Background: Irinotecan is indicated as a first line treatment for metastatic colorectal cancer. However, chemotherapy with irinotecan is restricted to i.v. route owing to poor and erratic oral bioavailability due to its excessive intestinal efflux by P-glycoprotein. Objective: Aim of the present study is to improve the oral pharmacokinetic profile of irinotecan (IRT) by merging the attributes of nano-particulate system and P-glycoprotein (P-gp) modulation activity of excipients. Methods: Gelucire 44/14 solid lipid nanoparticles (SLN) were developed and optimized by BoxBehnken design. Optimized formulation was evaluated for various in vitro attributes and in vivo pharmacokinetic profile. Results: Size of optimized SLN was found to be 179.8±15.3 nm with polydispersity index, 0.367±0.029 and drug entrapment, 78.2±4.6%. SLN showed biphasic release profile i.e. initial burst release followed by sustained release. Differential scanning calorimetric (DSC) and X-ray diffractometric (XRD) analyses of SLN demonstrated the loss of drug’s crystallinity in SLN. Further, confocal laser scanning microscopy showed higher permeation of Rhodamine 123 (P-gp substrate) across intestinal epithelium through SLN when compared with free rhodamine 123 solution. Furthermore, in-vivo studies exhibited superior pharmacokinetic profile; significantly high (p<0.001) Cmax (1471.6±190.9 ng/mL) was attained through SLN when compared with Cmax of oral suspension (1113.5±125.5 ng/mL), similarly, high Tmax (p<0.001) was observed which revealed sustained effect of SLN. Conclusively, 2.79 folds improvement in oral bioavailability of IRT could be achieved through SLN when compared with oral suspension. Conclusion: Outcomes of studies suggested the potential of developed SLN for oral delivery of irinotecan and possibility to replace pre-existing intravenous therapy. Key word: Gelucire 44/14, Lipid nanocarrier, Intestinal gut sac method, Pharmacokinetic study. DOI: 10.5530/ijper.50.2.33 Correspondence Address Dr. Sushama Talegaonkar, Assistant Professor Department of Pharmaceutics Faculty of Pharmacy Jamia Hamdard New Delhi, INDIA-110062 Phone no. +919818453518; fax: +91 11 26059663 Email id: stalegaonkar@ gmail.com; stalegaonkar@jamaiahamdard@ac.in INTRODUCTION Molecules with wide range of biological activities including antimicrobial, antiviral, and anticancer are available commercially however, oral administration of several of them is still a major challenge. In general, these molecules either exhibit a poor aqueous solubility or site specific permeability characteristics across gastro intestinal tract (GIT). In addition, most of these compounds are either substrate for the biological transporters (including P-glycoprotein) or a major metabolic enzyme, cytochrome P450 or both, resulting in a significant loss of drug due to expulsion or first pass metabolism. Furthermore, the unfavourable physicochemical properties as well as Submission Date : 08-11-15 Revised Date : 22-12-15 Accepted Date : 21-06-16 hostile environment of the gastrointestinal tract possess major challenges for successful oral delivery.1-5 A number of anticancer drugs suffer from these drawbacks and limit the possibilities of their oral administration. Despite these difficulties, the development of oral formu lations for anticancer drugs is always viable due to a number of reasons including noninvasive nature, flexibility in designing of dosage form, dosing frequency, better patient compliance and being economic.6 Furthermore, oral delivery of cytotoxic drugs would eliminate or reduce the need of hospitalization, medical and nursing care as well as infusion equipments etc.7 It is generally assumed that long Zulfiqar Ahmad et al.: Lipid nanoparticles for oral delivery of irinotecan Indian Journal of Pharmaceutical Education and Research | Vol 50 | Issue 2 (Suppl.) | Apr-Jun, 2016 S169 exposure of cancerous cell to a drug at modest concentrations is more effective than a pulsed supply at higher concentration.8 Unfortunately, most of the anticancer agents are administered via iv route which exhibit initial rapid increase followed by fast decay of plasma drug concentrations resulting into ineffective therapy and increased side effects.8-10 Orally administered drugs absorb gradually and can sustain an effective concentration of drug in plasma which may prolong the exposure to cancerous cells resulting into improved efficacy and lower adverse effects. Irinotecan is indicated as a first line treatment for metastatic colorectal cancer. However, chemotherapy with irinotecan is restricted to i.v. route often causes patient incompliance. Till date no oral formulation of irinotecan is available commercially due to the poor and erratic oral bioavailability owing to its excessive intestinal efflux by P-glycoprotein. P-gp mediated efflux and cytochrome P450 mediated metabolism have remained a major reason of multi drug resistance consequently failure of chemotherapy. Nano-encapsulation of drugs allows them to evade reorganization by P-gp and extremely small size of systems facilitates its penetration across physiological barriers. Various studies have also revealed that nanoparticulate systems could be a good alternative for oral delivery of such type of drugs.8, 11-16 However, P-gp mediated efflux cannot be circumvented by use of nanoparticles alone because released drug from nanoparticles is effluxed out of the cell membrane by P-gp.17 To surmount these limitations, numbers of classical and natural P-gp and cytochrome P450 inhibitors have been investigated to improve the oral efficacy.18-21 However, these inhibitors have also been reported to have high toxicity profile, inhibitory effect on unintended efflux transporters and unpredicted pharmacokinetic interactions.22 Subsequently, 3rd generation P-gp inhibitors (Tariquidar, Zosuquidar) were specifically developed to overcome the P-gp mediated multi drug resistant (MDR). Third generation P-gp inhibitors were supposed to have lowest toxicity and high specificity. However, a number of investigations have demonstrated their cross-reactivity with mitoxantrone resistance protein (MXR) and/or drug-metabolizing enzymes.23 Currently, number of excipients belonging to pharmaceutical grade have shown comparable P-gp inhibitory activity as well as lesser side-effects.24 Hence, application of pharmaceutical excipients including polymer, lipid, oil, surfactant and co-surfactant as efflux pump inhibitors in the improvement of peroral drug delivery has drawn enormous attention.25,26 Therefore, development of nanosized delivery systems with excipients having P-gp modulation activity could be a more effective approach for the cytotoxic drugs to bypass P-gp at tissue and cellular level. Among the lipid-based nanocarriers including lipid core micelles, liposomes, microemulsions, nanoemulsions, solid lipid nanoparticles and self-nanoemulsifying drug delivery system, solid lipid nanoparticles and self nano-emulsifying drug delivery systems have emerged as preferred formulations for delivering poorly watersoluble and least bioavailable drugs. Solid lipid nanoparticle (SLN) is a nanoparticulate delivery system which has combined advantages of nanoparticles, liposomes, emulsion excluding the disadvantages of these systems.27 SLN are up taken by payer’s patches and follow the lymphatic rout of absorption thus avoiding the hepatic first pass metabolism of drugs which may resulting into improved oral bioavailability.28-32 The other advantages including controlled drug release, high drug stability, and high drug entrapment, negligible biotoxicity makes them a carrier of choice for drug delivery. Scaling up of solid lipid nanoparticles is possible and can be useful for industrial research in future.27 The aim of the present study is to investigate the attributes of lipid nanocarriers as well as P-gp inhibitory effect of pharmaceutical excipients and explore their utilization for enhancement of oral bioavailability of irinotecan. In this perspective, solid lipid nanoparticles were developed using Gelucire 44/14 (lipid), a P-gp inhibitor and evaluated for various in-vitro attributes and in-vivo pharmacokinetic profile. MATERIAL AND METHODS Materials Irinotecan hydrochloride was provided ex-gratia by Fresenius Kabi Pvt Ltd, India. Dichloromethane, (AR grade), Acetonitrile (HPLC grade), Orthophosphoric acid (HPLC grade), Tween 20, cetyl alcohol, stearic acid, glyceryl monostearate, sodium dihydrogen phosphate dihydrate, potassium dihydrogen phosphate and sodium hydroxide were purchased from SD fine chemical, Mumbai, India. Different grades of Gelucire, Precirol, and compritol 888 ATO were obtained as a gift sample from Gattefosse, Gennevilliers, France. Water was obtained from Milli-Q water purification system (Millipore, MA, USA).
Development of Novel lipid Nanoparticles for oral Bioavailability Enhancement of Irinotecan: In-vitro and In-vivo Investigations
Zulfiqar Ahmad,S. Talegaonkar,M. Tariq,L. Negi
Published 2015 in Indian Journal of Pharmaceutical Education and Research
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2015
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Indian Journal of Pharmaceutical Education and Research
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2015-12-10
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Medicine, Materials Science, Chemistry
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