Advance of the application of nano-controlled release system in ophthalmic drug delivery

Abstract

The ocular prescription application of nanometer materials are mainly concentrated in controlled release systems. Due to the unique properties of nanometer materials such as higher bioavailability and less side effects, it has great advantages in carrying ocular drugs of eye diseases compared with the traditional dosing method. As a result, nano-controlled release system has good application prospect in eye diseases. At present, a variety of different types of nano-controlled release systems have been used to enhance the efficiency of the ocular drugs including nanomicelles, nanoparticles, nanosuspensions, liposomes and dendrimers. In this article, the research progress and the application of nano-controlled release system in ophthalmic drug delivery are reviewed.

Keywords:

• Drug controlled release system
• drug therapy
• eyes
• nanometer materials

Overview

In the field of ophthalmology, topical instillation is the most common dosing method to treat ocular diseases. As we all know, it is simple to operate and easy to be accepted by patients. However, the ocular bioavailability is very low with topical drop administration. This is because the eyes have many anatomical and physiological barriers that can not be penetrated easily. Thus, less than 5% of the dose reaches to deeper ocular tissues. Intravitreal injection is another common route of drug administration to treat the disease affecting the posterior segment. Nonetheless, the need of repeated eye puncture with intravitreal injections causes several side effects such as endophthalmitis, hemorrhage, retinal detachment and poor patient tolerance. Periocular administration route is another common dosing method, it is comparatively easy, less invasive and patient compliant. However, drug permeation is compromised by ocular static and dynamic barriers. To overcome the ocular drug delivery barriers and improve ocular bioavailability, various drug delivery systems have been developed such as emulsion, ointments and suspensions. All the dosing methods have some limitations in different extent. A better route of ocular administration with high bioavailability and low irritation is urgent to be developed.

Nanometer materials have received the widespread attention since it was applied in medical field in the 1990s. It has many ideal properties such as small size, biodegradable and less irritation. At the meantime, different kinds of nanomaterial can delivery drugs with different chemical characteristics. The preparation method of nanometer carrier includes emulsion polymerization, free radical polymerization and interfacial polymerization (Lee & Choo, 2014). The nanometer materials and drugs are usually connected physically, not in chemical ways. Existing research shows that the nano-controlled release system can improve the drug bioavailability obviously, reduce the side effects of drugs, prolong the drug retention in local tissue and reduce drug dosage and dosing frequency, showing obvious superiority in multiple ways. At present, the nano-controlled release system that is used commonly has the following categories: nanomicelle, nanoparticles, nanosuspensions, liposomes, dendrimers, etc. In this review, the research progress and the application of all kinds of nano-controlled release systems will be introduced in detail.

Nanomicelles

Nanomicelles are the most commonly used drug delivery system for the formulations formed by aqueous solution. It has many advantages in drug delivery. Normally, these nanomicelles are formed by amphoteric molecules. Nanomicelles formulation can enhance the bioavailability of drugs in the eye tissues. This is because the nanomicelles have the water solubility produced by a hydrophilic nanomicelle coronary and high drug coating capacity, what’s more, it is small in size and easy to prepare at the same time. Nanomicelles can delivery ocular drugs to both anterior and posterior segment of eyes.

Nanomicelles in drug delivery

So far, many researches have been carried out to explore the application of nanomicelles in ocular drug delivery. For example, Civiale et al. (2009) used the nanomicelle carrying dexamethasone to anterior eye segment by PEHAC (16). In vivo, Scientists took samples from the aqueous humor of rabbits to study the concentration–time curve of dexamethasone. The results showed that: the PEHAC (16) nanomicelles formulation carrying dexamethasone, compared with the dexamethasone suspension, had higher bioavailability. At the same time, the area under the concentration–time curve of the dexamethasone nanomicelles formulation was 40% higher than the dexamethasone suspension in control group. It was concluded that the nanomicelles formulations are the viable option to delivery ocular drugs to anterior segment of eyes.

The scientists made some attempts to delivery ocular drugs to posterior segment of eyes by nanomicelles. Patel et al. (2015) formulated nanomicelles by polyoxyl 40 stearate (P40S) and polysorbate 80 (P80) and developed dexamethasone nanomicelles. The mean diameter of blank and drug-loaded nanomicelles was 13.3 ± 0.4 and 14.5 ± 0.4 nm. Nanomicelles were found to be stable with respect to clarity, size and drug content at 4 and 25 °C for up to 6 months in rabbits. Therapeutic concentrations of dexamethasone were observed in the retina and choroid. It provided a non-invasive method to treat the posterior segment uveitis. Cholkar et al. (2015a) entrapped cyclosporine (CsA) within nanomicelles and studied ocular CsA tissue distribution. The studies were conducted in New Zealand White albino rabbits with topical drop instillation. Ocular tissue CsA distribution studies revealed high CsA concentrations in anterior ocular tissues. Moreover, high CsA level was detected in retina (53.7 ng/g tissue). At the same time, no perceptible toxicity was detected. According to the existing literature, some people successfully prepared the nanomicelles that load rapamycin and corticosteroid (Suresh & Sah, 2014; Cholkar et al., 2015b).

The safety of nanomicelles

There is less report of nanomicelles in the aspect of quality control and safety evaluation. Considering that we use less auxiliary material in the process of preparation. We speculate that the safety of nanomicelles is relatively higher. Though there are many researches about nanomicelles. Influence of various properties of nanomicelles such as size, shape, surface charge, rigidity of structure on ocular disposition need to be studied in further details to develop an efficient nano-controlled release system. In addition, the nanomicelles tend to gather in the preservation process. Thus, the stability of nanomicelles needs to be considered in farther research and development.

Nanoparticles

Nanoparticles are the colloidal carrier whose diameter is between 10 to 1000 nm. In the field of ophthalmology, nanoparticles are usually made of lipid, protein, natural or synthetic polymer composition. It can be divided into two types: nanocapsule and nanosphere. In nanocapsule, drug is usually enclosed in polymer shell. However, in the nanosphere, drug is uniformly distributed within the polymer. It causes less stimulation to the tissue than the nanocapsule, what’s more, it can prolong the residence time of drugs and avoid constant repeated administration of drugs. Experiments (Ideta et al., 2004) proved that nanoparticles can be attached on the mucosa. They last for a long time in precorneal tissue and cannot be cleared quickly. They have ideal biocompatible and biodegradable and can be combined with the ligands of drug targets (Pescina et al., 2015). As a result, nanoparticles can not only play the role of drug carrier, but also be the indispensable link of pharmacokinetics.

Nanoparticles in drug delivery

The common nanoparticles are polyethylene glycol, chitosan and hyaluronic acid (HA).

Chitosan

Chitosan shell is the nanoparticle which is used most commonly to improve the precorneal retention time of ocular drugs. The positive charge on the chitosan can bind to the negative charge on the corneal surface. In this way, it can improve the precorneal retention time of drugs and lower drug clearance. For example, the natamycin that is coated by chitosan perform a higher bioavailability than the natamycin suspension even when the times of administration and dose are decreased. After topical administration, the area under the time–concentration curve of nanoparticle formulation is 1.47 times that of suspension agent. At the same time, the clearance of nanoparticle formulation is reduced 7.4 times.

Fathalla et al. (2015) studied the formulation and corneal permeation of ketorolac tromethamine-loaded chitosan nanoparticles. In vitro, after topical instillation, the release profile of ketorolac tromethamine (KT) from chitosan nanoparticles (CS NPs) showed significant differences (p < 0.05) compared to KT solution. Furthermore, mucoadhesion studies revealed adhesive properties of the formulated NPs. These results demonstrate the potential of CS-based NPs for the ocular delivery of KT.

Poly (lactide-co-glycolide)

Poly (lactide-co-glycolide) [PLGA] is another kind of nanoparticle that has been studied in detail. In a study, Varshochian et al. (2015) tried to treat ocular neovascularization by albuminated PLGA nanoparticles containing bevacizumab. Nanoparticles were formulated by double-emulsion method and a single dose of nanoparticles was intravitreally injected to rabbits. Results revealed that the bevacizumab vitreous concentration maintained above 500 ngmL⁻¹ for about 8 weeks. The weak point of traditional dosing method is the short half-life of the drug in vitreous which necessitates frequent intravitreal injections. The PLGA-nanoparticles provided us with a new idea to reduce dosing frequency.

In another research, Vasconcelos et al. (2015) attempted to combine human immunodeficiency virus (HIV) transaction factor as well as a kind of peptide used for ocular administration with PLGA-PEG nanoparticles to improve the bioavailability of drugs. Result showed that drugs carried by nanoparticles have a longer retention time in topical tissue. After the positive charge on the surface of nanoparticles bind to positively charged drugs, it can promote the drugs to penetrate into the cornea so as to achieve a better therapeutic effect. This is because that a positive charge on the surface of the nanoparticles with positively charged peptide drug combination, can promote drug penetration into the cornea, so as to achieve a better therapeutic effect. Other drugs such as dexamethasone (Zhang et al., 2009), sparfloxacin (Gupta et al., 2010) and levofloxacin (Gupta et al., 2011) are reported to bind to nanoparticles successfully and improve the bioavailability significantly.

Hyaluronic acid

Hyaluronic acid has been successfully applied to deliver drugs to treat the disease in posterior segment of eyes. In posterior segment, the distribution of nanoparticle mainly depends on its size and surface properties. Scientists administrated nanoparticles into Sprague–Durer rat by periocular injections and found that the nanoparticles whose diameter is less than 20 nm were quickly removed. The possible reason is the circulation of conjunctival, sclerotic and other periocular circulation system. They cannot maintain stable drug concentration level due to their small size and they are cleared so quickly. On the other hand, the nanoparticle whose diameter is between 200 and 2000 nm can delay for at least 2 months in target area. Therefore, scientists (Amrite et al., 2008; Huu et al., 2015) concluded that the nanoparticle that is not easy to be cleared by blood and lymph circulation is an ideal choice to achieve carrying drugs from sclera to posterior segment of eyes. After administrate HA nanoparticle in eyes by intravitreal injection, the nanoparticle can penetrate the whole retina and locate in the retinal pigment epithelium of normal retina (Kim et al., 2009; Koo et al., 2012). It can also reach the choroid. Therefore, it can deliver drugs to the choroid to inhibit the neovascularization of choroid. In conclusion, the HA nanoparticles has a good application prospect in the treatment of AMD.

The safety of nanoparticles

Some articles reported the toxicity and safety of nano-controlled release system. Prow et al. (2008) compared the toxicity of chitosan, PCEP (poly{[(cholesteryl oxocarbonylamido ethyl) methyl bis(ethylene) ammonium iodide] ethyl phosphate}), and magnetic nanoparticles (MNPs). They found that administrating chitosan intravitreally can lead to the inflammation of eyes, whereas administrating PCEP and MNPs did not induce retinal pathology.

In farther study, Raju et al. (2011) evaluated the safety of magnetic nanoparticles and found that intravitreal or anterior chamber injections of magnetic nanoparticles showed little to no signs of toxicity on retinal structure, photoreceptor function or aqueous drainage in the eye.

Reports (Park et al., 2015a,b) showed that some kinds of nanoparticles can cause damage to body when taken by oral or intravenous. However, there is no systemic summary about the safety of nanoparticles with other dosing method. There is no nanoparticle applied in clinic yet, at the same time, there is less report about the osmotic pressure and quality control of nanoparticles. Kettiqer et al. (Kannan et al., 2012) reported that the silica nanoparticles may have potential hazards to cells. In addition, many kinds of nanoparticles are not stable. They cannot be preserved for a long term unless lyophilized preparation. Further researches are requested to create more simple preserving methods.

Nanosuspensions

Nanosuspension is a kind of colloid dispersed system. It is formed by ultramicroscopic drug particles and has small irritation to eyes. It can enhance the retention time of hydrophobic drugs in precorneal tissues and improve the bioavailability of drugs. In this way, it has a good application prospect of carrying hydrophobic molecules (Patravale et al., 2004). So far, a number of studies have proved the efficacy of nanosuspension in carrying corticosteroids. Corticosteroids such as prednisone, dexamethasone and hydrocortisone are the first choice for treatment of anterior segment inflammation. However, using these drugs in a large dose frequently may lead to cataracts, glaucoma and optic nerve injury. Therefore, scientists try to carry corticosteroid by nanosuspensions to improve its bioavailability. For example, Kassem et al. (2007) found that the corticosteroid coated by nanosuspensions have better solubility than different kinds of corticosteroid solution, which lead to a more remarkable effect. In another study, Ali et al. (2011) prepared the hydrocortisone nanosuspension by precipitation and grind. They chose the hydrocortisone solution as the control group. After topical administration to the eyes of rabbits, the hydrocortisone nanosuspension formulation performed a larger AUC and a longer retention time in topical tissue. The researches above demonstrate the superiority of nanosuspension in carrying hydrophobic drugs.

Nanosuspension can also delivery other drugs successfully. For instance, Abrego et al. (2014) prepared nanosuspensions and nanoparticles as ophthalmic delivery of pranoprofen. The result showed that the release profiles of pranoprofen from the primary nanosuspensions and nanoparticles were similar and exhibited a sustained drug delivery pattern. Nanosuspension is also reported to carry Moxifloxacin (Mudgil & Pawar, 2013), Eudragit (Khan et al., 2013) successfully.

The development of nanosuspensions is relatively slow than other nanomaterials. No reports have illustrated its safety. Farther researches are needed to create more novel nanosuspensions that can enhance the efficiency of drug delivery.

Liposomes

Liposomes can effectively carry drugs to anterior and posterior segment of eyes. They have many advantages such as higher bioavailability and less toxic effect. Liposomes are the lipid vesicles, it consists of a hydrous nuclear wrapped by one or more phospholipid bilayers. The diameters of liposomes are between 0.08–10.00μm. According to the size of the liposome and the characteristics of phospholipid bilayer, it can be divided into the following categories: small single layer lipid vesicles, large single layer lipid vesicles and multi-layer lipid vesicles (Kaur et al., 2004). In the field of ophthalmology, liposome become the ideal drug delivery systems because its structure is like cell membrane and it has good biocompatibility, what’s more, it can wrap both hydrophilic and hydrophobic drugs.

Liposome in drug delivery

Nicolosi et al. (2015) prepared the fusidic acid coated by liposome to improve its antibacterial effect and its ability of penetrating cells. The results showed that the antibacterial ability of fusidic acid has been improved dramatically when it was coated by liposome, at the same time, the effective drug concentration and the dose decreased. It is supposed that the liposome increase the liquidity of bacterial cell membrane. In another study, the Tacrolimus formulated by liposome has less toxic effect towards internal retinal cells (Zhang et al., 2010), compared with the non-liposome formulated Tacrolimus. After intravitreal injection, the concentrate of tacrolimus in vitreous body kept in 50 ng/mL for 14 days. It indicates that the liposome-coated tacrolimus has great superiority in the treatment of uveitis. Kaiser et al. (2013) have developed a kind of anionic liposomes which can package minocycline. After it is administrated into the streptozotocin model of diabetes by subconjunctival injection. The expression of proinflammatory factor of diabetes decreases obviously and the mRNA and protein levels decreased significantly, which proves that the liposomes can be widely used in ocular drug delivery system.

The safety of liposome

Most of the reports about the safety of liposomes focus on the pharmaceutics such as particle size, zeta potential, release characteristics in vivo and stability. However, there are less systemic reports about the irritations to ocular tissue. Considering that some liposome formulations have been applied to treat dry eye syndrome, we speculated that the liposome have no excitant to eyes.

Dendritic macromolecules

The dendritic macromolecules are the nanosized, highly branch, astroid copolymer system. Polyamide, amine type dendritic polymer (PAMAM), is often used for ocular drug delivery. Vandamme & Brobeck (2005) prepared PAMAM as the carrier of Pilocarpine nitrate and tropicamide in rabbit eyes experiments, on the other hand, some researchers (Shaunak et al., 2004) combine PAMAM and glucosamine, they found that the glucosamine with PAMAM had more effective function on anti-angiogenesis and immune regulation in rabbit eyes, which provides us with a new treatment to suppress the formation of scar tissues after the glaucoma filtration surgery in clinical practice.

There are few reports about the safety of dendritic macromolecules. Recent studies with PAMAM dendrimers in a rat model suggested that, in healthy eyes, the dendrimers were readily cleared from the retina upon intravitreal administration. In contrast, in the presence of retinal degeneration, the dendrimer was retained in the retina, mostly localized to the activated microglial cells even up to 30 days (Kannan et al., 2012). Such selective localization in cells associated with neuroinflammation may help the toxicity profile of these dendrimers.

Clinical application of nano-controlled release system

At present, most nano-controlled release system are at preliminary research stage, only a small part of these achievements have been applied in clinic. Visudyne® as well as Tears again® are two of them. The Visudyne® is the liposome formulation containing the sensitizer and the Verteporfin. It is used in the photodynamic therapy of subfoveal CNV and pathologic myopia (Wong et al., 2015). Tears again® is the liposome spray which is approved for the treatment of dry eye syndrome. It has better effect in clinical practice, compared with the eye gel with triglyceride (Craig et al., 2010; Lee & Tong, 2012).

Some nano-controlled release systems that are implanted into the eyes to achieve drug delivery have been applied to clinical practices (Lee et al., 2010). Vitrasert® is one of them. 4.5 mg galloway are formulated by PVA/EVA. It can release galloway chronically for 5–8 months without systemic toxicity to human body, which cut the costs of drugs obviously. Retisert® is also a control release system who is implanted to achieve drug delivery. It can release fluocinolone slowly for 3 years. With long-term drug retention, the Retisert® effectively suppresses the inflammation, reduce the recurrence of uveitis and improve vision. The Vitrasert® and Retisert® have no stimulation to normal tissue, but they cannot degrade completely in vivo, which restricts their application in clinic. Surodex™ and Ozurdex® are the biodegradable implants that have been applied in clinical practice. They can release dexamethasone slowly for a long term. The Surodex™ is implanted in the atria to treat the postoperative inflammation of cataract patients. It consists of PLGA, hydroxypropyl methylcellulose and dexamethasone. Due to its superior properties, it can produce the same effect of anti-inflammation as daily instillation of steroid drugs with a single administration. The Ozurdex® contains a PLGA polymer matrix which degrades slowly to lactic acid and glycolic acid allowing prolonged release of dexamethasone up to 6 months. Randomized clinical trials have demonstrated its potency in reducing vision loss and improving vision acuity in eyes with macular edema associated with branch retinal vein occlusion (BRVO) or central retinal vein occlusion.

Summary

At present, the nano-controlled release system that is widely used in ophthalmology is nanomicelles, nanoparticles, nanosuspension, liposome, dendritic molecules and so on. Most of them have not been applied to clinical. The research results show that using nano-drug controlled release system as carrier can improve the bioavailability of drugs, reduce drug dosage and dosing frequency, improve the retention time of drugs in local tissue and reduce the side effects of drugs, they are better for the treatment of ocular tissue lesions and can overcome the disadvantages of traditional drug delivery mode. In conclusion, nano-controlled release system has very good application prospect. It is believed that with the deepening of the research, more nano-controlled release system will be applied in ocular drug delivery applications will be in the clinical treatment.

Declaration of interest

Authors would like to thank the funding support from Science and Technology Department (20130413025GH) and Health Department of Jilin province, China (2013Q005).

All the authors have read and approved the final version and are responsible for any ethical issue that may arise after the publication of this manuscript.