Difficulty Delivering Drugs to the Eye Calls for Ingenuity and a Newer, Novel Approach

Within the past academic year, I have had the ability to do an in-depth study and evaluation of current research in the field of ocular drug delivery through a graduate-level drug delivery course at NC State University/UNC Chapel Hill instructed by Dr. Yevgeny Brudno. Specifically, I have investigated the current state of research in regards to using contact lenses as ocular drug delivery devices. I am publishing this article so that students beginning their journey into the field of scientific research can think beyond cancer. Although, cancer is a field that needs much research dedication and attention, it is saddening to see our academic institutions focus specifically only on a few major topics. I hope that this will give some of you insight and a desire to complete projects on this topic that needs more attention. Although, I do have research ideas for how these challenges could be overcome, it is outside of the scope of my knowledge and resources to truly have the capacity to tackle such challenges at this time. I hope this serves as a tool that will call upon researchers to turn their sights on this issue and critically survey possible avenues of how these challenges can be overcome.

"I am publishing this article so that students beginning their journey into the field of scientific research can think beyond cancer." - Brody M. Fogleman

The use of contact lenses has historically been used for vision correction and esthetic appearance. However, researchers have shifted to discovering novel approaches in which contact lenses can be used as devices to deliver drugs to help combat diseased states of the eye [1]. The most general form of intervention for common bacterial infections, eye injury, glaucoma, and dry eye is to use topical eye drops to prevent advancements of the eye pathology [1]. The administration of these topicals tends to levy high responsibility and patient compliance in order to have a possibility at being affective as a treatment option [1,2,3,4,5,6,7]. This complication is lengthened by strongly supported foundational research which suggest that of the drugs administered in topicals, only about 1 to 7% of the drug is absorbed into the eye where it is needed [1,2,3,4,5,6,7]. This absorption problem could be due to physical parameters which deter the drugs from entering the eye [2]. This is a problem because it requires that larger dosing be administered at more frequent time intervals, making this treatment difficult for patients to comply and follow through with [2]. Along with more frequent dosing with larger doses, excess drugs are rapidly excreted out of the eye and lost through nasolacrimal drainage [3]. This drainage may be the origin of undesirable systemic side effects from drugs administered to the eye via this treatment method [2,3,6]. In the case of ocular drug delivery, the term bioavailability does not refer to the amount of drug in circulation which can perform action. Rather, it refers to the amount of drug that stays in the eye and has activity that is useful for reversing or mitigating the symptoms of a specific pathology [8]. Additionally, throughout much research in this field the term ‘pH responsive system’ readily occurs. ‘pH responsive system’ refers to the ability of a drug delivery system to become active, release components, or degrade and become inactive as a result of changes in the ratio of acidity and basicity of the microenvironment of interest. In order to understand the logical processes and advancements which have been made in this specific field of drug delivery, it is important to first assure that fundamental eye anatomy is understood, as it will be used in the remainder of this article and all research in this field. As of 2018, the Center for Disease Control and Prevention (CDC) confirmed that there were “approximately 41 million contact lens wearers greater than 18 years old in the U.S.,” 90% of which wear a specific type known as soft contact lenses (SCLs) [10]. Since their introduction, contact lenses have been considered medical devices and are regulated by the U.S. Food and Drug Administration (FDA) [11].

Production Techniques of Contact Lenses for Ocular Drug Delivery

The four main approaches researchers are investigating today as means to loading and subsequently delivering drugs to the eye with contact lenses are molecular imprinting, supercritical soaking, solvent impregnation, and nanoparticle loading [2,4,5,7]. Molecular imprinting is used in order to allow for substrate recognition and binding in the polymer [5]. In this case, substrate binding sites are created and increase the affinity of the drugs that are intended to bind within the complex hydrogel polymer [5]. This technique was developed from research within the field of biochemistry and the innate specificity required for a substrate to bind to an enzyme [2]. Figure 2.0 shows the theoretical idea behind how and why this technique works with hydrogel polymers [2]. Moreover, this loading technique is highly “[dependent] on the stability and solubility of the functional monomers-target assemblies during polymerization” [2]. Many properties such as pH and temperature govern the ability of this technique to work and incorporate the drug of interest as intended [2, 5]. According to Alvarez-Lorenzo et al., the drugs that have been successfully incorporated by using this technique are: Timolol, Norfloxacin, Ketotifen, Polyvinylpyrrolidone, and Hyaluronic acid [5,9,12].

Another technique commonly used to load drugs to hydrogel-based contact lenses is supercritical soaking/solvent impregnation. Supercritical soaking is the most common and simplest method of drug loading in this field [4]. In this method, contact lenses are simply soaked in drug solutions and allowed to absorb the drug into the polymer matrix [4,5,7]. There are many challenges associated with this method which will be discussed in the following section. Since this method is driven by the concentration gradient between the solution and the contact lens and the diffusivity of the drug in the polymer matrix, changing concentrations of the drug in the solution can allow for control over how much drug is loaded in the lens [4,7]. This may be useful for delivering drugs to patients with different severity of a specific eye pathology.

Loading of nanoparticles is another method used to load contact lenses with drugs suitable to combat eye pathologies. In this technique, drugs are first loaded into the nanoparticle (or other colloidal particles) and then the nanoparticles are loaded into the interior of the polymer hydrogel matrix [5]. This increases steric hindrance and lessens the ability for the drug to diffuse readily out of the contact lens, thereby increasing the time which the drug could diffuse and decreasing the amount of drug released per time point [5].

Each of these loading techniques share a common goal in that they attempt to reduce the side effect generally seen in regular interventional treatment (e.g. eye drops) which never penetrate the cornea and instead go into systemic circulation. Although these methods have been tested and work to some degree, there are many physical and chemical barriers which hinder most of them from successful clinical translation.

Physical Parameters and Challenges

Although research continues to advance the possibility of using contact lenses to deliver such drugs, there are many challenges which include lens transparency, oxygen permeability, water content, drug release kinetics, and systemic side effects.

Lens Transparency

Lens transparency is one of the most important features of drug eluting contact lenses for obvious reasons such as clear vision [5]. Guzman-Aranuguez et al. report findings that suggest that loading of nanoparticles to the polymer matrix decreased the transparency by approximately 10% [5]. However, in cases of using solvent impregnation and molecular imprinting, contact lenses have upheld transparency levels at or above that of commercially available contact lenses [5]. C. Alvarez-Lorenzo et al. have also reported that molecularly imprinted contact lenses have been optically clear when loaded with Timolol, Norfloxacin, and Ketotifen in SCLs, and will be more extensively reviewed in the following section of this article [12].

Oxygen Permeability

Since the cornea is composed of living cells, it is important that it is continually supplied with oxygen and saturated at a threshold which can sustain cellular growth, proliferation, and longevity [13]. It has been shown that low oxygen saturation in or near the cornea can result in side effects which are not desirable [5]. Although many researchers agree that SCLs have limited oxygen permeability, it has been reported that silicon-based hydrogels have increased oxygen permeability and also have other promising physical parameters [1,5,12,14]. In order to accommodate for larger drug load capacity, contact lenses are generally made thicker [12]. However, by increasing the thickness of contact lenses the oxygen permeability decreases [12]. In regard to silicon-based hydrogels, it has been shown that as water content increases the oxygen permeability decreases [12]. Unlike silicon-based hydrogels, SCLs show direct proportionality of increased water content with increased oxygen permeability [12]. Although there are both positives and negatives associated with SCLs and silicon-based hydrogels, Ciolino et al. claim that silicon-based hydrogels are a better choice for long term contact lens wearers [2, 3]. Conversely, Kim et al. suggest that SCLs could potentially overcome the difficulty of both oxygen permeability and mechanical strength by incorporating nano-diamond (ND) infrastructure within the lens matrix to increase its mechanical strength [7]. Furthermore, it has been shown that incorporation of vitamin E into SCLs can both assist in slowing the release of drugs but also decrease oxygen permeability of the lens [6]. The trends and factors associated with oxygen permeability tend to be of popular interest in this field of drug delivery because of its importance at the expense of other negative consequences. The development of such devices with high oxygen permeability generally becomes a balancing act between many factors such as lens transparency, water content, drug release rate, and mechanical strength.

Water Content

Another important component of contact lenses to consider is water content of the SCL. Water content determines how the lens feels inside the eye of the wearer [5,12]. As discussed earlier, a high amount of water content in the lens is also important for increasing oxygen permeability in SCLs [3]. Water content is an important factor when loading SCLs via the soaking method [3,5,12,15]. Higher water content allows for more solute transport into the contact lens, thus allowing for more drug to be released over a more extended period of time [5,12]. It has been shown that water content does not seem to be impacted when loaded with ketotifen and norfloxacin via molecular imprinting [5]. It has been predicted by models assuming Fickian release kinetics that changes in water permeability, which generally happen when inserted into the eye, will not drastically influence the release of drugs from SCL contact lenses [15].

Drug Release Kinetics

The release of drugs into the cornea is of utmost importance when designing contact lenses for this use. As discussed in earlier sections, a release that is too fast can result in side effects and too slow of a release rate can have no discernable positive result. It is this challenging phenomenon that drives continued research in this area. Research conducted by C. Alvarez-Lorenzo et al. in rabbits suggest that using imprinted contact lenses allows for a more sustained release of drug over a longer period of time [12]. The drug release kinetics of Ketotifen can be seen in Figure 3.0a [12]. The SCL used in these experiments was made of polyhydroxyethylmethacrylate (pHEMA), a hydrogel that forms in water and is used in many SCLs used today. Many researchers suggest that incorporating vitamin E into the contact lens polymer can also assist with prolonging the release of drug from the contact lens [1,4,5,12,14,16]. It is shown in Figure 3.0b that incorporating vitamin E into the contact lens during the loading of drug via the soaking method can increase the time which the drug diffuses from lens [12]. This is demonstrated by measuring the amount of Dorzolamide and Timolol release at different time intervals in lenses with and without vitamin E [12]. This has also been simulated as a result of calculations based on the idea that mass transfer from the contact lens to the cornea is driven by the pre and post-lens tear films [12,14]. Many researchers reference the differential Fickian calculations presented by Chi-Chung Li et al. in order to predict the release kinetics of certain formulations in vivo after using the soaking method of loading drugs as seen in Figure 4.0 (a) and (b) [14].

Systemic Side Effects

The controlled release of many drugs used to treat eye pathologies are important in that, if applied at too high of a concentration, they can result in negative side effects on the heart, liver, kidneys, and brain [5]. In order to decrease the probability of negatively impacting these organ systems, it is integral that the release rate of drugs in the eye and onto the cornea are controlled, as discussed above. Although the majority of articles in this field of drug delivery address the concerns of side effects, there are few research articles that have actually investigated the mechanism behind why these drugs cause such harm.

Ocular Disorders of Interest

Few loading and delivery techniques have made it possible to advance investigations to in vivo models to better understand the possibility of using contact lenses to counter bacterial infections of the eye, corneal injury, glaucoma, and dry eye. Patients who experience dry eye (more than 50% of contact lens wearers) could potentially benefit from contact lenses that contain lubricating ability [5]. For example, it has been shown in vivo that using hyaluronic acid or hydroxypropyl methylcellulose can help increase the water content and thus reduce the symptoms associated with dry eye [5]. In the case of bacterial infections, it is highly important that the patient have the drug ciprofloxacin or norfloxacin in the therapeutic window for an extended period of time [5,12]. In the instance of using eye drops, this requires that the patient re-apply eye drops about every 30 minutes, a task that is unlikely to be followed through with among majority of patients [5,12]. Ana Guzman-Aranguez et al. report findings which suggest that silicon-based hydrogels could potentially release ciprofloxacin within the therapeutic window for approximately 1 month while also retaining relevant properties such as transparency, oxygen permeability, mechanical strength, and zero-order release kinetics (constant release over time) [5]. Corneal injury can arise from many different situations and result in a decreased amount of epithelium, an important component of the cornea which allows for the correct refractive indices to correctly project images on the retina [5,12]. It was shown through a human clinical trial that soaking SCLs with EGF can dramatically increase the healing rate at which patients redevelop the epithelial layer of their cornea which was present prior to the trauma [5].

Furthering Research

Beyond the copious amounts of information that have been discovered to this day, there are still many questions that remain unanswered when it comes to using contact lenses beyond their primary and intended function in human patients. In most research in this field, there is little evidence to allow understanding between drug release rate and toxicity effects on eye physiology. This concern should be addressed in order to advance to large scale clinical trials. Although many researchers in this field suggest the idea that systemic side effects result if eye drops are used, none of them address the important concern of toxicity on the cornea. Additionally, it can be seen that there is much dialogue between various researchers on whether silicon hydrogels are useful or not. It could be that different types of release rates and types of contacts are more useful for specific types of patients. As patient-specific medicine becomes more popularized across many scientific disciplines, it is integral that this field blaze the trail of learning more about patient-specific responses and needs in terms of drug delivery in reference to patient-specific eye pathologies. Additionally, it is of utmost importance for the physical property of refraction to be investigated in order to understand more about how this may change the formulation of the standard contact lens [2]. Holistically, the outlook of this field at this time seems promising, however, more novel approaches to loading and delivering specific drugs are needed.

Please note that this document was written solely by Brody M. Fogleman, an undergraduate student studying Biomedical Engineering at NC State University and UNC Chapel Hill. This document may have unidentified errors and should not be a direct source of information, but merely a starting point.

References

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