  • Examples of cells include stem cells and stromal cells, and the origin is not particularly limited, but examples thereof include bone marrow, adipose tissue, and cord blood.
  • examples of cells include ES cells and iPS cells.
  • Preferred examples of the cells include mesenchymal stem cells and mesenchymal stromal cells, and more preferred examples include bone marrow mesenchymal stem cells and bone marrow mesenchymal stromal cells.
  • Using cells means collecting the target cells from bone marrow, adipose tissue, umbilical cord blood, etc., concentrating them, or culturing them to increase the amount, and adding the prepared cells to the composition of the present invention Say to do. Specifically, for example, 1 ⁇ 10 4 cells / ml or more, or 1 ⁇ 10 5 cells / ml or more, preferably 1 ⁇ 10 4 cells / ml to 1 ⁇ 10 7 cells / ml are used in the present invention. It is said to be contained in the composition.
  • the composition of the present invention may contain a factor that promotes cell growth.
  • factors include BMP, FGF, VEGF, HGF, TGF- ⁇ , IGF-1, PDGF, CDMP, CSF, EPO, IL, and IF. These factors may be produced by recombinant methods or purified from the protein composition. It should be noted that the compositions of some embodiments of the present invention do not contain these growth factors.
  • composition of some embodiments of the present invention does not contain a curing agent of a monovalent metal salt of alginic acid.
  • the form of the composition that does not contain a curing agent is, for example, a liquid having fluidity, a solid such as a lyophilized product (particularly lyophilized powder).
  • the composition of some other embodiments of the present invention contains a curing agent of a monovalent metal salt of alginic acid.
  • the form of the composition containing the curing agent is, for example, a freeze-dried product (particularly freeze-dried powder), a solid material such as a sheet or sponge; or a gel.
  • the curing agent is immobilized by crosslinking a solution of a monovalent metal salt of alginic acid.
  • the curing agent examples include divalent or higher valent metal ion compounds such as Ca 2+ , Mg 2+ , Ba 2+ , and Sr 2+, and crosslinkable reagents having 2 to 4 amino groups in the molecule. More specifically, CaCl 2 , MgCl 2 , CaSO 4 , BaCl 2 , SrCl 2, etc. (preferably CaCl 2 , CaSO 4 , BaCl 2, etc.) are used as the divalent or higher valent metal ion compound in the molecule.
  • Diaminoalkanes that may have a lysyl group (—COCH (NH 2 ) — (CH 2 ) 4 —NH 2 ) on the nitrogen atom as crosslinkable reagents having ⁇ 4 amino groups, ie diaminoalkanes And derivatives in which the amino group is substituted with a lysyl group to form a lysylamino group, and specific examples include diaminoethane, diaminopropane, N- (lysyl) -diaminoethane, and the like.
  • the content of the curing agent in the composition of the present invention is, for example, 0.1 wt% to 10 wt%, preferably 1 wt% to 3 wt%.
  • the monovalent metal salt of alginic acid used in the present invention is a monovalent metal salt of low endotoxin alginic acid.
  • Carboxymethylcellulose or a pharmaceutically acceptable salt thereof used in the present invention is also preferably a low endotoxin carboxymethylcellulose or a pharmaceutically acceptable salt thereof.
  • Low endotoxins are those in which endotoxin levels are reduced to such an extent that they do not substantially cause inflammation or fever. That is, it has been subjected to low endotoxin treatment.
  • the low endotoxin treatment can be performed by a known method or a method analogous thereto.
  • the method of Takada et al. See, for example, JP-A-9-32001 for purifying sodium hyaluronate
  • the method of Yoshida et al. Eg, JP-A-8-269102 for purifying ⁇ 1,3-glucan. Etc.
  • a method of William et al. for example, see JP-T-2002-530440, etc.
  • biopolymer salts such as alginate, gellan gum, etc.
  • James et al. For example, international publication for purifying polysaccharides, etc.
  • the low endotoxin treatment of the present invention is not limited thereto, but is washed, filtered with a filter (such as an endotoxin removal filter or a charged filter), ultrafiltration, a column (an endotoxin adsorption affinity column, a gel filtration column, a column with an ion exchange resin, etc.) ), Adsorption to hydrophobic substances, resin or activated carbon, organic solvent treatment (extraction with organic solvent, precipitation / precipitation by addition of organic solvent, etc.), surfactant treatment (for example, JP-A-2005-036036) It can be carried out by a known method such as a gazette) or a combination thereof. These processing steps may be appropriately combined with known methods such as centrifugation. It is desirable to select appropriately according to the type of alginic acid, the type of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.
  • the endotoxin level can be confirmed by a known method, and can be measured, for example, by a method using Limulus reagent (LAL), a method using Enspercy (registered trademark) ES-24S set (Seikagaku Corporation), or the like. .
  • LAL Limulus reagent
  • Enspercy registered trademark
  • ES-24S set Seikagaku Corporation
  • the method for treating the endotoxin of the monovalent metal salt of alginic acid contained in the composition of the present invention is not particularly limited.
  • the endotoxin content of the monovalent metal salt of alginic acid is measured by the endorsin assay using the Limulus reagent (LAL) Is preferably 500 endotoxin units (EU) / g or less, more preferably 100 EU / g or less, particularly preferably 50 EU / g or less, and particularly preferably 30 EU / g or less.
  • LAL Limulus reagent
  • Low endotoxin-treated sodium alginate is commercially available, for example, Sea Matrix (sterilized) (Kimika Co., Ltd. Mochida International), PRONOVA TM UP LVG (FMC), and the like.
  • the endotoxin content of carboxymethylcellulose or a pharmaceutically acceptable salt thereof contained in the composition of the present invention is not limited.
  • the endotoxin content of carboxymethylcellulose or a pharmaceutically acceptable salt thereof is not limited. Is preferably 500 endotoxin units (EU) / g or less, more preferably 100 EU / g or less, particularly preferably 50 EU / g or less, particularly when endotoxin measurement using Limulus reagent (LAL) is performed. 30 EU / g or less.
  • EU endotoxin units
  • Such carboxymethylcellulose or a pharmaceutically acceptable salt thereof can be obtained by subjecting it to the above endotoxin treatment.
  • composition of some embodiments of the invention is a fluid liquid, ie, a solution.
  • the viscosity of the composition of the present invention of this embodiment is not particularly limited as long as the effects of the present invention can be obtained.
  • the viscosity is 5 mPa ⁇ s to 100,000 mPa ⁇ s, preferably 10 mPa ⁇ s to 20000 mPa ⁇ s.
  • the composition of some embodiments of the present invention is a viscosity that can also be applied to a subject, such as with a syringe.
  • the viscosity of the composition of the present invention is preferably about 10 mPa ⁇ s or more from the viewpoint of adhesion, and preferably about 20000 mPa ⁇ s or less from the viewpoint of easy handling of the composition, and more preferably 2000 mPa ⁇ s to 10,000 mPa. S, 1000 mPa ⁇ s to 5000 mPa ⁇ s, or 10 mPa ⁇ s to 10000 mPa ⁇ s.
  • the viscosity of the composition of the present invention includes, for example, alginic acid concentration, alginic acid molecular weight, alginic acid M / G ratio, carboxymethylcellulose or pharmaceutically acceptable salt concentration, carboxymethylcellulose or pharmaceutically acceptable salt thereof.
  • alginic acid concentration alginic acid molecular weight
  • alginic acid M / G ratio carboxymethylcellulose or pharmaceutically acceptable salt concentration
  • carboxymethylcellulose or pharmaceutically acceptable salt thereof By adjusting the molecular weight, the mixing ratio of the monovalent metal salt of alginic acid and carboxymethylcellulose or a pharmaceutically acceptable salt thereof, and the like.
  • the viscosity of the monovalent metal salt solution of alginic acid is high when the concentration of alginic acid in the solution is high, and is low when the concentration of alginic acid in the solution is low. Also, it is high when the molecular weight of alginic acid is large, and low when it is small. For example, in order to obtain a viscosity of 10 mPa ⁇ s to 20000 mPa ⁇ s using alginic acid having a molecular weight of about 200 to 500,000 Da, an aqueous alginate solution of about 1% w / v to 3% w / v may be used.
  • the viscosity of the aqueous alginate solution can be measured by a known method using, for example, a rotational viscometer (cone plate type) (TVE-20LT, TOKI SANGYO CO., LTD. JAPAN).
  • a known method is, for example, the 16th revision Japanese Pharmacopoeia, General Test Method Viscosity Measurement Method (cone-plate rotational viscometer).
  • the M / G ratio of alginic acid used in the present invention is about 0.4 to 4.0, preferably about 0.8 to 3.0, more preferably about 1.0 to 1.6.
  • the type of brown algae used as a raw material affects the viscosity of a monovalent metal salt solution of alginic acid.
  • the alginic acid used in the present invention is preferably derived from a brown algae of the genus Lessonia, Macrocystis, Laminaria, Ascofilum, Davilia, more preferably a brown alga of the genus Lessonia, particularly preferably Lessonia It is derived from Niscens (Lessonia nigrescens).
  • the viscosity of the solution of carboxymethylcellulose or a pharmaceutically acceptable salt thereof is high when the carboxymethylcellulose concentration in the solution is high, and is low when the carboxymethylcellulose concentration in the solution is low. Moreover, it is high when the molecular weight of carboxymethyl cellulose is large, and low when it is small.
  • an aqueous carboxymethyl cellulose solution of about 1% w / v to 2% w / v may be used. .
  • the viscosity of the aqueous carboxymethyl cellulose solution can be measured by a known method using, for example, a rotational viscosity measuring device (corn plate type) (TVE-20LT, TOKI SANGYO CO., LTD. JAPAN).
  • a known method is, for example, the 16th revision Japanese Pharmacopoeia, General Test Method Viscosity Measurement Method (cone-plate rotational viscometer).
  • the viscosity of the composition obtained by mixing the monovalent metal salt of alginic acid with carboxymethylcellulose or a pharmaceutically acceptable salt thereof is almost the same as before mixing if the viscosity of each solution before mixing is the same. Become. When the viscosity of one solution before mixing is high, the viscosity of the composition obtained can be lowered
  • the mixing method of the component (a) and the component (b) is not particularly limited as long as the component (a) and the component (b) can be mixed uniformly.
  • Examples of the mixing method include a method using a static mixer and a method using a double syringe.
  • a static mixer refers to a static mixing device without a drive unit. More specifically, a static mixer usually consists of a tube and a mixing element without a drive fixed in the tube, thereby splitting the flow and diverting or reversing the flow direction, so that the flow is longitudinal. It is a mixing device that mixes fluids by repeating division, conversion and inversion in the horizontal direction. Some types of static mixers are equipped with a jacket for heat exchange on the outer periphery of the tube, and others are equipped with a tube for heat exchange through which the heat medium passes through the mixing element itself. . Details on the static mixer can be found in, for example, Thakur et al. (2003) Trans IC ChemE, 81, Part A: 787-826, which can be referred to.
  • a known mixer can be used as the static mixer.
  • the known static mixer include, for example, Kenix type (for example, manufactured by Nordson and Noritake); Kenics (Chemineer Inc.); low pressure drop ( Ross Engineering Inc.); SMV (Koch-Glitsch Inc.); SMXL (Koch-Glitsch Inc.); Interfacial Surface Generator. InC (R) Eng. ); Inliner series 50 (Lightnin Inc.); Inliner series 45 . Lightnin Inc); Custody transfer mixer (Komax systems Inc.);. And SMR (Koch-Glitsch, Inc) and the like.
  • the double syringe is a device that has containers for separately filling the components to be mixed, and is uniformly mixed and released when the components are released from the double syringe.
  • a well-known thing can be used as a double syringe. Examples of known double syringes include those manufactured by Baxter. Alternatively, the static mixer and double syringe can be custom made to mix the compositions of the present invention.
  • antibiotics such as streptomycin, penicillin, tobramycin, amikacin, gentamicin, neomycin, and amphotericin B, aspirin
  • non- Concomitant drugs such as steroidal antipyretic analgesics (NSAIDs) and anti-inflammatory drugs such as acetaminophen may be administered.
  • NSAIDs steroidal antipyretic analgesics
  • anti-inflammatory drugs such as acetaminophen
  • Rat partial hepatectomy model A rat partial hepatectomy model was used to evaluate the formation of adhesions.
  • the rat partial hepatectomy model is a model capable of reproducibly observing the formation of adhesions that cause severe inflammation and have high strength (Shimizu A et al., (2014) Surg Today. (44): 314-314. 323). Specifically, the formation of adhesions was evaluated as follows.
  • MSC mesenchymal stem cells
  • MDSC mesenchymal stem cells
  • AL20 Lit NO. 3H19
  • Carboxymethylcellulose (CMC) was obtained from Sigma-Aldrich.
  • Seprafilm (Sodium Carboxymethyl Cellulose (Sigma) 419338-100G, weight average molecular weight: 700,000, substitution degree 0.9, counter ion Na type)
  • Seprafilm (trade name) is a sheet-like material obtained by mixing carboxymethylcellulose (CMC) and hyaluronic acid, and was obtained from Genzyme GmbH.
  • Interlaced (trade name) is a regenerated oxidized cellulose sheet and was obtained from Johnson & Johnson.
  • the double syringe used was DUPLOJECT System manufactured by Baxter Corporation.
  • Sodium alginate and CMC were dissolved in phosphate buffered saline (PBS) and physiological saline (0.9 w / v% NaCl) and used as a solution.
  • PBS phosphate buffered saline
  • physiological saline 0.9 w / v% NaCl
  • Alginate / CMC group (n 4): Prevention adhesion and low endotoxin alginic acid sodium 3 wt% solution 0.5mL, the Alginate / CMC gel 1mL prepared by mixing the double syringe 100mMCaCl 2 / 1wt% CMC solution 0.5mL Applied as a material. The content of sodium alginate in the Alginate / CMC gel was 3.0 wt%, the content of CMC was 1.0 wt%, and the content of CaCl 2 was 1.1 wt%.
  • Alginate / CMC + MSC group (n 4): a low endotoxin alginic acid 3 wt% solution 0.5mL, mesenchymal in Alginate / CMC gel 1mL prepared by mixing the double syringe 100mMCaCl 2 / 1wt% CMC solution 0.5mL Stem cells 5.0 ⁇ 10 6 cells were encapsulated and applied as an adhesion preventive material.
  • MSC i. p. Group (n 4): Immediately after hepatectomy, mesenchymal stem cells 5.0 ⁇ 10 6 cells suspended in 1 mL of physiological saline were intraperitoneally administered and the abdomen was closed. MSC i. v.
  • Rats were anesthetized by intraperitoneal administration equivalent to 35 mg / kg pentobarbital, and the body weight was measured with an electronic balance. The rats were then laparotomized with a midline incision. Next, the abdominal wall was pinched with tweezers and lifted to cut the abdominal wall. As a preparation prior to performing a hepatectomy, a left lateral lobe was drawn from the back of the abdominal cavity and a gauze was laid under it. Next, we moved on to actual hepatectomy. Specifically, a ruler was applied to the liver, a position where the separation cross-section was 3 cm was searched, and both ends were cauterized by bipolar and marked. A straight line was cut between the marked two points.
  • the abdomen was immediately closed and the treatment was terminated.
  • the anti-adhesive material was applied after removing the gauze.
  • MSC i. p. Group and MSC i. v. In the group, the mesenchymal stem cells were then immediately administered by injection. Next, the abdominal wall and skin were sutured twice and closed. A biodegradable thread was used for suturing the abdominal wall, and a non-absorbable thread was used for suturing the skin.
  • rats were sacrificed by administering about 2 mL of somnopentyl stock solution as an excessive amount of anesthesia, and the body weight was measured with an electronic balance. Thereafter, the abdomen was opened again, and the adhesion was evaluated as follows.
  • Adhesion was evaluated visually. An adhesion score was assigned to each of the following sites in the abdominal cavity based on the following scoring method. Site: Hepatic section, omentum, peritoneum, small intestine, directly under the median wound Adhesion score: Grade 0: No adhesion is seen at all. Grade 1: Adhesion to the extent that it peels off due to its own weight (physiological adhesion) Grade 2: Adhesion that can be peeled off with tweezers (blunt adhesion) Grade 3: Adhesion that cannot be removed without using scissors and scalpel (sharp adhesion)
  • Rat partial hepatectomy model The rat partial hepatectomy model described in Example 1 was used to evaluate the formation of adhesions. Specifically, the formation of adhesions was evaluated as follows.
  • Low endotoxin sodium alginate was obtained from Mochida Pharmaceutical.
  • AL20 Low endotoxin sodium alginate (sterile product) AL20 (Lot NO. 3H19), endotoxin amount 7 EU / g) (Low endotoxin sodium alginate (sterile product) AL100 (Lot NO. 5H08), endotoxin amount 7 EU / g) (low endotoxin alginic acid Sodium (sterilized product) AL500 (Lot NO. 3H17), endotoxin amount 15 EU / g) Carboxymethylcellulose (CMC) was obtained from Sigma-Aldrich.
  • Low endotoxin CMC was obtained from Mochida Pharmaceutical.
  • Low endotoxin CMC non-sterile
  • As Seprafilm trade name
  • Interceed trade name
  • Sodium alginate and CMC were dissolved in phosphate buffered saline (PBS) and physiological saline (0.9 w / v% NaCl) and used as a solution.
  • PBS phosphate buffered saline
  • physiological saline 0.9 w / v% NaCl
  • the composition of the PBS described in Example 1 was used.
  • the weight average molecular weight measured by each following method was described. [Pre-processing method] An eluent was added to the sample and dissolved, and then filtered through a 0.45 ⁇ m membrane filter to obtain a measurement solution.
  • Control group (n 8): The margin of the left lateral lobe was measured 3 cm, separated and coagulated and hemostatic (untreated control group).
  • Alginate / CMC group (n 5 ⁇ 9): About AL20 and AL100 means a sodium alginate 3 wt% solution 0.5 mL, a solution containing the 100mMCaCl 2 / 1wt% CMC solution (100mMCaCl 2 and 1 wt% CMC, The same applies hereinafter) 1 mL of Alginate / CMC gel prepared by mixing 0.5 mL with a double syringe was applied as an adhesion preventing material.
  • the content of sodium alginate in the Alginate / CMC gel was 3.0 wt%, the content of CMC was 1.0 wt%, and the content of CaCl 2 was 1.1 wt%.
  • the AL500 a sodium alginate 1 wt% solution 0.5mL, was applied Alginate / CMC gel 1mL prepared by mixing the double syringe 100mMCaCl 2 / 1wt% CMC solution 0.5mL as antiadhesive material.
  • the content of sodium alginate in the Alginate / CMC gel was 1.0 wt%, the content of CMC was 1.0 wt%, and the content of CaCl 2 was 1.1 wt%.
  • Alginate / CMC group a combination of alginic acid treated with low endotoxin (AL20) and CMC not treated with low endotoxin.
  • AL20 ( ⁇ ) / CMC ( ⁇ ) Combination of low endotoxin-treated alginic acid (AL20) and low endotoxin-treated CMC.
  • Rats were anesthetized by intraperitoneal administration equivalent to 35 mg / kg pentobarbital, and the body weight was measured with an electronic balance. The rats were then laparotomized with a midline incision. Next, the abdominal wall was pinched with tweezers and lifted to cut the abdominal wall. As a preparation prior to performing a hepatectomy, a left lateral lobe was drawn from the back of the abdominal cavity and a gauze was laid under it. Next, we moved on to actual hepatectomy. Specifically, a ruler was applied to the liver, a position where the separation cross-section was 3 cm was searched, and both ends were cauterized by bipolar and marked. A straight line was cut between the marked two points.
  • the abdomen was immediately closed and the treatment was terminated.
  • the anti-adhesive material was applied after removing the gauze.
  • the abdominal wall and skin were sutured twice and closed.
  • a biodegradable thread was used for suturing the abdominal wall, and a non-absorbable thread was used for suturing the skin.
  • rats were sacrificed by administering about 2 mL of somnopentyl stock solution as an excessive amount of anesthesia, and the body weight was measured with an electronic balance. Thereafter, the abdomen was opened again, and the adhesion was evaluated as follows.
  • Adhesion was evaluated as follows. (1) Separation Section The following (a) and (b) were evaluated for the liver separation section described in [Procedure] above. (A) Adhesion grade Adhesion was evaluated visually. An adhesion score was assigned to the hepatic section based on the following scoring method. Adhesion score: Grade 0: No adhesion is seen at all.
  • Grade 1 Adhesion to the extent that it peels off due to its own weight (physiological adhesion)
  • Grade 2 Adhesion that can be peeled off with tweezers (blunt adhesion)
  • Grade 3 Adhesion that cannot be removed without using scissors and scalpel (sharp adhesion)
  • B Adhesive Extent Of the 3 cm hepatic section, the width at which adhesions were formed was measured with a ruler and expressed in mm (thus, the maximum extent of the section is 30 mm).
  • Non-separation section Other than the hepatic section, the following evaluations (a) and (b) were performed on the liver surface, omentum, peritoneum, small intestine, directly under the midline, and the like.
  • Adhesion grade Adhesion was evaluated visually. Adhesion scores were assigned based on the following scoring method for sites other than the hepatic section. The site was not specified, and the maximum value of the observed adhesion score was recorded as the adhesion score of the test animal. Adhesion score: Grade 0: No adhesion is seen at all.
  • Grade 1 Adhesion to the extent that it peels off due to its own weight (physiological adhesion)
  • Grade 2 Adhesion that can be peeled off with tweezers (blunt adhesion)
  • Grade 3 Adhesion that cannot be removed without using scissors and scalpel (sharp adhesion)
  • B Adhesive Extent For sites other than the hepatic section, the width at which adhesions were formed was measured with a ruler and expressed in mm. Similar to (2) and (a) above, the site was not specified, and the maximum value of the width at which the observed adhesion was formed was recorded as the adhesion extent of the test animal.

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Abstract

La présente invention concerne une composition pour prévenir les adhésions au moyen d'une combinaison de (a) un sel de métal monovalent d'acide alginique pauvre en endotoxine, (b) carboxyméthylcellulose ou un sel pharmacologiquement acceptable de celle-ci, et (c) des cellules. Une composition pour prévenir les adhésions ayant un effet de prévention des adhésions élevé est produite ainsi.
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WO2019093505A1 (fr) * 2017-11-13 2019-05-16 持田製薬株式会社 Composition pour empêcher les adhérences
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JPWO2018164128A1 (ja) * 2017-03-07 2020-04-16 持田製薬株式会社 アルギン酸液剤
WO2018164128A1 (fr) * 2017-03-07 2018-09-13 持田製薬株式会社 Formulation liquide à base d'alginate
JPWO2019093505A1 (ja) * 2017-11-13 2020-11-19 持田製薬株式会社 癒着防止用組成物
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WO2019093505A1 (fr) * 2017-11-13 2019-05-16 持田製薬株式会社 Composition pour empêcher les adhérences
JPWO2019138583A1 (ja) * 2018-01-15 2021-01-28 持田製薬株式会社 癒着防止用組成物
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CN111936175A (zh) * 2018-01-15 2020-11-13 持田制药株式会社 防粘连用组合物
WO2019138583A1 (fr) * 2018-01-15 2019-07-18 持田製薬株式会社 Composition antiadhésive
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