CN110237055B - Pharmaceutical composition of silybin and simvastatin, and preparation method and application thereof - Google Patents
Pharmaceutical composition of silybin and simvastatin, and preparation method and application thereof Download PDFInfo
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- CN110237055B CN110237055B CN201910634004.8A CN201910634004A CN110237055B CN 110237055 B CN110237055 B CN 110237055B CN 201910634004 A CN201910634004 A CN 201910634004A CN 110237055 B CN110237055 B CN 110237055B
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
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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
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- 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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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
Abstract
The invention discloses a pharmaceutical composition of silybin and simvastatin, and a preparation method and application thereof, wherein the pharmaceutical composition comprises silybin and simvastatin with the mass ratio of 1: 0.2-1: 1; the pharmaceutical composition of the silybin and the simvastatin can reduce the damage of the simvastatin to the liver, promote the metabolism of the liver to fat so as to achieve the effect of enhancing the lipid-lowering effect, and also has obvious improvement effect on the side effect of the simvastatin transaminase increase after long-term use; the preparation method of the invention completes the preparation of the silybin nanoparticles with certain particle size under the condition of low temperature, thereby effectively improving the content uniformity of silybin in the nanoparticles; the silybin nanoparticles and the simvastatin nanoparticles are mixed by adopting horizontal and vertical matching stirring, the stirring speed, direction and time are controlled, the nanoparticles are effectively prevented from being damaged, and the stability of the whole preparation is improved.
Description
Technical Field
The invention relates to the field of preparation and application of a pharmaceutical composition, in particular to a pharmaceutical composition of silybin and simvastatin, and a preparation method and application thereof.
Background
Simvastatin was extracted from aspergillus terreus, was first developed by the merck pharmaceutical factory and began to enter medical use in 1992. The drug is named in the basic drug list of the world health organization and belongs to one of the essential drugs of the basic medical system. As an oral hypolipidemic drug, the trade name is commonly known as "zotor". The product can reduce the chance of attack of people with high heart disease risk. Is one of the most effective lipid-lowering medicines recognized by the world health organization at present, but the medicine has little side effect on the liver, and the transaminase is increased due to liver injury caused by long-term administration.
Silibinin has the effects of repairing liver cells and reducing transaminase and has an unobvious effect when being used alone for reducing blood fat, and the pharmaceutical composition of Silibinin and simvastatin can reduce the damage of simvastatin to the liver, promote the metabolism of the liver to fat so as to achieve the effect of enhancing the effect of reducing blood fat, and has an obvious improvement effect on the side effects of liver damage and glutamic-pyruvic transaminase increase caused by long-term use of simvastatin.
Disclosure of Invention
The purpose of the invention is as follows: in order to overcome the defects in the prior art, the invention provides a pharmaceutical composition of silybin and simvastatin; the second purpose of the invention is to provide a preparation method of the pharmaceutical composition, and the third purpose of the invention is to provide an application of the pharmaceutical composition, and the prepared pharmaceutical composition not only has obvious efficacy on reducing blood fat, but also can effectively reduce the damage of simvastatin to liver.
The technical scheme is as follows: in order to solve the technical problems, the technical scheme adopted by the invention is as follows: a pharmaceutical composition of silybin and simvastatin comprises silybin and simvastatin in a mass ratio of 1: 0.2-1: 1.
In some embodiments, the mass ratio of silybin to simvastatin is 1: 0.2-1: 0.4; is used for preparing medicines for treating hypercholesterolemia and hyperlipidemia and medicines for treating familial hypercholesterolemia and hyperlipidemia.
In some embodiments, the mass ratio of the silybin to the simvastatin is 1: 0.8-1: 1, and the silybin and simvastatin are used for preparing a medicine for treating coronary heart disease and hyperlipidemia and a medicine for treating family history hypertension and hyperlipidemia.
The invention also discloses a preparation method of the pharmaceutical composition of silybin and simvastatin, which comprises the following steps:
(1) preparing silybin liposome nanoparticles: dissolving silybin and phospholipid in ethanol with the mass concentration of 95-98% according to the mass ratio of 1: 1-1: 2, heating to completely dissolve the silybin and the phospholipid, evaporating the ethanol by using a thin film evaporator, performing microwave vacuum drying for 20-25 min, and performing superfine grinding at the low temperature of-10-0 ℃ to obtain 1-100 mu m nanoparticles;
(2) preparation of simvastatin nanoparticles: taking simvastatin and alpha-cyclodextrin according to the mass ratio of 1: 3-1: 10, and stirring at a high speed to form nanoparticles with the particle size of 1-100 mu m;
(3) preparing a mixed soft material: adding the nanoparticles prepared in the steps (1) and (2) into a high-speed wet granulator according to the required mass ratio of silybin to simvastatin, mixing, transversely cutting for 3-4 min, vertically cutting for 2-3 min, adding 50-70% ethanol, and stirring at a high speed for 3-5 min to obtain a mixed soft material;
(4) preparation of granules of the mixed preparation: sieving the soft material with a sieve of 18-20 meshes, granulating, drying at 60-70 ℃ for 1-2 h, and grading with a sieve of 18 meshes;
(5) tabletting or encapsulating the granules of the mixed preparation to obtain the finished medicinal composition.
Furthermore, the frequency of the microwave vacuum drying in the step (1) is 370Hz to 380 Hz; the vacuum degree is-0.01 to-1 MPa.
Furthermore, the high-speed stirring speed in the step (2) is 300-1000 r/min.
Furthermore, the mixing speed in the high-speed wet granulator in the step (3) is 300-1000 r/min.
Furthermore, the high-speed stirring speed in the step (3) is 300-1000 r/min.
The invention also discloses application of the pharmaceutical composition in preparing a medicament for treating hypolipidemia.
Has the advantages that: the invention has the following advantages: (1) the pharmaceutical composition of the silybin and the simvastatin can reduce the damage of the simvastatin to the liver, promote the metabolism of the liver to fat so as to achieve the effect of enhancing the lipid-lowering effect, and also has obvious improvement effect on the side effect of the simvastatin transaminase increase after long-term use; (2) the preparation of the silybin nanoparticles with certain particle size is completed under the low temperature condition, so that the content uniformity of silybin in the nanoparticles is effectively improved; (3) the silybin nanoparticles and the simvastatin nanoparticles are mixed by adopting horizontal and vertical matching stirring, the stirring speed, direction and time are controlled, the nanoparticles are effectively prevented from being damaged, and the stability of the whole preparation is improved.
Detailed Description
The present invention will be described in further detail with reference to the following examples:
the pharmaceutical drugs and instrumentation used in the examples and in the animal experiments were derived as follows:
silibinin is supplied by Jiangsu Hua Chinese medicinal industry Co., Ltd;
simvastatin tablets were supplied by Shandong Phoenix pharmaceutical Co., Ltd;
physiological saline is supplied by chenxin pharmaceutical industries, ltd;
the high-fat feed is provided by cooperative medical and biological engineering, Limited liability company of Jiangsu province;
the common feed is provided by the experimental animal breeding company Limited of Jinnanpunyue;
the high speed wet granulator manufacturer is Changzhou one-step drying equipment Limited.
Example 1:
a pharmaceutical composition of silybin and simvastatin comprises silybin and simvastatin with a mass ratio of 1: 0.5.
A preparation method of a pharmaceutical composition of silibinin and simvastatin comprises the following steps:
(1) preparing silybin liposome nanoparticles: dissolving 100g of silibinin and 100g of phospholipid in 95% ethanol, heating to dissolve completely, evaporating ethanol with a film evaporator, microwave vacuum drying for 23min, and micronizing at 0 deg.C to obtain nanoparticles of 50 μm; the microwave vacuum drying frequency is 370MHz, and the vacuum degree is-0.01 MPa;
(2) preparation of simvastatin nanoparticles: taking 50g of simvastatin and 150g of alpha-cyclodextrin, and stirring at a high speed at a rotating speed of 300r/min to form 50 mu m nanoparticles;
(3) preparing a mixed soft material: and (3) adding the nanoparticles prepared in the steps (1) and (2) into a high-speed wet granulator according to the mass ratio of 1:0.5 of silybin to simvastatin, mixing, transversely cutting for 3min, vertically cutting for 2min, adding ethanol with the mass concentration of 50%, and stirring at a high speed for 3min to obtain a mixed soft material.
(4) Preparation of granules of the mixed preparation: sieving the soft material with 18 mesh sieve, granulating, drying at 60 deg.C for 1 hr, and grading with 18 mesh sieve to obtain granule of mixed preparation;
(5) tabletting the granules of the mixed preparation to obtain the finished medicinal composition tablet (the specification is 0.3 g/tablet).
Example 2:
a pharmaceutical composition of silybin and simvastatin comprises silybin and simvastatin with a mass ratio of 1: 0.2.
A preparation method of a pharmaceutical composition of silibinin and simvastatin comprises the following steps:
(1) preparing silybin liposome nanoparticles: dissolving 100g of silybin and 150g of phospholipid in 97% ethanol, heating to completely dissolve, evaporating the ethanol by a thin film evaporator, performing microwave vacuum drying for 25min, and performing superfine grinding at a low temperature of-5 ℃ to obtain 1 micron nanoparticles; microwave vacuum drying frequency is 375MHz, vacuum degree is-0.05 MPa;
(2) preparation of simvastatin nanoparticles: taking 50g of simvastatin and 300g of alpha-cyclodextrin, and stirring at a high speed at a rotating speed of 700r/min to form 1 micron nanoparticles;
(3) preparing a mixed soft material: and (3) adding the nanoparticles prepared in the steps (1) and (2) into a high-speed wet granulator according to the mass ratio of 1:0.2 of silybin to simvastatin, mixing, transversely cutting for 4min, vertically cutting for 3min, adding ethanol with the mass concentration of 55%, and stirring at a high speed for 4min to obtain a mixed soft material.
(4) Preparation of granules of the mixed preparation: sieving the soft material with 19 mesh sieve, granulating, drying at 65 deg.C for 1.5h, and grading with 18 mesh sieve to obtain mixed granule;
(5) the granules of the mixed preparation are taken to prepare capsules to obtain finished product pharmaceutical composition capsules (the specification is 0.35 g/tablet).
Example 3:
a pharmaceutical composition of silybin and simvastatin comprises silybin and simvastatin in a mass ratio of 1: 1.
A preparation method of a pharmaceutical composition of silibinin and simvastatin comprises the following steps:
(1) preparing silybin liposome nanoparticles: dissolving 100g of silibinin and 200g of phospholipid in 98% ethanol, heating to dissolve completely, evaporating ethanol with a film evaporator, microwave vacuum drying for 20min, and micronizing at-10 deg.C to obtain 100 μm nanoparticles; the microwave vacuum drying frequency is 400MHz, and the vacuum degree is-0.01 MPa;
(2) preparation of simvastatin nanoparticles: taking 50g of simvastatin and 500g of alpha-cyclodextrin, and stirring at a high speed at a rotating speed of 1000r/min to form 100 mu m nanoparticles;
(3) preparing a mixed soft material: and (3) adding the nanoparticles prepared in the steps (1) and (2) into a high-speed wet granulator according to the mass ratio of 1:1 of silybin to simvastatin, mixing, transversely cutting for 3min, vertically cutting for 2min, adding 50% ethanol, and stirring at a high speed for 5min to obtain a mixed soft material.
(4) Preparation of granules of the mixed preparation: sieving the soft material with 19 mesh sieve, granulating, drying at 70 deg.C for 2 hr, and grading with 18 mesh sieve to obtain granule of mixed preparation;
(5) tabletting the granules of the mixed preparation to obtain the finished medicinal composition tablet (the specification is 0.5 g/tablet).
Animal experiments:
1. materials and instruments:
1-1, animal:
male mice of SPF grade (20 ± 2 g): provided by experimental animal breeding of Jinnanpunyue GmbH;
1-2, drugs and reagents:
silibinin is supplied by Jiangsu Hua Chinese medicinal industry Co., Ltd;
simvastatin tablets were supplied by Shandong Phoenix pharmaceutical Co., Ltd;
physiological saline is supplied by chenxin pharmaceutical industries, ltd;
the high-fat feed is provided by cooperative medical and biological engineering, Limited liability company of Jiangsu province;
the common feed is provided by the experimental animal breeding company of Jinnanpunyue.
1-3, instrument:
low-temperature high-speed centrifuge: supplied by Thermo Fisher Scientific; one-ten-thousandth balance: supplied by shanghai cyanine sea instruments ltd;
1-4, animal experiment:
1-4-1 animal feeding conditions:
the mouse is placed in an animal laboratory, the room temperature is controlled to be 20-25 ℃, the humidity is controlled to be 55% -65%, and the air conditioner is controlled. Ventilating for 2-3 times every day, and 1h each time. Controlling day and night illumination, avoiding excessive noise and other interference, raising the rats in cages, feeding the rats with grains, and taking drinking water by using cooling water boiled by tap water without limiting the food intake and the water intake.
1-4-2: the test method comprises the following steps:
80 mice were randomly divided into 7 groups, which were: a normal control group, a model control group, a silibinin low-dose group (administration dose of 0.5mg/10g), a silibinin medium-dose group (administration dose of 0.6mg/10g), a silibinin high-dose group (administration dose of 0.7mg/10g), a simvastatin positive control group (administration dose of 0.1mg/10g), an experiment 1 group (mass ratio of silibinin to simvastatin in the silibinin-simvastatin pharmaceutical composition is 1:0.2), and an experiment 2 group (mass ratio of silibinin to simvastatin in the silibinin-simvastatin pharmaceutical composition is 1: 1);
and feeding basal feed to a normal control group, feeding high-fat feed to a model control group, a silibinin low-dose group, a silibinin medium-dose group, a silibinin high-dose group, a simvastatin positive control group and an experimental group, feeding the normal control group and the model control group with normal saline for intragastric administration by 10mL/kg from beginning to end, respectively feeding the silibinin medium-dose group, the silibinin high-dose group, the simvastatin positive control group and the experimental group with medicaments for intragastric administration, continuously performing intragastric administration for 30d, weighing once every 5 days, recording data, adjusting the intragastric administration amount according to the body weight, and recording the food intake of the mice.
The experimental groups and the doses administered are specifically shown in table 1:
TABLE 1 Experimental groups and dosages administered
After the last administration, fasting is not forbidden for 24h, mice are sacrificed, blood is taken from the retrobulbar venous plexus of each group, the groups are placed in an EP tube, the tube is kept still for 10min, the centrifugation is carried out for 10min at 3000r/min, serum is separated to obtain serum, the contents of glutamic-pyruvic transaminase and triglyceride in the serum are measured, the glutamic-pyruvic transaminase and the triglyceride are measured by adopting a kit purchased by Nanjing institute of bioengineering, wherein the glutamic-pyruvic transaminase is measured by adopting an alanine aminotransferase (glutamic-pyruvic transaminase/ALT/GPT) test kit (ultraviolet colorimetry), and the triglyceride is measured by adopting a Triglyceride (TG) reagent kit (single GPO-PAP method) (spectrophotometer).
1-4-3, experimental results and analysis:
the effect of silybin and various doses of simvastatin used alone and in combination on glutamic-pyruvic transaminase and triglycerides in serum of fatty liver mice is shown in table 2:
TABLE 2 comparison of triglyceride and glutamic-pyruvic transaminase contents in serum of mice of different groups
From the data of table 2, the following conclusions can be drawn:
as can be seen from the data of the measurement of triglyceride in the serum of mice in the low, medium and high dose groups of silybin and the simvastatin group, the triglyceride reduction is reduced, but the triglyceride reduction in the silybin group alone is not as obvious as that in the simvastatin group, and in addition, the silybin group has a remarkable reduction effect from the data of glutamic-pyruvic transaminase, while the glutamic-pyruvic transaminase of the simvastatin group alone has a tendency to increase, causing damage to the liver. The experimental data of the drug combination of the silybin and the simvastatin in the experimental group 1 and the experimental group 2 show that the fineness of triglyceride is reduced and is better than that of a single silybin group and a single simvastatin group, and the glutamic-pyruvic transaminase has the effect of reducing the fineness, so that the damage of the simvastatin to the liver can be reduced, the metabolism of the liver to fat can be promoted, the effect of enhancing the lipid-lowering effect can be achieved, and meanwhile, the side effect of increasing the simvastatin transaminase after long-term use is also obviously improved.
Claims (6)
1. A pharmaceutical composition of silybin and simvastatin is characterized by comprising silybin and simvastatin in a mass ratio of 1: 0.8-1: 1.
2. A method for preparing a pharmaceutical composition of silibinin and simvastatin according to claim 1, comprising the steps of:
(1) preparing silybin liposome nanoparticles: dissolving silybin and phospholipid in ethanol with the mass concentration of 95-98% according to the mass ratio of 1: 1-1: 2, heating to completely dissolve the silybin and the phospholipid, evaporating the ethanol by using a thin film evaporator, performing microwave vacuum drying for 20-25 min, and performing superfine grinding at the low temperature of-10-0 ℃ to obtain 1-100 mu m nanoparticles;
(2) preparation of simvastatin nanoparticles: taking simvastatin and alpha-cyclodextrin according to the mass ratio of 1: 3-1: 10, and stirring at a high speed to form nanoparticles with the particle size of 1-100 mu m;
(3) preparing a mixed soft material: adding the nanoparticles prepared in the steps (1) and (2) into a high-speed wet granulator according to the required mass ratio of the silybin liposome to the simvastatin nanoparticles, mixing, transversely cutting for 3-4 min, vertically cutting for 2-3 min, adding ethanol with the mass concentration of 50-70%, and stirring at a high speed for 3-5 min to obtain a mixed soft material;
(4) preparation of granules of the mixed preparation: sieving the soft material with a sieve of 18-20 meshes, granulating, drying at 60-70 ℃ for 1-2 h, and grading with a sieve of 16-18 meshes;
(5) tabletting or encapsulating the granules of the mixed preparation to obtain the finished medicinal composition.
3. The method for preparing a pharmaceutical composition of silibinin and simvastatin according to claim 2, wherein: the frequency of the microwave vacuum drying in the step (1) is 370Hz to 380 Hz; the vacuum degree is-0.01 to-1 MPa.
4. The process for the preparation of a pharmaceutical composition of silybin and simvastatin according to claim 2, characterized in that: the high-speed stirring speed in the step (2) is 300-1000 r/min.
5. The method for preparing a pharmaceutical composition of silibinin and simvastatin according to claim 2, wherein: and (4) mixing speed in the high-speed wet granulator in the step (3) is 300-1000 r/min.
6. Use of a pharmaceutical composition according to claim 1 for the manufacture of a medicament for the treatment of hypolipidemic disorders.
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