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Exploring self- immolative prodrugs of hydroxychloroquine with aryl propionic acid NSAIDs for dual drug release in rheumatoid arthritis: Synthesis and pharmacokinetics
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| Author:
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SUNEELA DHANESHWAR, POORVASHREE JOSHI
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| Abstract:
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Incomplete absorption and poor oral bioavailability of hydroxychloroquine (HCQ) as well as gastrointestinal erosions of NSAIDs have attributed to major hurdles in the treatment of rheumatoid arthritis. To overcome these hurdles, we designed self- immolative dual delivery approach for disease modifying antirheumatic hydroxychloroquine and propionic acid derivatives of NSAIDs. Here, we report synthesis, stability, bio-conversion and pharmacokinetics of hydroxychloroquine esters with flurbiprofen (HF), zaltoprofen (HZ) and ketoprofen (HK). Chemical tethering was accomplished by CDI coupling. Characteristic C=O stretch of newly formed ester in IR, absence of singlet of HCQ–OH in NMR, molecular ion peaks of desired molecular weights in mass spectra, accurate percentage of C, H, N analysis in elemental analysis confirmed synthesis of projected structures. Bulky NSAIDs imparted higher lipophilicity. Stability of prodrugs in acidic pH (1.2) and stomach environment supported the reported mechanism of inhibition of gastrointestinal disturbances to minimize local gastrointestinal irritation. Our study elucidated pH (7.4) and intestinal esterases responsive hydrolysis of prodrugs. In vivo pharmacokinetic studies proved improvement in oral absorption (75-84%) and pharmacokinetic parameters like C max, T max, and AUC0-24 than parent HCQ. So, overall pharmacokinetics data implies that these self-immolative prodrugs can be ideal alternatives for extended release of HCQ and NSAIDs for management of RA. Extensive pre- clinical studies are underway to establish their utility in RA.
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| Keyword:
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Prodrugs; Hydroxychloroquine; NSAIDs; Arthritis; Disease modifying agent; CDI coupling, Absorption
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| EOI:
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| DOI:
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