Overview of Ocular Delivery Systems: History
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Contributor:
Mahmoud Mostafa
,
Adel Al Fatease
,
Raid G. Alany
,
Hamdy Abdelkader

Many disorders of the anterior region of the eye may be efficiently treated via topical administration; however, it is more challenging to target conventional therapeutic doses to the posterior of the eye in this manner. Thus, various nanocarriers have been created and investigated for the transport of drugs and genes to the anterior or the posterior portions of the eyes. Liposomes, nanoparticles, micelles, inserts, implants, hydrogel, and emulsions are some of the most frequently utilized drug delivery systems.

 

  • implants
  • ocular delivery

1. Introduction

Many disorders of the anterior region of the eye may be efficiently treated via topical administration; however, it is more challenging to target conventional therapeutic doses to the posterior of the eye in this manner. Thus, various nanocarriers have been created and investigated for the transport of drugs and genes to the anterior or the posterior portions of the eyes. The most popular nano-drug delivery systems are depicted in Figure 1, and these can be utilized to increase the activity and bioavailability, and/or lessen the toxicity of the active pharmaceutical ingredients used. Liposomes, nanoparticles, micelles, inserts, implants, hydrogel, and emulsions are some of the most frequently utilized drug delivery systems.
Figure 1. Nanocarrier systems investigated for ophthalmic uses.

2. Liposomes

Liposomes (Figure 1) are closed vesicles made of a phospholipid bilayer that can contain both drugs that are soluble in fat [1] and those that are soluble in water [2]. Due to their biodegradability, biocompatibility, and capacity to serve as drug carriers, liposomes have been thoroughly investigated for topical ocular administration (Table 1). Liposomes are particularly useful for large molecular weight and inadequately water-soluble drugs because they promote drug permeation through ocular tissues by virtue of their superior spreading ability and rheological properties that enable prolonging the drug availability on the surface of the eye [3][4]. Liposomes’ amphiphilic lipids form a tear compound-interacting sublayer when they make contact with tear lipid components. Polar heads and tails face the polar and non-polar tear lipid components, respectively, and help distribute the medication throughout the ocular surface [5]. Extensive research has examined the merits of liposomes for ocular use, minimizing potential drug toxicity and improving their absorption and bioavailability compared to an unencapsulated drug. These medications include vancomycin, tobramycin, ganciclovir, fluconazole, brinzolamide, triamcinolone acetonide, and cyclosporine A. Drug-loaded liposomal formulations injected intravitreally have a number of benefits. Some benefits include lengthening the half-life of drugs [6], safeguarding labile compounds [7], and prolonging the time that liposomes spend in the tissues of the eye [8].

3. Polymeric Micelles

Amphiphilic polymers can self-assemble into different structures, known as micelles (Figure 1). The formation of micelles within the nanometer range can efficiently improve the aqueous stability and enhance cell permeability. Prior research has demonstrated that the use of a nanomicelle formulation increased medication absorption in the eye [9][10]. Nanomicelle formulations are primarily used to improve the solubility of medications with low solubility and subsequently improve their bioavailability. Hesperidin, Sirolimus, Voriconazole, and Sunitinib are only a few of the medications that were made into polymeric nanomicelles with better solubility and therapeutic efficacy (Table 1).

4. Polymeric Nanoparticles

Polymeric nanoparticles (Figure 1) could be produced by the use of naturally occurring or synthetically produced polymers. Chitosan, hyaluronic acid, carboxymethylcellulose sodium, albumin, and sodium alginate are some examples of natural polymers, whereas poly(lactic-co-glycolic acid), poly(-caprolactone), and poly(ethylene glycol) are examples of synthetic polymers [11]. Some retinal drugs are currently not performing as expected due to the physical and chemical properties of the medications, as well as the distinctive anatomical structure of the eye. The bioavailability of these drugs was significantly increased [12], their toxicity was reduced [13], invasive procedures could be avoided [14], and pharmacokinetic modulation was achieved [15] via incorporation into polymeric nanoparticles (Table 1). These drugs include dexamethasone, cyclosporin, latanoprost, voriconazole, and ganciclovir. Hyaluronic acid, polyethylene glycol, and chitosan are examples of mucoadhesive polymers that may be employed to alter nanoparticles to lengthen their pericorneal residence duration [16]. Moreover, mucus penetrating nanoparticles, which possess low surface tension, low viscosity, and higher hydration water content, can enhance the penetration of therapeutic medicines through the cornea, increasing their bioavailability and resulting in better pharmacologic results. Consequently, mucus penetrating nanoparticles may significantly improve the treatment of posterior ocular problems, which include posterior uveitis, CMV, and retinal disorders [17].

5. Solid Lipid Nanoparticles

Lipids have been used to ameliorate the limited water solubility of several lipophilic drugs and adapt them as a drug delivery system [18]. Müller and Lucks initially developed solid lipid nanoparticles (SLNs, Figure 1) in 1996, which received the attention of scientists as a popular, stable, safe, and effective nanoscale drug delivery device. A surfactant layer that surrounds a solid lipid core in SLNs stabilizes and holds the medication [19]. Drug molecules can be found mostly in the center of particles or molecularly scattered throughout the matrix, depending on the drug solubility and the drug/lipid ratio [20]. SLNs are considered an efficient system intended for ocular drug delivery. SLNs can improve corneal drug absorptivity, enhance ocular tissue penetration and bioavailability, prolong residence time, and provide extended drug release properties [21]. SLNs were efficiently used to improve the delivery of bimatoprost [22], ofloxacin [23], and dorzolamide [24], as shown in Table 1.

6. Hydrogels

Hydrogels (Figure 1) are produced when polymeric solutions are crosslinked to form a network. The hydrogel complexation is formed on the basis of hydrophilic interactions between the polymer tail and water molecules [25]. Hydrogels are widely employed to provide ocularly applied or injectable dosage forms to a variety of eye regions. For ocular application, there are various hydrogel formulations that have FDA approval. A hydrogel sealant called ReSure® has been authorized for use in the non-operative treatment of clear corneal incisions. Hydrogels were also used to formulate and enhance the therapeutic activity of ocularly applied drugs, such as dexamethasone [26], bevacizumab [27], and timolol [28], as shown in Table 1.

7. Dendrimers

Dendrimers (Figure 1) are globular, negatively, positively, or neutrally branch-like nanostructured polymers. They derive their net charge from the functional groups, which are located at the ends of their branches [29]. These molecules consist of a fundamental unit called the “core”, which comprises the major component, and side chain units called “dendrons” [30]. Drugs may be conjugated to the ligands on the dendrimer surface or may be retained in the dendrimer core. Dendrimer manufacturing, generation, surface characteristics, and conjugation technique all have an impact on the drug-loading and drug-release kinetics of dendrimers [31]. As a result of their ability to selectively target inflammatory cells while causing no harm to healthy tissue, dendrimers have proven to be a viable drug delivery vehicle for the treatment of inflammatory eye conditions. The capacity to lower medication toxicity off-target is the key advantage of dendrimers’ targeting abilities [32]. Utilizing dendrimers effectively can increase the therapeutic effectiveness of various active pharmaceutical compounds (Table 1), including pilocarpine [33], tropicamide [33], dexamethasone [34], brimonidine, and timolol [35].

8. Nanocrystals

Nanocrystals (Figure 1) are crystals of therapeutic drugs with particle sizes as small as a few hundred nanometers, where pure drug crystals may occasionally be stabilized by the addition of surface active agents or polymeric solutions [36]. The benefits of nanocrystals over conventional nanocarriers, such as their high drug payload and comparative ease of manufacture, make them appealing candidates for the delivery of medications that are not readily water soluble [37][38]. The preparation of therapeutic drugs in the form of nanocrystals for ocular administration has various advantages. These advantages include better tolerability, increased ocular absorption, providing intermediated and prolonged release of drugs in the eye, and improved ocular permeation [39]. They also include improved ocular safety, increased formulation retention in cul-de-sac, and enhanced ocular permeation [40]. A number of medications used ocularly have been transformed into nanocrystals (Table 1) with enhanced properties, and these include dexamethasone [41], itraconazole [42], tedizolid [43], and brinzolamide [44]. Moreover, Novartis Pharmaceutical Corporation’s formulation of nepafenac nanocrystals received approval for commercial release (FDA, 2012) under the brand name Ilevro®.

9. Cubosomes

Cubosomes (Figure 1) are made up of two inner aqueous pathways that are separated into two arched interpenetrating lipid bilayers, which are structured in three dimensions resembling honeycombs [45]. These pathways can be occupied by a variety of bioactive molecules, including natural bioactives, chemical pharmaceuticals, peptides, polypeptides, and proteins [46]. Cubosomes are thought to be promising delivery systems because of their special characteristics, including thermodynamic stability, bioadhesion, the capacity to encapsulate different types of drugs, and their potential to control drug release [47]. Active medicines and macromolecules can successfully be applied topically to the posterior portion of the eye using cubosomes (Table 1). These drugs include beclomethasone [46], flurbiprofen [48], timolol [49], and brimonidine [50].

10. Niosomes

Niosomes, which are a type of vesicular system that includes a non-ionic surfactant, are closed bilayer structures produced once the nonionic surfactants self-assemble in an aqueous media to create nanocarriers (Figure 1). Researchers have begun using niosomal systems to treat severe inflammatory diseases and conditions, such various malignancies, because of their potential to boost the bioavailability and efficiency of the encapsulated therapeutics [51]. Niosomes are being investigated more and more for improving drug delivery to both segments of the eye, anterior and posterior, as well as promoting drug penetration and retention in ocular tissues. As a consequence, niosomes showed a considerable increase in the absorption and transcorneal permeability of topically applied drugs at the ocular surface (Table 1). These drugs include cyclopentolate [52], voriconazole [53], acetazolamide [54], gentamicin [55], brinzolamide [56], pilocarpine [57], and tacrolimus [58]. Additionally, niosomes, particularly charged vesicles, have been effectively used to transfer genes by subretinal or intravitreal injection to the retinal area [59].

11. Emulsions

An emulsion (Figure 1) is a uniform dispersion system that is formed upon mixing two or more immiscible liquids under certain circumstances [60]. Lipid-based emulsions have become a potential vehicle for ocular medication administration. The emulsions enhance ocular delivery using one of two major strategies, either by improving ocular permeability or by lengthening the period the formulation is retained on the ocular surface [61]. Both hydrophilic and lipophilic drug types may be loaded into emulsions [62][63]. Emulsions have been successfully used to create more effective formulations for several medications used intraocularly that have increased absorption and therapeutic effectiveness. These drugs include cyclosporine A [64], coumarin-6 [65], azithromycin, and disulfiram [66].

12. Bilosomes

One type of vesicular drug delivery system is the bilosome (Figure 1), which is made up of non-ionic amphiphilic compounds with integrated bile salt molecules. The negatively charged bile salts serve to maintain the bilosomal structure [67]. In comparison to niosomes and liposomes, these drug carriers are more stable and can effectively increase drug absorption through biological membranes [68]. Moreover, bilosomes can enhance the permeability of polysaccharides, proteins, and polypeptides, which are poorly transported through mucosal epithelial cells [69]. Previous research studies have assessed the effectiveness of bilosomes in the administration of ocular drugs (Table 1) and found that bilosomes are well tolerated by corneal tissues [70]. These drugs include terconazole [71], acetazolamide [70], ciprofloxacin [72], ciprofloxacin [72], agomelatine [73], and betaxolol [74].

13. Nanocapsules

Nanocapsules (Figure 1) are a subtype of nanoparticles that are comparable to vesicular systems, in which a medicine is contained in a hollow vessel with an inner liquid core encircled by a polymeric coating [75]. Nanocapsules are well-known to be retained in the cornea for a prolonged time and to enhance penetration throughout the deep ocular tissues [40]. Thus, the development of topically applied drug-loaded nanocapsules could reduce uncomfortable intravitreal injections and systemic delivery, which have serious side effects [40]. The therapeutic action of several medications was effectively potentiated via formulation in the form of nanocapsules (Table 1). These drugs include bevacizumab [76], prednisolone [77], tacrolimus [40], brinzolamide [44], and cyclosporine [78].

14. Spanlastics

Elastic niosomes, also known as spanlastics (Figure 1), are a subtype of vesicular drug delivery systems that are relatively new to the market. They resemble niosomes (non-ionic surfactant vesicles), except they contain an edge activator. They were first described as systems for ocular drug delivery [79], but since then, they have been used to deliver medications to a variety of bodily organs. The spanlastics’ bilayers become more elastic and deformable when an edge activator is present, which improves drug absorption across biological membranes. Spanlastics were efficiently used to payload hydrophilic, hydrophobic, and amphiphilic therapeutic pharmaceuticals for ocular use, especially the delivery to the posterior segment (Table 1). These drugs include ketoconazole [79], cyclosporine A [80], clotrimazole [81], and vanillic acid [82].
Table 1. Chronic eye conditions, available therapies, and drug delivery systems and their merits.
Disease Treatment Drug Delivery System Platform Advantages of Delivery Systems In Vivo Refs.
Dry eye syndrome Tear substitutes Hypromellose Solution   [83]
Methylcellulose and derivatives Solution   [84]
hyaluronic acid Solution   [85]
Aqueous secretagogues Diquafosol sodium Solution   [86]
Punctal plugs Collagen and atelocollagen In situ hydrogel Prolonged activity [87][88][89]
methacrylate-modified silk fibroin In situ hydrogel Prolonged activity [90]
Mucin secretagogues Rebamipide Nanoparticles Sustained release [91]
Liposomes Improved activity [92]
Micelles Improved penetration [93]
Anti-inflammatory and immunomodulatory drugs Cyclosporine Micelles Improved activity [94]
  Self-nanoemulsifying Improved efficacy [95]
  Liposomes Improved activity [96]
  Nanoparticles Improved activity [97]
  Nano-emulsion Improved penetration [98]
  Solid lipid nanoparticles Controlled release [99]
  In situ hydrogel Improved activity [94]
Epigallocatechin gallate Nanoparticles Extended activity [100]
  In situ gels Enhanced efficacy [101]
Lactoferrin Nanoparticles Enhanced efficacy [102]
  Nanocapsules Controlled release [103]
  Liposomes Reduced irritation [104]
  Nanostructured lipid carriers Controlled release [105]
Vitamin A Liposomes Improved activity [106]
Tacrolimus Nanoparticles Improved penetration [107]
  Progylcosomes Improved activity [108]
  Microcrystals Improved efficacy [109]
  Liposomes Improved retention time [110]
  Micelles Prolonged activity [111]
  Nanocapsules Improved activity [40]
Corticosteroids Dexamethasone Dendrimer Improved activity [32]
  Nano-wafer Improved activity [112]
  Nanostructured lipid carriers Improved activity [113]
  Nanoparticles Improved penetration [114]
  Micelles Release modulation [115]
  Nanosuspension Prolonged activity [116]
  Nano emulsion Improved activity [117]
  Nanosponges Improved permeability [118]
Fluorometholone Nanoparticles Improved activity [119]
Triamcinolone acetonide Micelles Release modulation [120]
  Nanoparticles Improved activity [121]
Hydrocortisone Nanosuspension Prolonged activity [116]
  Micelles Improved targeting [122]
  Nanoparticles Improved penetration [122]
  Nanosuspension Prolonged activity [116]
Prednisolone Nanoparticles Prolonged activity [123]
  Nano capsules Reduced toxicity [77]
Lotep
rednol etabonate		 Nanoparticles Improved penetration [124]
Non-steroidal anti-inflammatory drugs Diclofenac sodium Nanoparticles Improved bioavailability [125]
  Nanosuspension Prolonged activity [126]
Pranoprofen Nanosuspension Improved activity [127]
  Nanoparticles Improved activity [127][128]
Bromfenac sodium Liposomes Extended release [129]
  Nanoparticles Improved permeation [130]
  Cubosomes Improved bioavailability [131]
Ketorolac Nanoparticles Improved delivery [132]
lymphocyte function-associated antigen-1 antagonists Lifitegrast Solution   [133][134]
Glaucoma Prostaglandin analogues Latanoprost Nanoparticles Controlled release [135]
  PEGylated solid lipid Improved permeability [136]
  Micelles Extended release [137]
  Cubosomes Sustained release [138]
  Nanoparticles Improved permeability [139]
Travoprost Gold nanoparticles Improved stability [140]
  Liposomes Sustained release [141]
  Spanlastics Prolonged activity [142]
  Nanoemulsion Improved pharmacokinetics [143]
  Implant Controlled release [144]
Bimatoprost Nanoparticles Improved therapeutic activity [22]
  Gold nanoparticles Controlled release [145]
  Nanoparticle hydrogel Controlled release [146]
  Microemulsion Improved permeability [147]
  Graphene oxide-laden Controlled release [148]
  Implants Sustained release [149]
  Nanovesicular systems Sustained release [150]
  Inserts Extended release [151]
Unoprostone Transscleral device Sustained release [152]
Rho kinase inhibitors Fasudil Liposomes Enhanced bioavailability [153]
  Microspheres Sustained release [154]
Ripasudil Solution   [155]
Netarsudil Solution   [156]
β-adrenergic blockers Timolol Nanoparticles Extended release [157]
  Micelles Extended release [137]
  Cubosomes Improved bioavailability [49]
  Nanogel Sustained release [158]
  Gelatinized core liposomes Improved encapsulation [159]
  Microemulsion Improved bioavailability [160]
Levobunolol Nanoparticles Extended release [161]
  Microparticles Sustained release [162]
Carteolol Nanocapsules Improved activity [163]
  Nanoparticles Improved activity [164]
  Chitosomes Improved penetration [165]
Metipranolol Nanocapsules Reduced systemic side effects [166]
Betaxolol Liposomes Extended activity [167]
  Nanoparticles Controlled release [168]
  Niosomes Improved bioavailability [169]
  Bilosomes Improved transcorneal permeation [74]
α-adrenergic agonists Brimonidine Nanoparticles Sustained release [170]
  Inserts Controlled release [171]
  Niosomes Sustained release [172]
  Microspheres Sustained release [173]
  Liposomes Improved effectiveness [174]
  Implant Sustained release [175]
  Gelatin-core liposomes Improved drug loading [176]
Carbonic anhydrase inhibitors Dorzolamide Nanoparticles Improved activity [177]
  Nanoemulsion Enhanced ocular delivery [178]
  Liposomes Prolonged action [179]
  Microparticles Sustained release [180]
  Niosomes Improved activity [181]
  Implant Extended drug delivery [182]
  Inserts Improved activity [183]
Brinzolamide Nanoparticles Improved therapeutic activity [184]
  Nanocrystals Improved penetration [185]
  Liposomes Sustained release [186]
  Nanocapsules Improved bioavailability [44]
  Nanoemulsion Improved therapeutic efficacy [187]
  Nanofibers Improved patient compliance [188]
  Implant Sustained release [189]
Acetazolamide Cubosomes Improved therapeutic efficacy [190]
  Spanlastics Enhanced ocular delivery [191]
  Transgelosomes Enhanced ocular delivery [192]
  Implants Sustained release [193]
  Niosomes Improved permeability [194]
  Bilosomes Improved permeability [70]
  Microsponges Improved therapeutic efficacy [195]
  Dendrimers Sustained release [196]
Cholinergic agonists Pilocarpine Nanoparticles Sustained release [197]
  Nanocapsules Improved bioavailability [198]
  Dendrimers Prolonged residence time [33]
Uveitis Corticosteroids Fluocinolone acetonide Implant (Retisert®) Sustained release [199]
  Nanoparticles Improved bioavailability [200]
Difluprednate Microneedles Sustained release [201]
Fluormetholone Nanoparticles Improved penetration [202]
  Nanocrystals Improved sustained activity [203]
Triamcinolone acetonide Nano lipid carriers Improved penetration [204]
Immunomodulator drugs Adalimumab Hydrogel Improved permeability [205]
Infliximab Liposomes Prolonged activity [206]
Methotrexate Implant Sustained release [207]
Sirolimus (Rapamycin) Implant Extended release [208]
  Micelles Sustained release [209]
  Exosomes Improved therapeutic activity [210]
  Liposomes Improved therapeutic activity [3]
Endophthalmitis Antimicrobials Daptomycin Nanoparticles Noninvasive and improved activity [211]
Vancomycin Nanostructured lipid carriers Improved permeability and activity [212]
  Nanoparticles Sustained release [213]
  Thermoresponsive hydrogels Controlled release [214]
  Liposomes Improved permeability [215]
  Implant Controlled release [216]
  Niosomes Improved permeability [217]
Ceftazidime Nanoparticles Improved activity and permeability [218]
Antifungals Amphotericin B Liposomes Improved activity-reduce toxicity [219]
Voriconazole Thermo-sensitive in situ gel Sustained release [220]
  Nanoparticles Improved permeability [221]
  Microemulsion Controlled release [222]
  Elastosomes Improved activity and reduced toxicity [223]
  Micelles Improved stability [223]
  Liposomes Improved permeability [224]
Antivirals Cidofovir Micelles Prolonged activity [225]
  Liposomes Prolonged activity [226]
Foscarnet Liposomes Improved activity and permeability [227]
Ganciclovir Nanoparticles Sustained release [228]
  Glycerosomes Sustained release [229]
  Microemulsion Improved permeability [230]
  Vitrasert Prolonged activity [231]
  Minitablets Sustained release [232]
Retinal diseases Age-related macular degeneration Anti-VEGF Agents Ranibizumab Nanoparticles Improved activity [233]
(Antibody fragment) Microparticles Improved intravitreal delivery [234]
  Liposomes Increased encapsulation-release [235]
  Quantum dots Sustained release [236]
  Implant Sustained release [237]
Bevacizumab Nanoparticles Sustained delivery [238]
(Monoclonal antibody) Bi-layered capsule Sustained delivery [239]
  Nanocapsules Improved bioavailability [240]
  Implant Sustained release [241]
  Microparticles Sustained release [242]
  Liposomes Sustained release [243]
Aflibercept (VEGF-Trap) Nanoparticles Sustained drug release [244]
  Microspheres Extended release [245]
Sunitinib Nanoparticles Superior prolonged activity [246]
  Micelles Extended release [247]
Axitinib Nanoparticles Superior activity [248]
Pegaptanib PEGylated aptamer Prolonged activity [249]
Gene therapy VEGF-siRNA Liposomes Improved activity-stability [250]
  Nanoball Improved activity-targeting [251]
  Nanoparticles Improved therapeutic activity [252]
Integrin antagonists C16Y peptide Nanoparticles Sustained release [253]
Antioxidants Serine-threonine-tyrosine peptide Nanoparticles Targeting [254]
Resveratrol Nanoparticles Sustained release [255]
Curcumin Liposomes Improved activity [256]
Astragaloside Nanocapsules Improved activity [257]
Diabetic retinopathy Antiangiogenics Anti-Flt1 peptide Nanoparticles Sustained release [258]
  Micropump implant On-demand targeting [259]
Fenofibrate Nanoparticles Controlled release [260]
Pioglitazone Nanoparticles Controlled/improved activity [261]
Apatinib Nanoparticles Improved activity [262]
Silicate Nanoparticles Improved activity [263]
Tacrolimus Nanoparticles Improved activity [264]
Sorafenib tosylate Nanoparticles Improved activity [265]
Octreotide Nanoparticles Improved activity-targeting [266]
Anti-inflammatory and antioxidants p-Coumaric acid Nanoparticles Improved activity [267]
Connexin43 mimetic peptide Nanoparticles Targeting [268]
Inulin D α-tocopherol succinate Nanomicelles Improved activity [269]
Citicoline Liposomes Improved permeation [270]
Melatonin Nanoparticles Controlled release and enhanced tolerability [270]

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15061746

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