Research progress of ophthalmic preparations of immunosuppressants

Immune ophthalmopathy is a collection of autoimmune eye diseases. Immunosuppressants are drugs that can inhibit the body’s immune response. Considering drug side effects such as hepatorenal toxicity and the unique structure of the eye, incorporating immunosuppressants into ophthalmic nanodrug delivery systems, such as microparticles, nanoparticles, liposomes, micelles, implants, and in situ gels, has the advantages of improving solubility, increasing bioavailability, high eye-target specificity, and reducing side effects. This study reviews recent research and applications of this aspect to provide a reference for the development of an ophthalmic drug delivery system.

1. Introduction

Various immune disorders are caused by immunopathological changes in the eye, collectively known as immune eye diseases, which include corneal transplant rejection, uveitis, age-related macular degeneration, retinitis, diabetic retinopathy, and macular edema. The human eye comprises anatomical structures and physiological barriers that prevent the drug from reaching the pathological site (Madni et al., Citation2017). There are several administration methods, such as local drip application and local injection (anterior chamber, subconjunctival, and vitreous). As injections are risky, drips in the anterior segment are the most accepted by patients, especially for chronic eye diseases that require long-term treatment. Drip administration could also utilize a non-corneal route (sclera) for retroocular delivery. Therefore, molecules’ water solubility determines their transport through the sclera and their ability to escape conjunctival blood and lymphatic washout (Aydemir et al., 2004).

Immunosuppressants are a large class of chemical drugs that inhibit abnormal immune responses of the body and the proliferation of immune response cells (macrophages, such as T cells and B cells) by suppressing antibody production (Liu et al., 2016). In organ transplantation, postoperative immune rejection can inhibit the expansion and proliferation of cytokines. Inhibiting autoimmune responses can happen at many levels, including cell subsets, cytokines, and immune cells (Wang et al., 2021). It has been shown that immunosuppressive drugs can reduce rejection of transplanted organs, increase graft survival rates, and extend the life span of recipients (Bauer et al., 2020). When combined with antibiotics, it has the ability to effectively inhibit inflammation. Furthermore, immunosuppressive agents are effective in the treatment of cancer (Rollan et al., 2022) and some diseases caused by abnormal autoimmunity (Jayatilleke, 2022). Comparatively to other therapies, immunosuppressive therapies target immune cells, specifically regulating their immune response. Some researchers have studied the disorders of neuromyelitis optica pedigree during pregnancy. According to the findings, women without immunotherapy were more likely to recur the disease in the early postpartum period, and postpartum disability was more severe (Shi et al., 2017). Immunosuppressive therapy during pregnancy and postpartum can reduce the risk of recurrence and the degree of disability. Besides, researchers have used immunosuppressive therapy to treat patients with aplastic anemia secondary to cancer chemotherapy or radiotherapy, and 50% of patients have alleviated their aplastic anemia (Nakagawa et al., 2021). The overall survival rate was significantly different from that of patients without immunosuppressive therapy (p < 0.05).

Immune rejection caused by organ transplantation (including corneal transplantation) is most commonly treated through systemic administration, such as oral administration, which is prone to causing systemic immunosuppression and serious adverse reactions. The immunosuppressants may show organ specificity and/or systemic toxicity, such as hepatorenal toxicity, hypertension, new endpoint diabetes after transplantation (NODAT) or post-transplant diabetes media (PTDM) (Davidson et al., 2003), dyslipidemia (Laish et al., 2011, Lucey et al., 2013), increased risk of cardiovascular disease (Wojciechowski & Wiseman, 2021). Additionally, they also have been implicated in the pathogenesis of diabetes, hypertension, hyperlipidemia, and cosmetic stigma. Immunosuppressants mainly include corticosteroids, alkylating agents, antimetabolic agents, calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. Table 1 listed the classification of immunosuppressants, representative drugs and typical adverse reactions. Antibiotics are also required in organ transplantation to prevent infection, which may weaken immunity. Antimetabolic drugs are mainly used in severe patients, which can directly kill immune cells. They have a great inhibitory effect, accompanied by a great number of side effects, such as gastrointestinal superset, cytopenia, and hepatitis. Alkylating agents increase the risk of cancer related mortality. Therefore, it is recommended that the duration of alkylating agent treatment should not exceed 18 to 24 months (Guillevin et al., 1997). Besides, the side effects of corticosteroids are mainly manifested in the development of obesity, glucose intolerance, osteoporosis, ischemic necrosis, linear growth disorder (children), glaucoma, cataract, myopathy, and neuropsychiatric complications after transplantation (Danovitch, 2005). The acute toxicity of calcineurin inhibitors includes hypertension, renal dysfunction, and neurological disorders such as tremor and seizures (Bennett et al., 1996). Moreover, they play a role in the development of diabetes, hypertension, hyperlipidemia (Nankivell et al., 2003). mTOR inhibitors can lead to hyperglycemia, dyslipidemia, neurotoxicity, stomatitis, poor wound healing, pneumonia, vascular edema, lymphedema, Osteonecrosis (Nguyen et al., 2019).

Although these immunosuppressants cause many side effects, some drugs are not recommended for clinical use. For examples, antimetabolic drugs cause too much harm to the human body. It is rare to use antimetabolic drugs as part of immunosuppressive therapy. The risk of alkylating agents to cancer has led people to advocate non alkylating agents (Jabs, 2018). In addition, the main risks of corticosteroid use in the eyes are cataract, infection tendency and elevated intraocular pressure, which may lead to glaucoma (Burkholder & Jabs, 2021). As compared to the first three, this calcineurin inhibitor and mTOR inhibitor have relatively few side effects, including hepatotoxicity, hypertension, bone necrosis and other systemic side effects. The preparation of local eye nano preparation can better increase the eye targeting and reduce the side effects on the whole body. Therefore, clinical treatment drugs for ocular immune rejection are being developed in a hotspot (Cotovio et al., 2012).

The most commonly used ocular immunosuppressants are cyclosporine (cyclosporine A, CsA), tacrolimus, sirolimus (rapamycin), and everolimus. In addition to corneal transplant rejection, these immunosuppressants can also be used to treat scleritis, macular degeneration, uveitis, and dry ophthalmopathy. The blood-eye barrier limits the ocular bioavailability of systemic medications, whereas all four immunosuppressants are highly lipophilic and low in water solubility when administered as topical eye drops (solubility in water < 10 μg/mL, large molecular weight, approximately 1000 g/mol). Figure 1 depicts the structural formulas of some ocular immunosuppressants. Therefore, drugs prepared in various formulations, such as nanosuspension, nanoparticles, liposomes, micelles, and implants, can improve their solubility in water, reduce their toxicity, and facilitate their delivery.

The particle sizes range varies considerably from formulation to formulation, as shown in Figure 2. Microparticles include microspheres and microcapsules with particle sizes measured in micrometers. Microspheres are spherical particles formed by dispersing drugs in polymer materials, whereas microcapsules are microscopic capsules created by encapsulating drugs in polymer capsules. Notably, if the particle size of the particles administered to the eye exceeds 10 μm, a foreign body sensation will occur. Nanosuspensions are nano-controlled release systems consisting of colloidal discrete systems stabilized by surfactant (Wang et al., 2016). A nanosuspension protects solutions with poor dissolvability in lachrymal fluids with particle sizes between 100 nm and 1000 nm.

Compared to conventional ocular formulations, nanosuspensions have reduced particle sizes and increased specific surface areas. Typically, nanoparticles have a radius or characteristic size below 100 nm. Hybrid nanoparticles may penetrate posterior ocular tissues more effectively because of their hydrophilic properties. Liposomes are microscopic vesicles composed of phospholipid bilayers that enclose aqueous compartments with particle sizes from 25 nm to 1000 nm. As liposomes can be continuously administered and form deposits within the cornea, they have been widely used for targeted therapies for a long time (Karn et al., 2014). Unfortunately, some studies have mentioned that because of liposomes’ short half-life at the corneal surface, the concentrations of CsA in aqueous and vitreous humor after liposome treatment were low, leading to the release of free CsA before liposome penetration into the cornea (Nikoofal-Sahlabadi et al., 2013).

Therefore, CsA cannot enter the posterior end of the eye for treatment. Novel lipid carriers (NLCs) are formulated from a mixture of solid and liquid lipids, which prevents drug leakage. NLCs have good biocompatibility and can be produced on a large scale through high-pressure homogenization compared with other colloidal carriers (Li et al., 2008); however, the addition of many excipients resulted in low drug loading efficiency. Besides NLCs, polymeric micelles can be used to improve corneal and conjunctival penetration, maintain drug levels, and reduce systemic side effects. Micelles are amphiphilic spheres self-assembled by surfactants with a radius from 10 nm to 100 nm (Kwon, 2003). The surfactants create a hydrophobic core that encloses the hydrophobic molecules. Micelles are more dynamic than polymeric nanoparticles.

Nevertheless, drug leakage may occur during storage and transportation because of the drug diffusing out of micelles as the temperature fluctuates (Crean 2009). In some studies, insoluble drugs were prepared as aqueous solutions via solubilizers through a straightforward process. However, none of the aforementioned preparations can remain in the eye for a long time because of the eye’s unique structure; most of the drugs are lost on the ocular surface and are unable to exert better efficacy. In situ gel is a kind of preparation that undergoes phase transition immediately at the application site after administration in the solution state, forming a non-chemically cross-linked semi-solid gel from the liquid state. In vitro gel—the substance is in a liquid state—facilitates canning and transport. It is converted into a gel at the application site, thereby increasing the retention time in the eye, reducing administration frequency, and improving patient compliance.

However, some in situ gels can impair vision. In addition to these nanomedicines, eye implants comprise a mixture of drugs and polymeric materials contained in a miniature device or prepared according to a certain formulation. With accurate dosing, stable drug release, and high targeting, implants are surgically transplanted into the eye. A small drug dose could produce therapeutic effects. If the implant causes an adverse reaction or is no longer needed, it can be removed. Biodegradable implants can be degraded without surgical removal.

Excipients mentioned in the article besides others: Vitamin E TPGS, Poloxamer P 407

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