Preparation and rheological evaluation of ribavirin ophthalmic in situ-gel☆

Liu Zhi-dong, Li Jia-wei, Liu Rui, Zhang Xin-hua, Zhao Zheng

Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique，Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin   300193, China

Liu Zhi-dong★, Doctor, Assistant Researcher, Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique，Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin   300193, China   lonerliuzd@163.com 

Received: 2008-04-29   Accepted: 2008-05-16   (54200804280012/Y)

Liu ZD, Li JW, Liu R, Zhang XH, Zhao Z.Preparation and rheological evaluation of ribavirin ophthalmic in situ-gel.Zhongguo Zuzhi Gongcheng Yanjiu yu Linchuang Kangfu 2008;12(27): 5374-5376(China)
[www.zglckf.com/zglckf/ejournal/upfiles/ 08-27/27k-5374 (ps).pdf]

Abstract
BACKGROUND: Ribavirin is easily diluted by lacrimal fluid and has low bioavailability. In situ ophthalmic gel changes from liquid drug to gel phase upon exposure to physiological conditions, resulting in an increase in the precorneal residence time of drugs.
OBJECTIVE: To prepare ribavirin in situ ophthalmic gel and valuate its rheological feature.
DESIGN, TIME AND SETTING: In vitro controlled observation, performed at the Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique，Ministry of Education, Tianjin University of Traditional Chinese Medicine between September and October 2006.
MATERIALS: Sodium alginate, Carbopol, and ribavirin.
METHODS: Sodium alginate (1% and 2%) and Carbopol (0.3%, 0.6%, and 2%) were combined at different proportions to prepare in situ ophthalmic gel, then in which ribavirin was added.
MAIN OUTCOME MEASURES: Viscosity determinations of prepared different concentrations of formulations were determined using a cone and plate viscometer.
RESULTS: Ribavirin in situ ophthalmic gel prepared with 1% sodium alginate and 0.6% Carbopol had the largest viscosity. The viscosity change was not influenced by the addition of ribavirin. The in situ ophthalmic gel prepared with sodium alginate and Carbopol changed to the gel phase upon exposure to lacrimal fluid.
CONCLUSION: 1% sodium alginate and 0.6% Carbopol produced the best rheological feature and could prolonge the precorneal residence time of drug than that of conventional ophthalmic solution.

INTRODUCTION

In ocular delivery, the physiological constraints imposed by the protective mechanisms of the eye lead to low absorption of drugs, resulting in a short duration of the therapeutic effect. When a drug solution is dropped into the eye, the effective tear drainage and blinking action of the eye result in a 10-fold reduction in the drug concentration within 4-20 minutes [1]. The limited permeability of the cornea contributes to the low absorption of ocular drugs. Due to tear drainage, most of the administered dose passes via the naso-lacrimal duct into the gastrointestinal tract, leading to side effects. Rapid elimination of the eye drops administered often results in a short duration of the therapeutic effect making a frequent dosing regimen necessary.
Ocular therapy would be significantly improved if the pre-corneal residence time of drugs could be increased. This problem can be overcome by using in situ gel-forming ophthalmic drug delivery systems prepared from polymers that exhibit reversible phase transitions (sol-gel-sol) and pseudo-plastic behavior to minimize interference with blinking [2]. Such a system can be formulated as a liquid dosage form suitable to be administered by instillation into the eye which, upon exposure to physiological conditions, changes to the gel phase, thus increasing the pre-corneal residence time of the delivery system and enhancing ocular bioavailability. The aim of the present study was to prepare and evaluate an in situ gelling system for ribavirin .

MATERIALS AND METHODS

Design: Controlled observation.
Time and setting: This study was performed at the Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique，Ministry of Education, Tianjin University of Traditional Chinese Medicine between September and October 2006.

Methods
Preparation of formulation
Aqueous solutions of different concentrations of alginate and Carbopol (formulation codes F1, F2 … F6) were prepared and evaluated for gelling capacity in order to identify the compositions suitable for use as in situ gelling systems (Table 1). The gelling capacity was determined by placing 100 μL of the system in a vial containing 2 mL of artificial tear fluid freshly prepared and equilibrated at (35±1) ℃ and visually assessing the gel formation and noting the time for gelation and the time taken for the gel formed to dissolve.

The detailed procedure for preparing the in situ gel-forming system of ribavirin was as follows. The alginate solutions were prepared by dispersing the required amount in 75 mL distilled, deionized water with continuous stirring until completely dissolved. The alginate/carbopol solutions were prepared by dispersing the required amount of carbopol in the desired concentration of alginate with continuous stirring until completely dissolved. Ribavirin was dissolved in hydrochloric acid and the pH was adjusted to pH 4.5 using sodium hydroxide. Benzalkonium chloride (BKC) was then added to the above solution. The drug solution was added to the alginate or alginate/carbopol solution under constant stirring until uniform, clear solution was obtained. Distilled, deionized water was then added to make the volume up to 100 mL.

Rheological evaluation
Viscosity determinations of the prepared formulations (F1, F2, F4 and F5) were determined using a cone and plate viscometer on a 5 mL aliquot of the sample. The viscosity of sample solutions was measured at different angular velocities at a temperature of (35±0.5) ℃. A typical run involved changing the angular velocity from 1-100 r/min at a controlled ramp speed. After 6 seconds at 1 r/m, the velocity was increased to 100 r/m with a similar period at each speed. The hierarchy of angular velocity was reversed (100 r/min to 1 r/min) for a similar period of 6 seconds. The average of two readings was used to calculate the viscosity. Evaluations were conducted in triplicate [3].
To evaluate the viscosity change after instillation and mixing with artificial tear fluid, rheological measurements were taken after diluting the formulations containing drugs (F1, F2, F4 and F5) with artificial tear fluid [4]. The viscosity of sample solutions was measured as described above.

Main outcome measures
Gelatination time.

Design, enforcement, and evaluation
Liu Zhi-dong designed this study, all authors were included in the enforcement, and Liu Zhi-dong, Ji Jia-hui, and Liu Rui evaluated it. All authors received professional training.

RESULTS

Rheological profiles of the formulations with and without ribavirin (Figure 1)

The formulations without drug exhibited pseudoplastic rheology, as shown by shear thinning and a decrease in the viscosity with increased angular velocity (Figure 1). The rheological behaviors of all formulations were not affected by addition of ribavirin. The order of viscosity of all formulations with or without drug was F4 > F5 > F2 > F1, respectively.

Rheological profiles of the formulations with ribavirin diluted with artificial tear fluid (Figure 2)

As shown by Figure 2, the viscosities of the formulations diluted by artificial tear fluid were significantly increased. These results suggest that alginate and carbopol changed to the gel phase upon exposure to lacrimal fluid.

DISCUSSION

The administration of ophthalmic preparations should have as little effect as possible on the pseudo-plastic characteristic of the pre-corneal film [5]. Since the ocular shear rate is very high, ranging from 0.03 s-1 during inter-blinking periods to 4 250- 28 500 s-1 during blinking [6], viscoelastic fluids with a viscosity that is high under low shear rate conditions and low under the high shear rate conditions are often preferred.
The results of rheological study indicated that ribavirin in situ-gel undergo gelation when instilled into the cul-de-sac of the eye and provide sustained release of the drug during the treatment of uveitis.
In the next study, the ocular pharmacokinetic study will be carried out to evaluate its bioavailability.

REFERENCES

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