Anti-gastric ulcer granule and preparation method thereof

Abstract

The invention relates to anti-gastric ulcer granules and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The polaprezinc tablet comprises the following components in percentage by weight: 15% of polaprezinc, 10%-90% of a filling agent, 2.5%-5% of an adhesive and 0.25%-5% of a sweetening agent. Wherein mannitol is used as a filling agent, povidone K30 is used as an adhesive, sucralose is used as a sweetening agent, and the polaprezinc granules are prepared by changing the adding mode and dosage of the raw materials of the adhesive. The prepared polaprezinc granules have good stability and dissolution performance.

Description

Technical Field

[0001] The present application belongs to the technical field of pharmaceutical preparations, and specifically, relates to an anti-gastric ulcer preparation, and more specifically, to a polyprene zinc granule and a preparation method thereof. Background Art

[0002] Polyprezinc is a protective agent with antioxidant effect. It can directly protect cells and has the effect of eradicating Helicobacter pylori, so it can effectively treat gastric ulcers.

[0003] Polyprezinc is a new generation of anti-gastric ulcer drug developed by Hamari Pharmaceutical Co., Ltd. of Japan. It is the first zinc compound used in clinical practice. The drug was reviewed by the Ministry of Health, Labor and Welfare of Japan in 1994. Polyprezinc is a zinc L-carnosine complex. L-carnosine is a dipeptide composed of β-phenylalanine and L-histamine, which is an antioxidant. The new gastric mucosal protector was rated as the sixth of the top ten blockbuster prescription drugs in 2012. It is the first evidence-based medicine to prove that it can significantly increase the HP clearance rate and significantly inhibit inflammatory reactions, and reduce mucosal damage (triple therapy plus P can increase HP clearance by 20%). It is the first product that clearly and effectively inhibits gastric mucosal damage caused by non-steroidal anti-inflammatory drugs and alcohol. It is the only new gastric mucosal protector with both multi-layer repair mechanism and long-term physical coverage. It is the only one that can rebuild the submucosal tissue and its function, effectively reduce the recurrence rate of ulcers, and the only safe and long-term gastric mucosal protector.

[0004] Polyprezinc itself is hygroscopic, and it is necessary to consider improving the hygroscopicity in the formulation process design of granules in order to improve storage stability and improve the stringent requirements for the storage environment.

[0005] In the prior art of polyprene zinc granules, such as CN113769059A, a disintegrant (5%-10%) is contained, which may bring some disadvantages, such as increasing the complexity and cost of the granules, and the interaction with the main drug or other excipients may cause stability problems; CN103120646A contains ethanol, which, as an organic solvent, may chemically react with other ingredients in the granules, resulting in a decrease in the stability of the granules.

[0006] Therefore, in response to the above problems, how to improve the stability of polyprezinc granules while ensuring good dissolution still needs to be explored and studied. Summary of the invention

[0007] The purpose of the present application is to provide an anti-gastric ulcer granule and a preparation method thereof, by improving the components and preparation process to improve the stability of the granule while ensuring dissolution.

[0008] On the one hand, the present application provides an anti-gastric ulcer granule, which comprises, by weight percentage: 15% polyprene zinc, 10-90% filler, 2.5-5% binder, and 0.25-5.0% sweetener.

[0009] In one embodiment of the present invention, the filler may be one or more of corn starch, microcrystalline cellulose, mannitol, and lactose.

[0010] In one embodiment of the present invention, the binder is povidone K30.

[0011] In one embodiment of the present invention, the sweetener may be steviol glycoside or sucralose.

[0012] In one embodiment of the present invention, the polyprene zinc granules include, by weight percentage: 15% polyprene zinc, 81.5% filler, 3% binder, and 0.5% sweetener.

[0013] On the other hand, the present application also provides a method for preparing polyprene zinc granules, comprising the following steps:

[0014] Weighing: Weigh polyprezinc, mannitol, povidone K30, and sucralose according to the prescription composition;

[0015] Adhesive preparation: Prepare povidone K30 into a solution with a concentration of 8-12%, sucralose, povidone, and water;

[0016] Premixing: Add mannitol and polyprene zinc into the wet granulator and mix them at a stirring parameter of 100-150 rpm and a shear parameter of 800-1200 rpm for 3-8 minutes;

[0017] Granulation: stirring parameter 100-150rpm, shear parameter 800-1200rpm, atomization pressure 0.2Mpa, peristaltic pump speed 30rpm, add the binder within 6min, and continue granulation for 1min after addition;

[0018] Swing granulator granulation: nylon screen 20 mesh;

[0019] Drying: Inlet air temperature is 60℃, air volume is adjusted according to the amount of material, and drying is carried out to control the moisture content to less than 2%;

[0020] Granulation: After drying, the granules are sieved through 18-mesh and 80-mesh sieves respectively, and the granules between 18 and 80 mesh are collected, and the granules that do not pass 18 mesh are discarded. Use a swing granulator (nylon sieve 16 mesh) for granulation;

[0021] Total mixing: square cone mixer, 8rpm, mix for 5-10 minutes, take samples to test the content, and package the qualified ones.

[0022] Compared with the prior art, this application has the following beneficial effects:

[0023] 1. By removing disintegrants and ethanol, the present invention effectively avoids the stability problems that these two components may cause.

[0024] 2. Although disintegrants and ethanol may traditionally help improve the dissolution rate of the drug, the present invention achieves good dissolution performance without disintegrants and ethanol by optimizing other excipients and preparation processes. DETAILED DESCRIPTION

[0025] The following will be combined with the embodiments of the present application to clearly describe the technical solutions in the embodiments of the present application. 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 this application.

[0026] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the embodiments of the present invention belong. If the definitions set forth in this section are contrary to or otherwise inconsistent with the definitions set forth in the patents, patent applications, published patent applications, and other publications incorporated herein by reference, the definitions listed in this section take precedence over the definitions incorporated herein by reference.

[0027] In addition, the mass of the relevant components mentioned in the description of the embodiments of the present invention may not only refer to the specific content of each component, but also indicate the proportional relationship between the masses of the components. Therefore, as long as the content of the relevant components is proportionally enlarged or reduced according to the description of the embodiments of the present invention, it is within the scope disclosed in the description of the embodiments of the present invention. Specifically, the mass described in the description of the embodiments of the present invention may be a mass unit known in the chemical industry such as μg, mg, g, kg, etc.

[0028] The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, etc. used in the following examples are all commercially available unless otherwise specified. The present application will be described in detail below with reference to specific examples.

[0029] The present application provides an anti-gastric ulcer granule, which comprises, by weight percentage, 15% polyprene zinc, 10-90% filler, 2.5-5% binder, and 0.25-5.0% sweetener. The filler can be 81.5%, 82%, or 82.4%; the binder can be 2.5%, 3%, 3.5%, 4%, 4.5%, or 5%; the sweetener can be 0.25%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5%.

[0030] Preferably, the filler can be one or more of corn starch, microcrystalline cellulose, mannitol, and lactose; more preferably, the filler is mannitol.

[0031] In one embodiment of the present invention, the binder is povidone K30.

[0032] In one embodiment of the present invention, the sweetener may be steviol glycoside or sucralose, preferably sucralose.

[0033] In one embodiment of the present invention, the polyprene zinc granules include, by weight percentage: 15% polyprene zinc, 81.5% filler, 3% binder, and 0.5% sweetener.

[0034] The preparation method of polyprene zinc granules comprises the following steps:

[0035] Weighing: Weigh polyprezinc, mannitol, povidone K30, and sucralose according to the prescription composition;

[0036] Adhesive preparation: Prepare povidone K30 into a solution with a concentration of 8-12%, sucralose, povidone, and water;

[0037] Premixing: Add mannitol and polyprene zinc into the wet granulator and mix them at a stirring parameter of 100-150 rpm and a shear parameter of 800-1200 rpm for 3-8 minutes;

[0038] Granulation: stirring parameter 100-150rpm, shear parameter 800-1200rpm, atomization pressure 0.2Mpa, peristaltic pump speed 30rpm, add the binder within 6min, and continue granulation for 1min after addition;

[0039] Swing granulator granulation: nylon screen 20 mesh;

[0040] Drying: Inlet air temperature is 60℃, air volume is adjusted according to the amount of material, and drying is carried out to control the moisture content to less than 2%;

[0041] Granulation: After drying, the granules are sieved through 18-mesh and 80-mesh sieves respectively, and the granules between 18 and 80 mesh are collected, and the granules that do not pass 18 mesh are discarded. Use a swing granulator (nylon sieve 16 mesh) for granulation;

[0042] Total mixing: square cone mixer, 8rpm, mix for 5-10 minutes, take samples to test the content, and package the qualified ones.

[0043] In some embodiments, the mannitol is crushed by a Chinese herbal medicine crusher for 30 seconds.

[0044] In some embodiments, the binder may be formulated at a concentration of 8%, 9%, 10%, 11%, 12%, preferably 12%.

[0045] In some embodiments, the stirring parameter in the premixing granulation step may be 100 rpm, 110 rpm, 120 rpm, 130 rpm, 140 rpm, 150 rpm, preferably 150 rpm.

[0046] In some embodiments, the shear parameter in the premixing granulation step can be 800 rpm, 900 rpm, 1000 rpm, 1100 rpm, 1200 rpm, preferably 1000 rpm.

[0047] In some embodiments, the premixing time is 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, preferably 5 minutes.

[0048] In some embodiments, the total mixing time is 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, preferably 10 minutes.

[0049] The features and performance of the present application are further described in detail below in conjunction with the embodiments.

[0050] Reference Example:

[0051]

[0052] The dissolution curve test results of the reference preparation of polyprezinc granules (batch number: E325P) in four dissolution media are as follows:

[0053]

[0054]

[0055] Example 1

[0056] The single-dose prescription composition of Polyprezinc Granules: See Table 1

[0057] Table 1

[0058] The preparation process is as follows:

[0059]

[0060] Example 2

[0061] The single-dose prescription composition of Polyprezinc Granules: See Table 2 Table 2

[0062] name Unit dose / mg Polyprene Zinc 75 Mannitol 407.5 Povidone K30 15 Sucralose 2.5 Solvents used in the process and eventually removed water

[0063] The preparation process is as follows:

[0064]

[0065] Example 3

[0066] The single-dose prescription composition of Polyprezinc Granules: See Table 3 Table 3

[0067] name Unit dose / mg Polyprene Zinc 75 Mannitol 407.5 Povidone K30 17.5 Sucralose 2.5 Solvents used in the process and eventually removed water

[0068] The preparation process is as follows:

[0069]

[0070]

[0071] Example 4

[0072] The single-dose prescription composition of Polyprezinc Granules: See Table 4 Table 4

[0073] name Unit dose / mg Polyprene Zinc 75 Mannitol 407.5 Povidone K30 20 Sucralose 2.5 Solvents used in the process and eventually removed water

[0074] The preparation process is as follows:

[0075]

[0076]

[0077] Example 5

[0078] The single-dose prescription composition of Polyprezinc Granules: See Table 5 Table 5

[0079] name Unit dose / mg Polyprene Zinc 75 Mannitol 407.5 Povidone K30 25 Sucralose 2.5 Solvents used in the process and eventually removed water

[0080] The preparation process is as follows:

[0081]

[0082] Example 6

[0083] The single-dose prescription composition of Polyprezinc Granules: See Table 6 Table 6

[0084]

[0085]

[0086] The preparation process is as follows:

[0087]

[0088] Example 7

[0089] The single-dose prescription composition of Polyprezinc Granules: See Table 7 Table 7

[0090] name Unit dose / mg Polyprene Zinc 75 Mannitol 407.5 Povidone K30 15 Sucralose 2.5 Solvents used in the process and eventually removed water

[0091] The preparation process is as follows:

[0092]

[0093]

[0094] Example 8

[0095] The single-dose prescription composition of Polyprezinc Granules: See Table 8 Table 8

[0096] name Unit dose / mg Polyprene Zinc 75 Mannitol 407.5 Povidone K30 12.5 Sucralose 2.5 Solvents used in the process and eventually removed water

[0097] The preparation process is as follows:

[0098]

[0099]

[0100] Comparative Example 1

[0101] The single-dose prescription composition of Polyprezinc Granules: See Table 9 Table 9

[0102] name Unit dose / mg Polyprene Zinc 75 Mannitol 407.5 Povidone K30 7.5 Sucralose 2.5 Solvents used in the process and eventually removed water

[0103] The preparation process is as follows:

[0104]

[0105] Comparative Example 2

[0106] The single-dose prescription composition of Polyprezinc Granules: See Table 10 Table 10

[0107]

[0108]

[0109] The preparation process is as follows:

[0110]

[0111] Comparative Example 3

[0112] The single-dose prescription composition of Polyprezinc Granules: See Table 11 Table 11

[0113] name Unit dose / mg Polyprene Zinc 75 Mannitol 407.5 Povidone K30 27.5 Sucralose 2.5 Solvents used in the process and eventually removed water

[0114] The preparation process is as follows:

[0115]

[0116]

[0117] Comparative Example 4

[0118] The single-dose prescription composition of Polyprezinc Granules: See Table 12 Table 12

[0119] name Unit dose / mg Polyprene Zinc 75 Mannitol 407.5 Povidone K30 15 Sucralose 2.5 Solvents used in the process and eventually removed water

[0120] The preparation process is as follows:

[0121]

[0122] Comparative Example 5

[0123] The single-dose prescription composition of Polyprezinc Granules: See Table 13 Table 13

[0124] name Unit dose / mg Polyprene Zinc 75 Mannitol 407.5 Povidone K30 15 Sucralose 2.5 Solvents used in the process and eventually removed water

[0125] The preparation process is as follows:

[0126]

[0127] Comparative Example 6

[0128] The single-dose prescription composition of Polyprezinc Granules: See Table 14 Table 14

[0129] name Unit dose / mg Polyprene Zinc 75 Mannitol 407.5 Povidone K30 15 Sucralose 2.5 Solvents used in the process and eventually removed water

[0130] The preparation process is as follows:

[0131]

[0132] Comparative Example 7

[0133] The single-dose prescription composition of Polyprezinc Granules: See Table 15 Table 15

[0134] name Unit dose / mg Polyprene Zinc 75 Mannitol 407.5 Povidone K30 15 Sucralose 2.5 Solvents used in the process and eventually removed water

[0135] The preparation process is as follows:

[0136]

[0137]

[0138] Comparative Example 8

[0139] According to the prescription composition and process information of Haisike patent CN103120646A, the binder is a 50% ethanol solution of povidone K30, and the sample is prepared by wet granulation and fluidized bed drying process. The prescription composition is as shown in Table 16

[0140] Table 16

[0141] Element Unit dose / mg Polyprene Zinc 7.5 Mannitol 410 Povidone K30 15 Stevia 2.5 50% ethanol Moderate

[0142] See Table 17 for a list of the variable parameters in Examples 1-8 and Comparative Examples 1-8.

[0143] Table 17

[0144]

[0145] A: The particle size distribution of the polyprene zinc granules prepared in Example 1-8 and Comparative Example 1-8 was examined and measured according to the particle size and particle size distribution determination method (General Rule 0982 Double Sieving Method). The results are shown in Tables 18-1 to 18-2.

[0146] Table 18-1

[0147]

[0148] Table 18-2

[0149]

[0150] [Particle Size] Unless otherwise specified, the sum of the particles that cannot pass through the No. 1 sieve and the particles that can pass through the No. 5 sieve determined by the particle size and particle size distribution method (General Rule 0982 Double Screening Method) shall not exceed 15%.

[0151] B: Investigation of the content uniformity of the polyprene zinc granules prepared in Examples 1-8 and Comparative Examples 1-8

[0152] Take 1 bag of each sample, place it in a 250ml volumetric flask, add 25ml of 0.1mol / L hydrochloric acid solution, shake thoroughly to disintegrate and dissolve the main component, dilute to scale with mobile phase, shake well, filter, and take the filtrate as the test solution. Determine the content of each bag, all should meet the requirements. (Chinese Pharmacopoeia 2020 Edition Part IV 0941) The results are shown in Tables 19-1 to 19-2.

[0153] Table 19-1

[0154]

[0155] Table 19-2

[0156]

[0157]

[0158] C: Investigation of the dissolution performance of the polyprene zinc granules prepared in Examples 1-8 and Comparative Examples 1-8

[0159] Referring to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0931, Method 2), 0.1 mol / L HCl solution, pH 4.0 acetate buffer, and pH 6.8 phosphate buffer were used as dissolution media, respectively, at a speed of 50 rpm. The operation was carried out in accordance with the law, and samples were taken at 5 min, 10 min, 15 min, 20 min, and 30 min, respectively. The dissolution curves of the polyprezinc granules prepared in Examples 1-8 and Comparative Examples 1-8 and the reference reagent (trade name: Promac, batch number E325P) were detected. The results are shown in Tables 20-1 to 20-3.

[0160] Table 20-1

[0161]

[0162] Table 20-2

[0163]

[0164]

[0165] Table 20-3

[0166]

[0167] D: The stability of the polyprene zinc granules and the reference reagent prepared in Examples 1-8 and Comparative Examples 1-8 was investigated.

[0168] According to Examples 1-8, Comparative Examples 1-8 and reference reagents, and referring to the experimental method of influencing factors in the "Technical Guidance for Stability Studies of Chemical Drugs", the samples were placed under high temperature 60°C ± 2°C, high humidity RH 90% ± 5%, and light 4500lx ± 500lx for 6 months, and samples were taken at the 0th, 3rd, and 6th months for comparison. The results are shown in Tables 21 and 22.

[0169] Table 21

[0170]

[0171]

[0172]

[0173] Table 22

[0174]

[0175]

[0176] Impurity information:

[0177] Impurity name and structural formula

[0178] Impurity A (residue from starting material / degradation impurity)

[0179]

[0180] C 6 H 9 N 3 O 2 155.16

[0181] L-Histidine

[0182] Impurity B (intermediate residue)

[0183]

[0184] C 11 H 9 NO 4 219.20

[0185] Phthaloyl-β-alanine

[0186] Impurity C (intermediate residue)

[0187]

[0188] C 17 H 16 N 4 O 5 356.34

[0189] Phthaloyl-β-alanine-L-histidine

[0190] Impurity D (raw material residue (intermediate by-product))

[0191]

[0192] C 8 H 6 N 2 O 2 162.15

[0193] Phthalohydrazide

[0194] The above test results show that the polyprezinc granules of the present application are placed under the conditions of temperature 60°C ± 2°C, high humidity RH90% ± 5%, and light 4500lx ± 500lx for 6 months, and the various indicators have no significant changes compared with 0 months, indicating that the polyprezinc granules of the present application have good stability. Compared with the polyprezinc granules in the prior art, its stability is better than that of the prior art.

[0195] The embodiments of the present application are described above, but the present application is not limited to the above-mentioned specific implementation modes. The above-mentioned specific implementation modes are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can also 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.

Claims

1. An anti-gastric ulcer granule, comprising: Calculated by weight percentage, the granule comprises: 15% polyprene zinc, 10-90% filler, 2.5-5% binder, and 0.25-5.0% sweetener.

2. The granules according to claim 1, wherein the filler can be one or more of corn starch, microcrystalline cellulose, mannitol, and lactose. The granules according to claim 1 , wherein the binder is povidone K30. The granules according to claim 1 , wherein the sweetener is steviol glycoside or sucralose.

5. The granules according to claim 1, wherein the granules comprise, by weight percentage: 15% polyprene zinc, 81.5% filler, 3% binder, 0.5% sweetener.

6. The granules according to any one of claims 1 to 5, wherein the preparation method comprises the following steps: 1) Weighing: weigh polyprene zinc, mannitol, povidone K30, and sucralose according to the prescription composition; 2) Preparation of adhesive: prepare povidone K30 into a solution with a concentration of 8-12%, sucralose, povidone, and water; 3) Premixing: Add mannitol and polyprene zinc into a wet granulator and mix at a stirring parameter of 100-150 rpm and a shear parameter of 800-1200 rpm for 3-8 minutes; Granulation: stirring parameter 100-150rpm, shear parameter 800-1200rpm, atomization pressure 0.2Mpa, peristaltic pump speed 30rpm, add the binder within 6min, and continue granulation for 1min after addition; Swing granulator granulation: nylon screen 20 mesh; Drying: Inlet air temperature is 60℃, air volume is adjusted according to the amount of material, and the drying is carried out to control the moisture content to less than 2%; Granulation: After drying, the granules are sieved through 18-mesh and 80-mesh sieves respectively, and the granules between 18 and 80 mesh are collected, and the granules that do not pass 18 mesh are discarded. Use a swing granulator (nylon sieve 16 mesh) for granulation; Total mixing: square cone mixer, 8rpm, mix for 5-10 minutes, take samples to test the content, and package them if qualified.

7. The method for preparing the anti-gastric ulcer granules according to claim 6, characterized in that: The adhesive was formulated at a concentration of 12%.

8. The method for preparing the anti-gastric ulcer granules according to claim 6, characterized in that: The premixing time was 5 minutes.

9. The method for preparing the anti-gastric ulcer granules according to claim 6, characterized in that: The total mixing time was 10 minutes.

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