Research paperA new drug nanocarrier consisting of chitosan and hydoxypropylcyclodextrin
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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