CN102805739B - Fluvastatin sodium sustained-release coated dropping pills and preparation method thereof - Google Patents
Fluvastatin sodium sustained-release coated dropping pills and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a new medicine formulation for treating hyperlipidaemia, in particular to fluvastatin sodium sustained-release coated dropping pills prepared from fluvastatin sodium serving as a raw material, and aims to provide the new sustained-release high-efficiency long-acting formulation which overcomes the defect of conventional single clinical application formulation. According to the fluvastatin sodium sustained-release coated dropping pills, a release resistance agent, namely a hydrophobic framework material is added into preparation components of the conventional dropping pills, and the conventional dropping pills are coated, so that the release time of a medicine can be effectively prolonged; and therefore, the acting time of the medicine can be obviously prolonged, the obvious change of the content of main medicines and the relevant substances in the effective storage period of the medicine can be avoided, and the fluvastatin sodium sustained-release coated dropping pills simultaneously have the advantages that the medicine can be released fully, the release time can be controlled, people do not need to take the dropping pills for multiple times, and the dropping pills are high in bioavailability.
Description
Technical field
The invention belongs to the pharmaceutical technology field, be specifically related to treat the medicine of hyperlipemia, oral fluvastatin sodium sustained release coating drop pill once on the one.
Background technology
At present, the heart, cerebrovascular disease are one of important diseases of harm humans health, and dyslipidemia can increase the onset risk of multiple cardiovascular and cerebrovascular disease, and promote generation and the development of atherosclerosis, hypertension, coronary heart disease, even improved the incidence rate that the heart, cerebrovascular accident occur greatly.Therefore, the control blood fat for prevention and treatment, and delays the generation of the heart, cerebrovascular disease and develops significant.
Statins is by suppressing 3-hydroxyl-3-first glutaryl coenzyme A (HMG-CoA) reductase, blocking-up HMG-CoA transforms to methyldihydroxypentanoic acid, reduce the synthetic of body inner cholesterol, thereby reduce cholesterol (TC) content in serum, liver, the aorta, can reduce the level of C-VLDL (VLDL-C), low-density lipoprotein cholesterol (LDL-C), be widely used in treatment various hypercholesterolemias, hyperlipemia and the coronary heart disease that causes thereof and obtain good therapeutic effect.
The first oxylactone derivant that a fluorobenzene indole ring is arranged in the structure of fluvastatin sodium, the substrate of indole ring simulation HMG-CoA reductase, MVA lactone analog product-mevalonic acid, so fluvastatin sodium can be blocked substrate and the product of HMG-CoA reductase simultaneously, and then suppress to strengthen valeric acid generation cholesterol and bring into play the accent blood fat, effect is better than lovastatin, and especially the effect of fluvastatin sodium rising HDL-C (HDL-C) is obvious.Preformulation study shows that fluvastatin sodium is water-soluble, and the dissolution rate of its preparation is fast, and infiltration rate is fast, its activity form fluvastatin acid is eliminated rapidly in vivo, and plasma half-life is short, and blood concentration fluctuation is big, can produce certain untoward reaction, therefore, be necessary to be made into slow releasing preparation.
For these reasons, fluvastatin sodium is made sustained-release dropping pill, by delaying the release of medicine, the blood drug level of control medicine makes its long period maintain stabilizing effective level, thereby reaches long-acting and purpose efficiently.Fluvastatin sodium has hygroscopicity, and the moisture absorption easily degraded of back of making moist, and this sustained-release dropping pill adopts the mode of coating completely cut off other factors of the external world, and especially airborne moisture improves the stability of this sustained-release dropping pill for the influence of principal agent.Compare with the solid dispersion dosage form of other slow release, the sustained release coating method for preparing drop pills is simple, processing ease, and production cost is low, is suitable for industrialized great production.Simultaneously, sustained release coating dropping pill formulation supplementary product consumption is few, and production cost is low, no dust pollution in the production process, and the health that can reduce the staff endangers the pollution that reaches environment.
Summary of the invention
The purpose of this invention is to provide a kind of fluvastatin sodium sustained release coating drop pill.By 2 hours, 5 hours, 10 hours releases of relevant criterion monitoring control 10%～35%, 35%～65% respectively, more than 75%.
Another object of the present invention provides a kind of preparation method of fluvastatin sodium sustained release coating drop pill, increases the clinical application dosage form, the advantage of performance sustained release coating drop pill, the blood peak concentration of drug appearred in 4～5 hours in a drug, sustainable 24 hours of drug effect reduces administration number of times, improves the compliance of medication.
The present invention is achieved through the following technical solutions:
1. prescription is formed
1.1 raw material fluvastatin sodium 20～40g
English name: Fluvastatin Sodium
Chemical name: (±)-(3R*, 5S*, 6E)-and 7-[3-(4-fluorophenyl)-1-isopropyl indole-2-yl]-3,5-dihydroxy-6-heptenoic acid sodium
1.2 hydrophilic framework material 50～70g
Polyethylene glycol 6000, poloxamer 188, Polyethylene Glycol 12000, one or more mixture of the above-mentioned pharmaceutically suitable carrier material of optional usefulness is to regulate formability and the hardness of drop pill.
1.3 hydrophobicity framework material 80～100g
Stearic acid, glyceryl monostearate, one or both mixture of the above-mentioned pharmaceutically suitable carrier material of optional usefulness is with the saturation of the stability that increases substrate, medicine and delay the release of medicine.
1.4 coating material Opadry 4～6g
Select for use the coating material Opadry that the gained drop pill is carried out coating, with the degraded of isolated external influence factor to principal agent, guarantee that drug content and related substance obvious change can not occur before the deadline.
Get above-mentioned each material recipe quantity, make 1000 of finished product sustained release coating drop pill, fluvastatin sodium content 20mg/ grain～40mg/ grain, the heavy 150mg/ grain of ball～200mg/ grain.
2. the preparation of this sustained release coating of preparation method drop pill mainly is divided into two parts:
2.1 the preparation of sustained-release dropping pill
2.1.1 pulverize and porphyrize fluvastatin sodium raw materials, cross 100 mesh sieves;
2.1.2 get recipe quantity hydrophilic framework material and hydrophobicity framework material in the container that is fit to;
Place water-bath to be heated to eutectic point 2.1.3 will fill above-mentioned matrix container, make it be molten condition;
2.1.4 the fluvastatin sodium fine powder of getting recipe quantity is added to the substrate of molten condition, fully stirs, and makes it mixing;
2.1.5 under heat-retaining condition, above-mentioned solution is splashed in the condensation column gradient cooling, the system of dripping;
Take out the back 2.1.6 drop pill is shaped, and inhales the condensed fluid that goes to stick to the surface with absorbent paper, dry under field conditions (factors).
2.2 sustained-release dropping pill coating
2.2.1 get the Opadry of recipe quantity, add in 80% alcoholic solution of 11.5 times of recipe quantities, stir, filter, get coating solution.
Put into coating pan 2.2.2 will prepare sustained-release dropping pill, spray into a certain amount of Opadry alcoholic solution, make the sustained-release dropping pill surface evenly moistening.
Make solvent evaporation 2.2.3 be blown into the hot blast of mitigation.The aforesaid operations several times reach certain thickness repeatedly.
2.2.4 made it completion of cure in 6～8 hours in room temperature or a little more than placing naturally under the room temperature condition.
2.2.550 drying is 12～24 hours under ℃, makes it residual organic solvents to eliminate fully, the sustained release coating drop pill gets product.
3. condition control
3.1 in the above-mentioned preparation method, temperature is 60 ℃～90 ℃ during heating and melting.
3.2 in the above-mentioned preparation method, dripping feed temperature processed is 70 ℃～80 ℃.
3.3 in the above-mentioned preparation method, condensed fluid is dimethicone or liquid paraffin.
3.4 in the above-mentioned preparation method, dripping speed is 20 ± 3 droplets/minute.
3.5 in the above-mentioned preparation method, the condensed fluid upper temp is 20 ℃～35 ℃, bottom temp is-5 ℃～10 ℃.
3.6 in the above-mentioned preparation method, the temperature that is blown into hot blast is 38 ± 2 ℃.
Fluvastatin sodium sustained release coating drop pill processing technology of the present invention is simple, quality controllable, and has following characteristics:
1. the sustainable effective blood drug concentration of keeping of this sustained release coating of long action time drop pill is brought into play lastingly and is suppressed the cholesterol anabolic effect.
2. untoward reaction can make drug slow discharge gently by slow release method, avoids blood concentration fluctuation excessive, alleviates untoward reaction.
3. drug content is stablized the easy moisture absorption of fluvastatin sodium raw materials and is made moist, and it is wrapped film-coat, can effectively completely cut off the influence of materials such as extraneous light, moisture and Carbon Dioxide in Air, reduces the degraded of principal agent, guarantees its stability.
4. this sustained-release dropping pill of taking convenience volume is little, is easy to take, especially children's, old man and the patient of dysphagia is arranged.
5. the high long-term prescription of compliance, medication every day are once, and be convenient and drug cost is low, can improve patient's compliance.
6. production equipment is simple, cost is low, making is simple, no dust pollution, is conducive to environmental conservation and labor protection.
Beneficial effect
The chemical constitution of fluvastatin sodium is similar to HMG-CoA, competitive inhibition HMG-CoA reductase, and cholesterol is synthetic to be reduced thereby make, and reduces blood cholesterol level.Cholesterol is synthetic to be reduced, and can stimulate ldl receptor gene to express, and increases acceptor quantity, improves receptor active, thereby accelerates the removing of LDL in the blood.Therefore, fluvastatin sodium can reduce cholesterol and the LDL level of normal and hyperlipemia animal.Now the fluvastatin sodium peroral dosage form has tablet and capsule clinically.
Because preparation technique, exist after tablet and capsule are oral that dissolution time is long, dissolution is low, absorptions is relatively poor, medicining times is many, release uncontrollable with problems such as bioavailability is low, thereby influence the performance of drug effect.In addition, can produce bigger dust pollution in the preparation process of tablet and capsule, staff and environment are all caused certain harm.Drop pill can overcome the above-mentioned deficiency of tablet and capsule, but the drug release rate of common drop pill is fast than tablet and capsule, and principal agent fluvastatin sodium water soluble, and drug absorption speed is exceedingly fast, and the drug effect performance is applicable to critical critical patient rapidly.But its release is rapid, and blood concentration fluctuation is big, can bring bigger untoward reaction to the patient.Simultaneously, because drug release is rapid, the effective blood drug concentration weak point of holding time, medication has increased medication every day number of times and drug cost often accordingly, has brought inconvenience and economic pressures for patient's medication.And clinically, more be the patients that need control blood fat steady in a long-term, therefore, be necessary to develop a kind ofly can slowly discharge, infiltration rate is steady, duration of efficacy is long, bioavailability is high oral sustained release dosage form.This sustained release coating drop pill can reach above-mentioned requirements, and duration of efficacy is long, only need take medicine once, can improve the compliance of patient's medication in 1st.
The stability of fluvastatin sodium raw materials is not enough, and easily degraded needs to adopt certain mode to delay the degraded of principal agent in preparation process.In the Lovastatin sustained-release dropping pill preparation method (CN101269048A) of Zhengda-Luzhou Medicine Science-Technology Co., Ltd., Beijing's development, add vitamin A as stabilizing agent.Added the tertiary butyl-4-hydroxy methyl phenyl ethers anisole as antioxidant in drop pills of simvastatin (Granted publication CN1164268C) preparation method of Beijing state core hall medical sci-tech Development Co., Ltd development.The present invention finds add the degraded that the tertiary butyl-4-hydroxy methyl phenyl ethers anisole really can reduce principal agent, but this antioxidant not to have medicinal rank, and be proved suspicious carcinogenesis in development process, so do not advocate to use.And adopt vitamin A to be not enough to reach the purpose that reduces the degraded of principal agent fluvastatin sodium as stabilizing agent.Therefore, in the present invention, adopt the mode to the sustained-release dropping pill coating to completely cut off the alien influence factor for the influence of principal agent composition, guaranteed the stability of principal agent.
It is single to the objective of the invention is to replenish present clinical practice dosage form, and the novel form of slow release efficient long-acting is provided.Fluvastatin sodium sustained release coating drop pill involved in the present invention is to prepare in the constituent at existing drop pill, adds sustained-release agent hydrophobicity framework material and coating, can reach the effect that makes drug slow and steadily discharge, thus the action time of obvious prolong drug.The packaging technique that adopts among the present invention, effectively guaranteed the stability of principal agent, make medicine can not occur the significant change of drug content and related substance before the deadline, simplified prescription, and avoided using the antioxidant that body is had suspicious potential hazard.Simultaneously, it is abundant and the time is controlled that this sustained release coating drop pill also has release, and medicining times is few, the advantage that bioavailability is high.
Description of drawings
Fig. 1 is according to table 7 and 8 curve charts of drawing.
The specific embodiment
Embodiment 1
Get recipe quantity PEG6000, poloxamer 188, PEG12000, stearic acid, glyceryl monostearate in the heating in water bath fusion, the fluvastatin sodium that adds recipe quantity, fully stir, make it mixing, the feed liquid constant speed with fusion under heat-retaining condition splashes in the condensation column that fills dimethicone, the condensation column upper temp is 30 ℃, the temperature of bottom is 0 ℃, and dripping speed is 20 ± 3 droplets/minute, the gradient cooling, take out after being shaped, with Opadry alcoholic solution bag film-coat.
Embodiment 2
Press embodiment 1 technology and make the sustained release coating drop pill.
Embodiment 3
Press embodiment 1 technology and make the sustained release coating drop pill.
Comparative Examples (making the sustained-release dropping pill of stabilizing agent of vitamin A)
Get recipe quantity PEG6000, poloxamer 188, PEG12000, stearic acid, glyceryl monostearate in the heating in water bath fusion, the fluvastatin sodium that adds recipe quantity, fully stir, make it mixing, the feed liquid constant speed with fusion under heat-retaining condition splashes in the condensation column that fills dimethicone, and the condensation column upper temp is 30 ℃, the temperature of bottom is 0 ℃, dripping speed is 20 ± 3 droplets/minute, the gradient cooling, and take out the back that is shaped.
Result of the test
1. release check result
Table 1 embodiment release check result
| Embodiment | 45 minutes | 2 |
5 |
10 hours |
| Embodiment 1 | 9.8％ | 30.6％ | 61.8％ | 91.3％ |
| Embodiment 2 | 10.6％ | 33.9％ | 57.6％ | 82.9％ |
| Embodiment 3 | 9.7％ | 26.9％ | 53.6％ | 87.7％ |
| The fluvastatin sodium sheet | 95.7％ | 99.4％ | - | - |
Result of the test shows that this sustained release coating drop pill has the good slow release performance.
2. influence factor's result of the test
2.1 high humility test
Sample is placed the constant-temperature enclosed container 10 days of RH92.5%, RH75.3%, RH57.7% respectively, detect in the 5th day and sampling in the 10th day.
Table 2 moisture absorption weightening finish check result
Result of the test shows that the hygroscopicity of sustained-release dropping pill is stronger, and the moisture absorption weightening finish surpasses 10% under the environment of relative humidity 92.5%, and this sustained release coating drop pill can significantly reduce its hygroscopicity, thereby reduces airborne moisture for the influence of principal agent.
Table 3 high humility test content check result
Experimental result shows that this sustained release coating drop pill can guarantee that medicine content under the condition of high humility meets the requirements.
2.2 hot test
Because the fusing point of drop pill substrate is generally lower, during 60 ℃ of high temperature, the drop pill fusing, under 40 ℃ of conditions, drop pill profile no change, no deliquescing phenomenon is measured its content, and the result is as follows:
Table 4 hot test (40 ℃) content check result
| Time | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative Examples |
| 0 day | 102.6％ | 97.5％ | 98.4％ | 100.5％ |
| 5 days | 102.1％ | 97.7％ | 98.9％ | 101.1％ |
| 10 days | 101.7％ | 97.0％ | 97.8％ | 100.3％ |
Experimental result shows, there was no significant difference on 3 crowdes of this sustained release coating drop pill embodiment under the hot test condition and Comparative Examples sustained-release dropping pill changes of contents.
2.3 strong illumination test
Sample is placed the opening clean container, and placing illumination is the lighting box 10 days of 4500 ± 500lx, detects in the 5th day and sampling in the 10th day.
Table 5 strong illumination (4500 ± 500lx) content check results
| Time | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative Examples |
| 0 day | 102.6％ | 97.5％ | 98.4％ | 100.5％ |
| 5 days | 100.4％ | 98.1％ | 99.1％ | 99.4％ |
| 10 days | 101.7％ | 99.4％ | 100.4％ | 99.5％ |
Experimental result shows that this sustained release coating drop pill is comparatively stable to high light, and drug content does not have significant change, and with the vitamin A be the sustained-release dropping pill of stabilizing agent under strong illumination, content is on a declining curve, as seen it is subject to the light influence and unstable.Therefore, this sustained release coating drop pill is the sustained-release dropping pill of stabilizing agent being better than with the vitamin A aspect the assurance principal agent stability.
3. long term test release check result (embodiment 1)
Table 6 fluvastatin sodium sustained release coating drop pill long term test release check result
| Time | 2 |
5 |
10 |
| 0 month | 30.5％ | 61.7％ | 90.4％ |
| January | 33.7％ | 55.4％ | 88.5％ |
| February | 37.1％ | 63.2％ | 85.4％ |
| March | 31.8％ | 58.4％ | 93.8％ |
| June | 34.6％ | 64.8％ | 90.6％ |
Experimental result shows, the having good stability of this sustained release coating drop pill.
4. pharmacokinetic (embodiment 1)
Get 12 of rabbit, be divided into two groups at random, one group is fluvastatin sodium sheet group, and one group is fluvastatin sodium sustained release coating drop pill group, measures the Sanguis Leporis seu oryctolagi concentration respectively at different time points behind the medicine, and the gained data are as follows:
Table 7 fluvastatin sodium sheet blood drug level (ng/ml)
Table 8 fluvastatin sodium sustained release coating drop pill blood drug level (ng/ml)
According to data, curve chart as shown in Figure 1 when drawing medicine.
Can be found out that by accompanying drawing 1 sustained release performance of fluvastatin sodium sustained release coating drop pill is good, can keep in vivo and reach 5 hours stable release time, blood drug level be maintained within the valid density scope for a long time, thereby better bring into play effect for reducing blood fat.Under the same dose, the area under the drug-time curve AUC of fluvastatin sodium sustained release coating drop pill is 3 times of fluvastatin sodium sheet, and the bioavailability of this dosage form significantly is better than tablet as can be seen.
The data of test 3 and test 4 are all from embodiment 1, and embodiment 2 and embodiment 3 obtain similar data result through test.
Claims (7)
1. the preparation method of a fluvastatin sodium sustained release coating drop pill, its prescription comprises:
Fluvastatin sodium 20～40g;
Hydrophilic framework material 50～70g, its component is one or more mixture of polyethylene glycol 6000, poloxamer 188, Polyethylene Glycol 12000, to regulate formability and the hardness of drop pill;
Hydrophobicity framework material 80～100g, its component is one or both mixture of stearic acid, glyceryl monostearate, with the saturation of the stability that increases substrate, medicine and delay the release of medicine;
Coating material Opadry 4～6g with the degraded of isolated external influence factor to principal agent, guarantees that drug content and related substance obvious change can not occur before the deadline;
Get above-mentioned each material recipe quantity, make 1000 of finished product sustained release coating drop pill, fluvastatin sodium content 20mg/ grain～40mg/ grain, the heavy 150mg/ grain of ball～200mg/ grain;
It is characterized in that, comprise the steps:
(1), the preparation process of sustained-release dropping pill:
A, pulverizing and porphyrize fluvastatin sodium raw materials are crossed 100 mesh sieves;
B, get recipe quantity hydrophilic framework material and hydrophobicity framework material in the container that is fit to;
C, will fill above-mentioned matrix container and place water-bath to be heated to eutectic point, and make it be molten condition;
D, the fluvastatin sodium fine powder of getting recipe quantity are added to the substrate of molten condition, fully stir, and make it mixing;
E, under heat-retaining condition, above-mentioned solution is splashed in the condensation column gradient cooling, the system of dripping;
Take out after f, drop pill are shaped, inhale the condensed fluid that goes to stick to the surface with absorbent paper, dry under field conditions (factors);
(2), the preparation process of sustained-release dropping pill coating:
A, get the Opadry of recipe quantity, add in 80% alcoholic solution of 11.5 times of recipe quantities, stir, filter, get coating solution;
B, the sustained-release dropping pill that will prepare are put into coating pan, spray into a certain amount of Opadry alcoholic solution, make the sustained-release dropping pill surface evenly moistening;
C, the hot blast that is blown into mitigation make solvent evaporation; The aforesaid operations several times reach certain thickness repeatedly;
D, made it completion of cure in 6～8 hours in room temperature or a little more than placing naturally under the room temperature condition;
E, 50 ℃ dry 12～24 hours down make it residual organic solvents to eliminate fully, and the sustained release coating drop pill gets product.
2. preparation method as claimed in claim 1, temperature is 60 ℃～90 ℃ when it is characterized in that heating and melting.
3. preparation method as claimed in claim 1 is characterized in that dripping feed temperature processed is 70 ℃～80 ℃.
4. preparation method as claimed in claim 1 is characterized in that condensed fluid is dimethicone or liquid paraffin.
5. preparation method as claimed in claim 1 is characterized in that dripping speed is 20 ± 3 droplets/minute.
6. preparation method as claimed in claim 1 is characterized in that the condensed fluid upper temp is 20 ℃～35 ℃, and bottom temp is-5 ℃～10 ℃.
7. preparation method as claimed in claim 1, the temperature that it is characterized in that being blown into hot blast is 38 ± 2 ℃.
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| CO5140079A1 (en) * | 1998-10-14 | 2002-03-22 | Novartis Ag | PHARMACEUTICAL COMPOSITION OF SUSTAINED LIBERATION AND METHOD TO RELEASE A PHARMACEUTICALLY ACTIVE AGENT FROM SUSTAINED LIBERATION AND METHOD TO RELEASE A PHARMACEUTICALLY ACTIVE AGENT |
| US6242003B1 (en) * | 2000-04-13 | 2001-06-05 | Novartis Ag | Organic compounds |
| CN101426478A (en) * | 2006-02-24 | 2009-05-06 | 特瓦制药工业有限公司 | Fluvastatin sodium pharmaceutical compositions |
| CN101385729B (en) * | 2007-09-10 | 2010-07-21 | 鲁南制药集团股份有限公司 | Osmotic pump controlled release preparation composition for treating hyperlipemia and preparation method thereof |
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Address after: 250002 No. 5460 South Second Road, Shandong, Ji'nan, Shandong Medical College Patentee after: Song Yun Address before: 100081 Beijing Haidian District academy South Road No. 59 China Green Food Development Center logo management office Patentee before: Song Yun |
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