Application of chitosan in controlled transdermal drug delivery | |
| Author | Wah Wah Thein-Han |
| Call Number | AIT Diss. no.BP-03-05 |
| Subject(s) | Chitosan Drug delivery systems Veterinary drugs--Dosage forms |
| Note | A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Technical Science, School of Environment, Resources and Development |
| Publisher | Asian Institute of Technology |
| Series Statement | Dissertation ; no. BP-03-05 |
| Abstract | The natural cationic biopolymer chitosan has many applications in the medical and pharmaceutical sector. This research study is focused on the development and analysis of chitosan based membrane systems in vitro used for transdermal controlled delivery systems in viva. Chitosan is used for its biocompatibility, controlled release properties and the permeability of the chitosan membrane and hydro gel. First, the physio-chemical and functional properties of shrimp chitosan and its membranes were investigated for chitosan with various degree of deacetylation (%DD) with the same molecular weight. The chitosan with higher %DD showed a better absorption of fat and negatively charged dye. Swelling index and permeability of chitosan membranes with lower % DD were higher than that of higher % DD. Tensile strength and crystallinity were higher for higher % DD chitosan membrane. A chitosan transdermal system for controlled released application for the model drug lidocaine was designed, in which chitosan matrix was applied twice: chitosan as a membrane that controls only the rate of permeation of the drug. and chitosan as a hydrogel loaded with drug, acting as a reservoir from which the dmg can diffuse basically unhindered. Water-soluble lidocaine HCl, local anesthetic was chosen as a model drug to compare in vitro release through chitosan membranes with transsternal lidocaine delivery from a lidocaine chitosan system with skin uptake in human volunteer by non-invasive technique. Chitosan membranes to be used as rate-controlling membranes were prepared and characterized for their permeability for lidocaine. Chitosan membranes with 70%. 88% and 95 % with the same molecular weight were prepared by the cast-drying method. Membrane with a thickness was 10, 20 or 40 um. Permeation study was carried out in Franz diffusion cell. A lower but more prolonged release of lidocaine was observed in the case of membranes with higher % DD and thickness. Release rate constant and permeation coefficient of 20 um thick 95 % DD membrane were 0.16 and 6.5 * 10'3 cmzi’h respectively. When 70 % DD membrane of the same thickness was analyzed, the release rate constant and permeation coefficient increased to 0.36 and 24.4 respectively. The diffusion of chitosan membrane was found to be non-Fickian. These data showed that release in vitro can be controlled using chitosan membranes with varying DD and thickness of membrane. Chitosan membranes do not need to be additionally crosslinked or modified using chemical treatments. The swelling index of 70 “/0, 88 % and 95 % DD membranes was 315 %, 116 % and 105 % respectively. Chitosan membranes with lower % DD had a smoother surface than the higher % DD membranes under the scanning electron microscope. Moisture absorption of chitosan membranes was found to be dependent on relative humidity (RH). At 84 % RH. 70 % DD chitosan had 70% moisture uptake compared to 44 % and 41 % for 88 % DD and 95 % DD membrane respectively. In order to develop a drug reservoir for a lidocaine transdermal system, the drug was loaded in various chitosan hydrogels. A very clear chitosan hydrogel was obtained with 70 % DD chitosan with the amount of drug loading needed for anesthetic effect. Drug loaded chitosan hydrogel 'r'O % DD showed no drug-polymer interaction and the drug was iiiin well-dissolved state in the chitosan hydrogel. Drug loaded chitosan hydrogel with 88 % and 9S % DD were not transparent if the amount of drug was more than 5 mg/cmz. Membrane systems for controlled transdermal delivery were developed with various combinations of chitosan hydrogels and chitosan membranes. Agarose hydrogel and cellulose membrane were used as control. Drug release profile and fluxes from the 70 % and 95 ”/0 DD chitosan hydrogels reservoir were found not to be dependent on the % DD of chitosan reservoir. By application various %_ DD rate-controlling chitosan membranes it was found that drug flux decreased with increasing % DD and thickness, but flux was found to be dependent on the amount of drug in drug reservoir. Fluxes from the system containing 5 mg and 20mg drug for l-cm2 of hydrogel with same rate-controlling membrane were 23.6 and 79 mg/cmzlh respectively. From this, it can be concluded that drug release can be modified by using drug content in reservoir, % DD and thickness of rate-controlling membrane and using chitosan membrane instead of cellulose, but not by the % DD of drug reservoir. Moreover, new technology for the development of membrane systems for controlled delivery was investigated using the sealing of two chitosan membranes. Chitosan membranes were sealed at their circumference to form a sac as for dmg reservoir. This system is called chitosan bag. A homogeneous sealing technique is applied using chitosan solution as adhesive. Homogenous sealing can also be achieved by pressing chitosan membranes with an appropriate degree of casting and moisture content together. Well- sealed transparent smooth chitosan bags were obtained. Among those methods, sealing by controlling the moisture content of the chitosan membranes was found most suitable. This system is promising for development of both transdermal and implant delivery systems. A transdermal lidocaine system with chitosan hydrogel 70 % DD (20mg cmz) as a reservoir and 20 um thick chitosan membranes with different % DD as a rate-controlling membrane was analyzed in warm and in vivo. In vi‘rro data were fitted to power law and Hi guchi's equation and in this case chitosan transdermal delivery system fitted better the power law equation. The order of release constant observed was drug reservoir > with 70 % DD > 88 °/o DD> 95 “/0 DD chitosan rate-controlling membrane. It was shown that the initial charge density of the chitosan, attributed by different %DD.plays a significant role in the ability of the chitosan membrane to control drug release. Diffusion from chitosan membrane controlled system was found to be partially a non-Fickian diffusion process. Finally, the anesthetic effect of the lidocaine-chitosan system on human skin was assessed by recording warm, cool and sharp pain sensations, verbally expressed by human volunteers. The anesthetic effect was achieved faster by applying 20mg km2 of drug in reservoir compared to of 5 mg lcmz, using a 250 um thick hydrogel reservoir instead of 500 um and placing a hydrated layer on the t0p of the ding reservoir. The most suitable systems were using either 70 or 95% DD chitosan containing 20mg lidocaine HCLi’cm2 and a 20 pm thick rate controlling membrane. Moisture content of both chitosan hydrogel and membrane should be around 7'0 % to get good adhesiveness and good skin uptake. The anesthetic effect was dependent on the type of rate controlling membrane. The order of anesthetic observed was drug reservoir (no rate controlling membrane)> rate controlling membrane 7'0 “/0 DD % > rate-controlling membrane 95% DD. The kinetics of in w'rro release and skin permeation shown by verbal response in volunteers from the system with 95 % DD membrane were related linearly up to 6 h. It was found that the change in verbal response correlated with the in who lidocaine HCI release profiles. ivAdverse skin reactions ofthe volunteers due to the chitosan membrane or the drug did not occur. It is concluded that chitosan is an attractive material for application of controlled drug release system. The finding confirms that the assessment of drug release in vz‘zro has a predictive value for the anesthetic effect of a chitosan based lidocaine skin system. The knowledge on the use of chitosan to control drug release in transdennal delivery systems might be applicable to other transdermal drug delivery systems as well. It should be noted that the present system using lidocaine HCI as a model drug offers a unique opportunity to correlate in vitro and in viva behavior of a transversally acting drug since only a small number of drugs can be applied through the skin. Of these drugs, only a very limited number exert its effect topically and can be assessed in volunteers by a verbal response and/or by a non-invasive technique. |
| Year | 2003 |
| Corresponding Series Added Entry | Asian Institute of Technology. Dissertation ; no. BP-03-05 |
| Type | Dissertation |
| School | School of Environment, Resources, and Development (SERD) |
| Department | Department of Food, Agriculture and Natural Resources (Former title: Department of Food Agriculture, and BioResources (DFAB)) |
| Academic Program/FoS | Bioprocess Technology (BP) |
| Chairperson(s) | Stevens, Willem F.; |
| Examination Committee(s) | Suwalee Chandrkrachang;Athapol Noornhorm;Preeda Parkpian;Korbtham Sathirakul; |
| Scholarship Donor(s) | Minami, Saburo; |
| Degree | Thesis (Ph.D.) - Asian Institute of Technology, 2003 |