Skip to main content
SpringerLink
Log in

New Dosage Formulations for Targeted Delivery of Cyclo-Oxygenase-2 Inhibitors

Focus on Use in the Elderly

  • Leading Article
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

NSAIDS are a widely used class of analgesic and anti-inflammatory drugs that act by inhibiting the cyclo-oxygenase (COX) enzyme. However, because of their nonspecificity of action, use of these agents as long-term therapy for chronic pain in diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA) is often discouraged. Among NSAIDs, COX-2 inhibitors are promising candidates for long-term therapy of chronic diseases, particularly in the elderly, because of their reduced incidence of gastrointestinal adverse effects. However, in recent times these agents have also been shown to cause adverse effects such as cardiovascular effects (myocardial infarction, stroke and hypertension) and renal effects (decreased renal blood flow/glomerular filtration rate), which in 2004 led to the withdrawal of rofecoxib and in 2005 the withdrawal of valdecoxib from the US market. Importantly, these adverse effects can be effectively reduced by achieving site specific/targeted delivery through new formulation approaches. These formulations not only restrict the drug supply to specific organs but also reduce the dose required. As a result, use of new delivery systems such as nanoparticles, microparticles, microemulsions and nanogels has gained widespread applicability in the management of chronic disease, especially in the elderly, and particularly when there is a need to decrease dose-dependent adverse effects (as is the case with COX-2 inhibitors). This article reviews various new approaches to the delivery of COX-2 inhibitors and highlights issues related to the development of delivery systems for these agents for RA, OA, cancer (familial adenomatous polyposis, prostate, breast and non-small cell lung cancer), ocular diseases (such as diabetic retinopathy) and inflammatory diseases of the skin, with emphasis on their potential for use in the elderly. Emphasis is also placed on the preparation of these particulate systems, their release profile and behaviour in biological systems.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Marnett LJ, Kalgutkar AS. Cyclooxygenase 2 inhibitors: discovery, selectivity and the future. TiPS 1999; 20: 465–9

    PubMed  CAS  Google Scholar 

  2. McGeer PL. Cyclo-oxygenase-2 inhibitors rationale and therapeutic potential for Alzheimer’s disease. Drugs Aging 2000; 17(1): 1–11

    Article  PubMed  CAS  Google Scholar 

  3. Patrignani P, Tacconelli S, Sciulli MG, et al. New insights into OX-2 biology and inhibition. Brain Res Rev 2005; 48: 352–9

    Article  PubMed  CAS  Google Scholar 

  4. Chandrasekharan NV, Dai H, Roos KL, et al. COX-3, a yclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure and expression. Proc Natl Acad Sci U S A 2002; 99: 13926–31

    Article  PubMed  CAS  Google Scholar 

  5. Dannhardt G, Kiefer W. Cyclooxygenase inhibitors: current tatus and future prospects. Eur J Med Chem 2001; 36: 109–26

    Article  PubMed  CAS  Google Scholar 

  6. Lee JL, Mukhtar H, Bickers DR, et al. Cyclooxygenases in the skin: pharmacological and toxicological implications. Toxicol Appl Pharmacol 2003; 192(3): 294–306

    Article  PubMed  CAS  Google Scholar 

  7. Wallace JL. Clinical significance and potential of selective cox-2 inhibitors. TiPS 1999; 20: 389–90

    CAS  Google Scholar 

  8. Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004; 351: 1709–11

    Article  PubMed  CAS  Google Scholar 

  9. Cryer B, Feldman M. Cyclooxygenase-2 selectivity of widely used non steroidal anti-inflammatory drugs. Am J Med 1998; 104(5): 413–21

    Article  PubMed  CAS  Google Scholar 

  10. Hersh EV, Lally ET, Moore PA. Update on cyclooxygenase inhibitors: has a third COX isoform entered the fray? Curr Med Res Opin 2005; 21: 1217–26

    Article  PubMed  CAS  Google Scholar 

  11. Motsko SP, Rascati KL, Busti AJ, et al. Temporal relationship between use of NSAIDs, including selective COX-2 inhibitors, and cardiovascular risk. Drug Saf 2006; 29(7): 621–32

    Article  PubMed  CAS  Google Scholar 

  12. Savage R. Cyclo-oxygenase-2 inhibitors: when should they be used in the elderly? Drugs Aging 2005; 22(3): 185–200

    Article  PubMed  CAS  Google Scholar 

  13. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000 Nov 23; 343(21): 1520–8

    Article  PubMed  CAS  Google Scholar 

  14. Lim J. Pfizer’s voluntary suspension of sales of valdecoxib (BEXTRA®). Singapore: Centre for Drug Administration Health Sciences Authority, 2005

    Google Scholar 

  15. Tsujii M, Kawano S, Sawaoka H, et al. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998; 93: 705–16

    Article  PubMed  CAS  Google Scholar 

  16. Cusack BJ. Pharmacokinetics in older persons. Am J Geriatr Pharmacother 2004; 2(4): 275–302

    Article  Google Scholar 

  17. Thakkar H, Sharma RK, Mishra AK, et al. Albumin microspheres as carriers for the antiarthritic drug celecoxib. AAPS Pharm Sci Tech 2005; 6(1): E65–73

    Article  Google Scholar 

  18. Price DD, Mao J, Lu J, et al. Effects of the combined oral administration of NSAIDs and dextromethorphan on behavioral symptoms indicative of arthritic pain in rats. Pain 1996; 68: 119–27

    Article  PubMed  CAS  Google Scholar 

  19. Emery P, Kong SX, Ehrich EW, et al. Dose effect relationships of nonsteroidal anti-inflammatory drugs: a literature review. Clinic Ther 2002; 24(8): 1225–91

    Article  CAS  Google Scholar 

  20. Johnson AG. NSAIDs and blood pressure: clinical importance or older patients. Drugs Aging 1998; 12(1): 17–27

    Article  PubMed  CAS  Google Scholar 

  21. Thakkar H, Sharma RK, Mishra AK, et al. Efficacy of chitosan microspheres for controlled intra-articular delivery of celecoxib in inflamed joints. J Pharm Pharmacol 2004; 56: 1091–9

    Article  PubMed  CAS  Google Scholar 

  22. Lewis DA, Field WN, Hayes K, et al. The use of albumin microspheres in the treatment of carageenan-induced inflammation in the rat. J Pharm Pharmacol 1992; 44: 271–4

    Article  PubMed  CAS  Google Scholar 

  23. Srinath P, Chary MG, Vyas SP, et al. Long-circulating liposomes of indomethacin in arthritic rats: a biodisposition study. Pharm Acta Helv 2000; 74: 399–404

    Article  PubMed  CAS  Google Scholar 

  24. Dingle JT, Gordon JL, Hazleman BL, et al. Novel treatment for joint inflammation. Nature 1978; 271: 372–3

    Article  PubMed  CAS  Google Scholar 

  25. Thakkar H, Murthy RSR. Polyethylene glycol as a de-aggregating agent in the preparation of celecoxib loaded gelatin microspheres. Ars Pharm 2005; 46(1): 19–34

    Google Scholar 

  26. Marouf W, Donnelly RF, McCarron PA. Attenuation of the nitial burst release of celecoxib from loaded poly(lactide-coglycolide) nanoparticles prepared using a novel modification of the salting out procedure. J Pharm Pharmacol (Suppl) 2005; 57: S88

    Google Scholar 

  27. Freitas MN, Marchetti JM. Nimesulide PLA microspheres as a potential sustained release system for the treatment of inflammatory diseases. Int J Pharm 2005; 295: 201–11

    Article  PubMed  CAS  Google Scholar 

  28. Couvreur P, Dubernet C, Puisieux F. Controlled drug delivery ith nanoparticles: current possibilities and future trends. Eur J Pharm Biopharm 1995; 41: 2–13

    CAS  Google Scholar 

  29. Subbaramaiah K, Dannenberg AJ. Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci 2003; 24(2): 96–102

    Article  PubMed  CAS  Google Scholar 

  30. Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342: 1946–52

    Article  PubMed  CAS  Google Scholar 

  31. Miller K, Waye JD. Colorectal polyps in the elderly what should be done? Drugs Aging 2002; 19(6): 393–404

    Article  PubMed  Google Scholar 

  32. Maier TJ, Schilling K, Schmidt R, et al. Cyclooxygenase-2 (COX-2) dependent and independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. Biochem Pharm 2004; 67: 1469–78

    Article  PubMed  CAS  Google Scholar 

  33. Riedl K, Krysan K, Pold M, et al. Multifaceted roles of cyclooxygenase-2 in lung cancer. Drug Resist Updat 2004; 7: 169–84

    Article  PubMed  CAS  Google Scholar 

  34. Olsen SR. Taxanes and COX-2 inhibitors: from molecular pathways to clinical practice. Biomed Pharmacother 2005; 59: S306–10

    Article  PubMed  CAS  Google Scholar 

  35. Haupt S, Zionia T, Gatia I, et al. Luminal delivery and dosing considerations of local celecoxib administration to colorectal cancer. Eur J Pharm Sci 2006; 28: 204–11

    Article  PubMed  CAS  Google Scholar 

  36. Katsuma M, Watanabe S, Kawai H, et al. Studies on lactulose formulations for colon-specific drug delivery. Int J Pharm 2002; 249: 33–43

    Article  PubMed  CAS  Google Scholar 

  37. Friend DR. New oral delivery systems for treatment of inflammatory bowel disease. Adv Drug Deliv Rev 2005; 57: 247–65

    Article  PubMed  CAS  Google Scholar 

  38. Gasparini G, Longo R, Sarmiento R, et al. Inhibitors of cyclooxygenase 2: a new class of anticancer agents? Lancet Oncology 2003; 10: 605–15

    Article  Google Scholar 

  39. Park K, Yang JH, Choi Y, et al. Chemoprevention of 4-NQO-induced oral carcinogenesis by co-administration of all-trans retinoic acid loaded microspheres and celecoxib. J Control Rel 2005; 104: 167–79

    Article  CAS  Google Scholar 

  40. Haynes A, Shaik MS, Chatterjee A, et al. Evaluation of an aerosolized selective COX-2 inhibitor as a potentiator of doxorubicin in non small cell lung cancer cell lines. Pharm Res 2003; 20: 1485–95

    Article  PubMed  CAS  Google Scholar 

  41. Gautam A, Koshkina N. Paclitaxel (taxol) and taxoid derivatives for lung cancer treatment: potential for aerosol delivery. Curr Cancer Drug Targets 2003; 3: 287–96

    Article  PubMed  CAS  Google Scholar 

  42. Gautam A, Waldrep JC, Densmore CL, et al. Growth inhibition of established B16-F10 lung metastases by sequential aerosol delivery of p53 gene and 9-nitrocamptothecin. Gene Ther 2002; 9: 353–7

    Article  PubMed  CAS  Google Scholar 

  43. Estensen RD, Jordan MM, Wiedman TS, et al. Effect of chemopreventive agents on separate stage of progression of benzo[alpha] pyrene induced lung tumors in A/J mice. Carcinogenesis 2004; 25: 197–201

    Article  PubMed  CAS  Google Scholar 

  44. Lawson KA, Anderson K, Menchaca M, et al. Novel vitamin E analogue decreases syngeneic mouse mammary tumor burden and reduces lung metastasis. Mol Cancer Ther 2003; 2: 437–44

    PubMed  CAS  Google Scholar 

  45. Koshkina NV, Waldrep JC, Knight V. Camptothecins and lung cancer: improved delivery systems by aerosol. Curr Cancer Drug Targets 2003; 3: 251–64

    Article  PubMed  CAS  Google Scholar 

  46. Barnes PJ. Inhaled glucocorticoids for asthma. N Engl J Med 1995; 332: 868–75

    Article  PubMed  CAS  Google Scholar 

  47. Dolovich M. Lung dose, distribution and clinical response to therapeutic aerosols. Aerosol Sci Tech 1993; 18: 230–40

    Article  CAS  Google Scholar 

  48. Haynes A, Shaik MS, Chatterjee A, et al. Formulation and evaluation of aerosolized celecoxib for the treatment of lung cancer. Pharm Res 2005; 22(3): 427–39

    Article  PubMed  CAS  Google Scholar 

  49. Bourlais CL, Acar L, Zia H, et al. Ophthalmic drug delivery systems: recent advances. Prog Retin Eye Res 1998; 17(1): 33–58

    Article  PubMed  CAS  Google Scholar 

  50. Lang JC. Ocular drug delivery conventional ocular formulations. Adv Drug Deliv Rev 1995; 16: 39–43

    Article  CAS  Google Scholar 

  51. Assil KK, Lane J, Weinreb RN. Sustained release of the antimetabolite 5-fluorouridine-5′-monophosphate by multivesicular liposomes. Ophthalmic Surg 1988; 19(6): 408–13

    PubMed  CAS  Google Scholar 

  52. Chetoni P, Mariotti Bianchi L, Giannaccini B, et al. Ocular mini-tablets for controlled release of timolol: evaluation in rabbits. J Ocul Pharmacol Ther 1996; 12(3): 245–52

    Article  PubMed  CAS  Google Scholar 

  53. Amrite AC, Kompella UB. Size-dependent disposition of nanoparticles and microparticles following subconjunctival administration. J Pharm Pharmacol 2005; 57(12): 1555–63

    Article  PubMed  CAS  Google Scholar 

  54. Kunou N, Ogura Y, Honda Y, et al. Biodegradable scleral implant for controlled intraocular delivery of betamethasone phosphate. J Biomed Mater Res 2000; 51(4): 635–41

    Article  PubMed  CAS  Google Scholar 

  55. Wormald R. Delivery of eye care to the elderly: practical considerations. Community Eye Health 1999; 12(29): 6–7

    PubMed  CAS  Google Scholar 

  56. Singh MM, Murthy GV, Venkatraman R, et al. A study of ocular morbidity among elderly population in a rural area of central India. Indian J Ophthalmol 1997; 45(1): 61–5

    PubMed  CAS  Google Scholar 

  57. Ayalasomayajula SP, Kompella UB. Retinal delivery of celecoxib is several-fold higher following subconjunctival administration compared to systemic administration. Pharm Res 2004; 21(10): 1797–804

    Article  PubMed  CAS  Google Scholar 

  58. Klein R, Moss SE, Klein BE, et al. The Wisconsin epidemiologic study of diabetic retinopathy: XI. The incidence of macular edema. Ophthalmology 1989; 96(10): 1501–10

    PubMed  CAS  Google Scholar 

  59. Aiello LP, Gardner TW, King GL, et al. Diabetic retinopathy. Diabetes Care 1998; 21(1): 143–56

    PubMed  CAS  Google Scholar 

  60. Joussen AM, Murata T, Tsujikawa A, et al. NSAID prevent early diabetic retinopathy via TNFα suppression. FASEB J 2002; 16: 438–40

    PubMed  CAS  Google Scholar 

  61. Cheruvu NPS, Ayalasomayajula SP, Kompella UB. Retinal delivery of sodium fluorescein, budesonide and celecoxib following subconjunctival injection. Drug Deliv Technol 2003; 3(6): 62–7

    CAS  Google Scholar 

  62. Amrite AC, Ayalasomayajula SP, Cheruvu NP, et al. Single periocular injection of celecoxib-PLGA microparticles inhibits diabetes-induced elevations in retinal PGE2, VEGF, and vascular leakage. Invest Ophthalmol Vis Sci 2006; 47(3): 1149–60

    Article  PubMed  Google Scholar 

  63. Ayalasomayajula SP, Kompella UB. Subconjunctivally administered celecoxib-PLGA microparticles sustain retinal drug levels and alleviate diabetes-induced oxidative stress in a rat model. Eur J Pharmacol 2005; 511(2–3): 191–8

    Article  PubMed  CAS  Google Scholar 

  64. Chowdhury DK, Mitra AK. Kinetics of a model nucleoside (guanosine) release from biodegradable poly(DL-lactide-coglycolide) microspheres: a delivery system for long-term intraocular delivery. Pharm Dev Technol 2000; 5(2): 279–85

    Article  PubMed  CAS  Google Scholar 

  65. Barouch FC, Miyamoto K, Allport JR, et al. Integrin-mediated neutrophil adhesion and retinal leukostasis in diabetes. Invest Ophthalmol Vis Sci 2000; 41(5): 1153–8

    PubMed  CAS  Google Scholar 

  66. Ayalasomayajula SP, Amrite AC, Kompella UB. Inhibition of cyclooxygenase-2, but not cyclooxygenase-1, reduces prostaglandin E2 secretion from diabetic rat retinas. Eur J Pharmacol 2004; 498(1–3): 275–8

    Article  PubMed  CAS  Google Scholar 

  67. Eberhart CE, Coffey RJ, Radhika A, et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994; 107(4): 1183–8

    PubMed  CAS  Google Scholar 

  68. Panchagnula R. Transdermal delivery of drags. Indian J Pharmacol 1997; 29: 140–56

    CAS  Google Scholar 

  69. Kanikkannan N, Singh J, Ramarao P. In vitro transdermal iontophoretic transport of timolol maleate: effect of age and species. J Control Release 2001; 71: 99–105

    Article  PubMed  CAS  Google Scholar 

  70. Williams AC, Barry BW. Skin absorption enhancers. Crit Rev Ther Drag Carrier Syst 1992; 9(3–4): 305–53

    CAS  Google Scholar 

  71. Sengupta S, Velpandian T, Kabir SR, et al. Analgesic efficacy and pharmacokinetics of topical nimesulide gel in healthy human volunteers: double-blind comparison with piroxicam, diclofenac and placebo. Eur J Clin Pharmacol 1998; 54(7): 541–7

    Article  PubMed  CAS  Google Scholar 

  72. Erdogan F, Ergun H, Gokay NS, et al. The diffusion of nimesulide gel into synovial fluid: a comparison between administration routes. Int J Clin Pharmacol Ther 2006; 44(6): 270–5

    PubMed  CAS  Google Scholar 

  73. Inoo K, Hattori K, Shimizu N. Selective cox-2 inhibitor patch. USPTO No. 20050020658 (issued 2005 Oct 10)

  74. Castro V, Hadgraft LJ, Snowden MJ. pH-temperature sensitive microgels particles as transdermal drug delivery system. J Pharm Pharmacol (Suppl) 2005; 57: S85

    Google Scholar 

  75. Alves PM, Pohlmann AR, Guterres SS. Semisolid topical formulations containing nimesulide-loaded nanocapsules, nanospheres or nanoemulsion: development and rheological characterization. Pharmazie 2005; 60(12): 900–4

    PubMed  CAS  Google Scholar 

  76. Singh B, Mehta G, Kumar R, et al. Design, development and optimization of nimesulide-loaded liposomal systems for topical application. Curr Drag Deliv 2005; 2(2): 143–53

    Article  CAS  Google Scholar 

  77. Shahiwala A, Misra A. Studies in topical application of niosomally entrapped nimesulide. J Pharm Pharm Sci 2002; 5(3): 220–5

    PubMed  CAS  Google Scholar 

  78. Green PG, Hinz RS, Kim A, et al. Transdermal iontophoretic delivery of peptide drugs. J Control Release 1992; 21: 187–90

    Article  CAS  Google Scholar 

  79. Meidan VM, Walmsley AD, Irwin WJ. Phonophoresis: is it a reality? Int J Pharm 1995; 118: 129–49

    Article  CAS  Google Scholar 

  80. Bommannan DB, Tamada J, Leung L, et al. Effect of electroporation of transdermal iontophoretic delivery of luteinizing hormone releasing hormone (LHRH) in vitro. Pharm Res 1994; 11: 1809–14

    Article  PubMed  CAS  Google Scholar 

  81. Barry BW. Novel mechanisms and devices to enable successful transdermal drag delivery. Eur J Pharm Biopharm 2001; 14: 101–14

    CAS  Google Scholar 

  82. Park JH, Allen MG, Prausnitz MR. Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. J Control Release 2005; 104: 51–66

    Article  PubMed  CAS  Google Scholar 

  83. Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev 2004; 56(5): 603–18

    Article  PubMed  CAS  Google Scholar 

  84. Gungor S, Bergisadi N. Effect of penetration enhancers on in vitro percutaneous penetration of nimesulide through rat skin. Pharmazie 2004; 59(1): 39–41

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

No sources of funding were used to assist in the preparation of this article. The authors have no conflicts of interest that are directly relevant to the content of this article.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab, India

    Shyam S. Bansal & Abhijeet Joshi

  2. Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research, Section 67, SAS Nagar, Punjab, India

    Arvind K. Bansal

Authors
  1. Shyam S. Bansal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abhijeet Joshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arvind K. Bansal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arvind K. Bansal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bansal, S.S., Joshi, A. & Bansal, A.K. New Dosage Formulations for Targeted Delivery of Cyclo-Oxygenase-2 Inhibitors. Drugs Aging 24, 441–451 (2007). https://doi.org/10.2165/00002512-200724060-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002512-200724060-00001

Keywords

Search

Navigation