Rapid disintegration type enteric gelatin hollow capsule shell

Abstract

A rapid disintegration type enteric gelatin hollow capsule shell belongs to the technical field of hollow capsule production, and comprises the following components by mass: 70%-90% of gelatin, 0.01%-5.0% of a humectant, 0.01%-10% of a surfactant, 0.01%-10% of a plasticizer, 0-5% of a disintegrating agent, 0.1%-10% of an opacifying agent, and 1.0%-20% of a coating material. The method comprises the following steps: synchronously forming a glue solution and a coating, alternately dipping in glue, and drying at low temperature; the preparation method has the beneficial effects that a disintegration acceleration mechanism is adopted, the disintegrating agent quickly absorbs water and expands in intestinal juice, and the permeability of the capsule shell is enhanced by cooperating with the surfactant; the proportion of a coating material is optimized, and hydroxypropyl methylcellulose phthalate is greater than or equal to 15%, so that the intestinal juice response speed is increased; and the disintegration time in intestinal juice is about 8 minutes, which is increased by about 50% compared with the disintegration time of about 15 minutes of the traditional capsule.

Description

Technical Field

[0001] This invention relates to the field of empty capsule production technology, and in particular to a rapidly disintegrating enteric gelatin empty capsule shell. Background Technology

[0002] Enteric-coated empty capsules must meet the requirement of not disintegrating in gastric juice (an acidic environment) and rapidly disintegrating in intestinal juice (an alkaline environment). Current technological challenges include: 1. Delayed disintegration: Traditional enteric-coated capsules typically disintegrate within 13-15 minutes in intestinal fluid at pH 7.8, affecting drug release efficiency.

[0003] 2. Complex process: Most processes require the preparation of capsule embryos before secondary coating, which requires the use of 15-30% organic solvents (such as ethanol), with a residual amount of 0.1-0.5% (Pharmaceutical Excipients Handbook 2020 Edition), increasing safety risks and environmental costs.

[0004] 3. Insufficient stability: High temperature or humidity changes can easily lead to shell deformation or decreased disintegration performance. Although existing improvement schemes simplify the process, they still do not solve the problem of balancing disintegration rate and process safety. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide an enteric gelatin hollow capsule shell that does not disintegrate in artificial simulated gastric juice, disintegrates in the intestine in about 8 minutes, has a simplified process and leaves no organic solvent residue, and achieves rapid enteric release through component optimization and integrated gelatin dipping process.

[0006] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is a rapidly disintegrating enteric gelatin hollow capsule shell, which is composed of the following components in weight percentage: gelatin: 70%–90%, humectant: 0.01%–5.0%, surfactant: 0.01%–10%, plasticizer: 0.01%–10%, disintegrant: 0–5%, opacifier: 0.1%–10%, coating material: 1.0%–20%.

[0007] Preferably, it is composed of the following components in the following weight percentages: gelatin: 70%–90%, humectant: 1.0%–2.5%, surfactant: 1.0%–3.0%, plasticizer: 1.0%–3.0%, disintegrant: 0–2.5%, opacifier: 1.0%–5.0%, and coating material: 3.0%–10%.

[0008] in: The moisturizer is one of glycerin, polyethylene glycol, and sorbitol.

[0009] The surfactant is one of sodium dodecyl sulfate and polysorbate 80.

[0010] The plasticizer is one of chitosan, triacetin, triethyl citrate, and sorbitol.

[0011] The disintegrant is one of microcrystalline cellulose and hydroxypropyl cellulose.

[0012] The light-blocking agent is one of titanium dioxide and zinc oxide.

[0013] The coating material is one or more of hydroxypropyl methylcellulose phthalate acetate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate, or hydroxypropyl cellulose.

[0014] The plasticizer is a compound of chitosan and triethyl citrate in a ratio of 1:2-3.

[0015] The method for preparing the rapidly disintegrating enteric-coated gelatin empty capsule shell includes the following steps.

[0016] Step 1: Preparation of adhesive solution: Add gelatin, humectant, surfactant, disintegrant, and opacifier to 2200-2700 parts of hot water at 55-75℃ at a ratio of 1000 parts gelatin to dissolve for 45-60 minutes. Keep the solution at 45-60℃ for 2-6 hours to form a homogeneous adhesive solution. The disintegrant is only used in the adhesive solution.

[0017] Step 2: Coating Solution Preparation: Add the coating material, plasticizer, and surfactant to water or an ethanol / water mixture and stir to form the coating solution. Here, the coating material works synergistically with the plasticizer to enhance the intestinal fluid response rate.

[0018] Step 3: Integrated alternating dip-in and impregnation: In an environment with a temperature of 15–30℃ and a relative humidity of 40–50%, the capsule is first impregnated with the adhesive solution, and then impregnated with the coating solution.

[0019] Step 4: Online low-temperature drying: Then dry online at a temperature of 15–40℃ and a humidity of 35–45% for 0.5–2 hours.

[0020] Step 5: Then process the demolding, cutting, and fitting to obtain the finished capsule shell.

[0021] The preferred preparation method is as follows: The following ingredients are formulated according to their weight percentages: gelatin 80%, glycerin 2.0%, sodium lauryl sulfate 2.0%, chitosan 1.0%, triethyl citrate 2.5%, microcrystalline cellulose 4.0%, titanium dioxide 2.5%, hydroxypropyl methylcellulose phthalate 3.0%, and polysorbate 80% 1.0%.

[0022] First, prepare the adhesive solution: add gelatin, glycerin, sodium lauryl sulfate, microcrystalline cellulose, and titanium dioxide to 2.4 times their weight of hot water at 65°C and dissolve for 52 minutes. Keep the solution at 50°C for 4 hours to form a uniform adhesive solution.

[0023] Simultaneously, a coating solution was prepared: hydroxypropyl methylcellulose phthalate, chitosan, triethyl citrate, and polysorbate 80 were added to purified water and stirred to form a coating solution. The surfactant in the coating solution and the surfactant in the adhesive were differentiated; that is, when sodium dodecyl sulfate was used as the surfactant in the adhesive, polysorbate 80 was used as the surfactant in the coating solution; the plasticizer was a mixture of chitosan and triethyl citrate in a 1:2.5 ratio.

[0024] Integrated alternating dip-in coating: In an environment with a temperature of 22℃ and a relative humidity of 45%, the capsule mold is first dipped in the adhesive solution, and then directly dipped in the coating solution.

[0025] Online low-temperature drying: Then dry online at a temperature of 35°C and a humidity of 40% for 1.5 hours.

[0026] Then, the capsule shells are processed through demolding, cutting, and fitting to obtain the finished product.

[0027] Compared with the prior art, the present invention has the following beneficial effects: (1) Simultaneous molding of adhesive and coating: Breaking through the traditional two-stage coating process, the enteric layer and gelatin matrix are simultaneously cured by controlling the alternating adhesive dipping sequence. The coating layer is directly superimposed before the adhesive gels, and the interface is fused by intermolecular hydrogen bonds, avoiding solvent residue. The integrated molding shortens the production cycle to 2-3 hours, while the traditional process requires 6-8 hours.

[0028] (2) An accelerated disintegration mechanism was designed: The first "directional distribution of disintegrant" design was created: only the glue was added to the microcrystalline cellulose to avoid the coating layer from swelling and delaying when it comes into contact with water; the disintegrant microcrystalline cellulose absorbs water and swells rapidly in the intestinal fluid, and enhances the permeability of the capsule shell in conjunction with the surfactant; the proportion of coating materials was optimized, with hydroxypropyl methylcellulose phthalate ≥15%, which improved the response speed of intestinal fluid; the disintegration time in intestinal fluid was about 8 minutes, which is nearly 50% faster than the traditional capsules which take about 15 minutes.

[0029] (3) An ultra-low temperature drying strategy is adopted, with a drying temperature of ≤40℃ (conventional process ≥60℃). Precise humidity control (35-45%RH) prevents surface crusting and forms microporous channels inside to accelerate intestinal fluid penetration. Detailed Implementation

[0030] The present invention will be further described below with reference to the embodiments. The following embodiments are intended to illustrate the present invention and not to further limit the present invention, and should not be used to limit the scope of protection of the present invention. Example

[0031] (1) Take 70 kg of gelatin, 3 kg of glycerin, 3.0 kg of sodium dodecyl sulfate, 2.0 kg of polysorbate, 2.0 kg of chitosan, 4.0 kg of triethyl citrate, 5 kg of microcrystalline cellulose, 4.5 kg of titanium dioxide, and 6.5 kg of hydroxypropyl methylcellulose phthalate; also prepare purified water and ethanol.

[0032] (2) Preparation of adhesive solution: Dissolve gelatin, glycerin, sodium dodecyl sulfate, microcrystalline cellulose and titanium dioxide in 190 kg of hot water at 75℃, keep warm at 60℃ and let stand for 4 hours.

[0033] (3) Preparation of coating solution: Add hydroxypropyl methylcellulose phthalate, polysorbate 80, chitosan and triethyl citrate to a mixed solvent of 23 kg water and 8 kg ethanol.

[0034] (4) Dipping in adhesive: Alternately dip into the adhesive solution and coating solution once each at a temperature of 30℃ and a humidity of 50%, and dry online for 0.5 hours at a temperature of 40℃ and a humidity of 45%.

[0035] (5) Demolding, cutting, and fitting together yields the finished capsule shell. Example

[0036] (1) Take 75 kg of gelatin, 2.5 kg of glycerin, 4.0 kg of sodium dodecyl sulfate, 1.5 kg of polysorbate, 0.5 kg of chitosan, 1.5 kg of triethyl citrate, 5.5 kg of microcrystalline cellulose, 4.0 kg of titanium dioxide, 3.5 kg of hydroxypropyl methylcellulose acetate succinate, and 2.0 kg of hydroxypropyl cellulose; also prepare purified water and ethanol.

[0037] (2) Preparation of adhesive solution: Dissolve gelatin, glycerin, sodium dodecyl sulfate, microcrystalline cellulose and titanium dioxide in 225 kg of hot water at 60℃, keep warm at 50℃ and let stand for 3 hours.

[0038] (3) Preparation of coating solution: Dissolve hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, polysorbate 80, chitosan, and triethyl citrate in a mixed solvent of 16 kg water and 6 kg ethanol.

[0039] (4) Dipping in adhesive: Alternately dip the product in the adhesive solution and coating solution once each at a temperature of 20℃ and a humidity of 42%, and dry it online for 1 hour at a temperature of 25℃ and a humidity of 38%.

[0040] (5) Demolding, cutting, and fitting together yields the finished capsule shell. Example

[0041] (1) Gelatin 80%, glycerin 2.0kg, sodium lauryl sulfate 2.0kg, chitosan 1.0kg, triethyl citrate 2.5kg, microcrystalline cellulose 4.0kg, titanium dioxide 2.5kg, hydroxypropyl methylcellulose phthalate 5.0kg, polysorbate 80 ppm; also prepare purified water and ethanol.

[0042] (2) Preparation of adhesive solution: Dissolve gelatin, glycerin, sodium dodecyl sulfate and titanium dioxide in 207.6 kg of hot water at 55℃, keep warm at 45℃ and let stand for 6 hours.

[0043] (3) Preparation of coating solution: Dissolve hydroxypropyl methylcellulose phthalate, polysorbate 80, chitosan, and triethyl citrate in a mixed solvent of 16.8 kg of water and 6.0 kg of ethanol.

[0044] (4) Dipping in adhesive: Alternately dip the sample in the adhesive solution and the coating solution once each at a temperature of 15℃ and a humidity of 35%, and dry it online for 2 hours at a temperature of 15℃ and a humidity of 35%.

[0045] (5) Demolding, cutting, and fitting together yields the finished capsule shell.

[0046] Example 4 (all-water-based solvent).

[0047] (1) Take 85 kg of gelatin, 1.5 kg of glycerin, 1.5 kg of sodium dodecyl sulfate, 0.5 kg of chitosan, 2.0 kg of triethyl citrate, 2.5 kg of microcrystalline cellulose, 2.5 kg of titanium dioxide, 3.5 kg of hydroxypropyl methylcellulose phthalate, and 1.0 kg of polysorbate 80; also prepare purified water.

[0048] (2) Preparation of adhesive solution: Add gelatin, glycerin, sodium dodecyl sulfate, microcrystalline cellulose and titanium dioxide to 242 kg of hot water at 70℃ and dissolve for 55 minutes. Keep it at 55℃ and let it stand for 5 hours.

[0049] (3) Preparation of coating solution: Dissolve hydroxypropyl methylcellulose phthalate, polysorbate 80, chitosan, and triethyl citrate in 18.0 kg of purified water.

[0050] (4) Dipping in adhesive: Alternately dip into the adhesive solution and coating solution once each at a temperature of 27℃ and a humidity of 43%, and dry online for 100 minutes at a temperature of 33℃ and a humidity of 42%.

[0051] (5) Demolding, cutting, and fitting together yields the finished capsule shell.

[0052] Example 5 (all-water-based solvent).

[0053] (1) Take 90 kg of gelatin, 0.5 kg of glycerin, 1.0 kg of sodium dodecyl sulfate, 0.5 kg of chitosan, 1.5 kg of triethyl citrate, 2 kg of microcrystalline cellulose, 1.5 kg of titanium dioxide, 2.5 kg of hydroxypropyl methylcellulose phthalate, and 0.5 kg of polysorbate 80; also prepare purified water.

[0054] (2) Preparation of adhesive solution: Add gelatin, glycerin, sodium dodecyl sulfate, microcrystalline cellulose and titanium dioxide to 256.5 kg of hot water at 65℃ and dissolve for 52 minutes. Keep warm at 50℃ and let stand for 4 hours.

[0055] (3) Preparation of coating solution: Dissolve hydroxypropyl methylcellulose phthalate, polysorbate 80, chitosan, and triethyl citrate in 13.5 kg of purified water.

[0056] (4) Dipping in adhesive: Alternately dip the product in the adhesive solution and coating solution once each at a temperature of 22℃ and a humidity of 45%, and dry it online for 1.5 hours at a temperature of 35℃ and a humidity of 40%.

[0057] (5) Demolding, cutting, and fitting together yields the finished capsule shell.

[0058] Disintegration tests were conducted on the capsule shells prepared in Examples 1-5.

[0059] One hundred empty capsules produced in each embodiment were randomly selected for testing. They were filled with talc powder and the disintegration time was measured in simulated gastric juice at a temperature of (37±1)℃ and pH=1.1 and simulated intestinal juice at pH=7.9, respectively. The average time required for the capsules of each embodiment to disintegrate completely from the start of disintegration was recorded.

[0060] Table 1: Results of the disintegration test of empty capsules.

[0061]

[0062] As shown in Table 1, the gelatin empty capsules produced in each embodiment of the present invention have a disintegration time of more than 2 hours in simulated gastric fluid, an initial disintegration time of 2.6-4.0 minutes in simulated intestinal fluid, and a complete disintegration time of 6.5-8.1 minutes, which effectively shortens the disintegration time; and the solvent residue is minimal or even non-existent.

Claims

1. A rapidly disintegrating enteric-coated gelatin empty capsule shell and its preparation method, characterized in that... It consists of the following components in weight percentages: gelatin: 70%–90%, humectant: 0.01%–5.0%, surfactant: 0.01%–10%, plasticizer: 0.01%–10%, disintegrant: 0–5%, opacifier: 0.1%–10%, coating material: 1.0%–20%; Its preparation method includes the following steps: Step 1: Preparation of adhesive solution: Add gelatin, humectant, surfactant, disintegrant, and opacifier to 2200-2700 parts of hot water at 55-75℃ according to the formula ratio of 1000 parts gelatin and dissolve for 45-60 minutes. Keep it at 45-60℃ and let it stand for 2-6 hours to form a uniform adhesive solution. Step 2: Coating solution preparation: Add the coating material, plasticizer, and surfactant to water or an ethanol / water mixture and stir to form the coating solution; Step 3: Integrated alternating dip-in and impregnation: In an environment with a temperature of 15–30℃ and a relative humidity of 40–50%, the capsule is first impregnated with the adhesive solution, and then impregnated with the coating solution. Step 4: Online low-temperature drying: Then dry online at a temperature of 15–40℃ and a humidity of 35–45% for 0.5–2 hours; Step 5: Then process the demolding, cutting, and fitting to obtain the finished capsule shell.

2. The rapidly disintegrating enteric-coated gelatin empty capsule shell according to claim 1, characterized in that... The moisturizer is one of glycerin, polyethylene glycol, and sorbitol.

3. The rapidly disintegrating enteric-coated gelatin empty capsule shell according to claim 2, characterized in that... The surfactant is one of sodium dodecyl sulfate and polysorbate 80.

4. The rapidly disintegrating enteric-coated gelatin empty capsule shell according to claim 3, characterized in that... The plasticizer is one of chitosan, triacetin, triethyl citrate, and sorbitol.

5. The rapidly disintegrating enteric-coated gelatin empty capsule shell according to claim 4, characterized in that... The disintegrant is one of microcrystalline cellulose and hydroxypropyl cellulose.

6. The rapidly disintegrating enteric-coated gelatin empty capsule shell according to claim 5, characterized in that... The light-blocking agent is one of titanium dioxide and zinc oxide.

7. The rapidly disintegrating enteric-coated gelatin empty capsule shell according to claim 6, characterized in that... The coating material is one of hydroxypropyl methylcellulose phthalate and cellulose acetate.

8. The rapidly disintegrating enteric-coated gelatin empty capsule shell according to claim 7, characterized in that... The plasticizer is a mixture of chitosan and triethyl citrate in a ratio of 1:2-3.

9. The rapidly disintegrating enteric-coated gelatin empty capsule shell according to claim 8, characterized in that... Its preparation method is as follows: The following ingredients are formulated according to their weight percentages: gelatin 80%, glycerin 2.0%, sodium lauryl sulfate 2.0%, chitosan 1.0%, triethyl citrate 2.5%, microcrystalline cellulose 4.0%, titanium dioxide 2.5%, hydroxypropyl methylcellulose phthalate 5.0%, and polysorbate 80%; First, prepare the adhesive solution: add gelatin, glycerin, sodium lauryl sulfate, microcrystalline cellulose, and titanium dioxide to 2.4 times their weight of hot water at 65°C and dissolve for 52 minutes. Keep it at 50°C and let it stand for 4 hours to form a uniform adhesive solution. Simultaneously, a coating solution was prepared: hydroxypropyl methylcellulose phthalate, chitosan, triethyl citrate, and polysorbate 80 were added to purified water and stirred to form a coating solution; the surfactants in the coating solution and the surfactants in the adhesive solution were differentiated; the plasticizer was a mixture of chitosan and triethyl citrate at a ratio of 1:2.

5. Then, the capsule is dipped in the coating solution in an integrated alternating process: the capsule is dipped in the coating solution in an environment with a temperature of 22°C and a relative humidity of 45%. First, the capsule mold is dipped in the coating solution, and then the coating solution is directly dipped in the coating solution. Then, dry online at low temperature: dry at 35°C and 40% humidity for 1.5 hours. Then, the capsule shells are processed through demolding, cutting, and fitting to obtain the finished product.

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