CN101084880A - Biological solid dispersion of vitamin E esters derivatives and preparation method thereof - Google Patents
Biological solid dispersion of vitamin E esters derivatives and preparation method thereof Download PDFInfo
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- CN101084880A CN101084880A CN 200610087354 CN200610087354A CN101084880A CN 101084880 A CN101084880 A CN 101084880A CN 200610087354 CN200610087354 CN 200610087354 CN 200610087354 A CN200610087354 A CN 200610087354A CN 101084880 A CN101084880 A CN 101084880A
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Abstract
The invention relates to a solid dispersion of insoluble medicinal vitamin E esters derivant such as vitamine E nicotinate, acetic ester and succinic ester and its preparation method. The dissolving velocity in vitro and absorption eegree in vivo of the vitamin E esters derivant is remarkably improved after being treated by solid dispersion.
Description
Technical field
The present invention relates to solid dispersion of insoluble drug vitamin-e ester analog derivative, for example vitamin E Nicotinate, acetate and succinate and preparation method thereof, wherein preferably controlled, as can to improve curative effect and high bioavailability biological solid dispersion of vitamin E esters derivatives by solvent evaporation method prepared sizes narrowly distributing, mean diameter.
Background technology
Vitamin E Nicotinate (Tocopheryl Nicotinate, Vitamin E Nicotinate) be by two kinds of necessary important vitamin of human body---the ester type compound that vitamin E and nicotinic acid condensation form, be a kind of novel microcirculation activator, be mainly used in the treatment of vascular hypertension, hyperlipidemia and peripheral circulation disorders.
Vitamin E Nicotinate can directly act on blood vessel wall, diastole peripheral vessels, the blood circulation of promotion brain, skin, muscle, blood flow increasing lastingly and stably.The capillary permeability that kininase is caused is hyperfunction specific inhibitory effect, and can suppress the synthetic of cholesterol, prevents cholesterol deposits in blood vessel wall, promotes cholesterol to drain.Clinically, vitamin E Nicotinate is widely used in the caused various diseases of coronary heart disease, hyperlipemia, cerebral arteriosclerosis, arteriosclerosis, cerebral concussion or brain injury sequela, central serous chorioretinopathy and disturbance of blood circulation; Also be used for abnormalities of sugar/lipid metabolism, hypertension and coronary blood supply insufficiency etc.
Because vitamin-e ester analog derivative poorly water-soluble, its capsule dissolution rate in vitro is slower, and for example, with 2% lauryl sodium sulfate aqueous solution during as dissolution medium, vitamin E Nicotinate only can stripping 30% in three hours.In the treatment clinical course, the oral artifact availability of patient is lower, shows comparatively significant individual variation, is unfavorable for the performance of its curative effect.For this reason, thus improve vitamin-e ester analog derivative water solublity to increase its dissolution rate be very necessary.
Summary of the invention
The objective of the invention is the problem that exists in the vitamin E Nicotinate preparation in the prior art for overcoming, and then improve the dissolution rate in pharmaceutical preparation or the dissolution of vitamin-e ester analog derivative, for example vitamin E Nicotinate, acetate and succinate.
Therefore, the present invention relates to a kind of solid dispersion, this solid dispersion comprises vitamin-e ester analog derivative, for example vitamin E Nicotinate, acetate and succinate and as the carrier of dispersant, wherein carrier is 0.5 with the ratio of the weight of vitamin-e ester analog derivative: 1-10: 1.
The invention still further relates to a kind of pharmaceutical composition, it contains above-mentioned solid dispersion of the present invention and pharmaceutically acceptable carrier.
Another object of the present invention is to provide the preparation method of described biological solid dispersion of vitamin E esters derivatives.
According to the present invention, the above-mentioned carrier as dispersant comprises hydrophilic high molecular material or organic acid.Wherein hydrophilic high molecular material comprises PEG4000, PEG6000 or PEG8000, polyvinylpyrrolidone, poloxamer, dextrin or micropowder silica gel; Organic acid comprises citric acid, succinic acid, cholic acid, lecithin or deoxycholic acid.
According to the present invention, carrier is preferably 1: 1 with the ratio of the weight of vitamin-e ester analog derivative in the solid dispersion.
According to the present invention, the preferred vitamin esters derivative is vitamin E Nicotinate, Vitamin E acetate and vitamin e succinate, more preferably vitamin E Nicotinate.
According to the present invention, preferred carrier is micropowder silica gel.
The invention further relates to the preparation method of biological solid dispersion of vitamin E esters derivatives, it comprises solvent method, melting method, polishing etc.Specifically,
(1) solvent method, its step comprises: it is an amount of to take by weighing the vitamin-e ester analog derivative, adds anhydrous alcohol solution, and hydrophilic high molecular material is added in the above-mentioned solution, stirs, and evaporation under reduced pressure removes and desolvates vacuum drying then.Crushing screening obtains the solid dispersion of vitamin-e ester analog derivative.
With regard to solvent method, the material solution concentration of preferred vitamin esters derivative, for example vitamin E Nicotinate is 20% (w/v), preferred temperature range at 40～60 ℃, the rotating speed that stirs is 50～500rpm, preferred 80～200rpm.
(2) melting method, its step comprises: get the vitamin-e ester analog derivative and be heated to complete fusion in 50-60 ℃, suitable medicinal hydrophilic high molecular material or the organic acid of fusing point that adds one or more, stir evenly, continue to be heated to complete fusion, rapid cooling curing, crushing screening obtains the solid dispersion of vitamin-e ester analog derivative.
The preparation method of biological solid dispersion of vitamin E esters derivatives also comprises other preparation method, for example polishing etc.
The pharmaceutical composition that contains biological solid dispersion of vitamin E esters derivatives of the present invention can drop pill, the form of tablet, capsule or granule exists, and preferably exists with capsule form.
By the vitamin-e ester analog derivative of the present invention's preparation, the solid dispersion of for example vitamin E Nicotinate are compared with solid dispersion of the prior art, the existence of vitamin-e ester analog derivative improves, and has lot of advantages on drug absorption.
For example, results of grain size analysis shows: the mean diameter of vitamin E Nicotinate solid dispersion reaches 50～70 μ m, and the particle diameter span is less than 3.0, and particle diameter is little, is evenly distributed.
DSC result shows: variation has taken place in vitamin E Nicotinate its state in the solid dispersion that forms with micropowder silica gel.Do not see vitamin E Nicotinate melting peak in the DSC curve of vitamin E Nicotinate solid dispersion.According to the variation of endothermic peak in the vitamin E Nicotinate solid dispersion DSC curve, infer that the dispersity of medicine in solid dispersion is amorphous state.
The dissolution rate measurement result shows: compare with the commercially available capsule of vitamin E Nicotinate, the solid dispersion physical ability is significantly accelerated the dissolution rate of medicine.Micropowder silica gel solid dispersion dissolution rate is very fast, shows the stripping that helps medicine after vitamin E Nicotinate is with the amorphous state homodisperse.
Further the body giving drugs into nose of vitamin E Nicotinate solid dispersion and vitamin E Nicotinate raw material shows for the kinetics comparative result, compare with the former powder of vitamin E Nicotinate, degree of absorption significantly improves in vitamin E Nicotinate/micropowder silica gel (1: 1) solid dispersion mice body, does not have significant change and eliminate rule.After medicine was made solid dispersion, Cmax was about 2.49 times of the former powder of vitamin E Nicotinate, and AUC is about 2.67 times, and relative bioavailability is 267%.Result of study and dissolution rate in vitro measurement result dependency are good in the body.
The insoluble drug vitamin E Nicotinate exists with amorphous state in solid dispersion, compare with the former powder of vitamin E Nicotinate, prepared vitamin E Nicotinate solid dispersion good fluidity, adhesion, particle diameter be little, be evenly distributed, stable in properties, dissolution rate in vitro obviously improves, and bioavailability significantly improves.
Description of drawings
Fig. 1 has shown the DSC curve of vitamin E Nicotinate.
Fig. 2 shows the DSC curve of carrier micropowder silica gel.
Fig. 3 has shown that the weight ratio of micropowder silica gel and vitamin E Nicotinate is 1: 1 a solid dispersion DSC curve.
Fig. 4 has shown commercially available capsule of vitamin E Nicotinate and the capsular dissolution result of vitamin E Nicotinate solid dispersion of the present invention relatively.
Curve ratio when Fig. 5 showed the capsule of commercially available capsule and solid dispersion preparation.
The specific embodiment
The following examples are used to describe in detail the present invention, and do not limit protection scope of the present invention in all senses.
With the ethanol heating for dissolving of vitamin E Nicotinate with 4 times (W/V), add the PEG4000-8000 that has melted of 2 times (W/V) afterwards, stir mixing, cooling rapidly, after the curing, drying under reduced pressure or natural drying, pulverize, sieve, promptly get the solid dispersion that contains vitamin E Nicotinate/PEG.
The solid dispersion that embodiment 2, preparation contain vitamin E Nicotinate/polyvinylpyrrolidone with vitamin E Nicotinate and polyvinylpyrrolidone in 1: 1.5 the ratio input dissolving tank, the ethanol that adds 2 times (with the ratio of the weight/volume of vitamin E Nicotinate), after the backflow dissolving, under stirring condition, cooling makes it into thick or semi-solid state rapidly, take out drying or drying under reduced pressure, remove ethanol, pulverize, sieve promptly.
Embodiment 3, preparation contain the solid dispersion of vitamin E Nicotinate/citric acid
With the ethanol heating for dissolving of vitamin E Nicotinate with 5 times (W/V), add the citric acid ethanol liquid of 2 times (W/V) afterwards, stir mixing, cooling rapidly, after the curing, drying under reduced pressure or natural drying, pulverize, sieve, promptly get the solid dispersion that contains vitamin E Nicotinate/PEG.
Embodiment 4: the solid dispersion of preparation vitamin E Nicotinate/micropowder silica gel
Get the vitamin E Nicotinate crude drug, according to following method and according to listed formulation vitamin E Nicotinate solid dispersion in the following table.It is an amount of to get 60 mesh sieve solid dispersion, carries out the solid dispersion volume property and investigates.
| Project | Quality and | ||
| Prescription | |||
| 1 | |
Prescription 3 | |
| The quality of carrier and medicine is than vitamin E Nicotinate (g) micropowder silica gel (g) | 1∶2 10 20 | 1∶1 20 20 | 3∶2 30 20 |
Preparation method: get an amount of micropowder silica gel (pharmaceutical grade), place drying baker, heating makes the micropowder silica gel dehydrate; It is an amount of to take by weighing vitamin E Nicotinate, adds anhydrous alcohol solution, stirs fast; It is an amount of to take by weighing dried micropowder silica gel, adds in the above-mentioned ethanol solution, stirs fast, makes micropowder silica gel homodisperse in solution; Reclaim ethanol, the mixed liquor vacuum drying does not have the ethanol abnormal smells from the patient to the final solid micro-powder that forms.
Embodiment 5: the research of vitamin E Nicotinate solid dispersion
The solid dispersion of getting embodiment 4 prescriptions 2 carries out character and investigates:
[character] solid dispersion is white or off-white color attritive powder, and powder flowbility is good, and hands touches no greasy feeling, does not have inter-adhesive phenomenon.Microscopic examination, oil droplet is by the superfine micropowder silica gel parcel of granularity.
[bulk density] takes by weighing a certain amount of solid dispersion and puts in the 100ml graduated cylinder, falls from distance desktop 5cm, vibrates 10 times, measures its volume, and the calculating bulk density is 0.34g/ml.
[grain size analysis]
A. the mensuration of sieving
The solid dispersion that obtains after the solid dispersion operation is crossed sieve classification, and 99% solid dispersion is by 60 eye mesh screens (unification of the motherland standard screen aperture 0.30mm).
B. laser particle size is measured
After solid dispersion sieved, three parts of diverse location randomizations were carried out the particle size determination of solid dispersion; Particle proportion (%) and span in particle size distribution data each particle size range commonly used represent, the span little distribution of healing is narrower, and promptly particle size is more even.
Solid dispersion granulometry result: D
50Between 50-70 μ m, span is less than 3.0.The above results shows, the solid dispersion that this test prepares, and particle diameter is tiny, is evenly distributed.
[differential scanning calorimetric analysis] got vitamin E Nicotinate, micropowder silica gel and solid dispersion (weight ratio of micropowder silica gel and vitamin E Nicotinate is 1: 1) and carried out differential scanning calorimetric analysis.DSC can study the interaction between solid dispersion system Chinese medicine and the carrier and the residing state of medicine.(abscissa is represented temperature to the vertical coordinate of DSC curve for milliwatt, the mW) speed of expression neither endothermic nor exothermic with energy/time.The DSC curve of medicine, micropowder silica gel and solid dispersion is seen accompanying drawing 1-3 respectively.
By accompanying drawing 1 as seen, vitamin E Nicotinate has an absworption peak near 40 ℃ of its fusing points, locates all do not have this absworption peak in the relevant position (40 ℃) of the DSC curve of micropowder silica gel (accompanying drawing 2) and solid dispersion (mass ratio 1: 1) (accompanying drawing 3).The result shows that strong interaction has taken place for vitamin E Nicotinate and micropowder silica gel, and micropowder silica gel hinders the vitamin E Nicotinate crystallization, so medicine is amorphous state in solid dispersion system.
Embodiment 6: the capsule technical study and the drug release determination of vitamin E Nicotinate solid dispersion
Vitamin E Nicotinate solid dispersion 200g
Amylum pregelatinisatum 100g
Magnesium stearate 15g
70% ethanol is an amount of
Get the vitamin E Nicotinate solid dispersion and cross 60 mesh sieves, starch and magnesium stearate are crossed 100 mesh sieves, and be standby; Prepare 1000 samples, vitamin E Nicotinate solid dispersion (200g) mixes with amylum pregelatinisatum (100g) and mistake 60 mesh sieve mix homogeneously; Add 70% ethanol, be mixed with soft material, cross 20 mesh sieves and granulate; Granule 60 ℃ dry 2 hours down, take out and add magnesium stearate and mix, cross 18 mesh sieve granulate, the vitamin E Nicotinate granule, get this granule and measure medicament contg, determine that every capsule is heavy, take out detect, chemical examination packing, patent medicine.Altogether about 810, yield rate is higher to be 81%.
According to drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2000), adopt the device of dissolution method second method, with 2% lauryl sulphate acid aqueous solution 1000mL is dissolution medium, rotating speed is that per minute 100 changes, operation in accordance with the law, the capsular dissolution of measuring commercially available capsule and preparing according to the inventive method.The result shows that common commercially available capsule only discharged 30% in 3 hours; And according to the release of capsule in 3 hours of this method preparation greater than 85%; Its dissolution the results are shown in accompanying drawing 4.
Embodiment 7: release is measured in the capsule body of vitamin E Nicotinate solid dispersion
The solid dispersion body capsule of embodiment 6 preparations is tested in Beagle Canis familiaris L. body with 200mg/ dosage only, make reference preparation with commercially available capsule, get blood respectively at different time points, adopt high performance liquid chromatography to measure blood drug level after the sample treatment, curve when drawing medicine.The result shows that the capsular relative bioavailability of solid dispersion of the present invention is higher.Curve is shown in table 1, table 2 and accompanying drawing 5 during medicine.
The average blood drug level of capsule of commercially available capsule of table 1. and solid dispersion preparation relatively
| Sampling time (h) | Average blood drug level (μ g/mL) | |
| The solid dispersion body capsule | Commercially |
|
| 0 1 2 3 4 5 6 8 10 12 16 24 | 0 0.0725 0.1665 0.2725 0.3885 0.5229 0.6745 0.3767 0.2815 0.2058 0.0852 0.0662 | 0 0.2372 0.5304 1.2211 1.4847 1.6787 1.2744 0.8700 0.6287 0.4964 0.2827 0.1259 |
Oral commercially available capsule of table 2. beasle dog and solid dispersion body capsule
The pharmacokinetic parameters meansigma methods is (n=6) relatively
| Parameter | Commercially available capsule | Solid dispersion |
| T max(h) C max(μg/ml) AUC(μg/ml×h) | 6 1.6787 5.145 | 5 0.6745 13.75 |
The result shows, compares with the commercially available capsule of vitamin E Nicotinate, and vitamin E Nicotinate/micropowder silica gel of the present invention (1: 1) solid dispersion degree of absorption in Beagle Canis familiaris L. body significantly improves, and does not have significant change and eliminate rule.After medicine made solid dispersion, Cmax was about 2.49 times of the former powder of vitamin E Nicotinate, and AUC is about 2.67 times, and relative bioavailability is 267%.Result of study and dissolution rate in vitro measurement result dependency are good in the body.
Claims (10)
1. solid dispersion, it comprises the vitamin-e ester analog derivative and as the carrier of dispersant, wherein the ratio as the carrier of dispersant and the weight of vitamin E Nicotinate is 0.5: 1-10: 1.
2. according to the solid dispersion of claim 1, vitamin-e ester analog derivative wherein is vitamin B nicotinate, Vitamin E acetate or vitamin e succinate.
3. according to the solid dispersion of claim 1 or 2, wherein the carrier as dispersant comprises hydrophilic material or organic acid, and described hydrophilic high molecular material comprises micropowder silica gel, PEG4000, PEG6000, PEG8000, polyvinylpyrrolidone, poloxamer or dextrin; Organic acid comprises citric acid, succinic acid, cholic acid, lecithin or deoxycholic acid.
4. according to the solid dispersion of claim 3, wherein the carrier as dispersant is micropowder silica gel.
5, according to the solid dispersion of claim 1 or 2, it is 1: 1 wherein as the carrier of dispersant and the weight ratio of vitamin-e ester analog derivative.
6. claim 1 or 2 solid dispersion, the mean diameter of wherein said solid dispersion is 50～70 μ m, the particle diameter span is less than 3.0.
7. pharmaceutical composition, it comprises each described solid dispersion of claim 1-6 and pharmaceutically acceptable carrier.
8. the pharmaceutical composition of claim 7, described pharmaceutical composition exists with the form of drop pill, tablet, capsule or granule.
9. the method for preparing the described solid dispersion of claim 1, said method comprising the steps of: it is an amount of to take by weighing the vitamin-e ester analog derivative, add anhydrous alcohol solution, hydrophilic high molecular material is added in the above-mentioned solution, stir, evaporation under reduced pressure removes and desolvates vacuum drying then.Crushing screening obtains biological solid dispersion of vitamin E esters derivatives.
10. the method for preparing the described solid dispersion of claim 1, said method comprising the steps of: get the vitamin-e ester analog derivative and be heated to complete fusion in 50-60 ℃, add hydrophilic high molecular material, stir evenly, continue to be heated to complete fusion, rapid cooling curing, crushing screening obtains biological solid dispersion of vitamin E esters derivatives.
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| JPS51125755A (en) * | 1975-04-02 | 1976-11-02 | Eisai Co Ltd | A method for treating hyperpiesia |
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| CN102415986A (en) * | 2010-09-27 | 2012-04-18 | 复旦大学 | Insoluble medicament solid dispersion containing phosphatide and cholate and preparation method thereof |
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| CN105193826A (en) * | 2015-09-15 | 2015-12-30 | 黄玉萍 | Preparation method of vitamin D3 premix and vitamin D3 premix prepared through preparation method |
| CN105193826B (en) * | 2015-09-15 | 2019-01-08 | 黄玉萍 | The preparation method of vitamine D3 premix and its vitamine D3 premix obtained |
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| CN114886122B (en) * | 2022-05-12 | 2023-10-10 | 浙江花园营养科技有限公司 | Preparation method of vitamin E powder with improved performance |
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Inventor after: Mei Xingguo Inventor after: Li Yun Inventor after: Guo Qingdong Inventor after: Liu Yan Inventor after: Gong Wei Inventor before: Mei Xingguo Inventor before: Li Yun |
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