Ophthalmic adhesion preventing material and its manufacturing method

Abstract

To provide a material which prevents adhesion of membranes in an ophthalmology operation such as glaucoma treatment without using mitomycin C in a detailed embodiment, especially, which is easy to handle and free from melting of a tissue and a risk of infection.SOLUTION: A production method in a preferable form includes: preparing an aldehydized dextran (first reactant) having a weight-average molecular weight of 10,000-5,000,000, and an aldehyde group introduction amount (mol / AGU) of 0.4-0.7 per anhydrous glucose unit, and a succinic acid anhydride added poly-L-lysin (second reactant) having a weight-average molecular weight of 1,000-100,000 and a residual amination ratio of 80-99%; mixing the products so as to bring a reaction molar ratio of an aldehyde group / an amino group to 0.9-1.1; reacting the mixture in the existence of water, and at this time, bringing concentration of a polymer to 8-20%; and freeze-drying a hydrogel obtained by the reaction or a suspension before gelatinization so as to obtain a porous sheet of a thickness of 0.1-0.8 mm.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] The present invention relates to an anti-adhesion material made of a hydrogel (a hydrous polymer gel) with low toxicity and moderate durability to degradation, which can be used to prevent adhesion between the conjunctiva and sclera, fusion between sclera, or adhesion between other ophthalmic biological membranes, or to secure a space between them. In particular, the present invention relates to an adjuvant for glaucoma surgery that utilizes the anti-adhesion and adhesive effects of a hydrogel with low cytotoxicity. [Background technology]

[0002] Glaucoma is a disease characterized by functional and structural abnormalities of the eye, which exhibit characteristic changes in the optic nerve and visual field. Sufficient reduction of intraocular pressure (the pressure of the aqueous humor inside the cornea) can usually improve or prevent optic nerve damage. Treatment is necessary to prevent the progression of glaucoma-related visual field narrowing and subsequent blindness. The interior of the eye is filled with vitreous humor and aqueous humor. The volume of the vitreous humor remains virtually constant. Aqueous humor is constantly produced by the ciliary processes surrounding the lens and drains to the outside of the eye through the Schlemm's canal, which surrounds the cornea. Intraocular pressure is maintained by this balance between aqueous humor production and drainage. However, if drainage pathways such as the Schlemm's canal become blocked for some reason (mainly due to aging), the balance of intraocular pressure is disrupted, leading to the progression of visual field impairment.

[0003] The main treatments for glaucoma are the administration of eye drops and surgery. Eye drops lower intraocular pressure by suppressing the production of aqueous humor and promoting its drainage by reducing the resistance to its outflow. When drug therapy with eye drops or laser treatment does not sufficiently lower intraocular pressure, or when the deterioration of vision cannot be stopped even after the intraocular pressure has been lowered, surgery (trabeculectomy, filtration glaucoma surgery) is performed to create a new outlet (drainage pathway) for aqueous humor from inside the eye.

[0004] Specifically, the sclera surrounding the eyeball and its internal tissue (trabecular meshwork) are removed adjacent to the cornea to create a drainage channel. During this process, aqueous humor must be allowed to leak out gradually to prevent excessive reduction in intraocular pressure and excessive softening of the eyeball. To achieve this, a scleral flap (a scleral flap) is sutured over the drainage channel. However, because the area including the scleral flap is covered by the conjunctiva, adhesions between the conjunctiva and sclera, and between the sclera and the sclera, can form at the drainage channel, blocking the drainage channel and preventing reduction in intraocular pressure. To prevent these wound adhesions and ensure aqueous humor outflow, mitomycin C (MMC) is applied to the conjunctiva and sclera at this location.

[0005] However, mitomycin C is difficult to handle and can cause tissue melting and infection. Mitomycin C is an anticancer drug with a strong inhibitory effect on fibroblast proliferation. If the effect is too strong, such as when administered at a high concentration, it can melt the conjunctiva and sclera, thinning the tissue around the drainage channels and causing holes. This can lead to an abnormal drop in intraocular pressure, adversely affecting visual function, and can also lead to infections such as endophthalmitis that can lead to blindness. Conversely, if the effect of mitomycin C is too weak, the scleral flap can adhere to the inner sclera or the conjunctiva covering it, blocking the drainage channels created by the resection and negating the effectiveness of the surgery.

[0006] Research has been reported on the use of Seprafilm (registered trademark; a mixture of sodium hyaluronate and carboxymethylcellulose), which is primarily used as an anti-adhesion agent in intraperitoneal surgery, in glaucoma surgery (Non-Patent Document 1). Although inflammation was mild, the agent was absorbed within one month after surgery, so its long-term effects are unknown. Attempts have also been made to use trehalose or hyaluronic acid sheets, but these also disappear approximately one month after surgery, and their retention time in the body is too short, so neither has been put to practical use. Meanwhile, there have also been attempts to insert a collagen matrix to prevent excessive drops in intraocular pressure (Non-Patent Document 2).

[0007] On the other hand, a hydrogel-forming and adhesive material with low cytotoxicity and a freely adjustable in vivo degradation rate is known as LYDEX (registered trademark), a two-reaction type consisting of a powder mixture of aldehydedeglucan and modified poly-L-lysine, proposed by BMG Corporation, a company included in the present application (Patent Documents 1 and 2). This two-reaction type hydrogel-forming material (LYDEX; registered trademark) consists of the first and second reactants, which are derived from dextran, a commonly used medical material, and polylysine, a food additive, respectively. Therefore, the hydrogel obtained from this material is expected to be safe for the human body and to prevent the occurrence of serious complications. However, according to claim 7 of Patent Document 2, this hydrogel is expected to "autodegrade into a sol state after a gel-state retention period that can be arbitrarily set between one day and one month." [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication WO2008 / 066182 (Patent 4571693) [Patent Document 2] International Publication WO2006 / 080523 (Patent 4092512) [Non-patent literature]

[0009] [Non-Patent Document 1] Tsurumaru N, Arai M, Teruya K, Sueda J, Yamakawa R., “Seprafilm as a new antifibrotic agent following trabeculectomy in rabbit eyes.” Jpn J Ophthalmol.;53(2):164-70 (2009 Mar). doi: 10.1007 / s10384-008-0638-3. Epub 2009 Mar 31. [Non-patent document 2] https: / / www.nature.com / articles / eye201798, M Tanito, A Okada, Y Mori, I Sano, Y Ikeda and E Fujihara, “Subconjunctival implantation of ologen collagen matrix to treat ocular hypotony after filtration glaucoma surgery,” Eye (2017) 31, 1475-1479. Summary of the Invention [Problem to be solved by the invention]

[0010] In view of the above, the present invention aims to provide a material and method for preventing adhesions around the aqueous humor drainage pathway during ophthalmic surgery such as glaucoma treatment, without using drugs that slow wound healing, such as mitomycin C. In particular, the present invention aims to provide a material and method that is easy to handle and does not pose the risk of tissue melting or infection.

[0011] The present inventors first improved the previously manufactured LYDEX product, which was intended to disintegrate over a relatively short period of time, to create a product that maintains its hydrogel state for at least four months, and preferably six months to one year. Next, the present inventors attempted to use this type of LYDEX product, which can maintain its hydrogel state for a medium to long term, to prevent adhesions in very small areas during ophthalmic surgery.

[0012] Through extensive research, the present inventors have produced a hydrogel sheet from LYDEX under specific conditions, followed by freeze-drying to obtain a porous sheet in a specific state (referred to as "sponge-type LYDEX"). Small pieces were then appropriately cut from this sheet and placed between the conjunctiva and sclera in and around the scleral flap covering the drainage outlet during the above-mentioned glaucoma surgery. As a result, adhesion prevention was observed for at least four months. Furthermore, the hydrogel produced from "sponge-type LYDEX" possesses moderate adhesiveness, which is advantageous for gradually inducing leakage while adhering the conjunctiva to the sclera near the trabeculectomy and scleral flap sites (the above-mentioned drainage outlets). [Means for solving the problem]

[0013] According to a preferred embodiment of the manufacturing method of the present application, an aldehydedextran (first reactant) having a weight-average molecular weight of 10,000 to 5,000,000 and an aldehyde group introduction amount per anhydroglucose unit (mol / AGU) of 0.4 to 0.7 is prepared, and a succinic anhydride-added poly-L-lysine (second reactant) having a weight-average molecular weight of 1,000 to 100,000 and a residual amination rate of 80 to 99% is prepared. The two reactants are mixed so that the reaction molar ratio of aldehyde groups to amino groups is 0.9 to 1.1, and reacted in the presence of water, with the polymer concentration being 8 to 20%. The hydrogel obtained by the reaction, or the suspension before gelation, is freeze-dried to form a porous sheet having a thickness of 0.1 to 0.8 mm.

[0014] In a preferred embodiment of the present application, freeze-drying can be performed by preparing a mixed aqueous solution or suspension of the first reactant and the second reactant, storing it under refrigeration (for example, at 3 to 6°C) for, for example, 1 to 3 hours, then rapidly cooling it to -10°C or below, particularly -20°C or below, to freeze it, and then reducing the pressure to a temperature around the reduced pressure container of, for example, 25 to 30°C.

[0015] In a preferred embodiment of the present application, when forming a hydrogel by reaction between the first reactant and the second reactant, a moisturizing plasticizer made of glycerin or other water-soluble low-molecular-weight compound can be added in an amount of 30 to 100 wt % or 50 to 90 wt % relative to the total weight of the first reactant and the second reactant.

[0016] In a preferred embodiment of the present invention, the porous sheet obtained has substantially no large voids having a major axis diameter of 80 μm or more, 50 μm or more, or 30 μm or more when the surface or cut surface is observed with a stereomicroscope. For example, even if there are any, they have no large voids having a major axis diameter of 1 cm or more. 2 No more than 5, no more than 3, or no more than 1 per person.

[0017] In a preferred embodiment of the present invention, the porous sheet obtained has an apparent density (bulk density) of 0.1 to 0.25 g / cm 3 is.

[0018] In a preferred embodiment of the present application, the ophthalmic adhesion barrier in the form of a porous sheet is a porous sheet having interconnected pores, which is made of a resin material formed from a reaction product of: (1) an aldehyde-modified glycan as a first reactant having a weight-average molecular weight of 10,000 to 5,000,000 and an aldehyde group introduction amount per anhydroglucose unit (mol / AGU) of 0.4 to 0.7; and (2) a carboxylic acid anhydride-added poly-L-lysine as a second reactant having a weight-average molecular weight of 1,000 to 100,000 and a residual amination rate of 80 to 99%, (3) an aldehyde group / amino group reaction molar ratio of 0.9 to 1.1; and (4) an apparent density (bulk density) of 0.1 to 0.25 g / cm. 3 and (5) the thickness is 0.1 to 0.8 mm. [Effects of the Invention]

[0019] If the resulting porous sheet is used to prevent adhesions during ophthalmic surgery, the hydrogel maintains its solid form for four months or longer (medium- to long-term), preventing adhesions. It has low toxicity and irritation to cells and tissues, and even if inflammation occurs, it is minimal, making adhesions less likely to progress. In particular, when used as an auxiliary material in glaucoma surgery, it not only prevents the drainage pathway for aqueous humor from becoming blocked by adhesions, but also allows aqueous humor to drain through the holes, which is expected to have a long-term effect in reducing intraocular pressure. [Brief explanation of the drawings]

[0020] [Figure 1] 1 is a photograph showing the appearance of the obtained porous sheet ("Sponge-type LYDEX"). [Figure 2] This is a set of stereomicroscope photographs when the suspension concentration during the gel-forming reaction (SAPL concentration in Table 2) was 0.5%, 1%, 5%, and 10% (Example). [Figure 3] FIG. 1 is a schematic diagram showing the procedure of glaucoma surgery. [Figure 4] This is a photograph showing the appearance of a rabbit's eye immediately after glaucoma surgery (trabeculectomy). [Figure 5] This is the same photograph as in Figure 3, but taken 4 weeks after surgery. [Figure 6] This is the same photograph as in Figure 3, but taken 4 months after surgery. [Figure 7] 1 is a graph showing the change in intraocular pressure over time before and after surgery. [Figure 8] This is an image of the key areas extracted from a cross-section of the eyeball taken by CT four months after surgery. [Figure 9] This is a photograph (1) taken 1 year and 9 months after surgery, confirming the leakage of blue dye from the surgical site. [Figure 10] This is a photo (2) taken 1 year and 9 months after surgery, confirming the leakage of blue dye from the surgical site. DETAILED DESCRIPTION OF THE INVENTION

[0021] The ophthalmic adhesion preventing material of the present invention is a porous material obtained by freeze-drying or the like a hydrogel obtained from a two-reacting adhesive such as those described in WO2008 / 066182 (Patent Document 1) or WO2006 / 080523 (Patent Document 2). That is, a two-reacting adhesive in the form of a mixed powder or two-liquid is converted into a hydrogel via a mixed aqueous solution, and then a porous material is obtained by freeze-drying or another drying method that achieves fine porosity.

[0022] The porous body may be in the form of granules, strings, or meshes. However, for ease of production and convenience during ophthalmic surgery, a sheet-like form, i.e., a porous sheet, is preferred. When using a porous sheet, the two-component adhesive can be applied to a thin, uniformly thick (e.g., 0.3 to 1 mm) mixed aqueous solution, and then freeze-dried immediately or after a short period of natural drying (diffusion of moisture into room air). For example, the mixture can be rapidly cooled to -5 to -40°C or -10 to -30°C and then dried under reduced pressure, e.g., 50 to 500 hectopascals. On the other hand, a porous sheet can be cut to appropriate length and width dimensions depending on the size of the scleral flap to be formed during ophthalmic surgery. However, flake- or granular-shaped porous bodies can also be produced using, for example, an agitation-type freeze-drying device, and the resulting flakes or granules can be used as is, or after being appropriately divided or trimmed.

[0023] The two-component adhesive comprises a first reactant consisting of an aldehydedglycan and a second reactant consisting of carboxylic acid anhydride-added (partially carboxylated) poly-L-lysine. The first and second reactants are produced in the form of aqueous solutions for aldehydedation and partial carboxylation, but can be converted into powders by freeze-drying or other methods, particularly as a mixed powder containing the first and second reactants in an appropriate molar ratio. A mixed aqueous solution containing the first and second reactants in an appropriate molar ratio for producing a hydrogel can be obtained from a two-component adhesive in a two-liquid state by mixing an aqueous solution of the first reactant with an aqueous solution of the second reactant, or by dissolving the mixed powder in water.

[0024] The aldehyded glycan used as the first reactant is prepared by oxidizing a water-soluble or water-dispersible polysaccharide, such as glucan (a polymer of D-glucose), with periodic acid or periodate to introduce 0.4 to 1.0 aldehyde groups per anhydroglucose unit, particularly 0.4 to 0.8 or 0.4 to 0.7 aldehyde groups. In a preferred embodiment, the glycan is α-glucan, such as dextran or dextrin. The glycan (polysaccharide) may be a glycosaminoglycan such as hyaluronic acid, guar gum, locust bean gum, carrageenan, hydroxypropyl methylcellulose, or hydroxypropyl cellulose. The weight-average molecular weight of the aldehyded glycan (e.g., as determined by the SEC-MALLS method using DMSO as a solvent) may be 10,000 to 5,000,000, particularly 20,000 to 500,000 or 20,000 to 200,000.

[0025] The partially carboxylated poly-L-lysine used as the second reactant is prepared by reacting poly-L-lysine having a weight-average molecular weight of 1,000 to 1,000,000 or 2,000 to 100,000 with its amino groups (mainly side-chain amino groups) and a carboxylic acid anhydride (anhydride) such as succinic anhydride, particularly a dicarboxylic acid anhydride. In particular, the residual amino group ratio is adjusted to 70 to 95%, 75 to 95%, and especially 80 to 95%. In addition to succinic anhydride, glutaric anhydride, malic anhydride, etc. can also be used as the carboxylic acid anhydride in some cases. Meanwhile, the molar ratio of aldehyde groups to amino groups in the mixed aqueous solution used to form the hydrogel is preferably about 1, i.e., 0.8 to 1.3, 0.9 to 1.2, or 0.9 to 1.1.

[0026] By using the two-component adhesive as described above, the period until the gel disintegrates when the resulting hydrogel is kept in a saturated state in vivo or at a temperature similar to that of the body can be set to 4 months or more, 6 months or more, 1 to 1.5 years, or 1 to 2 years.

[0027] When a mixed powder is used to form a hydrogel, the mixed powder is preferably a porous body with a random shape (far from spherical), an average particle size (length average of biaxial mean diameter determined by image analysis) of 10 to 150 μm, and a water content of 2.0% or less. When such a mixed powder is dissolved in water, it is possible to rapidly obtain a strong hydrogel while forming an appropriate microscopically heterogeneous structure.

[0028] The mixed aqueous solution for forming the hydrogel as described above can contain a moisturizing plasticizer such as glycerin. The amount of moisturizing plasticizer added can be, for example, 30 to 100 wt %, 40 to 90 wt %, or 50 to 80 wt % based on the total weight of the first reactant and the second reactant. In addition to glycerin, other moisturizing plasticizers that can be added include propylene glycol, 1,3-butylene glycol, 1,2-pentanediol, 1,2-hexanediol, polyethylene glycol, sorbitol, maltitol, sodium dl-pyrrolidonecarboxylate, sodium lactate, polyglycerin, sodium hyaluronate, and trimethylglycine. These moisturizing components can be added, for example, by mixing them into the mixed powder of the two-component adhesive.

[0029] When forming the hydrogel, the ratio (concentration) of the total weight of the first reactant and the second reactant to the weight of the mixed aqueous solution is preferably 8 to 20% or 10 to 15%. If this concentration is, for example, 5% or less, the pore size cannot be made uniform, and the large pores described above may occur in a porous body such as a porous sheet. The presence of large pores can reduce the strength of the hydrogel, for example, one month or more after implantation in the body, and can adversely affect the adhesion prevention performance.

[0030] The resulting porous body has an apparent density (bulk density) of 0.1 to 0.25 g / cm 3 This range is preferable in that the gel strength can be maintained in vivo for a long period of time and the gel can be easily produced. [Example]

[0031] Hereinafter, the present invention will be described in detail with reference to examples, but the scope of the present invention is not limited thereto.

[0032] Example 1 A porous sheet was prepared as follows and used in the above-mentioned glaucoma surgery.

[0033] 1) Preparation of dextran aldehyde aqueous solution (ADaq) Dextran 70 (Dextran 70; dextran with a molecular weight of 70,000, Meito Sangyo Co., Ltd.) was added to water for injection (WFI) and stirred at 280 rpm for 30 min at 50°C until completely dissolved. Similarly, sodium metaperiodate (NaIO4) was added to water for injection (WFI) and stirred at 280 rpm for 10 min at 50°C until completely dissolved. The amount of aldehyde groups introduced into dextran could be varied by adjusting the NaIO4 / Dex70 ratio. The resulting aqueous Dextran 70 solution and the aqueous NaIO4 solution were stirred at 280 rpm for 3 hr at 50°C to obtain the reaction mixture. The reaction mixture was placed in a cellulose tube (molecular weight cutoff: 12,000–14,000) and dialyzed against tap water at room temperature for 70 hr, followed by four 45-min dialyses against ion-exchanged water to remove iodine and sodium. The dialysate was filtered to remove dust using a hydrophilic PTFE membrane filter with a pore size (φ) of 0.45 μm. The filtrate was shaken while being dried with hot air at 40°C for at least 20 hours. The concentrate was then inverted and similarly dried with hot air at 40°C for at least 20 hours. The concentrate thus obtained was dried under reduced pressure at room temperature for at least 15 hours to obtain a dried product. The dried product thus obtained was then coarsely crushed by hand into chunks of several centimeters, and then finely crushed using a small hammer mill (Wonder Crush Mill D3V-10, Osaka Chemical Co., Ltd.) with a screen pore size (φ) of 0.5 mm and a rotation speed of 10,000 rpm. The finely crushed product was dried under reduced pressure at 50°C for 15 hours to obtain a powder of aldehydedextran (AD), the first reactant.

[0034] As shown at the bottom of Table 1 below, the ratio of NaIO4 / Dextran 70 used in this aldehyde formation was 5.0 / 10. The amount of aldehyde groups introduced (mol / AGU) obtained in this case was 0.44 to 0.48, as determined by titration using a sodium thiosulfate-sulfuric acid system and a starch reagent. As shown in Table 1, comparative examples or reference examples were also prepared with a smaller amount of aldehyde groups introduced (mol / AGU).

[0035] Example of NaIO4 / Dextran 70 ratio and amount of aldehyde group introduced in AD powder TIFF0007766875000001.tif57132

[0036] The resulting dextran aldehyde (AD) powder was placed in water for injection (WFI) to a concentration of 0.5 to 10 wt %, and allowed to swell under refrigeration (3 to 6°C). The swollen AD was then stirred in a 50°C warm bath until completely dissolved. The resulting aqueous solution was sterilized by filtration using a 0.22 μm pore size (φ) polyethersulfone (PES) syringe filter to obtain the first reactant aqueous solution (ADaq).

[0037] 2) Preparation of succinic anhydride-treated polylysine aqueous solution (SAPLaq) Succinic anhydride was added to a 25% solution of polylysine (molecular weight 4,000, Chisso Corporation), and the mixture was stirred at 50°C for 1 hour to react. Water for injection (WFI) was then added until the product reached the desired concentration, and after gentle stirring, the mixture was sterilized by filtration using a PES syringe filter with a pore size (φ) of 0.22 μm to obtain an aqueous solution of the second reactant (APLaq). The product with a SA / PL (succinic anhydride / polylysine) charging ratio of 1.0 / 10 in the middle row of Table 2 below is an example, while the top and bottom rows are comparative examples or reference examples.

[0038] Examples of SAPL concentration and SA / PL ratio for SAPLaq TIFF0007766875000002.tif50148

[0039] The remaining percentage of free amino groups (amino groups in side chains and terminals not involved in peptide bond formation) (residual amino group percentage) was determined as follows: First, the sample was dissolved in water, and then ninhydrin solution and a pH 5.5 acetic acid / sodium acetate buffer solution were added. The mixture was heated in a boiling water bath for 3 minutes and then rapidly cooled to obtain a sample solution. The sample was then tested using the ultraviolet-visible absorbance measurement method of the Japanese Pharmacopoeia, and the absorbance at a wavelength of 570 nm was measured.

[0040] 3) Preparation of porous sheet ("Sponge-type LYDEX") from two types of aqueous solutions The first reactant aqueous solution (ADaq), the second reactant aqueous solution (SAPLaq), and distilled water (DW) were added to a soft silicone tray-shaped container, quickly mixed, and then allowed to stand at room temperature (25°C) for 10 minutes to obtain a suspension of the two-reactant adhesive (LYDEX suspension). The distilled water (DW) was added to achieve a two-reactant adhesive concentration (SAPL concentration in Table 2) of 0.5-10%. The tray-shaped container was filled to a uniform height (depth) of 0.7 mm. The aldehyde / amino molar reaction ratio was adjusted to 1.0.

[0041] The resulting suspension of the two-component adhesive (LYDEX suspension) was stored for 2 hours under refrigeration at 5°C, then rapidly cooled to -25°C and maintained at this temperature for at least 4 hours until completely frozen. The frozen LYDEX (registered trademark) suspension was then left to stand and dried under reduced pressure while maintaining an ambient temperature between room temperature (25°C) and 30°C. In other words, the water was removed by sublimation, yielding a dried sheet-like product 0.4 mm thick. This dried product is referred to as "sponge-type LYDEX" (LYDEX is a registered trademark).

[0042] The photograph in Figure 1 shows the appearance of the resulting porous sheet ("Sponge-type LYDEX").

[0043] 4) Observation of the porous sheet using a stereomicroscope Figure 2 shows a collection of stereomicroscope (Keyence VHX-5000) photographs taken when the suspension concentration during the gel formation reaction (SAPL concentration in Table 2) was set to four levels: 0.5%, 1%, 5%, and 10%.

[0044] As is clear from Figure 2, only at a concentration of 10% were large voids with a major axis diameter of 100 μm observed. Based on these observation results, the porous sheet obtained at a concentration of 10% was used in the ophthalmic treatment experiments.

[0045] 5) Trabeculectomy in rabbits A normal white rabbit underwent surgery similar to the glaucoma surgery described above. Figure 3 shows a schematic diagram of the surgical procedure.

[0046] For this operation, the "sponge-type LYDEX" of the example obtained above (aldehyde group introduction amount in the first reactant: 0.44-0.48 mol / AGU, residual amino group rate in the second reactant: 81-93%, concentration at the time of sheeting: 10%, height: 0.7 mm, product thickness: 0.4 mm) was used and cut into a rectangle of approximately 1.5 mm x 3 mm.

[0047] After creating a drainage channel as described above, small pieces of the porous sheet ("Sponge-type LYDEX") cut out as described above were attached under the pleural flap and between the conjunctiva and the pleural flap, and then the edges of the conjunctiva were sutured.

[0048] 5-1) From the time of surgery to 4 months after surgery The photograph in Figure 4 shows the condition at the end of surgery, the photograph in Figure 5 shows a photograph four weeks after surgery, and the photograph in Figure 6 shows a photograph four months after surgery. As can be seen from Figure 5, four weeks later, the hydrogel adhesion barrier remained at approximately the same size as immediately after surgery, and as can be seen from Figure 6, most of the hydrogel adhesion barrier remained even four months later.

[0049] Figure 7 shows the change in intraocular pressure over time. The reduction in intraocular pressure compared to pre-op (pre-op) was maintained for four months. The control group in Figure 5 shows the results for a case in which mycomycin C was used as before, without using the hydrogel of the present invention, and the effect of reducing intraocular pressure was unstable.

[0050] Figure 8 shows the peripheral area of ​​the eyeball extracted from a cross-section taken by CT four months after surgery. This also shows that a sufficient amount of the hydrogel adhesion barrier remains in place four months later.

[0051] 5-2) 1 year and 9 months after surgery Next, the photographs in Figures 9 and 10 show the condition one year and nine months after surgery. In these photographs, the surgical sites on the rabbit's left and right eyes are indicated by oval markings at the center. The surgical sites are colored blue in the color photographs, but appear as blemishes in the grayscale photographs in Figures 9 and 10.

[0052] Here, to confirm whether the surgical site was functioning, i.e., to check whether there was communication from the anterior chamber to outside the eye (from the anterior chamber under the scleral flap to the subconjunctival space), a blue dye (trypan blue) was administered into the anterior chamber. As a result, outflow of the blue dye to the outside of the eye (under the flap) was confirmed within 15-60 minutes. Furthermore, outflow into the subconjunctival space was not confirmed. This suggests that the flap was at least functioning 1 year and 9 months after surgery.

[0053] The results of other measurements and observations 1 year and 9 months after surgery are as follows: Left and right intraocular pressure: 8mmHg, 9mmHg Conjunctival mobility: Excellent in both eyes Anterior segment OCT: Both eyes had space under the flap, and no physical adhesion was confirmed.

[0054] These results demonstrate that the effects of glaucoma surgery persist even 1 year and 9 months after surgery.

[0055] <Example 2> The manufacturing conditions of the porous sheet were changed as shown in Table 3 below, and the ease of handling when used in trabeculectomy was evaluated. The results are shown in Table 4 below.

[0056] TIFF0007766875000003.tif40143

[0057] In Table 3 below, the items in the top row are as follows: "AD": The ratio of sodium periodate (NaIO4) to dextran used, as in the left half of Table 1. "5.0 / 20" in Table 3 is the same as "2.5 / 10" in Table 1, and the amount of aldehyde groups introduced (mol / AGU) is 0.25 to 0.27, which is slightly more than half that of "5.0 / 10" used in trabeculectomy in Example 1. "2.5 / 20" in Table 3 also has an amount of aldehyde groups introduced (mol / AGU) slightly more than half that of "2.5 / 10." "SAPL": the "SA / PL" (succinic anhydride / polylysine) feed ratio in the second column from the right in Table 2. This is the same as the "1.0 / 10" ratio used in trabeculectomy in Example 1. "AD:SAPL": a weight ratio of the materials used to produce a reaction molar ratio of aldehyde groups to amino groups of 1.0. This is the same as that used in the production of the porous sheet ("sponge-type LYDEX") in Example 1. "LYDEX concentration" and "liquid volume": The concentration and volume of the two-component adhesive (LYDEX) in the "LYDEX suspension" when manufacturing "sponge-type LYDEX" as described in "3)" above. - "Size": The diameter of the porous sheet is approximately 8.5 mm for "large" and approximately 3.6 mm for "small".

[0058] TIFF0007766875000004.tif51140

[0059] The grading criteria in Table 4 are as follows: Sheet thickness: 0: thin to 5: thick Ease of cutting the sheet: 0: Difficult to handle - 5: Good Expansion when wet: 0: none to 5: maximum -Ease of tearing when wet: 0: Unable to grip - 5: Unable to tear Subconjunctival inflammation (1 week) 0: Maximum to 5: None Subconjunctival inflammation (1 month) 0: Maximum to 5: None Conjunctival mobility (1 week) 0: no mobility ~ 5: good Conjunctival mobility (1 month) 0: no mobility ~ 5: good

[0060] All of the porous sheets ("Sponge-type LYDEX") tested were usable, but Lot No. 5 in particular had a uniform density throughout the sheet and was easy to handle.

[0061] Example 3 A porous sheet was obtained in the same manner as in Example 1, except that glycerin (glycerol) was added to the mixed aqueous solution during the gelling reaction. Specifically, the procedure was as follows.

[0062] The amounts of each solution were calculated and weighed so that the total solution volume would be equal to the base area of ​​the soft silicone container multiplied by 0.7 mm in height, with a ratio of first reactant solution (AD-aq):first reactant solution (ASAPL-aq):glycerol = 42.5:42.5:15. AD-aq and glycerol were added to the container and mixed well using a spatula or similar tool. SAPL-aq was then added and mixed in the same manner, resulting in a viscous mixture. At this stage, the mixture was spread over the entire bottom of the container and left to stand at room temperature for approximately 10 minutes to gel. After visually confirming gelation, the container was dried in a vacuum dryer. The temperature setting for this process was preferably below 30°C. After drying, the film was carefully peeled off the container to avoid tearing, and reshaped as necessary.

[0063] When a film was made with a liquid amount sufficient to reach a height of 0.7 mm, a film approximately 0.4 mm thick was produced. To make it thicker, the amount of liquid could be increased. To make it thinner, it was difficult because reducing the amount of liquid any further would prevent the liquid from spreading evenly across the bottom of the container.

[0064] <Reference example> Using the same procedure as above, fine spherical (microbead-like) porous materials were obtained. Specifically, liquid paraffin containing 2% sorbitan monooleate was placed in a beaker and stirred using a stirrer. Liquid LYDEX (AD-aq and SAPL-aq) was added dropwise to the stirring solution using a dual syringe at a rate at which the beads were visible, drop by drop. The size of the beads could be controlled by adjusting the stirring speed and the drop rate (amount added per drop). After addition, the solution became cloudy. Stirring continued for at least 10 minutes after the solution became cloudy. After stirring, the solution was left overnight at room temperature or 4°C to separate the cloudy sediment from the supernatant. The separated supernatant was discarded, and acetone was added to the sediment and stirred, revealing white particles. The particles in the supernatant were filtered through a mesh (of any size) and collected along with the sediment at the bottom of the beaker. The sediment was then placed in small amounts on filter paper and washed with acetone. Washing was repeated, using a new filter paper each time, until the paraffin stains disappeared. The resulting particles were dried until the acetone evaporated, yielding microbead-like LYDEX. The resulting porous bodies were all approximately spherical, with diameters ranging from 10 to 30 μm.

[0065] Although microbead-like porous materials can be injected into the surgical site using a syringe, they are not adhesive and are difficult to fix and place in a specific location. Microbead-like porous materials are thought to be usable when combined with mesh-like porous materials or block-like hydrogels.

Claims

1. an aldehydedglycan as a first reactant, which has a weight-average molecular weight of 10,000 to 5,000,000 and an aldehyde group introduction amount per anhydroglucose unit (mol / AGU) of 0.4 to 0.7; A porous sheet having interconnected pores made of a resin material containing a reaction product of poly-L-lysine with a carboxylic acid anhydride as a second reactant, the reaction product having a weight-average molecular weight of 1,000 to 100,000 and a residual amination rate of 80 to 99%, the reaction molar ratio of aldehyde group / amino group is 0.9 to 1.1; Apparent density (bulk density) of 0.1 to 0.25 g / cm 3 and An ophthalmic adhesion preventing material having a thickness of 0.1 to 0.8 mm.

2. 2. The ophthalmic adhesion preventing material according to claim 1, wherein the resin material contains a moisture-retaining plasticizer made of glycerin or other water-soluble low-molecular-weight compound in an amount of 30 to 100% by weight or 50 to 90% by weight relative to the total weight of the first reactant and the second reactant.

3. 3. The ophthalmic adhesion preventing material according to claim 1, wherein when the surface or cut surface is observed under a stereomicroscope, there are no voids with a major axis diameter of 80 μm or more.

4. The ophthalmic adhesion preventing material according to any one of claims 1 to 3, characterized in that the ophthalmic adhesion preventing material is used for glaucoma surgery.

5. A method for producing the ophthalmic adhesion preventing material according to any one of claims 1 to 3, comprising the steps of: A method for producing an ophthalmic adhesion barrier, comprising mixing the first reactant and the second reactant and reacting them in the presence of water so that the polymer concentration is 8 to 20%, and freeze-drying the hydrogel obtained by the reaction, or the suspension before gelation, to obtain a porous sheet.

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