Designand Evaluationof Fixed-Dose Combination of Bi-Layer Tablets of Dolutegravir, Lamivudine and Tenofovir Disoproxil Fumarate Tablets 50 Mg/300 Mg/300 Mg

Authors

  • Jonna Sankaraiah Department of Pharmaceutics, Bhagwant University, Ajmer, Rajasthan, India.
  • Neeraj Sharma Faculty of Pharmacy, Bhagwant University, Ajmer, Rajasthan, India.
  • Mohd Javed Naim Faculty of Pharmacy, Bhagwant University, Ajmer, Rajasthan, India.

DOI:

https://doi.org/10.22270/ajprd.v10i1.1080

Keywords:

Fixed-dose formulation, Human immunodeficiency virus (HIV-1) Infection, Bi-layer compression.

Abstract

Objective: The purpose of this research study is to design and evaluation of bi-layer tablet as single dosage regimen against the single dose of reference listed drugs of Brand TIVICAY (dolutegravir tablets 50 mg), EPIVER®(lamivudine tablets 300 mg), and VIREAD®(tenofovir disoproxil tablets 300 mg) to treat human immunodeficiency virus (HIV-1) infections in adults and pediatric patients weighing 40kg and greater.

Methods: Formulation was designed with two layers of blendthrough lamivudine and tenofovir disoproxil fumarate (layer-I) and dolutegravir(layer-II). Both layers were manufactured by using roller compaction processand wet granulation process followed by using bi-layer compression and film coating. Layer-I and II formulations were developed by using design of experiments (DOE) to match the dissolution with each branded formulation. Two level, fractional factorial (22+3) and full factorial design (23+3) by using a design expert (version 11.0) were used to evaluate the formulation variables to prepare a robust formulation forimprove the solubility of dolutegravir and improve the flowability and uniformity of lamivudine and tenofovir disoproxil fumarate.

Results: Drug–excipient compatibility results revealed that mixture of active substances resulted to increase the tenofovir impurity levels compared with individual layers. Exposed to hydrolysis and oxidation resulted to significant degradation of lamivudine and increases impurity A and C and new impurities were observed. Preformulation studies indicates that flow properties of active substances observed very, very poor and designed bi-layer compression for each blend manufactured by roller compaction (lamivudine and tenofovir) and wet granulation process (dolutegravir). Fractional factorial design (22+3) were used to identify the range of croscarmellose sodium and magnesium stearateto impact on the dissolution for Layer-I and full factorial design (23+3) were used to identify the range of sodium starch glycolate, povidone and magnesium stearate to impact on the dissolution through a design expert (version 11.0). Bi-layer compression followed by coating resulted to produce the comparable dissolution results with each branded formulation. Finally, X-ray diffraction (XRD) indicates that there are no polymorphic changes for the optimized formulation and there is no interaction between the three active substances.

Conclusion: Fixed–dose combination of single dosage regimen yielded consistent drug release against each branded drug to treat human immunodeficiency virus (HIV-1) infections

 

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Author Biographies

Jonna Sankaraiah, Department of Pharmaceutics, Bhagwant University, Ajmer, Rajasthan, India.

Department of Pharmaceutics, Bhagwant University, Ajmer, Rajasthan, India.

Neeraj Sharma, Faculty of Pharmacy, Bhagwant University, Ajmer, Rajasthan, India.

Faculty of Pharmacy, Bhagwant University, Ajmer, Rajasthan, India.

Mohd Javed Naim, Faculty of Pharmacy, Bhagwant University, Ajmer, Rajasthan, India.

Faculty of Pharmacy, Bhagwant University, Ajmer, Rajasthan, India.

References

1. R Ramjan, A Calmy, M.Vitoria, EJ Mills etal, systematic review and meta- analysis: Patient and program impact of fixed dose combination of antiretroviral therapy.Trop med int. health. 2014; 19 (5):501-13. doi:10.1111/tmi.12297.
2. Raffi F, Yazdanpanah y, Fagnani F, Laurendeau C, Lafuma A, Gourmelen J.etal, Persistence and adherence to single-tablet regimens in HIV treatment; a cohort study from the French National Healthcare insurance database. J Antimicrobchemother 2015;70:2121-8
3. Beatriz Larru, Jessica Eby, Elizabeth D Lowenthaletal. Antiretroviral treatment in HIV-I infected pediatric patients: focus on efavirenz, pediatric health med ther.2014 May ; 5: 29-42, doi:10.2147/PHMT.S47794.
4. Rajendra P. Singh, PhD,* Kimberly K. Adkison, PhD,† Mark Baker, PhD,‡ RidhiParasrampuria, PhD,* Allen Wolstenholme, PhD,* Mark Davies, MS,§ Nicola Sewell, MEng,§ Cindy Brothers, MSPH,† and Ann M. Buchanan, MD, MPH† Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Childrenpediatr Infect Dis J 2021;00:00-00, September 15,2021.
5. World Health Organization. Update of recommendations on first- and second-line antiretroviral regimens [WHO web site]. 2019. Available from: https://apps.who.int/iris/bitstream/handle/10665/325892/WHO-CDS-HIV19.15-eng.pdf. Accessed December 2, 2020.
6. Jiamsakul A, Kariminia A, Althoff KN, et al. HIV viral load suppression in adults and children receiving antiretroviral therapy—results from the IeDEA collaboration. J Acquir Immune DeficSyndr. 2017; 76:319–329.
7. Fokam J, Santoro MM, Takou D, et al. Evaluation of treatment response, drug resistance and HIV-1 variability among adolescents on first- and second-line antiretroviral therapy: a study protocol for a prospective observational study in the centre region of Cameroon (EDCTP READY-study). BMC Pediatr. 2019; 19:226.
8. Marukutira T, Yin D, Cressman L, et al. Clinical outcomes of a cohort of migrants and citizens living with human immunodeficiency virus in Botswana: implications for Joint United Nation Program on HIV and AIDS 90-90-90 targets. Medicine (Baltimore). 2019; 98:e15994.
9. US Food and Drug Administration. Drugs@FDA: FDA-approved drugs [FDA web site]. 2020. Available from: https://www.accessdata.fda.gov/ scripts/cder/daf/index.cfm. Accessed December 2, 2020.
10. Dhanish Joseph, Golda Maria Thomas et al. A Review on Current Applications of Bilayer Tablets. Research J Pharm and Tech. 2019:2539-44.
11. Tibalinda, P., Pius, D. , Shedafa, R. , Masota, N. , Temu, M. and Kaale, E et al. (2016) Pre-Formulation Development of Lamivudine 300 mg and Tenofovir Disoproxil Fumarate (TDF) 300 mg Fixed Dose Combination Tablets. Pharmacology & Pharmacy, 247-54. doi: 10.4236/pp.2016.77031.
12. https://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults.cfm
13. www.statease.com (DESIGN-EXPERT® VERSION 11 software).
14. Sundeep mupparaju, Vidyadharasuryadevara, Sailajayallam, Sandeep doppalapudi, sasidharreddyvallam LC, andRamuanne. “Formulation and evaluation of dolutegravir sodium solid dispersions and fast dissolving tablets using polaxamer-188 and jack fruit seed starch as excipients”. Asian journal of pharmaceutical and clinical research, 2019; 12(6):181-90.
15. Srinivas Martha, singh Dr. Anoop (2021) Formulation and Optimization of Dolutegravir Fast Dissolving Tablets Using Various Solubility Enhancement Methods. International Journal of pharma and Bio Sciences, 2011; 11(5)10:51-59.
16. https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm
17. Handbook of pharmaceutical excipients, ninth edition, edited by Paul J Sheskey, Brune C Hancock, Gary p Moss, David J Goldfarb.

Published

2023-01-07

How to Cite

Sankaraiah, J., Sharma, N., & Naim, M. J. (2023). Designand Evaluationof Fixed-Dose Combination of Bi-Layer Tablets of Dolutegravir, Lamivudine and Tenofovir Disoproxil Fumarate Tablets 50 Mg/300 Mg/300 Mg. Asian Journal of Pharmaceutical Research and Development, 10(1), 6–21. https://doi.org/10.22270/ajprd.v10i1.1080