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Leveraging the Exploratory and Predictive Capabilities of Design of Experiments in Development of Intraarticular Injection of Imatinib Mesylate Containing Lipospheres

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Abstract

An intraarticular, liposphere-based, formulation of Imatinib mesylate for weekly administration was developed. Lipospheres were prepared using double emulsion technique using dierucoyl phosphatidylcholine, 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt), cholesterol, and tricaprylin as lipid phase in dichloromethane in a four-step process. Primary emulsion, formed using a high-pressure homogenizer, was diluted using a secondary aqueous phase in an Inline mixer to form the liposomal dispersion. Nitrogen flushing was done to remove dichloromethane, and the dispersion was finally centrifuged and adjusted for potency. The amount of cholesterol and triglyceride was taken as formulation variables, and speed of homogenization was used as a process variable in the Box-Behnken design while particle size, % drug entrapment, and drug release at the end of 4 h and 5 days were taken as response variables. Multivariate data analysis grouped the variables in two latent variable sets, one based on the speed and the other on the composition of lipospheres. Multiple linear regression analysis was used to generate mathematical model for each response. Constraints were put on the values of responses, as per the requirements of the final product, and the “freedom to operate” design space was located using an overlay plot. The center point batch sufficed all the set criteria, and Monte Carlo simulations on the factor variables indicated a defect rate of 5%. The center point batch was characterized for viscosity, osmolality, pH, drug release, and lipocrit value. The dispersion was charged in a prefilled syringe and studied for stability. The product was found to be stable at 2–8°C over a period of 6 months.

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Abbreviations

RA:

Rheumatoid arthritis

IMB:

Imatinib mesylate

OFAT:

One factor at a time

DEPC :

Dierucoyl phosphatidylcholine

DPPG:

1,2-Dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt)

HPLC:

High-performance liquid chromatography

FTIR:

Fourier transform infrared

DSC:

Differential scanning calorimetry

BBD:

Box-Behnken design

IMB-LPS:

IMB liposphere dispersion

PPV:

Packed particle volume

GC:

Gas chromatography

PFS:

Prefilled syringe

SEM:

Scanning electron microscopy

PCA:

Principal component analysis

EFA:

Exploratory factor analysis

PS:

Particle size

ZP:

Zeta potential

EE:

Percentage entrapment efficiency

DR4h:

Drug release at the end of 4 h

DR5d:

Drug release at the end of 5 days

CQA:

Critical quality attribute

CMA:

Critical material attribute

CPP:

Critical process parameter

FTO:

Freedom to operate

VIF:

Variance inflation factor

LoF:

Lack of fit

DR:

Defect rate

References

  1. Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, et al. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014;73(7):1316–22. https://doi.org/10.1136/annrheumdis-2013-204627.

    Article  PubMed  Google Scholar 

  2. Crowson CS, Matteson EL, Myasoedova E, Michet CJ, Ernste FC, Warrington KJ, et al. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum. 2011;63(3):633–9. https://doi.org/10.1002/art.30155.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Rheumatoid Arthritis In: Arthritis Information. https://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/. Accessed 22 Aug 2022.

  4. Bas DB, Su J, Wigerblad G, Svensson CI. Pain in rheumatoid arthritis: models and mechanisms. Pain Manag. 2016;6(3):265–84. https://doi.org/10.2217/pmt.16.4.

    Article  PubMed  Google Scholar 

  5. Eklund KK, Joensuu H. Treatment of rheumatoid arthritis with imatinib mesylate: clinical improvement in three refractory cases. Ann Med. 2003;35(5):362–7. https://doi.org/10.1080/07853890310001339.

    Article  CAS  PubMed  Google Scholar 

  6. Paniagua RT, Sharpe O, Ho PP, Chan SM, Chang A, Higgins JP, et al. Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J Clin Invest. 2006;116(10):2633–42. https://doi.org/10.1172/JCI28546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ando W, Hashimoto J, Nampei A, Tsuboi H, Tateishi K, Ono T, et al. Imatinib mesylate inhibits osteoclastogenesis and joint destruction in rats with collagen-induced arthritis (CIA). J Bone Miner Metab. 2006;24(4):274–82. https://doi.org/10.1007/s00774-006-0684-1.

    Article  CAS  PubMed  Google Scholar 

  8. Rai MF, Pham CT. Intra-articular drug delivery systems for joint diseases. Curr Opin Pharmacol. 2018;40:67–73. https://doi.org/10.1016/j.coph.2018.03.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bowman S, Awad ME, Hamrick MW, Hunter M, Fulzele S. Recent advances in hyaluronic acid based therapy for osteoarthritis. Clin Transl Med. 2018;7(1):6. https://doi.org/10.1186/s40169-017-0180-3.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Pradal J, Maudens P, Gabay C, Seemayer CA, Jordan O, Allemann E. Effect of particle size on the biodistribution of nano- and microparticles following intra-articular injection in mice. Int J Pharm. 2016;498(1–2):119–29. https://doi.org/10.1016/j.ijpharm.2015.12.015.

    Article  CAS  PubMed  Google Scholar 

  11. Cao Y, Ma Y, Tao Y, Lin W, Wang P. Intra-articular drug delivery for osteoarthritis treatment. Pharmaceutics. 2021;13(12). https://doi.org/10.3390/pharmaceutics13122166.

  12. Bhanderi M, Shah J, Gorain B, Nair AB, Jacob S, Asdaq SMB, et al. Optimized rivastigmine nanoparticles coated with Eudragit for intranasal application to brain delivery: evaluation and nasal ciliotoxicity studies. Materials (Basel). 2021;14(21). https://doi.org/10.3390/ma14216291.

  13. Buyel JF. Statistical designs to improve downstream processing. Methods Mol Biol. 2022;2480:295–310. https://doi.org/10.1007/978-1-0716-2241-4_16.

    Article  PubMed  Google Scholar 

  14. Ya’acob A, Zainol N, Aziz NH. Application of response surface methodology for COD and ammonia removal from municipal wastewater treatment plant using acclimatized mixed culture. Heliyon. 2022;8(6): e09685. https://doi.org/10.1016/j.heliyon.2022.e09685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Garala KC, Patel JM, Dhingani AP, Dharamsi AT. Preparation and evaluation of agglomerated crystals by crystallo-co-agglomeration: an integrated approach of principal component analysis and Box-Behnken experimental design. Int J Pharm. 2013;452(1–2):135–56. https://doi.org/10.1016/j.ijpharm.2013.04.073.

    Article  CAS  PubMed  Google Scholar 

  16. Stagner WC, Jain A, Al-Achi A, Haware RV. Employing multivariate statistics and latent variable models to identify and quantify complex relationships in typical compression studies. AAPS PharmSciTech. 2020;21(5):186. https://doi.org/10.1208/s12249-020-01712-1.

    Article  CAS  PubMed  Google Scholar 

  17. Kannappan V, Mannemala SS. Multiple response optimization of a HPLC method for the determination of enantiomeric purity of S-Ofloxacin. Chromatographia. 2014;77(17):1203–11. https://doi.org/10.1007/s10337-014-2699-4.

    Article  CAS  Google Scholar 

  18. Kaur R, Saini S, Patel A, Sharma T, Kaur R, Katare OP, et al. Developing a validated HPLC method for quantification of Ceftazidime employing analytical quality by design and Monte Carlo simulations. J AOAC Int. 2021;104(3):620–32. https://doi.org/10.1093/jaoacint/qsab014.

    Article  PubMed  Google Scholar 

  19. Cortesi R, Esposjto E, Luca G, Nastruzzi C. Production of lipospheres as carriers for bioactive compounds. Biomaterials. 2002;23(11):2283–94. https://doi.org/10.1016/S0142-9612(01)00362-3.

    Article  CAS  PubMed  Google Scholar 

  20. Piraino LR, Benoit DSW, DeLouise LA. Optimizing soluble cues for salivary gland tissue mimetics using a design of experiments (DoE) approach. Cells. 2022;11(12):1962. https://doi.org/10.3390/cells11121962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Katre NV, Asherman J, Schaefer H, Hora M. Multivesicular liposome (DepoFoam) technology for the sustained delivery of insulin-like growth factor-I (IGF-I). J Pharm Sci. 1998;87(11):1341–6. https://doi.org/10.1021/js980080t.

    Article  CAS  PubMed  Google Scholar 

  22. Prefilled syringes — Part 8: Requirements and test methods for finished prefilled syringes In ISO 11040-8:2016(en). https://www.iso.org/obp/ui/#iso:std:iso:11040:-8:ed-1:v1:en. Accessed 22 Aug 2022.

  23. Prefilled syringes — Part 8: Requirements and test methods for finished prefilled syringes [Available from: https://www.iso.org/obp/ui/#iso:std:iso:11040:-8:ed-1:v1:en.

  24. Hasandoost L, Akbarzadeh A, Attar H, Heydarinasab A. In vitro effect of imatinib mesylate loaded on polybutylcyanoacrylate nanoparticles on leukemia cell line K562. Artif Cells Nanomed Biotechnol. 2017;45(3):665–9. https://doi.org/10.1080/21691401.2016.1175444.

    Article  CAS  PubMed  Google Scholar 

  25. Esfandyari-Manesh M, Abdi M, Talasaz AH, Ebrahimi SM, Atyabi F, Dinarvand R. S2P peptide-conjugated PLGA-Maleimide-PEG nanoparticles containing Imatinib for targeting drug delivery to atherosclerotic plaques. Daru. 2020;28(1):131–8. https://doi.org/10.1007/s40199-019-00324-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu Z, Chen H, Lv F, Wang J, Zhao S, Li Y, et al. Sequential release of paclitaxel and imatinib from core-shell microparticles prepared by coaxial electrospray for vaginal therapy of cervical cancer. Int J Mol Sci. 2021;22(16). https://doi.org/10.3390/ijms22168760.

  27. Sallam BN, Lu T, Yu H, Li Q, Sarfraz Z, Iqbal MS, et al. Productivity enhancement of cucumber (Cucumis sativus L.) through optimized use of poultry manure and mineral fertilizers under greenhouse cultivation. Horticulturae. 2021;7(8):256. https://doi.org/10.3390/horticulturae7080256.

  28. Haware RV, Shivagari R, Johnson PR, Staton S, Stagner WC, Gupta MR. Application of multivariate methods to evaluate the functionality of bovine- and vegetable-derived magnesium stearate. J Pharm Sci. 2014;103(5):1466–77. https://doi.org/10.1002/jps.23920.

    Article  CAS  PubMed  Google Scholar 

  29. Masoudzadeh A, Alami S, Naderi Rajeh Y, Taheri E, Sadeghi H. The role of relationship emotional schemas and personality dimensions on domestic violence in people referred to a forensics center in Iran. Iran J Psychiatry. 2022;17(1):44–51. https://doi.org/10.18502/ijps.v17i1.8048.

  30. Yoo H, Rheem I, Rheem S, Oh S. Optimizing medium components for the maximum growth of Lactobacillus plantarum JNU 2116 using response surface methodology. Korean J Food Sci Anim Resour. 2018;38(2):240–50. https://doi.org/10.5851/kosfa.2018.38.2.240.

    PubMed  PubMed Central  Google Scholar 

  31. Antonopoulou V, Goffe L, Meyer CJ, Grimani A, Graham F, Lecouturier J, et al. A comparison of seasonal influenza and novel Covid-19 vaccine intentions: a cross-sectional survey of vaccine hesitant adults in England during the 2020 pandemic. Human Vaccines & Immunotherapeutics. 2022:2085461. https://doi.org/10.1080/21645515.2022.2085461.

  32. Dewangan HK, Pandey T, Maurya L, Singh S. Rational design and evaluation of HBsAg polymeric nanoparticles as antigen delivery carriers. Int J Biol Macromol. 2018;111:804–12. https://doi.org/10.1016/j.ijbiomac.2018.01.073.

    Article  CAS  PubMed  Google Scholar 

  33. Auwal SM, Zarei M, Tan CP, Basri M, Saari N. Enhanced physicochemical stability and efficacy of angiotensin I-converting enzyme (ACE) - inhibitory biopeptides by chitosan nanoparticles optimized using Box-Behnken design. Scientific Reports. 2018;8. https://doi.org/10.1038/s41598-018-28659-5.

  34. Briuglia M-L, Rotella C, McFarlane A, Lamprou DA. Influence of cholesterol on liposome stability and on in vitro drug release. Drug Deliv Transl Res. 2015;5(3):231–42. https://doi.org/10.1007/s13346-015-0220-8.

    Article  CAS  PubMed  Google Scholar 

  35. Ahmed TA. Preparation of finasteride capsules-loaded drug nanoparticles: formulation, optimization, in vitro, and pharmacokinetic evaluation. Int J Nanomedicine. 2016;11:515–27. https://doi.org/10.2147/IJN.S98080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yang M, Xu B, Wang X, Li W, Cao J, Li W, et al. Effect of spray drying conditions on physical properties of Panax notoginseng Saponin (PNS) powder and the intra-batch dissolution variability of PNS hydrophilic matrix tablet. Drug Des Devel Ther. 2021;15:1425–40. https://doi.org/10.2147/DDDT.S295825.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Dinç-Zor Ş, Aksu DÖ. Box-Behnken design-desirability function approach in optimization of HPLC method for simultaneous determination of Ibuprofen along with additives in syrup formulation. J AOAC Int. 2021;104(1):78–83. https://doi.org/10.1093/jaoacint/qsaa096.

    Article  PubMed  Google Scholar 

  38. Dangre PV, Tattu AD, Borikar SP, Surana SJ, Chalikwar SS. Development and statistical optimization of alginate-Neusilin US2 micro-composite beads to elicit gastric stability and sustained action of hesperidin. Int J Biol Macromol. 2021;171:514–26. https://doi.org/10.1016/j.ijbiomac.2021.01.025.

    Article  CAS  PubMed  Google Scholar 

  39. Musazzi UM, Youm I, Murowchick JB, Ezoulin MJ, Youan BB. Resveratrol-loaded nanocarriers: formulation, optimization, characterization and in vitro toxicity on cochlear cells. Colloids Surf B Biointerfaces. 2014;118:234–42. https://doi.org/10.1016/j.colsurfb.2014.03.054.

    Article  CAS  PubMed  Google Scholar 

  40. ICH guideline Q9 on quality risk management 2015. In: ema.europa.eu, https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-3.pdf. Accessed 22 Aug 2022.

  41. Kanda H, Katsube T, Wahyudiono, Goto M. Preparation of liposomes from soy lecithin using liquefied dimethyl ether. Foods. 2021;10(8):1789. https://doi.org/10.3390/foods10081789.

  42. Lin X, Li B, Wen J, Wu J, Tang D, Yu Y, et al. Storage stability and in vitro bioaccessibility of liposomal betacyanins from red pitaya (Hylocereus polyrhizus). Molecules. 2022;27(4). https://doi.org/10.3390/molecules27041193.

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Acknowledgements

The authors are grateful to Amneal Pharmaceuticals for facilitating the research work.

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Authors and Affiliations

  1. R and D – Injectables, Amneal Pharmaceuticals, Ahmedabad, India

    Amruta Gorajiya

  2. K. B. Institute of Pharmaceutical Education and Research, Gh 6 Road, Sector 23, Gandhinagar, 382023, Gujarat, India

    Anita Lalwani

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Ms. Amruta designed and performed the experiments. Dr. Anita Lalwani is responsible for reviewing the manuscript, interpreting the results, and performing statistical analysis.

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Correspondence to Anita Lalwani.

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Gorajiya, A., Lalwani, A. Leveraging the Exploratory and Predictive Capabilities of Design of Experiments in Development of Intraarticular Injection of Imatinib Mesylate Containing Lipospheres. AAPS PharmSciTech 23, 275 (2022). https://doi.org/10.1208/s12249-022-02431-5

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