CN118903031A - Olmesartan medoxomil orally disintegrating tablet and preparation method thereof - Google Patents

Abstract

The invention discloses an olmesartan medoxomil orally disintegrating tablet and a preparation method thereof, and relates to the technical field of pharmaceutical preparations. The olmesartan medoxomil orally disintegrating tablet comprises the following components in parts by weight: 10-15 parts of olmesartan medoxomil, 25-50 parts of cyclodextrin, 6.95-15 parts of carboxymethyl cellulose, 23-50 parts of microcrystalline cellulose, 0.4-0.8 part of sucralose, 0.2-0.5 part of acesulfame potassium, 0.05-0.15 part of essence and 0.95-2.0 parts of magnesium stearate, wherein the particle size of the olmesartan medoxomil meets the following requirements: d90 is more than 5 μm and less than or equal to 30 μm. The olmesartan medoxomil orally disintegrating tablet disclosed by the invention has the advantages of good dissolution performance, higher stability, high consistency with the original grinding medicine and faster disintegration.

Description

Olmesartan medoxomil orally disintegrating tablet and preparation method thereof

Technical Field

The invention relates to the technical field of pharmaceutical preparations, in particular to an olmesartan medoxomil orally disintegrating tablet and a preparation method thereof.

Background Art

Olmesartan medoxomil is a prodrug with the chemical formula:

.

Olmesartan medoxomil is absorbed and hydrolyzed into Olmesartan through the gastrointestinal tract. Olmesartan is a selective angiotensin II type 1 receptor (AT1) antagonist. It blocks the vasoconstriction effect of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor of vascular smooth muscle, thereby playing a role in lowering blood pressure. At present, the varieties sold in the domestic market are commonly found in ordinary tablets. The tablets have poor patient compliance due to difficulty in swallowing, so an orodisintegrating tablet is prepared to improve the patient's medication compliance.

Olmesartan Medoxomil Orodisintegrating Tablets is an angiotensin receptor blocker antihypertensive drug developed by Daiichi Sankyo Co., Ltd. in 2015. The drug is currently only available in Japan and provides convenience for patients who have difficulty swallowing tablets, such as the elderly and children. The development of orodisintegrating tablets is not only suitable for specific groups of people, but also its feature of being able to be taken without water makes it more convenient to take the drug.

Chinese patent CN101066264A discloses a combination of a solid dispersion containing olmesartan medoxomil and one or more selected from polyvinyl pyrrolidone, poloxamer, polyethylene glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid esters, and polyoxyethylene castor oil, which effectively solves the shortcomings of olmesartan medoxomil in terms of poor solubility and poor solubility, and is beneficial to the preparation and quality improvement of pharmaceutical preparations.

Chinese patent CN118384117A discloses an olmesartan medoxomil orally disintegrating tablet and a preparation method thereof, which is composed of the following components by weight: 1-20 parts of olmesartan medoxomil, 20-80 parts of mannitol cross-polymerized co-processed product, 10-50 parts of filler, 1-20 parts of low-substituted hydroxypropyl cellulose, 0.02-2.0 parts of sweetener, 0.02-2.0 parts of acesulfame potassium, 0.02-2.0 parts of flavor, and 0.02-5.0 parts of magnesium stearate; the mannitol cross-polymerized co-processed product is composed of 50-80 parts of mannitol, 1-5 parts of cross-linked polyvinylpyrrolidone, 1-5 parts of copolyvinylpyrrolidone, 1-5 parts of maltitol, and 5-10 parts of sorbitol. By adding the co-processed novel auxiliary material mannitol cross-polymerized co-processed product, the problems in the existing production of orally disintegrating tablets are solved. It focuses on taste-masking performance, disintegration time, etc., but does not pay attention to the consistency of dissolution with the original drug.

At present, there is still a lack of Olmesartan medoxomil orodisintegrating tablets that are highly consistent with the original drug. It is particularly important for generic drugs to achieve consistency in quality and efficacy with reference preparations. Therefore, it is still necessary to develop Olmesartan medoxomil orodisintegrating tablets that are highly consistent with the original drug.

Summary of the invention

In view of this, the purpose of the present invention is to provide an olmesartan medoxomil orally disintegrating tablet and a preparation method thereof, so as to overcome the problem of slow disintegration when cyclodextrin is used as an excipient, achieve good dissolution performance, higher stability, and high consistency with the original drug.

To achieve the above-mentioned purpose of the invention, the technical solution of the present invention is as follows:

In one aspect, the present invention provides an olmesartan medoxomil orally disintegrating tablet, which is composed of the following ingredients in parts by weight:

Olmesartan medoxomil 10-15 parts, cyclodextrin 25-50 parts, carboxymethyl cellulose 6.95-15 parts, microcrystalline cellulose 23-50 parts, sucralose 0.4-0.8 parts, acesulfame potassium 0.2-0.5 parts, flavor 0.05-0.15 parts, magnesium stearate 0.95-2.0 parts, wherein the particle size of the olmesartan medoxomil satisfies: 5μm＜D90≤30μm.

Preferably, the Olmesartan Medoxomil orally disintegrating tablets are composed of the following ingredients in parts by weight:

Olmesartan medoxomil 12-13 parts, cyclodextrin 30-32 parts, carboxymethyl cellulose 12-13 parts, microcrystalline cellulose 41-42 parts, sucralose 0.5-0.7 parts, acesulfame potassium 0.3-0.35 parts, flavor 0.08-0.12 parts, magnesium stearate 1.0-1.2 parts.

Further preferably, the Olmesartan Medoxomil orally disintegrating tablets are composed of the following ingredients in parts by weight:

12.5 parts of Olmesartan Medoxomil, 31.25 parts of cyclodextrin, 12.5 parts of carboxymethyl cellulose, 41.71 parts of microcrystalline cellulose, 0.63 parts of sucralose, 0.31 parts of acesulfame potassium, 0.1 parts of flavor, and 1 part of magnesium stearate.

Preferably, the particle size of the olmesartan medoxomil satisfies: 5 μm＜D90≤27.2 μm.

More preferably, the particle size of the olmesartan medoxomil satisfies: 14.3 μm≤D90≤27.2 μm.

More preferably, the particle size of the olmesartan medoxomil satisfies: D90 is 14.3 μm or 27.2 μm.

Most preferably, the particle size of the olmesartan medoxomil satisfies: D90 is 14.3 μm.

In the present invention, the term "D90" refers to the particle size value corresponding to when the cumulative distribution percentage from small to large reaches 90% in the particle size distribution, that is, the particles with a particle size smaller than this value account for 90%.

The cyclodextrin is selected from at least one of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. Preferably, the cyclodextrin is β-cyclodextrin.

The flavor is selected from at least one of orange flavor, citrus flavor, strawberry flavor, cherry flavor, lemon flavor, mint flavor, and pineapple flavor. As a specific example in the present invention, the flavor is orange flavor, specifically orange powder flavor.

On the other hand, the present invention provides a method for preparing the above-mentioned Olmesartan Medoxomil orally disintegrating tablets, wherein the preparation method is a powder mixing direct compression process.

Preferably, the preparation method comprises the following steps:

(1) mixing olmesartan medoxomil, microcrystalline cellulose, cyclodextrin, carboxymethyl cellulose, sucralose, acesulfame potassium and flavor to obtain a mixed material;

(2) sieving the mixed material obtained in step (1) to obtain a sieved material;

(3) Mixing the sieved material obtained in step (2) and magnesium stearate to obtain a total mixture;

(4) The total mixture obtained in step (3) is tableted.

Further preferably, in step (1), the acesulfame potassium is first sieved through a 60-80 mesh sieve before mixing, and more preferably sieved through a 60 mesh sieve.

Further preferably, in step (1), the mixing conditions are: rotation speed 10-30 Hz, time 10-30 min, and further preferably: rotation speed 20 Hz, time 15 min.

Further preferably, in step (2), the sieving is through a 20-40 mesh sieve, and further preferably through a 30 mesh sieve.

Further preferably, in step (3), the total mixing conditions are: rotation speed 10-30 Hz, time 10-30 min, and further preferably: rotation speed 20 Hz, time 15 min.

Further preferably, in step (4), the tabletting parameters are: tablet weight 160 mg, hardness 20-60N, and more preferably 30-50N.

The beneficial effects of the present invention are:

(1) Olmesartan medoxomil orally disintegrating tablets with high consistency with the original drug were obtained by specifically selecting the composition and ratio of excipients.

(2) The orally disintegrating tablets of Olmesartan Medoxomil of the present invention overcome the problem of slow disintegration when cyclodextrin is used as an excipient, and have good dissolution performance. At the same time, compared with the original drug, they disintegrate faster and contain less impurities.

DETAILED DESCRIPTION

The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all weight contents. Unless otherwise specified, it is understood that the process is carried out at room temperature.

In the following examples, some of the raw materials are from the following sources:

Olmesartan medoxomil was purchased from Zhuhai Rundu Pharmaceutical Co., Ltd. with registration number Y20170000394;

β-Cyclodextrin was purchased from Hunan Jiudian Hongyang Pharmaceutical Co., Ltd. with registration number F20209990809;

Microcrystalline cellulose was purchased from Jiangsu Xidian Pharmaceutical Excipients Co., Ltd., model UF-702, registration number F20190000532;

Carboxymethyl cellulose was purchased from Xibixi Trading Co., Ltd., model NS-300, registration number F20180001743

Sucralose was purchased from Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd., registration number F20209990121;

Acesulfame potassium was purchased from Anhui Weiduo Food Ingredients Co., Ltd., registration number F20220000381;

Magnesium stearate was purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., model SH-YM-MM, registration number F20209990494;

Orange powder flavor was purchased from Senxin Flavor & Pigment Technology Co., Ltd., model number 98AF7429.

Example 1

The recipe is as follows:

Table 1.

The preparation process is as follows:

(1) Grind acesulfame potassium, pass through a 60-mesh sieve, and set aside;

(2) Weigh the formula amount of olmesartan medoxomil (D90 is 14.3 μm), microcrystalline cellulose, β-cyclodextrin, carboxymethyl cellulose, sucralose, acesulfame potassium and orange powder flavor, pour them into a mixing hopper for mixing, set the mixing speed to 20 Hz, and the mixing time to 15 min to obtain a mixed material;

(3) Passing the mixed material obtained in step (2) through a 30-mesh sieve to obtain a sieved material;

(4) adding the sieved material obtained in step (3) and the formulated amount of magnesium stearate into a mixer for total mixing, setting the mixer speed to 20 Hz and the mixing time to 15 min, and discharging the material to obtain a total mixture;

(5) The total mixture obtained in step (4) is tableted, and the tableting parameters are: tablet weight 160 mg, hardness 30-50N.

Example 2

The recipe is as follows:

Table 2.

The preparation process is the same as that of Example 1.

Example 3

The recipe is as follows:

Table 3.

The preparation process is the same as that of Example 1.

Example 4

The difference from Example 1 is that the D90 of Olmesartan Medoxomil is 27.2 μm, and the rest are the same.

Example 5

The difference from Example 1 is that the D90 of Olmesartan Medoxomil is 6.8 μm, and the rest are the same.

Example 6

The difference from Example 1 is that the tablet hardness is 20-30N, and the rest are the same.

Example 7

The difference from Example 1 is that the tablet hardness is 50-60N, and the rest is the same.

Comparative Example 1

The recipe is as follows:

Table 4.

The preparation process is the same as that of Example 1.

Comparative Example 2

The recipe is as follows:

Table 5.

The preparation process is the same as that of Example 1.

Comparative Example 3

The difference from Example 1 is that carboxymethyl cellulose is replaced by sodium carboxymethyl starch, and the rest is the same.

Comparative Example 4

The difference from Example 1 is that microcrystalline cellulose is replaced by pregelatinized starch, and the rest is the same.

Comparative Example 5

The difference from Example 1 is that the D90 of Olmesartan Medoxomil is 101.0 μm, and the rest are the same.

Comparative Example 6

The difference from Example 1 is that the D90 of Olmesartan Medoxomil is 5 μm, and the rest are the same.

Effect test

1. Properties and content

The results are as follows:

Table 6.

2. In vitro dissolution behavior

In vitro dissolution tests are often used to guide the development of pharmaceutical preparations, evaluate the consistency of quality within and between batches of preparations, and evaluate the consistency of quality and efficacy before and after changes in drug prescription processes. For ordinary oral solid preparations, the quality of generic preparations can be evaluated by comparing the similarity of multiple in vitro dissolution curves between generic preparations and reference preparations. The reference preparation is the original Olmesartan Medoxomil Orally Disintegrating Tablets (TNA3003).

Detection method:

Table 7.

2.1 Test results of pH 6.8 medium:

The results of Example 1-Example 5 are as follows:

Table 8.

The results of Comparative Example 1, Comparative Example 2, Comparative Example 5 and Comparative Example 6 are as follows:

Table 9.

The results of Comparative Examples 3 and 4 are as follows:

Table 10.

3. Disintegration time limit

Test method: According to the disintegration time limit inspection method of Part IV of the Chinese Pharmacopoeia 2020, the inspection method under the orodisintegrating tablet test item: fix the stainless steel tube on the bracket and immerse it in a 1000mL cup. The cup contains about 900mL of water at a temperature of 37℃±1℃. Adjust the water level so that the screen is 15mm±1mm below the water surface when the stainless steel tube is at the lowest position. Start the instrument. Take 1 tablet of this product and place it in the above-mentioned stainless steel tube for inspection. It should all disintegrate and pass through the screen within 60 seconds. If there is a small amount of light floating or adhering to the inner wall of the stainless steel tube or the screen, but there is no hard core, it can be considered as meeting the regulations. Repeat the measurement of 6 tablets, and all should meet the regulations. If 1 tablet does not meet the regulations, another 6 tablets should be taken for retest, and all should meet the regulations.

Table 11.

3. Content of related substances

Test method:

Table 12.

Taking the reference preparation and Example 1 as examples, the contents of related substances are compared as follows:

Table 13.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. An orally disintegrating tablet of Olmesartan Medoxomil, characterized in that it is composed of the following ingredients in parts by weight: Olmesartan medoxomil 10-15 parts, cyclodextrin 25-50 parts, carboxymethyl cellulose 6.95-15 parts, microcrystalline cellulose 23-50 parts, sucralose 0.4-0.8 parts, acesulfame potassium 0.2-0.5 parts, flavor 0.05-0.15 parts, magnesium stearate 0.95-2.0 parts, wherein the particle size of the olmesartan medoxomil satisfies: 5μm＜D90≤30μm. 2. The orally disintegrating tablet of Olmesartan Medoxomil according to claim 1, characterized in that it is composed of the following ingredients in parts by weight: Olmesartan medoxomil 12-13 parts, cyclodextrin 30-32 parts, carboxymethyl cellulose 12-13 parts, microcrystalline cellulose 41-42 parts, sucralose 0.5-0.7 parts, acesulfame potassium 0.3-0.35 parts, flavor 0.08-0.12 parts, magnesium stearate 1.0-1.2 parts. 3. The orally disintegrating tablet of Olmesartan Medoxomil according to claim 2, characterized in that it is composed of the following ingredients in parts by weight: 12.5 parts of Olmesartan Medoxomil, 31.25 parts of cyclodextrin, 12.5 parts of carboxymethyl cellulose, 41.71 parts of microcrystalline cellulose, 0.63 parts of sucralose, 0.31 parts of acesulfame potassium, 0.1 parts of flavor, and 1 part of magnesium stearate. 4 . The orally disintegrating tablet of Olmesartan Medoxomil according to claim 1 , wherein the particle size of the Olmesartan Medoxomil satisfies: 5 μm＜D90≤27.2 μm. 5 . The orally disintegrating tablet of Olmesartan Medoxomil according to claim 1 , wherein the particle size of the Olmesartan Medoxomil satisfies: 14.3 μm≤D90≤27.2 μm. 6 . The orally disintegrating tablet of Olmesartan Medoxomil according to claim 1 , wherein the particle size of the Olmesartan Medoxomil satisfies: D90 is 14.3 μm or 27.2 μm. 7 . The orally disintegrating tablet of Olmesartan Medoxomil according to claim 1 , wherein the particle size of the Olmesartan Medoxomil satisfies: D90 is 14.3 μm. 8. The method for preparing the orally disintegrating tablets of Olmesartan Medoxomil according to any one of claims 1 to 7, characterized in that the preparation method is a powder mixing direct compression process. 9. The method for preparing the orally disintegrating tablets of Olmesartan Medoxomil according to claim 8, characterized in that the method comprises the following steps: (1) mixing olmesartan medoxomil, microcrystalline cellulose, cyclodextrin, carboxymethyl cellulose, sucralose, acesulfame potassium and flavor to obtain a mixed material; (2) sieving the mixed material obtained in step (1) to obtain a sieved material; (3) Mixing the sieved material obtained in step (2) and magnesium stearate to obtain a total mixture; (4) The total mixture obtained in step (3) is tableted. 10. The method for preparing Olmesartan Medoxomil orally disintegrating tablets according to claim 9, characterized in that in step (4), the tableting parameters are: tablet weight 160 mg, hardness 20-60N.