Olmesartan medoxomil orally disintegrating tablet and preparation method thereof

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 is composed of the following components 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 parts of sucralose, 0.2-0.5 parts of acesulfame potassium, 0.05-0.15 parts of flavors, and 0.95-2.0 parts of magnesium stearate, wherein the particle size of the olmesartan medoxomil satisfies: 5μm<D90≤30μm. The olmesartan medoxomil orally disintegrating tablet of the present invention has good dissolution performance, higher stability, high consistency with the original drug, and faster disintegration.

Description

Technical Field

[0001] The present 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

[0002] Olmesartan medoxomil is a prodrug with the chemical formula:

[0003] .

[0004] Olmesartan medoxomil is absorbed and hydrolyzed into olmesartan through the gastrointestinal tract. Olmesartan is a selective angiotensin II type 1 receptor (AT1) antagonist. It selectively blocks the binding of angiotensin II to the AT1 receptors on vascular smooth muscle, thereby inhibiting the vasoconstrictive effect of angiotensin II and thereby lowering blood pressure. Currently, the most commonly available product on the domestic market is in the form of standard tablets. Patient compliance is poor due to swallowing difficulties, so an orally disintegrating tablet formulation has been developed to improve patient compliance.

[0005] Olmesartan Medoxomil orally disintegrating tablets are an angiotensin receptor blocker (ARB) antihypertensive medication developed by Daiichi Sankyo Co., Ltd. in 2015. Currently available only in Japan, they offer a more convenient solution for patients with difficulty swallowing tablets, such as the elderly and children. The orally disintegrating tablet is not only suitable for this specific population, but also allows for easier administration without water.

[0006] 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. This effectively solves the shortcomings of olmesartan medoxomil in terms of poor solubility and solubility, and is beneficial to the preparation and quality improvement of pharmaceutical preparations.

[0007] Chinese patent CN118384117A discloses an olmesartan medoxomil orally disintegrating tablet and its preparation method, which is composed of the following components by weight: 1-20 parts of olmesartan medoxomil, 20-80 parts of mannitol cross-polymerized maltitol 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 maltitol co-processed product is composed, by mass, of 50-80 parts of mannitol, 1-5 parts of cross-linked polyvinylpolypyrrolidone, 1-5 parts of copolyvinylpolypyrrolidone, 1-5 parts of maltitol, and 5-10 parts of sorbitol. By adding the new co-processed excipient mannitol cross-polymerized maltitol co-processed product, the problems in the existing orally disintegrating tablet production 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.

[0008] At present, there is still a lack of Olmesartan medoxomil orally disintegrating tablets that are highly consistent with the original drug. Achieving consistency in quality and efficacy with the reference preparation is particularly important for generic drugs. Therefore, it is still necessary to develop Olmesartan medoxomil orally disintegrating tablets that are highly consistent with the original drug. Summary of the Invention

[0009] In view of this, the purpose of the present invention is to provide an orally disintegrating tablet of Olmesartan Medoxomil 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.

[0010] In order to achieve the above-mentioned purpose of the invention, the technical solution of the present invention is as follows:

[0011] In one aspect, the present invention provides an Olmesartan Medoxomil orally disintegrating tablet, comprising the following ingredients in parts by weight:

[0012] 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 parts of sucralose, 0.2-0.5 parts of acesulfame potassium, 0.05-0.15 parts of flavor, and 0.95-2.0 parts of magnesium stearate, wherein the particle size of the Olmesartan medoxomil satisfies the following: 5μm<D90≤30μm.

[0013] Preferably, the Olmesartan Medoxomil orally disintegrating tablets are composed of the following ingredients in parts by weight:

[0014] 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.

[0015] Further preferably, the Olmesartan Medoxomil orally disintegrating tablets are composed of the following ingredients in parts by weight:

[0016] 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.

[0017] Preferably, the particle size of the olmesartan medoxomil satisfies: 5 μm<D90≤27.2 μm.

[0018] More preferably, the particle size of the olmesartan medoxomil satisfies: 14.3 μm≤D90≤27.2 μm.

[0019] More preferably, the particle size of the olmesartan medoxomil satisfies: D90 is 14.3 μm or 27.2 μm.

[0020] Most preferably, the particle size of the olmesartan medoxomil satisfies: D90 is 14.3 μm.

[0021] In the present invention, the term "D90" refers to the particle size value corresponding to when the cumulative distribution percentage from small to large in the particle size distribution reaches 90%, that is, the particles with a particle size smaller than this value account for 90%.

[0022] The cyclodextrin is selected from at least one of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. Preferably, the cyclodextrin is β-cyclodextrin.

[0023] 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.

[0024] On the other hand, the present invention provides a method for preparing the above-mentioned Olmesartan Medoxomil orally disintegrating tablets, which is a powder mixing direct compression process.

[0025] Preferably, the preparation method comprises the following steps:

[0026] (1) Olmesartan medoxomil, microcrystalline cellulose, cyclodextrin, carboxymethyl cellulose, sucralose, acesulfame potassium and flavor are mixed to obtain a mixed material;

[0027] (2) sieving the mixed material obtained in step (1) to obtain a sieved material;

[0028] (3) Mixing the sieved material obtained in step (2) and magnesium stearate to obtain a total mixture;

[0029] (4) The total mixture obtained in step (3) is tableted.

[0030] Further preferably, in step (1), the acesulfame potassium is first sieved through a 60-80 mesh sieve before mixing, and further preferably sieved through a 60 mesh sieve.

[0031] 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.

[0032] Further preferably, in step (2), the sieving is through a 20-40 mesh sieve, and more preferably through a 30 mesh sieve.

[0033] 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.

[0034] Further preferably, in step (4), the tableting parameters are: tablet weight 160 mg, hardness 20-60N, and more preferably 30-50N.

[0035] The beneficial effects of the present invention are:

[0036] (1) By specifically selecting the composition and ratio of excipients, Olmesartan medoxomil orally disintegrating tablets with high consistency with the original drug were obtained.

[0037] (2) The orally disintegrating tablets of the present invention overcome the problem of slow disintegration when cyclodextrin is used as an excipient, have good dissolution performance, and at the same time, disintegrate faster and contain less impurities than the original drug. DETAILED DESCRIPTION

[0038] The following non-limiting examples are provided to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the present invention in any way. The following are merely illustrative of the scope of the present invention, and those skilled in the art may 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.

[0039] The present invention will be further described below by way of specific examples. The various chemical reagents used in the examples of the present invention were obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all by weight. Unless otherwise specified, it is understood that the experiments were conducted at room temperature.

[0040] In the following examples, some of the raw materials were derived from the following sources:

[0041] Olmesartan medoxomil was purchased from Zhuhai Rundu Pharmaceutical Co., Ltd. with registration number Y20170000394;

[0042] β-Cyclodextrin was purchased from Hunan Jiudian Hongyang Pharmaceutical Co., Ltd. with registration number F20209990809;

[0043] Microcrystalline cellulose was purchased from Jiangsu Xidian Pharmaceutical Excipients Co., Ltd., model UF-702, registration number F20190000532;

[0044] Carboxymethyl cellulose was purchased from Xibixi Trading Co., Ltd., model NS-300, registration number F20180001743

[0045] Sucralose was purchased from Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd., registration number F20209990121;

[0046] Acesulfame potassium was purchased from Anhui Weiduo Food Ingredients Co., Ltd. with registration number F20220000381;

[0047] Magnesium stearate was purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., model SH-YM-MM, registration number F20209990494;

[0048] Orange powder flavor was purchased from Senxin Flavor and Pigment Technology Co., Ltd., model number 98AF7429.

[0049] Example 1

[0050] The recipe is as follows:

[0051] Table 1.

[0052]

[0053] The preparation process is as follows:

[0054] (1) Grind acesulfame potassium, pass through a 60-mesh sieve, and set aside;

[0055] (2) Weigh the formulated 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 and mix them, set the mixing speed to 20 Hz, and the mixing time to 15 min to obtain a mixed material;

[0056] (3) Passing the mixture obtained in step (2) through a 30-mesh sieve to obtain the sieved material;

[0057] (4) Add the sieved material obtained in step (3) and the formulated amount of magnesium stearate into a mixer for total mixing. Set the mixer speed to 20 Hz and the mixing time to 15 min. Discharge the material to obtain the total mixture.

[0058] (5) The total mixture obtained in step (4) is tableted. The tableting parameters are: tablet weight 160 mg, hardness 30-50N.

[0059] Example 2

[0060] The recipe is as follows:

[0061] Table 2.

[0062]

[0063] The preparation process is the same as that of Example 1.

[0064] Example 3

[0065] The recipe is as follows:

[0066] Table 3.

[0067]

[0068] The preparation process is the same as that of Example 1.

[0069] Example 4

[0070] The difference from Example 1 is that the D90 of Olmesartan Medoxomil is 27.2 μm, and the rest are the same.

[0071] Example 5

[0072] The difference from Example 1 is that the D90 of Olmesartan Medoxomil is 6.8 μm, and the rest are the same.

[0073] Example 6

[0074] The difference from Example 1 is that the tablet hardness is 20-30N, and the rest are the same.

[0075] Example 7

[0076] The difference from Example 1 is that the tablet hardness is 50-60N, and the rest are the same.

[0077] Comparative Example 1

[0078] The recipe is as follows:

[0079] Table 4.

[0080]

[0081] The preparation process is the same as that of Example 1.

[0082] Comparative Example 2

[0083] The recipe is as follows:

[0084] Table 5.

[0085]

[0086] The preparation process is the same as that of Example 1.

[0087] Comparative Example 3

[0088] The difference from Example 1 is that carboxymethyl cellulose is replaced by sodium carboxymethyl starch, and the rest are the same.

[0089] Comparative Example 4

[0090] The difference from Example 1 is that microcrystalline cellulose is replaced by pregelatinized starch, and the rest are the same.

[0091] Comparative Example 5

[0092] The difference from Example 1 is that the D90 of Olmesartan Medoxomil is 101.0 μm, and the rest are the same.

[0093] Comparative Example 6

[0094] The difference from Example 1 is that the D90 of Olmesartan Medoxomil is 5 μm, and the rest are the same.

[0095] Effect test

[0096] 1. Properties and content

[0097] Here are the results:

[0098] Table 6.

[0099]

[0100] 2. In vitro dissolution behavior

[0101] In vitro dissolution testing is commonly used to guide the development of pharmaceutical preparations, evaluate the consistency of quality within and between batches, and assess the consistency of quality and efficacy before and after changes to the formulation and process. For common oral solid dosage forms, the quality of generic dosage forms can be evaluated by comparing the similarity of multiple in vitro dissolution curves between generic and reference dosage forms. The reference dosage form is the original Olmesartan Medoxomil orally disintegrating tablets (TNA3003).

[0102] Detection method:

[0103] Table 7.

[0104]

[0105] 2.1 Test results of pH 6.8 medium:

[0106] The results of Example 1-Example 5 are as follows:

[0107] Table 8.

[0108]

[0109] The results of Comparative Example 1, Comparative Example 2, Comparative Example 5 and Comparative Example 6 are as follows:

[0110] Table 9.

[0111]

[0112] The results of Comparative Examples 3 and 4 are as follows:

[0113] Table 10.

[0114]

[0115] 3. Disintegration time limit

[0116] Test Method: Conducted in accordance with the Disintegration Time Limit Test Method in Part IV of the 2020 Chinese Pharmacopoeia, General Chapter 0921, under the Orally Disintegrating Tablets Test: Secure a stainless steel tube to a stand and immerse it in a 1000mL cup containing approximately 900mL of water at 37°C ± 1°C. Adjust the water level so that the screen is 15mm ± 1mm ​​below the water surface when the stainless steel tube is at its lowest position. Start the instrument. Place one tablet of this product in the aforementioned stainless steel tube for inspection. It should completely disintegrate and pass through the screen within 60 seconds. If a small amount of light material floats or adheres to the inner wall of the stainless steel tube or screen, but there is no hard core, it can be considered as meeting the requirements. Repeat the test for 6 tablets, and all should meet the requirements. If 1 tablet does not meet the requirements, retest 6 more tablets, and all should meet the requirements.

[0117] Table 11.

[0118]

[0119] 3. Content of related substances

[0120] Test method:

[0121] Table 12.

[0122]

[0123] Taking the reference preparation and Example 1 as examples, the contents of related substances are compared as follows:

[0124] Table 13.

[0125]

[0126] 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 principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. An orally disintegrating tablet of Olmesartan Medoxomil, characterized in that: The composition is as follows 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, wherein the particle size of the Olmesartan Medoxomil satisfies: D90 is 14.3μm or 27.2μm.

2. The orally disintegrating tablet of Olmesartan Medoxomil according to claim 1, characterized in that The particle size of the Olmesartan Medoxomil satisfies: D90 is 14.3 μm.

3. The method for preparing the orally disintegrating tablet of Olmesartan Medoxomil according to any one of claims 1 to 2, characterized in that: The preparation method is a powder mixing direct pressing process.

4. The method for preparing the orally disintegrating tablets of Olmesartan Medoxomil according to claim 3, characterized in that: 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.

5. The method for preparing the orally disintegrating tablets of Olmesartan Medoxomil according to claim 4, characterized in that: In step (4), the tableting parameters are: tablet weight 160 mg, hardness 20-60N.

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