Ketorolac entrapped in polymeric micelles: preparation, characterisation and ocular anti-inflammatory studies☆
Introduction
Ketorolac is a non-steroidal anti-inflammatory drug (NSAID), which has potent analgesic and anti-inflammatory activity due to prostaglandin related inhibitory effect of drug. Ketorolac (free acid) is sparingly soluble in water and, therefore, it is marketed in the form of tromethamine salt (KT), which increases its solubility in water. KT is effective in inhibiting postoperative inflammation of eyes. It is also effective in reducing conjunctivitis with no alteration of corneal opacity (Fraser-Smith and Mathews, 1988). It does not facilitate Herpes Simplex, bacterial or fungal infection of the eye (Buckley and Brogden, 1990). KT (0.5%w/v) eye drops are available in the market. A solution of KT (0.5%w/v) applied topically to eyes is non-irritant and does not increase intraocular pressure (Fu and Lidgate, 1986). Only a small amount of instilled dose (1–3%) from such a formulation penetrates the cornea and reaches intraocular tissues (Schoenwald, 1985). This is due to lachrymal drainage and drug dilution by tears.
To overcome the problems, several new approaches have been tried including the use of bioadhesive polymers (Duchene et al., 1988, Saettone et al., 1989, Krishnamoorty and Mitra, 1993, Slovin and Robinson, 1993, Saettone et al., 1994, Das et al., 1995), liposomes (Fitzgerald et al., 1987, Lee, 1995) and nanoparticles (Li et al., 1986, Fitzgerald et al., 1987, Losa et al., 1991, Marchal-Heussler et al., 1991, Calvo et al., 1996a, Calvo et al., 1996b, Bourlias et al., 1998), that improve the ocular bioavailability of the drug. Substantial efforts have been directed towards the development of ocular drug delivery systems that would prolong the drug retention, allowing the drug to remain in contact with the cornea for longer duration and thus increases bioavailability (Lee and Robinson, 1986, Lee, 1990, Keiser et al., 1991, Slovin and Robinson, 1993, Urtti and Salminen, 1993, Sasaki et al., 1999). Nanoparticulate technology is advocated as an ophthalmic drug delivery approach that may enhance dosage form acceptability while providing sustained release in the ocular milieu (Zimmer and Kreuter, 1995). There have been some studies over the years examining the mechanism of drug release and reporting the ocular therapeutic action of drug from nanoparticles (Harmia et al., 1986b, Deshpande et al., 1998). The particles utilised in these studies were made of mucoadhesive polymers, which impart increased precorneal retention time. The delivery of drug through these nanoparticles does not increase the ocular bioavailability to a considerable extent due to larger particle size resulting in a smaller retention time. To overcome the same further work needs to be done particularly on the use of ultra small size nanoparticles (<100 nm diameter) with mucoadhesiveness so that these are not washed away with tears quickly and having sustained release characteristics.
This paper describes the preparation of crosslinked copolymeric micelles made of N-isopropylacrylamide, N-vinylpyrrolidone and acrylic acid containing ketorolac entrapped into the polymeric network, their characterisation, in vitro release behaviour, in vitro transcorneal permeation characteristics and in vivo ocular anti-inflammatory effect. N-isopropylacrylamide was used to form stable micellar aggregates with hydrophobic core mainly composed of isopropyl moiety. Vinylpyrrolidone renders the hydrogel behaviour of the polymer while acrylic acid was added to have copolymer mucoadhesive (Robert et al., 1988).
Section snippets
Materials
N-Isopropylacrylamide (NIPAAM) was purchased from Ranbaxy Acros and was crystallised from n-hexane before polymerisation. N,N′-Methylene bis-acrylamide (MBA) was product of Sigma, USA and was used directly without further purification. Acrylic acid (AA), n-hexane, sodium monohydrogen phosphate and dihydrogen phosphate, ferrous ammonium sulphate (FAS) were procured from SRL (India). N-Vinylpyrrolidone (VP) was purchased from Fluka. Absolute ethanol (99.8%) was purchased from Merck (Germany). AA
Synthesis and characterisation of NIPAAM-VP-AA copolymeric micelles
Random copolymerisation of NIPAAM with VP and AA was done by radical polymerisation process of the micellar aggregates of the monomers. Polymer formed in this way has amphiphilic character with a hydrophobic core inside the micelles and hydrophilic outer shell composed of hydrated amides, pyrrolidone and carboxylic groups projected from the monomeric units. Water insoluble drug like ketorolac free acid was dissolved into the hydrophobic core of the polymeric micelles.
Conclusions
These copolymeric nanoparticles composed of NIPAAM, VP and AA are biocompatible and do not cause any corneal damage. Corneal penetration of ketorolac from nanoparticles was much higher compared to aqueous suspension of drug of equivalent concentration. The formulation also shows much higher anti-inflammatory activity for longer duration compared to that of aqueous suspension of drug. This could be attributed to the ultra small size (<50 nm diameter) of the polymeric micelles as well as their
Acknowledgements
The authors (AKG and ANM) are grateful to the Department of Biotechnology, Government of India, New Delhi, for financial assistance in the form of a research project.
References (35)
- et al.
Comparative in vitro evaluation of several colloidal systems, nanoparticles, nanocapsules, and nano-emlusions as ocular drug carriers
J. Pharm. Sci.
(1996) - et al.
A gamma scintigraphic evaluation of microparticulate ophthalmic delivery systems. Liposomes and nanoparticles
Int. J. Pharm.
(1987) - et al.
Enhancement of the meiotic response of rabbits with pilocarpine loaded poly(butylcyanoacrylate) nanoparticles
Int. J. Pharm.
(1986) - et al.
Minimizing systemic absorption of topically administered ophthalmic drugs
Surv. Ophthalmol.
(1993) - et al.
Microsphere and nanoparticles used in ocular delivery systems
Adv. Drug Del. Rev.
(1995) - et al.
Ophthalmic drug delivery systems-recent advances
Prog. Retinal Eye Res.
(1998) - et al.
Ketorolac: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential
Drugs
(1990) - et al.
Polyester nanocapsules as new topical ocular delivery systems for Cyclosporin A
Pharm. Res.
(1996) - et al.
Thermo-responsive drug delivery of polymeric micelles incorporating Adriamycin
Proc. Int. Symp. Control. Release Bioact. Mater.
(1998) - et al.
Evaluation of poly(isobutylcyanoacrylate) nanoparticles for mucoadhesive ocular drug delivery. 1. Effect of formulation variables on physicochemical characteristics of nanoparticles
Pharm. Res.
(1995)
Bioerodible polymers for ocular drug delivery
Crit. Rev. Ther. Drug Carrier Syst.
Controlled release of amylase from a thermal and pH sensitive macroporous hydrogel
J. Control. Release
Pharmaceutical and medical aspects of bioadhesive systems for drug administration
Drug Dev. Ind. Pharm.
Effect of ketorolac on pseudomonas aeruginosa ocular infection in rabbits
J. Ocular Pharmacol.
Drug Dev. Ind. Pharm.
A solid colloidal drug delivery system for the eye: encapsulation of pilocarpine in nanoparticles
J. Microencapsulation
Limits on optimizing ocular drug delivery
J. Pharm. Sci.
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Indian patent application No. 845Del/2000 dated 25th September, 2000.