CN103230376A

CN103230376A - Simvastatin tablet preparation method

Info

Publication number: CN103230376A
Application number: CN2012105725234A
Authority: CN
Inventors: 汪洋; 郑忠辉
Original assignee: Shandong Xinhua Pharmaceutical Co Ltd
Current assignee: Shandong Xinhua Pharmaceutical Co Ltd
Priority date: 2012-12-24
Filing date: 2012-12-24
Publication date: 2013-08-07

Abstract

The invention relates to a simvastatin tablet preparation method, and belongs to the field of statin medicine tablet preparation methods. The tablets are composed of simvastatin and auxiliary materials such as a filling material, an adhesive, a disintegrant, an antioxidant, a lubricant, and the like. The method is characterized in that compressible starch is adopted as the adhesive and the disintegrant, and the mass ratio of simvastatin to the compressible starch is 1: (0.5-1.5). The invention mainly solves a problem of simvastatin tablet dissolution stability, such that simvastatin dissolution curve is S-shaped. During dissolution, an in-vitro slow intermediate-release characteristic is shown. The release characteristic satisfies clinical requirements, and assists in providing a good hypolipidemic effect. The preparation method provided by the invention has the advantages of simple process, feasible operation, and suitability for large-scale productions.

Description

The preparation method of simvastatin sheet

Technical field

The present invention relates to a kind of preparation method of simvastatin sheet, belong to the preparation method field of statins tablet.

Background technology

Simvastatin is a kind of hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase inhibitor, is the derivant that methylates of lovastatin, is semi-synthetic.Similar to lovastatin, but stronger to the inhibitory action of HMG-CoA reductase.The non-activity of simvastatin own, hydrolyzate after the oral absorption suppresses the rate-limiting enzyme in the cholesterol building-up process---HMG-CoA reductase in vivo competitively, hydroxyl first valeric acid metabolic pathway in the blocking-up cell, make the synthetic minimizing of cell inner cholesterol, (low density lipoprotein, thereby LDL) acceptor quantity and activity increase, make serum cholesterol to remove increases feedback irritation cell film surface (being mainly hepatocyte) low density lipoprotein, LDL, level reduces.In addition, also can reduce the concentration of total triglyceride, C-VLDL and apolipoprotein apoB.Also has the effect of vascular smooth muscle cell proliferation, migration and the generation of minimizing extracellular matrix always.The main site of action of simvastatin is at liver, the result reduces cholesterolemia and low-density lipoprotein cholesterol level, moderate reduces serum triglyceride level and increases the blood hdl level, thus to the control generation effect of atherosclerosis and coronary heart disease.

Its chemical name is: and 2,2-acid dimethyl-8-{ (4R, 6R)-6-(2-[(1S, 2S, 6R, 8S, 8 α R)-1,2,6,7,8,8 α-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl] ethyl) } tetrahydrochysene-4-hydroxyl-2H-pyran-2-one ester.Its structural formula is as follows:

The patent that the preparation technology of simvastatin tablet delivers is more.

Chinese patent CN200610029655.7 discloses the pharmaceutical preparation that contains simvastatin, this pharmaceutical preparation is to contain simvastatin 10%, BHA0.3%, citric acid 10%, lactose 47.9%, sodium carboxymethyl cellulose 5%, microcrystalline Cellulose sodium 25%, propyl gallate 0.5%, magnesium stearate 1%, 30 POVIDONE K 30 BP/USP 300.3%, the pharmaceutical preparation pH in water-bearing media is no more than 3.5.US Patent No. 20030153617 discloses the prescription that simvastatin and excipient substance are formed, and its pH in water-bearing media is to guarantee stability of drug in the 5.0-7.5 scope, in this prescription with BHA as antioxidant.But literature search is found; simvastatin is lactonic ring hydrolysis rapidly in aqueous solution; but in the buffer system of acetonitrile/water or contain in the aqueous solution of surfactant and maintenance system or aqueous solution apparent pH be 7 o'clock these hydrolysis very slowly (Harry G.Brittain.Analytical Profiles of Drug Substances and Exicipents[M] .California:Academic Press; Inc.; 1993,22:357).

Chinese patent CN200510111264.5 discloses a kind of preparation method of simvastatin, with simvastatin 5-10%, and antioxidant 0.05-0.1%, filler 83-91%, fluidizer 2.5-5.5%, lubricant 1-2% mixes the back direct compression.Direct compression can effectively solve the problem of simvastatin related substance, is that import is additional but the problem that this method exists is vertical compression type adjuvant, and price is more expensive.In addition, the BHA consumption is few (to account for the 0.1%-0.5% of principal agent, mol ratio, Russll F.Lang, Reactivity of hydroxymethylglutaryl coenzyme A reductase inhibitors containing conjugated dienes with phenolic antioxidants in the solid-state, and be difficult in whole tablet, be uniformly dispersed US Pub No20080312458).BHA is insoluble in water, and fusing point low (47 ℃) easily forms pastel during pulverizing, be difficult to be ground into fine powder, is difficult to be uniformly dispersed after adding like this.

US Patent No. 20050186270 discloses the stabilization formulations of simvastatin, and the lactose consumption is not more than 75%, and the microcrystalline Cellulose consumption is not less than 25%.US Patent No. 20070202159 and WO2008006715 disclose the stabilization formulations of statins, and the preparation method of said preparation is that (i) one or more stabilizing agents are dispersed in the solvent; (ii) the solvent spray drying is on unbodied statins; (iii) remove solvent; Find by retrieval, (Florida:CRC Press LLC.2004 has announced the preparation method of simvastatin sheet in 1:421-422) at " Handbook of pharmaceutical manufacturing formulations:compressed solid products " book front page.Ascorbic acid 2.5g and citric acid 1.25g are dissolved in the water of 12g, BHA is dissolved in the ethanol of 5ml, behind both mixings as fountain solution, with simvastatin 10.1g and lactose 55.23g and pregelatinized Starch 15g, mixing, granulate, be dried to moisture less than 1.5%, add microcrystalline Cellulose 15g, add magnesium stearate 0.6g and micropowder silica gel 0.3g, mixing, tabletting, coating.Method in this book and US Patent No. 20050186270 and US20070202159 have bigger similarity.

Summary of the invention

According to the deficiencies in the prior art, the technical problem to be solved in the present invention is: a kind of preparation method of simvastatin sheet is provided, makes the stripping of simvastatin sheet in the external feature that presents slow rapid release, meet clinical needs, reach good lipid-lowering effect.

The technical solution adopted for the present invention to solve the technical problems is: the preparation method that a kind of simvastatin sheet is provided, formed by adjuvants such as simvastatin, filler, binding agent, disintegrating agent, antioxidant and lubricants, it is characterized in that amylum pregelatinisatum as binding agent and disintegrating agent, and the mass ratio of simvastatin and amylum pregelatinisatum is 1:(0.5 ~ 1.5).

Described each component of simvastatin sheet percent is by weight counted:

Simvastatin: 5～10%

Amylum pregelatinisatum: 2.5～15%

Filler: 70～92%

Antioxidant: 0.01～2%

Lubricant: 0.1～2%.

The problem that the present invention mainly solves is the stripping of simvastatin sheet.In regulation medium (the 0.01mol/L phosphate sodium dihydrogen buffer solution (regulating pH value to 7.0 with 50% sodium hydroxide solution) that contains 0.5% sodium lauryl sulphate), make the stripping curve of simvastatin present the S type, namely dissolution is 10 ~ 20% in the time of 5 minutes, dissolution was 80 ~ 90% when dissolution was 55 ~ 65%, 15 minutes in the time of 10 minutes.The present invention regulates the stripping behavior of simvastatin by amylum pregelatinisatum.

Preparation method provided by the invention is different from the above-mentioned patent of mentioning or the preparation method in the book.Have plenty of the pH value of regulating the Statins mixture and prepare (as US20030153617, CN200610029655.7, CN99814403.7), have plenty of the ratio that changes water-soluble filler and water-insoluble filler and prepare (as US20050186270), the adding mode of having plenty of open stabilizing agent (as is dissolved in the fountain solution, spray drying, desolventizing, the preparation of simvastatin among US20070202159, WO2008006715 and the Handbook of pharmaceutical manufacturing formulations:compressed solid products).These patents mainly are the stability that solves simvastatin.Be the stripping behavior of simvastatin and this patent mainly solves.

The preparation method that this patent provides makes the stripping of simvastatin sheet in the external feature that presents slow rapid release.The purpose of this release characteristic meets clinical needs, and reaches good lipid-lowering effect.

The invention has the beneficial effects as follows: mainly the problem of Xie Jueing is the stability of the stripping of simvastatin sheet, makes the stripping curve of simvastatin present the S type, in stripping in the external feature that presents slow rapid release.The purpose of this release characteristic meets clinical needs, and reaches good lipid-lowering effect; The preparation method that this patent provides, technology is simple, operation feasible, suitable for mass production.

Description of drawings

Fig. 1 is the stripping curve of embodiment 1-4 products obtained therefrom;

The specific embodiment

Below in conjunction with accompanying drawing embodiments of the invention are described further:

Embodiment 1

Prescription (1000):

⑴ the preparation of fountain solution is got 95% ethanol and is placed in the container, adds BHA and makes its dissolving, add water again, and mixing, as fountain solution, standby.

⑵ simvastatin, amylum pregelatinisatum, mannitol and microcrystalline Cellulose are got in film-making, cross 40 orders respectively, place wet granulator; the about 5min of mixed on low speed; add fountain solution, the about 2min of high speed shear and high-speed stirred, wet granular places boiling drier; it is 50 ℃ that inlet temperature is set; be dried to moisture less than 1.5%, 18 order granulate, add magnesium stearate; mixing, tabletting.

Above-mentionedly can make every tablet of tablet that contains simvastatin 10mg.

Embodiment 2

Prescription (1000):

⑵ simvastatin, amylum pregelatinisatum, lactose and microcrystalline Cellulose are got in film-making, cross 40 orders respectively, place wet granulator; the about 5min of mixed on low speed; add fountain solution, the about 2min of high speed shear and high-speed stirred, wet granular places boiling drier; it is 50 ℃ that inlet temperature is set; be dried to moisture less than 1.5%, 18 order granulate, add magnesium stearate; mixing, tabletting.

Embodiment 3

Prescription (1000):

⑴ the preparation of fountain solution is got 95% ethanol and is placed in the container, adds BHA and makes its dissolving, add water again and vitamin C, and mixing, as fountain solution, standby.

⑵ simvastatin, amylum pregelatinisatum, sorbitol and microcrystalline Cellulose are got in film-making, cross 40 orders respectively, place wet granulator; the about 5min of mixed on low speed; add fountain solution, the about 2min of high speed shear and high-speed stirred, wet granular places boiling drier; it is 50 ℃ that inlet temperature is set; be dried to moisture less than 1.5%, 18 order granulate, add magnesium stearate; mixing, tabletting.

Embodiment 4

Prescription (1000):

⑴ the preparation of fountain solution is got 95% ethanol and is placed in the container, adds BHA and makes its dissolving, add water again, vitamin C and citric acid, and mixing, as fountain solution, standby.

Stripping curve

With reference to " method of dissolution is drawn stripping curve under two simvastatin sheets of Chinese pharmacopoeia version in 2010 item.Sample point is set to 5,10,15,20,30,60 minutes.

The stripping curve of embodiment 1 to 4 as shown in Figure 1.

Claims

1. the preparation method of a simvastatin sheet, formed by adjuvants such as simvastatin, filler, binding agent, disintegrating agent, antioxidant and lubricants, it is characterized in that amylum pregelatinisatum as binding agent and disintegrating agent, and the mass ratio of simvastatin and amylum pregelatinisatum is 1:(0.5 ~ 1.5).