Physiologically activated phase transition systems for improved ocular retention of ketorolac tromethamine.

In present investigation, novel physiologically activated phase transition systems for Ketorolac Tromethamine was developed. In-situ gelling systems: pH sensitive gel using carbopol 980 and HPMC K100LV, ion sensitive gel using gallan gum and temperature sensitive gel using Poloxamer 407 and Poloxamer 188 were developed. The drug content, content uniformity, pH, optical transmittance, rheological property, bioadhesive strength, in-vitro drug release, ocular irritation and stability study were evaluated. Characterization revealed that gels were conforming to all criteria required for ocular delivery in terms of stability on sterilization, long residence time, non-irritability and sustained drug release without affecting vision. Thus, In-situ gels can be a promising alternative to the prevalent market formulations.

Physiologically activated phase transition systems are a promising approach for ocular delivery of anti-inflammatory drugs like Ketorolac Tromethamine. The study point to the potential of mucoadhesive ocular in-situ gels in terms of ease of administration, accuracy of dosing, prolonged ocular residence and improved drug bioavailability. The gel formation in contact with ocular mucosa was conferred via the use of temperature, ion and pH sensitive polymeric phase transition systems and optimized. In conclusion, the optimized Ketorolac Tromethamine in-situ gelling formulation had potential for using as a beneficial alternative to conventional eye drop in enhancing drug residence time and decreasing frequency of administration.

Materials and Methods

Materials

Ketorolac Tromethamine was obtained as a gift sample from Sun Pharmaceutical Industries limited, Vadodara. Sodium chloride, Sodium bicarbonate, Disodium hydrogen phosphate, Sodium hydroxide and Hydrochloric acid were purchased from Qualigens fine chemicals, Mumbai. Calcium chloride dihydrate, citric acid and Benzalkonium chloride were purchased from Suvidhanath chemicals, Vadodara. Carbopol 980 was obtained from Corel Pharmachem, Ahmedabad; HPMC K100 LV was obtained from Colorcon Asia private limited. Poloxamer 188 was obtained from Himedia laboratories, Mumbai. Poloxamer 407 was obtained from B.A.S.F, Germany. Gellan gum was obtained from Sisco Research Laboratories Pvt. Ltd., Mumbai. All other chemicals and reagents were of analytical grade.

Methods

Temperature, Ion and pH sensitive phase transition systems were prepared and evaluated for following parameters:

Solubility studies

Solubility of Ketorolac Tromethamine was tested in various solvents such as distilled water, different buffers, simulated tear fluid, methanol, acetone and acetonitrile.

Drug-excipient compatibility studies

Differential scanning calorimetry technique was used to investigate drug-excipient compatibility studies.

Rheological evaluation

Rheology was studied using Brookfield viscometer.

Drug content Determination

It was done by UV specrophotometry.

Bioadhesive strength measurement

It was measured by Modified physical balance method.

Ocular irritation test

Ocular irritation was studied by HET- CAM (Hen's Egg test - Chorio Allantoic membrane) test.

In vivo studies

Precorneal retention time and determination of potential to cure allergic conjunctivitis were studied.

Results and Discussion

Clarity is a highly desirable characteristic in ophthalmic formulations as non transparent formulations may blur the vision and are not patient acceptable. All the formulations were found to have % transmittance values greater than 90% indicating that they are transparent in nature.

The results obtained from rheological studies indicated that formulations were shear thinning and viscosity decreased as the angular velocity increased. So it was found that developed formulations meet the rheological requirements for ocular delivery. The mean value for % drug content of drug was found to be 99.78, 100.3 and 100.3% for pH, ion and temperature sensitive systems respectively which lies in acceptable range and indicating that there is no loss of drug during preparation and sterilization. The values of bioadhesive strength were found to be 0.02943, 0.02542 and 0.04414 for ion sensitive, pH sensitive and temperature sensitive phase transition systems respectively. The pH was found to be 6.01, 7.02 and 7.16 for pH, ion and temperature sensitive phase transition systems. The drug release from the marketed formulation continued upto 2 hours, while that from the formulated phase transition systems prolonged upto 8 hours. This clearly showed the prolonged release character of the formulated phase transition systems.

Ocular irritations of the developed formulations were developed by Hen's egg chorio allantoic membrane test. Results obtained were compared with positive and negative control, it was found that no sign of irritation was observed in the developed formulations.

Measurement of precorneal retention time is essential for a formulation claiming of improved ocular bioavailability. Precorneal retention time of developed ion sensitive phase transition system and marketed formulation were found to be 6 hours and 3 hours respectively in rabbits.

Conclusion

The results of the in vitro and in vivo studies conclusively demonstrated that developed in situ gelling formulations significantly improved ocular bioavailability as compared to conventional eye drops and hence, promise as viable alternative to marketed ophthalmic solution by virtue of its ability to enhance ocular bioavailability through its longer precorneal residence time and ability to sustain drug release.