CN1311823C - Indirubin phosphatide compound and its preparation method - Google Patents
Indirubin phosphatide compound and its preparation method Download PDFInfo
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- CN1311823C CN1311823C CNB2004100658008A CN200410065800A CN1311823C CN 1311823 C CN1311823 C CN 1311823C CN B2004100658008 A CNB2004100658008 A CN B2004100658008A CN 200410065800 A CN200410065800 A CN 200410065800A CN 1311823 C CN1311823 C CN 1311823C
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Abstract
The present invention relates to indirubin phosphatide compound and a preparation method thereof. The indirubin phosphatide compound is composed of indirubin and phosphatide. The molar ratio of the indirubin to the phosphatide is 1 to (1 to 15). The lipotropy of the indirubin phosphatide compound is higher than that of the parent medicine. The indirubin phosphatide compound of the present invention has high stability, is remarkably better than parent medicine in the aspects of absorption degree, effective speed, duration, etc., and can be made into various oral medicine.
Description
Technical field
The present invention relates to indirubin phosphatide compound and preparation method capable of being industrialized thereof, comprise pharmaceutical composition that contains indirubin phosphatide compound and preparation method thereof.
Background technology
Indirubin is the bisindole chemical compound that extracts from the Chinese medicine Indigo Naturalis, and chemical constituent is 2,2 '-Lian Ya indole-3,3 '-diketone, molecular formula C
16H
10N
2O
2, molecular weight 262.26, water insoluble for the aubergine crystal, at CHCl
3Etc. solvable in many organic solvents, but dissolubility is very little, and mp353.0 ℃, UV290nm.Indirubin is the antitumor effective ingredient of Indigo Naturalis, it can suppress the synthetic and proteinic translation process of DNA of chronic myeloid leukemia cell and transplanted tumor cell and the biosynthesis of Profilin matter, thereby the normal growth of anticancer does not have obvious inhibitory action to bone marrow.The slow grain of indirubin conventional tablet treatment remission rate 59.87%, effective percentage 87.26%, the curative effect of just controlling the patient is better than controlling again the patient, has good clinical application prospect.The indirubin curative effect is clear and definite, but own water solublity and fat-soluble all relatively poor, produce effects is slower during the oral administration administration, and oral absorption is incomplete, there is the medicine of 40%-50% to get rid of with Excreta, and bigger to the intravital the intestines and stomach stimulation of people, after patient takes medicine, gastrointestinal upset, vomiting easily take place, part patient will cause stomachache, diarrhoea, even gastrointestinal symptom such as have blood in stool, in clinical practice in order to improve its oral administration biaavailability, reduce dosage, be necessary further to improve the indirubin oral absorption.
Phospholipid is prevalent in the protoplasm and biomembrane of animal and plant cells, and the homergy of biomembranous physiologically active and body is had important regulatory function.Phospholipid is the lipid material of phosphorous acid group, belongs to the native element organic compound, its existing surface activity, and biologically active is a special surfactant again.Phospholipid molecule has a hydrophilic head and two hydrophobic long-chains, its structural formula as shown in the formula:
R wherein, R
1Be the saturated or unsaturated aliphatic carboxylic acid of C14-C20, and R
2Be choline, ethanolamine, serine etc.
Oxygen atom in the hydroxyl on the phosphorus atoms has the stronger tendency that gets electronics, and nitrogen-atoms has stronger betatopic tendency, so phospholipid can generate complex with the ingredient of some ad hoc structure under certain condition.The chemical constitution that research at present can form stable compound with phospholipid and can effectively improve parent drug biological characteristics and pharmacologically active has: the organic acid chemical compound, as salicylic acid, Arylacetic acids; Albumen, polypeptide class; Metal ion; And the saponin of Chinese medicine, flavones ingredient.The phosphatide complexes that forms can be used
1Spectrographic technique such as H-NMR and IR or DSC method prove (Bombardelli E, Patri G.Complexes of glycyrrhetinic acid with phospholipids and pharmaceutical and cosmeticcompositions containing then[P] .US Patent:5 147 859,1988-07-17; Wu Jianmei etc., research " Chinese Pharmaceutical Journal " the 36th the 3rd phase of volume of March calendar year 2001 of baicalin phosphatide complexes physicochemical property).The formation of complex is subjected to the influence of many-sided factor, as the quality of phospholipid, character, medium and the process conditions etc. of medicine, because the medicine of different structure all has different with proportion relation, solvent, response time and temperature that phospholipid carries out compound reaction, these factors not only influence the formation of complex, especially influence its stability and biological characteristics and pharmacologically active.
Summary of the invention
The technical problem to be solved in the present invention is the new structure that screening can form pharmaceutically active ingredient in the coming from of stable compound with phospholipid, especially research and develop the phosphatide complexes of the indole dione of effective components of Chinese medicinal, be specially indirubin phosphatide compound and preparation method capable of being industrialized thereof.Comprise that research indole dione class formation such as indirubin form proportion relation, solvent, response time and the temperature of phosphatide complexes, to form indirubin phosphatide compound and to make it stable, improve the dissolubility and the absorption program of indirubin, the action time of onset speed, prolongation indirubin, reduce its untoward reaction such as zest, improving it absorbs in gastrointestinal tract, obtain higher blood drug level and eliminate slower in vivo, the indirubin bioavailability is significantly improved, finally strengthen the pharmacological action and the curative effect of the slow grain of indirubin treatment.
The invention provides following technical scheme for addressing the above problem.
A kind of oral pharmaceutical composition, comprising indirubin and phospholipid with 1: the indirubin phosphatide compound that the 1-15 mol ratio is formed, it preferably includes indirubin and phospholipid with 1: the indirubin phosphatide compound of 8-10 mol ratio composition.Phospholipid is chosen natural phospholipid and/or synthetic phospholipid described in this pharmaceutical composition.Wherein natural phospholipid is selected from soybean phospholipid and/or egg yolk lecithin; Synthetic phospholipid is selected from dipalmitoyl phosphatidyl choline or two palmityl PHOSPHATIDYL ETHANOLAMINE; Also can comprise oral pharmaceutic adjuvant.
Aforementioned preparation of drug combination method, comprising the steps: to get mol ratio is 1: the indirubin of 1-15 and phospholipid, and after in the little organic solvent of dielectric constant, mixing, reacting, drying under reduced pressure or lyophilization, remove organic solvent, get indirubin phosphatide compound.Wherein organic solvent is selected from one or more mixture in chloroform, ether, acetone, dioxane, dichloromethane, oxolane, ethyl acetate, normal hexane, the C1-C6 straight or branched low-grade alkane alcohol.Wherein C1-C6 straight or branched low-grade alkane alcohol comprises methanol, ethanol, propanol or butanols.In the described preparation method, the temperature that indirubin is mixed in organic solvent, reacted with phospholipid is 10-80 ℃, and the time is 1-4 hour; The use amount of organic solvent is the organic solvent that 1 milligram of indirubin is not less than 5ml; After organic solvent is removed in drying under reduced pressure or lyophilization, promptly obtain indirubin phosphatide compound.The preferred purification process of indirubin phosphatide compound is: to not being in the 100% pure indirubin phosphatide compound, add atent solvent, the indirubin raw material post precipitation that does not form complex is separated, and indirubin phosphatide compound is dissolved in this atent solvent, after removing this atent solvent, the indirubin phosphatide compound purity that obtains can reach 100%, and the used atent solvent of purification indirubin phosphatide compound is preferably normal hexane.Aforementioned preparation method, temperature was 20-50 ℃ when wherein indirubin and phospholipid mixed to clarification in organic solvent, the time is 2-3 hour; The use amount of organic solvent is the organic solvent of 1 milligram of indirubin with 5-15ml.In the preparation method of the present invention, the indirubin phosphatide compound that obtains mixes with pharmaceutically acceptable oral formulations adjuvant, makes granule, tablet, hard capsule, soft capsule or oral administration mixed suspension.
Pharmaceutically Chang Yong phospholipid has natural phospholipid or synthetic phospholipid.Natural phospholipid has separate sources, comprises extracting skin from bean or animal, brain, liver etc. obtaining, for example: soybean phospholipid and egg yolk lecithin.Synthetic phospholipid has dipalmitoyl phosphatidyl choline (DPPC), two palmityl PHOSPHATIDYL ETHANOLAMINE (DPPE) etc.These phospholipid pharmaceutically commonly used all can be used for preparing phosphatide complexes of the present invention.The feature of indirubin phosphatide compound is obviously different with indirubin monomer and phospholipid: the choline part (R in the complex structure of phospholipid
2) proton signal significantly weakens, almost can't observe, and fatty acid chain part (R, R
1) then do not change; The P=0 basic feature absworption peak of phospholipid disappears in the composite I R spectrum.
Indirubin phosphatide compound of the present invention has improved the dissolubility of indirubin, and its dissolubility in water increases by 10 times than indirubin, and the dissolubility in n-octyl alcohol increases nearly 1.5 times.The indirubin phosphatide compound good stability, all significantly be better than common indirubin at aspects such as the absorption program of medicine, onset speed, persistent period, and can be made into all kinds peroral dosage form, can strengthen the pharmacological action and the curative effect of the slow grain of indirubin treatment, prolong the action time of indirubin, reduce its untoward reaction such as zest, improve it and in gastrointestinal tract, absorb, obtain higher blood drug level and eliminate slowlyer in vivo, the indirubin bioavailability is significantly improved.
The preparation of indirubin phosphatide compound will be carried out in aprotonic solvent, and the solvent that dielectric constant is little helps the formation of indirubin complex.The preparation method of indirubin phosphatide compound disclosed by the invention is to adopt following technical proposals to obtain: getting mol ratio is indirubin and phospholipid=1: 1-15, in the little organic solvent of dielectric constant, stir to clarify at 10-80 ℃, drying under reduced pressure or lyophilization, removing desolvates promptly gets complex.The mol ratio of indirubin and phospholipid is 1: 1 o'clock, and its recombination rate is on the low side; The mol ratio of indirubin and phospholipid is 1: 10, and recombination rate is greater than 95%; The mol ratio of indirubin and phospholipid is 1: 15, and recombination rate is greater than 98%.The molal quantity of phospholipid is compared with the molal quantity of indirubin, and ratio is high more, and recombination rate is high more.So consider the economy of preparation method, when indirubin was 1 mole, its used phospholipid was 1～10 mole, can reach excellent results of the present invention.The organic solvent that dielectric constant described in the technical solution of the present invention is little is selected from the low-grade alkane alcohol of chloroform, ether, acetone, dioxane, dichloromethane, oxolane, ethyl acetate, normal hexane and side chain or straight chain such as methanol, ethanol, propanol, butanols.Screening experiment shows: 1 milligram of indirubin needs the 5ml solvent at least because the solvability of indirubin is very poor, if solvent be lower than 5ml then when temperature is low medicine can not dissolve the carrying out that can influence reaction fully.Reaction temperature to medicine in solvent solvability and the stability of phospholipid certain influence is arranged, too low as can influence the carrying out of the dissolving and the reaction of medicine less than 10 degree, too high as can influence the stability of phospholipid greater than 80 degree, more suitable in 10-80 ℃ of scope, preferred 20-50 ℃.Response time with 2h-3h is advisable more than 1 hour at least, also can extend to 4 hours.
Description of drawings:
Fig. 1: phospholipid DSC scintigram
Fig. 2: indirubin DSC scintigram
Fig. 3: indirubin phosphatide compound DSC scintigram
The specific embodiment:
The indirubin highly finished product: the four seas, Haimen City plant essence company limited contains indirubin＞90%.
All the other pharmaceutic adjuvants are commercially available and meet standards of pharmacopoeia.
Embodiment 1: take by weighing indirubin 5mg, be dissolved in and get the aubergine clear liquid among the ethyl acetate 25ml, add soybean phospholipid (Shanghai Taiwei Pharmaceutical Co., Ltd., injection stage, lot number 040108, contain phospholipid 75～80%) 45mg (indirubin 5mg: phosphatidase 14 5mg is equivalent to mol than 1: 3), stirring is clear and bright until solution, 80 ℃ of insulations of limit heating limit oscillating reactions 2h, and reaction dissolvent is removed in decompression, conventional low-temperature vacuum drying gets aubergine semi-solid complex.Get phospholipid, indirubin and indirubin phosphatide compound and carry out dsc analysis (accompanying drawing 1-3), there is transformation temperature in indirubin at 353.0 ℃ as a result, and transformation temperature improves among the figure of complex, 353.0 ℃ of transformation temperatures of having can't see indirubin, proves formation " indirubin phosphatide compound ".
The dissolubility of this indirubin phosphatide compound in water increases by 10 times than indirubin, and the dissolubility in n-octyl alcohol increases nearly 1.5 times.
Embodiment 2: take by weighing indirubin 10mg, be dissolved among the oxolane 50ml the aubergine clear liquid, add soybean phospholipid 90mg, stirring is clear and bright until solution, 30 ℃ of insulations of limit heating limit oscillating reactions 2h, and reaction dissolvent is removed in decompression, low-temperature vacuum drying gets aubergine semi-solid complex.
Embodiment 3: take by weighing indirubin 10mg, be dissolved among the hot acetone 50ml the aubergine clear liquid, add egg yolk lecithin 90mg, stirring is clear and bright until solution, 60 ℃ of insulations of limit heating limit oscillating reactions 3h, and reaction dissolvent is removed in decompression, low-temperature vacuum drying gets aubergine semi-solid complex.
Embodiment 4: take by weighing indirubin 10mg, be dissolved among the dichloromethane 50ml the aubergine clear liquid, add egg yolk lecithin 150mg, stirring is clear and bright until solution, 40 ℃ of insulations of limit heating limit oscillating reactions 2h, and reaction dissolvent is removed in decompression, low-temperature vacuum drying gets aubergine semi-solid complex.
Embodiment 5: take by weighing indirubin 10mg, be dissolved among the chloroform 50ml the aubergine clear liquid, add synthetic phospholipid DPPC240mg, stirring is clear and bright until solution, 20 ℃ of insulations of limit heating limit oscillating reactions 2h, and reaction dissolvent is removed in decompression, low-temperature vacuum drying gets aubergine semi-solid complex.
Embodiment 6: take by weighing indirubin 10mg, be dissolved in and get the aubergine clear liquid among the normal hexane 50ml, add synthetic phospholipid dipalmitoyl phosphatidyl choline (DPPC) 300mg, stirring is clear and bright until solution, 50 ℃ of insulations of limit heating limit oscillating reactions 3h, reaction dissolvent is removed in decompression, and low-temperature vacuum drying gets aubergine semi-solid complex.Embodiment 7: take by weighing indirubin 10mg, be dissolved in and get the aubergine clear liquid among the normal hexane 50ml, add synthetic phospholipid two palmityl PHOSPHATIDYL ETHANOLAMINE (DPPE) 300mg, stirring is clear and bright until solution, 50 ℃ of insulations of limit heating limit oscillating reactions 3h, reaction dissolvent is removed in decompression, and low-temperature vacuum drying gets aubergine semi-solid complex.
Embodiment 8: take by weighing indirubin 5mg, be dissolved in and get the aubergine clear liquid among the ethyl acetate 25ml, add soybean phospholipid (Shanghai Taiwei Pharmaceutical Co., Ltd., injection stage, lot number 040108, contain phospholipid 75～80%) 225mg (indirubin 5mg: phosphatidase 12 25mg is equivalent to mol than 1: 15), stirring is clear and bright until solution, 80 ℃ of insulations of limit heating limit oscillating reactions 2h, and reaction dissolvent is removed in decompression, conventional low-temperature vacuum drying gets aubergine semi-solid complex.
Embodiment 9: with indirubin phosphatide compound (embodiment 1) preparation granule
Prescription is formed: indirubin phosphatide compound (being equivalent to the 25mg indirubin approximately): 200mg
Cane sugar powder: 1g
Essence: an amount of
Technical process: with complex and cane sugar powder mix homogeneously,, and cross 20 mesh sieve system granules,, get granule in 50 ℃ of aeration-dryings with 30% ethanol water system soft material of dissolving essence.
Embodiment 10: with indirubin phosphatide compound (embodiment 2) preparation tablet
Prescription is formed: indirubin phosphatide compound (being equivalent to the 25mg indirubin approximately): 200mg
Amylum pregelatinisatum: 0.37g
Cross-linked pvp (PPVP): 50mg
Micropowder silica gel: 10mg
HPMC (hydroxypropyl emthylcellulose, METHOCEL E4M, Ka Lekang present): an amount of
Magnesium stearate: 10mg
Technical process: behind complex and amylum pregelatinisatum mix homogeneously,, and cross 18 mesh sieve system granules with the 20% ethanol water system soft material of dissolving HPMC, in 50 ℃ of aeration-dryings, reuse 18 mesh sieve granulate add PPVP, micropowder silica gel, magnesium stearate, tabletting behind the mix homogeneously in the gained granule.
Embodiment 11: with indirubin phosphatide compound (embodiment 3) preparation hard capsule
Prescription is formed: indirubin phosphatide compound (being equivalent to the 25mg indirubin approximately): 200mg
Starch: 150mg
Microcrystalline Cellulose: 50mg
Micropowder silica gel: 10mg
Technical process: will adorn hard capsule behind complex and starch, microcrystalline Cellulose, the micropowder silica gel mix homogeneously, promptly.
Embodiment 12: with indirubin phosphatide compound (embodiment 4) preparation soft capsule
Prescription is formed: indirubin phosphatide compound (being equivalent to the 25mg indirubin approximately): 200mg
Ethyl oleate: 1g
Labrasol (the hot certain herbaceous plants with big flowers acid glyceride of Polyethylene Glycol, the present of the happy Kanggong of Shanghai card department): an amount of
Technical process: complex is dissolved in the mixed liquor of ethyl oleate and Labrasol, gets the transparent medicinal liquid of an aubergine; Get gelatin, glycerol, sorbitol, water preparation gelatin solution, put sprawl in the case standby.Under the condition of 23 ± 2 ℃ of room temperatures, relative humidity 40%, make soft gelatin capsule, and cold air drying 24 hours is promptly under 23 ± 2 ℃, the condition of relative humidity 40% with dropping preparation method.
Embodiment 13: with indirubin phosphatide compound (embodiment 5) preparation oral administration mixed suspension
Prescription is formed: indirubin phosphatide compound (being equivalent to the 25mg indirubin approximately): 200mg
Sucrose: 2g
Mannitol: 0.5g
Methylcellulose: 20mg
Sodium benzoate: 10mg
Essence: an amount of
Technical process: sucrose, mannitol, methylcellulose, sodium benzoate, essence is soluble in water, add complex at last, mix, promptly get oral administration mixed suspension.
Embodiment 14: the pharmacodynamic study of indirubin phosphatide compound
Indirubin phosphatide compound strengthens the pharmacological action and the curative effect of the slow grain of indirubin treatment, prolong the action time of indirubin, reduce its untoward reaction such as zest, improve it and in gastrointestinal tract, absorb, blood drug level is higher and elimination is slower in vivo, and the indirubin bioavailability is significantly improved.
Claims (9)
1, a kind of oral pharmaceutical composition, comprising indirubin and phospholipid with 1: after mixing, react in the organic solvent of one or more mixture of 1-15 mol ratio in being selected from chloroform, ether, acetone, dioxane, dichloromethane, oxolane, ethyl acetate, normal hexane, C1-C6 straight or branched low-grade alkane alcohol, drying under reduced pressure or lyophilization, remove organic solvent, the indirubin phosphatide compound of making.
2, the pharmaceutical composition of claim 1, wherein indirubin phosphatide compound be by indirubin and phospholipid with 1: the 8-10 mixed in molar ratio is made.
3, the pharmaceutical composition of claim 1 is characterized in that described phospholipid chooses natural phospholipid and/or synthetic phospholipid.
4, the pharmaceutical composition of claim 3 is characterized in that natural phospholipid is selected from soybean phospholipid and/or egg yolk lecithin; Synthetic phospholipid is selected from dipalmitoyl phosphatidyl choline or two palmityl PHOSPHATIDYL ETHANOLAMINE; Comprise oral pharmaceutic adjuvant.
5, the preparation of drug combination method of claim 1 comprises the steps:
Getting mol ratio is 1: the indirubin of 1-15 and phospholipid, after mixing in the organic solvent of one or more mixture in being selected from chloroform, ether, acetone, dioxane, dichloromethane, oxolane, ethyl acetate, normal hexane, C1-C6 straight or branched low-grade alkane alcohol, reacting, drying under reduced pressure or lyophilization, remove organic solvent, get indirubin phosphatide compound.
6, claim 5 preparation of drug combination method, wherein C1-C6 straight or branched low-grade alkane alcohol comprises methanol, ethanol, propanol or butanols.
7, claim 5 preparation of drug combination method, wherein the indirubin temperature of mixing in organic solvent, reacting with phospholipid is 10-80 ℃, the time is 1-4 hour; The use amount of organic solvent is the organic solvent that 1 milligram of indirubin is not less than 5ml; After organic solvent is removed in drying under reduced pressure or lyophilization, add atent solvent purification indirubin phosphatide compound, the indirubin post precipitation that does not form complex is separated, indirubin phosphatide compound is dissolved in atent solvent, after removing atent solvent, get pure indirubin phosphatide compound.
8, claim 7 preparation of drug combination method, temperature was 20-50 ℃ when wherein indirubin and phospholipid mixed to clarification in organic solvent, the time is 2-3 hour; The use amount of organic solvent is the organic solvent of 1 milligram of indirubin with 5-15ml; The atent solvent that the indirubin precipitate and separate is added is a normal hexane.
9, claim 8 preparation of drug combination method, the indirubin phosphatide compound that obtains mixes with pharmaceutically acceptable oral formulations adjuvant, makes granule, tablet, hard capsule, soft capsule or oral administration mixed suspension.
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| CN102228433B (en) * | 2011-06-29 | 2012-11-28 | 上海中医药大学 | Supersaturated self-microemulsion as well as preparation method and application thereof |
| CN105738536A (en) * | 2016-04-22 | 2016-07-06 | 广西壮族自治区梧州食品药品检验所 | Extraction method for indirubin in folium isatidis |
| CN106177976B (en) * | 2016-07-11 | 2019-06-21 | 贵州医科大学 | A kind of aspirin phosphatide complexes and preparation method thereof |
| CN109010844B (en) * | 2017-06-08 | 2022-01-04 | 沈阳药科大学 | Ibrutinib phospholipid complex and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5147859A (en) * | 1987-02-26 | 1992-09-15 | Indena S.P.A. | Complexes of glycerrhetinic acid with phospholipids and pharmaceutical and cosmetic compositions containing them |
| CN1359682A (en) * | 2001-12-25 | 2002-07-24 | 沈阳药科大学 | Breviscapine-phosphotide compound and its preparing process |
| CN1403086A (en) * | 2002-10-16 | 2003-03-19 | 上海中医药大学 | Coculine-phosphatide composite and its prepn |
-
2004
- 2004-11-19 CN CNB2004100658008A patent/CN1311823C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5147859A (en) * | 1987-02-26 | 1992-09-15 | Indena S.P.A. | Complexes of glycerrhetinic acid with phospholipids and pharmaceutical and cosmetic compositions containing them |
| CN1359682A (en) * | 2001-12-25 | 2002-07-24 | 沈阳药科大学 | Breviscapine-phosphotide compound and its preparing process |
| CN1403086A (en) * | 2002-10-16 | 2003-03-19 | 上海中医药大学 | Coculine-phosphatide composite and its prepn |
Non-Patent Citations (1)
| Title |
|---|
| 淫羊藿黄酮脂复合物的制备及其剂型研究 江永南等，中国中药杂志，第26卷第2期 2001 * |
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