CN114209669A - Sustained-release preparation and preparation method and application thereof - Google Patents
Sustained-release preparation and preparation method and application thereof Download PDFInfo
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- CN114209669A CN114209669A CN202210108925.2A CN202210108925A CN114209669A CN 114209669 A CN114209669 A CN 114209669A CN 202210108925 A CN202210108925 A CN 202210108925A CN 114209669 A CN114209669 A CN 114209669A
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- hydrochloride
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- polyvinylpyrrolidone
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Medicinal Preparation (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
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Abstract
The invention relates to a MT-1207 hydrochloride sustained-release preparation, a preparation method and an application thereof, wherein the sustained-release preparation comprises the following components in parts by weight: 30 parts of MT-1207 hydrochloride; 50-120 parts of D-lactose monohydrate; 0-40 parts of polyvinylpyrrolidone; 40-80 parts of hydroxypropyl methyl cellulose; 1-50 parts of ethyl cellulose;
0-80 parts of SR and 0.5-1.5 parts of ferric trioxide; 2-8 parts of silicon dioxide; 0.2-0.8 part of magnesium stearate; the structural formula of the MT-1207 hydrochloride is shown as a formula (I). MT-1207 hydrochloride in the hydrochloride sustained release preparation can be continuously released within 24 hours in one day in an in vitro testThe release of MT-1207 can meet the requirement of slow release.
Description
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 has the effect of ensuring the effective level of MT-1207 hydrochloride in plasma after the medicament is absorbed through gastrointestinal tracts and can continuously show linear dissolution within 24 hours a day. However, the MT-1207 hydrochloride preparation in the prior art cannot meet the requirement of slow release. Therefore, the prescription of MT-1207 hydrochloride formulations needs to be optimized to meet the requirement of sustained release once a day dosing.
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 ensure that MT-1207 hydrochloride can be continuously dissolved within 24 hours a day when dissolved.
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:
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):
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):
in a preferred embodiment of the invention, the amount of silicon dioxide is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
more preferably, the amount of silica is related to the amount of polyvinylpyrrolidone and hydroxypropyl methylcellulose as follows:
further preferably, the amount of silicon dioxide is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
in a preferred embodiment of the invention, the MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight:
more preferably, the hydrochloride sustained-release preparation comprises the following components in parts by weight:
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:
MT-1207 hydrochloride, silicon dioxide, D-lactose monohydrate,
SR or polyvinylpyrrolidone, and hydroxypropyl methylcellulose, optionally ethyl cellulose and ferric oxide, stirring, dripping one solvent selected from acetonitrile, isopropanol or ethanol into the powdery mixture, and stirring to obtain a wet mixed 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;
mixing the sieved granules with magnesium stearate, and stirring to obtain a granular mixture;
and (3) performing one-step compression on the mixture by a rotary tablet press to prepare a single-layer tablet, or performing two-step compression to prepare a double-layer tablet, thus obtaining the MT-1207 hydrochloride sustained-release preparation.
In a preferred embodiment of the present invention, the step of obtaining the mixed wet material comprises:
mixing the MT-1207 hydrochloride and silicon dioxide co-powder with D-lactose monohydrate for 2-8 min, and adding
SR or polyvinylpyrrolidone, hydroxypropyl methylcellulose, optionally ethyl cellulose and ferric oxide are mixed for 10-20 min to form a mixture, and one solvent selected from acetonitrile, isopropanol or ethanol is added 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 (3) performing two-step compression on the mixture by a rotary tablet press to prepare a double-layer tablet, thus obtaining 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 MT-1207 hydrochloride in the hydrochloride sustained release preparation can continuously release MT-1207 within 24 hours a day in an in vitro test, so that the sustained release requirement can be achieved, and the effective level of the MT-1207 hydrochloride in blood plasma after the medicine is absorbed through gastrointestinal tracts can be ensured.
Drawings
FIG. 1 shows the in vitro dissolution of MT-1207 hydrochloride from comparative examples and examples 1, 2, 3 and 4 according to the present invention; wherein an in vitro dissolution curve is plotted with time (h) as the abscissa and the dissolution rate of MT-1207 as the ordinate.
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 can be ensured to continuously reach the effective level in 24 hours a day after the medicament is absorbed by gastrointestinal tracts when the medicament exerts the medicament effect, so that the effect of once-a-day administration is achieved, and the aim of slowly releasing the MT-1207 hydrochloride preparation is required. However, the MT-1207 hydrochloride preparation in the prior art cannot 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; HPMC K35M had a weight average molecular weight of 675,000, both available from Kaschin-Nash chemical (Nanjing) Ltd.
The inventors of the present invention tried to replace HPMC K4M with HPMC K15M in the prior art MT-1207 hydrochloride formulation and found that the dissolution rate was significantly slowed. The inventors of the present invention continued to attempt to join
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium lauryl sulfate 0.8%), it was also found that the dissolution rate was significantly slowed. 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 tests, and carries out in-vitro dissolution test and in-vivo pharmacokinetic test, and the dissolution test result shows that the MT-1207 hydrochloride sustained-release preparation provided by the invention is usedIn the formula, the MT-1207 hydrochloride of the MT-1207 hydrochloride sustained-release preparation is continuously dissolved within 24 hours a day, the sustained-release requirement can be met, and the effective level of the MT-1207 hydrochloride in blood plasma after the medicament is absorbed by gastrointestinal tracts can be ensured.
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:
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):
chemical name of MT-1207 hydrochloride: 3- (4- (4- (1H-benzotriazol-1-yl) butyl) piperazin-1-yl) benzisothiazole hydrochloride of the formula: c21H24SN6HCl, 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:
in a preferred embodiment of the invention, the amount of silicon dioxide is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
more preferably, the amount of silica is related to the amount of polyvinylpyrrolidone and hydroxypropyl methylcellulose as follows:
further preferably, the amount of silicon dioxide is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
in a preferred embodiment of the invention, the MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight:
more preferably, the hydrochloride sustained-release preparation comprises the following components in parts by weight:
it should be noted that the technical problems to be solved by the present invention can be solved by the prescription of the sustained-release hydrochloride preparation provided by the present invention through experimental verification, and MT-1207 hydrochloride can be continuously released within 24 hours a day in dissolution. In the formulation of the sustained-release hydrochloride preparation provided by the present invention, example 2 is a preferred example of the sustained-release hydrochloride preparation of the present invention, and MT-1207 hydrochloride in the tablet prepared in example 2 is continuously linearly dissolved for 24 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 15-30 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:
the polyethylene oxide 8M is mixed with the polyethylene oxide,
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium lauryl sulfate 0.8%), spray-dried lactose, hydroxypropyl methylcellulose K100M, and silicon dioxide by mixing for 15min, adding magnesium stearate into the mixture, and further mixing for 5min to obtain gastric retention layer;
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, and paving the mixture on a gastric retention layer 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.
In a preferred embodiment of the present invention, the step of obtaining the mixed wet material comprises:
mixing the MT-1207 hydrochloride and silicon dioxide co-powder with D-lactose monohydrate for 2-8 min, adding polyvinylpyrrolidone and hydroxypropyl methylcellulose, 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:
the polyethylene oxide 8M is mixed with the polyethylene oxide,
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium lauryl sulfate 0.8%), spray-dried lactose, hydroxypropyl methylcellulose K100M, silicon dioxide were mixed for 15min, magnesium stearate was added to the mixture, and further mixed for 5min to obtain a gastric retentive layer.
And (3) spreading the sieved mixture of granules and magnesium stearate on a gastric retention layer for two-step tabletting 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 micronizing 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 hydroxypropylmethylcellulose (HPMC K15M) as a sustained release agent after size stabilization, 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 tablets of the comparative examples achieved the maximum dissolution rate within 12h and did not achieve the sustained release purpose, when added
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium lauryl sulfate 0.8%) and reducing the amount of D-lactose monohydrate and polyvinylpyrrolidone (example 1), the dissolution rate was significantly slowed. Through optimization studies, one formulation of the MT-1207 tablet (example 2) can not only meet the requirement of sustained release, but is also optimal because it can ensure a constant effective level of MT-1207 hydrochloride in plasma after the drug is absorbed through the gastrointestinal tract and can be continuously dissolved within 24 hours, and examples 3 and 4 can also meet the requirement of sustained release, although not optimal, and can also ensure that MT-1207 can be continuously dissolved within 24 hours, and the MT-1207 hydrochloride in plasma can be continuously kept at an effective level after the drug is absorbed through the gastrointestinal tract.
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
Example 1
Dosage of the single-layer tablet raw material medicine and the auxiliary materials: MT-1207 hydrochloride 30mg, D-lactose monohydrate 75mg, hydroxypropyl methylcellulose K15M70mg,
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium lauryl sulfate 0.8%), 45mg of silicon dioxide 6mg and magnesium stearate 05mg, total weight 226.5 mg.
The preparation method of the MT-1207 hydrochloride sustained-release preparation comprises the following steps:
mixing MT-1207 hydrochloride and silicon dioxide powder with D-lactose for 5min, adding adjuvant such as hydroxypropyl methylcellulose K15M,
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium dodecyl sulfate 0.8%), 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 by using screens of 25 meshes, 45 meshes and 170 meshes successively to remove the granules larger than 170 meshes to obtain the sieved granules;
mixing the sieved granulate with magnesium stearate for 5min, followed by tabletting using a Piccola rotary tablet press (
Argentina) to give a mono-layer tablet.
Example 2
Dosage of gastric retention layer auxiliary materials: polyethylene oxide 8M380mg was added,
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium lauryl sulfate 0.8%), 228mg of spray-dried lactose, 47mg of hydroxypropyl methylcellulose K100M16.2mg, 1.5mg of silicon dioxide, and 1.5mg of magnesium stearate.
The polyethylene oxide 8M is mixed with the polyethylene oxide,
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium dodecyl sulfate 0.8%), spray-dried lactose, and hydroxypropyl methyl celluloseVitamin K100M, silica were mixed for 15min, magnesium stearate was added to the mixture, and further mixed for 5 min.
The dosage of the raw material medicine and the auxiliary material of the slow-release medicine layer is as follows: MT-1207 hydrochloride 30mg, D-lactose monohydrate 74mg, hydroxypropyl methylcellulose K15M70mg,
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium dodecyl sulfate 0.8%), 45mg, ferric oxide 1mg, silicon dioxide 6mg, magnesium stearate 0.5mg, and total weight 226.5 mg.
The preparation method of the MT-1207 hydrochloride sustained-release preparation comprises the following steps:
mixing MT-1207 hydrochloride and silicon dioxide powder with D-lactose for 5min, adding adjuvant such as poly hydroxypropyl methylcellulose K15M,
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium dodecyl sulfate 0.8%) and ferric oxide, 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 by using screens of 25 meshes, 45 meshes and 170 meshes successively to remove the granules larger than 170 meshes to obtain the sieved granules;
mixing the sieved granulate with magnesium stearate for 5min, followed by a two-step tabletting operation using a Piccola rotary tablet press (
Argentina) firstly adding the gastric retention powder (namely the mixture of auxiliary materials of the gastric retention layer) into a mould for pre-compression, then adding a granular drug layer (namely a slow-release drug layer) on the gastric retention powder layer, and further compressing to obtain the double-layer tablet.
Example 3
Dosage of gastric retention layer auxiliary materials: polyethylene oxide 8M380mg was added,
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium lauryl sulfate 0.8%), 228mg of spray-dried lactose, 47mg of hydroxypropyl methylcellulose K100M16.2mg, 1.5mg of silicon dioxide, and 1.5mg of magnesium stearate.
The polyethylene oxide 8M is mixed with the polyethylene oxide,
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium lauryl sulfate 0.8%), spray dried lactose, hydroxypropyl methylcellulose K100M, silicon dioxide were mixed for 15min, magnesium stearate was added to the mixture, and further mixed for 5 min.
The dosage of the raw material medicine and the auxiliary material of the slow-release medicine layer is as follows: MT-1207 hydrochloride 30mg, D-lactose monohydrate 65mg, polyvinylpyrrolidone K3020 mg, hydroxypropylmethylcellulose K15M60mg, ethylcellulose 5mg, ferric oxide 1mg, silicon dioxide 6mg, magnesium stearate 0.5mg, total weight 187.5 mg.
The preparation method of the MT-1207 hydrochloride sustained-release preparation comprises the following steps:
mixing MT-1207 hydrochloride, silicon dioxide powder and D-lactose for 5min, adding auxiliary materials of polyvinylpyrrolidone K30, hydroxypropyl methylcellulose K15M, ethyl cellulose and ferric oxide, 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 by using screens of 25 meshes, 45 meshes and 170 meshes successively to remove the granules larger than 170 meshes to obtain the sieved granules;
mixing the sieved granules with magnesium stearate for 5min, and tabletting with a Piccola rotary tablet pressTwo-stage sheeting operation (
Argentina) firstly adding the gastric retention powder (namely the mixture of auxiliary materials of the gastric retention layer) into a mould for pre-compression, then adding a granular drug layer (namely a slow-release drug layer) on the gastric retention powder layer, and further compressing to obtain the double-layer tablet.
Example 4
The difference between this example and example 3 is only that the amounts of D-lactose monohydrate, hydroxypropylmethylcellulose K15M and ethylcellulose are different, and the rest are the same, specifically:
dosage of gastric retention layer auxiliary materials: polyethylene oxide 8M380mg was added,
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium lauryl sulfate 0.8%), 228mg of spray-dried lactose, 47mg of hydroxypropyl methylcellulose K100M16.2mg, 1.5mg of silicon dioxide, and 1.5mg of magnesium stearate.
The polyethylene oxide 8M is mixed with the polyethylene oxide,
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium lauryl sulfate 0.8%), spray dried lactose, hydroxypropyl methylcellulose K100M, silicon dioxide were mixed for 15min, magnesium stearate was added to the mixture, and further mixed for 5 min.
The dosage of the raw material medicine and the auxiliary material of the slow-release medicine layer is as follows: 30mg of MT-1207 hydrochloride, 99mg of D-lactose monohydrate, K3020 mg polyvinylpyrrolidone, K15M70mg hydroxypropyl methylcellulose, 1mg of ferric oxide, 6mg of silicon dioxide, 0.5mg of magnesium stearate, and 226.5mg of the total weight.
The preparation method of the MT-1207 hydrochloride sustained-release preparation comprises the following steps:
mixing MT-1207 hydrochloride, silicon dioxide powder and D-lactose for 5min, adding auxiliary materials of polyvinylpyrrolidone K30, hydroxypropyl methylcellulose K15M, ethyl cellulose and ferric oxide, 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 by using screens of 25 meshes, 45 meshes and 170 meshes successively to remove the granules larger than 170 meshes to obtain the sieved granules;
mixing the sieved granulate with magnesium stearate for 5min, followed by a two-step tabletting operation using a Piccola rotary tablet press (
Argentina) firstly adding the gastric retention powder (namely the mixture of auxiliary materials of the gastric retention layer) into a mould for pre-compression, then adding a granular drug layer (namely a slow-release drug layer) on the gastric retention powder layer, and further compressing to obtain the double-layer tablet.
Comparative examples
This comparative example differs from example 4 only in the amounts of ferric oxide and D-lactose monohydrate used, which are in this case single-layer tablets, and the rest are the same, in particular:
the dosage of the raw material medicine and the auxiliary materials is as follows: 30mg of MT-1207 hydrochloride, 100mg of D-lactose monohydrate, 100mg of polyvinylpyrrolidone K3020 mg, 15 mg of hydroxypropyl methylcellulose K15M70mg, 6mg of silicon dioxide, 0.5mg of magnesium stearate and 226.5mg of total weight.
The preparation method of the MT-1207 hydrochloride sustained-release preparation comprises the following steps:
mixing the MT-1207 hydrochloride and silicon dioxide co-powder with D-lactose for 5min, adding auxiliary materials of polyvinylpyrrolidone K30 and hydroxypropyl methyl cellulose 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 by using screens of 25 meshes, 45 meshes and 170 meshes successively to remove the granules larger than 170 meshes to obtain the sieved granules;
mixing the sieved granulate with magnesium stearate for 5min, followed by tabletting using a Piccola rotary tablet press (
Argentina) to give tablets.
Test examples
This test example compares the tablets prepared in examples 1 to 4 with those prepared in comparative example in terms of in vitro dissolution.
1 method
1.1 in vitro dissolution of MT-1207 tablets
In vitro dissolution A USP II dissolution apparatus (Kopril, Nongham, UK) equipped with a paddle shaft assembly was used at 75rpm, 500mL of 0.1M acetic acid buffer was added to the dissolution apparatus at a pH of 4.0 and a set temperature of 37. + -. 0.5 ℃. In order to prevent the tablet from sticking to the bottom of the vessel, a sedimentation basket was used for dissolution, and 1mL of the supernatant was transferred to a sample bottle and analyzed by HPLC after centrifugation (2300g,10min) at 1h, 2h, 4h, 6h, 8h, 12h, 16h, and 24h after dissolution. In vitro dissolution studies were required for the first, second and third replicates of the tablets of comparative example, examples 1-4, all in triplicate.
2 results
2.1MT-1207 in vitro dissolution test
The in vitro dissolution results of MT-1207 of different sustained release preparations are shown in figure 1. Examples 1, 2, 3, 4 showed complete dissolution of MT-1207 within 12 hours in an in vitro dissolution test compared to the comparative examples, while the remaining sustained release agents extended sustained dissolution of the Active Pharmaceutical Ingredient (API) to more than 24 hours.
Dissolution studies of these four sustained release formulations showed that MT-1207 was released continuously over 24 hours in vivo. The novel sustained-release tablet can ensure gastric retention of the drug in vivo for 24 hours through a gastric retention layer and contribute to sustained release of MT-1207. In addition to this, the present invention is,
SR (polyvinyl acetate 80%, polyvinylpyrrolidone 19%, sodium dodecyl sulfate 0.8%) helps to delay the dissolution of MT-1207 hydrochloride in vivo in a single-layer tablet. Hydrophilic and hydrophobic polymers may have good application prospects in 24-hour sustained release formulations.
Examples 1, 2, 3, 4 four sustained release formulations are believed to be available for once-a-day oral administration of MT-1207 hydrochloride.
Claims (10)
1. The MT-1207 hydrochloride sustained-release preparation is characterized by comprising the following components in parts by weight:
wherein the content of the first and second substances,
SR comprises 80% of polyvinyl acetate, 19% of polyvinylpyrrolidone and 0.8% of lauryl sodium sulfate;
the weight average molecular weight of the polyvinylpyrrolidone is 35,000-54,000, the weight average molecular weight of the hydroxypropyl methyl cellulose 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):
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:
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:
more preferably, the amount of silica is related to the amount of polyvinylpyrrolidone and hydroxypropyl methylcellulose as follows:
further preferably, the amount of silicon dioxide is related to the amount of polyvinylpyrrolidone and hydroxypropylmethylcellulose as follows:
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:
more preferably, the MT-1207 hydrochloride sustained-release preparation comprises the following components in parts by weight:
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:
MT-1207 hydrochloride, silicon dioxide, D-lactose monohydrate,
SR or polyvinylpyrrolidone, and hydroxypropyl methylcellulose, optionally ethyl cellulose and ferric oxide, stirring, dripping one solvent selected from acetonitrile, isopropanol or ethanol into the powdery mixture, and stirring to obtain a wet mixed 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;
mixing the sieved granules with magnesium stearate, and stirring to obtain a granular mixture;
and (3) performing one-step compression on the mixture by a rotary tablet press to prepare a single-layer tablet, or performing two-step compression to prepare a double-layer tablet, thus obtaining the MT-1207 hydrochloride sustained-release preparation.
7. The method of claim 6, wherein the step of obtaining a wet mix comprises:
mixing MT-1207 hydrochloride and silicon dioxide co-powder and D-lactose monohydrateMixing for 2-8 min, and adding
SR or polyvinylpyrrolidone, hydroxypropyl methylcellulose, optionally ethyl cellulose and ferric oxide are mixed for 10-20 min to form a mixture, and one solvent selected from acetonitrile, isopropanol or ethanol is added 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:
mixing the wet mixture with magnesium stearate, adding into a mold, pre-compressing with a rotary tablet press, adding the granular drug layer on the pre-compressed granular powder, and gradually increasing the compression force 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.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115304593A (en) * | 2022-09-19 | 2022-11-08 | 皮摩尔新药(辽宁)有限公司 | Benzisothiazole compound, and pharmaceutical composition and application thereof |
| CN115381827A (en) * | 2022-09-19 | 2022-11-25 | 皮摩尔新药(辽宁)有限公司 | Application of benzotriazole alkyl derivative in preparation of medicine for treating or preventing cardiovascular diseases |
| CN115381827B (en) * | 2022-09-19 | 2024-02-06 | 皮摩尔新药(辽宁)有限公司 | Application of benzotriazole derivative in preparation of medicine for treating or preventing cardiovascular diseases |
| CN115304593B (en) * | 2022-09-19 | 2024-02-23 | 皮摩尔新药(辽宁)有限公司 | Benzisothiazole compound, and pharmaceutical composition and application thereof |
| WO2024060911A1 (en) * | 2022-09-19 | 2024-03-28 | 皮摩尔新药(辽宁)有限公司 | Benzoisothiazole compound, and pharmaceutical composition and use thereof |
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