Rheological evaluation of poloxamer as an in situ gel for ophthalmic use

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Abstract

The contact time of a vehicle on the cornea is of utmost importance for ocular drug delivery. In the present study rheological measurements were performed to study the gel and the sol–gel transition of an in situ gel, Poloxamer 407. The rheological measurements and a small in vivo study of ocular residence times in humans were used to evaluate poloxamer as an ocular vehicle. An increasing concentration of poloxamer resulted in a slightly increasing elasticity of the gels and a decreasing sol–gel transition temperature. The contact time increased with increasing concentration of poloxamer which could be explained and correlated with the rheology of poloxamer solutions/gels mixed with simulated tear fluid. The maximum contact time for the preparations studied was about 1 h. The poloxamer system did not seem to be promising as an ophthalmic in situ gel due to the strong concentration dependence of the sol–gel transition temperature combined with the dilution that occurs in the eye.

Introduction

The eye is a very sensitive organ. The tear flow and the blinking reflex maintain a good environment and remove foreign material from the eye. These protective properties, however, also lead to an effective drainage of drugs when introduced into the eye. This results in low bioavailabilities and short ocular residence times reducing the desired therapeutic effect of the drug. Drug absorption is also dependent on the chemical nature of the drugs since the corneal permeability depends on the molecular size and the hydrophobicity of the drug (Grass and Robinson, 1984).

In order to increase the effectiveness of the drug a dosage form should be chosen which increases the contact time of the drug in the eye. This may then increase the bioavailability, reduce systemic absorption and reduce the need for frequent administration leading to improved patient compliance.

With conventional eyedrops most of the drug is drained away from the pre-corneal area in a few minutes. An insoluble drug in the form of a suspension has a longer contact time because of the slower removal of particles from the eye as compared with solution (Sieg and Robinson, 1975). The most common ways to increase the residence time of a solution is to decrease the drainage rate by increasing the viscosity of the vehicle (Grass and Robinson, 1984, Saettone et al., 1984). This, however, only moderately affects the contact time of the drug. Ointments provide long residence times but have a low patient compliance and are usually recommended for bedtime use. The residence time of an insert can almost be unlimited. An ocular insert may be designed to deliver the drug at a desired rate for a desired period of time, which determines the maximum contact time. Unfortunately the patient compliance of most inserts is rather low.

Gel systems are better retained in the eye than conventional eye drops and are better tolerated by patients than inserts and ointments. Like ointments, gels are also difficult to administer for some patients. In this respect in situ gels are interesting since these are conveniently dropped as a solution into the conjunctival sac, where they undergo a transition into a gel with its favourable residence time. The sol–gel transition occurs as a result of a chemical/physical change induced by the physiological environment. The transition could be induced by a shift in the pH as for cellulose acetate phthalate (Gurny et al., 1985) and for polycarbophil (Hui and Robinson, 1985, Middleton and Robinson, 1991). Gelrite has another mechanism for sol–gel transitions: the gelation in the eye is due to the presence of cations, calcium ions especially have a marked effect on the gelling ability (Deasy and Quigley, 1991).

In the present work a thermogelling in situ gel, Poloxamer 407, was studied. Poloxamer 407 is a block copolymer made of poly(oxy ethylene) and poly(oxy propylene), the sol–gel transition is induced by an increase in temperature, but depends on the concentration of the polymer and presence of additives such as salts and polymers (Miller and Drabik, 1984, Vadnere et al., 1984, Gilbert et al., 1987). Poloxamer has been evaluated as vehicles for drugs; lipophilic drugs, especially, have favourably slow release rates from poloxamer vehicles (Gilbert et al., 1986). Poloxamer has also been evaluated as an ophthalmic vehicle in animal models (Miller and Donovan, 1982)

There is no reliable correlation between the performance of an ophthalmic vehicle in rabbits and in humans (Saettone et al., 1982, Saettone et al., 1984, Edsman et al., 1996) The rabbit model is therefore of limited use for the optimisation of a vehicle. In this study a rheological characterisation of the gels was used for understanding the in vivo performance. The properties before and after the gel transition as well as the sol–gel transition have been studied, the polymer concentration of the gel system has been varied and the effect of additives was studied. As a complement to the rheological evaluation a small in vivo study of human contact times was made.

Section snippets

Materials

Poloxamer 407 (Synperonic F-127) was a kind gift from ICI. Polyethylene glycol (PEG) Mw 6000 was purchased from BDH. FITC-labelled Sephadex G25 superfine (10–40 μm, with a density of 1 g/ml) for the contact time measurements was a kind gift from the Department of Organic Chemistry at Pharmacia AB. All other chemicals were of pharmaceutical quality.

Preparation of gels

Poloxamer solutions with concentrations of 14–25% w/w were made by weighing into a cold solvent. The solutions were stirred in 8°C and were kept in

Contact time

Studies of the ocular contact times for different vehicles can be made using different techniques (Wilson et al., 1983, Ding et al., 1992). In most studies molecular drugs or markers were monitored which do not reflect the retention of the gel but rather the diffusion of the molecules. The use of a molecular marker will mimic the behaviour of a soluble drug, but in this study the retention of the gel was the prime goal. To reach this goal we dispersed fluorescent microparticles in the

Conclusions

There was a concentration dependence of the contact time of the poloxamer preparation that could be explained and correlated to the rheology of poloxamer solutions/gels mixed with simulated tear fluid. The maximum contact time obtained was around 1 h.

An increasing polymer concentration gives an increasing gel strength and a decreasing sol–gel transition temperature which leads to an increased ocular contact time. An increased ionic strength does not change the gel strength but decreases the

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1

Present address: Department of Pharmaceutics, University of Uppsala, POB 580, S-751 23 Uppsala, Sweden.

2

Present address: Department of Pharmaceutics, University of Uppsala, POB 580, S-751 23 Uppsala, Sweden.

3

Present address: Hospital Pharmacy Jönköping, Hospital Ryhov, S-551 85 Jönköping, Sweden.

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