Thiolated hemicellulose containing mucoadhesive and permeation-enhancing ocular films of levodopa for potential treatment of myopia

Abstract

The ocular bioavailability of a drug is inadequate due to physiological constraints. In this study, an ocular film of Levodopa (LD) using thiolated hemicellulose (THC) with improved mucoadhesion and permeation was made. Linseed hemicellulose (LHC) was extracted, and its esterification was done with thioglycolic acid (TGA), L cysteine (LC), and thiourea (TU). Maximum thiolation of LHC was confirmed by Ellman’s test, Fourier-transformed infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Primary eye irritation tests and histopathological studies of different ocular tissues like cornea, conjunctiva, and sclera conducted on rabbit eyes exhibited nontoxic and non-irritant behavior of LHC and optimized derivative of LHC with TGA (THT-960) which was further used for the preparation of LD-containing ocular films i.e., LD-THC, LD-THT960, and LD-THT960-THC, respectively. Ascorbic acid was added to the ocular film to prevent oxidation of LD. Ex-vivo permeation studies from bovine cornea showed a 1.8fold increase in corneal permeation of LD while ocular irritancy by hen egg chorioallantoic membrane (HET-CAM) test and histopathological analysis confirmed nonirritant and nontoxic nature of THT-960. Conclusively, LD-THT960 due to improved mucoadhesion and corneal permeation of LD can be used effectively for the potential treatment of myopia.

Introduction

Myopia, or shortsightedness, is a major public health issue [1]. According to the World Health Organization, uncorrected and under-corrected myopia are the main causes of visual impairment [2]. Treatment options for myopia are optical bifocal spectacles, defocus and contact lenses [3], orthokeratology [4], surgical procedures like trans-epithelial photorefractive keratectomy (Trans-PRK), laser-assisted in situ keratomileusis (LASIK), small incision lenticule extraction (SMILE) [5], and topical pharmaceutical agents such as atropine eye drops [6]. Refractive eye surgeries are associated with side effects like dry eyes, glare, and halos and may cause long-term complications like ocular infections, vision loss, chronic pain, and detachment of the retina. Although widely and effectively used, atropine eye drops are associated with drawbacks like blurred near vision, photophobia, and rebound after the termination of therapy [7]. Levodopa is another potential candidate to be used for the treatment of myopia. A study conducted on the Chick model recently showed that levodopa administration through intravitreal injection or topical eye drops was able to retard ocular growth and significantly inhibit, in a dose-dependent manner, the development of lens-induced myopia (LIM) and form-deprivation myopia (FDM) via a D2-like receptor-dependent mechanism. With a focus on potential clinical use in humans, the interpretation of this avian safety data in a mammalian model (the mouse) revealed the potential effectiveness of levodopa for the treatment of human myopia [8].

Several options are available for ocular drug delivery including topical, intravitreal, suprachoroidal, and retrobulbar routes. The topical route of drug delivery is the most widely used route owing to its simplicity, feasibility, and patient compliance due to its noninvasive approach. Eye drops are the most widely used ocular dosage form. A major fraction of the drug applied in the form of eye drops is wasted on account of low contact time due to factors like reflex blinking, excessive lachrymation, and nasolacrimal drainage. Other factors include low corneal permeation, blood-retina, and blood-aqueous humor barrier. These factors are responsible for the low bioavailability (5 %) of the applied drug. Furthermore, the need to repeat the dose frequently drastically reduces the level of patient compliance. A logical solution to the problem is to employ a dosage form with a longer contact time with the ocular tissue and use a drug carrier with increased mucoadhesion and enhanced ocular permeation. The use of ocular film is an efficient way to improve the contact time of the medicament to the ocular tissue.

Apart from their application in almost all spheres of life, polymers are truly considered the backbone of pharmaceutical drug delivery systems because of their ability to control the release of drugs from the dosage form. These macromolecules protect the drug against the physiological environment, modify its release pattern, and contribute to the stability of the drug and dosage form A polymer with excellent film-forming ability is a major requirement for the formulation of ocular films. Although an extensive variety of polymers are available for the fabrication of ocular films, polymers of natural origin are preferable due to biocompatibility, nontoxic nature, easy availability, and cost-effectiveness. In recent years linseed polysaccharides (hemicelluloses extracted from linseed) have been investigated for their potential to be used as a drug carrier. It is reported to have the potential to be used as a binder, disintegrant, suspending agent, thickening agent, matrix-forming agent, and release retardant agent in pharmaceutical preparations.

Thiolated polymers also termed as “thiomers” are obtained by the covalent attachment of the thiol group on the polymeric backbone of polymers. In the recent past thiol functionalization has been successfully used to improve the mucoadhesion property of the polymer significantly. Researchers have also reported an increased drug permeation after thiol modification. These post-thiolation outcomes can be exploited to increase the bioavailability and hence efficacy of our ocular drug delivery system. In the current study, LHC was extracted from linseed and used as a Levodopa carrier ultimately delivered at the posterior segment of the eye. The intrinsic mucoadhesive property of LHC was enhanced by converting it into THC with the addition of the -SH group. THT-960 was optimized based on maximum thiol content. Docking and computational studies were also performed which suggested the potential of expected changes to take place after thiol modification. Physicochemical and mechanical testing of ocular films, determination of mucoadhesion strength and time using bovine conjunctival mucosa, bovine corneal permeations, and ocular irritancy test by the hen egg chorioallantoic membrane method make the study more applicable to claim proposed formulation appropriate for ocular delivery.

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Materials

Linseed was used as raw material and was purchased from the local market. LD was received as a gift sample from Reko Pharmacal (Pvt) Ltd. Lahore Pakistan. 5,5-dithio-bis-(2-nitrobenzoic acid) (Ellman’s reagent), L-cysteine HCl,1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide HCl (EDAC HCl), Hydrochloric acid and n-hexane were purchased from Sigma Aldrich Germany. N- N-hydroxy succinimide was obtained from Fluka, USA. Thioglycolic Acid (TGA), thiourea, disodium hydrogen phosphate.

Fazal Rahman Sajid Chughtai, Muhammad Hanif, Muhammad Azeem, Khalid Mahmood, Nasreen Ramzan, Hafiz Muhammad Usman Abid, Muhammad Qaiser, Nabeela Ameer, Thiolated hemicellulose containing mucoadhesive and permeation-enhancing ocular films of levodopa for potential treatment of myopia, International Journal of Biological Macromolecules, 2025, 142901, ISSN 0141-8130, https://doi.org/10.1016/j.ijbiomac.2025.142901.

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