CN104306348B - A kind of Simvastatin Tablets and preparation method thereof - Google Patents
A kind of Simvastatin Tablets and preparation method thereof Download PDFInfo
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- CN104306348B CN104306348B CN201410514067.7A CN201410514067A CN104306348B CN 104306348 B CN104306348 B CN 104306348B CN 201410514067 A CN201410514067 A CN 201410514067A CN 104306348 B CN104306348 B CN 104306348B
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Abstract
The invention discloses a kind of simvastatin tablet and preparation method thereof, it includes active component Simvastatin and pharmaceutic adjuvant, the pharmaceutic adjuvant is ball-type lactose, Ac-Di-Sol, BHA, Hydroxypropyl methylcellulose, silica, magnesium stearate, film coating pre-mix dose, and auxiliary material is added with specific mass ratio and technique.There is incompatibility with various pharmaceutic adjuvants in Simvastatin, it is susceptible to hydrolyze and aoxidizes, lactone bond fracture open loop under conditions of high humidity generates its active metabolite Simvastatin carboxylic acid, under the high temperature conditions there is slow oxidation copolymerization reaction generation dimer or polymer in the ethylene linkage of intramolecule two, and the preparation for being prepared into stabilization has extreme difficulty.In recent years, as information is constantly disclosed, there is huge difference in the quality standard that the Simvastatin Tablets of different manufacturers production are performed, wherein it is the most notable with dissolved corrosion difference, so as to cause Simvastatin Tablets inhomogeneous situation of the same name clearly.Originally the formulation and technology determined can continue large-scale production Simvastatin Tablets, and the Simvastatin Tablets of preparation possess good dissolving out capability, good stability is kept in prolonged storage in various pH value dissolution mediums.
Description
Technical field
The present invention relates to a kind of medicine Simvastatin, more particularly to a kind of simvastatin tablet and preparation method thereof.
Background technology
In recent years, with eating habit change, living standard raising, operating pressure increase, hyperlipidemia and hyperproteinemia
Disease patient is more and more, and, patient population increasingly rejuvenation.With continuing to develop for medical science, it was recognized that courage is solid
The too high Basic disease cause for being to occur angiocardiopathy of alcohol, fatty equal size, high fat of blood is coronary heart disease and hypertension occur main
Hazards.Therefore, people start the emphasis as prevention and cure of cardiovascular disease using the exploitation of regulating plasma lipid medicine.Fat is exchanged by the world of medicine
Effect of the medicine in terms of prevention and cure of cardiovascular disease is filled with unbounded confidence, and adjusts fat therapy to turn into the main of 21 century prevention of cardiovascular disease
Method.
Simvastatin (simvastatin) is a kind of semi-synthetic lipid-regulation medicine of novel potent, by suppressing endogenous courage
The synthesis of sterol and reduce low-density lipoprotein (LDL) and VLDL (VLDL), moderate increasing high density fat
Albumen (HDLC), reduces triglycerides, so as to reduce cholesterol, has obvious curative effect to high cholesterol, coronary heart disease etc., is treatment
One of choice drug of high fat of blood.
There is incompatibility in Simvastatin, be susceptible to hydrolyze and aoxidize with various pharmaceutic adjuvants, interior under conditions of high humidity
Ester linkage breaking open loop generates its active metabolite Simvastatin carboxylic acid, and the ethylene linkage of intramolecule two occurs slow under the high temperature conditions
Oxidation copolymerization reaction generation dimer or polymer.
There are multiple manufacturer production Simvastatin Tablets both at home and abroad at present, the quality standard of production technology and execution has larger difference
It is different, detect that this index is illustrated in dissolution rate with Japanese orange paper and Chinese Pharmacopoeia, dissolution medium used and dissolution limit
There is significant difference：
| Quality standard | Dissolution medium | Rotating speed | Sampling time point | Detection method | Limit |
| Chinese Pharmacopoeia | 0.01mol/L phosphate sodium dihydrogen buffer solutions 900ml containing 0.5% lauryl sodium sulfate（pH7.0） | 50r/min | 30min | HPLC | 80% |
| Japanese orange paper | 0.3% Tween-80 aqueous solution 900ml | 50r/min | 30 minutes（5mg specifications）Or 45 minutes（10mg and 20mg specifications） | High-efficient liquid phase technique | 70% |
《Chinese Pharmacopoeia》Two Simvastatin Tablets for recording of version in 2010, use pH7.0 buffer solution conducts in quality standard
Dissolution medium carries out this product dissolution in vitro evaluation, and Simvastatin Tablets are regular pharmaceutics, after taking in stomach i.e. occur disintegration and
Dissolution, pH7.0 buffer solutions cannot simulate dissolved corrosion in this product body.Although Simvastatin Tablets are to have listed medicine for many years, matter
Amount evaluation method has much room for improvement, and the reasonability of formulation and technology also requires study.
The content of the invention
The present invention considers all ages and classes, various disease state crowd's digestive system pH othernesses, using different pH dissolutions
Medium（PH1.2HCL solution, pH4.0 buffer solutions, pH6.8 buffer solutions, pH7.0 buffer solutions, purified water）Carry out Simvastatin Tablets molten
Go out behavioral study, there is provided a kind of that good dissolving out capability is provided with the conditions of various pH, and can realize that industrialization prepares pungent cutting down
The formulation and technology of statin tablet.By numerous studies, in specific invention scope, the Simvastatin Tablets of preparation are except meeting piece
Outside all qualitative attributes that agent should reach in itself, possess good dissolving out capability and gentle dissolution in various dissolution mediums
Behavior, possesses controllability in scale large-scale production process, and Simvastatin Tablets keep quality stability in 48 months.
Simvastatin is main ingredient composition in the present invention, and BHA is a kind of antioxidant, with Hydroxypropyl methylcellulose
In the way of film forming is wrapped up, and stabilization main ingredient is reached with specific ratio, improves the hydrophilic effect of main ingredient.At this specific place
In square technique, Simvastatin Tablets prepared by formula of the BHA outside this proportion, it is impossible to kept for 24 months surely
It is qualitative.The adhesive that Hydroxypropyl methylcellulose had both been pelletized as Simvastatin, also serves as the dispersant of BHA, can be effective
Antioxidant is covered in Simvastatin surface, this research institute must not exceed 50cP using the viscosity of Hydroxypropyl methylcellulose.It is pungent to cut down him
Spit of fland, using alcohol-water as adhesive solvent, greatly improves preparation process quality stability to damp and hot more sensitive.Ball
Type lactose keeps good inertia as filler in this prescription, and the disintegration efficiency of disintegrant is not changed, is disintegrated by adjusting
The consumption of agent, can continue to be disintegrated behavior as many lot sample conditions of holding for reappearing.Ac-Di-Sol is in this prescription
Middle to be added with specific ratio as disintegrant, Simvastatin Tablets obtain gentle disintegration stripping capacity.Silica is in Ben Chu
As glidant in side, in the amount ranges of this research regulation, the mixing uniformity of each component in this product is effectively increased.Have
There is incompatibility in document report magnesium stearate, influence the stability of Simvastatin with Simvastatin Tablets, in our current research, due to
Simvastatin is wrapped up by Hydroxypropyl methylcellulose film forming, the influence of magnesium stearate is not affected by, using magnesium stearate as lubricant
Prescription, in the big production of scale, show superior compressing tablet depanning efficiency.This research also found, because Simvastatin is former
The particularity of material, market can directly buy acquisition general thin be coated pre-mixing agent be used for Simvastatin coating tablets, performance to light,
Damp and hot sensitiveness, after increasing polyvinyl alcohol, titanium dioxide protection against the tide lucifuge composition in film coating pre-mix dose in this research, sample
Stability is greatly improved.
Inventive formulation is as follows in parts by weight：
10 parts of Simvastatin
BHA 0.005-0.01 parts
Hydroxypropyl methylcellulose 0.5-1 parts
Appropriate amount of ethanol
100-200 parts of ball-type lactose
Ac-Di-Sol 3-5 parts
Silica 0.8-1.5 parts
Magnesium stearate 0.3-1 parts
3-5 parts of film coating powder
Preferably 0.07 part of wherein described BHA, the Hydroxypropyl methylcellulose viscosity is related to consumption, preferably hydroxyl
When third methylcellulose viscosity is 50CP, consumption is 0.5 part；Ball-type lactose basis in the range of 100-200 parts goes for
Tablet size adjustment, consumption do not influence Simvastatin tablet quality.Ac-Di-Sol energy in 3-5 parts of scope
Similar disintegration behavior is kept, scope is used beyond or less than this, different dissolved corrosions will be shown.The magnesium stearate
Preferably 0.5 part of weight portion, film coating powder is preferably the 3% of formulation weight.
Specific embodiment by the following examples is described in further detail to the above of the invention again.But
This scope for being interpreted as above-mentioned theme of the invention should not be only limitted to following example.Above-mentioned technological thought of the invention is not being departed from
In the case of, according to various replacements or change that ordinary skill knowledge and customary means are made, the present invention all should be included in
In the range of.
Specific embodiment
First, prescription and preparation method
Embodiment 1
Simvastatin 100g
BHA 0.05g
Hydroxypropyl methylcellulose 5.0g
Appropriate amount of ethanol
Purified Water q. s
Ball-type lactose 1000g
Ac-Di-Sol 30g
Silica 8.0g
Magnesium stearate 3.0g
Film coating powder 30.0g
Preparation method：
BHA is dissolved in ethanol in proper amount solution, after adding Hydroxypropyl methylcellulose to be uniformly dispersed, is added appropriate
Water is prepared into gelled adhesive.Adhesive is poured into Simvastatin raw material, is stirred into using stirring granulation loose uniform
Little particle, less than 50 DEG C of dryings, pellet moisture stops drying, is pressed into temperature when being less than 2% in transferring the material into boiling tower
Tablet.After using 60% ethanol solution, film coating pre-mix dose is suspended uniformly, even spraying is coated until label is completely uniform
Covering last layer film.
Embodiment 2
Simvastatin 100g
The g of BHA 0.07
The g of Hydroxypropyl methylcellulose 5.0
Appropriate amount of ethanol
Appropriate amount of water
The g of ball-type lactose 2000
The g of Ac-Di-Sol 50
The g of silica 15
The g of magnesium stearate 10
The g of film coating powder 50
Preparation method：
BHA is dissolved in ethanol in proper amount solution, after adding Hydroxypropyl methylcellulose to be uniformly dispersed, is added appropriate
Water is prepared into gelled adhesive.Adhesive is poured into Simvastatin raw material, is stirred into using stirring granulation loose uniform
Little particle, less than 50 DEG C of dryings, pellet moisture stops drying, is pressed into temperature when being less than 2% in transferring the material into boiling tower
Tablet.After using 60% ethanol solution, film coating pre-mix dose is suspended uniformly, even spraying is coated until label is completely uniform
Covering last layer film.
Embodiment 3
The g of Simvastatin 100.0
The g of BHA 0.1
The g of Hydroxypropyl methylcellulose 10.0
Appropriate amount of ethanol
Purified Water q. s
The g of ball-type lactose 2000.0
The g of Ac-Di-Sol 40.0
The g of silica 1 0.0
The g of magnesium stearate 10.0
The g of film coating powder 50.0
BHA is dissolved in ethanol in proper amount solution, after adding Hydroxypropyl methylcellulose to be uniformly dispersed, is added appropriate
Water is prepared into gelled adhesive.Adhesive is poured into Simvastatin raw material, is stirred into using stirring granulation loose uniform
Little particle, less than 50 DEG C of dryings, pellet moisture stops drying, is pressed into temperature when being less than 2% in transferring the material into boiling tower
Tablet.After using 60% ethanol solution, film coating pre-mix dose is suspended uniformly, even spraying is coated until label is completely uniform
Covering last layer film.
2nd, quality research
1st, according to《Chinese Pharmacopoeia》Carry out quality evaluation
The tablet of above-described embodiment 1,2,3 is taken, according to《Chinese Pharmacopoeia》Version two records the lower detection of Simvastatin within 2010
Outward appearance, hardness and disintegration time limited, content, relevant material, every Testing index meet standard requirement.
2nd, a plurality of stripping curve evaluation
Take the tablet of above-described embodiment 1,2,3, respectively with pH1.2HCL solution, pH4.0 buffer solutions, pH6.8 buffer solutions,
PH7.0 buffer solutions, purified water add 0.5% sodium dodecyl sulfate solution, dissolution as dissolution medium in each dissolution medium
Medium volume 900ml, dissolution rate detects the second method, and 50 revs/min, remaining action-item shines《Chinese Pharmacopoeia》Two dissolutions of version in 2010
Regulation carries out Simvastatin Tablets stripping curve measure under degree detection, and Simvastatin raw material can be degraded to tool under the conditions of relatively low pH
The simvastatin acid of standby activity, dissolution rate detection level is in terms of Simvastatin and Simvastatin total amount.Result shows this product five
Possesses good dissolved corrosion in kind pH dissolution mediums.Specific data see the table below：
The tablet of embodiment 1
| Sampling time point | 5min | 10min | 15min | 30min | 45min |
| Purified water | 12.1% | 47.2% | 67.1% | 85.4% | 91.5% |
| PH1.2 hydrochloric acid solutions | 8.2% | 44.4% | 65.3% | 83.2% | 95.6% |
| PH4.0 buffer solutions | 6.2% | 40.4% | 60.4% | 80.5% | 92.6% |
| PH6.8 buffer solutions | 10.4% | 41.5% | 64.7% | 82.5% | 92.7% |
| PH7.0 buffer solutions | 10.2% | 43.5% | 64.4% | 81.6% | 93.7% |
The tablet of embodiment 2
| Sampling time point | 5min | 10min | 15min | 30min | 45min |
| Purified water | 10.5% | 40.5% | 63.6% | 88.7% | 91.9% |
| PH1.2 hydrochloric acid solutions | 10.5% | 43.4% | 61.6% | 86.5% | 93.7% |
| PH4.0 phosphate buffers | 9.3% | 41.4% | 62.5% | 82.6% | 92.8% |
| PH6.8 phosphate buffers | 11.5% | 46.8% | 60.9% | 81.7% | 90.8% |
| PH7.0 buffer solutions | 7.2% | 44.2% | 61.6% | 83.8% | 90.9% |
The tablet of embodiment 3
| Sampling time point | 5min | 10min | 15min | 30min | 45min |
| Purified water | 7.3% | 41.3% | 59.5% | 81.6% | 89.9% |
| PH1.2 hydrochloric acid solutions | 5.2% | 37.6% | 56.4% | 80.7% | 89.2% |
| PH4.0 phosphate buffers | 5.3% | 36.6% | 52.4% | 80.6% | 88.7% |
| PH6.8 phosphate buffers | 6.2% | 33.5% | 53.6% | 79.4% | 91.6% |
| PH7.0 buffer solutions | 6.6% | 35.2% | 60.6% | 83.2% | 93.3% |
3rd, stability study
3.1 Acceleration studies：The tablet of above-described embodiment 1,2,3 is taken, under the conditions of 40 DEG C of+75%RH, after placing 6 months
Carry out proterties, content, relevant material, dissolution rate to detect, judge mass change trend.
The 3.2 long-term experiments that keep sample：The tablet of above-described embodiment 1,2,3 is taken, respectively at being placed naturally 24 months under normal temperature condition,
Proterties, content, relevant material, dissolution rate behavioral value are carried out, mass change trend is judged.
Claims (1)
1. a kind of preparation method of simvastatin tablet, it is characterised in that the preparation method is comprised the steps of：
1) the following raw material by weight, is prepared：
10 parts of Simvastatin
BHA 0.005-0.01 parts
Hydroxypropyl methylcellulose 0.5-1 parts
100-200 parts of ball-type lactose
Ac-Di-Sol 3-5 parts
Silica 0.8-1.5 parts
Magnesium stearate 0.3-1 parts
Appropriate amount of ethanol
Purified Water q. s
Film coating pre-mix dose 3-5 parts
The viscosity of the Hydroxypropyl methylcellulose is no more than 50cP, and the film coating pre-mix dose is that general thin is coated in pre-mixing agent
Add polyvinyl alcohol and titanium dioxide；
2) adhesive is prepared：BHA is dissolved in ethanol in proper amount-aqueous solution, is mixed with Hydroxypropyl methylcellulose
Composite adhesives；
3) granulation drying：Adhesive is poured into Simvastatin raw material, 24-80 mesh wet granulars are prepared into, keeps temperature of charge low
In 50 DEG C of dryings；
4) mixed pressuring plate：By Simvastatin dry particl whole grain into after single-size, with ball-type lactose, cross-linked carboxymethyl cellulose
Sodium, silica, magnesium stearate are well mixed, compressing tablet；
5) coating powder：General thin increases moistureproof lucifuge composition polyvinyl alcohol, titanium dioxide, retention tab bed temperature in being coated pre-mixing agent
Degree is less than 40 DEG C of coatings.
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| US10799504B2 (en) | 2012-01-13 | 2020-10-13 | ACEA Therapeutics, Inc. | Heterocyclic compounds and uses as anticancer agents |
| US9034885B2 (en) | 2012-01-13 | 2015-05-19 | Acea Biosciences Inc. | EGFR modulators and uses thereof |
| US9464089B2 (en) | 2012-01-13 | 2016-10-11 | Acea Biosciences Inc. | Heterocyclic compounds and uses thereof |
| CN112592334B (en) | 2013-07-11 | 2023-10-27 | 艾森医药公司 | Pyrimidine derivatives as kinase inhibitors |
| JP6889494B2 (en) | 2015-10-09 | 2021-06-18 | エイシア セラピューティクス， インコーポレイテッド | Pharmaceutical salts, physical forms, and compositions of pyrrolopyrimidine kinase inhibitors, and methods of making them. |
| JP2020516682A (en) | 2017-04-07 | 2020-06-11 | エイシア セラピューティクス， インコーポレイテッド | Pharmaceutical salts, physical forms and compositions of pyrrolopyrimidine kinase, and methods of making the same |
| CN112168801A (en) * | 2020-10-22 | 2021-01-05 | 哈药集团技术中心 | Preparation method of simvastatin tablets |
| CN114588121B (en) * | 2021-05-05 | 2024-01-26 | 鲁南贝特制药有限公司 | Simvastatin tablet and preparation method thereof |
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| AR040588A1 (en) * | 2002-07-26 | 2005-04-13 | Schering Corp | PHARMACEUTICAL FORMULATION INCLUDING AN INHIBITOR OF CHOLESTEROL ABSORPTION AND AN INHIBITOR OF A HMGCO TO REDUCTASE |
| CN1994296B (en) * | 2006-08-02 | 2010-06-16 | 浙江京新药业股份有限公司 | Pharmaceutical composition containing simvastatin |
| WO2008068217A2 (en) * | 2006-12-04 | 2008-06-12 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition comprising a coated hmg-coa reductase inhibitor and an inhibitor of the renin-angiotensin system |
| CN102091050A (en) * | 2011-01-31 | 2011-06-15 | 重庆科瑞制药有限责任公司 | Stable simvastatin oral tablet and preparation method thereof |
| CN103585146B (en) * | 2013-11-09 | 2015-04-01 | 北京中申专利科技有限公司 | Medicine composition of simvastatin |
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