A kind of Ivocasai tablet and preparation method thereof

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and specifically discloses an ivocate tablet and a preparation method thereof. The present invention uses microcrystalline cellulose and mannitol in a specific ratio as fillers, cross-linked polyvinyl pyrrolidone and / or cross-linked sodium carboxymethyl cellulose as disintegrants, and adds hydroxypropyl cellulose and / or hydroxypropyl methyl cellulose as binders, and raw materials with suitable particle sizes, and prepares ivocate tablets through wet granulation. The prepared ivocate tablets have significantly improved dissolution rate and stability during storage compared to the original preparation, and can achieve a good replacement for the original product, thereby providing more drug options for SHPT patients, and reducing the drug cost of patients, and have high clinical application value.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an ivocasert tablet and a preparation method thereof. Background Art

[0002] As the incidence of chronic kidney disease increases year by year around the world, secondary hyperparathyroidism (SHPT), as a common and serious complication of chronic kidney disease, is threatening the health of many patients. According to authoritative medical statistics, the incidence of SHPT is as high as over 80% in patients with mid- to late-stage chronic kidney disease. SHPT not only causes excessive secretion of parathyroid hormone (PTH) in patients, leading to a series of painful symptoms such as bone pain, bone deformity, and skin itching, but also aggravates the deterioration of kidney function, seriously affecting the quality of life and survival of patients.

[0003] As a new generation of calcium-sensitive receptor agonist, ivocase has shown unique advantages in the treatment of SHPT. It can accurately act on calcium-sensitive receptors on parathyroid cells, effectively inhibit the synthesis and secretion of PTH, and thus effectively alleviate the condition of SHPT patients. However, there are many deficiencies in the preparation process of ivocase tablets on the market. On the one hand, in terms of drug dissolution performance, ivocase tablets currently have the problem of slow dissolution, which makes the drug unable to be quickly and stably absorbed after entering the human body, and it is difficult to meet the clinical demand for rapid onset. Especially in SHPT patients in the acute attack period, when the drug is urgently needed to act quickly to relieve symptoms such as severe pain, the dissolution characteristics of existing tablets become a major obstacle. On the other hand, the active ingredient content of ivocase tablets on the market will be significantly reduced in a high temperature and high humidity environment, affecting the therapeutic effect of ivocase tablets and increasing the risk of adverse reactions. Therefore, it is necessary to develop an ivocase tablet with fast dissolution rate and good stability to provide SHPT patients with better therapeutic drugs. Summary of the invention

[0004] Aiming at the problems of slow and uneven dissolution of existing ivocate tablets and poor stability in high temperature and high humidity environments, the present invention provides an ivocate tablet and a preparation method thereof.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0006] An ivocasert tablet comprising ivocasert, a filler, a binder, a disintegrant, a glidant and a lubricant;

[0007] The filler is microcrystalline cellulose and mannitol in a mass ratio of 1:2 to 2:1; the disintegrant is one or both of cross-linked polyvinyl pyrrolidone and cross-linked sodium carboxymethyl cellulose; the binder is one or both of hydroxypropyl cellulose and hydroxypropyl methyl cellulose;

[0008] The content of the binder is 1% to 3%, and the content of the disintegrant is 1% to 3%.

[0009] Compared with the prior art, the ivocassep tablet provided by the present invention selects microcrystalline cellulose and mannitol in a specific ratio as fillers, which can not only exert the adsorption and dispersion effect of microcrystalline cellulose on the drug, so that ivocassep is evenly distributed inside the tablet, but also can use the rapid water-soluble characteristics of mannitol to synergistically promote the rapid dispersion and dissolution of ivocassep in the dissolution medium, and significantly improve the dissolution rate of the drug; further, selecting 1% to 3% of cross-linked polyvinyl pyrrolidone and / or cross-linked sodium carboxymethyl cellulose as disintegrants, not only can further improve the dissolution rate of the ivocassep tablet, but also can avoid the adverse effects of the disintegrant on the tableting process; adding a specific amount of binder can ensure that the particles have good formability and fluidity during the preparation process, meet the tableting process requirements, improve the content uniformity of the ivocassep tablet, and ensure that the ivocassep particles are evenly distributed inside the tablet, providing favorable conditions for subsequent dissolution, and promoting rapid and uniform dissolution of the drug.

[0010] The ivocasert tablet provided by the present invention not only ensures the fluidity and stability of ivocasert in the preparation process, but also improves the dissolution rate of ivocasert in the medium through the reasonable compatibility of multiple auxiliary materials and the synergy of microcrystalline cellulose and mannitol. Moreover, by selecting cross-linked polyvinyl pyrrolidone and / or cross-linked sodium carboxymethyl cellulose and an appropriate amount of adhesive for synergistic effect, the dissolution process is controlled, and the dissolution rate is further improved, especially the dissolution rate in a pH 4.5 medium. The rapid dissolution of the drug can be achieved, ensuring that the patient can absorb the drug in time and quickly relieve symptoms, and the stability of the drug can be significantly improved, so as to provide a safer, more effective and convenient therapeutic drug for SHPT patients.

[0011] Furthermore, the filler is microcrystalline cellulose and mannitol in a mass ratio of 2:1.

[0012] Microcrystalline cellulose and mannitol in a preferred ratio are used as fillers to further increase the dissolution rate of the ivocarb tablets.

[0013] Furthermore, the content of the adhesive is 1% to 2%.

[0014] The preferred amount of binder can not only improve the preparation properties of the raw materials and ensure the content uniformity of the ivocasert tablets, but also further improve the dissolution rate of the ivocasert tablets.

[0015] Furthermore, the D of the ivocasert 10 3μm~10μm, D 50 20μm~30μm, D 90 It is 30μm~50μm.

[0016] The preferred particle size distribution of the ivocasert raw material is beneficial to improving the dissolution rate. At the same time, the preferred particle size distribution is also helpful to maintain the physical stability and content uniformity of the tablets and improve the consistency of drug efficacy.

[0017] Furthermore, the glidant is one or both of colloidal silicon dioxide and micro-powder silica gel.

[0018] Furthermore, the lubricant is at least one of magnesium stearate, zinc stearate or talc.

[0019] Furthermore, the ivocasert tablet comprises the following components in percentage by mass: 0.5% to 2.0% ivocasert, 85% to 95% filler, 1% to 3% binder, 1% to 3% disintegrant, 0.3% to 3.0% glidant and 0.5% to 2.0% lubricant.

[0020] Preferably, the ivocasert tablet comprises the following components in percentage by mass: ivocasert 1.0% to 2.0%, filler 86% to 91%, binder 1% to 2%, disintegrant 1% to 2%, glidant 0.3% to 0.7% and lubricant 0.8% to 1.5%.

[0021] Furthermore, the ivocasert tablet also includes a coating premix.

[0022] Exemplarily, the coating premix can be selected from the One or more of the brands 39F620002-CN and 39F620005-CN, with a coating weight gain of 2.0-5.0%.

[0023] Furthermore, the ivocasert tablet comprises the following components in percentage by mass: 1.5% ivocasert, 90% filler, 1.5% binder, 1.5% disintegrant, 0.5% glidant, 1.0% lubricant, and 4.0% coating premix.

[0024] The present invention also provides a method for preparing the above-mentioned ivocassel tablet, comprising the following steps:

[0025] S1, weighing each component according to the designed ratio of the above-mentioned Ivocassel tablet, adding the prescribed amount of adhesive into purified water to obtain an adhesive solution with a mass concentration of 3% to 6%;

[0026] S2, wet granulating the prescribed amount of ivocate, filler and disintegrant, then adding the binder solution to prepare a soft material, granulating, drying, and sieving to obtain granules;

[0027] S3, uniformly mixing the granules with the glidant and the lubricant, tableting, and coating to obtain Ivocaser tablets.

[0028] The preparation method of the ivocasert tablets provided by the present invention adopts wet granulation, has a simple preparation process, and the prepared ivocasert tablets have good stability and a dissolution rate consistent with that of the original research product, can achieve a good replacement for the original research product, and provide more drug options for SHPT patients.

[0029] Furthermore, in S1, the mass concentration of the adhesive solution is 5.0%.

[0030] Furthermore, in S2, the drying temperature is 55°C to 65°C.

[0031] Furthermore, in S2, the aperture of the sieve is Φ2.0 mm.

[0032] Furthermore, in S3, a 7.0 mm round shallow concave punch is used for tableting, and the tablet weight difference is controlled within ±7.5%, and the friability is ≤1.0%.

[0033] Furthermore, in S3, the coating premix is ​​prepared into a coating solution with a concentration of 15%, the coating temperature is 35° C. to 55° C., and the coating weight gain is 2.0% to 5.0%.

[0034] The present invention uses microcrystalline cellulose and mannitol in a specific ratio as fillers, cross-linked polyvinyl pyrrolidone and / or cross-linked sodium carboxymethyl cellulose as disintegrants, and adds hydroxypropyl cellulose and / or hydroxypropyl methyl cellulose as binders, and raw materials with suitable particle sizes, and prepares ivocassep tablets through wet granulation. The prepared ivocassep tablets have significantly improved dissolution rate and stability during storage compared to the original preparation, and can achieve a good replacement for the original product, thereby providing more drug options for SHPT patients, and reducing the drug cost of patients, and have high clinical application value. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0036] In order to better illustrate the present invention, further examples are given below.

[0037] Example 1

[0038] This embodiment provides an ivocasert tablet, and the prescription dosage (1000 tablets) is shown in the following table:

[0039]

[0040] The preparation method of the above-mentioned Ivocassette tablet is as follows:

[0041] S1, weighing a prescribed amount of hydroxypropyl cellulose, adding it to purified water, stirring and dissolving, to obtain a binder solution with a mass concentration of 5.0%;

[0042] S2, placing the prescribed amount of ivocate, microcrystalline cellulose, mannitol, and cross-linked polyvinyl pyrrolidone in a wet granulator and mixing for 10 minutes, adding an aqueous binder solution under high-speed stirring and shearing to obtain a soft material, using a fast granulator for wet granulation, drying in a boiling dryer at 60° C., and passing the dry granules through a 2.0 mm dia. sieve to obtain granules;

[0043] S3, mixing the granules after granulation with magnesium stearate and colloidal silicon dioxide uniformly, and pressing the tablets with a 7.0 mm round shallow concave punch, with the tablet weight difference controlled within ±7.5% and the friability ≤1.0%, to obtain ivocate tablets;

[0044] S4, adding the coating powder into purified water to prepare a coating solution with a mass concentration of 15%, coating the ivocasert tablets, controlling the tablet bed temperature at 35-55° C., and obtaining ivocasert coated tablets.

[0045] Take D 10 3μm~10μm, D 50 20μm~30μm, D 90 The ivocarb raw material is 30 μm to 50 μm (prescription 1); D 10 10μm~20μm, D 50 30μm~50μm, D 90 The ivocarb raw material is 50 μm to 70 μm (prescription 2); D 10 30μm~50μm, D 50 50μm~70μm, D 90 The raw material of 70 μm to 100 μm of ivocad is prepared (prescription 3); three groups of ivocad coated tablets are prepared according to the above process.

[0046] The dissolution curves of the ivocasert coated tablets prepared by the above-mentioned prescriptions 1, 2 and 3 were tested in pH 1.0 hydrochloric acid solution and pH 4.5 acetate buffer.

[0047] Detection method: Take each sample, use pH 1.0 hydrochloric acid solution and pH 4.5 acetate buffer solution as dissolution medium, temperature 37°C, volume 900mL, rotation speed 50rpm, operate according to the law, and take samples to detect the dissolution amount after 5min, 10min, 15min, 20min, 30min, 45min, 60min, 90min, and 120min. The results are shown in Table 1 and Table 2.

[0048] Table 1 Dissolution curve in pH 1.0 hydrochloric acid solution

[0049]

[0050] Table 2 Dissolution curve in pH 4.5 acetate buffer

[0051]

[0052] The results showed that there was no significant difference in the dissolution of each prescription and the original research in pH 1.0 hydrochloric acid solution, and all were able to achieve rapid dissolution; however, in pH 4.5 acetate buffer, the dissolution of prescription 1 was better than that of prescription 2, prescription 3 and the original research, especially the dissolution rate in 20-30 min was better than that of the original research, achieving rapid dissolution of the drug, which is beneficial to ensure that SHPT patients can absorb the drug in time and quickly relieve symptoms.

[0053] Stability test

[0054] Prescription 1 and the original preparation were placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the 1st, 2nd, 3rd and 6th month to examine the changes in their properties, solubility, content and related substances. The results are shown in Table 3.

[0055] The dissolution test method is as follows: using pH 1.0 hydrochloric acid solution as the dissolution medium, the temperature is 37°C, the volume is 900mL, the rotation speed is 50rpm, and sampling is performed every 30 minutes to test the dissolution.

[0056] Table 3 Stability results

[0057]

[0058]

[0059] The results showed that the storage stability of Prescription 1 was significantly better than that of the original preparation. The impurity content was significantly reduced after being placed in a high temperature and high humidity environment for 6 months, making it an effective substitute for the original preparation.

[0060] Example 2

[0061] This embodiment provides an ivocasert tablet, and the prescription dosage (1000 tablets) is shown in the following table:

[0062]

[0063] The preparation method of the ivocasert tablet is exactly the same as that in Example 1, and will not be repeated here.

[0064] The dissolution curves of the above-prepared Prescriptions 4 and 5 in pH 4.5 acetate buffer were tested in the same manner as in Example 1. The results are shown in Table 4.

[0065] Table 4 Dissolution curve in pH 4.5 acetate buffer

[0066]

[0067] The results showed that the dissolution rate of prescription 5 was lower than that of the original research, and the final dissolution was also lower than that of the original research. The dissolution rate of prescription 4 was higher than that of prescription 5, but lower than that of prescription 1. Therefore, selecting microcrystalline cellulose and mannitol with a mass ratio of 2:1 as fillers can obtain better dissolution effect.

[0068] Example 3

[0069] This embodiment provides an ivocasert tablet, and the prescription dosage (1000 tablets) is shown in the following table:

[0070]

[0071]

[0072] The preparation method of the ivocasert tablet is exactly the same as that in Example 1, and will not be repeated here.

[0073] The dissolution curves of Prescriptions 6 to 9 prepared above in pH 4.5 acetate buffer were tested in the same manner as in Example 1. The results are shown in Table 5.

[0074] Table 5 Dissolution curve in pH 4.5 acetate buffer

[0075]

[0076] The results showed that a faster dissolution rate could be achieved when the dosage of the binder was in the range of 1% to 3%. The optimal dosage of the binder was 1% to 2%. When the dosage of the binder was 1.5% (i.e., prescription 1), the dissolution rate was better than that of the original research. When the dosage of the binder exceeded 3%, the dissolution rate (especially 5 to 30 minutes) was significantly reduced, which was not similar to the original research.

[0077] The ivocasert tablets prepared from Prescription 1 and Prescription 6 to Prescription 9 were tested for content, tablet weight difference, disintegration time and dissolution rate. The results are shown in Table 6.

[0078] The dissolution test method is as follows: using pH 1.0 hydrochloric acid solution as the dissolution medium, the temperature is 37°C, the volume is 900mL, the rotation speed is 50rpm, and sampling is performed every 30 minutes to test the dissolution.

[0079] Table 6

[0080] Detection items Prescription 1 Prescription 6 Prescription 7 Prescription 8 Prescription 9 content / % 101.1 99.5 99.4 98.7 99.6 Dissolution / % 100.5 95.8 92.1％ 89.3％ 79.6％ Tablet weight difference / % -2.3～1.5 -3.3～3.5 -2.3～3.5 -3.3～2.5 -4.8～4.2 Disintegration time 1'25” 1'45” 3'23” 7'55” 10'34”

[0081] Example 4

[0082] This embodiment provides an ivocasert tablet, and the prescription dosage (1000 tablets) is shown in the following table:

[0083]

[0084] The preparation method of the ivocate tablet is exactly the same as that of Example 1, which will not be described again. The ivocate tablet prepared in this example is recorded as Prescription 10.

[0085] The content, tablet weight difference, disintegration time and dissolution test of the above-prepared prescription 10 were carried out in the same manner as in Example 3. The results are shown in Table 7.

[0086] Table 7

[0087] Detection items Prescription 1 Prescription 10 content / % 101.1 98.6 Dissolution / % 100.5 90.8 Tablet weight difference / % -2.3～1.5 -4.5～3.9 Disintegration time 1'25” 5'05”

[0088] Example 5

[0089] This embodiment provides an ivocasert tablet, and the prescription dosage (1000 tablets) is shown in the following table:

[0090]

[0091]

[0092] The preparation method of the ivocasert tablet is exactly the same as that in Example 1, and will not be repeated here.

[0093] The dissolution curves of Prescriptions 11 to 14 prepared above in pH 4.5 acetate buffer were tested in the same manner as in Example 1. The results are shown in Table 8.

[0094] Table 8 Dissolution curve in pH 4.5 acetate buffer

[0095]

[0096] The results showed that when the disintegrant content was 0.5% (prescription 11), the dissolution rate was significantly lower than that of the original formulation and was not similar to the original formulation. When the disintegrant content was 1.5% (prescription 1), rapid dissolution (15min dissolution ≥ 85%) could be achieved. When the disintegrant content in the formulation was 1% to 3%, that is, prescriptions 12 to 14, the dissolution effect comparable to the original formulation could be achieved.

[0097] Example 6

[0098] This embodiment provides an ivocasert tablet, and the prescription dosage (1000 tablets) is shown in the following table:

[0099]

[0100]

[0101] The preparation method of the ivocasert tablet is exactly the same as that in Example 1, and will not be repeated here.

[0102] The content, tablet weight difference, disintegration time and dissolution test of Prescriptions 15 and 16 prepared above were carried out in the same manner as in Example 3. The results are shown in Table 9.

[0103] Table 9

[0104] Detection items Prescription 15 Prescription 16 content / % 99.6 98.7 Dissolution / % 82.3 75.2 Tablet weight difference / % -3.5～2.9 -3.5～3.1 Disintegration time 2'05” 8'34”

[0105] The results show that when cross-linked sodium carboxymethyl cellulose is used as a disintegrant, the solubility is only 82.3%, which basically meets the requirement of 80% dissolution in 30 minutes. However, when sodium starch glycolate is used as a disintegrant, the requirement of 80% dissolution in 30 minutes cannot be met.

[0106] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. An ivocassette tablet, characterized in that: Includes ivocate, filler, binder, disintegrant, glidant and lubricant; The filler is microcrystalline cellulose and mannitol in a mass ratio of 1:2 to 2:1; the disintegrant is one or both of cross-linked polyvinyl pyrrolidone and cross-linked sodium carboxymethyl cellulose; the binder is one or both of hydroxypropyl cellulose and hydroxypropyl methyl cellulose; The content of the binder is 1% to 3%, and the content of the disintegrant is 1% to 3%.

2. The ivocardia plug according to claim 1, characterized in that: The filler is microcrystalline cellulose and mannitol in a mass ratio of 2:

1.

3. The ivocardia plug according to claim 1, characterized in that: The content of the adhesive is 1% to 2%.

4. The ivocardia plug according to claim 1, characterized in that: The D of Evocasert 10 3μm~10μm, D 50 20μm~30μm, D 90 It is 30μm~50μm.

5. The ivocardia plug according to claim 1, characterized in that: The glidant is one or both of colloidal silicon dioxide and micro-powder silica gel.

6. The ivocardia plug according to claim 1, characterized in that: The lubricant is at least one of magnesium stearate, zinc stearate or talc.

7. The ivocardia plug according to any one of claims 1 to 6, characterized in that: The ivocasert tablet comprises the following components in percentage by weight: 0.5% to 2.0% of ivocasert, 85% to 95% of a filler, 1% to 3% of a binder, 1% to 3% of a disintegrant, 0.3% to 3.0% of a glidant and 0.5% to 2.0% of a lubricant.

8. The ivocardia plug according to any one of claims 1 to 6, characterized in that: The ivocasert tablet further comprises a coating premix.

9. The ivocardia plug according to claim 8, characterized in that: The ivocaser tablet comprises the following components in percentage by weight: 1.5% ivocaser, 90% filler, 1.5% binder, 1.5% disintegrant, 0.5% glidant, 1.0% lubricant, and 4.0% coating premix.

10. A method for preparing an ivocasert tablet, characterized in that: The steps include: S1, weighing each component according to the designed proportion of the ivocasert tablet according to claim 8 or 9, adding the prescribed amount of adhesive into purified water to obtain an adhesive solution with a mass concentration of 3% to 6%; S2, wet granulating the prescribed amount of ivocate, filler and disintegrant, then adding the binder solution to prepare a soft material, granulating, drying, and sieving to obtain granules; S3, uniformly mixing the granules with the glidant and the lubricant, tableting, and coating to obtain Ivocaser tablets.

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