Micronized salsalate in a parenteral formulation is a safe and effective analgesic for acute postoperative pain management
肠外制剂中的微粉化水杨酸是一种安全有效的止痛药,用于急性术后疼痛管理
基本信息
- 批准号:10394982
- 负责人:
- 金额:$ 70.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute PainAddressAdverse effectsAdverse eventAffectAmericanAnalgesicsAnimal ModelAnimalsAreaArea Under CurveBindingBiodistributionBiological AssayCanis familiarisCardiovascular systemCarrageenanChemicalsChemistryClinical ResearchCutaneousCyclic GMPDataDegenerative polyarthritisDoseDrug AddictionDrug KineticsEventExperimental Animal ModelFinancial HardshipFormulationGastrointestinal HemorrhageGoalsGuidelinesHealth Care CostsHealthcare SystemsHematologyHemorrhageHumanHumidityHyperalgesiaHypersensitivityHypotensionIndividualInflammationIntravenousLifeLightMaximum Tolerated DoseMethodsMindModelingNational Institute of Drug AbuseNausea and VomitingNeurologicNon-Steroidal Anti-Inflammatory AgentsNuclearOperative Surgical ProceduresOpiate AddictionOpioidOralOral AdministrationOrganOutcomeOutpatientsPainPain managementPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPharmacology StudyPharmacotherapyPhasePhosphotransferasesPopulationPostoperative PainPostoperative PeriodPre-Clinical ModelPreclinical TestingProcessPropertyProstaglandin-Endoperoxide SynthaseRattusRegulatory PathwayReproducibilityRespirationRheumatoid ArthritisRiskRodentRodent ModelRoleSafetySalicylic AcidsSavingsSchemeScienceSerious Adverse EventTemperatureTestingToxic effectToxicologyUnited StatesUrinary RetentionVentilatory DepressionWorkaddictionanimal painbasebrain tissuechronic paincombatcyclooxygenase 1dimerdosageefficacy studyexperimental studygastrointestinalhigh riskillicit opioidimprovedin vivoinhibitorinterestmeetingsmultimodalitynanodrugnon-opioid analgesicnovel therapeuticsopioid abuseopioid epidemicopioid mortalityopioid overdoseopioid sparingopioid useparenteral administrationparticleplatelet functionpre-clinicalprescription opioidreceptorresearch clinical testingsalicylsalicylic acidsmall moleculesocialsurgical painsurgical risktreatment strategy
项目摘要
SUMMARY: The White House has initiated an aggressive campaign to combat the current opioid crisis that is
affecting all levels of the American way of life. The opioid crisis has emerged from multiple fronts. Among these
various fronts, the continued use of opioids in the post-operative area is a growing addiction risk. Current post-
operative pain management utilizes a multimodal pain management strategy, which includes opioids and non-
opioids (NSAIDs). These two treatment strategies have significant health care cost implications due to their
adverse events and addiction risks. Opioids have serious adverse effects such as nausea, vomiting,
respiratory depression, urinary retention, hypotension, and long-term addiction risks. Non-opioids such as
NSAIDs, both in oral and parenteral formulations, are an essential part of a multimodal post-operative pain
management strategy for their opioid sparing capabilities. However, NSAIDs (Cyclooxygenase (Cox)-1/2
inhibitors) have serious adverse events such as GI bleeding, cardiovascular events, and systemic bleeding.
This current state of affairs has created an unmet need for an effective parenteral/oral analgesic for acute post-
operative pain management without the risks of opioid addiction. Salsalate, a dimer or salicylic acid, although a
non-FDA-approved drug, is currently available in oral dosage for the treatment of osteoarthritis and rheumatoid
arthritis. Salsalate works at multiple levels to target multiple steps along the surgical pain pathway. Salsalate
through its active metabolite, salicylic acid (SA), reduces NF-κB activation via IKK-kinase beta inhibition, and
has no direct binding to cyclooxygenase 1 (Cox-1); therefore, does not affect function of platelets, resulting in a
safer hematological and gastrointestinal safety profile 1. RH Nanopharmaceuticals (RH Nano) had a successful
Pre-IND application review for current oral salsalate through the FDA 505(b)(2) regulatory pathway to submit
an IND in the next few months. FDA has confirmed that salsalate is likely to be considered a new chemical
entity (NCE) for an initial New Drug Application (NDA). RH Nano has also developed a micronized version of
salsalate (M-salsalate) for oral and parenteral administration. Our preliminary testing shows that in comparison
with current oral salsalate, M-salsalate has an improved pharmacokinetic profile including a shorter Tmax,
higher Cmax, and larger area under the curve (AUC), resulting in enhanced biodistribution. It is expected to
have the same safety profile as the oral salsalate. The President’s Commission on “Combating Drug Addiction
and the Opioid Crisis” has recommended to the President of the United States that “individuals with acute or
chronic pain must have access to non-opioid pain management options”, and the National Institute on Drug
Abuse (NIDA) has a strong interest on “non-opioid medications to treat pain in outpatient subjects, including
opioid sparing strategies”. With these needs in mind, RH Nano proposes a plan for manufacturing and pre-
clinical testing of parenteral M-salsalate in two animal models to assess the efficacy and safety in the treatment
of acute postoperative pain management. In this proposal (Phase I), we will partner with Particle Sciences to
develop the optimal formulation under strict Chemistry Manufacturing and Control (CMC) guidelines. In Phase
II, we propose to conduct the pharmacokinetics and toxicology studies of M-salsalate in two species of animals
(rodent and non-rodent) through a partnership with Calvert Labs. We will also use an animal pain model for
preclinical efficacy studies, and an in vivo Receptor Occupancy (RO) assay in animal brain tissues to assess
the opioid sparing properties of M-salsalate through a partnership with Melior Discovery. The results from
these experiments will enable us to generate adequate data for a Pre-IND FDA meeting for discussion of
clinical testing in humans.
摘要:白宫发起了一场积极的运动,以对抗当前的阿片类药物危机
项目成果
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