In vivo drug delivery via contact lenses: The current state of the field from origins to present

Abstract

Over the past half century, contact lenses have been investigated for their potential as drug delivery devices for ocular therapeutics. Hundreds of studies have been published in the pursuit of the most effective and efficient release strategies and methods for contact lens drug delivery. This paper provides a thorough overview of the various contact lens drug delivery strategies, with a specific, comprehensive focus on in vivo studies that have been published since the field began in 1965. Significant accomplishments, current trends, as well as future strategies and directions are highlighted. In vivo study analysis provides a straightforward perspective and assessment of method success and commercialization potential in comparison to benchtop, in vitro studies. Analysis of the majority of published work indicates in vitro and in vivo studies do not correlate with a correlation coefficient of 0.25, with many in vitro studies grossly overestimating drug release duration and not showing appreciable drug release control. However, there has been an increase in activity in the last decade, and some methods have generated promising results exhibiting controlled release with commercialization potential. Clinical translation of drug releasing lenses is on the horizon and has high potential to impact a large number of patients providing efficacious treatment compared to current topical treatments.

Graphical Abstract

1. Introduction

Successful delivery of therapeutics to the eye is critical for the health and quality of life for millions worldwide. There exists a great need for medication to be directly applied to ocular tissue for a number of reasons to treat ocular disease or discomfort: preventing infection, preventing inflammation, relieving dry eye syndrome, treating glaucoma, etc. Though highly accessible, the eye is an extremely difficult site to deliver drugs. The challenges associated with ocular drug delivery are due to systemic blood ocular barriers and the protective physical barriers of the eye that naturally prevent transport of foreign molecules from the blood and prevent long residence times of foreign molecules in the tear fluid. The blood aqueous and blood retinal barriers selectively control the transport of molecules, and for topical administration characteristics such as small tear volume (7–30 µL) and a fast tear turnover rate (0.5–2.2 µL/min) result in a very low bioavailability [1]. There are a number of comprehensive reviews recommended for further insight on the specific physiological barriers and challenges related to ocular drug delivery [2–4].

The current standard of care for ocular drug administration and delivery are non-invasive topical formulations and applications as well as injections. Topical eye drops, in the form of solutions and suspensions, represent over 90% of the drug formulations designed for the eye [1,5]. Despite being the most prominent treatment form, eye drops are only marginally effective with a number of shortcomings that prevent efficient delivery of therapeutics to the eye. The residence time of drugs applied via topical eye drops is remarkably short, with just 1–7% of the applied drop being absorbed by the ocular tissues and the rest lost to systemic circulation [6]. To overcome low bioavailability, patients are often required to apply drops multiple times per day, worsening already-prevalent patient compliance issues such as incorrectly instilling drops or missing doses. A 2012 study designed to evaluate glaucoma patients found that nearly 9 out of 10 patients could not instill their prescribed eye drops correctly, which is extremely problematic and contributing to inadequate treatment and progression of disease [7]. Difficulties with eye drop application are well-documented, including issues maintaining a consistent drop height, squeeze force, and drop angle every time a drop is applied as well as patients struggling to stay on a consistent regimen [8–10]

Another strategy used to counteract low drug residence time is the application of higher concentrations of drug to ensure a therapeutic dose is absorbed. A high drug concentration in the tear fluid assures a high concentration driving force which must be high for enough drug to enter tissue before it is quickly washed away due to tear turnover. A vast majority of the applied drug is lost via the nasolacrimal duct, and the excess is systemically absorbed which can contribute to localized side effects and sometimes to systemic effects [11–14]. Localized ocular effects are commonly seen, such as how prostaglandin analogs used to treat glaucoma (e.g., latanoprost and bimatoprost) are known to contribute to conditions like conjunctival hyperemia, iris darkening, and eyelash changes [15]. Systemic effects can occur due to absorption of drugs through the blood vessels of the conjunctiva or via nasolacrimal routes when being cleared from the tear film, with a common example being systemic cardiac effects (i.e., bradycardia or hypotension) that are seen in a number of ocular medications such as pilocarpine, timolol, and epinephrine [14]. Despite high inefficiencies and potential side effects, the eye drop is still the standard of care because there are currently no options that compare to its convenience, cost effectiveness, and non-invasive nature. A number of alterations to eye drops have been studied in attempt to lengthen residence time and improve bioavailability such as adjusting the eye drop size or developing new applicators, increasing solution viscosity, using penetration enhancers, developing prodrugs, implementing drug carriers with mucoadhesive properties, etc. [16–19]. Despite these efforts, there is clearly still a significant need for a more sophisticated and efficacious delivery device or administration better designed to overcome the physiological barriers of the eye.

2. Contact Lenses for Drug Delivery

The concept of a drug-releasing contact lens has been around for over 50 years with the first mention of its drug releasing potential in Otto Wichterle’s patent describing the hydrogel contact lens in 1965 [20]. Since then and as contact lenses have become one of the most successfully used biomedical devices enhancing quality of life, there has been a very strong case made for contact lenses as ocular drug delivery devices [5,21–27]. As a biomaterial and a biomedical device, contact lenses have excellent safety and reliability, are well-established, and widely used clinically today. The population of contact lens wearers continues to grow and there are currently an estimated 45 million lens wearers in the United States alone [28]. There is clearly a large market for patients and physicians that are comfortable prescribing contact lenses for a variety of patients.

The physical and chemical makeup of the modern contact lens provides significant appeal for its use as a vehicle for drug delivery. Contact lenses can provide adequate volume for drug loading and a wide surface area for effective release into the eye, which has an average corneal surface area of 1.04±0.12 cm² [29]. For the most prominent contact lenses on the market today, the center thickness is typically less than 100 microns when measured at the center with a lens diameter between 14–14.5mm [30]. Additionally, the contact lens polymer chemistry is complex enough to be utilized for both covalent and non-covalent interactions and advanced drug delivery capabilities. Lastly, lenses can be easily placed and removed by patients compared to other types of drug delivery technologies and patients can visually ascertain correct placement.

It is imperative to define what constitutes a successful delivery vehicle for therapeutics to the eye. First, the duration of delivery should occur over a significantly longer time period than the eye drop, ideally treating for several days or weeks as needed. Second, a sufficient payload of stored drug must be available in order to deliver a therapeutically relevant dose over the desired time frame and be delivered leaving a relatively small amount of drug within the lens. The dosage of drug to be delivered is dictated by the condition being treated. Third, it is critical that a therapeutically relevant amount of drug is being delivered to the eye. And lastly, one of the most significant characteristics (and arguably the most difficult to attain) is showing control over the release rate of therapeutic throughout duration of treatment. An overarching goal for a novel ocular drug delivery device is optimization; the appropriate drug payload should be loaded and the majority of that payload delivered over the desired time frame to avoid wastage and potentially negative downstream effects.

In this review, therapeutic contact lenses are evaluated as ocular drug delivery devices, specifically focusing on a comprehensive listing of in vivo data and published in vivo studies, benchmarking progress in the field. It is important to note that there are a number of alternative ocular drug delivery systems such as: ocular inserts, punctal plugs, in-situ forming gels, and more. A few excellent reviews on the advances in ocular drug delivery systems covering contact lenses, especially including in vitro studies, and other devices being developed for the eye are recommended for further reading on these alternatives [31–36].

3. Contact Lens Drug Delivery Strategies that Reached In Vivo Experimentation

Various strategies have been used to produce drug-delivering contact lenses and a number of these strategies have been tested in vivo and include: drug soaking, carrier mediated methods, film encapsulation, inclusion and ion exchange complexes, diffusion barriers, molecular imprinting, ring implantation, and direct embedding. Figure 1 provides a broad overview of all the in vivo publications from 1965 to today, broken down by the primary release strategy. This figure helps to visualize the prevalence of each method, and which methods have been most thoroughly tested in vivo over the past 55 years. Drug soaking has been by far the most prevalent.

Figure 1.

Total in vivo publications in the field of drug-delivering contact lenses in 1965, broken down by method of release (as of December 2020).

All 66 of the published in vivo studies referenced throughout this review can be seen in Table 1 with the animal model, details on the drug molecule(s) released, and the year of publication.

Table 1.

Published in vivo studies since 1965. Abbreviations used: Carrier-Mediated Release (CMR), Diffusions Barriers (DB), Inclusion Complexes (IC)

Year	Technique	In Vivo Model	Drug/Molecule(Class);MW [logP]	Source
1965	Soaking	Human	Homatrope(Ocular Paralytic)	[37]
1970	Soaking	Rabbit & Human	Fluorescein(Model);332 [2.98]	[38]
1971	Soaking	Human	Pilocarpine(Glaucoma);208 [−0.09]	[39]
1971	Soaking	Human	Phenylphrine(Pupil Dilator);167 [−0.03]	[40]
1972	Soaking	Human	Pilocarpine(Glaucoma);208 [−0.09]	[41]
1973	Soaking	Primate	Pilocarpine(Glaucoma);208 [−0.09]	[42]
1974	Soaking	Rabbit	Prednisolone(Steroid);360 [1.50]	[43]
1974	Soaking	Human	Pilocarpine(Glaucoma);208 [−0.09]	[44]
1975	Soaking	Human	Pilocarpine(Glaucoma);208 [−0.09]	[45]
1975	Soaking	Human	Pilocarpine(Glaucoma);208 [−0.09]	[46]
1976	Soaking	Rabbit	Gentamicin(Antibiotic);477 [−1.89]	[47]
1976	Soaking	Human	Pilocarpine(Glaucoma);208 [−0.09]	[48]
1979	Soaking	Human	Dexamethasone Sodium Phosphate(Steroid);516 [1.56]	[49]
1980	Not Reported	Human	Gentamicin(Antibiotic);477 [−1.89]	[50]
1985	Soaking	Rabbit	Acetazolamide(Glaucoma);222 [−0.26]	[51]
1988	Soaking	Human	Gentamicin(Antibiotic);477 [−1.89] Chloromycetin(Antibiotic);323 [1.02] Carbenicillin(Antibiotic);378 [1.01]	[52]
1989	Not Reported	Rabbit	Dexamethasone Sodium Phosphate(Steroid);516 [1.56]	[53]
1997	Soaking	Rabbit	Levocabastine(Antihistimine);420 [4.29]	[54]
1999	Soaking	Human	Ciprofloxacin(Antibiotic);331 [0.65]	[55]
1999	Soaking	Human	Gentamicin(Antibiotic);477 [−1.89] Ciprofloxacin(Antibiotic);331 [0.65] Ofloxacin(Antibiotic);361 [0.84] Kanamycin(Antibiotic);484 [−2.58] Tobraymycin(Antibiotic);467 [−3.41	[56]
2001	Soaking	Rabbit	Lomefloxacin(Antibiotic);351 [1.71]	[57]
2001	Soaking	Rabbit	Amikacin(Antibiotic);585 [−3.34]	[58]
2005	Molecular Imprinting	Rabbit	Timolol(Glaucoma);316 [0.68]	[59]
2007	Direct Embedding	Human	Poly(vinyl alcohol)(Rewetting Agent);44 [0.26]	[60]
2009	Soaking	Human	Timolol Maleate(Glaucoma);432 [1.83] Brimonidine Tartrate(Glaucoma);442 [1.7]	[61]
2010	Soaking	Rabbit	Puerarin(Glaucoma);416 [1.95]	[62]
2010	Cyclodextrins (IC)	Rabbit	Puerarin(Glaucoma);416 [1.95]	[63]
2010	Soaking	Rabbit	Epidermal Growth Factor(Growth Factor)	[64]
2011	Soaking	Rabbit	Ketotifen fumarate(Antihistimine);425 [2.2]	[65]
2012	Vitamin E (DB)	Dog	Timolol Maleate(Glaucoma);432 [1.83]	[66]
2012	Vitamin E (DB)	Dog	Timolol Maleate(Glaucoma);432 [1.83]	[67]
2012	Molecular Imprinting	Rabbit	Ketotifen Fumarate(Antihistimine);425 [2.2]	[68]
2013	Ion Exchange (IC)	Rabbit	Gatifloxacin(Antibiotic);375 [1.21] Moxifloxacin(Antibiotic);401 [1.60]	[69]
2013	Soaking	Rabbit	Diadenosine Tetraphosphate(Secretegogue);926 [−0.16]	[70]
2013	Nanoparticles (CMR)	Dog	Timolol Maleate(Glaucoma);432 [1.83]	[71]
2014	Film Encapsulation	Rabbit	Latanoprost(Glaucoma);432 [3.65]	[72]
2014	Molecular Imprinting	Rabbit	Ciprofloxacin(Antibiotic);331 [0.65]	[73]
2015	Vitamin E (DB)	Dog	Timolol Maleate(Glaucoma);432 [1.83] Dorzolamide(Glaucoma);324 [−0.91]	[74]
2015	Direct Embedding	Rabbit	Hyaluronic Acid(Dry Eye);776 [−6.62]	[75]
2016	Cyclodextrins (IC)	Rabbit	Puerarin(Glaucoma);416 [1.95]	[76]
2016	Soaking	Rabbit	Pirfinedone(Anti-fibrotic);185 [1.82]	[77]
2016	Soaking	Human	Sodium Fluorescein(Model);376 [2.65]	[78]
2016	Nanoparticles (CMR)	Rabbit	Ketotifen Fumarate(Antihistimine);425 [2.2]	[79]
2016	Nanoparticles (CMR)	Rabbit	Timolol Maleate(Glaucoma);432 [1.83]	[80]
2016	Film Encapsulation	Primate	Latanoprost(Glaucoma);432 [3.65]	[81]
2017	Microemulsion (CMR)	Rabbit	Cyclosporine(Dry Eye);1202 [3.64]	[82]
2017	Ring Implantation	Rabbit	Hyaluronic Acid(Dry Eye);776 [−6.62]	[83]
2018	Ring Implantation	Rabbit	Timolol Maleate(Glaucoma);432 [1.83] Hyaluronic Acid(Dry Eye);776 [−6.62]	[84]
2018	Film Encapsulation	Rabbit	Betaxolol Hydrochloride(Glaucoma);344 [2.69]	[85]
2018	Soaking	Rabbit	Diquofosol(Dry Eye);790 [−5.03]	[86]
2018	Ring Implantation	Rabbit	Moxifloxacin(Antibiotic);401 [1.60]	[87]
2018	Film Encapsulation	Rabbit	Diclofenac Sodium(Model);318 [4.26]	[85]
2018	Vitamin E (DB)	Rabbit	Cysteamine(Anti-cystinosis);77 [0.11]	[88]
2018	Diffusion Barriers (Vitamin E)	Rabbit	Pirfenidone(Anti-fibrotic);185 [1.11]	[89]
2018	Film Encapsulation	Rabbit	Betaxolol Hydrocloride(Model);307 [1.44]	[90]
2019	Film Encapsulation	Rabbit	Dexamethasone Sodium Phosphate(Steroid);516 [1.56]	[91]
2019	Ion Exchange (IC)	Guinea Pig	Epinastine Hydrochloride(Antihistamine);286 [3.00]	[92]
2019	Micelles (CMR)	Rabbit	Cyclosporine(Dry Eye);1202 [3.64]	[93]
2019	Nanoparticles (CMR)	Rabbit	Timolol Maleate(Glaucoma);432 [1.83]	[94]
2019	Microemulsion (CMR)	Rabbit	Bimatoprost(Glaucoma);416 [3.17]	[95]
2020	Microemulsion (CMR)	Rabbit	Timolol Maleate(Glaucoma);432 [1.83]	[96]
2020	Film Encapsulation	Rabbit	Timolol Maleate(Glaucoma);432 [1.83] Bimatoprost(Glaucoma);416 [3.17] Hyaluronic Acid(Dry Eye);776 [−6.62]	[97]
2020	Cyclodextrins (IC)	Rabbit	Diclofenac Sodium(Model);318 [4.26]	[98]
2020	Direct Embedding	Rabbit	Gatifloxacin(Antibiotic);375 [2.51]	[99]
2020	Ring Implantation & CMR	Rabbit	Olopatadine(Antihistamine);337 [1.71]	[100]
2020	Molecular Imprinting	Rabbit	Bimatoprost(Glaucoma);416 [3.17]	[101]

3.1. Lens soaking.

When Wichterle and Lim mentioned the drug releasing potential in their 1965 patent [20], they were referring drug being in the aqueous portion of the hydrogel lens or soaking the lens with drug. Thus, it is no surprise that lens soaking was the technique that was first used in the exploration of therapeutic contact lenses as an alternative to topical eye drops due to its simplicity and relative ease of implementation. This method relies on the diffusion of drug molecules from a concentrated drug solution within the fluid-occupied space of the hydrogel lens. This loading occurs via equilibrium partitioning by soaking the lens in a drug solution and release is driven by concentration gradient-based diffusion when placed on the eye. Because this method can be easily applied to off-the-shelf commercially available lenses, lens soaking has been the most prominent strategy for drug loading and release via hydrogel contact lenses in the literature to date. Also, 90% of the field’s published human in vivo studies have utilized lens soaking, typically applying drug-soaked commercial lenses to patients’ eyes directly after being soaked in a concentrated drug solution [37,38,55,56,60,61,78,39,40,44–46,48,50,52]. These human in vivo studies and a majority of in vivo lens soaking studies claim that this method increased drug penetration and delivered greater cumulative drug content when compared to eye drop therapy. The appeal of lens soaking can be attributed to its simplicity and how easily it could be incorporated into current manufacturing schemes, pre-sterilization.

However, many of the reasons that contribute to this method’s convenience also contribute to its biggest downfalls. Upon examination of the literature, it has proven to fail and not lead to any appreciable control or delay of drug release nor any clinical relevance. Any marginal delay of release from lens soaking is highly dependent on the physiochemical properties of the drug molecule being delivered, the contact lens structure and material composition, and the non-covalent interactions between the drug and lens polymer network. Since loading and release for soaked lenses are diffusion-driven, there are significant limitations on the drugs that can be used. Larger molecules have been shown to be difficult to passively load into contact lenses, which greatly limits higher molecular weight therapeutics that this strategy could be applied to. Of the 35 different molecules used in in vivo lens soaking studies published to date, 91% of the drugs had a molecular weight under 600 Daltons. In terms of lens materials, a more hydrophilic lens with higher water content will exhibit diffusion characteristics more similar to diffusion through water, which may improve loading for hydrophilic molecules but contributes to a very fast, uninhibited release of drug from the lens when applied to the eye. Xu, et al. published a soaking study in 2011 that showed silicone hydrogel lenses with different hydrophilic content resulted in different drug loading capabilities and different release profiles in a rabbit model—the more hydrophilic silicone hydrogel loaded approximately 22% more ketotifen fumarate, but were unsuccessful in controlling or delaying release with a burst release and a 6.8 times shorter mean residence time in the tear film compared to a slightly more hydrophobic lens under the same conditions [102].

When applied to well-designed in vitro conditions or in vivo studies that exhibit drug concentration in the tear film over time, soaked lenses have displayed a very fast, uncontrolled burst release—usually less than an hour from initial drug concentration to final drug concentration—greatly resembling topical eye drop release properties. In a clinical study comparing hydrophilic contact lenses soaked in an antibiotic solution and a subconjunctival injection, antibiotics delivered with contact lenses exhibited a significant burst release, with peak concentrations being reached at 30 minutes [52]. It was stated that these lenses would need repeated application for consistently high drug penetration, much like eye drop therapy. In a similar study with rabbits, pre-soaked lenses delivered peak amounts of prednisolone to the tear film after only 15 minutes [43]. Prior to the publication of more recent experimental evidence that strongly suggests lens soaking results in poor drug loading, short elution times, and very limited control over release kinetics, nearly 80% of the in vivo studies published through 2011 utilized this method. In vivo studies of drug-soaking lenses dominated the field early on, likely because newer strategies were still being developed and promising in vitro data from poorly designed experiments was prevalent.

A thorough experimental study was published in 2014 that highlighted the significant effects that in vitro conditions have on the release properties of therapeutic contact lenses [103]. The results showed that small volume in vitro release studies of drug releasing lenses with no or little mixing, which are prevalent in the field, overestimate release duration greatly and should not be used as experimental evidence of release control [103]. In these systems, equilibrium is reached very quickly and the driving force for release diminishes very quickly. These small volume studies with no mixing or limited mixing showed a significant extension of release duration when compared to release studies that more closely mimic physiological release or those that successfully analyze equilibrium effects and combat misleading equilibrium effects. Without experimental verification of equilibrium effects being limited, in vitro release data cannot be considered experimentally relevant. This is likely why many promising in vitro studies, which showed in vitro controlled drug release, have shown poor correlation with directly compared in vivo studies and have exhibited very fast drug release in the eye [62, 86, 99]. Unfortunately, many in vitro release experiments are still being conducted using small volume experimental conditions, which could result in continued poor correlation between in vitro and in vivo results regardless of strategy.

Yet, from 2012 to today less than 13% of in vivo studies have utilized lens soaking, which suggests that the therapeutic contact lens field is shifting focus to other release strategies. Based on publication trends, it appears that drug-soaked lenses or equilibrium partitioning alone will not replace eye drop therapy and the field will continue to shift towards more sophisticated release methods.

3.2. Diffusion barriers.

Similar to lens soaking, diffusion barrier-mediated release strategies also aim to load therapeutics via equilibrium partitioning, but this method intends to slow drug release by increasing the tortuosity of the drug molecule’s path out of the polymer matrix. Through the incorporation of impermeable structures or large molecules (such as vitamin E) that the drug must diffuse around before leaving the lens, drug release can be delayed. This strategy is still relatively easy to implement and iterative to lens soaking by loading additional molecules that offer additional diffusional resistance along with drug. In a 2015 publication, purchased narafilcon B lenses were dried and soaked in a vitamin E-ethanol solution for 24 hours, then loaded with betaine drug aqueous solution for 2 days and in a dexpanthenol solution for another 2 days. Loaded lenses then underwent a small-volume in vitro release study where each lens was placed in 2 mL of phosphate buffered saline that was periodically replaced over time [104]. The greater the concentration of barrier molecule (vitamin E), the slower the drug release. The highest concentration of barrier molecule extended the release duration to approximately 5 hours when compared to a lens without barrier, which released in approximately 5 minutes. Increasing barrier molecule content to control release eventually reaches a point when critical physical and optical lens properties are affected, which limits the degree that release rate can be controlled utilizing diffusion barriers. Additionally, the presence of vitamin E resulted in 1.5x less drug being loaded and released than lenses without vitamin E. This introduces one of the notable weaknesses with the barrier diffusion strategy—there is finite volume fraction within the polymer structure, and barrier molecules, which are usually bulky and take up space, inhibit the loading of drug molecules into the lenses. Additionally, barrier molecules will also be released, and potential effects of barrier molecule elution into the eye must also be considered. For example, vitamin E was described as an appropriate choice for diffusion barrier because of potential benefits, such as UV-blocking [105]. Further issues with the diffusion barrier method are very similar to those with drug-soaked lenses: difficulty in loading large molecular weight drugs, misleading in vitro experimental data, a fast initial burst release, and a short duration of release.

Analyzing in vivo results, one group published 5 in vivo studies using the diffusion barrier method. All 5 incorporated vitamin E as a diffusion barrier—with either dog or rabbit animal models—where all of the drug molecules had molecular weight values lower than 500 Daltons [66,67,74,88,89]. In each of these studies, a straightforward drug release profile (drug concentration over time) was presented for in vitro release but not for the in vivo release studies. All in vivo studies only presented data of pharmacological effects over time (such as intraocular pressure, pupil dilation, or heartrate) or strictly to assess in vivo safety. Because of this, there is no clear validation of controlled release in the in vivo studies, but the in vitro experimental set up with small volumes suggests that release in the tear film would occur very quickly. Additionally, a long loading period (as long as 21 days [67]) is described in these studies, limiting this technology’s potential to fit into current lens manufacturing processes.

3.3. Direct embedding.

This is the first strategy covered in this review that involves altering the contact lens formulation prior to polymerization. Direct embedding refers to the addition of drug into the pre-polymer solution before lens creation. When contact lenses with added drug content are polymerized, the polymer network forms around the drug molecules. This method can be advantageous when applied to therapeutics that are too large to be loaded via soaking and has the potential to load a tailorable amount of drug payload into lenses and alter the drug release profile. The release of drug molecules embedded within the hydrogel macrostructure is driven by concentration gradient-based diffusion from the lens into the tear film, similar to drug-soaked lenses. Hence, it is arguable that a lens with directly embedded drug would behave similarly to a drug-soaked lens with enhanced loading. As previously described, a drug-soaked lens strategy has very limited to no extension of drug release.

Three publications describe in vivo studies of direct embedding: a 2007 human study releasing poly(vinyl alcohol) (PVA) [60], a 2015 rabbit study delivering hyaluronic acid [75], and a 2020 rabbit study with embedded gatifloxacin [99]. The 2007 study investigated the elution of poly(vinyl alcohol) (PVA) from commercial nelfilcon A lenses to limit contact lens drying and induced dry eye [60]. This study presented drug concentration data for small volume in vitro release with 100μL volumes. The in vivo data was subjective, presenting comfort scores from patients (scoring from “none” to “severe”) when compared to lenses with PVA “extracted” or washed out [60]. The other studies exhibited similar experimental plans and outcomes: a small volume in vitro release showing extended release profiles that were affected by the amount of embedded drug and in vivo data that revealed release durations that were 2–3 times shorter than the in vitro studies [75,99]. For both, the in vivo release kinetics are described as having an “initial burst release” and show a significant decrease in drug concentration in the tear film within 24 hours. Gatifloxacin-releasing lenses showed a decrease of tear film drug content of 90% within one hour [75]. Hyaluronic acid release showed a significant drop in concentration after 24 hours [99].

Longer chain and larger volume molecules such as comfort agents like PVA and hyaluronic acid will lead to longer release durations due to diffusional constraints of those molecules moving through the network structure. Fickian diffusion based on concentration driving force is the controlling mechanism and zero-order release control cannot be achieved. Also, for release durations longer than daily wear, the payload of embedded molecule must be higher and such loaded drug content has the potential to negatively influence lens physical properties [120, 121]. For example, in a study where hyaluronic acid was directly embedded into a contact lens for drug delivery, effects on water uptake, transmittance, and ion permeability were observed as a result of this additional drug content [75]. Thus, the amount of drug being loaded into a lens made for a longer release duration via direct embedding could result in physical property issues and must be considered when designing lenses with this strategy.

Direct embedding of smaller molecules will easily and very quickly release from the polymer structure and mimic eye drop release profiles. As the molecule increases in hydrophobicity, release duration can be extended further, but additional interactions are needed to sustain longer release durations. With these limitations in mind, direct embedding strategies do not have the potential to broadly apply to many therapeutics or molecules.

3.4. Inclusion and Ion Exchange complexes.

This method of loading and release involves the incorporation of inclusion molecules or specific chemistry within the polymer to increase drug loading and control release. Two forms of complexes exist in the field of drug releasing lenses , cyclodextrins (CDs) and ion exchange complexes (IECs) and five in vivo studies have studied lenses utilizing these methods [69,76,92,98,106]. As these methods include non-covalent interactions, they have advantages over methods such as diffusion barriers and drug soaking and have the potential to improve release rate control, especially with low molecular weight molecules.

Cyclodextrins are cyclical oligosaccharides that bind drug molecules within a hydrophobic cavity forming an inclusion complex. CDs have been used as additives both in ophthalmic solutions and hydrogels but are now being investigated for use within drug releasing contact lenses [106,107]. The concentration of hydroxyl groups within the ring structure allow CDs to form high-affinity complexes with some drugs, utilizing non-covalent interactions for delayed release. Currently, three in vivo studies have been published that use CD’s for the loading and release of drugs in rabbit animal models: two releasing puerarin [62,76] and another study with diclofenac sodium [98]. In two of these studies, the drug concentration in the tear film versus time was not determined and only the pharmacological effect of the drug noted. In the 2016 publication, polyHEMA lenses with CDs were synthesized and loaded with puerarin and tested in vitro and in vivo [76]. Decreased intraocular pressure in the animal model was shown to last for 5 days with the drug-eluting lenses, comparable to pharmacokinetics seen with eye drop therapy. In the 2020 publication, CD effectiveness was tested both in vitro and in vivo as well, this time evaluating in vivo effects by observing antibacterial effects from three different treatments (diclofenac eye drops, a diclofenac sodium-soaked HEMA lens, and a HEMA lens with CD content containing diclofenac sodium) for 72 hours and followed by histological analysis of the corneas. Drug concentration in the tear film over time was not obtained in these two in vivo studies which made it difficult to assess the nature of release kinetics or the extent of release control.

Additional studies can be highlighted for a better understanding of how CD release methods relate to in vivo drug concentrations. In work from Xu and colleagues, polyHEMA lenses were synthesized with increasing CD content and tested against control lenses with no CD content, all loaded with puerarin via equilibrium partitioning. In vitro and in vivo release studies were completed [106]. First, lenses with CDs had increased drug loading when compared to control lenses. Loaded lenses were then used for an in vitro release study in which loaded lenses were placed in 10 mL of distilled water and 5 mL of the release medium was replaced periodically. In vitro release data showed that all lenses tested resulted in a burst release of approximately 60% of the total drug content within 30 minutes regardless of CD content. This burst was contributed to free, unbound puerarin rapidly diffusing from the lenses. Following the burst release, CD containing lenses exhibited slower release rates compared to control lenses, and larger CD concentrations resulted in slower release rates over approximately 12 hours. When these lenses were tested in rabbits, however, release duration dropped substantially. Release from CD containing lenses ended at 360 minutes when the control lens release was complete, and the mean residence time of puerarin for CD-containing lenses was calculated to be approximately 116–119 minutes. The discrepancies in release duration is indicative of the in vitro experiments being a poor representation of physiological release conditions. The release duration of the in vitro study is overestimated due to equilibrium effects from the small volumes used. Also, the in vitro studies used distilled water as release media rather than an ionic solution like phosphate buffered saline or artificial lacrimal solution that matched the ionic strength of the tear film.

Ion exchange is the other non-covalent complexation strategy that has been used to produce drug releasing contact lenses. This method is considered a modification of lens soaking by utilizing ionic monomers in the polymer structure, specifically chosen to have electrostatic interactions with the drug to be released. The interactions between cationic and anionic components form complexes before being placed into the eye—the release of drug occurs when salt ions within the tear film replace the drug in the lens. Currently, two in vivo studies have been published utilizing IEC’s [69,92]. In a 2013 publication from Kakisu et al., lenses were prepared with anionic and cationic monomers for the in vitro and in vivo release of two antibiotics (gatifloxacin and moxifloxacin) [69]. The in vitro study was completed in 2 mL of PBS, refreshed at 2, 4, 8, 24, 48, and 72-hour time points, again prone to equilibrium effects from the small volumes. The in vivo study was completed with eighty-seven rabbits in which S. aureus bacteria was administered in the anterior chamber of each eye. Treatment effectiveness was analyzed in three ways: a control group with no treatment, antibiotic eye drop application, and IEC-containing contact lenses releasing antibiotic. Along with analyzing the progression of infection and inflammatory response over 72 hours, antibiotic concentrations were measured from the cornea, aqueous humor, and ocular lens at various time points (but not the tear film concentration). As a benchmark for comparison, 10, 30, and 60 minute time points were also taken after eye drops were applied [69].

In another IEC contact lens in vivo study, five different lenses with different ionicities were developed to test how the monomeric composition affected a number of lens properties, as well as in vitro and in vivo release of an antihistamine, epinastine hydrochloride, in guinea pigs [92]. The in vitro study was performed in 250 µL of PBS and replaced at various time points: 0.5, 1, 2, 4, 6, 8, 12, and 36 hours. Despite this extremely small volume for release, comparisons were made between lenses of different ionicities to understand the effects on release in an ionic medium. Lenses included cationic, bi-ionic (having both cationic and anionic monomeric content), and a non-ionic lens containing n-vinyl pyrrolidone (NVP). Anionic lenses, as expected due to oppositive charge of drug, exhibited delayed release for 12 hours. In vivo release was tested via Evans blue extravasation, for analysis of the effectiveness of delivered histamine from the lenses, but release drug concentration and associated kinetics were not explicitly shown [92].

One of the notable limitations of this strategy is the limited range of drug molecules that can be successfully incorporated into inclusion complexes. CDs require drugs that can non-covalently interact within the CD hydrophobic cavity and IECs require ionic, non-covalent bonding. Extended drug release can be greatly affected by release medium because these complexes are particularly sensitive to ions and ionic strength and controlled release can be achieved in aqueous media without ions and be completely disrupted when ions are present. Many of the published studies did use phosphate-buffered saline (PBS) in their in vitro release studies. However, with release volumes as low as 250 µL, the experimental conditions suggest an overestimation of release duration due to these small volume in vitro release conditions used [103].

3.5. Encapsulated diffusion barrier.

This strategy involves creating contact lenses that contain a separate polymer (a film or ring) within the lens material. Although this method is arguably a physical form of a diffusion barrier, it differs greatly in structure and loading because it involves the implantation of an entirely different polymer within the bulk contact lens polymer. This release method is highlighted as having great potential to be highly customizable in terms of what type of polymer film or ring is used, potentially allowing for a wide variety of molecules and polymers to be embedded within lenses that would otherwise not have adequate properties as the bulk portion of the contact lens. Currently there are seven film-encapsulated lens in vivo studies [72,81,85,90,91,97,108] and four ring-implanted lens in vivo studies in publication [83,84,87,100].

Two groups have contributed the most film-encapsulated in vivo work, and both had different approaches. One group published in vivo studies in 2014, 2016, and 2019, and directly added drug into a pre-polymer solution spin coated to create a drug-polymer film that was incorporated into methafilcon hydrogel contact lenses [72,81,91]. Ciolino, et al. published a study in 2014 where lenses were designed to deliver latanoprost (anti-glaucoma agent) to the eyes of rabbits for nearly a month [72]. For 28 days, the concentration of drug in the aqueous humor was measured to study how ‘pre-conditioning’ the lenses affected the burst release of drug. ‘Pre-conditioning’ was defined as submerging loaded lenses in PBS solution for 1 or 3 days prior to release. Without pre-conditioning, a significant burst in drug concentration can be seen where over 90% of the drug concentration was lost within the first two time points taken at day 1 and day 3, and this burst was slightly smaller with pre-conditioning. A single application of an eye drop was undetectable in the aqueous humor within 24 hours. Drug release concentration data from the tear film would have been crucial to understand the release kinetics directly from the lens, but extremely low concentrations of latanoprost were claimed to be present (as low as 1 ng per mL) for nearly a month.

Zhu et al. published three studies in 2018, all focusing on releasing a model drug molecule (either betaxolol hydrochloride or diclofenac sodium) where inner layers within lenses were described as having “ion-triggered” or “pH-triggered” release [85,90,108]. In one study, betaxolol hydrochloride was used to form IECs within the inner film of the lenses. When compared to eye drops and drug-soaked contact lenses, the film-encapsulated lenses produced a mean residence time of 7.22 ± 0.93 hours in the tear film, approximately 20 and 8 times longer than drops and soaked lenses, respectively [85]. A burst release was shown with all three, but the maximum concentration of drug in the tear film was delayed by an hour with the inner layer embedded lens. Similar data can be found in their other two publications: a somewhat delayed peak in drug concentration, a lower maximum concentration of drug reached, and an extended mean residence time with the film-encapsulated lenses when compared to soaked lenses or eye drops [90,108].

Most of the ring-implanted lens studies presented release data with many characteristics similar to the film-encapsulated studies just described: a significant burst release of therapeutic when applied to the animal, followed by an extended release duration surpassing eye drops and soaked lenses by varying degrees [83,84,87,100]. Collectively, these studies show some promise in relation to extending the total release duration of therapeutics but could not avoid a significant burst release upon placement on the eye, similar to direct embedding or IECs. These researchers were mindful of burst release kinetics and working towards minimizing the initial drop in drug concentration upon application of these lenses, which sometimes behaved nearly identically to eye drop application. Any pre-soaking leads to substantial wasted drug and is not a sustainable method for clinical translation.

One of the biggest concerns with separate polymers within the lens are the associated negative impact on the optical clarity, oxygen transport, mechanical properties as well as increased manufacturing time. The additional polymers decrease drug transport by a much tighter network structure, which decreases optical clarity in those lens regions that encapsulate the additional polymer. In most studies, optical clarity issues were circumvented by placing the polymer film to the “outer” regions of the contact lens, to maintain a transparent middle portion within the lens, which can be seen in illustrations and images in several publications [83,84]. However, lenses with affected optical clarity would likely have a negative response from consumers, even if only affecting peripheral vision. Along with a more thorough look into optical clarity and clinical feedback, further investigation of the entire range of properties is needed for improved evaluation of this strategy overall.

3.6. Carrier-mediated release.

Carrier-mediated release includes the use of any method where drug molecules are entrapped within a vesicle or particle and embedded into a contact lens hydrogel. Carriers can help overcome drug solubility and phase partitioning issues within the contact lens and are useful for the inclusion of otherwise insoluble drugs. Physiochemical parameters of the drug and carrier are extremely important factors to consider when designing these systems. Some carriers, like liposomes, involve a lipid bilayer that encases hydrophobic drug molecules with the potential for hydrophilic molecules to be contained in the core. It is critical that the carrier is soluble within the lens pre-polymer solution. There are limitations on the drugs that can be used in certain carrier-lens systems, depending on whether a completely hydrophilic material or a biphasic material with hydrophobic regions is used. Regardless, one of the major advantages of this strategy is the ability to deliver highly hydrophobic drugs from a hydrophilic lens material.

There are four types of carriers that have been utilized in drug releasing lens in vivo studies: nanoparticles, microemulsions, microparticles, and micelles. According to a 2004 in vitro study, nanoparticles, that were successfully loaded with lidocaine as a hydrophobic model drug, exhibited an exponentially decaying release rate over time [21]. With initial release rates being high and quickly decreasing over time, release profiles resembled the bolus dosage form that eye drops provide but were followed by a longer duration of release due to greater drug loading capabilities than soaked lenses. Four studies have been published that highlight in vivo results of nanoparticle-laden contact lenses: three delivering timolol maleate and one delivering ketotifen fumarate [71,79,80,94]. Timolol maleate is an anti-glaucoma drug and ketotifen fumarate is an antihistamine, and both molecules are similar in size (432 and 435 Dalton, respectively) and lipophilicity (1.83 and 2.2, respectively). Jung et al. soaked commercial lenses (Acuvue Oasys) in a nanoparticle solution and analyzed pharmacological effects (changes to intraocular pressure) and safety over 5 days in a dog model, but the paper did not provide release kinetics data from the in vivo model [71]. The other three publications utilizing nanoparticles showed significant burst release from the lenses when placed in an in vivo model, regardless of the manner in which the nanoparticles were embedded in the lens (contained in an implanted polymer ring or directly into the pre-polymer solution) [79,80,94]. In one case, nanoparticle-laden lenses showed release behavior nearly identically to a drug-soaked lens without nanoparticles when studied in a rabbit model [94].

Microemulsions are thermodynamically stable dispersions of “oil in water” (or vice versa) that utilize surfactants/amphiphiles to significantly lower the interfacial tension and allow complexes to form [109]. Microemulsions have been applied to several potential applications, including drug delivery because they can be used to encapsulate therapeutics and disperse insoluble drugs. Currently, three rabbit animal model studies represent microemulsions among in vivo publications: a 2017 cyclosporine study, a 2019 bimatoprost study, and a 2020 timolol study [82,95,96]. In 2019, Xu et al. published an in vivo study that exhibited a burst release from microemulsion-laden silicone hydrogel lenses where approximately 90% of the initial bimatoprost concentration in the tear film was depleted within 4 hours of application [95]. This was a significant discrepancy from the small-volume in vitro data that suggested release would occur gradually over 72 hours. Release kinetics were also analyzed in a 2017 publication from Maulvi, et al. in which HEMA-based hydrogel lenses were loaded with microemulsions with varying lengths of surfactants to deliver cyclosporine [82]. The data showed concentrations of cyclosporine in the tear film for up to 24 days. Three lenses were tested in vivo: a lens with cyclosporine directly embedded in the pre-polymer solution (the experimental control) and two microemulsion-laden lenses with varying surfactant lengths. The more stable microemulsion resulted in an extended release duration (approximately 3x as long) and the less stable microemulsion, which exhibited release nearly identical to the directly embedded lens. However, all three systems exhibited a burst release upon application and a steep increase in concentration followed by a decaying release rate over time. And it is important to note that polyHEMA materials are not FDA-approved for extended or overnight wear, and wearing contact lenses with low oxygen permeability for long durations of time can have significant side effects such as limbal hyperemia, vascularization, stromal striae and other issues tied to poor oxygen transport and fluid turnover under the lens [110]. Thus, despite being the second most studied method to reach in vivo experimentation, carrier-laden lenses have not exhibited significant drug release control and any benefit and clinical translation may be outweighed by additional manufacturing hurdles and costs.

3.7. Molecular imprinting and macromolecular memory.

Most imprinted polymers produced to date have been highly crosslinked in efforts to limit the flexibility of the associated binding cavities produced between polymer chains. It was assumed that flexibility of polymeric chains would lead to fatal deficiencies in the metrics by which imprinted structures are defined, namely template binding affinity, capacity, and selectivity. However, experimental work has proven that this is not the case [111].

The concept of molecular imprinting within hydrogels involves the creation of macromolecular memory for a template molecule within a polymer network. Since gel structures can have significant flexibility in the polymer chains, the term macromolecular memory or structural plasticity of polymer chains has been used to describe molecular imprinting in gels [111]. Effective self-assembly of the functional monomer(s)-template complex is crucial toward non-covalent imprinting efficacy. Macromolecular memory is primarily due to two synergistic effects: (i) network architecture that is similar in dimension to the template drug molecule, which provide stabilization of the chemistry in a crosslinked matrix, and (ii) chemical groups oriented to form multiple non-covalent complexation points with the drug template. Non-imprinted gels are prepared in the same manner but without the inclusion of template. It is important to note that direct embedding is not a form of molecular imprinting as there is no formation of macromolecular memory for the template drug within the polymer network. With direct embedding, there is no selection of chemical groups or additional functionality that are specifically incorporated to interact with the template molecules as seen with molecular imprinting.

Macromolecular memory delays the transport of drug from the polymer lens matrix via interaction of the drug with numerous functional groups organized within the network. The drug’s heightened interaction with the memory pockets slows its release from the hydrogel despite comparable free volume within the polymer chains for drug transport. This type of network formation can tune the drug loading and release profile with a proper optimization of drug affinity relating to number and strength of functional monomer interactions, crosslinking structure, and mobility of polymer chains. It may be ideally suited in thin film or ‘limited volume’ applications and can be applied as a platform application.

Implementation of this strategy can appear deceivingly simple but merely adding functional monomer and drug to the polymer mixture prior to polymerization does not guarantee the formation of an imprinted polymer network. Imprinting within a flexible polymer network is especially challenging, and traditional approaches to molecular imprinting that typically rely on polymer rigidity do not adequately contribute to the specificity or binding kinetics that produce desired “memory” effects in gels [112]. To successfully apply molecular imprinting principles to a hydrogel system, a biomimetic approach has been developed to mimic the diverse, multiple, non-covalent interactions that occur in nature [113]. Two significant factors have been identified via in vitro studies that have a profound effect on release kinetics and the degree of control over release that can be seen in therapeutic contact lens systems: the concentration of functional monomers to template drug, often referred to by the molar ratio of functional monomer to template (M/T ratio) [114] and the diversity of functional monomers used [113,115].

Currently, four drug releasing lens in vivo studies have been published that utilize molecular imprinting techniques [68,73,101,116]. Three of these studies exhibit poor release kinetics from the imprinted lenses that do not differ greatly from the non-imprinted, control lenses (drug-soaked).

The most successful in vivo work published to date involved the delivery of the antihistamine, ketotifen fumarate, in a rabbit model. Imprinted poly (hydroxyethylmethacrylate) lenses with acrylic acid (AA), n-vinyl 2-pyrrolidone (NVP), and acrylamide (AM) as functional monomers [68] exhibited controlled release with no burst and a sustained therapeutic concentration of drug maintained over 24 hours for the entire duration of approved wear. The diversity of the functional chemistry in the lens was crucial to imprinting effectiveness [115].

Without adequate functional chemistry within the network, effective imprinting cannot occur, and in vivo experiments have highlighted this issue as well as inconsistencies with in vitro experiments. An in vitro study of imprinted hydrogel lens for timolol (anti-glaucoma therapeutic) with methacrylic acid (MAA) as a sole functional monomer [59] appeared promising with 13 days of release; however, the experiment involved placing a loaded lens in 10 mL of saline solution at 37°C without mixing or replacing release media. When the lenses were tested in vivo, release occurred for only 90 minutes (less than 2% of the in vitro release duration) from the imprinted lens and burst release occurred and was only delayed by 5 minutes when compared to eye drops [59]. In a 2014 study, ciprofloxacin (an antibiotic) was delivered from polyHEMA lenses with 3-[tris(trimethylsiloxy)silyl]propyl methacrylate (TRIS) content that utilized acrylic acid (AA) as a functional monomer [73]. Small-volume in vitro release occurred for a duration of 3 days, but no drug-release profile was provided for the in vivo study—only an evaluation of antimicrobial activity in which eye drop therapy significantly out-performed any lenses tested. Lastly, in another in vivo study, imprinted silicone hydrogel lenses were synthesized to deliver bimatoprost (anti-glaucoma drug) in a rabbit animal model [101]. In vivo release from imprinted lenses delivered detectable bimatoprost content to the eye for 12 hours, but the data exhibited significant initial burst release in which approximately 80% of the tear film concentration was depleted within 2 hours. In these three studies, a diversity of functional monomer content non-covalently interacting with the drug was not pursued leading to decreased imprinting effectiveness and poor optimization of vital imprinting interactions. Also, in vitro studies should be further examined because there was poor correlation between in vitro and in vivo studies.

Figure 2 highlights release data and comparison of imprinted lenses to other studies. Figure 2a (in vitro) and 2b (in vivo) show ketotifen fumarate being released from polyHEMA lenses and silicone hydrogel lenses, respectively, utilizing drug soaking methods and exhibit insufficient drug loading and a very short release duration [65,117]. Figure 2c-f provides a direct comparison various in vivo molecular imprinting release profiles.

Figure 2.

Comparison of drug release results for various methods. (a) reproduced with permission from [118] demonstrates the in vitro release profile from drug soaked alphafilcon (PHEMA) lenses where (□) represents the ketotifen fumarate mass that released from the lens. (b) reproduced with permission from [65], shows in vivo release from a silicone hydrogel of an effective concentration (ED₅₀) in ~8hrs where (■) and (●) represent SCL1 and SCL3, two different soaked silicone hydrogel contact lenses, and (▲) represents the application of a 0.05% ketotifen fumarate eye drop. The lens release is Fickian in nature and is complete within 4 hours. Ketotifen loading was very low, with a peak ketotifen concentration of 133 μg/lens. In Figures 2a and 2b, very low control over release rate and low drug loading is observed. Soaking commercial silicone hydrogel and hydrogel contact lenses in ketotifen fumarate solutions does not result in sufficient loading or release duration for effective delivery from contact lenses. (c) reproduced with permission from [59] shows release of timolol from (■) imprinted lenses, (□) non-imprinted lenses, and two different concentrations of eye drops: (○) 0.068% and (●) 0.25%. The imprinted lens with a bioavailability of 57 μg*hr/mL was only a 3.5 fold increase over the bioavailability from topically applied eye drops for a duration of only 90 minutes. (d) reproduced with permission from [68] shows the first steady, extended release of a therapeutic concentration of ketotifen fumarate for duration of lens wear (24 hours), a significantly increased ketotifen fumarate residence time, and a significantly increased bioavailability of ketotifen fumarate (4365 μg*hr/mL) in the tear fluid of rabbits from an imprinted lens (94 fold greater than commercial topical eye drop) (■) for an extended duration compared to non-imprinted lenses (●) and topical drop therapy (▲). (e) reproduced with permission from [62] shows release of puerarin from cyclodextrin-containing lenses (●) and 1% puerarin eye drops (■). (f) reproduced with permission from [84] shows timolol release in rabbits from ring implanted lens (Δ), non-modified soaked lens (Δ, lower data line), and topical drop (●). Both (e) and (f) display a significant burst release with little control over release rate.

Based on a number of published in vitro studies, macromolecular memory can be applied to a wide variety of molecules and though some molecules can be more easily imprinted (containing higher chemical functionality and greater non-covalent bonding capabilities), this strategy is not limited to molecules within a particular range of size, partition coefficient, or drug type. Molecular imprinting has been implemented in a variety of lens types, wear schedules and modalities. Imprinting strategies also show promise for clinical translation to a commercial product, maintaining all lens commercial properties and capable of fitting into commercial lens manufacturing processes and requiring no additional steps. The key differences with imprinting is the inclusion of diversity of functional monomers and the amount of functionality—both are critical for success along with network architecture within these flexible systems, which many imprinting systems fail to include [111–113,119].

While the method can be applied to a large array of various molecules with different functionalities, the process of selecting the right combination and concentration of functional monomers can be cumbersome. Functional monomers must non-covalently bind with drug moieties, must be soluble in the pre-polymerization formulation, and must have the ability to react efficiently into the polymer chains during polymerization. Unlike lens soaking or direct embedding methods, this method requires alteration of the pre-existing lens formulation by adding additional monomers which may require additional time for regulatory approval and commercialization depending on past use and regulatory status of the monomer species.

4. Trends in Contact Lens Drug Delivery Based on In Vivo Experiments

Ocular therapeutic are not delivered efficiently and effectively and better drug delivery formulations and technology is an unmet need. For therapeutic contact lens technology to progress towards clinical translation and ultimately have a significant impact on patients, the current status and track record of in vivo work should be studied and well-understood.

Animal models have historically served as an “initial screen” for the development of new ophthalmic compounds and delivery systems, as a way to study safety and effectiveness before starting human clinical studies. Interestingly, as Figure 3a shows, contact lens drug delivery in vivo work actually began with mostly human clinical trials, beginning in 1965 when commercial contact lenses soaked in a homatrope solution were used on human subjects [37]. For the first 35 years since this first publication highlighting in vivo data, every 2 out of 3 studies were performed with human subjects. This curious trend of early studies primarily using human subjects can likely be credited to the prevalence of the lens soaking method, which largely comprised of commercial lenses already on the market soaked in commercial eye drop solutions or suspensions. Also, the field of biomaterials science and engineering was in its infancy in the 1970’s and as such early human studies were more prevalent. Lastly, the eye is very accessible and contact lenses can be easily placed and removed. Until 2005, the only release method reported being used was drug soaking. Figure 3 shows the correlation between in vivo subjects and the release methods. As more complex methods were introduced, human studies quickly decreased, and animal studies increased. Animal models, mostly rabbits, have been dominant since 2000. This notable increase in rabbit in vivo studies published in the past two decades is solidified in Figure 4a, which shows that 64% of all published studies as of May 2020 have used a rabbit animal model. If lens soaking had been shown to be effective and adequate for replacing eye drop therapy through the initial human studies, drug-soaked lenses for extended ocular treatment would already be on the market today.

Figure 3.

Timeline of published in vivo studies of drug-delivering contact lenses since 1965. Broken down by (a) the in vivo models and (b) the release method being highlighted in each publication. For Figure 3a, the bars represent the following animal models: guinea pig (), dog (), primate (), rabbit (), human (■). For Figure 3b, the bars represent the following release methods: soaking (■), molecular imprinting (), film encapsulation (), carrier-mediated (), inclusion complexes (■), direct embedding (), diffusion barriers (), or other ().

Figure 4.

Various depictions of significant trends observed throughout therapeutic lens in vivo studies since 1965. Figures broken down by (a) animal model prevalence, (b) type of molecule released, (c) molecular weight of molecules released, (d) partition coefficients of released molecules by release method.

Discovering trends related to the drug molecules being delivered via in vivo studies is less straightforward but still leads to some key observations regarding therapeutic contact lenses. Figures 4b, 4c, and 4d highlight critical properties of the ocular therapeutics (or model drug molecules) used throughout this collection of in vivo studies. Particularly at the inception of this field, little variability was seen in the first two decades regarding drug class with over half of the studies delivering a glaucoma therapeutic (almost always pilocarpine, the predominant drug at the time). Yet, that emphasis has remained strong, as Figure 4b suggests, where glaucoma drugs represent 40% of the molecules studied in the published in vivo experiments. Antibiotics representing the next biggest fraction at 24%, and it could be argued that a significant driving force behind drug selection in these studies is the prevalence and impact of the condition to be treated. Shifting focus to the drug molecules themselves, Figures 4c and 4d show two key molecular properties of the therapeutics: molecular weight and the partition coefficient (logP). Figure 4c reveals that a majority of the molecules released in these in vivo studies were between 400 and 500 daltons, and over 85% of the drugs tested had molecular weight values less than 500 dalton classifying them as small molecular weight drugs. Since many of these controlled release strategies only relied on diffusion constraints, it was not surprising when a drug molecule smaller than the polymeric network structure would easily move within and from the polymer matrix, exhibiting little to no control over release.

Another drug characteristic to note is the octanol-water partition coefficient, or logP, that indicates lipophilicity. Figure 4d is a timeline that shows the logP value of drugs released and the release method used throughout all of the in vivo studies published. Negative logP values indicate a drug is hydrophilic, and positive logP indicates hydrophobicity with larger values indicating more hydrophilicity or hydrophobicity. When the logP value is close to 0, a drug does not display a preference for the hydrophilic or hydrophobic phase. Overall, Figure 4d shows a gradual increase in logP diversity over time, and after 1985 nearly 75% of all molecules studied had a logP value between 0 and 4. This is primarily due to pharmacokinetic principles where successful drugs to treat ocular disease have certain properties, as more hydrophobic drugs have better corneal penetration, but aqueous solubility is needed to reach therapeutic concentrations. These values are not surprising in terms of drug release methods, because very hydrophilic molecules can be prone to extremely fast release profiles. Drug solubility and dispersion and polymer interactions can also disrupt a delicate hydrophobic/hydrophilic formulation balance affecting optical and mechanical properties and affect controlled release capabilities. This value is particularly important for lens release strategies that load drug or carriers prior to polymerization, such as molecular imprinting/macromolecular memory, inclusions complexes, and carrier-mediated release.

5. Conclusions

Despite all the in vivo studies and progress over several decades, therapeutic contact lenses are not commercially available today. Results from published studies are difficult to interpret due to variations in release conditions and data presented. Researchers have provided clarification of in vitro studies in the field, describing the significant effects that varying experimental conditions can have on release kinetics and results [103]. It is clear that poorly studied and reported in vitro work is misleading, and it has led to the vast majority of published work showing in vitro and in vivo studies do not correlate, with the many in vitro studies grossly overestimating drug release duration and not showing appreciable release control (Figure 5). In general, in vivo results tend to be more straightforward in depicting success, particularly when the concentration of drug in the tear film is analyzed over time. Drug eluting lenses release drug into the tear film, and drug tear film concentration data is important data to fully understand release dynamics without the added complexity of tissue transport. However, after studying all the in vivo studies published to date, it is clear that variations and inconsistencies in analysis are prevalent and the majority of studies do not measure or report drug tear film concentration data. Many studies report only the pharmacological effects of the drug over time while a smaller percentage report drug concentration values in the ocular tissues such as aqueous humor or within the cornea or conjunctiva over time (Figure 6). Although these values can provide insight on the penetration of delivered drug and to the desired ocular tissues, they are not as useful for analyzing the release kinetics of drug and comparing methods and strategies. Ocular tissue data also has considerable temporal variation with large gaps in time as tissue sampling usually requires a larger animal study population and euthanization at time of sample collection to not cross-contaminate drug concentration samples. Notably, many studies utilize logarithmic axis scales due to these issues which greatly affect the interpretation of the drug tissue concentration profiles being shown—that can easily go unnoticed particularly for burst drug release profiles. Additionally, without all critical lens physical properties being studied or reported (modulus, oxygen permeability, optical clarity, water content, contact angle, material expansion factor, etc.), it is not evident that a particular system could successfully translate to the clinic or have high commercial potential.

Figure 5.

Correlation between contact lens in vitro and in vivo release data from published in vivo studies. The average correlation value for all 67 in vivo publications published to date was 0.25. A value of 1 was assigned to publications where in vivo and in vitro results qualitatively matched in terms of release control (e.g., long in vitro release duration matched long in vitro release duration or effect). Publications where in vitro or in vivo results were scored a lower value depended on how strong the match was and those did not correlate were assigned a value of 0 (e.g., data that majorly overestimated release duration in vitro compared to in vivo results). Publications that did not present in vitro data or any form of in vitro release data were assigned a value of 0.

Figure 6.

Analysis of methods of in vivo data collection. Most in vivo publications vary on how drug release is demonstrated with studies presenting pharmacological effect, ocular tissue drug concentration, or tear film drug concentration.

Undoubtedly, a great deal of progress and new experimental work is needed to make additional statements about the potential of each method, many of which have been studied only recently. As additional in vivo studies continue to be published over the coming years and a wider variety of drugs, loading methods, and more stringent experimental conditions are utilized, more direct comparisons can be made to better analyze the overall progress of the field. Ultimately, the goal of the field is to provide more efficient and effective drug delivery to the eye, and it is apparent in the last decade that interest and research has increased substantially. Clinical translation of drug releasing lenses is on the horizon and has the potential to impact many patients and change the landscape of ocular drug delivery.