Formulation and ex vivo Evaluation of Solid Lipid Nanoparticles (SLNS) Based Hydrogel for Intranasal Drug Delivery

Risperidone (RISP) is an antipsychotic agent and has
low water solubility and nontargeted delivery results in numerous
side effects. Hence, an attempt was made to develop SLNs hydrogel
for intranasal delivery of RISP to achieve maximum bioavailability
and reduction of side effects. RISP loaded SLNs composed of 1.65%
(w/v) lipid mass were produced by high shear homogenization (HSH)
coupled ultrasound (US) method using glycerylmonostearate (GMS)
or Imwitor 900K (solid lipid). The particles were loaded with 0.2%
(w/v) of the RISP & surface-tailored with a 2.02% (w/v) non-ionic
surfactant Tween® 80. Optimization was done using 32 factorial
design using Design Expert® software. The prepared SLNs
dispersion incorporated into Polycarbophil AA1 hydrogel (0.5%
w/v). The final gel formulation was evaluated for entrapment
efficiency, particle size, rheological properties, X ray diffraction, in
vitro diffusion, ex vivo permeation using sheep nasal mucosa and
histopathological studies for nasocilliary toxicity. The entrapment
efficiency of optimized SLNs was found to be 76 ± 2%,
polydispersity index <0.3., particle size 278 ± 5 nm. This optimized
batch was incorporated into hydrogel. The pH was found to be 6.4 ±
0.14. The rheological behaviour of hydrogel formulation revealed no
thixotropic behaviour. In histopathology study, there was no
nasocilliary toxicity observed in nasal mucosa after ex vivo
permeation. X-ray diffraction data shows drug was in amorphous
form. Ex vivo permeation study shows controlled release profile of
drug.

• Pramod Jagtap
• Kisan Jadhav
• Neha Dand

• Ex vivo
• particle size
• risperidone
• solid lipid nanoparticles.

[1] W. M. Pardridge, “Brain drug targeting, the future of brain drug
development”, Cambridge University Press, Cambridge, 2001.
[2] A. Tsuji, “Specific mechanisms for transporting drugs into brain”. In:
Begley DJ, Bradbury MW, Kreuter J, editors. The Blood-Brain Barrier
and Drug Delivery to the CNS. Marcel Dekker. New York: 2000. pp.
121-144.
[3] S. Talegaonkar, P. R. Mishra, “Intranasal delivery: An approach to
bypass blood brain barrier”, Indian J Pharmacol, vol 36(3), pp. 140-147,
2004.
[4] L. Astic, D. Saucier, P.Coulon, “The CVS strain of rabies virus as
transneuronal tracer in the olfactory system of mice”, Brain Res., vol
619(1-2), pp. 146-156, 1993.
[5] V. Soni, M. K. Chaurasia, Y. Gupta, et al, “Novel approaches for drug
delivery to the brain”, Ind J Pharm Sci, vol 66(6), pp. 711-720, 2004.
[6] Gabathuler, “Approaches to transport therapeutic drugs across the bloodbrain
barrier to treat brain diseases”, Neurobiol Dis, vol 37, pp. 48-57,
2010.
[7] L. Illum, “Bioadhesive formulations for nasal peptide delivery:
fundamentals, novel approaches and development”, In: Mathiowitz E,
Chickering DE, Lehr CM editor. Marcel Dekker. New York: 1999. pp.
507-539.
[8] J. Aurora, “Development of nasal delivery systems: a review”, Drug
DelivTechnol, vol 2(7), pp.1-8, 2002.
[9] G. L. Amidon, H. Lennernas, V. P. Shah, et al, “A theoretical basis for a
biopharmaceutic drug classification: the correlation of in vitro drug
product dissolution and in vivo bioavailability”, Pharm Res, vol 12(3),
pp. 413-420, 1995.
[10] H. Van de Waterbeemd, “The fundamental variables of the
biopharmaceutics classification system (BCS): a commentary”, Eur J
Pharm Sci, vol 7(1), pp.1-3, 1998.
[11] J. B. Dressman, C. Reppas, “In vitro-in vivo correlations for lipophilic,
poorly water soluble drugs”, Eur J Pharm Sci, vol 11(2), pp. 73-80,
2000.
[12] G. Barratt, “Colloidal drug carriers: achievements and perspectives”,
Cell Mol Life Sci, vol 60(1), pp. 21-37, 2003.
[13] R. H. Muller, S. Heinemann, “Fat emulsions for parenteral nutrition. I.
evaluation of microscopic and laser light scattering methods for the
determination of the physical stability”, Clin Nutr, vol 11, pp. 223-236,
1992.
[14] C. Vitorino, F. A. Carvalho, A. J. Almeida et al, “The size of solid lipid
nanoparticles: An interpretation from experimental design”, Colloids
Surf B Biointerf, vol 84, pp. 117-130, 2011.
[15] J. S. Lucks, R. H. Müller, “Medication vehicles made of solid lipid
particles (solid lipid nanospheres (SLN)”, EP0000605497, 1996.
[16] P. Ekambaram, A. Abdul HasanSathali, K. Priyanka, “Solid lipid
nanoparticles: A review”, Sci Revs Chem Commun, vol 2(1), pp. 80-
102, 2012.
[17] S. Mukherjee, S. Ray, R. Thakur, “Solid lipid nanoparticles: A modern
formulation approach in drug delivery system”, Indian J Pharm Sci, vol
71(4), pp. 349-358, 2009.
[18] M. Uner, G. Yener, “Importance of solid lipid nanoparticles (SLN) in
various administration routes and future perspectives”, Int J
Nanomedicine, vol 2(3), pp. 289-300, 2007.
[19] C. R. Behl, H. K. Pimplaskar, A. P. Sileno et al, “Effects of
physicochemical properties and other factors on systemic nasal
delivery”, Adv Drug Del Rev, vol 29, pp. 89-116, 1998.
[20] L. Li, I. Nandi, K. H. Kim, “Development of an ethyl laurate based
microemulsion for rapid-onset intranasal delivery of diazepam”, Int J
Pharm, vol, 237, pp. 77-85, 2002.
[21] L. G. Candace, G. M. Pollock, “Nasal drug administration: potential for
targeted central nervous system delivery”, J Pharm Sci, vol 94, pp. 187-
195, 2005.
[22] Y. Lu, X. Tang, Y. Cui et al, “In vivo evaluation of risperidone SAIB in
situ system as a sustained release delivery system in rats”, Eur J Pharm
Biopharm, vol 68, pp. 422-429, 2008.
[23] A. C. Silva, M. H. Amaral, E. González-Mira et al, “Solid lipid
nanoparticles (SLN) - based hydrogels as potential carriers for oral
transmucosal delivery of risperidone: Preparation and characterization
studies” Colloids Surf B Biointerf, vol 93, pp. 241-248, 2012.
[24] U. Bertram, R. Bodmeier, “In situ gelling, bioadhesive nasal inserts for
extended drug delivery: In vitro characterization of a new nasal dosage
form”, Eur J Pharm Sci, vol 27, pp. 62-71, 2006.
[25] S. Singh, M. Kumar, T. Singh et al, “Hydrogels used as a potential drug
delivery system: A review”, International Journal of Pharmaceutical &
Biological Archives, vol 2(4), pp. 1068-1076, 2011.
[26] K. Vermani, S. Garg, L. J. Zaneveld, “Assemblies for in vitro
measurement of bioadhesive strength and retention characteristics in
simulated vaginal environment”, Drug DevInd Pharm, vol 28(9), pp.
1133-1146, 2002.
[27] M. Kumar, K. Pathak, “Formulation and characterization of
nanoemulsion-based drug delivery system of risperidone”, Drug DevInd
Pharm, vol 35, pp. 387-395, 2009.
[28] P. V. Pople, K. K. Singh, “Development and evaluation of colloidal
modified nanolipid carrier: application to topical delivery of tacrolimus”
Eur J Pharm Biopharm, vol 79(1), pp. 82-94, 2011.
[29] A. C. Silva, E. González-Mira, M. L. García et al, “Preparation,
characterization and biocompatibility studies on risperidone-loaded solid
lipid nanoparticles (SLN): High pressure homogenization versus
ultrasound”, Colloids Surf B Biointerf, vol 86, pp. 158-165, 2011.
[30] E. Gonzalez-Mira, M. A. Egea, M. L. Garcia et al, “Design and ocular
tolerance of flurbiprofen loaded ultrasound-engineered NLC”, Colloids
Surf B Biointerf, vol 81, pp. 412-421, 2010.
[31] J. Y. Fang, C. L. Fang, C. H. Liu et al, “Lipid nanoparticles as vehicles
for topical psoralen delivery: solid lipid nanoparticles (SLN) versus
nanostructured lipid carriers (NLC)”, Eur J Pharm Biopharm, vol 70, pp.
633-640, 2008.
[32] O. V. Olesen, K. Linnet, “Simplified high-performance liquid
chromatographic method for determination of risperidone and 9-
hydroxyrisperidone in serum from patients co-medicated with other
psychotropic drugs”, J Chromatography, vol 698, pp. 209-216, 1997.
[33] A. A. Date, N. Vador, A. Jagtap et al, “Lipid nanocarriers (GeluPearl)
containing amphiphilic lipid Gelucire 50/13 as a novel stabilizer:
fabrication, characterization and evaluation for oral drug delivery”,
Nanotechnology, vol; 22, pp. 1-12, 2011.
[34] Z. Rahman, A. S. Zidan, M. A. Khan, “Non-destructive methods of
characterization of risperidone solid lipid nanoparticles”, Eur J Pharm
Biopharm, vol 76, pp. 127-137, 2010.
[35] M. Kumar, A. Misra, K. Pathak, “Formulation and characterization of
nanoemulsion of olanzapine for intranasal delivery”, PDA J Pharm Sci
and Tech, vol 63, pp. 501-511, 2009.
[36] L. I. Giannola, V. D. Caro, G. Giandalia et al, “Release of naltrexone on
buccal mucosa: permeation studies, histological aspects and matrix
system design” Eur J Pharm Biopharm, vol 67, pp. 425-433, 2007.
[37] G. Samson, A. G. Calera, S. D. Girod et al, “Ex vivo study of
bevacizumab transport through porcine nasal mucosa”, Eur J Pharm
Biopharm, vol 80, pp. 465-469, 2012.
[38] V. Jenning, S. Gohla, “Comparison of wax and glyceride solid lipid
nanoparticles (SLN®)”, Int J Pharm, vol 196(2), pp. 219-22, 2000.
[39] B. D. Kim, H. K. Choi, “Preparation and characterization of solid lipid
nanoparticles (SLN) made of cacao butter and curdlan”, Eur J Pharm
Sci, vol 24(2-3), pp. 199-205, 2005.
[40] E. B. Souto, S. A. Wissing, C. M. Barbosa et al, “Evaluation of the
physical stability of SLN and NLC beforeand after incorporation into
hydrogel formulations”, Eur J Pharm Biopharm, vol 58, pp. 83-90, 2004.