The preparation of HEMA-MPC films for ocular drug delivery

There is a need to prolong drug residence time using a biocompatible formulation in the subconjunctival space after surgery to treat glaucoma. Drug releasing discs were prepared with 2-(hydroxyethyl)methacrylate (HEMA) and 2-methacryloyl-oxyethyl phosphorylcholine (MPC). The ratio of bound water (Wb) to free water (Wf) ratio increased from 1:0.3 to 1:6.8 with increasing MPC (0 to 50%, w/w). The optimal balance between water content, SR and mechanical strength were obtained with 10% MPC (w/w) hydrogels. Water-alcohol mixtures were examined to facilitate loading of poorly soluble drugs, and they showed greater hydrogel swelling than either water or alcohol alone. The SR was 1.2 ± 0.02 and 3.3 ± 0.1 for water and water:ethanol (1:1) respectively. HEMA-MPC (10%) discs were loaded with dexamethasone using either water:ethanol (1:1) or methanol alone. Drug release was examined in an outflow rig model that mimics the subconjunctival space in the eye. Dexamethasone loading increased from 0.3 to 1.9 mg/disc when the solvent was changed from water:ethanol (1:1) to methanol with the dexamethasone half-life (t½) increasing from 1.9 to 9.7 days respectively. These encouraging results indicate that HEMA-MPC hydrogels have the potential to sustain the residence time of a drug in the subconjunctival space of the eye

Développement de matériaux polymères à haute perméabilité d’oxygène

To design a material for contact lens application, the candidate materials must satisfy several requirements, including theoptical transparency, the chemical and thermal stability. In addition, since the material is directly in contact with the eyetissue, it should be tear wettable, biocompatible, biofouling resistant and oxygen permeable. Oxygen permeability (Dk) isan important parameter for the contact lens design as it is representative of the lens ability to diffuse oxygen at the eye.In this context, we are following two ways for a new formulation answering to these constrains. First, this research is focusedon the simultaneous or two-step synthesis of IPNs (interpenetrating polymer network) as a means to obtain a cocontinuousphases structure. Among the available biocompatible monomers, the work was initially focused on the achievement of IPN's based on a fluorinated acrylate - TFEM (2,2,2-trifluoroethyl methacrylate) and the 1 -vinyl-2 -pyrrolidone (NVP). Such a system is compared to IPN's based on a siloxane monomer - TRIS (3 - [tris (trimethylsiloxy) silyl] propyl methacrylate]), well known in the field of contact lens thanks to its properties of oxygen transport. These systems are chosen as a reference. In a second part, our research was concentrated on the development of IPN based on alginate and polyacrylamide which have demonstrated attractive properties for biomedical applications, especially their mechanical properties. Several formulations of biocompatible hydrogels were prepared and the influence of their composition on the interest properties is described. These hydrogels are characterized from a chemical point of view by FTIR spectroscopy and GC-MS chromatography, from themorphological point of view by SEM microscopy in order to prove the presence of co-continuous phases. The mechanicalproperties were also investigated. The differential scanning calorimetry (DSC) was used to determine and quantify theabsorbed water in its various thermodynamic states. The oxygen permeability was measured by polarographicelectrochemical method and relations between this parameter and gel swelling and structural properties discussed. Anotherpart of the project is computational simulation of hydrogel systems and its physico-chemical properties. Especially, wewere focused on modeling of various physic-chemical processes in hydrogels such as their swelling in water anddiffusion of gases molecules. We used molecular dynamics method (MD) with the COMPASS force field to be able tomodel polymer systems widely used in contact lens field.Développer un matériau pour une application dans le domaine des lentilles de contact nécessite de satisfaire plusieursexigences, notamment sur la transparence optique, sur la stabilité chimique et thermique. En outre, puisque le matériauest directement en contact avec le tissu de l'oeil, il doit être mouillable, biocompatible, résistant à l'encrassementbiologique, et perméable à l'oxygène. La perméabilité à l'oxygène (Dk) est un paramètre important pour la conceptionde lentilles de contact. Ce paramètre représente la facilité qu’aura l’oxygène à diffuser à travers la lentille vers l’oeil.Dans ce contexte, nous décrivons deux voies de recherche sur une nouvelle formulation afin de répondre à ces critères. Dans une première approche, cette recherche est axée sur la synthèse d’hydrogels de morphologie spécifique, en particulier, sur la synthèse simultanée et/ou séquentielle de réseaux polymères interpénétrés (IPN) permettant d’obtenir unemorphologie à phases co-continues. Parmi les nombreux monomères biocompatibles, nous nous sommes focalisésinitialement sur la combinaison d'un acrylate fluoré (2,2,2 -trifluoroéthyl méthacrylate, TFEM) et de la 1 -vinyl-2 -pyrrolidone (NVP), ce système étant comparé à un IPN constitué d’un monomère siloxane (3-[tris (triméthylsiloxy)-silyle] méthacrylate de propyle], TRIS), bien connu dans le domaine des lentilles de contact en raison de ses bonnes propriétés de transport de l'oxygène. Dans une deuxième approche, ces systèmes sont considérés comme une référence et nous avons prospecté l’élaboration d’IPN à base d’alginate et d’acrylamide, ces hydrogels ayant démontré des propriétés attractives, en particulier les propriétés mécaniques. Plusieurs formulations de gels ont été préparées et l'influence de leur composition sur les propriétés d’intérêt est décrite. En effet, ces hydrogels sont caractérisés d’un point de vue chimique par spectroscopie IRTF, chromatographie couplée GC-MS et d’un point de vue morphologie par microscopie MEB afin de mettre en évidence une morphologie avec des phases co-continues. Les propriétés mécaniques sont aussi déterminées. La perméabilité à l’oxygène étant en partie liée aux propriétés de gonflement du gel, la calorimétrie différentielle à balayage (DSC) a permis de déterminer et de quantifier l’eau absorbée dans ses différents états thermodynamiques et ces données sont reliées aux mesures de perméabilité. Une autre partie de ce projet est centrée sur la simulation numérique des hydrogels et de leurspropriétés physico-chimiques telles que le gonflement dans l’eau et la diffusion de molécules de gaz. Nous avons utilisé la méthode de dynamique moléculaire (MD) avec le champ de force COMPASS afin de modéliser les polymères les plus communs dans le domaine des lentilles de contact

Hydrogel Formulations for Ophthalmic Delivery

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