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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

Abstract

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.

Keywords

Prodrugs Hydroxychloroquine NSAIDs Arthritis Disease modifying agent CDI coupling Accumulation 

Abbreviations

HC

Healthy control

AAC

Acetic acid control

AC

Arthritic control

HCQ

Hydroxychloroquine

HBA, HIN, HA, HD, HL

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

DMARDs

Disease modifying anti- rheumatic drugs

CDI

1,1′-Carbonyldiimidazole

RBC

Red blood corpuscles

WBC

White blood corpuscles

SGOT

Serum glutamic-oxaloacetic transaminase

SGPT

Serum glutamic-pyruvic transaminase

CFA

Complete Freund’s Adjuvant

CMC

Carboxymethyl cellulose

Notes

Acknowledgements

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)

References

  1. 1.
    Kurkó J. Genetics of rheumatoid arthritis—a comprehensive review. Clin Rev Allergy Immunol. 2013;45(2):170–9.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Russak S, Sherbourne C, Lubeck D. Validation of a rheumatoid arthritis health related quality of life instrument, the CSHQ-RA. Arthritis Rheum. 2003;49(6):798–803.CrossRefPubMedGoogle Scholar
  3. 3.
    Dipiro J. Bone and Joint Disorders, in: Schwinghammer TL (eds.), Pharmacotherapy Handbook, 8th ed. MC graw Hill, 2011.Google Scholar
  4. 4.
    Schipper L. Ups and downs in the treatment strategies of rheumatoid arthritis. Rheumatology. 2011;50(5):818–20.CrossRefPubMedGoogle Scholar
  5. 5.
    Roy F. Don’t forget traditional DMARDs. Rheumatology. 2011;50(3):429–30.CrossRefGoogle Scholar
  6. 6.
    Castrejon I, Kathryn A. Efficacy and safety of methotrexate in combination with other non-biologic disease modifying antirheumatic drugs (DMARDs) in treatment of rheumatoid arthritis. Bull Hosp Joint Dis. 2013;71(1):S20–8.Google Scholar
  7. 7.
    Wahinuddin S, Ashraful T, Chandrashekhar G, Arshad A. The trends of DMARDS prescribed in rheumatoid arthritis patients in Malaysia. Oman Med J. 2009;24(4):260–6.Google Scholar
  8. 8.
    Pavelka K, Pelfskova Z, Vacha J, Trnavsk K. Hydroxychloroquine sulphate in the treatment of rheumatoid arthritis: a double blind comparison of two dose regimens. Ann Rheum Dis. 1989;48(7):542–6.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Joshi P, Dhaneshwar S. An update on disease modifying antirheumatic drugs. Inflamm Allergy Drug Target. 2014;13:249–61.CrossRefGoogle Scholar
  10. 10.
    Day R, Furst D. Antirheumatic therapy: Actions and outcomes, Birkh: 2005.Google Scholar
  11. 11.
    Ono C, Yamada M, Tanaka M. Absorption, distribution and excretion of 14C-chloroquine after single oral administration in albino and pigmented rats: binding characteristics of chloroquine-related radioactivity to melanin in-vivo. J Pharm Pharmacol. 2003;55(12):1647–54.CrossRefPubMedGoogle Scholar
  12. 12.
    Banks C. Melanin: blackguard or red herring? Another look at chloroquine retinopathy. Aust N Z Ophthalmol. 1987;15(4):15365–70.Google Scholar
  13. 13.
    Quan L, Thiele G, Tian J, Wang D. The development of novel therapies for rheumatoid arthritis. Expert Opin Ther Pat. 2008;18(7):723–38.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Patil K, Dhaneshwar S, Chopade S, Joshi P. Design, synthesis and in vitro release studies of co-drugs for rheumatoid arthritis. Inflamm Allergy Drug Targets. 2016;14(1):47–52.Google Scholar
  15. 15.
    Crofford L. Use of NSAIDs in treating patients with arthritis. Arthritis Res Ther. 2013;15(3):S2.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Elslager E, Tendick F, Wernbel L. Repository drugs. VIII Ester and amide congers of amodiaquine, hydroxychloroquine, oxychloroquine, primaquine, quinacrine and related substances as potential long –acting antimalarial agent. J Med Chem. 1969;12:600–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Eddy N, Leimbach D. Synthetic analgesics: II. Dithienylbutenyl- and dithienylbutylamines. J Pharmacol Exp Ther. 1953;107(3):385–93.PubMedGoogle Scholar
  18. 18.
    Winter C, Risley E, Nuss G. Carrageenan induced oedema in hind paw of the rats as an assay of anti-inflammatory drug. Proc Soc Exp Biol Med. 1962;111:544–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Snekhalatha U, Anburajan M, Venkatraman B, Menaka M. Evaluation of complete Freund’s adjuvant-induced arthritis in a Wistar rat model. Z Rheumatol. 2012;72(4):1–7.Google Scholar
  20. 20.
    Pathak N, Patel N, Kasture S. Free radical scavenging activity of albizialebbeck methanolic extract in arthritis rats. IJPRD. 2010;1:1–6.Google Scholar
  21. 21.
    Buckley C. Science, medicine and the future, treatment of rheumatoid arthritis. Brit Med J. 1997;315(7102):236–8.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kumar V, Roy S. Calotropis procera latex extract affords protection against inflammation and oxidative stress in Freunds complete adjuvant induced monoarthritis in rats. Mediat Inflamm. 2007;1:1–7.CrossRefGoogle Scholar
  23. 23.
    Cioli V, Putzolu S, Rotzolu S, Rossi V. The role of direct tissue contact in the production of gastrointestinal ulcers by anti-inflammatory drugs in rats. Toxicol Appl Pharmacol. 1979;50(2):283–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Wang Z, Wang L, Huang P. Improved convenient synthesis of benzoyl metronidazole: a nitroimidazole antibiotics. J Chem. 2013;93(2013):7–8.Google Scholar
  25. 25.
    Brain S, Philip K, editors. Pain and neurogenic inflammation. Basel: Springer; 2013. p. 81-101.Google Scholar
  26. 26.
    Bendele A. Animal models of rheumatoid arthritis. J Musculoskel Neuron Interact. 2001;1(4):377–85.Google Scholar
  27. 27.
    Brentano F, Kyburz D, Schorr O. The role of toll-like receptor signalling in the pathogenesis of arthritis. Cell Immunol. 2005;233:90–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Martin R. The role of nutrition and diet in rheumatoid arthritis. Proc Nutri Soc. 1998;57(2):231–4.CrossRefGoogle Scholar
  29. 29.
    Adebayo D, Bjarnason I. Is non-steroidal anti-inflammatory drug (NSAID) enteropathy clinically more important than NSAID gastropathy? Postgrad Med J. 2006;82(965):186–91.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Amos R, Constable T, Crockson R, Crockson A, Mcconkey B. Rheumatoid arthritis: relation of serum c-reactive protein and erythrocyte sedimentation rates to radiographic changes. Br Med J. 1977;1(6055):195–7.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Prajapati D, Shah J, Sen D. Modulatory effect of telmisartan on anti-inflammatory effect of rosiglitazone in adjuvant arthritis model. Int J Res Pharmaceut Biomed Sci. 2011;2(2):554–66.Google Scholar
  32. 32.
    Eric G, Lawrence J. The textbook of therapeutic drugs and disease management, rheumatoid arthritis and therapy, 6th ed. USA: Williams & Wilkins; 1996.Google Scholar
  33. 33.
    Harrison M. Erythrocyte sedimentation rate and C-reactive protein. Aust Prescr. 2015;38(3):93–4.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Khan H, Ashraf M, Hashmi A, Ahmad M, Anjum A. Papain induced progressive degenerative changes in articularcartilage of rat femorotibial joint and its histopathological grading. J Anim Plant Sci. 2013;23(3):350–8.Google Scholar
  35. 35.
    Brenner M, Meng H, Yarlett N. The non-MHC quantitative trait locus Cia10 contains a major arthritis gene and regulates disease severity, pannus formation and joint damage. Arthritis Rheum. 2005;52(1):52322–32.CrossRefGoogle Scholar
  36. 36.
    Jacobson J, Girish G, Jiang Y, Resnick D. Radiographic evaluation of arthritis: inflammatory conditions. Radiology. 2008;248(2):378–89.CrossRefPubMedGoogle Scholar
  37. 37.
    Omar F. Cyclic amide derivatives as potential prodrugs: synthesis and evaluation of N-hydroxymethylphthalimide esters of some non-steroidal anti-inflammatory carboxylic acid drugs. Eur J Med Chem. 1998;33(2):123–31.CrossRefGoogle Scholar
  38. 38.
    Kingsbury S, Tharmanathan P, Adamson J. Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis (HERO): study protocol for a randomized controlled trial. Trials. 2013;14:1–12.CrossRefGoogle Scholar
  39. 39.
    Cashman J. The mechanisms of action of NSAIDs in analgesia. Drugs. 1996;52(5):13–23.CrossRefPubMedGoogle Scholar
  40. 40.
    Borthakur A, Bhattacharyya S, Anbazhagan A, Kumar A, Dudeja P, Tobacman J. Prolongation of carrageenan-induced inflammation in human colonic epithelial cells by activation of an NFκB-BCL10 loop. Biochim Biophys Acta. 2012;1822(8):1300–7.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Necas J, Bartosikova L. Carrageenan: a review. Veterinarni Medicina. 2013;58(2013):187–205.Google Scholar
  42. 42.
    Posadas I, Bucci M, Roviezzo F. Carrageenan-induced mouse paw oedema is biphasic, age-weight dependent and displays differential nitric oxide cyclooxygenase-2 expression. Br J Pharmacol. 2004;142(2):331–8.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Pareek A, Chandurkar N, Saha R, Payghan R. Evaluation of anti-inflammatory activity of hydroxychloroquine and simvastatin combination in experimental animals. RJPBCS. 2014;2(1):464–8.Google Scholar
  44. 44.
    Miyachi Y, Yoshioka A, Imamura S, Niwa Y. Antioxidant action of antimalarials. Ann Rheum Dis. 1986;45(3):244–8.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Gómez-Guzmán M, Jiménez R, Romero M. Chronic hydroxychloroquine improves endothelial dysfunction and protects kidney in a mouse model of systemic lupus erythematous. Hypertension. 2014;64:330–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Burian M, Geisslinger G. COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites. Pharmacol Ther. 2005;107(2):139–54.CrossRefPubMedGoogle Scholar
  47. 47.
    Amdekar S, Roy P, Singh V, Kumar A, Singh R, Sharma P. Anti-Inflammatory activity of Lactobacillus on carrageenan-induced paw edema in male Wistar Rats. Int J Inflamm. 2012; 2012(2012): Article ID 752015.Google Scholar
  48. 48.
    Egan C, Lockhart J, Ferrell W. Pathophysiology of vascular dysfunction in rat model of chronic joint inflammation. J Physiol. 2004;557(2):635–43.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Billingham M, Davis G. Anti-inflammatory drugs. In: Vane JR, Fereira SH, editors. Handbook of experimental pharmacology. Berlin: Springer; 1979.Google Scholar
  50. 50.
    Jayaprakash T, Koduri S, Divyateja S, Ali F. Evaluation of anti-arthritic activity using Freund’s adjuvant induced arthritis in albino rats. JPR BioMedRx: An Int J. 2013;1(9):892-5.Google Scholar
  51. 51.
    Otari K, Shete R, Harpalani A. Evaluation of anti-inflammatory and anti-arthritic activities of ethanolic extract of vernonia anthelmintica seeds. J Cell Tissue Res. 2010;10(2010):2269–80.Google Scholar
  52. 52.
    Paul W. Fundamental Immunology. In: We P, editor. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2013.Google Scholar
  53. 53.
    Ong C, Lirk P, Tan C, Seymour RA. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res. 2007;5(1):19–34.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Felsher B, Redeker A. Effect of chloroquine on hepatic uroporphyrin metabolism in patients with porphyria cutaneatard. Medicine (Baltimore). 1966;45(6):575–83.CrossRefGoogle Scholar
  55. 55.
    Ruderman E, Crawford J, Maier A. Histologic liver abnormalities in an autopsy series of patients with rheumatoid arthritis. Br J Rheumatol. 1997;36(2):210–3.CrossRefPubMedGoogle Scholar
  56. 56.
    Fries J, Singh G, Lenert L, Furst D. Aspirin, hydroxychloroquine, and hepatic enzyme abnormalities with methotrexate in rheumatoid arthritis. Arthritis Rheum. 1990;33(11):1611–9.CrossRefPubMedGoogle Scholar
  57. 57.
    Curtis J, Beukelman T, Onofrei A. Elevated liver enzyme tests among rheumatoid arthritis and psoriatic arthritis patients treated with methotrexate and/or leflunomide. Ann Rheum Dis. 2010;69:43–7.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Selmi C, Santis M, Eric M. Liver involvement in subjects with rheumatic disease. Arthritis Res Ther. 2011;13(3):226.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Blackburn W, Prupas H, Silverfield J, Poiley J, Caldwell J, Collins R. Tenidap in rheumatoid arthritis. A 24-week double-blind comparison with hydroxychloroquine-plus-piroxicam, and piroxicam alone. Arthritis Rheum. 1995;38(10):1447-56.Google Scholar
  60. 60.
    Tarp S, Bartels E, Bliddal H, Furst D, Boers M, Danneskiold-Samsøe B. Effect of nonsteroidal anti-inflammatory drugs on the C-reactive protein level in rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheum. 2012;64(11):3511-21.Google Scholar
  61. 61.
    Shashikumar N, Shivamurthy M, Chandrashekara S. Evaluation of efficacy of combination of methotrexate and hydroxychloroquine with leflunomide in active rheumatoid arthritis. Indian J Pharmacol. 2010;42(6):358–61.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Tanenbaum L, Denny M, Tuffanelli M. Antimalarial agents. Arch Dermatol. 1980;116(5):587–91.CrossRefPubMedGoogle Scholar
  63. 63.
    Mackenzie A, Scherbel A. Chloroquine and hydroxychloroquine in rheumatological therapy. Clin Rheum Dis. 1980;6:545–66.Google Scholar
  64. 64.
    Mcchesney E, Conway W, Banks W, Rogers J, Shekosky J. Studies of metabolism of some compounds of the 4-amino-7-chloroquine series. J Pharmacol Exp Ther. 1996;151:482–93.Google Scholar
  65. 65.
    Rynes R. Antimalarial drugs in the treatment of rheumatological diseases. Br J Rheumatol. 1997;36(7):799–805.CrossRefPubMedGoogle Scholar
  66. 66.
    Pyoung J, Nayoung K, Joo-Hyon K. Comparison of indomethacin, diclofenac and aspirin-induced gastric damage according to age in rats. Gut Liver. 2012;6(2):210–7.CrossRefGoogle Scholar
  67. 67.
    Funk J, Oyarzo J, Frye J. Turmeric extract containing curcuminoids prevent experimental rheumatoid arthritis. J Nat Prod. 2006;69(3):351–5.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Romas E, Sims N, Hards D. Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Am J Pathol. 2002;161(4):1419–27.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Arend W. Cytokine imbalance in the pathogenesis of rheumatoid arthritis: the role of interleukin-1 receptor antagonist. Sem Arthritis Rheum. 2001;30(5):1–6.CrossRefGoogle Scholar
  70. 70.
    Oelzner P, Lehmann G, Eidner T. Hypercalcemia in rheumatoid arthritis with disease activity and bone metabolism. Rheumatol Int. 2006;26(10):908–15.CrossRefPubMedGoogle Scholar
  71. 71.
    Gravallese E. Bone destruction in arthritis. Ann Rheum Dis. 2002;61(2):84–6.CrossRefGoogle Scholar
  72. 72.
    Cruz da silva J, Mariz H, Pitta M. Hydroxychloroquine decreases Th17-releated cytokines in systemic lupus erythematous and rheumatoid arthritis patients. Clinics. 2013;68(6):766–71.CrossRefGoogle Scholar
  73. 73.
    Housby J, Cahill C, Chu B. Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. Cytokine. 1999;11(5):347–58.CrossRefPubMedGoogle Scholar

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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