A polaprezinc orally disintegrating tablet and a preparation method thereof

Abstract

The application discloses a kind of poly- zinc oral disintegrating tablets, belong to the technical field of pharmaceutical preparation.The tablet is with poly- zinc as active pharmaceutical ingredient, only compatibility mannitol as filler, low substitution hydroxypropyl cellulose and crosslinked polyvinylpyrrolidone as composite disintegrating agent, hydroxypropyl cellulose as binder, silicon dioxide as glidant, magnesium stearate as lubricant, formula system is simple, different from existing similar preparation, without adding microcrystalline cellulose and any flavoring agent.The application overcomes the defects of slow disintegration, dissolution lag, redundant excipient and poor process stability of existing poly- zinc preparation by optimizing the exclusive no-addition excipient compound system.The obtained oral disintegrating tablet can be quickly disintegrated in oral cavity, and the disintegration time is controlled within 30 seconds.The drug dissolution rate is excellent.Under the premise of simplifying excipient and avoiding the interference of additional additives, the tablet has excellent preparation forming property, stable production process and reliable product quality, and is suitable for rapid drug delivery treatment of gastrointestinal mucosa damage related diseases.

Description

Technical Field

[0001] This invention relates to pharmaceutical compositions containing polyprezed zinc and their preparation methods, belonging to the field of pharmaceutical technology. Background Technology

[0002] Against the backdrop of rapid social development and lifestyle changes (such as psychological stress and changes in dietary behavior), the incidence of diseases related to gastrointestinal mucosal alterations is on the rise. Polyprezinc, a gastric mucosal protectant, specifically adheres to sites of gastric mucosal injury, promotes cell proliferation in regenerating mucosa, and increases hydroxyproline content at ulcer sites, demonstrating a wound-healing effect. It can prevent the formation of acute injuries in rat models of gastric and duodenal ulcers and has a healing effect on chronic gastric ulcers in rat models.

[0003] PromacD zinc orally disintegrating tablets were developed by Zelia Pharmaceutical Co., Ltd. of Japan and launched in Japan in 2006 under the brand name "PromacD". The excipients described in its instructions and other public documents are mannitol, microcrystalline cellulose, hydroxypropyl cellulose, crospovidone, low-substituted hydroxypropyl cellulose, light anhydrous silica, sucralose, magnesium stearate, powdered reduced maltose syrup, L-menthol, and flavoring.

[0004] CN 107865827 B discloses a zinc polypreparative oral disintegrating tablet containing 20-40% zinc polypreparative, 20-60% water-soluble filler, a mixture of microcrystalline cellulose and low-substituted hydroxypropyl cellulose as disintegrant, and talc as lubricant, which can disintegrate rapidly.

[0005] Orally disintegrating tablets refer to tablets that can rapidly disintegrate or dissolve in the oral cavity without the need for water. They should disintegrate or dissolve rapidly in the oral cavity, have a good taste, be easy to swallow, and be non-irritating to the oral mucosa. The Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0921, Disintegration Time Limit Test Method, specifies the apparatus, method, and limits for determining the disintegration time limit of orally disintegrating tablets: Six tablets should be repeatedly tested in the specified apparatus, and all should meet the requirements (they should completely disintegrate and pass through the sieve within 60 seconds; if a small amount of light matter floats to the top or adheres to the inner wall of the stainless steel tube or the sieve, but there is no hard core, it can be considered as meeting the requirements). A study on PromacD (trade name: "PromacD"), a zinc orally disintegrating tablet produced by Zelia Pharmaceutical Co., Ltd. of Japan, found that, according to the above-mentioned Chinese Pharmacopoeia method, the time for the entire sample to disintegrate and pass through the sieve was approximately 60 seconds. Furthermore, in both accelerated testing (temperature 40±2℃, relative humidity 75%±5%) and long-term testing (temperature 30℃±2℃, relative humidity 65%±5%) over 3 months, the time for the entire sample to disintegrate and pass through the sieve exceeded 60 seconds. Summary of the Invention

[0006] Orally disintegrating tablets are characterized by their rapid disintegration in the oral cavity without the need for water, making them convenient to take or suitable for patients with difficulty swallowing or who are uncooperative with medication administration. The purpose of this invention is to overcome the shortcomings of existing technologies and provide a polypreparative zinc orally disintegrating tablet that disintegrates rapidly, has a good taste, meets the requirements of the Chinese Pharmacopoeia, and exhibits good stability.

[0007] The solution of this invention is to select a suitable disintegrant to formulate a palatable and rapidly disintegrating polyprednisolone orally disintegrating tablet. The formulation disclosed in the PromacD specification and CN 107865827 B both use microcrystalline cellulose as a disintegrant. Besides its disintegrant properties, microcrystalline cellulose is also a good filler to enhance the compressibility of tablets, but it is unsuitable as an excipient for orally disintegrating tablets because it produces a gritty feel. To improve palatability, this invention does not use microcrystalline cellulose as a disintegrant or filler, but instead uses low-substituted hydroxypropyl cellulose and crospovidone as disintegrants. The optimal weight ratio of these two disintegrants is 2:1 to 3:1.

[0008] The filler and flavoring agent selected in this invention is mannitol, which has a cool and slightly sweet taste. PromacD also uses sucralose, powdered reduced maltose syrup, L-menthol, and flavoring as flavoring agents. Since the optimal storage condition for sucralose is a temperature not exceeding 25°C, and it easily darkens in color when exposed to light and heat, and will produce color spots at room temperature affecting the product's appearance, and since P-prepared zinc orally disintegrating tablets are not for children and do not require increased sweetness, sucralose is not added to the formulation of this invention. Flavorings are commonly used flavoring agents, including esters and aldehydes (such as citral, vanillin, benzaldehyde, decanal, and acetaldehyde). Recent studies have shown that small molecule aldehydes are mutagenic impurities and require strict control. To minimize safety risks, flavorings and other flavoring agents are not added to the formulation.

[0009] The binder used in this invention is hydroxypropyl cellulose, which can be added as a solution during the granulation process. To maximize batch-to-batch repeatability, the hydroxypropyl cellulose binder is mixed directly with the raw materials, and a wetting agent is added during the granulation process.

[0010] The wetting agent used in this invention is an ethanol solution.

[0011] The polyprene zinc orally disintegrating tablets of this invention are composed of polyprene zinc, mannitol as a filler, low-substituted hydroxypropyl cellulose and cross-linked povidone as disintegrants, hydroxypropyl cellulose as a binder, silica as a flow aid, and magnesium stearate as a lubricant. The component content, in weight percentage, is as follows:

[0012] Polyprene Zinc 55-65%

[0013] Mannitol 15-25%

[0014] Low-substituted hydroxypropyl cellulose 6-10%

[0015] 1-5% crospovidone

[0016] Hydroxypropyl cellulose 1-3%

[0017] 1-3% silicon dioxide

[0018] 2-3% magnesium stearate

[0019] The specific preparation method of this invention is as follows: mannitol, low-substituted hydroxypropyl cellulose, crospovidone, and hydroxypropyl cellulose in the prescribed amounts are mixed evenly, and then polypred zinc in the prescribed amounts are added and mixed evenly; a wetting agent is added for granulation, and the mixture is dried at 60°C; the granules are sized to 20 mesh; silica and magnesium stearate are added and mixed evenly; and the mixture is compressed into tablets.

[0020] The advantages of this invention are as follows:

[0021] The first advantage is that it disintegrates quickly, has a good taste, and no gritty feeling, which improves patient compliance with medication.

[0022] The disintegration time of the three batches of products (batch size: 100,000 tablets) and the three batches of PromacD of this invention were determined according to the disintegration time test method of General Chapter 0921 of Part IV of the Chinese Pharmacopoeia 2020. The time for complete disintegration and passing through the sieve is shown in Table 1.

[0023] Table 1 Comparison of the crash time of this invention and PromacD

[0024]

[0025] The second advantage is rapid dissolution, allowing the medication to take effect quickly after administration.

[0026] The dissolution curves of three batches of products (batch size: 100,000 tablets) of this invention were studied using pH 1.2 hydrochloric acid solution, acetate buffer (pH 4.0), and pH 6.8 phosphate buffer as dissolution media. The average dissolution amount after 15 minutes was not less than 85%.

[0027] Dissolution curve determination method:

[0028] Test method: Dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II).

[0029] Instruments: Dissolution apparatus, high performance liquid chromatograph, analytical balance.

[0030] Dissolution medium:

[0031] ① pH 1.2 hydrochloric acid solution (take 7.65 ml of hydrochloric acid and dilute with water to 1000 ml); 900 ml.

[0032] ② pH 4.0 acetate buffer [Take 1.22g of sodium acetate, add 20.5ml of 2mol / L acetic acid solution [Take 120.0g (114ml) of glacial acetic acid, dilute with water to 1000ml, shake well], dissolve in water and dilute to 1000ml, shake well]; 900ml.

[0033] ③ pH 6.8 phosphate buffer [Mix 250ml of 0.2mol / L potassium dihydrogen phosphate solution (dissolve 27.22g of potassium dihydrogen phosphate in water and dilute to 1000ml) with 112ml of 0.2mol / L sodium hydroxide solution (dissolve 8.00g of sodium hydroxide in water and dilute to 1000ml), dilute to 1000ml with water and shake well]; 900ml.

[0034] Rotation speed: 50 revolutions per minute.

[0035] Sampling times: 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 45 minutes. Immediately after sampling at each time point, replenish the leaching medium with the same temperature and volume.

[0036] Quantitative method: High performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0037] Chromatographic conditions:

[0038] Column: Waters XTerra MS C 18 , 4.6mm×50mm, 3.5µm;

[0039] Mobile phase: Potassium dihydrogen phosphate buffer (dissolve 1.4g of potassium dihydrogen phosphate in 1000ml of water, adjust the pH to 3.5 with 1% dilute phosphoric acid. Dissolve 2g of sodium octane sulfonate in 900ml of the buffer) - acetonitrile (90:10);

[0040] Detection wavelength: 210 nm;

[0041] Flow rate: 1 ml / min;

[0042] Column temperature: 45℃;

[0043] Injection volume: 10µl.

[0044] Solution preparation:

[0045] pH 1.2 hydrochloric acid solution and acetate buffer (pH 4.0) medium test solution: Take 10 ml of the dissolution solution, filter it through a 0.45 µm filter membrane, and collect the filtrate.

[0046] pH 6.8 phosphate buffer solution: Take 10 ml of the dissolution solution, filter it through a 0.45 µm filter membrane, accurately measure 5 ml of the filtrate, place it in a 10 ml volumetric flask, add 1 ml of 0.2 mol / L hydrochloric acid solution, dilute to the mark with dissolution medium, and shake well.

[0047] pH 1.2 hydrochloric acid solution reference solution: Weigh approximately 13 mg of L-carnosine reference standard accurately, place it in a 10 ml volumetric flask, add water to dissolve and dilute to the mark, accurately measure 5 ml, place it in a 100 ml volumetric flask, add dissolution medium to dilute to the mark, and shake well.

[0048] pH 6.8 medium for reference solution: Weigh approximately 13 mg of L-carnosine reference standard accurately, place it in a 200 ml volumetric flask, add water to dissolve and dilute to the mark, accurately measure 5 ml, place it in a 10 ml volumetric flask, add 1 ml of 0.2 mol / L hydrochloric acid solution, add dissolution medium to dilute to the mark, and shake well.

[0049] Assay: Accurately inject 10 μl of each of the test solution and the reference solution into the liquid chromatograph, record the chromatogram, and calculate the dissolution amount and cumulative dissolution amount per tablet by peak area using the external standard method.

[0050] Measurement results: see Table 2.

[0051] Table 2 Dissolution curves under different dissolution conditions of the present invention

[0052]

[0053] The third advantage is good batch uniformity, indicating good process repeatability.

[0054] As can be seen from Table 2, the RSD of the dissolution results at the first sampling time point of the dissolution curves of the three batches of products of this invention does not exceed 20%, and the RSD of the dissolution results at the remaining time points does not exceed 10%, which meets the requirements of the "Guiding Principles for Determination and Comparison of Dissolution Curves of Ordinary Oral Solid Dosage Forms" and shows good batch-to-batch uniformity.

[0055] The fourth advantage is its stable quality.

[0056] In the accelerated test (temperature 40±2℃, relative humidity 75%±5%) and long-term test (temperature 30℃±2℃, relative humidity 65%±5%) of the three batches of products of this invention (batch size: 100,000 tablets) for 6 months, the disintegration time showed no significant change compared with 0 months, as shown in Table 3.

[0057] Table 3. Results of disintegration time determination in stability tests of this invention.

[0058] Detailed Implementation

[0059] The present invention will be further described below by way of embodiments, providing details of its implementation, but this is not intended to limit the scope of protection of the present invention.

[0060] Example 1: Preparation of Zinc P-P-R-Zinc Orally Disintegrating Tablets (Formulation Example for 1000 Tablets)

[0061] Polyprene Zinc 75g

[0062] Mannitol 20g

[0063] Low-substituted hydroxypropyl cellulose 13g

[0064] 6g of crospovidone

[0065] Hydroxypropyl cellulose 4g

[0066] 4g of silicon dioxide

[0067] 3g magnesium stearate

[0068] Total 125g

[0069] Preparation method:

[0070] Mix mannitol, low-substituted hydroxypropyl cellulose, crospovidone, and hydroxypropyl cellulose in the prescribed amounts, then add the prescribed amount of zinc polyprednisolone and mix well; add a wetting agent to granulate, dry at 60°C; granulate to 20 mesh; add silica and magnesium stearate and mix well; compress into tablets.

[0071] Example 2: Preparation of Polyprezinc Orally Disintegrating Tablets (Formulation Example of 1000 Tablets)

[0072] Polyprene Zinc 75g

[0073] Mannitol 32g

[0074] Low-substituted hydroxypropyl cellulose (added internally) 10g

[0075] Low-substituted hydroxypropyl cellulose (added) 3g

[0076] 5g of crospovidone

[0077] 3g of hydroxypropyl cellulose

[0078] 4g of silicon dioxide

[0079] 4g magnesium stearate

[0080] Total 133g

[0081] Preparation method:

[0082] Mix the prescribed amounts of mannitol, low-substituted hydroxypropyl cellulose (added internally), crospovidone, and hydroxypropyl cellulose evenly, then add the prescribed amount of polypred zinc and mix evenly; add a wetting agent to granulate, dry at 60℃; granulate with a 20-mesh sieve; add low-substituted hydroxypropyl cellulose (added externally), silica, and magnesium stearate and mix evenly; compress into tablets.

[0083] Example 3: Preparation of Polyprezinc Orally Disintegrating Tablets (Formulation Example of 1000 Tablets)

[0084] Polyprene Zinc 75g

[0085] Mannitol 30g

[0086] Low-substituted hydroxypropyl cellulose 12g

[0087] 3g of crospovidone (added internally)

[0088] Cross-linked polyvinylpyrrolidone (added) 3g

[0089] Hydroxypropyl cellulose 4g

[0090] 5g of silicon dioxide

[0091] 3g magnesium stearate

[0092] Total 133g

[0093] Preparation method:

[0094] Mix mannitol, low-substituted hydroxypropyl cellulose, crospovidone (added internally), and hydroxypropyl cellulose in the prescribed amounts, then add the prescribed amount of polypred zinc and mix well; add a wetting agent to granulate, dry at 60℃; granulate to 20 mesh; add crospovidone (added externally), silica, and magnesium stearate and mix well; compress into tablets.

Claims

1. A polyprene zinc orally disintegrating tablet, comprising polyprene zinc, mannitol as a filler, low-substituted hydroxypropyl cellulose and cross-linked povidone as disintegrants, hydroxypropyl cellulose as a binder, silica as a flow aid, and magnesium stearate as a lubricant, characterized in that... Its composition, expressed as a weight percentage, is as follows: Polyprene Zinc 55-65% Mannitol 15-25% Low-substituted hydroxypropyl cellulose 6-10% 1-5% crospovidone Hydroxypropyl cellulose 1-3% 1-3% silicon dioxide Magnesium stearate 2-3%.

2. The polyprene zinc orifice-disintegrating tablet according to claim 1, characterized in that... Low-substituted hydroxypropyl cellulose and crospovidone were used as disintegrants, and the optimal weight ratio of the two disintegrants was 2:1 to 3:

1.

3. The polyprene zinc disintegrating tablet according to claim 1, characterized in that... The preparation method includes the following steps: mixing mannitol, low-substituted hydroxypropyl cellulose, crospovidone, and hydroxypropyl cellulose in the prescribed amounts, then adding the prescribed amount of polypyrene zinc and mixing; adding a wetting agent to granulate, drying at 60°C; granulating with a 20-mesh sieve; adding silica and magnesium stearate and mixing; and tableting.

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