A kind of glipizide tablet composition and preparation method

Abstract

The present invention relates to a glipizide tablet composition and a preparation method. The glipizide tablet composition of the present invention contains glipizide 5g, stearic acid 7-11g, Eudragit RS100 15-19g, lactose 14SD 121-137g, microcrystalline cellulose 32-48g, and colloidal silicon dioxide 2g per 1000 tablets. Wherein, glipizide exists in the form of a dispersion, and stearic acid and Eudragit RS100 exist in the form of an internal carrier. The present invention provides a glipizide tablet and a preparation method that apply solid dispersion technology and have a simple preparation process and meet the consistency evaluation requirements.

Description

Technical Field

[0001] The invention relates to a glipizide tablet composition and a preparation method thereof, and belongs to the technical field of medicine. Background Art

[0002] Glipizide is a second-generation sulfonylurea oral hypoglycemic drug developed by Pfizer, USA. It was launched in the United States in 1984 and is suitable for patients with mild and moderate type 2 diabetes who are unsatisfied with the therapeutic effect of diet control and physical exercise for 2 to 3 months. At present, the approved glipizide dosage forms in China include tablets, capsules, dispersible tablets, sustained-release tablets, controlled-release tablets, etc. Among them, ordinary tablets have the most approval numbers due to their relatively simple preparation process and price advantages, and are also the focus of the present invention.

[0003] In April 2017, the State Food and Drug Administration announced the third and fourth batches of reference preparations for generic drugs, among which the reference preparation of glipizide tablets 5 mg was licensed by Pfizer Inc., with the trade name Glucotrol, which was included in the U.S. Orange Book. Many domestic glipizide tablet manufacturers used this to promote the quality and efficacy consistency evaluation of this product.

[0004] Both ZL201510490351.X and ZL201510626347.1 provide a method for preparing glipizide tablets, in which the raw materials need to be micronized. However, the micronized glipizide has severe electrostatic adsorption, is difficult to sieve, and has extremely poor fluidity, which can easily lead to problems with the content uniformity of the preparation and the stability of the dissolution curve.

[0005] ZL201711388932.8 provides a method for preparing glipizide into lipid nanoparticles and then preparing tablets. Although it overcomes the adverse effects of the raw material after micronization, the preparation process is relatively complicated. In addition, the quality and efficacy comparison target of the invented product is the commercially available glipizide controlled-release reference preparation (Reyining).

[0006] CN112535665A discloses a method for preparing glipizide solid dispersion and tablets by using solvent rotary evaporation method, the purpose of which is to improve bioavailability. However, it is not applicable to the requirement that the bioavailability is equivalent to that of the reference preparation in the consistency evaluation of drugs. In addition, the solvent rotary evaporation method is difficult to scale up for commercial production and is not easy to transform. Summary of the invention

[0007] Purpose of the invention:

[0008] The purpose of the present invention is to provide a glipizide tablet and a preparation method which utilize solid dispersion technology and have a simple preparation process and meet the requirements of consistency evaluation.

[0009] In the process of reverse analysis of the formulation and process composition of the reference preparation, the applicant broke through the conventional use and dosage of stearic acid as an external lubricant in the reference preparation (0.5%-2%), and unexpectedly found that stearic acid as a solid dispersion carrier can effectively prevent the drug recrystallization process, and can overcome the difficulties such as the decline in the dissolution curve of the reference preparation using the micronization and wet granulation process of the API during the stability process. However, when the amount of stearic acid is too high, it will lead to the problem of decreased compressibility of the self-developed product. Based on a large number of screenings of other carrier materials, it was unexpectedly discovered that Eudragit RS100 (insoluble in water, low permeability) as a sustained-release coating material can also be used in a non-conventional way as a solid dispersion carrier. When stearic acid and Eudragit RS100 are used in combination in a certain proportion, it can ensure that the self-developed glipizide tablets have excellent compressibility, a stable drug release curve, and bioavailability equivalent to the original preparation.

[0010] The technical solution of the present invention is:

[0011] A glipizide tablet composition, each 1000 tablets containing 5g of glipizide, 7-11g of stearic acid, 15-19g of Eudragit RS100, 121-137g of lactose 14SD, 32-48g of microcrystalline cellulose, and 2g of colloidal silicon dioxide, wherein the glipizide is present in the form of a dispersion, and the stearic acid and Eudragit RS100 are present in the form of an internal carrier.

[0012] Preferably, a glipizide tablet composition contains 5 g of glipizide, 9 g of stearic acid, 17 g of Eudragit RS100, 129 g of lactose 14SD, 40 g of microcrystalline cellulose, and 2 g of colloidal silicon dioxide per 1000 tablets.

[0013] The preparation method of the glipizide tablets of the present invention comprises the following steps:

[0014] Step 1. Preparing a solid dispersion, comprising:

[0015] (1) Dissolve the prescribed amount of glipizide, stearic acid, and Eudragit RS100 in a mixed solvent of acetone and methanol in a volume ratio of 1:1 and set aside;

[0016] (2) Set the spray dryer inlet temperature to 55°C, outlet temperature to 42°C, feed rate to 5 mL / min, and air flow rate to 4.7 m 3 / min, after the operation is stable, the above-mentioned raw material drug and carrier solution are sprayed into the dryer chamber in the form of fine droplets, and the solid dispersion is obtained after drying.

[0017] Step 2. Preparing glipizide tablets, comprising:

[0018] (1) The glipizide solid dispersion obtained in step 1 is uniformly mixed with the prescribed amount of lactose 14SD, microcrystalline cellulose, and colloidal silicon dioxide by a hopper mixer;

[0019] (2) Use a φ7mm shallow concave circular punch for tableting, with a hardness of not less than 45N. DETAILED DESCRIPTION Example 1

[0020] Prescription composition: glipizide 5g, stearic acid 9g, Eudragit RS100 17g, lactose 14SD 129g, microcrystalline cellulose 40g, colloidal silicon dioxide 2g.

[0021] Preparation method: Prepare 1000 tablets according to the preparation method described in the technical solution section. Example 2

[0022] Prescription composition: glipizide 5g, stearic acid 7g, Eudragit RS100 19g, lactose 14SD 121g, microcrystalline cellulose 48g, colloidal silicon dioxide 2g.

[0023] Preparation method: Prepare 1000 tablets according to the preparation method described in the technical solution section. Example 3

[0024] Prescription composition: glipizide 5g, stearic acid 11g, Eudragit RS100 15g, lactose 14SD 137g, microcrystalline cellulose 32g, colloidal silicon dioxide 2g.

[0025] Preparation method: Prepare 1000 tablets according to the preparation method described in the technical solution section.

[0026] Comparative Example 1

[0027] Prescription composition: glipizide 5g, stearic acid 5g, Eudragit RS100 21g, lactose 14SD 119g, microcrystalline cellulose 50g, colloidal silicon dioxide 2g.

[0028] Preparation method: Prepare 1000 tablets according to the preparation method described in the technical solution section.

[0029] Comparative Example 2

[0030] Prescription composition: glipizide 5g, stearic acid 13g, Eudragit RS100 13g, lactose 14SD 139g, microcrystalline cellulose 30g, colloidal silicon dioxide 2g.

[0031] Preparation method: Prepare 1000 tablets according to the preparation method described in the technical solution section.

[0032] Test Example 1. Dissolution curve investigation

[0033] Dissolution conditions: pH 6.8 medium, paddle method 50 revolutions (Method 2, General Chapter 0931 of the 2020 edition of the Chinese Pharmacopoeia), test the cumulative dissolution of glipizide at 5 min, 10 min and 20 min of the sample at the end of June at 0 day and accelerated test (40°C±2°C / 75%RH±5%RH), respectively. The data are shown in Table 1.

[0034]

[0035] Note: f2 *1 f2 is the comparison result of the dissolution curve of the embodiment or control sample on day 0 with the reference; *2 To accelerate the comparison of the dissolution curve of the example or control sample in June with its own 0-day dissolution curve, when f2≥50, the dissolution is judged to be similar; the higher the f2 value, the better the dissolution similarity.

[0036] It can be seen from the data in Table 1 that: at 0 days, Examples 1-3 and Control Example 2 can all be guaranteed to be similar to the reference preparation, while the dissolution curve of Control Example 1 is significantly slower than and not similar to the reference preparation; when accelerated for 6 months, the dissolution curve of the reference preparation is compared with its own 0 day, and the similarity is 53, which is on the edge of similarity, while the dissolution curves of Examples 1-3 and Control Examples 1-2 are compared with their own 0 day, and the similarities are greater than 70, indicating that the dissolution curves have good stability and are better than the reference preparation.

[0037] Test Example 2. Content uniformity and maximum tablet hardness

[0038] Determination method: Refer to the "Content Uniformity" method under the glipizide tablets included in the 2020 edition of the "Chinese Pharmacopoeia" for investigation, and monitor and evaluate the maximum hardness and friability of the tablets. The data are shown in Table 2.

[0039]

[0040] It can be seen from the data in Table 2 that the contents of all samples meet the requirements; the content uniformity of Examples 1-3 and Control Examples 1-2 is better than that of the reference preparation; the average hardness of Examples 1-3 and Control Example 1 is not lower than that of the reference preparation, while the compressibility of Control Example 2 is poor, and the average hardness is significantly lower than that of the reference preparation; the friability of the reference, Examples 1-3 and Control Example 1 is good, far below the pharmacopoeia limit requirement (1%), while the friability of Control Example 2 has exceeded the standard, which is related to its poor compressibility.

[0041] Test Example 3. Bioavailability Study

[0042] Experimental plan: A double-period, randomized, crossover experimental design was adopted. 18 healthy adult subjects were randomly divided into 2 experimental groups, with 9 subjects in each group. The test preparation Example 1 and the reference preparation (trade name: Glucotrol, 5 mg) were orally administered with a single dose and crossover. Venous blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, and 24 hours. The blood concentrations of glipizide at different times after fasting and postprandial administration were determined by ultra performance liquid chromatography-tandem mass spectrometry. The data are shown in Table 3.

[0043]

[0044] From the data in Table 3, it can be seen that the main pharmacokinetic parameters C of the self-developed Example 1 and the reference preparation, which are the most representative of the formulation process, are max The 90% confidence interval of AUC was in line with the requirements of bioequivalence guidelines (80%~125%).

Claims

1. A glipizide tablet composition, characterized in that: Each 1000 tablets contains 5g of glipizide, 7-11g of stearic acid, 15-19g of Eudragit RS100, 121-137g of lactose 14SD, 32-48g of microcrystalline cellulose, and 2g of colloidal silicon dioxide. The preparation method of the tablet comprises the following steps: Step 1. Prepare a solid dispersion, comprising: (1) Dissolve the prescribed amount of glipizide, stearic acid, and Eudragit RS100 in a mixed solvent of acetone and methanol in a volume ratio of 1:1 and set aside; (2) Spraying the above-mentioned API and carrier solution into the chamber of a dryer, and obtaining a solid dispersion after drying; Step 2. Prepare glipizide tablets, comprising: (1) The glipizide solid dispersion obtained in step 1 is uniformly mixed with the prescribed amount of lactose 14SD, microcrystalline cellulose, and colloidal silicon dioxide by a hopper mixer; (2) Tableting: hardness not less than 45N.

2. The glipizide tablet composition according to claim 1, characterized in that: Each 1000 tablets contains 5g of glipizide, 9g of stearic acid, 17g of Eudragit RS100, 129g of lactose 14SD, 40g of microcrystalline cellulose, and 2g of colloidal silicon dioxide.

3. The glipizide tablet composition according to claim 1, characterized in that The preparation method comprises the following steps: Step 1. Prepare a solid dispersion, comprising: Dissolve the prescribed amount of glipizide, stearic acid, and Eudragit RS100 in a mixed solvent of acetone and methanol in a volume ratio of 1:1 for later use; Set the spray dryer inlet temperature to 55°C, outlet temperature to 42°C, feed rate to 5 mL / min, and air flow rate to 4.7 m 3 / min, after the operation is stable, the above-mentioned raw material drug and carrier solution are sprayed into the dryer chamber in the form of fine droplets, and a solid dispersion is obtained after drying; Step 2. Prepare glipizide tablets, comprising: The glipizide solid dispersion obtained in step 1 is uniformly mixed with the prescribed amount of lactose 14SD, microcrystalline cellulose, and colloidal silicon dioxide by a hopper mixer; Use φ7mm shallow concave circular punch for tableting, with a hardness of not less than 45N.

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