Gastrointestinal motility promoting tablet and preparation method thereof

Abstract

The present invention discloses a gastrointestinal motility promoting tablet, which is characterized in that the tablet comprises, by weight, 0.91% of cinipride tartrate, 60.00-70.00% of lactose anhydrous, 22.00-33.00% of microcrystalline cellulose, 3.20-4.80% of carboxymethyl starch sodium, 0.15-0.50% of silica, and 1.10-1.50% of magnesium stearate, and the particle size D90 of the cinipride tartrate is less than or equal to 20 [mu] m. The total proportion of the anhydrous lactose and the microcrystalline cellulose is 92.00-93.00%, the total proportion of the silicon dioxide and the magnesium stearate is 1.20-1.80%, and the particle size D90 of the cenipride tartrate is less than or equal to 15 microns. The cenipride tartrate tablet provided by the invention is higher in stability, the dissolution performance is more similar to that of a reference preparation, and the bioequivalence is consistent with that of 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 drugs for the treatment of gastrointestinal diseases such as functional dyspepsia (FD) and gastroesophageal reflux disease (GERD), but there are few effective and safe drugs. Cinipride tartrate (Cinipride) is a prokinetic drug launched in my country in 2015. It is a 5-hydroxytryptamine receptor agonist and is mainly used to treat mild to moderate FD. The results of multiple clinical trials have shown that Cinipride is more effective than metoclopramide and domperidone in the treatment of gastrointestinal dysfunction, FD and GERD, and has good safety. Cinipride is metabolized in the liver not only by cytochrome P450 (CYP) 3A4, but also by CYP2C8, with a low risk of drug interactions. In addition, the free blood concentration of Cinipride is much lower than that of cisapride and domperidone, resulting in a lower risk of cardiac toxicity. It is a new choice for the treatment of FD and GERD.

[0003] It is a gastrointestinal prokinetic agent discovered by Almirall, SA. Under the terms of the license agreement signed with Almirall in March 2010, Eisai obtained exclusive rights from Almirall to develop, manufacture and distribute in China. Eisai is approved in China for the improvement of early satiety, postprandial fullness and abdominal distension symptoms 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 in the prescription compositions are slightly different. The inventors found that the Cinipride tartrate tablets prepared according to the above documents are inferior to 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 Cinipride tartrate tablet, which comprises, by weight percentage: 0.91% Cinipride 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 Cinipride tartrate is ≦20 μm.

[0007] Preferably, the total proportion of the anhydrous lactose and the 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 Cinipride tartrate is ≦15 μm.

[0010] Preferably, the total proportion of 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 include, 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 Cinipride tartrate is ≦15 μm.

[0014] Preferably, the particle size D90 of 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 auxiliary materials: Cinipride tartrate is crushed to a particle size of D90≤20μm, 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, ciprofloxacin tartrate, sodium starch glycolate and microcrystalline cellulose to obtain a premixed material;

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

[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 be 40-70N, and friability is not more than 0.5-1.5%.

[0021] Beneficial effects:

[0022] Microcrystalline cellulose is hygroscopic and may affect the stability of tablets in an environment with high humidity. However, anhydrous lactose does not contain crystal water and is more suitable for the formulation of water-sensitive drugs. Therefore, the adjustment of the dosage ratio of the two can balance the hygroscopicity and stability of tablets. The dosage of magnesium stearate and silicon dioxide can also affect the solubility, stability, bioavailability, etc. of the drug. The size of the raw material particle size can affect the dissolution, stability and long-term stability of the tablets. The inventors, through the particle size of the preferred raw materials and the weight composition of crystalline cellulose, anhydrous lactose, silicon dioxide and magnesium stearate in the auxiliary materials, surprisingly found that the obtained tartrate cilapride tablets have significantly improved stability under the accelerated test conditions of high temperature, high humidity and light than the reference preparation, and the dissolution performance is more similar to the reference preparation, and the bioequivalence is consistent with the reference preparation. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present application are clearly described below. Obviously, the described embodiments are part of the embodiments of the present application, rather than all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments in the present application belong to the scope of protection of the present application.

[0024] The terms "first", "second", etc. in the specification and claims of this application are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data used in this way can be interchangeable under appropriate circumstances, so that the embodiments of the present application can be implemented in an order other than those described here, and the objects distinguished by "first", "second", etc. are generally of one type, and the number of objects is not limited. For example, the first object can be one or more. In addition, "and / or" in the specification and claims represents at least one of the connected objects, and the character " / " generally indicates that the objects associated before and after are in an "or" relationship.

[0025] The present application is not limited to the above-mentioned specific implementation modes, 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 within the protection of the present application.

[0026] The present application provides a Cinipride tartrate tablet, which comprises, by weight percentage: 0.91% Cinipride 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 Cinipride 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%, 70.00%; the microcrystalline fiber 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 ≦20μm, and its D90 can be 10μm, 15μm, 20μm, but 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 that 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 it 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 that silicon dioxide accounts for 0.33% and magnesium stearate accounts for 1.33%; silicon dioxide accounts for 0.16% and magnesium stearate accounts for 1.50%; silicon dioxide accounts for 0.20% and magnesium stearate accounts for 1.46%; silicon dioxide accounts for 0.25% and magnesium stearate accounts for 1.41%; silicon dioxide accounts for 0.30% and magnesium stearate accounts for 1.36%; silicon dioxide accounts for 0.35% and magnesium stearate accounts for 1.31%; silicon dioxide accounts for 0.40% and magnesium stearate accounts for 1.26%; silicon dioxide accounts for 0.45% and magnesium stearate accounts for 1.21%; silicon dioxide accounts for 0.50% and magnesium stearate accounts for 1.16%, but it is not limited to the above.

[0029] As a specific embodiment of the present invention, the Cinipride tartrate tablets include, 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.

[0030] The present application also provides a method for preparing 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, ciprofloxacin tartrate, sodium starch glycolate, and microcrystalline cellulose in a mixer, set the mixing speed to 5-10 rpm, and the mixing time to 25-35 min;

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

[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 be 40-70N, and friability is not more than 0.5-1.5%.

[0035] The Cinipride tartrate tablets prepared by the invention have remarkable stability, and the dissolution performance and bioequivalence are consistent with those of the reference.

[0036] The following is further described in conjunction with specific examples and comparative examples:

[0037] The sources of the raw materials and auxiliary 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 auxiliary materials source Cinipride tartrate Active substances SYMED LABS LIMITED Anhydrous lactose Thinner DFE Pharma GmbH&Co.KG Microcrystalline Cellulose Thinner 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 Lubricants Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0040] Example 1

[0041] Prescription quantity; 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 crushed 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: Place anhydrous lactose, a mixture of cinipride tartrate and microcrystalline cellulose, and sodium starch glycolate in a laboratory hopper mixer, set the mixing speed to 8 rpm, and the mixing time to 30 min.

[0047] 3) Screening: Put silicon dioxide, magnesium stearate and premixed materials together in a crushing and granulating machine, select a 1.0 mm sieve for screening, and set the speed to 250 rpm.

[0048] 4) Total mixing: The sieved materials were placed in a laboratory hopper mixer for mixing, with the mixing speed set to 8 rpm and the mixing time set to 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 not exceed 1%.

[0050] Embodiment 2-3

[0051] The only difference between Examples 2 to 3 and Example 1 is that the particle size D90 of the raw material Cinipride tartrate after crushing is different. In Example 2, the particle size D90 of the raw material Cinipride tartrate after crushing is 20 μm; in Example 3, the particle size D90 of the raw material Cinipride tartrate after crushing is 10 μm, and other prescription compositions, prescription amounts and process conditions are consistent with those in Example 1.

[0052] Embodiment 4-5

[0053] The 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 dosage percentage of anhydrous lactose is 32.76%; in Example 5, the weight percentage of microcrystalline cellulose is 70.00%, and the dosage percentage of anhydrous lactose is 22.76%, and other prescription compositions, prescription amounts and process conditions are consistent with those of Example 1.

[0054] Embodiment 6-7

[0055] The difference between Examples 6 to 7 and Example 1 is only that the weight percentages of silicon dioxide and magnesium stearate are different. 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%. Other prescription compositions, prescription amounts and process conditions are consistent with those in Example 1.

[0056] Comparative Examples 1-2

[0057] The difference between Comparative Examples 1 to 2 and Example 1 is that the particle size D90 of the raw material Cinipride tartrate after crushing is different. In Comparative Example 1, the particle size D90 of the raw material Cinipride tartrate after crushing is 25 μm; in Comparative Example 2, the particle size D90 of the raw material Cinipride tartrate after crushing is 35 μm, and the other prescription compositions, prescription amounts and process conditions are consistent with those in Example 1.

[0058] Comparative Examples 3-4

[0059] The difference between Comparative Examples 3 and 4 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 Comparative Example 3, the weight percentage of microcrystalline cellulose is 56.76%, and the dosage percentage of anhydrous lactose is 36.00%; in Comparative Example 4, the weight percentage of microcrystalline cellulose is 73.00%, and the dosage percentage of anhydrous lactose is 19.76%. Other prescription compositions, prescription amounts and process conditions are consistent with those of Example 1.

[0060] Comparative Examples 5-6

[0061] The difference between Comparative Examples 5 to 6 and Example 1 is 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%. Other prescription compositions, prescription amounts and process conditions are consistent with those in Example 1.

[0062] The weight percentages of the key auxiliary materials set 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 The 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 are investigated.

[0066] Accelerated stability test

[0067] According to the requirements of the "9001 Guidelines for Stability Testing of APIs and Preparations" of Part IV of the "Chinese Pharmacopoeia" in 2020, the Cinipride tartrate tablets prepared in Examples 1 to 7 and Comparative Examples 1 to 6, and 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] Observing Table 4, we can draw the following conclusions:

[0073] By observing the appearance, active ingredient content and related substance changes of the tartrate cinipride 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, it was found that the tartrate cinipride tablets prepared in Examples 1 to 3 were still light yellow in appearance after being placed under high temperature, high humidity and light for 30 days, and the active ingredient content and related substances changed little. The tartrate cinipride tablets prepared in Comparative Examples 1 to 2 were yellow in appearance after being placed under high temperature, high humidity and light for 30 days, and the active ingredient content and related substances changed greatly. Therefore, under the same other conditions, 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%, the stability of the prepared tartrate cinipride tablets is better.

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

[0075] Long-term stability study

[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 long-term stability study at a temperature of 30±2° C. and a relative humidity of RH65%±5%. The results are shown in Table 5.

[0077] Table 5 Results of long-term stability experiments of 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] It can be seen from Table 5 that the appearance, active ingredient content and related substances of the tartrate cilnipride tablets prepared in Example 1 were placed under the conditions of temperature 30±2°C and relative humidity RH65%±5% for 12 months, and the changes were small, and still within the standard limits; the appearance, active ingredient content and related substances of the tartrate cilnipride tablets prepared in Comparative Example 1 were placed under the conditions of temperature 30±2°C and relative humidity RH65%±5% for 12 months, and the appearance, active ingredient content and related substances changed greatly, and the appearance was yellow in December, and the active ingredient content and related substances exceeded the standard limits; the reference preparation was placed under the conditions of temperature 30±2°C and relative humidity RH65%±5% for 12 months, and the appearance and active ingredient content did not change significantly, but the change range of related substances was larger than that of Example 1. Therefore, the long-term stability of the cilnipride tartrate tablets provided by the present invention is better.

[0081] Dissolution performance study

[0082] The formulation process development of this product refers to the technical guidelines for dissolution testing of common oral solid preparations and the Chinese Pharmacopoeia, and selects conventional dissolution media for in vitro dissolution behavior research to provide support for formulation development research. The standard medium dissolution method in the reference preparation import registration standard is the paddle method 75rpm. The specific method is shown in Table 6.

[0083] Table 6 Dissolution method used in the research and investigation of preparation prescription process

[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 satisfy the requirement that the dissolution amount is greater than 85% of the reference preparation in 15 min, 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 the reference preparation were observed. It can be seen that the f2 of the Cinipride tartrate tablets prepared in examples 1 to 3 and the reference preparation in the medium were both greater than 50, and the dissolution curves were similar. The f2 of the Cinipride tartrate tablets prepared in comparative examples 1 to 2 and the reference preparation in the medium were both less than 50, and the dissolution curves were not similar. Therefore, when other conditions were the same and the raw material particle size D90≦20 μm, the dissolution performance of the prepared Cinipride tartrate tablets was more similar to that of the reference preparation.

[0098] In a pH 6.8 phosphate solution, examples 1, 4 to 5, comparative examples 3 to 4 and the reference preparation were observed. It can be seen that the f2 of the Cinipride tartrate tablets prepared in examples 1, 4 to 5 and the reference preparation in the medium were both greater than 50, and the dissolution curves were similar. The f2 of the Cinipride tartrate tablets prepared in comparative examples 3 to 4 and the reference preparation in the medium were both less than 50, and the dissolution curves were not similar. Therefore, when other conditions were the same, 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 to 7, comparative examples 5 to 6 and the reference preparation were observed. It can be seen that the f2 of the Cinipride tartrate tablets prepared in examples 1, 6 to 7 and the reference preparation in the medium were both greater than 50, and the dissolution curves were similar. The f2 of the Cinipride tartrate tablets prepared in comparative examples 5 to 6 and the reference preparation in the medium were both less than 50, and the dissolution curves were not similar. Therefore, when other conditions were the same, and the weight percentages of silicon dioxide and magnesium stearate were 0.20 to 0.50% and 1.30 to 1.50%, respectively, the dissolution performance of the prepared Cinipride tartrate tablets was 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-preparation, 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: WinNonlin8.0 and above versions were used to perform pharmacokinetic calculations on the blood drug concentration data obtained by the measurement. The non-compartmental model (NCA) was used to calculate the pharmacokinetic parameters 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 parameters: T max ,λz,t 1 / 2 , AUC_ ％Extrap 、F rel (Relative bioavailability)

[0106] The main pharmacokinetic parameters of the test preparation and the reference preparation, namely the C of cilnipride in plasma, were evaluated after the subjects took the test preparation and the reference preparation orally under fasting conditions. max , AUC 0-t , AUC 0-∞ Whether it meets equivalent standards.

[0107] Bioequivalence analysis: C of cilnipride 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 criteria: Both the fasting and postprandial tests were designed with two cycles and double crossovers. The C of cilipride in plasma of the test preparation and the reference preparation were calculated. max , AUC 0-t , AUC 0-∞ The geometric mean, geometric mean ratio and its 90% confidence interval (CI) of the test and reference products were 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 to 10.

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

[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 Examples

[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 are all within the 80.00% to 125.00% equivalent interval (including the boundary values). Therefore, the Cinipride tartrate tablets provided by the present invention are bioequivalent to the reference preparation.

[0115] It is to be understood that the above embodiments are merely exemplary embodiments used to illustrate the principles of the present application, but the present application is not limited thereto. For those skilled in the art, various modifications and improvements can be made without departing from the spirit and essence of the present application, and these 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 invention 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.

2. The gastrointestinal prokinetic tablet according to claim 1, characterized in that: In terms of weight percentage, the total proportion of the anhydrous lactose and the microcrystalline cellulose is 92.00-93.00%.

3. 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 1.20-1.80%.

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

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

6. 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%.

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

8. The gastrointestinal prokinetic tablet according to claim 5, characterized in that: The particle size D90 of the Cinipride tartrate is ≦15 μm.

9. The gastrointestinal prokinetic tablet according to claim 5, characterized in that: The particle size D90 of Cinipride tartrate is 15 μm.

10. The gastrointestinal prokinetic tablet according to any one of claims 1 to 9, wherein the preparation thereof comprises the following steps: 1) Pretreatment of raw materials and auxiliary materials: Cinipride tartrate is crushed to a particle size of D90≤20μm, 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, ciprofloxacin tartrate, sodium starch glycolate and microcrystalline cellulose to obtain a premixed material; 3) Sieving: crushing, granulating and sieving silicon dioxide, magnesium stearate and premixed materials to obtain sieved materials; 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; 5) Tablet compression: Theoretical tablet weight is 150 mg, tablet hardness is controlled to be 40-70N, and friability is not more than 0.5-1.5%.

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