The objective of this study was the selection of the most influential variable for the preparation of gastroretentive mucoadhesive nanoparticles of acyclovir. Nanoparticles were prepared by one-step desolvation method; effect of formulation and processing variables on various response variables were studied by a Taguchi standard orthogonal array L8 design. Independent variables studied were the amount of gelatin, amount of glutaraldehyde, amount of Pluronic F-68, acetone addition rate, pH, stirring time, and stirring speed. The dependent variables studied were the particle size, polydispersity index, amount of drug released in 6？h, time required to release 60% of drug, entrapment efficiency, loading efficiency, and mucoadhesiveness. The size of all nanoparticulate formulations prepared as per the experimental design (Taguchi screening design) varied between 165 and 1610？nm, PDI between 0.360 and 1.00, bioadhesiveness between 3.959 and 11.02？g, cumulative percent drug release in 24？h between 40.74 and 72.48, entrapment efficiency between 15.70 and 83.12, and loading efficiency between 39.72 and 80.49. Pareto ranking analyses showed that the two most important factors affecting the selected responses were amount of gelatin and amount of Pluronic F-68 ( ). 1. Introduction Acyclovir is a cyclic analogue of the natural nucleoside 2-deoxyguanosine, clinically used in the treatment of Herpes simplex, Varicella zoster, Cytomegalovirus, and Epstein barr virus infections [1]. It is currently marketed as capsules (200？mg), tablets (200, 400 and 800？mg), and suspension for oral administration, topical ointment, and intravenous injection. Oral acyclovir is mostly used as 200？mg tablets, five times a day [2]. Absorption of orally administered acyclovir is slow, variable, and incomplete, with a bioavailability of 15%–30% and the elimination half-life of acyclovir is approximately 3？h [3]. It has narrow absorption window and is primarily absorbed from stomach and upper part of the small intestine [4–6]. Reduced bioavailability of acyclovir may be because of transportation of dosage form from the region of absorption window to site where it is less absorbed. Therefore there was a need to increase the gastroretention time of dosage form so that drug would be available at the site of absorption and results in improved bioavailability. Several attempts are being made to increase the gastric retention of drugs, like intragastric floating systems, hydrodynamically balanced systems, extendable or expandable, microporous compartment system, microballoons, bio/mucoadhesive
References
[1]
J. J. O'Brien and D. M. Campoli-Richards, “Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy,” Drugs, vol. 37, no. 3, pp. 233–309, 1989.
[2]
M. Ruhneck-Forsbeck, E. Sandstrom, and B. Andersson, “Treatment of recurrent genital herpes simplex infections with oral acyclovir,” Journal of Antimicrobial Chemotherapy, vol. 16, no. 5, pp. 621–628, 1985.
[3]
Z. Shao and A. K. Mitra, “Bile salt-fatty acid mixed micelles as nasal absorption promoters. III. Effects of nasal transport and enzymatic degradation of acyclovir prodrugs,” Pharmaceutical Research, vol. 11, no. 2, pp. 243–250, 1994.
[4]
R. Gr？ning, M. Berntgen, and M. Georgarakis, “Acyclovir serum concentrations following peroral administration of magnetic depot tablets and the influence of extracorporal magnets to control gastrointestinal transit,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 46, no. 3, pp. 285–291, 1998.
[5]
K. C. Meadows and J. B. Dressman, “Mechanism of acyclovir uptake in rat jejunum,” Pharmaceutical Research, vol. 7, no. 3, pp. 299–303, 1990.
[6]
K. Park and J. R. Robinson, “Bioadhesive polymers as platforms for oral-controlled drug delivery: method to study bioadhesion,” International Journal of Pharmaceutics, vol. 19, no. 2, pp. 107–127, 1984.
[7]
B. N. Singh and K. H. Kim, “Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention,” Journal of Controlled Release, vol. 63, no. 3, pp. 235–259, 2000.
[8]
A. Streubel, J. Siepmann, and R. Bodmeier, “Gastroretentive drug delivery systems,” Expert Opinion on Drug Delivery, vol. 3, no. 2, pp. 217–233, 2006.
[9]
A. A. Kharia, S. N. Hiremath, A. K. Singhai, L. K. Omray, and S. K. Jain, “Design and optimization of floating drug delivery system of acyclovir,” Indian Journal of Pharmaceutical Sciences, vol. 72, no. 5, pp. 599–606, 2010.
[10]
B. Singh, R. Kumar, and N. Ahuja, “Optimizing drug delivery systems using systematic “design of experiments.” Part I: fundamental aspects,” Critical Reviews in Therapeutic Drug Carrier Systems, vol. 22, no. 1, pp. 27–105, 2005.
[11]
B. Singh, S. K. Chakkal, and N. Ahuja, “Formulation and optimization of controlled release mucoadhesive tablets of atenolol using response surface methodology,” AAPS PharmSciTech, vol. 7, no. 1, pp. E19–E28, 2006.
[12]
B. Singh, S. Pahuja, R. Kapil, and N. Ahuja, “Formulation development of oral controlled release tablets of hydralazine: optimization of drug release and bioadhesive characteristics,” Acta Pharmaceutica, vol. 59, no. 1, pp. 1–13, 2009.
[13]
V. Venkata Dasu, T. Panda, and M. Chidambaram, “Determination of significant parameters for improved griseofulvin production in a batch bioreactor by Taguchi's method,” Process Biochemistry, vol. 38, no. 6, pp. 877–880, 2003.
[14]
H. L. Luessen, C.-M. Lehr, C.-O. Rentel et al., “Bioadhesive polymers for the peroral delivery of peptide drugs,” Journal of Controlled Release, vol. 29, no. 3, pp. 329–338, 1994.
[15]
G.-B. Park, Z. Shao, and A. K. Mitra, “Acyclovir permeation enhancement across intestinal and nasal mucosae by bile salt-acylcarnitine mixed micelles,” Pharmaceutical Research, vol. 9, no. 10, pp. 1262–1267, 1992.
[16]
R. Hejazi and M. Amiji, “Chitosan-based gastrointestinal delivery systems,” Journal of Controlled Release, vol. 89, no. 2, pp. 151–165, 2003.
[17]
C. J. Coester, K. Langer, H. Von Briesen, and J. Kreuter, “Gelatin nanoparticles by two step desolvation—a new preparation method, surface modifications and cell uptake,” Journal of Microencapsulation, vol. 17, no. 2, pp. 187–193, 2000.
[18]
A. H. Elshafeey, A. O. Kamel, and G. A. S. Awad, “Ammonium methacrylate units polymer content and their effect on acyclovir colloidal nanoparticles properties and bioavailability in human volunteers,” Colloids and Surfaces B, vol. 75, no. 2, pp. 398–404, 2010.
[19]
S. Das, R. Banerjee, and J. Bellare, “Aspirin loaded albumin nanoparticles by coacervation: implications in drug delivery,” Trends in Biomaterials and Artificial Organs, vol. 18, no. 2, pp. 203–211, 2005.
[20]
N. Ma, L. Xu, Q. Wang et al., “Development and evaluation of new sustained-release floating microspheres,” International Journal of Pharmaceutics, vol. 358, no. 1-2, pp. 82–90, 2008.
[21]
A. O. Kamel, G. A. S. Awad, A. S. Geneidi, and N. D. Mortada, “Preparation of intravenous stealthy acyclovir nanoparticles with increased mean residence time,” AAPS PharmSciTech, vol. 10, no. 4, pp. 1427–1436, 2009.
[22]
N. Thirawong, J. Nunthanid, S. Puttipipatkhachorn, and P. Sriamornsak, “Mucoadhesive properties of various pectins on gastrointestinal mucosa: an in vitro evaluation using texture analyzer,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 67, no. 1, pp. 132–140, 2007.
[23]
M. A. Schubert and C. C. Müller-Goymann, “Solvent injection as a new approach for manufacturing lipid nanoparticles—evaluation of the method and process parameters,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 55, no. 1, pp. 125–131, 2003.
