Category: Formulation and Quality
Purpose: In the present scenario, HIV-1 and AIDS form one of the principal disease accounting for global burden. Most of the current clinical therapies have bioavailability issues which is attributable to the presence of efflux transporter (e.g. P-glycoprotein) and drug metabolizing enzymes (e.g., cytochrome P-450), lack of permeation potential, non-targeted distribution and rapid clearance. Reduced bioavailability and short residence of antiretroviral agents have profound impact on clinical management of the HIV. Thus lipid architectonics (LA) / nanostructured lipid carriers (NLC) will overcome the accompanying hurdles in drug delivery and offer astounding advantages which includes drug defense against CYP3A4 and UGT1A1, encouraging lymphatic uptake thereby exhibiting superior metabolic stability, increased permeability, curtailing toxic drug effects etc. Elvitegravir (EVR), an integrase inhibitor proves to be an ideal candidate for research since it is a known substrate of cytochrome P450 3A4 (CYP3A4) and UGT 1A1 which are also considered to be the reasons for its poor oral bioavailability of around 20%. So far solid lipid nanoparticles (SLN), nanoparticles and gels of Elvitegravir have been formulated but did not yield significant outcomes. LA/NLC, a second generation SLN will indubitably alleviate the drawbacks of previous formulations. The lipids and surfactants incorporated bears intrinsic P-gp inhibitory activity and promote lymphatic uptake, a requisite for improvement in drug profile. Therefore the present research aims at formulating, characterizing and evaluating LA of Elvitegravir and performing in vitro assessment. The research would later be commenced for in vivo prospects as well. The formulation produced will contribute significantly in improving in vivo performance of Elvitegravir by modifying its pretentious behavior.
Methods: The method employed for the preparation of formulation was melt emulsification followed by sonication technique (ME technique). A comprehensive screening of lipids and surfactants were commenced in order to select the lipid with maximum solubilization potential for the drug and surfactant with best emulsifying potential. The selection is further based on the p-gp and cytochrome inhibitory activities of the lipids and surfactants. The formulation was optimized by using QbD approach (Box-Behnken design; BBD) to yield a superior output on the basis of particle size, entrapment efficiency and drug loading. The final optimized formulation (EVR-LA) was then used for further analysis in in vitro release study and determine the best suited release kinetic model. The in vitro permeation study and stability in gastrointestinal fluids was also carried out to establish the permeation potential and stability of the prepared LA. Lipolysis study was undertaken to evaluate the solubilization potential of the LA prepared and establish the fate of the drug upon oral administration.
Results: Based on the solubility of EVR in different solid and liquid lipids, Capryol 90 and was selected as liquid lipid and Compritol 888ATO as solid lipid while poloxamer 407 was selected as surfactant and tween 80 as co-surfactant owing to their high % transmittance. The formulation prepared was optimized using BBD (ICHQ8) (Total lipid 1% and Smix 3.5 % of the total formulation).. The optimized formulation exhibited a particle size of 84.6±2.3 nm, EE 90.7±1.8% and DL 8.9±0.7. The in vitro release was carried out which showed initial burst release followed by amplified sustained release when compared with EVR suspension. The intestinal permeability of EVR-LA was found to be superior in comparison to EVR suspension and exhibited 5 fold increase. The reason attributable to the increase in permeability might be owing to the p-gp inhibitory activity of the lipids and surfactants used in the formulation. The outcome of stability in gastrointestinal fluids study demonstrated that there was no significant change observed in mean particle size and PDI of the formulation in gastric and intestinal fluids. This further revealed that the drug is encapsulated within the lipid core confirming that there was no leakage. The result of in vitro lipolysis studies revealed that the solubilization potential of EVR-LA was significantly higher in aqueous phase (71.56 ± 3.24%) when compared to the lipid phase (2.19 ± 0.78%) which is a prerequisite for enhanced absorption.
Conclusion: The result obtained from intestinal permeability studies demonstrated higher permeation potential of the LA. Additionally lipolysis study also establishes superior solubilization potential of the LA. Thus the prepared formulation offers for drug protection and modified release on target cells, the formulation provides an ideal holistic solution by minimizing the serious and unpleasant side effects of drug and preventing damage to healthy tissues. The promising results obtained after the in vitro analysis warrants for further research in order to determine the in vivo prospects of the drug.
Saleha Rehman– Ph.D. SCHOLAR, JAMIA HAMDARD, New Delhi, Delhi, India
Sanjula Baboota– Associate Professor, Jamia Hamdard University, New Delhi, Delhi, India
Javed Ali– Associate Professor, Jamia Hamdard University, New Delhi, Delhi, India