An olmesartan medoxomil amlodipine hydrochlorothiazide triple combination preparation, a preparation method and application thereof

Abstract

The application discloses a triple combination of olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide and a preparation method thereof. The triple combination preparation comprises three active ingredients of olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide, and further comprises pre-gelatinized starch, silicified microcrystalline cellulose, cross-linked carboxymethyl cellulose, polylactic acid spray-dried powder and tocopherol as auxiliary materials. The triple combination of olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide is coated to obtain olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide tablets, which have the same dissolution stability as the original research product, a very smooth surface, no indentation and more stable quality.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a compound preparation of olmesartan medoxomil, amlodipine, and hydrochlorothiazide, its preparation method, and its application. Background Technology

[0002] Hypertension is a common and prevalent disease, and effectively and stably controlling blood pressure is the primary goal of current hypertension treatment. However, among patients currently receiving antihypertensive treatment, approximately 56% do not achieve the currently recommended blood pressure control targets. Furthermore, over 66% of hypertensive patients require the use of two or more antihypertensive drugs to achieve their desired blood pressure control goals.

[0003] Olmesartan medoxomil / hydrochlorothiazide tablets are a medication developed by Daiichi Sankyo for the treatment of hypertension, containing two active ingredients. In July 2010, Daiichi Sankyo announced that the U.S. FDA had approved Tribenzor (olmesartan medoxomil + amlodipine + hydrochlorothiazide), a combination product containing three active ingredients, for once-daily use, alone or in combination with other antihypertensive medications to treat hypertension, thereby lowering blood pressure; lowering blood pressure can reduce the risk of fatal and non-fatal cardiovascular events, primarily stroke and myocardial infarction.

[0004] Although Tribenzor combination therapy is very effective in controlling refractory hypertension, existing combination formulations containing olmesartan medoxomil, amlodipine, and hydrochlorothiazide may still have adverse effects on human health. One reason for this is that having the three active ingredients—olmesartan medoxomil, amlodipine, and hydrochlorothiazide—in the same smallest unit of formulation undoubtedly has several adverse effects on the release of the corresponding active ingredients in the intended manner and on ensuring the stability of the formulation. For example, the formulation process is complex, and during long-term storage, chemical compatibility changes may occur between the components, which can easily lead to the formation of byproducts, reduce efficacy, or increase side effects, resulting in less than ideal product stability.

[0005] The inventors of this application, during stability studies of a triple-combination formulation of olmesartan medoxomil, amlodipine, and hydrochlorothiazide, discovered that tablets containing olmesartan medoxomil, amlodipine, and hydrochlorothiazide, produced using conventional methods, exhibited no issues in terms of quality and safety. However, small indentations (typically approximately 200 to 300 μm in length) formed on the tablet surface. While these indentations do not affect the original function of the drug in the short term, in the long term, the coating thickness and strength at the indented areas become uneven with other areas, potentially leading to coating breakage during prolonged storage. This further affects the stability of the formulation and the dissolution properties after oral administration, resulting in inconsistencies with the initial tablet composition. Furthermore, even if these small indentations do not affect the original function of the drug, patients may be concerned about their impact on drug safety and stability, thereby affecting product sales.

[0006] To solve the above-mentioned problems, the inventors of this application screened and studied various excipients, and by adjusting the components of the tablet, completed the present invention and provided a highly stable film-coated tablet containing olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide, and having a very smooth surface, thereby substantially eliminating visible dents and solving the above-mentioned problems, thus completing the present invention. Summary of the Invention

[0007] The inventors of this application conducted arduous research to solve the above-mentioned problems, thereby completing the present invention and providing a tablet core with superior technical effects, thereby providing a highly stable film-coated tablet containing olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide, and having a very smooth surface on which virtually no visible dents are found.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0009] A solid composition comprising olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide is provided, the solid composition further comprising an anti-denting agent, preferably selected from a combination of polylactic acid and ascorbic acid salt or a pharmaceutically acceptable salt thereof; preferably, the ascorbic acid-acceptable salt is selected from sodium ascorbate.

[0010] Furthermore, the present invention provides a film-coated tablet comprising olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide, wherein the film-coated tablet comprises the above-mentioned solid composition comprising olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide.

[0011] Furthermore, the present invention provides the above-mentioned solid composition or film-coated tablet, wherein the particle size of the polylactic acid and ascorbate is 10-100 μm, preferably 10-50 μm; exemplaryly, the polylactic acid is a powder produced by spray drying and then sieved before use; the ascorbate is a commercially available product that has been ground and then sieved before use.

[0012] Furthermore, the present invention provides the above-described solid composition or film-coated sheet, wherein the polylactic acid and ascorbate constitute 1-5% and 1-5% by mass, respectively, preferably 2-4% and 2-4%, of the solid composition.

[0013] Furthermore, the present invention provides the above-described solid composition or film-coated sheet, wherein the solid composition or film-coated sheet further comprises a filler, a disintegrant, and a lubricant.

[0014] Furthermore, the present invention provides the above-described solid composition or film-coated tablets, wherein the disintegrant is selected from low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, or croscarmellose sodium; croscarmellose; chemically modified starch / cellulose, such as carboxymethyl starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, or croscarmellose sodium. Preferably, croscarmellose sodium is used.

[0015] Furthermore, the present invention provides the above-mentioned solid composition or film-coated tablet, wherein the disintegrant accounts for 3-7% by mass in the solid composition, preferably 4-6%, and most preferably 5%.

[0016] Furthermore, the present invention provides the above-mentioned solid composition or film-coated sheet, wherein the lubricant is selected from one or more of stearates (preferably magnesium stearate or calcium stearate), sodium stearate fumarate and talc, and preferably the mass percentage of the lubricant in the solid composition is 0.2-0.6%, more preferably 0.4-0.5%, and most preferably 0.4%.

[0017] Further, the present invention provides the above-described solid composition or film-coated sheet, wherein the filler is selected from one or more of sucrose, trehalose, mannitol or sorbitol; starch derivatives (preferably corn starch, potato starch, α-starch or dextrin, pregelatinized starch); and cellulose derivatives (preferably microcrystalline cellulose or silicified microcrystalline cellulose).

[0018] Furthermore, the present invention provides the above-mentioned solid composition or film-coated sheet, wherein the filler is selected from a combination of pregelatinized starch and silicified microcrystalline cellulose, wherein the mass ratio of the pregelatinized starch to the silicified microcrystalline cellulose is (1-3):(1-3).

[0019] Furthermore, the present invention provides the above-mentioned solid composition or film-coated tablet, wherein the disintegrant accounts for the remainder by mass in the solid composition; preferably, the filler accounts for 60-90% by mass in the solid composition, more preferably 65%-85%, and even more preferably 70-80% or 75%;

[0020] Furthermore, the present invention provides the above-mentioned film-coated sheet, the film-coated sheet comprising the above-mentioned solid composition and film coating layer, wherein the mass ratio of the solid composition to the film coating layer is 100:(2-6), preferably 100:(3-5), and more preferably 100:(3.5-4.5).

[0021] Furthermore, the present invention provides the above-mentioned film-coated tablet, wherein the coating material of the film-coated tablet is selected from Opadry, preferably gastric-soluble Opadry.

[0022] The term particle size used in this invention refers to "average particle size", which is the particle size obtained by laser diffraction / scattering method when the volume-based cumulative frequency is 50%.

[0023] The quality of the active pharmaceutical ingredients (APIs) in olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide of this invention can be consistent with that of commercially available Tribenzor combination formulations, such as 20 / 5 / 12.5 mg, 40 / 5 / 12.5 mg, 40 / 5 / 25 mg, 40 / 10 / 12.5 mg, or 40 / 10 / 25 mg. Reasonable fluctuations or adjustments in the quality of the APIs during production and quality control are within the scope of protection of this application.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The dissolution properties of the olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide compound preparation disclosed in this invention are consistent with those of commercially available products in the specified medium; it overcomes the technical problem of easy dents during the preparation process, and the resulting product has a high surface cleanliness and superior product quality. Attached Figure Description

[0026] Figure 1 Dissolution curves of the reference formulation (blue) and the self-made formulation olmesartan medoxomil from Example 2 in 0.3% SDS aqueous solution.

[0027] Figure 2 Dissolution curves of the reference formulation (blue) and the self-made formulation amlodipine from Example 2 in 0.3% SDS aqueous solution.

[0028] Figure 3 Dissolution curves of the reference formulation (blue) and the self-made formulation hydrochlorothiazide from Example 2 in 0.3% SDS aqueous solution.

[0029] Figure 4 Dissolution profiles of the reference formulation (blue) and the self-made formulation olmesartan medoxomil from Example 2 in phosphate buffer solution at pH 6.8.

[0030] Figure 5 The dissolution curves of the reference formulation (blue) and the self-made formulation amlodipine from Example 2 in a phosphate buffer solution at pH 6.8 are shown.

[0031] Figure 6 The dissolution curves of the reference formulation (blue) and the self-made formulation hydrochlorothiazide from Example 2 in phosphate buffer solution at pH 6.8 are shown.

[0032] Figure 7 Dissolution profiles of the reference formulation (blue) and the self-made formulation olmesartan medoxomil from Example 2 in 0.2% SDS pH 4.5 acetate buffer.

[0033] Figure 8 Dissolution profiles of the reference formulation (blue) and the self-made formulation amlodipine from Example 2 in 0.2% SDS pH 4.5 acetate buffer.

[0034] Figure 9 Dissolution profiles of the reference formulation (blue) and the self-made formulation hydrochlorothiazide from Example 2 in 0.2% SDS pH 4.5 acetate buffer.

[0035] Figure 10 The dissolution curves of the reference formulation (blue) and the self-made formulation olmesartan medoxomil from Example 2 in hydrochloric acid solution at pH 1.0 are shown.

[0036] Figure 11 The dissolution curves of the reference formulation (blue) and the self-made formulation amlodipine from Example 2 in hydrochloric acid solution at pH 1.0 are shown.

[0037] Figure 12 The dissolution curves of the reference formulation (blue) and the self-made formulation hydrochlorothiazide from Example 2 in hydrochloric acid solution at pH 1.0 are shown. Detailed Implementation

[0038] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below in conjunction with specific embodiments.

[0039] The raw materials of this invention, olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide, are fed according to their dry purity.

[0040] Some of the commercially available excipients used in this invention include: pregelatinized starch Starch 1500 2001-NEC, and microcrystalline cellulose colloidal silica co-treated product (silicified microcrystalline cellulose) PROSOLV. ® SMCC HD 90 (actual feed amount adjusted according to API conversion results), croscarmellose sodium Ac-Di-Sol® SD-711, magnesium stearate Ligamed ® MF-2-V, Film Coating Premix (Gastric-Soluble) - Opadry 85F640080 (Film Coating Premix 85F640080 Formulation Ingredients: Polyvinyl Alcohol, Titanium Dioxide, Polyethylene Glycol, Talc, Iron Oxide Black, Iron Oxide Yellow and Iron Oxide Red);

[0041] Purified water is used as a dispersion solvent for the film coating premix, and is used in the coating process and eventually removed.

[0042] The polylactic acid (PLA) of this invention has a repeating chemical structure of ‒O‒CH(CH3)CO‒, and its raw material is lactic acid.

[0043] The other solvents and reagents used in this invention are all commercially available common reagents and solvents.

[0044] General preparation example 1:

[0045] Polylactic acid is dissolved in acetone to prepare a 10% (mass-volume) solution. The solution enters the spray dryer through the feed inlet. Air is filtered and heated, and then enters the air distributor at the top of the dryer. The hot air enters the drying chamber evenly in a spiral pattern, and the outlet temperature is controlled at 50°C. The solution is sprayed into extremely fine mist droplets by a high-speed centrifugal atomizer at the top of the tower. The droplets come into contact with the hot air in parallel flow and are dried into the finished product. The finished product is continuously collected by a cyclone separator at the bottom of the drying tower, and then subjected to airflow pulverization, sieving, and classification to obtain products with different particle sizes. Products with particle sizes of 10-50 μM and 50-100 μM are selected for later use.

[0046] General preparation example 2:

[0047] Sodium ascorbate was thoroughly mixed in a mortar to obtain a powder, which was then sieved and classified to obtain products with different particle sizes. Products with particle sizes of 10-50 μM and 50-100 μM were selected for later use.

[0048] General preparation example 3:

[0049] According to the formulation ratio, the micronized active ingredients (olmesartan medoxomil, amlodipine besylate, hydrochlorothiazide) were mixed with pregelatinized starch, silicified microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, and mixed in a drum mixer at 40 rpm for 10 minutes; the powder mixture was then sieved in a sieve with a 1 mm sieve to prepare the first powder mixture.

[0050] Magnesium stearate was added to the first powder mixture according to the formulation ratio and mixed for 15 minutes at 40 rpm in a drum mixer; the powder mixture was then sieved using a 1 mm sieve to prepare the second powder mixture.

[0051] The second powder mixture is compressed using a tablet press at a pressure of approximately 7.5 kN into uncoated tablets, also known as plain tablets or tablet cores, with a tablet weight of approximately 200 mg.

[0052] The film coating premix was dispersed in purified water (12.5 w / w%) using a stirrer to obtain the coating solution. A coating machine was used at 70°C with pressurized air and a temperature of 1.0 m... 3 Uncoated tablets are coated at a pressurized airflow rate of approximately 8 g / min and a spraying rate of approximately 8 g / min, with a pan rotation speed of 25 rpm and an exhaust gas drying endpoint of approximately 55°C, thereby obtaining coated tablets.

[0053] Relative mass ratios of materials (per tablet) in the examples and comparative examples:

[0054] Element Example 1mg / tablet Example 2mg / tablet Example 3mg / tablet Example 4mg / tablet Comparative example 1mg / tablet Comparative example 2mg / tablet Comparative ratio 3mg / tablet Olmesartan medoxomil 20.00 40.00 40.00 40.00 40.00 40.00 40.00 Amlodipine besylate 6.94 6.94 6.94 6.94 6.94） 6.94） 6.94） Hydrochlorothiazide 12.50 12.50 25.00 12.50 12.50 12.50 12.50 Polylactic acid (particle size) 5 (10-50 uM) 6 (10-50 uM) 7 (10-50 uM) 6 (50-100 uM) NA NA 6 (10-50 uM) Sodium ascorbate (particle size) 5 (10-50 uM) 6 (10-50 uM) 6 (10-50 uM) 6 (50-100 uM) NA 6 (10-50 uM) NA Pregelatinized starch 70.00 59.00 52.50 59.00 59.00 59.00 59.00 Microcrystalline cellulose colloidal silica co-treated material 69.76 58.76 51.76 58.76 58.76 58.76 58.76 Cross-linked carboxymethyl cellulose sodium 10.00 10.00 10.00 10.00 10.00 10.00 10.00 magnesium stearate 0.80 0.80 0.80 0.80 0.80 0.80 0.80 Total chip cores 200 200 200 200 188 194 194 Film-coated premix (gastric-soluble) - Opadry 8 8 8 8 8 8 8

[0055] Test Example 1:

[0056] Following the method and proportions of General Preparation Example 3, 1000 tablets were prepared in each batch. 100 tablets were randomly selected from each batch. The tablets from Examples 1-4 and Comparative Examples 1-3 were placed under open conditions at 25°C / 75% RH for 4 weeks. The appearance was then observed using a microscope, and the number of tablets with indentations longer than 200 μm was counted. The test results are as follows:

[0057] Element Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Comparative Example 3 Number of tablets 0 0 0 11 87 79 98

[0058] Test Example 2:

[0059] Dissolution conditions

[0060] Dissolution apparatus: General provisions of Part IV of the 2020 edition of the Chinese Pharmacopoeia <0931> The second method, the paddling technique

[0061] Dissolution medium: pH 6.8 phosphate buffer (release medium)

[0062] Dissolution profiles: pH 1.0 hydrochloric acid solution, 0.2% SDS pH 4.5 acetate buffer, and 0.3% SDS aqueous solution.

[0063] Dissolution medium volume: 900ml

[0064] Rotation speed: 50 rpm

[0065] Temperature: 37.0 ± 0.5℃

[0066] Sampling times: 5, 10, 15, 20, 30, and 45 minutes (for dissolution profile acquisition).

[0067] Sampling volume: 10ml

[0068] Assay method: Take 10 ml of sample at the corresponding sampling point, filter it through a 0.45 μm PES membrane, and do not perform replenishment. Collect the filtrate and determine the drug concentration by liquid chromatography. Calculate the dissolution rate and plot the cumulative dissolution curve.

[0069] Liquid phase method:

[0070] Instrument: High Performance Liquid Chromatography (HPLC)

[0071] Column: Symmetry C8, 100 × 4.6 mm, 3.5 μm or equivalent.

[0072] Flow rate: 1.2 ml / min

[0073] Automated sampler: 5°C (pH 1.0 hydrochloric acid solution & pH 6.8 phosphate buffer); room temperature (pH 4.5 acetate buffer containing 0.2% SDS & purified water containing 0.3% SDS)

[0074] Detection wavelengths: 230nm (amlodipine and hydrochlorothiazide) and 240nm (olmesartan medoxomil)

[0075] Column temperature: 40°C

[0076] Injection volume: 20 μl

[0077] Elution method: Gradient elution (procedure as follows)

[0078] Gradient elution program

[0079]

[0080] For example, the dissolution profiles of the reference formulation (blue) and the homemade formulation of olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide in different media are shown in the attached figures of the instruction manual.

[0081] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

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 includes olmesartan medoxomil, amlodipine besylate, hydrochlorothiazide, an anti-denting agent, a disintegrant, a lubricant, and a filler. The anti-denting agent is a combination of polylactic acid and sodium ascorbate, and the mass percentages of polylactic acid and sodium ascorbate in the solid composition are 1-5% and 1-5%, respectively. The disintegrant is croscarmellose sodium cellulose, and the disintegrant accounts for 3-7% of the mass of the solid composition. The lubricant is magnesium stearate, and the mass percentage of the lubricant in the solid composition is 0.2% to 0.6%. The filler is a combination of pregelatinized starch and siliconized microcrystalline cellulose, wherein the mass ratio of the pregelatinized starch to the siliconized microcrystalline cellulose is (1-3):(1-3), and the filler accounts for 60-90% of the mass of the solid composition. 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. The film-coated sheet according to claim 1, characterized in that... The particle size of the polylactic acid and sodium ascorbate is 10–100 μm.

3. The film-coated sheet according to claim 1, characterized in that... The particle size of the polylactic acid and sodium ascorbate is 10-50 μm; the polylactic acid is a powder prepared by spray drying and is used after sieving; the sodium ascorbate is ground and then sieved before use.

4. The film-coated sheet according to claim 1, characterized in that... The polylactic acid and sodium ascorbate are present in the solid composition at mass percentages of 2-4% and 2-4%, respectively.

5. The film-coated sheet according to claim 1, characterized in that... The disintegrant accounts for 4-6% of the mass of the solid composition.

6. The film-coated sheet according to claim 1, characterized in that... The disintegrant accounts for 5% of the mass of the solid composition.

7. The film-coated sheet according to claim 1, characterized in that... The lubricant accounts for 0.4% to 0.5% of the mass of the solid composition.

8. The film-coated sheet according to claim 1, characterized in that... The lubricant accounts for 0.4% of the mass of the solid composition.

9. The film-coated sheet according to claim 1, characterized in that... The filler accounts for 65-85% of the mass of the solid composition.

10. The film-coated sheet according to claim 1, characterized in that... The filler accounts for 70-80% of the mass of the solid composition.

11. The film-coated sheet according to claim 1, characterized in that... The filler accounts for 75% of the mass of the solid composition.

12. The film-coated sheet according to claim 1, characterized in that... The mass ratio of the solid composition to the film coating layer is 100:(3-5).

13. The film-coated sheet according to claim 1, characterized in that... The mass ratio of the solid composition to the film coating layer is 100:(3.5-4.5).

14. The film-coated sheet according to claim 1, characterized in that... The coating material is selected from gastrosoluble Opadry.

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