WO2014129382A1 - 多糖粉末およびこれを含む癒着防止材 - Google Patents
多糖粉末およびこれを含む癒着防止材 Download PDFInfo
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- WO2014129382A1 WO2014129382A1 PCT/JP2014/053378 JP2014053378W WO2014129382A1 WO 2014129382 A1 WO2014129382 A1 WO 2014129382A1 JP 2014053378 W JP2014053378 W JP 2014053378W WO 2014129382 A1 WO2014129382 A1 WO 2014129382A1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/718—Starch or degraded starch, e.g. amylose, amylopectin
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- 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
- A61L31/042—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L3/00—Compositions of starch, amylose or amylopectin or of their derivatives or degradation products
- C08L3/02—Starch; Degradation products thereof, e.g. dextrin
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
Definitions
- the present invention relates to a polysaccharide powder and an adhesion preventing material containing the same.
- the present invention relates to an improvement for improving the solubility of polysaccharides in water.
- a living tissue may be damaged by a surgical operation.
- a living tissue is exposed to the air by incision, the living tissue is dried or oxidized, and as a result, the living tissue is damaged.
- damaged tissues are inflamed after surgery, there is a possibility that tissues that should originally be separated from each other may adhere to each other.
- Such post-operative tissue adhesion can cause serious complications such as intestinal obstruction and infertility, for example, in the abdominal cavity region. For this reason, various anti-adhesion materials have been developed to cover damaged parts of living tissue and prevent adhesion.
- the currently known anti-adhesion materials are mainly composed of biologically derived polymer materials such as polysaccharides and polypeptides that do not adversely affect the living body, and the form is also powder, sheet, jelly, or liquid. There are various. Among these, liquid adhesion prevention materials are particularly attracting attention because of their excellent operability in that they can be coated by spraying onto a target site of living tissue.
- Patent Document 1 discloses an adhesion prevention material comprising a crosslinkable polysaccharide derivative in which an active ester group capable of reacting with an active hydrogen-containing group is introduced into the polysaccharide side chain.
- the crosslinkable polysaccharide derivative can form a cross-linked product by a covalent bond between the active ester group and the active hydrogen-containing group by contact with water under alkaline conditions.
- an aqueous solution containing the crosslinkable polysaccharide derivative is applied to a target site of a biological tissue, and then an aqueous solution containing a pH adjusting agent for making the alkaline condition is sprayed from above.
- An adhesion prevention method for gelling a sexual polysaccharide derivative is disclosed.
- an applicator has been developed that can spray two liquid chemicals such as an aqueous solution containing the above-mentioned crosslinkable polysaccharide derivative and an aqueous solution containing a pH adjuster (for example, Patent Document 2).
- the adhesion preventing material can be applied to the target site by one spray.
- a polysaccharide in a state dissolved in water is more likely to deteriorate than a dry solid polysaccharide, it is desirable to prepare an aqueous polysaccharide solution each time by adding water to the dry solid polysaccharide at the operation site.
- JP 2008-289986 A (corresponding to US Patent Application Publication No. 2008/294099)
- the polysaccharides preferably used as the above-mentioned anti-adhesion material generally have poor water solubility due to having a hydrophobic functional group or a large molecular weight. Therefore, it takes time to dissolve the dry solid polysaccharide in water, and it is difficult to quickly prepare a polysaccharide aqueous solution. Therefore, the anti-adhesion material containing a poorly water-soluble polysaccharide has a problem that it cannot cope with a sudden application at the operation site.
- the present invention has been made in view of the above circumstances, and an object thereof is to provide means for improving the solubility of polysaccharides in water.
- polysaccharide powder having a specific particle size distribution exhibits significantly superior solubility (solubility in water), and the present invention has been completed.
- the above-mentioned object of the present invention is achieved by a powder containing a polysaccharide having a particle size distribution in which a particle size of 30% by volume or more of the total volume is 200 to 750 ⁇ m.
- FIG. 3 is a graph of the deposition frequency distribution (dynamic image analysis method) of polysaccharide powders (1) to (4) and comparative polysaccharide powders (1) to (5) obtained in Examples 1 to 4 and Comparative Examples 1 to 4.
- FIG. 3 is a graph of the deposition frequency distribution (dynamic image analysis method) of polysaccharide powders (1) to (4) and comparative polysaccharide powders (1) to (5) obtained in Examples 1 to 4 and Comparative Examples 1 to 4.
- the present invention relates to a powder containing a polysaccharide having a particle size distribution in which the particle size (diameter) of 30% by volume or more of the total volume is 200 to 750 ⁇ m (in the present specification, “polysaccharide powder of the present invention” or “polysaccharide powder”). Also referred to as).
- the solubility to the water of polysaccharide can be improved.
- the polysaccharide powder of this invention may be comprised only from polysaccharide, or may be comprised from structural components other than polysaccharide and polysaccharide.
- a polysaccharide solution (particularly an aqueous polysaccharide solution) has been used as an anti-adhesion material from the viewpoint of operability that a target site of a living tissue can be easily covered by spraying or the like.
- polysaccharides are generally poorly water soluble due to hydrophobic functional groups or high molecular weight. For this reason, the improvement of the water solubility of polysaccharide powder was a subject for the purpose of corresponding to the rapid application in an operation site.
- a method for pulverizing polysaccharides a method of filling polysaccharides in a vial and freeze-drying is generally used.
- the polysaccharide solution was filled in a sheet in a tray in order to improve the solubility by increasing the specific surface area (contact area with water).
- a manufacturing method can be considered in which a product is freeze-dried and then pulverized.
- mere powdering tends to increase the risk of poor solubility, such as powder forming lumps in the middle of dissolution or powder adhering to the bottom of the vial, and sufficient improvement effects are not seen. It was.
- the present invention is characterized in that the particle size distribution of the polysaccharide powder is a specific particle size distribution in which the particle size (diameter) of 30% by volume or more of the total volume is 200 to 750 ⁇ m.
- the particle size distribution of the polysaccharide powder is a specific particle size distribution in which the particle size (diameter) of 30% by volume or more of the total volume is 200 to 750 ⁇ m.
- the mechanism by which the polysaccharide powder according to the present invention exhibits excellent water solubility is unknown, but is presumed as follows.
- the present invention is not limited by the following estimation.
- van der Waals force acts between particles (powder). Since this van der Waals force is inversely proportional to the square of the particle size, the smaller the particle size, the larger the van der Waals force. Act in between.
- electrostatic force acts between particles (powder) under low humidity (dry) conditions, and liquid cross-linking force is applied to particles (powder) under moderate humidity (for example, RH 60% or more). ), The particles are aggregated together.
- the fine powders may be bound to each other by the action of van der Waals force, electrostatic force, liquid bridging force, etc., or lumps may be formed during dissolution. Adhering to the bottom side surface portion), it was not always possible to obtain good water solubility (uniform solubility). For this reason, as a result of intensive studies on the above phenomenon by the inventors of the present application, the polysaccharide powder having a particle size of 200 to 750 ⁇ m occupies a certain amount (30% by volume or more) contributes to the improvement of solubility. I found.
- the anti-adhesion material containing the polysaccharide powder of the present invention can quickly respond to sudden application in various medical sites such as in the preparation of injections and infusions at the operation site.
- the above effect can be exhibited particularly effectively when the polysaccharide has a hydrophobic group.
- X to Y indicating a range means “X or more and Y or less”, and “weight” and “mass”, “wt%” and “wt%”, “part by weight” and “Part by mass” is treated as a synonym. Unless otherwise specified, measurement of operation and physical properties is performed under conditions of room temperature (20 to 25 ° C.) / Relative humidity 40 to 50%.
- the polysaccharide powder of the present invention has a particle size distribution in which the particle size (diameter) of 30% by volume or more of the total volume is 200 to 750 ⁇ m.
- the polysaccharide powder having such a particle size distribution exhibits good water solubility.
- the content of the polysaccharide powder having a particle size distribution of 200 to 750 ⁇ m is less than 30% by volume of the total volume, it is inferior in water solubility and cannot cope with a sudden surgical site.
- the polysaccharide powder of the present invention has a particle size distribution in which the particle size of 40% by volume or more, more preferably 50% by volume or more, particularly preferably 60% by volume or more of the total volume is 200 to 750 ⁇ m.
- the upper limit of the content of the polysaccharide powder having a particle size distribution of 200 to 750 ⁇ m is not particularly limited, but it is preferably 70% by volume or less in consideration of improvement in water solubility, and is 65% by volume or less. More preferably, it is particularly preferably 55% by volume or less.
- “showing good water solubility” means that the shortest dissolution time is 90 seconds or less in the “solubility evaluation” of the following examples.
- the shortest dissolution time when measured by “solubility evaluation” in the following examples is preferably 60 seconds or less, and more preferably 30 seconds or less.
- the minimum of the shortest dissolution time is so preferable that dissolution time is short, it is not specifically limited, However, Considering the application in an operation field, 1 second or more is usually enough.
- the number of samples having the shortest dissolution time of 30 seconds or less is preferably the largest, and the shortest dissolution time of 60% or more of all samples is 30 seconds or less. It is more preferable that the shortest dissolution time of 70% or more of all the samples is 30 seconds or less.
- polysaccharide refers to a polymer in which monosaccharides are bonded by glycosidic bonds and has a molecular weight of 1000 or more.
- “content of a polysaccharide powder having a particle size distribution with a particle size of 200 to 750 ⁇ m is a dynamic image analysis method (measuring instrument: manufactured by Seishin Enterprise Co., Ltd., trade name) : Using PITA-2), 10000 particle images are converted, the equivalent circle diameter (particle diameter equal to the projected area) is calculated from the projected area, and the total volume is the number x particle volume. Based on this, the volume frequency distribution (Volume distribution (number basis)) is calculated and expressed as a ratio (volume%) obtained by dividing the volume of the polysaccharide powder in the range where the particle diameter (diameter) is 200 to 750 ⁇ m by the total volume.
- the peak top of the polysaccharide powder of the present invention is not particularly limited, but is preferably 100 to 500 ⁇ m, more preferably 120 to 350 ⁇ m, and particularly preferably 120 to 320 ⁇ m.
- the polysaccharide powder having such a peak top can intervene particularly efficiently between fine powders having a small particle size, and can suppress / prevent binding between fine powders, formation of lumps during dissolution, and adhesion to the container wall surface.
- peak top of polysaccharide powder refers to the particle size (particle size with the highest frequency) corresponding to the highest portion (peak) of the volume distribution (number basis) measured above ( Diameter) ( ⁇ m).
- the particle size distribution of the polysaccharide powder of the present invention is not particularly limited, but the polysaccharide powder preferably has a wide particle size distribution.
- the polysaccharide powder preferably has a particle size (D10) with a cumulative volume ratio of 10% of 60 to 120 ⁇ m, more preferably 65 to 110 ⁇ m.
- the polysaccharide powder preferably has a particle size (D90) with a cumulative volume ratio of 90% of 300 to 520 ⁇ m, more preferably 320 to 515 ⁇ m.
- the polysaccharide powder preferably has a particle size (D50) with a cumulative volume ratio of 50% of more than 120 ⁇ m and less than 300 ⁇ m, more preferably 130 to 270 ⁇ m.
- the monosaccharide constituting the polysaccharide powder of the present invention is not particularly limited, and examples thereof include ribose, xylose, arabinose, glucose, mannose, galactose, fructose, sorbose, rhamnose, fucose, and ribodeose, and any functional groups thereof. And monosaccharide derivatives into which is introduced.
- the polysaccharide may be composed of only one kind of these monosaccharides, may be composed of a combination of two or more kinds, may be linear, or may contain a branch. Good.
- naturally occurring polysaccharides may be used or synthesized.
- the polysaccharide that is the main chain of the polysaccharide is not particularly limited as long as it has two or more units of the monosaccharide structure in the main skeleton.
- disaccharides such as trehalose, sucrose, maltose, cellobiose, gentiobiose, lactose, and melibiose; formed by covalent bonding of polysaccharides of three or more sugars such as raffinose, gentianose, meletitol, stachyose, dextrin, dextran, and cellulose And derivatives having a functional group further introduced thereto.
- Such polysaccharides may be naturally occurring or artificially synthesized.
- polysaccharide containing glucose or a glucose derivative is preferable.
- the polysaccharide is selected from the group consisting of dextrin, dextran, and cellulose, and derivatives thereof. More preferably, it comprises at least one polysaccharide.
- Dextran is used as a blood plasma substitute and is available under the trade name “Dextran®T fractions” (Amersham Biosciences).
- Dextrin is a hydrolyzate of starch and a mixture of glucose polymers with different molecular chain lengths.
- the glucose units in dextrin are mainly ⁇ -1,4 bonds, and usually contain ⁇ -1,6 bonds in a certain proportion.
- the starch species as the dextrin raw material is not particularly limited, and therefore the abundance of ⁇ -1,6 bonds is not particularly limited.
- the dextrin used in the present invention typically has a molecular weight (Mw) of about 10 to 200 kDa in consideration of availability, physical properties at the time of use, ease of handling, film formation, and the like. Any polysaccharide that is generally commercially available can be used in the present invention.
- the polysaccharide having a proven record in the above medical use is a polysaccharide that can be suitably used in terms of safety.
- dextrin is a particularly preferred polysaccharide in that no anaphylactic shock has been reported, it has been used in peritoneal dialysis, and no defects in biological adaptation have been reported yet.
- the polysaccharide according to this embodiment preferably has at least one selected from the group consisting of a carboxyl group, an active ester group, a carboxylate, an amino group, and an aldehyde group.
- a functional group can be a cross-linking point for forming an ester bond or an amide bond, and thus is suitable as a constituent component of the adhesion preventing material.
- these functional groups are contained as an adhesion preventing material, when the aqueous solution containing the polysaccharide is subjected to an alkaline condition, the functional group contained in the polysaccharide, the hydroxy group, and the hydroxy group present on the surface of the living tissue, etc. Form an ester bond or an amide bond to crosslink.
- polysaccharide powder becomes a gel form, and can coat
- An example of a polysaccharide having a carboxyl group is a form in which a carboxyalkyl group is introduced into the hydroxy group of the polysaccharide.
- the carboxyalkyl group preferably includes a carboxyalkyl group having 2 to 5 carbon atoms, and specifically includes a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, a carboxyisopropyl group, and a carboxybutyl group. Is mentioned. Of these, a carboxymethyl group or a carboxyethyl group is preferable, and a carboxymethyl group (carboxymethylated polysaccharide) is more preferable.
- the carboxy group in the polysaccharide is preferably “non-salt type” in which the salt is not coordinated, and the finally obtained active esterified polysaccharide is preferably not in the salt form.
- the “salt” includes inorganic salts such as alkali metals and alkaline earth metals, quaternary amines such as tetrabutylammonium (TBA), and halogen salts such as chloromethylpyridylium iodide.
- TSA tetrabutylammonium
- halogen salts such as chloromethylpyridylium iodide.
- “Non-salt type” means that these “salts” are not coordinated, and “not in salt form” means that these salts are not included.
- the carboxylation reaction of the polysaccharide can be carried out without particular limitation using a known oxidation reaction.
- the type of reaction is not particularly limited, but examples include dinitrogen tetroxide oxidation, fuming sulfuric acid oxidation, phosphoric acid oxidation, nitric acid oxidation, and hydrogen peroxide oxidation
- the reaction can be oxidized by selecting a commonly known reaction using a reagent. Each reaction condition can be appropriately set depending on the amount of carboxy group introduced.
- an acid-type polysaccharide having a carboxylic acid can be prepared by oxidizing the hydroxyl group of the polysaccharide.
- a known method can be used for the carboxyalkylation reaction of the polysaccharide, and is not particularly limited. Specifically, in the case of the carboxymethylation reaction, a reaction using monochloroacetic acid is selected after alkalizing the polysaccharide. It is possible. The reaction conditions can be appropriately set depending on the amount of carboxymethyl group introduced.
- the polysaccharide here is usually subjected to the reaction in an aqueous solution.
- the acid-type polysaccharide introduced with a carboxy group is usually precipitated using a poor solvent (usually alcohol) and dried under reduced pressure.
- any of the above-mentioned carboxylation or carboxyalkylation methods can be used.
- the decrease in the molecular weight of the polysaccharide due to the carboxy group introduction reaction is small, and the introduction amount of the carboxy group is compared.
- Carboxyalkylation, particularly carboxymethylation is preferred because it can be easily controlled. This carboxymethyl group is also referred to as “CM-” hereinafter.
- an example of a polysaccharide having an active ester group is a form in which a carboxyl group contained in a polysaccharide having a carboxyl group and an N-hydroxyamine compound are esterified.
- the active ester group is formed by reacting a polysaccharide with an electrophilic group introducing agent.
- the polysaccharide may be one kind or a mixture of two or more kinds.
- the active ester group is a group in which an electrophilic group stronger than a normal alcohol is bonded to the carbonyl carbon of the carboxy group, and the ester bond is dissociated in the presence of water in the presence of an alkali.
- the electrophilic group-introducing agent that forms such an active ester group typically, an N-hydroxyamine compound that is available at a relatively low cost is used.
- N-hydroxysuccinimide N-hydroxynorbornene-2,3-dicarboxylic acid imide, 2-hydroxyimino-2-cyanoacetic acid ethyl ester, 2-hydroxyimino-2-cyanoacetic acid amide, N-hydroxypiperidine N-hydroxyphthalimide, N-hydroxyimidazole, N-hydroxymaleimide and the like are typical examples. These compounds may be one kind or a mixture of two or more kinds. Of these, N-hydroxyimide, particularly N-hydroxysuccinimide (NHS) is preferred because it has a track record in the field of peptide synthesis and is readily available commercially.
- the polysaccharide used for the active esterification is usually 0.1 to 5 mmol / g, preferably 0.4 to 3 mmol / g of carboxy group per 1 g of dry mass (assuming that group is regarded as one molecule). More preferably, it is 0.5 to 2 mmol / g.
- the ratio of the amount of carboxy groups is less than 0.1 mmol / g, the number of active ester groups derived from the groups and serving as crosslinking points is often insufficient.
- the ratio of the amount of carboxy groups is more than 5 mmol / g, the active esterified polysaccharide (uncrosslinked) may be difficult to dissolve in a solvent containing water.
- the amount of carboxy group of the polysaccharide can be quantified by acid-base back titration using phenolphthalein as an indicator (see the section (Method for measuring the amount of carboxy group of polysaccharide) in the Examples below).
- phenolphthalein as an indicator
- the amount of the carboxy group is the total amount of the active ester group and the non-active esterified carboxy group in the final active esterified polysaccharide.
- the polysaccharide is usually subjected to the esterification reaction as a solution of an aprotic polar solvent.
- the aprotic polar solvent is a polar solvent having no proton capable of forming a hydrogen bond with a nucleophile having an electrically positive functional group, and is not particularly limited, but includes dimethyl sulfoxide (DMSO), N, N— Examples include dimethylformamide, N-methyl-2-pyrrolidone, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone and the like.
- DMSO can be suitably used because of its good solubility in polysaccharide solvents.
- the preferred “non-salt type” acid-type polysaccharide can be dissolved in the above-mentioned solvent usually at about 20 ° C. to 120 ° C. (by heating if necessary).
- the esterification reaction between the polysaccharide and the electrophilic group introducing agent is usually performed in the presence of a dehydrating condensing agent.
- the dehydrating condensing agent is one that draws out one water molecule formed by the condensation of a carboxy group and an electrophilic group introducing agent, that is, dehydrates and ester bonds them.
- the dehydrating condensing agent is not particularly limited, and examples thereof include 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC), 1-cyclohexyl- (2-morpholin-4-ethyl) -carbodiimide meso p-toluenesulfonate. Etc.
- 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC) is more preferable because it has a track record in the field of peptide synthesis and is easily available commercially.
- the reaction temperature in the esterification reaction step is not particularly limited, but is preferably 0 ° C. to 70 ° C., more preferably 20 ° C. to 40 ° C. While the reaction time varies depending on the reaction temperature, it is generally 1 to 48 hours, preferably 12 to 24 hours.
- the active esterified polysaccharide produced by the esterification reaction may be crystallized and recovered, or the active esterified polysaccharide may be contacted with a polyvalent carboxylic acid before precipitation.
- the polyvalent carboxylic acid may be a dicarboxylic acid or more, but is usually selected from readily available dicarboxylic acids and tricarboxylic acids.
- succinic acid and malic acid are preferable as dicarboxylic acids that have been proven as conventional pharmaceutical additives, and citric acid is preferable as tricarboxylic acid. Two or more of these may be used in combination.
- the amount of the polyvalent carboxylic acid is usually an acid equivalent per 1 mol of the electrophilic group introduction agent, and is usually 1 equivalent or more, usually 1 to 10 equivalents. If it is this range, the active-esterified polysaccharide dry product which does not produce a water-insoluble matter finally can be obtained. Preferably it is 1.5 equivalents or more. If the amount is too large, the rate of change in average molecular weight Mw with time during drying tends to be high, and is preferably 9 equivalents or less, more preferably 7.5 equivalents or less. Typically 3 equivalents.
- the contact between the active esterified polysaccharide and the polyvalent carboxylic acid may be performed by adding the polyvalent carboxylic acid to the reaction solution after the esterification reaction and mixing them.
- the mixing time is not particularly limited, and is usually 1 to 60 minutes.
- the active esterified polysaccharide is precipitated and recovered in the same manner as before.
- the reaction solution is poured into a poor solvent such as an excessive amount of alcohol or acetone to be precipitated, and recovered by an appropriate method such as decantation, centrifugation, or filtration. It is preferable to purify the precipitate by washing with a poor solvent at least once.
- a poor solvent such as an excessive amount of alcohol or acetone to be precipitated
- filtration such as an excessive amount of alcohol or acetone to be precipitated
- unreacted electrophilic group-introducing agent, dehydrating condensing agent, reaction by-product and polyvalent carboxylic acid provided to the reaction system are also removed, and the final activity Substantially no polycarboxylic acid remains in the esterified polysaccharide.
- the active esterified polysaccharide is unstable in water, and the active esterified polysaccharide after the precipitation / purification step is usually dried under reduced pressure.
- the drying under reduced pressure is desirably performed at a temperature of 45 ° C. or lower, usually at least 1 hour, preferably 4 hours, usually about 24 hours.
- the active esterified polysaccharide obtained in the production process of the present invention is suppressed from increasing in molecular weight over time during drying under reduced pressure.
- the polysaccharide having a carboxylate is a polysaccharide formed by ion-bonding a carboxylate ion from which a hydrogen ion has been removed from a carboxyl group contained in a polysaccharide having a carboxyl group with a cation other than a hydrogen ion.
- the cation include alkali metal ions, alkaline earth metal ions, quaternary ammonium ions such as tetra (n-butyl) ammonium and tetra (n-propylmethyl) ammonium.
- examples of the polysaccharide having an amino group include polysaccharides containing amino sugars such as glucosamine and glucosamine, and polysaccharides containing an isourea intermediate (polysaccharide having the structure of the following chemical formula 1).
- examples of the polysaccharide having an aldehyde group include polysaccharides containing aldose at the reducing end of the polysaccharide.
- the polysaccharide having the above functional group may be obtained from nature, or a polysaccharide having these functional groups may be produced by chemical or biological techniques.
- a conventionally well-known means can be suitably employ
- the polysaccharide powder of the present invention may contain components other than the polysaccharide.
- components other than polysaccharides include, but are not limited to, oligosaccharides having a molecular weight of less than 1000.
- the weight average molecular weight (Mw) of the polysaccharide is not particularly limited, but is preferably 20,000 to 200,000, more preferably 30,000 to 120,000. Even with such a relatively large molecular weight, the polysaccharide powder having the particle size distribution of the present invention exhibits good water solubility. In addition, when a polysaccharide powder having such a molecular weight is used as an adhesion preventing material, the crosslinked polysaccharide can have a good gel hardness. In the present specification, a value obtained by GPC (standard substance: pullulan) under the following measurement conditions is adopted as the weight average molecular weight.
- the method for producing the polysaccharide of the present invention is not particularly limited, and known methods such as those described in WO 2005/087289 pamphlet, JP 2011-68827 A, JP 2008-29824 A, etc. Or it can modify and apply suitably.
- the particle size distribution of the polysaccharide powder is adjusted so that the content of the powder having a particle size of 200 to 750 ⁇ m is 30% by volume or more of the total volume of the powder.
- the method is not particularly limited as long as it can be performed, and may be adjusted by ordinary classification.
- the polysaccharide prepared as described above is dissolved in a solvent to prepare a polysaccharide solution (polysaccharide solution preparation step); the polysaccharide solution is lyophilized to obtain a lyophilized product (lyophilization step); Furthermore, a method of pulverizing the lyophilized product at a rotational speed of 6000 to 12000 rpm (pulverization step) is preferably applied.
- the present invention comprises preparing a polysaccharide solution by dissolving a polysaccharide in a solvent, lyophilizing the polysaccharide solution to obtain a lyophilized product, and further pulverizing the lyophilized product at a rotational speed of 6000 to 8000 rpm.
- a process for producing a polysaccharide dry powder having: According to such a method, the polysaccharide powder of the present invention having a particle size distribution in which the particle size of 30% by volume or more of the total volume is 200 to 750 ⁇ m can be efficiently produced.
- Polysaccharide solution preparation process In this step, the polysaccharide prepared as described above is dissolved in a solvent to prepare a polysaccharide solution.
- the solvent is not particularly limited as long as it can dissolve a polysaccharide.
- RO water water from which impurities have been removed by a reverse osmosis membrane
- distilled water distilled water for injection
- the amount of the solvent is not particularly limited, but is preferably 6 to 20 g, more preferably 8 to 15 g with respect to 1 g of polysaccharide.
- the polysaccharide solution may contain a stabilizer for the purpose of stabilizing the polysaccharide in the next step (lyophilization step).
- a stabilizer for the purpose of stabilizing the polysaccharide in the next step (lyophilization step).
- a well-known stabilizer can be used.
- non-reducing sugars such as sucrose, trehalose, stachyose, and raffinose
- polysaccharides such as dextran, soluble starch, dextrin, and inulin
- Monosaccharides such as rhamnose, allose, altrose, fructose, galactose, glucose, gulose, hamelose, idose, mannose and tagatose
- Disaccharides such as sophorose and solanose
- the amount of the stabilizer is not particularly limited. However, in view of stabilization of the polysaccharide in the next step (lyophilization step), the amount is preferably 0. 5 to 1.25 g, more preferably 0.75 to 1 g.
- the dissolution method when dissolving the polysaccharide in the solvent is generally performed by stirring.
- the dissolution may be performed with heating.
- the polysaccharide and, if necessary, the stabilizer may be added to the solvent and then dissolved by stirring at 0 to 10 ° C. for 50 minutes to 1 hour, or the stabilizer may be added to the solvent in advance.
- the polysaccharide may be further added and dissolved by stirring at 0 to 10 ° C. for 50 minutes to 1 hour.
- the solution may be filtered (for example, filter filtration).
- the freeze-drying conditions of the polysaccharide solution are not particularly limited as long as the polysaccharide can be brought into an appropriate dry state, and the same conditions as known can be applied.
- the freezing step ice crystals of the polysaccharide solution are formed.
- the cooling conditions of the polysaccharide solution in the freezing step at this time cannot be generally determined depending on the amount of the polysaccharide solution, the characteristics of the cooling device, etc.
- the cooling temperature is gradually lowered from 0 to 10 ° C. to ⁇ 30 to ⁇ 50 ° C. over a period of about 165 minutes. When a predetermined temperature of ⁇ 30 to ⁇ 50 ° C. is reached, the temperature is increased to 400 to Maintain for 500 minutes.
- the cooling step may be performed continuously or stepwise.
- the cooling / freezing device used for cooling is not particularly limited, but in order to achieve the above-described freezing process, it is preferably a cooling freezing device capable of adjusting the cooling freezing temperature, and the cooling freezing temperature and the cooling freezing time are controlled by a program. More preferably, it is possible. In order to smoothly perform the freezing process and the subsequent drying process, it is particularly preferable to use a freeze-drying apparatus.
- the water contained in the ice crystals is removed by sublimation under reduced pressure by the drying step.
- the decompression conditions at this time are not particularly limited, but are generally 0.5 to 5 Pa.
- the drying process may be performed in one stage or may be performed by changing conditions in a plurality of stages. Any drying apparatus may be used as long as it can be dried under reduced pressure under cooling, and a known apparatus can be appropriately employed.
- the freeze-dried product obtained above is pulverized at a rotational speed of 6000 to 12000 rpm.
- the freeze-dried product obtained above is pulverized by impact force to obtain the polysaccharide powder having the particle size distribution of the present invention.
- the freeze-dried product is pulverized at a rotational speed of 6000 to 8000 rpm.
- the grinder which can be used in this case will not be restrict
- the grinding conditions are not particularly limited as long as the polysaccharide powder having the particle size distribution of the present invention is obtained.
- the pulverization temperature is 20 to 30 ° C., more preferably around room temperature (25 ° C.).
- the pulverization time is 5 to 60 minutes, more preferably 10 to 30 minutes.
- additional pulverization may be performed using a screen having a hole diameter (diameter) of 1 to 10 mm.
- the freeze-dried product is pulverized by impact force or after being pulverized (primary pulverization), and further pulverized by shearing force, and then passes through a hole in a screen having a specific range of hole diameters (secondary pulverization). Therefore, the polysaccharide powder having the particle size distribution of the present invention can be obtained more efficiently.
- the hole diameter (diameter) of the screen is preferably 6 to 10 mm, more preferably no screen or 8 to 10 mm. In the present invention, it is particularly preferred to carry out grinding without a screen or to carry out additional grinding using a 10 mm screen during the grinding process.
- coarse pulverization may be performed before lyophilized product is pulverized.
- coarse pulverization may be performed by any method, and examples thereof include a manual pulverization method using a spatula, a spatula, a mortar, and the like.
- the coarse pulverization conditions are not particularly limited, but the lyophilized product is preferably coarsely pulverized under conditions such that the length of the largest side of the coarsely pulverized product is about 3 to 5 cm.
- the polysaccharide solution having the desired particle size distribution of the present invention can be obtained by the polysaccharide solution preparation step, the freeze-drying step, and the pulverization step.
- a sieving step (classification step) may be performed after the powder step. Good. By performing this step, excessively large powder can be removed.
- the opening of the sieve when performing this step is not particularly limited, but is preferably 710 to 1000 ⁇ m from the viewpoint of removing excessively large powder.
- the vibration conditions for sieving while vibrating are not particularly limited. For example, it is preferable to vibrate at 20 to 30 ° C. for 3 to 10 minutes with an amplitude of 1 to 2 mm / g.
- the polysaccharide powder having the desired particle size distribution of the present invention can be obtained by the above method.
- the polysaccharide powder of the present invention can exhibit excellent water solubility (can be quickly dissolved in water). Therefore, the polysaccharide powder of the present invention is preferable as an anti-adhesion material, and in this case, it can quickly respond to a sudden application at a surgical site. Therefore, the present invention also provides an anti-adhesion material comprising the polysaccharide powder of the present invention.
- the anti-adhesion material of the present invention may be composed of only the polysaccharide powder of the present invention, or may contain other components to form a polysaccharide composition.
- the other components may form a polysaccharide composition in contact with the polysaccharide powder, or may be in a non-contact state until mixing at the time of use.
- the other components are not particularly limited and are appropriately selected in consideration of the type of polysaccharide powder. Specific examples include a pH adjuster and a polymer material. Each of the other components may be used alone or in the form of a mixture of two or more, or used in combination with at least one pH adjuster and at least one polymer material. May be.
- the pH adjuster is mainly an aqueous solution for adjusting the pH of the polysaccharide powder / polysaccharide composition according to the present invention to 7.5 to 12, a solvent containing water, or a salt (powder). It is possible.
- the pH adjuster is not particularly limited, and specific examples include sodium hydrogen carbonate aqueous solution or powder, phosphate buffer (disodium hydrogen phosphate-potassium dihydrogen phosphate), acetic acid-ammonia buffer, and the like. It is done.
- sodium hydrogencarbonate can be suitably used in terms of safety since about 7% aqueous solution (pH 8.3) thereof is used as a intravenous injection solution as a medical pH adjuster.
- a two-component system comprising an aqueous solution having a polysaccharide powder concentration of 1 to 80% (w / v) and water adjusted to pH 7.5 to 10.5, which is maintained separately from the aqueous solution.
- both can be mixed at the time of use to obtain a mixed aqueous solution having a final polysaccharide powder concentration of 0.1 to 60% (w / v).
- a pH adjuster salt is added and dissolved in an aqueous solution having a polysaccharide powder concentration of 1 to 80% (w / v), and the final polysaccharide powder concentration is 0.1.
- a normal mixing method can be selected for mixing, but it is preferable to perform the mixing until the mixed state becomes uniform, and it may be uniform so long as a desired reaction proceeds.
- the polymer material is not particularly limited, but preferably has an effect of adjusting the hardness and properties of the hydrogel when the polysaccharide composition is crosslinked, for example.
- the polymer material preferably has two or more primary amino groups, thiol groups, or hydroxyl groups in one molecule of the polymer material. Specific examples include polyalkylene glycol derivatives, polypeptides, polysaccharides or derivatives thereof.
- the content of the polymer material in the polysaccharide composition according to the present invention is not particularly limited, but it is preferably 5 to 50% by weight based on the whole polysaccharide composition.
- polyalkylene glycol derivatives examples include polyethylene glycol (PEG) derivatives, polypropylene glycol derivatives, polybutylene glycol derivatives, polypropylene glycol-polyethylene glycol block copolymer derivatives, and random copolymer derivatives.
- PEG polyethylene glycol
- polypropylene glycol derivatives examples include polypropylene glycol derivatives, polybutylene glycol derivatives, polypropylene glycol-polyethylene glycol block copolymer derivatives, and random copolymer derivatives.
- the basic polymer skeleton of the polyethylene glycol derivative include ethylene glycol, diglycerol, pentaerythritol, and hexaglycerol.
- the molecular weight of the polyalkylene glycol derivative is not particularly limited, but is preferably 100 to 50,000, and more preferably 1,000 to 20,000.
- the polyethylene glycol derivative is not particularly limited, but, for example, an ethylene glycol type polyethylene glycol derivative having a thiol group at both ends and having a weight average molecular weight of 1,000, 2,000, 6,000, or 10,000, Ethylene glycol type polyethylene glycol derivatives having an amino group having a weight average molecular weight of 1,000, 2,000, 6,000 or 10,000, and a weight average molecular weight having a thiol group at three terminals of 5,000 or 10,000 Trimethylolethane type polyethylene glycol derivatives having 3 amino groups at the ends and a weight average molecular weight of 5,000 or 10,000, and 5 weight average molecular weights having thiol groups at the 4 ends.
- 000 10,000 or 20,000 diglycerol type polyethylene glycol derivatives, diglycerol type polyethylene glycol derivatives having amino groups at four ends, weight average molecular weights of 5,000, 10,000 or 20,000 at four ends
- weight-average molecular weight is one of numerical values representing the average molecular weight of a polymer. Since a polymer is a mixture of molecules having the same basic structural unit and different molecular lengths (chain lengths), it has a molecular weight distribution corresponding to the difference in molecular chain length. Average molecular weight is used to indicate its molecular weight. The average molecular weight includes a weight average molecular weight, a number average molecular weight, and the like. Here, the weight average molecular weight is used. In addition, the value (100%) of the weight average molecular weight in the present invention includes those having an upper limit of 110% and a lower limit of 90%.
- Polyethylene glycol derivatives can be produced, for example, according to the method described in Chapter 22 of Poly (ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J Milton Harris, Plenum Press, NY (1992). Alternatively, it can be chemically modified to contain multiple primary amino groups or thiol groups. Further, it can be purchased from Nippon Oil & Fats Co., Ltd. as a polyethylene glycol derivative (Sunbright HGEO-20TEA, Sunbright PTE-10TSH, etc.).
- the polypeptide is not particularly limited, and examples thereof include collagen, gelatin, albumin, and polylysine.
- the polysaccharide is not particularly limited, and examples thereof include pectin, hyaluronic acid, chitin, chitosan, carboxymethyl chitin, carboxymethyl chitosan, chondroitin sulfate, keratin sulfate, kerato sulfate, heparin, and derivatives thereof.
- suitable combinations of the polysaccharide powder and the polymer material are as follows.
- the shape for example, sheet form, powder form, liquid form
- the shape for example, sheet form, powder form, liquid form
- CM carboxymethyl
- SD / AP polysaccharide powder / polymer material (weight ratio)
- the polymer material is more than 80% by weight.
- the adhesion-preventing material comprising the polysaccharide composition can be provided in a desired form such as a sheet, powder or liquid.
- a powdery polysaccharide composition may be prepared by mixing the powdered polymer material with the polysaccharide powder of the present invention.
- a powdered polysaccharide composition containing the pH adjusting agent salt obtained by mixing the polysaccharide powder of the present invention or the powdered polysaccharide composition with a powdered pH adjusting salt may be prepared. .
- a granulated product can be prepared by granulating the powdered polysaccharide composition or the powdered polysaccharide composition containing a salt of a pH adjuster, and the powdered polysaccharide composition or pH adjuster.
- Sheets and plates can be prepared by pressing the powdered polysaccharide composition containing the salt of
- the sheet-like polysaccharide composition can be obtained by adhering the polymer material in powder form to the heat-dried sheet or freeze-dried sheet of the polysaccharide powder, or attaching the polymer material by a coating method.
- “attachment” refers to a state in which the surface of the sheet is covered with the polymer material by impregnating the surface of the sheet with the polymer material. When the sheet has a porous structure, the polymer material covers the surface of the sheet and the inner surface of the holes inside the sheet.
- an aqueous solution of a polysaccharide powder and an aqueous solution of a polymer material may be prepared, respectively, so as to be a two-part type.
- a hydrogel composed of polysaccharide powder and a polymer material can be prepared.
- the concentration of the aqueous solution of polysaccharide powder is preferably 1 to 80% (w / v)
- the concentration of the aqueous solution of the polymer material is preferably 1 to 80% (w / v).
- the water for dissolving the polymer material may be water adjusted to pH 7.5 to 10.5.
- the salt of a pH adjuster at the time of mixing using a pure water or a buffer solution.
- the combined concentration of the final polysaccharide powder and the polymer material is preferably 0.1 to 80% (w / v).
- the sheet-like polysaccharide composition can be crosslinked in the presence of moisture.
- the above-mentioned pH adjuster can be used as a water
- the pH adjuster is preferably an aqueous solution having a pH of 7.5 to 10.5. You may make the pH adjuster adhere to a sheet-like polysaccharide composition in powder form.
- the sheet-like polysaccharide composition is formed through an attaching process in which the polysaccharide powder is dissolved in water, the solution is developed into a desired shape and dried, and a polymer material is attached to the obtained polysaccharide powder sheet. Is done.
- the attaching step impregnates the polymer material without impairing the shape of the surface of the sheet-like polysaccharide powder by impregnating the sheet material with a polymer material and a solution containing a non-aqueous volatile organic solvent and drying the sheet material. It becomes possible to make it.
- the “non-aqueous volatile organic solvent” means an organic solvent that is not compatible with water and volatilizes.
- the non-aqueous volatile organic solvent is not particularly limited, and examples thereof include chloroform and dichloromethane.
- the dosage form of the anti-adhesion material is not particularly limited, and examples thereof include liquid, sheet, powder, paste, and aerosol.
- the polysaccharide powder or polysaccharide composition as an adhesion preventing material can be used by being developed into a desired shape as described above.
- the polysaccharide composition containing the polymer material can be used by further mixing with the pH adjusting agent.
- a polysaccharide composition with a pH adjuster you may mix beforehand (premix) and may mix suitably on the spot at the time of use.
- an aqueous solution such as a pH adjuster at the time of use, an adhesion preventing material can be applied to a desired local area.
- the polysaccharide composition can further contain widely known additives as long as the characteristics of the present invention are not impaired.
- additives are not particularly limited, but include curing catalysts, fillers, plasticizers, softeners, stabilizers, dehydrating agents, colorants, anti-sagging agents, thickeners, physical property modifiers, reinforcing agents, thixotropic agents, and deterioration.
- Specific additives include water, physiological saline, pharmaceutically acceptable organic solvents, gelatin, collagen, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, sodium polyacrylate, sodium alginate, water-soluble Dextran, sodium carboxymethyl starch, pectin, methylcellulose, ethylcellulose, xanthan gum, gum arabic, tragacanth, casein, agar, diglycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin (HSA) , Mannitol, sorbitol, lactose, PBS, nonionic surfactant, biodegradable polymer, serum-free medium, pharmaceutical supplement
- buffers at physiological pH acceptable in acceptable surfactant or in vivo can be mentioned as objects.
- the carrier to be used is selected appropriately or in combination from the above depending on the use site, but is not limited thereto. Moreover, it can prepare as preparations, such as aerosol and a paste, with a suitable propellant.
- the anti-adhesion material of the present invention can be provided as a kit containing the aforementioned pH adjuster in consideration of convenience during use.
- the anti-adhesion material can be included in the package or package together with or separately from the anti-adhesion material, with the polysaccharide powder, polysaccharide composition and / or pH adjuster each not being mixed.
- the package may contain other components that can be used as an anti-adhesion material.
- the polysaccharide powder or polysaccharide composition can be included in the kit as a powder, a sheet, or an aqueous solution with or without an aqueous solution or powdery pH adjuster.
- the “adhesion prevention material” means a substance used for the purpose of preventing adhesion at or near the adhesion prevention site of a living body, comprising a safe component having low toxicity harmful to the living body, It is acceptable for living organisms.
- the anti-adhesion material may be degradable in the living body or non-degradable, but is preferably biodegradable.
- Attaching an anti-adhesive material to the target location and covering the location where the adhesion has occurred or the location where the occurrence of the adhesion is predicted is obstructed, if necessary, thereby inhibiting the adhesion and exerting the anti-adhesion effect.
- An anti-adhesive material is attached to the target location, and other desired sites are bonded, fixed, allowed to stand, or crimped, and a certain time elapses. At that time, a fixing tool or the like can be used.
- the present invention provides a living body adhesion prevention method comprising bringing an adhesion prevention material into contact with a desired site in the presence of moisture.
- an adhesion prevention material In order to make it contact with a desired site
- a sheet-like anti-adhesion material In the case of a sheet-like anti-adhesion material, this is achieved by sticking, filling, covering, crimping, or standing.
- a liquid anti-adhesion material this is achieved by applying, spraying, dripping, applying, or applying.
- the polysaccharide powder of the present invention dissolves quickly in water, when used as an anti-adhesion material, it satisfies clinical requirements and does not use biological materials in terms of safety. Therefore, the risk of infectious diseases can be avoided.
- the polysaccharide powder of the present invention is designed such that the component itself or its degradation product has low toxicity, and the polysaccharide is a main skeleton, so that it has biodegradability and absorbability.
- the polysaccharide powder used in the present invention reduces the number of preparatory operations to be performed in advance and can respond quickly to sudden application, and no special equipment is required for its use, so anyone can easily Can be used.
- the polysaccharide powder can be provided alone or as a polysaccharide composition containing it, a wide variety of usage methods are possible.
- the said polysaccharide composition has not impaired the characteristic of the polysaccharide powder which has said characteristic.
- the polysaccharide powder and polysaccharide composition of the present invention can be processed into various shapes such as powder, sheet, granulated product, etc., and can be used properly according to the purpose.
- the method for producing the polysaccharide powder and the polysaccharide composition is simple without requiring a special apparatus or the like because it is sufficient to mix and heat necessary reagents. From the above characteristics, the polysaccharide powder and the composition thereof according to the present invention are suitable as an adhesion preventing material.
- Synthesis Example 1 Synthesis of polysaccharide
- 62.5 g of an aqueous solution was added and stirred at room temperature (25 ° C.) for 90 minutes. Thereto was added chloroacetic acid aqueous solution to which 75 g was added by adding distilled water to 10.31 g (109.1 mmol) of chloroacetic acid, and reacted at 60 ° C. for 6 hours.
- CM dextrin After cooling to room temperature (25 ° C.), 80 mL of 20% HCl aqueous solution was added to obtain a reaction solution containing CM dextrin. Next, the entire amount of the reaction solution obtained above was poured into a 5 L beaker containing 4450 mL of ethanol and 180 mL of water with stirring. The precipitate was collected by filtration, washed first with 2 L of 90% ethanol aqueous solution and then with 2 L of ethanol, and then dried under reduced pressure at room temperature (25 ° C.) for 24 hours to obtain CM dextrin. The CM group content of the CM dextrin thus obtained was 0.8 mmol / g. The CM base amount is measured according to the following method.
- the usage amount (V 0 (mL)) of 0.05 mol / L sulfuric acid in a blank to which no acid-type polysaccharide is added is measured, and the carboxy group amount (B mmol / g) of the polysaccharide is calculated according to the following formula (1).
- the titers of the 0.1 mol / L aqueous sodium hydroxide solution and 0.05 mol / L sulfuric acid used are 1.00.
- reaction solution 2 20.2 g of citric acid was added to reaction solution 1 and mixed for 20 minutes to obtain reaction solution 2.
- the filtrate was dried under reduced pressure at 40 ° C. for 24 hours to obtain NHS-modified CM dextrin (NHS introduction rate: 70 to 100%).
- the molecular weight of the NHS-modified CM dextrin thus obtained was 30,000 to 50,000.
- Example 1 Solution Preparation Step After flowing cooling water (set at 1.0 ° C.) through a jacket portion of a 20 L stainless steel tank, 3250 g of distilled water for injection was added, and 300 g of trehalose as a stabilizer was added thereto. To this solution, 300 g of the NHS-modified CM dextrin obtained in Synthesis Example 1 was added and stirred at 5.0 to 8.0 ° C. for about 1 hour to dissolve the NHS-modified CM dextrin in the solution. After dissolution, filter filtration was performed using a pump, and the filtrate was collected in a 20 L bag.
- Freeze-drying step The filtrate was dispensed from the 20-L bag collected in the above to a freeze-drying tray (size: 44 cm ⁇ 29 cm) to a volume of 2.5 L, and then freeze-dried according to the program shown in Table 1 below. As a result, a freeze-dried polysaccharide was obtained.
- the following drying step was performed under reduced pressure conditions of 1.7 to 5.1 Pa.
- the shelf temperature was continuously cooled from 5 ° C. to ⁇ 50 ° C. over 165 minutes using a freeze drying device (freeze drying device RL-201BS manufactured by Kyowa Vacuum Co., Ltd.), and ⁇ 50 Freeze at 480 minutes.
- the shelf temperature was gradually increased from ⁇ 50 ° C. to ⁇ 10 ° C. over 120 minutes and dried at ⁇ 10 ° C. for 3600 minutes.
- the shelf temperature was gradually increased from ⁇ 10 ° C. to 5 ° C. over 480 minutes and dried at 5 ° C. for 4200 minutes.
- the shelf temperature was gradually increased from 5 ° C. to 30 ° C. over 60 minutes, and dried at 30 ° C. for 600 minutes.
- Coarse pulverization and ultracentrifugation step 2 The polysaccharide freeze-dried product obtained in 1 above was roughly pulverized with a spatula (so as to have a size of about 3 cm ⁇ 3 cm ⁇ 3 cm), and then ultracentrifuge crusher (trade name: Ultracentrifuge crusher, manufactured by Lecce Co., Ltd. ) To obtain a polysaccharide pulverized product. At this time, a screen was not used in the ultracentrifugal mill.
- Example 2 Example 1 of Example 1 except that an ultracentrifugal mill (trade name: ultracentrifugal mill ZM200, manufactured by Lecce Co., Ltd.) equipped with a screen having a screen diameter (diameter) of 10 mm was used instead. ⁇ 4. This process was repeated to obtain a polysaccharide classifier (polysaccharide powder (2)).
- an ultracentrifugal mill trade name: ultracentrifugal mill ZM200, manufactured by Lecce Co., Ltd.
- Example 5 of Example 1 except that this polysaccharide classifier (polysaccharide powder (2)) was used. These steps were repeated to obtain a vial (2).
- Example 3 Example 1 of Example 1 except that an ultracentrifugal mill (trade name: ultracentrifugal mill ZM200, manufactured by Lecce Co., Ltd.) provided with a screen having a screen diameter (diameter) of 8 mm was used instead. ⁇ 4. These steps were repeated to obtain a polysaccharide classifier (polysaccharide powder (3)).
- an ultracentrifugal mill trade name: ultracentrifugal mill ZM200, manufactured by Lecce Co., Ltd.
- Example 5 of Example 1 except that this polysaccharide classifier (polysaccharide powder (3)) was used. These steps were repeated to obtain a vial (3).
- Example 4 Example 1 of Example 1 except that an ultracentrifugal mill (trade name: ultracentrifugal mill ZM200, manufactured by Lecce Co., Ltd.) provided with a screen having a screen diameter (diameter) of 6 mm was used instead. ⁇ 4. This process was repeated to obtain a polysaccharide classifier (polysaccharide powder (4)).
- an ultracentrifugal mill trade name: ultracentrifugal mill ZM200, manufactured by Lecce Co., Ltd.
- Example 1 an ultracentrifugal mill (trade name: ultracentrifugal mill ZM200, manufactured by Lecce Co., Ltd.) equipped with a screen having a screen diameter (diameter) of 2 mm was used instead, and the grinding speed was changed to 12000 rpm. Except for the above, 1. ⁇ 4. These steps were repeated to obtain a comparative polysaccharide classifier (comparative polysaccharide powder (1)).
- Example 1 In Example 1, 5. except that this comparative polysaccharide classifier (comparative polysaccharide powder (1)) was used. By repeating the above process, a comparative vial (1) was obtained.
- Example 2 In Example 1, an ultracentrifugal mill (trade name: ultracentrifugal mill ZM200, manufactured by Lecce Co., Ltd.) equipped with a screen having a screen diameter (diameter) of 6 mm was used instead, and the grinding speed was changed to 12000 rpm. Except for the above, 1. ⁇ 4. These steps were repeated to obtain a comparative polysaccharide classifier (comparative polysaccharide powder (2)).
- Example 5 of Example 1 except that this comparative polysaccharide classifier (Comparative polysaccharide powder (2)) was used. These steps were repeated to obtain a comparative vial (2).
- Comparative polysaccharide powder (2) Comparative polysaccharide powder (2)
- Example 3 In Example 1, an ultracentrifugal mill (trade name: ultracentrifugal mill ZM200, manufactured by Lecce Co., Ltd.) equipped with a screen having a screen diameter (diameter) of 8 mm was used instead, and the grinding speed was changed to 12000 rpm. Except for the above, 1. ⁇ 4. This process was repeated to obtain a comparative polysaccharide classifier (comparative polysaccharide powder (3)).
- Example 5 of Example 1 except that this comparative polysaccharide classifier (Comparative polysaccharide powder (3)) was used. These steps were repeated to obtain a comparative vial (3).
- Comparative polysaccharide powder (3) Comparative polysaccharide powder (3)
- Example 4 In Example 1, an ultracentrifugal mill (trade name: ultracentrifugal mill ZM200, manufactured by Lecce Co., Ltd.) equipped with a screen having a screen diameter (diameter) of 10 mm was used instead, and the grinding speed was changed to 12000 rpm. Except for the above, 1. ⁇ 4. The above-mentioned process was repeated to obtain a comparative polysaccharide classifier (comparative polysaccharide powder (4)).
- an ultracentrifugal mill trade name: ultracentrifugal mill ZM200, manufactured by Lecce Co., Ltd.
- a screen having a screen diameter (diameter) of 10 mm was used instead, and the grinding speed was changed to 12000 rpm. Except for the above, 1. ⁇ 4.
- the above-mentioned process was repeated to obtain a comparative polysaccharide classifier (comparative polysaccharide powder (4)).
- Example 5 of Example 1 except that this comparative polysaccharide classifier (Comparative polysaccharide powder (4)) was used. By repeating the above process, a comparative vial (4) was obtained.
- This comparative polysaccharide classifier Comparative polysaccharide powder (4)
- Comparative Example 5 In Example 1, except that the grinding speed was changed to 12000 rpm, 1. ⁇ 4. These steps were repeated to obtain a comparative polysaccharide classifier (comparative polysaccharide powder (5)).
- Example 5 of Example 1 except that this comparative polysaccharide classifier (Comparative polysaccharide powder (5)) was used. The process was repeated to obtain a comparative vial (5).
- This comparative polysaccharide classifier Comparative polysaccharide powder (5)
- Example 1 After completion of the solution preparation step, the filtrate was filled into 16 ml vials (Nihon Glass Industrial Co., Ltd., Vials White 30 ⁇ 50 products). About the obtained vial, Example 1 2. 4. Lyophilization step and The negative pressure stoppering process of was performed, and the comparative example (6) (bulk body) was obtained.
- the polysaccharide powder of the present invention can be dissolved in water significantly more rapidly than the polysaccharide powder of the comparative example.
- the anti-adhesion material containing the polysaccharide powder of the present invention is expected to dissolve within 1 minute at the shortest, and can be quickly applied to various medical sites such as injections and infusions at the surgical site. It is expected that it can respond to.
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Abstract
Description
本発明の多糖粉末は、全体積の30体積%以上の粒径(直径)が200~750μmである粒度分布を有する。このような粒度分布を有する多糖粉末は、良好な水溶性を示す。ここで、200~750μmである粒度分布を有する多糖粉末の含有量が全体積の30体積%未満である場合には、水溶性に劣り、急な手術現場に良好に対応できない。好ましくは、本発明の多糖粉末は、全体積の40体積%以上、より好ましくは50体積%以上、特に好ましくは60体積%以上の粒径が200~750μmである粒度分布を有する。ここで、200~750μmである粒度分布を有する多糖粉末の含有量の上限は、特に制限されないが、水溶性の向上などを考慮すると、70体積%以下であることが好ましく、65体積%以下であることがより好ましく、55体積%以下であることが特に好ましい。
本発明の多糖粉末の製造方法(粒度分布の調節方法)は、多糖粉末の粒度分布を粒径が200~750μmである粉末の含有量を粉末の全体積の30体積%以上となるように調節することができる方法であれば特に制限されず、通常の分級によって調節されてもよい。好ましくは、上記のようにして調製された多糖を溶媒に溶解して多糖溶液を調製し(多糖溶液調製工程);前記多糖溶液を凍結乾燥して、凍結乾燥物を得(凍結乾燥工程);さらに前記凍結乾燥物を6000~12000rpmの回転速度で粉砕する(粉砕工程)方法が好ましく適用される。すなわち、本発明は、多糖を溶媒に溶解して多糖溶液を調製し、前記多糖溶液を凍結乾燥して、凍結乾燥物を得、さらに前記凍結乾燥物を6000~8000rpmの回転速度で粉砕することを有する、多糖乾燥粉末の製造方法をも提供する。このような方法によると、全体積の30体積%以上の粒径が200~750μmである粒度分布を有する本発明の多糖粉末を効率的に製造できる。
本工程では、上記のようにして調製された多糖を溶媒に溶解して多糖溶液を調製する。
本工程では、上記で得られた多糖溶液を凍結乾燥して、凍結乾燥物を得る。
本工程では、上記で得られた凍結乾燥物を6000~12000rpmの回転速度で粉砕する。これにより、上記で得られた凍結乾燥物は衝撃力により粉砕されて、本発明の粒度分布を有する多糖粉末が得られる。好ましくは、凍結乾燥物を6000~8000rpmの回転速度で粉砕する。また、この際使用されうる粉砕機は、上記回転速度での粉砕が可能な機器であれば特に制限されない。例えば、超遠心粉砕機、カッターミル、ハンマーミル、フラッシュミル、ジェットミル、ボールミル、振動ボールミルなどが挙げられる。
上記多糖溶液調製工程、凍結乾燥工程及び粉砕工程によって、本発明の所望の粒度分布を有する多糖粉末が得られるが、必要であれば、上記粉末工程後、篩い工程(分級工程)を行ってもよい。当該工程を行うことにより、過度に大きな粉末を除去することができる。当該工程を行う場合の、篩の目開きは、特に制限されないが、過度に大きな粉末を除去するという観点からは、710~1000μmであることが好ましい。また、当該篩い工程(分級工程)は、必要であれば、振動させながら行ってもよい。振動させながら篩いを行うことによって、粉末の回収量を増加させることができる。振動させながら篩いを行う際の振動条件は、特に制限されないが、例えば、1~2mm/gの振幅で、20~30℃で3~10分間、振動させることが好ましい。
500mLフラスコ中、デキストリン(名糖産業株式会社製サンデックSD#100,Mw=15kDa)10gを、純水62.5gにダマや濁りがなくなるまで溶解した後、36wt%NaOH水溶液62.5gを添加して、室温(25℃)で90分間撹拌した。そこに、クロル酢酸10.31g(109.1mmol)に蒸留水を加え75gとしたクロル酢酸水溶液を添加し、60℃で6時間反応させた。室温(25℃)まで冷却した後、20%HCl水溶液を80mL添加し、CMデキストリンを含む反応液を得た。次に、エタノール4450mLおよび水180mLを含む5Lビーカー中に、撹拌下、上記で得た反応液全量を注ぎ込んだ。析出物を濾集し、最初に90%エタノール水溶液2Lで、次にエタノール2Lで洗浄した後、室温(25℃)で24時間減圧乾燥し、CMデキストリンを得た。このようにして得られたCMデキストリンのCM基量は0.8mmol/gであった。なお、CM基量は下記の方法に従って測定される。
多糖(CMデキストリン)0.2g(A(g))を秤取り、0.1mol/L水酸化ナトリウム水溶液20mLと80vol%メタノール水溶液10mLとの混合溶液に添加し、25℃で3時間撹拌した溶液に、1.0%フェノールフタレイン/90vol%エタノール水溶液を滴下し、0.05mol/L硫酸を使用して酸塩基逆滴定を行い、0.05mol/L硫酸の使用量(V1(mL))を測定する。酸型多糖を添加しないブランクでの0.05mol/L硫酸の使用量(V0(mL))を測定し、下記式(1)に従い、多糖のカルボキシ基量(Bmmol/g)を算出する。なお、使用した0.1mol/L水酸化ナトリウム水溶液、0.05mol/L硫酸の力価は、ともに1.00である。
1.溶液調製工程
20L容のステンレスタンクのジャケット部分に、冷却水(1.0℃に設定)を流した後、注射用蒸留水3250gを入れ、これに安定化剤としてのトレハロース300gを加えた。この溶液に、上記合成例1で得られたNHS化CMデキストリン300gを加え、5.0~8.0℃で1時間程度攪拌し、NHS化CMデキストリンを上記溶液中に溶解した。溶解後、ポンプを用いてフィルター濾過を行ない、20L容のバックにろ液を回収した。
上記1.で回収された20L容のバックから凍結乾燥用トレイ(大きさ:44cm×29cm)に、ろ液を容量2.5Lとなるように分注した後、下記表1に示されるプログラムに従って、凍結乾燥して、多糖凍結乾燥体を得た。なお、下記乾燥工程は、1.7~5.1Paの減圧条件下で行った。なお、下記予備凍結工程は、凍結乾燥装置(共和真空株式会社製 凍結乾燥装置 RL-201BS)を用いて、棚温度を5℃→-50℃まで165分かけて連続的に冷却し、-50℃で480分間凍結させた。次に、棚温度を-50℃から-10℃まで120分かけて徐々に上昇させ、-10℃で3600分間乾燥させた。次に、棚温度を-10℃から5℃まで480分かけて徐々に上昇させ、5℃で4200分間乾燥させた。次に、棚温度を5℃から30℃まで60分かけて徐々に上昇させ、30℃で600分間乾燥させた。
上記2.で得られた多糖凍結乾燥体を、へらで(3cm×3cm×3cm程度の大きさになるように)粗粉砕した後、超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を用いて、6000rpmで20分間粉砕し、多糖粉砕体を得た。この際、超遠心粉砕機にはスクリーンは使用しなかった。
このようにして得られた多糖粉砕物を電磁式篩い振とう機(株式会社 レッチェ製、商品名:電磁式ふるい振とう機 AS200)に設置し、篩い目開きが710μmの篩で、振幅1.2mm/gで、3分間分級し、710μmの篩いを通過したものを回収し、多糖分級体(多糖粉末(1))を得た。
粉末充填装置(粉末計量自動充填機 TM-F51Z3-L)を用いて、上記4.で篩いをかけた多糖分級体を、2.5±0.02gの精度で、バイアル(株式会社日本硝子産業株式会社、バイアル白30×50品)内に充填し、ゴム栓でバイアルを半打栓した。半打栓したバイアルを-700mmHg以上および-400mmHgの陰圧度となるように陰圧打栓した(バイアル(1))。
実施例1において、スクリーン径(直径)が10mmのスクリーンを備えた超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を代わりに使用した以外は、実施例1の1.~4.の工程を繰り返して、多糖分級体(多糖粉末(2))を得た。
実施例1において、スクリーン径(直径)が8mmのスクリーンを備えた超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を代わりに使用した以外は、実施例1の1.~4.の工程を繰り返して、多糖分級体(多糖粉末(3))を得た。
実施例1において、スクリーン径(直径)が6mmのスクリーンを備えた超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を代わりに使用した以外は、実施例1の1.~4.の工程を繰り返して、多糖分級体(多糖粉末(4))を得た。
実施例1において、スクリーン径(直径)が2mmのスクリーンを備えた超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を代わりに使用し、さらに、粉砕速度を12000rpmに変更した以外は、実施例1の1.~4.の工程を繰り返して、比較多糖分級体(比較多糖粉末(1))を得た。
1の5.の工程を繰り返して、比較バイアル(1)を得た。
実施例1において、スクリーン径(直径)が6mmのスクリーンを備えた超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を代わりに使用し、さらに、粉砕速度を12000rpmに変更した以外は、実施例1の1.~4.の工程を繰り返して、比較多糖分級体(比較多糖粉末(2))を得た。
実施例1において、スクリーン径(直径)が8mmのスクリーンを備えた超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を代わりに使用し、さらに、粉砕速度を12000rpmに変更した以外は、実施例1の1.~4.の工程を繰り返して、比較多糖分級体(比較多糖粉末(3))を得た。
実施例1において、スクリーン径(直径)が10mmのスクリーンを備えた超遠心粉砕機(株式会社 レッチェ製、商品名:超遠心粉砕機 ZM200)を代わりに使用し、さらに、粉砕速度を12000rpmに変更した以外は、実施例1の1.~4.の工程を繰り返して、比較多糖分級体(比較多糖粉末(4))を得た。
実施例1において、粉砕速度を12000rpmに変更した以外は、実施例1の1.~4.の工程を繰り返して、比較多糖分級体(比較多糖粉末(5))を得た。
実施例1において、溶液調製工程終了後に、ろ液を16mlバイアル(株式会社日本硝子産業株式会社、バイアル白30×50品)に充填した。得られたバイアルについて、実施例1 2.の凍結乾燥工程および5.の陰圧打栓工程を行い、比較例(6)(バルク体)を得た。
まず、多糖乾燥粉末(バイアル入り)の重量を測定する。次に、シリンジに溶解水として注射用蒸留水を吸い取り、JIGを用いて、一定の高さから溶解水(3.4~3.6ml)を注入する。溶解水注入直後のバイアルの底部およびバイアル壁面の観察を行い、写真を撮影する。人の手で振盪を開始し、振盪(人の手でふる操作)を開始した時を0秒として30秒毎に溶解状態を観察する。また、観察と同時に写真を撮影する。この操作を合計時間が150秒となるまで続ける。ただし、途中で完全に溶解した場合は、溶解時間を記録し終了する。溶解水注入後のバイアル重量を測定し、溶解水注入量を算出する。
Claims (6)
- 全体積の30体積%以上の粒径が200~750μmである粒度分布を有する、多糖を含む粉末。
- 累積体積比率が10%となる粒径(D10)が60~120μmである、請求項1に記載の粉末。
- 累積体積比率が90%となる粒径(D90)が300~520μmである、請求項1または2に記載の粉末。
- ピークトップが100~500μmである、請求項1~3のいずれか1項に記載の粉末。
- 前記多糖が3万~12万の分子量を有する、請求項1~4のいずれか1項に記載の粉末。
- 請求項1~5のいずれか1項に記載の粉末を含む、癒着防止材。
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Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63105004A (ja) * | 1986-10-22 | 1988-05-10 | Mitsubishi Acetate Co Ltd | ロ−カストビ−ンガムの精製法 |
JPH01275601A (ja) * | 1988-04-27 | 1989-11-06 | Kanegafuchi Chem Ind Co Ltd | セルロース系粒子 |
JP2000063565A (ja) * | 1998-08-20 | 2000-02-29 | Shin Etsu Chem Co Ltd | 粒状水溶性セルロースエーテル及びその製造方法 |
WO2004080502A1 (ja) * | 2003-03-10 | 2004-09-23 | Kawasumi Laboratories, Inc. | 癒着防止材 |
WO2005087289A1 (ja) | 2004-03-15 | 2005-09-22 | Terumo Kabushiki Kaisha | 癒着防止材 |
JP2008029824A (ja) | 2006-06-28 | 2008-02-14 | Terumo Corp | 医療用処置材 |
US20080294099A1 (en) | 2007-05-23 | 2008-11-27 | Terumo Kabushiki Kaisha | Sprayer |
JP2011505428A (ja) * | 2007-01-24 | 2011-02-24 | ダウ グローバル テクノロジーズ インコーポレイティド | アルカリセルロースまたはセルロース誘導体の製造方法 |
WO2011027706A1 (ja) | 2009-09-02 | 2011-03-10 | テルモ株式会社 | 多孔質構造体 |
WO2011027729A1 (ja) * | 2009-09-02 | 2011-03-10 | 日本曹達株式会社 | ヒドロキシプロピルセルロース粒子 |
JP2011509932A (ja) * | 2008-01-14 | 2011-03-31 | スターチ メディカル インコーポレーテッド | 生物相容性の止血、癒着防止、癒合促進、外科密封可能な変性澱粉材料 |
JP2011068827A (ja) | 2009-09-28 | 2011-04-07 | Terumo Corp | 活性エステル化多糖およびその製造方法 |
JP2011084588A (ja) * | 2009-09-16 | 2011-04-28 | Q P Corp | ヒアルロン酸および/またはその塩からなる粉末 |
WO2013077414A1 (ja) * | 2011-11-25 | 2013-05-30 | 株式会社大塚製薬工場 | 癒着防止又は止血に有用な医薬組成物 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW209174B (ja) * | 1991-04-19 | 1993-07-11 | Takeda Pharm Industry Co Ltd | |
AU648704B2 (en) * | 1991-11-25 | 1994-04-28 | National Starch And Chemical Investment Holding Corporation | Method of extruding starch under low moisture conditions using feed starch having coarse particle size |
US20030124087A1 (en) * | 2001-12-26 | 2003-07-03 | Amitie Co. Ltd. | Anti-adhesion barrier |
US20090062233A1 (en) | 2007-08-09 | 2009-03-05 | Xin Ji | Modified starch material of biocompatible hemostasis |
US9901662B2 (en) | 2013-05-29 | 2018-02-27 | Otsuka Pharmaceutical Factory, Inc. | Adhesion preventing material |
-
2014
- 2014-02-13 WO PCT/JP2014/053378 patent/WO2014129382A1/ja active Application Filing
- 2014-02-13 US US14/769,397 patent/US9738730B2/en active Active
- 2014-02-13 EP EP14754523.0A patent/EP2960254B1/en active Active
- 2014-02-13 JP JP2015501419A patent/JP6285413B2/ja active Active
Patent Citations (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63105004A (ja) * | 1986-10-22 | 1988-05-10 | Mitsubishi Acetate Co Ltd | ロ−カストビ−ンガムの精製法 |
JPH01275601A (ja) * | 1988-04-27 | 1989-11-06 | Kanegafuchi Chem Ind Co Ltd | セルロース系粒子 |
JP2000063565A (ja) * | 1998-08-20 | 2000-02-29 | Shin Etsu Chem Co Ltd | 粒状水溶性セルロースエーテル及びその製造方法 |
WO2004080502A1 (ja) * | 2003-03-10 | 2004-09-23 | Kawasumi Laboratories, Inc. | 癒着防止材 |
WO2005087289A1 (ja) | 2004-03-15 | 2005-09-22 | Terumo Kabushiki Kaisha | 癒着防止材 |
US20080058469A1 (en) | 2004-03-15 | 2008-03-06 | Yoshihiko Abe | Adhesion Preventive Material |
JP2008029824A (ja) | 2006-06-28 | 2008-02-14 | Terumo Corp | 医療用処置材 |
JP2011505428A (ja) * | 2007-01-24 | 2011-02-24 | ダウ グローバル テクノロジーズ インコーポレイティド | アルカリセルロースまたはセルロース誘導体の製造方法 |
JP2008289986A (ja) | 2007-05-23 | 2008-12-04 | Terumo Corp | 塗布具 |
US20080294099A1 (en) | 2007-05-23 | 2008-11-27 | Terumo Kabushiki Kaisha | Sprayer |
JP2011509932A (ja) * | 2008-01-14 | 2011-03-31 | スターチ メディカル インコーポレーテッド | 生物相容性の止血、癒着防止、癒合促進、外科密封可能な変性澱粉材料 |
WO2011027706A1 (ja) | 2009-09-02 | 2011-03-10 | テルモ株式会社 | 多孔質構造体 |
WO2011027729A1 (ja) * | 2009-09-02 | 2011-03-10 | 日本曹達株式会社 | ヒドロキシプロピルセルロース粒子 |
US20120157672A1 (en) | 2009-09-02 | 2012-06-21 | Terumo Kabushiki Kaisha | Porous structure |
JP2011084588A (ja) * | 2009-09-16 | 2011-04-28 | Q P Corp | ヒアルロン酸および/またはその塩からなる粉末 |
JP2011068827A (ja) | 2009-09-28 | 2011-04-07 | Terumo Corp | 活性エステル化多糖およびその製造方法 |
WO2013077414A1 (ja) * | 2011-11-25 | 2013-05-30 | 株式会社大塚製薬工場 | 癒着防止又は止血に有用な医薬組成物 |
Non-Patent Citations (2)
Title |
---|
"Poly(ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications", 1992, PLENUM PRESS |
See also references of EP2960254A4 |
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