Advertisement

AAPS PharmSciTech

, 20:276 | Cite as

Preparation and Comparison of Oral Bioavailability for Different Nano-formulations of Olaparib

  • Akshay D. Pathade
  • Nagavendra Kommineni
  • Upendra Bulbake
  • Mohit M. Thummar
  • Gananadhamu SamanthulaEmail author
  • Wahid KhanEmail author
Research Article
  • 142 Downloads

Abstract

Olaparib (OLA) is a poly ADP ribose polymerase (PARP) inhibitor approved for germline BRCA-mutated (gBRCAm) advanced ovarian cancer and breast cancer. Low oral bioavailability of this drug requires increase in the dose and frequency causing haematological toxicity in the patients. The purpose of this study is to prepare different nano-formulations of OLA lipospheres (LP) by melt dispersion and nano-suspensions (NSP) by solvent evaporation (SE) and wet milling (WM) techniques and compare oral bioavailability of these formulations. Size of the nano-formulations OLA-LP, OLA-NSPSE and OLA-NSPWM were found to be 126.71 ± 4.54, 128.6 ± 2.34 and 531.1 ± 5.34 nm with polydispersity index below 0.3. In vitro release studies were performed by dialysis bag method where the sustained drug release was observed from nano-formulations until 9 h with Higuchi for OLA suspended in 2.5% w/v sodium carboxy methyl cellulose (OLA-SP), OLA-LP and OLA-NSPWM and Peppas for OLA-NSPSE-based drug release kinetics. In vivo pharmacokinetic studies, haematological toxicity and distribution studies were performed on rats. Results showed that there was an improvement in Cmax, AUCtotal, t1/2 and MRT by OLA nano-formulations when compared with OLA-SP. OLA-SP has shown reduction in WBC, platelets and lymphocytes at 12 and 36 h time points; however, no reduction in cell count was observed with OLA nano-formulations. Distribution studies proved FITC nano-formulations were most rapidly absorbed and distributed when compared with FITC-loaded suspension. From the above results, it was concluded that OLA nano-formulations can be an alternative to enhance the oral bioavailability and to reduce the haematological toxicity of OLA.

KEY WORDS

Olaparib PARP inhibitor Nano-formulations Bioavailability 

Abbreviations

OLA

Olaparib

PARP

Polyadenosine 5′diphosphoribose polymerase

TC

Tricaprin

NMP

N-methylpyrrolidone

HPLC

High-performance liquid chromatography

LP

Lipospheres

NSPWM

Nano-suspension by wet milling

NSPSE

Nano-suspension by solvent evaporation

SP

Suspension

DLS

Dynamic light scattering

PDI

Poly dispersity index

FITC

Fluorescein isothiocyanate

TM

Trimyristin

TA

Triacetin

TO

Triolein

Notes

Acknowledgements

Authors are thankful to Director, NIPER-Hyderabad for providing required facilities, support and encouragement throughout the project.

Funding Information

Financial assistance for this work was provided by Ministry of Chemicals & Fertilizers, Govt. of India.

Compliance with Ethical Standards

Complying with Ethics of Experimentation

The animal protocol was approved by Institutional Animal Ethics Committee (IAEC) of National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, India. Animal experiments were carried out in accordance with the guidelines of CPCSEA, India.

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Races A. SEER cancer statistics review 1973–1999. Bethesda: National Cancer Institute; 2002.Google Scholar
  2. 2.
    Welcsh PL, King M-C. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet. 2001;10(7):705–13.PubMedCrossRefGoogle Scholar
  3. 3.
    Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376(9737):235–44.PubMedCrossRefGoogle Scholar
  4. 4.
    Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117–30.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Narod SA. Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer. 2002;2(2):113–23.PubMedCrossRefGoogle Scholar
  6. 6.
    Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108(2):171–82.PubMedCrossRefGoogle Scholar
  7. 7.
    Ford D, Easton D, Stratton M, Narod S, Goldgar D, Devilee P, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet. 1998;62(3):676–89.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Foulkes WD, Stefansson IM, Chappuis PO, Bégin LR, Goffin JR, Wong N, et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. JNCI: J Natl Cancer Inst. 2003;95(19):1482–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Ricks TK, Chiu H-J, Ison G, Kim G, McKee AE, Kluetz P, et al. Successes and challenges of PARP inhibitors in cancer therapy. Front Oncol. 2015;5:222.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Deeks ED. Olaparib: first global approval. Drugs. 2015;75(2):231–40.PubMedCrossRefGoogle Scholar
  11. 11.
    Plummer R, Swaisland H, Leunen K, van Herpen CM, Jerusalem G, De Grève J, et al. Olaparib tablet formulation: effect of food on the pharmacokinetics after oral dosing in patients with advanced solid tumours. Cancer Chemother Pharmacol. 2015;76(4):723–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Friedlander M, Banerjee S, Mileshkin L, Scott C, Shannon C, Goh J. Practical guidance on the use of olaparib capsules as maintenance therapy for women with BRCA mutations and platinum-sensitive recurrent ovarian cancer. Asia Pac J Clin Oncol. 2016;12(4):323–31.PubMedCrossRefGoogle Scholar
  13. 13.
    Butler T, Maravent S, Boisselle J, Valdes J, Fellner C. A review of 2014 cancer drug approvals, with a look at 2015 and beyond. Pharm Ther. 2015;40(3):191–205.Google Scholar
  14. 14.
    Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274–84.PubMedCrossRefGoogle Scholar
  15. 15.
    Robert M, Patsouris A, Frenel J-S, Gourmelon C, Augereau P, Campone M. Emerging PARP inhibitors for treating breast cancer. Expert Opin Emerg Drugs. 2018;23(3):211–21.PubMedCrossRefGoogle Scholar
  16. 16.
    Johannes JW, Almeida L, Daly K, Ferguson AD, Grosskurth SE, Guan H, et al. Discovery of AZ0108, an orally bioavailable phthalazinone PARP inhibitor that blocks centrosome clustering. Bioorg Med Chem Lett. 2015;25(24):5743–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Pandi P, Jain A, Kommineni N, Ionov M, Bryszewska M, Khan W. Dendrimer as a new potential carrier for topical delivery of siRNA: a comparative study of dendriplex vs. lipoplex for delivery of TNF-α siRNA. Int J Pharm. 2018;550(1–2):240–50.PubMedCrossRefGoogle Scholar
  18. 18.
    Das S, Chaudhury A. Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery. AAPS PharmSciTech. 2011;12(1):62–76.PubMedCrossRefGoogle Scholar
  19. 19.
    Agrawal U, Sharma R, Gupta M, Vyas SP. Is nanotechnology a boon for oral drug delivery? Drug Discov Today. 2014;19(10):1530–46.PubMedCrossRefGoogle Scholar
  20. 20.
    Elgart A, Cherniakov I, Aldouby Y, Domb AJ, Hoffman A. Lipospheres and pro-nano lipospheres for delivery of poorly water soluble compounds. Chem Phys Lipids. 2012;165(4):438–53.PubMedCrossRefGoogle Scholar
  21. 21.
    Junyaprasert VB, Morakul B. Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs. Asian J Pharm Sci. 2015;10(1):13–23.CrossRefGoogle Scholar
  22. 22.
    Shegokar R, Müller RH. Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. Int J Pharm. 2010;399(1–2):129–39.PubMedCrossRefGoogle Scholar
  23. 23.
    Junghanns J-UA, Müller RH. Nanocrystal technology, drug delivery and clinical applications. Int J Nanomedicine. 2008;3(3):295–309.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Thummar M, Kuswah BS, Samanthula G, Bulbake U, Gour J, Khan W. Validated stability indicating assay method of olaparib: LC-ESI-Q-TOF-MS/MS and NMR studies for characterization of its new hydrolytic and oxidative forced degradation products. J Pharm Biomed Anal. 2018;160:89–98.PubMedCrossRefGoogle Scholar
  25. 25.
    Khan W, Aldouby YH, Avramoff A, Domb AJ. Cyclosporin nanosphere formulation for ophthalmic administration. Int J Pharm. 2012;437(1–2):275–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Jain A, Pooladanda V, Bulbake U, Doppalapudi S, Rafeeqi TA, Godugu C, et al. Liposphere mediated topical delivery of thymoquinone in the treatment of psoriasis. Nanomedicine. 2017;13(7):2251–62.PubMedCrossRefGoogle Scholar
  27. 27.
    Kommineni N, Saka R, Bulbake U, Khan W. Cabazitaxel and thymoquinone co-loaded lipospheres as a synergistic combination for breast cancer. Chem Phys Lipids. 2018.Google Scholar
  28. 28.
    Dong Y, Ng WK, Shen S, Kim S, Tan RB. Preparation and characterization of spironolactone nanoparticles by antisolvent precipitation. Int J Pharm. 2009;375(1–2):84–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Gera S, Talluri S, Rangaraj N, Sampathi S. Formulation and evaluation of naringenin nanosuspensions for bioavailability enhancement. AAPS PharmSciTech. 2017;18(8):3151–62.PubMedCrossRefGoogle Scholar
  30. 30.
    Ghosh I, Schenck D, Bose S, Ruegger C. Optimization of formulation and process parameters for the production of nanosuspension by wet media milling technique: effect of vitamin E TPGS and nanocrystal particle size on oral absorption. Eur J Pharm Sci. 2012;47(4):718–28.PubMedCrossRefGoogle Scholar
  31. 31.
    Doppalapudi S, Jain A, Chopra DK, Khan W. Psoralen loaded liposomal nanocarriers for improved skin penetration and efficacy of topical PUVA in psoriasis. Eur J Pharm Sci. 2017;96:515–29.PubMedCrossRefGoogle Scholar
  32. 32.
    Mahira S, Kommineni N, Husain GM, Khan W. Cabazitaxel and silibinin co-encapsulated cationic liposomes for CD44 targeted delivery: a new insight into nanomedicine based combinational chemotherapy for prostate cancer. Biomed Pharmacother. 2019;110:803–17.PubMedCrossRefGoogle Scholar
  33. 33.
    Doppalapudi S, Mahira S, Khan W. Development and in vitro assessment of psoralen and resveratrol co-loaded ultradeformable liposomes for the treatment of vitiligo. J Photochem Photobiol B Biol. 2017;174:44–57.CrossRefGoogle Scholar
  34. 34.
    Mahira S, Kommineni N, Doppalapudi S, Khan W. Edge activated ultradeformable cationic liposomes of psoralen and its derivatives: development and comparative evaluation for vitiligo therapy. J Drug Deliv Sci Technol. 2019;52:83–95.  https://doi.org/10.1016/j.jddst.2019.02.033.CrossRefGoogle Scholar
  35. 35.
    Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm. 2010;67(3):217–23.Google Scholar
  36. 36.
    Sharma AK, Keservani RK, Kesharwani RK. Nanobiomaterials: applications in drug delivery: CRC Press; 2018.Google Scholar
  37. 37.
    SH P. A phase 3 study of gemtuzumab ozogamicin during induction and post-consolidation therapy inryoimger patients with acute myeloid leukemia. Blood. 2013;121:4854–60.CrossRefGoogle Scholar
  38. 38.
    Kommineni N, Mahira S, Domb AJ, Khan W. Cabazitaxel-loaded nanocarriers for cancer therapy with reduced side effects. Pharmaceutics. 2019;11(3):141.PubMedCentralCrossRefGoogle Scholar
  39. 39.
    Korkmaz-Icöz S, Szczesny B, Marcatti M, Li S, Ruppert M, Lasitschka F, et al. Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats. Br J Pharmacol. 2018;175(2):246–61.PubMedCrossRefGoogle Scholar
  40. 40.
    Harris N, Jou JM, Devoto G, Lotz J, Pappas J, Wranovics D, et al. Performance evaluation of the ADVIA 2120 hematology analyzer: an international multicenter clinical trial. Lab Hematol. 2005;11(1):62–70.PubMedCrossRefGoogle Scholar
  41. 41.
    Liu M, Zhong X, Yang Z. Chitosan functionalized nanocochleates for enhanced oral absorption of cyclosporine A. Sci Rep. 2017;7:41322.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Jain A, Doppalapudi S, Domb AJ, Khan W. Tacrolimus and curcumin co-loaded liposphere gel: synergistic combination towards management of psoriasis. J Control Release. 2016;243:132–45.PubMedCrossRefGoogle Scholar
  43. 43.
    Sawant KK, Patel MH, Patel K. Cefdinir nanosuspension for improved oral bioavailability by media milling technique: formulation, characterization and in vitro–in vivo evaluations. Drug Dev Ind Pharm. 2016;42(5):758–68.PubMedCrossRefGoogle Scholar
  44. 44.
    D’Souza S. A review of in vitro drug release test methods for nano-sized dosage forms. Adv Pharm. 2014;2014.Google Scholar
  45. 45.
    Li S-D, Huang L. Pharmacokinetics and biodistribution of nanoparticles. Mol Pharm. 2008;5(4):496–504.PubMedCrossRefGoogle Scholar
  46. 46.
    Desai PP, Date AA, Patravale VB. Overcoming poor oral bioavailability using nanoparticle formulations–opportunities and limitations. Drug Discov Today Technol. 2012;9(2):e87–95.CrossRefGoogle Scholar
  47. 47.
    Bulbake U, Doppalapudi S, Kommineni N, Khan W. Liposomal formulations in clinical use: an updated review. Pharmaceutics. 2017;9(2):12.PubMedCentralCrossRefGoogle Scholar
  48. 48.
    Muntimadugu E, Kommineni N, Khan W. Exploring the potential of nanotherapeutics in targeting tumor microenvironment for cancer therapy. Pharmacol Res. 2017;126:109–22.PubMedCrossRefGoogle Scholar
  49. 49.
    Müller R, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy: rationale for development and what we can expect for the future. Adv Drug Deliv Rev. 2001;47(1):3–19.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Akshay D. Pathade
    • 1
  • Nagavendra Kommineni
    • 1
  • Upendra Bulbake
    • 1
  • Mohit M. Thummar
    • 2
  • Gananadhamu Samanthula
    • 2
    Email author
  • Wahid Khan
    • 1
    Email author
  1. 1.Department of PharmaceuticsNational Institute of Pharmaceutical Education and Research (NIPER)HyderabadIndia
  2. 2.Department of Pharmaceutical AnalysisNational Institute of Pharmaceutical Education and Research (NIPER)HyderabadIndia

Personalised recommendations