Project Name: การประเมินการใช้ไคโตซานเป็นระบบนำส่งยาหยอดตาแวนโคไมซิน (Evaluation of the use of chitosan in ocular drug delivery for vancomycin)

Researcher: Phuriwat Leesawat

Organization:Pharmacy/Pharmaceutical Science

Time:1 October 2006 - 30 September 2007


  1. Phuriwat Leesawat (Head of project)


  1. BioMedical Engineering Center 100,000 Baht


Topical application of drugs to the eye is the most popular and well-accepted route of administration for the treatment of various eye disorders. The bioavailability for ophthalmic drug is, however, very poor due to efficient protective mechanisms of the eye. Blinking, baseline and reflex lachrymation, and drainage remove rapidly foreign substances, including drugs, from the surface of the eye. Moreover, the anatomy, physiology and barrier function of the cornea compromise the rapid absorption of drugs.(1) In addition, the relative impermeability of the cornea to both hydrophilic and hydrophobic molecules accounts for the poor ocular bioavailability and systemic adverse effects as well.
Ophthalmic drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientist. The anatomy, physiology, and biochemistry of the eye render this organ highly impervious to foreign substances. A significant challenge to the formulator is to circumvent the protective barriers of the eye without causing permanent tissue damage. The goal of pharmacotherapeutics is to treat a disease in a consistent and predictable fashion. Whenever an ophthalmic drug is applied topically to the eye, only a small amount (<5%) actually penetrates the cornea and reaches the internal anterior tissues of the eyes. The amount of the drug that ultimately penetrates the cornea is often determined during the first 4-6 min after topical dosing. Frequent instillation of eye drops are necessary to maintain a therapeutic drug level in the tear film or at the site of action. But the frequent use of highly concentrated solutions may induce toxic side effects and cellular damage at the ocular surface.  As a results, optimal absorption depends on achieving a satisfactory and rapid penetration rate across the cornea to minimize the competing, but non-absorptive factor.(2)
Basic research concerning the physiochemical properties of the tears and cornea and their potential impact on ocular drug delivery was performed (3-5), and this knowledge is still exploited now in the development of new ophthalmic delivery systems. The various approaches that have been attempted to increase the bioavailability and the duration of the therapeutic action of ocular drugs can be divided into two categories.(2)   The first  one is based on the use of sustained drug delivery systems, which provide the controlled and continuous delivery of ophthalmic drugs. The second involves maximizing corneal drug absorption and minimizing precorneal drug loss (viscosity and penetration enhancers, prodrugs, colloids). Cationic dispersions can provide simultaneously both advantages, by interacting with the negatively charged corneal surface components and the epithelium cellular membrane. In addition, their administration via conventional liquid dosage form is an attractive feature for patient acceptability and compliance.

 Fig 1.Chemical structure of chitosan
As Lehr et al. (6)suggested, cationic polymers were probably superior mucoadhesive due to an ability to develop molecular attraction forces by electrostatic interactions with the negative charges of the mucus, the polycationic chitosan (see fig 1) was investigated as an ophthalmic vehicle. The polymer is biodegradable, biocompatible and non toxic. It possesses antimicrobial and wound-healing properties. Moreover, chitosan exhibits a pseudoplastic and viscoelastic
behavior. (7,8) The mucoadhesive properties of chitosan are determined by the formation of either secondary chemical bonds such as hydrogen bonds or ionic interactions between the positive charged amino groups of chitosan and the negative charged sialic acid residued of mucins, depending on environmental pH. The mucoadhesive performance of chitosan is significantly highly at neutral or slightly alkaline pH as in the tear film.(6) The rationale for choosing chitosan as a
viscosifying agent in artificial tear formulations was based on its excellent tolerances after topical application, bioadhesive properties, hydrophilicity, and good spreading over the entire cornea. (9) The antibacterial activity of chitosan is an advantage, because in keratoconjuctivitis sicca, secondary infections due to the diminished tear secretion, which contains antibacterial lysozyme and lactoferrin, are frequently observed. In rabbits, a radiolabeled chitosan formulation remained  at the ocular surface as long as a 5 fold more viscous PVP solutions. (9) A 3-folds increase of the precorneal residence time of tobramycin was achieved when adding chitosan to the formulations, compared to the commercial solution of the drug. Only a minimum influence was observed from the concentration and molecular weight of chitosan employed, indicating a saturable bioadhesive mechanism based on ionic interactions of the cationic polymer with the negative charges of the ocular mucus.(7) Various chitosan derivatives were synthesized not only to improve the mucoadhesion, but also to enhance the penetration of drugs and peptides through the mucosa by opening the tight juctions between epithelial cells or by intracellular routes.(8) Felt et al. (7) reported that co-administration of ofloxacin and chitosan in eyedrops resulted in increased antibiotic bioavialbility and time of efficacy in tear fluid compared to commercial eye drops and this effect to the high viscosity of the chitosan solution. These results are of relevance to the treatment of external ocular infections. The purpose of the present study will be evaluation of chitosan in ocular drug delivery for vancomycin.
Fig 2. Chemical structure of vancomycin

Vancomycin, as shown in Figure 2, is an antibiotic produced by Streptococcus orientalis. Vancomycin is a glycopeptides of molecular weight 1500. Vancomycin inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide. This inhibits the transglycosylase, preventing futher elongation of peptidoglycan and cross-linking. The peptidoglycan is thus weakened and the cell becomes susceptible to lysis.(31) The cell membrane is also damaged, which contributes to antibacterial effect. Vancomycin eye drops (25-50 mg/ml) is use for the treatment of certain eye infections.(10-11) Ophthalmic infection by Staphylococcus aureus and Staphylococcus epidermidis are two causes of conjunctivitis and blepharoconjuctivitis. Over time, these pathogens have become resistant to cephalosporin therapy. Furthermore, strains of methicillin-resistant S. aureus (MRSA) have become prevalent infectious pathogens on many hospitals and long term facilities. Conventional therapy for MRSA and methicillin-resistant S. epidermidis includes the use of  vancomycin. (12) Depending on the serious of the condition and the bacterial combinations implicated need strengthened eye drops containing a high concentration of antibiotics.(13) As these are not commercially available, they are made up for the treatment of eye infections due to sensitive bacterial combinations after isolation. The vancomycin 50 mg/ml eye drops will be prepared by adding 10 ml of Tears Naturale IITM to vancomycin 500 mg inj.(12,14) In this study chitosan solution will be used as a vehicle for vancomycin and evaluation of chitosan in ocular drug delivery for vancomycin eye drops.