Development of a Sustained Release Injectable Formulation for Long-Term Delivery of ELQs
Development of a Sustained Release Injectable Formulation for Long-Term Delivery of ELQs
批准号:
10412947
负责人:
Michael Kevin RISCOE
金额:
$80.56万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-06-05 至 2024-05-31
关键词:
AddressAnimal ModelAnimalsAntimalarialsAntioxidantsAreaBloodBlood CirculationCarbonatesChemistryChemopreventionChemoprotectionChloroguanideClinicalCollaborationsCytochrome bc1 ComplexDevelopmentDisease OutbreaksDoseDrug CombinationsDrug Delivery SystemsDrug KineticsEstersEthyl EtherExhibitsFormulationGoalsHIVHalf-LifeHeadHumanInfectionInfection preventionInjectableInjectionsInternationalIntramuscularIntramuscular InjectionsJournalsKnowledgeLengthLife Cycle StagesLiverMalariaMalaria VaccinesMedicalMedicineMidgutModelingMulti-Drug ResistanceMusOilsOocystsOralParasitesPerformancePharmaceutical PreparationsPlasmodium falciparumPolyethylene GlycolsPopulationPositioning AttributePre-Clinical ModelProdrugsPropertyProphylactic treatmentPublished CommentPublishingQiRattusRegimenResearchResistanceRouteSafetySchizophreniaSeasonsSideSiteSolubilitySolventsSporozoitesSuspensionsSystemTechnologyTimeUnited States National Institutes of HealthUpdateVariantWaterWorkalkyl groupatovaquonebaseclinical developmentcostcrystallinitydesigndisease transmissionexperienceimprovedinhibitornovelnovel therapeuticspre-clinicalresistant strainvectorvector mosquitowater solubilityzygote
中文摘要
《项目摘要》/《摘要》
世界抗疟疾药物联盟(MMV)最近发布了一份关于治疗疟疾的主要药物种类的新“路线图”。
需要更多的支持来实现根除疟疾的长期目标目标。新的路线图包括一份目标的愿望清单。
候选药物配置文件(TCP)和药品配置文件(目标产品)配置文件,即TPP)。与最新的药品修订版本一起发布。
在最新的MMV报告中,抗疟疾药物的候选药物和产品简介强调了进一步确定新的治疗药物的迫切需要。
对于化学保护和化学预防,需要使用长效药物分子、药物和/或肠外药物制剂(即)。
Tcp-2)和(Burrow,JN等人,2017年,《疟疾杂志》,16:26)。根据他们最新的全球路线图,新药正在开发中。
在全球消灭疟疾的最后三个阶段,需要采取措施来保护这些人口,防止他们进入流行程度较高的地区。
此外,化学预防措施还需要有可能导致肝脏疾病活动的药物,以防止新的感染或暴发风险。
耐药性是在疟疾流行季节出现的。但这一次的tcp还没有完全仿效药物他托瓦酮的新组合。
普罗瓜尼。根据MMV的设想,一种可注射的缓释制剂可以作为一种长期的药物开发。
采取预防性措施,提供最多3%至400万个月的保护。
作为疟原虫主要细胞色素Bc1复合体的高效抑制剂和选择性酶抑制剂,EELQ-300主要针对疟原虫。
恶性疟原虫出现在蚊子的血液循环和肝脏发育阶段,甚至可以在蚊子媒介的中肠段杀死发育中的寄生虫。
在美国国立卫生研究院和美国国防部的大力支持下,我们已经成功地开发了一种非口服的前药配方。
ELQ-331英镑用于人类每周一次的疟疾预防,这项工作是在我们的合作中完成的。
在目前的申请中,我们可以寻求NIH的支持,以建立一个全面的ELQ评估体系。
300种前体药物用于肌肉注射,以改善从中国石油和石油仓库(或其他药物)释放的药物的缓释效果。
延长(释放(矩阵))进入主要宿主体内的血流浓度高于所需的最低有效浓度。
为了阻止肝脏通过具有传染性的子孢子虫感染。我们将与斯里兰卡国际机场合作,继续发挥杠杆作用。
我们对前体药物的化学、结晶度、稳定性、溶剂/溶剂的溶解度的最新知识与他们的知识相一致。
在配方、设计方案和方案优化方面拥有专业知识,以帮助确定最优的EELQ-300前药方案设计方案。
有了一个最优的动物储存库配方,可以为动物提供长期的动物保护,使其免受子孢子虫和感染。
我们还将对不同的前药和化学制剂进行全面评估和比较,包括不同的R-基团和链长,以进一步优化方案。
主要药物的物化性质和性能,以进一步增强其在未获批准用于生产的车辆和混合物中的溶解度。
人类使用。我们的总体目标是开发一种新的长效、持续释放的前药制剂。
用于预防疟疾的化学保护。
英文摘要
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.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
BLR&D Research Career Scientist Renewal Award Application
-
批准号:10293572
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2019
-
负责人:Michael Kevin RISCOE
-
依托单位:
Development of a Sustained Release Injectable Formulation for Long-Term Delivery of ELQs
-
批准号:9816269
-
项目类别:
-
资助金额:$83.32万
-
财政年份:2019
-
负责人:Michael Kevin RISCOE
-
依托单位:
BLR&D Research Career Scientist Renewal Award Application
-
批准号:10047237
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2019
-
负责人:Michael Kevin RISCOE
-
依托单位:
BLR&D Research Career Scientist Renewal Award Application
-
批准号:10515311
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2019
-
负责人:Michael Kevin RISCOE
-
依托单位:
Pharmachin Optimization and Testing
-
批准号:10620168
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2016
-
负责人:Michael Kevin RISCOE
-
依托单位:
Design and Optimization of Novel Antimalarial Drugs
-
批准号:9898269
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2016
-
负责人:Michael Kevin RISCOE
-
依托单位:
Pharmachin Optimization and Testing
-
批准号:10398114
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2016
-
负责人:Michael Kevin RISCOE
-
依托单位:
Pharmachin Optimization and Testing
-
批准号:10260927
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2016
-
负责人:Michael Kevin RISCOE
-
依托单位:
Design and Optimization of Novel Antimalarial Drugs
-
批准号:9248787
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2016
-
负责人:Michael Kevin RISCOE
-
依托单位:
Optimizing ELQs for Treatment and Prevention of Malaria
-
批准号:8776262
-
项目类别:
-
资助金额:$61.34万
-
财政年份:2013
-
负责人:Michael Kevin RISCOE
-
依托单位:
Optimizing ELQs for Treatment and Prevention of Malaria
-
批准号:8603528
-
项目类别:
-
资助金额:$65.39万
-
财政年份:2013
-
负责人:Michael Kevin RISCOE
-
依托单位:
Optimizing ELQs for Treatment and Prevention of Malaria
-
批准号:9186993
-
项目类别:
-
资助金额:$61.34万
-
财政年份:2013
-
负责人:Michael Kevin RISCOE
-
依托单位:
Optimizing Pharmachins for Treatment and Prevention of Drug Resistant Malaria
-
批准号:8598060
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2012
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负责人:Michael Kevin RISCOE
-
依托单位:
Novel Therapeutics to Target Parasite Cytochrome bc1
-
批准号:10665031
-
项目类别:
-
资助金额:$62.01万
-
财政年份:2012
-
负责人:Michael Kevin RISCOE
-
依托单位:
Optimizing ELQs for Treatment and Prevention of Malaria
-
批准号:8484660
-
项目类别:
-
资助金额:$57.44万
-
财政年份:2012
-
负责人:Michael Kevin RISCOE
-
依托单位:
Optimizing Pharmachins for Treatment and Prevention of Drug Resistant Malaria
-
批准号:8774172
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2012
-
负责人:Michael Kevin RISCOE
-
依托单位:
Development of a Synergistic Drug Combination for Prevention and Treatment of Malaria
-
批准号:10066258
-
项目类别:
-
资助金额:$57.26万
-
财政年份:2012
-
负责人:Michael Kevin RISCOE
-
依托单位:
Optimizing Pharmachins for Treatment and Prevention of Drug Resistant Malaria
-
批准号:8331842
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2012
-
负责人:Michael Kevin RISCOE
-
依托单位:
Optimizing Pharmachins for Treatment and Prevention of Drug Resistant Malaria
-
批准号:8460421
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2012
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负责人:Michael Kevin RISCOE
-
依托单位:
Development of a Chloroquine Replacement Drug
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批准号:7828905
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项目类别:
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资助金额:$51.81万
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财政年份:2009
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负责人:Michael Kevin RISCOE
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依托单位:
海外基金