Polymeric Nanosuspensions for Enhanced Dissolution of Water Insoluble Drugs

Hindawi Publishing Corporation Journal of Nanomaterials Volume 2013, Article ID 170201, 10 pages http://dx.doi.org/10.1155/2013/170201 Research Article Polymeric Nanosuspensions for Enhanced Dissolution of Water Insoluble Drugs Roya Yadollahi,1 Krasimir Vasilev,1,2 Clive A. Prestidge,3 and Spomenka Simovic3 1 Mawson Institute, University of South Australia, Mawson Lakes, SA 5095, Australia School of Engineering, University of South Australia, Mawson Lakes, SA 5095, Australia 3 Ian Wark Research Institute, University of South Australia, Mawson Lakes, Adelaide, SA 5095, Australia 2 Correspondence should be addressed to Spomenka Simovic; Received 2 August 2013; Accepted 1 September 2013 Academic Editor: Haifeng Chen Copyright © 2013 Roya Yadollahi 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. The aim of the present research is to formulate and evaluate polymeric nanosuspensions containing three model water insoluble drugs, nifedipine (NIF), carbamazepine (CBZ), and ibuprofen (IBU) with various physicochemical properties. The nanosuspensions were prepared from hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) by a cosolvent technique with polyethylene glycol (PEG-300) and water as the cosolvents. Physicochemical and morphological characteristics of the nanosuspensions (particle size, polydispersity index, and crystallinity) have been correlated with the drug release behaviour. The effects of polymer, drug ratio on the physical, morphological, and dissolution characteristics of the drugs are reported. Drug release is significantly enhanced from the nanosuspensions; for example, the maximum NIF, IBU, and CBZ concentrations after 8hour dissolution are increased approximately 37, 2, and 1.2 times, respectively, in comparison with the pure powdered drugs. Based on this solubilization enhancement performance, the nanosuspensions have potential for increasing the orally dosed bioavailability of NIF, IBU, and CBZ. 1. Introduction More than 40% of new chemical entities (NCE) are water insoluble compounds which currently make up 1/3 of the United States Pharmacopeia recognised drugs [1, 2]. Water insoluble compounds (BCS Class II) have poor aqueous solubility and imperfect dissolution, which causes their low bioavailability [3]. Generation of drug nanosuspensions presents one solution to delivery of water insoluble drugs. Nanosuspensions have been defined as drug carriers with particle size range within 10–1000 nm [4]. Therefore, formulating new dosage forms to achieve adequate bioavailability has become a serious and challenging scientific, industrial, and medical issue. Water insoluble drugs are typically formulated with the help of various excipients whose aim is to improve drug dissolution rate and storage stability. Interaction of reactive functional groups of excipients with the drug molecules increases active surface area and consequently dissolution rate [5]. The use of excipients in formulations of insoluble drugs has proven ability to increase drug dissolution rate, but limitations such as toxicity of some surfactant compounds and limited drug loading have been identified [6]. According to the Noyes-Whitney equation, smaller particle size with higher surface area in contact with biological media leads to an enhanced drug dissolution rate [7, 8]. Hence, scaling down convention drug powders to nanoparticles enhances drug solubility and bioavailability. Nanosuspensions can be prepared by different methods such as high pressure homogenization and media milling. However these techniques have drawbacks such as contamination of final products, broad particle size distributions, and the need for high energy input [9, 10]. The co-solvent technique has been extensively used to prepare in situ nanosuspensions [11–17] and has numerous advantages over evaporation or heating-cooling techniques, such as being fast and easy to perform and suitable for thermolabile compounds. The aim of this work is to explore solid-state and dissolution characteristics of polymeric nanosuspensions prepared by a co-solvent technique. Water insoluble drugs nifedipine (NIF), carbamazepine (CBZ), and ibuprofen (IBU) with 2 different physiochemical properties (Table 1) were selected and used in realistic extended release doses. Commonly used pharmaceutical polymers hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were used as stabilisers/crystal growth inhibitors [18–21]. In addition to crystal inhibition, the HPMC polymer acts as a hydrophilic matrix agent which forms a strong viscous gel in contact with aqueous media, facilitating extended drug release [22]. The influence of polymer : drug ratio on nanoparticle formation, drug stabilization, and dissolution characteristics were explored. Drug crystallinity and polymorphic forms in nanosuspension polymeric matrices consisting of different polymers ratio were investigated using differential scanning calorimetry (DSC). The molecular structure and specifications of model drugs (nifedipine, carbamazepine, and ibuprofen) and excipients (mannitol, PEG-300, HPMC, and PVP) which were used in this study are presented in Table 1. 2. Materials and Method 2.1. Materials. High-purity (Milli-Q) water was used throughout the study (ph = 6.5 ± 0.5). PEG-300 (Sigma Aldrich, Australia) was used as the co-solvent. Hydroxypropyl methylcellulose (HPMC) containing 28–30% methoxyl and 7–12% hydroxypropyl content, polyvinylpyrrolidone (PVP), and mannitol: ≥98% (SigmaAldrich) were used as received. Model drugs (NIF: ≥98% TLC, CBZ: ≥98% TLC, IBU: ≥98% GC) and phosphate buffer (pH = 7.4) were also purchased from Sigma-Aldrich. 2.2. Preparation of Nanosuspensions. Nanosuspensions of model drugs were prepared by the co-solvent technique [30]. This technique includes mixing of two different phases. The first phase (organic phase) is PEG-300 with dissolved model drugs (NIF: 30 mg, CBZ: 400 mg, IBU: 400 mg dissolved in 5 gr of PEG-300). The second phase (aqueous phase) where the model drugs are almost insoluble contains dissolved polymers (HPMC & PVP) (Table 2). The two phases were sonicated for 2 hours. Upon subsequent addition of mannitol (10% w/v), the system was additionally sonicated for 2 hours. 2.3. Freeze Drying/Lyophilization and Redispersibility of Nanosuspensions. Nanosuspension formulations were lyophilized using mannitol as cryoprotectant. The freeze drying (Alpha 1-2 LDplus) was performed at a temperature of −70∘ C and vacuum 0.09 mbar for 72 hours. The redispersibility of lyophilized samples was investigated by manual shaking of 5 mg in glass vial with 20 mL PBS (pH = 7.4). Formation of aggregates or precipitates was monitored visually. 2.4. Particle Size Analysis. Size and polydispersity index (the width of particle size distribution) of nanosuspensions we (...truncated)