Self nanoemulsifying drug delivery system (SNEDDS) of Rosuvastatin calcium: Design, formulation, bioavailability and pharmacokinetic evaluation

doi:10.1016/j.colsurfb.2013.08.025

Colloids and Surfaces B: Biointerfaces

Volume 112, 1 December 2013, Pages 337-343

https://doi.org/10.1016/j.colsurfb.2013.08.025 Get rights and content

Highlights

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Self nanoemulsifying drug delivery system (SNEDDS) of Rosuvastatin calcium.
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Rosuvastatin SNEDDS (CN7) showed 2.45 time's greater bioavailability.
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Pharmacokinetic analysis of CN7 SNEDDS best fit in to one compartment model.

Abstract

The aim of the present study is to improve solubility and bioavailability of Rosuvastatin calcium using self nanoemulsifying drug delivery system (SNEDDS). Self emulsifying property of various oils including essential oils was evaluated with suitable surfactants and co-surfactants. Ternary phase diagrams were constructed based on Rosuvastatin calcium solubility analysis for optimizing the system. The prepared formulations were evaluated for self emulsifying time, robustness to dilution, droplet size determination and zeta potential analysis. The system was found to be robust in different pH media and dilution volume. The globule size of the optimized system was less than 200 nm which could be an acceptable nanoemulsion size range. The zeta potential of the selected CN 7 SNEDDS formulation (cinnamon oil 30%; labrasol 60%; Capmul MCM C8 10%) was −29.5 ± 0.63 with an average particle size distribution of 122 nm. In vitro drug release studies showed remarkable increase in dissolution of CN7 SNEDDS compared to marketed formulation. In house developed HPLC method for determination of Rosuvastatin calcium in rat plasma was used in the bioavailability and pharmacokinetic evaluation. The relative bioavailability of self nanoemulsified formulation showed an enhanced bioavailability of 2.45 times greater than that of drug in suspension. The obtained plasma drug concentration data was processed with PKSolver 2.0 and it was best fit into the one compartment model.

Graphical abstract

Introduction

Lipid based drug delivery system has attained increasing interest in oral route of administration of poorly bioavailable drug as a means to bypass the drug passage in the hepatic portal vein and consequently its hepatic degradation. This hypothesis was believed to be attained chiefly, by lymphatic transport via Peyer's patches along the GI tract [1]. Self emulsifying drug delivery system is one among the lipid based drug delivery systems that has been currently investigated for its advantages, providing a large interfacial area for partitioning the drug between oil and GI fluid [2]. This technique improves the oral bioavailability of poorly soluble drugs by enhancing the solubility and maintaining the drug in a dissolved state, in small droplets of oil, all over its transit through the gastrointestinal tract [3], [4].

Self nanoemulsifying drug delivery system (SNEDDS) is an isotropic mixture of oil, surfactants and co-surfactants that form fine oil-in-water nanoemulsion, upon mild agitation, followed by administration into aqueous media, such as GI fluids [5]. Upon dilution, SNEDDS typically produces droplet sizes between 20 and 200 nm. These nano-sized droplets may offer an improvement in dissolution rates as well as bioavailability which results in more reproducible blood–time profiles. SNEDDS is a physically more stable formulation when compared to emulsions, and easier to manufacture in a large scale. The rationale to use SNEDDS for the delivery of poorly soluble drugs is that, they are presented in the form of preconcentrated solution. Hence, the dissolution step required for solid crystalline compounds shall be avoided. In addition, the formation of a variety of colloidal species on dispersion and subsequent digestion of SNEDDS facilitates drug absorption [6], [7]. Rosuvastatin calcium (ROS) is a synthetic lipid-lowering agent, chemically known as (3R,5S,6E)-7-{4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl}-3,5-dihydroxyhept-6-enoic acid calcium salt (2:1) [8]. It is also used in the treatment of osteoporosis, benign prostatic hyperplasia, and Alzheimer's disease [9]. The oral bioavailability of ROS is 20% because of low aqueous solubility due to its crystalline nature and is extensively metabolized by liver via oxidation, lactonisation, and glucuronidation. The metabolites are eliminated by biliary secretion and direct secretion from the blood to the intestine [10], [11], [12]. For these reasons, enhancing the solubility and by passing hepatic metabolism of Rosuvastatin calcium is a desirable approach to improve its therapeutic performance. After oral administration of ROS, the peak plasma concentration was attained within 3–5 h, the volume of distribution was 1.1–1.4 liter/kg, and plasma protein binding was 90%.

The present study is aimed to design and develop Rosuvastatin calcium loaded SNEDDS with the objective of increasing its solubility and achieving higher bioavailability. To accomplish this, the formulation was studied for drug solubility in various oils, surfactants and co-surfactants. From this, essential oils showed higher solubility data when compared to others. Hence, the essential oils were evaluated for their self emulsifying properties with surfactants and co-surfactants. Generally essential oils are recognized as GRAS (generally recognized as safe) compositions by the Code of Federal Regulations [13]. Further, Benet et al. (1998) studies revealed that the oral bioavailability of cyclosporine was improved with essential oils by inhibiting cytochrome P450 in the gut wall and by inhibiting P-glycoprotein efflux transporter. The prepared ROS loaded SNEDDS was evaluated for self emulsification time, robustness to dilution, droplet size of the dispersion, in vitro drug release and bioavailability.

Section snippets

Materials

Rosuvastatin calcium was gifted by Microlabs Pvt. Ltd., Bangalore; cinnamon oil, lavender oil, peppermint oils were purchased from S.D. Fine Chemicals, Mumbai, India. Labrasol was a gifted sample from Gattefosse limited, Mumbai, India. Capmul MCM, Capmul MCM C8 were obtained as gift samples from Abitech Corporation, USA. Brij, Ethyl oleate, Isopropyl myristate, Cremophore EL, Cremophore RH 40, Span 80, Tween 80, Acetonitrile and Methanol were purchased from Sigma Aldrich, USA. Formic acid was

Solubility study

The purpose of drug solubility in various excipients used in SNEDDS was to provide a robust self emulsifying region with large boundary size in the ternary phase diagram and to form nano droplet size to improve in vivo behavior [17], [25]. The solubility of ROS in various essential oils, surfactants and co-surfactants is shown in Fig. 2. It was evident that ROS exhibited highest solubility in cinnamon oil (99.56 ± 1.43 mg/ml) and lavender oil (98.74 ± 1.69 mg/ml) and least solubility was observed in

Self emulsification time

The rate of emulsification was a major index for assessment of the efficiency of self-emulsification. The SNEDDS should disperse completely and quickly when subjected to dilution under mild agitation [31]. Formulations LAV 17, CN7, CN10 and CN12 showed very less emulsification time (<1 min) when compared to others.

Robustness to dilution

Uniform emulsion formation from SNEDDS is very important at different dilutions because drugs may precipitate at higher dilution in vivo which affects the drug absorption significantly

Conclusion

In conclusion, we have developed different self emulsifying formulations of ROS based on its solubility data. In that, cinnamon oil (30%), labrasol (60%) and Capmul MCM C8 (10%) compositions have shown best self emulsifying property for ROS. The droplet size of the CN7 SNEDDS formulation was less than 200 nm, which resulted in better solubility of the compound. The optimized formulation complied with the requirement of zeta potential for stability. In house HPLC method for ROS in rat plasma was

Acknowledgements

The authors are thankful to Mr. S.M. Habibur Rahman and Mr. M. Siva Selvakumar, Associate Professors, PSG College of Pharmacy, Coimbatore for contributing in pharmacokinetics and bioanalytical studies and Dr. M.S. Muthu, Assistant Professor, BHU, Varanasi for proof reading the article.

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Self nanoemulsifying drug delivery system (SNEDDS) of Rosuvastatin calcium: Design, formulation, bioavailability and pharmacokinetic evaluation

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Materials

Solubility study

Self emulsification time

Robustness to dilution

Conclusion

Acknowledgements

Eur. J. Pharm. Sci.

J. Colloid Interface Sci.

Eur. J. Pharm. Sci.

Int. J. Pharm.

Int. J. Pharm.

Int. J. Pharm.

Int. J. Pharm.

J. Pharm. Sci.

Eur. J. Pharm. Biopharm.

Int. J. Pharm.

Colloids Surf. A: Physicochem. Eng. Aspects.

Adv. Drug Deliv. Rev.

Eur. J. Pharm. Biopharm.

In vitro and in vivo comparative study of itraconazole bioavailability when formulated in highly soluble self-emulsifying system and in solid dispersion

Biopharm. Drug Dispos.

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J. Young Pharm.

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Ther. Clin. Risk Manag.

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