Development of a Sustained Release Injectable Formulation for Long-Term Delivery of ELQs

开发用于长期递送 ELQ 的缓释注射制剂

• 批准号: 9816269
• 负责人: Michael Kevin RISCOE
• 金额: $ 83.32万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-05 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816269
• 关键词: Address; Animal Model; Animals; Antimalarials; Antioxidants; Area; Blood; Blood Circulation; Carbonates; Chemistry; Chemoprevention; Chemoprotection; Chloroguanide; Clinical; Collaborations; Cytochrome bc1 Complex; Development; Disease Outbreaks; Dose; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Esters; Ethyl Ether; Exhibits; Formulation; Goals; HIV; Half-Life; Head; Human; Infection; Infection prevention; Injectable; Injections; International; Intramuscular; Intramuscular Injections; Journals; Knowledge; Length; Life Cycle Stages; Liver; Malaria; Malaria Vaccines; Medical; Medicine; Midgut; Modeling; Multi-Drug Resistance; Mus; Oils; Oocysts; Oral; Parasites; Performance; Pharmaceutical Preparations; Plasmodium falciparum; Polyethylene Glycols; Population; Positioning Attribute; Pre-Clinical Model; Prodrugs; Property; Prophylactic treatment; Published Comment; Publishing; Qi; Rattus; Regimen; Research; Resistance; Route; Safety; Schizophrenia; Seasons; Side; Site; Solubility; Solvents; Sporozoites; Suspensions; System; Technology; Time; United States National Institutes of Health; Update; Variant; Water; Work; alkyl group; atovaquone; base; clinical development; cost; crystallinity; design; disease transmission; experience; improved; inhibitor/antagonist; novel; novel therapeutics; pre-clinical; resistant strain; vector; vector mosquito; water solubility; zygote

Project Summary / Abstract  The  Medicines  for  Malaria  Venture  (MMV)  recently  published  a  “roadmap”  for  the  types  of  medicines  that  are  needed  to  support  the  long-­term  goal  of  malaria  eradication.  The  roadmap  consists  of  a  wish  list  of  target  candidate profiles (TCP) and medicines (target product profiles, i.e., TPP). With the most recent revision to the  anti-­malarial target candidates and product profiles the MMV highlighted the need for identifying new medicines  for  chemo-­protection  and  chemo-­prevention  with  long-­acting  molecules,  and/or  parenteral  formulations  (i.e.,  TCP-­2) (Burrows, JN et al., 2017, Malaria Journal, 16:26). According to their updated roadmap new drugs are  needed  to  protect  populations  entering  areas  of  high  endemicity  during  the  final  stages  of  malaria  elimination.   And  drugs  with  causal  liver-­stage  activity  are  needed  for  chemoprevention  to  prevent  infection  or  outbreak  of  resistance  during  malarial  seasons.  This  TCP  has  been  modeled  on  the  combination  drug  atovaquone  +  proguanil. The MMV envisions that an injectable sustained-­release formulation could be developed as a long-­ acting preventative providing up to 3 to 4 months of protection.    As  a  potent  and  selective  inhibitor  of  the  parasite’s  cytochrome  bc1  complex,  ELQ-­300  targets  Plasmodium  falciparum in the blood and liver stages and even kills parasites developing in the midgut of the mosquito vector.  With support from the NIH and US DOD we have been successful in developing an oral formulation of prodrug  ELQ-­331  for  use  in  humans  for  weekly  prophylaxis  against  malaria,  work  that  was  performed  in  collaboration  with SRI International.  In the present application we seek NIH support for a comprehensive assessment of ELQ-­ 300  prodrugs  for  intramuscular  injection  to  effect  the  sustained-­release  of  drug  from  an  oil  depot  (or  other  extended release matrix) into the host bloodstream at levels above the minimum effective concentration needed  to  block  liver  stage  infection  by  infectious  sporozoites.  In  collaboration  with  SRI  International  we  will  leverage  our  knowledge  of  ELQ-­300  prodrug  chemistry,  crystallinity,  stability,  and  solvent/vehicle  solubility  with  their  expertise  in  formulation  design  and  optimization  to  identify  the  optimal  ELQ-­300  prodrug  design  that  is  paired  with  an  optimal  depot  formulation  to  provide  long-­term  protection  of  animals  from  sporozoite  infection.  Four  different  prodrug  chemistries  will  be  evaluated  and  compared,  varying  R-­group  chain  length  to  optimize  the  physiochemical properties of the drug and to enhance solubility in vehicles and mixtures that are approved for  human use. The overall goal is to develop a long-­acting sustained release formulation of an ELQ-­300 prodrug  for chemo-­protection against malaria.

项目摘要/摘要