CN100536921C - Supersaturated cationic self-emulsified drug delivery system and its preparation method - Google Patents
Supersaturated cationic self-emulsified drug delivery system and its preparation method Download PDFInfo
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- CN100536921C CN100536921C CNB2006100259401A CN200610025940A CN100536921C CN 100536921 C CN100536921 C CN 100536921C CN B2006100259401 A CNB2006100259401 A CN B2006100259401A CN 200610025940 A CN200610025940 A CN 200610025940A CN 100536921 C CN100536921 C CN 100536921C
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Abstract
The invention provides an over saturation cation self-emulsifying drug delivery system and the preparation method. The indissoluble medicine is delivered by way of over saturation cation self-emulsifying drug delivery system. It is characterized in that it comprises indissoluble medicine, oil phase, surface activate agent, adjuvant surface activate agent, cation surface active agent and high molecular polymer. The drug delivery system can improve the biological utilization rate for indissoluble medicine, and the process is simple and suitable for industrial production.
Description
Technical field
The present invention relates to a kind of drug-supplying system, be specifically related to a kind of supersaturated cationic self-emulsified drug delivery system that is used for poorly water soluble drugs and preparation method thereof.
Background technology
Insoluble drug is more and more.At present, about 40% or more noval chemical compounds that obtains through high flux screening be insoluble in water (Lipinski, C.A., Lombardo, F., Dominy, B.W., et al, 1997.Experimental and computational approaches to estimate solubility andpermeability in drug discovery and development setting.Adv.Drug Deliv.Rev.23,3-25.).Many effective sites of extracting from Chinese medicine or monomer also are insoluble in water.When preparing the preparation of these insoluble drugs with traditional method, some problems appear in bioavailability regular meeting clinically, the big and influence that is subject to diet of, individual patient differences low as bioavailability, thus curative effect is reduced.
For improving the bioavailability of these insoluble drugs, existing many preparation new techniques are applied in the middle of the preparation production of these medicines, as cyclodextrin inclusion technique, solid dispersion technology, nanotechnology and self emulsifying technology or the like.Self-emulsifying drug drug-supplying system (Self-emulsifying Drug DeliverySystem, be called for short SEDDS) be solid or the liquid dosage form that comprises oil phase, surfactant and cosurfactant, spontaneous one-tenth breast under the gastrointestinal wriggling forms small emulsion droplet (particle diameter≤5 μ m) under external 37 ℃ of water-baths, gentle agitation or in the body.When the ratio of surfactant, cosurfactant and oil phase is suitable, just can form meticulousr Emulsion (particle diameter＜100nm), be called the self-emulsifying microemulsion drug delivery system (Self-Microemulsifying drug delivery system, SMEDDS).Compare with other new technique, SEDDS (or SMEDDS) has the advantage of highly significant: the required free energy of (1) emulsifying is very low, at the slight O/W Emulsion of spontaneous formation particle diameter in the 1-5000nm scope under the wriggling condition of gastrointestinal tract; (2) insoluble drug and fat-soluble medicine had higher solubilising power; (3) can be filled in soft capsule or the hard capsule, preparation technology is simple, is easy to suitability for industrialized production; (4) be non-aqueous pharmaceutical carrier, can improve the facile hydrolysis stability of drug.Therefore, medication preparation such as existing cyclosporin A, ritonavir and Saquinavir become SEDDS (or SMEDDS) launch.
In recent years studies show that, in SEDDS (or SMEDDS), add some cationic materials, oral back can form the positively charged microemulsion emulsion droplet in surface in gastrointestinal tract, produce adsorption with electronegative gastrointestinal tract epithelial cell by electrostatic attraction, further increase absorption (TatyanaGershanika, the Simon Benita of medicine.Self-dispersing lipid formulations for improvingoral absorption of lipophilic drugs European Journal of Pharmaceutics andBiopharmaceutics 50 (2000) 179-188), this system is called cationic self-emulsified drug delivery system (Positive Self-emulsifying Drug Delivery System is called for short P-SEDDS).In addition, among the part SEDDS (or SMEDDS),, prevent that drug crystallization from separating out, add relatively large surfactant usually, thereby cause the generation of gastrointestinal side effect for obtaining enough big drug loading.Add some macromolecular materials in SEDDS (or SMEDDS), separate out in the crystallization that can suppress medicine in the gastrointestinal tract in the emulsion droplet dilution oral back, increases the saturation solubility of medicine, forms the supersaturated solution of medicine, can further increase the absorption of medicine; Can reduce simultaneously the consumption of surfactant, this system is called supersaturation self-emulsified drug delivery system (Supersatuable Self-emulsifying DrugDelivery System is called for short S-SEDDS).
In view of this, SEDDS (or SMEDDS) is modified, can further increase the absorption of poorly water soluble drugs, and/or reduce the consumption of surfactant, prevent the generation of gastrointestinal side effect.
Summary of the invention
The invention discloses a kind of supersaturated cationic self-emulsified drug delivery system (SupersatuablePositive Self-emulsifying Drug Delivery System, be called for short SP-SEDDS), it combines the advantage of P-SEDDS and S-SEDDS, can obviously improve the bioavailability of poorly water soluble drugs.The invention also discloses the preparation method of this supersaturated cationic self-emulsified drug delivery system, to adapt to the needs of industrialized great production.
Supersaturated cationic self-emulsified drug delivery system of the present invention comprises following component and percentage by weight and forms:
Medicine 0.1-30%
Oil phase 0.1-50%
Surfactant 5-90%
Cosurfactant 5-70%
Cationic surfactant 0.1-10%
High molecular polymer 0.1-10%
Each weight percentages of components is all in the gross weight of supersaturated cationic self-emulsified drug delivery system.
Preferred ingredients and weight are formed:
Medicine 1-15%
Oil phase 0.1-20%
Surfactant 20-70%
Cosurfactant 10-40%
Cationic surfactant 0.1-5%
High molecular polymer 0.1-5%
Each weight percentages of components is all in the gross weight of supersaturated cationic self-emulsified drug delivery system.
The representative example of oil phase that supersaturated cationic self-emulsified drug delivery system of the present invention comprises comprises:
(1) fatty acid triglyceride, preferred MCT Oil, for example Oleum Cocois C8/C10 triglyceride (Miglyol 182);
(2) glycerol list, two acid esters, preferably glycerine list or dioleate are as Oleum Cocois C8/C10 monoglyceride or dibasic acid esters (Capmul MCM);
(3) ester of fatty acid and monovalent alcohol, the ester of preferred C8-20 fatty acid and C2-3 monovalent alcohol is as isopropyl myristate, isopropyl palmitate, Ethyl linoleate and ethyl oleate etc.;
(4) crude vegetal or animal oil are as Semen Maydis oil, olive oil, Oleum Glycines and fish oil etc.;
(5) carbohydrate is as Squalene and squalane etc.;
(6) free fatty is as oleic acid, linoleic acid etc.
In above-mentioned oil, the present invention preferably uses the ester of MCT Oil, glycerol list/two acid esters and fatty acid and monovalent alcohol.
The representative example of surfactant that supersaturated cationic self-emulsified drug delivery system of the present invention comprises comprises:
(1) product of natural or hydrogenated vegetable oil and oxirane is as polyoxyethylene castor oil or polyoxyethylene hydrogenated Oleum Ricini etc.;
(2) Polyoxyethylene Sorbitol Fatty Acid Esters and polyoxyethylene sorbitan fatty acid ester, as polysorbas20, polysorbate40, polysorbate60, Tween 80, polysorbate65, polysorbate85, tween 21, tween 61, sorbimacrogol oleate100, span 20, span 40, sorbester p18, sorbester p17, span 25, sorbester p38, sorbester p37 etc., wherein preferred Tween 80 and polysorbate85;
(3) polyoxyethylene fatty acid ester is as Myrj 45 etc.;
(4) polyoxyethylene-propylene copolymer is as Pluronic F68 etc.;
(5) phospholipid is as soybean phospholipid, lecithin etc.;
(6) propylene glycol list or di fatty acid ester, as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate and propylene glycol sad-capric acid diester etc.;
(7) the transesterification product of crude vegetal triglyceride and Polyethylene Glycol is as Labrasol, Labrafac, Labrafil M etc.;
(8) polyoxy ethyl vitamin e derivative is as d-alpha-tocopherol cetomacrogol 1000-succinate (TPGS);
(9) polyoxy ethyl hydroxy fatty acid is as polyoxyethylene 660-hydroxy stearic acid ester (Solutol HS15);
In above-mentioned surfactant, the present invention preferably uses transesterification product, polyoxy ethyl vitamin e derivative and the polyoxy ethyl hydroxy fatty acid etc. of polyoxyethylene castor oil or polyoxyethylene hydrogenated Oleum Ricini, Polyoxyethylene Sorbitol Fatty Acid Esters, crude vegetal triglyceride and Polyethylene Glycol.
The cosurfactant that supersaturated cationic self-emulsified drug delivery system of the present invention comprised is selected from one or more in Polyethylene Glycol, propylene carbonate, TC, Isosorbide dimethyl ether, methyl pyrrolidone, ethyl pyrrolidone, propyl pyrrole alkane ketone, glycerol, xylitol, Sorbitol, glucose, mannitol of ethanol, propylene glycol, molecular weight 200-600 etc.Preferred cosurfactant is Polyethylene Glycol, propylene carbonate, TC, Isosorbide dimethyl ether and the methyl pyrrolidone of propylene glycol, molecular weight 200-600.
The cationic surfactant that supersaturated cationic self-emulsified drug delivery system of the present invention comprised is selected from stearmide (SA); oleamide (OA); N-[1-(2; 3-two oily acyloxy) propyl group]-N; N; N-trimethyl ammonium chloride (DOTMP); 1; 2-two oleoyl oxygen propyl group-N; N; N-trimethylammonium bromide (DOTAP); 3 β-[N-(N '; N '-dimethyl aminoethyl) carbamoyl] cholesterol (DC-Chol); 2; 3-two oleoyl oxygen-N-[2 (spermine Carboxylamide) ethyl-N; N-dimethyl-1-propyl group-trifluoroacetic acid ammonium (DOSPA); 1,2-two oleoyl oxygen propyl group-3-dimethyl-ethoxy ammonium bromide (DORIE); Dodecyl trimethyl ammonium chloride (DTAB); Tetradecyl Trimethyl Ammonium Bromide (TTAB); cetyl trimethyl ammonium bromide (CTAB); the two octadecyl trimethylammonium bromides (DDAB) of dimethyl; in chitosan and the derivant etc. thereof one or more.Preferred cationic surfactants is stearmide, oleamide, 1,2-two oleoyl oxygen propyl group-N, N, N-trimethylammonium bromide and chitosan and derivant thereof etc.
It is in the Polyethylene Glycol, polyvinylpyrrolidone, hydroxypropyl emthylcellulose, dextran, arabic gum, gelatin etc. more than 1000 one or more that the high molecular polymer that supersaturated cationic self-emulsified drug delivery system of the present invention comprised is selected from molecular weight.Preferred high molecular polymer is that molecular weight is Polyethylene Glycol, polyvinylpyrrolidone and the hydroxypropyl emthylcellulose etc. more than 1000.
If necessary, supersaturated cationic self-emulsified drug delivery system of the present invention also can contain other pharmaceutic adjuvants such as antioxidant, antibacterial, thickening agent, coloring agent, flavoring agent.
Supersaturated cationic self-emulsified drug delivery system of the present invention is mainly used in the oral administration biaavailability that improves poorly water soluble drugs.These poorly water soluble drugs comprise baicalin, glycyrrhizic acid, silymarin, cyclosporin A, paclitaxel, Progesterone, DALAZUO, itraconazole or the like, and preferred medicine comprises baicalin, glycyrrhizic acid, silymarin or the like.
The preparation method of supersaturated cationic self-emulsified drug delivery system of the present invention: take by weighing recipe quantity medicine, surfactant, cosurfactant and oil phase, mix homogeneously adds the dissolving of cationic surfactant and high molecular polymer then or is suspended in wherein and gets final product.If SP-SEDDS is liquid or semisolid, but direct packaging is in soft capsule or hard capsule, also available silicon dioxide or the absorption of other solid medicinal adjuvants change solid into, and then are prepared into oral solid formulations such as tablet, micropill, hard capsule, granule, dispersible tablet, effervescent tablet, slow releasing tablet; As SP-SEDDS is solid, then can directly be prepared into oral solid formulation with other pharmaceutic adjuvants.
Supersaturated cationic self-emulsified drug delivery system of the present invention is compared with general self-emulsified drug delivery system, can further improve the bioavailability of poorly water soluble drugs, and/or reduces the consumption of surfactant, prevents the generation of gastrointestinal side effect.In addition, compare with other administration nano-drug administration systems, preparation technology is simple for this drug-supplying system, and cost is lower, is easy to suitability for industrialized production.
The specific embodiment
Embodiment 1
Take by weighing recipe quantity surfactant, cosurfactant, oil phase and cationic surfactant by the listed mass percent of table 1, mix homogeneously adds the polyethylene glycol 6000 dissolving and wherein gets final product.
Table 1
Embodiment 2
Take by weighing recipe quantity surfactant, cosurfactant and oil phase by the listed mass percent of table 2, mix homogeneously adds hydroxypropyl emthylcellulose and chitosan then and is suspended in wherein and gets final product.
Table 2
Embodiment 3
Take by weighing recipe quantity DOTAP, surfactant, cosurfactant and oil phase by the listed mass percent of table 3, mix homogeneously adds polyvinylpyrrolidone then and is dissolved in wherein and gets final product.
Table 3
Embodiment 4
Take by weighing recipe quantity surfactant, cosurfactant and oil phase by the listed mass percent of table 4, mix homogeneously adds hydroxypropyl emthylcellulose and chitosan then and is suspended in wherein and gets final product.
Table 4
Embodiment 5
Take by weighing recipe quantity DOTAP, surfactant, cosurfactant and oil phase by the listed mass percent of table 5, mix homogeneously adds polyvinylpyrrolidone then and is dissolved in wherein and gets final product.
Table 5
Embodiment 6
Take by weighing recipe quantity surfactant, cosurfactant and oil phase by the listed mass percent of table 6, mix homogeneously adds hydroxypropyl emthylcellulose and chitosan then and is suspended in wherein and gets final product.
Table 6
Embodiment 7
Take by weighing recipe quantity surfactant, cosurfactant, oil phase and cationic surfactant by the listed mass percent of table 1, mix homogeneously adds the polyethylene glycol 6000 dissolving and wherein gets final product.
Table 7
Claims (5)
1, supersaturated cationic self-emulsified drug delivery system is characterized in that comprising poorly water soluble drugs, oil phase, surfactant, cosurfactant, cationic surfactant and high molecular polymer, and each weight percentages of components is as follows:
Poorly water soluble drugs 1-15%
Oil phase 0.1-20%
Surfactant 20-70%
Cosurfactant 10-40%
Cationic surfactant 0.1-5%
High molecular polymer 0.1-5%
Each weight percentages of components is all in the supersaturated cationic self-emulsified drug delivery system gross weight,
Wherein said poorly water soluble drugs is baicalin, glycyrrhizic acid or silymarin;
Wherein said surfactant is selected from (1) polyoxyethylene castor oil or polyoxyethylene hydrogenated Oleum Ricini, (2) Polyoxyethylene Sorbitol Fatty Acid Esters and polyoxyethylene sorbitan fatty acid ester, (3) polyoxyethylene fatty acid ester, (4) polyoxyethylene-propylene copolymer, (5) phospholipid, (6) propylene glycol list or di fatty acid ester, (7) Labrasol, Labrafac or Labrafil M, (8) d-alpha-tocopherol cetomacrogol 1000-succinate, (9) polyoxy ethyl hydroxy fatty acid;
It is in the Polyethylene Glycol more than 1000 one or more that wherein said high molecular polymer is selected from polyvinylpyrrolidone, hydroxypropyl emthylcellulose, dextran, arabic gum, gelatin, molecular weight.
2, supersaturated cationic self-emulsified drug delivery system as claimed in claim 1 is characterized in that, also comprises other pharmaceutic adjuvant that is selected from antioxidant, antibacterial, thickening agent, coloring agent, flavoring agent.
3; supersaturated cationic self-emulsified drug delivery system as claimed in claim 1; wherein said cationic surfactant is selected from stearmide; oleamide; N-[1-(2; 3-two oily acyloxy) propyl group]-N; N; the N-trimethyl ammonium chloride; 1; 2-two oleoyl oxygen propyl group-N; N; the N-trimethylammonium bromide; 3 β-[N-(N '; N '-dimethyl aminoethyl) carbamoyl] cholesterol; 2; 3-two oleoyl oxygen-N-[2 (spermine Carboxylamide) ethyl-N; N-dimethyl-1-propyl group-trifluoroacetic acid ammonium; 1,2-two oleoyl oxygen propyl group-3-dimethyl-ethoxy ammonium bromide; Dodecyl trimethyl ammonium chloride; Tetradecyl Trimethyl Ammonium Bromide; cetyl trimethyl ammonium bromide; the two octadecyl trimethylammonium bromides of dimethyl; in the chitosan one or more.
4, supersaturated cationic self-emulsified drug delivery system as claimed in claim 3, wherein said cationic surfactant are selected from stearmide, oleamide, 1,2-two oleoyl oxygen propyl group-N, N, one or more in N-trimethylammonium bromide and the chitosan.
5, the preparation method of the described supersaturated cationic self-emulsified drug delivery system of claim 1: take by weighing the recipe quantity poorly water soluble drugs, surfactant, cosurfactant and oil phase, mix homogeneously, add the dissolving of cationic surfactant and high molecular polymer then or be suspended in wherein and get final product, wherein said surfactant is selected from (1) polyoxyethylene castor oil or polyoxyethylene hydrogenated Oleum Ricini, (2) Polyoxyethylene Sorbitol Fatty Acid Esters and polyoxyethylene sorbitan fatty acid ester, (3) polyoxyethylene fatty acid ester, (4) polyoxyethylene-propylene copolymer, (5) phospholipid, (6) propylene glycol list or di fatty acid ester, (7) Labrasol, Labrafac or Labrafil M, (8) d-alpha-tocopherol cetomacrogol 1000-succinate, (9) polyoxy ethyl hydroxy fatty acid.
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| CN102389405A (en) * | 2011-11-18 | 2012-03-28 | 中国药科大学 | Tripterine oral self-emulsification dispersible tablet and its preparation method |
| CN102415995B (en) * | 2011-12-09 | 2013-11-13 | 广东众生药业股份有限公司 | Oversaturated self-microemulsified progesterone composition and preparation method of same |
| CN103611214A (en) * | 2013-12-03 | 2014-03-05 | 上海交通大学 | Needle drug microsystem and preparation method thereof |
| CN105168129B (en) * | 2015-07-29 | 2018-02-23 | 山东迅达康生物科技有限公司 | A kind of vitamin E nano-emulsion and preparation method thereof |
| CN106667908A (en) * | 2016-12-29 | 2017-05-17 | 广州新济药业科技有限公司 | Supersaturated solid self-emulsifying preparation and preparation method thereof |
| CN108260820A (en) * | 2016-12-30 | 2018-07-10 | 内蒙古蒙牛乳业（集团）股份有限公司 | A kind of method of vitamin E online-emulsification |
| CN111729093B (en) * | 2020-06-29 | 2022-05-24 | 南京超维景生物科技有限公司 | Contrast agent film-forming agent composition, contrast agent film-forming lipid liquid, contrast agent and preparation method thereof |
| CN112023032B (en) * | 2020-09-14 | 2022-03-18 | 广东鼎信医药科技有限公司 | Pharmaceutical composition containing digestive enzyme and preparation method thereof |
| CN114948893A (en) * | 2022-04-30 | 2022-08-30 | 浙江工业大学 | Self-emulsifying soft capsule content containing hydrophilic macromolecule and preparation method thereof |
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