CN1277840A - Tanshinone solid disperser and its prepn. method - Google Patents
Tanshinone solid disperser and its prepn. method Download PDFInfo
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- CN1277840A CN1277840A CN 00119431 CN00119431A CN1277840A CN 1277840 A CN1277840 A CN 1277840A CN 00119431 CN00119431 CN 00119431 CN 00119431 A CN00119431 A CN 00119431A CN 1277840 A CN1277840 A CN 1277840A
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Abstract
The present invention relates to a tanshinone solid dispersion and its preparation method. It uses polyvinyl pyrrolidone (PVP) and low viscosity ethyl cellulose (EC) as combined carrier, ethyl alcohol as solvent, and adopts spray-drying method to prepare tanshinone solid dispersion. The tanshinone in amorphous state is made highly disperse in the combined carrier, and further by regulating the ratio of EC and PVP to adjust the releasing speed of tanshinone to attain the result of both quick effect and slow-release, and by regulating the spray-drying condition to obtain ball-shaped powder particles with good fluidity.
Description
The invention belongs to slow releasing preparation and preparing technical field thereof, relate to the Chinese herbal medicine effective ingredients slow releasing preparation, relate in particular to TANSHINONES slow releasing preparation and preparation method thereof.
TANSHINONES is the fat-soluble effective ingredient in the Chinese herbal medicine Radix Salviae Miltiorrhizae, mainly aspect following three curative effect is preferably arranged: aspect cardiovascular, the total liposoluble constituent of Radix Salviae Miltiorrhizae has the anoxia of resisting myocardial ischemia and has the effect of the logical blocker of myocardium calcium; Aspect anti-inflammation, TANSHINONES particularly has stronger inhibitory action to staphylococcus aureus to gram positive bacteria; At anti-tumor aspect, TANSHINONES has the cell toxicant lethal effect to kinds of tumor cells, is a kind of tumor cell differentiation revulsant of high-efficiency low-toxicity.
Yet TANSHINONES is an insoluble drug.Show that this medicine assimilation effect in vivo is poor for the experiment of rat oral gavage the fat-soluble effective ingredient of Radix Salviae Miltiorrhizae.With Tanshinone I, Tanshinone I I
AGive animal successive administration one month respectively, the result does not see curative effect yet.And with Tanshinone I I
ASulfonation, make it become water-soluble products-sodium tanshinone IIA sulfate after, through the animal hypoxia endurance test, the result shows effectively, and finds Tanshinone I I by 108 routine coronary heart disease observation of curative effect
ASodium sulfonate has certain curative effect to angina pectoris and symptom uncomfortable in chest, and can improve the ischemic electrocardiogram, and toxicity is little, becomes a kind of medicine of novel treatment coronary heart disease.
Tanshinone I I
ASodium sulfonate is Tanshinone I I
AIn the presence of acetic anhydride, with concentrated acid sulfonation, saltout, get with methanol crystallization.Concentrated sulphuric acid and methanol are all harmful to human body, and wherein methanol is poisonous medicine.In addition, TANSHINONES is heat-labile chemical compound, in removing the process of methanol, if temperature is too high or heat time heating time is long, then causes the degraded of TANSHINONES inevitably.
Therefore, TANSHINONES is prepared into solid dispersion so that its have quick-acting simultaneously and slow releasing function to improve its bioavailability, be that people institute is very expected.Solid dispersion technology mainly is the bioavailability that is used for improving insoluble drug by at first propositions such as Sekiguchi.Its preparation method mainly contains fusion method, solvent method and solvent-fusion method etc.In recent years, this technology has begun to be applied to the research of slow releasing preparation.The all available solid dispersion technology of water soluble drug and insoluble drug prepares slow-release solid and disperses thing, and particularly insoluble drug is developed slow release product with solid dispersion technology, particularly a kind of new way of worth research.At present, for TANSHINONES being prepared into solid dispersion this patent and bibliographical information is not on the one hand arranged as yet.In addition, be the solid dispersion also little bibliographical information of joint vector with water-soluble material PVC and water-insoluble material EC with the preparation insoluble drug.
The object of the present invention is to provide a kind of tanshinone solid disperser that has quick-acting and slow releasing function simultaneously and preparation method thereof, to satisfy people's needs.
The design of invention is such:
With polyvinylpyrrolidone and low viscous ethyl cellulose is joint vector, is solvent with ethanol, adopts the spray drying method for preparation tanshinone solid disperser.Make TANSHINONES with unformed shape (comprising states such as individual molecule and molecular cluster group) high degree of dispersion in joint vector.Ethyl cellulose works to stop the TANSHINONES rapid release of upper state as insoluble mesh skeleton material; Polyvinylpyrrolidone plays raising TANSHINONES and EC wettability and the generation duct to water as water-soluble material.Ratio by adjusting carrier EC and PVP to be to regulate the rate of release of TANSHINONES, reaches the effect of not only quick-acting but also slow release; By adjusting spray-dired condition to obtain the spherical powder particle of good fluidity.
The technical scheme that realizes the object of the invention is as follows:
The said tanshinone solid disperser of the present invention is a compositions, and its component and content are:
TANSHINONES powder 5～30%
Water-soluble material 60～90%
Water-insoluble material 2～20%
More than be mass percent.
Said TANSHINONES powder is a Radix Salviae Miltiorrhizae extract, the extracting method of this extract is a prior art, document " institute of Materia Medica,Chinese Academy of Medical Sciences; the prosperous pharmaceutical factory in Hebei province, Chinese herbal medicine communication .1977,12:12 " and " Lei Qiyun; Zhu new people; Zhu Suqin, etc. Shaanxi new medicine .1984,13 (3): 61 " in have disclosed report;
Said water-soluble material be polyvinylpyrrolidone (the import packing, K30);
Said water-insoluble material is low viscous ethyl cellulose (7-11cp).
Because ethyl cellulose is as insoluble mesh skeleton material, can work to stop the TANSHINONES rapid release of upper state, polyvinylpyrrolidone is as water-soluble material, can play a part to TANSHINONES and ethyl cellulose wettability and generation duct to water, therefore the ratio by adjusting carrier ethyl cellulose and polyvinylpyrrolidone to be to regulate the rate of release of TANSHINONES, can reach the effect of not only quick-acting but also slow release.Therefore, the ratio of above-mentioned composition is preferably:
TANSHINONES powder 5～25%
Water-soluble material 65～88%
Water-insoluble material 2～15%
More than be mass percent.
Preferred ratio is:
TANSHINONES powder 5～20%
Water-soluble material 70～85%
More than be mass percent.
Above-mentioned tanshinone solid disperser also is preparation like this:
Be dissolved in the dehydrated alcohol jointly with mass percent 5～30%, 60～90%, 2～20% TANSHINONES powder, polyvinylpyrrolidone and ethyl cellulose respectively, the dehydrated alcohol consumption so that TANSHINONES reaches or near saturated for well, then with the ultrasonic mixing 3～15 minutes in ultrasonic washing unit of this mixed solution, again with this mixed liquor spray drying in spray dryer.The spray drying condition is: inlet temperature is 30-60 ℃; Charging rate is the 15-100 ml/min, and the nebulizer rotating speed is 40-50Hz, and cyclone separator pressure reduction is 50 millimeters of water, and dried powder is tanshinone solid disperser.
The tanshinone solid disperser that is obtained is carried out the dissolution in vitro test, the accelerated stability test of tanshinone solid disperser, physico-chemical analysis, its result shows, said tanshinone solid disperser has improved the dissolution in vitro of insoluble drug TANSHINONES, make it not only reach rapid release in the short period of time, and can in the long time, continue to discharge.Simultaneously, technical process does not change the chemical constitution of TANSHINONES, and the adjuvant of use is nontoxic, pollution-free, and is easy and simple to handle, and preparation stabilization can be realized suitability for industrialized production.
Test method:
(1) TANSHINONES Determination on content in the sample:
Test to such an extent that TANSHINONES standard curve regression equation is: C=11.8509A-0.1121 (r=0.9998).In the formula, C is TANSHINONES concentration (unit is μ g/mL), and A is the absorbance of TANSHINONES.
It is an amount of accurately to take by weighing sample, place the 100mL volumetric flask, it is all dissolved and be diluted to scale with dehydrated alcohol, in 760CRT dual-beam ultraviolet spectrophotometer, measure the absorbance at 268nm place then, again by the content of TANSHINONES in the standard curve calculation sample.
(2) dissolution in vitro assay method:
Adopt the slurry method algoscopy in the Chinese Pharmacopoeia nineteen ninety-five version.Dissolution medium is respectively the no enzyme simulated gastric fluid of pH=1.2, distilled water and the pH=6.8 phosphate buffer of pH=5.8, and volume is 900mL.Accurately take by weighing sample an amount of (being equivalent to pure TANSHINONES 150mg), be sprinkled into the preheating that stirring (rotating speed is 100r/min) and remain in 37 ± 0.5 ℃ the above-mentioned dissolution medium.When rigidly connecting, sample picks up counting when touching solution, respectively at 5min, and 10min, 15min, 20min, 30min, 40min, 50min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h location draw solution 3mL, with 0.8 μ m filtering with microporous membrane, in dissolution medium, add equality of temperature medium 3mL simultaneously immediately, after filtrate is diluted with dehydrated alcohol.With the absorbance of 760CRT type dual-beam ultraviolet-uisible spectrophotometer, calculate the dissolution of TANSHINONES by standard curve according to measured value in 268nm place mensuration diluent.The test triplicate.(through uv scan, carrier material and dissolution medium that this work is adopted all do not have absworption peak near the 268nm wavelength, and they can be ignored the interference that TANSHINONES in the sample detects).
(3) physico-chemical analysis:
Adopt X-ray diffraction, scanning electron microscope and infrared spectrum that solid dispersion is carried out physico-chemical analysis respectively.Wherein, the working condition of X-ray diffraction is: Cuk α target, voltage 40kV, electric current 60mA, 4 °/min of scanning speed, 0.02 °/RP of step-length.The scanning electron microscope working condition is: high pressure 15kV, and the dried sample that is spread on of sample covers metal spraying; The infrared spectrum working condition is: wave-number range 400-4000cm
-1, precision 4 wave numbers, scanning times 32, KBr tabletting.
(4) accelerated stability test of tanshinone solid disperser:
It is that 40 ℃, relative humidity are that 75% calorstat was preserved 3 months that the tanshinone solid disperser of preparation is placed temperature, measures its dissolution then.
(5) test used instrument:
Ultrasonic washing unit (ultrasonic instrument factory must be believed in Shanghai); Spray dryer (the former drying equipment company limited in great river, Shanghai); RC-1A type dissolution test instrument (Shanghai Huanghai Sea medicine inspection instrument plant); 760CRT dual-beam ultraviolet-uisible spectrophotometer (Shanghai the 3rd analytical tool factory); Rlga Ku3030E3 type x-ray diffractometer (Japan is of science); S-250 scanning electron microscope (Cambridge), FI-IR520 infrared spectrometer (Nicolot).
(6) preparation of contrast mechanical impurity:
With the ratio uniform mixing in the solid dispersion, and be crushed to can be all by 100 mesh sieves with TANSHINONES, PVP, EC.
Below will be further described related content of the present invention by embodiment.
Embodiment 1
With 3 gram TANSHINONES powder, 16 gram polyvinylpyrrolidone (import packing, K30) and 1 gram low viscosity ethyl cellulose (7-11cp, new town chemical industry one factory) is dissolved in the 600ml dehydrated alcohol, then with this mixed solution in ultrasonic washing unit behind the ultrasonic mixing 10min, the elimination insoluble impurities is again with this mixed liquor spray drying.The spray drying condition is: inlet temperature is 45 ℃; Charging rate is 35ml/min, and the nebulizer rotating speed is 45Hz; Cyclone separator pressure reduction is the 50mm water column.Dried powder is tanshinone solid disperser.
Fig. 1 is the comparison diagram of the dissolution in vitro of TANSHINONES and above-mentioned tanshinone solid disperser.
Fig. 2 is the dissolution comparison diagram of solid dispersion in the different medium of pH value.
Fig. 3, Fig. 4, Fig. 5, Fig. 6 be TANSHINONES, polyvinylpyrrolidone and ethyl cellulose (16: 1 respectively, w/w) the blank carrier of mixing, the X-ray diffracting spectrum of the tanshinone solid disperser of TANSHINONES, polyvinylpyrrolidone and ethyl cellulose three mechanical impurity and embodiment 1.
Fig. 7,8 are respectively the SEM photo of the solid dispersion of TANSHINONES and embodiment 1.
Fig. 9 is a TANSHINONES, the infrared spectrogram of TANSHINONES, polyvinylpyrrolidone and ethyl cellulose three mechanical impurity and embodiment 1 solid dispersion.
Among Fig. 1, used medium is the no enzyme simulated gastric fluid of pH=1.2. Among the figure, curve 1 is said solid Dispersion, curve 2 is tanshinone. Ordinate is the tanshinone cumulative leaching rate, and abscissa is dissolution time. As can be seen from Figure 1, the solid dispersion of embodiment 1 has significantly improved the dissolution rate of tanshinone, 1 hour Accumulation stripping percentage is 38.5%, is 15.4 times of the former medicine of tanshinone; 12 hours accumulation stripping percentage Being 73.8%, is 19.8 times of the former medicine of tanshinone. Because the water-solubility carrier polyvinylpyrrolidone occupies very big Ratio, in 1 hour in the solid dispersion tanshinone stripping very fast, and after this stripping becomes slowly, release Dynamics and Higuchi model are near (coefficient correlation is 0.9664).
Among Fig. 2, curve 1,2 and 3 is respectively solid dispersion at PBS, the pH=5.8 of pH=6.8 Distilled water and the dissolution rate in the no enzyme simulated gastric fluid of pH=1.2. As seen from Figure 2, although tanshinone solid The dissolution rate of dispersion increases with the increase of the pH value of dissolution medium, but the increase value is very little.
By Fig. 3,4,5,6 as seen, still has tanshinone in the mechanical impurity of tanshinone and carrier The crystal diffraction peak, and in the tanshinone solid disperser of embodiment 1, the crystal diffraction peak of tanshinone is base This is suppressed. This shows that the tanshinone in the said tanshinone solid disperser exists with amorphous state.
From Fig. 7 and 8 as can be seen, TANSHINONES is the crystal of shapes such as lamellar and column, and after coarse pulverization, the largest particles length still surpasses 100 μ m.As can be seen from Figure 8, the solid dispersion composition granule of present technique preparation is spherical in shape, and granularity is not found the crystallization of TANSHINONES less than 10 μ m, and this is consistent with the X-ray diffraction result.This has proved that further TANSHINONES is embedded among the carrier with amorphous state, and may be dispersive with upper state such as molecule or molecular cluster groups.Because the chemical potential and the specific surface area of TANSHINONES enlarge markedly than the former powder of TANSHINONES, so the dissolution of TANSHINONES has improved significantly.
Among Fig. 9, curve 1,2,3 are respectively TANSHINONES, the infrared spectrogram of TANSHINONES, polyvinylpyrrolidone and ethyl cellulose three's mechanical impurity and the solid dispersion of embodiment 1.Be not difficult relatively to find from Fig. 9, the infrared spectrum of the mechanical impurity that solid dispersion is identical with proportion of composing is a basically identical in the number and the position at finger print region and other regional peak, do not show between TANSHINONES and PVP and the EC hydrogen bonded is arranged, this shows, between TANSHINONES and the carrier chemical reaction does not take place in the solid dispersion, they only are physical actions.
The accumulation stripping percentage rate of solid dispersion is shown in table 1 before and after the stability accelerated test.
Accumulation stripping percentage (%) time/h 0.5 123456789 12 of table 1 Accelerated stability test front and back solid dispersion in the artificial gastric juice of no enzyme of pH=1.2 accelerates experiment front 30.1 38.5 48.0 53.9 58.0 61.9 66.0 69.0 71.6 72.3 73.8 and accelerates experiment rear 31.6 37.4 46.3 54.8 59.2 63.0 66.9 69.5 70.7 69.8 72.6
Be not difficult relatively from table 1 to find that the dissolution of solid dispersion is no significant difference before and after stability experiment.This shows that the tanshinone solid disperser of this method preparation is stable.
With 3g TANSHINONES powder, (the import packing of 15g polyvinylpyrrolidone, K30) and the 2g ethyl cellulose (newly press down chemical industry one factory, 7-11cp) be dissolved in jointly in the 600ml dehydrated alcohol, with this mixed solution about 10min of ultrasonic mixing in ultrasonic washing unit, again that this mixed solution spraying is dry then.Spray-dired condition is: inlet temperature is 45 ℃, and charging rate is 35ml/min, and the nebulizer rotating speed is 45Hz, and cyclone separator pressure is 50mmH
2O.Dried powder is tanshinone solid disperser.
Figure 10 is that the tanshinone solid disperser of tanshinone and embodiment 2 preparations is the no enzyme people of pH=1.2 Dissolution rate in worker's gastric juice. Curve 1 is the solid dispersion of embodiment 2, and curve 2 is tanshinone. Among the figure, Abscissa is dissolution time, and ordinate is tanshinone accumulation stripping percentage.
As can be seen from Figure 10, solid dispersion has significantly improved the dissolution rate of tanshinone, and 1 hour accumulation is molten Going out percentage is 28.5%, is 11.4 times of tanshinone bulk drug; 12 hours accumulation stripping percentage is 52.6%, be 14.1 times of tanshinone bulk drug. Because the EC ratio increases, the PVP ratio reduces, and implements The rate of releasing drug of the solid dispersion of example 2 behind 1h is starkly lower than the solid dispersion of embodiment 1.
Claims (5)
1. tanshinone solid disperser is characterized in that component and content are:
TANSHINONES powder 5～30%
Water-soluble material 60～90%
Water-insoluble material 2～20%
More than be mass percent;
Said TANSHINONES powder is a Radix Salviae Miltiorrhizae extract;
Said water-soluble material is a polyvinylpyrrolidone;
Said water-insoluble material is low viscous ethyl cellulose;
2. tanshinone solid disperser as claimed in claim 1 is characterized in that component and content are:
TANSHINONES powder 5～25%
Water-soluble material 65～88%
Water-insoluble material 2～15%
More than be mass percent.
3. tanshinone solid disperser as claimed in claim 2 is characterized in that component and content are:
TANSHINONES powder 5～20%
Water-soluble material 70～85%
Insoluble material 2～10%
More than be mass percent.
4 preparation methoies as the arbitrary described tanshinone solid disperser of claim 1-3 is characterized in that:
TANSHINONES powder, polyvinylpyrrolidone and ethyl cellulose are dissolved in the dehydrated alcohol in described ratio, and with the ultrasonic mixing of this mixed solution 3～15 minutes, with this mixed liquor spray drying, the spray drying condition was again then: inlet temperature is 30-60 ℃; Charging rate is the 15-100 ml/min, and the nebulizer rotating speed is 40-50Hz, and cyclone separator pressure reduction is 50 millimeters of water, and dried powder is tanshinone solid disperser.
5. the preparation method of tanshinone solid disperser as claimed in claim 4 is characterized in that, the dehydrated alcohol consumption is so that TANSHINONES reaches or near saturated.
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| CN 00119431 CN1277840A (en) | 2000-07-11 | 2000-07-11 | Tanshinone solid disperser and its prepn. method |
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| CN 00119431 CN1277840A (en) | 2000-07-11 | 2000-07-11 | Tanshinone solid disperser and its prepn. method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002055070A1 (en) * | 2001-01-16 | 2002-07-18 | Zhongshan University | Dihydrofuran cyclic tanshintones used in treating hyperammonemia and hepatic encephalopathy |
| CN108645597A (en) * | 2018-05-30 | 2018-10-12 | 威海威高血液净化制品有限公司 | dialyzer pressure drop performance test liquid |
-
2000
- 2000-07-11 CN CN 00119431 patent/CN1277840A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002055070A1 (en) * | 2001-01-16 | 2002-07-18 | Zhongshan University | Dihydrofuran cyclic tanshintones used in treating hyperammonemia and hepatic encephalopathy |
| CN108645597A (en) * | 2018-05-30 | 2018-10-12 | 威海威高血液净化制品有限公司 | dialyzer pressure drop performance test liquid |
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