CN102940608A - Tripterine controlled-release solid dispersion - Google Patents
Tripterine controlled-release solid dispersion Download PDFInfo
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- CN102940608A CN102940608A CN 201210461883 CN201210461883A CN102940608A CN 102940608 A CN102940608 A CN 102940608A CN 201210461883 CN201210461883 CN 201210461883 CN 201210461883 A CN201210461883 A CN 201210461883A CN 102940608 A CN102940608 A CN 102940608A
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- tripterine
- stearic acid
- modified
- solid dispersion
- nanometer caco
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Abstract
The invention provides a tripterine controlled-release solid dispersion taking stearic acid modified nano CaCO3 as a carrier.
Description
Technical field
The present invention relates to a kind of tripterine slow-release solid dispersion, belong to medical technical field.
Background technology
Solid dispersion means by solid dispersion technology and makes medicine be dispersed in system in the solid-state carrier material with forms such as microgranule, crystallite or molecularities.Utilize the slightly solubility carrier to prepare the stripping that solid dispersion not only can increase medicine, improve bioavailability, can also control drug release, reach the purpose of slow release.Yet insoluble drug slow-release solid dispersion is the difficult problem of galenic pharmacy research always, this is owing to the package action of conventional slightly solubility carrier ethyl cellulose, stearic acid etc. and the slightly water-soluble of insoluble drug self, cause the final release rate of medicine often very low, can not reach the application requirements of slow releasing preparation.Nanometer CaCO
3Be the inorganic material that a kind of density is little, specific surface area is large, safety is good, cheap, realized at present the industrialization preparation.Tripterine is one of bioactive ingredients of Chinese medicine Radix Tripterygii Wilfordii, is a kind of quinone methyl triterpene, and chemical constitution is shown in (I).Pharmacological research shows that it has definite antiinflammatory, immunosuppressant and antitumor action, but it all has in various degree toxicity to digestive system, urinary system, blood system and reproductive system.In addition, because it is fat-soluble strong, stripping is slow, causes its oral administration biaavailability low.So also there is not the marketing drugs of tripterine at present.
Summary of the invention
Purpose of the present invention provides a kind of tripterine slow-release solid dispersion.
For the foregoing invention purpose, the invention provides following technical scheme:
A kind of tripterine slow-release solid dispersion is characterized in that: contain the nanometer CaCO after tripterine and the stearic acid surface-modified
3Nanometer CaCO after tripterine and the stearic acid surface-modified
3Mass ratio be preferably 1: 2～1: 10.
Nanometer CaCO after the stearic acid surface-modified of the present invention
3, its preparation process is as follows:
With nanometer CaCO
3Be scattered in the water, heating is then at nanometer CaCO
3The stearic acid that adds melting in the dispersion liquid reacts, filtered while hot after reaction finishes, and washing leaching cake is dried filter cake, grind, sieve, and namely gets the nanometer CaCO after the stearic acid surface-modified
3
Tripterine slow-release solid dispersion of the present invention, tripterine slow-release solid dispersion of the present invention, its preparation process is as follows:
Tripterine is dissolved in the solvent, then adds the nanometer CaCO after the stearic acid surface-modified
3, mix homogeneously, desolventizing, drying namely gets tripterine slow-release solid dispersion.The solvent of dissolving tripterine is one or more in dehydrated alcohol, aquiferous ethanol, the ethyl acetate preferably.
Beneficial effect of the present invention mainly is:
(1) utilize stearic acid to nanometer CaCO
3Carry out surface treatment, make stearate radical functional group firmly be adsorbed in particle surface, can prepare hydrophobic nano CaCO
3Modified Nano CaCO
3Have larger specific surface area, medicine can be adsorbed in its surface, forms solid dispersion, simultaneously because stearic hydrophobic interaction can realize the slow release of its surface adsorption medicine.
(2) the tripterine slow-release solid dispersion of the present invention preparation not only can the slow release tripterine, reduces adverse effect, strengthen drug effect, and drug release is complete,
(3) tripterine slow-release solid dispersion preparation method of the present invention is simple, and cost is low, is suitable for commercial application.
Description of drawings
Fig. 1: the nanometer CaCO after the stearic acid surface-modified
3Transmission electron microscope picture
Fig. 2: stearic acid (A), nanometer CaCO
3(B) and the nanometer CaCO after the stearic acid surface-modified
3(C) FTIR figure
Fig. 3: tripterine (A), tripterine slow-release solid dispersion (B) transmission electron microscope picture
Fig. 4: the nanometer CaCO after tripterine (A), the stearic acid surface-modified
3(B), the nanometer CaCO after tripterine and the stearic acid surface-modified
3The DSC figure of the physical mixture of (1: 8) (C), tripterine slow-release solid dispersion (D)
Fig. 5: the nanometer CaCO after tripterine (A), the stearic acid surface-modified
3(B), the nanometer CaCO after tripterine and the stearic acid surface-modified
3The XRD figure of the physical mixture of (1: 8) (C), tripterine slow-release solid dispersion (D)
Fig. 6: the nanometer CaCO after tripterine (A), the stearic acid surface-modified
3(B), the nanometer CaCO after tripterine and the stearic acid surface-modified
3(C), the FTIR of tripterine slow-release solid dispersion (D) figure
The specific embodiment
The present invention is described in further detail below in conjunction with embodiment, but should notice that scope of the present invention is not subjected to any restriction of these examples.
(1) the nanometer CaCO after the stearic acid surface-modified
3Preparation
Get nanometer CaCO
310g and stearic acid 0.2g; With nanometer CaCO
3Be scattered in the 250ml water, put into water bath with thermostatic control and be heated to 90 ℃; Nanometer CaCO will be added after the melting of stearic acid direct heating
3In the dispersion liquid, 90 ℃ of lower modification 1h, filtered while hot is also used hot absolute ethanol washing filter cake 3 times, dries, grinds, sieves, and get final product.
To modified Nano CaCO
3Carry out activity rating, it the results are shown in Table 1:
Nanometer CaCO after table 1 stearic acid surface-modified
3The activity rating result
Nanometer CaCO after the stearic acid surface-modified
3Transmission electron microscope analysis as shown in Figure 1, by the accompanying drawing 1 nanometer CaCO after the stearic acid surface-modified as can be known
3Particle be cube, mean diameter is 60～90nm, crystal form is complete, intergranular border is very clear, dispersibility is better, can infer that its modified effect is desirable.
Accompanying drawing 2 has provided stearic acid, nanometer CaCO
3With the nanometer CaCO after the stearic acid surface-modified
3FTIR figure.To the nanometer CaCO before and after the modification
3Carry out infrared spectrum analysis and find modified Nano CaCO
3At 3427.63cm
-1The hydroxyl peak intensity at place obviously weakens, and shows nanometer CaCO
3Surface hydroxyl in building-up process, be consumed; At 1402.51cm
-1About the absorption band width significantly widen, this is because the distinctive bands of a spectrum of stearic acid and CO
3 2-Characteristic peak form the coupling vibration; At 2917.21cm
-1And 2849.55cm
-1The place has occurred in the stearic acid-CH
3With-CH
2-stretching vibration peak, show stearic acid and nanometer CaCO
3Between formed firmly chemical bonding in the mode of ionic bond.
Stearic acid modified nanometer CaCO
3Mechanism may be: stearic acid is adsorbed in CaCO with the form of ionic bond
3Surface activity the best part and and its surperficial Ca
+Ion, Ca (OH)
+The reaction such as ion generates the fatty acid calcium precipitate.Along with reaction is carried out, CaCO
3The precipitate on surface deposits gradually and forms a skim it is coated.Simultaneously because the interaction between the long hydrocarbon chain of molecule has produced the stearic acid of physical absorption.The chain alkyl of outer end makes calcium carbonate surface hydrophilic originally become lipophile, so that be difficult between the powder reuniting, thereby improved the dispersibility of particle, improve the compatibility with high molecular polymer.
(2) preparation of tripterine slow-release solid dispersion
Take by weighing the tripterine crude drug an amount of, add anhydrous alcohol solution, take by weighing nanometer CaCO after the stearic acid surface-modified at 1: 8 by medicine and carrier mass ratio
3, add in the Radix Tripterygii Wilfordii alcoholic solution, abundant mixing, under 40 ℃ of reduced pressure, the rotary evaporation desolventizing, drying is ground, and crosses 80 mesh sieves, and get final product.
(3) the release in vitro evaluation of tripterine slow-release solid dispersion
By " the slurry method mensuration of 2010 editions two regulations of Chinese pharmacopoeia takes by weighing solid dispersion or the tripterine raw material is an amount of, places the aqueous solution that contains an amount of tween 80 of 900mL, and rotating speed is 50rmin
-1Medium temperature is (37.0 ± 0.5) ℃, respectively at 0.5,1,2,3,4,6,8,10, the 12h time point regularly pipettes 5mL solution, mend simultaneously with equal-volume equitemperature release medium, 0.45 μ m filtering with microporous membrane, precision measures 10 μ L, in the injection liquid chromatography, the record peak area, calculation sample concentration draws the cumulative release degree of corresponding time point medicine.The results are shown in Table 2.
The vitro release of table 2 tripterine slow-release solid dispersion
(4) sign of tripterine slow-release solid dispersion
Transmission electron microscope analysis:
Be coated in respectively the powder sample of tripterine crude drug, tripterine slow-release solid dispersion on the sample stage, carry out surface topography scanning behind the vacuum metal spraying, result's (seeing accompanying drawing 3) shows, solid dispersion Raw medicine drug crystal forms disappears, granularity is uniformly dispersed, the preliminary proof tripterine with the amorphous form high degree of dispersion in modified Nano CaCO
3In.
Differential calorimetric scanning (DSC) is analyzed:
Get the nanometer CaCO after tripterine, the stearic acid surface-modified
3, the nanometer CaCO after tripterine and the stearic acid surface-modified
3The physical mixture of (1: 8), tripterine slow-release solid dispersion place respectively an aluminum pot in right amount, take empty aluminum pincers pot as reference substance.The scanning temperature range is 0-500 ℃, and regulating heating rate is 10 ℃ of min
-1, record respectively the differential calorimetric scanning curve of sample, see accompanying drawing 4.Demonstration tripterine crude drug locates to occur respectively an endothermic peak and an exothermic peak about 170 ℃ and 220 ℃; Nanometer CaCO after the stearic acid surface-modified
3Located exothermic peak at 370 ℃; Nanometer CaCO after tripterine and the stearic acid surface-modified
3Physical mixture one endothermic peak is arranged about 170 ℃, an exothermic peak is arranged about 220 ℃, illustrate that drug crystal forms does not change, the two only is physical mixed; Solid dispersion has only been located an exothermic peak at 370 ℃, and the characteristic peak of crude drug all disappears, illustrates that tripterine may exist with amorphous form in the solid dispersion, and is dispersed in the nanometer CaCO after the stearic acid surface-modified
3In.
X-ray powder diffraction (XRD) is analyzed:
Get the nanometer CaCO after tripterine, the stearic acid surface-modified
3, the nanometer CaCO after tripterine and the stearic acid surface-modified
3The physical mixture of (1: 8), tripterine slow-release solid dispersion are carried out respectively the X-ray powder diffraction analysis in right amount.Test condition is Cu target (40kV, 40mV), and step-scan is 0.01 °/step, and sweep limits is 5 °～70 °, and scanning speed is 4 ° of min
-1Record respectively the X-ray powder diffraction curve of sample, see accompanying drawing 5.The result shows: the tripterine crude drug then has a plurality of strong crystalline characteristics diffraction maximums in 5 °～40 ° scopes; Nanometer CaCO after the stearic acid surface-modified
3In 20 °～70 ° scopes a plurality of characteristic diffraction peaks are arranged, tripterine still has the crystal diffraction peak to exist in the spectral line of physical mixture, and strength reduction illustrates that medicine still is present in the physical mixture with crystal form; And in the spectral line of solid dispersion, the tripterine characteristic peak almost disappears, and the nanometer CaCO of tripterine after stearic acid surface-modified is described
3In the carrier with the noncrystalline state high degree of dispersion in carrier.
Infrared spectrum (FTIR) is analyzed:
Get the nanometer CaCO after tripterine, the stearic acid surface-modified
3, the nanometer CaCO after tripterine and the stearic acid surface-modified
3The physical mixture of (1: 8), tripterine slow-release solid dispersion in right amount respectively with KBr after mixing film-making under the dry environment, in 4000～400cm-1 scope, carry out infrared spectrum measurement.Obtain accompanying drawing 6.Characteristic peak by the visible tripterine crude drug of figure A is 3319.43,2940.32,1700.78 and 1220.92
-1Cm
-1Characteristic peak in the physical mixture is the nanometer CaCO after tripterine and the stearic acid surface-modified
3The simple superposition at peak, the characteristic peak strength reduction of crude drug, the nanometer CaCO after the stearic acid surface-modified
3Covered to a certain extent its functional group peak; The peak shape of solid dispersion and physical mixture is basic identical, has no new absworption peak, and the nanometer CaCO after tripterine and the stearic acid surface-modified is described
3Between only be physisorption, mutual chemical action does not occur.
Embodiment 2
Press the nanometer CaCO after tripterine and the stearic acid surface-modified
3Mass ratio is 1: 2,1: 4,1: 6,1: 10, takes by weighing the nanometer CaCO after tripterine crude drug and the stearic acid surface-modified
3, prepare respectively the tripterine slow-release solid dispersion of different drug loading.Preparation method is as follows: take by weighing tripterine an amount of, add anhydrous alcohol solution, take by weighing the nanometer CaCO after the stearic acid surface-modified
3, add in the Radix Tripterygii Wilfordii alcoholic solution, abundant mixing, under 40 ℃ of reduced pressure, the rotary evaporation desolventizing, drying is ground, and crosses 80 mesh sieves, and get final product.
By " the slurry method mensuration of 2010 editions two regulations of Chinese pharmacopoeia takes by weighing above-mentioned solid dispersion or the tripterine raw material is an amount of, places the aqueous solution that contains an amount of tween 80 of 900mL, and rotating speed is 50rmin
-1Medium temperature is (37.0 ± 0.5) ℃, respectively at 0.5,1,2,3,4,6,8,10, the 12h time point regularly pipettes 5mL solution, mend simultaneously with equal-volume equitemperature release medium, 0.45 μ m filtering with microporous membrane, precision measures 10 μ L, in the injection liquid chromatography, the record peak area, calculation sample concentration draws the cumulative release degree of corresponding time point medicine.The results are shown in Table 3.
The vitro release of table 3 tripterine slow-release solid dispersion
Claims (5)
1. tripterine slow-release solid dispersion is characterized in that: contain the nanometer CaCO after tripterine and the stearic acid surface-modified
3
2. tripterine slow-release solid dispersion according to claim 1 is characterized in that: the nanometer CaCO after tripterine and the stearic acid surface-modified
3Mass ratio be 1: 2～1: 10.
3. the nanometer CaCO after the stearic acid surface-modified according to claim 1
3, its preparation process is as follows:
With nanometer CaCO
3Be scattered in the water, heating is then at nanometer CaCO
3The stearic acid that adds melting in the dispersion liquid reacts, filtered while hot after reaction finishes, and washing leaching cake is dried filter cake, grind, sieve, and namely gets the nanometer CaCO after the stearic acid surface-modified
3
4. tripterine slow-release solid dispersion according to claim 1, its preparation process is as follows:
Tripterine is dissolved in the solvent, then adds the nanometer CaCO after the stearic acid surface-modified
3, mix homogeneously, desolventizing, drying namely gets tripterine slow-release solid dispersion.
5. the solvent of dissolving tripterine according to claim 4, it is in dehydrated alcohol, aquiferous ethanol, the ethyl acetate one or more.
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|---|---|---|---|
| CN 201210461883 CN102940608A (en) | 2012-11-16 | 2012-11-16 | Tripterine controlled-release solid dispersion |
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|---|---|---|---|
| CN 201210461883 CN102940608A (en) | 2012-11-16 | 2012-11-16 | Tripterine controlled-release solid dispersion |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019531325A (en) * | 2016-10-21 | 2019-10-31 | オムヤ インターナショナル アーゲー | Use of surface-reacted calcium carbonate to prepare supersaturated aqueous systems |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019531325A (en) * | 2016-10-21 | 2019-10-31 | オムヤ インターナショナル アーゲー | Use of surface-reacted calcium carbonate to prepare supersaturated aqueous systems |
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|---|---|---|---|
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| PB01 | Publication | ||
| DD01 | Delivery of document by public notice |
Addressee: Suzhou Haijinsha Biological Technology Co., Ltd. Document name: Notification of Passing Preliminary Examination of the Application for Invention |
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| DD01 | Delivery of document by public notice |
Addressee: Suzhou Haijinsha Biological Technology Co., Ltd. Document name: Notification of Publication of the Application for Invention |
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| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130227 |