CN103381138B - Statins oral self-micro-emulsification medicine-releasing preparation and preparation method thereof - Google Patents
Statins oral self-micro-emulsification medicine-releasing preparation and preparation method thereof Download PDFInfo
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Abstract
The invention provides a kind of statins oral self-micro-emulsification medicine-releasing preparation and preparation method thereof, preparation comprises the statins self-emulsifying microemulsion concentrated solution for the treatment of effective dose and medically acceptable carrier.Described self-emulsifying microemulsion concentrated solution is made up of the component of following percentage by weight: (3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium 1%-10%, oil phase 10%-60%, emulsifying agent 20%-75%, co-emulsifier 2%-45%, additives 0%-5%.It can increase drug solubility, and improve oral absorbability, and cost is low, technique is simple.Drug loading of the present invention not only drug loading is higher, and can ensure the whole stripping of medicine; Pharmaceutical pack is rolled in microemulsion and is protected in addition, improves stability in vivo, has no simultaneously and increases blood drug concentration and the drug level that significantly improves in target site liver.
Description
Technical field
The present invention relates to a kind of tading kind medicinal preparation and preparation method thereof, specifically, relate to (3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium oral self-micro-emulsification medicine-releasing preparation and preparation method thereof.
Background technology
It is one of main cause causing cardiovascular disease that plasma low density lipoprotein cholesterol (LDL-C) concentration raises.3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, i.e. statins, the synthesis of the key substance mevalonic acid in Biosynthesis of cholesterol rate-limiting step can be suppressed, effectively reduce LDL-C concentration, thus reduce the risk of cardiovascular disease.Due to the effectiveness and reliability of statins, become the choice drug for the treatment of hypercholesterolemia.The statins that gone on the market has lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, Rosuvastatin and Pitavastatin.
(3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium is statins (Chinese patent CN200910199486.5), and its chemical structural formula is as follows:
It is 6-isopropyl-2-(N-methyl-N-first sulfo group) amino-4-substituent phenoxy pyrimidines, this kind of compound water soluble is poor, has had a strong impact on drug-eluting and absorption.
(3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium belongs to statin one kind new medicine, compare with atorvastatin with Pitavastatin existing in prior art, Rosuvastatine, this medicine has the activity of better or at least equivalent suppression HMG-CoA reductase.In prior art, the structure of statins is made up of female ring (indole ring, pyrrole ring, quinoline ring, pyrimidine ring etc.) and side chain two parts.(3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium has carried out to Pitavastatin the medicine stronger to HMG-CoA reductase inhibit activities that a series of structure of modification obtains.In addition the representative medicine of pyrimidines is Rosuvastatine, and it is external to HMG-CoA reductase IC
50for 5nM, be that in 7 statins (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, Rosuvastatin and Pitavastatin) gone on the market, drug effect is best.In existing statins except pravastatin and fluvastatin become sodium salt after dissolubility better, all there is solubility problem in other statins.
At present, it is low to there is drug loading in statin compound SMEDDS, after forming microemulsion, stripping is incomplete, the problems such as medicine precipitation, blood circulation drug concentration is not improved in addition while raising liver target site drug level, in order to avoid cause side effect, it is also the key issue of the needs solution that statin compound SMEDDS exists.
Summary of the invention
An object of the present invention is to provide a kind of statins self-emulsifying microemulsion concentrated solution, to overcome the above-mentioned defect that prior art exists.
Another object of the present invention is to provide a kind of statins oral self-micro-emulsification medicine-releasing preparation and preparation method thereof, to meet the needs of clinical practice.
Described statins self-emulsifying microemulsion concentrated solution, is made up of the component of following percentage by weight:
The percentage ratio sum of each component above-mentioned is 100%.
Wherein, (3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium is described statins;
Described oil phase is selected from C
8-C
10fatty glyceride (MCT), oleic acid, Ethyl linoleate, ethyl oleate, isopropyl myristate, glyceryl linoleate (Maisine, HLB=3), sad certain herbaceous plants with big flowers acid glycerol three ester (LabrafacLipophile WL 1349, HLB=1), C
8-C
10triglyceride (Labrafac CC, HLB=1) or propylene glycol caprylic certain herbaceous plants with big flowers acid esters (Labrafac PG, HLB=2) in more than one;
Described emulsifying agent is selected from polyoxyethylene castor oil (Cremophor EL), polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH), the sad certain herbaceous plants with big flowers acid esters of PEG-8 glycerol (Labrasol, HLB=14), Tween 80, polyethyleneglycol-12-hydroxy stearin (Solutal, HLB=15) more than one or in Gelucire 44/14 (Gelucire 44/14, HLB=14);
Described co-emulsifier is selected from ethanol, glycerol, propylene glycol, PEG400, oleic acid polyethyleneglycol glyceride (Labrafil M1944CS, HLB=4) more than one, in Capryol 90 (Capryol 90, HLB=6) or ethylene glycol monomethyl ether (Transcutol HP);
Described additives are selected from vitamin E, vitamin C, P-hydroxybenzoic acid and so on or benzalkonium bromide;
Preferably, described statins self-emulsifying microemulsion concentrated solution, is made up of the component of following percentage by weight:
(3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium 2.50%-7.5%
The percentage ratio sum of each component above-mentioned is 100%.
Described statins oral self-micro-emulsification medicine-releasing preparation, comprise the described statins self-emulsifying microemulsion concentrated solution for the treatment of effective dose and medically acceptable carrier, described carrier refers to the pharmaceutical carrier of pharmaceutical field routine.If diluent, excipient are as water etc., filler, as starch, microcrystalline Cellulose, pregelatinized Starch etc., binding agent, as hypromellose, hyprolose etc., disintegrating agent, as polyvinylpolypyrrolidone, carboxymethylstach sodium etc., lubricant, as micropowder silica gel, magnesium stearate etc.;
The preparation method of described statins oral self-micro-emulsification medicine-releasing preparation, comprises the steps:
By oil phase, emulsifying agent, co-emulsifier, additives and (3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium, is heated to 10 ~ 80 DEG C, stirs, make medicine dissolution, obtain (3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium self-emulsifying microemulsion concentrated solution;
Described statins self-emulsifying microemulsion concentrated solution is mixed with carrier, adopts method well known in the art, tablet, capsule, soft capsule, oral liquid, granule etc. can be prepared as;
Or by described statins self-emulsifying microemulsion concentrated solution, adopt method fill well known in the art in capsule, can capsule be obtained;
Described statins oral self-micro-emulsification medicine-releasing preparation, for a kind of oral self-micro-emulsification medicine-releasing preparation, described self-micro-emulsification medicine-releasing preparation, refer to the Thermodynamically stable formed by oil phase, emulsifying agent and co-emulsifier, homogeneous, transparent or semitransparent, isotropic solution, after adding aqueous medium when ambient temperature (being often referred to about 37 DEG C) and gentle agitation, spontaneous emulsification forms the Emulsion of particle diameter <100nm.
The inventive method is very simple, is easy to operation.
Inventor, through research extensively and profoundly, is surprised to find that, the drug loading of preparation of the present invention is compared with the drug loading of the statin compound reported in document, and not only drug loading is higher, and can ensure the whole stripping of medicine; Pharmaceutical pack is rolled in microemulsion and is protected in addition, improves stability in vivo; The having no of preparation of the present invention increases blood drug concentration and the drug level that significantly improves in target site liver.
Accompanying drawing explanation
Fig. 1 is (3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing system grain size distribution.
Fig. 2 is (3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing system and (3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium ordinary tablet stripping curve comparison diagram in water.
Fig. 3 is the releasing curve diagram of (3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing system in different medium.
Fig. 4 is (3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing system and (3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium 2.5% Tween 80/2.5%DMSO solution liver drug distribution comparison diagram in Mice Body.
In order to set forth the present invention further, provide a series of embodiment below.These embodiments are illustrative completely, and they are only used for being specifically described the present invention, not should be understood to limitation of the present invention.
Detailed description of the invention
Embodiment 1
Prescription forms
Preparation technology: make medicine dissolution complete 40 DEG C of stirrings each component, (3R, 5S, 6E)-7-[6-fluoro-4 can be obtained, 7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium self-emulsifying microemulsion concentrated solution, is then potted in hard capsule, (the 3R described in acquisition, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium preparation.
Embodiment 2
Prescription forms:
Preparation method is with embodiment 1.
Embodiment 3
Prescription forms:
Preparation method is with embodiment 1.
Embodiment 4
Prescription forms:
Preparation method is with embodiment 1.
Embodiment 5
Prescription forms:
Preparation method is with embodiment 1.
Embodiment 6
Prescription forms:
Preparation method is with embodiment 1.
Embodiment 7
Prescription forms:
Preparation method is with embodiment 1.
Embodiment 8
Prescription forms:
Preparation method is with embodiment 1.
Embodiment 9
Prescription forms:
Preparation method is with embodiment 1.
Embodiment 10
Prescription forms:
Preparation method is with embodiment 1.
Embodiment 11
Prescription forms:
Preparation method is with embodiment 1.
Embodiment 12
(3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing preparation physicochemical property prepared by embodiment 1:
Get (3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing system concentrated solution is appropriate, and at 37 DEG C, 50r/min magnetic agitation is added to the water stirring, obtains the solution of clear band blue-opalescent.Adopt Laser Scattering Particle analyzer to measure its size and distribution above-mentioned solution, obtaining particle diameter is 41.4nm, and grain size distribution is shown in accompanying drawing.
Embodiment 13
(3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing preparation prepared by embodiment 1 compares with ordinary tablet dissolution:
Carry out according to the second law regulation in " Chinese Pharmacopoeia " (2010 editions) annex XC, rotating speed of agitator 50r/min, bath temperature (37 ± 0.5) DEG C, release medium is water 900ml.Drop into (3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing capsule and conventional tablet, respectively at 5,10,20,30,45,60min samples 2ml, 0.45 μm of filtering with microporous membrane, supplement synthermal 2ml release medium simultaneously, get subsequent filtrate 10 μ l and carry out HPLC mensuration.Result shows (3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing preparation 60min stripping percentage composition 102.88% in water is 4 times of ordinary tablet (24.35%).(3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing preparation and ordinary tablet stripping curve comparison diagram in water are shown in accompanying drawing 2.
Embodiment 14
(3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing preparation prepared by embodiment 1 is at different medium dissolution study:
Carry out according to the second law regulation in " Chinese Pharmacopoeia " (2010 editions) annex XC, rotating speed of agitator 50r/min, bath temperature (37 ± 0.5) DEG C, release medium is water, 0.1mol/ml hydrochloric acid, simulated intestinal fluid (pH=6.8) 900ml.Drop into (3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing capsule and conventional tablet, respectively at 5,10,20,30,45,60min samples 2ml, 0.45 μm of filtering with microporous membrane, supplement synthermal 2ml release medium simultaneously, get subsequent filtrate 10 μ l and carry out HPLC mensuration.Result shows (3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing preparation is in water, 0.1mol/ml hydrochloric acid, simulated intestinal fluid (pH=6.8) 60min all strippings.The stripping curve figure of (3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing preparation in different medium is shown in accompanying drawing 3.
Embodiment 15
(3R prepared by embodiment 1,5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing preparation and (3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] liver drug distribution research in base-3,5-dihydroxy-6-heptenoic acid calcium 2.5% Tween 80/2.5%DMSO solution Mice Body:
Healthy mice 90, body weight 22-26g, be divided at random 2 groups (often organizing 45), gavage gives (3R respectively, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing preparation and (3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium 2.5% Tween 80/2.5%DMSO solution (24mg/kg).
Fasting 12 hours before experiment, administration on an empty stomach in morning, whole experimentation can't help water.After administration, 5min, 10min, 1h, 2h, 3h, 5h, 7h and 9h put to death, and anatomical acquisition liver immediately, washes down remained on surface blood and content with cold saline, after blotting, posts label, with the homogenate of 2mL/g normal saline, obtains tissue homogenate LC-MS and measures.
Result shows, give (3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3, after 5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing preparation, medicine is give (3R, 5S, 6E)-7-[6-fluoro-4 in the amount that liver is assembled, 7-diphenyl sulfide yl-quinoline-3] after base-3,5-dihydroxy-6-heptenoic acid calcium 2.5% Tween 80/2.5%DMSO solution 4 times.
(3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing preparation and (3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] liver concentration-time plot is shown in accompanying drawing 4 in base-3,5-dihydroxy-6-heptenoic acid calcium 2.5% Tween 80/2.5%DMSO solution Mice Body.
Embodiment 16
Embodiment 2 ~ 11 prepare (3R, 5S, 6E)-7-[fluoro-4, the 7-diphenyl sulfide yl-quinolines-3 of 6-] base-3,5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing preparation particle diameter, dissolution, liver drug distribution research in Mice Body:
Experimental technique is with embodiment 12 ~ 15.
Result shows, (3R prepared by embodiment 2 ~ 11, 5S, 6E)-7-[6-fluoro-4, 7-diphenyl sulfide yl-quinoline-3] base-3, 5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing preparation particle diameter is 22.4 ~ 92.7nm, dissolution is greater than 90%, calculate liver drug distribution time area under curve (AUC) in Mice Body, and compared with solution group in embodiment 13, (3R, 5S, 6E)-7-[6-fluoro-4, 7-diphenyl sulfide yl-quinoline-3] base-3, 5-dihydroxy-6-heptenoic acid calcium self-micro-emulsification medicine-releasing preparation AUC is 2 ~ 4 times of solution group, illustrate that it can be assembled to target site liver in vivo, and have no raising blood drug level, be expected to improve curative effect of medication and reduce side effect.
The foregoing is only preferred embodiment of the present invention, and be not used to limit substantial technological context of the present invention, substantial technological content of the present invention is broadly defined in the right of application, any technology entities that other people complete or method, if with application right define identical, also or a kind of change of equivalence, be all covered by being regarded as among this right.
Claims (5)
1. statins self-emulsifying microemulsion concentrated solution, is characterized in that, is made up of the component of following percentage by weight:
The percentage ratio sum of each component above-mentioned is 100%;
Described oil phase is selected from C
8-C
10fatty glyceride, oleic acid, Ethyl linoleate, ethyl oleate, isopropyl myristate, glyceryl linoleate, HLB=3, sad certain herbaceous plants with big flowers acid glycerol three ester, HLB=1, C
8-C
10triglyceride, HLB=1 or propylene glycol caprylic certain herbaceous plants with big flowers acid esters, more than one in HLB=2;
Described emulsifying agent is selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, the sad certain herbaceous plants with big flowers acid esters of PEG-8 glycerol, HLB=14, Tween 80, polyethyleneglycol-12-hydroxy stearin, HLB=15 or Gelucire 44/14, more than one in HLB=14;
Described co-emulsifier is selected from ethanol, glycerol, propylene glycol, PEG400, oleic acid polyethyleneglycol glyceride, HLB=4, Capryol 90, more than one in HLB=6 or ethylene glycol monomethyl ether.
2. statins self-emulsifying microemulsion concentrated solution according to claim 1, it is characterized in that, described additives are selected from vitamin E, vitamin C, P-hydroxybenzoic acid or benzalkonium bromide.
3. according to claim 1 or described statins self-emulsifying microemulsion concentrated solution, it is characterized in that, described statins self-emulsifying microemulsion concentrated solution, is made up of the component of following percentage by weight:
The percentage ratio sum of each component above-mentioned is 100%.
4. statins oral self-micro-emulsification medicine-releasing preparation, is characterized in that, comprises the statins self-emulsifying microemulsion concentrated solution described in any one of claims 1 to 3 for the treatment of effective dose and medically acceptable carrier.
5. the preparation method of statins oral self-micro-emulsification medicine-releasing preparation according to claim 1, it is characterized in that, comprise the steps: oil phase, emulsifying agent, co-emulsifier, additives and (3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium, is heated to 10 ~ 80 DEG C, stirs, make medicine dissolution, obtain (3R, 5S, 6E)-7-[6-fluoro-4,7-diphenyl sulfide yl-quinoline-3] base-3,5-dihydroxy-6-heptenoic acid calcium self-emulsifying microemulsion concentrated solution;
Described statins self-emulsifying microemulsion concentrated solution is mixed with carrier, is prepared as tablet, capsule, oral liquid or granule;
Or by described statins self-emulsifying microemulsion concentrated solution, fill, in capsule, can obtain capsule.
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| CN110865160B (en) * | 2019-10-25 | 2022-05-03 | 广东嘉博制药有限公司 | Method for measuring in-vitro release degree of propofol fat emulsion |
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| CN101570510A (en) * | 2008-04-30 | 2009-11-04 | 上海医药工业研究院 | Quinoline compound, pharmaceutical composition, preparation method and application thereof |
| CN102079726A (en) * | 2009-11-27 | 2011-06-01 | 上海医药工业研究院 | Miazine compounds, intermediates of miazine compounds, preparation method of intermediates and miazine compounds as well as application of miazine compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101570510A (en) * | 2008-04-30 | 2009-11-04 | 上海医药工业研究院 | Quinoline compound, pharmaceutical composition, preparation method and application thereof |
| CN102079726A (en) * | 2009-11-27 | 2011-06-01 | 上海医药工业研究院 | Miazine compounds, intermediates of miazine compounds, preparation method of intermediates and miazine compounds as well as application of miazine compound |
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