Pharmaceutical preparation of piveronium bromide and preparation process of pharmaceutical preparation

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical preparation of piveronium bromide and a preparation process of the pharmaceutical preparation. According to the preparation composition, the antioxidant vitamin E polyethylene glycol succinate and microcrystalline cellulose colloidal silicon dioxide co-treatment substance is added, so that the high temperature resistance, high humidity resistance and illumination resistance of the piveronium bromide are effectively improved. The light stability is greatly improved, the stability of the tablet is greatly improved, and the dissolution rate is also improved, so that the bioavailability of the medicine is improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a pivamidone bromide pharmaceutical preparation and its preparation process. Background Technology

[0002] Pinaverium bromide was registered as pinaverium bromide by Solvay Pharmaceuticals in 1975 and marketed under the brands Dicetel® and Eldicet®. Used for the treatment of irritable bowel syndrome, it was the first calcium antagonist with a highly selective antispasmodic effect on the gastrointestinal tract. Pinaverium bromide achieves its antispasmodic effect by blocking the inflow of calcium ions into the intestinal wall smooth muscle cells, preventing excessive muscle contraction, eliminating intestinal smooth muscle hyperresponsiveness, and increasing intestinal motility. The structure of pinaverium bromide is as follows: CN200710308440.3 discloses a pinaverium bromide sustained-release tablet, which comprises 150 parts pinaverium bromide, 10-150 parts binder, 10-300 parts sustained-release material, 0-100 parts plasticizer, 0-100 parts anti-adhesive, and 10-500 parts filler. The tablet is prepared with ethanol, and the anti-adhesive is 1% of the weight of ethanol. This invention provides slow drug release, maintaining a relatively stable blood drug concentration and a longer duration of action, resulting in fewer side effects and greater convenience of administration.

[0003] CN200710308441.8 discloses the preparation and application of pinaverium bromide dry suspension, characterized by containing, but not limited to, the following pharmaceutically acceptable excipients: fillers such as sucrose and mannitol; flavoring agents such as sodium chloride, aspartame, and strawberry flavoring; and suspending agents such as carbomer, sodium carboxymethyl cellulose, and sodium carboxymethyl starch. It is used to treat abdominal pain, bowel disorders, and intestinal discomfort associated with irritable bowel syndrome. It is also used for preparation before barium enema.

[0004] CN200810034607.6 discloses a pharmaceutical composition containing pinaverium bromide; Examples 5-10 of the specification disclose the formulations of pinaverium bromide tablets and capsules.

[0005] CN201410322869.8 discloses a pinaverium bromide preparation, in which amorphous pinaverium bromide and a diluent are mixed and sieved to obtain a mixed powder, a lubricant is added to the mixed powder, mixed evenly, tableted, and coated. The excipients are all commonly used pharmaceutical excipients.

[0006] CN202311499011.4 discloses a pinaverium bromide co-treated compound, its preparation method, and a pharmaceutical formulation containing the same. The preparation method involves dissolving pinaverium bromide and vanillin in a mixed solution of dichloromethane and dioxane, followed by drying. In the pinaverium bromide co-treated compound, vanillin and pinaverium bromide form hydrogen bonds, existing in a more stable manner and significantly improving photostability.

[0007] CN202310426277.X relates to a pinaverium bromide composition, formulation, and its use. The pinaverium bromide composition of this invention comprises pinaverium bromide and hexadecyl ester wax, solving the problems of pinaverium bromide's instability and easy decomposition upon exposure to light and heat. Furthermore, it provides a pinaverium bromide formulation prepared from the pinaverium bromide composition and pharmaceutically acceptable excipients, which exhibits superior light and heat stability compared to commercially available formulations.

[0008] CN202311548846.4 discloses a pinaverium bromide tablet and its preparation method. The exemestane tablet comprises the following components by weight percentage: 35-41% pinaverium bromide, 0.1-0.5% magnesium stearate, 1.2-2.0% pregelatinized starch, 1.4-2.6% carnauba wax, 2.5-4.4% micronized silica gel, 0.4-0.8% modified kaolinite, 0.2-0.5% hexadecyl ester wax, 7.5-10.4% filler, 10.3-11.5% binder, and the balance being a sustained-release material. The sustained-release material is selected from one or more of polyacrylic acid resin IV, hydroxypropyl methylcellulose K4M, dibutyl sebacate, and trimethylaminoethyl methacrylate. The filler is selected from microcrystalline cellulose and / or sodium alginate. The pinaverium bromide tablet of this invention has a good sustained-release effect, reduces gastric irritation, improves the stability of the pinaverium bromide tablet, and enhances its efficacy in treating gastrointestinal diseases.

[0009] CN202311709762.4 discloses a pharmaceutical composition containing pinaverium bromide, its preparation method, and a pharmaceutical formulation comprising the same. The pharmaceutical composition containing pinaverium bromide includes pinaverium bromide, and further includes one or two of lanolin and aluminum silicate. In this invention, coating pinaverium bromide with lanolin or aluminum silicate improves the stability of the prepared pharmaceutical composition containing pinaverium bromide; furthermore, co-coating pinaverium bromide with lanolin and aluminum silicate significantly improves the stability of the prepared pharmaceutical composition.

[0010] CN202411707505.1 relates to a composition, preparation process, and uses of pinaverium bromide and Rosa laevigata extract. The tablets comprise pinaverium bromide, Rosa laevigata extract, disintegrant, lubricant, and filler. Pharmacological experiments in rats have shown that the tablets have a significant therapeutic effect on diarrhea-predominant irritable bowel syndrome, completely dissolve within 15 minutes, and have low levels of related substances, exceeding pharmacopoeia requirements, making them suitable for further industrial-scale production. This invention solves the problem of instability of the active ingredient in pinaverium bromide during storage and its easy decomposition upon exposure to light and heat.

[0011] JPH0344325A discloses the formulas for pinaverium bromide tablets and capsules.

[0012] MX2015003956A relates to a pharmaceutical composition comprising micronized pinaverium bromide and dimethicone in a soft gelatin capsule, plus a pharmaceutically acceptable carrier or excipient; and the use of said composition in the preparation of a medicament for the prevention and / or treatment of irritable bowel syndrome (IBS).

[0013] MX2024014727A relates to a dual-capsule complex pharmaceutical composition comprising pinaverium bromide, dimethyl silicone oil, and Bacillus cladominis for the comprehensive treatment of gastrointestinal disorders. This formulation is characterized by a hard capsule containing immediate-release granules of pinaverium bromide and dimethyl silicone oil, and an inner capsule containing acid-resistant Bacillus cladominis. The combination of these three components provides an innovative solution for effectively relieving various gastrointestinal symptoms, thereby improving patients' quality of life.

[0014] Pinaverium bromide is unstable and easily decomposes when exposed to light and heat. Therefore, the packaging and storage conditions for pinaverium bromide preparations are quite stringent, requiring protection from light and low temperatures. The existing technologies described above have addressed the issues of pinaverium bromide's instability and easy decomposition when exposed to light and heat to some extent. However, practical results have not been significant. Summary of the Invention

[0015] In view of the problems existing in the prior art, the present invention provides a pharmaceutical formulation of pinaverium bromide and its preparation process. The tablet composition of the present invention solves the problems of pinaverium bromide's instability and easy decomposition upon exposure to light and heat. The preparation method disclosed in the present invention is simple and suitable for industrial production.

[0016] Pinaverium bromide is unstable and easily decomposes when exposed to light and heat. During formulation, the inventors attempted to add the antioxidant vitamin E polyethylene glycol succinate; however, investigations revealed that the stability effect was not significant, especially under high temperature and high humidity conditions. Further investigations showed that adding colloidal silica to the vitamin E polyethylene glycol succinate granulation process resulted in even worse stability. Finally, the inventors experimented with granulation using a co-treated product of vitamin E polyethylene glycol succinate and microcrystalline cellulose colloidal silica with the active ingredient pinaverium bromide. Stability studies showed a significant improvement in stability under high temperature, high humidity, and light conditions.

[0017] Specifically, the present invention is achieved through the following technical solution: A pinaverium bromide tablet composition comprising pinaverium bromide, vitamin E polyethylene glycol succinate, microcrystalline cellulose colloidal silica co-treated material, and other pharmaceutically acceptable fillers, binders, disintegrants, and lubricants.

[0018] Preferably, in the tablet composition of pinaverium bromide, the mass ratio of pinaverium bromide to vitamin E polyethylene glycol succinate and microcrystalline cellulose colloidal silica co-treated material is 1:0.1-0.3:0.4-0.8; more preferably 1:0.25:0.6.

[0019] Preferably, the filler is selected from one or more of starch, mannitol, lactose, and microcrystalline cellulose. Lactose is further preferred.

[0020] Preferably, the adhesive is selected from one or more of water, pregelatinized starch, methylcellulose, and ethylcellulose. Pregelatinized starch is more preferred.

[0021] Preferably, the disintegrant is selected from one or more of dry starch, sodium carboxymethyl starch, sodium croscarmellose, and hydroxypropyl methylcellulose. Hydroxypropyl methylcellulose is further preferred.

[0022] Preferably, the lubricant is selected from one or more of magnesium stearate, silicon dioxide, and sodium fumarate stearate. Magnesium stearate is further preferred.

[0023] In a preferred embodiment, the pinaverium bromide tablets are composed of the following components: .

[0024] In one specific embodiment, the pinaverium bromide tablets are composed of the following components: .

[0025] Another object of the present invention is to provide a method for preparing the above-mentioned pinaverium bromide tablets, which mainly includes the following steps: a) Dissolve the prescribed amount of vitamin E polyethylene glycol succinate in a 90-95% ethanol aqueous solution for later use; b) Mix the prescribed amount of pinaverium bromide and microcrystalline cellulose colloidal silica co-treated material, then granulate the mixture using the solution from step a), dry it, and granulate it. c) Add filler, binder, disintegrant, and lubricant to the granules obtained in b) and mix thoroughly; d) Compress the mixture obtained in c) into tablets; or further coat and dry to obtain the final product.

[0026] The tablets provided by this invention can be film coated if necessary.

[0027] The preferred coating material is Opadry II coating or film coating Orange 2 (methyl butyl acrylate copolymer, sodium dodecyl sulfate, hydroxypropyl methylcellulose, iron oxide yellow, and iron oxide red), with a coating weight gain of 3.0%.

[0028] Compared with the prior art, the present invention achieves the following technical effects: The pinaverium bromide tablets prepared by this invention effectively improve the high-temperature, high-humidity, and light-exposure resistance of pinaverium bromide through the addition of the antioxidant vitamin E polyethylene glycol succinate and a microcrystalline cellulose colloidal silica co-treated product. This significantly improves photostability, resulting in greatly enhanced tablet stability and improved dissolution, thereby increasing the bioavailability of the drug. The tablet preparation process is simple and suitable for industrial production. Detailed Implementation

[0029] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely provided for illustrative purposes and are not intended to limit the present invention. Therefore, any simple modifications to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.

[0030] The parameters or operations not detailed in this invention are those commonly understood or performed by those skilled in the art.

[0031] Example 1 Make 10,000 pieces Preparation process: a) Dissolve the prescribed amount of vitamin E polyethylene glycol succinate in a 90-95% ethanol aqueous solution for later use; b) Mix the prescribed amount of pinaverium bromide and microcrystalline cellulose colloidal silica co-treated material, then granulate the mixture using the solution from step a), dry it, and granulate it. c) Add lactose, pregelatinized starch, hydroxypropyl methylcellulose, and magnesium stearate to the granules obtained in b) and mix well; d) Compress the mixture obtained in c) into tablets to obtain the final product.

[0032] Example 2 Make 10,000 pieces Preparation process: Same as in Example 1.

[0033] Example 3 Make 10,000 pieces Preparation process: Same as in Example 1.

[0034] Example 4 Make 10,000 pieces Preparation process: Same as in Example 1.

[0035] Example 5 Make 10,000 pieces Preparation process: Same as in Example 1.

[0036] Example 6 Make 10,000 pieces Preparation process: Same as in Example 1.

[0037] Example 7 Make 10,000 pieces Preparation process: Same as in Example 1.

[0038] Example 8 Make 10,000 pieces Preparation process: Same as in Example 1.

[0039] Example 9 Make 10,000 pieces Preparation process: Same as in Example 1.

[0040] Example 10 Make 10,000 pieces Preparation process: Same as in Example 1.

[0041] Comparative Example 1 Make 10,000 pieces Preparation process: a) Prepare a 90-95% ethanol aqueous solution for later use; b) Mix the prescribed amount of pinaverium bromide and microcrystalline cellulose colloidal silica co-treated material, then granulate the mixture using the solution from step a), dry it, and granulate it. c) Add lactose, pregelatinized starch, hydroxypropyl methylcellulose, and magnesium stearate to the granules obtained in b) and mix well; d) Compress the mixture obtained in c) into tablets to obtain the final product.

[0042] Comparative Example 2 Make 10,000 pieces Preparation process: a) Dissolve the prescribed amount of vitamin E polyethylene glycol succinate in a 90-95% ethanol aqueous solution for later use; b) Add the prescribed amount of pinaverium bromide to a granulator and granulate using the solution from step a), then dry and granulate. c) Add lactose, pregelatinized starch, hydroxypropyl methylcellulose, and magnesium stearate to the granules obtained in b) and mix well; d) Compress the mixture obtained in c) into tablets to obtain the final product.

[0043] Comparative Example 3 Make 10,000 pieces Preparation process: a) Dissolve the prescribed amount of vitamin E polyethylene glycol succinate in a 90-95% ethanol aqueous solution for later use; b) Mix the prescribed amounts of pinaverium bromide, microcrystalline cellulose, and colloidal silica, then granulate the mixture using the solution from step a), dry it, and granulate it. c) Add lactose, pregelatinized starch, hydroxypropyl methylcellulose, and magnesium stearate to the granules obtained in b) and mix well; d) Compress the mixture obtained in c) into tablets to obtain the final product.

[0044] Comparative Example 4 Make 10,000 pieces Preparation process: a) Mix the prescribed amounts of pinaverium bromide, vitamin E polyethylene glycol succinate, and microcrystalline cellulose colloidal silica co-treated product; b. Add lactose, pregelatinized starch, hydroxypropyl methylcellulose, and magnesium stearate to the mixture obtained in a), and mix thoroughly. c) Compress the mixture obtained in b into tablets to obtain the final product.

[0045] Verification Example: 1. Stability Study Following the relevant methods in the General Chapters, Part IV of the 2020 edition of the Chinese Pharmacopoeia, the content, related substances, and dissolution of the samples after stability studies were tested.

[0046] Determination of related substances: Refer to high performance liquid chromatography (General Chapter 0512 of the Chinese Pharmacopoeia). Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase, acetonitrile-sodium dodecyl sulfate buffer (70:30) was used as the mobile phase, the detection wavelength was 245 nm, the column temperature was 25 ℃, the flow rate was 1.0 mL / min, and the injection volume was 20 μL.

[0047] Preparation method of sodium dodecyl sulfate buffer: Take 13.0g of sodium dodecyl sulfate, dissolve it in 1500mL of water, add 5.0mL of phosphoric acid, mix well, adjust the pH to 2.5 with triethylamine, and filter to obtain the buffer.

[0048] Content determination: An Agilent Extend-C18 column (4.6 mm × 250 mm, 5 μm) was used. The mobile phase was methanol-citric acid buffer (5.83 g of trisodium citrate trihydrate was dissolved in 900 mL of water, the pH of the solution was adjusted to 5.0 with 1.0 mol / L citric acid solution, and then diluted to 1000 mL with water) (70:30). The detection wavelength was 285 nm, the flow rate was 1.0 mL / min, the injection volume was 20 μL, and the theoretical plate number calculated based on the pinaverium bromide peak should not be less than 1500.

[0049] High temperature conditions: 60℃; High temperature and high humidity conditions: 60℃, relative humidity 92%; Light intensity: (4500±500lx).

[0050] Table 1-1 Observation Results Table 1-2 Observation Results Table 1-3 Observation Results Table 1-4 Observation Results Table 1-5 Observation Results Table 2-1 Results of Accelerated Stability Study Stability testing conditions: 40℃±2℃, 75%RH±5%, accelerated for 6 months.

[0051] Table 2-2 Results of Accelerated Stability Study Stability testing conditions: 40℃±2℃, 75%RH±5%, accelerated for 6 months.

[0052] The stability test results in Tables 1-1-5, 2-1, and 2-2 show that Comparative Examples 1 and 2, which only used microcrystalline cellulose colloidal silica co-treated material and vitamin E polyethylene glycol succinate, respectively, exhibited poor stability. Comparative Example 3, which used microcrystalline cellulose and colloidal silica instead of the microcrystalline cellulose colloidal silica co-treated material, showed better photostability, but a significant increase in related substances under high temperature and high humidity conditions. Comparative Example 4 used direct compression with a mixture, but the effect was not as good as wet granulation. This may be because wet granulation tightly aggregates the microcrystalline cellulose colloidal silica co-treated material, vitamin E polyethylene glycol succinate, and the main component, making it difficult for light, moisture, and high temperature to degrade the active ingredient. The performance in terms of light resistance and resistance to high temperature and humidity was significantly improved. Furthermore, excessive amounts of microcrystalline cellulose colloidal silica co-treated material and vitamin E polyethylene glycol succinate can increase the hygroscopicity of the tablets, affecting their stability.

[0053] 2 Dissolution test Dissolution tests were performed on the samples after the accelerated 6-month observation period. Dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). Dissolution media were prepared using pH 1.0, hydrochloric acid solution, and phosphate buffer solution (pH 6.8), respectively. The dissolution was performed at 50 rpm, following the prescribed procedure. Samples were taken at 5, 10, 15, and 30 min (with replenishment of the same volume and temperature of dissolution media). Absorbance was measured at 243 nm (calculated as pinaverium bromide) using UV-Vis spectrophotometry (General Chapter 0401). Dissolution results are shown in Tables 3-1 and 3-2 below.

[0054] Table 3-1 Dissolution rate of tablets in each example Table 3-2 Dissolution rate of tablets in each example As can be seen from Tables 3-1 and 3-2, the tablets prepared in the embodiments of the present invention all showed good dissolution effects after 6 months of accelerated testing, which were better than those of commercially available formulations.

Claims

1. A tablet composition of pinaverium bromide, characterized in that, The composition comprises pinaverium bromide, vitamin E polyethylene glycol succinate, microcrystalline cellulose colloidal silicon dioxide co-treatment and other pharmaceutically acceptable fillers, binders, disintegrants, lubricants.

2. The tablet composition of pinaverium bromide according to claim 1, characterized in that, The tablet composition of the pinaverium bromide contains pinaverium bromide, vitamin E polyethylene glycol succinate, microcrystalline cellulose colloidal silicon dioxide co-treatment in a mass ratio of 1:0.1-0.3:0.4-0.8; preferably 1:0.25:0.

6.

3. The tablet composition of pinaverium bromide according to claim 1, characterized in that, The filler is selected from one or more of starch, mannitol, lactose and microcrystalline cellulose; preferably lactose.

4. The tablet composition of pinaverium bromide according to claim 1, characterized in that, The binder is selected from one or more of water, pregelatinized starch, methyl cellulose and ethyl cellulose; preferably pregelatinized starch.

5. The tablet composition of pinaverium bromide according to claim 1, characterized in that, The disintegrant is selected from one or more of dry starch, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose; preferably hydroxypropyl methyl cellulose.

6. The tablet composition of pinaverium bromide according to claim 1, characterized in that, The lubricant is selected from one or more of magnesium stearate, silicon dioxide, sodium stearate fumarate; preferably magnesium stearate.

7. The tablet composition of pinaverium bromide according to claim 1, characterized in that, The pinaverium bromide tablet is composed of the following ingredients: Pinaverium bromide 50 parts Vitamin E polyethylene glycol succinate 5-15 parts Microcrystalline cellulose colloidal silicon dioxide co-treatment 20-40 parts Filler 90-110 parts Binder 10-30 parts Disintegrant 10-15 parts Lubricant 1-2 parts.

8. A method for preparing a tablet composition of pinaverium bromide according to any one of 1-7, characterized in that, The process comprises the following steps: a) Dissolve the prescribed amount of vitamin E polyethylene glycol succinate in 90-95% aqueous ethanol solution for use; b) Mix the prescribed amount of pinaverium bromide and microcrystalline cellulose colloidal silicon dioxide co-treatment, then granulate with the solution of step a), dry and size; c) Add the filler, binder, disintegrant and lubricant to the granules obtained in b) and mix well; d) Press the mixture obtained in c) into tablets, or further coat, dry and obtain the product.

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