Development and characterization of chitosan/hyaluronan film for transdermal delivery of thiocolchicoside
Introduction
Chitosan and hyaluronan are receiving a great deal of attention for biomedical applications due to their interesting chemical and biological properties. Chitosan, a natural derivative of chitin, is a polysaccharide consisting of copolymers of glucosamine and N-acetylglucosamine connected by β(1–4) glucosidic bonds. It is a weak base with an intrinsic pKa near 6.3 and a low charge density. Hyaluronan is also a naturally occurring linear polysaccharide with a high molecular weight consisting of copolymer of N-acetyl-d-glucosamine and d-glucuronic acid connected by alternating β(1–3) and β(1–4) glucosidic bonds. It is a weak polyacid with an intrinsic pKa near 2.9 and a very low charge density as only one charge can be present for every two residues (Luo & Wang, 2014). In pharmaceutical and medical field, chitosan and hyaluronan are widely used as a component in hydrogels, that are basically three-dimensional hydrophilic or amphiphilic polymer networks formed by chemical or physical crosslinking and capable of retaining large amounts of water or biological fluids yet remaining insoluble in physiological conditions. On the basis of the type of interactions (entanglement, physical and chemical interactions), chitosan and hyaluronan can produce networks with chemico-physical and functional properties different from those of the starting materials, and at the same time preserving interesting original properties, such as nontoxicity, biocompatibility, biodegradability and hydrophilicity (Berger et al., 2004a, Berger et al., 2004b, Muzzarelli, 2010, Muzzarelli et al., 2014, Muzzarelli et al., 2012). Moreover, hyaluronan is able to produce very strong polyelectrolyte complexes with chitosan both in its acidic or salt form (Denuziere et al., 1996, Lee et al., 2003, Luppi et al., 2009). Since chitosan/hyaluronan complexes are quite stable whatever the pH (Muzzarelli, Stanic, Gobbi, Tosi, & Muzzarelli, 2004) and not easily dissolved in organic or aqueous solvent, it is interesting to observe that they cannot be easily used. Nevertheless in the last decade, the research focused on the use of chitosan/hyaluronan based polyelectrolyte complexes as a biomaterial for drug delivery and tissue engineering applications. The delivery systems are mainly in the particulate forms, including microparticles and nanoparticle colloidal systems and in other forms such as composite films, membranes and scaffolds (Luo & Wang, 2014). In the present work, chitosan and hyaluronan are intended to be used for formulation of films able to guarantee systemic delivery of thiocolchicoside through the skin. Thiocolchicoside is a semi-synthetic sulfur derivative of colchicoside, acting as agonist of the GABA receptors in the central nervous system and showing muscle-relaxant, anti-inflammatory, and analgesic properties. It is traditionally administered orally (tablets or capsules), parenterally (i.m.) and topically (creams, ointments and foams). Even if the physicochemical properties of thiocolchicoside (relatively high MW, 563.3; low octanol/water partition coefficient, log P = −2.71) are not ideal for the permeation of the drug (Aguzzi et al., 2008), its transdermal administration has also been studied (Artusi et al., 2004, Artusi et al., 2003) with the aim to overcome disadvantages such as the low systemic availability (approximately 25%) associated to oral administration (Trellu et al., 2004). It is known that this approach offers the possibility to elude the first-pass metabolism and the gastrointestinal incompatibility, and at the same time the choice of an appropriate dosage form (e.g. polymeric film) is able to provide a predictable and extended duration of activity, eliminate multiple dosing schedules, reduce side effects due to the optimization of hematic profiles and improve patient compliance.
The objective of this study was the development of chitosan/hyaluronan transdermal films to improve bioavailability of thiocolchicoside. Initially polymeric films were prepared by polymer solution casting method and characterized in terms of physico-chemical properties, morphology and water uptake ability; then in vitro release and permeation studies were carried out to evaluate drug release from films and its permeation through skin.
Section snippets
Materials
Sodium hyaluronate (molecular weight 1650 kDa) was purchased from ACEF (Piacenza, Italy). Low-viscosity chitosan (molecular weight 150 kDa; deacetylation degree 97%) was purchased from Fluka (Buchs, Switzerland). Thiocolchicoside (molecular weight 563.60 g/mol) was a kind gift of Indena (Milan, Italy). Methanol and acetonitrile (both HPLC grade) were purchased from Carlo Erba (Milan, Italy). All other chemicals (99% formic acid, 85% orthophosphoric acid, glacial acetic acid, ethanol 96°, potassium
Results and discussion
In this study, we prepared polymeric thin films based on polyelectrolyte complexes by means of a very simple and easily reproducible preparative method and without the addition of crosslinkers. The only addition to the preparative mixture was formic acid that was chosen for its high solubilizing capacity toward chitosan/hyaluronan complexes and for its high volatility, useful in the film drying process (Vasconcelos, Freddi, & Cavaco-Paulo, 2008). Indeed chitosan/hyaluronan complexes were
Conclusions
Chitosan and hyaluronan are two natural polysaccharides able to produce in solution polyelectrolyte complexes without any chemical cross-linker and they have received significant interest especially for their pharmaceutical and biomedical applications including drug delivery. Ours results confirmed the importance of chitosan/hyaluronan polyelectrolyte complexes as new materials to develop flexible dosage forms able to allow minimal dosage and frequency, characterized by minimal impact on
Acknowledgements
The authors would like to thank Indena for thiocolchicoside, and Stefano Censori and Domenica Marchitelli for their contribution to this work.
References (26)
- et al.
Effect of chemical enhancers and iontophoresis on thiocolchicoside permeation across rabbit and human skin in vitro
Journal of Pharmaceutical Sciences
(2004) - et al.
Buccal delivery of thiocolchicoside: in vitro and in vivo permeation studies
International Journal of Pharmaceutics
(2003) - et al.
Structure and interactions in chitosan hydrogels formed by complexation or aggregation for biomedical applications
European Journal of Pharmaceutics and Biopharmaceutics
(2004) - et al.
Structure and interactions in covalently and ionically crosslinked chitosan hydrogels for biomedical applications
European Journal of Pharmaceutics and Biopharmaceutics
(2004) - et al.
Chitosan-chondroitin sulfate and chitosan-hyaluronate polyelectrolyte complexes. Physico-chemical aspects
Carbohydrate Polymers
(1996) - et al.
Recent development of chitosan-based polyelectrolyte complexes with natural polysaccharides for drug delivery
International Journal of Biological Macromolecules
(2014) - et al.
Spray-drying of solutions containing chitosan together with polyuronans, and characterization of the microspheres
Carbohydrate Polymers
(2004) - et al.
Chitosan, hyaluronan and chondroitin sulfate in tissue engineering for cartilage regeneration: a review
Carbohydrate Polymers
(2012) - et al.
Kinetic study of chondroitin sulphate release from chondroitin sulphate/chitosan complex hydrogel
Journal of Molecular Liquids
(2010) - et al.
Drug transport mechanisms and release kinetics from molecularly designed poly(acrylic acid-g-ethylene glycol) hydrogels
Biomaterials
(2006)
Hydration of polymeric components of cartilage – an infrared spectroscopic study on hyaluronic acid and chondroitin sulfate
International Journal of Biological Macromolecules
Penetration and distribution of thiocolchicoside through human skin: comparison between a commercial foam (Miotens®) and a drug solution
AAPS PharmSciTech
In vitro permeation screening of a new formulation of thiocolchicoside containing various enhancers
Drug Delivery
Cited by (54)
A polyethylene glycol-grafted pullulan polysaccharide adhesive improves drug loading capacity and release efficiency
2024, International Journal of Biological MacromoleculesRhamnose-PEG-induced supramolecular helices: Addressing challenges of drug solubility and release efficiency in transdermal patch
2024, Journal of Controlled ReleaseApplications of bioresins and biopolymers derived from natural resources as composites in drug delivery
2023, Green Sustainable Process for Chemical and Environmental Engineering and Science: Biomedical Applications of Green CompositesProgress in natural polymer engineered biomaterials for transdermal drug delivery systems
2021, Materials Today ChemistrySemi-interpenetrating chitosan/ionic liquid polymer networks as electro-responsive biomaterials for potential wound dressings and iontophoretic applications
2021, Materials Science and Engineering CCitation Excerpt :Moreover, it was observed that the thermal degradation temperature of s-IPNs (in terms of Tonset and Tmax) was lower (p-value <0.05) than that measured for deprotonated CS (Table 2). This result suggests that the presence of the copolymer structure between CS chains may somehow affect inter-chain interactions characteristic of pristine CS, and consequently decrease its thermal stability [100,101]. From the calorimetric profiles (Fig. S4, Supplementary data), it is possible to observe that only s-IPNs present glass transition temperatures (Tg) at 31.5 ± 0.6 °C for s-IPN/PIL and 43.9 ± 4.1 °C for s-IPN/COP samples, which were attributed to the poly(BVImCl) and poly(HEMA-co-BVImCl) networks, respectively.