Formulation and in-vivo Evaluation of Novel Topical Gel of Lopinavir for Targeting HIV

Author(s): Huda Ansari*, Prabha Singh.

Journal Name: Current HIV Research

Volume 16 , Issue 4 , 2018

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Abstract:

Background: Lopinavir is a specific reversible inhibitor of the enzyme HIV protease with mean oral bioavailability of less than 20 % due to extensive hepatic metabolism by cytochrome P450 3A4. The reported half-life of Lopinavir is 5-6 hours and the maximum recommended daily dose is 400 mg/day. All the marketed tablet and capsule formulations of lopinavir are generally combined with Ritonavir, a potent inhibitor of cytochrome P450 3A4, to minimize presystemic metabolism of lopinavir. Hence, to overcome limitations associated with oral administration of lopinavir and to promote single drug administration, utilization of vesicular nanocarriers through topical route could prove to be effective, as the approach combines the inherent advantages of topical route and the drug-carrying potential of vesicular nanocarriers across the tough and otherwise impervious skin barrier layer, i.e., stratum corneum.

Objective: The objective was to develop solid lipid nanoparticles (SLN) of lopinavir and formulate a topical gel for improved systemic bioavailability of lopinavir.

Method: SLNs were prepared using high-pressure homogenization technique and optimized. The nanoparticles were characterized by SEM to confirm their spherical shape. Differential Scanning Calorimetry (DSC) analysis was carried out to ensure the entrapment of drug inside the SLNs. A comparative evaluation was done between SLN based gel and plain gel of drug by performing exvivo skin permeation studies using Franz diffusion cell. To explore the potential of topical route, invivo bioavailability study was conducted in male Wistar rats.

Results: The optimized formulation composed of Compritol 888ATO (0.5 %) as a lipid, Poloxamer 407 (0.25 %) as a surfactant and Labrasol (0.25 %) as a co-surfactant gave the maximum entrapment of 69.78 % with mean particle size of 48.86nm. The plain gel of the drug gave a release of 98.406 ± 0.007 % at the end of 4hours whereas SLN based gel gave a more sustained release of 71.197 ±0.006 % at the end of 12hours ex-vivo. As observed from the results of in-vivo studies, highest Cmax was found with SLN based gel (20.3127 ± 0.6056) µg/ml as compared to plain gel (8.0655 ± 1.6369) µg/ml and oral suspension (4.2550 ± 16.380) µg/ml of the drug. Also, the AUC was higher in the case of SLN based gel indicating good bioavailability as compared to oral suspension and plain gel of drug.

Conclusion: Lopinavir SLN based gel was found to have modified drug release pattern providing sustained release as compared to plain drug gel. This indicates that Lopinavir when given topically has a good potential to target the HIV as compared to when given orally.

Keywords: Lopinavir, HIV, antiretroviral therapy, Solid Lipid Nanoparticles (SLN), topical, in-vivo bioavailability study.

[1]
Pau AK, George JM. Antiretroviral therapy: current drugs. Infect Dis Clin North Am 2014; 28(3): 371-402.
[2]
Antimisiaris SG, Mourtas S. Recent advances on anti-HIV vaginal delivery systems development. Adv Drug Deliv Rev 2015; 92: 123-45.
[4]
Sánchez-Rodríguez J, Vacas-Córdoba E, Gómez R, De La Mata FJ, Muñoz-Fernández MÁ. Nanotech-derived topical microbicides for HIV prevention: the road to clinical development. Antiviral Res 2015; 113: 33-48.
[5]
Ojewole E, Mackraj I, Naidoo P, Govender T. Exploring the use of novel drug delivery systems for antiretroviral drugs. Eur J Pharm Biopharm 2008; 70(3): 697-710.
[6]
Freed EO. HIV-1 replication. Somat Cell Mol Genet 2001; 26(1-6): 13-33.
[7]
Cohen MS, Hellmann N, Levy JA, DeCock K, Lange J. The spread, treatment, and prevention of HIV-1: evolution of a global pandemic. J Clin Invest 2008; 118(4): 1244-54.
[8]
Ranjita Shegokar. Nanotechnology—is there any hope for treatment of hiv infections or is it simply impossible? in: nanotechnology in diagnosis, treatment and prophylaxis of infectious diseases berlin. Germany: Elsevier 2015; pp. 233-49.
[9]
Temesgen Z, Warnke D, Kasten MJ. Current status of antiretroviral therapy. Expert Opin Pharmacother 2006; 7(12): 1541-54.
[10]
Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008; 372(9635): 293-9.
[11]
Thompson MA, Aberg JA, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the international AIDS society–USA panel. JAMA 2010; 304(3): 321-33.
[12]
Phillips KD. Protease inhibitors: a new weapon and a new strategy against HIV. J Assoc Nurses AIDS Care 1996; 7(5): 57-71.
[13]
Patel D, Kumar P, Thakkar HP. Lopinavir metered-dose transdermal spray through microporated skin: Permeation enhancement to achieve therapeutic needs. J Drug Deliv Sci Technol 2015; 29: 173-80.
[14]
Singh Malik D, Mital N, Kaur G. Topical drug delivery systems: a patent review. Expert Opin Ther Pat 2016; 26(2): 213-28.
[15]
Patel KK, Kumar P, Thakkar HP. Formulation of niosomal gel for enhanced transdermal lopinavir delivery and its comparative evaluation with ethosomal gel. AAPS PharmSciTech 2012; 13(4): 1502-10.
[16]
Cai S, Yang Q, Bagby TR, Forrest ML. Lymphatic drug delivery using engineered liposomes and solid lipid nanoparticles. Adv Drug Deliv Rev 2011; 63(10-11): 901-8.
[17]
das Neves J. Amiji MM, Bahia MF, Sarmento B. Nanotechnology-based systems for the treatment and prevention of HIV/AIDS. Adv Drug Deliv Rev 2010; 62(4): 458-77.
[18]
Kingsley JD, Dou H, Morehead J, Rabinow B, Gendelman HE, Destache CJ. Nanotechnology: a focus on nanoparticles as a drug delivery system. J Neuroimmune Pharmacol 2006; 1(3): 340-50.
[19]
Mukherjee S, Ray S, Thakur RS. Solid lipid nanoparticles: a modern formulation approach in drug delivery system. Indian J Pharm Sci 2009; 71(4): 349-58.
[20]
Müller RH. MaÈder K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery–a review of the state of the art. Eur J Pharm Biopharm 2000; 50(1): 161-77.
[21]
Müller RH, Radtke M, Wissing SA. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv Drug Deliv Rev 2002; 54: S131-55.
[22]
Qi J, Lu Y, Wu W. Absorption, disposition and pharmacokinetics of solid lipid nanoparticles. Curr Drug Metab 2012; 13(4): 418-28.
[23]
Wang J, Chen J, Ye N, et al. Absorption, pharmacokinetics and disposition properties of solid lipid nanoparticles (SLNs). Curr Drug Metab 2012; 13(4): 447-56.
[24]
Pouton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci 2006; 29(3-4): 278-87.
[25]
Patel KP, Pathak CJ, Patel RP. Formulation consideration of nanotechnology based drug delivery systems Drug invent 2014; 6(1): 88-97.
[26]
Abdel-Salam FS, Elkheshen SA, Mahmoud AA, Ammar HO. Diflucortolone valerate loaded solid lipid nanoparticles as a semisolid topical delivery system. Bull Fac Pharm Cairo Univ 2016; 54(1): 1-7.
[27]
Jeon HS, Seo JE, Kim MS, et al. A retinyl palmitate-loaded solid lipid nanoparticle system: effect of surface modification with dicetyl phosphate on skin permeation in vitro and anti-wrinkle effect in vivo. Int J Pharm 2013; 452(1): 311-20.
[28]
Pardeshi C, Rajput P, Belgamwar V, et al. Solid lipid based nanocarriers: an overview/Nanonosači na bazi čvrstih lipida: Pregled. Acta Pharm 2012; 62(4): 433-72.
[29]
Üner M, Yener G. Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives. ‎. Int J Nanomedicine 2007; 2(3): 289-300.
[30]
Balguri SP, Adelli GR, Majumdar S. Topical ophthalmic lipid nanoparticle formulations (SLN, NLC) of indomethacin for delivery to the posterior segment ocular tissues. Eur J Pharm Biopharm 2016; 109: 224-35.
[31]
He H, Wang P, Cai C, Yang R, Tang X. VB12-coated gel-core-sln containing insulin: another way to improve oral absorption. Int J Pharm 2015; 493(1-2): 451-9.
[32]
Kushwaha AK, Vuddanda PR, Karunanidhi P, Singh SK, Singh S. Development and evaluation of solid lipid nanoparticles of raloxifene hydrochloride for enhanced bioavailability. BioMed Res Int 2013; 1-9.
[33]
Ankola DD, Durbin EW. Bu xton GA, Schäfer J, Bakowsky U, Kumar MR. Preparation, characterization and in silico modeling of biodegradable nanoparticles containing cyclosporine A and coenzyme Q10. Nanotechnology 2010; 21(6): 065104.
[34]
Jelvehgari M, Rashidi MR. Adhesive and spreading properties of pharmaceutical gel composed of cellulose polymer Jundishapur J Nat Pharm Prod 2007; 2007(01, Winter): 45-58.
[35]
Vats R, Murthy AN, Ravi PR. Simple, rapid and validated LC determination of lopinavir in rat plasma and its application in pharmacokinetic studies. Sci Pharm 2011; 79(4): 849-64.
[36]
Alex MA, Chacko AJ, Jose S, Souto EB. Lopinavir loaded solid lipid nanoparticles (SLN) for intestinal lymphatic targeting. Eur J Pharm Sci 2011; 42(1): 11-8.
[37]
Das SK, Yuvaraja K, Khanam J, Nanda A. Formulation development and statistical optimization of ibuprofen-loaded polymethacrylate microspheres using response surface methodology. Chem Eng Res Des 2015; 96: 1-4.
[38]
Deshmukh RK, Naik JB. Optimization of sustained release aceclofenac microspheres using response surface methodology. Mater Sci Eng C 2015; 48: 197-204.
[39]
Ghosal K, Ghosh D, Das SK. Preparation and evaluation of naringin-loaded polycaprolactone microspheres based oral suspension using Box-Behnken design. J Mol Liq 2018; 256: 49-57.
[40]
Setty CM, Babubhai SR, Pathan IB. Development of veldecoxib topical gels: effect of formulation variables on the release of valdecoxib. Int J Pharm Pharma Sci 2010; 2(1): 70-3.


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Article Details

VOLUME: 16
ISSUE: 4
Year: 2018
Page: [270 - 279]
Pages: 10
DOI: 10.2174/1570162X16666180924101650

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