A MT-1207 hydrochloride sustained-release preparation and its preparation method and application

Abstract

The present invention relates to a MT-1207 hydrochloride sustained-release preparation and a preparation method and application thereof. The MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight: 20 parts of MT-1207 hydrochloride; 100-150 parts of D-lactose monohydrate; 15-25 parts of polyvinyl pyrrolidone; 30-80 parts of hydroxypropyl methylcellulose; 2-6 parts of silicon dioxide; 0.2-0.8 parts of magnesium stearate; the structural formula of the MT-1207 hydrochloride is shown in formula (I). The MT-1207 hydrochloride in the hydrochloride sustained-release preparation reaches a dissolution rate of more than 85% after dissolution for 24 hours, which can meet the requirements of sustained release. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an MT-1207 hydrochloride sustained-release preparation and a preparation method and application thereof. Background Art

[0002] MT-1207 hydrochloride has the advantages of definite antihypertensive effect, rapid onset, mild heart rate slowing, no effect on cardiac conduction system, favorable effect on hemodynamics, and protective effect on organ damage caused by hypertension when used for a long time. When MT-1207 hydrochloride exerts its efficacy, it is best to ensure the effective level of MT-1207 hydrochloride in plasma after the drug is absorbed through the gastrointestinal tract, which requires that the MT-1207 hydrochloride preparation can achieve the purpose of sustained release. However, the MT-1207 hydrochloride preparation in the prior art cannot meet the requirements of sustained release. Therefore, it is necessary to optimize the prescription of the MT-1207 hydrochloride preparation to meet the requirements of sustained release. Summary of the invention

[0003] In view of this, the purpose of the present invention is to provide a MT-1207 hydrochloride sustained-release preparation and a preparation method and application thereof, wherein the MT-1207 hydrochloride sustained-release preparation can achieve the requirement of sustained-release of MT-1207 hydrochloride.

[0004] Based on the above purpose, one aspect of the present invention provides a MT-1207 hydrochloride sustained-release preparation, wherein the MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight:

[0005]

[0006] Wherein, the weight average molecular weight of polyvinyl pyrrolidone is 35,000-54,000, the weight average molecular weight of hydroxypropyl methylcellulose is 550,000-650,000, and the particle size of silicon dioxide is 1-100 μm;

[0007] Wherein, the structural formula of the MT-1207 hydrochloride is shown in formula (I):

[0008]

[0009] In a preferred embodiment of the present invention, the amount of MT-1207 hydrochloride used and the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose used (the amounts are in parts by weight according to the aforementioned proportions, the same below) have the following relationship:

[0010]

[0011] More preferably, the amount of MT-1207 hydrochloride used has the following relationship with the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose used:

[0012]

[0013] Further preferably, the amount of MT-1207 hydrochloride used has the following relationship with the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose used:

[0014]

[0015] In a preferred embodiment of the present invention, the amount of silicon dioxide used has the following relationship with the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose used:

[0016]

[0017] More preferably, the amount of silicon dioxide used has the following relationship with the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose used:

[0018]

[0019] Further preferably, the amount of silicon dioxide used has the following relationship with the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose used:

[0020]

[0021] In a preferred embodiment of the present invention, the MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight:

[0022]

[0023] More preferably, the hydrochloride sustained-release preparation comprises the following components in parts by weight:

[0024]

[0025] In a preferred embodiment of the present invention, the MT-1207 hydrochloride sustained-release preparation is a tablet, capsule, granule, powder, pill or film.

[0026] Based on the same inventive concept, another aspect of the present invention provides a method for preparing the above-mentioned MT-1207 hydrochloride sustained-release preparation, comprising the following steps:

[0027] Mixing a solvent selected from acetonitrile, isopropanol or ethanol with MT-1207 hydrochloride, silicon dioxide, D-lactose monohydrate, polyvinyl pyrrolidone and hydroxypropyl methylcellulose to obtain a mixed wet material;

[0028] The mixed wet material is screened for the first time and then dried to obtain dried granules;

[0029] The dried particles are sieved for a second time in a manner of increasing sieve mesh numbers to obtain sieved particles;

[0030] The sieved granules are mixed with magnesium stearate to obtain the MT-1207 hydrochloride sustained-release preparation.

[0031] In a preferred embodiment of the present invention, the step of obtaining the mixed wet material comprises:

[0032] The co-powder of MT-1207 hydrochloride and silicon dioxide is diluted with D-lactose monohydrate in geometric multiples, mixed for 2 to 8 minutes, polyvinyl pyrrolidone and hydroxypropyl methylcellulose are added, and mixed for 10 to 20 minutes to form a mixture, and a solvent selected from acetonitrile, isopropanol or ethanol is added to the mixture to obtain a mixed wet material;

[0033] The mass volume ratio of the MT-1207 hydrochloride to the solvent is (4-6):1, and the unit is mg / mL.

[0034] In a preferred embodiment of the present invention, the method for preparing the above-mentioned MT-1207 hydrochloride sustained-release preparation further comprises the following steps:

[0035] The mixture of the sieved granules and magnesium stearate is tableted to obtain tablets of the MT-1207 hydrochloride sustained-release preparation.

[0036] In a preferred embodiment of the present invention, the mesh size of the first screening is 10 to 14 meshes;

[0037] And / or, the drying condition is drying at 50-70° C. for 1-3 hours;

[0038] And / or, the second screening is performed successively using sieves of 20-30 mesh, 40-50 mesh and 140-200 mesh;

[0039] And / or, the time for mixing the sieved particles with magnesium stearate is 2 to 8 minutes.

[0040] Based on the same inventive concept, another aspect of the present invention provides the use of the above-mentioned MT-1207 hydrochloride sustained-release preparation in the preparation of drugs for preventing, treating and delaying hypertension, target organ damage caused by hypertension and hypertension-related diseases.

[0041] From the above description, it can be seen that the present invention provides a hydrochloride sustained-release preparation and its preparation method and application. The MT-1207 hydrochloride in the hydrochloride sustained-release preparation reaches a dissolution rate of more than 85% after 24 hours of dissolution, which can meet the requirements of sustained release and ensure the effective level of MT-1207 hydrochloride in plasma after the drug is absorbed through the gastrointestinal tract. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1a The linear curve of MT-1207 hydrochloride of the present invention is plotted with concentration as the abscissa and peak area as the ordinate under the conditions of 0.1M pH 6.8 phosphate buffer: methanol 95:5 (% v / v) (the first repeated test of the tablets prepared in Example 3);

[0043] Figure 1b The linear curve of MT-1207 hydrochloride of the present invention is drawn with concentration as the abscissa and peak area as the ordinate under the conditions of 0.1M pH 6.8 phosphate buffer: methanol 95:5 (% v / v) (the second repeated test of the tablets prepared in Example 3);

[0044] Figure 1c The linear curve of MT-1207 hydrochloride of the present invention is plotted with concentration as the abscissa and peak area as the ordinate under the conditions of 0.1M pH 6.8 phosphate buffer: methanol 95:5 (% v / v) (the third repeated test of the tablets prepared in Example 3);

[0045] Figure 2a The in vitro release curves of MT-1207 hydrochloride in the tablets prepared in the comparative example, example 1, example 2 and example 3 of the present invention in 0.1M pH 6.8 phosphate buffer solution containing 0.2% (w / v) SDS (n=3); wherein a represents the tablet prepared in the comparative example, b represents the tablet prepared in example 1, c represents the tablet prepared in example 2, and d represents the tablet prepared in example 3;

[0046] Figure 2b The in vitro release curves of MT-1207 hydrochloride of three batches of tablets prepared in Example 3 of the present invention in 0.1M pH 6.8 phosphate buffer solution containing 0.2% (w / v) SDS (Tablet batch 1 prepared in Example 3, n=3; Tablet batch 2 prepared in Example 3, n=3; Tablet batch 3 prepared in Example 3, n=3; wherein, Representative Example 3 was repeated for the first time, Representative Example 3 was repeated for the second time, Representative Example 3 was repeated for the third time. DETAILED DESCRIPTION

[0047] It should be noted that, unless otherwise defined, the technical terms or scientific terms used in one or more embodiments of the present specification should have the common meanings understood by persons having ordinary skills in the field to which the present disclosure belongs.

[0048] In the present invention, unless otherwise stated, all operations are carried out at room temperature and normal pressure.

[0049] In the present invention, unless otherwise stated, the content ratios of the components in the preparation are based on weight.

[0050] As described in the background technology section, MT-1207 hydrochloride has the advantages of definite antihypertensive effect, rapid onset, mild heart rate reduction, no effect on the cardiac conduction system, favorable effect on hemodynamics, and protective effect on organ damage caused by hypertension when used for a long time. When MT-1207 hydrochloride exerts its efficacy, it is best to ensure the effective level of MT-1207 hydrochloride in plasma after the drug is absorbed through the gastrointestinal tract, which requires that the MT-1207 hydrochloride preparation can achieve the purpose of sustained release. However, the MT-1207 hydrochloride preparation in the prior art cannot meet the requirements of sustained release. Therefore, it is necessary to optimize the prescription of the MT-1207 hydrochloride preparation to meet the requirements of sustained release.

[0051] Hydroxypropyl methylcellulose (HPMC) K series has different specifications such as K4M, K15M and K35M. Different specifications of HPMC have different weight-average molecular weights. For example, the weight-average molecular weight of HPMC K4M is 400,000; the weight-average molecular weight of HPMC K15M is 575,000; the weight-average molecular weight of HPMC K35M is 675,000. All of them are purchased from Ashland Chemical (Nanjing) Co., Ltd.

[0052] The inventors of the present invention tried to add HPMC K4M to the MT-1207 hydrochloride preparation in the prior art, and found that the dissolution rate of MT-1207 hydrochloride within 1 hour was greater than 85%, and it could not play the role of a sustained-release agent. Even if the amount of HPMCK4M added was increased, it could not be shown that it could slowly dissolve the drug within 24 hours. The inventors of the present invention continued to try to replace HPMCK4M with HPMC K15M, and found that the dissolution rate was significantly slowed down. On this basis, the inventors determined the prescription of the MT-1207 hydrochloride sustained-release preparation provided by the present invention through a large number of experiments, and conducted a dissolution test. The dissolution test results showed that when the prescription of the MT-1207 hydrochloride sustained-release preparation provided by the present invention was used, the MT-1207 hydrochloride of the MT-1207 hydrochloride sustained-release preparation reached a dissolution rate of more than 85% after dissolution for 24 hours, which can meet the requirements of sustained release and ensure the effective level of MT-1207 hydrochloride in plasma after the drug is absorbed through the gastrointestinal tract.

[0053] One aspect of the present invention provides a MT-1207 hydrochloride sustained-release preparation, wherein the MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight:

[0054] The MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight:

[0055]

[0056] Wherein, the weight average molecular weight of polyvinyl pyrrolidone is 35,000-54,000, the weight average molecular weight of hydroxypropyl methylcellulose is 550,000-650,000, preferably 570,000-600,000, and the particle size of silicon dioxide is 1-100 μm;

[0057] Wherein, the structural formula of the MT-1207 hydrochloride is shown in formula (I):

[0058]

[0059] The chemical name of MT-1207 hydrochloride: 3-(4-(4-(1H-benzotriazole-1-yl)butyl)piperazine-1-yl)benzisothiazole hydrochloride, molecular formula: C 21 H 24 SN62HCl, molecular weight: 428.98, appearance is white powder.

[0060] In a preferred embodiment of the present invention, the amount of MT-1207 hydrochloride used has the following relationship with the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose used:

[0061]

[0062] More preferably, the amount of MT-1207 hydrochloride used has the following relationship with the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose used:

[0063]

[0064] Further preferably, the amount of MT-1207 hydrochloride used has the following relationship with the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose used:

[0065]

[0066] In a preferred embodiment of the present invention, the amount of silicon dioxide used has the following relationship with the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose used:

[0067]

[0068] More preferably, the amount of silicon dioxide used has the following relationship with the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose used:

[0069]

[0070] Further preferably, the amount of silicon dioxide used has the following relationship with the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose used:

[0071]

[0072] In a preferred embodiment of the present invention, the MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight:

[0073]

[0074]

[0075] More preferably, the hydrochloride sustained-release preparation comprises the following components in parts by weight:

[0076]

[0077] It should be noted that the formula of the hydrochloride sustained-release preparation provided by the present invention can solve the technical problem to be solved by the present invention through experimental verification, can meet the requirements of sustained release, and can ensure the effective level of MT-1207 hydrochloride in plasma after the drug is absorbed through the gastrointestinal tract. In the formula of the hydrochloride sustained-release preparation provided by the present invention, Example 3 is a preferred embodiment of the hydrochloride sustained-release preparation of the present invention. The MT-1207 hydrochloride in the tablet prepared in Example 3 reaches about 93% release after 24 hours of dissolution, and the release linearity is maintained for 20 hours. This is ideal because it can ensure a constant effective level of MT-1207 hydrochloride in plasma after the drug is absorbed through the gastrointestinal tract.

[0078] In the present invention, the name of D-lactose monohydrate may also be D-lactose (monohydrate) or α-d-lactose (monohydrate), specifically: O-β-D-galactopyranosyl-(1→4)-α-D-pyranose glucose monohydrate, molecular formula C 12 H 22 O 11 H2O, molecular weight 360.13, was purchased from Shanghai Mairui Chemical Technology Co., Ltd.

[0079] Polyvinylpyrrolidone (PVP) includes types such as K15, K30, K60 and K90. Different types of PVP have different weight average molecular weights. For example, the weight average molecular weight of PVP K30 is 35,000 to 54,000, and can be purchased from Guangzhou Quanao Biochemical Co., Ltd.

[0080] The silicon dioxide of the present invention is pharmaceutical excipient silicon dioxide with a particle size of 1 to 100 μm, which is purchased from Zhejiang Zhongwei Pharmaceutical Co., Ltd.

[0081] The magnesium stearate of the present invention is purchased from Zhejiang Zhongwei Pharmaceutical Co., Ltd.

[0082] The components of the sustained-release preparation of the present invention are mixed and prepared into any pharmaceutically acceptable dosage form according to conventional preparation methods. The dosage form is tablets, capsules, granules, powders, pills or films. More preferably, the dosage form of the sustained-release preparation is tablets, and each tablet of MT-1207 sustained-release preparation contains 15 to 25 mg of MT-1207 hydrochloride.

[0083] As described above, the components of the hydrochloride sustained-release preparation of the present invention are mixed and prepared into any pharmaceutically permitted dosage form according to conventional preparation methods. More preferably, the dosage form of the hydrochloride sustained-release preparation is a tablet, and the tablet is prepared by first mixing the raw materials and excipients to form a total mixed powder, and then directly compressing the total mixed powder. In order to ensure that the raw materials and excipients can be evenly dispersed in the tablet, direct tableting has very high requirements for the fluidity of the total mixed powder. With reference to relevant information from the United States Pharmacopoeia, the inventor of the present invention evaluated the fluidity of the total mixed powder of the MT-1207 hydrochloride preparation in the prior art and found that its fluidity could not meet the requirements. Therefore, the inventor tried to improve the fluidity of the total mixed powder of MT-1207 hydrochloride by a wet granulation method.

[0084] Based on the same inventive concept, another aspect of the present invention provides a method for preparing the above-mentioned MT-1207 hydrochloride sustained-release preparation, comprising the following steps:

[0085] Mixing a solvent selected from acetonitrile, isopropanol or ethanol with MT-1207 hydrochloride, silicon dioxide, D-lactose monohydrate, polyvinyl pyrrolidone and hydroxypropyl methylcellulose to obtain a mixed wet material;

[0086] The mixed wet material is screened for the first time and then dried to obtain dried granules;

[0087] The dried particles are sieved for a second time in a manner of increasing sieve mesh numbers to obtain sieved particles;

[0088] The sieved granules are mixed with magnesium stearate to obtain the MT-1207 hydrochloride sustained-release preparation.

[0089] In wet granulation, there are many organic solvents that can help change the size of the particles to achieve the purpose of increasing fluidity. In the present invention, water was first used as a solvent for granulation, but agglomeration occurred during the mixing process, and then acetonitrile, isopropanol or ethanol was used as a solvent. According to the United States Pharmacopoeia <467> Isopropanol is a low-toxic substance and is classified as a Class III solvent. When acetonitrile, isopropanol or ethanol is added to the total mixed powder, the particle size can be effectively increased, and after drying, particles of suitable size can be screened out for tableting. The results of wet granulation were evaluated using the Carr index, Hausner ratio and angle of repose. The results showed that the optimized wet granulation had good fluidity and compression molding properties.

[0090] In a preferred embodiment of the present invention, the step of obtaining the mixed wet material comprises:

[0091] The co-powder of MT-1207 hydrochloride and silicon dioxide is diluted with D-lactose monohydrate in geometric multiples, mixed for 2 to 8 minutes, polyvinyl pyrrolidone and hydroxypropyl methylcellulose are added, and mixed for 10 to 20 minutes to form a mixture, and a solvent selected from acetonitrile, isopropanol or ethanol is added to the mixture to obtain a mixed wet material;

[0092] The mass volume ratio of the MT-1207 hydrochloride to the solvent is (4-6):1, and the unit is mg / mL.

[0093] In a preferred embodiment of the present invention, the method for preparing the above-mentioned MT-1207 hydrochloride sustained-release preparation further comprises the following steps:

[0094] The mixture of the sieved granules and magnesium stearate is tableted to obtain tablets of the MT-1207 hydrochloride sustained-release preparation.

[0095] In a preferred embodiment of the present invention, the mesh number of the first screening is 10 to 14 meshes, more preferably, the mesh number is 12 meshes;

[0096] And / or, the drying condition is drying at 50-70°C for 1-3h, more preferably, drying at 60°C for 2h;

[0097] And / or, the second screening is performed successively with 20-30 mesh, 40-50 mesh and 140-200 mesh sieves; more preferably, the second screening is performed successively with 25 mesh, 45 mesh and 170 mesh sieves, at which time, among the sieved particles, the percentage content of particles with a particle size of less than 90 μm is 3-10%, the percentage content of particles with a particle size of 90 μm < particle size < 315 μm is 32-46%, and the percentage content of particles with a particle size of greater than 315 μm is 48-62%; particles with a particle size of greater than 315 μm account for the majority, and this part of particles with a content of less than 10% is likely to contribute to the fluidity and compression molding of the total mixed powder.

[0098] And / or, the time for mixing the sieved particles with magnesium stearate is 2 to 8 minutes, more preferably, the mixing time is 5 minutes.

[0099] In the present invention, the co-powder refers to a mixture obtained by co-grinding MT-1207 hydrochloride and silicon dioxide to a raw material particle size of less than 10 μm.

[0100] In the present invention, the total mixed powder refers to the mixture of all components before tableting.

[0101] Each prescription of the MT-1207 hydrochloride sustained-release preparation provided by the present invention can be compressed into tablets after optimizing wet granulation. The inventor of the present invention tried to add 18% (w / w) hydroxypropyl methylcellulose (HPMCK4M) as a sustained-release agent after granulation, and then compressed the tablets. According to the United States Pharmacopoeia, the content uniformity, fluidity, hardness, and in vitro dissolution (UPS dissolution instrument, 0.1M phosphate, pH 6.8, 0.2% w / v sodium dodecyl) of the MT-1207 tablets (comparative example) were tested. The dissolution rate of the tablets of the comparative example within 1 hour was greater than 85%, and the purpose of sustained release was not achieved. When HPMC K4M was replaced with HPMC K15M (Example 1), the dissolution rate was significantly slowed down. After optimization research, a formulation of MT-1207 tablets (Example 3) can not only meet the requirements of sustained release (dissolution rate> 85%, 24h), but also is the most ideal because it can ensure a constant effective level of MT-1207 hydrochloride in plasma after the drug is absorbed through the gastrointestinal tract. Although Examples 1 and 2 are not the most ideal, they can also meet the requirements of sustained release and ensure the effective level of MT-1207 hydrochloride in plasma after the drug is absorbed through the gastrointestinal tract.

[0102] Based on the same inventive concept, another aspect of the present invention provides the use of the above hydrochloride sustained-release preparation in the preparation of drugs for preventing, treating and delaying hypertension, target organ damage caused by hypertension and hypertension-related diseases.

[0103] In a preferred embodiment of the present invention, the target organ damage is damage to the heart, brain, kidney or blood vessels caused by hypertension; the hypertension-related diseases include atherosclerosis, hyperlipidemia, obesity, coronary heart disease, aortic dissection and hyperglycemia, impaired glucose tolerance, metabolic syndrome, and diabetes.

[0104] In a preferred embodiment of the present invention, the target organ damage is left ventricular hypertrophy, cerebral stroke, renal cortical atrophy or aortic thickening, angina pectoris, myocardial infarction, heart failure, renal failure, retinal arteriosclerosis, and hypertensive fundus lesions.

[0105] The technical solution provided by the present invention is further described below in conjunction with specific examples and comparative examples. The following examples are only used to illustrate the present invention and will not limit the protection scope of the present invention.

[0106] The molecular weight of the polymer is measured as weight average molecular weight, which is determined by gel permeation chromatography (GPC) in accordance with the National Standard of the People's Republic of China GB / T 21863-2008 (equivalent to the German Standard DIN55672-1:2007 "Gel Permeation Chromatography (GPC) Part 1: Using Tetrahydrofuran (THF) as Elution Solvent").

[0107] The formulations involved in the following examples are summarized in Table 1.

[0108] Table 1: Formulation of MT-1207 hydrochloride tablets

[0109]

[0110]

[0111] Example 1

[0112] Dosage of raw materials and excipients: MT-1207 hydrochloride 20 mg, D-lactose monohydrate 140 mg, polyvinylpyrrolidone K30 20 mg, hydroxypropyl methylcellulose K15M 40 mg, silicon dioxide 4 mg, magnesium stearate 0.5 mg, total weight 224.5 mg.

[0113] The preparation method of MT-1207 hydrochloride sustained-release preparation comprises the following steps:

[0114] The co-powder of MT-1207 hydrochloride and silicon dioxide was diluted with D-lactose in geometric multiples, mixed for 5 minutes, and then the auxiliary materials polyvinyl pyrrolidone K30 and hydroxypropyl methylcellulose K15M were added. After mixing for 15 minutes, 4 mL of isopropanol was manually added to the mixture to obtain a mixed wet material;

[0115] The mixed wet material was manually passed through a 12-mesh standard sieve, and then spread flat on a tray and placed in a blast dryer for drying at 60°C for 2 hours to obtain dried granules;

[0116] The dried particles were sieved successively with 25-mesh, 45-mesh and 175-mesh sieves (with apertures of 710 μm, 315 μm and 90 μm, respectively), and particles larger than 1710 mesh were removed to obtain sieved particles;

[0117] The sieved granules were mixed with magnesium stearate for 5 min and then tableted using a Piccola rotary tablet press ( Argentina), to obtain tablets.

[0118] Example 2

[0119] The difference between this embodiment and embodiment 1 is that the dosage of D-lactose monohydrate and hydroxypropyl methylcellulose K15M is different, and the rest are the same, specifically:

[0120] Dosage of raw materials and excipients: MT-1207 hydrochloride 20 mg, D-lactose monohydrate 130 mg, polyvinylpyrrolidone K30 20 mg, hydroxypropyl methylcellulose K15M 50 mg, silicon dioxide 4 mg, magnesium stearate 0.5 mg, total weight 224.5 mg.

[0121] The preparation method of MT-1207 hydrochloride sustained-release preparation comprises the following steps:

[0122] The co-powder of MT-1207 hydrochloride and silicon dioxide was diluted with D-lactose in geometric multiples, mixed for 5 minutes, and then the auxiliary materials polyvinyl pyrrolidone K30 and hydroxypropyl methylcellulose K15M were added. After mixing for 15 minutes, 4 mL of isopropanol was manually added to the mixture to obtain a mixed wet material;

[0123] The mixed wet material was manually passed through a 12-mesh standard sieve, and then spread flat on a tray and placed in a blast dryer for drying at 60°C for 2 hours to obtain dried granules;

[0124] The dried particles are sieved successively with 25-mesh, 45-mesh and 170-mesh sieves (with apertures of 710 μm, 315 μm and 90 μm, respectively), and particles larger than 1710 mesh are removed to obtain sieved particles;

[0125] The sieved granules were mixed with magnesium stearate for 5 min and then tableted using a Piccola rotary tablet press ( Argentina), to obtain tablets.

[0126] Example 3

[0127] The difference between this embodiment and embodiment 1 is that the dosage of D-lactose monohydrate and hydroxypropyl methylcellulose K15M is different, and the rest are the same, specifically:

[0128] Dosage of raw materials and excipients: MT-1207 hydrochloride 20 mg, D-lactose monohydrate 110 mg, polyvinylpyrrolidone K30 20 mg, hydroxypropyl methylcellulose K15M 70 mg, silicon dioxide 4 mg, magnesium stearate 0.5 mg, total weight 224.5 mg.

[0129] The preparation method of MT-1207 hydrochloride sustained-release preparation comprises the following steps:

[0130] The co-powder of MT-1207 hydrochloride and silicon dioxide was diluted with D-lactose in geometric multiples, mixed for 5 minutes, and then the auxiliary materials polyvinyl pyrrolidone K30 and hydroxypropyl methylcellulose K15M were added. After mixing for 15 minutes, 4 mL of isopropanol was manually added to the mixture to obtain a mixed wet material;

[0131] The mixed wet material was manually passed through a 12-mesh standard sieve, and then spread flat on a tray and placed in a blast dryer for drying at 60°C for 2 hours to obtain dried granules;

[0132] The dried particles are sieved successively with 25-mesh, 45-mesh and 170-mesh sieves (with apertures of 710 μm, 315 μm and 90 μm, respectively), and particles larger than 1710 mesh are removed to obtain sieved particles;

[0133] The sieved granules were mixed with magnesium stearate for 5 min and then tableted using a Piccola rotary tablet press ( Argentina), to obtain tablets.

[0134] Comparative Example

[0135] The difference between this comparative example and Example 1 is that the type of hydroxypropyl methylcellulose is different, and the rest are the same, specifically:

[0136] Dosage of raw materials and excipients: MT-1207 hydrochloride 20 mg, D-lactose monohydrate 140 mg, polyvinylpyrrolidone K30 20 mg, hydroxypropyl methylcellulose K4M 40 mg, silicon dioxide 4 mg, magnesium stearate 0.5 mg, total weight 224.5 mg.

[0137] The preparation method of MT-1207 hydrochloride sustained-release preparation comprises the following steps:

[0138] The co-powder of MT-1207 hydrochloride and silicon dioxide was diluted with D-lactose in geometric multiples, mixed for 5 minutes, and then the auxiliary materials polyvinyl pyrrolidone K30 and hydroxypropyl methylcellulose K4M were added, mixed for 15 minutes, and then 4 mL of isopropanol was manually added to the mixture to obtain a mixed wet material;

[0139] The mixed wet material was manually passed through a 12-mesh standard sieve, and then spread flat on a tray and placed in a blast dryer for drying at 60°C for 2 hours to obtain dried granules;

[0140] The dried particles are sieved successively with 25-mesh, 45-mesh and 170-mesh sieves (with apertures of 710 μm, 315 μm and 90 μm, respectively), and particles larger than 1710 mesh are removed to obtain sieved particles;

[0141] The sieved granules were mixed with magnesium stearate for 5 min and then tableted using a Piccola rotary tablet press ( Argentina), to obtain tablets.

[0142] Test example

[0143] This test example compares the tablets prepared in Examples 1-3 and the tablets prepared in Comparative Example in terms of the flowability of the total mixed powder and in vitro dissolution.

[0144] 1 Method

[0145] 1.1 Linearity

[0146] The linearity was determined by HPLC, with a concentration range of 0.001-0.05 mg / mL. First, a basic standard solution was prepared by diluting 1 mg / mL of MT-1207 stock solution to 0.05 mg / mL with methanol. Other standard solutions were prepared from this basic standard solution. One of the standard solutions was prepared by mixing the dissolution medium and ethanol at a ratio of 95:1 (v / v). Three standard curves need to be drawn in the experiment, and the R of the three curves needs to be calculated. 2 , to evaluate the stability of the test.

[0147] 1.2 In vitro dissolution of MT-1207 tablets

[0148] The in vitro dissolution was performed in a USP II dissolution apparatus (Copley, Nottingham, UK) equipped with a paddle assembly at a speed of 75 rpm. 900 mL of 0.1 M phosphate buffer prepared with 0.2% (w / v) sodium dodecyl sulfate was added to the dissolution apparatus, pH 6.8, and the set temperature was 37 ± 0.5 °C. A sinker was used during dissolution. To prevent the tablets from adhering to the bottom of the container, samples were centrifuged (2300 g, 10 min) at 0.08 h, 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h, and 24 h after dissolution, and 1 mL of the supernatant was transferred to a sample bottle for analysis by HPLC. The first, second and third replication tests of the tablets of Comparative Example, Example 1, Example 2 and Example 3 all required in vitro dissolution studies, and all tests were performed in triplicate.

[0149] 2 Results

[0150] 2.1 Flowability and compression molding of the total mixed powder

[0151] According to the United States Pharmacopoeia, the bulk density, tap density and angle of repose of the total mixed powder were measured before tableting. The results are shown in Tables 2 and 3.

[0152] Table 2: Test results of bulk density, tap density and angle of repose

[0153]

[0154] Table 3: Bulk density, tap density and angle of repose results of the second and third repeated tests of Example 3 (n=3, mean ± standard deviation)

[0155]

[0156] The fluidity of the total mixed powder is very important because it determines the matching degree of the powder in the die ring, and then determines the weight and size of the tablets and the uniformity of the content. The fluidity and compression moldability of the total mixed powder can be evaluated by the Carr index, Hausner ratio and angle of repose. Compression moldability is also very important, which shows the compression ability of the powder when pressure is applied. The Carr index is an important indicator that can reflect fluidity and compression moldability. When the Carr index of the powder is between 5% and 16%, it means that it has good fluidity and compression moldability. It can be seen from Tables 2 and 3 that the Carr index of the total mixed powders of the comparative example, Example 2 and Example 3 are all within this range, and have good fluidity and compression moldability. The total mixed powder of Example 1 has higher compression moldability and better fluidity, and can flow well in the tablet press.

[0157] The Hausner ratio is another indicator of the flowability of the total powder mix. It provides information about the degree of densification of the powder after compression. As can be seen from Tables 2 and 3, the Hausner ratio values ​​of all the total powder mixes reflect good flowability of the powders and are completely consistent with the respective Carr's index results. According to the United States Pharmacopeia, both the Hausner ratio and the Carr's index are calculated from the bulk density and the tapped density.

[0158] The angle of repose can also be used to reflect the fluidity of solids. It is a property related to the adhesion between particles or the resistance to movement. The larger the angle of repose, the greater the adhesion of the powder and the worse the fluidity. However, the test results are greatly affected by the method used. If the powder is formed into a cone, the test results will be biased due to the properties of the powder and the viscosity of the powder or the surrounding air flow. Despite its shortcomings, the angle of repose is still used as a measurement indicator in the pharmaceutical industry. In Tables 2 and 3, the values ​​of the angle of repose of different total mixed powders can be seen. The results of the angle of repose of the total mixed powders of the comparative example, Example 1 and Example 2 are completely consistent with the corresponding loose density and tap density results in terms of fluidity. In the first repeated test of Example 3, the angle of repose deviated from the results of the loose density and true density. The former proved that the fluidity of the total mixed powder was acceptable, while the latter showed that the fluidity of the same total mixed powder was good. This may be because the angle of repose may have errors when measuring, because the height and base of the cone are subjective measurements, while the loose density and tap density are carried out in a graduated cylinder device, and the possibility of error is small.

[0159] 2.2 Linearity

[0160] The linearity of the HPLC method was verified in the concentration range of 0.001-0.05 mg / mL. Within this concentration range, three calibration curves were prepared on three different days. The regression coefficient should be equal to or greater than 0.99. The dissolution method was also confirmed because the MT-1207 dissolution samples were quantified using the standard matrix.

[0161] Table 4: Concentration and peak area values ​​of MT-1207 linearity under the conditions of 0.1M pH 6.8 phosphate buffer: methanol 95:5 (% v / v) (first repeat test of Example 3)

[0162] Concentration (mg / mL) Peak area (mAU*min) 0.001 1.5872 0.002 2.6935 0.005 6.0083 0.007 9.0453 0.01 12.8738 0.02 25.9631 0.05 64.9897

[0163] Table 5: Concentration and peak area values ​​of MT-1207 linearity under the conditions of 0.1M pH 6.8 phosphate buffer: methanol 95:5 (% v / v) (second repeat test of Example 3)

[0164] Concentration (mg / mL) Peak area (mAU*min) 0.001 1.4479 0.002 2.5809 0.005 6.1665 0.007 9.4091 0.01 13.4194 0.02 26.3017 0.05 65.5137

[0165] Table 6: Concentration and peak area values ​​of MT-1207 linearity under the conditions of 0.1M pH 6.8 phosphate buffer: methanol 95:5 (% v / v) (third repeat test of Example 3)

[0166] Concentration (mg / mL) Peak area (mAU*min) 0.001 1.3857 0.002 2.5248 0.005 6.6079 0.007 8.9321 0.01 12.9395 0.02 25.8331 0.05 63.6373

[0167] The calibration curves and their data used for linearity verification are shown in Figure 1a , Figure 1b , Figure 1c and Table 4, Table 5, Table 6. Figure 1a In the equation, y=1299.8x-0.0463, R 2 =0.9999, in Figure 1b In the equation, y=1310.2x+0.0522, R 2 =0.9999, in Figure 1c In the equation, y=1271.8x+0.1489, R 2 =1, in three different repetition periods, the regression coefficient (R 2 ) are all greater than 0.999, so the HPLC and dissolution methods are accurate from a linearity perspective.

[0168] 2.3 In vitro dissolution of MT-1207 hydrochloride from tablets

[0169] The dissolution profiles of tablets from different batches are shown in Figure 2a The dissolution effects of tablets from different batches are shown in Table 7.

[0170] Table 7: Dissolution effect of tablets prepared in Comparative Example and Examples 1-3

[0171]

[0172] Since HPMC has the ability to swell when in contact with water, it is used as a sustained-release agent. In this example, HPMC polymers of different molecular weights were studied in different formulations. When HPMC K4M was added in an amount of 18% (w / w) (Comparative Example), it could not function as a sustained-release agent. The relevant literature found that when this polymer is used as the only disintegrant in a matrix tablet, it can provide sustained drug dissolution. However, in this experiment, even if the addition amount is increased, it cannot be shown that it can slowly dissolve the drug within 24 hours. Therefore, in the remaining batches of experiments, it was replaced by HPMC K15M, a polymer with a higher molecular weight.

[0173] In Example 1, Example 2 and Example 3, HPMC K15M is used as a sustained-release agent to achieve sustained-release of MT-1207 hydrochloride. Figure 2a As can be seen from Table 7, these tablets achieve sustained release of MT-1207. Referring to the relevant literature, it is known that as the concentration of HPMC increases, the drug dissolution of the matrix tablet will decrease. The reason may be that the strength and thickness of the gel layer formed when the polymer swells increase, and the diffusion of the drug through the polymer chain becomes more difficult. On the other hand, lactose promotes the drug dissolution rate by promoting matrix hydration, gel formation and free body. Increasing the concentration of HPMC K15M from Example 1 to Example 3, the dissolution rate of MT-1207 hydrochloride slows down and remains linear for a long time. Therefore, the results of this example are completely consistent with the results of the literature. The drug release curves obtained from Example 1 (18% w / w HPMC K15M) and Example 2 (22% w / w HPMC K15M) reached more than 85% release after 24 hours of dissolution. The desired drug release curve was obtained from Example 3 (31% w / w HPMCK15M), and about 93% release was achieved after 24 hours of dissolution, and the release linearity was maintained for 20 hours. This is ideal because it ensures constant effective levels of MT-1207 in plasma following absorption of the drug through the gastrointestinal tract.

[0174] To ensure the reproducibility of the results, the tablets of Example 3 were tested twice and their drug dissolution kinetics were evaluated. Figure 2b In the figure, we can see the release curves of MT-1207 in the three batches of Example 3. There is no statistical difference in the dissolution curves of the three different batches (two-sample equal variance t-test, p>0.05). Therefore, it is concluded that the dissolution curve of the raw material MT-1207 hydrochloride of the tablets produced by this formula and process is reproducible.

Claims

1. A MT-1207 hydrochloride sustained-release preparation, characterized in that: The MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight: Wherein, the weight average molecular weight of polyvinyl pyrrolidone is 35,000-54,000, the weight average molecular weight of hydroxypropyl methylcellulose is 550,000-650,000, and the particle size of silicon dioxide is 1-100 μm; Wherein, the structural formula of the MT-1207 hydrochloride is shown in formula (I):

2. The MT-1207 hydrochloride sustained-release preparation according to claim 1, characterized in that: The relationship between the dosage of MT-1207 hydrochloride and the dosage of polyvinyl pyrrolidone and hydroxypropyl methylcellulose is as follows:

3. The MT-1207 hydrochloride sustained-release preparation according to claim 2, characterized in that: The relationship between the dosage of MT-1207 hydrochloride and the dosage of polyvinyl pyrrolidone and hydroxypropyl methylcellulose is as follows:

4. The MT-1207 hydrochloride sustained-release preparation according to claim 3, characterized in that: The relationship between the dosage of MT-1207 hydrochloride and the dosage of polyvinyl pyrrolidone and hydroxypropyl methylcellulose is as follows:

5. The MT-1207 hydrochloride sustained-release preparation according to claim 1, characterized in that: The relationship between the amount of silicon dioxide and the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose is as follows:

6. The MT-1207 hydrochloride sustained-release preparation according to claim 5, characterized in that: The relationship between the amount of silicon dioxide and the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose is as follows:

7. The MT-1207 hydrochloride sustained-release preparation according to claim 6, characterized in that: The relationship between the amount of silicon dioxide and the amount of polyvinyl pyrrolidone and hydroxypropyl methylcellulose is as follows:

8. The MT-1207 hydrochloride sustained-release preparation according to claim 1, characterized in that: The MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight:

9. The MT-1207 hydrochloride sustained-release preparation according to claim 8, characterized in that: The MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight:

10. The MT-1207 hydrochloride sustained-release preparation according to any one of claims 1 to 9, characterized in that: The MT-1207 hydrochloride sustained-release preparation is in the form of tablets, capsules, granules, powders, pills or films.

11. A method for preparing the MT-1207 hydrochloride sustained-release preparation according to any one of claims 1 to 10, characterized in that: The following steps are involved: Mixing a solvent selected from acetonitrile, isopropanol or ethanol with MT-1207 hydrochloride, silicon dioxide, D-lactose monohydrate, polyvinyl pyrrolidone and hydroxypropyl methylcellulose to obtain a mixed wet material; The mixed wet material is screened for the first time and then dried to obtain dried granules; The dried particles are sieved for a second time in a manner of increasing sieve mesh numbers to obtain sieved particles; The sieved granules are mixed with magnesium stearate to obtain the MT-1207 hydrochloride sustained-release preparation.

12. The method for preparing MT-1207 hydrochloride sustained-release preparation according to claim 11, characterized in that: The step of obtaining the mixed wet material comprises: The co-powder of MT-1207 hydrochloride and silicon dioxide is diluted with D-lactose monohydrate in geometric multiples, mixed for 2 to 8 minutes, polyvinyl pyrrolidone and hydroxypropyl methylcellulose are added, and mixed for 10 to 20 minutes to form a mixture, and a solvent selected from acetonitrile, isopropanol or ethanol is added to the mixture to obtain a mixed wet material; The mass volume ratio of the MT-1207 hydrochloride to the solvent is (4-6):1, and the unit is mg / mL.

13. The method for preparing MT-1207 hydrochloride sustained-release preparation according to claim 12, characterized in that: The following steps are also included: The mixture of the sieved granules and magnesium stearate is tableted to obtain tablets of the MT-1207 hydrochloride sustained-release preparation.

14. The method for preparing a sustained-release preparation of MT-1207 hydrochloride according to any one of claims 11 to 13, characterized in that: The mesh number of the first screening is 10 to 14 meshes; And / or, the drying condition is drying at 50-70° C. for 1-3 hours; And / or, the second screening is performed successively using sieves of 20-30 mesh, 40-50 mesh and 140-200 mesh; And / or, the time for mixing the sieved particles with magnesium stearate is 2 to 8 minutes.

15. Use of the MT-1207 hydrochloride sustained-release preparation according to any one of claims 1 to 10 in the preparation of drugs for preventing and treating hypertension-related diseases.

16. The use according to claim 15, wherein the prevention and treatment of hypertension-related diseases refers to delaying hypertension-related diseases.

17. The use according to claim 15 or 16, wherein the hypertension-related diseases are hypertension and target organ damage caused by hypertension.

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