CN100435791C - Solid bicyclic alcohol dispersion - Google Patents
Solid bicyclic alcohol dispersion Download PDFInfo
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- CN100435791C CN100435791C CNB2003101018907A CN200310101890A CN100435791C CN 100435791 C CN100435791 C CN 100435791C CN B2003101018907 A CNB2003101018907 A CN B2003101018907A CN 200310101890 A CN200310101890 A CN 200310101890A CN 100435791 C CN100435791 C CN 100435791C
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- bicyclol
- solid dispersion
- medicine
- pvp
- physical mixture
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title abstract description 7
- 239000006185 dispersion Substances 0.000 title abstract 4
- 125000002619 bicyclic group Chemical group 0.000 title abstract 3
- 239000007787 solid Substances 0.000 title 1
- 239000007962 solid dispersion Substances 0.000 claims abstract description 118
- 239000000463 material Substances 0.000 claims abstract description 20
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000008118 PEG 6000 Substances 0.000 claims abstract description 7
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 claims abstract description 7
- KXMTXZACPVCDMH-UHFFFAOYSA-N methyl 4-[5-(hydroxymethyl)-7-methoxy-1,3-benzodioxol-4-yl]-7-methoxy-1,3-benzodioxole-5-carboxylate Chemical compound COC(=O)C1=CC(OC)=C2OCOC2=C1C1=C2OCOC2=C(OC)C=C1CO KXMTXZACPVCDMH-UHFFFAOYSA-N 0.000 claims description 183
- 229920001223 polyethylene glycol Polymers 0.000 claims description 52
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 24
- 229920001983 poloxamer Polymers 0.000 claims description 24
- 229960000502 poloxamer Drugs 0.000 claims description 24
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 230000003285 pharmacodynamic effect Effects 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
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- 239000001267 polyvinylpyrrolidone Substances 0.000 claims 1
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- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 20
- 229920001993 poloxamer 188 Polymers 0.000 description 20
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 3
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- 239000004380 Cholic acid Substances 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 108010078233 Thymalfasin Proteins 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 2
- 235000019416 cholic acid Nutrition 0.000 description 2
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- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 2
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
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- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 2
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- LTTQKYMNTNISSZ-MWTRTKDXSA-N (2S)-(-)-kurarinone Chemical compound C1([C@H]2OC=3C(C[C@@H](CC=C(C)C)C(C)=C)=C(O)C=C(C=3C(=O)C2)OC)=CC=C(O)C=C1O LTTQKYMNTNISSZ-MWTRTKDXSA-N 0.000 description 1
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- KDADHLPROOOPIC-UHFFFAOYSA-N neokurarinol Natural products COc1cc(O)ccc1C1CC(=O)c2c(OC)cc(O)c(CC(CCC(C)(C)O)C(C)=C)c2O1 KDADHLPROOOPIC-UHFFFAOYSA-N 0.000 description 1
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- LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CO)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](CCC(O)=O)C(O)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 description 1
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Abstract
The present invention discloses bicyclic alcohol, a macromolecular material PEG6000, a PVP and a Poloxemer 188 carrier. A melting method is adopted for processing the dispersion bodies of the PEG 6000 and the Poloxemer 188, and a solvent method is adopted for processing the dispersion body of the PVP; solid dispersion bodies are prepared, and a physical mixture is prepared by a direct medicine and carrier mixing method. The X-powder diffraction, the differential thermal analysis and the measurement of the dissolvability and the dissolution speed rate are carried out on the prepared sample, the improvement functions of a medicine dispersion state and solid dispersion technology on the medicine water solubility and the medicine dissolution speed rate are investigated. The promotional functions of the solid dispersion body technology on the absorption inside a body of the bicyclic alcohol and the correlativity of the inside of the body and the outside of the body are studied and discovered outside the body.
Description
Technical field
The present invention relates to solid dispersion, it comprises bicyclol and hydrophilic material.Particularly relate to the solid dispersion of bicyclol and carriers such as macromolecular material PEG6000, PVP and Poloxemer188, and contain this solid dispersion and pharmacodynamics on the pharmaceutical composition of acceptable carrier.
Background technology
Viral hepatitis is higher at China's sickness rate, is one of commonly encountered diseases of serious harm people ' s health.According to seroepidemiological survey, it is 80.9% that hepatitis A virus infects prevalence rate, and hepatitis b virus infected prevalence rate reaches 57.6%, and hepatitis B surface antigen (HBsAg) positive rate is 9.75%, the infection with hepatitis C virus rate is 3.2%, and fourth type and hepatitis E also have popular.Viral hepatitis except that hepatitis C, mostly is self-limited disease in acute phase, and especially first type and hepatitis E can spontaneous recoverys.But B-mode, third type and hepatitis D can develop into chronic hepatitis, and the course of disease through 10-20 has about 20% will develop into liver cirrhosis approximately, and 1-5% is transformed into hepatocarcinoma.There are 3,000 ten thousand chronic hepatitis patients to flow socially at present approximately.Because hepatitis B can be by mother-to-baby transmission, influence is of future generation, so very harmful.In addition, though the not high case fatality rate of hepatitis gravis incidence rate is high.Therefore, the treatment of chronic viral hepatitis is a significant problem anxious to be solved.
It is a lot of to be used for the treatment of chronic hepatitis pharmacopoeia class at present both at home and abroad, concludes and gets up can be divided into four big classes: (1) hepatitis virus resisting medicine, as interferon and lamivudine; (2) immunomodulator is as thymosin (Zadaxin), specific immune ribonucleic acid and transfer factor; (3) improve the liver function medicine, as bifendate, glycyrrhizin; (4) Chinese herbal medicine is as kurarinone, anti-hepatic fibrosis Chinese medicine compound " 861 ".Said medicine respectively has certain curative effect, and its certain problem is also all respectively arranged.
Interferon and lamivudine (Lamivudin) are present internationally recognized hepatitis virus resisting medicines.The effective percentage that the acute hepatitis C of interferon therapy is turned out cloudy viral HCV-RNA can reach about 60%, the effective percentage for the treatment of chronic third type and hepatitis B is about 30%, but relapse rate height after the drug withdrawal, rate of side effects is more heavier, and cost an arm and a leg, the long term injections administration is used inconvenient.Lamivudine is a nucleoside medicine, be DNA polymerase inhibitor, the treatment chronic hepatitis B in the time of 1 year the HBV-DNA negative conversion rate can reach 80%, but the HBeAg negative conversion rate is only about 20-30%, and very fast recurrence after the drug withdrawal, the sudden change of long-term prescription hepatitis B virus appearance point produces drug resistance, annual incidence rate about 20% increases progressively, as to treat 2 years virus variation rates be about 40%.It is Zadaxin that immunomodulator is used more, be used in mostly can not the application of interference extract for treating patient, or as drug combination, treatment chronic hepatitis B HBeAg negative conversion rate is about 20-30%.The definite curative effect of this type of Drug therapy hepatitis is still waiting more checking, and price is also quite expensive.Bifendate be early eighties China formulate on the medicine Fructus Schisandrae Chinensis basis under study for action successfully improve the liver function new drug, it is remarkable that the ALT effect is fallen in chronic hepatitis B, low price, side reaction is few.The problem that exists is a rebound rate height after the drug withdrawal, though find that hepatitis B virus duplication is also had certain inhibition effect, lacks polycentric clinical verification, and in addition, bifendate does not have patent protection, and is therefore nocompetitive in the world.It is reported, many Chinese medicine compound and Chinese herbal and crude drugs preparations have certain curative effect to chronic hepatitis B, what wherein have has a hepatitis virus resisting effect on animal model, the certain curative effect of having turned out cloudy to HBeAg is also observed in the clinical practice that has, but mostly through the double blinding of clinical multicenter strictness, at random, the contrast checking, quality of the pharmaceutical preparations instability.
In a word, at present China has 3,000 ten thousand hepatitis patients to be badly in need of treatment approximately, though treatment chronic hepatitis types of drugs is a lot, can be limited for the medicine that the patient selects, and clinically press for safe, effective, low-cost treatment hepatitis new drug.
Bicyclol is the anti-hepatitis initiative new drug of being developed by Chinese medical courses in general institute medicine; the bicyclol achievement in research protection that patented 14 countries and regions at present; through Beijing, Duo Jia hospital in Shanghai carries out clinical observation on the therapeutic effect to 500 many cases chronic viral hepatitis Bs, hepatitis C patient; show that this medicine not only can reduce serum glutamic pyruvic transminase and glutamic oxaloacetic transaminase, GOT; and has an effect that certain inhibition hepatovirus duplicates; do not find apparent side effect, its resultant effect obviously is better than bifendate.2001.10 bicyclol crude drug and conventional tablet thereof are produced by National Drug Administration's approval.
Because bicyclol poorly water-soluble in the prior art, its conventional tablet dissolution rate in vitro is slower, when being dissolution medium with the distilled water, only can stripping 60%-70% in two hours, in the treatment clinical course, the oral artifact availability of patient is lower, shows comparatively significant individual variation, is unfavorable for the performance of its curative effect.
Summary of the invention
In order to overcome the problem that exists in the bicyclol preparation in the prior art, the object of the present invention is to provide a kind of bicyclol solid dispersion.
Another object of the present invention is to also provide the preparation method of bicyclol solid dispersion.
A further object of the present invention is to provide the medical composition and its use that contains this bicyclol solid dispersion.
In order to realize purpose of the present invention, the present invention adopts following technical scheme.
The present invention has put down in writing a kind of solid dispersion, and this solid dispersion comprises bicyclol and hydrophilic material.Described hydrophilic material comprises hydrophilic high molecular material, cyclodextrin derivative, organic acid.Described hydrophilic high molecular material comprises PEG4000, PEG6000 or PEG8000, PVP, Poloxemer188.Described organic acid comprises citric acid, succinic acid, cholic acid, lecithin, deoxycholic acid.The mass content of hydrophilic material is 30%-95%.Be preferably and be 66%-91%.
In addition, the present invention also puts down in writing a kind of pharmaceutical composition, and it contains acceptable carrier on above-mentioned solid dispersion of the present invention and the pharmacodynamics.
In other words, the invention provides a kind of solid dispersion, this solid dispersion comprises the medicine bicyclol with slightly solubility, is dispersed in and makes solid dispersion in the hydrophilic carrier.
Described hydrophilic material comprises hydrophilic high molecular material, cyclodextrin derivative, organic acid.
Described hydrophilic high molecular material, preferably Polyethylene Glycol (this paper is called for short PEG) comprises PEG4000, PEG6000 or PEG8000, polyethylene pyrrolidone (this paper is called for short PVP), poloxamer (this paper is called for short Poloxemer188).
Described organic acid comprises citric acid, succinic acid, cholic acid, lecithin, deoxycholic acid.
The preferred macromolecular material that uses, preferred PEG4000, PEG6000, PEG8000, PVP, Poloxemer188 in the macromolecular material.
According to the present invention, the mass content of described hydrophilic material is 30%-95%, and preferred content is 66%-91%.
According to the preparation method that the invention still further relates to the bicyclol solid dispersion, it comprises solvent method, melting method, polishing.
(1) solvent method.Its step comprises: macromolecular material is dissolved in the solvent of certain volume, preferred organic is a dehydrated alcohol, adds bicyclol again, and heating is dissolved bicyclol fully.Rotary evaporation removes and desolvates vacuum drying under reduced pressure then.Crushing screening obtains the bicyclol solid dispersion.
(2) melting method.Its step comprises: get hydrophilic material, preferred PEG8000, Poloxemer188 are heated to complete fusion in 70～80 ℃, add bicyclol, stir evenly, and continue to be heated to complete fusion, cooling curing rapidly, and crushing screening obtains the bicyclol solid dispersion.
The preparation method of bicyclol solid dispersion also comprises other preparation method, for example polishing etc.
The solid dispersion of the bicyclol by the present invention preparation is compared with solid dispersion of the prior art, and the state of existence is improved, and has lot of advantages on drug absorption.
X-powder diffraction measurement result shows: bicyclol still exists with crystal form in the PVP physical mixture, has then formed coprecipitate in solid dispersion, exists with amorphous state; In PEG physical mixture and solid dispersion, all exist with microcrystalline form, formed simple eutectic mixture; In Poloxamer188 physical mixture and solid dispersion, all exist with microcrystalline form, formed simple eutectic mixture.
DSC result shows: exist with crystal state in the physical mixture that bicyclol and PVP form, and variation has taken place its state in solid dispersion, the result is consistent with the X-diffraction pattern.The physical mixture of bicyclol and PEG and solid dispersion have all formed simple low mixture, and medicine exists with microcrystalline form, there is no bicyclol melting peak in both DSC curves.According to the position difference of endothermic peak in bicyclol and PEG physical mixture and the solid dispersion DSC curve, infer that the crystallite dispersity of medicine in solid dispersion is better than physical mixture.A peak all only appears in the DSC curve of each ratio solid dispersion of bicyclol and Poloxamer188, and is low than Poloxamer188 fusing point peak about 54 ℃, and the fusing point peak of bicyclol disappears; An endothermic peak also only appears in the DSC curve of each ratio physical mixture of bicyclol and Poloxamer188, about 57 ℃, matches with the fusing point peak of carrier, and bicyclol fusing point peak disappears.According to the position difference of endothermic peak in bicyclol and Poloxamer188 physical mixture and the solid dispersion DSC curve, infer that the crystallite dispersity of medicine in solid dispersion is better than physical mixture.
The solubility test experimental result shows: compare with the former powder of bicyclol, the physical mixture of employing direct mixing method preparation does not have obvious improvement effect to the dissolubility of medicine, and the solid dispersion of three kinds of carriers of melting method or solvent method preparation all can significantly improve the dissolubility of medicine, and along with the increase of carrier ratio, dissolubility has the trend that increases gradually.Three kinds of carriers are compared, and increase the drug solubility best results with the PVP solid dispersion.
The dissolution rate measurement result shows: compare with 100 order bicyclols, the physical mixture of various preparing carriers does not improve significantly to the dissolving out capability of medicine, and solid dispersion all can significantly be accelerated the dissolution rate of medicine, and along with the increase of carrier ratio, the dissolution rate of medicine is accelerated.Each carrier is compared, and is the fastest with PVP solid dispersion dissolution rate, shows that there is the stripping that more helps medicine in bicyclol with amorphous state.
Further the body giving drugs into nose of bicyclol solid dispersion and bicyclol raw material shows for the kinetics comparative result, compares with the former powder of bicyclol, and degree of absorption significantly improves in bicyclol/PVP (1: 2) solid dispersion mice body, does not have significant change and eliminate rule.After medicine was made solid dispersion, Cmax was about 4 times of the former powder of bicyclol, and AUC is about 4.9 times, and relative bioavailability is 490%.Result of study and dissolution rate in vitro measurement result dependency are good in the body.
The insoluble drug bicyclol exists with amorphous state or microcrystalline form in solid dispersion, compares with the former powder of bicyclol, and its dissolution rate in vitro obviously improves, and bioavailability significantly improves.
The present invention also provides a kind of pharmaceutical composition, and it contains acceptable carrier or adjuvant on solid dispersion of the present invention and other pharmacodynamicss.Described pharmaceutical composition comprises drop pill, tablet, capsule, granule.The solid dispersion that bicyclol and hydrophilic carrier form can be made into drop pill, or makes efficient oral formulations such as tablet, capsule, granule with other mixed with excipients, is used for the clinical efficacy of chronic hepatitis better.
Description of drawings
Fig. 1 is the X-powder diagram, is followed successively by a, b, c, d from bottom to top, (a) bicyclol wherein, (b) PVP, (c) bicyclol/PVP, (1: 2) physical mixture, (d) bicyclol 1/PVP (1: 2) solid dispersion.
Fig. 2 is the X-powder diagram, is followed successively by a, b, c, d from top to bottom, (a) bicyclol wherein, (b) PEG, (c) bicyclol/PEG (1: 10) physical mixture, (d) bicyclol/PVP (1: 10) solid dispersion.
Fig. 3 is the X-powder diagram, is followed successively by a, b, c, d from top to bottom, (a) bicyclol wherein, (b) Poloxamer188, (c) bicyclol/Poloxamer188 (1: 10) physical mixture, (d) bicyclol/Poloxamer (1: 10) solid dispersion.
Fig. 4 is the DSC curve chart, is followed successively by a, b, c, d, e, f, g, h, I, j from top to bottom, wherein:
(a) bicyclol (b) PVP
(c) bicyclol/PVP (1: 2) physical mixture (d) bicyclol/PVP (1: 4) physical mixture
(e) bicyclol/PVP (1: 6) physical mixture (f) bicyclol/PVP (1: 8) physical mixture
(g) bicyclol/PVP (1: 2) solid dispersion (h) bicyclol/PVP (1: 4) solid dispersion
(i) bicyclol/PVP (1: 6) solid dispersion (j) bicyclol/PVP (1: 8) solid dispersion.
Fig. 5 is the .DSC curve chart, is followed successively by a, b, c, d, e, f, g, h, I, j from top to bottom, wherein:
(a) bicyclol (b) PEG
(c) bicyclol/PEG (1: 4) physical mixture (d) bicyclol/PEG (1: 6) physical mixture
(e) bicyclol/PEG (1: 8) physical mixture (f) bicyclol/PEG (1: 10) physical mixture
(g) bicyclol/PEG (1: 4) solid dispersion (h) bicyclol/PEG (1: 6) solid dispersion
(i) bicyclol/PEG (1: 8) solid dispersion (j) bicyclol/PEG (1: 10) solid dispersion
Fig. 6 is the DSC curve chart, is followed successively by a, b, c, d, e, f, g, h, i, j. from top to bottom
(a) bicyclol (b) Poloxamer
(c) bicyclol/Poloxamer (1: 4) physical mixture (d) bicyclol/Poloxamer (1: 6) physical mixture
(e) bicyclol/Poloxamer (1: 8) physical mixture (f) bicyclol/Poloxamer (1: 10) physical mixture
(g) bicyclol/Poloxamer (1: 4) solid dispersion (h) bicyclol/Poloxamer (1: 6) solid dispersion
(i) bicyclol/Poloxamer (1: 8) solid dispersion (j) bicyclol/Poloxamer (1: 10) solid dispersion.
Fig. 7 is bicyclol/PVP solid dispersion and physical mixture curve chart when molten, and wherein Fig. 7 A is bicyclol/PVP solid dispersion s, and Fig. 7 B is bicyclol/PVP physical mixture.
Fig. 8 is bicyclol/PEG solid dispersion and physical mixture curve chart when molten, and wherein Fig. 8 A is bicyclol/PEG solid dispersion, and Fig. 8 B is bicyclol/PEG physical mixture.
Fig. 9 is bicyclol/Poloxamer188 solid dispersion and physical mixture curve chart when molten, and wherein Fig. 9 A is bicyclol/Poloxamer solid dispersion s, and Fig. 9 B is bicyclol/Poloxamer physical mixture s.
Curve chart when Figure 10 is the former powder of bicyclol (100 mesh sieve) with bicyclol/PVP solid dispersion mice medicine.
The specific embodiment
The present invention is further illustrated for following examples.But the present invention is not limited to these embodiment.
Embodiment 1: bicyclol/PVP solid dispersion preparation
Medicine and carrier rate of charge:According to the form below is carried out.
Table 1 medicine/PVP solid dispersion rate of charge
| Tested number | 1 | 2 | 3 | 4 | |
| Medicine: PVP | 1∶2 | 1∶4 | 1∶6 | 1∶8 | |
| Medicine throwing amount | 2g | 2g | 2g | 2g | |
| PVP throwing amount | | 8g | 12g | 16 |
Preparation method:The preparation of employing solvent method.Press table 1 inventory, take by weighing PVP and be dissolved in the dehydrated alcohol of certain volume, add bicyclol, 50 ℃ of heating make dissolving fully.Rotary evaporation places vacuum drying oven, 40 ℃ of dried overnight except that desolvating under 50 ℃ of reduced pressure then.Take out next day, pulverized 60 mesh sieves, gets four groups of bicyclol/PVP solid dispersion.
Embodiment 2: bicyclol/PVP physical mixture preparation
Medicine and carrier rate of charge:According to the form below is carried out.
Table 2 medicine/PVP physical mixture rate of charge
| Tested number | 1 | 2 | 3 | 4 |
| Medicine: PVP | 1∶2 | 1∶4 | 1∶6 | 1∶8 |
| Medicine throwing amount | 2g | 2g | 2g | 2g |
| PVP throwing amount | | 8g | 12g | 16 |
Preparation method:Straight by the mixing method preparation.PVP and bicyclol are crossed 80 mesh sieves respectively, feed intake by table 2 proportioning, the mixing of sieving promptly gets four groups of bicyclols/PVP physical mixture.
Embodiment 3: bicyclol/PEG solid dispersion preparation
Medicine and carrier rate of charge:According to the form below is carried out.
Table 3 medicine/PEG solid dispersion rate of charge
| Tested number | 1 | 2 | 3 | 4 |
| Medicine: PEG | 1∶4 | 1∶6 | 1∶8 | 1∶10 |
| Medicine throwing amount | 2g | 2g | 2g | 2g |
| PEG throwing amount | 8g | 12g | 16g | 20g |
Preparation method:The preparation of employing melting method.Press table 3 inventory, take by weighing PEG8000, be heated to complete fusion in 70 ~ 80 ℃, add bicyclol, stir evenly, continue to be heated to complete fusion, put into the ice-water bath cooling curing rapidly, pulverized 60 mesh sieves, promptly get four groups of bicyclols/PEG solid dispersion.
Embodiment 4: bicyclol/PVP physical mixture preparation
Medicine and carrier rate of charge:According to the form below is carried out.
Table 4 medicine/PEG physical mixture rate of charge
| Tested number | 1 | 2 | 3 | 4 |
| Medicine: PEG | 1∶4 | 1∶6 | 1∶8 | 1∶10 |
| Medicine throwing amount | 2g | 2g | 2g | 2g |
| PEG throwing amount | 8g | 12g | 16g | 20g |
Preparation method:Straight by the mixing method preparation.Get PEG8000 and bicyclol, cross 80 mesh sieves respectively, feed intake by table 4 proportioning, the mixing of sieving promptly gets four groups of bicyclols/PEG physical mixture.
Embodiment 5: bicyclol/Poloxemer188 solid dispersion preparation
Medicine and carrier rate of charge:According to the form below is carried out.
Table 5 medicine/Poloxemer188 solid dispersion rate of charge
| Tested number | 1 | 2 | 3 | 4 |
| Medicine: Poloxemer188 | 1∶4 | 1∶6 | 1∶8 | 1∶10 |
| Medicine throwing amount | 2g | 2g | 2g | 2g |
| Poloxemer188 throwing amount | 8g | 12g | 16g | 20g |
Preparation method:The preparation of employing melting method.Press table 5 inventory, take by weighing Poloxemer188, be heated to complete fusion in 70 ~ 80 ℃, add bicyclol, stir evenly, continue to be heated to complete fusion, put into the ice-water bath cooling curing rapidly, pulverized 60 mesh sieves, promptly get four groups of bicyclols/Poloxemer188 solid dispersion.
Embodiment 6: bicyclol/Po1oxemer188 physical mixture preparation
Medicine and carrier rate of charge:According to the form below is carried out.
Table 6 medicine/Poloxemer188 physical mixture rate of charge
| Tested number | 1 | 2 | 3 | 4 |
| Medicine: Poloxemer188 | 1∶4 | 1∶6 | 1∶8 | 1∶10 |
| Medicine throwing amount | 2g | 2g | 2g | 2g |
| Poloxemer188 throwing amount | 8g | 12g | 16g | 20g |
Preparation method:Straight by the mixing method preparation.Get Poloxemer188 and bicyclol, cross 80 mesh sieves respectively, feed intake by table 6 proportioning, the mixing of sieving promptly gets four groups of bicyclols/Poloxemer188 physical mixture.
Embodiment 7:X-powder diffraction measurement result
● bicyclol/PVP:
Laboratory sample: (a) bicyclol crude drug, (b) PVP, (c) bicyclol/PVP (1: 2) solid dispersion among bicyclol/PVP (1: 2) physical mixture (d) embodiment 2 among the embodiment 1
X-ray result:
Bicyclol, bicyclol raw material have been located strong diffraction maximum at 10.06 °, 13.22 °, 17.54 °, 18.54 °, 23.36 °, 23.52 °, 24.12 ° and 24.90 °, and the PVP carrier has been located two wide diffraction maximums at 11.76 ° and 19.98 °; All bicyclol diffraction maximums have appearred in bicyclol/PVP (1: 2) physical mixture, and bicyclol/PVP (1: 2) solid dispersion only locates to occur two wide diffraction maximums at 12.44 ° and 21.30 °, and the diffraction maximum of bicyclol itself all disappears.Show that medicine still exists with crystal form in the PVP physical mixture, in solid dispersion, then formed coprecipitate, exist with amorphous state.
The X-powder diagram is seen accompanying drawing 1.
● bicyclol/PEG:
Laboratory sample:
(a) bicyclol/PVP (1: 10) solid dispersion among bicyclol/PEG (1: 10) physical mixture (d) embodiment 4 among bicyclol (b) PEG (c) embodiment 3.
X-ray result:
Bicyclol, bicyclol raw material have been located strong diffraction maximum at 10.06 °, 13.22 °, 17.54 °, 18.54 °, 23.36 °, 23.52 °, 24.12 ° and 24.90 °, the PEG carrier has been located strong diffraction maximum at 19.28 °, 23.16 ° and 23.40 °, and does not have diffraction maximum between 15.30 ° ~ 19.00 °; Bicyclol/PEG (1: 10) physical mixture and solid dispersion all go out the strong diffraction maximum of expression vector, simultaneously 17.50 °, 18.50 ° and 24.10 ° of diffraction maximums of locating to occur bicyclol, show that medicine is in PEG physical mixture and solid dispersion, all exist, formed simple eutectic mixture with microcrystalline form.The X-powder diagram is seen accompanying drawing 2.
● bicyclol/Poloxamer188:
(a) bicyclol (b) Poloxamer188 (c) bicyclol/Poloxamer188
(1: 10) physical mixture (d) bicyclol/Poloxamer (1: 10) solid dispersion.
X-ray result:
Bicyclol, bicyclol raw material have been located strong diffraction maximum at 10.06 °, 13.22 °, 17.54 °, 18.54 °, 23.36 °, 23.52 °, 24.12 ° and 24.90 °, the Poloxamer188 carrier has been located strong diffraction maximum at 19.08 °, 23.20 ° and 23.42 °, and does not have diffraction maximum between 15.30 ° ~ 19.00 °; Bicyclol/Poloxamer188 (1: 10) physical mixture and solid dispersion all go out outside the strong diffraction maximum of expression vector, simultaneously 17.48 °, 18.48 ° and 24.10 ° of diffraction maximums of locating to occur bicyclol, illustrate that medicine is in Poloxamer188 physical mixture and solid dispersion, all exist, formed simple eutectic mixture with microcrystalline form.
The X-powder diagram is seen accompanying drawing 3.
Embodiment 8:DSC measurement result
● bicyclol/PVP:
Laboratory sample:
(a) bicyclol (b) PVP
(c) bicyclol/PVP (1: 2) physical mixture (d) bicyclol/PVP (1: 4) physical mixture
(e) bicyclol/PVP (1: 6) physical mixture (f) bicyclol/PVP (1: 8) physical mixture
(g) bicyclol/PVP (1: 2) solid dispersion (h) bicyclol/PVP (1: 4) solid dispersion
(i) bicyclol/PVP (1: 6) solid dispersion (j) bicyclol/PVP (1: 8) solid dispersion
DSC result:
Bicyclol DSC curve locates to occur an endothermic peak at 140 ℃, is the fusing point peak of medicine; A wide endothermic peak appears in the DSC curve of PVP between 90 ~ 100 ℃, be the evaporation of water peak; Two endothermic peaks have all appearred in the DSC curve of each ratio physical mixture of bicyclol and PVP, and one is about 90 ℃, is the evaporation of water peak, and one is about 140 ℃, are the fusing point peak of bicyclol; A peak all only appears in the DSC curve of each ratio solid dispersion of bicyclol and PVP, about 90 ℃, is the evaporation of water peak, and the fusing point peak of bicyclol disappears.This explanation: medicine exists with crystal state in the physical mixture that forms with PVP, and variation has taken place its state in solid dispersion, and the result is consistent with the X-diffraction pattern.The DSC curve is seen accompanying drawing 4.
● bicyclol/PEG:
Laboratory sample:
(a) bicyclol (b) PEG
(c) bicyclol/PEG (1: 4) physical mixture (d) bicyclol/PEG (1: 6) physical mixture
(e) bicyclol/PEG (1: 8) physical mixture (f) bicyclol/PEG (1: 10) physical mixture
(g) bicyclol/PEG (1: 4) solid dispersion (h) bicyclol/PEG (1: 6) solid dispersion
(i) bicyclol/PEG (1: 8) solid dispersion (j) bicyclol/PEG (1: 10) solid dispersion
DSC result:
The DSC curve of PEG locates to occur an endothermic peak at 64.1 ℃, is the fusing point peak of PEG; A peak all only appears in the DSC curve of each ratio solid dispersion of bicyclol and PEG, and is low than PEG fusing point peak about 61 ℃, and the fusing point peak of bicyclol disappears; An endothermic peak also appears in the DSC curve of each ratio physical mixture of bicyclol and PEG, about 64.7 ℃, matches with the fusing point peak of carrier, and bicyclol fusing point peak disappears.
According to X-diffraction result, the physical mixture of medicine and PEG and solid dispersion have all formed simple low mixture, and medicine exists with microcrystalline form, therefore, there is no bicyclol melting peak in both DSC curves.According to the position difference of heat absorption Yi in physical mixture and the solid dispersion DSC curve, infer that the crystallite dispersity of medicine in solid dispersion is better than physical mixture.The DSC curve is seen accompanying drawing 5.
● bicyclol/Poloxamer188:
Laboratory sample:
(a) bicyclol (b) Poloxamer
(c) bicyclol/Poloxamer (1: 4) physical mixture (d) bicyclol/Poloxamer (1: 6) physical mixture
(e) bicyclol/Poloxamer (1: 8) physical mixture (f) bicyclol/Poloxamer (1: 10) physical mixture
(g) bicyclol/Poloxamer (1: 4) solid dispersion (h) bicyclol/Poloxamer (1: 6) solid dispersion
(i) bicyclol/Poloxamer (1: 8) solid dispersion (j) bicyclol/Poloxamer (1: 10) solid dispersion
DSC result:
The DSC curve of Poloxamer188 an endothermic peak occurs at 57.5 ℃, is the fusing point peak of Poloxamer188; A peak all only appears in the DSC curve of each ratio solid dispersion of bicyclol and Poloxamer188, and is low than Poloxamer188 fusing point peak about 54 ℃, and the fusing point peak of bicyclol disappears; An endothermic peak also only appears in the DSC curve of each ratio physical mixture of bicyclol and Poloxamer188, about 57 ℃, matches with the fusing point peak of carrier, and bicyclol fusing point peak disappears.The DSC curve is seen accompanying drawing 6.
Embodiment 9: the solubility test result
Get an amount of solid dispersion and physical mixed matter sample respectively in test tube, add the 10ml distilled water and make saturated solution, in 25 ℃ water-bath, placed 24 hours and jolting frequently.With the membrane filtration of 0.45 μ m, get subsequent filtrate is measured each saturated solution with ultraviolet method concentration.Measurement result sees Table 7:
Table 7 solubility test result
Experimental result shows: compare with the former powder of bicyclol, adopt of the dissolubility not improvement effect of the physical mixture of direct mixing method preparation to medicine, and the solid dispersion of three kinds of carriers of melting method or solvent method preparation all can significantly improve the dissolubility of medicine, and along with the increase of carrier ratio, dissolubility has the trend that increases gradually.Three kinds of carriers are compared, and increase the drug solubility best results with the PVP solid dispersion.
Embodiment 10: the dissolution rate measurement result
Get an amount of solid dispersion and physical mixture an amount of (being equivalent to bicyclol 25mg approximately) respectively, wrap in the gauze, drop in the stripping rotor, press the operation of oar method, with distilled water 900ml is solvent, rotating speed is that per minute 100 changes, and operation is taken a sample respectively in different time in accordance with the law, filter, get subsequent filtrate,, measure trap at 279nm wavelength place according to spectrophotography; It is an amount of that precision takes by weighing the bicyclol reference substance in addition, add dissolve with ethanol and make the solution that concentration is 1mg/ml, precision is measured in right amount, the contrast liquid that concentration is about 20 μ g/ml is made in the adding distil water dilution, measuring with method, calculate dissolution, is abscissa with time, the accumulation dissolution is that vertical coordinate is drawn curve chart when molten, and curve chart the results are shown in shown in accompanying drawing 7,8 and 9 when three kinds of carriers were molten.
The result shows that the physical mixture of various preparing carriers does not improve significantly to the dissolving out capability of medicine, and solid dispersion all can significantly be accelerated the dissolution rate of medicine, and along with the increase of carrier ratio, the dissolution rate of medicine is accelerated.Each carrier is compared, and is the fastest with PVP solid dispersion dissolution rate.
According to above-mentioned result of study, preferred bicyclol/PVP (1: 2) solid dispersion carries out absorption test in the body.
Get Kunming mouse, with bicyclol/PVP (1: 2) solid dispersion is trial drug, the former powder of bicyclol (100 mesh sieve) is the reference sample, press 25mg/kg dosage gastric infusion, handle in the different time blood sample collection, measure blood drug level, result's 3P87 software processes according to the HPLC method, calculate pharmacokinetic parameter, the results are shown in Table 8.With blood drug level is vertical coordinate, and curve when the time is abscissa drafting medicine the results are shown in accompanying drawing 10.
Table 8: bicyclol/PVP (1: 2) solid dispersion and bicyclol raw material (processing of 100 mesh sieves) mice body giving drugs into nose compares (n=3) for kinetics
The result shows, compares with the former powder of bicyclol, and degree of absorption significantly improves in bicyclol/PVP (1: 2) solid dispersion mice body, does not have significant change and eliminate rule.After medicine was made solid dispersion, Cmax was about 4 times of the former powder of bicyclol, and AUC is about 4.9 times, and relative bioavailability is 490%.Result of study and dissolution rate in vitro measurement result dependency are good in the body.
Claims (5)
1, a kind of solid dispersion, it is characterized in that: this solid dispersion contains bicyclol and hydrophilic high molecular material, hydrophilic high molecular material is selected from Polyethylene Glycol, polyvinylpyrrolidone, poloxamer, and the mass content of hydrophilic material in solid dispersion is 30%-95%.
2, according to the solid dispersion of claim 1, it is characterized in that: described Polyethylene Glycol is selected from PEG4000, PEG6000 or PEG8000.
3, according to the solid dispersion of claim 1, it is characterized in that: the mass content of hydrophilic material is 66%-91%.
4, a kind of pharmaceutical composition is characterized in that: contain acceptable carrier on the solid dispersion of claim 1 and the pharmacodynamics.
According to the pharmaceutical composition of claim 4, it is characterized in that 5, described pharmaceutical composition comprises drop pill, tablet, capsule, granule.
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| CNB2003101018907A CN100435791C (en) | 2003-10-23 | 2003-10-23 | Solid bicyclic alcohol dispersion |
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| CN100435791C true CN100435791C (en) | 2008-11-26 |
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| CN100364526C (en) * | 2004-08-11 | 2008-01-30 | 中国医学科学院药物研究所 | Application of bicychol in preparation of medicine for preventing and/or treating acute alcoholism and acute/chronic alcoholic liver injury |
| CN101524349B (en) * | 2007-09-20 | 2014-01-15 | 中国医学科学院药物研究所 | Phospholipids compound of bicyclo-ethanol and preparation method thereof |
| CN102091052B (en) * | 2009-12-15 | 2012-11-07 | 北京协和药厂 | Bicyclol double-layer osmotic pump control-released tablet and preparation method thereof |
| CN114073680B (en) * | 2020-08-13 | 2023-08-15 | 北京协和药厂 | Dicyclo alcohol dry suspension |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4868207A (en) * | 1988-07-28 | 1989-09-19 | Taisho Pharmaceutical Co., Ltd. | Bis (methylenedioxy) biphenyl compounds useful for the treatment of liver diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4868207A (en) * | 1988-07-28 | 1989-09-19 | Taisho Pharmaceutical Co., Ltd. | Bis (methylenedioxy) biphenyl compounds useful for the treatment of liver diseases |
Non-Patent Citations (2)
| Title |
|---|
| 尼莫地平固体分散体的制备及体外研究. 吴伟等.中国药学杂志，第33卷第1期. 1998 * |
| 百赛诺. 翁吉敏.中国新药杂志，第10卷第11期. 2001 * |
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