CN113712929A - MT-1207 hydrochloride sustained-release preparation and preparation method and application thereof - Google Patents

MT-1207 hydrochloride sustained-release preparation and preparation method and application thereof Download PDF

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CN113712929A
CN113712929A CN202010455245.9A CN202010455245A CN113712929A CN 113712929 A CN113712929 A CN 113712929A CN 202010455245 A CN202010455245 A CN 202010455245A CN 113712929 A CN113712929 A CN 113712929A
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王朋
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Shenyang Haiwang Biological Technology Co ltd
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Abstract

The invention relates to a MT-1207 hydrochloride sustained-release preparation and a preparation method and application thereof, wherein 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 polyvinylpyrrolidone; 30-80 parts of hydroxypropyl methyl cellulose; 2-6 parts of silicon dioxide; 0.2-0.8 part of magnesium stearate(ii) a The structural formula of the MT-1207 hydrochloride is shown as a formula (I). The MT-1207 hydrochloride in the hydrochloride sustained-release preparation reaches the dissolution rate of more than 85 percent after being dissolved out for 24 hours, and can meet the requirement of sustained release.
Figure DDA0002509113470000011

Description

MT-1207 hydrochloride sustained-release preparation and preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a MT-1207 hydrochloride sustained-release preparation as well as a preparation method and application thereof.
Background
MT-1207 hydrochloride has the advantages of definite antihypertensive effect, quick response, mild heart rate slowing down accompanied by antihypertensive, no influence on a heart conduction system, favorable influence on hemodynamics and protective effect on organ damage caused by hypertension after long-term administration. MT-1207 hydrochloride preferably can ensure the effective level of MT-1207 hydrochloride in blood plasma after the medicament is absorbed through gastrointestinal tracts when the medicament exerts the medicament effect, so that the MT-1207 hydrochloride preparation can achieve the aim of slow release. However, the MT-1207 hydrochloride preparation in the prior art can not meet the requirement of slow release. Therefore, the prescription of MT-1207 hydrochloride preparation needs to be optimized to meet the requirement of slow release.
Disclosure of Invention
In view of the above, the invention aims to provide an MT-1207 hydrochloride sustained-release preparation, and a preparation method and an application thereof, wherein the MT-1207 hydrochloride sustained-release preparation can enable the dissolution of MT-1207 hydrochloride to meet the sustained-release requirement.
Based on the above purpose, one aspect of the present invention provides an MT-1207 hydrochloride sustained release preparation, which comprises the following components in parts by weight:
Figure BDA0002509113450000011
wherein the weight average molecular weight of the polyvinylpyrrolidone is 35,000-54,000, the weight average molecular weight of the hydroxypropyl methylcellulose is 550,000-650,000, and the particle size of the silicon dioxide is 1-100 mu m;
wherein the structural formula of the MT-1207 hydrochloride is shown as the formula (I):
Figure BDA0002509113450000021
in a preferred embodiment of the present invention, the amount of MT-1207 hydrochloride is in the following relationship with the amounts of polyvinylpyrrolidone and hydroxypropylmethylcellulose (in parts by weight in the aforementioned ratio, hereinafter the same):
Figure BDA0002509113450000022
more preferably, the amount of MT-1207 hydrochloride is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
Figure BDA0002509113450000023
further preferably, the amount of MT-1207 hydrochloride is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
Figure BDA0002509113450000024
in a preferred embodiment of the invention, the amount of silicon dioxide is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
Figure BDA0002509113450000025
more preferably, the amount of silica is related to the amount of polyvinylpyrrolidone and hydroxypropyl methylcellulose as follows:
Figure BDA0002509113450000026
further preferably, the amount of silicon dioxide is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
Figure BDA0002509113450000027
in a preferred embodiment of the invention, the MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight:
Figure BDA0002509113450000031
more preferably, the hydrochloride sustained-release preparation comprises the following components in parts by weight:
Figure BDA0002509113450000032
in a preferred embodiment of the invention, the sustained-release preparation of MT-1207 hydrochloride is a tablet, a capsule, a granule, a powder, a pill or a film agent.
Based on the same inventive concept, another aspect of the present invention provides a method for preparing the above-described MT-1207 hydrochloride sustained-release preparation, comprising the steps of:
mixing one solvent selected from acetonitrile, isopropanol or ethanol with MT-1207 hydrochloride, silicon dioxide, D-lactose monohydrate, polyvinylpyrrolidone and hydroxypropyl methyl cellulose to obtain a mixed wet material;
sieving the mixed wet material for the first time, and then drying to obtain dried particles;
sieving the dried granules for the second time in a mode of gradually increasing the sieving mesh number to obtain sieved granules;
and mixing the sieved granules with magnesium stearate to obtain the MT-1207 hydrochloride sustained-release preparation.
In a preferred embodiment of the present invention, the step of obtaining the mixed wet material comprises:
diluting the co-powder of MT-1207 hydrochloride and silicon dioxide by using D-lactose monohydrate in geometric multiple, mixing for 2-8 min, adding polyvinylpyrrolidone and hydroxypropyl methyl cellulose, mixing for 10-20 min to form a mixture, and adding one solvent selected from acetonitrile, isopropanol or ethanol into 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.
In a preferred embodiment of the present invention, the method for preparing the above-mentioned sustained-release preparation of MT-1207 hydrochloride further comprises the steps of:
and tabletting the sieved mixture of granules and magnesium stearate to obtain the tablet of the MT-1207 hydrochloride sustained-release preparation.
In a preferred embodiment of the present invention, the mesh number of the first sieving is 10 to 14 meshes;
and/or drying for 1-3 h at 50-70 ℃;
and/or, the second sieving is carried out by sequentially sieving with 20-30 meshes, 40-50 meshes and 140-200 meshes of screens;
and/or mixing the sieved particles with magnesium stearate for 2-8 min.
Based on the same inventive concept, the invention further provides the application of the MT-1207 hydrochloride sustained-release preparation in preparing medicines for preventing, treating and delaying hypertension, target organ damage caused by the hypertension and hypertension-related diseases.
From the above, the invention provides a hydrochloride sustained release preparation, a preparation method and an application thereof, wherein the dissolution rate of MT-1207 hydrochloride in the hydrochloride sustained release preparation reaches more than 85% after 24 hours of dissolution, the requirement of sustained release can be achieved, and the effective level of MT-1207 hydrochloride in blood plasma after the drug is absorbed by gastrointestinal tracts can be ensured.
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FIG. 1a is a plot of MT-1207 hydrochloride of the invention plotted linearly on the abscissa for concentration and on the ordinate for peak area under 0.1M pH 6.8 phosphate buffer, methanol 95:5 (% v/v) (first replicate tablet from example 3);
FIG. 1b is a plot of MT-1207 hydrochloride of the invention plotted linearly with concentration as abscissa and peak area as ordinate under 0.1M pH 6.8 phosphate buffer, methanol 95:5 (% v/v) (second replicate test on tablets made in example 3);
FIG. 1c is a plot of MT-1207 hydrochloride of the invention plotted linearly on the abscissa for concentration and on the ordinate for peak area under 0.1M pH 6.8 phosphate buffer, methanol 95:5 (% v/v) (third replicate of the tablet prepared in example 3);
figure 2a is an in vitro release profile of MT-1207 hydrochloride in tablets prepared according to comparative, example 1, example 2 and example 3 of the present invention at 0.1M pH 6.8 in phosphate buffered saline with 0.2% (w/v) SDS (n-3); wherein a represents the tablet obtained in comparative example, b represents the tablet obtained in example 1, c represents the tablet obtained in example 2, and d represents the tablet obtained in example 3;
figure 2b is a graph showing the in vitro release profile of three batches of MT-1207 hydrochloride of the tablets obtained in example 3 according to the invention in 0.1M pH 6.8 phosphate buffered saline containing 0.2% (w/v) SDS (tablet batch 1, n-3 obtained in example 3; tablet batch 2, n-3 obtained in example 3; tablet batch 3, n-3 obtained in example 3; wherein,
Figure BDA0002509113450000051
representative example 3 was repeated for the 1 st time,
Figure BDA0002509113450000052
the representative example 3 was repeated 2 times,
Figure BDA0002509113450000053
repeat 3 times on behalf of example 3.
Detailed Description
It is to be noted that unless otherwise defined, technical or scientific terms used in one or more embodiments of the present specification should have the ordinary meaning as understood by those of ordinary skill in the art to which this disclosure belongs.
In the present invention, unless otherwise specified, all operations are carried out under ambient temperature and pressure conditions.
In the present invention, the content ratio between the components in the preparation is by weight unless otherwise specified.
As described in the background section, MT-1207 hydrochloride has the advantages of definite antihypertensive effect, quick response, mild heart rate slowing down accompanied by hypotension, no influence on a heart conduction system, favorable influence on hemodynamics and protective effect on organ damage caused by hypertension after long-term administration. MT-1207 hydrochloride preferably can ensure the effective level of MT-1207 hydrochloride in blood plasma after the medicament is absorbed through gastrointestinal tracts when the medicament exerts the medicament effect, so that the MT-1207 hydrochloride preparation can achieve the aim of slow release. However, the MT-1207 hydrochloride preparation in the prior art can not meet the requirement of slow release. Therefore, the prescription of MT-1207 hydrochloride preparation needs to be optimized to meet the requirement of slow release.
Hydroxypropyl methylcellulose (HPMC) K series have different specifications of K4M, K15M, and K35M, HPMC of different specifications have different weight average molecular weights, for example HPMC K4M has a weight average molecular weight of 400,000; HPMC K15M has a weight average molecular weight of 575,000; HPMCK35M had a weight average molecular weight of 675,000, both available from Kaschin-Nash chemical (Nanjing) Ltd.
The inventor of the invention tries to add HPMC K4M into the MT-1207 hydrochloride preparation in the prior art, and finds that the dissolution rate of the MT-1207 hydrochloride in 1 hour is more than 85 percent and the MT-1207 hydrochloride can not play the role of a sustained-release agent. Even if the addition amount of the HPMC K4M is increased, the slow dissolution of the medicine within 24 hours cannot be shown. The inventor of the invention continuously tries to replace HPMC K4M with HPMC K15M, and finds that the dissolution speed is obviously slowed down, on the basis, the inventor determines the prescription of the MT-1207 hydrochloride sustained-release preparation provided by the invention through a large number of experiments and carries out dissolution experiments, and the dissolution experiment result shows that when the prescription of the MT-1207 hydrochloride sustained-release preparation provided by the invention is used, the MT-1207 hydrochloride of the MT-1207 hydrochloride sustained-release preparation reaches the dissolution rate of more than 85 percent after being dissolved for 24 hours, can meet the requirement of sustained release, and can ensure the effective level of the MT-1207 hydrochloride in blood plasma after the medicament is absorbed through gastrointestinal tracts.
The invention provides an MT-1207 hydrochloride sustained-release preparation, which comprises the following components in parts by weight:
the MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight:
Figure BDA0002509113450000061
wherein the weight average molecular weight of the polyvinylpyrrolidone is 35,000-54,000, the weight average molecular weight of the hydroxypropyl methylcellulose is 550,000-650,000, preferably 570,000-600,000, and the particle size of the silicon dioxide is 1-100 μm;
wherein the structural formula of the MT-1207 hydrochloride is shown as the formula (I):
Figure BDA0002509113450000062
chemical name of MT-1207 hydrochloride: 3- (4- (4- (1H-benzotriazol-1-yl) butyl) piperazin-1-yl) benzisothiazole hydrochloride of the formula: c21H24SN62HCl, molecular weight: 428.98, the appearance is white powder.
In a preferred embodiment of the invention, the amount of MT-1207 hydrochloride is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
Figure BDA0002509113450000071
more preferably, the amount of MT-1207 hydrochloride is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
Figure BDA0002509113450000072
further preferably, the amount of MT-1207 hydrochloride is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
Figure BDA0002509113450000073
in a preferred embodiment of the invention, the amount of silicon dioxide is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
Figure BDA0002509113450000074
more preferably, the amount of silica is related to the amount of polyvinylpyrrolidone and hydroxypropyl methylcellulose as follows:
Figure BDA0002509113450000075
further preferably, the amount of silicon dioxide is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
Figure BDA0002509113450000076
in a preferred embodiment of the invention, the MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight:
Figure BDA0002509113450000077
Figure BDA0002509113450000081
more preferably, the hydrochloride sustained-release preparation comprises the following components in parts by weight:
Figure BDA0002509113450000082
it should be noted that the prescription of the sustained-release preparation of hydrochloride provided by the invention can solve the technical problems to be solved by the invention through experimental verification, can meet the requirement of sustained release, and can ensure the effective level of MT-1207 hydrochloride in blood plasma after the medicament is absorbed by gastrointestinal tract. In the formulation of the sustained release preparation of hydrochloride provided by the present invention, example 3 is a preferred example of the sustained release preparation of hydrochloride of the present invention, and the tablet prepared in example 3 achieves about 93% release of MT-1207 hydrochloride after dissolution for 24 hours, and the release linearity is maintained for 20 hours. This is most desirable because it ensures a constant effective level of MT-1207 hydrochloride in the plasma after absorption of the drug through the gastrointestinal tract.
In the present invention, the name of D-lactose monohydrate can also be D-lactose (monohydrate) or α -D-lactose (monohydrate), specifically: O-beta-D-galactopyranosyl- (1 → 4) -alpha-D-glucopyranose monohydrate, formula C12H22O11H2O, molecular weight 360.13, available from the limited noble company of michelil chemical technology, shanghai.
Polyvinylpyrrolidone (PVP) includes species K15, K30, K60 and K90, different PVP species having different weight average molecular weights, for example PVP K30 having a weight average molecular weight of 35,000 to 54,000 are available from guangzhou global-oriented biochemical limited.
The silicon dioxide is a medicinal auxiliary material silicon dioxide, has the particle size of 1-100 mu m, and is purchased from Zhejiang Uwei pharmaceutical industry Co.
The magnesium stearate of the present invention is purchased from Zhejiang Uwei pharmaceutical industries, Inc.
The components of the sustained-release preparation are mixed and then prepared into any pharmaceutically acceptable dosage form according to a conventional preparation method. The dosage form is tablet, capsule, granule, powder, pill or pellicle. More preferably, the sustained release preparation is a tablet, and each sustained release preparation of MT-1207 contains 15-25 mg of MT-1207 hydrochloride.
As described above, the components of the hydrochloride sustained release preparation of the present invention are mixed and then made into any pharmaceutically acceptable dosage form according to the conventional preparation method, more preferably, the dosage form of the hydrochloride sustained release preparation is a tablet, and the tablet is prepared by mixing the raw materials and the auxiliary materials to form a total mixed powder and then directly tabletting the total mixed powder. In order to ensure that the raw and auxiliary materials can be uniformly dispersed in the tablet, the direct compression has high requirement on the fluidity of the total mixed powder. Referring to the information related to the United states pharmacopoeia, the inventor of the invention evaluates the fluidity of the total mixed powder of the MT-1207 hydrochloride preparation in the prior art, and finds that the fluidity can not meet the requirement. Therefore, the inventors tried to improve the flowability of the total powder blend of MT-1207 hydrochloride by wet granulation.
Based on the same inventive concept, another aspect of the present invention provides a method for preparing the above-described MT-1207 hydrochloride sustained-release preparation, comprising the steps of:
mixing one solvent selected from acetonitrile, isopropanol or ethanol with MT-1207 hydrochloride, silicon dioxide, D-lactose monohydrate, polyvinylpyrrolidone and hydroxypropyl methyl cellulose to obtain a mixed wet material;
sieving the mixed wet material for the first time, and then drying to obtain dried particles;
sieving the dried granules for the second time in a mode of gradually increasing the sieving mesh number to obtain sieved granules;
and mixing the sieved granules with magnesium stearate to obtain the MT-1207 hydrochloride sustained-release preparation.
In wet granulation, a wide variety of organic solvents may be used to help modify the particle size for increased flowability. In the present invention, granulation is first performed using water as a solvent, but agglomeration occurs during mixing, and then one of acetonitrile, isopropanol or ethanol is used as a solvent, according to the U.S. pharmacopoeia <467>, isopropanol is a low-toxic substance, and is classified as a third type of solvent. After one of acetonitrile, isopropanol or ethanol is added into the total mixed powder, the particle size of the particles can be effectively increased, and the particles with proper size can be screened out for tabletting after drying. The results of the wet granulation were evaluated using the carr index, Hausner ratio and angle of repose values, and the results showed that the optimized wet granulation had good flowability and compression moldability.
In a preferred embodiment of the present invention, the step of obtaining the mixed wet material comprises:
diluting the co-powder of MT-1207 hydrochloride and silicon dioxide by using D-lactose monohydrate in geometric multiple, mixing for 2-8 min, adding polyvinylpyrrolidone and hydroxypropyl methyl cellulose, mixing for 10-20 min to form a mixture, and adding one solvent selected from acetonitrile, isopropanol or ethanol into 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.
In a preferred embodiment of the present invention, the method for preparing the above-mentioned sustained-release preparation of MT-1207 hydrochloride further comprises the steps of:
and tabletting the sieved mixture of granules and magnesium stearate to obtain the tablet of the MT-1207 hydrochloride sustained-release preparation.
In a preferred embodiment of the present invention, the mesh number of the first sieving is 10 to 14 meshes, more preferably, the mesh number is 12 meshes;
and/or the drying condition is drying for 1-3 h at 50-70 ℃, more preferably drying for 2h at 60 ℃;
and/or, the second sieving is carried out by sequentially sieving with 20-30 meshes, 40-50 meshes and 140-200 meshes of screens; more preferably, the second sieving is performed by using 25-mesh, 45-mesh and 170-mesh sieves in sequence, and then the percentage content of the granules with the particle size of less than 90 μm in the sieved granules is 3-10%, the percentage content of the granules with the particle size of less than 315 μm in the granules with the particle size of less than 90 μm in the sieved granules is 32-46%, and the percentage content of the granules with the particle size of more than 315 μm in the sieved granules is 48-62%; the majority of the particles with a particle size of > 315 μm, and the proportion below 10% probably contributes to the flowability and compression moldability of the total blend.
And/or mixing the sieved granules and magnesium stearate for 2-8 min, and more preferably mixing for 5 min.
In the present invention, the co-powder refers to a mixture obtained by co-pulverizing MT-1207 hydrochloride and silicon dioxide to a raw material particle size of < 10 μm.
In the present invention, the total blend powder refers to the mixture of all components before tableting.
The MT-1207 hydrochloride sustained-release preparation provided by the invention can be subjected to tabletting after optimized wet granulation to obtain tablets. The inventors of the present invention tried to add 18% (w/w) of hydroxypropylmethylcellulose (HPMC K4M) as a sustained-release agent after size-adjustment, and then tabletting. The content uniformity, flowability, hardness, and in vitro dissolution (UPS dissolution apparatus, 0.1M phosphate, pH 6.8, 0.2% w/v sodium dodecyl) of MT-1207 tablets (comparative example) were tested according to the United states pharmacopoeia. The dissolution rate of the tablet of the comparative example is more than 85% in 1h, the slow release purpose is not achieved, and the dissolution speed is obviously reduced when HPMC K4M is replaced by HPMC K15M (example 1). Through optimization studies, one formulation of the MT-1207 tablet (example 3) can not only meet the requirement of sustained release (dissolution rate > 85%, 24h), but also is optimal because it can ensure the constant effective level of MT-1207 hydrochloride in the plasma after the drug is absorbed through the gastrointestinal tract, and examples 1 and 2 can also meet the requirement of sustained release and ensure the effective level of MT-1207 hydrochloride in the plasma after the drug is absorbed through the gastrointestinal tract, although not optimal.
Based on the same inventive concept, the invention further provides the application of the hydrochloride sustained-release preparation in preparing medicines for preventing, treating and delaying hypertension, target organ damage caused by the hypertension and hypertension-related diseases.
In a preferred embodiment of the invention, the target organ injury is hypertension-induced damage to the heart, brain, kidney or blood vessels; the hypertension related diseases comprise atherosclerosis, hyperlipemia, obesity, coronary heart disease, aortic dissection and hyperglycemia, abnormal sugar tolerance, metabolic syndrome and diabetes.
In a preferred embodiment of the invention, the target organ damage is left ventricular hypertrophy, stroke, renal cortex atrophy or aortic thickening, angina, myocardial infarction, heart failure, renal failure, retinal arteriosclerosis, hypertensive fundus oculi disease.
The technical solution provided by the present invention is further described below with reference to specific examples and comparative examples. The following examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention.
The molecular weight of the polymer was measured as a weight average molecular weight by Gel Permeation Chromatography (GPC) according to the national Standard for people's republic of China GB/T21863-2008 (equivalent to German Standard DIN55672-1:2007 section 1 of Gel Permeation Chromatography (GPC) using Tetrahydrofuran (THF) as an eluting solvent).
The following examples relate to formulations summarized in table 1.
Table 1: formulation of MT-1207 hydrochloride tablet
Figure BDA0002509113450000111
Figure BDA0002509113450000121
Example 1
The dosage of the raw material medicine and the auxiliary materials is as follows: 20mg of MT-1207 hydrochloride, 140mg of D-lactose monohydrate, 140mg of polyvinylpyrrolidone K3020 mg, 15 mg of hydroxypropyl methylcellulose K15M 40mg, 4mg of silicon dioxide, 0.5mg of magnesium stearate and 224.5mg of total weight.
The preparation method of the MT-1207 hydrochloride sustained-release preparation comprises the following steps:
diluting the co-powder of MT-1207 hydrochloride and silicon dioxide with D-lactose by geometric multiple, mixing for 5min, adding auxiliary materials of polyvinylpyrrolidone K30 and hydroxypropyl methylcellulose K15M, mixing for 15min, and manually adding 4mL of isopropanol into the mixture to obtain a mixed wet material;
manually sieving the mixed wet material by a 12-mesh standard sieve, then flatly paving the mixed wet material in a tray, and drying the mixed wet material in a blast drier under the conditions of 60 ℃ and 2 hours to obtain dried particles;
sieving the dried granules successively with 25 mesh, 45 mesh and 175 mesh sieves (aperture of 710 μm, 315 μm and 90 μm respectively) to remove granules larger than 1710 mesh to obtain sieved granules;
mixing the sieved granulate with magnesium stearate for 5min, followed by tabletting using a Piccola rotary tablet press (
Figure BDA0002509113450000122
Argentina) to give tablets.
Example 2
The difference between this example and example 1 is only that the amounts of D-lactose monohydrate and hydroxypropylmethylcellulose K15M are different, and the rest are the same, specifically:
the dosage of the raw material medicine and the auxiliary materials is as follows: 20mg of MT-1207 hydrochloride, 130mg of D-lactose monohydrate, K3020 mg polyvinylpyrrolidone, K15M 50mg of hydroxypropyl methylcellulose, 4mg of silicon dioxide, 0.5mg of magnesium stearate, and 224.5mg of total weight.
The preparation method of the MT-1207 hydrochloride sustained-release preparation comprises the following steps:
diluting the co-powder of MT-1207 hydrochloride and silicon dioxide with D-lactose by geometric multiple, mixing for 5min, adding auxiliary materials of polyvinylpyrrolidone K30 and hydroxypropyl methylcellulose K15M, mixing for 15min, and manually adding 4mL of isopropanol into the mixture to obtain a mixed wet material;
manually sieving the mixed wet material by a 12-mesh standard sieve, then flatly paving the mixed wet material in a tray, and drying the mixed wet material in a blast drier under the conditions of 60 ℃ and 2 hours to obtain dried particles;
sieving the dried granules successively with 25 mesh, 45 mesh and 170 mesh sieves (aperture of 710 μm, 315 μm and 90 μm respectively) to remove granules larger than 1710 mesh to obtain sieved granules;
mixing the sieved granulate with magnesium stearate for 5min, followed by tabletting using a Piccola rotary tablet press (
Figure BDA0002509113450000131
Argentina) to give tablets.
Example 3
The difference between this example and example 1 is only that the amounts of D-lactose monohydrate and hydroxypropylmethylcellulose K15M are different, and the rest are the same, specifically:
the dosage of the raw material medicine and the auxiliary materials is as follows: 20mg of MT-1207 hydrochloride, 110mg of D-lactose monohydrate, K3020 mg polyvinylpyrrolidone, K15M 70mg of hydroxypropyl methylcellulose, 4mg of silicon dioxide, 0.5mg of magnesium stearate, and 224.5mg of total weight.
The preparation method of the MT-1207 hydrochloride sustained-release preparation comprises the following steps:
diluting the co-powder of MT-1207 hydrochloride and silicon dioxide with D-lactose by geometric multiple, mixing for 5min, adding auxiliary materials of polyvinylpyrrolidone K30 and hydroxypropyl methylcellulose K15M, mixing for 15min, and manually adding 4mL of isopropanol into the mixture to obtain a mixed wet material;
manually sieving the mixed wet material by a 12-mesh standard sieve, then flatly paving the mixed wet material in a tray, and drying the mixed wet material in a blast drier under the conditions of 60 ℃ and 2 hours to obtain dried particles;
sieving the dried granules successively with 25 mesh, 45 mesh and 170 mesh sieves (aperture of 710 μm, 315 μm and 90 μm respectively) to remove granules larger than 1710 mesh to obtain sieved granules;
mixing the sieved granulate with magnesium stearate for 5min, followed by tabletting using a Piccola rotary tablet press (
Figure BDA0002509113450000132
Argentina) to give tablets.
Comparative examples
The comparative example is different from example 1 only in that the model of hydroxypropyl methylcellulose is different, and the rest is the same, specifically:
the dosage of the raw material medicine and the auxiliary materials is as follows: 20mg of MT-1207 hydrochloride, 140mg of D-lactose monohydrate, 140mg of polyvinylpyrrolidone K3020 mg, 4mg of hydroxypropyl methylcellulose K4M 40, 4mg of silicon dioxide, 0.5mg of magnesium stearate, and 224.5mg of total weight.
The preparation method of the MT-1207 hydrochloride sustained-release preparation comprises the following steps:
diluting the co-powder of MT-1207 hydrochloride and silicon dioxide with D-lactose by geometric multiple, mixing for 5min, adding auxiliary materials of polyvinylpyrrolidone K30 and hydroxypropyl methylcellulose K4M, mixing for 15min, and manually adding 4mL of isopropanol into the mixture to obtain a mixed wet material;
manually sieving the mixed wet material by a 12-mesh standard sieve, then flatly paving the mixed wet material in a tray, and drying the mixed wet material in a blast drier under the conditions of 60 ℃ and 2 hours to obtain dried particles;
sieving the dried granules successively with 25 mesh, 45 mesh and 170 mesh sieves (aperture of 710 μm, 315 μm and 90 μm respectively) to remove granules larger than 1710 mesh to obtain sieved granules;
mixing the sieved granulate with magnesium stearate for 5min, followed by tabletting using a Piccola rotary tablet press (
Figure BDA0002509113450000141
Argentina) to give tablets.
Test examples
The tablets prepared in examples 1 to 3 and the tablets prepared in comparative example were compared in terms of both the flowability and in vitro dissolution of the total blended powder in this test example.
1 method
1.1 Linear
The linearity was determined by HPLC and the concentration was in the range of 0.001-0.05 mg/mL. First, a base standard solution was prepared, and 1mg/mL of MT-1207 stock solution was diluted to 0.05mg/mL with methanol. The other standard solutions are prepared by the basic standard solution. One of the standard solutions was prepared by mixing dissolution media and ethanol at 95:1 (v/v). Three standard curves need to be drawn in the test, and R of the three curves is calculated2The stability of the test was evaluated.
1.2 in vitro dissolution of MT-1207 tablet
The apparatus used for in vitro dissolution was a USP II dissolution apparatus (Kopril, Nongham, UK) equipped with a paddle block, rotating at 75rpm, to which 900mL of 0.1M phosphate buffer in 0.2% (w/v) sodium lauryl sulfate was added, pH 6.8, set at 37. + -. 0.5 ℃. In order to prevent the tablet from sticking to the bottom of the vessel, a sedimentation basket was used for elution, and after 0.08h, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 14h, 16h, 18h, 20h, 22h, and 24h of elution, the sample was centrifuged (2300g,10min), and 1mL of the supernatant was transferred to a sample bottle and analyzed by HPLC. First, second and third replicate tests on tablets of comparative example, example 1, example 2 and example 3 all required in vitro dissolution studies, all in triplicate.
2 results
2.1 flowability and compression moldability of the Total Mixed powder
Bulk density, tap density and angle of repose of the total blended powder were determined according to the united states pharmacopoeia before tableting. The results are shown in tables 2 and 3.
TABLE 2 apparent density, tap density, angle of repose test results
Figure BDA0002509113450000151
TABLE 3 Loose Density, tap Density, and Angle of repose results for the second and third replicates of example 3 (n-3, mean. + -. standard deviation)
Figure BDA0002509113450000152
The flowability of the total blend is important because it determines the degree of powder fit in the die, which in turn determines the weight and size of the tablet and the content uniformity. The flowability and compression moldability of the total blended powder can be evaluated by the carr index, Hausner ratio and angle of repose. Compression moldability is also very important, and it shows the ability of the powder to compress when pressure is applied. The carr index is an important index that can reflect fluidity and compression moldability. When the Carl index of the powder is 5% to 16%, it is indicated that it has good flowability and compression moldability. As can be seen from tables 2 and 3, the Carl index of the total mixed powders of comparative example, example 2 and example 3 was within this range, and good flowability and compression moldability were exhibited. The total powder blend of example 1 had high compression moldability and good flowability, and could flow well in a tablet press.
The Hausner ratio is another measure of the flowability of the total powder blend. It provides information about the degree of powder densification after compression. As can be seen from tables 2 and 3, the Hausner ratios for all the total powders reflected good powder flow and were in good agreement with the respective Carl index results. According to the United states pharmacopoeia, the Hausner ratio and the Carl index are calculated from the apparent and tap densities.
The angle of repose can also be used to reflect the fluidity of a solid, a property related to the adhesion between particles or the resistance to movement. The larger the angle of repose indicates the larger the adhesiveness of the powder, the worse the flowability, but the test results are greatly affected by the method used, and if the powder is tapered, the test results are deviated due to the powder properties and the stickiness of the powder or the surrounding air flow. Despite the disadvantages, the angle of repose is still a measure in the pharmaceutical industry. In tables 2 and 3, the angle of repose values for different total mixes can be seen. The results of the total mixed powder angle of repose of comparative example, example 1 and example 2 correspond completely to the corresponding results of the bulk density and the tap density in terms of flowability. In the first trial repetition of example 3, the angle of repose was biased with respect to the apparent and true density results, the former demonstrating acceptable flowability of the total blended powder, while the latter demonstrated good flowability of the same total blended powder. This is probably because the angle of repose may be subject to errors in the measurement, because the height and base of the cone are subjective measurements, while the loose and tap densities are made in a graduated cylinder device, with less likelihood of error.
2.2 linearity
The HPLC method was verified at a concentration range of 0.001-0.05mg/mL for linearity. 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 elution method was confirmed because MT-1207-eluted samples were quantified using a standard substrate.
Table 4: MT-1207 Linear concentration and Peak area values under 0.1M pH 6.8 phosphate buffer methanol 95:5 (% v/v) (example 3 first replicate)
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
Table 5: MT-1207 Linear concentration and Peak area values under 0.1M pH 6.8 phosphate buffer methanol 95:5 (% v/v) (example 3 second replicate)
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
Table 6: MT-1207 Linear concentration and Peak area values under 0.1M pH 6.8 phosphate buffer methanol 95:5 (% v/v) (example 3 third replicate)
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
The calibration curves and their data for linearity verification are shown in fig. 1a, 1b, 1c and table 4, 5, 6, respectively. In fig. 1a, y is 1299.8x-0.0463, R20.9999, in fig. 1b, y 1310.2x +0.0522, R20.9999, in fig. 1c, y 1271.8x +0.1489, R2Regression coefficient (R) of three repetitions over three different repetition periods (1)2) Both are greater than 0.999, so at linear angles, the HPLC and dissolution methods are accurate.
2.3 in vitro dissolution of MT-1207 hydrochloride in tablets
The dissolution profiles of the tablets of different batches are shown in figure 2a, and the dissolution effects of the tablets of different batches are shown in table 7.
Table 7: dissolution effect of tablets obtained in comparative example and examples 1 to 3
Figure BDA0002509113450000181
HPMC is used as a sustained release agent because of its ability to swell when contacted with water. In this example, different formulations of HPMC polymers of different molecular weights were studied, and HPMC K4M (comparative example) did not function as sustained release agent when added at 18% (w/w). The related art found that when this polymer is used as the sole disintegrant in a matrix tablet, it can provide sustained drug dissolution. However, in this test, even if the amount of the drug to be added is increased, it cannot be said that the drug can be slowly dissolved within 24 hours. Thus, in the rest of the batch trials it was replaced by HPMC K15M, HPMC K15M being a higher molecular weight polymer.
In example 1, example 2 and example 3, HPMC K15M was used as a sustained release agent to achieve sustained release of MT-1207 hydrochloride. As can be seen in FIG. 2a and Table 7, these tablets achieved sustained release of MT-1207. It is known from the literature that as the concentration of HPMC increases, the drug dissolution of the matrix tablet decreases. The reason for this may be that the strength and thickness of the gel layer formed when the polymer swells increases and diffusion of the drug through the polymer chain becomes more difficult. Lactose, on the other hand, serves to enhance the rate of drug release 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 slowed and remained linear over a longer period of time. Therefore, the results of this example are completely consistent with the literature results. The drug release profiles obtained from example 1 (18% w/w HPMC K15M) and example 2 (22% w/w HPMC K15M) achieved more than 85% release after 24 hours of dissolution. The desired drug release profile was obtained from example 3 (31% w/w HPMC K15M), reaching a release of about 93% after 24 hours of dissolution and the release linearity was maintained for 20 hours. This is most desirable as it ensures a constant effective level of MT-1207 in the plasma after absorption of the drug through the gastrointestinal tract.
To ensure reproducibility of the results, the tablet of example 3 was subjected to two replicates and its pharmacokinetics were evaluated. In FIG. 2b, the MT-1207 release profile can be seen in three batches of example 3. The dissolution curves of the three different batches were not statistically different (double sample equal variance t-test, p > 0.05). Therefore, it was concluded that the dissolution profile of MT-1207 hydrochloride as the drug substance was reproducible in the tablets produced by this formulation and process.

Claims (10)

1. The MT-1207 hydrochloride sustained-release preparation is characterized by comprising the following components in parts by weight:
Figure FDA0002509113440000011
wherein the weight average molecular weight of the polyvinylpyrrolidone is 35,000-54,000, the weight average molecular weight of the hydroxypropyl methylcellulose is 550,000-650,000, and the particle size of the silicon dioxide is 1-100 mu m;
wherein the structural formula of the MT-1207 hydrochloride is shown as the formula (I):
Figure FDA0002509113440000012
2. the sustained-release preparation of MT-1207 hydrochloride according to claim 1, wherein the amount of MT-1207 hydrochloride is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
Figure FDA0002509113440000013
more preferably, the amount of MT-1207 hydrochloride is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
Figure FDA0002509113440000014
further preferably, the amount of MT-1207 hydrochloride is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
Figure FDA0002509113440000015
3. the sustained-release formulation of MT-1207 hydrochloride according to claim 1 or 2, wherein the amount of silicon dioxide is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
Figure FDA0002509113440000021
more preferably, the amount of silica is related to the amount of polyvinylpyrrolidone and hydroxypropyl methylcellulose as follows:
Figure FDA0002509113440000022
further preferably, the amount of silicon dioxide is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
Figure FDA0002509113440000023
4. the sustained-release preparation of MT-1207 hydrochloride according to any one of claims 1 to 3, wherein the sustained-release preparation of MT-1207 hydrochloride comprises the following components in parts by weight:
Figure FDA0002509113440000024
more preferably, the MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight:
Figure FDA0002509113440000025
5. the sustained-release preparation of MT-1207 hydrochloride according to any one of claims 1 to 4, wherein the sustained-release preparation of MT-1207 hydrochloride is a tablet, capsule, granule, powder, pill or film.
6. A process for the preparation of a sustained release formulation of MT-1207 hydrochloride according to any of claims 1 to 5, comprising the steps of:
mixing one solvent selected from acetonitrile, isopropanol or ethanol with MT-1207 hydrochloride, silicon dioxide, D-lactose monohydrate, polyvinylpyrrolidone and hydroxypropyl methyl cellulose to obtain a mixed wet material;
sieving the mixed wet material for the first time, and then drying to obtain dried particles;
sieving the dried granules for the second time in a mode of gradually increasing the sieving mesh number to obtain sieved granules;
and mixing the sieved granules with magnesium stearate to obtain the MT-1207 hydrochloride sustained-release preparation.
7. The method of claim 6, wherein the step of obtaining a wet mix comprises:
diluting the co-powder of MT-1207 hydrochloride and silicon dioxide by using D-lactose monohydrate in geometric multiple, mixing for 2-8 min, adding polyvinylpyrrolidone and hydroxypropyl methyl cellulose, mixing for 10-20 min to form a mixture, and adding one solvent selected from acetonitrile, isopropanol or ethanol into 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.
8. The method for preparing an MT-1207 hydrochloride sustained release formulation according to claim 6 or 7, further comprising the steps of:
and tabletting the sieved mixture of granules and magnesium stearate to obtain the tablet of the MT-1207 hydrochloride sustained-release preparation.
9. The method for preparing an MT-1207 hydrochloride sustained release preparation according to one of claims 6 to 8, wherein the mesh number of the first sieving is 10 to 14 meshes;
and/or drying for 1-3 h at 50-70 ℃;
and/or, the second sieving is carried out by sequentially sieving with 20-30 meshes, 40-50 meshes and 140-200 meshes of screens;
and/or mixing the sieved particles with magnesium stearate for 2-8 min.
10. Use of the sustained-release MT-1207 hydrochloride preparation according to any one of claims 1 to 5 for the preparation of a medicament for the prevention, treatment and delay of hypertension, target organ damage caused by hypertension and hypertension-related diseases.
CN202010455245.9A 2020-05-26 2020-05-26 MT-1207 hydrochloride sustained-release preparation and preparation method and application thereof Pending CN113712929A (en)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114209669A (en) * 2022-01-28 2022-03-22 皮摩尔新药(辽宁)有限公司 Sustained-release preparation and preparation method and application thereof

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