Ketorolac entrapped in polymeric micelles: preparation, characterisation and ocular anti-inflammatory studies

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Abstract

Polymeric micelles made of copolymer of N-isopropylacrylamide (NIPAAM), vinyl pyrrolidone (VP) and acrylic acid (AA) having cross-linkage with N,N′-methylene bis-acrylamide (MBA) were used as host carrier in which up to 30%w/w ketorolac (free acid) was entrapped to make the formulation. The lyophilised powder was used for physical characterisation. The drug entrapment was found to be about 80% and the formulation was stable for 8–10 days at room temperature. The smaller the amount of ketorolac dissolved into the micelles, the longer was the formulation shelf life. The size of the particles as measured by dynamic light scattering was found to be around 35 nm diameter at 25°C. TEM picture showed spherical particles. The structure of the polymer and its morphology were characterised by FTIR, NMR and XRD measurements. IR data indicated weak interaction between polymer and ketorolac in the encapsulated system. NMR spectra indicated rigid polymer backbone with intermittent iso-propyl group in the chain. XRD spectra showed significant loss of crystallinity of the drug while being entrapped in the polymeric micelles. The release of drug in aqueous buffer (pH 7.2) from the polymeric micelles at 25°C were 20 and 60% after 2 and 8 h respectively and is temperature and pH dependent. In vitro corneal permeation studies through excised rabbit cornea indicated two fold increase in ocular availability with no corneal damage compared to an aqueous suspension containing same amount of drug as in nanoparticles. The formulation showed significant inhibition of lid closure up to 3 h and PMN migration up to 5 h compared to the suspension containing non-entrapped drug, which did not show any significant effect.

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.

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