CN102961751A - Composition for improving oral bioavailability of alkaloid and preparation method - Google Patents
Composition for improving oral bioavailability of alkaloid and preparation method Download PDFInfo
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- CN102961751A CN102961751A CN2012105594825A CN201210559482A CN102961751A CN 102961751 A CN102961751 A CN 102961751A CN 2012105594825 A CN2012105594825 A CN 2012105594825A CN 201210559482 A CN201210559482 A CN 201210559482A CN 102961751 A CN102961751 A CN 102961751A
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Abstract
The invention provides a composition for improving oral bioavailability of alkaloid and a preparation method of the composition. The composition is prepared by compounding and processing a low-bioavailability alkaloid compound, phospholipid, a hydrophobic component and a surfactant. The composition can be formed into microemulsion and submicron emulsion in body, and thus the oral absorption of low-bioavailability alkaloid can be improved.
Description
Technical field
The present invention a kind of compositions and preparation method for increasing the drug oral bioavailability are specifically for increasing compositions and the preparation method of alkaloid oral administration biaavailability.
Background technology:
Oral formulations is owing to dosage form taking convenience, safe, in occupation of main medical market share.Yet the gastrointestinal absorption of medicine is subject to the impact of the factors such as fat-soluble, the dissolubility, first pass effect, mucosa permeability, efflux pump of medicine, and bioavailability difference is very big.Biopharmaceutics categorizing system (BCS) according to oral drugs, according to parameter evaluations such as the dissolubility of medicine, dissolution, permeabilitys, because large, the fat-soluble difference of polarity or polarity is little, water solublity is low or relative molecular mass is larger, cause oral absorption poor, thereby cause bioavailability low.Alkaloids is the nitrogenous alkaline organic compound of a class that is present in the organism (being mainly plant), is one of effective ingredient important in the Chinese herbal medicine, and great majority have complicated circulus, and nitrogen is included in the ring more, and significant biological activity is arranged.Most of alkaloids have the effects such as anti-inflammation, analgesia, heart tonifying, blood pressure lowering, antitumor, use clinically more extensive.But owing to having dissolubility or fat-soluble reason, affected greatly the interior bioavailability of body of alkaloid compound, limited clinical use.
The research of medicine phospholipid composite has drawn attention since the eighties in 20th century gradually, and its research is used day by day deep.Chanced in the research liposome by people such as Italian scholar Bombardelli: the natural flavone compounds has special affinity to phospholipid, the two can be in conjunction with forming compositions and showing biological characteristics and the pharmacologically active significantly different from parent drug, research is afterwards found, very eurypalynous natural component and natural extract can be made phospholipid composite, and this class phospholipid composite is named as phytosomes/phospholipid complex.Its principle is that the oxygen atom in the hydroxyl has the stronger tendency to electronics on the phosphorus atoms, and nitrogen-atoms has stronger betatopic tendency, therefore under certain condition, can generate compositions and the compound multiple phospholipid composite (Phytosomes) that obtains of other active skull cap components with the medicine of a fixed structure.By with compound carrier system or the prodrug of forming of phospholipid, can effectively improve in the body of active skull cap components and absorb, improve significantly its biological effectiveness.The active skull cap components phospholipid composite forms the micelle shape of similar liposome during by water treatment.The difference of the two is: although liposome also is by Lipid composition, but its volume ratio phospholipid composite is much bigger, and the more important thing is, in liposome, be combined with wrapped drug molecule in the actual also end of phospholipid, and the phospholipid composite new molecule that to be phospholipid be combined with natural component produces, significant change has occured in its biological characteristics.Active skull cap components in the liposome is dissolved in medium or is wrapped between the rete; Active skull cap components phospholipid composite active component is fixed to as a whole by the polar end interaction with phospholipid, a plurality of phospholipid composite molecular ordered arrangements form the spheroid that is different from liposome.
In recent years, the research of the phospholipid composite of relevant active skull cap components report also increases gradually, abroad existing silymarin and silibinin, enoxolone; The patent of the tens of kinds of phospholipid composites such as green tea extract, Semen Ginkgo extrac, Semen Vitis viniferae extract, Radix Ginseng extract and health-oriented products go on the market and the multiple dosage forms such as hard capsule, soft capsule, cream, gel, granule, Emulsion are arranged.
But phospholipid composite belongs to physical bond, is subjected in vivo the impact of environmental change unstable.Very easily decompose and transfer former chemical compound to, do not reach the requirement that changes compound property.Self-emulsifying drug delivery system (Self-emulsifying drug delivery system, SEDDS) have following characteristics: self emulsifying is under the body temperature condition in (1) body, self-emulsifiable preparation can have higher solubilising power to slightly solubility or fat-soluble medicine by spontaneous formation O/W type Emulsion (2) after meeting body fluid under gastrointestinal motility, can increase cell membrane fluidity, promote the medicine Lymphatic, thereby improving its biological utilisation (3) compares with traditional tablet or capsule, SEDDS can be quicker, equably that drug delivery is simple to gastrointestinal pessimal stimulation (5) preparation to hydrolysis and the medicine that absorption site (4) reduces the water unstable medicine, stable in properties.Nowadays have Cyclosporin A soft capsule, Norvir
(ritonavir) and Fortovas
Three pharmaceutical preparatioies of e (saquinavir) are successfully gone on the market.
Summary of the invention:
Purpose of the present invention is to start with from the medicines structure physical modification, explores by alkaloid and amphiphilic species-soybean lecithin and forms physical composition, in the hope of reaching the lipotropy that improves alkaloid compound.And by being wrapped in the self-emulsifiable preparation, reach the effect that improves the oral absorption rate.Can find out from the result of embodiment, profit breadth coefficient generation significant change behind the alkaloid compound formation phospholipid composite, the dissolubility in oily carrier obviously improves; After forming self-emulsifying composition, have the ability of spontaneous formation microemulsion in vivo or submicron emulsion, bioavailability significantly improves in the body.
A kind of compositions for increasing the alkaloid oral administration biaavailability of the present invention, described compositions comprises alkaloid compound, phospholipid, hydrophobicity composition and the surfactant of low bioavailability, wherein, the content of described alkaloid compound in compositions is 1%-50%, the content of phospholipid is 4%-60%, the content of hydrophobicity composition is 10%-80%, the content of surfactant is 5%-60%, said composition in vivo can spontaneous formation microemulsion, submicron emulsion, can be used for improving the alkaloidal oral absorption of low bioavailability.
Above-described alkaloid compound is selected from the alkaloid compound of matrine, oxymatrine, berberine, Rhizoma Corydalis total alkaloids, sinomenine, sophocarpine, N-oxysophocarpine and other low bioavailability.
The above phospholipid can be selected from lecithin, soybean phospholipid, egg yolk lecithin, phosphatidylcholine.
The above compositions, wherein the hydrophobicity composition is selected from pharmaceutically acceptable glyceride, fatty ester, fragrant fat, wax, lipid, fat, lipid soluble vitamin, hydrocarbon, polysiloxanes, vitamin E and relevant chemical compound or their mixture.
The above surfactant is selected from pharmaceutically acceptable ethers, Semen Ricini oils, Tweens surfactant and cosurfactant.
The above surfactant is selected from polyoxyethylene castor oil, TC, Tween 80, polysorbas20, PEG400 or their mixture, selects the kind of surfactant between 1 to 3 kind.
The above also comprises the composition that is selected from pharmaceutically acceptable, viscous regulator, antibacterial and coloring agent in the other adding compositions, and its weight percentage is the heavy 0%-10% of compositions.
A kind of compositions for increasing the alkaloid oral administration biaavailability of the present invention takes by weighing alkaloid compound and phospholipid according to a certain percentage, adopts solvent evaporated method to be prepared into alkaloid phospholipid physical composition thing; Hydrophobicity composition and surfactant are mixed to get the oily carrier by a certain percentage; Alkaloid phospholipid physical composition thing and oily carrier are mixed in proportion to get compositions, add in addition antibacterial, viscous regulator and coloring agent, and get final product.
The present composition, it has the ability of spontaneous formation microemulsion in vivo or submicron emulsion.
The present composition, the emulsion droplet diameter of its formation is between 10 to 2000nm.
Have been found that now compositions that phospholipid and polytype chemical compound form can change the physicochemical characteristics of chemical compound.Useful especially is that said composition is safety, nontoxic, and can play in vivo synergism, increases curative effect.But said composition is physical bond, easily decomposes under the environment in vivo.In order to improve its stability and dissolubility in vivo, but a kind of oily carrier of in vivo spontaneous emulsification comprises oil phase, (helping) surfactant, is used in the present invention.
Alkaloid of the present invention and amphiphilic species-soybean lecithin forms physical composition, reached the lipotropy that improves alkaloid compound, profit breadth coefficient generation significant change behind the alkaloid compound formation phospholipid composite, behind the obvious raising of dissolubility in oily carrier and the formation self-emulsifying composition, this chemical compound has the ability of spontaneous formation microemulsion in vivo or submicron emulsion, makes that bioavailability significantly improves in the body.
Description of drawings:
Fig. 1: microemulsion or submicron emulsion scanning electron microscope (SEM) photograph (matrine) that compositions forms;
Shown among the figure for matrine composition and formed physical aspect behind microemulsion or the submicron emulsion.Hydrophobic ingredient has wrapped up phospholipid composite preferably, has avoided the leakage of phospholipid composite, has effectively prevented decomposition, thereby has improved stability.
Fig. 2. the interior bioavailability of the body of matrine composition is figure (20 mg/kg) as a result.Matrine-matrine; MPC-matrine phospholipid composite; MPC-SNEDDS--matrine-phospholipid composite oil carrier
The bioavailability result has better proved advantage of the present invention in the body of compositions, and matrine-phospholipid composite oil carrier organism availability is greatly improved as described in Figure 2.
The present invention is further illustrated by following test and embodiment:
1, profit breadth coefficient result of the test was such as table before and after alkaloid compound formed phospholipid composite
Claims (10)
1. compositions for increasing the alkaloid oral administration biaavailability, it is characterized in that described compositions comprises alkaloid compound, phospholipid, hydrophobicity composition and the surfactant of low bioavailability, wherein, the weight percentage of described alkaloid compound in compositions is 1%-50%, phospholipid is 4%-60%, the hydrophobicity composition is 10%-80%, surfactant is 5%-60%, said composition in vivo can spontaneous formation microemulsion, submicron emulsion, can be used for improving the alkaloidal oral absorption of low bioavailability.
2. a kind of compositions for increasing the alkaloid oral administration biaavailability according to claim 1 is characterized in that described alkaloid compound is selected from the alkaloid compound of matrine, oxymatrine, berberine, Rhizoma Corydalis total alkaloids, sinomenine, sophocarpine, N-oxysophocarpine and other low bioavailability.
3. a kind of compositions for increasing the alkaloid oral administration biaavailability according to claim 1 is characterized in that described phospholipid can be selected from lecithin, soybean phospholipid, egg yolk lecithin, phosphatidylcholine.
4. a kind of compositions for increasing the alkaloid oral administration biaavailability according to claim 1, it is characterized in that the hydrophobicity composition is selected from pharmaceutically acceptable glyceride, fatty ester, fragrant fat, wax, lipid, fat, lipid soluble vitamin, hydrocarbon, polysiloxanes, vitamin E and relevant chemical compound or their mixture.
5. a kind of compositions for increasing the alkaloid oral administration biaavailability according to claim 1 is characterized in that surfactant is selected from pharmaceutically acceptable ethers, Semen Ricini oils, Tweens surfactant and cosurfactant.
6. a kind of compositions for increasing the alkaloid oral administration biaavailability according to claim 5, it is characterized in that surfactant is selected from polyoxyethylene castor oil, TC, Tween 80, polysorbas20, PEG400 or their mixture, select the kind of surfactant between 1 to 3 kind.
7. a kind of compositions for increasing the alkaloid oral administration biaavailability according to claim 1, characterized by further comprising the composition that is selected from pharmaceutically acceptable, viscous regulator, antibacterial and coloring agent in the other adding compositions, its weight percentage is the heavy 0%-10% of compositions.
8. a kind of compositions for increasing the alkaloid oral administration biaavailability according to claim 1 is characterized in that taking by weighing according to a certain percentage alkaloid compound and phospholipid, adopts solvent evaporated method to be prepared into alkaloid phospholipid physical composition thing; Hydrophobicity composition and surfactant are mixed to get the oily carrier by a certain percentage; Alkaloid phospholipid physical composition thing and oily carrier are mixed in proportion to get compositions, add in addition antibacterial, viscous regulator and coloring agent, and get final product.
9. a kind of compositions for increasing the alkaloid oral administration biaavailability according to claim 1 is characterized in that it has the ability of spontaneous formation microemulsion in vivo or submicron emulsion.
10. a kind of compositions for increasing the alkaloid oral administration biaavailability according to claim 1 is characterized in that the emulsion droplet diameter of its formation is between 10 to 2000nm.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012105594825A CN102961751A (en) | 2012-12-21 | 2012-12-21 | Composition for improving oral bioavailability of alkaloid and preparation method |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1403086A (en) * | 2002-10-16 | 2003-03-19 | 上海中医药大学 | Coculine-phosphatide composite and its prepn |
| CN100998592A (en) * | 2007-01-04 | 2007-07-18 | 中国人民解放军第二军医大学 | Microemulsion containing matrine |
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- 2012-12-21 CN CN2012105594825A patent/CN102961751A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1403086A (en) * | 2002-10-16 | 2003-03-19 | 上海中医药大学 | Coculine-phosphatide composite and its prepn |
| CN100998592A (en) * | 2007-01-04 | 2007-07-18 | 中国人民解放军第二军医大学 | Microemulsion containing matrine |
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Application publication date: 20130313 |