CN1760231A - Preparation method of degradable polymer material for punctal plug - Google Patents

Abstract

The invention belongs to the technical field of polymer materials, and in particular relates to a method for preparing a degradable polymer material used for punctum plugs. The invention uses lactic acid and glycolic acid or lactic acid, glycolic acid and caprolactone as monomers for direct co-condensation Synthesize a degradable polymer material with a glass transition temperature of 32±1°C by lactide and glycolide or lactide, glycolide and polycaprolactone ring-opening polymerization method, and extrude the obtained material Molding, that is, the product. The punctal plug prepared by the method of the present invention can be used to treat dry eye, because its glass transition temperature is compatible with the temperature of the human lacrimal point, and because the temperature during the operation is higher than or reaches the glass transition temperature, its properties are rubbery. shape, it is easy to insert into the lacrimal duct, and its diameter becomes thicker, so that the punctal plug is not easy to fall off. In addition, the punctal plug can be degraded, and the final products of degradation are carbon dioxide and water, which can be discharged with tears, so that the previous dry eye can be avoided. Surgery to remove the punctal plug is required in the later stage of symptomatic treatment.

Description

Preparation method of degradable polymer material for punctal plug

technical field

The invention belongs to the technical field of polymer materials, and in particular relates to a method for preparing a degradable polymer material for punctal plugs, in particular to a synthesis and preparation of degradable punctal plug materials for treating dry eye. Preparation method of punctal plug.

Background technique

For any reason, the abnormal structure of the tear layer of the eyeball or the insufficient secretion of components in each layer can cause dry eye syndrome. Patients with dry eye syndrome are troubled by many symptoms. In mild cases, the symptoms are dry eyes, red eyes, burning sensation, and foreign body sensation. Or eye soreness, severe cases appear diffuse corneal epithelial punctate or flake staining.

At present, there are many treatments for dry eye syndrome, mainly including: (1) eliminating the cause; (2) artificial tears; (3) physical therapy, such as hot compress, eyelid massage, etc.; (4) punctum or lacrimal duct embolization. Elimination of triggers is the first choice for the treatment of dry eye, but for intractable dry eye, blocked tear ducts or puncta may still be the best method at present, allowing them to retain their own natural tears. The initial method of sealing the puncta with thermal punctal cautery is simple and effective, but scarring, painful and irreversible. Later, people used laser to seal the puncta, but according to long-term follow-up observations, 20% of the puncta reopened after surgery. The advantage of the laser method over thermal ablation is that there will be no punctal scars.

Punctal plugging is a newer punctal closure technique in which the mechanical blocking action of a punctal plug reduces tear drainage. At present, the materials of punctal plugs can be roughly divided into two categories, one is non-degradable synthetic polymer materials, such as silica gel, polyethylene, cyanoacrylate, etc. It can be taken out at any time. The most commonly used is the silicone punctal plug. Due to the elastic characteristics and design characteristics of the silicone material, it can completely prevent the tear flow when there is little tear flow. The automatic adjustment of the power system re-establishes the balance of tears, thereby greatly increasing the corneal surface moisture. Another type of punctal plug is self-dissolving punctal plug represented by natural polymer materials such as collagen. This type of punctal plug will dissolve by itself within a week after implantation, and can be used as a temporary type of punctal plug. After the trial product is inserted, if the symptoms or signs improve, a permanent punctal plug can be inserted.

Contents of the invention

The purpose of the present invention is to propose a method for preparing a degradable polymer material used for punctal plugs.

The preparation method of the degradable polymer material used for the punctal plug proposed by the present invention uses lactic acid and glycolic acid or lactic acid, glycolic acid and caprolactone as monomers with direct co-condensation polymerization, or with lactide and glycolide Or lactide, glycolide and polycaprolactone ring-opening polymerization method to synthesize a degradable polymer material with a glass transition temperature of 32±1°C, and extruding the obtained material to obtain the product. The polymerization conditions are:

(1) Direct co-condensation method: polymerization of lactic acid and glycolic acid or lactic acid, glycolic acid and caprolactone, direct polymerization in the presence of a catalyst after removing water from the monomer, polymerization temperature 150-180 ° C, time 12-18 hours, pressure 50-70Pa, after the polymerization is completed, add a solvent to dissolve, then add a precipitant to precipitate the polymer, purify the product, and dry it in vacuum to obtain a white powdery degradable polymer material. The molar ratio of the reactants is:

Lactic acid: the molar ratio of glycolic acid is 3: 7～7: 3;

Lactic acid: glycolic acid: the molar ratio of caprolactone is 3.92: 5.88: 2～4.8: 3.2: 2;

(2) Ring-opening polymerization method: polymerization of lactide and glycolide or lactide, glycolide and polycaprolactone, melt polymerization in the presence of a catalyst, polymerization temperature 150-180 ° C, time 12-18 hours , the pressure is 50-70Pa, after the polymerization is completed, add a solvent to dissolve, then add a precipitant to precipitate, purify the product, and dry it in vacuum to obtain a white powdery degradable polymer material. The molar ratio of the reactants is:

The molar ratio of lactide:glycolide is 3:7～7:3;

The molar ratio of lactide:glycolide:polycaprolactone is 3.92:5.88:2˜4.8:3.2:2.

In the present invention, the molar ratio of lactic acid to glycolic acid is 4:6˜6:4.

In the present invention, the molar ratio of lactide to glycolide is 4:6˜6:4.

In the present invention, the catalyst is one of stannous octoate, stannous chloride, tin or zinc oxide, etc., and the added amount of the catalyst is 0.4-0.8% of the total amount of monomers.

In the present invention, the solvent added after the polymerization is one of tetrahydrofuran, chloroform or N,N-dimethylformamide and the like.

In the present invention, the precipitating agent added after the polymerization is one of methanol or ethanol.

In the present invention, the obtained material is melt-extruded, and the extrusion temperature is 180-230°C.

In the present invention, extrusion molding is processed into a cylindrical punctal plug with a diameter of 0.4-0.6 mm and a length of 8-10 mm.

The application of the degradable synthetic polymer material punctal plug prepared in the present invention in dry eye syndrome. The punctal plug prepared by the method of the present invention can be processed into a cylindrical punctal plug with a diameter of 0.4-0.6 mm and a length of 9±1 mm by extrusion molding (see FIG. 1 ). The punctal plug prepared by the present invention is degradable. After being implanted into the punctum for a certain period of time, the punctal plug can be degraded automatically with the cure of dry eye. 2) The degradation products are carbon dioxide and water, which are harmless to the human body and can be discharged with tears, avoiding secondary operations, and the glass transition temperature is 32±1°C, making the operation easy.

Advantages of the present invention: the punctum plug can be used to treat dry eye syndrome, and it is plastic at room temperature, but because its glass transition temperature is 32±1°C, which is compatible with the temperature of the human punctum, it can be used during the operation. Among them, because the temperature is higher than or reaches the glass transition temperature, its properties are rubbery, easy to deform, it is easy to insert into the lacrimal duct, and its diameter becomes thicker, so that the punctal plug is not easy to fall off. In addition, the punctal plug is biodegradable, and can be degraded after a certain period of time after being implanted in the punctum. The final products of degradation are carbon dioxide and water, which can be discharged with the tear fluid, thus eliminating the need for surgery to remove the punctal plug in the later stage of dry eye disease treatment.

Description of drawings

Figure 1 shows the shape of the punctal plug before implantation.

Figure 2 shows the shape of the punctum plug after a period of time after the puncta were implanted.

Detailed ways

Example 1

Using D, L-lactic acid as raw material, add equimolar glycolic acid, after water removal treatment, add catalyst stannous octoate (0.8%), polymerize at 165°C and pressure 60Pa for 14 hours. After the reaction, tetrahydrofuran was added to dissolve, then methanol was added to precipitate and purify the product, and vacuum-dried to obtain PLGA in the form of white powder with a glass transition temperature of about 31°C. The obtained white powdery PLGA was melt-extruded at a temperature of 180° C. to prepare a punctal plug as shown in FIG. 1 .

Example 2

Using D, L-lactic acid and glycolic acid as raw materials, the molar ratio of D, L-lactic acid and glycolic acid is 40:60, after dehydration treatment, adding catalyst stannous chloride (0.5%), at 150°C and pressure 70Pa Next, polymerize for 18 hours. After the reaction, add N,N-dimethylformamide to dissolve, then add ethanol to precipitate and purify the product, and vacuum dry to obtain PLGA in the form of white powder with a glass transition temperature of about 31.5°C. The obtained white powdery PLGA was melt-extruded at a temperature of 220° C. to prepare a punctal plug as shown in FIG. 1 .

Example 3

Using L-lactic acid as raw material, adding equimolar glycolic acid, after dehydration treatment, adding catalyst zinc oxide (0.8%), polymerizing at 180°C and pressure 50Pa for 14 hours. After the reaction was completed, chloroform was added to dissolve, then methanol was added to precipitate and purify the product, and vacuum-dried to obtain PLGA in the form of white powder with a glass transition temperature of about 33°C. The obtained white powdery PLGA was melt-extruded at a temperature of 190° C. to prepare a punctal plug as shown in FIG. 1 .

Example 4

Using L-lactic acid and glycolic acid as raw materials, the molar ratio of L-lactic acid and glycolic acid is 45:55, after dehydration treatment, add catalyst tin (0.5%), polymerize at 165°C and pressure 60Pa for 14 hours. After the reaction, tetrahydrofuran was added to dissolve, then ethanol was added to precipitate and purify the product, and vacuum-dried to obtain PLGA in the form of white powder with a glass transition temperature of about 32°C. The obtained white powdery PLGA was melt-extruded at a temperature of 210° C. to prepare a punctal plug as shown in FIG. 1 .

Example 5

Using D, L-lactide and glycolide as raw materials, the molar ratio of D, L-lactide and glycolide is 65:35, adding catalyst stannous octoate (0.8%), at 170°C and pressure 60Pa , melt polymerization for 16 hours. After the reaction, the solvent tetrahydrofuran was added to dissolve, and then ethanol was added to precipitate and purify the product, and vacuum-dried to obtain PLGA in the form of white powder with a glass transition temperature of about 32.5°C. The obtained white powdery PLGA was melt-extruded at a temperature of 180° C. to prepare a punctal plug as shown in FIG. 1 .

Example 6

Using L-lactide and glycolide as raw materials, the molar ratio of L-lactide and glycolide is 40:60, add catalyst stannous chloride (0.5%), melt at 170°C and pressure 65Pa Polymerized for 12 hours. After the reaction, add N,N-dimethylformamide to dissolve, then add methanol to precipitate and purify the product, and dry it in vacuum to obtain white powder PLGA with a glass transition temperature of about 31°C. The obtained white powdery PLGA was melt-extruded at a temperature of 230° C. to prepare a punctal plug as shown in FIG. 1 .

Example 7

With L-lactic acid, glycolic acid, and caprolactone as raw materials, the molar ratio of L-lactic acid, glycolic acid, and caprolactone is 3.92:5.88:2. After water removal treatment, a catalyst zinc oxide (0.8%) is added. Polymerization was carried out for 12 hours at 175° C. and a pressure of 70 Pa. After the reaction, add N,N-dimethylformamide to dissolve, then add methanol to precipitate and purify the product, and vacuum dry to obtain a white powdery copolymer with a glass transition temperature of about 32.2°C. The obtained white powdery PLGA was melt-extruded at a temperature of 190° C. to prepare a punctal plug as shown in FIG. 1 .

Example 8

With L-lactide, glycolide, polycaprolactone as raw materials, the molar ratio of L-lactide, glycolide, polycaprolactone is 4.8: 3.2: 2, add catalyst stannous octoate (0.8% ), at 170°C and a pressure of 65Pa, melt polymerization for 12 hours. After the reaction, tetrahydrofuran was added to dissolve, and then a precipitant was added to ethanol to precipitate and purify the product, and vacuum-dried to obtain a white powder PLGA with a glass transition temperature of about 31°C. The obtained white powdery PLGA was melt-extruded at a temperature of 230° C. to prepare a punctal plug as shown in FIG. 1 .

Claims (9)

1, a kind of preparation method of the degradable macromolecule material that is used for punctal plug, it is characterized in that take lactic acid and glycolic acid or lactic acid, glycolic acid and caprolactone as monomer with direct co-condensation method, or with lactide and Synthesize degradable polymer materials by ring-opening polymerization of glycolide or lactide, glycolide and polycaprolactone, and extrude the obtained materials to obtain the product. The polymerization conditions are: (1) Direct co-condensation method: polymerization of lactic acid and glycolic acid or lactic acid, glycolic acid and caprolactone, direct polymerization in the presence of a catalyst after removing water from the monomer, polymerization temperature 150-180 ° C, time 12-18 hours, pressure 50-70Pa, after the polymerization is completed, add a solvent to dissolve, then add a precipitant to precipitate the polymer, purify the product, and dry it in vacuum to obtain a white powdery degradable polymer material. The molar ratio of the reactants is: Lactic acid: the molar ratio of glycolic acid is 3: 7～7: 3; Lactic acid: glycolic acid: the molar ratio of caprolactone is 3.92: 5.88: 2～4.8: 3.2: 2; (2) Ring-opening polymerization method: polymerization of lactide and glycolide or lactide, glycolide and polycaprolactone, melt polymerization in the presence of a catalyst, polymerization temperature 150-180 ° C, time 12-18 hours , the pressure is 50-70Pa, after the polymerization is completed, add a solvent to dissolve, then add a precipitant to precipitate, purify the product, and dry it in vacuum to obtain a white powdery degradable polymer material. The molar ratio of the reactants is: The molar ratio of lactide:glycolide is 3:7～7:3; The molar ratio of lactide:glycolide:polycaprolactone is 3.92:5.88:2˜4.8:3.2:2. 2. The method for preparing a degradable polymer material for a punctal plug according to claim 1, characterized in that the molar ratio of lactic acid to glycolic acid is 4:6-6:4. 3. The method for preparing a degradable polymer material for a punctal plug according to claim 1, characterized in that the molar ratio of lactide to glycolide is 4:6-6:4. 4. The method for preparing a degradable polymer material for a punctal plug according to claim 1, wherein the catalyst is one of stannous octoate, stannous chloride, tin or zinc oxide, and the catalyst is added The amount is 0.5-0.8% of the total amount of monomers. 5. The method for preparing a degradable polymer material for a punctal plug according to claim 1, wherein the solvent added after the polymerization is one of tetrahydrofuran, chloroform or N,N-dimethylformamide . 6. The method for preparing a degradable polymer material for a punctal plug according to claim 1, wherein the precipitating agent added after the polymerization is one of methanol or ethanol. 7. The preparation method of the degradable polymer material for the punctal plug according to claim 1, characterized in that the obtained material is melt-extruded, and the extrusion temperature is 180-230°C. 8. The method for preparing a degradable polymer material for a punctal plug according to claim 7, characterized in that it is extruded and processed into a cylindrical punctal plug with a diameter of 0.4-0.6 mm and a length of 8-10 mm. 9. The application of the degradable synthetic polymer material punctal plug according to claim 1 in dry eye syndrome.

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