Imprinted Contact Lenses for Ocular Administration of Antiviral Drugs.

A variety of ocular diseases are caused by viruses, and most treatments rely on the use of systemic formulations and eye drops. The efficient ocular barriers that oppose antiviral drug penetration have prompted the development of improved topical delivery platforms. The aim was to design hydrogel contact lenses endowed with an affinity for acyclovir (ACV) and its prodrug valacyclovir (VACV), first-choice drugs against herpes simplex virus (HSV) ocular keratitis, and that can sustain the release of therapeutic doses during daily wearing. Functional monomers suitable for interaction with these drugs were screened using computational modeling. Imprinted and non-imprinted hydrogels were prepared with various contents in the functional monomer methacrylic acid (MAA) and characterized in terms of swelling, transmittance, mechanical properties, and ocular compatibility (hen's egg test on chorioallantoic membrane (HET-CAM) assay). The values were in the range typical of soft contact lenses. Compared to ACV, the capability to load VACV was remarkably higher due to stronger electrostatic interactions with MAA. The advantages of the imprinting technology were evidenced for VACV. Stability of VACV loading solution/hydrogels under steam heat sterilization and subsequent drug release was investigated. Permeability studies through bovine and porcine cornea and sclera of the drug released from the hydrogels revealed that VACV accumulates in the cornea and can easily cross the sclera, which may facilitate the treatment of both anterior and posterior eye segments diseases.

Polypseudorotaxanes of Pluronic® F127 with Combinations of α- and ß-Cyclodextrins for Topical Formulation of Acyclovir.

Acyclovir (ACV) is one of the most used antiviral drugs for the treatment of herpes simplex virus infections and other relevant mucosal infections caused by viruses. Nevertheless, the low water solubility of ACV limits both its bioavailability and antiviral performance. The combination of block copolymer micelles and cyclodextrins (CDs) may result in polypseudorotaxanes with tunable drug solubilizing and gelling properties. However, the simultaneous addition of various CDs has barely been investigated yet. The aim of this work was to design and characterize ternary combinations of Pluronic® F127 (PF127), αCD and ßCD in terms of polypseudorotaxane formation, rheological behavior, and ACV solubilization ability and controlled release. The formation of polypseudorotaxanes between PF127 and the CDs was confirmed by FT-IR spectroscopy, X-ray diffraction, and NMR spectroscopy. The effects of αCD/ßCD concentration range (0-7% w/w) on copolymer (6.5% w/w) gel features were evaluated at 20 and 37 °C by rheological studies, resulting in changes of the copolymer gelling properties. PF127 with αCD/ßCD improved the solubilization of ACV, maintaining the biocompatibility (hen's egg test on the chorio-allantoic membrane). In addition, the gels were able to sustain acyclovir delivery. The formulation prepared with similar proportions of αCD and ßCD provided a slower and more constant release. The results obtained suggest that the combination of Pluronic with αCD/ßCD mixtures can be a valuable approach to tune the rheological features and drug release profiles from these supramolecular gels.

Cytosine-functionalized bioinspired hydrogels for ocular delivery of antioxidant transferulic acid.

Contact lenses (CLs) are being pointed out as feasible platforms for controlled delivery of ophthalmic drugs. Bioinspired strategies may endow CLs with affinity for a given drug by mimicking its physiological receptor using adequate functional monomers and tuning their conformation in the space through the molecular imprinting technology. However, there are some active substances, such as efficient antioxidant agents, that cannot be used as templates because they degrade during polymerization or even hinder the polymerization itself. Therefore, the development of CLs able to sustain the release of antioxidants for the prevention and/or treatment of several age-related and light-induced eye diseases has not been explored yet. Searching for an alternative bioinspired strategy, the present work relies on the fact that some drugs owe their therapeutic action to their ability to interact with nucleotides that build up DNA and RNA. Thus, the aim of this work was to design hydrogels functionalized with the nitrogenous base cytosine for the controlled uptake and release of transferulic acid (TA) having a complementary chemical structure in terms of hydrogen bonding and π-π stacking ability. Hydrogels were prepared from mixtures of 2-hydroxyethyl methacrylate (HEMA), glycidyl methacrylate (GMA) and ethyleneglycolphenylether methacrylate (EGPEM). GMA was used as a bridge to immobilize cytosine after hydrogel synthesis, while EGPEM was added to reinforce hydrophobic interactions with TA. The hydrogels were characterized in terms of suitability to be used as CLs (swelling, light transmission, mechanical properties, biocompatibility) and capability to host TA and sustain its release in lachrymal fluid while maintaining the antioxidant activity. Relevantly, the bioinspired CLs favored TA accumulation in cornea and sclera tissues.

Bioinspired hydrogels for drug-eluting contact lenses.

Efficient ocular drug delivery that can overcome the challenges of topical application has been largely pursued. Contact lenses (CLs) may act as light-transparent cornea/sclera bandages for prolonged drug release towards the post-lens tear fluid, if their composition and inner architecture are fitted to the features of the drug molecules. In this review, first the foundations and advantages of using CLs as ocular drug depots are revisited. Then, pros and cons of common strategies to prepare drug-loaded CLs are analyzed on the basis of recent examples, and finally the main section focuses on bioinspired strategies that can overcome some limitations of current designs. Most bioinspired strategies resemble a reverse engineering process to create artificial receptors for the drug inside the CL network by mimicking the human natural binding site of the drug. Related bioinspired strategies are being also tested for designing CLs that elute comfort ingredients mimicking the blinking-associated renewal of eye mucins. Other bioinspired approaches exploit the natural eye variables as stimuli to trigger drug release or take benefit of bio-glues to specifically bind active components to the CL surface. Overall, biomimicking approaches are being revealed as valuable tools to fit the amounts loaded and the release profiles to the therapeutic demands of each pathology. STATEMENT OF SIGNIFICANCE: Biomimetic and bioinspired strategies are remarkable tools for the optimization of drug delivery systems. Translation of the knowledge about how drugs interact with the natural pharmacological receptor and about components and dynamics of anterior eye segment may shed light on the design criteria for obtaining efficient drug-eluting CLs. Current strategies for endowing CLs with controlled drug release performance still require optimization regarding amount loaded, drug retained in the CL structure during storage, regulation of drug release once applied onto the eye, and maintenance of CL physical properties. All these limitations may be addressed through a variety of recently growing bioinspired approaches, which are expected to pave the way of medicated CLs towards the clinics.

Soluplus micelles for acyclovir ocular delivery: Formulation and cornea and sclera permeability.

Nearly 20% of people affected by the herpes simplex virus (HSV) suffer from vision problems. The virus can infect all layers of the cornea or cause inflammatory diseases of the sclera. The aim of this work was to test whether encapsulation of acyclovir in Soluplus or Solutol polymeric micelles increases its solubility, corneal permeability and sclera penetration. The aqueous solubility of acyclovir is known to be low, and therefore approaches that increase both its solubility and ability to penetrate through the eye may favor the efficacy of the treatments. Copolymer dispersions (covering wide range of concentrations) were prepared in water and PBS 7.4 and characterized regarding size and Z-potential (close to zero). Solutol micelles increased their size when the drug was incorporated (135 vs. 19 nm), while Soluplus micelles showed little difference (137 nm). Only Soluplus micelles significantly enhanced acyclovir solubility and withstood dilution stability tests. Soluplus (12-20%) formulations showed a progressive increase in viscoelasticity as temperature rose, which may allow for easy dropping onto the eye and subsequent retention in the gel form. Drug permeability through bovine cornea and sclera was investigated in detail. Although similar permeability coefficients were recorded for the drug when applied as the free drug in solution or formulated in Soluplus micelles, the micelle formulation significantly shortened the permeation lag time through the cornea. Moreover, Soluplus micelles were advantageous compared to the drug solution in terms of greater amount of acyclovir accumulated in both cornea and sclera, and higher steady state flux. If compared with cornea, the amounts of drug permeated through the sclera were approx. 10 times greater, which opens the possibility of drug delivery to the posterior eye segment.

Cyclodextrin-based poly(pseudo)rotaxanes for transdermal delivery of carvedilol.

This work aimed to design supramolecular gels combining Soluplus or Solutol and alfa- and hydroxypropyl-ß-cyclodextrin (α-CD, HPß-CD) for carvedilol (CAR) transdermal delivery. Poly(pseudo)rotaxane formation (appearance, SEM, 1H NMR), drug solubilization, rheological properties and in vitro release were investigated. CAR-CD complexes were prepared in situ or by spray drying. For Solutol, poly(pseudo)rotaxanes were formed immediately after mixing with α-CD and did not influence CAR solubility. Differently, Soluplus poly(pseudo)rotaxanes took 24-48 h to be formed and CAR solubility decreased compared to Soluplus micelles. Soluplus 20% + α-CD (5-10%) showed higher G' and G'' but also faster CAR release than Solutol poly(pseudo)rotaxanes, which is explained by the different location of PEG chains in the two amphiphilic polymers. Faster drug release was achieved incorporating HPß-CD or CAR-HPß-CD spray-dried complexes. The results evidenced the versatility of the formulations in terms of rheological behavior and drug release patterns, which can be adjusted for CAR transdermal delivery.