Nik Amanina Farhanah Abu Hassan, Shariza Sahudin, Zahid Hussain, Mumtaz Hussain, Mumtaz Hussain


Objective: Chitosan (CS)–tripolyphosphate (TPP)–nanoparticles (NPs) have been extensively studied during the past few decades due to their well-recognized applicability in various fields. The present study attempts to optimise the development of these nanoparticles to enhance the percutaneous delivery of caffeine.

Methods: CS-TPP-NPs were prepared via ionic cross-linking of CS and TPP and were characterized. The influence of several formulation conditions (CS: TPP mass ratio and concentration of caffeine) and process parameters (stirring speed, stirring time and ultra-sonication time) on the colloidal characteristics of CS-TPP-NPs were investigated and the resulting nanoparticles were characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) and x-ray diffraction (XRD) analyses. Physicochemical properties, including particle size, zeta potential and polydispersity index (PDI) were examined, and in vitro release studies were conducted to ascertain the release profile of caffeine from the nanoparticles. In addition, the colloidal stability of the prepared NPs was also assessed on storage.

Results: Process parameters appeared to exert a significant effect on the physicochemical characteristics of the CS-TPP-NPs. The CS-TPP-NPs prepared under optimum conditions (CS concentration of 0.2 mg/ml, CS: TPP volume ratio of 25:12 ml, stirred at 700 rpm for 60 min, with 0.97 mg/ml caffeine concentration and treatment with low ultra-sonication for 30 min) had shown a mean particle size of ~143.43±1.69 nm, zeta potential of+43.13±1.10 mV, PDI of ~0.30±0.01. A drug loading capacity and encapsulation efficiency of 48.89% and 60.69%, respectively, were obtained. Cumulative release study for drug-loaded CS-NPs was significantly (p<0.001, paired t-test) higher (58.7% caffeine released) compared to control formulation (41.5% caffeine released) after 72 h. Stability studies conducted for 28 d showed that caffeine-loaded CS-NPs degraded much quicker when stored at 25 ⁰C than 4 ⁰C. It was also noted that caffeine-loaded CS-NPs in the freeze-dried form were unstable as the surface charge of nanoparticles dropped from positive zeta potential to-3.55 mV within 2 d at 4 ⁰C and at 25 ⁰C, surface charge dropped to-3.16 mV within 14 d of the experiment.

Conclusion: Chitosan (CS)–tripolyphosphate (TPP)–nanoparticles (NPs) appear to be a promising strategy to achieve sustained percutaneous delivery of caffeine.


Chitosan nanoparticles, Drug delivery, Caffeine, Ionic gelation

| PDF | HTML |


Randall VA, Thornton MJ, Hamada K, Redfern CP, Nutbrown M, Ebling FJ, et al. Androgens and the hair follicle: cultured human dermal papilla cells as a model system. Ann N Y Acad Sci 1991;642:355-75.

Omkar Hemant Lele, Jinesh Anant Maniar, Rohit Lalit Chakravorty, Shashikant Prabhakar Vaidya, Abhay Shadashiv Chowdhary. Assessment of biological activities of caffeine. Int J Curr Microbiol Appl Sci 2016;5:45-53.

Kim C, Shim J, Han S, Chang I. The skin permeation-enhancing effect of phosphatidylcholine: caffeine as a model active ingredient. J Cosmet Sci 2002;53:363–74.

Trauer S, Patzelt A, Otberg N, Knorr F, Rozycki C, Balizs G, et al. Permeation of topically applied caffeine through the human skin–a comparison of in vivo and in vitro data. Br J Clin Pharmacol 2009;68:181–6.

Nehlig A, Daval JL, Debry G. Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev 1992;17:139–70.

Fabricant DS, Farnsworth NR. The value of plants used in traditional medicine for drug discovery. Environ Health 2001;109 Suppl 1:69.

Dodd SL, Herb RA, Powers SK. Caffeine and exercise performance. Sports Med 1993;15:14–23.

Panchal SK, Poudyal H, Waanders J, Brown L. Coffee extract attenuates changes in cardiovascular and hepatic structure and function without decreasing obesity in high-carbohydrate, high-fat diet-fed male rats. J Nutr 2012;142:690–7.

Vogelgesang B, Bonnet I, Godard N, Sohm B, Perrier E. In vitro and in vivo efficacy of sulfo-carrabiose, a sugar-based cosmetic ingredient with anti-cellulite properties. Int J Cosmet Sci 2011;33:120–5.

Koo SW, Hirakawa S, Fujii S, Kawasumi M, Nghiem P. Protection from photodamage by topical application of caffeine after ultraviolet irradiation. Br J Dermatol 2007;156:957–64.

Kawasumi M, Lemos B, Bradner JE, Thibodeau R, Kim Y, Schmidt M, et al. Protection from UV-induced skin carcinogenesis by genetic inhibition of the ataxia telangiectasia and Rad3-related (ATR) kinase. Proc Nat Acad Sci USA 2011. Doi:10.1073/pnas.1111378108.

Fischer TW, Hipler UC, Elsner P. Effect of caffeine and testosterone on the proliferation of human hair follicles in vitro. Int J Dermatol 2007;46:27–35.

Souto EB, Almeida AJ, Müller RH. Lipid nanoparticles (SLN®, NLC®) for cutaneous drug delivery: structure, protection and skin effects. J Biomed Nanotechnol 2007;3:317–31.

CL Fang, IA Aljuffali, YC Li, JY Fang. Delivery and targeting of nanoparticles into hair follicles. Ther Delivery 2014;5:991–1006.

GM Gelfuso, T Gratieri, PS Simao, LAP de Freitas, RFV Lopez. Chitosan microparticles for sustaining the topical delivery of minoxidil sulphate. J Microencapsul 2011;28:650–8.

Huabing Chen, Xuelin Chang, Danrong Du, Wei Liu, Jie Liu, Ting Weng, et al. Podophyllotoxin-loaded solid lipid nanoparticles for epidermal targeting. J Controlled Release 2006;110:296–306.

Smijs TGM, Bouwstra JA. Focus on the skin as a possible port of entry for solid nanoparticles and the toxicological impact. J Biomed Nanotechnol 2010;6:469–84.

K Ziani, I Fernandez Pan, M Royo, JI Mate. Antifungal activity of films and solutions based on chitosan against typical seed fungi. Food Hydrocolloids 2009;23:2309–14.

E Marin, MI Briceno, C Caballero George. Critical evaluation of biodegradable polymers used in nanodrugs. Int J Nanomed 2013;8:3071-91.

Alvarez Roman R, Barre G, Guy RH, Fessi H. Biodegradable polymer nanocapsules containing a sunscreen agent: preparation and photoprotection. Eur J Pharm Biopharm 2001;52:191–5.

P Manimekalai, R Dhanalakshmi, R Manavalan. Preparation and characterization of ceftriaxone sodium encapsulated chitosan nanoparticles. Int J Appl Pharm 2017;9:10–5.

Lademann J, Richter H, Teichmann A, Otberg N, Blume Peytavi U, Luengo J, et al. Nanoparticles–an efficient carrier for drug delivery into the hair follicles. Eur J Pharm Biopharm 2007;66:159–64.

Colonna C, Conti B, Perugini P, Pavanetto F, Modena T, Dorati R, et al. Ex vivo evaluation of prolidase loaded chitosan nanoparticles for the enzyme replacement therapy. Eur J Pharm Biopharm 2008;70:58–65.

Calvo P, Remunan Lopez C, Vila-Jato JL, Alonso MJ. Novel hydrophilic chitosan–polyethylene oxide nanoparticles as protein carriers. J Appl Polym Sci 1997;63:125–32.

Huang Y, Lapitsky Y. Monovalent salt enhances colloidal stability during the formation of chitosan/tripolyphosphate microgels. Langmuir 2011;27:10392–9.

Yang HC, Hon MH. The effect of the degree of deacetylation of chitosan nanoparticles and its characterization and encapsulation efficiency on drug delivery. Polym Plast Technol Eng 2010;49:1292–6.

Thandapani, Supriya Prasad, Sudha, Sukumaran. Size optimization and in vitro biocompatibility studies of chitosan nanoparticles. Int J Biol Macromol 2017;104:1794-806.

Hussain Z, Sahudin S. Preparation, characterization, and colloidal stability of chitosan-TPP nanoparticles: optimization of formulation and process parameters. Int J Pharm Pharm Sci 2016;8:297-308.

Nie KB, Wang XJ, Wu K, Xu L, Zheng MY, Hu XS, et al. Processing, microstructure and mechanical properties of magnesium matrix nanocomposites fabricated by semisolid stirring assisted ultrasonic vibration. J Alloys Compd 2011;509:8664–9.

M Jahanshahi, AW Pacek, AW Nienow, A Lyddiatt. Fabrication by three-phase emulsification of pellicular adsorbent customized for liquid fludized bed adsorption products. Chem Technol Biotechnol 2003;78:1111-20.

B Ruan, AM Jacobi. Ultrasonication effects on thermal and rheological properties of carbon nanotube suspensions. Nanoscale Res Lett 2012;7:127.

Matos B, Reis T, Gratieri, Gelfuso. Chitosan nanoparticles for targeting and sustaining minoxidil sulphate delivery to hair follicles. Int J Biol Macromol 2015;75:225–9.

Xu YM, Du YM. Effect of molecular structure of chitosan on protein delivery properties of chitosan nanoparticles. Int J Pharm 2003;250:215–26.

Wu W, Yang W, Wang CC, Hu JH, Fu SK. Chitosan nanoparticles as a novel delivery system for ammonium glycyrrhizinate. Int J Pharm 2005;295:235–45.

Y Zhang, RX Zhu. Synthesis and drug release behavior of poly(trimethylene carbonate)-poly(ethylene glycol)-poly (trimethylene carbonate) nanoparticles. Biomaterials 2005;26: 2089-94.

T Lopez Leon, ELS Carvalho, B Seijo, JL Ortega Vinuesa, D Bastos Gonzalez. Physicochemical characterization of chitosan nanoparticles: electrokinetic and stability behavior. J Colloid Interface Sci 2005;283:344–35.

Paul Baldrick. The safety of chitosan as a pharmaceutical excipient. J Regul Toxicol Pharmacol 2010;56:290-9.

Yangchao Luo, Boce Zhang, Monica Whent, Liangli (Lucy) Yu, Qin Wang. Preparation and characterization of zein/chitosan complex for encapsulation of α-tocopherol, and its in vitro controlled release study. Colloids Surf B 2011;85:145–52.

Yang Wei Wang, Chi Hsiung Jou, Chia Chun Hung, Ming Chien Yang. Cellular fusion and whitening effect of a chitosan derivative coated liposome. Colloids Surf B 2012;90:169–76.

Raditya Iswandana, Kurnia Sari Setio Putri, Randika Dwiputra, Tryas Yanuari, Santi Purna Sari, Joshita Djajadisastra. Formulation of chitosan tripolyphosphate-tetrandrine beads using ionic gelation method: in vitro and in vivo evaluation. Int J Appl Pharm 2017;9:109-15.

About this article




Chitosan nanoparticles, Drug delivery, Caffeine, Ionic gelation





Additional Links

Manuscript Submission


International Journal of Applied Pharmaceutics
Vol 10, Issue 4 (July-Aug), 2018 Page: 172-185

Online ISSN


Authors & Affiliations

Nik Amanina Farhanah Abu Hassan
Department of Pharmaceutics, Faculty of Pharmacy, Universiti Teknologi Mara, Puncak Alam Campus 42300 Selangor, Malaysia

Shariza Sahudin
Department of Pharmaceutics, Faculty of Pharmacy, Universiti Teknologi Mara, Puncak Alam Campus 42300 Selangor, Malaysia

Zahid Hussain
Department of Pharmaceutics, Faculty of Pharmacy, Universiti Teknologi Mara, Puncak Alam Campus 42300 Selangor, Malaysia

Mumtaz Hussain
Department of Pharmaceutics, Faculty of Pharmacy, Universiti Teknologi Mara, Puncak Alam Campus 42300 Selangor, Malaysia

Mumtaz Hussain
Department of Pharmaceutics, Faculty of Pharmacy, Universiti Teknologi Mara, Puncak Alam Campus 42300 Selangor, Malaysia


  • There are currently no refbacks.