Characterisation of Ilomastat for Prolonged Ocular Drug Release
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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 WORDSocular drug delivery enantiotrope dissolution biorelevant media solid–solid transition
This research was supported by the Freemasons Grand Charity and was also supported in part by the Medical Research Council Developmental Pathway Funding Scheme (G801650), The Dorothy Hodgkins DHPA Scheme, The Helen Hamlyn Trust in memory of Paul Hamlyn, Fight for Sight, Moorfields Special Trustees, the Michael and Ilse Katz Foundation and the National Institute for Health Biomedical Research Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology. The authors would like to thank Dr. Hardyal Gill for help with the HPLC method development of ilomastat. The scientific discussions with Dr. Aktham Aburub are gratefully acknowledged. The support and help of Mrs. Peggy Khaw in the preparation of this manuscript is much appreciated.
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