CN101507707B - Fasudil hydrochloride lipo-microballoons carrier preparation and preparation method thereof - Google Patents
Fasudil hydrochloride lipo-microballoons carrier preparation and preparation method thereof Download PDFInfo
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- CN101507707B CN101507707B CN2009101311986A CN200910131198A CN101507707B CN 101507707 B CN101507707 B CN 101507707B CN 2009101311986 A CN2009101311986 A CN 2009101311986A CN 200910131198 A CN200910131198 A CN 200910131198A CN 101507707 B CN101507707 B CN 101507707B
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- fasudic hydrochloride
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- 238000002360 preparation method Methods 0.000 title claims abstract description 81
- 229960002435 fasudil Drugs 0.000 title abstract description 8
- NGOGFTYYXHNFQH-UHFFFAOYSA-N fasudil Chemical compound C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 NGOGFTYYXHNFQH-UHFFFAOYSA-N 0.000 title abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 61
- 239000004005 microsphere Substances 0.000 claims abstract description 55
- 239000007924 injection Substances 0.000 claims abstract description 40
- 238000002347 injection Methods 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 13
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 13
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 6
- 235000019197 fats Nutrition 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 210000000582 semen Anatomy 0.000 claims description 23
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 21
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 21
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 18
- 239000008347 soybean phospholipid Substances 0.000 claims description 18
- 235000010265 sodium sulphite Nutrition 0.000 claims description 14
- 239000008215 water for injection Substances 0.000 claims description 13
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 12
- 235000006708 antioxidants Nutrition 0.000 claims description 12
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 claims description 11
- 239000007957 coemulsifier Substances 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 9
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 7
- HBOQXIRUPVQLKX-UHFFFAOYSA-N 2,3-di(octadeca-9,12-dienoyloxy)propyl octadeca-9,12-dienoate Chemical compound CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC HBOQXIRUPVQLKX-UHFFFAOYSA-N 0.000 claims description 7
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 7
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 7
- 239000005642 Oleic acid Substances 0.000 claims description 7
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 7
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 7
- 230000003204 osmotic effect Effects 0.000 claims description 7
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 7
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 7
- 150000003840 hydrochlorides Chemical class 0.000 claims description 6
- 239000003643 water by type Substances 0.000 claims description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 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 4
- 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 4
- 239000000194 fatty acid Substances 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 4
- 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 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-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
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 210000000481 breast Anatomy 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 235000019256 formaldehyde Nutrition 0.000 claims description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 235000021313 oleic acid Nutrition 0.000 claims description 2
- 230000000065 osmolyte Effects 0.000 claims description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 239000003921 oil Substances 0.000 abstract description 27
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 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 abstract description 2
- 239000000787 lecithin Substances 0.000 abstract description 2
- 229940067606 lecithin Drugs 0.000 abstract description 2
- 235000010445 lecithin Nutrition 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- 244000068988 Glycine max Species 0.000 abstract 1
- 235000010469 Glycine max Nutrition 0.000 abstract 1
- 239000002285 corn oil Substances 0.000 abstract 1
- 235000005687 corn oil Nutrition 0.000 abstract 1
- 235000019198 oils Nutrition 0.000 abstract 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
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- 238000012360 testing method Methods 0.000 description 20
- 239000002245 particle Substances 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000013112 stability test Methods 0.000 description 5
- 102000016349 Myosin Light Chains Human genes 0.000 description 4
- 108010067385 Myosin Light Chains Proteins 0.000 description 4
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
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- XSTJTOKYCAJVMJ-GVTSEVKNSA-N (z)-but-2-enedioic acid;(e)-1-[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one Chemical compound OC(=O)\C=C/C(O)=O.COC1=C(OC)C(OC)=CC(\C=C\C(=O)N2CCN(CC(=O)N3CCCC3)CC2)=C1 XSTJTOKYCAJVMJ-GVTSEVKNSA-N 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 2
- 206010047139 Vasoconstriction Diseases 0.000 description 2
- 206010047163 Vasospasm Diseases 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
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- 210000004204 blood vessel Anatomy 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229960004201 cinepazide Drugs 0.000 description 2
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- ARIWANIATODDMH-AWEZNQCLSA-N 1-lauroyl-sn-glycerol Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)CO ARIWANIATODDMH-AWEZNQCLSA-N 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 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 description 1
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- 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 description 1
- ARIWANIATODDMH-UHFFFAOYSA-N Lauric acid monoglyceride Natural products CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 1
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- 229910052783 alkali metal Inorganic materials 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a hydrochloric acid Fasudil fat microsphere preparation and a method for preparing the same. By taking soyabean lecithin as an emulsifying agent and corn oil for injection as an oil phase solvent and comprising an antioxidant commonly used in pharmaceutical products, the preparation is prepared. The preparation has the advantages of simple process, low cost and easy industrialized production; and compared with the prior hydrochloric acid Fasudil injection, the injection prepared by the method has obviously improved stability.
Description
Technical field
The present invention relates to a kind of fat micro sphere preparation, be specifically related to a kind of Fasudic hydrochloride fat micro sphere preparation and preparation method thereof, belong to medical technical field.
Background technology
Fasudic hydrochloride, chemical name are six hydrogen-1-(5-isoquinolinesulfonylcompounds)-1H-1,4-diazepine hydrochlorate, molecular formula C
14H
17N
3O
2SHCl, molecular weight 327.83, structural formula is:
Be that a kind of kinases inhibitor is the intracellular calcium antagonist.The contraction of vascular smooth muscle is because the interior Ca of smooth muscle cell
2+Concentration significantly increases the cause that has activated key enzyme, works as Ca
2+When reaching finite concentration, with Ca
2+Conjugated protein calmodulin combination activates the myosin light chain phosphorylase, with the myosin light chain phosphorylation, causes muscle contraction.During subarachnoid hemorrhage, the various vasoconstrictor substances that discharge in the blood vessel participate in vasospasm, finally cause vasoconstriction by the myosin light chain phosphorylation.Fasudic hydrochloride is by the terminal stage of blocking-up vasoconstriction process, and the myosin light chain phosphorylation is come blood vessel dilating, suppresses vasospasm.Brain spasm after being applicable to improvement clinically and preventing subarachnoid hemorrhage and the symptoms of cerebral ischemia that causes.
At present, the listing preparation of Fasudic hydrochloride is an aqueous injection, is produced without competition by Tianjin Chasesun Pharmaceutical Co., Ltd.A kind of preparation method of fasudil hydrochloride injection is disclosed among the Chinese patent CN1729985A, prepare hydrochloric fasudil, and the solution of sodium chloride, glucose, aminoacid or other pharmaceutically acceptable diluent, the adjusting pH value is 4.0-7.5, decolouring, sterilization.Disclose a kind of preparation method of freeze dry formulation of fasudil hydrochloride among the Chinese patent CN1729984A, made through lyophilization by the solution that contains pharmaceutically acceptable excipient such as Fasudic hydrochloride and mannitol, lactose, sodium chloride, glucose, glycine.There is the mass defect of less stable in the Fasudic hydrochloride injection of above-mentioned prior art for preparing, is difficult to reach the standard-required of effect duration.
Summary of the invention
At the defective of present Fasudic hydrochloride injection poor stability, the object of the present invention is to provide a kind of stability to obtain the Fasudic hydrochloride injection that obviously improves.
The technical scheme that the present invention solves is as follows:
The invention provides a kind of Fasudic hydrochloride fat micro sphere preparation, it is characterized in that with the Fasudic hydrochloride being active component, is emulsifying agent with the soybean phospholipid, comprises the lipoid microsphere ejection preparation that antioxidant, injection Semen Maydis oil, water for injection are prepared from.
Wherein, above-mentioned described Fasudic hydrochloride fat micro sphere preparation is characterized in that by weight percentage, Fasudic hydrochloride 0.5%-5%, soybean phospholipid 5%-30%, antioxidant 0.1%-5%, injection Semen Maydis oil 1%-50%, water for injection 20%-80%.
Preferably, above-mentioned described Fasudic hydrochloride fat micro sphere preparation is characterized in that by weight percentage, Fasudic hydrochloride 1%-3%, soybean phospholipid 10%-20%, antioxidant 0.5%-2%, injection Semen Maydis oil 5%-30%, water for injection 30%-70%.
The above-mentioned described Fasudic hydrochloride fat micro sphere preparation of the present invention, it can also comprise co-emulsifier, for example can comprise the co-emulsifier that percentage by weight is 1%-5%.Wherein said co-emulsifier is not particularly limited, and can be co-emulsifier conventional on the medicament, and for example preferred co-emulsifier is C
10-C
20Fatty acid or its physiology in the acceptable salt one or more, wherein said fatty acid is preferably stearic acid, oleic acid, linoleic acid, Palmic acid, linolein acid or tetradecanoic acid.Described salt for example can be alkali metal salt, as sodium salt, potassium salt etc., perhaps is alkali salt, for example calcium salt, magnesium salt etc.
The above-mentioned described Fasudic hydrochloride fat micro sphere preparation of the present invention, it can also comprise osmotic pressure regulator, for example can comprise the osmotic pressure regulator that percentage by weight is 0.1%-5%.Wherein said osmotic pressure regulator is not particularly limited, and can be osmotic pressure regulator conventional on the medicament, and for example preferred osmotic pressure regulator is one or more in glycerol, sodium chloride, glucose, mannitol, sorbitol or the xylitol.
The above-mentioned described Fasudic hydrochloride fat micro sphere preparation of the present invention, wherein said antioxidant, be not particularly limited, can be antioxidant conventional on the medicament, for example preferred antioxidant is that sodium sulfite, sodium pyrosulfite, formaldehyde close one or more in sodium sulfite, ascorbic acid, thiourea or the sodium thiosulfate.
As preferred preferred forms of the present invention, described Fasudic hydrochloride fat micro sphere preparation is characterized in that by weight, 30 parts of Fasudic hydrochlorides, 50 parts of soybean phospholipids, 40 parts of glycerol, 5 parts of oleic acid, 12 parts of sodium sulfitees, 120 parts of injection Semen Maydis oil, 1000 parts of waters for injection.
As second preferred preferred forms of the present invention, described Fasudic hydrochloride fat micro sphere preparation is characterized in that by weight, 30 parts of Fasudic hydrochlorides, 80 parts of soybean phospholipids, 20 parts of tetradecanoic acids, 25 parts in sodium thiosulfate, 90 parts of injection Semen Maydis oil, 800 parts of waters for injection.
As the 3rd preferred preferred forms of the present invention, described Fasudic hydrochloride fat micro sphere preparation, it is characterized in that by weight, 15 parts of Fasudic hydrochlorides, 130 parts of soybean phospholipids, 20 parts of linolein acid, 14 parts in sodium chloride, formaldehyde closes 15 parts of sodium sulfitees, 200 parts of injection Semen Maydis oil, 1000 parts of waters for injection.
The present invention also provides a kind of preparation method of above-mentioned described Fasudic hydrochloride fat micro sphere preparation, it is characterized in that making the lipoid microsphere ejection preparation by the method that comprises following steps:
(1) Fasudic hydrochloride is dissolved in the injection Semen Maydis oil, gets oil phase;
(2) emulsifying agent, co-emulsifier, Osmolyte regulator and antioxidant are dissolved in the water for injection, get water;
(3) oil phase and water are mixed, stir breast and spare into lipoid microsphere.
The present invention finds unexpectedly, with the soybean phospholipid is emulsifying agent, with the injection Semen Maydis oil as the oil phase solvent, comprise antioxidant conventional on the medicament, the Fasudic hydrochloride lipoid microsphere ejection preparation that is prepared from, not only technology is simple, cost is low, be easy to suitability for industrialized production, and the gained injection has the stability of obvious improvement with respect to existing Fasudic hydrochloride injection.
Fasudic hydrochloride fat micro sphere preparation provided by the invention carries out stability test and investigates, and places 10 days under 60 ℃ of high temperature, illumination 4500Lx condition, and every detection index has no significant change; Accelerated test is 6 months under 40 ℃ of high temperature, relative humidity 75% ± 5% condition, and every detection index does not have significant change; Long term test is 18 months under 25 ℃ of high temperature, relative humidity 60% ± 10% condition, and every detection index does not have significant change.
Fasudic hydrochloride fat micro sphere preparation provided by the invention carries out acute toxicity test, abnormal toxicity test and heat source check, and is all up to specification, and safety obtains proof.
Fasudic hydrochloride fat micro sphere preparation provided by the invention and preparation method thereof, its outstanding advantage shows:
(1) Fasudic hydrochloride is wrapped in the lipoid microsphere, has improved stability of formulation greatly, has guaranteed product quality;
(2) pharmaceutical carrier lipoid microsphere vivo degradation, avirulence and non-immunogenicity, and can improve the Drug therapy index, reduce drug toxicity and reduce drug side effect;
(3) adopt conventional process equipment, but commercial scale, high efficiency production, and constant product quality is a kind of uniqueness and blanket, the low-cost industrial preparation method.
The specific embodiment
Further specify the present invention by the following examples, but should not be construed as limitation of the present invention.
The preparation of embodiment 1 Fasudic hydrochloride fat micro sphere preparation
Prescription (1000 bottles): Fasudic hydrochloride 30g
Soybean phospholipid 50g
Glycerol 40g
Oleic acid 5g
Sodium sulfite 12g
Injection Semen Maydis oil 120g
Water for injection 1000g
Preparation technology
(1) the 30g Fasudic hydrochloride is added in the 120g injection Semen Maydis oil, get oil phase;
(2) 50g soybean phospholipid, 40g glycerol, 5g oleic acid, 12g sodium sulfite is soluble in water, water;
(3) oil phase and water are mixed, be transferred in the tissue mashing machine, rotating speed 8000r/min, high-speed stirred 10 minutes, filtering with microporous membrane fills nitrogen, embedding, 115 ℃ of autoclavings, promptly.
The preparation of embodiment 2 Fasudic hydrochloride fat micro sphere preparations
Prescription (1000 bottles): Fasudic hydrochloride 30g
Soybean phospholipid 80g
Tetradecanoic acid 20g
Sodium thiosulfate 25g
Injection Semen Maydis oil 90g
Water for injection 800g
Preparation technology
(1) the 30g Fasudic hydrochloride is added in the 90g Semen Maydis oil, get oil phase;
(2) 80g soybean phospholipid, 20g tetradecanoic acid, 25g sodium thiosulfate is soluble in water, water;
(3) oil phase and water are mixed, be transferred in the tissue mashing machine, rotating speed 12000r/min, high-speed stirred 30 minutes, filtering with microporous membrane fills nitrogen, embedding, 115 ℃ of autoclavings, promptly.
The preparation of embodiment 3 Fasudic hydrochloride fat micro sphere preparations
Prescription (1000 bottles): Fasudic hydrochloride 15g
Soybean phospholipid 130g
Linolein acid 20g
Sodium chloride 14g
Formaldehyde closes sodium sulfite 15g
Injection Semen Maydis oil 200g
Water for injection 1000g
Preparation technology
(1) the 15g Fasudic hydrochloride is added in the 200g Semen Maydis oil, get oil phase;
(2) with 130g soybean phospholipid, the acid of 20g linolein, 14g sodium chloride, that 15g formaldehyde closes sodium sulfite is soluble in water, water;
(3) oil phase and water are mixed, be transferred in the tissue mashing machine, rotating speed 10000r/min, high-speed stirred 20 minutes, filtering with microporous membrane fills nitrogen, embedding, 115 ℃ of autoclavings, promptly.
The mensuration of test example 1 particle diameter
Particle diameter to the fat micro sphere preparation of embodiment 1-3 preparation detects, and concrete grammar is: get the lipid microsphere injection 5ml of the present invention's preparation, be added in the 300ml water, detect with H3LA920 laser light scattering particle size analyzer.As a result, 70% particle diameter is less than 150nm, and 90% particle diameter meets the related request of used for intravenous injection fat micro sphere preparation less than 200nm.
The mensuration of test example 2 envelop rates
With the fat micro sphere preparation high speed centrifugation of embodiment 1-3 preparation, 5000r/min, centrifugal 30min gets clear liquid 1ml, uses dissolve with ethanol, with high effective liquid chromatography for measuring Cinepazide Maleate content, determines entrapped content M
1, the Cinepazide Maleate total amount is M in the fat micro sphere preparation
0, envelop rate N is:
N＝M
1/M
0×100％
As a result, the fat micro sphere preparation envelop rate of the present invention's preparation is all greater than 97%.
Test example 3 safety testings
Get the fat micro sphere preparation of embodiment 1-3 preparation, carry out aseptic and heat source check by 2005 editions methods of Chinese Pharmacopoeia respectively, the result is all up to specification.
Get the fat micro sphere preparation of the present invention's preparation, carry out the test of anaphylaxis and hemolytic respectively, the result does not have anaphylaxis, no hemolytic, and safety is protected.
Test example 4 stability tests
With the sample of above embodiment 1-3 preparation and (the Tianjin Chasesun Pharmaceutical Co., Ltd's production of the fasudil hydrochloride injection of listing, lot number 20080514) under 60 ℃ of high temperature, illumination 4500Lx condition, places and carried out the influence factor in 10 days and test investigation, the results are shown in Table 1; Under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test and investigate, the results are shown in Table 2; 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 results are shown in Table 3.
Table 1 influence factor result
Table 2 accelerated test result
Table 3 long-term test results
Quickened March, June by above found that, long-term December, the fasudil hydrochloride injection clarity of listing is against regulation 18 months the time, and pH value descends bigger, and content reduces obviously, and related substance raises; And the sample appearance character of the present invention's preparation does not have significant change, is the clear and bright solution of milky, and clarity, pH value, content and related substance do not have obvious variation yet.The sample stable quality after long time storage that the present invention's preparation is described is better.
The preparation of Comparative Examples 1 Fasudic hydrochloride fat micro sphere preparation
Prescription (1000 bottles): Fasudic hydrochloride 30g
Ovum Gallus domesticus Flavus lecithin 50g
Glycerol 40g
Oleic acid 5g
Sodium sulfite 12g
Injection Semen Maydis oil 120g
Water for injection 1000g
Preparation technology is with embodiment 1, and the fat micro sphere preparation envelop rate that the result makes is lower, detect by test example 2 methods, and only be 79%; Test example 4 stability tests, content obviously reduces, and related substance raises, and pH value changes greatly, and clarity is against regulation; The lipoid microsphere particle diameter detects by test example 1 method, and particle diameter is 200-700nm, and skewness does not meet intravenous related request.
The preparation of Comparative Examples 2 Fasudic hydrochloride fat micro sphere preparations
Prescription (1000 bottles): Fasudic hydrochloride 30g
Cholesterol 80g
Tetradecanoic acid 20g
Sodium thiosulfate 25g
Injection Semen Maydis oil 90g
Water for injection 800g
Preparation technology is with embodiment 2, and the fat micro sphere preparation envelop rate that the result makes is lower, detect by test example 2 methods, and only be 66%; Test example 4 stability tests, content obviously reduces, and pH value changes greatly;
The preparation of Comparative Examples 3 Fasudic hydrochloride fat micro sphere preparations
Prescription (1000 bottles): Fasudic hydrochloride 15g
Glycerol monolaurate 130g
Linolein acid 20g
Sodium chloride 14g
Formaldehyde closes sodium sulfite 15g
Injection Semen Maydis oil 200g
Water for injection 1000g
Preparation technology is with embodiment 3, and the fat micro sphere preparation envelop rate that the result makes is lower, detect by test example 2 methods, and only be 70%; Test example 4 stability tests, content obviously reduces, and related substance raises, and clarity is against regulation; The lipoid microsphere particle diameter detects by test example 1 method, and particle diameter is 500-800nm, and skewness does not meet intravenous related request.
The present invention is described according to preferred embodiment.Should be understood that the description of front and embodiment are just to illustrating the present invention.Under prerequisite without departing from the spirit and scope of the present invention, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (9)
1. Fasudic hydrochloride fat micro sphere preparation, it is characterized in that with the Fasudic hydrochloride being active component, with the soybean phospholipid is emulsifying agent, comprises the lipoid microsphere ejection preparation that antioxidant, injection Semen Maydis oil, water for injection are prepared from, by weight percentage, Fasudic hydrochloride 1%-3%, soybean phospholipid 10%-20%, antioxidant 0.5%-2%, injection Semen Maydis oil 5%-30%, co-emulsifier 1%-5%, water for injection 30%-70%.
2. Fasudic hydrochloride fat micro sphere preparation according to claim 1 is characterized in that described co-emulsifier is C
10-C
20Fatty acid or its physiology in the acceptable salt one or more.
3. Fasudic hydrochloride fat micro sphere preparation according to claim 2 is characterized in that described fatty acid is stearic acid, oleic acid, linoleic acid, Palmic acid, linolein acid or tetradecanoic acid.4, according to each described Fasudic hydrochloride fat micro sphere preparation of claim 1-3, it is characterized in that also comprising the osmotic pressure regulator that percentage by weight is 0.1%-5%.
5. Fasudic hydrochloride fat micro sphere preparation according to claim 4 is characterized in that described osmotic pressure regulator is one or more in glycerol, sodium chloride, glucose, mannitol, sorbitol and the xylitol.
6. according to each described Fasudic hydrochloride fat micro sphere preparation of claim 1-3, it is characterized in that described antioxidant is that sodium sulfite, sodium pyrosulfite, formaldehyde close one or more in sodium sulfite, ascorbic acid, thiourea and the sodium thiosulfate.
7. a Fasudic hydrochloride fat micro sphere preparation is characterized in that by weight, 30 parts of Fasudic hydrochlorides, 50 parts of soybean phospholipids, 40 parts of glycerol, 5 parts of oleic acid, 12 parts of sodium sulfitees, 120 parts of injection Semen Maydis oil, 1000 parts of waters for injection.
8. a Fasudic hydrochloride fat micro sphere preparation is characterized in that by weight, 30 parts of Fasudic hydrochlorides, 80 parts of soybean phospholipids, 20 parts of tetradecanoic acids, 25 parts in sodium thiosulfate, 90 parts of injection Semen Maydis oil, 800 parts of waters for injection.
9. a Fasudic hydrochloride fat micro sphere preparation is characterized in that by weight, 15 parts of Fasudic hydrochlorides, and 130 parts of soybean phospholipids, 20 parts of linolein acid, 14 parts in sodium chloride, formaldehyde close 15 parts of sodium sulfitees, 200 parts of injection Semen Maydis oil, 1000 parts of waters for injection.
10. method for preparing according to claim 4,5,7 or 9 described Fasudic hydrochloride fat micro sphere preparations is characterized in that being prepared from the lipoid microsphere ejection preparation by the method that comprises following steps:
(1) Fasudic hydrochloride is dissolved in the injection Semen Maydis oil, gets oil phase;
(2) emulsifying agent, co-emulsifier, Osmolyte regulator and antioxidant are dissolved in the water for injection, get water;
(3) oil phase and water are mixed, stir breast and spare into lipoid microsphere.
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| CN2009101311986A CN101507707B (en) | 2009-04-08 | 2009-04-08 | Fasudil hydrochloride lipo-microballoons carrier preparation and preparation method thereof |
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|---|---|---|---|
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| CN102138901B (en) * | 2011-03-30 | 2012-12-19 | 天津红日药业股份有限公司 | Nasal spray or aerosol containing Fasudil |
| WO2023174948A2 (en) * | 2022-03-14 | 2023-09-21 | TRx Biosciences Limited | Compositions having improved bioavailability of therapeutics and uses thereof |
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