Nanosuspension: An Emerging Trend for Bioavailability Enhancement of Etodolac

Hindawi Publishing Corporation International Journal of Polymer Science Volume 2015, Article ID 938594, 16 pages http://dx.doi.org/10.1155/2015/938594 Research Article Nanosuspension: An Emerging Trend for Bioavailability Enhancement of Etodolac Samar A. Afifi,1,2 Maha A. Hassan,1,3 Ali S. Abdelhameed,4 and Kadria A. Elkhodairy1,5 1 Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia Department of Pharmaceutics, National Organization for Drug Control and Research, P.O. Box 35521, Giza, Egypt 3 Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, P.O. Box 71515, Assiut, Egypt 4 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia 5 Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, P.O. Box 21500, Alexandria, Egypt 2 Correspondence should be addressed to Kadria A. Elkhodairy; Received 5 October 2014; Accepted 13 January 2015 Academic Editor: Alenka Vesel Copyright © 2015 Samar A. Afifi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Etodolac (ET) (poorly soluble drug) nanosuspensions were prepared by both pH shift method and antisolvent techniques in order to increase its dissolution rate. Various stabilizers were used, namely, Tween 20 and 80, HPMC, PVP K44, PVA, PEG 400, NaCMC, and 𝛽-cyclodextrin. The prepared nanosuspensions were characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM) and evaluated for their particle size, particle size distribution, and in vitro dissolution rate. In general, it was found that the antisolvent method for the preparation of ET nanosuspensions reduced the drug particle size to a higher extent compared to the pH shift method. The dissolution rate of ET in distilled water was markedly enhanced in the nanosized system, as more than 65% of drug dissolved in 10 min from all the nanosuspension formulations except F5 (stabilized with PVP K44) and F8 (stabilized with Tween 20), as compared to less than 20% of crude drug. Nanoparticles prepared by antisolvent method using Tween 80 as a stabilizer were selected for further in vivo study. The in vivo test demonstrated that nanoparticles of ET were well absorbed with a percentage drug absorption value 2.7 times more than that of micrometric size of crude ET. 1. Introduction Formulation of a poor water soluble drug has always been a challenging problem to pharmaceutical industry [1, 2]. There are many conventional methods that have been reported for improving solubility of poorly soluble drugs. Among these methods are micronization [3], solubilization using cosolvents [4], solid dispersions [5], and precipitation [6]. The limitation of this precipitation technique is that the drug needs to be soluble in at least one solvent and this solvent needs to be miscible with antisolvent. Moreover, precipitation technique is not applicable to drugs, which are simultaneously poorly soluble in aqueous and nonaqueous media [7, 8]. Nanosuspensions are colloidal dispersions and biphasic system consisting of drug particles dispersed in an aqueous medium in which the diameter of the suspended particles is less than 1 𝜇m in size [9, 10]. Nanosuspension can be produced by an appropriate size-reduction method and stabilized by a suitable stabilizer [8, 11, 12]. According to Noyes–Whitney and Ostwald–Freundlich principles, the particle size in the nanometer range can lead to increased dissolution velocity and saturation solubility for a nanosuspension, which is usually accompanied by an increase in bioavailability [8, 13, 14]. Nanosuspensions can be prepared by two methods, namely, “bottom up technology” and “top down technology” [15]. Bottom up technology is a method to form nanoparticles like precipitation, microemulsion, and melt emulsification methods. Top down technology involves the disintegration of larger particles into nanoparticles, examples of which are high-pressure homogenization and milling methods [16–18]. In bottom up technology, the nanoprecipitation method presents numerous advantages, as being a straightforward technique and being rapid and easy to perform. The drug is dissolved in a solvent, which is then added to nonsolvent 2 that causes precipitation of the fine drug particles [19]. Nanosuspension of Danazol, Naproxen, and zaltoprofen has been prepared by precipitation technique to improve their dissolution rate and oral bioavailability [1, 20, 21]. The solubility and dissolution rates as well as the antioxidant of curcumin nanoparticles prepared by antisolvent method were significantly higher than those of the original curcumin [22]. Nitrendipine, furosemide, and acyclovir nanosuspensions to enhance the drug dissolution rate and oral bioavailability were prepared by the precipitation-ultrasonication method [23–25]. Controlled nanoprecipitation by pH-shift method has been also reported [8, 26]. Etodolac (ET) is a nonsteroidal anti-inflammatory (NSAI) drug prescribed for the treatment of acute pain, osteoarthritis, and rheumatoid arthritis at an oral dose of 200 mg twice daily [27–30]. Recent studies have proved that ET has antitumor effect on different human cancer cells [31, 32]. ET is one of the selective COX-2 inhibitors; it possesses 10-fold COX-2 selectivity over COX-1 [32, 33]. COX-2 inhibitors are responsible for the production of prostaglandins which is involved in cytoprotection of gastric mucosa and regulation of the renal blood flow. Thus, ET safely treats inflammatory disorders without causing gastric irritation, ulceration, or bleeding [33, 34]. ET is administered as a racemate. Both enantiomers are stable and there is no evidence of R- to S-conversion in vivo [35]. Similar to other NSAIDs, the drug is highly plasma protein bound (>99% bound, primarily to albumin) and undergoes virtually complete biotransformation to oxidized metabolites and acyl-glucuronides. ET is well absorbed, with maximal plasma concentrations attained within 1 to 2 hours in healthy volunteers. The area under the plasma concentration-time curve of racemic ET increases linearly with doses used clinically. The elimination half-life of ET is between 6 and 8 hours in plasma and is similar for both enantiomers. Depending on the biopharmaceutical classification system [36], dissolution rate is the rate-controlling step in the absorption process for drugs possessing high membrane permeability but low aqueous solubility (class II drugs). ET is practically water insoluble (75 𝜇g/mL) and is belonging to class II drugs [37]. Thus, its oral bioavailability is expected to be limited by its dissolution rate, which might be increased using nanosuspension technology. In the present study, nanosuspensions of ET were prepared by t (...truncated)