Application of Box-Behnken design for optimization of formulation parameters for nanostructured lipid carriers of candesartan cilexetil
Main Article Content
Abstract
for improving its oral bioavailability. From solubility and lipid‑water partition studies of CC in various lipids, glyceryl
monostearate (GMS) and glyceryl monocaprylate were selected as solid lipid and liquid lipid, respectively. NLCs were
formulated by hot melt‑emulsification‑ultrasonication method. A three‑factor, three‑level Box–Behnken design was used to
optimize the independent variables, lipid: drug ratio (X1), solid lipid: liquid lipid ratio (X2) and surfactant concentration (X3).
Different batches were prepared and evaluated for responses, particle size (Y1), zeta potential (Y2) and % entrapment
efficiency (Y3). Response surface plots and perturbation plots were constructed to study the effect of factors on responses.
The optimized formulation containing X1 -Â 22.47:1, X2 -Â 7.23:1 and X3 -Â 1.97% was prepared and evaluated. Observed
values for Y1, Y2, and Y3 were found to be closer to the predicted values thus validating the optimization method. Differential
scanning calorimetry thermograms of pure drug, GMS and lyophilized drug loaded NLCs indicated complete miscibility
of drug into lipids. The release of CC from the NLCs conducted in artificial gastric fluid (pH 1.2) was much higher than in
phosphate buffer solution (pH 6.8). The formulated NLCs were found to be more stable at refrigerated condition (5°C ± 3°C)
as compared with room temperature (25°C ± 2°C/60% RH% ± 5% RH). The use of design approach helped to identify
critical formulation parameters in CC loaded NLCs preparation.
Key words: Candesartan, hypertension, nanostructured lipid carriers, oral bioavailability partition study
Downloads
Article Details
This is an Open Access article distributed under the terms of the Attribution-Noncommercial 4.0 International License [CC BY-NC 4.0], which requires that reusers give credit to the creator. It allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, for noncommercial purposes only.
References
Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J.
Global burden of hypertension: Analysis of worldwide data. Lancet
;365:217‑23.
High blood pressure and cholesterol: out of control in US.
Atlanta. Available from: http://www.cdc.gov/Features/Vitalsigns/
CardiovascularDisease. [Last cited on 2013 Apr 25].
Tadevosyan A, Maclaughlin EJ, Karamyan VT. Angiotensin II type 1
receptor antagonists in the treatment of hypertension in elderly
patients: Focus on patient outcomes. Patient Relat Outcome Meas
;2:27‑39.
David PW. Antihypertensive drugs. In: Charles R, Craig RE, editors.
Modern Pharmacology with Clinical Applications. Beltimore: Lippincott
Williams and Wilkins; 1997. p. 225‑38.
Ferreiros N, Dresen S, Alonso RM, Weinmann W. Hydrolysis and
transesterification reactions of candesartan cilexetil observed during
the solid phase extraction procedure. J Chromatogr B Analyt Technol
Biomed Life Sci 2007;855:134‑8.
Nishida Y, Takahashi Y, Nakayama T, Soma M, Asai S. Comparative effect
of olmesartan and candesartan on lipid metabolism and renal function
in patients with hypertension: A retrospective observational study.
Cardiovasc Diabetol 2011;10:74.
Nekkanti V, Karatgi P, Prabhu R, Pillai R. Solid self‑microemulsifying
formulation for candesartan cilexetil. AAPS PharmSciTech 2010;11:9‑17.
Al Omari AA, Al Omari MM, Badwan AA, Al‑Sou’od KA. Effect of
cyclodextrins on the solubility and stability of candesartan cilexetil in
solution and solid state. J Pharm Biomed Anal 2011;54:503‑9.
Sayyad FJ, Tulsankar SL, Kolap UB. Design and development of liquisolid
compact of candesartan cilexetil to enhance dissolution. J Pharm Res
;7:381‑8.
Zhang Z, Gao F, Bu H, Xiao J, Li Y. Solid lipid nanoparticles loading
candesartan cilexetil enhance oral bioavailability: In vitro characteristics
and absorption mechanism in rats. Nanomedicine 2012;8:740‑7.
Gao F, Zhang Z, Bu H, Huang Y, Gao Z, Shen J, et al. Nanoemulsion
improves the oral absorption of candesartan cilexetil in rats:
Performance and mechanism. J Control Release 2011;149:168‑74.
Burcham DL, Maurin MB, Hausner EA, Huang SM. Improved oral
bioavailability of the hypocholesterolemic DMP 565 in dogs following
oral dosing in oil and glycol solutions. Biopharm Drug Dispos
;18:737‑42.
Shafiq S, Shakeel F, Talegaonkar S, Ahmad FJ, Khar RK, Ali M.
Development and bioavailability assessment of ramipril nanoemulsion
formulation. Eur J Pharm Biopharm 2007;66:227‑43.
Venishetty VK, Chede R, Komuravelli R, Adepu L, Sistla R, Diwan PV.
Design and evaluation of polymer coated carvedilol loaded solid lipid
nanoparticles to improve the oral bioavailability: A novel strategy
to avoid intraduodenal administration. Colloids Surf B Biointerfaces
;95:1‑9.
Severino P, Andreani T, Macedo AS, Fangueiro JF, Santana MH, Silva AM,
et al. Current state‑of‑art and new trends on lipid nanoparticles (SLN
and NLC) for oral drug delivery. J Drug Deliv 2012;2012:750891.
Müller RH, Mäder K, Gohla S. Solid lipid nanoparticles (SLN) for
controlled drug delivery‑A review of the state of the art. Eur J Pharm
Biopharm 2000;50:161‑77.
Muchow M, Maincent P, Muller RH. Lipid nanoparticles with a solid
matrix (SLN, NLC, LDC) for oral drug delivery. Drug Dev Ind Pharm
;34:1394‑405.
Kasongo KW, Shegokar R, Müller RH, Walker RB. Formulation
development and in vitro evaluation of didanosine‑loaded nanostructured
lipid carriers for the potential treatment of AIDS dementia complex.
Drug Dev Ind Pharm 2011;37:396‑407.
Gohel MC, Amin AF. Formulation optimization of controlled release
diclofenac sodium microspheres using factorial design. J Control
Release 1998;51:115‑22.
Nazzal S, Khan MA. Response surface methodology for the optimization
of ubiquinone self‑nanoemulsified drug delivery system. AAPS Pharm
Sci Tech 2002;3:E3.
Gareth A. Lewis DM, Phan‑Tan‑Luu R. Pharmaceutical Experimental
Design. New York, Basel: Marcel Deckker Inc.; 2005.
Joshi M, Patravale V. Formulation and evaluation of nanostructured
lipid carrier (NLC)‑based gel of valdecoxib. Drug Dev Ind Pharm
;32:911‑8.
Doktorovová S, Araújo J, Garcia ML, Rakovský E, Souto EB. Formulating
fluticasone propionate in novel PEG‑containing nanostructured lipid
carriers (PEG‑NLC). Colloids Surf B Biointerfaces 2010;75:538‑42.
Aji Alex MR, Chacko AJ, Jose S, Souto EB. Lopinavir loaded solid lipid
nanoparticles (SLN) for intestinal lymphatic targeting. Eur J Pharm Sci
;42:11‑8.
Box GE, Behnken DW. Some new three‑level designs for the study of
quantitative variables. Technometrics 1960;2:455‑75.
Dong CH, Xie XQ, Wang XL, Zhan Y, Yao YJ. Application of
Box‑Behnken design in optimisation for polysaccharides extraction
from cultured mycelium of Cordyceps sinensis. Food Bioprod Process
;87:139‑44.
Gulbake A, Jain A, Khare P, Jain SK. Solid lipid nanoparticles bearing
oxybenzone: In‑vitro and in‑vivo evaluation. J Microencapsul
;27:226‑33.
Unruh T, Bunjes H, Westsen K. Observation of size‑dependent melting
in lipid nanoparticles. J Phys Chem 1999;103:10373‑7.
ICH Q 1 A (R2). Stability Testing of New Drug Substances and
Products (CPMP/ICH/2736/99); 2003.
Gonzalez‑Mira E, Egea MA, Garcia ML, Souto EB. Design and ocular
tolerance of flurbiprofen loaded ultrasound‑engineered NLC. Colloids
Surf B Biointerfaces 2010;81:412‑21.
Uner M, Yener G. Importance of solid lipid nanoparticles (SLN) in various
administration routes and future perspectives. Int J Nanomedicine
;2:289‑300.
Woitiski CB, Veiga F, Ribeiro A, Neufeld R. Design for optimization of
nanoparticles integrating biomaterials for orally dosed insulin. Eur J
Pharm Biopharm 2009;73:25‑33.
Gannu R, Yamsani VV, Yamsani SK, Palem CR, Yamsani MR. Optimization
of hydrogels for transdermal delivery of lisinopril by Box‑Behnken
statistical design. AAPS Pharm Sci Tech 2009;10:505‑14.
Jia LJ, Zhang DR, Li ZY, Feng FF, Wang YC, Dai WT, et al. Preparation
and characterization of silybin‑loaded nanostructured lipid carriers.
Drug Deliv 2010;17:11‑8.
Finney J. The structural basis of the hydrohobic interaction.
In: Bellissent‑Funel MC, editor. Hydration Processes in Biology:
Theoretical and Experimental Approaches. France: IOS Press; 1998.
p. 115‑26.
Han F, Sanming L, Yin R, Liu H, Xu L. Effect of surfactants on the
formation and characterization of a new type of colloidal drug delivery
system: Nanostructured lipid carriers. Colloids Surf A Physicochem Eng
Asp 2008;315:210‑6.
Unruh T, Bunjes H, Westesen K, Koch MH, Investigations on the
melting behaviour of triglyceride nanoparticles. Colloid Polym Sci
;279:398‑403.
Nekkanti V, Pillai R, Venkateshwarlu V, Harisudhan T. Development and
characterization of solid oral dosage form incorporating candesartan
nanoparticles. Pharm Dev Technol 2009;14:290‑8.
Chakraborty S, Shukla D, Mishra B, Singh S. Lipid – An emerging
platform for oral delivery of drugs with poor bioavailability. Eur J Pharm
Biopharm 2009;73:1‑15.
Beloqui A, SolinÃs MÃ, Delgado A, Evora C, Isla A, RodrÃguez‑Gascón A.
Fate of nanostructured lipid carriers (NLCs) following the oral route:
Design, pharmacokinetics and biodistribution. J Microencapsul
;31:1‑8.
Joshi M, Patravale V. Nanostructured lipid carrier (NLC) based gel of
celecoxib. Int J Pharm 2008;346:124‑32.