A gastroenteric prokinetic tablet and a method for preparing the same

Abstract

The application discloses a gastrointestinal prokinetic tablet, characterized in that the tablet comprises the following components in percentage by weight: 0.91% of senagiline citrate, 60.00-70.00% of anhydrous lactose, 22.00-33.00% of microcrystalline cellulose, 3.20-4.80% of sodium carboxymethyl starch, 0.15-0.50% of silicon dioxide, and 1.10-1.50% of magnesium stearate, wherein the particle size D90 of the senagiline citrate is less than or equal to 20 microns; the total percentage of the anhydrous lactose and the microcrystalline cellulose is 92.00-93.00%; the total percentage of the silicon dioxide and the magnesium stearate is 1.20-1.80%; and the particle size D90 of the senagiline citrate is less than or equal to 15 microns. The senagiline citrate tablet provided by the application has higher stability, more similar dissolution performance to a reference preparation, and consistent bioequivalence with the reference preparation.

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical technology and relates to a gastrointestinal prokinetic tablet, specifically a Cinipride tartrate tablet and a preparation method thereof. Background Art

[0002] Prokinetic drugs are effective treatments for gastrointestinal disorders such as functional dyspepsia (FD) and gastroesophageal reflux disease (GERD), but relatively effective and safe drugs are currently limited. Cinipride tartrate (Cinipride) is a prokinetic drug launched in my country in 2015. It is a serotonin receptor agonist primarily used to treat mild to moderate FD. Multiple clinical trials have shown that Cinipride is more effective than metoclopramide and domperidone in the treatment of gastrointestinal disorders, FD, and GERD, and has a good safety profile. Cinipride is metabolized in the liver not only by cytochrome P450 (CYP) 3A4 but also by CYP2C8, minimizing the risk of drug interactions. Furthermore, the free plasma concentration of Cinipride is much lower than that of cisapride and domperidone, resulting in a lower risk of cardiotoxicity. Cinipride is a new treatment option for FD and GERD.

[0003] This is a gastrointestinal prokinetic agent discovered by Almirall, SA. Under the terms of a license agreement signed with Almirall in March 2010, Eisai acquired exclusive rights from Almirall for development, manufacturing, and sales in China. Eisai has received approval in China for the treatment of early satiety, postprandial fullness, and bloating in mild to moderate functional dyspepsia.

[0004] In US5026858A (Example 26) and CN1022830C (Example 4), a prescription for preparing Cinipride tartrate tablets is provided. The prescription compositions of the above documents are consistent, and the prescription amounts of the excipients are slightly different. The inventors found that the Cinipride tartrate tablets prepared according to the above documents were inferior to those of The stability of the reference preparation itself needs to be improved. Summary of the Invention

[0005] The present application provides a Cinipride tartrate tablet, which has higher stability, a dissolution performance that is more similar to a reference preparation, and a bioequivalence that is consistent with the reference preparation.

[0006] The present application provides a cipride tartrate tablet, which comprises, by weight percentage: 0.91% cipride tartrate, 60.00-70.00% anhydrous lactose, 22.00-33.00% microcrystalline cellulose, 3.20-4.80% sodium starch glycolate, 0.15-0.50% silicon dioxide, and 1.10-1.50% magnesium stearate. The particle size D90 of the cipride tartrate is ≦20 μm.

[0007] Preferably, the total proportion of the anhydrous lactose and microcrystalline cellulose is 92.00-93.00%.

[0008] Preferably, the total proportion of silicon dioxide and magnesium stearate is 1.20-1.80%.

[0009] Preferably, the particle size D90 of the cispride tartrate is ≦15 μm.

[0010] Preferably, the total proportion of the anhydrous lactose and microcrystalline cellulose is 92.76%,

[0011] Preferably, the total proportion of silicon dioxide and magnesium stearate is 1.66%.

[0012] Preferably, the above-mentioned Cinipride tartrate tablets comprise, by weight percentage, 0.91% Cinipride tartrate, 66.09% anhydrous lactose, 26.67% microcrystalline cellulose, 4.67% sodium starch glycolate, 0.33% silicon dioxide, and 1.33% magnesium stearate.

[0013] Preferably, the particle size D90 of the cispride tartrate is ≦15 μm.

[0014] Preferably, the particle size D90 of the Cinipride tartrate is 15 μm.

[0015] The preparation method of the above-mentioned Cinipride tartrate tablets comprises the following steps:

[0016] 1) Pretreatment of raw materials and excipients: Cinipride tartrate is ground to a particle size D90 ≤ 20 μm, anhydrous lactose is passed through a 30-50 mesh sieve, and magnesium stearate is passed through a 50-70 mesh sieve;

[0017] 2) Premixing: mixing anhydrous lactose, cinipride tartrate, sodium starch glycolate, and microcrystalline cellulose to obtain a premixed material;

[0018] 3) Sieving: Grinding, granulating, and sieving the silicon dioxide, magnesium stearate, and premixed materials to obtain a sieved material;

[0019] 4) Total mixing: After sieving, the materials are mixed again, and the mixing speed is set to 5-10 rpm and the mixing time is 5-10 min;

[0020] 5) Tablet compression: Theoretical tablet weight is 150 mg, tablet hardness is controlled to 40-70N, and friability does not exceed 0.5-1.5%.

[0021] Beneficial effects:

[0022] Microcrystalline cellulose is hygroscopic and may affect tablet stability in high-humidity environments. Anhydrous lactose, on the other hand, does not contain water of crystallization and is more suitable for formulations of water-sensitive drugs. Therefore, adjusting the dosage ratio of the two can balance the tablet's hygroscopicity and stability. The dosage of magnesium stearate and silicon dioxide can also affect the drug's solubility, stability, and bioavailability. The size of the raw material particle size can affect tablet dissolution, stability, and long-term stability. The inventors, by optimizing the raw material particle size and adjusting the weight composition of crystalline cellulose, anhydrous lactose, silicon dioxide, and magnesium stearate in the excipients, surprisingly found that the resulting Cinipride tartrate tablets exhibited significantly improved stability compared to a reference formulation under accelerated testing conditions of high temperature, high humidity, and light, and exhibited dissolution properties more similar to those of the reference formulation, with consistent bioequivalence. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present application are clearly described below. Obviously, the embodiments described are only part of the embodiments of the present application, not all of them. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present application are within the scope of protection of this application.

[0024] The terms "first," "second," and the like in the specification and claims of this application are used to distinguish similar objects, and are not used to describe a specific order or precedence. It should be understood that the terms used in this manner are interchangeable where appropriate, so that the embodiments of this application can be implemented in an order other than that described herein, and that the objects distinguished by "first," "second," and the like are generally of the same type, and do not limit the number of objects; for example, the first object can be one or more. In addition, the term "and / or" in the specification and claims refers to at least one of the connected objects, and the character " / " generally indicates that the objects connected are in an "or" relationship.

[0025] The present application is not limited to the above-mentioned specific implementation methods, which are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can make many forms without departing from the purpose of the present application and the scope of protection of the claims, all of which are protected by the present application.

[0026] The present application provides a cipride tartrate tablet, which comprises, by weight percentage: 0.91% cipride tartrate, 60.00-70.00% anhydrous lactose, 22.00-33.00% microcrystalline cellulose, 3.20-4.80% sodium starch glycolate, 0.15-0.50% silicon dioxide, and 1.10-1.50% magnesium stearate. The particle size D90 of the cipride tartrate is ≦20 μm. The anhydrous lactose can be any value between 60.00% and 70.00%, which can be 61.00%, 62.00%, 63.00%, 64.00%, 65.00%, 66.00%, 66.09%, 67.00%, 68.00%, 69.00%, or 70.00%; the microcrystalline cellulose can be 22.00%, 23.00%, 24.00%, 25.00%, 26.00%, 26.67%, 27.00%, 28.00%, 29.00%, 30.00%, 31. 00%, 32.00%, 33.00%; the silicon dioxide can be 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%; the magnesium stearate can be 1.10%, 1.15%, 1.20%, 1.25%, 1.30%, 1.35%, 1.40%, 1.45%, 1.50%; the particle size D90 of Cinipride tartrate is ≦20 μm, and its D90 can be 10 μm, 15 μm, 20 μm, but is not limited to the above.

[0027] As a specific embodiment of the present invention, the total proportion of anhydrous lactose and microcrystalline cellulose is 92.76%. It can be: anhydrous lactose accounts for 66.09% and microcrystalline cellulose accounts for 26.67%; anhydrous lactose accounts for 64.00% and microcrystalline cellulose accounts for 28.67%; anhydrous lactose accounts for 62.00% and microcrystalline cellulose accounts for 30.67%; anhydrous lactose accounts for 60.00% and microcrystalline cellulose accounts for 32.67%; anhydrous lactose accounts for 68.00% and microcrystalline cellulose accounts for 24.67%; anhydrous lactose accounts for 70.00% and microcrystalline cellulose accounts for 22.67%, but is not limited to the above.

[0028] As a specific embodiment of the present invention, the total proportion of silicon dioxide and magnesium stearate is 1.66%. It can be: silicon dioxide accounts for 0.33%, magnesium stearate accounts for 1.33%; silicon dioxide accounts for 0.16%, magnesium stearate accounts for 1.50%; silicon dioxide accounts for 0.20%, magnesium stearate accounts for 1.46%; silicon dioxide accounts for 0.25%, magnesium stearate accounts for 1.41%; silicon dioxide accounts for 0.30%, magnesium stearate accounts for 1.36%; silicon dioxide accounts for 0.35%, magnesium stearate accounts for 1.31%; silicon dioxide accounts for 0.40%, magnesium stearate accounts for 1.26%; silicon dioxide accounts for 0.45%, magnesium stearate accounts for 1.21%; silicon dioxide accounts for 0.50%, magnesium stearate accounts for 1.16%, but are not limited to the above.

[0029] As a specific embodiment of the present invention, the cipride tartrate tablets include, by weight percentage: 0.91% cipride tartrate, 66.09% anhydrous lactose, 26.67% microcrystalline cellulose, 4.67% sodium starch glycolate, 0.33% silicon dioxide, and 1.33% magnesium stearate.

[0030] The present application also provides a preparation method of Cinipride tartrate tablets, comprising the following steps: 1) pretreatment of raw materials and auxiliary materials: Cinipride tartrate is crushed to a particle size D90 ≤ 20 μm, anhydrous lactose is passed through a 30-50 mesh sieve, and magnesium stearate is passed through a 50-70 mesh sieve;

[0031] 2) Premixing: Place anhydrous lactose, cinipride tartrate, sodium starch glycolate, and microcrystalline cellulose in a mixer, set the mixing speed to 5-10 rpm, and mix for 25-35 minutes;

[0032] 3) Sieving: Grinding, granulating, and sieving the silicon dioxide, magnesium stearate, and premixed materials to obtain a sieved material;

[0033] 4) Total mixing: After sieving, the materials are mixed again, and the mixing speed is set to 5-10 rpm and the mixing time is 5-10 min;

[0034] 5) Tablet compression: Theoretical tablet weight is 150 mg, tablet hardness is controlled to 40-70 N, and friability does not exceed 0.5-1.5%.

[0035] The cispride tartrate tablets prepared by the present invention have significant stability, and their dissolution performance and bioequivalence are consistent with those of a reference.

[0036] The following is further described with reference to specific embodiments and comparative examples:

[0037] The sources of the raw materials used in the following examples and comparative examples are as follows:

[0038] Table 1 Sources of raw materials and auxiliary materials in the following examples and comparative examples

[0039] Raw materials Function of excipients source Cinipride tartrate Active substances SYMED LABS LIMITED anhydrous lactose diluent DFE Pharma GmbH&Co.KG microcrystalline cellulose diluent Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Sodium starch glycolate disintegrants Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Silicon dioxide glidants Anhui Shanhe Pharmaceutical Excipients Co., Ltd. magnesium stearate lubricant Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0040] Example 1

[0041] Prescription dosage: see Table 2.

[0042] Table 2 Prescription composition and prescription amount in Example 1

[0043]

[0044] Preparation process:

[0045] 1) Pretreatment of raw materials and auxiliary materials: Cinipride tartrate was ground to a particle size D90 of 15 μm, anhydrous lactose was passed through a 40-mesh sieve, and magnesium stearate was passed through a 60-mesh sieve.

[0046] 2) Premixing: anhydrous lactose, a mixture of cinipride tartrate and microcrystalline cellulose, and sodium starch glycolate were placed in a laboratory hopper mixer, and the mixing speed was set to 8 rpm and the mixing time was 30 min.

[0047] 3) Screening: Place silicon dioxide, magnesium stearate and premixed materials in a crushing and granulating machine, select a 1.0 mm sieve and screen at a speed of 250 rpm.

[0048] 4) Total mixing: The sieved materials were placed in a laboratory hopper mixer for mixing, with the mixing speed set at 8 rpm and the mixing time set at 5 min.

[0049] 5) Tabletting: Use 7.5 mm round punch tablets, adjust appropriate tabletting parameters, and perform tableting based on a theoretical tablet weight of 150 mg. Control the tablet hardness to 50 N and the friability to no more than 1%.

[0050] Examples 2-3

[0051] The only difference between Examples 2 and 3 and Example 1 is that the particle size D90 of the raw material cinipride tartrate after pulverization is different. In Example 2, the particle size D90 of the raw material cinipride tartrate after pulverization is 20 μm; in Example 3, the particle size D90 of the raw material cinipride tartrate after pulverization is 10 μm. The other formulation compositions, formulation amounts and process conditions are the same as those in Example 1.

[0052] Examples 4-5

[0053] The only difference between Examples 4 and 5 and Example 1 is that the total amount of diluent is the same, but the dosage composition of microcrystalline cellulose and anhydrous lactose is different. In Example 4, the weight percentage of microcrystalline cellulose is 60.00%, and the weight percentage of anhydrous lactose is 32.76%; in Example 5, the weight percentage of microcrystalline cellulose is 70.00%, and the weight percentage of anhydrous lactose is 22.76%. The other formulation compositions, formulation amounts, and process conditions are consistent with those of Example 1.

[0054] Examples 6-7

[0055] The only difference between Examples 6 and 7 and Example 1 is the weight percentages of silicon dioxide and magnesium stearate. In Example 4, the weight percentage of silicon dioxide is 0.20%, and the weight percentage of magnesium stearate is 1.46%; in Example 5, the weight percentage of silicon dioxide is 0.50%, and the weight percentage of magnesium stearate is 1.16%. The other formulation compositions, formulation amounts, and process conditions are consistent with those of Example 1.

[0056] Comparative Examples 1-2

[0057] The difference between Comparative Examples 1 and 2 and Example 1 is only that the particle size D90 of the raw material cinipride tartrate after pulverization is different. In Comparative Example 1, the particle size D90 of the raw material cinipride tartrate after pulverization is 25 μm; in Comparative Example 2, the particle size D90 of the raw material cinipride tartrate after pulverization is 35 μm. The other formulation compositions, formulation amounts and process conditions are the same as those in Example 1.

[0058] Comparative Examples 3-4

[0059] Comparative Examples 3-4 differ from Example 1 only in that the total amount of diluent is the same, but the dosages of microcrystalline cellulose and anhydrous lactose are different. In Comparative Example 3, the weight percentage of microcrystalline cellulose is 56.76%, and the weight percentage of anhydrous lactose is 36.00%. In Comparative Example 4, the weight percentage of microcrystalline cellulose is 73.00%, and the weight percentage of anhydrous lactose is 19.76%. The other formulations, formulation amounts, and process conditions are consistent with those of Example 1.

[0060] Comparative Examples 5-6

[0061] The difference between Comparative Examples 5 and 6 and Example 1 is only that the weight percentages of silicon dioxide and magnesium stearate are different. In Comparative Example 5, the weight percentage of silicon dioxide is 0.10%, and the weight percentage of magnesium stearate is 1.56%; in Comparative Example 6, the weight percentage of silicon dioxide is 0.60%, and the weight percentage of magnesium stearate is 1.06%. The other formulation compositions, formulation amounts and process conditions are consistent with those in Example 1.

[0062] The weight percentages of the key auxiliary materials provided in each embodiment and comparative example are shown in Table 3.

[0063] Table 3 Weight percentage of key auxiliary materials in Examples 1 to 7 and Comparative Examples 1 to 6

[0064]

[0065] Select the specification of 1mg (calculated as Cinipride) Cinipride tartrate tablets, the trade name is Batch number 28T is the reference preparation, and the stability, dissolution performance and bioequivalence of the Cinipride tartrate tablets prepared by the present invention and the reference preparation were investigated.

[0066] Accelerated stability study

[0067] According to the requirements of the "9001 Guidelines for Stability Testing of Active Pharmaceutical Ingredients and Preparations" of Part IV of the "Chinese Pharmacopoeia" in 2020, the ciprofloxacin tablets prepared in Examples 1 to 7 and Comparative Examples 1 to 6, as well as the reference preparations, were placed at a temperature of 40°C ± 2°C, a humidity of RH75% ± 5%, and an illumination of 5000 lux. Samples were taken on the 0th day and the 30th day, respectively, to examine the appearance, active substance content, and related substances. The results of the inspection are shown in Table 4.

[0068] Table 4 Accelerated stability test results of Cinipride tartrate tablets prepared in Examples 1 to 7 and Comparative Examples 1 to 6

[0069]

[0070]

[0071]

[0072] By observing Table 4, we can draw the following conclusions:

[0073] The appearance, active ingredient content, and related substance changes of the cipride tartrate tablets prepared in Examples 1 to 3 and Comparative Examples 1 to 2 after being placed under high temperature, high humidity, and light for 30 days were observed. It was found that the cipride tartrate tablets prepared in Examples 1 to 3 still had a light yellow appearance after being placed under high temperature, high humidity, and light for 30 days, and the active ingredient content and related substance changes were small. The cipride tartrate tablets prepared in Comparative Examples 1 to 2 had a yellow appearance after being placed under high temperature, high humidity, and light for 30 days, and the active ingredient content and related substance changes were large. Therefore, under the same other conditions, the stability of the cipride tartrate tablets prepared when the weight percentage of microcrystalline cellulose in the diluent is 60.00-70.00% and the weight percentage of anhydrous lactose is 22.00-33.00% is better.

[0074] The appearance, active ingredient content, and related substance changes of the cipride tartrate tablets prepared in Examples 1, 4-5 and Comparative Examples 3-4 after being placed under high temperature, high humidity, and light for 30 days were observed. It was found that the cipride tartrate tablets prepared in Examples 1 and 4-5 still had a light yellow appearance after being placed under high temperature, high humidity, and light for 30 days, and the active ingredient content and related substance changes were small. The cipride tartrate tablets prepared in Comparative Examples 3-4 had a yellow appearance after being placed under high temperature, high humidity, and light for 30 days, and the active ingredient content and related substance changes were large. Therefore, under the same other conditions, the stability of the cipride tartrate tablets prepared when the weight percentage of silicon dioxide is 0.2-0.5% and the weight percentage of magnesium stearate is 1.10-1.50% is better.

[0075] Long-term stability investigation

[0076] The Cinipride tartrate tablets prepared in Example 1 and Comparative Example 1 and the reference preparation were packaged in ordinary aluminum-plastic blisters and subjected to a long-term stability study at a temperature of 30±2°C and a relative humidity of RH 65%±5%. The results are shown in Table 5.

[0077] Table 5 Results of long-term stability experiments on Cinipride tartrate tablets and reference preparations prepared in Example 1 and Comparative Example 1

[0078]

[0079] The following conclusions can be drawn from Table 5:

[0080] Observation Table 5 shows that after the tartrate tablets of Cinipride prepared in Example 1 were placed under the conditions of temperature 30 ± 2 ° C and relative humidity RH65% ± 5% for 12 months, the appearance, active ingredient content and related substances changed little and were still within the standard limits; after the tartrate tablets of Cinipride prepared in Comparative Example 1 were placed under the conditions of temperature 30 ± 2 ° C and relative humidity RH65% ± 5% for 12 months, the appearance, active ingredient content and related substances changed greatly, and at 12 months the appearance was yellow, and the active ingredient content and related substances exceeded the standard limits; after the reference preparation was placed under the conditions of temperature 30 ± 2 ° C and relative humidity RH65% ± 5% for 12 months, the appearance and active ingredient content did not change significantly, but the change in the relevant substances was greater than that in Example 1. Therefore, the long-term stability of the Cinipride tartrate tablets provided by the present invention is better.

[0081] Dissolution performance investigation

[0082] The formulation process development for this product was based on the Technical Guidelines for Dissolution Testing of Oral Solid Preparations and the Chinese Pharmacopoeia. A conventional dissolution medium was selected for in vitro dissolution behavior studies to support formulation development. The standard medium dissolution method in the import registration standard for the reference product is a paddle method at 75 rpm. The specific method is shown in Table 6.

[0083] Table 6 Dissolution method used in preparation formulation process research

[0084]

[0085]

[0086] The dissolution data of the reference preparation in the above media are shown in Table 7.

[0087] Table 7 Dissolution curve results of reference preparations in different media (n=12)

[0088]

[0089] The dissolution data of Cinipride tartrate tablets prepared in Examples 1 to 7 and Comparative Examples 1 to 6 in various media are shown in Table 8.

[0090] Table 8 Dissolution curve results of Cinipride tartrate tablets prepared in Example 1 and Comparative Example 1 in different media (n=12)

[0091]

[0092]

[0093]

[0094]

[0095] By observing Tables 7 and 8, we can draw the following conclusions:

[0096] In pH 1.0 hydrochloric acid solution and pH 4.5 acetate solution, all examples and comparative examples meet the requirement that the dissolution amount is greater than 85% of the reference preparation in 15 minutes, and the dissolution curves are similar. There is no obvious differentiation between these two media.

[0097] In a pH 6.8 phosphate solution, examples 1 to 3, comparative examples 1 to 2, and a reference preparation were observed. It can be seen that the f2 of the cispride tartrate tablets prepared in examples 1 to 3 and the reference preparation in this medium were both greater than 50, and the dissolution curves were similar. The f2 of the cispride tartrate tablets prepared in comparative examples 1 to 2 and the reference preparation in this medium were both less than 50, and the dissolution curves were not similar. Therefore, when other conditions are the same and the raw material particle size D90 ≦ 20 μm, the dissolution performance of the prepared cispride tartrate tablets is more similar to that of the reference preparation.

[0098] In a pH 6.8 phosphate solution, observation of Examples 1, 4-5, Comparative Examples 3-4, and a reference preparation revealed that the f2 of the Cinipride tartrate tablets prepared in Examples 1, 4-5 and the reference preparation in this medium was greater than 50, and the dissolution curves were similar. However, the f2 of the Cinipride tartrate tablets prepared in Comparative Examples 3-4 and the reference preparation in this medium was less than 50, and the dissolution curves were dissimilar. Therefore, when other conditions were the same, and the weight percentages of microcrystalline cellulose and anhydrous lactose were 60.00-70.00% and 22.00-33.00%, respectively, the dissolution performance of the prepared Cinipride tartrate tablets was more similar to that of the reference preparation.

[0099] In a pH 6.8 phosphate solution, examples 1, 6-7, comparative examples 5-6, and a reference preparation were observed. It can be seen that the f2 of the cispride tartrate tablets prepared in examples 1, 6-7 and the reference preparation in this medium was greater than 50, and the dissolution curves were similar. However, the f2 of the cispride tartrate tablets prepared in comparative examples 5-6 and the reference preparation in this medium was less than 50, and the dissolution curves were not similar. Therefore, when other conditions are the same, when the weight percentages of silicon dioxide and magnesium stearate are 0.20-0.50% and 1.30-1.50%, respectively, the dissolution performance of the prepared cispride tartrate tablets is more similar to that of the reference preparation.

[0100] Bioequivalence study

[0101] The bioequivalence of the Cinipride tartrate tablets prepared in Example 1 and the reference preparation was investigated.

[0102] Experimental methods: A randomized, open-label, single-dose, two-period double-crossover bioequivalence study was conducted in healthy adult Chinese subjects, with 12 subjects in each group before and after meals.

[0103] Evaluation indicators: The blood drug concentration data obtained by measurement were used for pharmacokinetic calculation using WinNonlin 8.0 and above. The pharmacokinetic parameters were calculated using the non-compartmental model (NCA) based on the individual blood drug concentration of each subject and the actual blood sampling time point.

[0104] (1) Main PK parameters: C max , AUC 0-t , AUC 0-∞

[0105] (2) Secondary PK parameter: T max ,λz,t 1 / 2 、AUC_ ％Extrap 、F rel (Relative bioavailability)

[0106] The main pharmacokinetic parameters of Cinipride in plasma were evaluated after oral administration of the test preparation and the reference preparation under fasting conditions. max , AUC 0-t , AUC 0-∞ Whether it meets the equivalent standards.

[0107] Bioequivalence analysis: C of Cinipride in plasma of two preparations max , AUC 0-t , AUC 0-∞ After natural logarithm transformation, bioequivalence evaluation was performed using analysis of variance followed by confidence interval method.

[0108] Bioequivalence determination criteria: Both fasting and postprandial studies were designed with two cycles and double crossover. The C values ​​of cilnipride in plasma of the test and reference preparations were calculated. max , AUC 0-t , AUC 0-∞ The geometric mean, geometric mean ratio and its 90% confidence interval (CI) of the test preparation and the reference preparation. max , AUC 0-t , AUC 0-∞ If the 90% confidence interval of the geometric mean ratio is within the equivalence interval of 80.00% to 125.00% (including the boundary values), the test preparation and the reference preparation can be determined to be bioequivalent.

[0109] The experimental data results of the experiment using the Cinipride tartrate tablets prepared in Example 1 as the "test preparation" are shown in Tables 9-10.

[0110] Table 9 Bioequivalence of Cinipride Tartrate Tablets Prepared in Example 1 in Fasting Preliminary Test - 12 Cases

[0111] Dependent Ratio_%Ref CI_90_Lower CI_90_Upper <![CDATA[Ln(C max )]]> 108.87 93.29 124.04 <![CDATA[Ln(AUC 0-t )]]> 101.68 88.70 116.54 <![CDATA[Ln(AUC 0-∞ )]]> 102.78 89.50 118.03

[0112] Table 10 Bioequivalence of Cinipride Tartrate Tablets Prepared in Example 1 in Postprandial Preliminary Test - 12 Cases

[0113] Dependent Ratio_%Ref_ CI_90_Lower CI_90_Upper <![CDATA[Ln(C max )]]> 98.04％ 81.86％ 117.42％ <![CDATA[Ln(AUC 0-t )]]> 106.32％ 94.61％ 119.49％ <![CDATA[Ln(AUC 0-∞ )]]> 107.17％ 95.35％ 120.45％

[0114] Observe Tables 9 to 10, it can be seen that in the fasting pre-test and the post-meal pre-test, the C of the Cinipride tartrate tablets prepared in Example 1 and the reference preparation max , AUC 0-t , AUC 0-∞ The 90% confidence intervals of the geometric mean ratios were all within the 80.00% to 125.00% equivalence interval (including the boundary values). Therefore, the Cinipride tartrate tablets provided by the present invention were bioequivalent to the reference preparation.

[0115] It is understood that the above embodiments are merely exemplary embodiments for illustrating the principles of the present application, and the present application is not limited thereto. Those skilled in the art may make various modifications and improvements without departing from the spirit and substance of the present application, and such modifications and improvements are also considered to be within the scope of protection of the present invention.

Claims

1. A gastrointestinal prokinetic tablet, characterized in that: The composition comprises, by weight percentage, 0.91% of ciprofloxacin tartrate, 60.00-70.00% of anhydrous lactose, 22.00-33.00% of microcrystalline cellulose, 3.20-4.80% of sodium starch glycolate, 0.15-0.50% of silicon dioxide, and 1.10-1.50% of magnesium stearate. The particle size D90 of ciprofloxacin tartrate is ≤20 μm. Wherein, in terms of weight percentage, the total proportion of the anhydrous lactose and microcrystalline cellulose is 92.00-93.00%, In terms of weight percentage, the total proportion of silicon dioxide and magnesium stearate is 1.20-1.80%.

2. The gastrointestinal prokinetic tablet according to claim 1, characterized in that The particle size D90 of the Cinipride tartrate is ≤15 μm.

3. The gastrointestinal prokinetic tablet according to claim 1, characterized in that In terms of weight percentage, the total proportion of the anhydrous lactose and microcrystalline cellulose is 92.76%.

4. The gastrointestinal prokinetic tablet according to claim 1, characterized in that In terms of weight percentage, the total proportion of silicon dioxide and magnesium stearate is 1.66%.

5. The gastrointestinal prokinetic tablet according to claim 1, characterized in that Calculated by weight percentage, it comprises: 0.91% of cinipride tartrate, 66.09% of anhydrous lactose, 26.67% of microcrystalline cellulose, 4.67% of sodium starch glycolate, 0.33% of silicon dioxide, and 1.33% of magnesium stearate.

6. The gastrointestinal prokinetic tablet according to claim 3, characterized in that The particle size D90 of the Cinipride tartrate is ≤15 μm.

7. The gastrointestinal prokinetic tablet according to claim 3, characterized in that The particle size D90 of the Cinipride tartrate is 15 μm.

8. The gastrointestinal prokinetic tablet according to any one of claims 1 to 7, wherein the preparation thereof comprises the following steps: 1) Pretreatment of raw materials and excipients: Cinipride tartrate is crushed to a particle size D90 ≤ 20 μm, anhydrous lactose is passed through a 30-50 mesh sieve, and magnesium stearate is passed through a 50-70 mesh sieve; 2) Premixing: mixing anhydrous lactose, cinipride tartrate, sodium starch glycolate, and microcrystalline cellulose to obtain a premix; 3) Sieving: Grind, granulate, and sieve the silicon dioxide, magnesium stearate, and premixed materials to obtain the sieved material; 4) Total mixing: After sieving, mix the materials again, set the mixing speed to 5-10 rpm and the mixing time to 5-10 minutes; 5) Tablet compression: Theoretical tablet weight is 150 mg, tablet hardness is controlled at 40-70 N, and friability does not exceed 0.5-1.5%.

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