Gelatin empty capsule with effect of resisting cross-linking of macrolide drugs and preparation method of gelatin empty capsule

Abstract

The invention discloses a gelatin hollow capsule with an effect of resisting crosslinking of macrolide drugs and a preparation method, and belongs to the technical field of hollow capsule production, the gelatin hollow capsule comprises gelatin, an antioxidant, a humectant, a surfactant, a pH regulator, a coloring agent and other raw materials; the preparation method comprises the following steps: adding and dissolving gelatin and auxiliary materials to obtain a gelatin solution, vacuumizing and defoaming, automatically dipping the gelatin, pulling, cutting and sleeving a capsule product, inspecting and selecting appearance, packaging and the like, thereby obtaining the anti-crosslinking gelatin hollow capsule. The preparation method provided by the invention can improve the anti-crosslinking performance and stability of the gelatin hollow capsule.

Description

Technical Field

[0001] The invention relates to the technical field of hollow capsule production, in particular to a gelatin hollow capsule with anti-macrolide drug cross-linking effect and a preparation method thereof. Background Art

[0002] Macrolide drugs are processed into different dosage forms due to different uses, such as tablets, capsules, etc. Among them, capsules have many advantages, including masking the bad smell of drugs, improving drug stability, rapid drug onset, high bioavailability, sustained release, controlled release and targeted release of drugs, etc., and are currently the most popular drug dosage forms, and gelatin hollow capsules are the most widely used. Gelatin is one of the degradation products of collagen, containing arginine, lysine and histidine, which are easy to produce cross-linking reactions and affect the in vitro dissolution test of capsules. The capsule cross-linking phenomenon refers to the phenomenon that the preparation disintegrates, dissolves and reduces the release efficiency in the dissolution medium without enzymes. It often appears in stability test. In the dissolution test, the capsule will become a water-insoluble film similar to colloid swelling, which is completely or partially wrapped in the drug powder, which reduces the drug dissolution rate or even causes the drug to be completely unable to dissolve, thus making it impossible to control the quality of the drug.

[0003] The cross-linking of gelatin can be divided into three aspects: first, the cross-linking reaction of gelatin itself. The lysine side chain contained in gelatin is oxidized to remove amino groups, and the terminal aldehyde functional group undergoes a series of hydroxyacetal reactions with adjacent amino acids to obtain pyridine ring cross-linking products; second, the capsule excipients contain aldehyde groups, ketone groups, etc., which undergo cross-linking reactions with amino groups in gelatin; third, environmental factors. High temperature and high humidity will promote gelatin cross-linking. High temperature will destroy the gelatin structure, accelerate the oxidation of amino acid residues, and increase the degree of cross-linking of gelatin itself. When the temperature remains unchanged, the relative change of humidity has little effect. In addition, ultraviolet rays promote the oxidation of free amino acids on the amino acid side chains into aldehyde groups, and sunscreens and colorants can be added to reduce the impact. Therefore, the development of anti-cross-linking gelatin hollow capsules has practical positive significance for the rapid development of the capsule industry. Summary of the invention

[0004] Technical problem to be solved: In view of the problems existing in the use of hollow gelatin capsules in the background technology, the present invention provides a hollow gelatin capsule with anti-macrolide drug cross-linking effect and a preparation method, thereby improving the anti-cross-linking performance and stability of the hollow gelatin capsule.

[0005] Technical solution: The hollow gelatin capsule with anti-macrolide drug cross-linking effect described in the present invention is characterized in that the hollow gelatin capsule comprises the following materials: gelatin, antioxidant, humectant, surfactant, pH regulator, and colorant.

[0006] Preferably, the antioxidant is one or a combination of L-cysteine, glycine and tea polyphenols.

[0007] Preferably, the moisturizing agent is one or a combination of glycerin, propylene glycol, sorbitol, polyethylene glycol 6000, polyethylene glycol 4000, and sucrose.

[0008] Preferably, the surfactant is one or a combination of sodium dodecyl sulfate, Tween 80, betaine, and Triton X-100.

[0009] Preferably, the pH adjuster is one or two of citric acid, sodium hydroxide and sodium bicarbonate.

[0010] Preferably, the colorant is one or a combination of food coloring, titanium dioxide, calcium carbonate, and iron oxide.

[0011] The present invention also discloses a method for preparing a cross-linked gelatin hollow capsule containing an anti-macrolide drug, the method comprising the following steps: Step 1: Inject purified water and gelatin into a sol tank according to the mass ratio of purified water to the total mass of gelatin (3-6):1, heat and keep warm to 60-85°C, after gelatin is dissolved, adjust the pH of the gelatin solution to 3.0-4.0, filter through a ceramic membrane, and concentrate the filtrate to a gelatin solid content of 15-30%, to obtain a gelatin solution with a total amino acid content of no more than 85%; Step 2: Based on the total mass of gelatin, add 1-5% antioxidant, 1-3% moisturizer, 0.5-3% pH adjuster and 1-10% surfactant by mass into the sol tank, mix and dissolve, and then color match and stand for natural defoaming to obtain a glue solution; Step 3: Vacuum the sol tank until there is no bubble overflowing from the glue solution, filter it with a clean filter bag, transfer it to a glue barrel and control the glue solution to be kept at a temperature of ≤45°C, and keep it warm and defoam for 4-8 hours; Step 4: Pour the defoamed glue into the glue basin, turn on the machine to automatically dip the glue, and dry the glue after it solidifies on the mold. Adjust the viscosity of the glue and control the drying temperature according to the glue state and the test results of the formed capsules; Step 5: After drying, the capsule products are cut, inspected for appearance, and packaged to obtain cross-linked anti-gelatin hollow capsules.

[0012] Preferably, the pore size of the ceramic membrane is C, the membrane surface flow rate is 3~4.6m / s, and the operating pressure is 0.2~0.3MPa.

[0013] Preferably, in step 3, the vacuum degree is ≤-0.08 MPa, and the vacuum treatment is performed for 15 to 45 minutes.

[0014] Preferably, the mesh size of the clean filter bag in step 3 is 200-300 meshes.

[0015] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention controls the amino acid content in the gelatin hollow capsule to prevent the gelatin from self-crosslinking reaction, thereby increasing the drug release rate and reducing the dissolution residue; 2. The preparation method controls the temperature of the gelatin solution to prevent the gelatin and the auxiliary materials from further cross-linking under high temperature conditions; 3. The preparation method adds a pH regulator to control the acid-base environment of the hollow capsule, and a saponification reaction occurs between the pH regulator and the demoulding oil to form a protective film to prevent the cross-linking reaction of the hollow gelatin capsule; 4. Antioxidants are added to the hollow gelatin capsules to eliminate free radicals in the hollow capsules and further prevent the occurrence of cross-linking reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 The present invention is a flow chart of the preparation of hollow gelatin capsules according to an embodiment of the present invention. DETAILED DESCRIPTION

[0017] To make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the following will be combined with the attached Figure 1 The technical solutions of the embodiments of the present invention are described clearly and completely. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.

[0018] The present invention provides a hollow gelatin capsule with anti-macrolide drug cross-linking effect, and the hollow gelatin capsule comprises the following materials: gelatin, antioxidant, moisturizing agent, surfactant, pH regulator, and colorant. Among them, the antioxidant is one or a combination of L-cysteine, glycine, and tea polyphenols; the moisturizing agent is one or a combination of glycerol, propylene glycol, sorbitol, polyethylene glycol 6000, polyethylene glycol 4000, and sucrose; the surfactant is one or a combination of sodium dodecyl sulfate, Tween 80, betaine, and Triton X-100; the pH regulator is one or two of citric acid, sodium hydroxide, and sodium bicarbonate; the colorant is one or a combination of food coloring, titanium dioxide, calcium carbonate, and iron oxide.

[0019] like Figure 1 As shown, the present invention also discloses a method for preparing a cross-linked gelatin hollow capsule with anti-macrolide drugs, the preparation method comprising the following steps: Step 1: Inject purified water and gelatin into a sol tank at a mass ratio of purified water to the total mass of gelatin of (3-6):1, heat and keep warm to 60-85°C, after the gelatin is dissolved, adjust the pH of the gelatin solution to 3.0-4.0, filter through a ceramic membrane, and concentrate the filtrate to a gelatin solid content of 15-30%, to obtain a gelatin gelatin solution with a total amino acid content of not more than 85%; wherein the pore size of the ceramic membrane is C, the membrane surface flow rate is 3-4.6 m / s, and the operating pressure is 0.2-0.3 MPa.

[0020] Step 2: Based on the total mass of gelatin, add 1-5% by mass of antioxidant, 1-3% by mass of moisturizer, 0.5-3% by mass of pH adjuster and 1-10% by mass of surfactant into the sol tank, mix and dissolve, and then color match and let stand for natural defoaming to obtain a gel solution.

[0021] Step 3: Vacuum the sol tank at a vacuum degree of ≤-0.08MPa for 15~45min until there is no bubble overflowing from the glue solution. Filter it with a clean filter bag (mesh size is 200~300 mesh), transfer it to a glue barrel and control the glue solution to be kept at ≤45℃, and keep it warm and defoam for 4~8h.

[0022] Step 4: Pour the defoamed glue into the glue basin, turn on the machine to automatically dip the glue, and dry the glue after it solidifies on the mold. Adjust the viscosity of the glue and control the drying temperature according to the state of the glue and the test results of the molded capsules.

[0023] Step 5: After drying, the capsule products are cut, inspected for appearance, and packaged to obtain cross-linked anti-gelatin hollow capsules.

[0024] Example 1: Purified water and gelatin are injected into the sol tank according to the mass ratio of purified water to the total mass of gelatin of 3:1, and heated to 75°C. After the gelatin is dissolved, the pH of the gelatin solution is adjusted to 3.0. After the ceramic membrane is filtered under the conditions of the pore size of the ceramic membrane being C, the membrane surface flow rate being 4.0m / s, and the operating pressure being 0.2MPa, the filtrate is concentrated to a gelatin solid content of 20%, and a gelatin gelatin solution with a total amino acid content of 85% is obtained. Based on the total mass of gelatin, 1% L-cysteine, 1% glycerol, 0.5% sodium bicarbonate and 6% Tween 80 are added to the sol tank in a mass percentage, and mixed and dissolved. The sol tank is vacuumed at a vacuum degree of -0.05MPa for 15min until the gelatin solution has no bubbles overflowing, filtered with a 200-mesh clean filter bag, and transferred to an insulated glue barrel, and an appropriate amount of pigment and titanium dioxide are added. The gelatin solution is kept at a temperature of 45°C and kept for defoaming for 4h. The defoamed glue is poured into the glue basin, and the machine is turned on to automatically dip the glue. After the glue solidifies on the mold, it is dried. According to the glue state and the test results of the formed capsules, hot pure water is used to adjust the viscosity of the glue and control the drying temperature. The dried capsule products are cut, inspected and packaged to obtain cross-linked gelatin hollow capsules.

[0025] Example 2: Purified water and gelatin are injected into the sol tank according to the mass ratio of purified water to the total mass of gelatin of 4:1, and heated to 80°C. After the gelatin is dissolved, the pH of the gelatin solution is adjusted to 3.2. After the ceramic membrane is filtered under the conditions of the pore size of the ceramic membrane being C, the membrane surface flow rate being 3.0m / s, and the operating pressure being 0.2MPa, the filtrate is concentrated to a gelatin solid content of 25%, and a gelatin gelatin solution with a total amino acid content of 83% is obtained. Based on the total mass of gelatin, 2% glycine, 1.5% polyethylene glycol 6000, 0.5% sodium hydroxide and 5% betaine are added to the sol tank in a mass percentage, and mixed and dissolved. The sol tank is vacuumed at a vacuum degree of -0.05MPa for 30min until the gelatin solution has no bubble overflow, filtered with a 250-mesh clean filter bag, and transferred to an insulated glue barrel, and an appropriate amount of pigment and titanium dioxide are added. The gelatin solution is kept at a temperature of 43°C and kept for 4h for defoaming. The defoamed glue is poured into the glue basin, and the machine is turned on to automatically dip the glue. After the glue solidifies on the mold, it is dried. According to the glue state and the test results of the formed capsules, hot pure water is used to adjust the viscosity of the glue and control the drying temperature. The dried capsule products are cut, inspected and packaged to obtain cross-linked gelatin hollow capsules.

[0026] Example 3: Purified water and gelatin were injected into the sol tank at a mass ratio of 6:1 to the total mass of purified water and gelatin, and heated to 85°C. After the gelatin was dissolved, the pH of the gelatin solution was adjusted to 3.5. After the ceramic membrane was filtered under the conditions of a pore size of C, a membrane flow rate of 4.6 m / s, and an operating pressure of 0.3 MPa, the filtrate was concentrated to a gelatin solid content of 30%, and a gelatin gelatin solution with a total amino acid content of 80% was obtained. Based on the total mass of gelatin, 3% tea polyphenols, 1.5% polyethylene glycol 4000, 1% sodium bicarbonate, 3% betaine, and 1% sodium dodecyl sulfate were added to the sol tank in mass percentage, and mixed and dissolved. The sol tank is vacuumed at a vacuum degree of -0.05MPa for 30 minutes until there is no bubble overflow from the glue. After filtering with a 300-mesh clean filter bag, it is transferred to an insulated glue barrel, and an appropriate amount of pigment and titanium dioxide are added. The glue is kept at 44°C and kept for defoaming for 4 hours. The defoamed glue is injected into the glue basin, and the machine is turned on to automatically dip the glue. After the glue is solidified on the mold, it is dried. According to the state of the glue and the test results of the formed capsules, the viscosity of the glue is adjusted with hot pure water and the drying temperature is controlled. The dried capsule product is cut, inspected for appearance, and packaged to obtain anti-cross-linked gelatin hollow capsules.

[0027] Performance analysis of the hollow gelatin capsules prepared in Examples 1 to 3 of the present invention: Ordinary gelatin hollow capsules and anti-cross-linked gelatin hollow capsules prepared in Examples 1 to 3 were filled with macrolide powder, and accelerated stability tests were carried out for 0, 10, 30, 60, 90, and 180 days. The dissolution was tested according to the capsule dissolution test method of the 2020 edition of the "Chinese Pharmacopoeia" to confirm the anti-cross-linking effect. The experimental results are shown in Tables 1 to 3.

[0028] Table 1 Dissolution results of macrolide powder filled ordinary gelatin empty capsules:

[0029] .

[0030] Table 2 Dissolution results of macrolide powder filled anti-crosslinked gelatin empty capsules of Example 1:

[0031] .

[0032] Table 3 Dissolution results of macrolide powder filled anti-crosslinked gelatin empty capsules of Example 2:

[0033] .

[0034] Table 4 Dissolution results of macrolide powder filled anti-crosslinked gelatin empty capsules of Example 3:

[0035] .

[0036] It can be seen from Tables 1 to 4 that the hollow gelatin capsules prepared in Examples 1 to 3 of the present invention have obvious anti-crosslinking effects, and can avoid crosslinking reactions in accelerated stability (0, 10, 30, 60, 90, 180 days) experiments, have little effect on the dissolution of the preparation, no crosslinking reaction occurs, and the dissolution is stable and qualified.

[0037] The above are preferred embodiments of the present invention. It should be pointed out that, for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A hollow gelatin capsule having anti-macrolide drug cross-linking effect, characterized in that: The gelatin hollow capsule comprises the following materials: Gelatin, antioxidant, humectant, surfactant, pH adjuster, colorant.

2. The hollow gelatin capsule having anti-macrolide drug cross-linking effect according to claim 1, characterized in that: The antioxidant is one or a combination of L-cysteine, glycine and tea polyphenols.

3. The hollow gelatin capsule with anti-macrolide drug cross-linking effect according to claim 1, characterized in that: The moisturizing agent is one or a combination of glycerin, propylene glycol, sorbitol, polyethylene glycol 6000, polyethylene glycol 4000, and sucrose.

4. The hollow gelatin capsule having anti-macrolide drug cross-linking effect according to claim 1, characterized in that: The surfactant is one or a combination of sodium dodecyl sulfate, Tween 80, betaine, and Triton X-100.

5. The hollow gelatin capsule having anti-macrolide drug cross-linking effect according to claim 1, characterized in that: The pH regulator is one or two of citric acid, sodium hydroxide and sodium bicarbonate.

6. The hollow gelatin capsule with anti-macrolide drug cross-linking effect according to claim 1, characterized in that: The colorant is one or a combination of food coloring, titanium dioxide, calcium carbonate, and iron oxide.

7. A method for preparing cross-linked gelatin hollow capsules containing anti-macrolide drugs as claimed in any one of claims 1 to 6, characterized in that: The preparation method comprises the following steps: Step 1: Inject purified water and gelatin into a sol tank according to the mass ratio of purified water to the total mass of gelatin (3-6):1, heat and keep warm to 60-85°C, after gelatin is dissolved, adjust the pH of the gelatin solution to 3.0-4.0, filter through a ceramic membrane, and concentrate the filtrate to a gelatin solid content of 15-30%, to obtain a gelatin solution with a total amino acid content of no more than 85%; Step 2: Based on the total mass of gelatin, add 1-5% antioxidant, 1-3% moisturizer, 0.5-3% pH adjuster and 1-10% surfactant by mass into the sol tank, mix and dissolve, and then color match and stand for natural defoaming to obtain a glue solution; Step 3: Vacuum the sol tank until there is no bubble overflowing from the glue solution, filter it with a clean filter bag, transfer it to a glue barrel and control the glue solution to be kept at a temperature of ≤45°C, and keep it warm and defoam for 4-8 hours; Step 4: Pour the defoamed glue into the glue basin, turn on the machine to automatically dip the glue, and dry the glue after it solidifies on the mold. Adjust the viscosity of the glue and control the drying temperature according to the glue state and the test results of the formed capsules; Step 5: After drying, the capsule products are cut, inspected for appearance, and packaged to obtain cross-linked anti-gelatin hollow capsules.

8. The method for preparing cross-linked gelatin hollow capsules containing anti-macrolide drugs according to claim 7, characterized in that: The pore size of the ceramic membrane is C, the membrane surface flow rate is 3-4.6 m / s, and the operating pressure is 0.2-0.3 MPa.

9. The hollow gelatin capsule with anti-macrolide drug cross-linking effect according to claim 1, characterized in that: In step 3, the vacuum degree is ≤-0.08MPa, and the vacuum treatment is carried out for 15 to 45 minutes.

10. The hollow gelatin capsule having anti-macrolide drug cross-linking effect according to claim 1, characterized in that: The mesh size of the clean filter bag in step 3 is 200~300 mesh.

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