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Timolol maleate (TM) has been used for many years for the reduction of intraocular pressure (IOP) in glaucoma patients. However, the topical mode of administration (eyedrops) is far from optimal because of the issues of low bioavailability, high drug wastage, and lack of patient compliance. Suboptimal control of the IOP leads to disease progression and eventually to blindness. Ideally, TM is delivered to the patient so that its action is both localized and sustained for 3 months or more. In this work, we developed a subconjunctival TM microfilm for sustained, long-term delivery of TM to the eyes, using the biodegradable elastomer poly(lactide-co-caprolactone) (PLC). The copolymer is biocompatible and has flexibility and mechanical characteristics suitable for a patient-acceptable implant. Controlling the release of TM for 3 months is challenging, and this work describes how, by using a combination of multilayering and blending with poly(ethylene glycol) (PEG) copolymers, we were able to develop a TM-incorporated biodegradable film that can deliver TM at a therapeutic dose for 90 days in vitro. The data was further confirmed in a diseased primate model, with sustained IOP-lowering effects for 5 months with a single implant, with acceptable biocompatibility and partial degradation.

Nanocarriers have been explored for delivering drugs and other bioactive molecules for well over 35years. Since the introduction of Doxil®, a nanoliposomal delivery system for the cancer drug doxorubicin, several products have been approved worldwide. The majority of these products focus on cancer chemotherapy, and utilize the size advantage of nanocarriers to obtain a favourable distribution of the drug carrier in the human body. In general, such carriers do not sustain drug release over more than a few days at best. In this review, we explore the reasons for this, and present an overview of successful research that is capable of generating sustained-release products in non-cancer applications. A variety of nanocarriers have been studied, and their advantages and shortcomings are highlighted in this review. The achievement of sustained release of bioactive molecules opens new doors in nanotherapeutics., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In this work, we focused on the development and investigation of controlled release matrices for a novel cardiotherapeutic peptide, cenderitide (CD-NP) that has shown to be useful for control of ventricular remodeling. To circumvent the hydrophilicity disparity between CD-NP and hydrophobic polymer matrix, a cosolvent system (water/dichloromethane) was selected for investigation. The effect of emulsification conditions, addition of poly(ethylene glycol) (PEG) and its copolymer on the release mechanism and profile were investigated. To verify the retention of bioactivity of entrapped CD-NP in different formulations, the generation of 3',5' cyclic guanosine monophospate (cGMP) and the inhibition of human cardiac fibroblast (HCF) were evaluated. The results showed that neat poly(ε-caprolactone) matrices carried out via two distinct emulsification conditions had either an unacceptably high burst or incomplete release of CD-NP; and the addition of PEG and its copolymer obtained intermediate profiles. Our confocal laser scanning microscopy and surface morphological investigations showed that the copolymer excipient was superior in playing stabilizer role by colocalizing and redistributing peptide throughout the matrix, making the release less sensitive to emulsification conditions. Furthermore, the released CD-NP is able to generate the cGMP and inhibit the HCF proliferation. Our investigations showed that CD-NP-loaded platforms can be a feasible option to provide sustained antifibrotic moderation of fibrotic scar formation and be potentially used to alleviate the adverse effects of cardiac remodeling., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Cenderitide, also known as CD-NP, is a designer peptide developed by combining native mammalian c-type natriuretic peptide (CNP) and the C-terminus isolated from the dendroapis natriuretic peptide (DNP) of the venom from the green mamba. In early studies, intravenous and subcutaneous infusion of cenderitide was reported to reduce left ventricular (LV) mass and ameliorate cardiac remodelling. In this work, biodegradable polymeric films encapsulating CD-NP were developed and were investigated for their in vitro release and degradation characteristics. Subsequently, the bioactivity of released peptide and its effects on human cardiac fibroblast (HCF) were explored. We achieved sustained release from three films with low, intermediate and high release profiles for 30 days. Moreover, the bioactivity of released peptide was verified from the elevated production of cyclic guanosine monophospate (cGMP). The CD-NP released from films was able to inhibit the proliferation of hypertrophic HCF as well as suppress DNA synthesis in HCF. Furthermore, the sustained delivery from films showed comparable or superior suppressive actions on hypertrophic HCF compared to daily infusion of CD-NP. The results suggest that these films could be used to inhibit fibrosis and reduce cardiac remodelling via local delivery as cardiac patches.