CN110051636B

CN110051636B - Preparation method of simvastatin dispersible tablets

Info

Publication number: CN110051636B
Application number: CN201910286642.5A
Authority: CN
Inventors: 霍碧姗; 许小春; 马明; 韦永吉; 王晓蓉
Original assignee: GUANGZHOU NANXIN PHARMACEUTICAL CO Ltd
Current assignee: GUANGZHOU NANXIN PHARMACEUTICAL CO Ltd
Priority date: 2019-04-10
Filing date: 2019-04-10
Publication date: 2020-04-24
Anticipated expiration: 2039-04-10
Also published as: CN110051636A

Abstract

The invention relates to a simvastatin dispersible tablet, a preparation method thereof and application thereof in preparing a medicament for treating hypolipidemia, wherein the simvastatin dispersible tablet comprises 8-12 wt% of simvastatin and 45-60 wt% of microcrystalline cellulose. The simvastatin dispersible tablet disclosed by the invention is good in dispersion uniformity, quick in medicine disintegration and quick in dissolution, and the bioavailability of simvastatin is obviously improved, and the maximum blood concentration of simvastatin is obviously reduced, so that adverse reactions are obviously reduced, and the compliance of a patient is improved.

Description

Preparation method of simvastatin dispersible tablets

Technical Field

The invention relates to the field of medicines, in particular to simvastatin dispersible tablets, a preparation method and application thereof.

Background

Statins are the most used of the lipid-lowering drugs in the market at present, and the market share of the statins already accounts for more than 85%. Statins sold in markets at home and abroad comprise lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin and the like, wherein the simvastatin is the largest in prescription amount.

Simvastatin, which is commercially available under the name of Shudao (Zocor) and is known as Simvastatin in English, was developed by American Merck corporation and first marketed in Sweden in 1988, was approved by the FDA in U.S. 12 months in 1991, and was introduced into China in 1997 by Hangzhou Mo Shadong pharmacy.simvastatin is a fat-soluble substance and has the chemical name of 2, 2-dimethylbutyrate-8- { (4R,6R) -6- (2- [ (1S,2S,6R,8S,8aR) -1,2,6,7,8,8- α -hexahydro-8-hydroxy-2, 6-dimethyl-1-naphthyl ] ethyl) } tetrahydro-4-hydroxy-2H-pyran-2-one ester.

Simvastatin tablets (shudao) manufactured by mosahandong is a coated tablet comprising 10 wt% of simvastatin, 70.7 wt% of lactose as a diluent, 0.02 wt% of antioxidant BHA and 2 wt% of vitamin C, 2% of citric acid monohydrate as a pH adjuster, and coating components of hydroxypropyl cellulose, hypromellose, titanium dioxide and talc, etc., based on the total weight. Wherein the content of the diluent lactose is up to more than 70 percent. Although lactose is a conventional pharmaceutical adjuvant, lactose is an animal-derived adjuvant, the starting material is milk, which may be from milk cows infected with TSE/BSE, and there is a potential safety hazard when used in pharmacy; moreover, each person has different constitution, most Chinese people have certain lactose intolerance, and a large amount of lactose (for example, more than 40 percent, even more than 50 percent) used in a pharmaceutical product is taken as an auxiliary material, so that serious lactose intolerance can be generated sometimes; in addition, the addition of large amounts of lactose leads to increased related impurities in the product, making the product unstable. And the citric acid has strong hygroscopicity, is easy to cause sticking problem during tabletting, is easy to agglomerate during storage, and influences the appearance and the whole effect of the tablet. Based on this, the general applicability of comfort and reduction is greatly limited, and there is a potential safety hazard.

Furthermore, clinically, since some patients with hyperlipidemia suffer from other diseases such as cerebral infarction or aging, dysphagia, inability or difficulty in swallowing food, and general tablets or pills also reduce clinical medication compliance. This also limits the use of comfort.

Moreover, although it has been widely proven that the sudorma has a better blood lipid reducing effect, clinical application shows that the sudorma within the recommended dosage range for long-term administration can produce myalgia and muscle inflammation, muscle toxicity such as rhabdomyolysis and the like of severe patients, and side effects such as in vivo metabolic disorder, gastrointestinal adverse reactions, liver loss and the like of some patients. The literature reports that 90% of foreign statin adverse reactions belong to myopathy adverse reactions. For example, the national drug adverse reaction monitoring center "drug alert express" phase 12 (overall phase 116) of 2012, which describes important safety information for the risk of simvastatin-related dose-escalating myopathy/rhabdomyolysis published by Merck canada limited, indicated that in 41413 patient clinical trials of the therapy of libido-reduction (of which 24747, approximately 60% of median follow-up period was at least 4 years), the incidence of myopathy with treatments of 20, 40 and 80 mg/daily dose of libido-reduction was approximately 0.03%, 0.08% and 0.61%, respectively, in which patients were strictly monitored and drugs interacting with simvastatin were excluded. In a clinical trial of 12064 subjects with a history of myocardial infarction treated with 80 mg/day of sudao (mean follow-up of 6.7 years), the incidence of myopathies was approximately 1.0%, with approximately half of these myopathies occurring during the first year of treatment.

Research shows that simvastatin can increase incidence rate of adverse reactions such as myopathy and the like and is related to high blood concentration. The national drug adverse reaction monitoring center "drug alert express" at stage 10 of 2012 (total stage 114)) states that the drug safety update of united kingdom in month 5 of 2010 issued a notification about simvastatin, stating that, in view of the risks associated with the use of simvastatin in myopathy, based on analysis of clinical trial data, spontaneously reported cases and drug interaction studies, an increase in blood levels of simvastatin is believed to result in a significant increase in the risk of myopathy and/or rhabdomyolysis.

Therefore, the field urgently needs a novel simvastatin preparation which can reduce the blood concentration of simvastatin under the condition of remarkably improving the bioavailability of simvastatin, thereby remarkably reducing the myopathy side effects caused by taking the existing known simvastatin preparation such as relieving and reducing the side effects and improving the clinical compliance.

The inventor of the application discovers that the content of lactose in a simvastatin preparation is reduced and the content of microcrystalline cellulose is improved to more than 45% through long-term research, and meanwhile, the preparation method adopts atomization liquid adding granulation, repeated micronization technology and fluidized bed drying technology, so that simvastatin is prepared into dispersible tablets, the dissolution of a medicine can be obviously improved, the bioavailability of simvastatin is obviously improved, the maximum blood concentration of simvastatin is obviously reduced, adverse reactions are reduced, and the safety and clinical compliance of the product are improved. Thus, a simvastatin dispersion containing a high content of microcrystalline cellulose was prepared, thereby completing the present invention.

Disclosure of Invention

The invention aims to provide a simvastatin dispersible tablet, which comprises simvastatin and microcrystalline cellulose, wherein based on the total weight of the dispersible tablet, the content of the simvastatin is 8-12 wt%, and the content of the microcrystalline cellulose is 45-60 wt%.

In a preferred technical scheme, the simvastatin content is 10 wt%, and the microcrystalline cellulose content is 50 wt%.

In the above embodiment, the simvastatin dispersible tablet further comprises other excipients commonly used in dispersible tablets known in the art, such as other types of diluents, disintegrants, binders, lubricants and antioxidants, wherein the diluent content is 20-35 wt%, the disintegrant content is 1-5 wt%, the binder content is 3-6 wt%, the lubricant content is 1-2 wt% and the antioxidant content is 0.1-0.5 wt% based on the total weight of the dispersible tablet.

In a preferred embodiment, in the simvastatin dispersible tablet according to the present invention, the diluent is present in an amount of 30.15 wt%, the disintegrant is present in an amount of 2 wt%, the binder is present in an amount of 5.75 wt%, the lubricant is present in an amount of 2 wt%, and the antioxidant is present in an amount of 0.1 wt%, based on the total weight of the dispersible tablet.

In a more preferred embodiment, the present invention provides a simvastatin dispersible tablet comprising 10 wt% simvastatin, 50 wt% microcrystalline cellulose, 30.15 wt% diluent, 2 wt% disintegrant, 5.75 wt% binder, 2 wt% lubricant, and 0.1 wt% antioxidant, based on the total weight of the dispersible tablet.

In a preferred embodiment, the diluent is lactose, the disintegrant is low-substituted hydroxypropyl cellulose, the binder is pregelatinized starch, the lubricant is magnesium stearate, and the antioxidant is BHA (butylated hydroxyanisole).

In a preferred embodiment, a simvastatin dispersible tablet is provided, which comprises simvastatin, 45-60 wt% (based on the total weight of the dispersible tablet) of microcrystalline cellulose, lactose, low-substituted hydroxypropyl cellulose, pregelatinized starch, magnesium stearate and BHA, or consists of the above components. More preferably, the simvastatin dispersible tablet comprises simvastatin 10 wt%, microcrystalline cellulose 50 wt%, lactose 30.15 wt%, pregelatinized starch 5.75 wt%, low-substituted hydroxypropyl cellulose 2 wt%, magnesium stearate 2 wt%, BHA 0.1 wt%, based on the total weight of the dispersible tablet.

Another object of the present invention is to provide a method for preparing the simvastatin dispersible tablet, which comprises the following steps: weighing raw materials and auxiliary materials according to the weight parts, mixing simvastatin with a proper amount of diluent, atomizing, adding the mixture into a BHA isopropanol solution, adding the rest diluent, mixing, drying, and micronizing the dried particles; then, mixing the adhesive with the materials, atomizing, adding isopropanol, performing wet granulation, finishing granules and drying; and then, mixing the dried material with a disintegrating agent, microcrystalline cellulose and a lubricating agent, inspecting an intermediate product, tabletting, inspecting plain tablets, and packaging to obtain a finished product.

In the preparation method of the present invention, there is no particular requirement for the isopropyl alcohol solution of the antioxidant, and an isopropyl alcohol solution of an appropriate concentration commonly used in the art for tablet preparation may be used.

In the above preparation method of the simvastatin dispersible tablet, the drying is performed by using a hot air drying oven or a fluidized bed.

In a more preferred embodiment, the preparation method of the simvastatin dispersible tablet comprises the following steps:

step 1, preparing materials: weighing raw materials and auxiliary materials in parts by weight;

step 2, granulating:

step 2.1 dissolving tert-butyl-4-hydroxyanisole (BHA) with appropriate amount of isopropanol;

step 2.2, mixing simvastatin and lactose with the same amount, atomizing, adding BHA isopropanol solution, and mixing;

step 2.3, adding the rest lactose into the material in the step 2.2, and mixing;

step 2.4, drying the material obtained in the step 2.3 until no alcohol smell exists, and taking out the dried particles;

step 2.5, crushing the material obtained in the step 2.4 (preferably, the particle D70 is less than or equal to 45 mu m);

step 2.6 mixing the pregelatinized starch with the material of step 2.5;

step 2.7, starting the wet mixing granulator, adding the isopropanol into the material obtained in the step 2.6 by atomization while stirring, and granulating to the end point;

2.8, after the granulation is finished, drying the material until the drying weight loss meets the requirement;

step 2.9, dry granulation is carried out on the material obtained in the step 2.8;

step 3, mixing: mixing the low-substituted hydroxypropyl cellulose, microcrystalline cellulose and magnesium stearate with the material obtained in the step 2.9; detecting an intermediate product;

and 4, inspecting the mixture obtained in the step 3, tabletting, performing plain film inspection, and packaging to obtain a finished product.

In the above preparation method, the mixing in step 2.3 is preferably mixed with a mill.

In the above preparation method, the drying in step 2.4 and step 2.8 is preferably performed using a hot air circulation drying oven; preferably, fluidized bed drying is adopted (preferably, the air inlet temperature is 35 ℃, and the fan frequency is 10-30 Hz); when drying with a hot air circulation drying oven, the temperature is preferably 50 ℃.

In the above production method, the pulverization is preferably carried out in step 2.5 using a jet mill, 1 to 3 times, preferably 2 to 3 times, so that the particles D70 ≦ 45 μm or less, for example, preferably D70 ═ 43 μm, more preferably D70 ═ 35 μm.

In the above preparation method, the dispersion uniformity should meet the requirement when the test is conducted on the plain film.

In the above preparation method, the material used for packaging in step 4 may be polyvinylidene chloride solid pharmaceutical composite film (PVDC) or aluminum foil packaging material, and after packaging, a box may be placed to obtain the finished product.

The invention also aims to provide application of the simvastatin dispersible tablet in preparation of a medicine for reducing blood fat. In the present invention, if not specifically stated, the amounts or use amounts are in parts by weight, and the apparatuses, raw materials, methods, preparation conditions, etc. used are well known in the art or easily obtained by those skilled in the art in combination with the prior art according to the description of the application.

The simvastatin dispersible tablet disclosed by the invention has the advantages that the content of microcrystalline cellulose reaches more than 45%, preferably more than 50%, in the preparation method, atomization liquid adding granulation, multiple micronization technology and drying process (preferably fluidized bed drying) are adopted, and the microcrystalline cellulose is added after the granules are sized, so that the dispersion uniformity is good, the medicine is quickly disintegrated and dissolved out, the bioavailability of simvastatin is obviously improved, the maximum blood concentration of simvastatin is obviously reduced, the adverse reaction is obviously reduced, and the compliance of a patient is improved. The improvement of clinical compliance is obviously superior to that of the currently marketed simvastatin tablets in the aspects of improving the dissolution of the medicament, improving the bioavailability, reducing the maximum blood concentration and reducing adverse reactions, and an unexpected technical effect is generated.

Detailed Description

The present invention will be further fully and clearly described in connection with the following specific examples so as to enable those skilled in the art to understand the contents of the present invention, but it should be understood that the following examples are only illustrative and are not intended to limit the scope of the present invention in any way. Based on the embodiments of the present invention, those skilled in the art can make appropriate modifications and improvements to the present invention, which are within the scope of the present invention.

If not otherwise stated, the sources of the raw materials and the auxiliary materials are all commercial medicinal raw materials or auxiliary material grades, the concentration or the dosage of the solvent in the preparation process is well known in the field, and the determination method is specified in the pharmacopoeia of the people's republic of China or a method well known in the field.

Example 1

The simvastatin dispersible tablet comprises 10 parts by weight of simvastatin, 60 parts by weight of microcrystalline cellulose, 20.15 parts by weight of lactose, 5.75 parts by weight of pregelatinized starch, 2 parts by weight of magnesium stearate, 0.1 part by weight of BHA and 2 parts by weight of low-substituted hydroxypropyl cellulose.

The preparation method comprises the following steps: weighing raw materials and auxiliary materials according to parts by weight, mixing 10 parts by weight of simvastatin with an equal amount (10 parts by weight) of lactose, atomizing and adding an isopropanol solution of BHA, adding the rest 10.15 parts by weight of lactose, mixing by using a mill, drying by a hot air circulation drying oven until no alcohol smell exists, and crushing the obtained dried substance twice by using an airflow crusher, wherein D70 is 43 mu m; then, 5.75 parts by weight of pregelatinized starch is mixed with the dried substance, the mixture is atomized and added with isopropanol to carry out wet granulation, wet granulation and drying are carried out in a hot air circulation drying oven at 50 ℃ until the drying weight loss meets the requirement, and dry granulation is carried out to obtain dry granules; then, the dry granules are uniformly mixed with 2 parts by weight of low-substituted hydroxypropyl cellulose, 60 parts by weight of microcrystalline cellulose and 2 parts by weight of lubricant, and the finished product is obtained after the inspection, tabletting, secondary inspection, aluminum-plastic packaging and outer packing.

Example 2

The simvastatin dispersible tablet comprises 10 parts by weight of simvastatin, 50 parts by weight of microcrystalline cellulose, 30.15 parts by weight of lactose, 5.75 parts by weight of pregelatinized starch, 2 parts by weight of magnesium stearate, 0.1 part by weight of BHA and 2 parts by weight of low-substituted hydroxypropyl cellulose.

The preparation method comprises the following steps: weighing raw materials and auxiliary materials according to parts by weight, mixing 10 parts by weight of simvastatin with an equivalent amount of lactose, atomizing and adding an isopropanol solution of BHA, then adding the rest 20.15 parts by weight of lactose, mixing by using a flour mill, drying by using a hot air circulation drying oven until no alcohol smell exists, and crushing the obtained dried substance twice by using a jet mill, wherein D70 is 43 mu m; then, 5.75 parts by weight of pregelatinized starch is mixed with the dried substance, the mixture is atomized and added with isopropanol to carry out wet granulation, wet granulation and drying are carried out in a hot air circulation drying oven at 50 ℃ until the drying weight loss meets the requirement, and dry granulation is carried out to obtain dry granules; then, the dry granules are uniformly mixed with 2 parts by weight of low-substituted hydroxypropyl cellulose, 50 parts by weight of microcrystalline cellulose and 2 parts by weight of lubricant, and the finished product is obtained after the inspection, tabletting, secondary inspection, aluminum-plastic packaging and outer packing.

Example 3

The simvastatin dispersible tablet comprises 10 parts by weight of simvastatin, 45 parts by weight of microcrystalline cellulose, 35.15 parts by weight of lactose, 5.75 parts by weight of pregelatinized starch, 2 parts by weight of magnesium stearate, 0.1 part by weight of BHA and 2 parts by weight of low-substituted hydroxypropyl cellulose.

The preparation method comprises the following steps: weighing raw materials and auxiliary materials according to parts by weight, mixing 10 parts by weight of simvastatin with an equivalent amount of lactose, atomizing and adding an isopropanol solution of BHA, adding the rest 25.15 parts by weight of lactose, mixing by using a flour mill, drying by using a hot air circulation drying oven until no alcohol smell exists, and crushing the obtained dried substance twice by using a jet mill, wherein D70 is 43 mu m; then, 5.75 parts by weight of pregelatinized starch is mixed with the dried substance, the mixture is atomized and added with isopropanol to carry out wet granulation, wet granulation and drying are carried out in a hot air circulation drying oven at 50 ℃ until the drying weight loss meets the requirement, and dry granulation is carried out to obtain dry granules; then, the dry granules are uniformly mixed with 2 parts by weight of low-substituted hydroxypropyl cellulose, 45 parts by weight of microcrystalline cellulose and 2 parts by weight of lubricant, and the finished product is obtained after the inspection, tabletting, secondary inspection, aluminum-plastic packaging and outer packing.

Example 4

The simvastatin dispersible tablet comprises 10 parts by weight of simvastatin, 50 parts by weight of microcrystalline cellulose, 30.15 parts by weight of lactose, 5.75 parts by weight of pregelatinized starch, 2 parts by weight of magnesium stearate, 0.1 part by weight of BHA and 2 parts by weight of substituted hydroxypropyl cellulose.

The preparation method comprises the following steps: weighing raw materials and auxiliary materials according to parts by weight, mixing 10 parts by weight of simvastatin with an equivalent amount of lactose, atomizing and adding an isopropanol solution of BHA, then adding the rest 20.15 parts by weight of lactose, mixing by using a flour mill, drying by using a hot air circulation drying oven until no alcohol smell exists, and crushing the obtained dried substance three times by using a jet mill, wherein D70 is 35 mu m; then, 5.75 parts by weight of pregelatinized starch is mixed with the dried substance, the mixture is atomized and added with isopropanol to carry out wet granulation, wet granulation and drying are carried out in a hot air circulation drying oven at 50 ℃ until the drying weight loss meets the requirement, and dry granulation is carried out to obtain dry granules; then, the dry granules are uniformly mixed with 2 parts by weight of low-substituted hydroxypropyl cellulose, 50 parts by weight of microcrystalline cellulose and 2 parts by weight of lubricant, and the finished product is obtained after the inspection, tabletting, secondary inspection, aluminum-plastic packaging and outer packing.

Example 5

The preparation method comprises the following steps: weighing raw materials and auxiliary materials according to parts by weight, mixing 10 parts by weight of simvastatin with an equivalent amount of lactose, atomizing and adding an isopropanol solution of BHA, then adding the rest 20.15 parts by weight of lactose, mixing by using a flour mill, drying by using a fluidized bed, wherein the air inlet temperature is 35 ℃, the fan frequency is 10-30 Hz, drying until no alcohol smell exists, and crushing the obtained dried substance three times by using a jet mill, wherein D70 is 35 mu m; then, mixing 5.75 parts by weight of pregelatinized starch with the dried substance, atomizing, adding isopropanol, performing wet granulation, performing fluidized bed drying, drying at an air inlet temperature of 35 ℃ and a fan frequency of 10-30 Hz until the drying weight loss meets the requirement, and performing dry granulation to obtain dry granules; then, the dry granules are uniformly mixed with 2 parts by weight of low-substituted hydroxypropyl cellulose, 50 parts by weight of microcrystalline cellulose and 2 parts by weight of lubricant, and the finished product is obtained after the inspection, tabletting, secondary inspection, aluminum-plastic packaging and outer packing.

Test example 1 dissolution and dispersion uniformity test

Dissolution test: the dissolution rates of the examples 1-5 and the reference formulation (Shu-Jiang, Hangzhou Mo Shi Shadong pharmaceutical Co., Ltd., batch No. M039482) were determined according to the four dissolution and release determination method (general 0931 second method) in the pharmacopoeia 2015 edition of China.

The measurement conditions were as follows: dissolution medium: 900ml of 0.01mol/L sodium dihydrogen phosphate buffer solution (pH value adjusted to 7.0 with 50% sodium hydroxide solution) of 0.5% sodium dodecyl sulfate; rotating speed: paddle method, 50 rpm.

Dispersion uniformity test: the dispersion uniformity of examples 1-5 and the reference formulation (Shujiang, Hangzhou Mo Shadong pharmaceutical Co., Ltd., batch No.: M039482) was determined according to the four disintegration time limit assay (general 0921) of the Chinese pharmacopoeia 2015 year edition.

The test results are listed in table 1.

TABLE 1 test results

As can be seen from the results in table 1, the simvastatin dispersible tablet of the present invention disintegrated rapidly and had significantly better dissolution effect than the reference formulation. Particularly, the dissolution effect of the preparation of the present invention was remarkably improved with respect to the dissolution effect for 10 minutes, and among them, the dissolution effects of examples 1 to 5 were all excellent, and the dissolution effect of example 5 was the best. Regarding the dispersion uniformity, the dispersion uniformity of examples 1 to 5 all satisfied the specifications, and the dispersion uniformity of the inventive formulation was significantly better than that of the reference formulation.

Test example 2 bioavailability test

Study subjects: healthy volunteers, 24 in total;

the test method comprises the following steps: the fasting and postprandial studies were performed using single-center, randomized, open, two-cycle double crossover trials, self-control. Subjects were randomly assigned, 12 persons on a fasting single dose and 12 persons on a postprandial single dose.

Test formulations: simvastatin dispersible tablets of examples 1-5, administered at a dose of 40mg (40 mg/tablet)

Reference formulation: shujiang, produced by Hangzhou Minshadong pharmaceutical Co., Ltd, lot number: m039482, administration dose 40mg, (40 mg/tablet)

The administration method comprises the following steps:

fasting administration group: the subjects began to fast without water for 10h overnight after dinner for 1 day before the administration, and then the test preparation/reference preparation was administered once in the next morning on an empty stomach with 40mg and was taken with 240mL of warm boiled water. The reference/test formulations were cross-dosed 7 days after washing.

Group for postprandial administration: the subjects began to fast and no-water-supply for 10 hours overnight after dinner 1 day before the administration, high-fat and high-heat meals were taken in the morning, the meals were completed within half an hour from the start of the meals, and 40mg of the test preparation or the reference preparation was orally taken at 30 minutes after the start of the meals and was taken with 240mL of warm water. The reference/test formulations were cross-dosed 7 days after washing.

Drinking water is forbidden in 1 hour before all the groups take the medicine, drinking water can be given 2 hours after the medicine is taken, standard meals are unified in 4 hours, and standard diets are unified in the test period. The subjects were kept from strenuous exercise after taking the drug, smoking alcohol and caffeine-containing drinks were prohibited during the trial, and any other drugs were prohibited from taking the drug from 1 week before the trial to the trial. The weekly interval of administration was 7 days.

Blood sample collection: the half-life of the medicine is about 6 hours, and blood is collected for 48 hours. A blank blood sample is collected before taking medicine (0h), 4mL of upper limb elbow venous blood is collected 0.25, 0.5, 0.75, 1, 1.33, 1.67, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 30, 36 and 48h after taking medicine, a test tube for anticoagulation of EDTA-K2 is adopted for blood collection, and 21 points are collected in each period.

After sample collection, the plasma was divided into two equal portions, one for measurement and one for backup, by centrifugation at 3500rpm at 2-8 ℃ for 10 minutes.

And (3) biological sample detection, namely detecting the blood concentration of simvastatin and a metabolite simvastatin acid (β -carboxylic acid) in blood plasma after fasting and postprandial oral administration of a test preparation and a reference preparation by a healthy volunteer subject by adopting LC-MS/MS (liquid chromatography-mass spectrometry).

And (4) investigation indexes are as follows: pharmacokinetic parameters, AUC of simvastatin_0-t，AUC_0-∞，C_max，T_max，t_1/2AUC of simvastatin metabolite statin acid (β -carboxylic acid)_0-t，AUC_0-∞，C_max，T_max，t_1/2。

Evaluation of bioequivalence: WinNonlin software is used for model fitting of blood concentration at different time points, and pharmacokinetic parameters are calculated by adopting non-atrioventricular model analysis.

The results of the pharmacokinetic parameters determined are shown in tables 2 to 11 below. In the following table, R is the reference formulation; t is the test agent.

TABLE 2

90% confidence intervals for the pharmacokinetic parameters of the fasting test VS reference simvastatin

As can be seen from Table 2 above, under fasting conditions, simvastatin AUC for the test and reference formulations_0-∞Geometric mean ratio of150.222 simvastatin AUC_0-tThe geometric mean ratio was 145.549, respectively, and it can be seen that AUC of the test formulation was compared with that of the reference formulation_0-∞And AUC_0-tAre all improved by about 150 percent; c_maxGeometric mean ratio 77.477%, 90% confidence interval (64.614-92.900), slightly lower bound, C_maxThe test formulation was lower than the reference formulation.

TABLE 3

Open-web test formulation VS reference formulation simvastatin hydroxy acid pharmacokinetic parameters at 90% confidence intervals

As can be seen from Table 3 above, under fasting conditions, the subject and reference simvastatin hydroxy acids AUC_0-∞The geometric mean ratio is 147.085, and the AUC of simvastatin hydroxy acid_0-tThe geometric mean ratio was 135.377, respectively, and it can be seen that AUC of the test formulation was compared with that of the reference formulation_0-∞And AUC_0-tAre all improved by about 140 percent; c_maxGeometric mean ratio 97.069%, 90% confidence interval (73.503-128.192), lower limit slightly lower.

TABLE 4

90% confidence intervals for the pharmacokinetic parameters of the postprandial test formulation VS reference formulation simvastatin

As can be seen from Table 4 above, under postprandial conditions, simvastatin AUC for the test and reference formulations_0-∞The geometric mean ratio is 110.559, and the simvastatin AUC_0-tThe geometric mean ratio is 110.200 respectively, and is slightly improved by about 110 percent; c_maxGeometric mean ratio 89.613%, 90% confidence interval (67.7489-118.530), lower limit slightly lower.

TABLE 5

90% confidence intervals for the pharmacokinetic parameters of the postprandial test formulation VS reference formulation simvastatin hydroxy acid

As can be seen from Table 5 above, under postprandial conditions, the simvastatin hydroxy acid AUC for the test and reference formulations_0-∞The geometric mean ratio is 99.8677, and the AUC of simvastatin hydroxy acid_0-tThe geometric mean ratios are 99.7095 respectively; c_maxGeometric mean ratio 80.6396%, 90% confidence interval (59.7666-108.802), lower limit.

TABLE 6

Fasting simvastatin group T_1/2Comparison

Multiple sets of comparative adjustment test levels α ═ 0.025

As can be seen from the above table 6, under fasting condition, the half-life period of the reference preparation simvastatin is 5.33h, the half-life period of the test preparation simvastatin is 4.66h, and the half-life period of the test preparation simvastatin is longer.

TABLE 7

Tmax comparison between fasting simvastatin groups

Multiple sets of comparative adjustment test levels α ═ 0.025

As can be seen from the above Table 7, under fasting condition, the peak reaching time of the simvastatin of the reference preparation is 1.58h, the peak reaching time of the simvastatin of the tested preparation is 4.83h, and the peak reaching time of the simvastatin of the tested preparation is obviously delayed.

TABLE 8

Comparison of fasting simvastatin hydroxy acid between groups T1/2

Multiple sets of comparative adjustment test levels α ═ 0.025

As can be seen from the above table 8, under the fasting condition, the half-life period of the simvastatin hydroxy acid in the reference preparation is 5.81h, and the half-life period of the simvastatin hydroxy acid in the test preparation is 11.64h, and the half-life period of the simvastatin hydroxy acid in the test preparation is obviously longer.

TABLE 9

Tmax comparison between fasting simvastatin hydroxy acid groups

Multiple sets of comparative adjustment test levels α ═ 0.025

As can be seen from Table 9 above, under fasting condition, the peak-reaching time of the reference formulation simvastatin hydroxy acid is 4.27h, the peak-reaching time of the tested formulation simvastatin hydroxy acid is 6.88h, and the peak-reaching time of the tested formulation simvastatin hydroxy acid is delayed.

Watch 10

T1/2 comparison between two groups of postprandial simvastatin

Multiple sets of comparative adjustment test levels α ═ 0.025

As can be seen from the above table 10, under the postprandial condition, the half-life period of the reference preparation simvastatin is 2.92h, and the half-life period of the test preparation simvastatin is 3.31h, which are basically consistent and have little difference.

Tmax comparison between two groups of postprandial simvastatin

Multiple sets of comparative adjustment test levels α ═ 0.025

As can be seen from the above table 10, under the postprandial condition, the peak reaching time of the simvastatin of the reference preparation is 2.24 hours, the peak reaching time of the simvastatin of the tested preparation is 2.21 hours, and the peak reaching time of the simvastatin of the tested preparation is basically consistent.

TABLE 11

T1/2 comparison between two groups of simvastatin hydroxy acids after meal

Multiple sets of comparative adjustment test levels α ═ 0.025

As can be seen from the above table 11, under the postprandial condition, the half-life period of the simvastatin hydroxy acid of the reference preparation is 3.44h, the half-life period of the simvastatin hydroxy acid of the tested preparation is 3.42h, and the half-life periods of the simvastatin hydroxy acid of the tested preparation are basically consistent.

TABLE 12

Tmax comparison between two groups of prandial simvastatin hydroxy acid

Multiple sets of comparative adjustment test levels α ═ 0.025

As can be seen from the above table 12, under the postprandial condition, the peak reaching time of the simvastatin hydroxy acid in the reference preparation is 4.86h, the peak reaching time of the simvastatin hydroxy acid in the tested preparation is 5.29h, and the peak reaching time of the simvastatin hydroxy acid in the tested preparation is slightly delayed.

From the pharmacokinetics measured in tables 2-12 above, it can be seen that, in both fasting and postprandial tests, the bioavailability of the tested formulation is significantly improved compared to the reference formulation; the fasting relative bioavailability is 150.22%, the postprandial relative bioavailability is 110.10%, and therefore, the preparation provided by the invention obviously improves the bioavailability of simvastatin; the maximum blood concentration Cmax of the tested preparation is obviously lower than that of the reference preparation, the reduction ratio reaches 77%, and the curve is smoother during medicine taking.

Claims

1. A preparation method of simvastatin dispersible tablets comprises simvastatin or a pharmaceutically acceptable salt thereof and microcrystalline cellulose, wherein based on the total weight of the dispersible tablets, the content of simvastatin is 10-12 wt%, the content of microcrystalline cellulose is 45-60 wt%, and the simvastatin dispersible tablets further comprise a diluent, a disintegrating agent, a binding agent, a lubricant and an antioxidant; the preparation method of the simvastatin dispersible tablet comprises the following steps: weighing raw materials and auxiliary materials according to the weight parts, mixing simvastatin with a proper amount of diluent, atomizing, adding the mixture into a BHA isopropanol solution, adding the rest diluent, mixing, drying, and micronizing the dried particles; then, mixing the adhesive with the materials, atomizing, adding isopropanol, performing wet granulation, finishing granules and drying; then, mixing the material with a disintegrating agent, microcrystalline cellulose and a lubricant, inspecting intermediate products, tabletting, inspecting plain tablets, and packaging to obtain finished products;

the diluent is lactose, the disintegrating agent is low-substituted hydroxypropyl cellulose, the binding agent is pregelatinized starch, the lubricant is magnesium stearate, and the antioxidant is BHA.

2. Process for the preparation of simvastatin dispersible tablets according to claim 1, wherein the simvastatin is present in an amount of 10 wt.% and the microcrystalline cellulose is present in an amount of 50 wt.%, based on the total weight of the dispersible tablet.

3. Process for the preparation of simvastatin dispersible tablets according to claim 1 or 2, wherein the diluent is present in an amount of 20-35 wt.%, the disintegrant is present in an amount of 1-5 wt.%, the binder is present in an amount of 3-6 wt.%, the lubricant is present in an amount of 1-2 wt.% and the antioxidant is present in an amount of 0.1-0.5 wt.%, based on the total weight of the dispersible tablet.

4. The process for the preparation of simvastatin dispersible tablets according to claim 3, wherein the diluent is present in an amount of 30.15 wt.%, the disintegrant is present in an amount of 2 wt.%, the binder is present in an amount of 5.75 wt.%, the lubricant is present in an amount of 2 wt.%, and the antioxidant is present in an amount of 0.1 wt.%.

5. The process for the preparation of simvastatin dispersible tablets according to claim 1, wherein the simvastatin dispersible tablets comprise simvastatin 10 wt%, microcrystalline cellulose 50 wt%, lactose 30.15 wt%, pregelatinized starch 5.75 wt%, low-substituted hydroxypropyl cellulose 2 wt%, magnesium stearate 2 wt%, BHA 0.1 wt%, based on the total weight of the dispersible tablet.

6. The process for the preparation of simvastatin dispersible tablets according to claim 1, wherein the drying is performed using a hot air drying oven or a fluidized bed.