CN102871950B - A kind of ursolic acid solid dispersion and preparation method thereof - Google Patents
A kind of ursolic acid solid dispersion and preparation method thereof Download PDFInfo
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- CN102871950B CN102871950B CN201110199273.XA CN201110199273A CN102871950B CN 102871950 B CN102871950 B CN 102871950B CN 201110199273 A CN201110199273 A CN 201110199273A CN 102871950 B CN102871950 B CN 102871950B
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- ursolic acid
- organic solvent
- solid dispersion
- hypromellose
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- 229940096998 ursolic acid Drugs 0.000 title claims abstract description 65
- 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 65
- 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 62
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 54
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 24
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 24
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 24
- 229960003943 hypromellose Drugs 0.000 claims abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 25
- 239000012467 final product Substances 0.000 claims description 23
- 238000001291 vacuum drying Methods 0.000 claims description 23
- 239000012876 carrier material Substances 0.000 abstract description 18
- -1 polyoxyethylene Polymers 0.000 abstract description 10
- 229920000036 polyvinylpyrrolidone Polymers 0.000 abstract description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 abstract description 6
- 239000004925 Acrylic resin Substances 0.000 abstract description 4
- 229920001503 Glucan Polymers 0.000 abstract description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 abstract description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 abstract description 4
- 229950010118 cellacefate Drugs 0.000 abstract description 4
- 150000002148 esters Chemical class 0.000 abstract description 4
- 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 abstract 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 abstract description 4
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 abstract description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 abstract description 4
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 abstract description 2
- 150000003675 ursolic acids Chemical class 0.000 abstract 2
- 229920003136 Eudragit® L polymer Polymers 0.000 abstract 1
- 239000008118 PEG 6000 Substances 0.000 abstract 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 24
- 239000003814 drug Substances 0.000 description 24
- 229940079593 drug Drugs 0.000 description 16
- 238000004090 dissolution Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 9
- 239000012530 fluid Substances 0.000 description 7
- 230000000968 intestinal effect Effects 0.000 description 7
- 239000006069 physical mixture Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000002671 adjuvant Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 229920003135 Eudragit® L 100-55 Polymers 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 2
- 239000012982 microporous membrane Substances 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 238000005063 solubilization Methods 0.000 description 2
- 230000007928 solubilization Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 244000178870 Lavandula angustifolia Species 0.000 description 1
- 235000010663 Lavandula angustifolia Nutrition 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 240000005049 Prunus salicina Species 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 235000021028 berry Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000002443 hepatoprotective effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 235000009018 li Nutrition 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000005477 standard model Effects 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000002220 ursolic acid group Chemical group 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of ursolic acid solid dispersion and preparation method thereof.This ursolic acid solid dispersion formula contains ursolic acid and carrier material, described ursolic acid and carrier material mass ratio are 1: 2 ~ 1: 20, described carrier material is PEG6000, polyvidone k29/33, hypromellose E5, polyvinyl alcohol, F68, GELUCIRE? 50/13, polyacrylic resin EPO, Eudragit L? 100-55, polyvidone-vinyl alcohol, hypromellose AS-HG, hypromellose AS-LG, hypromellose AS-MG, low-substituted hydroxypropyl methylcellulose, HP-55, cellacefate, glucosan, polyoxyethylene, one or more in polyoxyethylene stearic acid ester and polyvinyl acetate phthalate.This preparation method comprises step: be dissolved in organic solvent by formula by ursolic acid and carrier material, and removing organic solvent, pulverizes.This ursolic acid solid dispersion dissolubility is good, has higher bioavailability.
Description
Technical field
The present invention relates to a kind of ursolic acid solid dispersion and preparation method thereof.
Background technology
Ursolic acid (ursolicacid, UA) has another name called maloic acid, ursolic acid, belongs to pentacyclic triterpene carboxylic acid.It is extensively present in each kind of plant, 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 pharmacologically active widely, as anticancer, antiulcer, antiinflammatory, antibacterial, antiviral, hepatoprotective, lipidemia, the various biological such as antioxidation and sedation effect, these physiological roles make it in cancer, especially hepatocarcinoma, fatty liver, in disease treatment, or even is all widely used in Cosmetic Market.
The molecular weight of ursolic acid is 456.7, belong to micromolecular compound, rod-like crystal is shown as under microscope, dissolubility in water is only 3 μ g/mL, it is the compound that dissolubility is low, permeability is low, thus it belongs to one of four compounds of having a headache the most in Biopharmaceutics Classification system (BCS classification), and ursolic acid also has outside significantly absorption problems such as arranging, bioavailability is low.For this compounds, the key affecting drug bioavailability is the dissolubility of medicine, is therefore necessary to adopt pharmaceutics means to improve the dissolubility of medicine.Improve drug solubility in prior art to mainly contain and prepare solid dispersion, liposome, nanoparticle, microsphere, micropore etc. by method such as application solubilizing agent, cosolvent, cosolvent, enclose, change drug crystal forms etc.At present, known ursolic acid preparation mainly contains fat milk injection (as CN1771968A), microsphere (as CN1857273A), clathrate (as CN1893937A), lyophilized injectable powder (as CN1231209C, etc., but the bioavailability of these known ursolic acid preparations is still not ideal enough CN1243538C).This present situation is urgently to be resolved hurrily.
Summary of the invention
Technical problem to be solved by this invention be overcome the poorly water-soluble of ursolic acid in ursolic acid in prior art and pharmaceutical preparation not of the same race thereof, bioavailability is low, actual needs cannot be met, and routine to prepare the supplementary product kind that solid dispersal agent formulation needs relate to numerous, and preparation technology's also defect such as comparatively complicated, provide a kind of dissolubility good, there is ursolic acid solid dispersion of higher bioavailability and preparation method thereof.
Ursolic acid solid dispersion formula 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, low-substituted hydroxypropyl methylcellulose, HP-55, cellacefate, glucosan, polyoxyethylene, one or more in polyoxyethylene stearic acid ester and polyvinyl acetate phthalate.
In the present invention, described ursolic acid is the ursolic acid described in the routine of this area, and commercially or according to this area traditional extraction obtain, its structural formula is such as formula shown in I.
Formula I
In the present invention, the concrete material appellation that described carrier material relates to and model all with the pharmaceutical arts appellation that uses of routine and standard model corresponding consistent, all commercially.Described carrier material is preferably polyethylene glycol 6000, polyvidone k29/33, hypromellose E5, one or more in F68 and Gelucire 44/14 50/13.
In the present invention, described ursolic acid and carrier material mass ratio are preferably 1: 5 ~ 1: 20, and better is 1: 15.
Ursolic acid solid dispersion formula of the present invention is preferably made up of ursolic acid and carrier material, and the kind of described ursolic acid and carrier material mass ratio and described carrier material all as previously mentioned.
Other additives various that ursolic acid solid dispersion of the present invention can also be added containing this area routine and other active component, as long as it does not have antagonism or not appreciable impact ursolic acid solid dispersion effect of the present invention.
Ursolic acid solid dispersion of the present invention preferably also can according to making other dosage forms as tablet, capsule, granule in the usual manner of this area, drop pill, the forms such as powder are easy to use.
The invention still further relates to the preparation method of above-mentioned ursolic acid solid dispersion, it comprises the following steps: by described formula, is dissolved in organic solvent, removes organic solvent afterwards, pulverize ursolic acid and carrier material.
In the present invention, described organic solvent is the smaller organic solvent being easy to volatilization and concentrating of a class toxicity of the solubilized raw material that this area routine uses, and is preferably one or more in ethanol, dichloromethane, oxolane, dioxane and dimethyl acetylamide.
In the present invention, described organic solvent and the consumption of carrier material are that this area routine is used, preferably for volume mass ratio is 1: 5mL/mg ~ 1: 50mL/mg.
In the present invention, the mode of described dissolving is that this area is conventional, and general stirring or ultrasonic dissolution are preferably ultrasonic dissolution.
In the present invention, the mode of described removing organic solvent is that this area is conventional, and general boulton process, traditional vacuum concentration method or fluid-bed drying are preferably traditional vacuum concentration method.
Wherein, the operating condition of described traditional vacuum concentration method is that this area is conventional, is preferably temperature control 30 DEG C ~ 80 DEG C, concentration time 2h ~ 12h.
In the present invention, preferably also dry by this area usual manner after described removing organic solvent.Described drying is preferably in 25 DEG C ~ 50 DEG C vacuum drying 12h ~ 24h.
In the present invention, described pulverizing is that this area is conventional, preferably after pulverizing, crosses 10 order ~ 200 mesh sieves.
Agents useful for same of the present invention and raw material except specified otherwise all commercially.
On the basis meeting this area general knowledge, each technical characteristic optimum condition above-mentioned in the present invention combination in any can 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 far away higher than the dissolubility 2 ~ 20 times of crude drug in simulated intestinal fluid, accumulation stripping percent also improves a lot, In Vitro Dissolution is all right, has important practical significance and wide market prospect.
Accompanying drawing explanation
Fig. 1 is the solid dispersion of embodiment 1 ~ 5 and the dissolubility picture of comparative example 1,7 sample.
Fig. 2 is the solid dispersion of embodiment 1 ~ 5 and the In Vitro Dissolution curve chart of comparative example 1 sample.
Fig. 3 is the solid dispersion of embodiment 6 ~ 10 and the dissolubility picture of comparative example 1 sample.
Fig. 4 is the solid dispersion of embodiment 6 ~ 10 and the In Vitro Dissolution curve chart of comparative example 1 sample.
Fig. 5 is the XRD figure of effect example 5 solid dispersion.
Detailed description of the invention
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.
The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.
" room temperature " described in embodiment refers to the temperature of carrying out the operation room tested, and is generally 5 ~ 30 DEG C.
The following raw material sources of the present invention in:
Polyvidone-K29/32 is purchased from POVIDONEUSP company, hypromellose E5 is purchased from BiddleSawyerCorp-Distributor company, polyvinyl alcohol, F68, Gelucire 44/14 44/14, Gelucire 44/14 50/13, polyvidone-vinyl alcohol, Soluplus available from BASF, polyacrylic resin EPO, Eudragit L 100-55 is purchased from Degussa company, hypromellose, hypromellose p55, hypromellose AS-HG, hypromellose-AS-MG, hypromellose-AS-LG, low-substituted hydroxypropyl methylcellulose is purchased from BiddleSawyerCorp-Distributor company, HP-55, cellacefate, polyoxyethylene, polyoxyethylene stearic acid ester, polyvinyl acetate phthalate is purchased from Fluka company, glucosan available from BASF.
Embodiment 1
Get 10g ursolic acid and 150g polyethylene glycol 6000, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent temperature control scope to be 30 DEG C, concentration time is 2h, takes out, the organic solvent that 12h removing is residual is placed in 25 DEG C of vacuum drying ovens, take out, pulverized 10 order ~ 200 mesh sieves, and to obtain final product.
Embodiment 2
Get 10g ursolic acid and 150g polyvidone k29/33, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent, temperature control scope is 40 DEG C, concentration time is 3h, take out, in 30 DEG C of vacuum drying ovens, place the organic solvent that 14h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 3
Get 10g ursolic acid and 150g hypromellose E5, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent, temperature control scope is 50 DEG C, concentration time is 12h, take out, in 50 DEG C of vacuum drying ovens, place the organic solvent that 16h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 4
Get 10g ursolic acid and 150g F68, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent, temperature control scope is 40 DEG C, concentration time is 4h, take out, in 40 DEG C of vacuum drying ovens, place the organic solvent that 18h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 5
Get 10g ursolic acid and 150g Gelucire 44/14 50/13, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent, temperature control scope is 40 DEG C, concentration time is 5h, take out, in 40 DEG C of vacuum drying ovens, place the organic solvent that 22h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 6
Get 10g ursolic acid and 20g F68, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent, temperature control scope is 40 DEG C, concentration time is 4h, take out, in 50 DEG C of vacuum drying ovens, place the organic solvent that 16h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 7
Get 10g ursolic acid and 50g F68, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent, temperature control scope is 60 DEG C, concentration time is 5h, take out, in 25 DEG C of vacuum drying ovens, place the organic solvent that 24h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 8
Get 10g ursolic acid and 100g F68, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent, temperature control scope is 80 DEG C, concentration time is 6h, take out, in 45 DEG C of vacuum drying ovens, place the organic solvent that 16h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 9
Get 10g ursolic acid and 150g F68, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent, temperature control scope is 70 DEG C, concentration time is 7h, take out, in 25 DEG C of vacuum drying ovens, place the organic solvent that 15h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 10
Get 10g ursolic acid and 200g F68, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent, temperature control scope is 45 DEG C, concentration time is 8h, take out, in 50 DEG C of vacuum drying ovens, place the organic solvent that 10h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 11
Get 10g ursolic acid and 150g polyvinyl alcohol, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent, temperature control scope is 45 DEG C, concentration time is 8h, take out, in 50 DEG C of vacuum drying ovens, place the organic solvent that 10h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 12
Get 10g ursolic acid and 150g polyacrylic resin EPO, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent, temperature control scope is 45 DEG C, concentration time is 8h, take out, in 50 DEG C of vacuum drying ovens, place the organic solvent that 10h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 13
Get 10g ursolic acid and 150g Eudragit L 100-55, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent, temperature control scope is 45 DEG C, concentration time is 8h, take out, in 50 DEG C of vacuum drying ovens, place the organic solvent that 10h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 14
Get 10g ursolic acid and 150g F68, put in 10L bottle, add that 4L dichloromethane is ultrasonic makes dissolving, adopt GeneVac traditional vacuum removing organic solvent, temperature control scope is 60 DEG C, concentration time is 8h, take out, in 25 DEG C of vacuum drying ovens, place the organic solvent that 16h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 15
Get 10g ursolic acid and 150g F68, put in 10L bottle, add that 4L oxolane is ultrasonic makes dissolving, adopt GeneVac traditional vacuum removing organic solvent, temperature control scope is 70 DEG C, concentration time is 11h, take out, in 25 DEG C of vacuum drying ovens, place the organic solvent that 18h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 16
Get 10g ursolic acid and 150g F68, put in 10L bottle, add that 4L dioxane is ultrasonic makes dissolving, adopt GeneVac traditional vacuum removing organic solvent, temperature control scope is 80 DEG C, concentration time is 12h, take out, in 25 DEG C of vacuum drying ovens, place the organic solvent that 20h removing is residual, take out, pulverized 10 order ~ 200 mesh sieves, to obtain final product.
Embodiment 17 ~ 27
Embodiment 17 ~ 27 except carrier material replaces with respectively following listed by: 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, wherein, embodiment 18 organic solvent used is ethanol and dimethyl acetylamide, and other all operate with embodiment 1.
Comparative example 1
Get 10g ursolic acid, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum removing organic solvent, temperature control scope is 50 DEG C, and concentration time is 9h, takes out, and places the organic solvent that 14h removing is residual in 25 DEG C of vacuum drying ovens, take out, pulverize, to obtain final product.
Comparative example 2
Get 10g ursolic acid and 150g F68, put in mortar and grind, mix homogeneously, to obtain final product.
Comparative example 3
Get 10g ursolic acid and 150g sodium carboxymethyl cellulose, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum removing organic solvent, temperature control scope is 50 DEG C, concentration time is 9h, take out, in 25 DEG C of vacuum drying ovens, place the organic solvent that 14h removing is residual, take out, pulverize, to obtain final product.The solid dispersion dissolubility obtained is poor.
Comparative example 4
Get 10g ursolic acid and 150g methylcellulose, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum removing organic solvent, temperature control scope is 50 DEG C, concentration time is 9h, take out, in 25 DEG C of vacuum drying ovens, place the organic solvent that 14h removing is residual, take out, pulverize, to obtain final product.The solid dispersion dissolubility obtained is poor.
Comparative example 5
Get 10g ursolic acid and 150g ethyl cellulose, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum removing organic solvent, temperature control scope is 50 DEG C, concentration time is 9h, take out, in 25 DEG C of vacuum drying ovens, place the organic solvent that 14h removing is residual, take out, pulverize, to obtain final product.The solid dispersion dissolubility obtained is poor.
Comparative example 6
By mass ratio be 1: 1 ursolic acid and polyethylene glycol 6000 prepare dispersion, but dispersion effect is very poor, cannot detect further.
Comparative example 7
Get 10g ursolic acid and 150g Gelucire 44/14 44/14 is put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent, temperature control scope is 40 DEG C, and concentration time is 5h, takes out, the organic solvent that 20h removing is residual is placed in 25 DEG C of vacuum drying ovens, take out, pulverized 10 order ~ 200 mesh sieves, and to obtain final product.
Effect example 1
Drug solubility test determination method: Example 1 ~ embodiment 5 and comparative example 1, comparative example 7 prepare sample, precision weighing, be placed in 2ml bottle, (Chinese Pharmacopoeia annex version in 2005 two is shown in configuration to solubilization matchmaker simulated intestinal fluid, annex XA-72 page), ultrasonic 15s ~ 60s, is placed on shaking table and rotates 16h ~ 20h.Take off sample, 0.45 μm of 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: ZorbaxBonus-RP (3.5 μm, 4.6 × 75mm), SN:USTM002175; Flow velocity: 1.0 (mL/min); Column temperature: 25 DEG C; Sample size: 5 μ L.
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 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, comparatively 69 μ g/ml of crude drug (comparative example 1), Gelucire 44/14 44/14 is 66 μ g/ml of carrier material (comparative example 7) and the physical mixture (comparative example 2 of crude drug and adjuvant, physical mixture is powder body, cannot dissolution be measured) 65 ~ 73 μ g/ml be significantly increased.
Effect example 2
Dissolution in vitro test determination method: Example 1 ~ 5 and comparative example 1 prepare sample, measure dissolution, medium is simulated intestinal fluid, solvent volume 20ml, dissolving device are constant water bath box rotating speed 100rpm, temperature 37 ± 0.5 DEG C, sample time 0.25h, 1h, 2h.
Result as shown in Figure 2, show the solid dispersion that medicine of the present invention and different carriers are made, wherein carrier polyethylene glycol 6000, 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%, comparatively 8% of crude drug (comparative example 1) be significantly increased.
Effect example 3
Drug solubility test determination method: Example 6 ~ 10 and comparative example 1 prepare sample, precision weighing, be placed in 2ml bottle, solubilization matchmaker simulated intestinal fluid, ultrasonic 15 ~ 60 seconds, be placed on shaking table and rotate 16 ~ 20h.Take off sample, 0.45 μm of 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: ZorbaxBonus-RP (3.5 μm, 4.6 × 75mm), SN:USTM002175; Flow velocity: 1.0 (mL/min); Column temperature: 25 DEG C; Sample size: 5 μ L.
Result as shown in Figure 3, show the solid dispersion that medicine is made with identical adjuvant different ratio, drug solubility is 250 ~ 450 μ g/ml, wherein 5 kinds of proportionings 1: 2, 1: 5, 1: 10, 1: 15, the dissolubility that 1: 20 solid dispersion made 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, compared with the 69 μ g/ml (comparative example 1) of crude drug and the physical mixture (comparative example 2 of crude drug and adjuvant, physical mixture is that powder body cannot measure dissolution) dissolubility 65 ~ 73 μ g/ml be significantly increased.
Effect example 4
Dissolution in vitro test determination method: Example 6 ~ 10 and comparative example 1 prepare sample, measure dissolution, medium is simulated intestinal fluid, solvent volume 20ml, dissolving device are constant water bath box rotating speed 100rpm, temperature 37 ± 0.5 DEG C, sample time 0.25h, 1h, 2h.
Result as shown in Figure 4, show the solid dispersion that medicine is made with identical adjuvant different ratio, wherein 5 kinds of proportionings 1: 2,1: 5,1: 10, the accumulation stripping percent that 1: 15,1: 20 solid dispersion made records is respectively 20.50 ± 3.52%, 25.15 ± 3.23%, 32.92 ± 3.67%, 41.06 ± 4.48%, 28.68 ± 3.72%, comparatively crude drug (comparative example 1) 8% is significantly increased.
Effect example 5
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 (comparative example 2) of F68 (1: 15), d, ursolic acid: the solid dispersion (embodiment 4) of F68 (1: 15).
Experiment condition: x-ray powder diffraction instrument; Model: D8ADVANCE; X-ray source: CuK (λ=1.54056Angstrom); Running voltage: 40Kv, operating amperage: 40mA, detector: PSD, scanning angle: 4deg. ~ 40deg, step value: 0.05deg./step, scanning speed: 1sec/step.
X-ray diffraction result as shown in Figure 5, show that the physical mixture of ursolic acid crude drug and crude drug and various carrier is in 2 θ=5.2 °, all there is strong diffraction maximum at 10.5 ° of places, wherein, in the physical mixture of c ursolic acid and F68, the amount of adjuvant F68 is much larger than the amount of raw material, the X-ray diffraction result of F68 to a certain degree masks the diffraction maximum of raw material, thus its diffraction maximum is less, but still can find out, and after the present invention makes solid dispersion, the crystal diffraction peak of medicine disappears completely, it can thus be appreciated that, drug main will be highly dispersed in carrier material with noncrystalline state.
Claims (1)
1. a ursolic acid solid dispersion, it is prepared by the following method: get 10g ursolic acid and 150g hypromellose E5, put in 10L bottle, add 4L EtOH Sonicate and make dissolving, adopt GeneVac traditional vacuum method removing organic solvent, temperature control scope is 50 DEG C, and concentration time is 12h, takes out, the organic solvent that 16h removing is residual is placed in 50 DEG C of vacuum drying ovens, take out, pulverized 10 order ~ 200 mesh sieves, and to obtain final product.
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