Characterisation of Ilomastat for Prolonged Ocular Drug Release
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Research Article Characterisation of Ilomastat for Prolonged Ocular Drug Release Gary Parkinson,1 Simon Gaisford,1 Qian Ru,1,2 Alastair Lockwood,1,2 Ashkan Khalili,1,2 Rose Sheridan,3 Peng T. Khaw,2 Steve Brocchini,1,2 and Hala M. Fadda1,2,4,5
Received 2 May 2012; accepted 24 July 2012; published online 18 August 2012 Abstract. We are developing tablet dosage forms for implantation directly into the subconjunctival space of the eye. The matrix metalloproteinase inhibitor, ilomastat, has previously been shown to be efficacious at suppressing scarring following glaucoma filtration surgery (GFS). We report on the physical characterisation of ilomastat which is being developed for ocular implantation. Since ilomastat is being considered for implantation it is necessary to examine its polymorphs and their influence on aspects of the in vitro drug release profile. X-ray powder diffraction identified two polymorphs of ilomastat from different commercial batches of the compound. Tablets were prepared from the two different polymorphs. Isothermal perfusion calorimetry was used to show that amorphous content is not increased during tablet formulation. The melting points of the two polymorphs are 188 and 208°C as determined by differential scanning calorimetry. Utilising single crystal X-ray diffraction, the structural conformations and packing arrangements of the different polymorphs were determined. The orthorhombic crystal crystallised as a monohydrate while the second monoclinic crystal form is non-solvated. Ilomastat tablets prepared from the two different solid forms exhibited similar drug release profiles in vitro under conditions mimicking the aqueous composition, volume and flow of the subconjunctival space after GFS. This suggests that a reproducible dose at each time point during release after implantation should be achievable in vivo with ilomastat tablets prepared from the two polymorphs identified. KEY WORDS: ocular drug delivery; enantiotrope; dissolution; biorelevant media; solid–solid transition.
INTRODUCTION Small molecular weight active ingredients commonly exhibit polymorphism and/or pseudo-polymorphism and may crystallise to different habits. This has very important implications because these different solid forms can display different physicochemical properties that impact drug development and performance. Hydrate forms often have very different physicochemical properties compared to the anhydrous crystals (1). Mechanical drug properties that may be influenced by differences in crystal habit, and which are important for the reproducible manufacture of dosage forms, include powder flow, compactibility and tensile strength (2). Performance parameters such as dissolution rate, bioavailability and stability can also be highly influenced by the crystal arrangements that the compound may adopt (3). In particular, implantable dosage forms that are designed for dissolution over several days require that that the polymorphic forms of the active ingredient 1
UCL School of Pharmacy, London, WC1N 1AX, UK. NIHR Bi
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