A controlled release hydroxypropyl methylcellulose hollow capsule and a method for preparing the same

Abstract

The application provides a controllable release hydroxypropyl methyl cellulose hollow capsule and a preparation method thereof. The hollow capsule comprises hydroxypropyl methyl cellulose, a curing agent, a potassium salt, sodium dodecyl sulfate, a solubilizer and triethanolamine. The application uses triethanolamine as an anti-potassium agent, and the triethanolamine is complexed with potassium ions in the potassium salt, so that the sensitivity of the capsule shell to potassium ions is reduced, and the technical problem that the disintegration and dissolution of the capsule shell are limited by potassium ions is solved.

Description

Technical Field

[0001] This invention relates to the field of empty capsule technology, and more particularly to a controlled-release hydroxypropyl methylcellulose empty capsule and its preparation method. Background Technology

[0002] Pharmaceutical empty capsules have a significant impact on drug release, safety, efficacy, and clinical treatment, playing a crucial role in new drug development and drug quality control. In recent years, research and application of plant-based empty capsules have gradually emerged, primarily using hydroxypropyl methylcellulose (HPMC) empty capsules. With the implementation of national policies and regulations such as the generic drug consistency evaluation, developing HPMC empty capsules that meet drug disintegration and dissolution requirements is particularly important.

[0003] The invention patent with patent number CN103877067A discloses a hollow capsule with controllable disintegration time. The hollow capsule contains potassium chloride as a coagulant. When the hollow capsule disintegrates and dissolves, it is easily restricted by potassium ions, which affects the disintegration time. Therefore, a hydroxypropyl methylcellulose hollow capsule with controllable release that is less sensitive to potassium ions is needed. Summary of the Invention

[0004] In view of this, the present invention proposes a controlled-release hydroxypropyl methylcellulose empty capsule with low sensitivity to potassium ions and a method for preparing the same.

[0005] The technical solution of the present invention is achieved as follows: On the one hand, the present invention provides a controllable release hydroxypropyl methylcellulose empty capsule, comprising hydroxypropyl methylcellulose, a curing agent, a potassium salt, sodium dodecyl sulfate, a solubilizer, and triethanolamine.

[0006] Based on the above technical solutions, the preferred embodiment, calculated by weight, includes the following components: 15-25 parts of hydroxypropyl methylcellulose, 0.1-5 parts of curing agent, 0.1-3 parts of potassium salt, 0.1-5 parts of sodium dodecyl sulfate, 0.5-1 parts of solubilizer, and 0.5-1 parts of triethanolamine.

[0007] Based on the above technical solutions, preferably, it also includes 0.1-3 parts by weight of xylitol.

[0008] Based on the above technical solutions, preferably, it also includes 0.1-3 parts by weight of silicified microcrystalline cellulose.

[0009] Based on the above technical solutions, preferably, the siliconized microcrystalline cellulose has a D90 of 100-300μm and a D50 of 50-100μm.

[0010] Based on the above technical solutions, preferably, the curing agent is one or a combination of carrageenan, xanthan gum, and gellan gum.

[0011] Based on the above technical solutions, the preferred solubilizer is Tween 20.

[0012] Based on the above technical solutions, preferably, the potassium salt is potassium acetate or potassium citrate.

[0013] On the other hand, the present invention provides a method for preparing controlled-release hydroxypropyl methylcellulose empty capsules, comprising the following steps:

[0014] S1, Sol: Add hydroxypropyl methylcellulose and xylitol to purified water at 80-90℃, stir for 30-60 minutes, then add silicified microcrystalline cellulose and continue stirring for 30-60 minutes. Add 0.1-5 parts of curing agent and continue stirring for 30-60 minutes. As the sol begins to cool, add potassium salt, solubilizer, sodium dodecyl sulfate and potassium inhibitor. Degas under vacuum for 30-60 minutes while stirring, maintaining the sol temperature at 50-60℃. Then transfer the sol to a curing tank for later use.

[0015] S2, Heat preservation and color adjustment: Add the pigment to the curing tank and stir evenly. Let it stand for 3-6 hours for later use.

[0016] S3, Molding: Dip the material in adhesive at a temperature of 50-60℃, and set the temperature at 15-30℃;

[0017] S4, Drying: Dry at a temperature of 20-40℃;

[0018] S5, Demolding, Cutting, and Assembly: After the dried blank is demolded and passes quality inspection, it is cut and assembled to obtain a hollow capsule.

[0019] Based on the above technical solutions, preferably, after degassing, the viscosity of the adhesive is controlled at 400-1500 mPa·s, and then the adhesive is transferred to a curing tank.

[0020] The controlled-release hydroxypropyl methylcellulose empty capsule and its preparation method of the present invention have the following advantages over the prior art:

[0021] (1) The present invention uses triethanolamine as an antipotassium agent. Triethanolamine complexes with potassium ions in potassium salt, reducing the sensitivity of capsule shell to potassium ions and effectively solving the technical problem that capsule shell disintegration and dissolution are limited by potassium ions.

[0022] (2) Although the addition of potassium antagonist solved the technical problem of capsule shell disintegration and dissolution being limited by potassium ions, the disintegration and dissolution time was relatively long. Therefore, xylitol, a pore-forming agent, was added. Xylitol dissolves in water to form pores, which further regulates the disintegration and dissolution process of empty capsules.

[0023] (3) The addition of pore-forming agents has a certain impact on the strength of empty capsules. Therefore, silicified microcrystalline cellulose is added as a reinforcing agent. On the one hand, silicified microcrystalline cellulose is uniformly dispersed in the capsule shell as a filler, which improves the mechanical strength of the empty capsule and reduces its brittleness. On the other hand, the strong hydrophilicity of silicified microcrystalline cellulose improves the sol-gel transition performance of the empty capsule and solves the problem that the curing agent disintegrates slowly in acidic media, which is not conducive to drug dissolution. Detailed Implementation

[0024] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0025] All materials used in the empty capsules of this invention were purchased from the market. Hydroxypropyl methylcellulose was purchased from Shin-Etsu Chemical Co., Ltd., Japan, with specifications E3 / E5 / E15 / E30 / E50; siliconized microcrystalline cellulose was purchased from Shenzhen Youpuhui Pharmaceutical Co., Ltd., with specification TMS635L; xylitol was purchased from Shanghai Yuanye Biotechnology Co., Ltd., with product number S11039; and the pigment used was pharmaceutical grade tartrazine.

[0026] Example 1

[0027] The controlled-release hydroxypropyl methylcellulose empty capsule of this embodiment comprises, by weight, 150g of hydroxypropyl methylcellulose with a viscosity of 3mPa·s, 1g of carrageenan, 1g of potassium acetate, 1g of sodium dodecyl sulfate, 5g of Tween 20, 5g of triethanolamine, 10g of tartrazine, and 600g of purified water.

[0028] The method for preparing the controlled-release hydroxypropyl methylcellulose empty capsules in this embodiment includes the following steps:

[0029] S1, Sol: Add hydroxypropyl methylcellulose to purified water at 80℃, stir for 30 minutes, then add carrageenan and continue stirring for 30 minutes. As the solution begins to cool, add potassium acetate, Tween 20, sodium dodecyl sulfate and triethanolamine. Stir and degas under vacuum for 30 minutes, maintaining the solution temperature at 50℃ and controlling the solution viscosity at 400 mPa·s. Then transfer the solution to a curing tank for later use.

[0030] S2, Heat preservation and color adjustment: Add lemon yellow pigment to the curing tank and stir evenly, let stand for 3 hours for later use;

[0031] S3, Molding: Dip the material in adhesive at 50°C, and set it at 15°C;

[0032] S4, Drying: Dry at 20°C;

[0033] S5, Demolding, Cutting, and Assembly: After the dried blank is demolded and passes quality inspection, it is cut and assembled to obtain a hollow capsule.

[0034] Example 2

[0035] The controlled-release hydroxypropyl methylcellulose empty capsule of this embodiment comprises, by weight, 150g of hydroxypropyl methylcellulose with a viscosity of 3mPa·s, 1g of carrageenan, 1g of potassium acetate, 1g of sodium lauryl sulfate, 5g of Tween 20, 5g of triethanolamine, 1g of xylitol, 10g of tartrazine, and 600g of purified water.

[0036] S1, Sol: Add hydroxypropyl methylcellulose and xylitol to purified water at 80℃, stir for 30 minutes, add carrageenan, continue stirring for 30 minutes, the solution begins to cool down, add potassium acetate, Tween 20, sodium dodecyl sulfate and triethanolamine, stir and vacuum degas for 30 minutes, keep the solution temperature at 50℃, control the solution viscosity at 400 mPa·s, and then transfer the solution to a curing tank for later use;

[0037] S2, Heat preservation and color adjustment: Add lemon yellow pigment to the curing tank and stir evenly, let stand for 3 hours for later use;

[0038] S3, Molding: Dip the material in adhesive at 50°C, and set it at 15°C;

[0039] S4, Drying: Dry at 20°C;

[0040] S5, Demolding, Cutting, and Assembly: After the dried blank is demolded and passes quality inspection, it is cut and assembled to obtain a hollow capsule.

[0041] Example 3

[0042] The controlled-release hydroxypropyl methylcellulose empty capsule of this embodiment comprises, by weight: 150g of hydroxypropyl methylcellulose with a viscosity of 3mPa·s, 1g of carrageenan, 1g of potassium acetate, 1g of sodium lauryl sulfate, 5g of Tween 20, 5g of triethanolamine, 1g of xylitol, 1g of silanized microcrystalline cellulose, 10g of tartrazine, and 600g of purified water. The silanized microcrystalline cellulose has a D90 of 100μm and a D50 of 50μm.

[0043] The method for preparing the controlled-release hydroxypropyl methylcellulose empty capsules in this embodiment includes the following steps:

[0044] S1, Sol: Add hydroxypropyl methylcellulose and xylitol to purified water at 80℃ and stir for 30 min. Then add silicified microcrystalline cellulose and continue stirring for 30 min. Add carrageenan and continue stirring for 30 min. As the solution begins to cool down, add potassium acetate, Tween 20, sodium dodecyl sulfate and triethanolamine. Degas under vacuum for 30 min while stirring. Maintain the solution temperature at 50℃ and control the solution viscosity at 400 mPa·s. Then transfer the solution to a curing tank for later use.

[0045] S2, Heat preservation and color adjustment: Add lemon yellow pigment to the curing tank and stir evenly, let stand for 3 hours for later use;

[0046] S3, Molding: Dip the material in adhesive at 50°C, and set it at 15°C;

[0047] S4, Drying: Dry at 20°C;

[0048] S5, Demolding, Cutting, and Assembly: After the dried blank is demolded and passes quality inspection, it is cut and assembled to obtain a hollow capsule.

[0049] Example 4

[0050] The controlled-release hydroxypropyl methylcellulose empty capsule of this embodiment comprises, by weight: 250g of hydroxypropyl methylcellulose with a viscosity of 3mPa·s, 50g of xanthan gum, 30g of potassium citrate, 50g of sodium lauryl sulfate, 10g of Tween 20, 10g of triethanolamine, 30g of xylitol, 30g of silicified microcrystalline cellulose, 50g of pigment, and 600g of purified water. The silicified microcrystalline cellulose has a D90 of 110μm and a D50 of 60μm.

[0051] The method for preparing the controlled-release hydroxypropyl methylcellulose empty capsules in this embodiment includes the following steps:

[0052] S1, Sol: Add hydroxypropyl methylcellulose and xylitol to purified water at 90℃ and stir for 60 min. Then add silicified microcrystalline cellulose and continue stirring for 60 min. Add xanthan gum and continue stirring for 60 min. As the solution begins to cool down, add potassium citrate, Tween 20, sodium dodecyl sulfate and triethanolamine. Degas under vacuum for 60 min while stirring, keeping the solution temperature at 60℃ and controlling the solution viscosity at 1500 mPa·s. Then transfer the solution to a curing tank for later use.

[0053] S2, Heat preservation and color adjustment: Add lemon yellow pigment to the curing tank and stir evenly, let stand for 6 hours for later use;

[0054] S3, Molding: Dip the material in adhesive at 60°C, and set it at 30°C;

[0055] S4, Drying: Dry at 40℃;

[0056] S5, Demolding, Cutting, and Assembly: After the dried blank is demolded and passes quality inspection, it is cut and assembled to obtain a hollow capsule.

[0057] Example 5

[0058] The controlled-release hydroxypropyl methylcellulose empty capsule of this embodiment comprises, by weight parts: 220g of hydroxypropyl methylcellulose with a viscosity of 5mPa·s, 40g of gellan gum, 20g of potassium acetate, 30g of sodium dodecyl sulfate, 8g of Tween 20, 8g of triethanolamine, 20g of xylitol, 25g of silanized microcrystalline cellulose, 40g of pigment, and 670 parts of purified water. The silanized microcrystalline cellulose has a D90 of 150μm and a D50 of 65μm.

[0059] The method for preparing the controlled-release hydroxypropyl methylcellulose empty capsules in this embodiment includes the following steps:

[0060] S1, Sol: Add hydroxypropyl methylcellulose and xylitol to purified water at 85℃ and stir for 55 min. Then add silicified microcrystalline cellulose and continue stirring for 50 min. Add gellan gum and continue stirring for 50 min. The solution begins to cool down. Add potassium acetate, Tween 20, sodium dodecyl sulfate and triethanolamine. Stir and degas under vacuum for 50 min. Maintain the solution temperature at 55℃ and control the solution viscosity at 1200 mPa·s. Then transfer the solution to a curing tank for later use.

[0061] S2, Heat preservation and color adjustment: Add lemon yellow to the curing tank and stir evenly, let stand for 4 hours for later use;

[0062] S3, Molding: Dip the material in adhesive at 55°C, and set it at 25°C;

[0063] S4, Drying: Dry at 30℃;

[0064] S5, Demolding, Cutting, and Assembly: After the dried blank is demolded and passes quality inspection, it is cut and assembled to obtain a hollow capsule.

[0065] Example 6

[0066] The controlled-release hydroxypropyl methylcellulose empty capsule of this embodiment comprises, by weight parts: 200g of hydroxypropyl methylcellulose with a viscosity of 15mPa·s, 30g of carrageenan, 10g of potassium acetate, 10g of sodium dodecyl sulfate, 6g of Tween 20, 10g of triethanolamine, 10g of xylitol, 20g of silanized microcrystalline cellulose, 30g of pigment, and 720 parts of purified water. The silanized microcrystalline cellulose has a D90 of 150μm and a D50 of 70μm.

[0067] The method for preparing the controlled-release hydroxypropyl methylcellulose empty capsules in this embodiment includes the following steps:

[0068] S1, Sol: Add hydroxypropyl methylcellulose and xylitol to purified water at 80℃ and stir for 50 min. Then add silicified microcrystalline cellulose and continue stirring for 50 min. Add carrageenan and continue stirring for 50 min. As the solution begins to cool, add potassium acetate, Tween 20, sodium dodecyl sulfate and triethanolamine. Degas under vacuum for 50 min while stirring. Maintain the solution temperature at 50℃ and control the solution viscosity at 1000 mPa·s. Then transfer the solution to a curing tank for later use.

[0069] S2, Heat preservation and color adjustment: Add lemon yellow to the curing tank and stir evenly, let stand for 4 hours for later use;

[0070] S3, Molding: Dip the material in adhesive at 55°C, and set it at 20°C;

[0071] S4, Drying: Dry at 25°C;

[0072] S5, Demolding, Cutting, and Assembly: After the dried blank is demolded and passes quality inspection, it is cut and assembled to obtain a hollow capsule.

[0073] Example 7

[0074] The controlled-release hydroxypropyl methylcellulose empty capsule of this embodiment comprises, by weight parts: 180g of hydroxypropyl methylcellulose with a viscosity of 30mPa·s, 15g of xanthan gum, 10g of potassium citrate, 5g of sodium lauryl sulfate, 5g of Tween 20, 5g of triethanolamine, 20g of xylitol, 10g of silanized microcrystalline cellulose, 20g of pigment, and 750 parts of purified water. The silanized microcrystalline cellulose has a D90 of 200μm and a D50 of 90μm.

[0075] The method for preparing the controlled-release hydroxypropyl methylcellulose empty capsules in this embodiment includes the following steps:

[0076] S1, Sol: Add hydroxypropyl methylcellulose and xylitol to purified water at 80℃ and stir for 40 min. Then add silicified microcrystalline cellulose and continue stirring for 40 min. Add xanthan gum and continue stirring for 40 min. As the solution begins to cool down, add potassium citrate, Tween 20, sodium dodecyl sulfate and triethanolamine. Degas under vacuum for 40 min while stirring. Maintain the solution temperature at 50℃ and control the solution viscosity at 800 mPa·s. Then transfer the solution to a curing tank for later use.

[0077] S2, Heat preservation and color adjustment: Add lemon yellow to the curing tank and stir evenly, let stand for 4 hours for later use;

[0078] S3, Molding: Dip the material in adhesive at 50°C, and set it at 20°C;

[0079] S4, Drying: Dry at 25°C;

[0080] S5, Demolding, Cutting, and Assembly: After the dried blank is demolded and passes quality inspection, it is cut and assembled to obtain a hollow capsule.

[0081] Example 8

[0082] The controlled-release hydroxypropyl methylcellulose empty capsule of this embodiment comprises, by weight parts: 150g of hydroxypropyl methylcellulose with a viscosity of 50mPa·s, 10g of xanthan gum, 5g of potassium citrate, 10g of sodium lauryl sulfate, 5g of Tween 20, 5g of triethanolamine, 10g of xylitol, 10g of silanized microcrystalline cellulose, 10g of pigment, and 800 parts of purified water. The silanized microcrystalline cellulose has a D90 of 300μm and a D50 of 100μm.

[0083] The method for preparing the controlled-release hydroxypropyl methylcellulose empty capsules in this embodiment includes the following steps:

[0084] S1, Sol: Add hydroxypropyl methylcellulose and xylitol to purified water at 85℃ and stir for 30 minutes. Then add silicified microcrystalline cellulose and continue stirring for 30 minutes. Add xanthan gum and continue stirring for 30 minutes. As the solution begins to cool down, add potassium citrate, Tween 20, sodium dodecyl sulfate and triethanolamine. Degas under vacuum for 30 minutes while stirring. Maintain the solution temperature at 50℃ and control the solution viscosity at 600 mPa·s. Then transfer the solution to a curing tank for later use.

[0085] S2, Heat preservation and color adjustment: Add lemon yellow to the curing tank and stir well. Let it stand for 3 hours for later use.

[0086] S3, Molding: Dip the material in adhesive at 50°C, and set it at 15°C;

[0087] S4, Drying: Dry at 20°C;

[0088] S5, Demolding, Cutting, and Assembly: After the dried blank is demolded and passes quality inspection, it is cut and assembled to obtain a hollow capsule.

[0089] Comparative Example 1

[0090] The difference between Comparative Example 1 and Example 1 is that Triethanolamine is missing, while the other components are the same.

[0091] Comparative Example 2

[0092] The difference between Comparative Example 2 and Example 2 is that triethanolamine is missing, xylitol is retained, and the other components are the same.

[0093] Comparative Example 3

[0094] The difference between Comparative Example 3 and Example 3 is that it lacks triethanolamine, retains xylitol and silicified microcrystalline cellulose, and the other components are the same.

[0095] Comparative Example 4

[0096] The difference between Comparative Example 4 and Example 3 is that it lacks triethanolamine and xylitol, retains silicified microcrystalline cellulose, and the other components are the same.

[0097] Comparative Example 5

[0098] The difference between Comparative Example 5 and Example 3 is that xylitol is missing, while triethanolamine and silicified microcrystalline cellulose are retained, and the other components are the same.

[0099] Comparative Example 6

[0100] The difference between Comparative Example 6 and Example 8 is that the viscosity of hydroxypropyl methylcellulose is 60 mPa·s, and the viscosity of the adhesive is controlled at 1800 mPa·s, which exceeds the limit of the present invention. The other components are the same.

[0101] Comparative Example 7

[0102] The difference between Comparative Example 7 and Example 3 is that the amount of xylitol used is 0.5g, while the other components are the same.

[0103] Comparative Example 8

[0104] The difference between Comparative Example 8 and Example 4 is that the amount of xylitol used is 60g, which exceeds the scope of the present invention, while the other components are the same.

[0105] Comparative Example 9

[0106] The difference between Comparative Example 9 and Example 3 is that the amount of siliconized microcrystalline cellulose used is 0.3g, which exceeds the scope of the present invention, while the other components are the same.

[0107] Comparative Example 10

[0108] The difference between Comparative Example 10 and Example 4 is that the amount of siliconized microcrystalline cellulose used is 40g, which exceeds the scope of the present invention, while the other components are the same.

[0109] The fragility, disintegration time, and drug dissolution properties of the empty capsules prepared in the test examples and comparative examples were evaluated. The test methods are as follows, and the test results are shown in Tables 1-3.

[0110] Friability test: Take 100 capsules of this product and divide them equally into two petri dishes. Place the petri dishes containing the samples into a desiccator containing blue silica gel. Place four batches of samples at a time. Place them under these conditions for 24 hours. During the entire experiment, the humidity in the desiccator should be controlled within the range of 8% to 20%. Take them out and immediately place them one by one into a glass tube (24 mm inner diameter and 200 mm long) that is placed upright on a wooden board (2 cm thick). Let a cylindrical weight (made of polytetrafluoroethylene, 22 mm in diameter, and weighing 20 g ± 0.1 g) fall freely from the opening of the glass tube. Observe whether the empty capsules break and record the number of broken capsules.

[0111] Disintegration time test: Referring to the disintegration time test method in General Chapter 0921 of the 2020 edition of the Chinese Pharmacopoeia, the disintegration time of the capsules was observed using water, hydrochloric acid at pH 1.2, acetate at pH 4.5, and phosphate at pH 6.8 as media.

[0112] Dissolution observation test: The rotating basket method was used at a speed of 100 rpm and a temperature of 37.0±0.5℃. The contents were amoxicillin, and the dissolution media were purified water, hydrochloric acid at pH 1.2, acetate at pH 4.5, and phosphate at pH 6.8. The capsule breakage during the dissolution process was observed.

[0113] Table 1 Results of Friability Test

[0114] sample Accessibility (%) Crispness (particle size) Example 1 99.5 2 Example 2 99.5 1 Example 3 99.9 0 Example 4 99.9 0 Example 5 99.9 0 Example 6 99.9 0 Example 7 99.9 0 Example 8 99.9 0 Comparative Example 1 95.0 6 Comparative Example 2 95.0 5 Comparative Example 3 95.5 4 Comparative Example 4 95.0 4 Comparative Example 5 95.0 4 Comparative Example 6 85.0 10 Comparative Example 7 96.0 2 Comparative Example 8 83 5 Comparative Example 9 94.0 3 Comparative Example 10 80 15

[0115] Table 1 shows that the friability of Example 1 was 0-2 capsules / 100 capsules, which is within the standard range. Examples 3-8, containing triethanolamine, xylitol, and silicified microcrystalline cellulose, had a friability of 0, high strength, and a success rate of 99.9%, indicating that the addition of triethanolamine, xylitol, and silicified microcrystalline cellulose reduced friability, increased the strength of the empty capsules, and increased the success rate. Comparative Example 6 shows that increasing the viscosity of the adhesive solution reduced the strength and success rate of the empty capsules. This is because increasing the viscosity of hydroxypropyl methylcellulose and the adhesive solution resulted in poor film formation of the empty capsules and a lower pass rate. Comparative Examples 7-10: Adding excessive xylitol or silicified microcrystalline cellulose reduced capsule smoothness and decreased success rate.

[0116] Table 2 Disintegration time of empty capsules

[0117]

[0118] Table 2 shows that the adjustable disintegration time of the hollow capsules prepared in this embodiment is 2′43″-20′42″ in purified water at pH 7.0, 3′45″-19′05″ in hydrochloric acid aqueous solution at pH 1.2, 4′32″-19′45″ in acetate aqueous solution at pH 4.5, and 5′07″-19′08″ in phosphate aqueous solution at pH 6.8. Furthermore, the higher the viscosity of hydroxypropyl methylcellulose, the longer the disintegration time. The disintegration time of Examples 1 and 2 is longer than that of Example 3. Comparative Example 1, which lacks a potassium-resistant agent, shows a relatively long disintegration time in purified water, hydrochloric acid at pH 1.2, acetate at pH 4.5, and phosphate at pH 6.8 as dissolution media. This indicates that increasing triethanolamine, xylitol, and silicified microcrystalline cellulose can shorten the disintegration time and reduce the limitation of potassium ions on the disintegration time of hollow capsules. Compared to Example 8, Comparative Example 6 showed a significantly prolonged disintegration time. This was because the increased viscosity of hydroxypropyl methylcellulose and the adhesive reduced the water solubility of the empty capsules, thus slowing down the disintegration rate. Comparative Examples 7-10: Continuing to increase the amount of xylitol did not further reduce the disintegration time, as it had reached the limit for xylitol solubility. Since silicified microcrystalline cellulose itself is insoluble in water, it can only reduce the disintegration time to a certain extent through dispersibility; adding excessive silicified microcrystalline cellulose would actually increase the disintegration time.

[0119] In summary, the technical effect of regulating the disintegration time is achieved by adjusting the viscosity of hydroxypropyl methylcellulose and the composition of triethanolamine, xylitol, and silicified microcrystalline cellulose.

[0120] Table 3 Drug dissolution time

[0121]

[0122]

[0123] Note: "Start" indicates the time when hatching begins (min), and "End" indicates the total time when hatching begins (min).

[0124] As shown in Table 3, the empty capsules prepared in the embodiments of the present invention have an adjustable shell-breaking time of 2-23 min and a dissolution time of 4-7 min in purified water at pH 7.0; an adjustable shell-breaking time of 3-25 min and a dissolution time of 2-8 min in hydrochloric acid aqueous solution at pH 1.2; an adjustable shell-breaking time of 3-23 min and a dissolution time of 2-7 min in acetate aqueous solution at pH 4.5; and an adjustable shell-breaking time of 2-24 min and a dissolution time of 3-8 min in phosphate aqueous solution at pH 6.8. Furthermore, the higher the viscosity of hydroxypropyl methylcellulose, the longer the drug dissolution time. The drug dissolution time in Examples 1 and 2 was longer than that in Example 3. In Comparative Example 1, which lacked an anti-potassium agent, the drug dissolution time of the empty capsules was longer in purified water, hydrochloric acid (pH 1.2), acetate (pH 4.5), and phosphate (pH 6.8) as dissolution media. This indicates that increasing triethanolamine, xylitol, and silicified microcrystalline cellulose can shorten the drug dissolution time and reduce the limitation of potassium ions on the disintegration time of the empty capsules. Compared with Example 8, Comparative Example 6 showed a significantly prolonged drug dissolution time. This is because the increased viscosity of hydroxypropyl methylcellulose and the gel reduces the water solubility of the empty capsules. Comparative Examples 7-10 show that further increasing the amount of xylitol does not continuously reduce the dissolution time, as it has reached the limit of xylitol solubility. Since silicified microcrystalline cellulose itself is insoluble in water, it can only reduce the dissolution time to a certain extent through dispersibility; adding excessive silicified microcrystalline cellulose will actually increase the dissolution time.

[0125] In summary, by adjusting the viscosity of hydroxypropyl methylcellulose and the composition of triethanolamine, xylitol, and silicified microcrystalline cellulose, the technical effect of regulating drug dissolution time can be achieved.

[0126] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A controlled-release hydroxypropyl methylcellulose empty capsule, characterized in that: According to the weight percentages, the raw material components of the hollow capsule include 15-25 parts of hydroxypropyl methylcellulose, 0.1-5 parts of curing agent, 0.1-3 parts of potassium salt, 0.1-5 parts of sodium dodecyl sulfate, 0.5-1 parts of solubilizer, 0.5-1 parts of triethanolamine, 0.1-3 parts of xylitol and 0.1-3 parts of silanized microcrystalline cellulose; The viscosity of the hydroxypropyl methylcellulose is 3-50 mPa·s, and the D90 of the siliconized microcrystalline cellulose is 100-300 μm, and the D50 is 50-100 μm. The curing agent is one or more combinations of carrageenan, xanthan gum and gellan gum, the solubilizer is Tween 20, and the potassium salt is potassium acetate or potassium citrate.

2. The method for preparing a controlled-release hydroxypropyl methylcellulose empty capsule as described in claim 1, characterized in that: Includes the following steps: S1, Sol: Add hydroxypropyl methylcellulose and xylitol to purified water at 80-90℃ and stir for 30-60 minutes. Then add silicified microcrystalline cellulose and continue stirring for 30-60 minutes. Add 0.1-5 parts of curing agent and continue stirring for 30-60 minutes. As the sol begins to cool, add potassium salt, solubilizer, sodium dodecyl sulfate and triethanolamine. Degas under vacuum for 30-60 minutes while stirring, keeping the sol temperature at 50-60℃. Then transfer the sol to a curing tank for later use. S2, Heat preservation and color adjustment: Add the pigment to the curing tank and stir evenly. Let it stand for 3-6 hours for later use. S3, Molding: Dip the material in adhesive at a temperature of 50-60℃, and set the temperature at 15-30℃; S4, Drying: Dry at a temperature of 20-40℃; S5, Demolding, Cutting, and Assembly: After the dried blank is demolded and passes quality inspection, it is cut and assembled to obtain a hollow capsule.

3. The method for preparing a controlled-release hydroxypropyl methylcellulose empty capsule as described in claim 2, characterized in that: After degassing, control the viscosity of the adhesive to 400-1500 mPa·s, and then transfer the adhesive to a curing tank.

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