Drug Delivery and Translational Research

, Volume 7, Issue 5, pp 709–730 | Cite as

Novel drug delivery of dual acting prodrugs of hydroxychloroquine with aryl acetic acid NSAIDs: Design, kinetics and pharmacological study

  • Joshi Poorvashree
  • Dhaneshwar SuneelaEmail author
Original Article


Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by restricted movements of joints of hand, feet, elbow, knees and neck but principally the synovial joints. Though etiopathology is not exactly known, treatment paradigms are evolving to provide a tighter control over symptoms and disease progression. Current trend is introduction of disease modifying anti-rheumatoid drugs (DMARDs) at early stages. Hydroxychloroquine (HCQ) and nonsteroidal anti-inflammatory drugs (NSAIDs) are two mechanistically different categories widely used in the management of RA where the first arrests the disease progression while the latter offers symptomatic relief. Present work aims at minimizing problems of slow onset and accumulation of HCQ in non-targeted sites and local gastric intolerance to NSAIDs by designing their mutual ester prodrugs. Synthesis of prodrugs was achieved by CDI coupling and structures were confirmed by IR, 1H–NMR, 13C–NMR, mass spectroscopy and elemental analysis. Prodrugs resisted hydrolysis in acidic environment of the stomach but exhibited significant release in small intestine. Upon oral administration of prodrugs to rats, 40.5–49% HCQ and 53.4–66.8% of NSAIDs were recovered in 8.5–10 h in blood. Urine and feces samples pooled over a period of 24 h exhibited 2.3–3.5% and 0.75–0.9% of HCQ, respectively, without any presence of intact prodrugs or NSAIDs. Prodrugs were pharmacologically evaluated for analgesic and anti-inflammatory activities using standard animal models. Among all, prodrugs of HCQ with licofelone (HL) and aceclofenac (HA) produced superior analgesia, improved weight gain, normalization of joint diameter/paw volume than HCQ and physical mixtures of HCQ and NSAIDs. Hematological and biochemical studies indicated significant step up in RBC, Hb, platelet count, total protein nutrient (TPN) levels and step down in WBC, serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) by the treatment with HL and HA. Through these novel codrugs, problems of slow onset and accumulation of HCQ in non-targeted sites and local gastric intolerance to NSAIDs were well addressed. These dual acting mutual prodrugs of two mechanistically different anti-arthritic agents could be explored further as promising strategy for effective management of RA.


Prodrugs Hydroxychloroquine NSAIDs Arthritis Disease modifying agent CDI coupling Accumulation 



Healthy control


Acetic acid control


Arthritic control




Prodrugs of HCQ with biphenyl acetic acid, indomethacin, aceclofenac, diclofenac and licofelone, respectively

HCQ + BPA, HCQ + Indo HCQ + Aceclo, HCQ + Diclo, HCQ + Lico

Physical mixtures of HCQ with biphenyl acetic acid, indomethacin, aceclofenac, diclofenac and licofelone, respectively


Disease modifying anti- rheumatic drugs




Red blood corpuscles


White blood corpuscles


Serum glutamic-oxaloacetic transaminase


Serum glutamic-pyruvic transaminase


Complete Freund’s Adjuvant


Carboxymethyl cellulose



One of the authors (PJ) is thankful to Basic Scientific Research Scheme, University Grants Commission, New Delhi, for financial support. We are also thankful to IPCA Laboratories, Mumbai, India; Enaltec Laboratories, Mumbai; and Zim Laboratories, Nagpur, India for the gift samples of HCQ and NSAIDs, respectively.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Animal studies

All institutional and national guidelines for the care and use of laboratory animals were followed.

Supplementary material

13346_2017_420_MOESM1_ESM.doc (45 kb)
ESM 1 (DOC 45 kb)


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Copyright information

© Controlled Release Society 2017

Authors and Affiliations

  1. 1.Department of Pharmaceutical Chemistry, Poona College of PharmacyBharati Vidyapeeth UniversityPuneIndia

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