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CN-121015662-B - Olmesartan medoxomil amlodipine hydrochlorothiazide three-compound preparation and preparation method and application thereof

CN121015662BCN 121015662 BCN121015662 BCN 121015662BCN-121015662-B

Abstract

The invention discloses an olmesartan medoxomil amlodipine hydrochlorothiazide three-compound composition and a preparation method thereof, wherein the three-compound preparation comprises three active ingredients of olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide, and further comprises auxiliary materials such as pregelatinized starch, silicified microcrystalline cellulose, crosslinked carboxymethyl cellulose, polylactic acid spray-dried powder, tocopherol and the like, and the dissolution stability of the olmesartan medoxomil hydrochlorothiazide tablet obtained after the coating operation of the three-compound composition of olmesartan medoxomil amlodipine hydrochlorothiazide is consistent with that of an original ground product, and the tablet has very smooth surface, no dent and more stable quality.

Inventors

  • FU DONGJUN
  • LIU YINGBO
  • HUANG JUNQIN
  • LI ZHENGWU
  • WANG ZHAODONG
  • GUAN LUFAN
  • FENG JIAQI

Assignees

  • 上海腾瑞制药股份有限公司

Dates

Publication Date
20260512
Application Date
20250718

Claims (14)

  1. 1. A film coated tablet comprising olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide, said film coated tablet comprising a solid composition and a film coating layer; The solid composition comprises olmesartan medoxomil, amlodipine besylate, hydrochlorothiazide, an anti-dent generating agent, a disintegrating agent, a lubricant and a filler, wherein the anti-dent generating agent is a combination of polylactic acid and sodium ascorbate, and the mass ratio of the polylactic acid to the sodium ascorbate in the solid composition is 1-5% and 1-5% respectively; The disintegrating agent is croscarmellose sodium, and the mass ratio of the disintegrating agent in the solid composition is 3-7%; the lubricant is magnesium stearate, and the mass ratio of the lubricant in the solid composition is 0.2-0.6%; the filler is a combination of pregelatinized starch and silicified microcrystalline cellulose, the mass ratio of the pregelatinized starch to the silicified microcrystalline cellulose is (1-3): (1-3), and the mass ratio of the filler in the solid composition is 60-90%; The coating material of the film coating layer is selected from Opadry, and the mass ratio of the solid composition to the film coating layer is 100 (2-6).
  2. 2. The film-coated tablet according to claim 1, wherein the particle diameters of the polylactic acid and sodium ascorbate are 10 to 100 μm.
  3. 3. The film-coated tablet according to claim 1, wherein the particle size of the polylactic acid and sodium ascorbate is 10-50 μm, the polylactic acid is powder prepared by a spray drying method, the powder is sieved and used, and the sodium ascorbate is ground and sieved and used.
  4. 4. Film-coated tablet according to claim 1, characterized in that the polylactic acid and sodium ascorbate are present in the solid composition in a mass ratio of 2-4% and 2-4%, respectively.
  5. 5. Film-coated tablet according to claim 1, characterized in that the mass ratio of the disintegrant in the solid composition is 4-6%.
  6. 6. Film-coated tablet according to claim 1, characterized in that the disintegrant is present in the solid composition in a mass ratio of 5%.
  7. 7. Film-coated tablet according to claim 1, characterized in that the lubricant accounts for 0.4-0.5% by mass of the solid composition.
  8. 8. Film-coated tablet according to claim 1, characterized in that the lubricant is present in the solid composition in a mass ratio of 0.4%.
  9. 9. Film-coated tablet according to claim 1, characterized in that the filler is present in the solid composition in a mass ratio of 65-85%.
  10. 10. Film-coated tablet according to claim 1, characterized in that the filler is present in the solid composition in a mass ratio of 70-80%.
  11. 11. Film-coated tablet according to claim 1, characterized in that the filler is present in the solid composition in a mass ratio of 75%.
  12. 12. The film-coated tablet according to claim 1, wherein the mass ratio of the solid composition to the film-coating layer is 100 (3-5).
  13. 13. The film-coated tablet according to claim 1, wherein the mass ratio of the solid composition to the film-coating layer is 100 (3.5-4.5).
  14. 14. Film coated tablet according to claim 1, characterized in that the coating material is selected from the group consisting of gastric soluble opadry.

Description

Olmesartan medoxomil amlodipine hydrochlorothiazide three-compound preparation and preparation method and application thereof Technical Field The invention belongs to the field of pharmaceutical preparations, and in particular relates to an olmesartan medoxomil amlodipine hydrochlorothiazide three-compound preparation as well as a preparation method and application thereof. Background Hypertension is a common multiple disease, and effective and stable control of blood pressure is a main target for treating hypertension at present. However, about 56% of patients currently undergoing antihypertensive therapy have failed to achieve current recommended goals in terms of blood pressure control. In addition, more than 66% of patients with hypertension need to be combined with 2 or more antihypertensive drugs to achieve the desired blood pressure control goal. Olmesartan medoxomil hydrochlorothiazide tablet is a drug for hypertension treatment developed by Daiichi Sankyo company, and contains two active ingredients. 7 months 2010, daiichi Sankyo corporation announced that U.S. FDA approved Tribenzor (olmesartan medoxomil + amlodipine + hydrochlorothiazide), a compound product containing three active ingredients, was useful for treating hypertension alone or in combination with other antihypertensive agents 1 time a day to lower blood pressure, which can reduce the risk of fatal and non-fatal cardiovascular events, mainly stroke and myocardial infarction. Although Tribenzor three compound preparations are very effective in controlling refractory hypertension, the existing compound preparation containing olmesartan medoxomil, amlodipine and hydrochlorothiazide can still cause adverse effects on human health, one of the reasons is that three active ingredients of olmesartan medoxomil, amlodipine and hydrochlorothiazide are released in the same minimum preparation unit in an expected mode, and various adverse effects are assuredly caused on the stability of the preparation, for example, the preparation process is complex, when the preparation is stored for a long time, by-products are easy to generate due to the fact that chemical compatibility changes can occur between the ingredients, the effect is reduced or side effects are increased, the stability of the product is not ideal enough, and the like. The present inventors have found that when conducting stability studies on three compound formulations of olmesartan medoxomil, amlodipine and hydrochlorothiazide, tablets containing olmesartan medoxomil, amlodipine and hydrochlorothiazide produced by conventional methods have no problems in terms of quality and safety, but form small dents (generally having a length of about 200 to 300 uM) on the surface of the tablets. These dimples do not affect the original function as a drug in a short period, and when the coating thickness and strength at the dimples are not uniform in the long term, breakage of the coating may occur during long-term placement, thereby further affecting the stability of the formulation and the subsequent dissolution profile after oral administration being inconsistent with the tablet at the initial stage. In addition, small dimples, if not affecting the original function as a drug, patients may be concerned about the impact of these dimples on the safety and stability of the drug, which in turn affects the sales of the product. The present inventors have conducted screening and research of various auxiliary materials in order to solve the above problems, and have completed the present application by adjusting ingredients as tablets and provided highly stable film coated tablets containing olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide and having very smooth surfaces, thereby substantially eliminating visible dents, and have been able to solve the above problems, thereby completing the present application. Disclosure of Invention The present inventors have made intensive studies to solve the above problems, thereby completing the present application and providing a tablet core having more excellent technical effects, and further providing a highly stable film-coated tablet containing olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide and having a very smooth surface on which substantially no visible dents are found. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: There is provided a solid composition comprising olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide, said solid composition further comprising an anti-dent agent, preferably said anti-dent agent is selected from the group consisting of polylactic acid and ascorbate or a pharmaceutically acceptable salt thereof, preferably said ascorbate acceptable salt is selected from sodium ascorbate. Further, the present invention provides a film coated tablet comprising olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide, which comprises th