Cyclodextrins and Selective Reversal Binding Agents环糊精和选择性反转粘合剂.pptVIP

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Cyclodextrins and Selective Reversal Binding Agents环糊精和选择性反转粘合剂.ppt

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Cyclodextrins and Selective Reversal Binding Agents环糊精和选择性反转粘合剂.ppt

What are cyclodextrins? What are cyclodextrins? Cyclic oligosaccharides composed of dextrose units 3D structure resembles a hollow truncated cone Very water soluble hydrophilic exterior Hydrophobic interior, which binds the nucleus of molecules that are poorly water soluble 6 major forms of cyclodextrins (gamma form has eight dextrose subunits) How do they work? Encapsulate water insoluble compounds Bind with van der Waals forces The complex is water soluble due to hydrophilic exterior of cyclodextrin molecule What are they used for? Increasing water solubility of poorly water soluble drugs (1) Have been used to formulate different agents used in anaesthesia including propofol (2) In vivo scavenger for steroid based muscle relaxants Cyclodextrin use to reverse NMB Idea for rocuronium specific cyclodextrin developed from its use as a solubiliser Sugammadex (Org 25969) developed as first ‘selective relaxant binding agent’. Org 25969 tailored to rocuronium by: Using gamma-cyclodextrin molecule Increasing depth of cavity Attaching anionic functional groups at cavity rim Ring structure of sugammadex How does sugammadex reverse NMB? Encapsulate steroidal NMB, tight 1:1 complexes in plasma Rocuronium diffuses away from NM junction into plasma Causes rapid reversal (recovery of the TOF ratio 0.9 within a few minutes). Complex then rapidly eliminated in the urine History and future of Selective Relaxant Binding Agents 1999 Org 25969 identified 2001 first public announcement - Belfast, Ireland. Animal experiments 2001-2002 Phase I trial 2002 Phase II trials June 2004-May 2005. Phase III trials commenced June 2005 Scheduled launch (Phase IV) of suggamadex in 2007/2008. Org 25969 trials Single ascending dose given 3 min after 0.6 mg/kg rocuronium (study 101) Dose-finding, given at second twitch (T2) after 0.6 mg/kg rocuronium (201) Dose-finding, given at 3, 5, or 15 min after 0.6 mg/kg rocuronium (202) Dose-finding, given at T2 after profound block induced by rocuro