Ashkan Khalili, Garima Sharma, Alastair Lockwood, Sahar Awwad, Steve Brocchini, Peng Khaw; Proteins in solid dosage form (implantable tablets) for ocular delivery. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1088.
Purpose: Protein-based medicines (e.g. antibodies) are increasingly being used for ocular applications with many in the developmental pipeline. Optimised ocular pharmacokinetics are required to achieve the best clinical efficacy possible. The risk of complicating side effects (e.g. endophthalmitis and retinal detachment) also rises with a higher dosing frequency. It is therefore crucial to extend the half-life of protein therapeutics in different ocular tissues (e.g. subconjunctival space, cornea, posterior segment). We have developed an implantable tablet derived from bevacizumab for subconjuctival implantation during glaucoma filtration surgery (GFS). The tablet showed prolonged release while in vivo studies confirmed efficacy to decrease fibrosis in a rabbit model of GFS. Our aim now is to examine the potential for other proteins to be used in a solid ocular implantable dosage form. This study focused on tablet fabrication using different proteins and the physicochemical characterisation of the proteins during tablet dissolution.
Methods: Proteins including RNase, lyzozyme, trastuzumab, holo- and apo-transferrin (1.25 mg) were fabricated into solid dosage form (diameter 3 mm) using a combination of excipients to protect the protein during fabrication and to prolong its release. The fabricated protein tablet was dissolved in PBS (12.5 mL) at pH 7.4,overnight at ambient temperature. The stability of the dissolved proteins was determined using SDS-PAGE and size exclusion chromatography (SEC).
Results: A range protein was evaluated including, bevacizumab (149 kDa), RNase (13.7 kDa), lysosome (14.7 kDa), trastuzumab (148 kDa), holo-transferrin (≈70kDa) and apo-transferrin (≈70kDa). They were all successfully fabricated into a solid dosage form for implantation (diameter 3 mm). An aseptic fabrication process can be performed when required for biological studies. Both SEC and SDS PAGE studies showed minimum aggregation of the proteins evaluated upon tablet dissolution after 12 h.
Conclusions: Using a bevacizumab tablet that we developed as a template, we have found that different proteins can be used to fabricate solid tablets for ocular implantation. Dissolution of these tablets occurs without significant protein aggregation.