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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关于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.Pharmaceutics2022,14, 90. https://doi.org/10.3390/pharmaceutics14010090
眼药递送的赋形剂(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
固体脂质是脂质，其形成高度有序的结晶晶格。它们是固体在体温下，允许受控和持续的药物释放[14]。固体脂质是脂质纳米颗粒中制剂的主要成分。因此，使用固体脂质使用的决定是高度相关的，并且使用脂质筛选用作选择具有更好的溶解性与活性化合物的脂质的工具。然而，没有用于测定药物分子在固体脂质赋形剂中的溶解度的标准方法[86,87]。用药物确定固体脂质的最佳溶解度的方法的实例是A.Kovačević的使用方法[88]。它们将活性化合物的量加入到不同的固体脂质中，它们熔化它。将混合物降至24小时并通过光学显微镜进行分析。凝固后，通过光学显微镜检查混合物用于存在药物晶体，并且选择的脂质是具有较少药物晶体的脂质。
Solid lipids used in the preparation of lipid nanoparticles for ocular drug delivery areCompritol® 888 ATO[89],前的irol® ATO[90], glyceryl monostearate [91],Gelucire® 44/14[92],Phospholipon® 90G[93], stearylamine [94],Dynasan® 116，硬脂酸[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 areLutrol® F68[100],Miglyol® 812蓖麻油[102],[101]和油酸[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
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.
表面活性剂
表面活性剂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.
- 阳离子表面活性剂 - 它们对极性头组具有正电荷。用于脂质纳米颗粒的一些阳离子表面活性剂是以下：十六烷基吡啶[105]，十六烷基三甲基溴溴铵[107]，二甲基二乙二烷基溴化铵[79]，十八烷基胺[95]和苯并氯化铵[108]。然而，在高浓度下，它们会导致眼睛刺激。
– 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 areTranscutol®andLabrasol®because of their ability to enhance corneal penetration [113,114].
Fatty Acids
脂肪酸能够通过改变细胞膜性能和松开紧密结来增强眼药渗透。辛酸和癸酸是渗透增强剂的实例[105,115]。作为由癸酸，Chi-Hsien Liu等人形成的脂质基质的一个例子。制备了两种叶黄素装载的NLC，以研究角膜分布，以便治疗黄斑变性[112]。一种配方含有环糊精（NLC-D）。NLC-D配方比裸NLC（分别为360和190nm），但通过NLC-D改善了叶黄素的角膜积累和分配系数。因此，添加环糊精增强了角膜细胞的活力。
4.2.3. Viscosity-Enhancing Agents
通过提高配方粘度，粘度增强剂通过提高局部滴剂来改善预甲型停留时间和生物利用度。由于其高粘度，凝胶通常用于制剂。经典凝胶含有赋形剂，使制剂粘稠，它们可以直接施加到眼表面上。然而，作为一种缺点，它们可以在应用过程中导致视力模糊。此外，由于高粘度，难以施用精确剂量的凝胶。为了改善这个问题，还有其他粘度增强剂需要暴露于特定的生理条件，以增加它们的粘度，例如温度，pH或离子浓度。在这些刺激的存在下，它们在原位凝胶中增加它们的粘度[82,116]。然而，由于在给药前凝胶的风险，一些原位凝胶具有一些缺点，例如热响应凝胶[82]。在这个领域，A. Tatke等。制备的抗甘油酮加载的加载Slns，具有Gellan Gum，其是形成与眼睛泪膜中存在的离子接触的凝胶的多糖[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。生物粘附/粘液粘附
为了改善角膜表面的保留时间，通过角膜上皮细胞通过内吞吸收改善角膜渗透，可以使用具有粘合性能的赋形剂。为此目的，可以将阳离子脂质或生物粘合聚合物加入制剂中[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].
生物粘合聚合物
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],壳聚糖[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.