Improved triamcinolone acetonide-eluting contact lenses based on cyclodextrins and high hydrostatic pressure assisted complexation.

Contact lenses (CLs) constitute an advantageous platform for the topical release of corticosteroids due to their prolonged contact with the eye. However, the lipophilic nature of corticosteroids hampers CLs' ability to release therapeutic amounts. Two approaches to improve loading and release of triamcinolone acetonide (TA) from poly(2-hydroxyethyl methacrylate)-based hydrogels were investigated: adding 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) to the monomers solution before polymerization (HEMA/i-CD) and an hydrogels' post-treatment with HP-ß-CD (HEMA/p-CD). The effect of HP-ß-CD and sterilization by high hydrostatic pressure (HHP) on the hydrogel properties (water content, oxygen and ion permeability, roughness, transmittance, and stiffness) was evaluated. The HEMA/i-CD hydrogels had stronger affinity for TA, sustaining its release for one day. HHP sterilization promoted the formation of cyclodextrin-TA complexes within the hydrogels, improving their drug-loading capacity ¼60 %. Cytotoxicity and irritability tests confirmed the safety of the therapeutic CLs. TA released from the hydrogels permeated through ocular tissues ex vivo and showed anti-inflammatory activity. Finally, a previously validated mathematical model was used to estimate the ability of the TA-loaded CLs to deliver therapeutic drug concentrations to the posterior part of the eye. Overall, HP-ß-CD-containing CLs are promising candidates for the topical ocular application of TA as an alternative delivery system to intraocular injections.

Dexamethasone phosphate and penetratin co-eluting contact lenses: a strategy to enhance ocular drug permeability.

Contact lenses (CLs) have been suggested as drug delivery platforms capable of increasing the drug residence time on the cornea and therefore its bioavailability. However, when targeting the posterior segment of the eye, the drug released from CLs still encounters the barrier effect of the ocular tissues, which considerably reduces the efficacy of administration. This work aims at the development of CLs able to simultaneously deliver an anti-inflammatory drug (dexamethasone sodium phosphate) and a cell-penetrating peptide (penetratin), the latter acting as a drug carrier across the tissues. Hydroxyethyl methacrylate (HEMA)-based hydrogels were functionalized with acrylic acid (AAc) and/or aminopropyl methacrylamide (APMA) to serve as CL materials with increased affinity for the drug and peptide. APMA-functionalized hydrogels sustained the dual release for 8 h, which is compatible with the wearing time of daily CLs. Hydrogels demonstrated suitable light transmittance, swelling capacity and in vitro biocompatibility. The anti-inflammatory activity of the drug was not compromised by the presence of the peptide nor by sterilization. The ocular distribution of the drug after 6 h of CL wearing was evaluated in vivo in rabbits and revealed that the amount of drug in the cornea and aqueous humor significantly increased when the drug was co-delivered with penetratin.

A Physiology-Based Mathematical Model to Understand Drug Delivery from Contact Lenses to the Back of the Eye.

OBJECTIVE: Therapeutic contact lenses, able to store drug and deliver it to the eye surface in a sustained fashion, gained interest as an effective and patient-friendly alternative to eye drops. Recent animal studies also demonstrated the presence of therapeutic drug levels in the back of the eye after wearing drug-loaded contact lenses, thus opening the possibility of treating the posterior segment without need of invasive intraocular injections. The drug pathways from contact lenses to the back of the eye require further investigation. METHODS: A mechanistic mathematical model was developed to evaluate the drug concentration over time in the tears, sclera and choroid, retina, aqueous humor and vitreous humor after the application of a therapeutic contact lens. The main drug transport mechanisms of the eye and the barrier properties of the different tissues were included in the model. Validation was performed by comparison with experimental data in literature. RESULTS: The model predictions of drug concentration over time reflected the experimental data both in the anterior and posterior segment of the eye. The model can differentiate between contributions to transport from different pathways. CONCLUSIONS: The model constitutes a first step towards the possibility of predicting the ocular drug distribution and the treatment efficacy in the early stage of contact lens development, and it may help reduce both the need for in vivo tests (with ethical and economic advantages) and the gap between the lens design and clinical application. It also allows for an improved understanding of drug transport in the eye.

Drug-Loaded Hydrogels for Intraocular Lenses with Prophylactic Action against Pseudophakic Cystoid Macular Edema.

Pseudophakic cystoid macular edema (PCME), caused by chronic inflammation, is the most common cause of visual impairment in the medium-term after cataract surgery. Therefore, the prophylactic topical administration of combined steroidal and non-steroidal anti-inflammatory drugs is commonly done. Drug-eluting intraocular lenses (IOLs) gained interest as an efficient way to overcome the compliance issues related to the use of ocular drops without the need for additional surgical steps. The incorporation of functional monomers and molecular imprinting were herein applied to design hydrogels suitable as IOLs and able to co-deliver steroidal (dexamethasone sodium phosphate) and non-steroidal (bromfenac sodium) drugs. The incorporation of N-(2-aminopropyl) methacrylamide (APMA) increased the drug uptake and improved the in vitro release kinetics. Imprinting with bromfenac resulted in a decreased drug release due to permanent drug bonding, while imprinting with dexamethasone increased the amount of dexamethasone released after dual-drug loading. The application of a mathematical model to predict the in vivo drug release behavior suggests the feasibility of achieving therapeutic drug concentrations of bromfenac and dexamethasone in the aqueous humor for about 2 and 8 weeks, respectively, which is compatible with the current topical prophylaxis after cataract surgery.

Asymmetry in Drug Permeability through the Cornea.

The permeability through the cornea determines the ability of a drug or any topically applied compound to cross the tissue and reach the intraocular area. Most of the permeability values found in the literature are obtained considering topical drug formulations, and therefore, refer to the drug permeability inward the eye. However, due to the asymmetry of the corneal tissue, outward drug permeability constitutes a more meaningful parameter when dealing with intraocular drug-delivery systems (i.e., drug-loaded intraocular lenses, intraocular implants or injections). Herein, the permeability coefficients of two commonly administered anti-inflammatory drugs (i.e., bromfenac sodium and dexamethasone sodium) were determined ex vivo using Franz diffusion cells and porcine corneas in both inward and outward configurations. A significantly higher drug accumulation in the cornea was detected in the outward direction, which is consistent with the different characteristics of the corneal layers. Coherently, a higher permeability coefficient was obtained for bromfenac sodium in the outward direction, but no differences were detected for dexamethasone sodium in the two directions. Drug accumulation in the cornea can prolong the therapeutic effect of intraocular drug-release systems.

Plant Tissues as 3D Natural Scaffolds for Adipose, Bone and Tendon Tissue Regeneration.

Decellularized tissues are a valid alternative as tissue engineering scaffolds, thanks to the three-dimensional structure that mimics native tissues to be regenerated and the biomimetic microenvironment for cells and tissues growth. Despite decellularized animal tissues have long been used, plant tissue decellularized scaffolds might overcome availability issues, high costs and ethical concerns related to the use of animal sources. The wide range of features covered by different plants offers a unique opportunity for the development of tissue-specific scaffolds, depending on the morphological, physical and mechanical peculiarities of each plant. Herein, three different plant tissues (i.e., apple, carrot, and celery) were decellularized and, according to their peculiar properties (i.e., porosity, mechanical properties), addressed to regeneration of adipose tissue, bone tissue and tendons, respectively. Decellularized apple, carrot and celery maintained their porous structure, with pores ranging from 70 to 420 µm, depending on the plant source, and were stable in PBS at 37°C up to 7 weeks. Different mechanical properties (i.e., Eapple = 4 kPa, Ecarrot = 43 kPa, Ecelery = 590 kPa) were measured and no indirect cytotoxic effects were demonstrated in vitro after plants decellularization. After coating with poly-L-lysine, apples supported 3T3-L1 preadipocytes adhesion, proliferation and adipogenic differentiation; carrots supported MC3T3-E1 pre-osteoblasts adhesion, proliferation and osteogenic differentiation; celery supported L929 cells adhesion, proliferation and guided anisotropic cells orientation. The versatile features of decellularized plant tissues and their potential for the regeneration of different tissues are proved in this work.