Research paper
A new drug nanocarrier consisting of chitosan and hydoxypropylcyclodextrin

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Abstract

The objective of the present work was to develop a new drug nanocarrier consisting of nanoparticles made of chitosan and cyclodextrins. The rationale behind the design of this new nanosystem was to simultaneously implement the cyclodextrin drug complexation power and the inherent properties of chitosan nanoparticles, in a unique delivery system. The complexation with the cyclodextrin permits the solubilization as well as the protection for sensitive drugs, whereas the entrapment in the chitosan network is expected to facilitate their absorption. Chitosan nanoparticles including hydroxypropylcyclodextrins could be prepared by the ionic crosslinking of chitosan with sodium tripolyphosphate in the presence of cyclodextrins. Two hydrophobic drugs, triclosan and furosemide, were selected as models for complexation with the cyclodextrin and further entrapment in the chitosan nanocarrier. The resulting nanosystems were thoroughly characterized for their size and zeta potential and also for their ability to associate and deliver the complexed drugs. The results showed that the size of the nanoparticles was slightly affected by the incorporation of cyclodextrins, whereas the ζ potential did not suffer a significant modification. Moreover, the complexation of the drugs with the cyclodextrin facilitated their entrapment into the nanoparticles, increasing up to 4 and 10 times (for triclosan and furosemide, respectively) the final drug loading of the nanoparticles. These results led to the conclusion that the drug–cyclodextrin complex was efficiently retained in the nanoparticulate structure. Finally, the in vitro release profile observed for these nanoparticles was characterized by an initial fast release followed by a delayed release phase. In conclusion, this new nanosystem offers an interesting potential for the transmucosal delivery of hydrophobic compounds.

Introduction

Together with a good toxicity profile, adequate biopharmaceutical/pharmacokinetic characteristics are essential for the clinical success of drug candidates [1]. Currently, a high percentage of drugs with good efficacy/toxicity ratio fail to go through the drug discovery pipeline due to their low intestinal absorption [2]. The two main causes of low oral bioavailability of drugs are poor solubility [3] and low permeability through biological membranes [4]. The Biopharmaceutics Classification System gives specific guidelines to classify drugs by their solubility and permeability characteristics into: class 1 (high solubility, high permeability), class 2 (low solubility, high permeability), class 3 (high solubility, low permeability) and class 4 (low solubility, low permeability) [5]. Drug classes 2–4 are expected to have their bioavailability constrained by their physicochemical characteristics [6]. Two main alternatives have been chosen in order to solve the problem related to the increasing number of drug candidates with low bioavailability: (i) dropping drug candidates with poor biopharmaceutical characteristics early on the drug development process and (ii) designing new delivery systems capable of overcoming the bioavailability problems of drugs. Although the first approach has often been the first option for many pharmaceutical companies, the second one is gaining increasing attention due to the difficulties encountered over the last years in the area of drug discovery.

Among the drug delivery strategies intended to increase the bioavailability of drugs, the use of polymeric nanocarriers has shown a significant degree of success. More concretely, in our laboratory, we have developed nanocarriers made of the polysaccharide chitosan (CS) which have shown a great capacity to increase the systemic absorption of peptides [7], [8], [9], [10]. The experiments aimed at investigating the mechanism of action of these nanocarriers have suggested that the mucoadhesive properties of CS play a significant role in this positive behaviour [11]. Although mucoadhesion is a property inherent to CS, its presentation in a nanoparticulate form makes feasible the oral administration avoiding the uncontrolled precipitation of CS in the intestinal medium. In addition, it has been suggested that CS nanoparticles interact with the mucus layer providing the delivery of the associated drug to the underlying epithelium.

On the other hand, cyclodextrins are well-known cyclic oligosaccharides with a lipophilic central cavity and a hydrophilic outer surface, able to form inclusion complexes with hydrophobic molecules. Cyclodextrin complexation has been thoroughly investigated for bettering the unfavourable biopharmaceutical properties of drugs, such as poor solubility and/or stability [12], [13]. In practice, cyclodextrin derivatives such as hydroxypropylcyclodextrin (HPCD) are preferred to natural cyclodextrins for drug formulation because they have higher water-solubility and a better biocompatibility profile.

Based on this previous information, our purpose in the present work was to develop a new nanoparticulate drug carrier that combines the benefits of CS nanoparticles and cyclodextrins with regard to their potential for enhancing the bioavailability of drugs. In our understanding, such a system would be of special interest for the formulation of class 2 and 4 drugs (low solubility and low permeability). With this objective in mind, we chose two model drugs, triclosan and furosemide, and evaluated the feasibility of their incorporation and delivery from the new nanosystem.

Section snippets

Materials

Triclosan (TRI), 5-chloro-2(2,4-dichlorophenoxy)phenol, was kindly donated by Carlo Erba, Italy; Furosemide (FUR) was from Sigma (Spain); Chitosanase-RD (from Bacillus sp.) was from Pias Co. (Japan); hydroxypropyl-α (HPαCD), hydroxypropyl-β (HPβCD) cyclodextrins with an average molar substitution degree (MS, i.e., the mole number of substituents per mole of glucose in the CD) of 0.6 were a gift of Wacker-Chemie GmbH (München, Germany). Tripolyphosphate (TPP) was from Sigma (Spain). Chitosan

Preparation of blank cyclodextrin-containing CS nanoparticles

Preliminary studies were intended to determine the range of conditions suitable for the formation of NPs in the presence of cyclodextrins. As a first step, we studied the possibility to form NPs with different TPP/CS ratios, in the presence of HPCD. More specifically, the volume of the TPP solution (2 mg/ml) added to the 0.2% w/v CS solution was changed in order to obtain TPP/CS w/w ratios from 1:3 to 1:6 (the ratios typically used for the formation of CS NPs in the absence of cyclodextrin). In

Discussion

The recent methods used in the drug discovery process have led to an increasing number of drug candidates which display poor solubility and, frequently, poor permeability characteristics [4]. These inadequate biopharmaceutical properties have often been the reason for failure of many drug candidates [2]. In this work, our aim was to design a new delivery approach that could, in principle, combine the advantage of CS NPs, in terms of increasing the drug permeability through epithelia, with the

Conclusions

This paper reports, for the first time, the possibility to entrap cyclodextrins within CS nanoparticles using a very simple ionic gelation technique. This new approach permits to enhance the entrapment of hydrophobic drugs by forming molecular inclusion complexes with cyclodextrins in aqueous media. Such a device could be of interest for increasing the absorption of poorly soluble and poorly permeable drugs and also for conferring a protection to some specific drug molecules through the

Acknowledgment

This work was supported by the Spanish Government (CICYT: SAF2003-08765-C03-03).

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