CN101491500A - Meglumine adenosine cyclphosphate microspheres and production method thereof - Google Patents
Meglumine adenosine cyclphosphate microspheres and production method thereof Download PDFInfo
- Publication number
- CN101491500A CN101491500A CNA2009100142529A CN200910014252A CN101491500A CN 101491500 A CN101491500 A CN 101491500A CN A2009100142529 A CNA2009100142529 A CN A2009100142529A CN 200910014252 A CN200910014252 A CN 200910014252A CN 101491500 A CN101491500 A CN 101491500A
- Authority
- CN
- China
- Prior art keywords
- preparation
- meglumine
- cycle phosphate
- lyophilized preparation
- microballoon lyophilized
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 title claims abstract description 108
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 title claims abstract description 67
- 229960003194 meglumine Drugs 0.000 title claims abstract description 67
- 239000002126 C01EB10 - Adenosine Substances 0.000 title claims abstract description 54
- 229960005305 adenosine Drugs 0.000 title claims abstract description 54
- 239000004005 microsphere Substances 0.000 title claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 title description 3
- 238000002360 preparation method Methods 0.000 claims abstract description 56
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 claims abstract description 16
- 239000004094 surface-active agent Substances 0.000 claims abstract description 16
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 15
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 13
- 229920001610 polycaprolactone Polymers 0.000 claims abstract description 13
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 13
- 239000004632 polycaprolactone Substances 0.000 claims abstract description 11
- 229910019142 PO4 Inorganic materials 0.000 claims description 51
- 239000010452 phosphate Substances 0.000 claims description 49
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000012153 distilled water Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- 239000012071 phase Substances 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- 230000000065 osmolyte Effects 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- 239000004471 Glycine Substances 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 6
- 239000000839 emulsion Substances 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 5
- -1 NaTDC Substances 0.000 claims description 5
- 239000008346 aqueous phase Substances 0.000 claims description 5
- 238000004108 freeze drying Methods 0.000 claims description 5
- 229920001993 poloxamer 188 Polymers 0.000 claims description 5
- 229940044519 poloxamer 188 Drugs 0.000 claims description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000002504 physiological saline solution Substances 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- NWGKJDSIEKMTRX-MDZDMXLPSA-N Sorbitan oleate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(O)C1OCC(O)C1O NWGKJDSIEKMTRX-MDZDMXLPSA-N 0.000 claims description 3
- 238000013019 agitation Methods 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 210000002381 plasma Anatomy 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 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 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000000413 hydrolysate Substances 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 2
- 229940068977 polysorbate 20 Drugs 0.000 claims description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 2
- 235000011067 sorbitan monolaureate Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 235000010445 lecithin Nutrition 0.000 claims 1
- 239000000787 lecithin Substances 0.000 claims 1
- 229940067606 lecithin Drugs 0.000 claims 1
- 235000021317 phosphate Nutrition 0.000 description 41
- 241000699670 Mus sp. Species 0.000 description 13
- 239000003814 drug Substances 0.000 description 13
- 238000012360 testing method Methods 0.000 description 11
- 239000007924 injection Substances 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000036571 hydration Effects 0.000 description 3
- 238000006703 hydration reaction Methods 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- 206010018910 Haemolysis Diseases 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000008176 lyophilized powder Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 238000012372 quality testing Methods 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- GDWYWCNMRAOMAW-MCDZGGTQSA-N [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C=NC=2C(N)=NC=NC12.[P] Chemical compound [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C=NC=2C(N)=NC=NC12.[P] GDWYWCNMRAOMAW-MCDZGGTQSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 230000000680 avirulence Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000000254 damaging effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a meglumine adenosine cyclphosphate microsphere lyophilized preparation. The preparation is characterized in that the preparation is mainly prepared from adenosine cyclophosphate, meglumine, polycaprolactone, polyvinyl alcohol, a surfactant, an osmosis regulator and a lyophilized supporting agent.
Description
Technical field
The present invention relates to a kind of new medicinal preparation, particularly a kind of meglumine adenosine cycle phosphate microballoon lyophilized preparation and preparation method thereof.
Background technology
Adenosine cyclophosphate is slightly soluble in water, add meglumine and can increase its dissolubility, yet, in meglumine adenosine cycle phosphate solution, prolongation along with the holding time, adenosine cyclophosphate can be separated out gradually, it is rotten, muddy that medicinal liquid is taken place, thereby influence the curative effect of medicine, influence the safety of medication simultaneously, meglumine adenosine cycle phosphate solution is in solution state preservation process, easily meeting light changes, make drug degradation, cause that clinical anaphylaxis increases curative effect and descends, and meglumine adenosine cycle phosphate solution is subject to Effect of Environmental oxidation, polymerization and the medicine structure is changed.CN1459288A provides a kind of infusion solutions of meglumine adenosine cycle phosphate, is prepared from by meglumine adenosine cycle phosphate, glucose, citric acid adding distil water, and shortcoming is to place and poor storage stability, transportation inconvenience.CN1579413A provides a kind of meglumine cyclic adenosine for injecta, and it directly makes common lyophilized formulations with adenosine cyclophosphate, meglumine and excipient, and shortcoming is that lyophilized powder cannot not subside loosely, sticks together easily, is difficult for aquation.Above technology all is to adopt meglumine adenosine cycle phosphate as raw material, has also further increased its production cost.
The closure globule that microsphere is made up of biodegradable macromolecular material is a kind of novel form of current targeting drug delivery system.Microsphere enters behind the human body mainly by reticuloendothelial system phagocytic, medicine is accumulated in the abundant histoorgan of macrophages such as liver, spleen and bone marrow, has increased local drug concentration, improve curative effect of medication, reduce the distribution of medicine simultaneously, reduce poisonous side effect of medicine at whole body.
CN1533765A provides a kind of lyophilized formulations of anticarcinogen colchicine microsphere, and its preparation method is hereby incorporated by.
The inventor is by long-term creationary discovering, the phosphorus adenosine Portugal amine microballoon lyophilized preparation of selecting for use certain excipient to make, not only improved the storage stability of meglumine adenosine cycle phosphate widely, improve its drug level but also be beneficial to, increase curative effect of medication and drug safety, be a kind of new preparation method, domesticly do not see similar report as yet.
Summary of the invention
The object of the present invention is to provide a kind of meglumine adenosine cycle phosphate microballoon lyophilized preparation and preparation method thereof.
The invention provides the agent of a kind of meglumine adenosine cycle phosphate microballoon lyophilized preparation, it is characterized in that said preparation mainly is to be made by adenosine cyclophosphate, meglumine, polycaprolactone, polyvinyl alcohol, surfactant, Osmolyte regulator, frozen-dried supporting agent.
Described each ingredients weight parts of meglumine adenosine cycle phosphate microballoon lyophilized preparation is counted:
1.7～63 parts of adenosine cyclophosphate
1.0～37 parts of meglumines
5.4～100 parts of polycaprolactones
1.8～10 parts of polyvinyl alcohol
2.5～10 parts in surfactant
1～100 part of Osmolyte regulator
10～300 parts of frozen-dried supporting agents
Wherein surfactant is selected from one or more in polyoxyethylene sorbitan monoleate, polysorbate 20, poloxamer 188, NaTDC, sodium lauryl sulphate, dodecyl sodium sulfate, sorbester p17, span 20, the lecithin series; Osmolyte regulator is a sodium chloride.
Described frozen-dried supporting agent is selected from one or more in mannitol, lactose, glucose, sorbitol, sucrose, maltose, glycine, glycine, the gelatin hydrolysate.
A kind of preparation method of meglumine adenosine cycle phosphate microballoon lyophilized preparation is characterized in that: polyvinyl alcohol, Osmolyte regulator and surfactant dissolves in distilled water, are got water; Adenosine cyclophosphate, meglumine and polycaprolactone are dissolved in the organic solvent, get oil phase; Oil phase slowly is injected into aqueous phase, and heating is stirred, and adds frozen-dried supporting agent again, carries out lyophilization, obtains the white loose block.
A kind of preparation method of meglumine adenosine cycle phosphate microballoon lyophilized preparation is characterized in that may further comprise the steps:
(1) polyvinyl alcohol is used dissolved in distilled water earlier, add surfactant and sodium chloride again, stirring and dissolving is complete, obtains and the isoosmotic aqueous solution of blood plasma, is water;
(2) adenosine cyclophosphate, meglumine and polycaprolactone are dissolved in the organic solvent altogether, stir;
(3) oil phase is slowly added aqueous phase, and continue to stir, solution temperature maintains 50～60 ℃, and oil phase is diffused into water rapidly, forms O/W or w/o type Emulsion;
(4) Emulsion that obtains is heated under magnetic agitation, remove organic solvent, get suspension, centrifugal, residual with distilled water wash organic solvent and surfactant, get the microsphere precipitate;
(5) with microsphere solid precipitate 0.9% physiological saline solution that obtains, add frozen-dried supporting agent, to stir 10～30 minutes, vacuum lyophilization gets the white loose block.
Organic solvent described in the above preparation process is preferably from chloroform, dichloromethane, ethanol, acetone, methanol, normal hexane or any two kinds of mixture.
Surfactant is preferably from polyoxyethylene sorbitan monoleate or poloxamer 188.
Frozen-dried supporting agent is preferably from mannitol or glycine.
The invention has the beneficial effects as follows meglumine adenosine cycle phosphate microballoon lyophilized preparation 0.9% physiological saline solution with method for preparing, then be dispersed into uniform meglumine adenosine cycle phosphate microsphere aqueous solution immediately, its effective ingredient is a meglumine adenosine cycle phosphate microsphere wherein, scanning electron microscope records the mean diameter of liposome after the hydration less than 1um, and 80% particle diameter is between 200～300nm.Because after the meglumine adenosine cycle phosphate microballoon lyophilized preparation of the present invention hydration, the particle diameter of meglumine adenosine cycle phosphate microsphere is little, can be compatible in vivo.By microsphere is medicine degradable, the avirulence in vivo of carrier, has the advantages that to discern mutant.The particle diameter of meglumine adenosine cycle phosphate is little, and liver, spleen tissue are had natural targeting, has therefore improved the accumulation of meglumine adenosine cycle phosphate in hepatic tissue, has improved the therapeutical effect of meglumine adenosine cycle phosphate.The safety investigation of sample has been carried out in this experiment, comprises the test of irritation test and hemolytic, and result of the test shows, experimental animal there is no stimulates the sexual abnormality reaction, the meglumine adenosine cycle phosphate microballoon lyophilized preparation is safe and reliable, nonirritant, and do not have hemolytic reaction.The method technology of the meglumine adenosine cycle phosphate microballoon lyophilized preparation that the present invention produces is simple, need not special installation, thereby production cost is low, is suitable for large-scale industrial production.
The specific embodiment
The preparation that embodiment 1 meglumine adenosine cycle phosphate is microballoon lyophilized dose
Adenosine cyclophosphate 30g
Meglumine 17.8g
Polycaprolactone 95.6g
Polyvinyl alcohol 31.8g
Polyoxyethylene sorbitan monoleate 45g
Sodium chloride 18g
Mannitol 180g
Ethanol 500ml
Distilled water 2000ml
Preparation technology
(1) take by weighing the 31.8g polyvinyl alcohol and use the 500ml dissolved in distilled water earlier, add 45g polyoxyethylene sorbitan monoleate and 18g sodium chloride again, stirring and dissolving is complete, obtains and the isoosmotic aqueous solution of blood plasma, is water;
(2) take by weighing 30g adenosine cyclophosphate, 17.8g meglumine and 95.6g polycaprolactone and be dissolved in altogether in the 500ml ethanol, stir;
(3) oil phase is slowly added aqueous phase, and continue to stir, solution temperature maintains 55 ℃, and oil phase is diffused into water rapidly, forms O/W or w/o type Emulsion;
(4) Emulsion that obtains is heated under magnetic agitation, remove ethanol, get suspension, centrifugal, residual with distilled water wash organic solvent and surfactant, get the microsphere precipitate;
(5) with microsphere solid precipitate 0.9% physiological saline solution that obtains, add 180g mannitol, to stir 30 minutes, vacuum lyophilization gets the white loose block.
The preparation that embodiment 2 meglumine adenosine cycle phosphates are microballoon lyophilized dose
Adenosine cyclophosphate 60g
Meglumine 35.6g
Polycaprolactone 95.6g
Polyvinyl alcohol 9.56g
Sorbester p17 9.56g
Sodium chloride 27g
Lactose 285g
Chloroform 700ml
Distilled water 3000ml
Preparation technology makes the white loose block with embodiment 1.
The preparation that embodiment 3 meglumine adenosine cycle phosphates are microballoon lyophilized dose
Adenosine cyclophosphate 90g
Meglumine 53.4g
Polycaprolactone 215.1g
Polyvinyl alcohol 43g
Poloxamer 188 107.5g
Sodium chloride 36g
Glycine 430g
Acetone 1000ml
Distilled water 4000ml
Preparation technology makes the white loose block with embodiment 1.
The particle size determination of embodiment 4 meglumine adenosine cycle phosphate microballoon lyophilized preparations
Get the meglumine adenosine cycle phosphate microsphere of embodiment 1-3 preparation, the distilled water dissolving is observed with current potential particle diameter instrument.The mean diameter of liposome is less than 1um after the hydration of current potential particle diameter instrument mensuration meglumine adenosine cycle phosphate microsphere of the present invention, and 80% particle diameter is between 200～300nm.
The stability study of embodiment 5 meglumine adenosine cycle phosphate microballoon lyophilized preparations
The meglumine adenosine cycle phosphate microballoon lyophilized preparation prepared to each embodiment carries out quality testing and stability study, simultaneously with the comparison of the lyophilized powder (product B) of the transfusion (product A) of itself and CN1459288 embodiment 1 and CN1579413A embodiment 1.With above product under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months respectively, carry out accelerated test and investigate; Under 25 ℃ of high temperature, relative humidity 60% ± 10% condition 18 months, carry out long term test and investigate, detect the variation of every quality index, the gained data are shown in table 1-3:
0 day quality testing result of table 1
Table 2 accelerated test result
Table 3 long-term test results
Conclusion: by above data result as can be seen, the sample quality conformance with standard requirement that the present invention makes, after quickening June and long-term 18 months experiment, every quality index does not have significant change, all meets quality standard.And compare with the product of prior art, find out that obviously product of the present invention has improved storage stability greatly.
The irritation test of embodiment 6 meglumine adenosine cycle phosphate microballoon lyophilized preparations
1, white mice intravenous injection
Test method: select 10 of healthy mices, body weight 21.0～25.0g is divided into two groups at random.The microballoon lyophilized system of meglumine adenosine cycle phosphate that adopts embodiment 2 to make.One group of 5 white mice, tail vein injection 0.4ml meglumine adenosine cycle phosphate microballoon lyophilized preparation injection, 5 white mice of matched group, tail vein injection is with dosage 0.9% normal saline.In one hour, observe the administration mice and do not have any Deviant Behavior after the administration, the nonirritant reaction, mice is movable and diet is unaffected, and the meglumine adenosine cycle phosphate microballoon lyophilized preparation injection of being injected is to the blood vessel nonirritant; After giving mouse tail vein injection, the mice vascular venous is organized non-stimulated damaging action.
2, mice by intraperitoneal injection method
Test method: select 10 of healthy mices, body weight 21.0～25.0g is divided into two groups at random.The microballoon lyophilized system of meglumine adenosine cycle phosphate that adopts embodiment 2 to make.One group of 5 white mice, lumbar injection 0.2ml meglumine adenosine cycle phosphate microballoon lyophilized preparation injection, 5 white mice of matched group, lumbar injection is with dosage 0.9% normal saline.In one hour, observe the administration mice and do not have any Deviant Behavior after the administration, the nonirritant reaction, mice is movable and diet is unaffected, and the meglumine adenosine cycle phosphate microballoon lyophilized preparation injection of being injected is to nonirritant.
This experiment has simultaneously been carried out the safety investigation to prepared sample, comprises the test of irritation test and hemolytic, and the result shows meglumine adenosine cycle phosphate microballoon lyophilized preparation safety, reliable, nonirritant, and do not have hemolytic reaction.
In above-mentioned each experiment, experimental animal there is no stimulates the sexual abnormality reaction.Result of the test shows that the meglumine adenosine cycle phosphate microballoon lyophilized preparation is safe and reliable.
Claims (10)
1, a kind of meglumine adenosine cycle phosphate microballoon lyophilized preparation is characterized in that said preparation mainly is to be made by adenosine cyclophosphate, meglumine, polycaprolactone, polyvinyl alcohol, surfactant, Osmolyte regulator, frozen-dried supporting agent.
2, the described meglumine adenosine cycle phosphate microballoon lyophilized preparation of claim 1 is characterized in that each component counts by weight:
1.7～63 parts of adenosine cyclophosphate
1.0～37 parts of meglumines
5.4～100 parts of polycaprolactones
1.8～10 parts of polyvinyl alcohol
2.5～10 parts in surfactant
1～100 part of Osmolyte regulator
10～300 parts of frozen-dried supporting agents.
3, the described meglumine adenosine cycle phosphate microballoon lyophilized preparation of claim 1-2 is characterized in that described surfactant is selected from one or more in polyoxyethylene sorbitan monoleate, polysorbate 20, poloxamer 188, NaTDC, sodium lauryl sulphate, dodecyl sodium sulfate, sorbester p17, span 20, the lecithin.
4, the described meglumine adenosine cycle phosphate microballoon lyophilized preparation of claim 1-2 is characterized in that Osmolyte regulator is a sodium chloride.
5, the described meglumine adenosine cycle phosphate microballoon lyophilized preparation of claim 1-2 is characterized in that frozen-dried supporting agent is selected from one or more in mannitol, lactose, glucose, sorbitol, sucrose, maltose, glycine, glycine, the gelatin hydrolysate.
6, the preparation method of each described meglumine adenosine cycle phosphate microballoon lyophilized preparation of claim 1-5 is characterized in that: polyvinyl alcohol, Osmolyte regulator and surfactant dissolves in distilled water, are got water; Adenosine cyclophosphate, meglumine and polycaprolactone are dissolved in the organic solvent, get oil phase; Oil phase slowly is injected into aqueous phase, and heating is stirred, and adds frozen-dried supporting agent again, carries out lyophilization, obtains the white loose block.
7, the preparation method of the described meglumine adenosine cycle phosphate microballoon lyophilized preparation of claim 6 is characterized in that may further comprise the steps:
(1) polyvinyl alcohol is used dissolved in distilled water earlier, add surfactant and sodium chloride again, stirring and dissolving is complete, obtains and the isoosmotic aqueous solution of blood plasma, is water;
(2) adenosine cyclophosphate, meglumine and polycaprolactone are dissolved in the organic solvent altogether, stir;
(3) oil phase is slowly added aqueous phase, and continue to stir, solution temperature maintains 50～60 ℃, and oil phase is diffused into water rapidly, forms O/W or w/o type Emulsion;
(4) Emulsion that obtains is heated under magnetic agitation, remove organic solvent, get suspension, centrifugal, residual with distilled water wash organic solvent and surfactant, get the microsphere precipitate;
(5) with microsphere solid precipitate 0.9% physiological saline solution that obtains, add frozen-dried supporting agent, to stir 10～30 minutes, vacuum lyophilization gets the white loose block.
8, the preparation method of the described meglumine adenosine cycle phosphate microballoon lyophilized preparation of claim 6～7 is characterized in that described organic solvent is selected from chloroform, dichloromethane, ethanol, acetone, methanol, normal hexane or any two kinds of mixture.
9, by the preparation method of the described meglumine adenosine cycle phosphate microballoon lyophilized preparation of claim 6～8, it is characterized in that surfactant is selected from polyoxyethylene sorbitan monoleate or poloxamer 188.
10, by the preparation method of the described meglumine adenosine cycle phosphate microballoon lyophilized preparation of claim 6～9 agent, it is characterized in that frozen-dried supporting agent is selected from mannitol or glycine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100142529A CN101491500B (en) | 2009-02-19 | 2009-02-19 | Meglumine adenosine cyclphosphate microspheres and production method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100142529A CN101491500B (en) | 2009-02-19 | 2009-02-19 | Meglumine adenosine cyclphosphate microspheres and production method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101491500A true CN101491500A (en) | 2009-07-29 |
| CN101491500B CN101491500B (en) | 2011-02-02 |
Family
ID=40922404
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100142529A Expired - Fee Related CN101491500B (en) | 2009-02-19 | 2009-02-19 | Meglumine adenosine cyclphosphate microspheres and production method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101491500B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103417474A (en) * | 2012-05-15 | 2013-12-04 | 袁璐 | Calcium dibutyacyladenosine cyclophosphate-containing composition for injection |
-
2009
- 2009-02-19 CN CN2009100142529A patent/CN101491500B/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103417474A (en) * | 2012-05-15 | 2013-12-04 | 袁璐 | Calcium dibutyacyladenosine cyclophosphate-containing composition for injection |
| CN103417474B (en) * | 2012-05-15 | 2014-09-03 | 袁璐 | Calcium dibutyacyladenosine cyclophosphate-containing composition for injection |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101491500B (en) | 2011-02-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPS5823630A (en) | Remedy for drug abstinence symptom | |
| CN100496609C (en) | Stable liposome composition | |
| CN103169670B (en) | A kind of acetic acid copaxone microsphere and preparation method thereof | |
| WO2016124162A1 (en) | Propanidid pharmaceutical composition and preparation method therefor | |
| WO2023109801A1 (en) | Supramolecular hydrogel capable of lipophilic drug delivery, preparation method therefor, and use thereof | |
| CN103948911B (en) | A kind of echinocandin antifungal agent thing sustained release microsphere agents and preparation method thereof | |
| CN101984958A (en) | Nanoscale albendazole micropowder and preparation method thereof | |
| CN101700229B (en) | Prostaglandin E1 long-circulation fat microsphere preparation for intravenous injection and preparation method thereof | |
| Liu et al. | Thermosensitive selenium hydrogel boosts antitumor immune response for hepatocellular carcinoma chemoradiotherapy | |
| CN101491500B (en) | Meglumine adenosine cyclphosphate microspheres and production method thereof | |
| CN105997889B (en) | A kind of subcutaneous injection Amifostine sustained-release micro-spheres and preparation method thereof | |
| CN101474159B (en) | Creatine phosphate sodium microballoon lyophilized preparation and method for producing the same | |
| CN102311512A (en) | Cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer and preparation method thereof | |
| CN101768279B (en) | Hydroxypropy rotaxane-phospholipid polymer, preparation method thereof and application thereof | |
| CN105311622B (en) | A kind of combination medicine that treating pain and its preparation, preparation method | |
| CN105832744B (en) | A kind of Alprostadil freeze-dried emulsion composition of injection | |
| CN101444491A (en) | Ozagrel sodium microballoon lyophilized preparation and preparation method thereof | |
| CN112190567B (en) | Preparation method and application of ivermectin sustained-release microspheres | |
| CN103637985B (en) | A kind of stable PGE1 lyophilizing breast and preparation method thereof | |
| CN102753151B (en) | Particulate medicinal composition | |
| CN104606130B (en) | A kind of Tropisetron HCl parenteral solution and preparation method thereof | |
| CN110856746B (en) | Freeze-dried micelle preparation containing carfilzomib and preparation method thereof | |
| CN103509066A (en) | Lipid derivative containing sialic acid fragment and application thereof | |
| CN101428142B (en) | Process for producing recombinant human vascular endothelial inhibitor composition sustained-release microsphere | |
| Tulsani et al. | Immobilization of hormones for drug targeting |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: HAINAN YONGTIAN PHARMACEUTICAL INSTITUTE CO., LTD. Free format text: FORMER OWNER: TAO LINGGANG Effective date: 20130723 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 570125 HAIKOU, HAINAN PROVINCE TO: 570216 HAIKOU, HAINAN PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20130723 Address after: 570216 C03, Haikou Free Trade Zone, Hainan, China Patentee after: Hainan Yongtian Pharmaceutical Institute Co., Ltd. Address before: The new business building No. 48 570125 Hainan city of Haikou province China World Trade Center Road, room 2601 Patentee before: Tao Linggang |
|
| DD01 | Delivery of document by public notice |
Addressee: Hainan Yongtian Pharmaceutical Institute Co., Ltd. Document name: Notification to Pay the Fees |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110202 Termination date: 20160219 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |