Block copolymer micelles as ocular drug delivery systems
Abstract
Block copolymer micelles, formed by the self-assembly of amphiphilic polymers, address formulation challenges, such as poor drug solubility and permeability. These micelles offer advantages including a smaller size, easier preparation, sterilization, and superior solubilization, compared with other nanocarriers. Preclinical studies have shown promising results, advancing them toward clinical trials. Their mucoadhesive properties enhance and prolong contact with the ocular surface, and their small size allows deeper penetration through tissues such as the cornea. Additionally, copolymeric micelles improve the solubility and stability of hydrophobic drugs, sustain drug release, and allow for surface modifications to enhance biocompatibility. Despite these benefits, long-term stability remains a challenge. In this review, we highlight their preclinical performance, structural frameworks, preparation techniques, physicochemical properties, current developments, and prospects as ocular drug delivery systems.
Highlights
- Amphiphilic polymers self-assemble into block copolymer micelles in solution.
- Polymeric micelles have longer and better contact with the ocular surface.
- Describes their structure, preparation methods, and physicochemical qualities.
- Micelles are industrial scalable due to their simple and economical fabrication processes.
Introduction
Ocular diseases, such as age-related macular degeneration (AMD), cataracts, corneal injury, diabetic retinopathy (DR), glaucoma, and refractive errors, can cause vision impairment or be vision threatening. Other ocular disorders, particularly those affecting the front of the eye, such as conjunctivitis, pinguecula, dry eye, blepharitis, pterygium, chelation, hordeolum, and subconjunctival hemorrhage, do not cause visual impairment.
A prevalent approach in the clinical management of anterior segment disorders typically revolves around administering the required medication through topical formulations, ideally as eye drops or suspensions. (p3) For instance, eye conditions affecting the front part of the eye often respond well to treatment with eye drops. Recent research has focused on innovative drug delivery methods, including implants, patches, nanosuspension, microneedles, hydrogels, and contact lenses, tailored for ocular applications. This is in contrast to the more invasive treatment strategies typically used to treat posterior segment diseases, such as periocular or intravitreal injections, and long-acting implants.
The presence of biological barriers within the ocular environment hinders the efficacy of numerous drugs and often necessitates frequent high-dose treatments that can result in adverse effects. (p12) This presents a notable obstacle to developing ocular drug delivery systems that are both safe and efficient. (p13) Nonetheless, recent studies have shown that polymer nanomicelles have distinctive traits, such as mucosal adhesion and small size, which can improve drug bioavailability, promote enhanced penetration into the cornea and absorption within the eye, decrease ocular irritation, and mitigate adverse reactions to medications. (p14) Copolymeric micelles have been particularly successful in nanocarrier systems and are easily produced through self-assembly. Their chemical, physical, and surface properties can be modified by altering the structure of the copolymer or modifying the surface.(p15)
Copolymeric micelles have made significant progress in clinical and preclinical trials, with several treatments reaching various developmental stages. For instance, rapamycin nanomicelle eye drops have been authorized for immune rejection inhibition, whereas terbinafine hydrochloride nanomicelles are now used to combat fungal infections in the eye. Moreover, Cequa®, an ophthalmic solution containing 0.09% cyclosporine, has gained approval for dry eye treatment. Nonetheless, despite these advances, the number of efficacious formulations brought to the market and integrated into clinical settings remains low.
An amphiphilic block copolymer comprises multiple unique monomer units (two or more) arranged in a sequence, resulting in discernible interfaces between various blocks. The structural distinction between block copolymers endows them with unique physical and chemical properties. Block polymer nanomicelles have a decreased likelihood of being identified as foreign substances, and their hydrophilic shells facilitate evasion of detection by the endothelial network, which minimizes the exclusion of micelles from the bloodstream.(p19)
Focusing on attaining both thermodynamic and kinetic stability is essential for the development of polymer nanomicelles. The equilibrium between hydrophilicity and hydrophobicity within amphiphilic block copolymers has a pivotal role in determining the critical micelle concentration, and enhancing stability involves fine-tuning this balance. Hydrogels made from amphiphilic block polymers offer a convenient solution by obviating the necessity for surface treatment, while simultaneously delivering the dual advantages of hydration and deterring surface deposition. Nanoparticle (NP) stability can be effectively modulated through chemical alterations. For instance, augmenting the benzyl group proportion within a polyethylene glycol-b-benzyl-protected polyaspartic acid amphiphilic block copolymer resulted in a tenfold decrease in the critical micelle concentration, thereby significantly bolstering the copolymer stability. Amphiphilic block copolymers can form micelles and NPs, which have garnered considerable attention for drug delivery. Furthermore, they can be utilized to eliminate organic pollutants from water through the formation of micelles or the preparation of films.
Once a drug is released from the copolymeric micelles, the fate of the micelles in the eye is an important consideration. Tear and tear clearance, aqueous humor (AH) clearance, vitreous humor (VH) clearance, and ocular blood flow can all affect the fate of micelles in the eye. Tear flow and clearance can remove micelles from the eye (Figure 1), whereas ocular blood flow can also affect micelle distribution and clearance. The properties of a drug, such as its size, charge, lipophilicity, solubility in eye fluid, and metabolic stability, can affect the behavior of micelles.
(p23) For example, inulin-based micelles functionalized with permeation enhancers can enhanced the penetration and permeation of dexamethasone (DEX) through bovine cornea. Although copolymeric micelles are promising for ocular drug delivery, further research is needed to optimize the system and address the challenges associated with this approach.
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Excipients mentioned in the paper: TPGS, PEG, poloxamer 407, chitosan, Pluronic® L61 and F127, Labrasol, Soluplus
Ahmad A. Assiri, Katie Glover, Deepakkumar Mishra, David Waite, Lalitkumar K. Vora, Raghu Raj Singh Thakur, Block copolymer micelles as ocular drug delivery systems, Drug Discovery Today, 2024, 104098, ISSN 1359-6446, https://doi.org/10.1016/j.drudis.2024.104098.
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