CN1757414A - Method for preparing visible polysaccharide membrane used as carrier of medicine for treating eye surface diseases - Google Patents

Abstract

A method for manufacturing a drug-loaded visible polysaccharide film for treating ocular surface diseases, which is characterized in that chitosan is prepared with carboxymethyl chitin or carboxymethyl chitosan or hyaluronic acid or hydroxyethyl chitosan To form a colloidal aqueous solution, the colloidal aqueous solution is driven by a motor with a rotating centrifugal stainless steel concave mold and heated with an electric light source or hot air to make a dry film. The dry film is neutralized by acid and alkali, and the obtained wet film is exchanged. Then, the membrane is sterilized, and the obtained aseptic membrane is put into an antibiotic aqueous solution to obtain a drug-loaded visible polysaccharide membrane. The advantage of the present invention is that the prepared drug-loaded visible polysaccharide film for the treatment of ocular surface diseases can be attached to the eye surface, and the medicine in the film is slowly released to the wound surface, and the medicine stays for a long time, reducing the number of conventional medications; chitosan has a certain The antibacterial and antibacterial effect can improve the antibacterial ability of the wound surface, accelerate the healing of the wound surface, and reduce the pain response of the wound surface.

Description

A method for manufacturing a drug-loaded visible polysaccharide membrane for treating ocular surface diseases

technical field

The invention relates to a method for manufacturing a drug-loaded visible curvature membrane for treating ocular surface diseases by using biological polysaccharides.

Background technique

Ocular surface disease is a common disease, including corneal ulcers caused by pathogenic bacteria infection, ocular surface trauma caused by ophthalmic surgery or mechanical force, ocular surface burns caused by chemical substances such as acid and alkali, ocular surface burns caused by heat source factors Injuries and other ocular surface diseases, etc., are currently treated with eye drops or ointment, in order to achieve sterilization and antibacterial of the wound, or prevent infection of the injured wound, and promote wound healing. However, due to the short retention time of the drug in the eyes, in order to maintain the efficacy of the drug, it is often required to instill the drug solution every 0.5 to 1 hour in clinical practice. Due to the frequent number of medications, it is difficult for patients to follow the doctor's advice, which often affects the therapeutic effect or makes some patients' eye diseases aggravate.

Contents of the invention

The purpose of the present invention is to provide a method for manufacturing a biopolysaccharide curvature membrane that can absorb drugs and is suitable for eye surface attachment, so as to overcome the above-mentioned shortcomings of eye drops in the treatment of ocular surface diseases.

A method for manufacturing a drug-loaded visible polysaccharide film for treating ocular surface diseases, which is characterized in that chitosan is prepared with carboxymethyl chitin or carboxymethyl chitosan or hyaluronic acid or hydroxyethyl chitosan To form a colloidal aqueous solution, the colloidal aqueous solution is driven by a motor with a rotating centrifugal stainless steel concave mold and heated with an electric light source or hot air to make a dry film. The dry film is neutralized by acid and alkali, and the obtained wet film is exchanged. Then, the membrane is sterilized, and the obtained aseptic membrane is put into an antibiotic aqueous solution to obtain a drug-loaded visible polysaccharide membrane.

The advantage of the present invention is that the prepared drug-loaded visible polysaccharide film for the treatment of ocular surface diseases can be attached to the ocular surface, and: 1. The film is in close contact with the wound surface, and the medicine in the film is slowly released to the wound surface, and the residence time of the medicine Long, good curative effect, reduce the frequency of conventional medication. 2. Chitosan has a positive charge and has certain antibacterial and antibacterial effects. 3. Chitosan can increase the secretion of lysozyme in ocular tissue, thereby improving the antibacterial ability of the wound. 4. Chitosan is degraded by lysozyme to produce small molecular chitosan oligosaccharides, which can promote the growth of wound epithelial cells and accelerate wound repair and healing. 5. Chitosan can inhibit the conduction of peripheral nerves and reduce the pain response of wounds. 6. It has the function of adjusting the pH value of acid and alkali. 7. The membrane has good biocompatibility and does not cause adverse reactions such as inflammation.

Detailed ways

Example 1

(1) preparation of colloidal aqueous solution: take by weighing respectively molecular weight and be that the degree of deacetylation of 700KD is 80% chitosan 0.7g (the degree of deacetylation of chitosan is the sugar residue number that removes acetyl group in chitosan molecule Accounting for the percentage of the total sugar residue number in the chitosan molecule, the same below) and the carboxymethylation degree of 500KD as the carboxymethyl chitin 0.3g (the carboxymethylation of carboxymethyl chitin) of 92% Degree is the carboxymethyl number of sugar residues in the carboxymethyl chitin molecule accounts for the percentage of the total sugar residues in the carboxymethyl chitin molecule, the same below), put in a clean glass container, add 48.5g water , add 0.5g of glacial acetic acid to dissolve under stirring, and place it at 4-8°C until all the polysaccharides are dissolved into a transparent and clear colloidal solution. The weight ratio of chitosan and carboxymethyl chitin is 1:0.1-1.0, and the total weight percentage in the glue is 0.5%-5%.

Changing the carboxymethyl chitin in the above process to carboxymethyl chitosan can also achieve the same effect.

(2) Preparation of curvature diaphragm: Add 0.1-0.5ml of the above-mentioned colloidal aqueous solution to a rotating centrifugal stainless steel concave mold driven by a motor, with an adjustable rotation speed, and an R value of 7.9 mm. Turn on the motor to rotate the mold, and use electric heating The stainless steel mold is heated by wind or electric light source, the surface temperature is 40℃～80℃, and the rotation speed of the mold is adjusted to 600～1000 rpm, so that the colloid solution forms a film with uniform thickness on the concave surface, and evaporates with water to form a dry film . The R value of the rotary centrifugal stainless steel concave mold can be 7.9mm ~ 8.6mm.

(3) Post-treatment and processing of the above-mentioned dry membrane: add 1ml of 0.1-2mol/L NaOH aqueous solution into the mold that has formed the dry curvature membrane, after neutralization reaction, take out the curvature polysaccharide membrane made by rotation, and use Fully wash the strips with sterile normal saline until the pH is neutral, immerse in 50ml of an aqueous solution containing 0.01-0.5% (weight percentage concentration) of glutaraldehyde to carry out cross-linking reaction for 5-30min, take it out, and cut it into 6-30 minutes with an ophthalmic trephine 20mm, curvature diaphragm with neat edges, fully washed with sterile distilled water or normal saline, autoclaved in water at 121°C, and then put the diaphragm into a glass containing 0.1-0.5% ofloxacin antibiotic aqueous solution Preserved in the ampoule bottle, the drug-loaded visible polysaccharide film for treating ocular surface diseases can be obtained.

Example 2

(1) Preparation of colloidal solution: take by weighing 0.9 g of chitosan whose deacetylation degree is 90% with a molecular weight of 500KD, place in a clean glass container, add 28.8 g of water, add 0.3 g of glacial acetic acid under stirring, and make chitosan The sugar is all dissolved. Take another 0.1g of hyaluronic acid with a molecular weight of 400KD, put it in another clean glass container, add 19.9g of water and stir to dissolve it into a colloid, and slowly add the chitosan glue into the hyaluronic acid glue under stirring conditions Mix evenly, remove air bubbles under vacuum, and place at 4-10°C. The weight ratio of chitosan and hyaluronic acid can be 1:0.1-1.0, and the total weight percentage in the glue solution can be 0.5%-5%.

(2) The preparation of the curvature diaphragm is the same as that in (2) of Example 1.

(3) Post-treatment and processing of the curvature membrane: Add 1ml of 0.1-2.0mol/L NaOH solution into the mold that has formed the dry curvature membrane, soak for neutralization reaction, and take out the curvature polysaccharide membrane made by rotation , immersed in 50ml of 0.1mol/L NaOH solution containing 0.01-1% (weight percentage concentration) of hydroxypropyl bisglycidyl ether, and carried out cross-linking reaction at 10-80°C for 10-30min, the curvature film after cross-linking The slices are fully washed in normal saline for several times until the pH is neutral, taken out, cut into 6-20mm curvature membranes with neat edges with an ophthalmic trephine, fully washed in sterile normal saline, and autoclaved in water at 121°C and then put the film into a glass ampoule filled with 0.1-0.5% Tobrex aqueous solution for preservation, thus obtaining the drug-loaded visible polysaccharide film for treating ocular surface diseases.

Example 3

(1) Preparation of colloidal solution: take by weighing 0.9g of chitosan with a molecular weight of 300KD and a deacetylation degree of 94%, place it in a clean glass container, add 28.8g of water, add 0.3g of glacial acetic acid under stirring, and make the shell All glycans are dissolved. Another get molecular weight is that the hydroxyethylation degree of 500KD is the hydroxyethyl chitosan 0.5g of 85% (the hydroxyethylation degree of hydroxyethyl chitosan is the sugar residue in the hydroxyethyl chitosan molecule). The number of hydroxyethyl groups accounts for the percentage of total sugar residues in hydroxyethyl chitosan molecules, the same below), in another clean glass container, add 20g of distilled water, stir until completely dissolved, and stir the chitosan glue Next, add hydroxyethyl chitosan glue, mix well, and store at 4-10°C. The weight ratio of chitosan and hydroxyethyl chitosan used is 1:0.1-1.0, and the total weight percentage in the colloid solution is 0.5-5%.

(2) The preparation of the curvature diaphragm is the same as that in (2) of Example 1.

(3) Post-processing and processing of the curvature membrane: take 1ml of 0.1-2.0mol/L NaOH solution, add it to the mold that has formed the dry curvature membrane, and after neutralization reaction, take out the curvature polysaccharide film made by rotation Wash the film with sterile normal saline until the pH is neutral, then immerse the film in 50ml of an aqueous solution containing 0.01-0.5% (weight percentage concentration) of carbodiimide (EDC), and cross-link for 10-30 minutes , take it out, use an ophthalmic trephine to cut into 6-20mm curvature diaphragms with neat edges, wash them with sterile normal saline for several times, sterilize the diaphragms in water at 121°C, and then put the diaphragms into a container with a concentration of The 0.1-0.5% rifampicin aqueous solution is stored in a glass ampoule to obtain a drug-loaded visible polysaccharide film for treating ocular surface diseases.

The molecular weight range of chitosan described in the present invention is 100KD～800KD, and the deacetylation degree is 65%～100%; The molecular weight range of carboxymethyl chitin is 100KD～800KD, and the carboxymethylation degree is 55%～105 %; the molecular weight range of hyaluronic acid is 100KD-800KD; the molecular weight range of hydroxyethyl chitosan is 100KD-800KD, and the degree of hydroxyethylation is 60%-120%. The 121°C autoclaving can also be ⁶⁰ Co irradiation sterilization or ethylene oxide sterilization or 75% ethanol aqueous solution sterilization, which has the same effect. The ofloxacin antibiotic can also be Tobrex or levofloxacin or ciprofloxacin or rifampicin, which have the same effect.

The present invention uses natural biological polysaccharide chitosan (chitosan) as the main material, and makes highly transparent colloids with water-soluble polysaccharide carboxymethyl chitin, carboxymethyl chitosan, hyaluronic acid and hydroxyethyl chitosan respectively Solution, by adding a certain volume of colloidal solution to the motor-driven rotary centrifugal stainless steel concave mold, the mold curvature R value is 7.9mm ~ 8.6mm, controlling the rotation speed and heating temperature, the colloid can form a dry and transparent polysaccharide with a certain thickness Curvature membrane, and then neutralized with lye, the wet curvature membrane prepared has an R value of 7.9mm to 8.6mm, and the crosslinking agent glutaraldehyde or hydroxypropyl bisglycidyl ether or carbodiimide Cross-link the polysaccharide in the membrane, use 0.1-1.0mol/L NaH ₄ B for reduction reaction, fully wash the curvature membrane with normal saline, sterilize by wet method, and combine the sterilized membrane with antibiotic adsorption to produce A drug-loaded visible polysaccharide patch for the treatment of ocular surface diseases.

Claims (7)

1, a kind of manufacture method for the treatment of the visible polysaccharide membrane used as carrier of medicine of eye surface diseases, it is characterized in that chitosan and carboxymethyl chitin or carboxymethyl chitosan or hyaluronic acid or hydroxyethyl chitosan are mixed with colloid aqueous solution, this colloid aqueous solution is made dry diaphragm with motor-driven rotating centrifugal rustless steel concave surface mould and with electric light source or hot blast heating, this drying diaphragm reacts through acid-base neutralization, and the wet film sheet of gained carried out cross-linking reaction, again diaphragm is sterilized, the aseptic diaphragm that obtains is put into the antibiotic aqueous solution, makes visible polysaccharide membrane used as carrier of medicine.

2, manufacture method as claimed in claim 1 is characterized in that described chitosan molecule weight range is 100KD～800KD, and deacetylation is 65%～100%; Carboxymethyl chitin or carboxymethyl chitosan molecular weight ranges are 100KD～800KD, and the carboxy methylation degree is 55%～105%; The hyaluronan molecule weight range is 100KD～800KD; The hydroxyethyl chitosan molecular weight ranges is 100KD～800KD, and the hydroxyethylation degree is 60%～120%.

3, manufacture method as claimed in claim 1, the part by weight that it is characterized in that described chitosan and carboxymethyl chitin or carboxymethyl chitosan or hyaluronic acid or hydroxyethyl chitosan is 1: 0.1～1.0, and their weight percentages in described colloid aqueous solution are 0.5～5%.

4, manufacture method as claimed in claim 1 is characterized in that the concave R value of described rotating centrifugal film tool is 7.9mm～8.6mm, and described hygrometric state diaphragm curvature R value is 7.9mm～8.6mm.

5, manufacture method as claimed in claim 1 is characterized in that the cross-linking agent that described cross-linking reaction is used is glutaraldehyde or hydroxypropyl bisglycidyl ether or carbodiimides, and the cross-linking agent weight percent concentration is 0.01～1.0%.

6, manufacture method as claimed in claim 1, it is characterized in that described with diaphragm sterilize be 121 ℃ of autoclavings or ⁶⁰Co irradiation sterilization or ethylene oxide sterilizing or the sterilization of 75% ethanol water.

7, manufacture method as claimed in claim 1 is characterized in that described antibiotic is a positively charged or electronegative antibiotic water-soluble under the pH neutrallty condition, as ofloxacin or Tobrex or levofloxacin or ciprofloxacin or rifampicin.