Abstract
Statins are widely prescribed for hyperlipidemia, cancer, and Alzheimer’s disease but are facing some inherent challenges such as low solubility and drug loading, higher hepatic metabolism, as well as instability at gastric pH. So, relatively higher circulating dose, required for exerting the therapeutic benefits, leads to dose-mediated severe toxicity. Furthermore, due to low biocompatibility, high toxicity, and other regulatory caveats such as product conformity, reproducibility, and stability of conventional formulations as well as preferentially higher bioabsorption of lipids in their favorable cuboidal geometry, enhancement in in vivo biopharmaceutical performance of Rosuvastatin could be well manifested in Quality by Design (QbD) integrated cuboidal-shaped mucoadhesive microcrystalline delivery systems (Limicubes). Here, quality-target-product-profile (QTPPs), critical quality attributes (CQAs), Ishikawa fishbone diagram, and integration of risk management through risk assessment matrix for failure mode and effects analysis (FMEA) followed by processing of Plackett-Burman design matrix using different statistical test for the first time established an approach to substantiate the claims that controlling levels of only these three screened out independent process variables, i.e., Monoolein (B = 800–1100 μL), Poloxamer (C = 150–200 mg), and stirring speed (F = 700–1000 rpm) were statistically significant to modulate and improve the biopharmaceutical performance affecting key attributes, viz., average particle size (Y1 = 1.40–2.70 μ), entrapment efficiency (Y2 = 62.60–88.80%), and drug loading (Y3 = 0.817–1.15%), in QbD-enabled process. The optimal performance of developed Limicubes exhibited an average particle size of 1.8 ± 0.2 μ, entrapment efficiency 80.32 ± 2.88%, and drug loading 0.93 ± 0.08% at the level of 1100 μL (+ 1), 200 mg (+ 1), and 700 rpm (− 1) for Monoolein, Poloxamer, and stirring speed, respectively.
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The authors are thankful to the Department of Pharmaceutics, School of Pharmaceutical Education and Research (formerly Faculty of Pharmacy), Jamia Hamdard, New Delhi, India for providing all instrument facilities required for carrying out research effectively.
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Highlights
• Monoolein-Poloxamer integrated novel biocompatible, mucoadhesive, and cuboidal-shaped microcrystalline system, Limicubes, of hydrophobic drug Rosuvastatin was assessed.
• Quality target product profile (QTPPs), critical quality attributes (CQAs), Ishikawa fishbone diagram, and risk assessment matrix for failure mode and effects analysis (FMEA) were generated for QbD-based product profile.
• Plackett-Burman design screened out Monoolein, Poloxamer, and stirring speed as vital factors which were further analyzed at their three different levels to optimize shape, size, entrapment efficiency, and drug loading.
• Monoolein enhanced drug entrapment, drug loading, and particle size, while higher loading and entrapment of drug with reduced particle size were manifested by Poloxamer.
• Although high stirring speed produced particles with lower dimension due to high association matrix with drug, drug loading and entrapment efficiency were statistically unaffected.
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Javed, M.N., Kohli, K. & Amin, S. Risk Assessment Integrated QbD Approach for Development of Optimized Bicontinuous Mucoadhesive Limicubes for Oral Delivery of Rosuvastatin. AAPS PharmSciTech 19, 1377–1391 (2018). https://doi.org/10.1208/s12249-018-0951-1
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DOI: https://doi.org/10.1208/s12249-018-0951-1