Anti-crosslinking gelatin hollow capsule and preparation method thereof

Abstract

The invention discloses an anti-crosslinking gelatin hollow capsule and a preparation method thereof, and belongs to the field of biological medicine manufacturing, and the preparation method comprises the following steps: adding purified water and gelatin into a sol tank according to a mass ratio of (3-5): 1, mixing, heating to 60-85 DEG C, and dissolving; adding 0.01-0.1% of a chelating agent, stirring, and adding a pH regulator to regulate the pH value of the glue solution to 4-6; based on the total mass of the gelatin, adding 1-4% of an antioxidant, 1-3% of a plasticizer and 0.5-3% of a filler into the gelatin dissolving tank, and uniformly mixing and dissolving to obtain a gelatin solution; the sol tank is vacuumized to be smaller than or equal to-0.05 MPa, and the vacuum condition is kept for 15-30 min; filtering, transferring to a glue barrel, and carrying out heat preservation defoaming treatment for 4-6 hours under the condition that the heat preservation temperature is less than or equal to 50 DEG C; and injecting the de-foamed gelatin solution into a mold, curing, drying, pulling, selecting and packaging to obtain the gelatin hollow capsule, so that the preparation process is simplified, and the anti-crosslinking effect of the gelatin hollow capsule is remarkably improved.

Description

Technical Field

[0001] This invention relates to the field of biopharmaceutical manufacturing, and in particular to an anti-crosslinking gelatin empty capsule and its preparation method. Background Technology

[0002] Capsules are currently the most popular drug dosage form due to their ability to mask unpleasant odors and tastes, improve drug stability, provide rapid onset of action, high bioavailability, and offer sustained, controlled, and targeted release. Gelatin hollow capsules are widely used in pharmaceutical preparations. Gelatin is a degradation product of collagen and contains arginine, lysine, and histidine, which readily undergo cross-linking reactions, affecting the in vitro dissolution test of capsules. Capsule cross-linking often occurs in stability studies, manifesting as a swollen, water-insoluble film resembling a gelatinous substance during dissolution tests, completely or partially encapsulating the drug powder. This reduces the drug dissolution rate or even prevents complete dissolution, thus compromising drug quality control.

[0003] Crosslinking of gelatin mainly includes its own crosslinking reaction, especially the oxidation and deamination of the lysine side chain in gelatin, where the terminal aldehyde functional group undergoes a series of hydroxyacetal reactions with adjacent amino acids to obtain pyridine ring crosslinked products. Simultaneously, metal ions in gelatin also promote crosslinking reactions. Capsule excipients containing aldehyde and ketone groups react with the amino groups in gelatin to form crosslinks. Furthermore, the capsule storage environment also affects crosslinking; high temperature, high humidity, and ultraviolet radiation can all promote crosslinking reactions and affect product quality. While some anti-crosslinking measures exist in existing technologies, they often suffer from unstable effectiveness, complex processes, or high costs. Summary of the Invention

[0004] Technical problem solved: In view of the technical problems existing in the prior art, the present invention provides an anti-crosslinking gelatin empty capsule and a preparation method thereof, which simplifies the preparation process and significantly improves the anti-crosslinking effect of the gelatin empty capsule.

[0005] Technical solution: The present invention provides a method for preparing anti-crosslinking gelatin empty capsules, comprising the following steps: Step 1: Add purified water and gelatin to a sol-gel container at a mass ratio of (3-5):1 and mix. Heat to 60-85℃ to dissolve. Step 2: After dissolving the adhesive, add 0.01-0.1% chelating agent to the adhesive solution, stir for 30-60 minutes, and then add pH adjuster to adjust the pH of the adhesive solution to 4-6; Step 3: Based on the total mass of gelatin, add 1-4% antioxidant, 1-3% plasticizer, and 0.5-3% filler by mass percentage to the solvent tank. After mixing and dissolving, color the mixture and allow it to stand naturally to defoam, thus obtaining the gel solution. Step 4: Evacuate the solvent tank to ≤-0.05MPa and maintain the vacuum condition for 15-30 minutes; after filtering with a 200-300 mesh filter bag, transfer to a glue bucket and keep it at a temperature ≤50℃ for 4-6 hours for defoaming treatment. Step 5: Spray the release agent onto the mold surface and let it form a film for later use; Step 6: Inject the defoamed adhesive into the mold, and after curing, drying, cutting, inspection and packaging, obtain anti-crosslinking gelatin hollow capsules.

[0006] Preferably, the chelating agent is one or both of disodium EDTA and GLDA.

[0007] Preferably, the antioxidant is one or more of sodium metabisulfite, glutathione, and ascorbic acid.

[0008] Preferably, the plasticizer is one or more of glycerol, sorbitol, and propylene glycol.

[0009] Preferably, the filler is one or both of mannitol and microcrystalline cellulose.

[0010] Preferably, the release agent is a PVP-ethanol solution or a stearamide-ethanol solution, with concentrations of 5-15% and 0.5-2%, respectively.

[0011] Preferably, the pH adjuster is one or more of citric acid, sodium hydroxide, and ammonium bicarbonate.

[0012] Preferably, a colorant is also added to the adhesive solution, which is one or more of food coloring, titanium dioxide, calcium carbonate, and iron oxide.

[0013] The present invention also discloses an anti-crosslinking gelatin empty capsule, which is prepared by the above method and has a dissolution retention rate of not less than 85% within 6 months in accelerated stability test.

[0014] Compared with the prior art, the present invention has at least the following beneficial effects: 1. The gelatin hollow capsules of the present invention simplify the preparation process and significantly improve the anti-crosslinking effect of the gelatin hollow capsules; 2. A chelating agent is added to the gelatin solution to form a chelate with the metal ions in the gelatin, thereby inhibiting the cross-linking reaction. Then, the solution is adjusted to acidity so that the remaining amino groups in the solution remain in a protonated state, further reducing the occurrence of cross-linking reactions. 3. The filler mannitol is compounded with microcrystalline cellulose, which can accelerate capsule disintegration under certain conditions and further improve in vitro dissolution. 4. Release agents PVP and stearamide have excellent film-forming properties and surface activity, and can form a protective film on the gelatin surface to prevent direct contact and cross-linking reaction between gelatin molecules and drug powder. Attached Figure Description

[0015] Figure 1 This is a flowchart illustrating the preparation process of the anti-crosslinking hollow capsule of the present invention. Detailed Implementation

[0016] To make the objectives, technical solutions, and advantages of this invention clearer, the following description will be provided in conjunction with the appendix. Figure 1 The technical solutions of the present invention are clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the described embodiments of the present invention are within the scope of protection of the present invention.

[0017] like Figure 1 As shown, the present invention discloses a method for preparing anti-crosslinking gelatin empty capsules, comprising the following steps: (1) Add purified water and gelatin to a sol tank at a mass ratio of (3-5):1 and heat to 60-85℃ to dissolve.

[0018] (2) After dissolving, add 0.01-0.1% chelating agent to the glue solution, stir for 30-60 min, and then add pH adjuster to adjust the pH of the glue solution to 4-6; the chelating agent is one or two of disodium EDTA or GLDA; the pH adjuster is one or more of citric acid, sodium hydroxide, and ammonium bicarbonate.

[0019] (3) Based on the total mass of gelatin, add 1-4% antioxidant, 1-3% plasticizer and 0.5-3% filler by mass percentage to the sol tank, mix and dissolve, then color and let stand to defoam naturally to obtain the gel solution; the antioxidant is one or more of sodium metabisulfite, glutathione and ascorbic acid; the plasticizer is one or more of glycerin, sorbitol and propylene glycol; the filler is one or two of mannitol and microcrystalline cellulose; coloring agent is also added to the gel solution, the coloring agent is one or more of food coloring, titanium dioxide, calcium carbonate and iron oxide.

[0020] (4) Evacuate the solvent tank to ≤-0.05MPa and maintain the vacuum condition for 15-30min; after filtration with a 200-300 mesh filter bag, transfer it to the glue bucket and keep it at a temperature of ≤50℃ for 4-6h for defoaming treatment.

[0021] (5) Preparation and application of release agent: PVP is completely dissolved in 80% ethanol solution to obtain a 5-15% (w / v) solution, which is then sprayed onto a clean and dry mold and allowed to form a film for later use; or stearamide is dissolved in ethanol solution and heated and stirred until completely dissolved to obtain a 0.5-2% (w / v) solution, which is then cooled to room temperature and sprayed onto a clean and dry mold and allowed to form a film for later use. (6) The defoamed adhesive liquid is injected into the mold, and after curing, drying, cutting, inspection and packaging, anti-crosslinking gelatin hollow capsules are obtained.

[0022] The present invention also discloses an anti-crosslinking gelatin empty capsule, which is prepared by the above method and has a dissolution retention rate of not less than 85% within 6 months in accelerated stability test.

[0023] Example 1: Purified water and gelatin were mixed in a sol tank at a mass ratio of 4:1 and heated to 70°C to dissolve. After dissolution, 0.05% disodium EDTA was added to the gel solution, and after stirring for 45 minutes, an appropriate amount of citric acid or sodium hydroxide was added to adjust the pH of the gel solution to 5. Based on the total mass of gelatin, 2% glutathione, 2% sorbitol, and 0.5% mannitol were added to the sol tank by mass percentage, mixed and dissolved, and then subjected to color matching and natural defoaming to obtain the gel solution. The sol tank was evacuated to -0.03 MPa and kept under vacuum for 30 minutes. After filtration using a 250-mesh filter bag, the gel solution was transferred to a glue tank and kept at a temperature ≤50°C for 4 hours for defoaming treatment. An appropriate amount of PVP is dissolved in an 80% ethanol solution to prepare an 8% release agent solution. This solution is then sprayed onto a clean and dry mold and allowed to form a film for later use. The viscosity of the adhesive solution is adjusted with hot pure water and used in a fully automated capsule production line for capsule dipping. The defoamed adhesive solution is then injected into the mold, and after curing, drying, cutting, inspection, and packaging, anti-crosslinking gelatin empty capsules are obtained.

[0024] Example 2: Purified water and gelatin were mixed in a sol tank at a mass ratio of 3.5:1 and heated to 75°C to dissolve. After dissolution, 0.07% disodium EDTA was added to the solution, and after stirring for 45 minutes, citric acid or sodium hydroxide was added to adjust the pH of the solution to 4.5. Based on the total mass of gelatin, 1.5% sodium metabisulfite, 2.5% glycerol, and 1.0% microcrystalline cellulose were added to the sol tank by mass percentage, mixed and dissolved, and then subjected to color matching and natural defoaming to obtain the solution. The sol tank was evacuated to -0.03 MPa and maintained under vacuum for 20 minutes. After filtration using a 300-mesh filter bag, the solution was transferred to a glue tank and kept at a temperature ≤50°C for 5 hours for defoaming treatment. PVP was dissolved in 80% ethanol to prepare a 10% (w / v) release agent solution, which was sprayed onto a clean and dry mold and set aside after film formation. The viscosity of the adhesive solution was adjusted with hot pure water and used in a fully automated capsule production line for capsule dipping. The defoamed adhesive solution was injected into the mold, and after curing, drying, cutting, inspection and packaging, anti-crosslinking gelatin empty capsules were obtained.

[0025] Example 3: Purified water and gelatin were mixed in a sol tank at a mass ratio of 3:1 and heated to 85°C to dissolve. After dissolution, 0.1% GLDA was added to the solution, and after stirring for 60 minutes, citric acid or sodium hydroxide was added to adjust the pH of the solution to 5.5. Based on the total mass of gelatin, 1% ascorbic acid, 1% propylene glycol, 2.0% mannitol, and 1% microcrystalline cellulose were added to the sol tank by mass percentage, mixed and dissolved, and then subjected to color matching and natural defoaming to obtain the solution. The sol tank was evacuated to -0.03 MPa and kept under vacuum for 30 minutes. After filtration using a 300-mesh filter bag, the solution was transferred to a glue tank and kept at a temperature ≤50°C for 6 hours for defoaming treatment. Stearamide was dissolved in an ethanol solution to prepare a release agent solution with a concentration of 0.5~2% (w / v). After cooling to room temperature, the solution was sprayed onto a clean and dry mold and set aside to form a film. The viscosity of the adhesive solution was adjusted with hot pure water and used in a fully automated capsule production line for capsule dipping. The defoamed adhesive solution was injected into the mold, and after curing, drying, cutting, inspection, and packaging, anti-crosslinking gelatin empty capsules were obtained.

[0026] Example 4: Purified water and gelatin were mixed in a sol tank at a mass ratio of 4:1 and heated to 60°C to dissolve. After dissolution, 0.01% disodium EDTA was added to the gel solution, and after stirring for 30 minutes, citric acid or sodium hydroxide was added to adjust the pH of the gel solution to 4. Based on the total mass of gelatin, 2% glutathione, 2% sorbitol, and 2.0% mannitol were added to the sol tank by mass percentage, mixed and dissolved, and then subjected to color matching and natural defoaming to obtain the gel solution. The sol tank was evacuated to -0.03 MPa and kept under vacuum for 15 minutes. After filtration using a 200-mesh filter bag, the gel solution was transferred to a gel tank and kept at a temperature ≤50°C for 4 hours for defoaming treatment. A 5% (w / v) release agent solution was prepared by dissolving PVP in 80% ethanol solution and sprayed onto a clean and dry mold. After film formation, it was ready for use. The viscosity of the adhesive solution was adjusted with hot pure water and used in a fully automated capsule production line for capsule dipping. The defoamed adhesive solution was injected into the mold, and after curing, drying, cutting, inspection, and packaging, anti-crosslinking gelatin empty capsules were obtained.

[0027] Example 5: Purified water and gelatin were mixed in a sol tank at a mass ratio of 5:1 and heated to 85°C to dissolve. After dissolution, 0.1% disodium EDTA was added to the gel solution, and after stirring for 60 minutes, citric acid or sodium hydroxide was added to adjust the pH of the gel solution to 6. Based on the total mass of gelatin, 4% glutathione, 3% sorbitol, and 3% mannitol were added to the sol tank by mass percentage, mixed and dissolved, and then subjected to color matching and natural defoaming to obtain the gel solution. The sol tank was evacuated to -0.03 MPa and kept under vacuum for 30 minutes. After filtration using a 300-mesh filter bag, the gel solution was transferred to a glue tank and kept at a temperature ≤50°C for 6 hours for defoaming treatment. A 15% (w / v) release agent solution was prepared by dissolving PVP in 80% ethanol solution and sprayed onto a clean and dry mold. After film formation, it was ready for use. The viscosity of the adhesive solution was adjusted with hot pure water and used in a fully automated capsule production line for capsule dipping. The defoamed adhesive solution was injected into the mold, and after curing, drying, cutting, inspection, and packaging, anti-crosslinking gelatin empty capsules were obtained.

[0028] Comparative Example 1: Commercially available gelatin capsules were purchased.

[0029] Multiple gelatin hollow capsules and conventional gelatin hollow capsules of Comparative Example 1 were prepared according to Examples 1-5. Ordinary gelatin hollow capsules and anti-crosslinking gelatin hollow capsules were filled with clarithromycin powder, respectively. Accelerated stability tests were conducted at 0, 1, 2, 3, 4, 5, and 6 months. The anti-crosslinking effect was confirmed by testing the dissolution rate of capsules according to the 2020 edition of the Chinese Pharmacopoeia. The experimental statistical results are shown in Tables 1-6.

[0030] Table 1. Dissolution results (%) of ordinary gelatin empty capsules filled with clarithromycin powder in Comparative Example 1: .

[0031] Table 2 Dissolution results (%) of anti-crosslinking gelatin empty capsules filled with clarithromycin powder in Example 1: .

[0032] Table 3 Dissolution results (%) of anti-crosslinking gelatin empty capsules filled with clarithromycin powder in Example 2: .

[0033] Table 4 Dissolution results (%) of the anti-crosslinking gelatin empty capsules filled with clarithromycin powder in Example 3: .

[0034] Table 5 Dissolution results (%) of the anti-crosslinking gelatin empty capsules filled with clarithromycin powder in Example 4: .

[0035] Table 6 Dissolution results (%) of the anti-crosslinking gelatin empty capsules filled with clarithromycin powder in Example 5: .

[0036] This invention involves adding a chelating agent to the gelatin solution to form a chelate with the metal ions in the gelatin, inhibiting cross-linking reactions. The solution is then adjusted to acidity to maintain the protonated state of residual amino groups, further reducing cross-linking. The filler mannitol is compounded with microcrystalline cellulose, which, under certain conditions, can accelerate capsule disintegration and further improve in vitro dissolution. The release agent PVP and stearamide possess excellent film-forming properties and surface activity, forming a protective film on the gelatin surface to prevent direct contact and cross-linking reactions between gelatin molecules and the pharmaceutical powder. Tables 1-4 show that the gelatin empty capsules obtained in Examples 1-5 exhibit significant anti-cross-linking effects and can avoid cross-linking reactions in accelerated stability tests (0, 1, 2, 3, 4, 5, 6 months), with minimal impact on the dissolution rate of the formulation, achieving stable and acceptable dissolution.

[0037] The above are preferred embodiments of the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing anti-crosslinking gelatin empty capsules, characterized in that, Includes the following steps: Step 1: Add purified water and gelatin to a sol-gel container at a mass ratio of (3-5):1 and mix. Heat to 60-85℃ to dissolve. Step 2: After dissolving the adhesive, add 0.01-0.1% chelating agent to the adhesive solution, stir for 30-60 minutes, and then add pH adjuster to adjust the pH of the adhesive solution to 4-6; Step 3: Based on the total mass of gelatin, add 1-4% antioxidant, 1-3% plasticizer, and 0.5-3% filler by mass percentage to the solvent tank. After mixing and dissolving, color the mixture and allow it to stand naturally to defoam, thus obtaining the gel solution. Step 4: Evacuate the solvent tank to ≤-0.05MPa and maintain the vacuum condition for 15-30 minutes; after filtering with a 200-300 mesh filter bag, transfer to a glue bucket and keep it at a temperature ≤50℃ for 4-6 hours for defoaming treatment. Step 5: Spray the release agent onto the mold surface and let it form a film for later use; Step 6: Inject the defoamed adhesive into the mold, and after curing, drying, cutting, inspection and packaging, obtain anti-crosslinking gelatin hollow capsules.

2. The method for preparing anti-crosslinking gelatin empty capsules according to claim 1, characterized in that, The chelating agent is one or both of disodium EDTA and GLDA.

3. The method for preparing anti-crosslinking gelatin empty capsules according to claim 1, characterized in that, The antioxidant is one or more of sodium metabisulfite, glutathione, and ascorbic acid.

4. The method for preparing anti-crosslinking gelatin empty capsules according to claim 1, characterized in that, The plasticizer is one or more of glycerin, sorbitol, and propylene glycol.

5. The method for preparing anti-crosslinking gelatin empty capsules according to claim 1, characterized in that, The filler is one or both of mannitol and microcrystalline cellulose.

6. The method for preparing anti-crosslinking gelatin empty capsules according to claim 1, characterized in that, The release agent is a PVP-ethanol solution or a stearamide-ethanol solution, with concentrations of 5-15% and 0.5-2%, respectively.

7. The method for preparing anti-crosslinking gelatin empty capsules according to claim 1, characterized in that, The pH adjuster is one or more of citric acid, sodium hydroxide, and ammonium bicarbonate.

8. The method for preparing anti-crosslinking gelatin empty capsules according to claim 1, characterized in that, The adhesive also contains a colorant, which is one or more of the following: food coloring, titanium dioxide, calcium carbonate, and iron oxide.

9. An anti-crosslinking gelatin empty capsule, characterized in that, Prepared by the method described in any one of claims 1-8.

10. The anti-crosslinking gelatin empty capsule according to claim 9, characterized in that, Its dissolution retention rate is no less than 85% within 6 months in accelerated stability tests.

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