Pullulan as a sustained release carrier for ocular drug delivery: a review

Abstract

Pullulan, an exopolysaccharide, obtained from the fungus Aureobasidium pullulans, is a non-ionic, hydrophilic, biodegradable, biocompatible, and tolerogenic polymers that is used for the formulation of bioconjugates in the therapeutic delivery to target different cells and tissues. It is known to possess outstanding film-casting qualities and can produce a clear and biodegradable film. Furthermore, appropriate derivatizing pullulan provides active surfaces that facilitate binding with active pharmaceutical ingredients to the polymer backbone to produce micro/nanoparticulate systems for controlled or sustained drug release. Ophthalmic problems like glaucoma, age-related macular degeneration, and cataracts are very prevalent across the globe, and their treatment options mainly include conventional topical solutions and gels, which possess very low drug-contact time and poor bioavailability, leading to frequent dosing and patient incompliance. Sustained release dosage forms like ocuserts, ocular films, and in-situ gels can help in achieving the intended therapeutic outcomes for an extended duration by minimizing the number of doses. Here, we present a comprehensive critical review of the utilization and application of pullulan, together with its derivatives, to combat problems with ocular medication administration. This article also provides insight for further research on this topic to utilize its advantages to the fullest in the future for improved delivery of therapeutics in the treatment of ocular disorders.

Introduction

The intricate anatomical structure of the eye, one of the main organs of the visual system, is created by the coordinated growth of numerous tissues with different functionalities. [1]. Impairment in retinal tissue contributes to visual disabilities, which affects an individual’s capacity to remain independent, thereby deteriorating the standard of living. [2]. The two identifiable sources of vision impairment are retinal and optical damage. [3]. Age-related eye conditions are more common than ever, and the most prevalent causes, including glaucoma, age-related macular degeneration, and cataracts, have all been seen to be on the rise. [4]. Treatment of posterior ophthalmic ailments, specifically of the retina, is still challenging owing to the eye’s intricate and distinct anatomy and physiology. Achieving efficient and long-lasting intraretinal medication concentrations while limiting unfavorable effects of the therapeutic agents on other ocular structures is the major drawback in pharmacotherapy for retinal disease. [5]. The traditional methods of drug administration have been proven to be ineffective in medication delivery to the posterior portion due to various ocular obstacles and restrictions of several routes.

There have been several reviews from different researchers highlighting the role of novel formulations like stimuli-responsive [6] over traditional ones. In an exhaustive review by Nguyen and Lai, drug delivery strategies via stimuli-responsive polymers, viz., thermo-responsive, pH-responsive, and ion-triggered, have been magnificently elaborated concerning biocompatibility and degradability in an ocular environment [7]. The same cohort explained a novel concept of nanoparticles, which shows therapeutic efficacy without any drug. These nanoparticles become self-activated when engaged with biological targets and demonstrate therapeutic efficacy in terms of inhibiting oxidative stress, infection, neovascularization, and inflammatory conditions of macular degeneration [8]. Furthermore, 3D printing has also been established in terms of corneal and retinal printing to overcome the issues associated with traditional drug delivery. [9].

To achieve the desired drug concentrations at a specific site, substantial dosages of the medicine or repeated injections are necessary, however, these are not devoid of resulting toxicity or unfavorable effects on the eye as well as other organs [10]. Due to drug delivery restrictions imposed by the drug administration route and obstacles connected to the anatomy and physiology of the eye, the ideal efficacy and safety conditions are frequently challenging to obtain in ophthalmic settings. Advancements in drug delivery show advantages over traditional approaches and deliver the drug to the eye without interfering with its normal function [11]. Therefore, to develop advanced drug delivery carriers for the improvement of ocular drug administration, polymeric carriers and suitable excipients from synthetic and natural sources are currently incorporated [12]. The anterior ocular segment can be treated with topical ophthalmic preparations, unlike the posterior part.

Numerous barriers that cause low retinal bioavailability (0.01 %) after topical application are the rapid solution drainage from the eye with tears, systemic conjunctival absorption, corneal epithelium, choroidal blood flow, etc. [13]. Fig. 1 shows the various barriers to the eye along with the different routes of drug administration [14]. Therefore, intravitreal injections are used to treat numerous retinal illnesses to achieve desired medication concentrations at the target site. Luo et al. synthesized metformin and poly-catechin co-loaded gold nanoparticles for age-related macular degeneration (AMD). The rationale that the cohort utilized is the anti-inflammatory and antioxidant properties of poly-catechin and the anti-angiogenic characteristic of metformin and developed this nanocomposite. The nanoparticles were targeted actively with the help of the complement component protein C3 to the lesion site, which was confirmed by a white light-induced AMD rat model.

The developed nanocomposite demonstrated significant biocompatibility in preclinical and cell line studies [15]. Likewise, Nguyen et al developed polycaprolactone nanoparticles loaded with resveratrol via aminolysis for AMD. The synthesized nanoparticles were then subjected to the formation of amide bonds between the carboxyl group of the cell-penetrating peptide and metformin. In preclinical studies, a single dose administration of the developed formulation resulted in 15 times increment in the enhancement of retinal permeability, thus, the biological activity of both actives, i.e. resveratrol and metformin, was significantly expressed in terms of antioxidant and anti-angiogenic effects, specifically in the retinal pigment region [16]. Another cohort developed a carbonized nano donut-like structure for the treatment of ocular angiogenesis, which is a symptom of diabetic retinopathy. The researchers used sodium alginate and 1,8-diamino octane to develop nano donuts via the formation of amide bonds between both excipients via partial carbonization. During the study on retinal pigment epithelial cells exposed to hydrogen peroxide, the developed formulation demonstrated five times suppression in the generation of reactive species. In rabbit eyes and chicken embryos, significant biological compatibility and suppressed new blood vessel production were achieved [17].

To administer drugs for reducing inflammation, such as corticosteroids and vascular endothelial growth factor (VEGF) inhibitors that are anti-neovascular, clinics routinely use intravitreal injections [18,19]. While intravitreal shots have been considered safe, repeated injections can cause serious complications such as infections and detached retinal tissue, which decreases patient compliance [20]. Conversely, implants featuring a regulated release and extended ocular presence have decreased frequent dosing of essential therapeutic agents (e.g., Ozurdex).

Nowadays, nanotechnology has successfully entered in medical field for improved patient care through diagnosis of disease, treatment, gene therapy, regenerative medicine, drug delivery, and oncology [21]. For example, to transport small (e.g., dexamethasone) or large (e.g., nucleic acids) molecules to the retina, nanocarriers and peptide conjugates have recently been reported as beneficial over conventional deliveries [22,23]. The selection of excipients for the fabrication of such nanocarriers is very important concerning the safety of the patients, and when it is intended to be applied to the eyes, it attracts more attention from pharmaceutical scientists. In this respect, modified polysaccharides like pullulan are intriguing options for fabricating ocular delivery systems [24]. Polymeric drug conjugates have been thoroughly studied as target-specific and extended drug-release formulations [[25], [26], [27], [28], [29], [30]].

In this article, our comprehensive critical review is on pullulan and its derivatives which were originally a fungus polysaccharide [[31], [32], [33]] which is regarded as a biologically compatible polymer. It has previously been utilized as a foundation in the creation of bioconjugates for the transport of drugs to the pancreas and liver [25,31,[34], [35], [36]]. Furthermore, we investigated various roles of pullulan in ophthalmic formulations for retinal drug delivery, determination of ocular pharmacokinetics, and ocular safety of the users.

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Aarushi Kaith, Unnati Garg, Neha Jain, Manisha Pandey, Shreya Kaul, Bapi Gorain, Mohd Cairul Iqbal Mohd Amin, Pullulan as a sustained release carrier for ocular drug delivery: a review, International Journal of Biological Macromolecules, Volume 309, Part 4, 2025, 143146, ISSN 0141-8130, https://doi.org/10.1016/j.ijbiomac.2025.143146.

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