Elsevier

Polymer

Volume 135, 17 January 2018, Pages 85-102
Polymer

Bio-derived cellulose nanofibril reinforced poly(N-isopropylacrylamide)-g-guar gum nanocomposite: An avant-garde biomaterial as a transdermal membrane

https://doi.org/10.1016/j.polymer.2017.12.015Get rights and content

Highlights

  • Synthesis of cellulose nanofibril from waste jute.

  • Synthesis of guar gum-g-poly(N-isopropylacrylamide) via free radical polymerization.

  • Nanocomposite membrane was formulated by using co-polymer and NCF.

  • Nanocomposite based membrane control and sustains drug release.

  • Nanocomposite membrane is nontoxic and nonirritant.

Abstract

The delivery of diltiazem hydrochloride in therapeutical doses has attracted an immense research interest. However, its slower penetration through the transdermal route has stipulated to develop a competent transdermal membrane. Therefore, a nanocomposite based patch was formulated by exploring co-polymer and jute derived nano-cellulose. Poly(N-isopropylacrylamide) was grafted into guar gum (GG-g-PNIPAAm) with different feeding ratios. The co-polymer formation was authenticated by FTIR and 13C NMR spectra. The nanocomposite were prepared by incorporating nanofibre (0.5–2 wt%) into GG-g-PNIPAAm. The structural and morphological studies supported good interactions and presence of nano-cellulose on co-polymer. GG-g-PNIPAAm has showed higher thermostability than guar gum. Moreover, the addition of CNF has improved the thermo-mechanical and barrier properties of the nanocomposite. The nanocomposite containing 1 wt% CNF was found to be best performing. The patch showed in-vitro cyto-compatibility and non-irritant behaviour. The in-vitro release study of best nanocomposite revealed controlled drug release capability with 7.78 and 22.9% after 5 and 20 h, respectively.

Introduction

Diltiazem hydrochloride (DH) is a very important drug which is used in the treatment of hypertension (HT). It belongs to benzothiazepines class and function as a calcium channel blocker [1]. The steep increasing risk of HT that leads to stroke, coronary artery disease, loss of vision, is needed to be addressed properly [2]. Another important aspect of drug delivery is to maintain the effective dose of drug (DH) for a prolonged period to manage this disease. Generally, DH is delivered intravenously or orally to those patients suffering from HT. However, DH possessess a short biological life time hence upon oral administration it requires frequent and multiple dosing to maintain its therapeutic index. Additionally on oral administration, DH undergoes hepatic pass metabolism and offers only 40% drug bioavailability. Further, these treatments are co-linked with harsh side effects, to cite dizziness, headache, heart problems and nausea [3]. Therefore to overcome these impediments, the administration of DH through transdermal route has found an ample of research attraction. Foremost, DH through transdermal route could evade the enzymatic degradation and hepatic pass metabolism as imposes by the oral route as drugs are directly released to the blood vessels. Therefore, though DH has a short half life time, but via transdermal route it could be released into the blood stream in therapeutical doses. Thus, in transdermal route the drug bioavailability is more in comparison to the oral route. Further, drugs are released in a controlled and sustained manner from patches for a prolonged period. However, it is likely to mention that the penetration of drug through skin is reported to be too slow in delivery DH. Therefore, the prerequisite is to develop a transdermal patch that could assist in the delivery of optimal dose of drug at an interval of require time period. To address the aforementioned issue, a novel cellulose nanofibril (CNF) incorporated guar gum-g-poly(N-isopropylacrylamide) (GG-g-PNIPAAm) nanocomposite was designed in this study as a biocompatible transdermal path for the delivery of DH.

Guar gum (GG) with excellent biocompatibility and biodegradability has triggered significant research interest, especially in transdermal drug delivery system (TDDS) [4]. However its high swelling feature, burst out effect on drug release accompanied with inadequate physico-mechanical strength to meet biological demands has limited its practical applicability in TDDS [5].

Therefore, poly(N-isopropyl acrylamide) (PNIPAAm) was grafted on GG to achieve better performance. PNIPAAm is a biocompatible polymer with thermoresponsive properties. Grafting of PNIPAAm may likely improve the drug-nanocomposite interaction as well as could aid in the slow release of drug molecules while shrinking near body temperature. Further, literature have revealed that the poly(N-isopropylacrylamide) grafts on polysaccharides have been already exploited to improve the drug release profile. Therefore, the thrust of this study is the addition of cellulose nanofibre (CNF) on the grafted co-polymer to enhance the performance and to examine the pronounced and remarkable effect of adding small amounts of CNF on drug release rate.

CNF a biopolymer with astonishing properties has attained mammoth interest in drug delivery system. It is a biocompatible, biodegradable, easily available and nontoxic vehicle for the release of active drug molecules [6]. Moreover CNF is also being explored in the realm of polymeric drug delivery system. The most specific feature of CNF is that its glucose unit has three hydroxyl groups, thereby bestowing it a reactive surface embedded with several active hydroxyl groups. The functional groups take vital part in nanocomposite formation, especially when it is utilized in conjugation with polymers and drugs. Polymer's properties show a rapid improvement by the incorporation of a minute amount of CNF. It is due to a high surface area that permits a better polymer-filler interaction [7]. Other desired properties of CNF exclusively that assist TDDS include excellent physico-mechanical, surface reactivity, barrier properties, and biocompatibility for good drug-matrix interaction, metabolic endurance and controlled drug release [7].

In term of biological properties, it could be asserted that CNF and guar gum being biopolymers would invoke an insignificant foreign body reaction within host. However, the synthetic procedure and precursor material play a pivotal role in attaining biocompatibility. The mild is the extraction process, better is the biocompatibility. It is also relevant to mention that CNF can be obtained from variety of sources which has a direct influence on its properties. The impetus of various research strategies is to fabricate promising biomaterials from natural resource.

In this context, jute was entwined as the starting material for the synthesis of CNF for its easy bioavailability and cost effectiveness. Furthermore, the performance of the nanocomposites by incorporating CNF in the synthesized co-polymer was investigated, in terms of mechanical strength, viscosity, thermostability, swelling and barrier property, biocompatibility and drug release profile. To examine the effect of CNF, the performance of the nanocomposites were compared with the co-polymer. Therefore it is speculated that the developed biocompatible formulation has the potency to be used as transdermal patch.

Section snippets

Material

Guar gum was purchased from Sisco Research Laboratories Pvt. Ltd., Maharashtra, India. Potassium persulphate (K2S2O8), caustic soda (97% pure), sulphuric acid (98%) and hydrogen peroxide (50%)standard laboratory grade, were purchased from Merck Specialties Pvt. Ltd., Worli, Mumbai, India. Hydroquinone and Sodium chlorite (80% pure) were purchased from Loba chem., Mumbai, India. Diltiazem hydrochloride of molecular weight 450.98 was a gift sample received from Ranbaxy Int., Gurgaon, Haryana,

Effect of monomer concentration

It was observed that up to the 7.5 × 10−2 mol dm−3 concentration of NIPAAm monomer (at a constant potassium persulfate concentration of 0.1 wt% with respect to NIPAAm weight) there was a linear increase in the %G of the product (Fig. 3). But a deviation was observed from linear increase (Fig. 3) as the concentration of the NIPAAm was further increased beyond 7.5 × 10−2 mol dm−3. It is quite obvious that with the increase in monomer concentration, simultaneously the viscosity of the reaction

Conclusion

In this study, CNF based nanocomposites were fabricated as transdermal drug delivery membrane for the controlled release of DH. CNF with length within 153–160 nm and diameter ranging between 11.88 and 30 nm as observed from FESEM images was isolated from jute fibres. The nanofibres in different wt% were incorporated into GG-g-PNIPAAm co-polymer membrane. CNF acted as a reinforcing agent and a steep improvement in the overall performance of the co-polymers was observed. The brittle nature of GG-g

Acknowledgements

Koushik Dutta like to thanks West Bengal DST and Aripita Adhikari like to thanks the TEQIP, India, for there fellowship. Beauty Das like to thanks UGC Kothari. Dipankar Mondal likes to thank UGC, Govt. of India for Rajiv Gandhi National Fellowship. Also, we like to thank the Centre for Research in Nanoscience and Nanotechnology, University of Calcutta for providing FESEM and TEM facilities.

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