CN100352439C - Compound nicotinic acid slow releasing capsule and its preparing method - Google Patents
Compound nicotinic acid slow releasing capsule and its preparing method Download PDFInfo
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- CN100352439C CN100352439C CNB2005101126987A CN200510112698A CN100352439C CN 100352439 C CN100352439 C CN 100352439C CN B2005101126987 A CNB2005101126987 A CN B2005101126987A CN 200510112698 A CN200510112698 A CN 200510112698A CN 100352439 C CN100352439 C CN 100352439C
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Abstract
The present invention provides compound nicotinic acid sustained-release capsules and a preparation method thereof. Each compound capsule of the present invention contains 200 to 500 mg of nicotinic acid and 10 mg of lovastatin. The preparation method of the compound nicotinic acid sustained-release capsules comprises the following steps: the preparation of empty pellet, the preparation of nicotinic acid sustained-release pellets, the preparation of lovastatin quick-release pillets and the preparation of capsules. The products of the present invention are suitable for treating primary hypercholesterolemia and mixed blood fat anomaly. The nicotinic acid is used as a sustained-release part, and the lovastatin is used as a quick-release part for preparing the compound preparation according to the respective characteristics of the nicotinic acid and the lovastatin. All of the components can perform synergistic effect in vivo, and the medicine effect is furthest performed. Moreover, the side effect and the toxic effect of the medicine can be reduced, the in vivo fluctuation of blood concentration can be reduced, and the administration frequency of patients can be reduced. The therapeutic effect of the capsules of the present invention for relieving hypercholesterolemia is obviously better than that of any preparation with a single component.
Description
Technical field
The present invention relates to a kind of retard capsule of compound nicotinic acid and its preparation method, belong to field of pharmaceutical preparations.
Background technology
Primary hypercholesterolemia is a kind of common clinical, frequently-occurring disease with mixing dyslipidemia, between the order of severity of cardiovascular disease such as serum cholesterol concentration and atherosclerosis, coronary heart disease significant correlation is arranged.When serum cholesterol concentration raise, atherosclerotic generation probability also increased substantially.The treatment of cardiovascular disease has become global problem, and its M ﹠ M is the first place, and the annual life that seizes 1,200 ten thousand people in the whole world is near 1/4 of the total death toll of world population.
Hyperlipidemia is the one of the main reasons that causes coronary heart disease and apoplexy, and cardiovascular and cerebrovascular diseases such as coronary heart disease, apoplexy are the underlying cause of deaths of global population.Along with the change of China's aged tendency of population and growth in the living standard, particularly dietary habit, the hyperlipidemia patient is also increasing.
Blood lipid regulation medicine commonly used clinically at present mainly is divided into two classes, one class is the Statins based on cholesterol reducing, another kind of is fibric acid based on triglyceride reducing, though they all have drug effect preferably, but curative effect is single, and have some untoward reaction, study new blood lipid regulation medicine thus and be significant.
Nicotinic acid name: Nicotinicum Acidum, molecular formula: C
6H
5NO
2, molecular weight: 123.11, chemical structural formula is:
Nicotinic acid belongs to vitamin(e) B group, compare with above-mentioned two class medicines, cheap, blood lipid regulation is sure, it is a unique medicine that can make all lipid compositions towards the positive direction development and change, can have been reduced the sickness rate and the general mortality rate of cardiovascular disease by clinical proof, because the half-life of nicotinic acid is extremely short, only 25-45 minute, and heavy dose of nicotinic acid that uses, two kinds of side effect of flushing and liver toxicity often occur, needed one to take medicine a 100-200mg three times because this medicine is used for the hyperlipidemia aspect in addition.
Lovastatin: (S)-2-Methyl Butyric Acid-(1S, 3R, 7S, 8S, 8aR)-1,2,3,7,8, and 8a-six hydrogen-3,7-dimethyl-8-{2-[(2R, 4R)-4-hydroxyl-6-oxygen-2-THP trtrahydropyranyl]-ethyl }-1-naphthalene ester, molecular formula: C
24H
36O
5, molecular weight: 404.55, chemical structural formula is:
Lovastatin is the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, international efficient blood lipid-lowering medicine.This medicine effect is strong, the curative effect height, and side effect is slight, because of its safety, characteristics efficient, low toxicity have become the most frequently used class blood lipid-lowering medicine in the present whole world, be mainly used in the treatment hypercholesterolemia at present clinically, blood fat reducing improves blood flow, antithrombotic etc., common dose is 20mg, and the FDA maximum permissible dose is 80mg, and it absorbs good, side effect is little, and the half-life is longer.
From pharmacological mechanism, nicotinic acid passes through to suppress proteic synthetic the synthetic of cholesterol that influence of density, the HDL that can raise under the heavy dose, reduction TG, and effect significantly has slight reduction LDL effect simultaneously; But, liver toxicity is often arranged because instantaneous blood drug level is too high.Lovastatin is the HMG-CoA reductase inhibitor, by the synthetic rate-limiting enzyme HMG-CoA reductase of competitive inhibition endogenous cholesterol, mevalonic acid metabolic pathway in the blocking-up cell, make the synthetic minimizing of cell inner cholesterol, thereby feedback irritation cell film surface (being mainly hepatocyte) ldl receptor quantity and active increasing, serum cholesterol is removed to be increased, and significantly reduces LDL, but a little less than the effect of rising HDL-C.
Therefore, the two is used simultaneously, might produce the good effect for reducing fat of curative effect and help to reduce side effect.
Summary of the invention
The object of the present invention is to provide a kind of compound nicotinic acid slow releasing capsule.
Another object of the present invention is to provide a kind of preparation method of compound nicotinic acid slow releasing capsule.
In the compound capsule of the present invention, every capsules contains nicotinic acid 200-500mg, lovastatin 10mg; Further preferably contain nicotinic acid 250-320mg, lovastatin 10mg.
Compound nicotinic acid slow releasing capsule preparation method of the present invention comprises the steps:
V. the preparation of blank piller;
VI. the preparation of niacin sustained release piller;
VII. the preparation of lovastatin release pills;
VIII. capsular preparation.
Specific as follows:
The preparation method of blank piller is: respectively starch 500g and sucrose 500g were pulverized 100 mesh sieves, mix homogeneously is a wetting agent with 50% alcoholic solution, molding in the coating pelletizing machine, and pill-rolling, after 60 ℃ of oven dry, screening 30-40 order piller is standby;
The preparation method of niacin sustained release piller is: nicotinic acid 250g is pulverized and crosses 100 mesh sieves; Getting blank piller 70g puts in the coating pelletizing machine, keeping rotating speed is 100 rev/mins, when piller sprays 30% alcoholic solution, nicotinic acid evenly is sprinkled into, be sprinkled into and finish back continuation rolling 10 minutes, take out piller, put 60 ℃ of oven dry, screening 20-24 order piller is put plain ball in the coating pelletizing machine, and keeping rotating speed is 100 rev/mins, being blown into hot blast makes the piller temperature remain on 50 ℃, spray into 15% Sulisi aqueous solution 450ml, make piller weightening finish 15-25%, screening 18-24 order piller, measure content and release, promptly get the niacin sustained release piller;
The preparation method of lovastatin release pills: with 10g lovastatin, 15g dextrin and 60g Pulvis Talci pulverize separately, and cross 100 mesh sieves, by equivalent incremental method mix homogeneously; Getting blank piller puts in the coating pelletizing machine; keeping rotating speed is 100 rev/mins; spraying 30% alcoholic solution to piller evenly is sprinkled into mixed-powder simultaneously; be sprinkled into and finish back continuation rolling 10 minutes; take out piller; put in 60 ℃ of baking ovens and dry; screening 20-24 order piller is put in the coating pelletizing machine, and keeping rotating speed is 100 rev/mins; being blown into hot blast makes the piller temperature remain on 50 ℃; spray into 6% Opadry alcoholic solution, make piller weightening finish 1-5%, screening 18-24 order piller; measure dissolution and content, promptly get the lovastatin release pills.
Capsular preparation: according to nicotinic acid and the lovastatin content measured in the piller, according to calculating the ratio of two kinds of pillers in capsule, take by weighing two kinds of pillers in proportion respectively, put in the mixer, mix homogeneously will mix piller by the loading amount of calculating and incapsulate, measure content, lovastatin uniformity of dosage units, nicotinic acid release and lovastatin dissolution, after qualified, packing, promptly.
Beneficial effect:
Product of the present invention is applicable to treatment primary hypercholesterolemia and mixed dyslipidemia; Because nicotinic acid is different with the lovastatin mechanism of action, when the blood fat reducing level characteristics is arranged respectively, has stronger complementarity, after share, the two is expected to blood lipid level is improved comprehensively, according to characteristic separately, as slow-released part, lovastatin is as immediate release section with the nicotinic acid part, make compound preparation, both make each component bring into play synergism in vivo, brought into play drug effect to greatest extent, can reduce the toxic and side effects of medicine again, reduce blood drug level fluctuation in vivo, reduce patient's medicining times.Clinical research also proves, use this compound preparation treatment after 1 year, this compound recipe sheet can increase HDL41%, reduces LDL45%, reduce triglyceride 42%, illustrate that the alleviation hypercholesterolemia curative effect of taking these two kinds of medicines simultaneously and producing obviously is better than only taking arbitrary single preparations of ephedrine.
Description of drawings
Fig. 1 is the preparation flow figure of blank piller; Fig. 2 is the preparation flow figure of niacin sustained release piller;
Fig. 3 is the preparation flow figure of lovastatin release pills; Fig. 4 is capsular preparation flow figure;
Fig. 5-1 embodiment 1 nicotinic acid differentiates that figure Fig. 5-2 is that embodiment 2 nicotinic acid are differentiated figure
Fig. 5-3 is that embodiment 3 nicotinic acid differentiate that figure Fig. 6-1 is embodiment 1 a lovastatin identification color spectrogram
Fig. 6-2 is that embodiment 2 lovastatin identification color spectrogram Fig. 6-3 are embodiment 3 lovastatin identification color spectrograms
Fig. 7-1 is that embodiment 1 lovastatin stripping curve figure Fig. 7-2 is embodiment 2 lovastatin stripping curve figure
Fig. 7-3 is that embodiment 3 lovastatin stripping curve figure Fig. 8 are the blank adjuvant ultraviolet of nicotinic acid figure
Fig. 9 is that nicotinic acid linear relationship chart Figure 10-1 is embodiment 1 a nicotinic acid releasing curve diagram
Figure 10-2 is that embodiment 2 nicotinic acid releasing curve diagram Figure 10-3 are embodiment 3 nicotinic acid releasing curve diagrams
Figure 11 is that blank adjuvant liquid chromatogram Figure 12-1 is sour failure test liquid chromatogram
Figure 12-2 is that alkali failure test liquid chromatogram Figure 12-3 is an oxidation failure test liquid chromatogram
Figure 13-1 is that embodiment 1 related substance figure Figure 13-2 is embodiment 2 related substance figure
Figure 13-3 is that embodiment 3 related substance figure Figure 14 are the lovastatin linear relationship chart
The specific embodiment
The preparation method of blank piller is: respectively starch 500g and sucrose 500g were pulverized 100 mesh sieves, mix homogeneously is a wetting agent with 50% alcoholic solution, molding in the coating pelletizing machine, and pill-rolling, after 60 ℃ of oven dry, screening 30-40 order piller is standby;
The preparation method of niacin sustained release piller is: nicotinic acid 250g is pulverized and crosses 100 mesh sieves; Getting blank piller 70g puts in the coating pelletizing machine, keeping rotating speed is 100 rev/mins, when piller sprays 30% alcoholic solution, nicotinic acid evenly is sprinkled into, be sprinkled into and finish back continuation rolling 10 minutes, take out piller, put 60 ℃ of oven dry, screening 20-24 order piller is put plain ball in the coating pelletizing machine, and keeping rotating speed is 100 rev/mins, being blown into hot blast makes the piller temperature remain on 50 ℃, spray into 15% Sulisi aqueous solution 450ml, make piller weightening finish 20%, screening 18-24 order piller, measure content and release, promptly get the niacin sustained release piller;
The preparation method of lovastatin release pills: with 10g lovastatin, 15g dextrin and 60g Pulvis Talci pulverize separately, and cross 100 mesh sieves, by equivalent incremental method mix homogeneously; Getting blank piller puts in the coating pelletizing machine; keeping rotating speed is 100 rev/mins; spraying 30% alcoholic solution to piller evenly is sprinkled into mixed-powder simultaneously; be sprinkled into and finish back continuation rolling 10 minutes; take out piller; put in 60 ℃ of baking ovens and dry; screening 20-24 order piller is put in the coating pelletizing machine, and keeping rotating speed is 100 rev/mins; being blown into hot blast makes the piller temperature remain on 50 ℃; spray into 6% Opadry alcoholic solution, make piller weightening finish 1%, screening 18-24 order piller; measure dissolution and content, promptly get the lovastatin release pills.
Capsular preparation: according to nicotinic acid and the lovastatin content measured in the piller, according to calculating the ratio of two kinds of pillers in capsule, take by weighing two kinds of pillers in proportion respectively, put in the mixer, mix homogeneously will mix piller by the loading amount of calculating and incapsulate, measure content, lovastatin uniformity of dosage units, nicotinic acid release and lovastatin dissolution, after qualified, packing, promptly.
Every of gained compound capsule contains nicotinic acid 250mg, lovastatin 10mg.
The preparation method of blank piller is: respectively starch 500g and sucrose 500g were pulverized 100 mesh sieves, mix homogeneously is a wetting agent with 50% alcoholic solution, molding in the coating pelletizing machine, and pill-rolling, after 60 ℃ of oven dry, screening 30-40 order piller is standby;
The preparation method of niacin sustained release piller is: nicotinic acid 500g is pulverized and crosses 100 mesh sieves; Getting blank piller 70g puts in the coating pelletizing machine, keeping rotating speed is 100 rev/mins, when piller sprays 30% alcoholic solution, nicotinic acid evenly is sprinkled into, be sprinkled into and finish back continuation rolling 10 minutes, take out piller, put 60 ℃ of oven dry, screening 20-24 order piller is put plain ball in the coating pelletizing machine, and keeping rotating speed is 100 rev/mins, being blown into hot blast makes the piller temperature remain on 50 ℃, spray into 15% Sulisi aqueous solution 450ml, make piller weightening finish 15%, screening 18-24 order piller, measure content and release, promptly get the niacin sustained release piller;
The preparation method of lovastatin release pills: with 10g lovastatin, 15g dextrin and 60g Pulvis Talci pulverize separately, and cross 100 mesh sieves, by equivalent incremental method mix homogeneously; Getting blank piller puts in the coating pelletizing machine; keeping rotating speed is 100 rev/mins; spraying 30% alcoholic solution to piller evenly is sprinkled into mixed-powder simultaneously; be sprinkled into and finish back continuation rolling 10 minutes; take out piller; put in 60 ℃ of baking ovens and dry; screening 20-24 order piller is put in the coating pelletizing machine, and keeping rotating speed is 100 rev/mins; being blown into hot blast makes the piller temperature remain on 50 ℃; spray into 6% Opadry alcoholic solution, make piller weightening finish 2%, screening 18-24 order piller; measure dissolution and content, promptly get the lovastatin release pills.
Capsular preparation: according to nicotinic acid and the lovastatin content measured in the piller, according to calculating the ratio of two kinds of pillers in capsule, take by weighing two kinds of pillers in proportion respectively, put in the mixer, mix homogeneously will mix piller by the loading amount of calculating and incapsulate, measure content, lovastatin uniformity of dosage units, nicotinic acid release and lovastatin dissolution, after qualified, packing, promptly.
Every of gained compound capsule contains nicotinic acid 500mg, lovastatin 10mg.
The preparation method of blank piller is: respectively starch 500g and sucrose 500g were pulverized 100 mesh sieves, mix homogeneously is a wetting agent with 50% alcoholic solution, molding in the coating pelletizing machine, and pill-rolling, after 60 ℃ of oven dry, screening 30-40 order piller is standby;
The preparation method of niacin sustained release piller is: nicotinic acid 350g is pulverized and crosses 100 mesh sieves; Getting blank piller 70g puts in the coating pelletizing machine, keeping rotating speed is 100 rev/mins, when piller sprays 30% alcoholic solution, nicotinic acid evenly is sprinkled into, be sprinkled into and finish back continuation rolling 10 minutes, take out piller, put 60 ℃ of oven dry, screening 20-24 order piller is put plain ball in the coating pelletizing machine, and keeping rotating speed is 100 rev/mins, being blown into hot blast makes the piller temperature remain on 50 ℃, spray into 15% Sulisi aqueous solution 450ml, make piller weightening finish 25%, screening 18-24 order piller, measure content and release, promptly get the niacin sustained release piller;
The preparation method of lovastatin release pills: with 10g lovastatin, 15g dextrin and 60g Pulvis Talci pulverize separately, and cross 100 mesh sieves, by equivalent incremental method mix homogeneously; Getting blank piller puts in the coating pelletizing machine; keeping rotating speed is 100 rev/mins; spraying 30% alcoholic solution to piller evenly is sprinkled into mixed-powder simultaneously; be sprinkled into and finish back continuation rolling 10 minutes; take out piller; put in 60 ℃ of baking ovens and dry; screening 20-24 order piller is put in the coating pelletizing machine, and keeping rotating speed is 100 rev/mins; being blown into hot blast makes the piller temperature remain on 50 ℃; spray into 6% Opadry alcoholic solution, make piller weightening finish 3%, screening 18-24 order piller; measure dissolution and content, promptly get the lovastatin release pills.
Capsular preparation: according to nicotinic acid and the lovastatin content measured in the piller, according to calculating the ratio of two kinds of pillers in capsule, take by weighing two kinds of pillers in proportion respectively, put in the mixer, mix homogeneously will mix piller by the loading amount of calculating and incapsulate, measure content, lovastatin uniformity of dosage units, nicotinic acid release and lovastatin dissolution, after qualified, packing, promptly.
Every of gained compound capsule contains nicotinic acid 350mg, lovastatin 10mg.
The preparation method of blank piller is: respectively starch 500g and sucrose 500g were pulverized 100 mesh sieves, mix homogeneously is a wetting agent with 50% alcoholic solution, molding in the coating pelletizing machine, and pill-rolling, after 60 ℃ of oven dry, screening 30-40 order piller is standby;
The preparation method of niacin sustained release piller is: nicotinic acid 320g is pulverized and crosses 100 mesh sieves; Getting blank piller 70g puts in the coating pelletizing machine, keeping rotating speed is 100 rev/mins, when piller sprays 30% alcoholic solution, nicotinic acid evenly is sprinkled into, be sprinkled into and finish back continuation rolling 10 minutes, take out piller, put 60 ℃ of oven dry, screening 20-24 order piller is put plain ball in the coating pelletizing machine, and keeping rotating speed is 100 rev/mins, being blown into hot blast makes the piller temperature remain on 50 ℃, spray into 15% Sulisi aqueous solution 450ml, make piller weightening finish 20%, screening 18-24 order piller, measure content and release, promptly get the niacin sustained release piller;
The preparation method of lovastatin release pills: with 10g lovastatin, 15g dextrin and 60g Pulvis Talci pulverize separately, and cross 100 mesh sieves, by equivalent incremental method mix homogeneously; Getting blank piller puts in the coating pelletizing machine; keeping rotating speed is 100 rev/mins; spraying 30% alcoholic solution to piller evenly is sprinkled into mixed-powder simultaneously; be sprinkled into and finish back continuation rolling 10 minutes; take out piller; put in 60 ℃ of baking ovens and dry; screening 20-24 order piller is put in the coating pelletizing machine, and keeping rotating speed is 100 rev/mins; being blown into hot blast makes the piller temperature remain on 50 ℃; spray into 6% Opadry alcoholic solution, make piller weightening finish 5%, screening 18-24 order piller; measure dissolution and content, promptly get the lovastatin release pills.
Capsular preparation: according to nicotinic acid and the lovastatin content measured in the piller, according to calculating the ratio of two kinds of pillers in capsule, take by weighing two kinds of pillers in proportion respectively, put in the mixer, mix homogeneously will mix piller by the loading amount of calculating and incapsulate, measure content, lovastatin uniformity of dosage units, nicotinic acid release and lovastatin dissolution, after qualified, packing, promptly.
Every of gained compound capsule contains nicotinic acid 320mg, lovastatin 10mg.
Experimental example 1
This example is the measurement result of lovastatin dissolution and nicotinic acid release in the embodiment 1-4 product:
Lovastatin dissolution standard: 45 minutes should be greater than 80%;
Nicotinic acid release standard: the 20-40% that should be labelled amount in 2 hours should be the 40-75% of labelled amount in 5 hours
Should be more than 75% of labelled amount in 10 hours
| The lovastatin dissolution | 45 minutes | 96.48％ | 93.70％ | 93.79％ |
| 90.86％ | 92.86％ | 93.59％ | ||
| The |
2 hours | 22.00％ | 24.69％ | 23.30％ |
| 25.59％ | 22.70％ | 23.79％ | ||
| 5 hours | 54.56％ | 53.66％ | 52.57％ | |
| 55.45％ | 54.36％ | 56.85％ | ||
| 10 hours | 87.41％ | 88.60％ | 85.02％ | |
| 85.82％ | 86.81％ | 85.42％ |
Experimental example 2
This example is the testing data of quality research work such as the physicochemical constant, purity test, assay of embodiment of the invention product.
Character: capsule, content are circular bead.
Differentiate:
A. get the need testing solution under the release item, measure at 200-400nm according to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2000), the results are shown in Figure 5, visible embodiment 1-3 product all has absorption maximum at 262nm.
B. embodiment 1-3 product is with the content of HPLC method mensuration lovastatin, and the liquid chromatogram of sample and reference substance is seen Fig. 6.The embodiment 1-3 product all main peak retention time with reference substance is consistent.
Check: uniformity of dosage units: every of embodiment 1-3 product contains only 10mg of lovastatin, so should carry out uniformity of dosage units inspection (two appendix XE of Chinese Pharmacopoeia version in 2000).Get 1 of this product,, be transferred to fully in the 100ml measuring bottle, measure content, calculate uniformity of dosage units according to method under the assay item with the content porphyrize.The results are shown in Table 1.
Table 1: embodiment 1-3 product compound nicotinic acid slow releasing capsule uniformity of dosage units is checked
| Embodiment | Content % | On average | A+1.8 |
||||
| 1 | 98.78 | 102.8 | 97.18 | 98.52 | 100.6 | 99.62 | 3.81 |
| 99.15 | 101.1 | 97.41 | 98.72 | 102.0 | |||
| 2 | 95.36 | 97.54 | 96.41 | 96.98 | 97.32 | 97.22 | 5.56 |
| 97.86 | 100.8 | 95.36 | 97.90 | 96.71 | |||
| 3 | 99.08 | 96.44 | 99.21 | 99.36 | 98.75 | 98.30 | 4.21 |
| 98.60 | 100.1 | 95.77 | 97.12 | 98.59 | |||
As seen, the uniformity of dosage units of embodiment 1-3 product is all up to specification.
The dissolution of lovastatin
The selection of dissolution medium: lovastatin is water-soluble hardly, is the dissolution that dissolution medium is measured lovastatin tablet with reference to the USP25 version with following solvent: get the 1.38g sodium dihydrogen phosphate and the 20g sodium lauryl sulphate adds the 900ml water dissolution, regulate pH to 7.0 with the 1mol/L sodium hydroxide solution, add water to 1000ml promptly.
The selection of assay method: with reference to the method for assay, with the dissolution of high effective liquid chromatography for measuring this product.
Stripping curve: (U.S. KOS company produces to get embodiment 1-3 product and import compound niacin sustained release tablet, lot number 08/30/02), according to the method operation down of drug release determination method item, 5ml takes a sample respectively at 10 ' 20 ' 30 ' 45 ' time, replenish the 5ml solvent simultaneously, measure the stripping quantity of each time point.The results are shown in Table 2, stripping curve is seen Fig. 7-1,7-2,7-3.By scheming and show as seen, lovastatin basic all strippings in the time of 45 minutes in the embodiment 1-3 product.
Table 2: compound nicotinic acid slow releasing capsule stripping curve measurement result
| Embodiment | Time/ |
1 | 2 | 3 | 4 | 5 | 6 | |
| 1 | 10 | 43.77 | 42.31 | 35.19 | 40.07 | 41.33 | 42.28 | 40.83±3.02 |
| 20 | 68.07 | 70.18 | 59.55 | 62.17 | 67.82 | 68.71 | 66.08±4.21 | |
| 30 | 90.82 | 92.27 | 87.12 | 90.85 | 88.50 | 89.66 | 89.87±1.85 | |
| 45 | 97.28 | 99.87 | 96.38 | 98.77 | 101.0 | 97.99 | 98.52±1.72 | |
| 2 | 10 | 44.95 | 43.22 | 41.35 | 39.49 | 41.42 | 40.18 | 41.77±2.01 |
| 20 | 68.16 | 64.58 | 69.73 | 69.19 | 66.96 | 68.65 | 67.88±1.87 | |
| 30 | 84.84 | 81.74 | 85.27 | 81.90 | 86.08 | 84.41 | 84.04±1.81 | |
| 45 | 97.40 | 99.22 | 98.70 | 97.34 | 95.26 | 98.77 | 97.78±1.46 | |
| 3 | 10 | 45.79 | 46.21 | 48.17 | 46.91 | 49.28 | 47.35 | 47.29±1.29 |
| 20 | 79.11 | 71.93 | 72.63 | 74.70 | 78.44 | 73.25 | 75.01±3.06 | |
| 30 | 82.55 | 80.85 | 79.44 | 83.44 | 80.40 | 80.59 | 81.21±1.49 | |
| 45 | 94.56 | 94.21 | 97.41 | 94.80 | 93.43 | 96.34 | 95.13±1.47 |
Dissolution method: get the sample of embodiment 1-3 product release item in the time of following 45 minutes,, calculate every stripping quantity according to method operation under the lovastatin assay item.The dissolution of embodiment 1-3 product the results are shown in Table 3.
Table 3: lovastatin dissolution determination result
| |
1 | 2 | 3 |
| Dissolution % | 98.52 | 97.78 | 95.13 |
The release of nicotinic acid
The selection of release medium: in order to take into account the lovastatin determination of dissolution rate, this product adopts following solvent to measure release: get the 1.38g sodium dihydrogen phosphate and the 20g sodium lauryl sulphate adds the 900ml water dissolution, regulate pH to 7.0 with the 1mol/L sodium hydroxide solution, add water to 1000ml promptly.(is release medium hereinafter to be referred as this solution)
The selection of assay method: because nicotinic acid has stronger uv absorption, get the nicotinic acid reference substance and make the solution photograph spectrophotometry that every 1ml contains 20 μ g with release medium, as seen nicotinic acid has absorption maximum in 262nm in release medium, other gets the blank adjuvant (containing lovastatin) of embodiment 1-3 product corresponding proportion with the method operation, and visible blank adjuvant does not almost have absorption at 262nm.The results are shown in Figure 8.
Linear relationship: precision takes by weighing the about 20mg of nicotinic acid reference substance, adds release medium melt into 100ml, shakes up, precision is measured in this solution 2.0,4.0,6.0,8.0,10.0,12.0ml to the 100ml measuring bottle, adds release medium and is diluted to scale, shakes up, measure trap at 262nm, the results are shown in Table 4.
Table 4: nicotinic acid linear relationship measurement result
| Concentration (μ g/ml) | 4.024 | 8.048 | 12.072 | 16.096 | 20.12 | 24.144 |
| Trap | 0.102 | 0.198 | 0.307 | 0.398 | 0.505 | 0.603 |
Linear equation is A=4.67 * 10
-4+ 2.497 * 10
-2
As seen, nicotinic acid in release medium in the concentration range of 4.024-24.144 μ g/ml, favorable linearity in absorption value and the concentration.Linear relationship chart is seen Fig. 9.
The response rate: because the concentration range broad of drug release determination, so the ratio of the sample principal agent of determination of recovery rates and adjuvant is decided to be the 20-120% of theoretical amount.Get that the nicotinic acid reference substance is about 200,1000, each three parts of 1200mg, accurately claim surely, add the about 1320mg of blank adjuvant (containing lovastatin) respectively, grind well.Precision takes by weighing in right amount, adds release medium and makes the solution that every 1ml contains 20 μ g and measure according to method under the drug release determination method item, and calculate recovery rate the results are shown in Table 5.
Table 5: nicotinic acid drug release determination recovery test result
| Concentraton gradient | Contrast addition (mg) | The amount of recording (mg) | The response rate (%) | Average recovery rate (%) | |
| |
1 | 208.3 | 102.4 | ||
| 2 | 203.4 | 208.4 | 102.5 | ||
| 3 | 207.7 | 102.1 | |||
| |
1 | 1048.0 | 101.5 | ||
| 2 | 1032.7 | 1043.5 | 101.0 | 101.3 | |
| 3 | 1046.1 | 101.3 | |||
| |
1 | 1207.9 | 100.5 | ||
| 2 | 1201.9 | 1210.7 | 100.7 | ||
| 3 | 1204.3 | 100.2 | |||
As seen, the response rate is 101.4%, and this can be by being subjected to for drug release determination.
The solution shelf-stability: the need testing solution of getting under this product drug release determination item the results are shown in Table 6 respectively at 0,1,2,4,8,12 hour mensuration trap.
Table 6: nicotinic acid is the stability test result in release medium
| |
0 | 1 | 2 | 4 | 8 | 12 |
| Trap | 0.465 | 0.464 | 0.467 | 0.465 | 0.463 | 0.465 |
As seen, nicotinic acid is stable to being less than in 12 hours in release medium.
Release profiles: get embodiment 1-3 compound niacin sustained release tablet, respectively at 1,2,3,5,8,10,12 hour sampling 5ml, replenish the 5ml solvent simultaneously according to the method operation (wherein import sheet release solvent volume is 1000ml) under the drug release determination method item.Dilute by following method: the 1st hour sample precision got 2ml and added release medium to 10ml; The the 2nd to 5 hour sample precision got 2ml and added release medium to 25ml; Precision is got 2ml and is added release medium to 50ml after the 8th hour.Measure the burst size of each time point.The results are shown in Table 7, release profiles is seen Figure 10-1,10-2,10-3.
Table 7: compound nicotinic acid slow releasing capsule release profiles measurement result
| Embodiment | Time/ |
1 | 2 | 3 | 4 | 5 | 6 | Release (%) |
| 1 | 1 | 18.48 | 19.43 | 19.91 | 18.72 | 18.12 | 19.36 | 19.00±0.67 |
| 2 | 26.03 | 28.72 | 27.23 | 27.92 | 25.24 | 22.95 | 26.35±2.08 | |
| 3 | 34.38 | 34.48 | 36.86 | 36.27 | 34.88 | 35.97 | 35.47±1.04 | |
| 5 | 53.76 | 56.54 | 54.85 | 53.46 | 54.35 | 55.45 | 54.73±1.14 | |
| 8 | 72.54 | 73.73 | 71.34 | 76.31 | 72.93 | 71.34 | 73.03±1.86 | |
| 10 | 90.22 | 81.28 | 85.06 | 85.85 | 88.63 | 82.87 | 85.65±3.38 | |
| 12 | 97.97 | 93.20 | 94.99 | 95.59 | 92.01 | 96.18 | 94.99±2.13 | |
| 2 | 1 | 17.31 | 17.03 | 17.86 | 16.43 | 18.22 | 18.34 | 17.53±0.74 |
| 2 | 25.16 | 26.55 | 24.76 | 27.05 | 25.66 | 23.97 | 25.53±1.14 | |
| 3 | 35.70 | 36.20 | 37.30 | 34.01 | 35.11 | 32.52 | 35.14±1.69 | |
| 5 | 54.20 | 53.51 | 55.60 | 55.99 | 55.79 | 54.40 | 54.92±1.02 | |
| 8 | 72.20 | 71.21 | 73.40 | 73.80 | 70.02 | 69.42 | 71.67±1.78 | |
| 10 | 83.14 | 86.73 | 84.14 | 81.35 | 83.94 | 82.35 | 83.61±1.84 | |
| 12 | 93.89 | 91.70 | 90.70 | 93.09 | 93.69 | 89.11 | 92.03±1.88 | |
| 3 | 1 | 18.74 | 17.95 | 18.23 | 16.52 | 17.27 | 18.46 | 17.86±0.83 |
| 2 | 27.30 | 26.60 | 28.09 | 25.71 | 27.70 | 27.90 | 27.22±0.91 | |
| 3 | 37.92 | 36.83 | 36.63 | 35.04 | 35.74 | 37.13 | 36.55±1.02 | |
| 5 | 55.39 | 54.20 | 56.29 | 53.11 | 56.68 | 56.49 | 55.26±1.43 | |
| 8 | 73.46 | 76.44 | 72.27 | 74.45 | 68.50 | 70.09 | 72.53±2.90 | |
| 10 | 86.37 | 85.18 | 89.54 | 87.36 | 86.76 | 84.58 | 86.63±1.76 | |
| 12 | 98.50 | 94.51 | 94.31 | 91.93 | 97.09 | 90.93 | 94.04±2.27 |
By table 7 and Figure 10-1,10-2,10-3 as seen, embodiment 1-3 product with batch each sheet release conditions than homogeneous.
Determining of sampling time point and burst size: according to 2000 editions two appendix XIXD slow release of Chinese Pharmacopoeia, controlled release preparation guideline regulation about sampling time point, measured result in conjunction with this product and external comparison film, determine that sample point is 2 hours, 5 hours and 10 hours, burst size is tentative to be: more than 20-40%, the 40-70% and 75%.
Drug release determination method: get embodiment 1-3 product, according to dissolution test method (two appendix XC first methods of Chinese Pharmacopoeia version in 2000), with following solution 500ml is solvent: get the 1.38g sodium dihydrogen phosphate and the 20g sodium lauryl sulphate adds the 900ml water dissolution, regulate pH to 7.0 with the 1mol/L sodium hydroxide solution, add water to 1000ml.Rotating speed is that per minute 100 changes, and operation in the time of 2,5,10 hours, is got solution 5ml respectively in accordance with the law, replenish the 5ml solvent simultaneously, filter, get subsequent filtrate with the 0.8um microporous filter membrane, precision is measured 2ml respectively, and the 2nd, 5 hour diluted sample is to 25ml, and diluted sample was to 50ml in the 10th hour.According to the trap of each sample of spectrophotometry at the 262nm place, other gets precision, and to take by weighing the nicotinic acid reference substance an amount of, adds release medium and make the solution that every 1ml contains 20 μ g and measure with method.Calculate release.The results are shown in Table 8.
Table 8: compound nicotinic acid slow releasing capsule nicotinic acid drug release determination result (%)
| |
1 | 2 | 3 |
| 2 hours | 26.35 | 25.53 | 27.22 |
| 5 hours | 54.73 | 54.92 | 55.26 |
| 10 hours | 85.65 | 83.61 | 86.63 |
Catabolite is checked: for cooperating the study on the stability of this product, set up the catabolite inspection method, embodiment 1-3 product carries out this inspection with the HPLC method.
The chromatographic condition foundation that catabolite is checked: lovastatin Ministry of Public Health standard (WS-126 (X-109)-96) is measured the related substance of lovastatin with following chromatographic condition.With octadecylsilane chemically bonded silica is filler, is mobile phase with acetonitrile-0.1% phosphoric acid liquid (65: 35), and flow velocity is 1.5ml/min, and the detection wavelength is 238nm, and number of theoretical plate should be not less than 3000 by lovastatin.Carry out the catabolite inspection of embodiment 1-3 product with reference to this condition.
The chromatographic condition that catabolite is checked:
Instrument: Tianjin, island 10A chromatograph of liquid
Chromatographic column: Kromasil C18 post, 5um, 4.6 * 250mm
Mobile phase: acetonitrile-0.1% phosphoric acid liquid (65: 35).
Detect wavelength: 238nm.
Detect the selection of wavelength: because the amount of lovastatin is less in embodiment 1-3 product, and nicotinic acid also has stronger absorption at 238nm, therefore selects for use the maximum wavelength 238nm of lovastatin to make to detect wavelength to take into account the detection of two components.
Blank adjuvant interference test: get the blank adjuvant of embodiment 1-3 product prescription ratio, be mixed with blank solution inspection according to the catabolite inspection technique, the result shows that blank adjuvant is noiseless.See Figure 11.
Destructive testing:, carry out destructive testing for investigating the feasibility of chromatographic condition.Get this product fine powder an amount of (being equivalent to lovastatin 8mg) totally three parts, put in the 100ml measuring bottle first part respectively and add 0.1mol/L hydrochloric acid 5ml, put in 100 ℃ of baking ovens and heated 30 minutes: second part adds 0.1mol/L sodium hydroxide solution 5ml, put in 100 ℃ of baking ovens and heated 30 minutes: the 3rd part adds 30% hydrogen peroxide solution 5ml, puts in 100 ℃ of baking ovens and heats 30 minutes.Carry out adding mobile phase after acid, alkali, oxidation destroy respectively and be diluted to scale, filter, as need testing solution.Check related substance respectively by the related substance inspection technique, the result shows that this product all produces catabolite and separates well with main peak after each destructive testing destroys, and chromatogram is seen Figure 12-1,12-2,12-3.
The catabolite inspection technique: get this product fine powder an amount of (being equivalent to lovastatin 20mg approximately), put in the 100ml measuring bottle, it is an amount of to add mobile phase, and supersound process makes dissolving, is diluted to scale with mobile phase, shakes up, and filters, as need testing solution.The accurate need testing solution 20 μ l that draw inject chromatograph of liquid, and the record chromatogram calculates the ratio that each impurity peaks peak area summation accounts for total peak area to 2 times of lovastatin peak retention time.The results are shown in Table 9, chromatogram is seen Figure 13-1,13-2,13-3.
Table 9: compound nicotinic acid slow releasing capsule catabolite check result
| |
1 | 2 | 3 |
| Catabolite | 0.18 | 0.17 | 0.12 |
Assay:
Lovastatin: this product is with the content of high effective liquid chromatography for measuring lovastatin.
Chromatographic condition:
Instrument: Tianjin, island 10A chromatograph of liquid
Chromatographic column: Kromasil C18 post, 5um, 4.6 * 250mm
Mobile phase: acetonitrile-0.1% phosphoric acid liquid (65: 35).
Detect wavelength: 238nm.
Flow velocity 1.5ml/min.
Linear relationship: the accurate title, decided the about 20mg of lovastatin reference substance, puts in the 100ml measuring bottle, and the release medium that adds under the drug release determination item is an amount of, and supersound process makes dissolving, and is diluted to scale, shakes up.Precision measures 2.0,4.0,6.0,8.0,10.0,12.0ml puts respectively in the 100ml measuring bottle, adds release medium to scale, shakes up, and presses chromatographic condition sample introduction 20 μ l respectively, and (μ g/ml) is abscissa with concentration C, and peak area A is a vertical coordinate, carries out linear regression.The results are shown in Table 10.Linear relationship chart is seen Figure 14.
Table 10: lovastatin assay linear relationship result
| C(μg/ml) | 4.046 | 8.092 | 12.138 | 16.184 | 20.23 | 24.276 |
| A | 156104 | 308560 | 462832 | 617804 | 765448 | 923376 |
Linear equation is: A=2.821 * 10
3+ 3.7864 * 10
4C.
The response rate; Precision takes by weighing about 80,100, the 120mg of lovastatin reference substance, claims the fixed about 5700mg mixing of blank adjuvant (containing nicotinic acid) with precision respectively.According to method operation under the determination item, measure content, calculate recovery rate the results are shown in Table 11.
Table 11: lovastatin assay recovery test result
| Concentraton gradient | Contrast addition (mg) | The amount of recording (mg) | The response rate (%) | Average recovery rate (%) | RSD | |
| |
1 | 81.47 | 100.3 | |||
| 2 | 81.24 | 80.56 | 99.16 | |||
| 3 | 81.35 | 100.1 | ||||
| |
1 | 100.7 | 99.08 | |||
| 2 | 101.6 | 101.9 | 100.3 | 99.73 | 0.68 | |
| 3 | 101.4 | 99.82 | ||||
| |
1 | 124.6 | 100.7 | |||
| 2 | 123.7 | 122.3 | 98.85 | |||
| 3 | 122.6 | 99.15 | ||||
Sample introduction precision: the solution of 20.23 μ g/ml concentration under the line taking sexual relationship item, continuous sample introduction 6 times, record peak area.The results are shown in Table 12.
Table 12: lovastatin sample introduction Precision test result
| The sample introduction number of |
1 | 2 | 3 | 4 | 5 | 6 | RSD |
| Peak area | 764007 | 764158 | 767204 | 765869 | 765413 | 766035 | 0.16 |
As seen, sample introduction precision is good.
Replica test: get totally 6 parts of embodiment 1 products,, calculate precision, the results are shown in Table 13 respectively according to determination time-and-motion study content.
Table 13: lovastatin replica test result
| |
1 | 2 | 3 | 4 | 5 | 6 | On average | RSD |
| Content (%) | 100.7 | 100.3 | 99.79 | 100.2 | 100.5 | 101.8 | 100.6 | 0.70 |
As seen, repeatability is good.
Between precision: get embodiment 1 product, adopt different instruments to measure content respectively on different date, totally 6 parts, the results are shown in Table 14 by different experimenters.
Table 14: Precision test result in the middle of the lovastatin
| |
1 | 2 | 3 | 4 | 5 | 6 | RSD％ |
| Content (%) | 100.7 | 100.3 | 99.79 | 99.66 | 100.1 | 100.9 | 0.48 |
Determination: according to high effective liquid chromatography for measuring (two appendix VD of Chinese Pharmacopoeia version in 2000).
The system suitability test: with octadecylsilane chemically bonded silica is filler, is mobile phase with acetonitrile-0.1% phosphoric acid liquid (65: 35), and flow velocity is 1.5ml/min, and the detection wavelength is 238nm, and number of theoretical plate should be not less than 3000 by lovastatin.
Algoscopy: it is an amount of to get under the content uniformity item content, porphyrize, and precision takes by weighing in right amount, the release medium that adds under the drug release determination item is made the solution that every 1ml contains lovastatin 20 μ g, filters, and precision is measured subsequent filtrate 20 μ l, inject chromatograph of liquid, the record chromatogram; Other gets the lovastatin reference substance, measures with method, presses external standard method with calculated by peak area, promptly.
The measurement result of embodiment 1-3 sees Table 15.
Table 15: lovastatin assay result
| |
1 | 2 | 3 |
| Content (%) | 100.6 | 97.24 | 99.45 |
The assay of nicotinic acid
The selection of assay method: two ones of Chinese Pharmacopoeias with the sodium hydroxide titration measuring content of nicotinic acid tablet.This product is measured content through the research of related side's science of law with this method.
Blank adjuvant interference test: get the blank right amount of auxiliary materials of this product according to the determination operation, the result only adds 1 sodium hydroxide volumetric solution, and indicator is variable color.As seen blank adjuvant is noiseless.
The response rate: precision takes by weighing that the nicotinic acid reference substance is about 800,1000, each three parts of 1200mg, the accurate respectively about 1320mg of blank adjuvant (containing lovastatin) that adds, and mixing, precision takes by weighing in right amount and operates according to determination respectively, calculate recovery rate.The results are shown in Table 16.
Table 16: nicotinic acid assay recovery test result
| Concentraton gradient | Contrast addition (mg) | The survey amount of leading (mg) | The response rate (%) | Average recovery rate (%) | RSD | |
| |
1 | 797.0 | 99.21 | |||
| 2 | 803.5 | 793.9 | 98.83 | |||
| 3 | 797.7 | 99.31 | ||||
| |
1 | 994.6 | 99.33 | |||
| 2 | 1001.3 | 1007.5 | 100.6 | 99.65 | 0.69 | |
| 3 | 999.2 | 99.79 | ||||
| |
1 | 1203.4 | 99.34 | |||
| 2 | 1211.4 | 1222.7 | 100.9 | |||
| 3 | 1204.8 | 99.46 | ||||
As seen the response rate is good.
Replica test: get totally 6 parts of embodiment 1 products,, calculate precision, the results are shown in Table 17 respectively according to determination time-and-motion study content.
Table 17: nicotinic acid replica test result
| |
1 | 2 | 3 | 4 | 5 | 6 | On average | RSD |
| Content (%) | 98.57 | 98.67 | 98.40 | 98.96 | 98.26 | 99.26 | 98.69 | 0.37 |
As seen, repeatability is good.
Middle precision: get embodiment 1 product, measure content respectively on the different dates, totally 6 parts, the results are shown in Table 18 by different experimenters.
Table 18: Precision test result in the middle of the nicotinic acid
| |
1 | 2 | 3 | 4 | 5 | 6 | RSD％ |
| Content (%) | 98.57 | 98.67 | 98.40 | 98.71 | 99.11 | 98.20 | 0.32 |
Determination: get content porphyrize under the content uniformity item, precision takes by weighing in right amount (being equivalent to nicotinic acid 0.2g approximately), add the cold water 50ml that newly boiled, put in the water-bath and heat, and after jolting constantly makes nicotinic acid dissolving, put and be chilled to room temperature, add 3 of instructions phenolphthalein solutions, with sodium hydroxide volumetric solution (0.1mol/L) titration.Every 1ml sodium hydroxide volumetric solution (0.1mol/L) is equivalent to the C of 12.31mg
6H
6NO
2
The measurement result of embodiment 1-3 product sees Table 19.
Table 19: nicotinic acid assay result
| |
1 | 2 | 3 |
| Content (%) | 98.69 | 99.53 | 101.4 |
Experimental example 3
This example is according to the requirement about stability test of two ones of Chinese Pharmacopoeia versions in 2000 and guideline, embodiment of the invention product compound nicotinic acid slow releasing capsule is carried out study on the stability, comprise the investigation that keeps sample of influence factor's test, accelerated test and room temperature, test with the quality standard draft by clinical research, investigate index and comprise outward appearance, content, lovastatin dissolution, nicotinic acid release and related substance.
Influence factor's test
Exposure experiments to light: get embodiment 1 product, put on the 4500LX lamp inspection desk and to place 10 days, respectively at 5,10 days sample analysis, and with compared in 0 day.The results are shown in Table 20.
Table 20: compound nicotinic acid slow releasing capsule exposure experiments to light result
| Natural law | Character | Dissolution % | Release % | Content (%) | Related substance (%) | |
| | Nicotinic acid | |||||
| 0 | Content is circular bead | 98.52 | 26.35 | 100.6 | 98.69 | 0.18 |
| 54.73 | ||||||
| 85.65 | ||||||
| 5 | Content is circular bead | 93.12 | 26.39 | 100.7 | 8.42 | 0.16 |
| 54.40 | ||||||
| 86.62 | ||||||
| 10 | Content is circular bead | 95.15 | 24.17 | 99.72 | 98.18 | 0.44 |
| 55.43 | ||||||
| 87.29 | ||||||
*Three data are respectively 2,5,10 hours release, down with.
Hot test (60 ℃): get embodiment 1 product, remove packing, put in 60 ℃ of calorstats and placed 10 days, respectively at 5,10 days sample analysis, and with compared in 0 day.The results are shown in Table 21.
Table 21 compound nicotinic acid slow releasing capsule hot test result
| Natural law | Character | Dissolution % | Release % | Content (%) | Related substance (%) | |
| The Lip river is cut down | |
|||||
| 0 | Content is circular bead | 98.52 | 26.35 | 100.6 | 98.69 | 0.18 |
| 54.73 | ||||||
| 85.65 | ||||||
| 5 | Content is circular bead | 93.87 | 24.91 | 100.6 | 98.20 | 0.18 |
| 53.69 | ||||||
| 85.46 | ||||||
| 10 | Content is circular bead | 93.38 | 24.72 | 100.4 | 98.72 | 0.39 |
| 53.74 | ||||||
| 85.57 |
High humility test (75%RH): because capsule shells can be drawn wet can't the sampling under 92.5% damp condition, so reduce humidity to 75%RH.Get this product, remove packing, putting relative humidity is to place 10 days in the 75%RH container, respectively at 5,10 days sample analysis, and with compared in 0 day.The results are shown in Table 22.
Table 22 compound nicotinic acid slow releasing capsule high humidity result of the test
| Natural law | Character | Dissolution % | Release % | Content (%) | Related substance (%) | |
| The Lip river is cut down | |
|||||
| 0 | Content is circular bead | 98.52 | 26.35 | 100.6 | 98.69 | 0.18 |
| 54.73 | ||||||
| 85.65 | ||||||
| 5 | Content is circular bead | 93.02 | 25.23 | 100.1 | 98.47 | 0.21 |
| 54.12 | ||||||
| 88.18 | ||||||
| 10 | Content is circular bead | 93.51 | 25.23 | 100.6 | 98.32 | 0.14 |
| 54.69 | ||||||
| 86.50 | ||||||
Accelerated test: get this product, simulation listing packing (plastic bottle airtight package) places the 75%RH container to place 6 months in 40 ℃ of calorstats, sample analysis in the time of 1,2,3,6 month respectively, and with result and comparison in 0 o'clock.The results are shown in Table 23.
Table 23 compound nicotinic acid slow releasing capsule accelerated test result
| Month | Embodiment | Character | Dissolution (%) | Release (%) | Content % | Related substance % | |
| The Lip river is cut down | |
||||||
| 0 | 1 | Content is circular bead | 98.52 | 26.35 | 100.6 | 98.69 | 0.18 |
| 54.73 | |||||||
| 85.65 | |||||||
| 2 | Content is circular bead | 97.78 | 25.53 | 97.24 | 99.53 | 0.17 | |
| 54.92 | |||||||
| 83.61 | |||||||
| 3 | Content is circular bead | 95.13 | 27.22 | 99.45 | 101.4 | 0.12 | |
| 55.26 | |||||||
| 86.63 | |||||||
| 1 | 1 | Content is circular bead | 95.73 | 25.25 | 100.4 | 98.65 | 0.32 |
| 54.51 | |||||||
| 83.23 | |||||||
| 2 | Content is circular bead | 95.08 | 24.36 | 98.54 | 99.12 | 0.34 | |
| 55.44 | |||||||
| 87.58 | |||||||
| 3 | Content is circular bead | 94.95 | 26.08 | 100.4 | 101.5 | 0.35 | |
| 55.93 | |||||||
| 85.48 | |||||||
| 2 | 1 | Content is circular bead | 94.74 | 25.16 | 100.3 | 98.27 | 0.39 |
| 55.14 | |||||||
| 86.63 | |||||||
| 2 | Content is circular bead | 94.34 | 24.13 | 98.49 | 99.44 | 0.36 | |
| 54.18 | |||||||
| 83.25 | |||||||
| 3 | Content is circular bead | 94.16 | 23.13 | 99.72 | 100.8 | 0.36 | |
| 56.22 | |||||||
| 87.19 | |||||||
| 3 | 1 | Content is circular bead | 94.01 | 23.86 | 98.31 | 98.32 | 0.39 |
| 53.57 | |||||||
| 83.93 | |||||||
| 2 | Content is circular bead | 93.57 | 24.40 | 99.67 | 100.2 | 0.44 | |
| 55.08 | |||||||
| 86.39 | |||||||
| 3 | Content is circular bead | 93.70 | 25.72 | 101.3 | 97.38 | 0.36 | |
| 56.38 | |||||||
| 86.36 | |||||||
| 6 | 1 | Content is circular bead | 96.40 | 24.18 | 100.3 | 98.21 | 0.47 |
| 54.89 | |||||||
| 85.09 | |||||||
| 2 | Content is circular bead | 94.26 | 23.35 | 99.18 | 99.40 | 0.47 | |
| 55.52 | |||||||
| 83.63 | |||||||
| 3 | Content is circular bead | 95.07 | 24.46 | 99.55 | 101.3 | 0.49 | |
| 53.13 | |||||||
| 85.92 |
Long term test: simulation listing packing (plastic bottle airtight package) is placed at ambient temperature, regular sampling analysis, and with result and comparison in 0 o'clock.The results are shown in Table 24.
Table 24 compound nicotinic acid slow releasing capsule long-term test results
| Month | Embodiment | Character | Dissolution (%) | Release (%) | Content % | Related substance % | |
| The Lip river is cut down | |
||||||
| 0 | 1 | Content is circular bead | 98.52 | 26.35 | 100.6 | 98.69 | 0.18 |
| 54.73 | |||||||
| 85.65 | |||||||
| 2 | Content is circular bead | 97.78 | 25.53 | 97.24 | 99.53 | 0.17 | |
| 54.92 | |||||||
| 83.61 | |||||||
| 3 | Content is circular bead | 95.13 | 27.22 | 99.45 | 101.4 | 0.12 | |
| 55.26 | |||||||
| 86.63 | |||||||
| 3 | 1 | Content is circular bead | 94.64 | 24.88 | 100.1 | 98.47 | 0.43 |
| 55.33 | |||||||
| 85.26 | |||||||
| 2 | Content is circular bead | 94.02 | 24.01 | 99.13 | 99.38 | 0.49 | |
| 54.42 | |||||||
| 84.13 | |||||||
| 3 | Content is circular bead | 94.02 | 23.11 | 99.63 | 101.0 | 0.51 | |
| 54.78 | |||||||
| 86.56 | |||||||
| 6 | 1 | Content is circular bead | 93.50 | 23.48 | 100.0 | 98.27 | 0.49 |
| 53.96 | |||||||
| 84.42 | |||||||
| 2 | Content is circular bead | 95.05 | 25.25 | 98.05 | 99.31 | 0.51 | |
| 54.57 | |||||||
| 85.68 | |||||||
| 3 | Content is circular bead | 95.08 | 24.66 | 99.53 | 101.5 | 0.28 | |
| 55.52 | |||||||
| 87.61 | |||||||
1, product of the present invention was placed 10 days under each influence factor, and every quality index was compared no significant change with 0 o'clock;
2, product accelerated test of the present invention in the time of 6 months every quality index compared no significant change with 0 o'clock;
3, product room temperature of the present invention is placed 6 months every quality index and was compared no significant change with 0 o'clock;
Conclusion: the aforementioned stable result of the test shows that product stability of the present invention is good.
Experimental example 4
This experimental example is the therapeutic effect of the embodiment of the invention 1,2 products to the cardiovascular patient hyperlipemia.
The hyperlipidemia patient that cardiology department is in hospital.60 ± 8 years old mean age, male 23 examples, women 17 examples, wherein concurrent primary hypertension patient 25 examples, concurrent coronary disease patient 15 examples are all got rid of the Secondary cases hyperlipemia.Hepatic and renal function is normal, and the CK value is normal, and routine is accepted blood pressure lowering, coronary dilating, protected heart treatment, not with immunosuppressant and other liver toxicity medicine.
The patient is divided into two groups at random, takes embodiment 1,2 products respectively 4 months, diet control standard basically identical.
The result is as follows:
| Untoward reaction | ALT | | CK | |
| Embodiment | ||||
| 1 group/20 | The slight upper abdomen of 4 examples is glutted, nauseating, accounts for 25% | 1 example is 59.6 μ/L, accounts for 5% | 1 example is 51.6 μ/L, accounts for 5% | No |
| Embodiment | ||||
| 2 groups/20 | Limbs fatigue appears in 5 examples, and far-end of limb is numb, giddy; 6 routine upper abdomens are glutted, nauseating, account for 55% | 7 examples surpass 120 μ/L, account for 35% | 13 examples surpass 120 μ/L, account for 65% | 15 examples obviously raise, and account for 75% |
The ALT normal value is 0-40 μ/L;
The AST normal value is 0-40 μ/L.
This shows that all there is side effect in various degree in embodiment 1,2 products, should arouse attention during use.Clinical demonstration uses the treatment of embodiment 1 product after 1 year, and 20 routine patients on average increase HDL41%, reduce LDL45%, reduce triglyceride 42%.
Claims (5)
1, a kind of compound nicotinic acid slow releasing capsule is characterized in that, in the described compound nicotinic acid slow releasing capsule, every capsules contains nicotinic acid 200-500mg and lovastatin 10mg; Described compound nicotinic acid slow releasing capsule is prepared by following steps:
I. the preparation of blank piller;
II. the preparation of niacin sustained release piller: nicotinic acid 250g is pulverized and crosses 100 mesh sieves; Getting blank piller 70g puts in the coating pelletizing machine, keeping rotating speed is 100 rev/mins, spraying 30% alcoholic solution to piller evenly is sprinkled into nicotinic acid simultaneously, be sprinkled into and finish back continuation rolling 10 minutes, take out piller, put 60 ℃ of oven dry, screening 20-24 order piller is put plain ball in the coating pelletizing machine, and keeping rotating speed is 100 rev/mins, being blown into hot blast makes the piller temperature remain on 50 ℃, spray into 15% Sulisi aqueous solution 450ml, make piller weightening finish 15-25%, screening 18-24 order piller, measure content and release, promptly get the niacin sustained release piller;
III. the preparation of lovastatin release pills: with 10g lovastatin, 15g dextrin and 60g Pulvis Talci pulverize separately, and cross 100 mesh sieves, by equivalent incremental method mix homogeneously; Getting blank piller puts in the coating pelletizing machine, keeping rotating speed is 100 rev/mins, spraying 30% alcoholic solution to piller evenly is sprinkled into mixed-powder simultaneously, be sprinkled into and finish back continuation rolling 10 minutes, take out piller, put in 60 ℃ of baking ovens and dry, screening 20-24 order piller is put in the coating pelletizing machine, and keeping rotating speed is 100 rev/mins, being blown into hot blast makes the piller temperature remain on 50 ℃, spray into 6% Opadry alcoholic solution, make piller weightening finish 1-5%, screening 18-24 order piller, measure dissolution and content, promptly get the lovastatin release pills;
IV. capsular preparation.
2, compound nicotinic acid slow releasing capsule according to claim 1 is characterized in that, in the described compound nicotinic acid slow releasing capsule, every capsules contains nicotinic acid 250-320mg and lovastatin 10mg.
3, a kind of preparation method of compound nicotinic acid slow releasing capsule is characterized in that, described compound nicotinic acid slow releasing capsule is prepared by following steps:
I. the preparation of blank piller;
II. the preparation of niacin sustained release piller: nicotinic acid 250g is pulverized and crosses 100 mesh sieves; Getting blank piller 70g puts in the coating pelletizing machine, keeping rotating speed is 100 rev/mins, spraying 30% alcoholic solution to piller evenly is sprinkled into nicotinic acid simultaneously, be sprinkled into and finish back continuation rolling 10 minutes, take out piller, put 60 ℃ of oven dry, screening 20-24 order piller is put plain ball in the coating pelletizing machine, and keeping rotating speed is 100 rev/mins, being blown into hot blast makes the piller temperature remain on 50 ℃, spray into 15% Sulisi aqueous solution 450ml, make piller weightening finish 15-25%, screening 18-24 order piller, measure content and release, promptly get the niacin sustained release piller;
III. the preparation of lovastatin release pills: with 10g lovastatin, 15g dextrin and 60g Pulvis Talci pulverize separately, and cross 100 mesh sieves, by equivalent incremental method mix homogeneously; Getting blank piller puts in the coating pelletizing machine, keeping rotating speed is 100 rev/mins, spraying 30% alcoholic solution to piller evenly is sprinkled into mixed-powder simultaneously, be sprinkled into and finish back continuation rolling 10 minutes, take out piller, put in 60 ℃ of baking ovens and dry, screening 20-24 order piller is put in the coating pelletizing machine, and keeping rotating speed is 100 rev/mins, being blown into hot blast makes the piller temperature remain on 50 ℃, spray into 6% Opadry alcoholic solution, make piller weightening finish 1-5%, screening 18-24 order piller, measure dissolution and content, promptly get the lovastatin release pills;
IV. capsular preparation.
4, according to the preparation method of the described compound nicotinic acid slow releasing capsule of claim 3; it is characterized in that; the preparation method of described blank piller is: respectively starch 500g and sucrose 500g were pulverized 100 mesh sieves; mix homogeneously; with 50% alcoholic solution is wetting agent, molding in the coating pelletizing machine, pill-rolling; after 60 ℃ of oven dry, screening 30-40 order piller is standby.
5, the preparation method of compound nicotinic acid slow releasing capsule according to claim 3, it is characterized in that described capsular preparation: according to nicotinic acid and the lovastatin content measured in the piller, according to calculating the ratio of two kinds of pillers in capsule, take by weighing two kinds of pillers in proportion respectively, put in the mixer, mix homogeneously will mix piller by the loading amount of calculating and incapsulate, measure content, lovastatin uniformity of dosage units, nicotinic acid release and lovastatin dissolution, after qualified, packing, promptly.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1485037A (en) * | 2002-09-29 | 2004-03-31 | 中国人民解放军军事医学科学院附属医 | Medication comprising nicotinic acid and tatin-like medicine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1485037A (en) * | 2002-09-29 | 2004-03-31 | 中国人民解放军军事医学科学院附属医 | Medication comprising nicotinic acid and tatin-like medicine |
Non-Patent Citations (1)
| Title |
|---|
| 洛伐他汀烟酸缓释片的释放度研究 张婉直等.西北药学杂志，第20卷第3期 2005 * |
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