http://informahealthcare.com/ddi ISSN: 0363-9045 (print), 1520-5762 (electronic) Drug Dev Ind Pharm, Early Online: 1–12 ! 2013 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2012.746362 RESEARCH ARTICLE Nanosuspension of efavirenz for improved oral bioavailability: formulation optimization, in vitro, in situ and in vivo evaluation Greeshma V. Patel 1 , Vaibhav B. Patel 2 , Abhishek Pathak 1 , and Sadhana J. Rajput 1 1 Quality Assurance Laboratory, Centre of Relevance and Excellence in Novel Drug Delivery System and 2 Pharmacology Laboratory, Pharmacy Department, The Maharaja Sayajirao University of Baroda, Fatehgunj, Vadodara, Gujarat, India Abstract Context: Nanosuspensions (NSs) of poorly water-soluble drugs are known to increase the oral bioavailability. Objectives: The purpose of this study was to develop NS of efavirenz (EFV) and to investigate its potential in enhancing the oral bioavailability of EFV. Materials and methods: EFV NS was prepared using the media milling technique. The Box– Behnken design was used for optimization of the factors affecting EFV NS. Sodium lauryl sulfate and PVP K30 were used to stabilize the NS. Freeze-dried NS was completely re-dispersed with double-distilled filtered water. Results: Mean particle size and zeta potential of the optimized NS were found to be 320.4  3.62 nm and –32.8  0.4 mV, respectively. X-ray diffraction and differential scanning calorimetric analysis indicated no phase transitions. Rate and extent of drug dissolution in the dissolution medium for NS was significantly higher compared to marketed formulation. The parallel artificial membrane permeability assay revealed that NS successfully enhanced the permeation of EFV. Results of in situ absorption studies showed a significant difference in absorption parameters such as K a , t 1/2 and uptake percentages between lyophilized NS and marketed formulation of EFV. Oral bioavailability of EFV in rabbits resulting from NS was increased by 2.19-fold compared to the marketed formulation. Conclusion: Thus, it can be concluded that NS formulation of EFV can provide improved oral bioavailability due to enhanced solubility, dissolution velocity, permeability and hence absorption. Keywords Bioavailability, Box–Behnken, efavirenz, media milling, nanosuspension History Received 25 June 2012 Revised 15 October 2012 Accepted 30 October 2012 Published online 16 January 2013 Introduction Worldwide, approximately 35–40 million people are reported to be infected with human immunodeficiency virus (HIV) 1 . High activity antiretroviral therapy (HAART) introduced in 1996 combines at least three antiretroviral drugs and, for over a decade, has been used to extend the lifespan of the HIV-infected patients 2 . Chronic intake of HAART is mandatory to control HIV infection 3 . Non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs were first introduced in 1998. According to the guidelines, HAART usually includes at least one NNRTI as a first-choice drug, The British HIV Association, the US Department of Health and Human Services and the International AIDS Society guidelines indicate efavirenz (EFV) as preferred NNRTI 4 . Molecular structure of EFV is [(S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4- (trifluoromethyl)-2H-3,1-benzoxazin-2-one]. According to the biopharmaceutical classification system guidance by Food and Drug Administration (FDA), EFV comes under a class II category drug, which means that it has low solubility and high intestinal permeability 5,6 . It is a crystalline lipophilic solid with an aqueous solubility of 3–9 mg/ml and with a low intrinsic dissolution rate of 0.037 mg/cm 2 /min. Hence, it has very low bioavailability 7 . To achieve effective therapy against viral diseases for orally administered drugs, it is essential that the drug should be adequately and consistently absorbed. Frequent administration of EFV in relatively high doses, because of its low solubility hindering its absorption and biodistribution, is a main cause of patient incompliance 8 . Thus, there is a need for some innovative formulation approach to enhance the oral bioavailability. However, this problem can be overcome by increasing the solubility of the drug. Reduction of the particle size to nanometer range is suitable approach to improve the solubility of drugs. Over a decade, nanosuspensions (NSs) are considered to be the best alternative and universal approach for poorly water-soluble drugs to enhance oral bioavailability 9 . Several production techniques such as precipitation 10 , jet milling, pearl milling 11–13 and high-pressure homogenization (HPH) 14,15 have been applied to produce NSs. Currently, media milling is preferred over HPH technique because it is easy to scale up to industrial pharmaceutical unit operations 16–19 . Also, Address for correspondence: Greeshma V. Patel, Quality Assurance Laboratory, G. H. Patel Pharmacy Building, Donor’s Plaza, The Maharaja Sayajirao University of Baroda, Fatehgunj, Vadodara-390002, Gujarat, India. Tel: (O) 091-265-2434187. Fax: 091-265-2418927. E-mail: grish.vab@gmail.com Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by University of Alberta on 04/03/13 For personal use only.