Pharmaceutical composition for treating hypertension and preparation method thereof

Abstract

The invention relates to a pharmaceutical composition for treating hypertension and a preparation method thereof, in particular to a pharmaceutical composition containing valsartan and levamlodipine besylate. The valsartan and the levamlodipine besylate are combined for use, so that the valsartan and the levamlodipine besylate not only can play a synergistic effect and enhance a treatment effect, but also have relatively high safety and relatively low adverse reaction occurrence rate, and are worthy of wide popularization and application. By controlling the crystal form of levamlodipine besylate and the particle sizes of valsartan, levamlodipine besylate, filler, disintegrating agent, lubricant and glidant and packaging with medicinal aluminum foil, polyvinyl chloride solid medicinal hard tablets and polyamide / aluminum cold-formed solid medicinal composite hard tablets, the dissolution rate and stability of the medicine are optimized. According to the method, direct powder tabletting is adopted, the powder fluidity is good, tabletting is easy, the production time is shortened, the production efficiency is improved, and the product stability is also improved. In-vitro dissolution experiments show that the dissolution curve of the composition is consistent with that of a control preparation, and the composition has good bioavailability.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to a pharmaceutical composition for treating hypertension and a preparation method thereof. Background Art

[0002] Valsartan is an angiotensin II receptor antagonist that can block the binding of angiotensin II to its receptor, control vasoconstriction, reduce aldosterone release, and improve the relaxation of vascular smooth muscle, thereby achieving the effect of dilating blood vessels and lowering blood pressure. Amlodipine besylate is a common drug for the treatment of hypertension. It is a calcium channel blocker. Its efficacy acts on vascular smooth muscle, which can reduce vascular smooth muscle tension and peripheral vascular resistance, thereby effectively lowering blood pressure levels.

[0003] Valsartan amlodipine tablets are a compound preparation composed of valsartan and amlodipine. By combining valsartan and amlodipine besylate, and utilizing their respective different mechanisms of action, it is possible to rapidly lower blood pressure and maintain a lasting antihypertensive effect. Studies have shown that amlodipine tablets contain equal amounts of dextrorotatory and levorotatory isomers, and the calcium channel blocking activity of the levorotatory isomer is 1,000 times that of the dextrorotatory isomer. In addition, the incidence of adverse reactions of levorotatory amlodipine besylate is low, which helps to control blood pressure more smoothly. Therefore, the combined use of valsartan and levorotatory amlodipine besylate can not only exert a synergistic effect and enhance the therapeutic effect, but also has high safety and a low incidence of adverse reactions, and is worthy of wide promotion and application.

[0004] The known methods for preparing the pharmaceutical composition containing valsartan and levamlodipine besylate include wet preparation, dry granulation and direct compression of powder.

[0005] The wet granulation process has the problem that valsartan has a high viscosity and is prone to producing hard granules. In addition, amlodipine besylate is unstable when heated, and the granules are prone to yellowing and producing impurities during the drying process, which seriously affects the product quality and dissolution.

[0006] Although dry granulation solves the heat and moisture problem of wet granulation, when levamlodipine besylate and valsartan are dry granulated at the same time, valsartan will seriously affect the release effect of levamlodipine besylate. Although there is a preparation method in which levamlodipine besylate and valsartan are separately composed into a composition and then finally mixed, the particle size distribution of the material is not controlled during the preparation process of the composition, which seriously affects the fluidity and formability of the material. The formed particles are prone to uneven content. In addition, the production process is complicated and the production cost is high, which is not conducive to large-scale production.

[0007] The existing direct powder compression process does not control the particle size distribution of levamlodipine besylate, valsartan, fillers, disintegrants, lubricants, and glidants. The powder lacks fluidity, resulting in poor compressibility of the tablets, which seriously affects the uniformity and dissolution of the product content. Although the levamlodipine besylate crystals and particle size are controlled in the direct powder compression process, the preparation of the levamlodipine besylate crystals uses a composite solvent, which is not conducive to the stability of the crystal form, seriously affecting the stability of the levamlodipine besylate crystal form, and the process is complicated and the production cost is high. In addition, the use of large-particle crystals of 80 to 120 um also seriously affects the release effect of levamlodipine besylate.

[0008] Therefore, it is necessary to provide a composition and a preparation method thereof with simpler process, lower cost and easier industrialization, which can not only ensure the stability of the composition but also increase the solubility of the two active ingredients. Summary of the invention

[0009] The first object of the present invention is to provide a pharmaceutical composition for treating hypertension, characterized in that it is composed of valsartan, levamlodipine, a filler, a disintegrant, a lubricant, a glidant, and a coating agent. The composition contains levamlodipine besylate crystals, the crystals have a stable crystal form and a uniform particle size distribution, and the pharmaceutical composition composed of the crystals, valsartan, and pharmaceutically acceptable excipients has a more significant therapeutic effect.

[0010] The second purpose of the present invention is to provide a method for preparing the composition, which adopts direct powder tableting. The powder has good fluidity and is easy to tablet, which not only reduces the production time but also improves the production efficiency. The coated tablets are packaged with medicinal aluminum foil, polyvinyl chloride solid medicinal hard tablets, and polyamide / aluminum cold-formed solid medicinal composite hard tablets. Because of their good light-shielding and sealing properties, they can effectively reduce the generation of related substances and improve product stability.

[0011] To achieve the first objective of the present invention, the present invention adopts the following technical solution:

[0012] A pharmaceutical composition for treating hypertension, comprising valsartan, levamlodipine, a filler, a disintegrant, a lubricant, a glidant, and a coating agent, wherein the composition contains levamlodipine besylate crystals, and the mass ratio of each component is as follows: 1) or 2) or 3)

[0013] 1) 80 parts of valsartan, 3.47 parts of levamlodipine besylate, 40-60 parts of diluent, 30-60 parts of disintegrant, 2-4 parts of glidant, 1-3 parts of lubricant, and 10-20 parts of coating agent;

[0014] 2) 160 parts of valsartan, 3.47 parts of levamlodipine besylate, 40-60 parts of diluent, 70-100 parts of disintegrant, 4-8 parts of glidant, 2-6 parts of lubricant, and 20-30 parts of coating agent;

[0015] 3) 160 parts of valsartan, 6.94 parts of levamlodipine besylate, 40-60 parts of diluent, 70-100 parts of disintegrant, 4-8 parts of glidant, 2-6 parts of lubricant, and 20-30 parts of coating agent;

[0016] The levamlodipine besylate raw material medicine is a stable crystal form. Using XRD powder diffraction measurement, the XRD powder diffraction patterns of three batches of raw materials (batch numbers: Y220606, Y220403, and Y190301) have consistent X-ray diffraction angles, indicating that the crystal form is consistent, indicating that the raw material synthesis process is stable, and the crystal form will not change during the storage of the raw material medicine. The characteristic peaks in the diffraction pattern are 6.860°, 10.219°, 12.420°, 13.619°, 14.140°, 15.141°, 20.360°, 21.899°, 23.859°, 25.100°, and 27.220° at 2θ.

[0017] According to the aforementioned pharmaceutical composition, wherein the levamlodipine besylate raw material is prepared by the following method:

[0018] 1) Add 40 to 60 parts by volume of purified water (60 to 75° C.) to the levamlodipine besylate solution, stir and react until the solution becomes clear, and filter the reaction solution under reduced pressure while hot into a crystallization tank.

[0019] 2) Stir and cool the reaction solution in the crystallization tank to ≤20°C to precipitate an off-white solid.

[0020] 3) The crystallization liquid is filtered under reduced pressure, and the filter cake is washed with about 6 to 9 times purified water and drained to obtain the wet product of levamlodipine besylate.

[0021] 4) Drying in a vacuum drying oven at a reduced pressure of 0.07-0.1 MPa until the moisture content is ≤ 2.0%, and sieving through 80-120 mesh to obtain the levamlodipine besylate bulk drug.

[0022] The particle size D10 of the valsartan is 7-10um, D50 is 20-25um, and D90 is 40-80um, preferably D10 is 8.5um, D50 is 23um, and D90 is 60um;

[0023] The particle size of the levamlodipine besylate is D10 of 7-10um, D50 of 20-25um, and D90 of 40-80um, preferably D10 of 8um, D50 of 25um, and D90 of 60um;

[0024] The filler is pregelatinized starch with a D90 of 40 to 80 um, preferably a D90 of 80 um;

[0025] The disintegrant is low-substituted hydroxypropyl cellulose with a D50 of 50-110 um and a D90 of 300 um, preferably a D50 of 80 um and a D90 of 300 um;

[0026] The disintegrant is cross-linked polyvinylpyrrolidone, with D10 of 8-12um, D50 of 20-30um, and D90 of 35-85um, preferably D10 of 10um, D50 of 25um, and D90 of 50um;

[0027] The lubricant is magnesium stearate with a D50 of 5 to 30 um, preferably a D50 of 18 um;

[0028] The flow aid is silicon dioxide with a D50 of 5 to 30 um, preferably a D50 of 20 um;

[0029] The coating agent may be a film coating premix (gastric soluble).

[0030] To achieve the second object of the present invention, a method for preparing a pharmaceutical composition for treating hypertension comprises the following steps:

[0031] S1, mixing the prescribed amount of levamlodipine besylate and pregelatinized starch to obtain premixed powder 1;

[0032] S2, mixing the mixed powder 1 with the prescribed amount of valsartan, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpyrrolidone to obtain premixed powder 2;

[0033] S3, mixing the mixed powder 2 with the prescribed amount of lubricant and glidant, and tableting to obtain tablet cores;

[0034] S4, coating the tablet cores obtained in step S3 to obtain valsartan levamlodipine tablets.

[0035] S5. The coated tablets obtained in step S3 are packaged with medicinal aluminum foil, polyvinyl chloride solid medicinal hard tablets, or polyamide / aluminum cold-formed solid medicinal composite hard tablets.

[0036] In the above preparation method, in step S1, the mixing conditions are as follows:

[0037] Cutting speed: 1000-3000 rpm, stirring speed: 100-300 rpm, mixing for 3-5 minutes.

[0038] In the above preparation method, in step S2, the mixing conditions are as follows:

[0039] Cutting speed: 1000-3000 rpm, stirring speed: 100-300 rpm, mixing for 3-5 minutes.

[0040] In the above preparation method, in step S3, the mixing conditions are as follows:

[0041] The mixing speed is 6 to 10 rpm, and the mixing time is 50 to 70 minutes.

[0042] In the above preparation method, in step S3, the tableting conditions are as follows:

[0043] The main pressure of the tablet press is 4-11KN, the feeder speed is 10-30HZ, the vacuum degree is 0.04-0.06MPa, the tablet pressing speed is 10,000-50,000 tablets / hour, and the tablet core hardness is 5-8kg / cm2.

[0044] In the above preparation method, in step S4, the coating conditions are as follows:

[0045] The spraying speed is 50-100 ml / min, the drum speed is 3-8 rpm, and the heating temperature is ≤60°C.

[0046] In the above preparation method, in step S5, the packaging conditions are as follows:

[0047] Molding temperature: 120±20℃, heat sealing temperature 1: 150±20℃, heat sealing temperature 2: 150±20℃.

[0048] The compound valsartan levamlodipine tablets prepared by the method of the present invention have uniform particles, good fluidity, are easy to tablet, have a tablet weight difference of ±4%, a uniformity of the central controlled dose unit (calculated as levamlodipine) of RSD≤6%, and an in vitro dissolution experiment shows that the dissolution curve of the composition is consistent with that of the control preparation. The method not only reduces production time, improves production efficiency, is suitable for large-scale production, but also improves drug dissolution and product stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Attached Figure 1 These are the X-ray diffraction patterns of three batches of amlodipine besylate raw material.

[0050] Attached Figure 2 The dissolution curves of amlodipine and the control preparation in Example 3 of Formulation 1 are shown.

[0051] Attached Figure 3 The dissolution curves of amlodipine and the control preparation in Example 6 of Formulation 4 are shown.

[0052] Attached Figure 4 This is the dissolution curve of amlodipine in Formulation 7-Example 8 and the control formulation.

[0053] Attached Figure 5 The dissolution curves of valsartan and control preparations in Preparation Implementation 1-Example 3 are shown.

[0054] Attached Figure 6 This is the dissolution curve of valsartan and control preparations in Formulation 4-Example 9. DETAILED DESCRIPTION

[0055] The following are specific embodiments of the present invention, and the embodiments are intended to further describe the present invention rather than to limit the present invention.

[0056] Example 1. Preparation of Stable Crystalline Form of Levoamlodipine Besylate API

[0057] 1) Add 40 to 60 parts by volume of purified water (60 to 75° C.) to the levamlodipine besylate solution, stir and react until the solution becomes clear, and filter the reaction solution under reduced pressure while hot into a crystallization tank.

[0058] 2) Stir and cool the reaction solution in the crystallization tank to ≤20°C to precipitate an off-white solid.

[0059] 3) The crystallization liquid is filtered under reduced pressure, the filter cake is washed with purified water, and then dried to obtain the wet product of levamlodipine besylate.

[0060] 4) Drying in a vacuum drying oven under reduced pressure of 0.07-0.1 MPa until the moisture content is ≤ 2.0%, and sieving through a sieve of 80-120 mesh to obtain the levamlodipine besylate bulk drug.

[0061] The obtained levoamlodipine besylate crystal form has consistent X-ray diffraction angles in the XRD powder diffraction patterns of three batches of raw materials (batch numbers: Y220606, Y220403, and Y190301), indicating that the crystal form is consistent, indicating that the raw material synthesis process is stable, and the crystal form will not change during the storage of the raw material. The characteristic peaks in the diffraction pattern obtained by XRD powder diffraction measurement are 6.860°, 10.219°, 12.420°, 13.619°, 14.140°, 15.141°, 20.360°, 21.899°, 23.859°, 25.100°, and 27.220° at 2θ, as shown in FIG. Figure 1 shown.

[0062] The crystal form of the obtained levamlodipine besylate raw material drug was detected by a laser particle size analyzer. The results of three batches of raw materials (batch numbers: Y220606, Y220403, and Y190301) are as follows:

[0063] Table 1 Particle size test results of amlodipine besylate

[0064] API batch number Serial number <![CDATA[D 90 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 10 (μm)]]> Y190301 1 40.402 20.954 7.499 Y220403 2 60.689 22.551 8.715 Y220606 3 80.172 25.129 10.600

[0065] [Preparation Example 1] Valsartan Levoamlodipine Tablets (Specifications 80 mg / 2.5 mg)

[0066] Table 2 Composition of the prescription of valsartan levamlodipine tablets

[0067]

[0068] The powder direct compression process was adopted, using batch Y190301 of levamlodipine besylate API, and the process is shown in the table:

[0069] Table 3 Powder direct compression process steps

[0070]

[0071]

[0072] [Preparation Example 2] Valsartan Levoamlodipine Tablets (Specifications 80 mg / 2.5 mg)

[0073] Table 4 Composition of the prescription of valsartan levamlodipine tablets

[0074]

[0075] The powder direct pressing process is used, as shown in the table:

[0076] The process steps are the same as those in Preparation Example 1, using batch Y220403 of levamlodipine besylate bulk drug.

[0077] Table 5 Powder direct compression process steps

[0078]

[0079]

[0080] [Preparation Example 3] Valsartan levamlodipine tablets (specification 80 mg / 2.5 mg) Table 6 Composition of the prescription of valsartan levamlodipine tablets

[0081]

[0082]

[0083] The powder direct pressing process is used, as shown in the table:

[0084] The process steps are the same as those in Preparation Example 1, using batch Y220606 of levamlodipine besylate bulk drug.

[0085] Table 7 Powder direct compression process steps

[0086]

[0087]

[0088] [Preparation Example 4] Valsartan Levoamlodipine Tablets (Specifications 160 mg / 2.5 mg)

[0089] Table 8 Composition of Valsartan Levoamlodipine Tablets Prescription

[0090]

[0091] The powder direct pressing process is used, as shown in the table:

[0092] The process steps are the same as those in Preparation Example 1, using batch Y190301 of levamlodipine besylate bulk drug.

[0093] Table 9 Powder direct compression process steps

[0094]

[0095]

[0096] [Preparation Example 5] Valsartan Levoamlodipine Tablets (Specifications 160 mg / 2.5 mg)

[0097] Table 10 Composition of the prescription of valsartan levamlodipine tablets

[0098]

[0099] The powder direct pressing process is used, as shown in the table:

[0100] The process steps are the same as those in Preparation Example 1, using batch Y220403 of levamlodipine besylate bulk drug.

[0101] Table 11 Powder direct compression process steps

[0102]

[0103] [Preparation Example 6] Valsartan levamlodipine tablets (specification 160mg / 2.5mg) Table 12 Composition of the prescription of valsartan levamlodipine tablets

[0104]

[0105]

[0106] The powder direct pressing process is used, as shown in the table:

[0107] The process steps are the same as those in Preparation Example 1, using batch Y220606 of levamlodipine besylate bulk drug.

[0108] Table 13 Powder direct compression process steps

[0109]

[0110]

[0111] [Preparation Example 7] Valsartan Levoamlodipine Tablets (Specifications 160 mg / 5 mg)

[0112] Table 14 Composition of Valsartan Levoamlodipine Tablets Prescription

[0113]

[0114] The powder direct pressing process is used, as shown in the table:

[0115] The process steps are the same as those in Preparation Example 1, using batch Y190301 of levamlodipine besylate bulk drug.

[0116] Table 15 Powder direct compression process steps

[0117]

[0118]

[0119] [Preparation Example 8] Valsartan Levoamlodipine Tablets (Specification 160mg / 5mg) Table 16 Composition of Valsartan Levoamlodipine Tablets Prescription

[0120]

[0121] The powder direct pressing process is used, as shown in the table:

[0122] The process steps are the same as those in Preparation Example 1, using batch Y220403 of levamlodipine besylate bulk drug.

[0123] Table 17 Powder direct compression process steps

[0124]

[0125] [Preparation Example 9] Valsartan Levoamlodipine Tablets (Specifications 160 mg / 5 mg)

[0126] Table 18 Composition of Valsartan Levoamlodipine Tablets Prescription

[0127]

[0128] The powder direct pressing process is used, as shown in the table:

[0129] The process steps are the same as those in Preparation Example 1, using batch Y220606 of levamlodipine besylate bulk drug.

[0130] Table 19 Powder direct compression process steps

[0131]

[0132]

[0133] Effect evaluation:

[0134] 1) Preparation Example 1 to Preparation Example 9 were tested for content determination (limit requirement: 95.0%-105.0% of the labeled amount of valsartan, 95.0%-105.0% of the labeled amount of levamlodipine besylate) and related substances (limit requirement: impurity D ≤ 0.3%, impurity 1 ≤ 0.3%, impurity E ≤ 0.2%, other single impurities ≤ 0.2%, valsartan single impurity ≤ 0.2%, valsartan total impurities ≤ 0.7%), and the results were in compliance with the regulations. The results are shown in Table 20:

[0135] Table 20 Content and related substance test results of formulation examples 1 to 9

[0136]

[0137] 2) Preparation Examples 2, 5, and 8 were subjected to stability studies at accelerated intermediate conditions (30°C ± 2°C / RH 65% ± 5%) in accordance with the 2020 edition of the Chinese Pharmacopoeia Stability Guidelines. The results of the 6-month stability tests were good and in compliance with the regulations. The results are shown in Table 21:

[0138] Table 21 Accelerated stability study results of formulation examples 2, 5, and 8

[0139]

[0140] 3) The valsartan levamlodipine tablets obtained in Example 1 to Example 9 were compared with the marketed control preparation (valsartan amlodipine tablets: specification: each tablet contains 160 mg valsartan and 5 mg amlodipine, batch number: 20241204) in pH 4.5 acetate buffer (volume 900 ml, basket method 100 turns). The results showed that the dissolution of levamlodipine besylate was similar to that of the control preparation, and both were rapid dissolution (more than 90% dissolution in 15 minutes), as shown in the table and figure. The dissolution of valsartan was also consistent with that of the control preparation, as shown in Table 22, Table 23, Table 24 and Figure 2 , Figure 3 , Figure 4 , Figure 5 , Figure 6 .

[0141] Table 22: Table of dissolution results of formulation implementation 1-Example 6 levamlodipine and control formulations

[0142]

[0143] Table 23: Table of dissolution results of formulation implementation 7-Example 9 levamlodipine and control formulations

[0144]

[0145] Table 24: Table of dissolution results of valsartan and control preparations in Example 9

[0146]

[0147] From the above data and Figures 2 to 6 It can be seen that the valsartan levamlodipine tablets prepared by the present invention have a reasonable prescription, a simple preparation process, good powder fluidity, and are easy to tablet, which not only reduces production time and improves production efficiency, but also improves product stability.

Claims

1. A pharmaceutical composition for treating hypertension, characterized in that: It is composed of valsartan, levamlodipine, a filler, a disintegrant, a lubricant, a glidant, and a coating agent; The valsartan includes its pharmaceutically acceptable salts, optical isomers and hydrates; The levoamlodipine includes its pharmaceutically acceptable salts, hydrates, etc.; The filler is one of microcrystalline cellulose, starch, pregelatinized starch, lactose, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, or a mixture of two or more thereof; The disintegrant is one of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, or a mixture of two or more thereof; The lubricant is one of magnesium stearate, hydrogenated castor oil, carnauba wax, talcum powder or a mixture of two or more thereof; The glidant is one or a mixture of silicon dioxide and talc; The levoamlodipine is a levoamlodipine besylate raw material drug and is a stable crystalline form. The characteristic peaks 2θ in the diffraction pattern measured by XRD powder diffraction are 6.860°, 10.219°, 12.420°, 13.619°, 14.140°, 15.141°, 20.360°, 21.899°, 23.859°, 25.100°, and 27.220°. The particle size D10 of the valsartan is 7 to 10 um, D50 is 20 to 25 um, and D90 is 40 to 80 um; The particle size of the amlodipine besylate is D10 of 7 to 10um, D50 of 20 to 25um, and D90 of 40 to 80um; The filler is pregelatinized starch D90 is 40 to 80 um; The disintegrant is low-substituted hydroxypropyl cellulose with a D50 of 50 to 110 um and a D90 of 300 um; The disintegrant is cross-linked polyvinylpyrrolidone D10 is 8 to 12 um, D50 is 20 to 30 um, and D90 is 35 to 85 um; The lubricant is magnesium stearate D50 of 5 to 30 um; The flow aid is micro powder silica gel with a D50 of 5 to 30 um.

2. A method for preparing a pharmaceutical composition for treating hypertension, comprising the following steps: S1, mixing the prescribed amount of levamlodipine besylate and pregelatinized starch to obtain premixed powder 1; S2, mixing the mixed powder 1 with the prescribed amount of valsartan, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpyrrolidone to obtain premixed powder 2; S3, mixing the mixed powder 2 with the prescribed amount of lubricant and glidant, and tableting to obtain tablet cores; S4, coating the tablet cores obtained in step S3 to obtain valsartan levamlodipine tablets.

3. S5, the coated tablets obtained in step S4 are packaged with medicinal aluminum foil, polyvinyl chloride solid medicinal hard tablets, or polyamide / aluminum cold-formed solid medicinal composite hard tablets.

4. The mixing conditions in step S1 are: cutting speed: 1000-3000 rpm, stirring speed: 100-300 rpm, and mixing for 3-5 minutes.

5. The mixing conditions in step S2 are: cutting speed: 1000-3000 rpm, stirring speed: 100-300 rpm, and mixing for 3-5 minutes.

6. The mixing conditions in step 3 are a mixing speed of 6 to 10 rpm and a mixing time of 50 to 70 minutes.

7. The tableting conditions in step 3 are as follows: the main pressure of the tablet press is 4 to 11 kN, the feeder speed is 10 to 30 Hz, the vacuum degree is 0.04 to 0.06 MPa, the tableting speed is 10,000 to 50,000 tablets / hour, and the tablet core hardness is 5 to 8 kg / cm2.

8. The coating conditions in step S4 are as follows: a spraying speed of 50 to 100 ml / min, a drum speed of 3 to 8 rpm, and a heating temperature of ≤60°C.

9. The packaging conditions in step S5 are: molding temperature: 120±20°C, heat sealing temperature 1: 150±20°C, heat sealing temperature 2: 150±20°C.

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