Enteric capsule and preparation method thereof

Abstract

The invention provides an enteric capsule and a preparation method thereof, the capsule takes modified chitosan derivatives, such as quaternized chitosan and phthalic anhydride grafted copolymer, as main materials, and cooperates with polyvinylidene chloride-maleic anhydride copolymer, nano silicon dioxide-sodium alginate composite particles, a plasticizer and a stabilizer in a specific ratio to prepare the enteric capsule. The enteric system is constructed by optimizing the proportion. The thickness of a capsule shell is 80-120 microns, the inner wall of the capsule is of a 50-200 nm nano-microporous structure, multifunctional composite particles are prepared through a reversed-phase microemulsion method, and the microporous structure is regulated and controlled through a sol-gel method. According to the design, the drug stability and the targeted release efficiency are remarkably improved, and the drug carrier has good mechanical strength and pH sensitivity, can effectively cover bad properties of drugs, is suitable for controlled release carriers of various enteric drugs, and has industrial production potential.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical biotechnology, and particularly to an enteric capsule and a preparation method thereof. Background Art

[0002] As the core carrier of the targeted drug delivery system, the performance of the enteric capsule directly determines the precise release efficiency and treatment safety of the drug at specific sites in the intestine. However, the existing enteric capsule technology has the following significant defects:

[0003] Although traditional enteric materials (such as cellulose acetate phthalate CAP and polyacrylic acid resin Eudragit L / S) have pH sensitivity, the rigidity of the molecular chain leads to insufficient mechanical strength, and microcracks are easily generated during gastrointestinal peristalsis. At the same time, gelatin capsules containing formaldehyde are restricted from use due to potential carcinogenic risks, and non-aldehyde cross-linking agents (such as isocyanates) have weather resistance defects caused by moisture absorption and degradation. In addition, the existing systems mostly rely on a single pH-responsive group (such as carboxylic acid group, pKa≈4.5 - 5.5), which only adapts to the environment in the upper part of the small intestine (pH 5.0 - 6.8) and cannot respond to the physiological gradient changes from the terminal ileum to the colon (pH 6.8 - 7.5), resulting in about 40% of enteric preparations having a reduced bioavailability due to a release time lag exceeding 2 hours.

[0004] In terms of drug loading, traditional processes (such as direct powder compression) are prone to cause problems with the interfacial compatibility between the drug and the capsule material. Lipophilic drugs (such as paclitaxel) are easily adsorbed on the surface of the capsule shell to form a non-uniform distribution, and the encapsulation efficiency of poorly soluble drugs is generally lower than 70%, lacking a sustained release regulation function.

[0005] At the industrial level, the multi-layer composite coating technology requires precise control of temperature and humidity (±2°C / ±5%RH), and the reproducibility between batches is poor. The physical blending method, on the other hand, results in fluctuations in the porosity of the capsule shell (15 - 40%) due to solvent residues or phase separation, seriously affecting the kinetic stability of drug release.

[0006] In summary, there is an urgent need to develop enteric capsule materials and preparation methods with high mechanical strength, multi-stage pH responsiveness, precise drug controlled release, and a green process to break through the existing technical barriers. Summary of the Invention

[0007] In view of this, the present invention proposes an enteric capsule and a preparation method thereof to solve the above problems.

[0008] The technical solution of the present invention is realized as follows: An enteric-coated capsule: comprising the following raw materials in parts by weight: 40-60 parts of a modified chitosan derivative, 15-25 parts of a polyvinylidene chloride-maleic anhydride copolymer, 5-10 parts of a nano-silica-sodium alginate composite particle, 3-8 parts of a plasticizer, and 1-3 parts of a stabilizer. The thickness of the capsule shell is 10-30 μm, and the inner wall has a nano-scale microporous structure with a pore size of 50-200 nm.

[0009] Further, an enteric-coated capsule: comprising the following raw materials in parts by weight: 50 parts of a modified chitosan derivative, 20 parts of a polyvinylidene chloride-maleic anhydride copolymer, 8 parts of a nano-silica-sodium alginate composite particle, 5 parts of a plasticizer, and 2 parts of a stabilizer.

[0010] Further, the modified chitosan derivative is a graft copolymer of quaternized chitosan and phthalic anhydride, with a degree of substitution of 0.3-0.6, a molecular weight of 50-80 kDa, a dissolution temperature in an acetic acid aqueous solution of 40-50 °C, and a stirring time ≥ 1 hour.

[0011] Further, the nano-silica-sodium alginate composite particle is prepared by the reverse microemulsion method, with a particle size of 20-50 nm, and a pH-responsive polyethylene glycol-polycaprolactone block copolymer is loaded on the surface.

[0012] Further, the plasticizer is dioctyl sebacate and hydroxypropyl methylcellulose acetate succinate in a mass ratio of 1:2-5.

[0013] Further, the stabilizer is selected from one or a combination of benzyl benzoate, dioctyl sebacate, and triacetin.

[0014] Further, a preparation method of an enteric-coated capsule comprises the following steps:

[0015] S1. Sol preparation: Dissolve the modified chitosan derivative in a 2-5% acetic acid aqueous solution, and stir at 40-50 °C until completely dissolved; dissolve the polyvinylidene chloride-maleic anhydride copolymer in acetone, then mix it with the above-mentioned modified chitosan derivative solution, and stir at 30-40 °C for 30 minutes; add the nano-silica-sodium alginate composite particle to anhydrous ethanol, and ultrasonically disperse it at a power of 200-300 W for 10-15 minutes to form a suspension, add it to the above-mentioned mixed solution, then add the plasticizer and the stabilizer, continue to stir for 1-3 hours to form a uniform sol, and finally perform vacuum degassing treatment;

[0016] S2. Gel forming: Inject the degassed sol into a mold preheated to 45-50 °C, and keep it at 40-45 °C for a certain time to gelate and form a soft capsule shape;

[0017] S3. Solidification: The above capsules are solidified in ventilation at 25 - 30 °C for 4 - 6 hours, and then soaked in pH 7.4 phosphate buffer solution for 20 - 40 minutes to form nano - micropores on the inner wall. After filling the core material, they are sealed.

[0018] Furthermore, the dosage of the acetic acid aqueous solution is 10 - 15 times the weight of the modified chitosan derivative, the dosage of acetone is 8 - 10 times the weight of the copolymer, and the mass - volume ratio of the composite particles to absolute ethanol (g / mL) is 1:5 - 10.

[0019] Furthermore, the vacuum degree of the vacuum degassing treatment is - 0.05~ - 0.08 MPa, and the vacuum time is 15 - 20 minutes.

[0020] Furthermore, the preparation method of the core material includes: co - grinding the drug active ingredient with the porous starch carrier, loading PLGA microspheres, and then coating a pH - responsive coating by the fluidized bed coating technology. The coating material contains a composite of methacrylic acid copolymer and nano - hydroxyapatite.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] Through technologies such as the modified chitosan - nano - silica composite particle material system, the nano - fiber double - layer membrane structure, the preparation of multifunctional composite particles by the reverse microemulsion method, and the regulation of the microporous structure by the sol - gel method, the present invention systematically solves the core problems in the prior art, including instability in the stomach (≤2.5% in the present invention), slow release in the intestine (≥90% / 1h in the present invention), inaccurate targeting (≥98% colon release in the present invention), and low mechanical strength (17 - 19 MPa in the present invention). It breaks through the synergistic limitations of material - structure - process - targeting, is applicable to high - requirement scenarios such as protein drugs and colon - targeted preparations, and fills the blank in the prior art. Specific Embodiments

[0023] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0024] The experimental methods used in the embodiments of the present invention are all conventional methods unless otherwise specified.

[0025] The materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial channels unless otherwise specified.

[0026] Example 1

[0027] An enteric capsule comprising the following raw materials in parts by weight: 40 parts of a modified chitosan derivative, 15 parts of a polyvinylidene chloride - maleic anhydride copolymer, 5 parts of a nano - silica - sodium alginate composite particle, 3 parts of a plasticizer, and 1 part of a stabilizer. The thickness of the capsule shell is 10 μm, and the inner wall has a nano - scale microporous structure with a pore diameter of 50 nm;

[0028] The modified chitosan derivative is a graft copolymer of quaternized chitosan and phthalic anhydride, with a degree of substitution of 0.3, a molecular weight of 50 kDa, a dissolution temperature in an aqueous acetic acid solution of 40 °C, and a stirring time ≥ 1 hour;

[0029] The nano - silica - sodium alginate composite particle is prepared by the reverse microemulsion method, with a particle size of 20 nm, and the surface is loaded with a pH - responsive polyethylene glycol - polycaprolactone block copolymer

[0030] The plasticizer is dioctyl sebacate and hydroxypropyl methylcellulose acetate succinate in a mass ratio of 1:2;

[0031] The stabilizer is selected from benzyl benzoate.

[0032] Example 2

[0033] An enteric capsule comprising the following raw materials in parts by weight: 60 parts of a modified chitosan derivative, 25 parts of a polyvinylidene chloride - maleic anhydride copolymer, 10 parts of a nano - silica - sodium alginate composite particle, 8 parts of a plasticizer, and 3 parts of a stabilizer. The thickness of the capsule shell is 30 μm, and the inner wall has a nano - scale microporous structure with a pore diameter of 200 nm;

[0034] The modified chitosan derivative is a graft copolymer of quaternized chitosan and phthalic anhydride, with a degree of substitution of 0.6, a molecular weight of 80 kDa, a dissolution temperature in an aqueous acetic acid solution of 50 °C, and a stirring time ≥ 1 hour;

[0035] The nano - silica - sodium alginate composite particle is prepared by the reverse microemulsion method, with a particle size of 50 nm, and the surface is loaded with a pH - responsive polyethylene glycol - polycaprolactone block copolymer

[0036] The plasticizer is dioctyl sebacate and hydroxypropyl methylcellulose acetate succinate in a mass ratio of 1:5;

[0037] The stabilizer is selected from triacetin.

[0038] Example 3

[0039] An enteric capsule, comprising the following raw materials in parts by weight: 50 parts of a modified chitosan derivative, 20 parts of a polyvinylidene chloride - maleic anhydride copolymer, 8 parts of nano - silica - sodium alginate composite microparticles, 5 parts of a plasticizer, and 2 parts of a stabilizer. The thickness of the capsule shell is 20μm, and the inner wall has a nano - scale microporous structure with a pore diameter of 100nm;

[0040] The modified chitosan derivative is a graft copolymer of quaternized chitosan and phthalic anhydride, with a degree of substitution of 0.5, a molecular weight of 70 kDa, a dissolution temperature in acetic acid aqueous solution of 45°C, and a stirring time ≥ 1 hour;

[0041] The nano - silica - sodium alginate composite microparticles are prepared by the inverse microemulsion method, with a particle size of 30nm, and the surface is loaded with a pH - responsive polyethylene glycol - polycaprolactone block copolymer

[0042] The plasticizer is dioctyl sebacate and hydroxypropyl methylcellulose acetate succinate with a mass ratio of 1:4;

[0043] The stabilizer is selected from dioctyl sebacate;

[0044] The above Examples 1 - 3 adopt the following preparation method:

[0045] S1. Sol Preparation: Dissolve the modified chitosan derivative in 3% acetic acid aqueous solution and stir at 45°C until completely dissolved; dissolve the polyvinylidene chloride - maleic anhydride copolymer in acetone, then mix it with the above - mentioned modified chitosan derivative solution and stir at 35°C for 30 minutes; add the nano - silica - sodium alginate composite microparticles to anhydrous ethanol, ultrasonically disperse them at a power of 250W for 12 minutes to form a suspension, add it to the above - mentioned mixed solution, then add the plasticizer and the stabilizer, continue to stir for 2 hours to form a uniform sol, and finally perform vacuum degassing treatment;

[0046] S2. Gel Molding: Inject the degassed sol into a mold preheated to 48°C and keep it at 45°C for a certain time to gelate and form a soft - capsule shape;

[0047] S3. Curing: Cure the above - mentioned capsule at 25 - 30°C in ventilation for 5 hours, then soak it in pH 7.4 phosphate buffer solution for 30 minutes to form nano - micropores on the inner wall, fill the core material and then seal it.

[0048] Comparative Example 1 - Traditional Enteric Capsule

[0049] Formulation: Gelatin capsule shell (thickness 30μm) + L100 coating (thickness 10μm, plasticizer diethyl phthalate).

[0050] Comparative Example 2 - Single Chitosan Capsule (without composite microparticles)

[0051] Formulation: 50 parts of chitosan (unmodified), 5 parts of plasticizer (glycerol), and 2 parts of stabilizer (citric acid).

[0052] Comparison of experimental data

[0053]

[0054]

[0055] The enteric capsules of the present invention (Examples 1-3) achieve all-dimensional breakthroughs in extreme gastric stability (release rate ≤ 2.5%, < 5% pharmacopoeia standard), ultra-rapid intestinal release (≥ 90% within 1 h, far exceeding the traditional 75%), high-strength mechanical properties (tensile strength 17-19 MPa, 50% improvement compared to gelatin capsules), and precise colon targeting (release rate ≥ 98%, dual regulation of enzyme response + targeting peptide segments) through the synergistic innovation of modified chitosan derivatives, nano-silica-alginate composite microparticles (20-50 nm), double-layer nanofiber membranes, and enzyme-responsive targeted core materials.

[0056] Compared with Comparative Example 1, the modified chitosan (quaternization and phthalic anhydride grafting) in the example group synergistically acts with the nano-composite microparticles to form an acid-resistant barrier. The traditional Eudragit coating material has insufficient acid resistance, and acidolysis leads to premature drug release (> 5% pharmacopoeia standard).

[0057] Compared with Comparative Example 2, the PEG-PCL block copolymer (pH-responsive) on the surface of the nano-composite microparticles in the example group rapidly swells in intestinal fluid, increasing the release rate. The single chitosan membrane in Comparative Example 2 has no pH-responsive design and dissolves and releases slowly in intestinal fluid.

[0058] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims

1. An enteric-coated capsule, characterized in that: It comprises the following raw materials in parts by weight: 40 - 60 parts of modified chitosan derivative, 15 - 25 parts of poly(vinylidene chloride - maleic anhydride) copolymer, 5 - 10 parts of nano - silica - sodium alginate composite microparticles, 3 - 8 parts of plasticizer, and 1 - 3 parts of stabilizer. The thickness of the capsule shell is 80 - 120 μm, and the inner wall has a nano - scale microporous structure with a pore size of 50 - 200 nm.

2. The enteric-coated capsule according to claim 1, wherein: It comprises the following raw materials in parts by weight: 50 parts of modified chitosan derivative, 20 parts of poly(vinylidene chloride - maleic anhydride) copolymer, 8 parts of nano - silica - sodium alginate composite microparticles, 5 parts of plasticizer, and 2 parts of stabilizer.

3. An enteric capsule according to claim 1, characterized in that: The modified chitosan derivative is a graft copolymer of quaternized chitosan and phthalic anhydride, with a substitution degree of 0.3 - 0.6, a molecular weight of 50 - 80 kDa, a dissolution temperature in acetic acid aqueous solution of 40 - 50 °C, and a stirring time ≥ 1 hour.

4. An enteric capsule according to claim 1, wherein: The nano - silica - sodium alginate composite microparticles are prepared by the inverse microemulsion method, with a particle size of 20 - 50 nm, and the surface is loaded with a pH - responsive polyethylene glycol - polycaprolactone block copolymer.

5. An enteric capsule according to claim 1, characterized in that: The plasticizer is dioctyl sebacate and hydroxypropyl methylcellulose acetate succinate with a mass ratio of 1:2 - 5.

6. An enteric capsule according to claim 1, characterized in that: The stabilizer is selected from one or a combination of benzyl benzoate, dioctyl sebacate, and triacetin.

7. The preparation method of an enteric capsule according to claim 1, characterized in that: It comprises the following steps: S1. Sol preparation: Dissolve the modified chitosan derivative in 2 - 5% acetic acid aqueous solution, and stir at 40 - 50 °C until completely dissolved; dissolve the poly(vinylidene chloride - maleic anhydride) copolymer in acetone, then mix it with the above - mentioned modified chitosan derivative solution, and stir at 30 - 40 °C for 30 minutes; add the nano - silica - sodium alginate composite microparticles to anhydrous ethanol, ultrasonically disperse them at a power of 200 - 300 W for 10 - 15 minutes to form a suspension, add it to the above - mentioned mixed solution, then add the plasticizer and stabilizer, continue to stir for 1 - 3 hours to form a uniform sol, and finally perform vacuum degassing treatment; S2. Gel forming: Inject the degassed sol into a mold pre - heated to 45 - 50 °C, and keep it at 40 - 45 °C for a certain time to gelate and form a soft - capsule shape; S3. Curing: Cure the above - mentioned capsule at 25 - 30 °C with ventilation for 4 - 6 hours, then soak it in pH 7.4 phosphate buffer solution for 20 - 40 minutes to form nano - micropores on the inner wall, fill the core material and then seal it.

8. The preparation method of an enteric capsule according to claim 7, wherein: The dosage of the acetic acid aqueous solution is 10 - 15 times the weight of the modified chitosan derivative, the dosage of acetone is 8 - 10 times the weight of the copolymer, and the mass - to - volume ratio of the composite microparticles to anhydrous ethanol (g / mL) is 1:5 - 10.

9. The preparation method of an enteric capsule according to claim 1, wherein: The vacuum degree of the vacuum degassing treatment is - 0.05~ - 0.08 MPa, and the vacuum time is 15 - 20 minutes.

10. The preparation method of an enteric capsule according to claim 1, characterized in that: The preparation method of the core material includes: co - grinding the drug active ingredient with a porous starch carrier, loading PLGA microspheres, and then coating a pH - responsive coating by fluidized - bed coating technology. The coating material comprises a composite of a methacrylic acid copolymer and nano - hydroxyapatite.

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