Development of Atovaquone Nanosuspension: Quality by Design Approach

Author(s): Pratik Kakade, Sandip Gite, Vandana Patravale*

Journal Name: Current Drug Delivery

Volume 17 , Issue 2 , 2020

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Graphical Abstract:


Objective: The present study reports the use of MicrofluidizerTM technology to form a stable nanosuspension of atovaquone (ATQ) using quality by design (QbD) approach.

Methods: The patient-centric quality target product profile and critical quality attributes (CQAs) were identified. A Box-Behnken design was employed for the optimization of dependent variables, while CQAs like particle size and PDI were evaluated as response variables. Effective optimization of ATQ nanosuspension preparation using Microfluidizer processor as a novel green technology was achieved using QbD approach.

Result: The prepared nanosuspension had a mean particle size of 865 nm ± 5%, PDI of 0.261 ± 3%, and zeta potential of -1.79 ± 5 mV. The characterization of the prepared nanosuspension by SEM, DSC, and XRD revealed its nano-crystalline nature whereas FTIR spectroscopic analysis confirmed the absence of any physicochemical interaction because of process parameters between the drug and excipients.

Conclusion: In vitro dissolution studies of the nanosuspension using USP-IV exhibited a 100% cumulative drug release over 90 minutes, which is significantly better than that of ATQ pure API. In vivo pharmacokinetic studies revealed bioequivalence of ATQ nanosuspensions by Microfluidizer homogenization process to the marketed formulation1.

Keywords: QbD, atovaquone, pneumonia, microfluidizer technology, bioavailability, dissolution.

Sareen, S.; Mathew, G.; Joseph, L. Improvement in solubility of poor water-soluble drugs by solid dispersion. Int. J. Pharm. Investig., 2012, 2(1), 12-17.
[] [PMID: 23071955]
Serajuddin, A.T. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci., 1999, 88(10), 1058-1066.
[] [PMID: 10514356]
Navale, S.; Das, S.; Singh, G.; Mathur, R. S. Pharmaceutical Composition Comprising Atovaquone Particles, 2008. US20080241254A1
Comley, J.C.; Yeates, C.L.; Frend, T.J. Antipneumocystis activity of 17C91, a prodrug of atovaquone. Antimicrob. Agents Chemother., 1995, 39(10), 2217-2219.
[] [PMID: 8619570]
Baggish, A.L.; Hill, D.R. Antiparasitic agent atovaquone. Antimicrob. Agents Chemother., 2002, 46(5), 1163-1173.
[] [PMID: 11959541]
Darade, A.; Pathak, S.; Sharma, S.; Patravale, V. Atovaquone oral bioavailability enhancement using electrospraying technology. Eur. J. Pharm. Sci., 2018, 111, 195-204.
[] [PMID: 28974387]
Khadka, P.; Ro, J.; Kim, H.; Kim, I.; Kim, J.T.; Kim, H.; Cho, J.M.; Yun, G.; Lee, J. Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability. Asian J. Pharm. Sci., 2014, 9(6), 304-316.
Ali, H.S.M.; York, P.; Blagden, N. Preparation of hydrocortisone nanosuspension through a bottom-up nanoprecipitation technique using microfluidic reactors. Int. J. Pharm., 2009, 375(1-2), 107-113.
[] [PMID: 19481696]
Fiorillo, M.; Lamb, R.; Tanowitz, H.B.; Mutti, L.; Krstic-Demonacos, M.; Cappello, A.R.; Martinez-Outschoorn, U.E.; Sotgia, F.; Lisanti, M.P. Repurposing atovaquone: Targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells. Oncotarget, 2016, 7(23), 34084-34099.
[] [PMID: 27136895]
Santos-Magalhães, N.S.; Mosqueira, V.C.F. Nanotechnology applied to the treatment of malaria. Adv. Drug Deliv. Rev., 2010, 62(4-5), 560-575.
[] [PMID: 19914313]
Borhade, V.; Pathak, S.; Sharma, S.; Patravale, V. Formulation and characterization of atovaquone nanosuspension for improved oral delivery in the treatment of malaria. Nanomedicine (Lond.), 2014, 9(5), 649-666.
[] [PMID: 23927590]
Borhade, V.B.; Nair, H.A.; Hegde, D.D. Development and characterization of self-microemulsifying drug delivery system of tacrolimus for intravenous administration. Drug Dev. Ind. Pharm., 2009, 35(5), 619-630.
[] [PMID: 18979309]
Sangshetti, J.; Deshpande, M.; Arote, R.; Zaheer, Z.; Shinde, D. Quality by Design Approach: Regulatory Need. Arab. J. Chem., 2014, 101
Amidon, G.L.; Lennernäs, H.; Shah, V.P.; Crison, J.R. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res., 1995, 12(3), 413-420.
[] [PMID: 7617530]
Kim, M-S.; Ha, E-S.; Choo, G-H.; Baek, I-H. Preparation and in vivo evaluation of a dutasteride-loaded solid-supersaturatable self-microemulsifying drug delivery system. Int. J. Mol. Sci., 2015, 16(5), 10821-10833.
[] [PMID: 25984604]
Kalvakuntla, S.; Deshpande, M.; Attari, Z.; Kunnatur, B.K. Preparation and characterization of nanosuspension of aprepitant by H96 process. Adv. Pharm. Bull., 2016, 6(1), 83-90.
[] [PMID: 27123422]
Cotton, D. Food and Drug Administration. Atovaquone (Mepron) suspension approved by FDA. AIDS Clin. Care, 1995, 7(7), 62.
[PMID: 11362554]

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Article Details

Year: 2020
Page: [112 - 125]
Pages: 14
DOI: 10.2174/1567201817666191227095019
Price: $65

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