Secondary Logo

Journal Logo

Review Article

Polymeric Drug Delivery Devices: Role in Cornea and External Disease

Roy, Aravind M.B.B.S., M.S.; Krishna Venuganti, Venkata V. Ph.D.; Chauhan, Shreya S. M. Pharm.; Garg, Prashant M.B.B.S., M.S.

Author Information
Eye & Contact Lens: Science & Clinical Practice: March 2022 - Volume 48 - Issue 3 - p 119-126
doi: 10.1097/ICL.0000000000000874
  • Free

Abstract

INTRODUCTION TO POLYMERIC DRUG DELIVERY VEHICLES

Classic drug delivery methods most often used for delivery of therapeutic agents to the ocular tissues include topical eye drops, gels, ointments, and ocular inserts. These modalities are limited by the need for a pulsed delivery, dilution by the precorneal tear film, and clearance by the nasolacrimal drainage. Additional barrier to the ocular drug delivery includes the tight junctions of ocular surface epithelial cells.1,2 On account of these factors, a conventional ocular drug delivery strategy results in delivery of 1% to 7% of the delivered dose of the drugs.3 Therefore, repeated dosing becomes essential which in turn demands patient compliance for adequate therapeutic effects. It is obvious that newer strategies are needed for efficient ophthalmic drug delivery. A large variety of strategies have been experimented and include polymeric formulations, contact lenses (CLs), microneedle patches, and ocular inserts. These drug delivery modalities work by the following mechanisms: (1) slow clearance of the drug from the ocular surface, (2) increased precorneal residence time, (3) improved penetration of drugs, and (4) bypassing the epithelial barrier. In this review article, we will discuss both CLs and alternative novel strategies and their clinical implications in improving drug concentrations in the anterior eye.

CONTACT LENS–BASED STRATEGIES FOR DRUG DELIVERY TO OCULAR TISSUES

Contact lens–based drug delivery systems are based on drug loading in the aqueous compartment of the lens matrix, binding of drugs to the polymeric skeleton, and slow turnover of the postlens tear film. The strategies can be broadly classified into two groups: (1) commercial CLs–based strategy and (2) a strategy using customized CLs incorporating special monomers (Table 1).

TABLE 1. - Different Methods of Drug Loading Within CL Systems
CL System Drug/s Encapsulated Method of Drug Loading Material Used Objective of the Study Target Disease Reference
Commercially available CL Prednisolone sodium Soaking Hefilcon A copolymer To determine the efficacy of presoaking of CL in drug solution on ocular tissue distribution Ocular inflammation or injury 5
Gentamicin, tobramycin, ciprofloxacin, ofloxacin, and kanamycin Soaking Hefilcon A copolymer (80% 2-hydroxyethyl methacrylate and 20% N-vinyl 2- pyrrolidone) Enhanced bioavailability in AH Ocular bacterial infection 7
Timolol maleate Soaking HEMA Sustained drug delivery to the eye Glaucoma 12
Tetracaine, bupivacaine, ketotifen, diclofenac, flurbiprofen; and fatty acids (oleic acid, linoleic, and linolenic acid) Soaking Silicone or HEMA hydrogel Effect of ionizing surface of commercially available CLs using fatty acids for controlled release of drugs Anesthesia before surgery 13
Dexamethasone, vitamin E Soaking Silicone Sustained drug release Ocular inflammation 16
Timolol maleate, vitamin E Soaking Narafilcon A silicone Sustained drug release Glaucoma 17,18
Levofloxacin Immobilization of liposomes by NeutrAvidin and subsequent soaking Hioxifilcon B; DSPC, cholesterol, PEG Controlled drug release Bacterial keratitis 33
Timolol maleate Soaking Silicone, PGT Sustained drug release through encapsulation in nanoparticles Glaucoma 31
Modified CLs
 Polymerization; mold casting Timolol maleate, brimonidine, vitamin E, vitamin A Soaking Silicone or HEMA hydrogel Coloading of lipophilic molecules, such as vitamin E and A, to increase drug loading Glaucoma 14
Dexamethasone During polymerization Methafilcon silicone Drug delivery to the retina Inflammation of the eye 22
Recombinant adeno-associated virus, rAAV Soaking HEMA, APMA Sustained gene therapy for corneal complications Efficacy in triggering cell proliferation 10
Triamcinolone acetonide UV irradiation, soaking HEMA, EGDMA, NVP, and MA Improved drug loading and sustained release Allergy 11
Bimatoprost UV irradiation, soaking Siloxane, DMA, EGDMA, HEMA, Irgacure Sustained drug release Glaucoma 15
 Solvent casting Moxifloxacin, dexamethasone During solution preparation Chitosan, glycerol, PEG 400 Sustained combination drug release Ocular infections 39
Modified CLs—films
 Drug-loaded film embedded in hydrogel-based CLs Latanoprost During polymerization with UV PLGA, methafilcon Sustained release for about a month Glaucoma 23,24
Ciprofloxacin PLGA, pHEMA Sustained drug release Postoperative treatment with antimicrobials 8
Econazole PLGA, pHEMA Sustained drug release Ocular fungal infections 9
Modified CLs—liposomes
 Liposomes embedded in hydrogel CL Lidocaine During free-radical solution polymerization DMPC liposomes, pHEMA hydrogels Sustained drug release Anesthetic 25
Modified CLs—nanoparticles
 Nanoparticle microemulsion-loaded CL Lidocaine During polymerization pHEMA, EGDMA, AIBN Sustained delivery of microemulsion-stabilized hydrophobic drug to the eye Anesthetic 26
 Nanoparticle-loaded CL Cyclosporine A Eudragit S-100; HEMA, EGDMA, MAA pH triggered sustained release without drug leaching in storage Dry eye condition 27
 Nanoparticle-loaded CL Lidocaine HEMA, EGDMA, AIBN, OTMS, Brij 97, Tween 80 Enhanced drug loading and release Anesthetic 38
 Nanoparticle microemulsion–loaded CL Ketotifen fumarate During UV photopolymerization HEMA, MAA, EGDMA, OTMS, Pluronic F127, Tween 80, PEG 400 Extended drug release Anti-allergy, conjunctivitis 28
 Gold nanoparticles–loaded CL Timolol maleate HEMA, DMA, EGDMA, NVP, TRIS, siloxane Enhanced drug loading in CLs Glaucoma 32
 Drug-loaded nanoparticle ring–implanted CL Timolol maleate During partial polymerization of 2 layers with ring sandwiched in the middle HEMA, MAA, EGDMA, Pluronic P123, PVA Controlled drug delivery Glaucoma 29
Modified CLs—molecular imprinting
 Molecularly imprinted hydrogel CL Timolol maleate Soaking HEMA, DEAA, DMA, SiMA, MMA Enhanced drug loading and faster release Glaucoma 73
 Molecularly imprinted hydrogel CL Acyclovir, valacyclovir During polymerization HEMA, EGDMA, MAA, AIBN Sustained release of drug Ocular viral infections 37
Modified CLs—microneedles
 Liposome-loaded microneedle ocular patch (MOP) mimicking CL Amphotericin B During polymeric solution preparation Soya lecithin, PVA, sodium cholate Enhanced drug delivery Fungal keratitis 43
AIBN, azobisisobutyronitrile; APMA, poly (propoxylated glyceryl triacrylate); pHEMA, poly (2-hydroxyethyl methacrylate); HEMA, hydroxyethyl methacrylate; DSPC, distearoylphosphatidylcholine; DEAA, N,N-diethylacetoacetamide; DMA, dimethylacetamide; EGDMA, ethylene glycol dimethylacrylate; MAA, methacrylic acid; MMA, methyl methacrylate; NVP, N-vinylpyrrolidone; OTMS, octadecyltrimethoxysilane; PEG, polyethylene glycol; PGT, poly (propoxylated glyceryl triacrylate); PLGA, poly (lactic-co-glycolic acid); PVA, polyvinyl alcohol; SiMA, 1-(tristrimethylsiloxysilylpropyl)-methacrylate; TRIS, tris (hydroxymethyl) aminomethane.

Commercial Contact Lens–Based Systems

Commercially available CLs can be loaded with therapeutic moieties using three approaches: dip coating in aqueous concentrated drug solution,4 drop coating on the concave surface of the lens before placement in the eye,5,6 and placing droplets of drug solution on the lens surface after insertion or placement on the eye (Fig. 1A, B). Primarily, the thin layer of tear film present on the surface of the cornea comes in contact with the drug, which then further distributes the drug to the anterior and posterior parts of the eye. In an experimental study involving CLs made of hefilcon A copolymer (80% 2-hydroxyethyl methacrylate and 20% N-vinyl 2- pyrrolidone) and prednisolone sodium phosphate, it was found that presoaked lens showed twofolds to threefolds of higher corticosteroid levels than in the eyes that received topical drug solution without the lens. Drug solution administered topically with the lens already placed showed a diminished result compared with the presoaked group.5 A comparative study between commercially available silicone hydrogel hydrophilic CLs (ACUVUE, Vistacon, Johnson & Johnson, and Norderstedt, power −1.0 D), loaded with five topically applied aminoglycosides, and fluoroquinolones were conducted by Hehl et al.7 Gentamicin, tobramycin, ciprofloxacin, and ofloxacin, but not kanamycin, effectively penetrated the aqueous humor and achieved higher concentration when the lens was presoaked in 0.3% eye drop solution for various time durations as opposed to the topical administration of eye drops. Various hydrophilic hydrogel-forming polymers, such as poly (hydroxyethyl methacrylate) pHEMA,8–15 silicones,13,16–20 hyaluronan,21 siloxanes,15 methafilcon,22–24 poly (dimethyl acrylamide), glycidyl methacrylate, N-vinyl pyrrolidone, and polyethylene glycol (PEG), were used individually or in combination to fabricate CLs containing a variety of therapeutic agents. They are modified to cater to the specific needs of the treatment, such as immediate, sustained, and prolonged release.

F1
FIG. 1.:
Mechanism of contact lens–based drug delivery systems. Commercially available contact lenses can be soaked in a drug solution that allows drug to diffuse into a aqueous component of contact lens architecture and bind to the polymeric matrix (A). Charged drugs can bind to specific binding sites on the polymeric matrix (B). Contact lens monomers can be mixed with chemicals mimicking natural receptors of drugs to facilitate incorporation of drugs within contact lenses (C). In addition, contact lenses can be soaked with nanoformulations that allow slow release of drugs by release or binding to specific surfactants (D).

However, this strategy has several disadvantages: (1) available CL materials do not exhibit affinity for drugs or irreversibly bind them, (2) soaking does not lead to therapeutic loading, and (3) most of the drug is released immediately on placing the lens on the eye.

Studies have been conducted to find out the superior technique of drug loading, which will result in a higher residence time and, thus, increased bioavailability of the drugs to the targeted sites.4,6,11

In an attempt to further prolong the retention and release of the drugs to the eye, delivery systems, such as liposomes25 and nanoparticles,26–32 can be incorporated into film-forming agents, which can be further integrated into commercially available CLs or directly fabricated to mimic them. Levofloxacin-loaded liposomes were immobilized on the surface of commercially available CLs (Hioxifilcon B, Opti-Gel 45G) with chemical reactions involving PEI and NeutrAvidin.33 In vitro studies revealed the release of the drug for more than 6 days. The effect was increased when multiple layers of immobilized liposomes were coated over one another. Similarly, timolol was encapsulated in PCT (propoxylated glyceryl triacrylate) nanoparticles which in turn were incorporated into the prefabricated CLs by soaking overnight in its solution in ethanol. Timolol was released from the CLs for about a month in PBS at room temperature.31

Modified Contact Lenses

Apart from solvent casting and CL soaking methods, novel methods such as molecular imprinting and supercritical fluid–assisted molecular imprinting are being studied to overcome the limitations associated with the former (Fig. 1C). Molecular imprinting technology, or bioinspired approach in simple terms, is generally described as “a method of making a molecular lock for matching a molecular key.”34 Molecularly imprinted polymers are created by copolymerization of the monomers used for CL fabrication with functional monomers that interact with drugs.34–36 The process is drug-specific; hence, it naturally inspires a higher affinity between drug molecule and polymer. As a result, a sustained release is achieved.37 Acyclovir-imprinted and valacyclovir-imprinted hydrogel CL were fabricated to attain a sustained release for the treatment of the herpes simplex virus in the eye. Valacyclovir was found to have a higher affinity to the matrix and thus released over 10 hr, whereas; acyclovir was completely released in 4 hr.37 Clearly, drug–polymer affinity plays a significant role in drug release.

Yet another strategy involves drug carriers, such as nanoparticles, liposomes, and microemulsions, being dispersed in the hydrophilic CL matrix during the polymerization reaction26,38 or attached to the surfactants (Fig. 1D). In this way, the drug will first be released from the carrier system, and then, by crossing, the hydrogel matrix will reach the postlens tear film. A burst release and potential drug loss will be mitigated with more quantities of drug being released for longer times.

A mucoadhesive polymeric CL was fabricated containing separately, and in combination, moxifloxacin hydrochloride (MF) and dexamethasone sodium phosphate (DM) to treat ocular infections such as keratitis and conjunctivitis.39 A polymeric mixture of chitosan, glycerol, and PEG was loaded with the drugs and molded, mimicking the shape of the commercially available CLs. The cationic NH2 groups present in chitosan were seen to bind to the anionic groups of mucin present on the outer surface of the corneal tissue, thereby increasing the residence time of drugs. Drug-loaded polymeric solutions were layered on each other using a stainless-steel master mold. In vitro drug release studies of MF showed a sustained release for up to 24 hr, with almost 80% drug eluted from the CLs. Dexamethasone sodium phosphate showed a >90% release in 24 hr. Ex vivo corneal permeation coefficient of MF and DM after application of the CL was significantly greater (P<0.01) compared with the standard drug solutions. An in vivo drug distribution study revealed a greater amount of drug in cornea, sclera, aqueous humor (AH), vitreous humor, lens, and plasma when CLs were administered as compared with free drug solutions (Fig. 2).39

F2
FIG. 2.:
Digital images of (a) stainless-steel mold; (b) polymeric contact lens; (c) CL application on rabbit eye; (d) Antibacterial activity of free moxifloxacin and moxifloxacin CL against S. aureus in ex vivo infected cornea models. (e) Tissue distribution of moxifloxacin in the rabbit model. AH - aqueous humour, VH - vitreous humour. n = 4 animals in a group. Asterisk (*) represents that the values are significantly different at P < 0.05. (Gade et al., 2020).

Drug Delivery Using Microneedle Contact Lens

In recent years, microneedle technology has proven to be a promising approach for the topical and systemic delivery of drugs. The needles ranging from 500 to 800 μm in size with a tip diameter of approximately 20 μm helps penetrate the upper layers of the skin, thereby resulting in effective drug delivery. These microneedles can also be used for drug delivery to the anterior and posterior regions of the eye. The microneedles have been found to have sufficient mechanical strength with the fast dissolution of the coated drug and bioavailability of 60 times that of topical administration.

Park et al.40 proposed development of an applicator microneedle pen to control the depth of microneedle penetration in the sclera. The applicator assembly consisted of a spring which precisely controls the depth and insertion speeds of the attached photo-crosslinked SU-8 microneedle. The histological analysis and optical coherence tomography studies in ex vivo porcine eyes and in vivo beagle eyes revealed increased insertion depth with the increase in insertion speeds using higher spring constants. The “medium” spring setting was found to be effective in achieving insertion depth without fully penetrating the sclera.

Biocompatible polymers, such as polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP), were used for making MN arrays for ocular drug delivery.41 Polyvinyl pyrrolidone polymers with different molecular weights were used for fabrication of dissolving microneedles (3 × 3 array, planar) encapsulating three model molecules with increasing MW, namely, fluorescein sodium and fluorescein isothiocyanate–dextrans (with MW of 70 k and 150 k Da). Higher MW polymer MNs were seen to withstand higher forces with rapid dissolution properties. In vitro studies confirmed a higher permeation of molecules with MN use across both scleral and corneal tissues.

Most recently, Wu et al.43 optimized a model protein ovalbumin-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles using the water-in-oil-in-water (W/O/W) double emulsion method. Primary sonication time was a variable in the production process of NPs and affected the stability of the formulation. The optimized NPs were then incorporated in the PVA polymer matrix to fabricate rapidly dissolving planar-based MNs to be administered to the eye. To avoid dose loss and wastage, the NPs were concentrated in the tips of the needles by high-speed centrifugation. An ex vivo study in an excised porcine sclera showed good mechanical strength, insertion strength, and rapid dissolution kinetics (less than 3 min). The proteins and NPs were seen to be localized in the scleral tissue when observed under a multiphoton microscope. The polymers used, such as PLGA and PVA, were seen to be biocompatible with the retinal cells (ARPE-19).

Both drug loading onto prefabricated CLs and using microneedles (single or multiple) for penetrating the cornea or sclera, and thereby delivering drugs directly into the eye tissue, have shown superior results to topical application of drug solution. Using the best of both techniques, Roy et al.44 proposed a unique design wherein a microneedle ocular patch was fabricated, which mimicked the concave shape of CL with a microneedle array patch at the center.

NONCONTACT LENS–BASED STRATEGIES FOR DRUG DELIVERY

  • Noncontact lens–based systems for drug delivery are summarized in Table 2.

TABLE 2. - Different Methods of Drug Loading in Nanocarriers and Polymeric Systems
Carrier System Drug/s Encapsulated Method of Drug Loading Material Used Objective of the Study Target Disease Reference
Microneedles
 Microneedle pen (MNP) Dip coating SU-8 Targeted delivery to the sclera 40
 Microneedle patch During polymeric solution preparation PVP Drug delivery to anterior and posterior regions of eye 41
 Nanoparticle loaded-bilayer microneedles Ovalbumin Concentrated into MN tips by high-speed centrifugation PLGA, PVA, PVP Protein delivery to the sclera Neovascular ocular diseases 42
Nanoparticles
 Nanosuspension Levofloxacin During polymeric solution preparation Chitosan, PLGA Enhanced and sustained drug release Conjunctivitis 46
Sparfloxacin PLGA, PVA Sustained drug delivery 53
Levofloxacin PLGA Sustained drug delivery 54
Triamcinolone acetonide β-cyclodextrin, PLGA Sustained drug delivery Ocular inflammation 55
 Solid lipid nanoparticle (SLN) Levofloxacin Stearic acid, Tween 80, sodium deoxycholate Enhanced drug delivery Conjunctivitis 56
Methazolamide Chitosan, giyceryl monostearate Enhanced drug delivery Glaucoma 57
Natamycin Precirol ATO 5, Pluronic F-68 Sustained drug delivery, enhanced penetration through cornea Deep fungal keratitis 58
 Niosome Acetazolamide Reverse phase evaporation method Span 60, cholesterol Enhanced bioavailability Glaucoma 63
Ocular inserts
 Nanostructured lipid carrier–based insert Ofloxacin Solvent casting evaporation Compritol HD5 ATO, oleic acid, Tween 80 Enhanced drug release Bacterial keratitis 47
In situ gelling system
 Injectable micelle–loaded in situ gelling system Triamcinolone acetonide Emulsion-sonication/extrusion PNIPAAm, PSHU Sustained drug release up to a year Ocular inflammation 64
 In situ gel forming system Moxifloxacin hydrochloride During polymeric solution preparation Sodium alginate, HPMC Sustained drug release Ocular microbial infection 68
HPMC, hydroxypropyl methylcellulose; PNIPAAm, poly (N-isopropylacrylamide); PSHU, poly (serinol hexamethylene urea); PVP, polyvinyl pyrrolidone.

Microinserts

Ocular inserts consist of developing thin biopermeable and solid or semisolid drug-impregnated devices which can be implanted into the eye for sustained release of drugs. These devices typically increase the precorneal residence time of drugs, provide accurate dosing of the drug, provide better compliance to therapy, and target deeper ocular tissues while preventing the need for preservatives and reducing systemic absorption. Often they are combined with polycaprolactone, polylactic acid, and polyethylene glycol to improve the porosity and release rate of drugs.44,45 Drugs are released by diffusion, osmosis, and bioerosion. The drugs are incorporated into a polymer or a biodegradable matrix system that allows slow diffusion from the delivery vehicle. Electrospun nanofiber inserts have thinner dimensions than solvent cast–polymeric inserts. The nanofiber inserts were found to have consistent drug release rates, reduced concentration of excipients, and lesser ocular toxicity than solvent cast inserts. Levofloxacin administered through chitosan-coated PLGA nanoparticles had increased contact time, extended release, strong mucoadhesion, and slow drainage from the ocular surface. Levofloxacin had enhanced molecular dispersion with higher tissue permeation and antibacterial activity compared with commercial preparation.46 Nanostructured lipid carrier–based ocular inserts loaded with 0.3% ofloxacin and chitosan oligosaccharide lactate increased preocular concentration and retention time by six times and significantly controlled Staphylococcal keratitis in rabbits.47

Nano Formulations

Nanoparticles are small-sized controlled release drug delivery vehicles that allow effective and efficient drug concentrations in the target tissues. It improves the local drug residence time while reducing the need for frequent dosing and improving compliance. Nano-based drug vehicles encapsulate the drugs improving their bioavailability while decreasing the toxicity. Several strategies have been deployed for nano-based drug delivery; these include nanosuspensions, nanomicelles, nanohydrogels, solid lipid nanoparticles, niosomes, and liposomes.48,49

Poly (Lactic-Co-Glycolic Acid) Nanocarriers

Poly (lactic-co-glycolic acid) is a copolymer of lactic acid and glycolic acid that is biocompatible, biodegradable, and allows sustained and controlled release of drugs. The PLGA nanoparticle has drug encapsulation properties that prevents inactivation of drugs, provides slow and sustained release of drugs, and facilitates targeted drug delivery. The PLGA polymer has affinity for hydrophilic and hydrophobic drugs, macromolecules, peptides, and nucleic acids.50–52 Poly (lactic-co-glycolic acid)–based drug delivery has been found to have uses in ocular drug delivery. Sparfloxacin and levofloxacin conjugated to PLGA NP–based colloidal suspension were found to have improved precorneal residence, good penetration, and stable shelf life compared with commercial preparations.53,54 Triamcinolone acetonide loaded into 2-HP-beta-cyclodextrin PLGA nanoparticles had sustained release of drug into the AH and increased bioavailability.55

Solid Lipid Nanoparticles

Solid lipid nanoparticles (SLNs) consist of steroid or fatty acid core, combined with Tween 80 and sodium deoxycholate. SLNs can encapsulate hydrophilic and lipophilic drugs to attain a controlled release. The particle size of SLNs ranges from 50 to 1,000 nm. The small size allows penetration onto the blood aqueous barrier, blood retina barrier, and epithelium.56 Chitosan is a natural cationic polysaccharide, and it has mucoadhesive properties, and the molecule is nontoxic, biodegradable, and biocompatible. Chitosan-coated SLNs have favorable effects on the stability of the compound in particle size, zeta potential, drug loading, and entrapment efficiency.57 Natamycin-SLN prepared using an emulsification-ultrasonication technique, adopting an orthogonal and Box–Behnken design, was found to have significant antifungal activity, improved corneal penetration, and reduced minimum inhibitory concentration with no cytotoxic or local irritation effects in deep corneal mycoses.58

Lipososmes

Liposomes are double-layered vesicles made of phospholipids that have a lipophilic shell and hydrophilic core component. The particle size of liposomes range from 50 to 500 nm. Liposomes have charged particles on their surface depending on the lipid used and allow delivery of lipophilic and hydrophilic drugs.59,60 Surface charge could be positive, negative, or neutral. Positively charged liposomes have enhanced ocular retention in and around the site of administration. Furthermore, the addition of lipids increases the clearance time. The sizes of these complexes are >250 nm. Negatively charged and neutral liposomes have smaller size and are distributed preferentially to the limbus.61

Niosomes

Niosomes consist of complexes of Spans, Tweens, and other nonionic surfactants with cholesterol-forming closed bilayer structures. These complexes form alternatives to liposomes because of ease of sterilization, stability, and mass production. The complexes have enhanced surface adhesive properties with increased local retention. It allows hydrophilic, hydrophobic, or amphoteric drugs to be encapsulated into them and has comparatively controlled release, adequate tissue permeation, and nonimmunogenic properties.62 Encapsulating acetazolamide into positively charged niosomes led to enhanced entrapment efficiency, controlled corneal permeability, and increased retention compared with neutral polymers. The intraocular pressure–lowering effect is comparable with commercially available preparations.63

Gel Formulations

Gel-forming systems are natural or semisynthetic polymers that undergo a sol–gel transition. Based on the environmental triggers for their sol to gel transition, they are categorized into thermo-responsive, pH-responsive, or ion-responsive systems. Thermo-responsive gels have a lower critical solution temperature (LCST) above which they undergo a transition from a transparent free flowing solution into a cloudy viscous gel. Thermo-responsive polymers have three important categories: PNIPAMS, poloxamers, and cellulose derivatives. PNIPAMS are some of the most widely used polymers and have a phase transition LCST of 32°C beyond which it transforms into a hydrophobic gel. Triamcinolone acetonide encapsulated onto drug-loaded micelles in a PNIPAM polymer has been described as an injectable ocular drug delivery system. The polymer is coupled to a poly (serinol hexamethylene urea) backbone and has reverse thermal gelling properties and allows improved drug release and good tissue tolerance.64

Another class of gels is a pH-responsive polyacrylic acid (PAA) which is also known as carbomers or Carbopol. They undergo sol to gel transition from lower to higher pH environments. They have also been combined with other pH-responsive and thermo-responsive polymers to have increased cellular permeability and mucoadhesive properties.65 Pranoprofen-loaded PLGA nanoparticles in carbomer 934 hydrogel containing 1% azone improved the anti-inflammatory efficacy and allowed sustained drug release and corneal permeation while having no ocular irritation.66

Ion-activated polymers include gellan gum and alginic acid. These are biocompatible and biodegradable polymers from algae that have a double helix structure with weak covalent bonds in aqueous solution and on exposure to cationic charges they transform into gel form because of cross-linking of helices. This allows encapsulation of drugs with sustained drug release and increased retention in the precorneal tear film. Pilocarpine, ganciclovir, moxifloxacin, and azathioprine have been used in gel-based drug delivery systems.67,68

CONCLUSIONS AND FUTURE RESEARCH

Contact lenses as drug delivery vehicles have been described to provide sustained therapeutic concentrations after several hours of instillation. Busin et al. reported bactericidal concentrations of gentamycin-soaked hydrogel CLs on the ocular surface after 3 days of application without systemic or topical side effects.69 Another study reported that hydrogel CLs allow 0.002% of the drug to permeate under the lens after topical application, and computer-generated simulations suggest that most of the topical drugs move around the edge of the lenses.70 Therefore, drug kinetics through the substance of the CLs may be variable. The advent of 3D printing of drug-eluting implants has manifold ramifications in the field of catheters, meshes, and bone implants. 3D printing allows the implant to be shaped as per the individual requirement and release profiles. They provide a source of sustained and site-specific drug release without the need for rapid, frequent dosing and avoid repeated instillation or injections, thereby improving patient compliance and comfort.71,72 Drug delivery vehicles aid in providing site-specific sustained concentrations of the drug; however, these need to be balanced with systemic and topical toxicity due to excessive drug penetration or possibility of drug resistance. Further studies on drug pharmacokinetics for the duration and concentration of drugs after topical instillation will help improve understanding clinical efficacy of diverse drug delivery vehicles.

REFERENCES

1. Ban Y, Dota A, Cooper LJ, et al. Tight junction-related protein expression and distribution in human corneal epithelium. Exp Eye Res 2003;76:663–669.
2. Huang AJ, Tseng SC, Kenyon KR. Paracellular permeability of corneal and conjunctival epithelia. Invest Ophthalmol Vis Sci 1989;30:684–689.
3. Mishima S, Gasset A, Klyce SD, et al. Determination of tear volume and tear flow. Invest Ophthalmol 1966;5:264–276.
4. Waltman SR, Kaufman HE. Use of hydrophilic contact lenses to increase ocular penetration of topical drugs. Invest Ophthalmol 1970;9:250–255.
5. Hull DS, Edelhauser HF, Hyndiuk RA. Ocular penetration of prednisolone and the hydrophilic contact lens. Arch Ophthalmol 1974;92:413–416.
6. Matoba AY, McCulley JP. The effect of therapeutic soft contact lenses on antibiotic delivery to the cornea. Ophthalmology 1985;92:97–99.
7. Hehl EM, Beck R, Luthard K, et al. Improved penetration of aminoglycosides and fluoroquinolones into the aqueous humour of patients by means of Acuvue contact lenses. Eur J Clin Pharmacol 1999;55:317–323.
8. Ciolino JB, Hoare TR, Iwata NG, et al. A drug-eluting contact lens. Invest Ophthalmol Vis Sci 2009;50:3346–3352.
9. Ciolino JB, Hudson SP, Mobbs AN, et al. A prototype Antifungal contact lens. Invest Ophthalmol Vis Sci 2011;52:6286–6291.
10. Alvarez-Rivera F, Rey-Rico A, Venkatesan JK, et al. Controlled release of rAAV vectors from APMA-functionalized contact lenses for corneal gene therapy. Pharmaceutics 2020;12:335.
11. García-Millán E, Koprivnik S, Otero-Espinar FJ. Drug loading optimization and extended drug delivery of corticoids from pHEMA based soft contact lenses hydrogels via chemical and microstructural modifications. Int J Pharm 2015;487:260–269.
12. Maulvi FA, Soni TG, Shah DO. Effect of timolol maleate concentration on uptake and release from hydrogel contact lenses using soaking method. J Pharm Appl Sci 2014;1:16–22.
13. Torres-Luna C, Hu N, Fan X, et al. Extended delivery of cationic drugs from contact lenses loaded with unsaturated fatty acids. Eur J Pharm Biopharm 2020;155:1–11.
14. Lee D, Cho S, Park HS, et al. Ocular drug delivery through pHEMA-Hydrogel contact lenses co-loaded with lipophilic vitamins. Sci Rep 2016;6:1–8.
15. Xu W, Jiao W, Li S, et al. Bimatoprost loaded microemulsion laden contact lens to treat glaucoma. J Drug Deliv Sci Tec 2019;54:101330.
16. Kim J, Peng CC, Chauhan A. Extended release of dexamethasone from silicone-hydrogel contact lenses containing vitamin E. J Control Release 2010;148:110–116.
17. Peng CC, Burke MT, Carbia BE, et al. Extended drug delivery by contact lenses for glaucoma therapy. J Control Release 2012;162:152–158.
18. Peng CC, Kim J, Chauhan A. Extended delivery of hydrophilic drugs from silicone-hydrogel contact lenses containing vitamin E diffusion barriers. Biomaterials 2010;31:4032–4047.
19. Galante R, Oliveira AS, Topete A, et al. Drug-eluting silicone hydrogel for therapeutic contact lenses: Impact of sterilization methods on the system performance. Colloids Surf B Biointerfaces 2018;161:537–546.
20. Lasowski F, Rambarran T, Rahmani V, et al. PEG-containing siloxane materials by metal-free click-chemistry for ocular drug delivery applications. J Biomater Sci Polym Edition 2021;32:581–594.
21. Li R, Guan X, Lin X, et al. Poly(2-hydroxyethyl methacrylate)/β-cyclodextrin-hyaluronan contact lens with tear protein adsorption resistance and sustained drug delivery for ophthalmic diseases. Acta Biomater 2020;110:105–118.
22. Ross AE, Bengani LC, Tulsan R, et al. Topical sustained drug delivery to the retina with a drug-eluting contact lens. Biomaterials 2019;217:119285.
23. Ciolino JB, Stefanescu CF, Ross AE, et al. In vivo performance of a drug-eluting contact lens to treat glaucoma for a month. Biomaterials 2014;35:432–439.
24. Ciolino JB, Ross AE, Tulsan R, et al. Latanoprost-eluting contact lenses in glaucomatous monkeys. Ophthalmology 2016;123:2085–2092.
25. Gulsen D, Li CC, Chauhan A. Dispersion of DMPC liposomes in contact lenses for ophthalmic drug delivery. Curr Eye Res 2005;30:1071–1080.
26. Gulsen D, Chauhan A. Ophthalmic drug delivery through contact lenses. Invest Ophthalmol Vis Sci 2004;45:2342–2347.
27. Maulvi FA, Choksi HH, Desai AR, et al. pH triggered controlled drug delivery from contact lenses: Addressing the challenges of drug leaching during sterilization and storage. Colloids Surf B Biointerfaces 2017;157:72–82.
28. Maulvi FA, Mangukiya MA, Patel PA, et al. Extended release of ketotifen from silica shell nanoparticle-laden hydrogel contact lenses: In vitro and in vivo evaluation. J Mater Sci Mater Med 2016;27:113.
29. Maulvi FA, Lakdawala DH, Shaikh AA, et al. In vitro and in vivo evaluation of novel implantation technology in hydrogel contact lenses for controlled drug delivery. J Control Release 2016;226:47–56.
30. Yu Y, Xu S, Yu S, et al. A hybrid genipin-cross-linked hydrogel/nanostructured lipid carrier for ocular drug delivery: Cellular, ex vivo, and in vivo evaluation. ACS Biomater Sci Eng 2020;6:1543–1552.
31. Jung HJ, Abou-Jaoude M, Carbia BE, et al. Glaucoma therapy by extended release of timolol from nanoparticle loaded silicone-hydrogel contact lenses. J Control Release 2013;165:82–89.
32. Maulvi FA, Patil RJ, Desai AR, et al. Effect of gold nanoparticles on timolol uptake and its release kinetics from contact lenses: In vitro and in vivo evaluation. Acta Biomater 2019;86:350–362.
33. Danion A, Arsenault I, Vermette P. Antibacterial activity of contact lenses bearing surface-immobilized layers of intact liposomes loaded with levofloxacin. J Pharm Sci 2007;96:2350–2363.
34. Chen L, Wang X, Lu W, et al. Molecular imprinting: Perspectives and applications. Chem Soc Rev 2016;45:2137–2211.
35. Alvarez-Lorenzo C, Concheiro A. Molecularly imprinted polymers for drug delivery. J Chromatogr B Analyt Techol Biomed Life Sci 2004;804:231–245.
36. Cunliffe D, Kirby A, Alexander C. Molecularly imprinted drug delivery systems. Adv Drug Deliv Rev 2005;57:1836–1853.
37. Varela-Garcia A, Gomez-Amoza JL, Concheiro A, et al. Imprinted contact lenses for ocular administration of antiviral drugs. Polymers (Basel) 2020;12:10.
38. Gulsen D, Chauhan A. Dispersion of microemulsion drops in HEMA hydrogel: A potential ophthalmic drug delivery vehicle. Int J Pharm 2005;292:95–117.
39. Gade SK, Nirmal J, Garg P, et al. Corneal delivery of moxifloxacin and dexamethasone combination using drug-eluting mucoadhesive contact lens to treat ocular infections. Int J Pharm 2020;591:120023.
40. Park SH, Jo DH, Cho CS, et al. Depthwise-controlled scleral insertion of microneedles for drug delivery to the back of the eye. Eur J Pharm Biopharm 2018;133:31–41.
41. Thakur RR, Tekko IA, Al-Shammari F, et al. Rapidly dissolving polymeric microneedles for minimally invasive intraocular drug delivery. Drug Deliv Translational Res 2016;6:800–815.
42. Wu Y, Vora LK, Wang Y, et al. Long-acting nanoparticle-loaded bilayer microneedles for protein delivery to the posterior segment of the eye. Eur J Pharm Biopharm 2021;165:306–318.
43. Roy G, Galigama RD, Thorat VS, et al. Amphotericin B containing microneedle ocular patch for effective treatment of fungal keratitis. Int J Pharm 2019;572:118808.
44. Khan A, Raza SN, Itoo A, et al. Ocular inserts: A novel approach in ocular drug delivery. J Drug Deliv Ther 2019;9:693–703.
45. Stewart SA, Domínguez-Robles J, McIlorum VJ, et al. Poly(caprolactone)-based coatings on 3D-printed biodegradable implants: A novel strategy to prolong delivery of hydrophilic drugs. Mol Pharm 2020;17:3487–3500.
46. Ameeduzzafar N, Khan N, Alruwaili NK, et al. Improvement of ocular efficacy of levofloxacin by bioadhesive chitosan coated PLGA nanoparticles: Box-behnken design, in-vitro characterization, antibacterial evaluation and scintigraphy study. Iran J Pharm Res 2020;19:292–311.
47. Üstündağ-Okur N, Gökçe EH, Bozbıyık Dİ, et al. Novel nanostructured lipid carrier-based inserts for controlled ocular drug delivery: Evaluation of corneal bioavailability and treatment efficacy in bacterial keratitis. Expert Opin Drug Deliv 2015;12:1791–1807.
48. Qamar Z, Qizilbash FF, Iqubal MK, et al. Nano-based drug delivery system: Recent strategies for the treatment of ocular disease and future perspective. Recent Pat Drug Deliv Formul 2019;13:246–254.
49. Joseph RR, Venkatraman SS. Drug delivery to the eye: What benefits do nanocarriers offer? Nanomedicine (Lond) 2017;12:683–702.
50. Danhier F, Ansorena E, Silva JM, et al. PLGA-based nanoparticles: An overview of biomedical applications. J Control Release 2012;161:505–522.
51. Tsai CH, Wang PY, Lin IC, et al. Ocular drug delivery: Role of degradable polymeric nanocarriers for ophthalmic application. Int J Mol Sci 2018;19:E2830.
52. Cheng J, Teply BA, Sherifi I, et al. Formulation of functionalized PLGA-PEG nanoparticles for in vivo targeted drug delivery. Biomaterials 2007;28:869–876.
53. Gupta H, Aqil M, Khar RK, et al. Sparfloxacin-loaded PLGA nanoparticles for sustained ocular drug delivery. Nanomedicine 2010;6:324–333.
54. Gupta H, Aqil M, Khar RK, et al. Biodegradable levofloxacin nanoparticles for sustained ocular drug delivery. J Drug Target 2011;19:409–417.
55. Li F, Wen Y, Zhang Y, et al. Characterisation of 2-HP-β-cyclodextrin-PLGA nanoparticle complexes for potential use as ocular drug delivery vehicles. Artif Cell Nanomed Biotechnol 2019;47:4097–4108.
56. Baig MS, Ahad A, Aslam M, et al. Application of Box-Behnken design for preparation of levofloxacin-loaded stearic acid solid lipid nanoparticles for ocular delivery: Optimization, in vitro release, ocular tolerance, and antibacterial activity. Int J Biol Macromol 2016;85:258–270.
57. Wang FZ, Zhang MW, Zhang DS, et al. Preparation, optimization, and characterization of chitosan-coated solid lipid nanoparticles for ocular drug delivery. J Biomed Res 2018;32:411–423.
58. Khames A, Khaleel MA, El-Badawy MF, et al. Natamycin solid lipid nanoparticles—Sustained ocular delivery system of higher corneal penetration against deep fungal keratitis: Preparation and optimization. Int J Nanomedicine 2019;14:2515–2531.
59. Bhattacharjee A, Das PJ, Adhikari P, et al. Novel drug delivery systems for ocular therapy: With special reference to liposomal ocular delivery. Eur J Ophthalmol 2019;29:113–126.
60. Yadav KS, Rajpurohit R, Sharma S. Glaucoma: Current treatment and impact of advanced drug delivery systems. Life Sci 2019;221:362–376.
61. Chaw SY, Novera W, Chacko AM, et al. In vivo fate of liposomes after subconjunctival ocular delivery. J Control Release 2021;329:162–174.
62. Verma A, Tiwari A, Saraf S, et al. Emerging potential of niosomes in ocular delivery. Expert Opin Drug Deliv 2021;18:55–71.
63. Aggarwal D, Garg A, Kaur IP. Development of a topical niosomal preparation of acetazolamide: Preparation and evaluation. J Pharm Pharmacol 2004;56:1509–1517.
64. Famili A, Kahook MY, Park D. A combined micelle and poly(serinol hexamethylene urea)-co-poly(N-isopropylacrylamide) reverse thermal gel as an injectable ocular drug delivery system. Macromol Biosci 2014;14:1719–1729.
65. Al-Kinani AA, Zidan G, Elsaid N, et al. Ophthalmic gels: Past, present and future. Adv Drug Deliv Rev 2018;126:113–126.
66. Abrego G, Alvarado H, Souto EB, et al. Biopharmaceutical profile of pranoprofen-loaded PLGA nanoparticles containing hydrogels for ocular administration. Eur J Pharm Biopharm 2015;95:261–270.
67. Baranowski P, Karolewicz B, Gajda M, et al. Ophthalmic drug dosage forms: Characterisation and research methods. ScientificWorldJ 2014;2014:861904.
68. Mandal S, Thimmasetty MK, Prabhushankar G, et al. Formulation and evaluation of an in situ gel-forming ophthalmic formulation of moxifloxacin hydrochloride. Int J Pharm Investig 2012;2:78–82.
69. Busin M, Spitznas M. Sustained gentamicin release by presoaked medicated bandage contact lenses. Ophthalmology 1988;95:796–798.
70. McCarey BE, Schmidt FH, Wilkinson KD, et al. Gentamicin diffusion across hydrogel bandage lenses and its kinetic distribution on the eye. Curr Eye Res 1984;3:977–989.
71. Liaskoni A, Wildman RD, Roberts CJ. 3D printed polymeric drug-eluting implants. Int J Pharm 2021;597:120330.
72. Elkasabgy NA, Mahmoud AA, Maged A. 3D printing: An appealing route for customized drug delivery systems. Int J Pharm 2020;588:119732.
73. Hiratani H, Alvarez-Lorenzo C. The nature of backbone monomers determines the performance of imprinted soft contact lenses as timolol drug delivery systems. Biomaterials 2004;25:1105–1113.
Keywords:

Contact lens; Drug delivery; Microneedle patch; Drug delivery vehicles; Precorneal tear film; Microinserts; Nano carriers; Gel formulations

© 2021 Contact Lens Association of Ophthalmologists