Mucoadhesive gellan gum/poly(2-ethyl-2-oxazoline) films for ocular delivery of pilocarpine hydrochloride

Introduction

The term “glaucoma” describes a group of ocular conditions with several characteristic features: firstly, it is a constant or periodic increase in intraocular pressure (IOP) above the individually tolerated levels; secondly, it is the development of specific visual field lesions and optic nerve atrophy, which can ultimately lead to blindness [1]. This disease has a profound negative effect on the psychological, social, and emotional well-being of the patients. There are two most common forms of glaucoma: open-angle glaucoma (leads to excessive fluid production) and closed-angle glaucoma (leads to rapid, painful, and irreversible loss of vision up to blindness). Unfortunately, modern ophthalmology is not yet able to completely cure a person from glaucoma, but with regular medication, intraocular pressure can be controlled and the damage to the optic nerve can be prevented. Ophthalmologists use various therapeutic agents to treat glaucoma, such as β-blockers, prostaglandin analogues, carbonic anhydrase inhibitors, sympathomimetics and miotics [2]. Drug therapy is usually prescribed in the form of antiglaucoma eye drops, which require strict adherence to the administration schedule. Patients diagnosed with glaucoma are typically required to administer eye drops throughout their life.

Pilocarpine is one of the drugs used to treat angle-closure glaucoma. It is available as eye drops of 1–2% pilocarpine hydrochloride or pilocarpine nitrate. However, due to the physiological barriers, topically administered pilocarpine drops result in a low drug bioavailability of 1–3% in the eye [3]. In this regard, there is a strong interest in developing effective drug delivery systems for glaucoma therapy [4].

Various mucoadhesive delivery systems for pilocarpine targeting eye tissues have been developed for the therapy of glaucoma. Durrani et al. [5] explored the use of Carbopol 1342 as a mucoadhesive polymer to improve the intensity and duration of the miotic response of pilocarpine nitrate incapsulated in liposomes using albino rabbits. Saettone with co-workers [6] reported the design of cylindrical ocular inserts based on blends of poly(vinyl alcohol), glyceryl behenate and different polymers (xanthan gum, jota-carrageenan, hydroxypropyl methylcellulose, and hyaluronic acid) for formulating pilocarpine nitrate using an extrusion technique. These inserts were then coated with a mixture of Eudragit RL and RS. The miotic activity tests conducted using these inserts established prolonged drug release and improved performance in the case of the coated formulations compared to uncoated ones. Choy et al. [7] demonstrated the sustained release of pilocarpine using mucoadhesive microparticles in a rapidly dissolving tablet, while İnce et al. [8] developed a pilocarpine microemulsion with good physicochemical properties and stability. The potential of mucoadhesive poly((2-dimethylamino)ethyl methacrylate) nanogels for sustained release of pilocarpine was also reported by Brannigan et al. [9].

Ocular films have gained significant attention as emerging drug delivery platforms, offering sustained drug release, improved bioavailability, and enhanced patient comfort [10,11]. These thin, transparent polymeric matrices, when applied directly onto the ocular surface, provide prolonged contact time, reduced systemic absorption, and minimized side effects compared to traditional eye drops. Incorporating pilocarpine, a well-established miotic agent, into ocular films presents a promising approach for optimizing glaucoma therapy. Hsiue et al. [12] has reported that polymers such as poly(2-hydroxyethylmethacrylate) can significantly improve the bioavailability and retention of pilocarpine in the ocular tissues. Wafa et al. [13] studied ocular inserts and in situ film-forming liquids, finding comparable efficacy for delivering pilocarpine. Alotaibi et al. [14] reported the development of ocular inserts (films) based on blends of hydroxypropylmethylcellulose with poly(vinyl alcohol) and loaded these with pilocarpine hydrochloride encapsulated in niosomes. They demonstrated that these inserts could ensure a sustained release of the drug over 24 h in in vitro experiments. These studies collectively highlight the potential of mucoadhesive films for ocular pilocarpine delivery, with the need for further research to optimize their performance.

The development of drug delivery vehicles relies on different natural and synthetic polymers, each with their own advantages and challenges [[15], [16], [17], [18]]. Natural polysaccharides exhibit remarkable properties, making them widely favored and valuable for a range of biomedical applications [19]. Among them, gellan gum, a polysaccharide derived from aerobic fermentation, stands out as a promising material with excellent film-forming properties due to its malleability and high efficiency. The films based on gellan gum have found applications in formulations for wound healing, bone regeneration, and drug delivery systems. Gellan gum is already used as a component of ocular formulations for the therapy of glaucoma, for example, eye drops called Timoptol TM with timolol maleate are available commercially [20]. Previously, Agibayeva et al. [21] reported chemically modified gellan gum with enhanced mucoadhesive properties for delivery of pilocarpine hydrochloride to the eye.

Formulation of ocular films using water-soluble polymers often requires optimization of their properties to meet several requirements such as mechanical properties and integrity, swellability, and tailored mucoadhesive properties. One of the strategies to achieve these optimal film formulations is blending of different water-soluble polymers. Previously, we reported optimization of polymeric films by blending chitosan with poly(2-ethyl-2-oxazoline) as a non-ionic water-soluble polymer [22]. Although we did achieve some optimal film characteristics, this study did not involve any model drug formulation and its efficiency evaluation.

In this study we explored the preparation of ophthalmic films with pilocarpine hydrochloride by blending gellan gum with poly(2-ethyl-2-oxazoline). The physicochemical properties of these films were evaluated at different polymer ratios using thermal methods, Fourier-transform infrared spectroscopy and scanning electron microscopy. Mucoadhesive properties of these films were studied with ex vivo ocular tissues using a tensile test. Non-invasive in vivo experiments performed on rabbits provided valuable information about the efficiency of these formulations. As far as we are aware, this is the first investigation into the miscibility of these polymers and application of their blends in ocular drug delivery.

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