Lipid Nanoparticles for the Posterior Eye Segment

This review highlights the application of lipid nanoparticles (Solid Lipid Nanoparticles, Nanostructured Lipid Carriers, or Lipid Drug Conjugates) as effective drug carriers for pathologies affecting the posterior ocular segment. Eye anatomy and the most relevant diseases affecting the posterior segment will be summarized. Moreover, preparation methods and different types and subtypes of lipid nanoparticles will also be reviewed. Lipid nanoparticles used as carriers to deliver drugs to the posterior eye segment as well as their administration routes, pharmaceutical forms and ocular distribution will be discussed emphasizing the different targeting strategies most recently employed for ocular drug delivery.

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About this article: Bonilla, L.; Espina, M.; Severino, P.; Cano, A.; Ettcheto, M.; Camins, A.; García, M.L.; Souto, E.B.; Sánchez-López, E. Lipid Nanoparticles for the Posterior Eye Segment. Pharmaceutics 2022, 14, 90.

Excipients for Ocular Drug Delivery (from this article)

The eye is a sensitive organ, which means that toxicity of every component of the formulations must be studied. Excipients play an important role in lipid nanoparticles because they could confer additional properties to the formulations, such as the control of the release rate of the drug. Excipients for ocular delivery should (i) accomplish safety with no local and systemic side effects, (ii) increase the ocular residence time of the drug administered, (iii) control drug release, (iv) be stable and easy to handle, (v) be compatible with the drug, and (vi) be biodegradable and biocompatible. Excipients in ophthalmic drug delivery systems can be classified according to their function in the drug delivery systems [81,82]. In the following sections, excipients for lipid nanoparticles are classified.

4.2.1. Lipids
Lipid nanoparticles are formed by solid lipids (SLNs) and liquid lipids (NLCs), which are physiological, biodegradable and nontoxic [83,84]. Lipids have been approved by the European and United States regulatory authorities for ocular applications, and they are Generally Regarded as Safe (GRAS) [84,85].

Solid Lipids
Solid lipids are lipids which form a highly ordered crystalline lattice. They are solid at body temperature, which allows a controlled and sustained drug release [14]. Solid lipids are the main component of the formulation in lipid nanoparticles. For this reason, the decision of which solid lipid to use is highly relevant, and lipid screening is used as a tool to choose the lipid that has a better solubility with the active compound. However, there are no standard methods for determining the solubility of a drug molecule in a solid lipid excipient [86,87]. An example of a method to determine the best solubility of a solid lipid with a drug is the used by A. Kovačević [88]. They added an amount of the active compound to a different solid lipids, and they melted it. The mixtures were cooled down for 24 h and analyzed by light microscope. After solidification, the mixture was inspected for the presence of drug crystals by light microscopy, and the lipid chosen was the one with fewer drug crystals.
Solid lipids used in the preparation of lipid nanoparticles for ocular drug delivery are Compritol® 888 ATO [89], Precirol® ATO [90], glyceryl monostearate [91], Gelucire® 44/14 [92], Phospholipon® 90G [93], stearylamine [94], Dynasan® 116 [95], stearic acid [96], Softisan® 100 [97].

Liquid Lipids
Liquid lipids are incorporated in the NLCs in order to overcome disadvantages of SLNs. Liquid lipid influences physicochemical properties of nanoparticles, such as particle size, viscosity, and drug distribution. A few liquid lipids are biodegradable and nontoxic [98]. There are no standard methods to determine the highest solubility between liquid lipid and the drug. However, one of the most widely used screening methods for liquid lipids is the described by P. Sathe et al. [99]. They studied the maximum solubility of the active compound by HPLC. They mixed the drug with several liquid lipids and incubated them for 24 h. The mixtures were centrifugated and the supernatant was diluted to quantify the active compound. The mixture which contained a higher amount of drug was considered the most suitable for drug solubilization.
Some of the most widely used liquid lipids for ocular drug delivery are Lutrol® F68 [100], Miglyol® 812 [101], castor oil [102], and oleic acid [103].

4.2.2. Penetration Enhancers
Penetration enhancers allow the nanoparticle to penetrate the cornea and decrease barriers resistance. These excipients increase the permeability of the ocular tissues temporarily and allow nanoparticles—and, consequently, the drug—to pass through ocular tissues. Surfactants are the most used penetration enhancers in lipid nanoparticles preparation. In addition, they play an important role in the physical stability of the nanoparticle and drug permeability into ocular cells [104]. Cyclodextrins can be also used as penetration enhancers, but they have not been extensively used in lipid nanoparticles. Moreover, the lipids of the matrix can also act as penetration enhancers [82,105].

Cyclodextrins are water-soluble cyclic oligosaccharides. They have lipophilic cavities where the active compound can reside; meanwhile, it is protected but not covalently bound. However, cyclodextrins are large molecules; they cannot permeate through lipophilic membranes, such as the corneal epithelium. For this reason, F. Wang et al. synthesized nanoliposomes encapsulating a complex of brinzolamide and an hydropropyl-β-cyclodextrin [105,106]. With this novel strategy, the presence of cyclodextrin in the aqueous compartment of nanoliposomes would not affect the characteristics of conventional liposomes but prolong drug release compared to conventional liposomes. The formulation was prepared in order to improve local brinzolamide glaucomatous therapeutic effect. They obtained nanoliposomes with a particle size of 80 nm, PDI of 0.21 and a ZP almost neutral, about −3 mV. The entrapment efficiency of the formulation was high; more than 90% of the drug was encapsulated. Furthermore, they studied the corneal permeation, and they obtained a sustained release of the active compound. Finally, they tested their formulation in an in vivo model of glaucoma. The results showed that in 1 h after the administration of the novel formulation, the IOP decreased and maintained for 12 h, even the dosage of brinzolamide was just 10% compared to the commercially available formulation. Therefore, this strategy may also be useful for lipid nanoparticles.

Surfactants are substances that reduce the surface tension. As it is mentioned above, surfactants used in preparation of lipid nanoparticles have influence on the physical stability, drug permeability, and also, they can contribute to the safety of lipid nanoparticles when administered to the body [104,105]. Three types of surfactants can be incorporated into lipid nanoparticles, and these can be classified in terms of their charge: cationic, anionic, and non-ionic.

– Cationic surfactants—they have a positive charge on the polar head group. Some of the cationic surfactants used for lipid nanoparticles are the following: cetylpyridinium chroride [105], cetyltrimethylammonium bromide [107], dimethyldioctadecylammonium bromide [79], octadecylamine [95], and benzalkonium chloride [108]. However, at high concentrations, they can cause ocular irritation.

– Anionic surfactants—they have a negative charge, but they are not recommended for ocular drug delivery because they can cause ocular irritation [109].

– Non-ionic—they have neutral charge. Non-ionic surfactants are the compounds of choice for ocular drug delivery, bringing enhanced drug solubility, formulation stability, biocompatibility, and low toxicity compared with cationic and anionic surfactants [105]. The most used non-ionic surfactants are polysorbate 80 [110], poloxamer 188 and 407 [111], and sorbitane monostearate 60 [112].

Other surfactants used for ocular delivery are Transcutol® and Labrasol® because of their ability to enhance corneal penetration [113,114].

Fatty Acids
Fatty acids are able to enhance ocular drug permeation by altering cell-membrane properties and loosening tight junctions. Caprylic acid and capric acids are examples of penetration enhancers [105,115]. As an example of lipid matrix formed by capric acid, Chi-Hsien Liu et al. prepared two formulations of lutein loaded NLCs to study the corneal distribution, in order to treat macular degeneration [112]. One formulation contained cyclodextrins (NLC-D). NLC-D formulation was bigger than the naked NLC (360 and 190 nm, respectively), but the corneal accumulation and partition coefficient of lutein were improved by NLC-D. Therefore, the addition of cyclodextrins enhanced the viability of corneal cells.

4.2.3. Viscosity-Enhancing Agents
Viscosity enhancers improve precorneal residence time and bioavailability upon topical drop administration by enhancing formulation viscosity. Gels are commonly used for the preparations due to their high viscosity. Classical gels contain excipients which make the formulations viscous, and they can be directly applied to the ocular surface. However, as a disadvantage, they can result in blurred vision during the application. Moreover, it is difficult to administer an exact dose of the gel due to the high viscosity. In order to improve this issue, there are other viscosity enhancers that need exposure to specific physiological conditions to increase their viscosity, such as temperature, pH, or ion concentration. In the presence of these stimuli, they increase their viscosity forming in situ gels [82,116]. However, some in situ gels have some disadvantages due to the risk of gelling before administration, such as thermally-responsive gels [82]. In this area, A. Tatke et al. prepared triamcinolone acetonide loaded SLNs with gellan gum, which is a polysaccharide that forms a gel in contact with the ions present in the tear film of the eye [117]. The formation of the gel is due to the presence of cations that causes the cross-link of the polymer. The study showed that the formulation provided higher drug concentration in tear and in the anterior and posterior segments compared to water-dispersed SLNs. Therefore, in situ gel enhanced active compound penetration.
Additional examples of excipients for the formation of gels are hydroxy methyl cellulose, hydroxy ethyl cellulose, sodium carboxy methyl cellulose, hydroxypropyl methyl cellulose, and polyalcohol [116].

4.2.4. Bioadhesives/Mucoadhesives
To improve retention time at the corneal surface and improve corneal permeation through endocytic uptake by cornea epithelial cells, excipients with adhesive properties can be used. Cationic lipids or bioadhesive polymers can be added into the formulation for this purpose [82,118].

Cationic Lipids
Cationic lipids provide a positive surface charge to the nanoparticles, leading to an electrostatic attraction between the particle and the negative surface of ocular mucosa. This approach increase drug retention time in the eye, improving nanoparticles bioadhesion [97,107].

Bioadhesive Polymers
These polymers can be associated with lipid nanoparticles to improve the residence time of the particles in the precorneal area, enhancing drug penetration across epithelia [82,119]. Most widely used polymers are hydroxypropyl methyl cellulose [120], polyvinyl alcohol [121], sodium hyaluronate [122], chitosan [123]. As an example of application of these systems, F. Wang et al. prepared SLNs loaded methazolamide coated with chitosan for the treatment of glaucoma [124]. The results showed that the combination of SLNs with chitosan, conferred a positive surface charge and higher bio-adhesivity, improving the retention time of the formulation. Furthermore, they compared the in vivo efficacy of their novel formulation against commercial methazolamide eye drop and SLNs without chitosan. The results of the assay showed a sustained and longer antiglaucomatous effect of the chitosan coated SLNs, indicating the favorable properties of the novel formulation.

4.2.5. Other Excipients
There are other excipients that can be added into the formulation to offer prevention against microbial growth (preservatives), against undesirable physical/chemical reactions, maintenance of pH, enhancement of stability, or cryoprotection of the formula [82]. These excipients are used also in the conventional formulations and they are approved by regulatory administrations such as FDA and EMA.

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