Polysaccharide derivative hydrogel

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is using the material for the purpose of neural dysfunction recovery with the above material containing a polysaccharide derivative hydrogel wherein 0.5 wt % of the aqueous solution contains a complex module in the amount of 1 to 1000 N/m2, while a loss factor makes 0.01 to 2.0 that is measured at angular velocity 10 rad/sec with using a dynamic viscoelasticity meter. The above material for neural dysfunction recovery may represent hydrogel injected with using a syringe and has an excellent body residence, and has a restorative effect on the damaged or degenerated nerve function.

EFFECT: preparing the material for neural dysfunction recovery.

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The technical field to which the invention relates.

The present invention relates to injectable material to cure the dysfunction of the nerves, which includes a derivative of the polysaccharide.

The level of technology

Serious injury, overload of the organism or similar causes damage and/or degeneration of the nerves, the weakening of their functions. In particular, examples of diseases involving dysfunction of the nerves associated with peripheral nerves include nerve damage, carpal tunnel syndrome and cubital tunnel syndrome. Restoring such a nerve with impaired function takes an extended period of time, the load on the patient loud.

Recently reported effective implementation of decompression, such as neurosis, against carpal tunnel syndrome, cubital tunnel syndrome and similar syndromes infringement. However, there are a number of related problems, including post-operative scar tissue around the nerve fibrosis in a bundle of nerve fibers and thepaper, although the frequency of failures eliminate carpal tunnel syndrome is 3%, the main reason for recurrence of symptoms, as is, is in postoperative adhesion or fibrosis inside or outside of the nerve, and it is expected that by reducing post-operative adhesion healing is created dysfunction will increase.

Meanwhile, to solve such problems in the United States was proposed and approved under the name "ADCON" (Gliatech) bioabsorbable anti-adhesion material used in clinical practice. However, this anti-adhesion material of concern associated with side effects due to the delay healing at the site of surgical intervention. That is, even if postoperative adhesion can be prevented, healing nerve dysfunction after decompression may be hampered by the delay healing, etc.

Previously to restore nerve function have been proposed various applications of polysaccharide, biocompatible material. For example, it was discovered therapeutic material for neurological disorders, in which the active ingredient used is associated with the lipid glycosaminoglycan or its salts (JP-A-9-30979). Although this therapeutic material for neurological disorders can be entered in the formulation of any of the dosage form, there is no description of a gel having an average viscosity that is associated with retention in the body. In addition, there is no description or assumptions associated with postoperative adhesion.

Next was uncovered material for nerve regeneration, which includes a cross-linked polysaccharide, obtained by covalent binding of the polysaccharide, sod is rasego carboxyl group and/or its salts with cross-linking reagent, including a connection based on amine (JP-A-2000-198738). However, there are lingering concerns about security, for example, relative to an inflammatory reaction on the residual cross-linking reagent. In addition, because of the heterogeneity of chemically cross-linked gel can undergo changes in properties, and in this regard it is possible to improve stability. In addition, there are descriptions or assumptions about post-operative adhesion.

In addition, it was reported that in a rabbit model of adhesion of the sciatic nerve, hyaluronic acid inhibits postoperative adhesion of peripheral nerves and inhibits the delay latent period of peripheral nerve (The British Association of Plastic Surgeons 56, pp 342-347, 2003). This hyaluronic acid is not effective unless it is in the beginning of the operation, and this represents an obstacle in the case of surgery in the real world, and therefore it is possible to improve convenience of use.

Meanwhile, as for the gel material, in which the polysaccharide is applied cellulose, WO 2007/015579 in the description of the disclosed derivative, obtained by modification of carboxymethyl cellulose by fosfatidiletanolamina, which dissolved in water to form a gel. However, no descriptions or assumptions about the effect of recovery of nerve dysfunction.

Reported effective is Yunosti at relieving the pain in my hands after surgery of peripheral nerves or syndrome Tines (Made 27 (1), page 2-7, 2007) auto-crosslinking hyaluronic acid that is used as a material for the prevention of postoperative adhesion of peripheral nerves "HYALOGLIDE®" ("Fidia Advanced Biopolymers) in clinical practice in Europe.

Although to restore nerve function using polysaccharides were nominated described above, various proposals have not been studies of hydrogel using modified phospholipid derivative of the polysaccharide, which has the effect of healing the dysfunction of the nerves, has a high viscosity, causes less postoperative adhesion, and which is easy to handle. In particular, the derivative of the polysaccharide, demonstrating the effect of improving the speed of conduction of nerve, it is still not known.

Disclosure of inventions

The objective of the invention is to provide a material for treatment of dysfunction of the nerves to restore the function of damaged or degenerated nerves, and, in particular, in providing material for treatment of dysfunction of the nerves, which may be a hydrogel, with the ability to inetservices with a syringe and has excellent retention in the body.

The authors conducted extensive research materials for treatment of nerve dysfunction, which restore function of damaged or degenerated nerves. In is the result, they found hydrogel derived polysaccharide characterized in that 0.5 wt.% an aqueous solution of a complex module is from 1 to 1000 N/m2and the loss factor ranges from 0.01 to 2.0, which is measured when the angular velocity of 10 rad/sec using a device for measuring the dynamic viscoelasticity. They also found that the hydrogel is useful when restoring the function of damaged nerves and causes less postoperative adhesion than the achieved objectives of the invention.

In particular, the invention is a material for healing the dysfunction of the nerves, including the hydrogel derived polysaccharide, characterized in that 0.5 wt.% an aqueous solution of a complex module is from 1 to 1000 N/m2and the loss factor ranges from 0.01 to 2.0, which is measured when the angular velocity of 10 rad/sec using a device for measuring the dynamic viscoelasticity.

When used in the invention is derived polysaccharide is dissolved in water, it turns into a hydrogel having a specific modulus and viscosity, which allow you to do the injections. When such a hydrogel is used as injectable gel for medical use, it has the effect of material for treatment of dysfunction of the nerves, for example, the effect of increasing the speed of conduction of nerve.

Furthermore, the material DL the cure dysfunction of nerves according to the invention has a high viscoelasticity and/or excellent retention in the body, and, therefore, very easy to use and can be applied in areas with complex configurations at the time of surgical intervention with the help of an endoscope, etc.

Brief description of drawings

Figure 1 shows the effect of increasing the speed of nerve conduction material to cure the dysfunction of nerves according to the invention 20 days after surgery.

Figure 2 shows the increase in complex modulus of the material for treatment of dysfunction of nerves according to the invention at physiological concentrations of salts.

Figure 3 shows the regeneration perineurial the hydrogel derived polysaccharide according to the invention one week after surgery. Arrow indicates perimetry.

Figure 4 shows the regeneration perineurial one week after surgical intervention in the case without the use of hydrogel derived polysaccharide according to the invention. Arrow indicates perimetry.

Figure 5 shows the regeneration of the myelin sheath of the hydrogel derived polysaccharide according to the invention 6 weeks after surgery. The arrow indicates the myelin sheath.

Figure 6 shows the regeneration of the myelin sheath 6 weeks after surgery in the case without the use of hydrogel derived polysaccharide on izaberete the Oia. The arrow indicates the myelin sheath.

The best option of carrying out the invention

The invention is a material for treatment of dysfunction of the nerves, including the hydrogel derived polysaccharide, characterized in that 0.5 wt.% an aqueous solution of a complex module is from 1 to 1000 N/m2and the loss factor ranges from 0.01 to 2.0, which is measured when the angular velocity of 10 rad/sec using a device for measuring the dynamic viscoelasticity.

Complex modulus is in the range from 1 to 200 N/m2and more preferably in the range from 1 to 100 N/m2. In addition, the loss coefficient is preferably in the range from 0.01 to 1.5.

Derived polysaccharide used in the invention preferably is a derivative of cellulose, and preferably may be a derivative of cellulose having a repeating unit represented by the following formula:

where R1, R2and R3each independently selected from the group consisting of the following formulas (a), (b) (c) and (d):

; and

where

X in the formula (c) is an alkaline or alkaline-earth metal,

R4and R5in the formula (d) each independent who are about 9-27alkyl group or alkenylphenol group,

the total degree of substitution (b) and (C) is from 0.3 to 2.0, and

the degree of substitution (d) is in the range from 0.001 to 0.05, and more preferably 0.005 to 0.015.

In the above formula, R4and R5each independently are C9-27alkyl group or alkenylphenol group. In particular, preferably, if R4and R5are9-19alkenylamine groups. Among them, preferably, if R4CO - and/or R5CO - is olololol group, and especially preferably, if R4CO - and R5CO - are oleylamine groups.

Material to cure the dysfunction of nerves according to the invention preferably is a material for treatment of dysfunction of the nerves, which is the injectable hydrogel containing from 0.1 to 1.5 mass parts derived polysaccharide used in the invention, 100 mass. parts of water. Even more preferably from 0.5 to 1.0 mass. parts.

Among them, preferably, if the complex modulus at 0.5 wt.% aqueous solution is in the range from 1 to 200 N/m2measured when the angular velocity of 10 rad/sec using a device measuring the dynamic viscoelasticity. Even more preferably, if it is in the range of 1 to 100 N/m2. In addition, preferably, if the ratio of loss is at this time is from 0.01 to 1.5.

In addition, preferably, if the material to cure the dysfunction of nerves according to the invention includes a hydrogel derived polysaccharide, and that at physiological salt concentrations, the complex modulus of 1.0 wt.% an aqueous solution is increased from 1 to 1000 N/m2measured when the angular velocity of 10 rad/sec, using a device for measuring the dynamic viscoelasticity. The zoom range of viscosity is more preferably an increase from 50 to 700 N/m2and even more preferably increased from 100 to 500 N/m2.

The physiological concentration of salt in this document means the physiological salt concentration of the salt solution, adjusted for survival of cells. As a specific salt concentrations physiological solution (0.9% aqueous NaCl solution), ringer's solution, phosphate buffer and tpout be mentioned as examples.

The invention is a material for treatment of nerve dysfunction. For example, it is properly used to restore the function of the nerves is damaged and/or degenerated as a result of serious injury, overload of the body, etc.

If the polysaccharide derivative for the preparation of material for treatment of nervous dysfunction according to the invention using a derivative of cellulose, obtaining, for example, can battledome.

The method of obtaining the derivative of cellulose

The above-mentioned derivative of cellulose used in the invention can be obtained by a process comprising a stage in which the carboxymethyl cellulose having a repeating unit represented by the below formula and molecular weight from j to j:

and phosphatidylethanolamine, represented by the following formula:

in such proportions in which the amount of phosphatidylethanolamine is from 0.1 to 100 equivalents per 100 equivalents of the carboxyl groups of the carboxymethyl cellulose (i.e. the total number of substituents (b)+(c)) dissolved in a mixed solvent comprising water and Volosovsky organic solvent in which water is from 20 to 70 vol.%, with the subsequent reaction in the presence of a condensing means.

R1, R2and R3in this document each independently selected from the following formulas (a), (b) and (c):

; and

where

X in the formula (C) is an alkaline or alkaline-earth metal, the total degree of substitution (b) and (c) is from 0.3 to 2.0, and

R4and R5each independently are C9-27alkyl group or alkenylphenol group.

Carboxymethylcellulose in to the important source material preferably has a molecular weight of from 5×10 3up to 5×106, more preferably from 5×104up to 5×106and even more preferably from 5×104up to 1×106.

The carboxymethyl cellulose as a starting material can be obtained, for example, dissolving pulp in a solution of sodium hydroxide, and esterification of her monochloracetic acid or its sodium salt, with subsequent cleaning.

Alkaline metal X in the formula (c), is preferably sodium, potassium, lithium or the like, and alkaline earth metal is preferably magnesium, calcium or the like

The total degree of substitution (b) and (c) is from 0.3 to 2.0, preferably from 0.5 to 1.8, and more preferably from 0.6 to 1.5. Share (b) and (c) nothing specific is not limited. However, in the context of solubility in water, preferably, if (c) is in excess relative to (b).

Specific structural formula preferred carboxymethyl cellulose as a starting material shown in the formula below. With regard to the replacement carboxymethyl group in the skeleton of cellulose, it is preferable to position C-6.

In the phosphatidylethanolamine is represented in the formula above for use in the production method of a derivative of cellulose, R4and R5each independently are C9-27alkyl group or alkenylphenol group. Site is preferably, if R4and R5each is9-27alkenylphenol group. Preferably, if R4CO - and/or R5CO - are olololol group, and especially preferably, if R4CO - and R5CO - are oleylamine groups.

The phosphatidylethanolamine as the starting material can be either extracted from animal tissue or obtained synthetically. Specific examples include drawroundedrectangle, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, durahide the phosphatidylethanolamine, europeanintegration, Palmitoyl the phosphatidylethanolamine, tilinluontitoimintoa, distearoylphosphatidylcholine, directorpotaratrue, ministryofeducation, dioleoyl the phosphatidylethanolamine, talinolol the phosphatidylethanolamine, garagedoorsofamerica.com and geocodelocation.setlatlong. Among them dioleoylphosphatidylcholine is preferred in terms of solubility in an organic solvent used for the synthesis. The phosphatidylethanolamine is a safe substance of biological origin.

It is believed that the derivative of cellulose used in the invention, phosphatidylethanolamine enhances hydrophobic interactions between molecules derived a is wlosy, and, as a result, a derivative of cellulose used in the invention, forms a hydrogel.

Carboxymethylcellulose and phosphatidylethanolamine, which are the starting materials used in the invention can react in such proportions that the amount of phosphatidylethanolamine is in the range from 0.1 to 50 equivalents, preferably from 1 to 40 equivalents, more preferably from 3 to 30 equivalents, per 100 equivalents of the carboxyl groups of the carboxymethyl cellulose. If the amount is less than 0.1 equivalent, the resulting derivative of cellulose does not form a hydrogel. If the quantity is more than 40 equivalents, no increase of viscosity is not observed at physiological concentrations of salts.

In the condensation reaction between carboxymethyl cellulose and phosphatidylethanolamine, the reaction efficiency may be reduced depending on the reactivity of the condensing means, used for condensation or depending on the reaction conditions. Therefore, preferably, if the phosphatidylethanolamine is used in excess relative to the calculated values of the desired degree of substitution.

Carboxymethylcellulose and phosphatidylethanolamine dissolved in a mixed solvent comprising water and Volosovsky organic solvent (A), in which water presence is there in the amount of from 20 to 70 vol.%. If the water content is less than 20 vol.%, carboxymethylcellulose less soluble, whereas if the water content is more than 70 vol.%, the phosphatidylethanolamine less soluble, resulting in a reaction takes place. The water content is preferably from 30 to 60 vol.%.

Specific examples Volosovsky organic solvent (A) include organic solvents having a cyclic ether bond, such as tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, 1,3-dioxolane and morpholine, an organic solvent having an amide bond, such as dimethylacetamide, dimethylformamide and N-methyl-2-pyrrolidone, amines, such as pyridine, piperidine and piperazine, and sulfoxidov, such as dimethylsulfoxide. Among them, cyclic ethers and sulfoxidov are preferred. In particular, tetrahydrofuran, dioxane and dimethyl sulfoxide are preferred.

As the reagents used in the reaction, carboxylesterase means and condensing means are preferred. Examples carboxylesterase means include N-hydroxysuccinimide, p-NITROPHENOL, N-hydroxybenzotriazole, N-hydroxypiperidine, N-hydroxysuccinimide, 2,4,5-trichlorophenol and N,N-dimethylaminopyridine. Examples of the condensing means include 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholin chloride, 1-ethyl-3-(dimethyl shall aminopropyl)-carbodiimide and its hydrochloride, diisopropylcarbodiimide, dicyclohexylcarbodiimide and N-hydroxy-5-norbornene-2,3-dicarboximide. Among them, it is preferable to use N-hydroxybenzotriazole as carboxylesterases funds, and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholin chloride or 1-ethyl-3-(dimethylaminopropyl)-carbodiimide hydrochloride as a condensing means.

The reaction temperature preferably ranges from 0°C to 60°C. For inhibition of the production of by-products, the reaction is more preferably carried out at a temperature from 0 to 10°C. the reaction Environment is preferably slightly acidic, and more preferably, if the pH is in the range from 6 to 7.

Cleaning method derived cellulose

The method of obtaining the derivative of cellulose used in the invention, obtained for the derivative of cellulose may include purification stage of a derivative of cellulose with an organic solvent (B), which substantially does not dissolve carboxymethylcellulose, but is compatible with water.

Organic solvent which substantially does not dissolve carboxymethylcellulose, herein means an organic solvent in which the solubility of the sodium salt of carboxymethyl cellulose or carboxymethyl cellulose (COOH type) is available in powder or lyophilizer the Anna form if the solubility of carboxymethyl cellulose in an organic solvent checks in the absence of water, is 3% or less. Specific examples include alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, and tert-butyl alcohol, polyhydric alcohols such as ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, and glycerin; ketones such as acetone, and aromatic alcohols such as phenol. Among them, those which have a boiling point less than 100°C are preferred. For example, methanol, ethanol, isopropyl alcohol are preferred. The use of in vivo ethanol is particularly preferred.

If cleaning is carried out using an organic solvent (B) of these groups, it is possible to use a method in which an organic solvent is added to the derivative of cellulose in a mixture of water, organic solvent (A), etc. for sediment, leading thus to the destruction of a derivative of cellulose. Otherwise, it is also possible to use a method in which an organic solvent (B) is added to the previously obtained precipitate, dry powder or sponge or similar body obtained by lyophilization, thereby carrying out washing. Using these methods of cleaning can be removed catalysts, such as con is serouse tool and carboxylesterase means, used in the reaction, unreacted phospholipid remaining in the system and TPS obtain the desired product, suspended in an organic solvent (B), apply the method, such as centrifugation or filtration. Also for washing with an organic solvent (B) can be applied extraction in to conventional Soxhlet extractions.

Hydrogel derived cellulose

Material for treatment of dysfunction of the nerves of the invention is a hydrogel containing the above derivative of cellulose. The hydrogel contains a derivative of cellulose in an amount of from 0.1 to 1.5 mass. parts, preferably from 0.5 to 1.0 mass. parts, per 100 mass. parts of water.

This hydrogel can be easily deformed when you touch a metal spatula, and is located in a state that allows easy application to the affected area. The hydrogel can also be injected with a tool having a thin tube, such as a syringe.

The gel preferably has a complex modulus in the range from 1 to 200 N/m2even more preferably in the range from 1 to 100 N/m2measured when the angular velocity of 10 rad/sec using a device for measuring dynamic viscoelasticity under conditions in which the concentration of polymer is 0.5 wt.%, and the temperature is 37°C. it is also preferable if the greater the losses at this time is from 0.01 to 1.5. This range is the most effective in restoring the function of damaged or degenerated nerves.

In addition, the hydrogel of the invention is transparent and colorless. When industrial production is advantageous in that even if in the process of getting included extraneous substances such as dust, such foreign matter can be detected.

Possible examples of non-water components contained in the hydrogel include condensing means, used as catalysts; the by-products such as urea produced by the condensing means during a given chemical reaction; carboxylesterase agents, unreacted phosphatidylethanolamine, extraneous substances which can be included at each stage of the reaction; and ions that are used to adjust pH. However, these components are removed by cleaning or washing using the above-mentioned organic solvent (C), and preferably, if the levels of all compounds is maintained at a low level, so that their penetration into the body is not recognized as a reaction to a foreign body.

The method of storing material to cure the dysfunction of nerves according to the invention is not restricted. For example, the material may be stored in a cool, dark place and transferred to room temperature p is ed use. The method of sterilization material to cure the dysfunction of nerves according to the invention also is not limited, and can be applied to the method for ordinary sterilization of medical instruments and materials, such as sterilization with gaseous ethylene oxide, sterilization by autoclaving, sterilization, gamma radiation or electron beam sterilization.

In addition, in the case of use after surgery material to cure the dysfunction of nerves according to the invention, for example, when applied to the area of surgical intervention and the surrounding area from about 0.1 to 5.0 ml with a syringe to cover all the area of surgical intervention, is expected to restore the function of damaged or degenerated nerves.

Examples

(1) In the examples used the following materials:

(1) CMCNa: sodium carboxymethyl cellulose (produced by "Dai-Ichi Kogyo Seiyaku, degree of substitution: 0,73; or production "Nippon Paper Chemicals, the degree of substitution: 0,69),

(ii) tetrahydrofuran (manufactured by "Wako Pure Chemical Industries))),

(iii) 0.1 M HCl (manufactured by "Wako Pure Chemical Industries))),

(iv) 0.1 M NaOH (manufactured by "Wako Pure Chemical Industries))),

(v) 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholin chloride (manufactured "Kokusan Chemical))),

(vi) L-α-dioleoylphosphatidylcholine (COATSOME ME-8181, production NOF Corporation))),

(vii) ethanol (production Wao Pure Chemical Industries))),

(viii) distilled water for injection (manufactured "Otsuka Pharmaceutical))),

(ix) canal for disinfection (manufactured by "Wako Pure Chemical Industries))),

(x) pentobarbital sodium (injection of Nembutal, production Dainippon Sumitomo Pharma"), and

(xi) NaCl (manufactured by "Wako Pure Chemical Industries))).

(2) Measurement of the content of phospholipids in the derived cellulose

The proportion of phospholipid derived cellulose was determined by analysis of the total content of phosphorus vanadomolybdate absorbtiometry.

(3) measurement of complex modulus and loss factor of the hydrogel. Complex modulus and loss factor of the hydrogel was measured at 37°C and the angular velocity of 10 rad/sec using Rheometer RFIII" ("TA Instrument))), devices for the measurement of dynamic viscoelasticity.

The integrated module is called a constant that represents the ratio between stress and deformation of the elastic body. The loss factor is the constant that represents the ratio between the storage modulus and loss modulus shear.

Example 1

Derived cellulose

3000 mg CMCNa (production Dai-Ichi Kogyo Seiyaku, degree of substitution: 0, 73), was dissolved in 600 ml of water then was added 600 ml of tetrahydrofuran. To this solution was added 1405 mg (1,889 mol) of L-α-dioleoylphosphatidylcholine (20 equivalents per 100 equivalents of the carboxyl groups CMCNa) and 575 mg (2,08 mol) of 4-(4,-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholin chloride as a condensing means, and then was stirred overnight. After mixing, the tetrahydrofuran was removed, the water evaporated, to some extent, and then the mixture was added ethanol to cause precipitation. The ethanol was removed by filtration, followed by repeated washing with ethanol. The residue was dried by vacuum drying to obtain a derivative of cellulose and measured the content of phospholipids in it. If we assume that the degree of substitution of carboxymethyl cellulose to the reaction was 0.73, and that all carboxymethyl groups were kationirovannykh sodium ions, the degree of substitution by the formula (d) was determined by calculation of the contents of phosopholipid. The degree of substitution of the formula (d) was 0.78 mol%sugar.

The hydrogel

Composition made from dried by vacuum derivative of cellulose, sterilized, and then was dissolved in distilled water for injection to prepare 0, 5 wt.% hydrogel. Measured complex modulus and loss factor of the obtained hydrogel, the results amounted to 18.3 N/m2and 0.63, respectively.

Example 2

Creating a dysfunction of the sciatic nerve in rats

Dysfunction of the sciatic nerve was obtained in accordance with the method Ohsumi et al., [Hidehiko ohsumi, Hitoshi Hirata, Takeshi Nagakura, Masaya Tsuj ii, Toshiko Sugimoto, Keiichi Miyamoto, Takeshi Horiuchi: Plastic and Reconstructive Surgery 116 (3): 823-30, 2005] on the Lewis rats (three rats from Charles River Laboratories), Japan. And the military, the rat was fixed in a lateral position with anesthesia intraperitoneally introduced by pentobarbital sodium, gluteal region was shaved and then disinfected with ethanol for disinfection. From the abdominal region towards the dorsal region, was made the cut 4-5 cm paterlini area for disclosure of the sciatic nerve. Epineurium and perineurium sciatic nerve was removed by 1.5 cm, and optionally cauterized the surrounding muscle tissue. Then the hydrogel of example 1 (0.5 ml) was applied around the sciatic nerve, with a detached epineurium and perineurium, and muscle layer and the skin incision was sutured. The site of the wound disinfected using a disinfectant "Isodine", after which the rat was returned to its cage. 20 days after surgery, animals were again exposed sciatic nerve under the influence of anaesthesia pentobarbital sodium, and measured the conduction velocity of nerve using NeuroPack" ("Nihon Kohden"). Significant differences were tested using t-test t-test (student test). As a result, the conduction velocity of nerve 20 days after surgery was 18.8±3.3 m/s (average±standard deviation) in each case.

Comparative example 1

As a control, the same operation as in example 2 was carried out without the use of hydrogel and measured the conduction velocity of nerve. As a result, / min net is ü conduction of nerve was 11.8±3.6 m/s (mean±standard deviation).

The results of measuring the speed of conduction of nerve 20 days after surgery in example 2 and comparative example 1 are presented in figure 1.

As above, the conduction velocity of nerve 20 days after surgery in example 2 was statistically more significant than in comparative example 1. Therefore, it presents evidence that the hydrogel obtained in example 1, is highly effective for restoring a damaged or degenerated nerves in vivo.

Example 3

The increase in complex modulus salt

3500 mg CMCNa (produced by Nippon Paper Chemicals, the degree of substitution: 0,69) was dissolved in 100 ml of water and then added 100 ml of tetrahydrofuran. To this solution was added 413,7 mg (0,0000795 mol) L-a-dioleoylphosphatidylcholine (5 equivalents per 100 equivalents of the carboxyl groups CMCNa) and 169,4 mg (0,0000874 mol) of 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholin chloride as a condensing means, and then was stirred overnight. After stirring, to the mixture was added ethanol to cause precipitation. Then, to obtain a derivative of cellulose was carried out by the same operation as in example 1. The degree of substitution was 1.0 mol%sugar. 20 mg of the composition is made of a derivative of cellulose was dissolved in 1800 mg distilled water for inj the capabilities of and then 200 mg 9% NaCl was added to obtain a final concentration of 0.9%. Thus prepared hydrogel with a final concentration of 1.0 wt.%. Measured complex modulus of the resulting hydrogel. The result was 134,5±1.4 N/m2(mean±standard deviation).

Comparative example 2

The hydrogel was prepared as in example 3, except that instead of 9% NaCl was added 200 mg distilled water for injection. Measured complex modulus of the resulting hydrogel. The result was 8,0±0,5 N/m2(mean±standard deviation).

The results of a comprehensive module in example 3 and comparative example 2 are shown in figure 2.

As above, the increase in complex modulus is greater in example 3 than in comparative example 2, it was confirmed that the complex modulus of the hydrogel, represents only 5 to 200 N/m2increases when adding NaCl to a concentration of 0.9 wt.%, the same level as in vivo.

Example 4

Derived cellulose

3000 mg CMCNa (production Dai-Ichi Kogyo Seiyaku, degree of substitution: 0, 73), was dissolved in 600 ml of water and added to 600 ml of tetrahydrofuran. To this solution was added 1405 mg (1,889 mol) of L-α-dioleoylphosphatidylcholine (20 equivalents per 100 equivalents of the carboxyl groups CMCNa) and 575 mg (2,08 mol) of 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholin chloride as a condensing means, and then was stirred overnight. PEFC is stirring, the tetrahydrofuran was removed, the water evaporated, to some extent, and then the mixture was added ethanol to cause precipitation. The ethanol was removed by filtration, followed by repeated washing with ethanol. The residue was dried by vacuum drying to obtain a derivative of cellulose and measured its content of phospholipids. If we assume that the degree of substitution of carboxymethyl cellulose to the reaction was 0.73, and that all carboxymethyl groups were kationirovannykh sodium ions, the degree of substitution of the formula (d) was determined by calculating the content of phospholipids. The degree of substitution of the formula (d) was 0.78 mol%sugar.

The hydrogel

Composition made from dried by vacuum derivative of cellulose, sterilized and then dissolved in distilled water for injection to prepare a 0.5 wt.% hydrogel. Measured complex modulus and loss factor of the obtained hydrogel, the results amounted to 18.3 N/m2and 0.63, respectively.

Example 5

Creating a degeneration of the sciatic nerve in rats

Degeneration of the sciatic nerve caused in accordance with the method Ohsumi et al., [Hidehiko ohsumi, Hitoshi Hirata, Takeshi Nagakura, Masaya Tsuj ii, Toshiko Sugimoto, Keiichi Miyamoto, Takeshi Horiuchi: Plastic and Reconstructive Surgery 116 (3): 823-30, 2005] on the Lewis rats (three rats from Charles River Laboratories), Japan. Namely, the rat was fixed in a lateral position with anesthesia inside the peritoneal entered pentobarbital sodium, gluteal region was shaved and then disinfected with ethanol for disinfection. From the abdominal region towards the dorsal region, was made the cut 4-5 cm paterlini area for disclosure of the sciatic nerve. Epineurium and perineurium sciatic nerve was removed by 1.5 cm, and optionally cauterized the surrounding muscle tissue. Then the hydrogel of example 4 (0.5 ml) was applied around the sciatic nerve, with a detached epineurium and perineurium, and muscle layer and the skin incision was sutured. The site of the wound disinfected using a disinfectant "Isodine), after which the rat was returned to its cage. One week after surgery, animals were selected sciatic nerve in the conditions of anesthesia pentobarbital sodium, and has been painting trigram by Masson for histological observation of the sciatic nerve. In the regeneration perineurial found a week after the surgical treatment.

Comparative example 3

As a control, the same operation as in example 5 was carried out without the use of hydrogel and histologically observed sciatic nerve. As a result, regeneration of perineurial one week after surgery was inadequate.

The results of staining of trigram by Masson week after surgery of example 5 and comparative example 3 presented the ENES in figure 3 and 4, respectively. As above, in case of histological observations within a week after surgery, regeneration perineurial in example 5 was much better than in comparative example 3. Therefore, it presents evidence that the hydrogel obtained in example 4, is highly effective for restoring a damaged or degenerated nerves in vivo.

Example 6

Creating a degeneration of the sciatic nerve in rats

Degeneration of the sciatic nerve caused in accordance with the method Ohsumi et al., [Hidehiko ohsumi, Hitoshi Hirata, Takeshi Nagakura, Masaya Tsuj ii, Toshiko Sugimoto, Keiichi Miyamoto, Takeshi Horiuchi: Plastic and Reconstructive Surgery 116 (3): 823-30, 2005] on the Lewis rats (three rats from Charles River Laboratories), Japan. Namely, the rat was fixed in a lateral position with anesthesia intraperitoneally introduced by pentobarbital sodium, gluteal region was shaved and then disinfected with ethanol for disinfection. From the abdominal region towards the dorsal region, was made the cut 4-5 cm paterlini area for disclosure of the sciatic nerve. Epineurium and perineurium sciatic nerve was removed by 1.5 cm, and optionally cauterized the surrounding muscle tissue. Then the hydrogel of example 4 (0.5 ml) was applied around the sciatic nerve, with a detached epineurium and perineurium, and muscle layer and the skin incision was sutured. The site of the wound disinfected using a disinfectant"Isodine", then the rat was returned to its cage. 6 weeks after surgery, the animals were deprived of the sciatic nerve in the conditions of anesthesia pentobarbital sodium, and has been painting toluidine blue for histological observation of the sciatic nerve. In the regeneration of the myelin sheath was found 6 weeks after surgical treatment.

Comparative example 4

As a control, the same operation as in example 6 was carried out without the use of hydrogel and histologically observed sciatic nerve. As a result, regeneration of the myelin sheath 6 weeks after surgery was inadequate.

The results of staining toluidine blue 6 weeks after the surgical intervention of example 6 and comparative example 4 are presented in figure 5 and 6, respectively. As above, in case of histological observations after 6 weeks after surgery, the regeneration of the myelin sheath of example 6 was better than in comparative example 4. Therefore, it presents evidence that the hydrogel obtained in example 4, is highly effective for restoring a damaged or degenerated nerves in vivo.

Industrial applicability

Material to cure the dysfunction of nerves according to the invention is, in the example, medical material, which is injected by syringe and has excellent retention in the body, and is used for surgical operations.

1. Applying a material comprising a hydrogel derivative of cellulose, to restore the dysfunction of the nerves, in which 0.5 wt.%-Mr. aqueous solution of the complex modulus material is from 1 to 1000 N/m2and the loss factor ranges from 0.01 to 2.0, which is measured when the angular velocity of 10 rad/s using a device for measuring the dynamic viscoelasticity, and wherein a derivative of cellulose has a repeating unit represented by the following formula:

where R1, R2and R3each independently selected from the group consisting of the following formulas (a), (b), (C) and (d):


and

where X in the formula (C) is an alkaline or alkaline-earth metal,
R4and R5in the formula (d) each independently is C9-27alkyl group or alkenylphenol group,
the total degree of substitution (b) and (C) is from 0.3 to 2.0 and
the degree of substitution (d) is from 0.001 to 0.05.

2. The use according to claim 1, in which R4and R5are C9-19alkenylamine groups.

3. The use according to claim 1, in to the or R 4CO - and/or R5CO - are OleOle group.

4. The use according to any one of claims 1 to 3, wherein the material contains from 0.1 to 1.5 parts by weight of a derivative of cellulose per 100 parts by weight of water.

5. The use according to any one of claims 1 to 3, wherein restore the dysfunction of peripheral nerves.

6. The use according to claim 5, in which dysfunction of peripheral nerves is a syndrome infringement.

7. The use according to any one of claims 1 to 3, wherein restore the dysfunction of the Central nerves.

8. The use according to any one of claims 1 to 3, wherein restore the dysfunction of the sciatic nerve.

9. The use according to any one of claims 1 to 3, wherein the material has the effect of improving the speed of conduction of nerve.

10. The use according to any one of claims 1 to 3, wherein the material has the effect of regeneration perineurial.

11. The use according to any one of claims 1 to 3, wherein the material has the effect of regeneration of the myelin sheath.

12. The use of material containing hydrogel derived cellulose to restore the dysfunction of the nerves, which at physiological concentrations of salt complex modulus of the material in 1.0 wt.%-Mr. aqueous solution is increased by from 1 to 200 N/m2as measured at an angular velocity of 10 rad/s using a device for measuring the dynamic viscoelasticity, and wherein a derivative of cellulose has povtoreaiusi the camping unit, the following formula

where R1, R2and R3each independently selected from the group consisting of the following formulas (a), (b), (C) and (d):


and

where X in the formula (C) is an alkaline or alkaline-earth metal,
R4and R5in the formula (d) are each independently C9-27alkyl group or alkenylphenol group,
the total degree of substitution (b) and (C) is from 0.3 to 2.0, and the degree of substitution (d) is from 0.001 to 0.05.

13. The application of item 12, wherein restore the dysfunction of peripheral nerves.

14. Use item 13, in which dysfunction of peripheral nerves is a syndrome infringement.

15. The application of item 12, wherein restore the dysfunction of the Central nerves.

16. The application of item 12, wherein restore the dysfunction of the sciatic nerve.

17. The application of item 12, wherein the material has the effect of improving the speed of conduction of nerve.

18. The application of item 12, wherein the material has the effect of regeneration perineurial.

19. The application of item 12, wherein the material has the effect of regeneration of the myelin sheath.



 

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2 cl, 2 ex

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2 cl, 1 ex

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6 dwg, 2 ex

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3 tbl

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1 ex

FIELD: medicine.

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1 ex

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3 cl, 3 tbl, 12 ex

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1 ex

FIELD: medicine.

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14 cl, 23 tbl, 15 dwg, 12 ex

FIELD: medicine.

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6 ex

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17 cl, 1 ex

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3 ex

FIELD: medicine, pharmaceutics.

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7 cl, 16 ex

FIELD: medicine.

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1 ex

FIELD: medicine.

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2 cl, 1 dwg, 3 ex

FIELD: medicine, pharmaceutics.

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7 cl

FIELD: medicine.

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2 dwg

FIELD: medicine.

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2 ex

FIELD: medicine.

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4 cl, 1 ex, 2 dwg

FIELD: medicine.

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EFFECT: increased sensitivity and stability and high ratio "signal/noise".

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