A pharmaceutical preparation containing bisacodyl and a preparation method and application thereof

Abstract

The present application relates to the technical field of pharmaceutical preparation, and discloses a pharmaceutical preparation containing bisacodyl and a preparation method and application thereof.The pharmaceutical preparation containing bisacodyl provided by the present application comprises a tablet core and a coating film wrapping the tablet core;the tablet core comprises, in parts by weight, 4-6 parts of bisacodyl, 30-40 parts of a filler, 6-12 parts of bentonite and 0.5-2 parts of a lubricant; and the coating film comprises, in parts by weight, 6-10 parts of an enteric material, 3-9 parts of N-trimethyl chitosan, 1-3 parts of a plasticizer and 2-6 parts of an anti-adhesion agent.The pharmaceutical preparation of the present application reduces the difference in drug release speed caused by batch difference and individual difference by adding bentonite to the tablet core and adding N-trimethyl chitosan to the coating film, and improves the drug release uniformity of the pharmaceutical preparation containing bisacodyl.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to a pharmaceutical preparation containing bisacodyl, its preparation method, and its application. Background Technology

[0002] Bisacodyl is a stimulant laxative that primarily acts on the large intestine. It enhances intestinal peristalsis by directly stimulating sensory nerve endings through contact with the intestinal mucosa, thus inducing gas and defecation. Bisacodyl is activated only in the colon, and the enteric coating must ensure the tablet passes intact through the stomach (acidic) and small intestine (neutral to weakly alkaline), disintegrating at a specific colonic pH (around 7). However, batch-to-batch variability (changes in coating thickness and uniformity) and individual variability (colonic pH is significantly affected by disease, diet, and gut microbiota activity) can lead to premature or delayed drug release, significantly impacting drug release behavior and limiting the therapeutic effect of bisacodyl. Therefore, improving the release uniformity of bisacodyl formulations is of paramount importance. Summary of the Invention

[0003] This invention provides a bisacodyl-containing pharmaceutical preparation, its preparation method, and its application, to solve the problem of poor drug release uniformity in existing bisacodyl pharmaceutical preparations.

[0004] In a first aspect, the present invention provides a pharmaceutical formulation containing bisacodyl, comprising a tablet core and a coating film encapsulating the tablet core; By weight, the core comprises 4-6 parts bisacodyl, 30-40 parts filler, 6-12 parts bentonite, and 0.5-2 parts lubricant; By weight, the coating film comprises 6-10 parts of enteric material, 3-9 parts of N-trimethyl chitosan, 1-3 parts of plasticizer, and 2-6 parts of anti-adhesion agent.

[0005] In one alternative embodiment, the coating weight gain of the pharmaceutical preparation is 30-50%.

[0006] In one optional embodiment, the mass ratio of the bentonite to N-trimethyl chitosan is 1-3:1.

[0007] In one alternative embodiment, the filler includes at least one of lactose monohydrate, starch, and microcrystalline cellulose 101.

[0008] In one alternative embodiment, the lubricant includes at least one of magnesium stearate and stearic acid.

[0009] In one alternative embodiment, the enteric material comprises an acrylic resin.

[0010] In one alternative embodiment, the plasticizer includes at least one of polyethylene glycol and triethyl citrate.

[0011] In one alternative embodiment, the anti-adhesion agent includes at least one of talc and glyceryl monostearate.

[0012] Secondly, the present invention provides a method for preparing the above-mentioned bisacodyl-containing pharmaceutical preparation, comprising the following steps: Step S1: Bisacodyl, filler and water are first mixed, granulated, lubricant is added for second mixing, tableting is performed to obtain tablet cores; Step S2: Disperse the enteric material, N-trimethyl chitosan, plasticizer, and anti-adhesive in a solvent to obtain a coating solution. Coat the tablet core with the coating solution to obtain a pharmaceutical formulation containing bisacodyl.

[0013] In one alternative embodiment, the mass ratio of the water to the total mass of bisacodyl and lactose monohydrate is 1:0.8-1.3.

[0014] In one alternative embodiment, the solvent comprises an aqueous solution of ethanol with a mass fraction of 90-96%.

[0015] In one optional embodiment, the coating liquid has a solid content of 5-8%.

[0016] In one alternative embodiment, the first mixing speed is 100-300 rpm and the time is 5-15 min.

[0017] In one optional embodiment, the granulation process involves a mixing speed of 100-300 rpm, a cutting speed of 1100-1300 rpm, and a time of 80-100 s.

[0018] In one alternative embodiment, the granulation process further includes a drying step.

[0019] In one alternative implementation, the drying method includes fluidized bed drying.

[0020] In one optional embodiment, the blower frequency of the fluidized bed dryer is 15-25Hz, the inlet air temperature is 50-70℃, the outlet air temperature is 35-45℃, and the material temperature is 35-45℃.

[0021] In one alternative embodiment, the second mixing speed is 10-15 rpm and the time is 3-10 min.

[0022] In one optional embodiment, the coating rotation speed is 3-20 rpm, the atomization pressure is 2-3 bar, the fan pressure is 2-3 bar, the inlet air temperature is 50-70℃, the outlet air temperature is 30-40℃, the pump speed is 5-15 rpm, and the tablet bed temperature is 30-40℃.

[0023] In one alternative implementation, the coating process further includes an aging step.

[0024] In one optional embodiment, the aging temperature is 35-45°C and the time is 1-3 hours.

[0025] Thirdly, the present invention provides the use of the above-mentioned bisacodyl-containing pharmaceutical preparation or the bisacodyl-containing pharmaceutical preparation prepared by the above-mentioned preparation method in the preparation of a drug for treating constipation.

[0026] The technical solution of this invention has the following advantages: 1. This invention provides a pharmaceutical formulation containing bisacodyl, comprising a tablet core and a coating film encapsulating the tablet core; by weight, the tablet core comprises 4-6 parts bisacodyl, 30-40 parts filler, 6-12 parts bentonite, and 0.5-2 parts lubricant; by weight, the coating film comprises 6-10 parts enteric coating material, 3-9 parts N-trimethyl chitosan, 1-3 parts plasticizer, and 2-6 parts anti-adhesive. The tablet core of this invention uses bisacodyl, lactose monohydrate, bentonite, and magnesium stearate, while the coating film uses acrylic resin, N-trimethyl chitosan, polyethylene glycol, and talc, enabling the pharmaceutical formulation to pass completely through the stomach and small intestine, and releasing the drug as the pH gradually increases. In this invention, if the drug formulation ruptures before entering the colon, the bentonite in the tablet core will form a mucus-like gel layer covering the intestinal mucosa under a strongly alkaline environment, thus preventing the burst release of bisacodyl. As the intestinal pH subsequently increases, the coating slowly dissolves. At this point, the positively charged N-trimethyl chitosan can flocculate with the negatively charged bentonite, allowing for rapid drug release. If the drug formulation ruptures at the posterior end of the colon, the higher intestinal pH can accelerate the dissolution of acrylic resin. The positively charged N-trimethyl chitosan can directly flocculate with the negatively charged bentonite. In this case, the bentonite does not have time to form a mucus-like gel layer, and the drug is released rapidly. Therefore, the drug formulation of this invention, by adding bentonite to the tablet core and N-trimethyl chitosan to the coating, works synergistically to reduce the differences in drug release rate caused by batch and individual variations, thereby improving the release uniformity of bisacodyl-containing drug formulations.

[0027] 2. The preparation method of the above-mentioned bisacodyl-containing pharmaceutical formulation provided by the present invention includes the following steps: S1 step: Bisacodyl, filler and water are first mixed, granulated, lubricant is added for a second mixing, and tableting is performed to obtain a tablet core; S2 step: enteric coating material, N-trimethyl chitosan, plasticizer and anti-adhesion agent are dispersed in a solvent to obtain a coating solution, and the tablet core is coated with the coating solution to obtain a bisacodyl-containing pharmaceutical formulation. The present invention adopts a stepwise preparation process. First, the active pharmaceutical ingredient and tablet core excipients are mixed and wet-granulated, then magnesium stearate is added for tableting to ensure uniform mixing of all components; then, the coating raw materials are prepared into a coating solution for coating. The process is simple and controllable, and can stably prepare a bisacodyl-containing pharmaceutical formulation with good drug release uniformity. Detailed Implementation

[0028] The following embodiments are provided to better understand the present invention, but the following embodiments do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the scope of protection of the present invention.

[0029] Unless otherwise specified, all experimental steps or conditions in the examples were performed according to conventional experimental procedures and conditions in the art. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0030] The raw materials used in the embodiments and comparative examples of this invention are as follows: Bisaccharide: Purchased from KREATIVE ORGANICS PRIVATE LIMITED; Lactose monohydrate: purchased from Jiangsu Daoning Pharmaceutical Co., Ltd., specification: 200 mesh; Benzoic clay: purchased from Luofu Pharmaceutical Technology (Shanghai) Co., Ltd.; Magnesium stearate: purchased from Shandong Liaocheng Ahua Pharmaceutical Co., Ltd.; Acrylic resin S100: EUDRAGIT® S 100, purchased from Evonik; N-Trimethyl Chitosan: Purchased from Chongqing Yusi Pharmaceutical Technology Co., Ltd.; Talc powder: purchased from Shanghai Yuxin Pharmaceutical Co., Ltd.

[0031] In this invention, loss on drying refers to the percentage of mass reduction of a sample after drying to constant weight at a specified temperature relative to its initial mass. The detection method is as follows: Take 3-5g of the sample to be tested and test it in an HB43-S halogen moisture analyzer (purchased from Mettler Toledo). Set the heating temperature to 105℃ and the heating time to 3min. Calculate the percentage of loss on drying based on (original mass of sample before heating - mass of sample after heating) / original mass of sample before heating × 100%.

[0032] Example 1 This embodiment provides a pharmaceutical formulation containing bisacodyl, comprising a tablet core and a coating film encapsulating the tablet core; the tablet core comprises 5 mg of bisacodyl, 35 mg of lactose monohydrate, 9 mg of bentonite, and 1 mg of magnesium stearate, and the coating film comprises 8 mg of acrylic resin S100, 6 mg of N-trimethyl chitosan, 2 mg of polyethylene glycol 6000, and 4 mg of talc.

[0033] This embodiment also provides a method for preparing the above-mentioned drug formulation containing bisacodyl, including the following steps: (1) Weigh out the above weights of bisacodyl, lactose monohydrate, and bentonite and premix them in a wet granulator at a speed of 200 rpm for 5 min. Then add 33 mg of water and granulate at a mixing speed of 200 rpm and a cutting speed of 1200 rpm for 90 s. Dry the obtained wet granules in a fluidized bed with the fan frequency set to 20 Hz, the inlet air temperature to 60 ℃, the outlet air temperature to 40 ℃, and the material temperature to 40 ℃. Control the drying loss to within 3% to obtain dry granules. Continue mixing the above weights of magnesium stearate and dry granules at a speed of 12 rpm for 5 min. Then compress the obtained granules into tablets to obtain tablet cores. (2) The above weight of acrylic resin S100, N-trimethyl chitosan, polyethylene glycol 6000 and talc powder were dispersed in 313g of 95% ethanol aqueous solution to obtain a coating solution (solid content of 6%). The coating solution was coated onto the tablet core. The rotation speed of the coating pan was set to 10 rpm, the atomization pressure was 2 bar, the fan pressure was 2 bar, the inlet air temperature was 60℃, the outlet air temperature was 35℃, the pump speed was 10 rpm, and the tablet bed temperature was 35℃. The coating weight gain was controlled at 20mg / tablet. After coating, the tablet was aged at 40℃ for 2h to obtain a drug preparation containing bisacodyl.

[0034] Example 2 This embodiment provides a pharmaceutical formulation containing bisacodyl, comprising a tablet core and a coating film encapsulating the tablet core; the tablet core comprises 5 mg of bisacodyl, 35 mg of lactose monohydrate, 6 mg of bentonite, and 1 mg of magnesium stearate, and the coating film comprises 8 mg of acrylic resin S100, 6 mg of N-trimethyl chitosan, 2 mg of polyethylene glycol 6000, and 4 mg of talc.

[0035] This embodiment also provides a method for preparing the above-mentioned drug formulation containing bisacodyl, including the following steps: (1) Weigh out the above weights of bisacodyl, lactose monohydrate and bentonite and premix them in a wet granulator at a speed of 100 rpm for 15 min. Then add 50 mg of water and granulate for 100 s at a mixing speed of 300 rpm and a cutting speed of 1100 rpm. Dry the wet granules in a fluidized bed with the fan frequency set to 15 Hz, the inlet air temperature to 50 ℃, the outlet air temperature to 35 ℃, and the material temperature to 35 ℃. Control the drying loss to within 3% to obtain dry granules. Continue mixing the above weights of magnesium stearate and dry granules at a speed of 10 rpm for 10 min. Then compress the obtained granules into tablets to obtain tablet cores. (2) The above weight of acrylic resin S100, N-trimethyl chitosan, polyethylene glycol 6000 and talc powder were dispersed in 380g of 95% ethanol aqueous solution to obtain a coating solution (solid content of 5%). The coating solution was coated onto the tablet core. The rotation speed of the coating pan was set to 3rpm, the atomization pressure to 3bar, the fan pressure to 3bar, the inlet air temperature to 50℃, the outlet air temperature to 40℃, the pump speed to 5rpm, and the tablet bed temperature to 40℃. The coating weight gain was controlled to 20mg / tablet. After coating, the tablet was aged at 35℃ for 3h to obtain a drug formulation containing bisacodyl.

[0036] Example 3 This embodiment provides a pharmaceutical formulation containing bisacodyl, comprising a tablet core and a coating film encapsulating the tablet core; the tablet core comprises 5 mg of bisacodyl, 35 mg of lactose monohydrate, 12 mg of bentonite, and 1 mg of magnesium stearate, and the coating film comprises 8 mg of acrylic resin S100, 6 mg of N-trimethyl chitosan, 2 mg of polyethylene glycol 6000, and 4 mg of talc.

[0037] This embodiment also provides a method for preparing the above-mentioned drug formulation containing bisacodyl, including the following steps: (1) Weigh out the above weights of bisacodyl, lactose monohydrate, and bentonite and premix them in a wet granulator at a speed of 300 rpm for 10 min. Then add 40 mg of water and continue granulating at a mixing speed of 100 rpm and a cutting speed of 1200 rpm for 80 s. Dry the obtained wet granules in a fluidized bed with the fan frequency set to 25 Hz, the inlet air temperature to 70 ℃, the outlet air temperature to 45 ℃, and the material temperature to 45 ℃. Control the drying loss to within 3% to obtain dry granules. Continue mixing the above weights of magnesium stearate and dry granules at a speed of 15 rpm for 3 min. Then compress the obtained granules into tablets to obtain tablet cores. (2) The above weight of acrylic resin S100, N-trimethyl chitosan, polyethylene glycol 6000 and talc powder were dispersed in 230g of 95% ethanol aqueous solution to obtain a coating solution (solid content of 8%). The coating solution was coated onto the tablet core. The rotation speed of the coating pan was set to 20rpm, the atomization pressure to 2bar, the fan pressure to 2bar, the inlet air temperature to 70℃, the outlet air temperature to 30℃, the pump speed to 15rpm, and the tablet bed temperature to 30℃. The coating weight gain was controlled to 20mg / tablet. After coating, the tablet was aged at 45℃ for 1h to obtain a drug preparation containing bisacodyl.

[0038] Example 4 This embodiment provides a pharmaceutical preparation containing bisacodyl and its preparation method, which is basically the same as that in Example 1, except that the mass of N-trimethyl chitosan is adjusted to 3 mg.

[0039] Example 5 This embodiment provides a pharmaceutical preparation containing bisacodyl and its preparation method, which is basically the same as that in Example 1, except that the mass of N-trimethyl chitosan is adjusted to 9 mg.

[0040] Comparative Example 1 This comparative example provides a pharmaceutical preparation containing bisacodyl and its preparation method, which is basically the same as that in Example 1, except that bentonite is omitted.

[0041] Comparative Example 2 This comparative example provides a pharmaceutical preparation containing bisacodyl and its preparation method, which is basically the same as that in Example 1, except that N-trimethyl chitosan is omitted.

[0042] Comparative Example 3 This comparative example provides a pharmaceutical preparation containing bisacodyl and its preparation method, which is basically the same as that in Example 1, except that bentonite and N-trimethyl chitosan are omitted.

[0043] Comparative Example 4 This comparative example provides a pharmaceutical preparation containing bisacodyl and its preparation method, which is basically the same as that in Example 1, except that bentonite is replaced with an equal mass of calcium silicate.

[0044] Comparative Example 5 This comparative example provides a pharmaceutical preparation containing bisacodyl and its preparation method, which is basically the same as that in Example 1, except that N-trimethyl chitosan is replaced with an equal mass of chitosan.

[0045] Comparative Example 6 This comparative example provides a pharmaceutical preparation containing bisacodyl and its preparation method, which is basically the same as that in Example 1, except that the amount of bentonite is adjusted to 5 mg and the amount of N-trimethyl chitosan is adjusted to 1.5 mg.

[0046] Comparative Example 7 This comparative example provides a pharmaceutical preparation containing bisacodyl and its preparation method, which is basically the same as that in Example 1, except that the amount of bentonite is adjusted to 12.5 mg and the amount of N-trimethyl chitosan is adjusted to 13 mg.

[0047] Experimental Example 1 1. Test conditions (1) Solution preparation: Hydrochloric acid solution with pH 1.0: Take 9 mL of hydrochloric acid and dilute it with water to 1000 mL.

[0048] pH 7.5 phosphate buffer: Take 8.9g of disodium hydrogen phosphate dihydrate, add 10g of sodium dodecyl sulfate, add 800mL of water to dissolve it, adjust the pH to 7.5±0.05 with hydrochloric acid solution of pH 1.0, and add water to 1000mL.

[0049] (2) Test method: The dissolution and release determination method of the Chinese Pharmacopoeia 2020 edition, Part IV was used for the test. First, the drug preparation samples of each example and comparative example were placed in 500 mL of hydrochloric acid solution with pH 1.0 and subjected to acid resistance for 2 h at a speed of 100 rpm using the basket method. Then, the samples were transferred to 900 mL of phosphate buffer solution with pH 7.5 and subjected to dissolution test at a speed of 100 rpm using the slurry method. 10 mL of dissolution solution was taken for testing at 20 min and 30 min after transfer. The taken dissolution solution was filtered through a 0.22 μm filter membrane and detected by high performance liquid chromatography to obtain the dissolution rate. Bisacodyl enteric-coated tablets (purchased from Opella Healthcare France SAS, specification 5 mg) were used as reference reagent in the test, and 12 replicates were set up for each sample.

[0050] (3) Chromatographic conditions: Welch Xtimate C18 4.6×100mm, 5μm; the mobile phase was prepared by mixing 350mL of ammonium acetate solution (1000mL of 0.1% ammonium acetate aqueous solution was taken and the pH was adjusted to 8.0 with dilute ammonia) with 650mL of acetonitrile; the flow rate was 0.5mL / min; the column temperature was 25℃; the injection volume was 70μL; the detection wavelength was 230nm; and isocratic elution was performed.

[0051] 2. Test Results Table 1. Dissolution rate (%) of the pharmaceutical formulations in each example and comparative example at 20 min.

[0052] Table 2 Dissolution rate (%) of the pharmaceutical formulations in each example and comparative example at 30 min

[0053] As shown in Tables 1 and 2, the dissolution RSDs of the drug formulations in Examples 1-5 provided by the present invention at 20 min and 30 min are significantly lower than those in Comparative Examples 1-7. This indicates that the combined action of bisacodyl, bentonite and N-trimethyl chitosan can improve the drug release uniformity of bisacodyl-containing drug formulations and achieve precise control of drug release in the colon.

[0054] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A pharmaceutical preparation containing bisacodyl, characterized in that, Includes the wafer core and the coating film that encapsulates the wafer core; By weight, the core comprises 4-6 parts bisacodyl, 30-40 parts filler, 6-12 parts bentonite, and 0.5-2 parts lubricant; By weight, the coating film comprises 6-10 parts of enteric material, 3-9 parts of N-trimethyl chitosan, 1-3 parts of plasticizer, and 2-6 parts of anti-adhesion agent.

2. The pharmaceutical preparation containing bisacodyl according to claim 1, characterized in that, The coating weight gain of the pharmaceutical preparation is 30-50%; And / or, the mass ratio of the bentonite to N-trimethyl chitosan is 1-3:

1.

3. The pharmaceutical preparation containing bisacodyl according to claim 1 or 2, characterized in that, The filler includes at least one of lactose monohydrate, starch, and microcrystalline cellulose 101; And / or, the lubricant includes at least one of magnesium stearate and stearic acid; And / or, the enteric material includes acrylic resin; And / or, the plasticizer includes at least one of polyethylene glycol and triethyl citrate; And / or, the anti-adhesive includes at least one of talc and glyceryl monostearate.

4. The method for preparing a pharmaceutical preparation containing bisacodyl according to any one of claims 1-3, characterized in that, Includes the following steps: Step S1: Bisacodyl, filler and water are first mixed, granulated, lubricant is added for second mixing, tableting is performed to obtain tablet cores; Step S2: Disperse the enteric material, N-trimethyl chitosan, plasticizer, and anti-adhesive in a solvent to obtain a coating solution. Coat the tablet core with the coating solution to obtain a pharmaceutical formulation containing bisacodyl.

5. The method for preparing a bisacodyl-containing pharmaceutical formulation according to claim 4, characterized in that, The mass ratio of water to the total mass of bisacodyl and lactose monohydrate is 1:0.8-1.3; And / or, the solvent comprises an aqueous solution of ethanol with a mass fraction of 90-96%; And / or, the solid content of the coating solution is 5-8%.

6. The method for preparing a bisacodyl-containing pharmaceutical formulation according to claim 4, characterized in that, The first mixing speed is 100-300 rpm, and the time is 5-15 min; And / or, the granulation mixing speed is 100-300 rpm, the cutting speed is 1100-1300 rpm, and the time is 80-100 s; And / or, the granulation process further includes a drying step; Optionally, the drying method includes fluidized bed drying; more preferably, the fan frequency of the fluidized bed dryer is 15-25Hz, the inlet air temperature is 50-70℃, the outlet air temperature is 35-45℃, and the material temperature is 35-45℃.

7. The method for preparing a bisacodyl-containing pharmaceutical formulation according to claim 4, characterized in that, The second mixing speed is 10-15 rpm, and the time is 3-10 min.

8. The method for preparing a pharmaceutical formulation containing bisacodyl according to claim 4, characterized in that, The coating speed is 3-20 rpm, the atomization pressure is 2-3 bar, the fan pressure is 2-3 bar, the inlet air temperature is 50-70℃, the outlet air temperature is 30-40℃, the pump speed is 5-15 rpm, and the tablet bed temperature is 30-40℃.

9. The method for preparing a pharmaceutical formulation containing bisacodyl according to claim 4, characterized in that, The coating process further includes an aging step; optionally, the aging temperature is 35-45℃ and the time is 1-3 hours.

10. The use of the bisacodyl-containing pharmaceutical preparation according to any one of claims 1-3 or the bisacodyl-containing pharmaceutical preparation prepared by the preparation method according to any one of claims 4-9 in the preparation of a medicament for treating constipation.

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