CN102871950A - Ursolic acid solid dispersion and preparation method thereof - Google Patents
Ursolic acid solid dispersion and preparation method thereof Download PDFInfo
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- CN102871950A CN102871950A CN201110199273XA CN201110199273A CN102871950A CN 102871950 A CN102871950 A CN 102871950A CN 201110199273X A CN201110199273X A CN 201110199273XA CN 201110199273 A CN201110199273 A CN 201110199273A CN 102871950 A CN102871950 A CN 102871950A
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- ursolic acid
- organic solvent
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- hypromellose
- carrier material
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- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 0.000 title claims abstract description 70
- 229940096998 ursolic acid Drugs 0.000 title claims abstract description 70
- PLSAJKYPRJGMHO-UHFFFAOYSA-N ursolic acid Natural products CC1CCC2(CCC3(C)C(C=CC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(=O)O PLSAJKYPRJGMHO-UHFFFAOYSA-N 0.000 title claims abstract description 70
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000003960 organic solvent Substances 0.000 claims abstract description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 29
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- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 29
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- 239000012876 carrier material Substances 0.000 claims abstract description 24
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 8
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- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims abstract description 7
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- 229920001503 Glucan Polymers 0.000 claims abstract description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 5
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- 238000000034 method Methods 0.000 claims description 26
- 239000012467 final product Substances 0.000 claims description 24
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- 238000001035 drying Methods 0.000 claims description 5
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical class OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 4
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 claims description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 4
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 3
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 abstract description 2
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an ursolic acid solid dispersion and a preparation method thereof. The formula of the ursolic acid solid dispersion comprises ursolic acid and a carrier material; the mass ratio of the ursolic acid to the carrier material is 1:2 to 1:20; and the carrier material is one or more of PEG6000 (polyethylene glycol 6000), povidone k29/33, hypromellose E5, polyving alcohol, poloxamer 68, GELUCIRE 50/13, polyacrylic resin EPO, polyacrylic resin L 100-55, povidone-vinyl alcohol, hypromellose AS-HG, hypromellose AS-LG, hypromellose AS-MG, low substituted hypromellose, hypromellose phthalate, cellulose acetate phthalate, glucan, polyoxyethylene, polyoxyethylene stearates and polyvinyl acetate phthalate. The preparation method comprises the following steps: dissolving the ursolic acid and the carrier material into an organic solvent according to the formula; removing the organic solvent; and grinding. The ursolic acid solid dispersion has good solubility and has high bioavailability.
Description
Technical field
The present invention relates to a kind of ursolic acid solid dispersion and preparation method thereof.
Background technology
Ursolic acid (ursolic acid, UA) has another name called maloic acid, ursolic acid, belongs to the pentacyclic triterpene carboxylic acid.It extensively is present in each kind of plant, such as Fructus Mali pumilae, Fructus Rubi, berry, Ramulus Sambuci Williamsii, Fructus Piperis, lavandula angustifolia, Herba Menthae, Herba thymi vulgaris, Fructus Crataegi, Japanese plum etc.Ursolic acid has widely pharmacologically active, such as anticancer, antiulcer, antiinflammatory, antibiotic, antiviral, hepatoprotective, lipidemia, the various biological such as antioxidation and sedation effect, these physiological roles make it in cancer, especially hepatocarcinoma, fatty liver in the disease treatment, or even all is widely used in the Cosmetic Market.
The molecular weight of ursolic acid is 456.7, belong to micromolecular compound, microscopically shows as shaft-like crystallization, dissolubility in the water only is 3 μ g/mL, it is the chemical compound that dissolubility is low, permeability is low, thereby it belongs to the most one of four compounds of headache in biopharmaceutics categorizing system (BCS classification), and ursolic acid also has and significantly absorbs the problem such as efflux, bioavailability is low.For this compounds, the key that affects drug bioavailability is the dissolubility of medicine, therefore is necessary to adopt the pharmaceutics means to improve the dissolubility of medicine.The raising drug solubility mainly contains by using the methods such as solubilizing agent, cosolvent, cosolvent, enclose, change drug crystal forms and prepares solid dispersion, liposome, nanoparticle, microsphere, micropore etc. in the prior art.At present, known ursolic acid preparation mainly contains fat milk injection (such as CN1771968A), microsphere (such as CN1857273A), clathrate (such as CN1893937A), lyophilized injectable powder (such as CN1231209C, but the bioavailability of these known ursolic acid preparations is still not ideal enough CN1243538C) etc..This present situation needs to be resolved hurrily.
Summary of the invention
Technical problem to be solved by this invention is that to have overcome poorly water-soluble, the bioavailability of ursolic acid in ursolic acid in the prior art and the pharmaceutical preparation not of the same race thereof low, can't satisfy actual needs, and the supplementary product kind that conventional preparation solid dispersion preparation need to relate to is numerous, and preparation technology is the defective such as comparatively complicated also, provide a kind of dissolubility good, had ursolic acid solid dispersion of higher bioavailability and preparation method thereof.
Ursolic acid solid dispersion prescription of the present invention contains ursolic acid and carrier material, described ursolic acid and carrier material mass ratio are 1: 2～1: 20, described carrier material is Polyethylene Glycol (PEG) 6000, polyvidone k29/33, hypromellose E5, polyvinyl alcohol, F68, Gelucire 44/14 50/13, polyacrylic resin EPO, Eudragit L 100-55, polyvidone-vinyl alcohol, hypromellose AS-HG, hypromellose AS-LG, hypromellose AS-MG, the low-substituted hydroxypropyl methylcellulose, HP-55, cellacefate, glucosan, polyoxyethylene, one or more in polyoxyethylene stearic acid ester and the polyvinyl acetate phthalate ester.
Among the present invention, described ursolic acid is the conventional described ursolic acid in this area, commercially availablely gets or obtains according to conventional extraction the in this area, and its structural formula is suc as formula shown in the I.
Formula I
Among the present invention, the concrete material appellation that described carrier material relates to and model are all corresponding consistent with conventional appellation and the standard model of using in medicament field, all commercially available getting.What described carrier material was better is polyethylene glycol 6000, polyvidone k29/33, hypromellose E5, one or more in F68 and the Gelucire 44/14 50/13.
Among the present invention, what described ursolic acid and carrier material mass ratio were better is 1: 5～1: 20, and better is 1: 15.
Better being comprised of ursolic acid and carrier material of ursolic acid solid dispersion prescription of the present invention, the kind of described ursolic acid and carrier material mass ratio and described carrier material all as previously mentioned.
Ursolic acid solid dispersion of the present invention can also contain conventional various other additives that add in this area and other active component, as long as it does not have antagonism or not appreciable impact ursolic acid solid dispersion of the present invention effect.
What ursolic acid solid dispersion of the present invention was better also can be according to making other dosage forms such as tablet in the usual manner of this area, capsule, granule, drop pill, the convenient use of the forms such as powder.
The invention still further relates to the preparation method of above-mentioned ursolic acid solid dispersion, it may further comprise the steps: by described prescription, ursolic acid and carrier material are dissolved in the organic solvent, remove afterwards organic solvent, pulverizing gets final product.
Among the present invention, described organic solvent is the smaller concentrated organic solvent that volatilizees that is easy to of a class toxicity of the conventional solubilized raw material that uses in this area, one or more that better is in ethanol, dichloromethane, oxolane, dioxane and the dimethyl acetylamide.
Among the present invention, the consumption of described organic solvent and carrier material is that this area routine is used, better for the volume mass ratio be 1: 5mL/mg～1: 50mL/mg.
Among the present invention, the mode of described dissolving is that this area is conventional, generally stir or ultrasonic dissolution all can, better is ultrasonic dissolution.
Among the present invention, described mode of removing organic solvent is that this area is conventional, general boulton process, traditional vacuum concentration method or fluid-bed drying all can, better is the traditional vacuum concentration method.
Wherein, the operating condition of described traditional vacuum concentration method is that this area is conventional, and better is 30 ℃～80 ℃ of temperature controls, concentration time 2h～12h.
Among the present invention, described remove after the organic solvent better also dry by this area usual manner.What described drying was better is in 25 ℃～50 ℃ vacuum drying 12h～24h.
Among the present invention, described pulverizing is that this area is conventional, and better crosses 10 orders～200 mesh sieves for after pulverizing.
Agents useful for same of the present invention and raw material equal commercially available getting except specified otherwise.
On the basis that meets this area general knowledge, each above-mentioned among the present invention technical characterictic optimum condition can combination in any obtain preferred embodiments.
Positive progressive effect of the present invention is: ursolic acid solid dispersion dissolubility of the present invention is large, drug-eluting speed is high, its dissolubility in simulated intestinal fluid is higher than 2～20 times of the dissolubility of crude drug in simulated intestinal fluid far away, accumulation stripping percent also improves a lot, In Vitro Dissolution is all right, has important practical significance and wide market prospect.
Description of drawings
Fig. 1 is the dissolubility picture of the solid dispersion of embodiment 1～5 and Comparative Examples 1,7 samples.
Fig. 2 is the solid dispersion of embodiment 1～5 and the In Vitro Dissolution curve chart of Comparative Examples 1 sample.
Fig. 3 is the solid dispersion of embodiment 6～10 and the dissolubility picture of Comparative Examples 1 sample.
Fig. 4 is the solid dispersion of embodiment 6～10 and the In Vitro Dissolution curve chart of Comparative Examples 1 sample.
Fig. 5 is the XRD figure of effect embodiment 5 solid dispersion.
The specific embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.
The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
" room temperature " described in the embodiment refers to the temperature of the operation room tested, is generally 5～30 ℃.
The following raw material sources of the present invention in:
Polyvidone-K29/32 is available from POVIDONE USP company, hypromellose E5 is available from Biddle Sawyer Corp-Distributor company, polyvinyl alcohol, F68, Gelucire 44/14 44/14, Gelucire 44/14 50/13, polyvidone-vinyl alcohol, Soluplus is available from BASF AG, polyacrylic resin EPO, Eudragit L 100-55 is available from Degussa company, hypromellose, hypromellose p55, hypromellose AS-HG, hypromellose-AS-MG, hypromellose-AS-LG, the low-substituted hydroxypropyl methylcellulose is available from Biddle Sawyer Corp-Distributor company, HP-55, cellacefate, polyoxyethylene, polyoxyethylene stearic acid ester, the polyvinyl acetate phthalate ester is available from Fluka company, and glucosan is available from BASF AG.
Get 10g ursolic acid and 150g polyethylene glycol 6000, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopting Gene Vac traditional vacuum method to remove organic solvent temperature control scope is 30 ℃, and concentration time is 2h, takes out, in 25 ℃ of vacuum drying ovens, place 12h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Get 10g ursolic acid and 150g polyvidone k29/33, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum method to remove organic solvent, the temperature control scope is 40 ℃, concentration time is 3h, take out, in 30 ℃ of vacuum drying ovens, place 14h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Embodiment 3
Get 10g ursolic acid and 150g hypromellose E5, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum method to remove organic solvent, the temperature control scope is 50 ℃, concentration time is 12h, take out, in 50 ℃ of vacuum drying ovens, place 16h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Embodiment 4
Get 10g ursolic acid and 150g F68, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum method to remove organic solvent, the temperature control scope is 40 ℃, concentration time is 4h, take out, in 40 ℃ of vacuum drying ovens, place 18h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Get 10g ursolic acid and 150g Gelucire 44/14 50/13, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum method to remove organic solvent, the temperature control scope is 40 ℃, concentration time is 5h, take out, in 40 ℃ of vacuum drying ovens, place 22h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Embodiment 6
Get 10g ursolic acid and 20g F68, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum method to remove organic solvent, the temperature control scope is 40 ℃, concentration time is 4h, take out, in 50 ℃ of vacuum drying ovens, place 16h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Embodiment 7
Get 10g ursolic acid and 50g F68, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum method to remove organic solvent, the temperature control scope is 60 ℃, concentration time is 5h, take out, in 25 ℃ of vacuum drying ovens, place 24h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Embodiment 8
Get 10g ursolic acid and 100g F68, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum method to remove organic solvent, the temperature control scope is 80 ℃, concentration time is 6h, take out, in 45 ℃ of vacuum drying ovens, place 16h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Embodiment 9
Get 10g ursolic acid and 150g F68, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum method to remove organic solvent, the temperature control scope is 70 ℃, concentration time is 7h, take out, in 25 ℃ of vacuum drying ovens, place 15h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Get 10g ursolic acid and 200g F68, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum method to remove organic solvent, the temperature control scope is 45 ℃, concentration time is 8h, take out, in 50 ℃ of vacuum drying ovens, place 10h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Embodiment 11
Get 10g ursolic acid and 150g polyvinyl alcohol, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum method to remove organic solvent, the temperature control scope is 45 ℃, concentration time is 8h, take out, in 50 ℃ of vacuum drying ovens, place 10h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Embodiment 12
Get 10g ursolic acid and 150g polyacrylic resin EPO, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum method to remove organic solvent, the temperature control scope is 45 ℃, concentration time is 8h, take out, in 50 ℃ of vacuum drying ovens, place 10h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Embodiment 13
Get 10g ursolic acid and 150g Eudragit L 100-55, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum method to remove organic solvent, the temperature control scope is 45 ℃, concentration time is 8h, take out, in 50 ℃ of vacuum drying ovens, place 10h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Embodiment 14
Get 10g ursolic acid and 150g F68, put in the 10L bottle, add that the 4L dichloromethane is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum to remove organic solvent, the temperature control scope is 60 ℃, concentration time is 8h, take out, in 25 ℃ of vacuum drying ovens, place 16h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Get 10g ursolic acid and 150g F68, put in the 10L bottle, add that the 4L oxolane is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum to remove organic solvent, the temperature control scope is 70 ℃, concentration time is 11h, take out, in 25 ℃ of vacuum drying ovens, place 18h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Embodiment 16
Get 10g ursolic acid and 150g F68, put in the 10L bottle, add that the 4L dioxane is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum to remove organic solvent, the temperature control scope is 80 ℃, concentration time is 12h, take out, in 25 ℃ of vacuum drying ovens, place 20h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Embodiment 17～27
Embodiment 17～27 replaces with respectively following listed except carrier material: polyvidone-vinyl alcohol, hypromellose AS-HG, hypromellose AS-LG, hypromellose AS-MG, low-substituted hydroxypropyl methylcellulose, HP-55, cellacefate, glucosan, polyoxyethylene, polyoxyethylene stearic acid ester and polyvinyl acetate phthalate ester, wherein, embodiment 18 used organic solvents are ethanol and dimethyl acetylamide, and other are all with embodiment 1 operation.
Comparative Examples 1
Get the 10g ursolic acid, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum to remove organic solvent, the temperature control scope is 50 ℃, and concentration time is 9h, takes out, and places 14h and remove residual organic solvent in 25 ℃ of vacuum drying ovens, take out, pulverize, and get final product.
Comparative Examples 2
Get 10g ursolic acid and 150g F68, put in the mortar and grind, mix homogeneously, and get final product.
Comparative Examples 3
Get 10g ursolic acid and 150g sodium carboxymethyl cellulose, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum to remove organic solvent, the temperature control scope is 50 ℃, concentration time is 9h, take out, in 25 ℃ of vacuum drying ovens, place 14h and remove residual organic solvent, take out, pulverize, and get final product.The solid dispersion dissolubility that obtains is relatively poor.
Comparative Examples 4
Get 10g ursolic acid and 150g methylcellulose, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum to remove organic solvent, the temperature control scope is 50 ℃, concentration time is 9h, take out, in 25 ℃ of vacuum drying ovens, place 14h and remove residual organic solvent, take out, pulverize, and get final product.The solid dispersion dissolubility that obtains is relatively poor.
Comparative Examples 5
Get 10g ursolic acid and 150g ethyl cellulose, put in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum to remove organic solvent, the temperature control scope is 50 ℃, concentration time is 9h, take out, in 25 ℃ of vacuum drying ovens, place 14h and remove residual organic solvent, take out, pulverize, and get final product.The solid dispersion dissolubility that obtains is relatively poor.
Comparative Examples 6
Be that 1: 1 ursolic acid and polyethylene glycol 6000 prepares dispersion with mass ratio, but dispersion effect is very poor, can't further detect.
Comparative Examples 7
Getting 10g ursolic acid and 150g Gelucire 44/14 44/14 puts in the 10L bottle, add that 4L ethanol is ultrasonic to make dissolving, adopt Gene Vac traditional vacuum method to remove organic solvent, the temperature control scope is 40 ℃, and concentration time is 5h, takes out, in 25 ℃ of vacuum drying ovens, place 20h and remove residual organic solvent, take out, pulverized 10 orders～200 mesh sieves, and get final product.
Drug solubility test determination method: get embodiment 1～embodiment 5 and Comparative Examples 1, the preparation sample of Comparative Examples 7, precision weighing, place the 2ml bottle, (two ones of Chinese Pharmacopoeia appendix versions in 2005 are seen in configuration to solubilization matchmaker worker intestinal juice, appendix XA-72 page or leaf), ultrasonic 15s～60s places and rotates 16h～20h on the shaking table.Take off sample, 0.45 μ m filtering with microporous membrane.
Experiment condition: instrument: Agilent 1200, UV-detector, wavelength: 202nm; Mobile phase ratio: 0.1% trifluoroacetic acid water-0.1% trifluoroacetic acid acetonitrile; Chromatographic column: Zorbax Bonus-RP (3.5 μ m, 4.6 * 75mm), SN:USTM002175; Flow velocity: 1.0 (mL/min); Column temperature: 25 ℃; Sample size: 5 μ L.
The result as shown in Figure 1, show the solid dispersion that medicine of the present invention and different carriers are made, the dissolubility of medicine in the solvent simulated intestinal fluid is 66～500 μ g/ml, wherein said carrier is selected from polyethylene glycol 6000, polyvidone k29/33, hypromellose E5, F68, the dissolubility that the solid dispersion that Gelucire 44/14 50/13 is made records is respectively 148.74 μ g/ml, 592.05 μ g/ml, 666.02 μ g/ml, 681.14 μ g/ml, 204.21 μ g/ml are than 69 μ g/ml of crude drug (Comparative Examples 1), Gelucire 44/14 44/14 is the physical mixture (Comparative Examples 2 of 66 μ g/ml and crude drug and the adjuvant of carrier material (Comparative Examples 7), physical mixture is powder body, can't measure dissolution) 65～73 μ g/ml be significantly increased.
Dissolution in vitro test determination method: the preparation sample of getting embodiment 1～5 and Comparative Examples 1, measure dissolution, medium is that simulated intestinal fluid, solvent volume 20ml, dissolving device are 37 ± 0.5 ℃ of constant water bath box rotating speed 100rpm, temperature, sample time 0.25h, 1h, 2h.
The result as shown in Figure 2, show the solid dispersion that medicine of the present invention and different carriers are made, carrier polyethylene glycol 6000 wherein, polyvidone k29/33, hypromellose E5, F68, Gelucire 44/14 44/14, the accumulation stripping percent that the solid dispersion that Gelucire 44/14 50/13 is made records is respectively 15.12 ± 4.84%, 24.08 ± 3.78%, 18.14 ± 5.08%, 43.20 ± 3.08%, 13.01 ± 4.85%, 18.37 ± 4.37%, be significantly increased than 8% of crude drug (Comparative Examples 1).
Effect embodiment 3
Drug solubility test determination method: get the preparation sample of embodiment 6～10 and Comparative Examples 1, precision weighing places the 2ml bottle, and solubilization matchmaker worker intestinal juice ultrasonic 15～60 seconds, places and rotates 16～20h on the shaking table.Take off sample, 0.45 μ m filtering with microporous membrane.
Experiment condition: instrument: Agilent 1200, UV-detector, wavelength: 202nm; Mobile phase ratio: 0.1% trifluoroacetic acid water-0.1% trifluoroacetic acid acetonitrile; Chromatographic column: Zorbax Bonus-RP (3.5 μ m, 4.6 * 75mm), SN:USTM002175; Flow velocity: 1.0 (mL/min); Column temperature: 25 ℃; Sample size: 5 μ L.
The result as shown in Figure 3, show the solid dispersion that the different proportionings from identical adjuvant of medicine are made, drug solubility is 250～450 μ g/ml, wherein 5 kinds of proportionings are 1: 2,1: 5,1: 10,1: 15, the dissolubility that the solid dispersion of making at 1: 20 records is respectively 263.39 μ g/ml, 337.63 μ g/ml, 391.81 μ g/ml, 473.76 μ g/ml, 452.62 μ g/ml is significantly increased than dissolubility 65～73 μ g/ml of the 69 μ g/ml (Comparative Examples 1) of crude drug and the physical mixture of crude drug and adjuvant (Comparative Examples 2, physical mixture are that powder body can't be measured dissolution).
Effect embodiment 4
Dissolution in vitro test determination method: the preparation sample of getting embodiment 6～10 and Comparative Examples 1, measure dissolution, medium is that simulated intestinal fluid, solvent volume 20ml, dissolving device are 37 ± 0.5 ℃ of constant water bath box rotating speed 100rpm, temperature, sample time 0.25h, 1h, 2h.
The result as shown in Figure 4, show the solid dispersion that the different proportionings from identical adjuvant of medicine are made, wherein 5 kinds of proportionings are 1: 2,1: 5,1: 10,1: 15, the accumulation stripping percent that the solid dispersion of making at 1: 20 records was respectively 20.50 ± 3.52%, 25.15 ± 3.23%, 32.92 ± 3.67%, 41.06 ± 4.48%, 28.68 ± 3.72%, be significantly increased than crude drug (Comparative Examples 1) 8%.
Adopt X-ray diffraction (XRD), prepared all kinds of solid dispersion are investigated; Wherein a, ursolic acid, b, F68, c, ursolic acid: the physical mixture of F68 (1: 15) (Comparative Examples 2), d, ursolic acid: the solid dispersion of F68 (1: 15) (embodiment 4).
Experiment condition: x-ray powder diffraction instrument; Model: D8ADVANCE; X-ray source: Cu K (λ=1.54056Angstrom); Running voltage: 40Kv, operating current intensity: 40mA, detector: PSD, scanning angle: 4deg.～40deg, step value: 0.05deg./step, scanning speed: 1sec/step.
The X-ray diffraction result as shown in Figure 5, the physical mixture that shows ursolic acid crude drug and crude drug and various carriers is in 2 θ=5.2 °, 10.5 ° locate that strong diffraction maximum is all arranged, wherein, the amount of adjuvant F68 is much larger than the amount of raw material in the physical mixture of c ursolic acid and F68, the X-ray diffraction result of F68 has to a certain degree covered the diffraction maximum of raw material, thereby its diffraction maximum is less, but still can find out, and after the present invention makes solid dispersion, the crystal diffraction peak complete obiteration of medicine, hence one can see that, and drug main will be with the noncrystalline state high degree of dispersion in carrier material.
Claims (10)
1. ursolic acid solid dispersion, it is characterized in that: its prescription contains ursolic acid and carrier material, described ursolic acid and carrier material mass ratio are 1: 2～1: 20, described carrier material is polyethylene glycol 6000, polyvidone k29/33, hypromellose E5, polyvinyl alcohol, F68, Gelucire 44/14 50/13, polyacrylic resin EPO, Eudragit L 100-55, polyvidone-vinyl alcohol, hypromellose AS-HG, hypromellose AS-LG, hypromellose AS-MG, the low-substituted hydroxypropyl methylcellulose, HP-55, cellacefate, glucosan, polyoxyethylene, one or more in polyoxyethylene stearic acid ester and the polyvinyl acetate phthalate ester.
2. ursolic acid solid dispersion as claimed in claim 1, it is characterized in that: described ursolic acid and carrier material mass ratio are 1: 5～1: 20, better is 1: 15.
3. the preparation method of ursolic acid solid dispersion as claimed in claim 1 or 2, it is characterized in that: it may further comprise the steps: by described prescription, ursolic acid and carrier material are dissolved in the organic solvent, remove afterwards organic solvent, pulverizing gets final product.
4. preparation method as claimed in claim 3, it is characterized in that: described organic solvent is one or more in ethanol, dichloromethane, oxolane, dioxane and the dimethyl acetylamide.
5. preparation method as claimed in claim 3, it is characterized in that: described organic solvent is that the volume mass ratio is 1 with the consumption of carrier material: 5mL/mg～1: 50mL/mg.
6. preparation method as claimed in claim 3 is characterized in that: the mode of described dissolving is for stirring or ultrasonic dissolution.
7. preparation method as claimed in claim 3, it is characterized in that: described mode of removing organic solvent is boulton process, traditional vacuum concentration method or fluid-bed drying.
8. preparation method as claimed in claim 3, it is characterized in that: the operating condition of described traditional vacuum concentration method is 30 ℃～80 ℃ of temperature controls, concentration time 2h～12h.
9. preparation method as claimed in claim 3 is characterized in that: described pulverizing is crossed 10 orders～200 mesh sieves for after pulverizing.
10. preparation method as claimed in claim 3 is characterized in that: describedly also carry out drying after removing organic solvent; Described drying is in 25 ℃～50 ℃ vacuum drying 12h～24h.
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| JP2016505029A (en) * | 2013-01-22 | 2016-02-18 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | Pharmaceutical composition having improved bioavailability |
| US9427427B2 (en) | 2013-01-22 | 2016-08-30 | Hoffmann-La Roche Inc. | Pharmaceutical composition with improved bioavailability |
| WO2014114575A1 (en) * | 2013-01-22 | 2014-07-31 | F. Hoffmann-La Roche Ag | Pharmaceutical composition with improved bioavailability |
| US10034854B2 (en) | 2013-01-22 | 2018-07-31 | Hoffman-La Roche Inc. | Pharmaceutical composition with improved bioavailability |
| CN103204895A (en) * | 2013-04-08 | 2013-07-17 | 南昌大学 | Method for separating ursolic acid from apple peel |
| CN103204895B (en) * | 2013-04-08 | 2015-08-12 | 南昌大学 | A kind of method of separating ursolic acid from Pericarpium Mali pumilae |
| CN106109418A (en) * | 2016-07-01 | 2016-11-16 | 佳木斯大学 | Ursolic acid solid dispersion and preparation method thereof |
| CN106265683A (en) * | 2016-09-14 | 2017-01-04 | 江南大学 | A kind of preparation method with the pathogenic bacterium biomembrane new inhibitor wearing film targeting characteristic |
| WO2020108495A1 (en) * | 2018-11-30 | 2020-06-04 | 浙江立恩生物科技有限公司 | Beta-glucan solid dispersion and preparation method therefor |
| CN109673736A (en) * | 2019-01-23 | 2019-04-26 | 浙江大学 | A kind of preparation method of ellagic acid-PVP food fresh keeping solid dispersions |
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