UCL logo

UCL Discovery

UCL home » Library Services » Electronic resources » UCL Discovery

Hydrogel Formulations for Ophthalmic Delivery

Al-Shohani, ADH; (2017) Hydrogel Formulations for Ophthalmic Delivery. Doctoral thesis , UCL (University College London). Green open access

[img]
Preview
Text
Hydrogels for ophthalmic formulations.pdf

Download (7MB) | Preview

Abstract

Going blind is incomprehensible and with an aging population the number of people with blinding disease is increasing. Glaucoma and age related macular degeneration (AMD) are two major causes of blindness affecting people as they age. The only proven treatment for glaucoma is lowering of the intraocular pressure (IOP) which is best done by surgically placing a channel from the anterior chamber to allow aqueous outflow to drain into the subconjunctival space. The drainage channel can be formed by the use of a glaucoma drainage device (GDD) or by glaucoma filtration surgery (GFS). Both GFS and the use of a GDD often fail over time because local fibrosis (scarring) in the subconjunctival space blocks aqueous outflow resulting in the increase of IOP and disease progression. It was hypothesised that a more biocompatible GDD could be fabricated from a hydrogel, and that the hydrogel material could be used to restrict aqueous outflow to control the IOP. Hydrogels are widely used in ophthalmic applications including contact lens and intraocular lens. Since hydrogels are widely examined for use in drug delivery, it was also hypothesised that a hydrogel implant could be made for the subconjunctival space after GFS to stop tissue adhesion and to deliver locally an anti-fibrotic or anti-inflammatory drug to increase the chances for long-term surgical success. For AMD, the current treatment is intravitreal (IVT) injections of anti-VEGF antibodies approximately every 4-6 weeks. IVT injections are an invasive procedure and associated with some complications, but it is also becoming apparent that many healthcare systems around the world cannot cope with the increasing demands for IVT injections to treat AMD. To reduce the frequency for IVT injections, there is a need to develop formulations that allow a longer duration of action for therapeutic proteins in the back of the eye. Maintaining protein stability is a major challenge in formulation science and clinical use. It was further hypothesied that injectable hydrogels could also be used to formulate an antibody for IVT injection to display an extended residence time in the vitreous cavity. Free radical polymerisations of 2-hydroxyethyl methacrylate (HEMA) and 2-methacryloyloxyethyl phosphoryl choline (MPC) in the presence of a cross-linker, poly¬(ethylene glycol diacrylate) (PEGDA) were conducted to prepare HEMA-MPC co-polymer hydrogel films. Both HEMA and MPC are widely used in ophthalmic hydrogel products and MPC is known to be exceptionally biocompatible, although it must only be used as a co-polymer to ensure there are suitable processing and mechanical properties in the resulting hydrogel. Different HEMA-MPC hydrogels with increasing relative stoichiometries of MPC (0%-100% (w/w)) were prepared and characterised to determine if water flow through the gel was possible. Unfortunately the hydrogel films formed have low permeability (1.1×10-18 m2 s-1 pas-1) compared to the permeability required to control flow at a rate of 2 µL/min under 10-15 mmHg IOP, which is (6 ×10-14 m2 s-1 pas-1). Although the HEMA-MPC hydrogel films could not be used for flow control, they were further examined for use as potential implants for local tissue site drug delivery in subconjunctiva. HEMA-MPC hydrogels with 10% MPC were found to offer the best balance between water content, mechanical strength and drug loading and release that was required for the possible implantation drug loaded films derived from a range drugs (dexamethasone, pirfenidone and doxycycline). The process used for drug loading of dexamethasone was optimised by using, methanol and the in vitro half-life of DEX was increased from 1.8 to 9.1 days with release being sustained for more than 3 weeks. There are other causes of subconjunctival scarring, in particular trachoma, which is the main cause of blindness due to infection. Doxycycline is thought to be a good candidate drug for treating patients after trachoma surgery because it has both anti-bacterial and anti-fibrotic properties. As a water-soluble drug, doxycycline release could not be sustained for more than 3 days, so the 10% MPC films were modified with the incorporation of β-cyclodextrin (β-CD) in an effort exploit the possible affinity of doxycycline with β-CD to prolong doxycycline release. Several methods were examined to introduce β-CD into the HEMA-MPC films including the formation of HEMA-MPC films with pendant β-CD, the embedding of β-CD cross-linked particles within the hydrogel network and formation of an interpenetrating network (IPN) of β-CD and HEMA-MPC. Unfortunately, the release profile of doxycycline was similar in the modified and non-modified HEMA-MPC hydrogels. To evaluate hydrogels for use in IVT injections of antibodies, N-isopropylacylamide (NIPAAm) thermoresponsive hydrogels were evaluated. Three different macromolecular hydrophilic cross-linkers were evaluated; PEGDA, phosphorylcholine 3059 (PC 3059) and acrylated hyaluronic acid (Ac-HA). The prepared hydrogels were characterised regarding physical properties such as water content, water retention thermoresponsivness and protein release. The thermal responsiveness decreased with increasing cross-linker percentage. Modification in the type and percentage of cross-linker used allowed the preliminary screening of the different formulations. Hydrogel formulations made with 40 mg NIPAAm as monomer and 8 µL PEGDA, 20 mg PC3059 or 4 mg Ac-HA were able to sustain the release of antibodies for a month in a validated in vitro model of the eye.

Type: Thesis (Doctoral)
Title: Hydrogel Formulations for Ophthalmic Delivery
Event: UCL SCHOOL OF PHARMACY
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Hydrogels, MPC, Glaucoma
URI: http://discovery.ucl.ac.uk/id/eprint/1540916
Downloads since deposit
655Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item