CN104856947A - Alprostadil hydroxypropyl-alpha-cyclodextrin inclusion compound injection - Google Patents
Alprostadil hydroxypropyl-alpha-cyclodextrin inclusion compound injection Download PDFInfo
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- CN104856947A CN104856947A CN201510267786.8A CN201510267786A CN104856947A CN 104856947 A CN104856947 A CN 104856947A CN 201510267786 A CN201510267786 A CN 201510267786A CN 104856947 A CN104856947 A CN 104856947A
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- China
- Prior art keywords
- alprostadil
- cyclodextrin
- hydroxyproply
- injection
- comparative example
- 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.)
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- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 229960000711 alprostadil Drugs 0.000 title claims abstract description 67
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 title claims abstract description 67
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 title claims abstract description 51
- 229940043377 alpha-cyclodextrin Drugs 0.000 title claims abstract description 51
- 238000002347 injection Methods 0.000 title claims abstract description 32
- 239000007924 injection Substances 0.000 title claims abstract description 32
- 150000001875 compounds Chemical class 0.000 title abstract 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 8
- 229920002307 Dextran Polymers 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 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
- 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 6
- 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 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- 239000008103 glucose Substances 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- 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 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
- 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
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-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
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 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
- 230000000052 comparative effect Effects 0.000 description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 46
- 239000000243 solution Substances 0.000 description 37
- 238000003756 stirring Methods 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 238000001914 filtration Methods 0.000 description 16
- 229920000858 Cyclodextrin Polymers 0.000 description 15
- 229960004756 ethanol Drugs 0.000 description 15
- 238000000034 method Methods 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 9
- 238000005262 decarbonization Methods 0.000 description 9
- 230000001954 sterilising effect Effects 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 8
- 229910000397 disodium phosphate Inorganic materials 0.000 description 8
- 235000019800 disodium phosphate Nutrition 0.000 description 8
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 8
- 235000019799 monosodium phosphate Nutrition 0.000 description 8
- 238000010792 warming Methods 0.000 description 8
- 239000008215 water for injection Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 235000001727 glucose Nutrition 0.000 description 6
- 239000008363 phosphate buffer Substances 0.000 description 6
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- 238000004659 sterilization and disinfection Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 4
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 4
- 150000003180 prostaglandins Chemical class 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
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- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- -1 carbon fatty acids Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
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- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000024883 vasodilation Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 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 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
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- 102000030621 adenylate cyclase Human genes 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
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- 230000007423 decrease Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
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- 229940119744 dextran 40 Drugs 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
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- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
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- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
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- NFIYTPYOYDDLGO-UHFFFAOYSA-N phosphoric acid;sodium Chemical compound [Na].OP(O)(O)=O NFIYTPYOYDDLGO-UHFFFAOYSA-N 0.000 description 1
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- 235000002639 sodium chloride Nutrition 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 1
- LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CO)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](CCC(O)=O)C(O)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention provides an alprostadil hydroxypropyl-alpha-cyclodextrin inclusion compound injection. The inclusion compound injection is prepared through inclusion of alprostadil with hydroxypropyl-alpha-cyclodextrin, and the solubility of the alprostadil and the stability of the injection are greatly improved.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation of Alprostadil, be specifically related to a kind of Hydroxyproply-α-cyclodextrin clathrate injection of Alprostadil, belong to medical art.
Background technology
Alprostadil, also known as PGE1, is the one in natural prostaglandins class material.Prostaglandin is present in most of mammalian tissues, and basic structure is 20 carbon fatty acids containing a Pentamethylene. and two aliphatic side chainses.Can several types be divided into according to position of double bond on Pentamethylene. and substituent difference, wherein mainly contain four classes such as E/F/A/B.Each class has different hypotypes, has biological effect widely.
Alprostadil is a kind of efficient bio-active material, and chemical name is 11a, the anti-prostenoic acid of 15 (S)-dihydroxy-9-carbonyl-13-, molecular formula C
20h
34o
5, molecular weight 354.48, structural formula is:
Alprostadil has the generation of anticoagulant, thromboxane A2, tremulous pulse medicated porridge sample Lipid Plaque is formed and the effect of immune complex, and can expand periphery and arteria coronaria blood vessel.This strain Exogenous prostaglandins E1 (PGE1) is a kind of vasodilation and anticoagulant agent.PGE1, by adenyl cyclase in active cell, makes the cyclic adenosine monophosphate of platelet and vascular smooth intramuscular (cAMP) level increase exponentially, causes and produces inertia platelet and vasodilation.It is all low to the reaction of general induced polymerization inhibitor that patient injects the platelet in vitro tests after this product.After the quiet note of Alprostadil, be faintly combined with plasma protein, T1/2 is 5 ~ 10 minutes.Metabolism is complete in vivo, and 68% of dosage to reach a standard effect metabolism, with metabolite form through renal excretion through liver head.The Patients with Lung of serious respiratory failure removes the decline of this product, and Alprostadil plasma concentration can be made to raise.
Up to the present, Alprostadil experienced by three generations's dosage form altogether and develops, and first on behalf of sterile powder injection, due to the aqueous solution extremely unstable of Alprostadil, therefore needs to make injectable powder type and is easy to storage and transport.This dosage form manufacturer is many, side effect is reported for work also a lot, the side effect of having reported for work mainly contains intravenous drip bright sample swelling pain in various degree or pruritus more, " red line " is there is in some patients along vein skin, generally can tolerate, when instiling too fast, pain increases the weight of, and pain and " red line " disappear after stopping injection, but have then there is nonseptic phlebitis; Second on behalf of cyclodextrin clathrate, and commercially available prod is Alprostadil-alpha-cyclodextrin clathrate, and it utilizes the cavity of cyclodextrin to be entered by Alprostadil enclose, but stability is not good and toxic and side effects still exists; The third generation is liplid emulsions, also has commercially available prod at present, but the current technique of this dosage form is not very ripe, and technics comparing is complicated, and suitability for industrialized production degree is lower.
Clathrate refers to that a kind of drug molecular structure is wholly or partly enclose and enters the complex forming unique forms in the molecule chamber of another kind of material.Clathrate is very active in pharmaceutical preparation research field, the 1950's research worker have realized that the character of clathrate medicine has impact, as clathrate increase drug solubility and stability, affect medicine absorption in vivo, distribution, onset time etc.
Prior art is known, and cyclodextrin has α, β and γ tri-kinds, is made up of respectively 6,7 and 8 glucoses.Prove through X-ray diffraction and nuclear magnetic resonance research, the stereochemical structure of cyclodextrin is circular hollow cylindrical shape that is wide at the top and narrow at the bottom, both ends open, entered in cylinder by enclose material molecule, form clathrate, not only dissolubility can be increased, can also bad smell be improved, improve stability and bioavailability.At present, beta-schardinger dextrin-and derivant thereof are most widely used, and alpha-cyclodextrin and derivant thereof, owing to yielding poorly and unstability reason, do not become the conventional excipients of cyclodextrin clathrate.For a long time, do not use α and γ cyclodextrin to prepare common recognition and the convention that clathrate has become this area at pharmaceutical field.
Chinese patent CN02126054.0 discloses a kind of aseptic freeze-dried prostaglandin preparation and its production and use, and it is made up of Alprostadil, alpha-cyclodextrin, HP-β-CD or gamma-cyclodextrin, thymosin, dextran.Chinese patent CN201210190612.2 discloses a kind of Alprostadil freeze-dried injectable powder and preparation method thereof, and its component is Alprostadil, HP-β-CD and Dextran 40.Chinese patent CN200310102253.1 discloses a kind of injection containing Alprostadil, is made up of Alprostadil, dehydrated alcohol, PEG400, dimethyl acetylamide, 2-HP-BETA-CD, cysteine, sterilized water for injection.
In prior art, beta-schardinger dextrin-or HP-β-CD is normally adopted to carry out enclose to Alprostadil.But, by studying discovery further, the stability of the Alprostadil clathrate that beta-schardinger dextrin-and analog thereof obtain and bioavailability over time, become, still Shortcomings.Clinically for storing the pharmaceutical formulation still after certain hour with the Alprostadil that good biological utilizes, have in the urgent need to.
Summary of the invention
The object of this invention is to provide a kind of Alprostadil pharmaceutical formulation still after storing certain hour with good bioavailability.
The present inventor overcomes in prior art and does not use α and γ cyclodextrin to prepare the technology prejudice of clathrate, be have been surprisingly found that by research, the stability of the Alprostadil clathrate using Hydroxyproply-α-cyclodextrin to prepare and bioavailability are far superior to the Alprostadil product that in prior art, other cyclodextrin existing comprise.
The object of the present invention is to provide a kind of clathrate containing Alprostadil and Hydroxyproply-α-cyclodextrin.
The object of the present invention is to provide a kind of injection prepared by the clathrate of Alprostadil and Hydroxyproply-α-cyclodextrin, first Alprostadil Hydroxyproply-α-cyclodextrin is carried out enclose, then add the injection that Alprostadil Hydroxyproply-α-cyclodextrin clathrate made by pharmaceutically acceptable excipient.
A kind of pharmaceutical composition of the present invention, comprises Alprostadil, Hydroxyproply-α-cyclodextrin and pharmaceutically acceptable excipient.
Pharmaceutical composition of the present invention, wherein, described Alprostadil and Hydroxyproply-α-cyclodextrin are present in pharmaceutical composition with the form of clathrate, and the excipient pharmaceutically accepted is preferred for the excipient preparing injection.
One or more in mannitol, lactose, dextran, xylitol, sorbitol, glucose, sodium chloride are comprised for the preparation of the excipient of injection in the present invention.
The purity of Alprostadil of the present invention is 80% ~ 110%, preferably 90% ~ 100%.
In the clathrate of Alprostadil of the present invention and Hydroxyproply-α-cyclodextrin, wherein the part by weight of Alprostadil and Hydroxyproply-α-cyclodextrin is 1:3 ~ 3000, preferred 1:50 ~ 1500.
The injection of the clathrate of Alprostadil of the present invention and Hydroxyproply-α-cyclodextrin, the part by weight shared in whole preparation of the excipient wherein pharmaceutically accepted is 0.1 ~ 90%, preferably 0.3 ~ 60%.
As the preferred embodiment of the invention, pharmaceutical composition of the present invention comprises, based on parts by weight, and row ground that 1 part, Hydroxyproply-α-cyclodextrin 3 ~ 3000 parts, excipient 5 ~ 2000 parts.
As further preferred embodiment, pharmaceutical composition of the present invention comprises, based on parts by weight, and row ground that 1 part, Hydroxyproply-α-cyclodextrin 50 ~ 1500 parts, excipient 100 ~ 1300 parts.
Present invention also offers the preparation method of the injection of the clathrate of a kind of Alprostadil and Hydroxyproply-α-cyclodextrin, specific as follows:
(1) take the Hydroxyproply-α-cyclodextrin of recipe quantity, add water for injection, stirring and dissolving is complete, obtained solution A;
(2) take the Alprostadil of recipe quantity, add ethanol and make dissolving complete, obtained solution B;
(3) solution A and solution B are merged, regulate pH to 4.0 ~ 7.0 by pH adjusting agent, stir 3 ~ 5 hours, to dissolving completely, in clear and bright uniform solution;
(4) take the pharmaceutic adjuvant of recipe quantity, be stirred to dissolve completely, concentrating under reduced pressure, removing ethanol and part water;
(5) charcoal absorption, filtering decarbonization, aseptic filtration;
(6) fill;
(7) lyophilization, obtained injection Alprostadil Hydroxyproply-α-cyclodextrin clathrate injectable powder; Or, sterilizing, obtained Alprostadil Hydroxyproply-α-cyclodextrin inclusion complexes injection.
As the present invention one preferred embodiment, in above-mentioned steps (1), the ratio of Hydroxyproply-α-cyclodextrin and water for injection is 1:3 ~ 100, preferred 1:5 ~ 80.
As the present invention one preferred embodiment, in above-mentioned steps (2), the ratio of Alprostadil and ethanol is 1:30 ~ 3000, preferred 1:60 ~ 2000.
As the present invention one preferred embodiment, in above-mentioned steps (3), pH adjusting agent is selected from one or more in citric acid, sodium citrate, sodium hydrogen phosphate, sodium dihydrogen phosphate, hydrochloric acid, sodium hydroxide, preferably phosphoric acid sodium dihydrogen and sodium hydrogen phosphate combination.
As the present invention one preferred embodiment, 40 ~ 50 DEG C of concentrating under reduced pressure in above-mentioned steps (4), preferably 45 DEG C of concentrating under reduced pressure.
As the present invention one preferred embodiment, in above-mentioned steps (5), add the active carbon of overall solution volume 0.02 ~ 0.2% (w/v), stirring and adsorbing 5 ~ 50 minutes, filtering decarbonization; Preferably add the active carbon of overall solution volume 0.05% (w/v), stirring and adsorbing 20 ~ 30 minutes, filtering decarbonization.
As the present invention one preferred embodiment, in above-mentioned steps (7), freeze drying process is :-40 ~-50 DEG C are incubated 3 ~ 5 hours; Be warming up to-15 DEG C with 5 ~ 8 hours, be incubated to ice crystal and disappear; Be warming up to 30 DEG C with 4 hours again, be incubated 3 ~ 6 hours, to sample drying.
As the present invention one preferred embodiment, sterilization process is in above-mentioned steps (7): 121 DEG C of moist heat sterilizations 15 minutes.
Alprostadil Hydroxyproply-α-cyclodextrin clathrate injection of the present invention, technique is simple, workable, is suitable for suitability for industrialized production.Meanwhile, this product, compared to current commercially available prod, has carried out enclose owing to have employed Hydroxyproply-α-cyclodextrin to Alprostadil, and make stability better, bioavailability is higher, and toxicity is less.
Detailed description of the invention
Embodiment 1 injection Alprostadil Hydroxyproply-α-cyclodextrin clathrate
Prescription:
Preparation process
(1) take 20g Hydroxyproply-α-cyclodextrin, add 1500g water for injection, stirring and dissolving is complete, obtained solution A;
(2) take 20mg Alprostadil, add 20g ethanol and make dissolving complete, obtained solution B;
(3) solution A and solution B being merged, with sodium hydrogen phosphate and the sodium dihydrogen phosphate buffer adjustment pH to 4.9 of pH5.0, stirring 5 hours, to dissolving completely, in clear and bright uniform solution;
(4) take 20g dextran, be stirred to dissolve completely, 45 DEG C of concentrating under reduced pressure, removing ethanol and part water;
(5) 0.75g active carbon stirring and adsorbing is added 20 minutes, filtering decarbonization, aseptic filtration;
(6) fill; 1.5g/ bottle.
(7) lyophilization :-40 ~-50 DEG C are incubated 3 ~ 5 hours; Be warming up to-15 DEG C with 5 ~ 8 hours, be incubated to ice crystal and disappear; Be warming up to 30 DEG C with 4 hours again, be incubated 3 ~ 6 hours, to sample drying.
Embodiment 2 injection Alprostadil Hydroxyproply-α-cyclodextrin clathrate
Prescription:
Preparation process
(1) take 80g Hydroxyproply-α-cyclodextrin, add 2400g water for injection, stirring and dissolving is complete, obtained solution A;
(2) take 100mg Alprostadil, add 50g ethanol and make dissolving complete, obtained solution B;
(3) solution A and solution B being merged, with sodium hydrogen phosphate and the sodium dihydrogen phosphate buffer adjustment pH to 4.8 of pH5.0, stirring 3 hours, to dissolving completely, in clear and bright uniform solution;
(4) take 32g lactose, be stirred to dissolve completely, 40 DEG C of concentrating under reduced pressure, removing ethanol and part water;
(5) 1.2g active carbon stirring and adsorbing is added 30 minutes, filtering decarbonization, aseptic filtration;
(6) fill; 2.4g/ bottle.
(7) lyophilization :-40 ~-50 DEG C are incubated 3 ~ 5 hours; Be warming up to-15 DEG C with 5 ~ 8 hours, be incubated to ice crystal and disappear; Be warming up to 30 DEG C with 4 hours again, be incubated 3 ~ 6 hours, to sample drying.
Embodiment 3 injection Alprostadil Hydroxyproply-α-cyclodextrin clathrate
Prescription:
Preparation process
(1) take 300g Hydroxyproply-α-cyclodextrin, add 6000g water for injection, stirring and dissolving is complete, obtained solution A;
(2) take 200mg Alprostadil, add 150g ethanol and make dissolving complete, obtained solution B;
(3) solution A and solution B being merged, with sodium hydrogen phosphate and the sodium dihydrogen phosphate buffer adjustment pH to 5.1 of pH5.0, stirring 4 hours, to dissolving completely, in clear and bright uniform solution;
(4) take 100g mannitol, be stirred to dissolve completely, 50 DEG C of concentrating under reduced pressure, removing ethanol and part water;
(5) 3g active carbon stirring and adsorbing is added 25 minutes, filtering decarbonization, aseptic filtration;
(6) fill; 6g/ bottle.
(7) lyophilization :-40 ~-50 DEG C are incubated 3 ~ 5 hours; Be warming up to-15 DEG C with 5 ~ 8 hours, be incubated to ice crystal and disappear; Be warming up to 30 DEG C with 4 hours again, be incubated 3 ~ 6 hours, to sample drying.
Embodiment 4 Alprostadil Hydroxyproply-α-cyclodextrin inclusion complexes injection
Prescription:
Preparation process
(1) take 20g Hydroxyproply-α-cyclodextrin, add 1500g water for injection, stirring and dissolving is complete, obtained solution A;
(2) take 20mg Alprostadil, add 20g ethanol and make dissolving complete, obtained solution B;
(3) solution A and solution B being merged, with sodium hydrogen phosphate and the sodium dihydrogen phosphate buffer adjustment pH to 5.0 of pH5.0, stirring 5 hours, to dissolving completely, in clear and bright uniform solution;
(4) take 13.5g sodium chloride, be stirred to dissolve completely, 45 DEG C of concentrating under reduced pressure, removing ethanol and part water;
(5) 0.75g active carbon stirring and adsorbing is added 20 minutes, filtering decarbonization, aseptic filtration;
(6) fill; 1.5ml/ bottle.
(7) sterilizing: 121 DEG C of moist heat sterilizations 15 minutes.
Embodiment 5 Alprostadil Hydroxyproply-α-cyclodextrin inclusion complexes injection
Prescription:
Preparation process
(1) take 80g Hydroxyproply-α-cyclodextrin, add 2400g water for injection, stirring and dissolving is complete, obtained solution A;
(2) take 100mg Alprostadil, add 50g ethanol and make dissolving complete, obtained solution B;
(3) solution A and solution B being merged, with sodium hydrogen phosphate and the sodium dihydrogen phosphate buffer adjustment pH to 4.9 of pH5.0, stirring 3 hours, to dissolving completely, in clear and bright uniform solution;
(4) take 120g glucose, be stirred to dissolve completely, 40 DEG C of concentrating under reduced pressure, removing ethanol and part water;
(5) 1.2g active carbon stirring and adsorbing is added 30 minutes, filtering decarbonization, aseptic filtration;
(6) fill; 2.4ml/ bottle.
(7) sterilizing: 121 DEG C of moist heat sterilizations 15 minutes.
Embodiment 6 Alprostadil Hydroxyproply-α-cyclodextrin inclusion complexes injection
Prescription:
Preparation process
(1) take 300g Hydroxyproply-α-cyclodextrin, add 6000g water for injection, stirring and dissolving is complete, obtained solution A;
(2) take 200mg Alprostadil, add 150g ethanol and make dissolving complete, obtained solution B;
(3) solution A and solution B being merged, with sodium hydrogen phosphate and the sodium dihydrogen phosphate buffer adjustment pH to 5.0 of pH5.0, stirring 4 hours, to dissolving completely, in clear and bright uniform solution;
(4) take 54g sodium chloride, be stirred to dissolve completely, 50 DEG C of concentrating under reduced pressure, removing ethanol and part water;
(5) 3g active carbon stirring and adsorbing is added 25 minutes, filtering decarbonization, aseptic filtration;
(6) fill; 6ml/ bottle.
(7) sterilizing: 121 DEG C of moist heat sterilizations 15 minutes.
Comparative example
| Supplementary material | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 | The present invention |
| Alprostadil | 20mg | 20mg | 20mg | 20mg | 20mg | 20mg |
| Hydroxyproply-α-cyclodextrin | / | / | / | / | / | 20g |
| HP-β-CD | 20g | / | / | / | / | / |
| Hydropropyl-y-cyclodextrin | / | 20g | / | / | / | / |
| Alpha-cyclodextrin | / | / | 20g | / | / | / |
| Beta-schardinger dextrin- | / | / | / | 20g | / | / |
| Gamma-cyclodextrin | / | / | / | / | 20g | / |
Each comparative example in upper table adopts different cyclodextrin to carry out enclose respectively, and preparation technology, with embodiment 1, obtains the cyclodextrin clathrate of Alprostadil.
Embodiment 7 inclusion rate measures
By ether elution method, the clathrate that the invention process 1 and comparative example 1-5 adopt different cyclodextrin to prepare is carried out to the mensuration of inclusion rate, method is as follows: precision takes clathrate 0.2g, put in suitable measuring bottle, add 50ml ether jolting 10 minutes, filter, get filtrate evaporate to dryness, use dissolve with methanol residue, the concentration of the Alprostadil dissociated with Syrups by HPLC, calculates inclusion rate.Result is as follows.
Table 1 inclusion rate measurement result
| Embodiment | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 | Embodiment 1 |
| Inclusion rate | 48.6％ | 51.1％ | 49.3％ | 55.7％ | 53.4％ | 88.5％ |
Conclusion, from above-mentioned result of the test, the sample inclusion rate of the embodiment 1 adopting Hydroxyproply-α-cyclodextrin of the present invention to prepare, far away higher than the sample of the comparative example 1-5 adopting other cyclodextrin to prepare, has absolutely proved that Alprostadil of the present invention adopts the superiority of Hydroxyproply-α-cyclodextrin enclose.
Embodiment 8 study on the stability
Sample prepared by the embodiment of the present invention 1 and comparative example 1 ~ 5 is carried out study on the stability compare, the condition of investigation is (1) high temperature 60 DEG C 10 days; (2) intense light irradiation 4500Lx 10 days; (3) high temperature 40 DEG C 6 months, Testing index is character, content, pH and related substance.Result is as follows:
Table 20 day result
Table 3 high temperature 60 DEG C of 10 days results
Table semi-finals illumination 4500Lx 10 days results
Table 5 high temperature 40 DEG C of 6 months results
Conclusion: from above result of the test, sample stability prepared by the embodiment of the present invention 1 is better than product prepared by comparative example 1 ~ 5 far away, absolutely prove that the present invention adopts Hydroxyproply-α-cyclodextrin to carry out the useful effect of enclose, substantially increase the stability of Alprostadil, ensure that product quality.
Embodiment 9 bioavailability study
The product of comparative example 1-5 is adopted excipient respectively: dextran a, mannitol b, lactose c, sodium chloride d and glucose e, freeze-dried powder and injection is made according to the technique of the embodiment of the present invention 1 and embodiment 4 and excipient, after storing a period of time, the sample prepared with the embodiment of the present invention 1 and embodiment 4 carries out comparing of bioavailability.
Method: 30 Beagle dogs are divided into 6 groups at random, often organizes 5.Intravenous injection Alprostadil 40 μ g/ only, before administration (0 hour) and after taking medicine 10min, 20min, 30min, 45min, 1h, 1.5h, 2h, 3h, 4h and 6h get blood from dog hind leg vein and be about 1ml.Put in heparinization EP pipe, then add derivatization reagent, vibration, frozen centrifugation separated plasma.HPLC-MS/MS method is adopted to detect the content of Alprostadil in dog plasma sample.Blood concentration-time data, through DAS3.2 process, by the pharmacokinetic parameter of test preparation, must calculate relative bioavailability according to by test preparation AUC.
Result is as follows:
The bioavailability comparative result (dextran) of table 6 lyophilized formulations
| Freeze-dried powder | Embodiment 1a | Comparative example 1a | Comparative example 2a | Comparative example 3a | Comparative example 4a | Comparative example 5a |
| 10 days | 73.6％ | 58.3％ | 55.7％ | 59.6％ | 53.4％ | 54.4％ |
| 30 days | 73.8％ | 55.1％ | 53.8％ | 56.4％ | 49.6％ | 51.2％ |
| 2 months | 73.4％ | 50.2％ | 49.6％ | 52.2％ | 47.7％ | 47.0％ |
| 3 months | 73.5％ | 44.7％ | 45.5％ | 46.1％ | 40.5％ | 41.5％ |
| 4 months | 73.2％ | 37.6％ | 38.3％ | 39.6％ | 33.4％ | 32.5％ |
| 5 months | 73.0％ | 32.3％ | 30.0％ | 34.7％ | 29.5％ | 30.1％ |
| 6 months | 73.3％ | 30.4％ | 27.5％ | 31.1％ | 25.2％ | 27.6％ |
The bioavailability comparative result (mannitol) of table 7 lyophilized formulations
| Freeze-dried powder | Embodiment 1b | Comparative example 1b | Comparative example 2b | Comparative example 3b | Comparative example 4b | Comparative example 5b |
| 10 days | 74.1％ | 59.4％ | 58.7％ | 56.3％ | 58.0％ | 55.7％ |
| 30 days | 74.0％ | 56.3％ | 55.5％ | 53.7％ | 54.2％ | 52.0％ |
| 2 months | 73.8％ | 52.2％ | 50.9％ | 49.2％ | 51.3％ | 48.7％ |
| 3 months | 73.6％ | 48.4％ | 46.7％ | 44.9％ | 45.7％ | 42.2％ |
| 4 months | 73.5％ | 41.7％ | 40.5％ | 37.1％ | 41.8％ | 36.4％ |
| 5 months | 73.3％ | 35.8％ | 34.2％ | 32.0％ | 33.9％ | 31.0％ |
| 6 months | 73.2％ | 32.2％ | 31.9％ | 30.1％ | 32.6％ | 26.3％ |
The bioavailability comparative result (lactose) of table 8 lyophilized formulations
| Freeze-dried powder | Embodiment 1c | Comparative example 1c | Comparative example 2c | Comparative example 3c | Comparative example 4c | Comparative example 5c |
| 10 days | 75.3％ | 57.3％ | 56.3％ | 56.9％ | 54.8％ | 55.5％ |
| 30 days | 75.1％ | 53.5％ | 53.0％ | 53.3％ | 50.4％ | 50.7％ |
| 2 months | 75.0％ | 48.6％ | 48.9％ | 49.7％ | 46.1％ | 44.9％ |
| 3 months | 75.0％ | 43.2％ | 44.6％ | 44.0％ | 42.2％ | 40.4％ |
| 4 months | 74.8％ | 38.7％ | 39.5％ | 37.5％ | 36.1％ | 35.8％ |
| 5 months | 74.7％ | 34.1％ | 35.2％ | 33.3％ | 31.0％ | 32.3％ |
| 6 months | 74.5％ | 31.9％ | 32.3％ | 32.0％ | 28.4％ | 29.0％ |
The bioavailability comparative result (sodium chloride) of table 9 injection
| Injection | Embodiment 4d | Comparative example 1d | Comparative example 2d | Comparative example 3d | Comparative example 4d | Comparative example 5d |
| 10 days | 72.6％ | 60.4％ | 56.3％ | 57.7％ | 55.0％ | 53.7％ |
| 30 days | 72.2％ | 57.3％ | 53.0％ | 54.2％ | 50.5％ | 50.8％ |
| 2 months | 72.4％ | 52.2％ | 47.5％ | 51.3％ | 48.3％ | 46.5％ |
| 3 months | 72.0％ | 45.4％ | 43.9％ | 47.8％ | 43.2％ | 39.7％ |
| 4 months | 72.2％ | 38.1％ | 39.6％ | 40.1％ | 36.9％ | 33.3％ |
| 5 months | 71.4％ | 33.6％ | 31.4％ | 36.8％ | 32.8％ | 31.5％ |
| 6 months | 70.7％ | 31.8％ | 26.2％ | 30.9％ | 27.4％ | 28.6％ |
The bioavailability comparative result (glucose) of table 10 injection
| Freeze-dried powder | Embodiment 4e | Comparative example 1e | Comparative example 2e | Comparative example 3e | Comparative example 4e | Comparative example 5e |
| 10 days | 73.3％ | 59.6％ | 58.0％ | 56.8％ | 57.4％ | 58.2％ |
| 30 days | 73.3％ | 56.2％ | 54.4％ | 52.7％ | 53.2％ | 55.1％ |
| 2 months | 73.1％ | 52.7％ | 50.9％ | 48.5％ | 49.8％ | 51.4％ |
| 3 months | 73.0％ | 48.3％ | 45.5％ | 43.2％ | 45.1％ | 46.7％ |
| 4 months | 72.9％ | 43.5％ | 41.3％ | 37.1％ | 42.0％ | 41.9％ |
| 5 months | 72.7％ | 36.8％ | 36.9％ | 32.9％ | 37.5％ | 36.6％ |
| 6 months | 72.5％ | 32.7％ | 33.7％ | 28.7％ | 31.6％ | 30.3％ |
Conclusion: from above result of the test, after storing a period of time, the bioavailability of the embodiment of the present invention 1 is far superior to comparative example 1 ~ 5 and obtains freeze-dried powder with mannitol, lactose, dextran; And the sample bioavailability prepared of embodiment 4 is far superior to comparative example 1 ~ 5 and sodium chloride and glucose and obtains sample prepared by injection, describe the superiority of the present invention in guarantee bioavailability.
Claims (6)
1. a pharmaceutical composition, is characterized in that comprising Alprostadil, Hydroxyproply-α-cyclodextrin and pharmaceutically acceptable excipient.
2. pharmaceutical composition according to claim 1, it is characterized in that described Alprostadil and Hydroxyproply-α-cyclodextrin are present in pharmaceutical composition with the form of clathrate, pharmaceutically acceptable excipient is preferred for the excipient preparing injection.
3. pharmaceutical composition according to claim 1 and 2, is characterized in that in the clathrate of described Alprostadil and Hydroxyproply-α-cyclodextrin, and wherein the part by weight of Alprostadil and Hydroxyproply-α-cyclodextrin is 1:3 ~ 3000, preferred 1:50 ~ 1500.
4. pharmaceutical composition according to claim 1, is characterized in that it is injection.
5. pharmaceutical composition according to claim 4, it is characterized in that the injection of the clathrate of described Alprostadil and Hydroxyproply-α-cyclodextrin, the part by weight shared in whole preparation of the excipient wherein pharmaceutically accepted is 0.1 ~ 90%, preferably 0.3 ~ 60%.
6. according to claim 1
-pharmaceutical composition described in 4 any one, is characterized in that described pharmaceutically acceptable excipient is selected from as one or more in mannitol, lactose, dextran, xylitol, sorbitol, glucose, sodium chloride.
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| CN104069114A (en) * | 2014-07-10 | 2014-10-01 | 韩彬 | Alprostadil oral preparation |
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| WO2003101476A1 (en) * | 2002-05-29 | 2003-12-11 | New River Pharmaceuticals Inc. | Active agent delivery systems and methods for protecting and administering active agents |
| WO2005046699A1 (en) * | 2003-11-13 | 2005-05-26 | Ono Pharmaceutical Co., Ltd. | Freeze-dried article containing prostaglandin |
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