Production method of an ocular implant coated with drug-loaded biopolymer nanofibers obtained by electrospinning technique

Abstract

The present invention relates to a method for the production of an ocular implant, wherein dexamethasone — commonly employed in the treatment of macular edema resulting from retinal vein occlusion (RVO) and diabetic macular edema (DME) — is encapsulated within a nanofibrous matrix fabricated via electrospinning, and said nanofibers are subsequently coated onto a contact lens surface.

Description

[0001] DESCRIPTION

[0002] PRODUCTION METHOD OF AN OCULAR IMPLANT COATED WITH DRUG-LOADED BIOPOLYMER NANOFIBERS OBTAINED BY ELECTROSPINNING TECHNIQUE

[0003] Technical Field

[0004] The present invention relates to a method for the production of an ocular implant, wherein dexamethasone — commonly employed in the treatment of macular edema resulting from retinal vein occlusion (RVO) and diabetic macular edema (DME) — is encapsulated within a nanofibrous matrix fabricated via electrospinning, and said nanofibers are subsequently coated onto a contact lens surface.

[0005] Prior Art

[0006] Retinal vein occlusion (RVO) is the second most common vascular disorder of the eye and can lead to severe vision impairment. One of the main causes of vision loss in RVO is macular edema. Macular edema associated with retinal vein occlusion occurs due to the breakdown of the inner blood-retinal barrier, leading to the leakage of fluid from the blood vessels into the retinal tissue. Prolonged macular edema causes structural alterations in the macula, which may result in permanent vision loss. Therefore, therapeutic strategies must aim to shorten the duration of edema and minimize visual damage. Dexamethasone is one of the most commonly used active pharmaceutical ingredients in the treatment of such conditions. It is available in the form of eye drops and intravitreal injections. While the bioavailability of eye drops is relatively low (approximately 5%), injectable forms provide significantly higher bioavailability. However, intravitreal injections are invasive, difficult to administer, carry the risk of infection, and are often costly due to the reliance on imported pharmaceutical products. In advanced cases, surgical interventions such as laser treatments may also be considered. Despite the variety of treatment methods available, complications are frequently encountered, and the search for an optimal treatment strategy continues. Notably, the intravitreal injection of active compounds increases the risk of ocular infections.

[0007] In the prior art, European Patent Document EP4146664A2 discloses heterodimer compositions and methods for treating ocular disorders.

[0008] Additionally, European Patent Document EP3011383A4 describes extended- release drug-loaded contact lenses and their production methods.

[0009] Upon review of the existing literature and technologies, it has been identified that there is a need for the development of a novel ocular implant production method in which dexamethasone, used in the treatment of macular edema associated with retinal vein occlusion (RVO) and diabetic macular edema (DME), is encapsulated within nanofibers produced by electrospinning and subsequently coated onto contact lenses.

[0010] Objects of the Invention

[0011] The primary objective of the present invention is to provide a method for producing an ocular implant in which dexamethasone, used in the treatment of macular edema associated with retinal vein occlusion (RVO) and diabetic macular edema (DME), is encapsulated within a nanofiber structure via electrospinning, and subsequently coated onto contact lenses.

[0012] Another objective of the invention is to provide a production method for an ocular implant in which dexamethasone is encapsulated using the electrospinning technique in either a uniaxial or coaxial configuration.

[0013] Yet another objective of the invention is to develop a method for producing an ocular implant that enables the controlled and sustained release of the active pharmaceutical ingredient within the eye over time, in a safe and non-invasive manner, minimizing the risk of infection and improving treatment convenience. Detailed Description of the Invention

[0014] Figures illustrating the method of manufacturing ocular implants according to the present invention are provided herein.

[0015] These figures are:

[0016] Figure 1: Scanning Electron Microscopy (SEM) image of uniaxial gelatin nanofibers encapsulating dexamethasone, produced using the inventive method.

[0017] Figure 2: Scanning Electron Microscopy (SEM) image of coaxial gelatin nanofibers encapsulating dexamethasone, produced using the inventive method.

[0018] Each component shown in the figures is individually numbered, and the corresponding references are detailed in the figure legends.

[0019] The present invention relates to a method for producing an ocular implant, wherein dexamethasone — commonly used for the treatment of macular edema associated with retinal vein occlusion (RVO) and diabetic macular edema (DME) — is encapsulated within nanofibers produced via the electrospinning technique, and these drug-loaded nanofibers are subsequently coated onto contact lenses; comprising the steps

[0020] - Undiluted dexamethasone is added to a gelatin solution prepared in dilute acetic acid to form the feed solution,

[0021] - Uniaxial or coaxial nanofibers are fabricated from the feed solution using the electrospinning method,

[0022] - During the electrospinning process, contact lenses are temporarily placed onto the collector plate, allowing the drug-loaded nanofibers (either uniaxial or coaxial) to be directly deposited onto the lens surface,

[0023] Alternatively, uniaxial or coaxial nanofibers are fabricated from the feed solution using the electrospinning method The electrospun nanofibers loaded with dexamethasone are collected and dispersed in phosphate-buffered saline (PBS) or physiological saline at room temperature.

[0024] The contact lenses are then immersed into this nanofiber dispersion to form the final drug-coated ocular implant.

[0025] In the method of the present invention, dexamethasone is directly added in undiluted form to a 30% (w / v) gelatin solution (30 g gelatin per 100 mL water), which is prepared using a 20% (v / v) acetic acid solution (composed of 20 mL acetic acid and 80 mL water). The two solutions are combined at a volume ratio of 1 :5 (v / v), with one part of the acetic acid solution mixed with five parts of the gelatin solution. In alternative embodiments of the invention, different active pharmaceutical ingredients (APIs) may be used in place of dexamethasone. Likewise, alternative biopolymers such as collagen, sodium alginate, chitosan, polylactic acid (PLA), pullulan, pectin, dextran, zein, or mixtures thereof can be used instead of gelatin. In addition to water and acetic acid, other solvents such as citric acid, ethanol, dimethylformamide (DMF), trifluoroacetic acid (TFA), dimethyl sulfoxide (DMSO), or combinations thereof may also be employed to dissolve the polymer or biopolymer. The resulting feed solution is introduced into an electrospinning apparatus at a minimum flow rate of 0.5 mL / hour. Nanofibers are produced by applying a voltage in the range of 20-30 kV, with a collector plate placed at a distance of 10-12 cm. Contact lenses are temporarily positioned on the collector plate during the electrospinning process, allowing the drug-loaded nanofibers to be directly deposited onto their surfaces.

[0026] For coaxial fiber production, two separate feed solutions are prepared and introduced into the electrospinning device via a coaxial nozzle system. The inner solution consists of dexamethasone, while the outer (shell) solution comprises a 30% (w / v) gelatin solution prepared in 20% (v / v) acetic acid. During electrospinning, the dexamethasone solution is fed at a flow rate of 0.1 mL / hour, and the gelatin solution at 0.5 mL / hour. The same voltage and collector distance used in the uniaxial process are applied here. By feeding the core and shell materials through separate syringe pumps, coaxial nanofibers are formed with the active agent encapsulated in the core and the polymeric matrix forming the outer layer.

[0027] Figure 1 displays the SEM image of dexamethasone-loaded uniaxial gelatin nanofibers and Figure 2 presents the SEM image of coaxial gelatin nanofibers encapsulating dexamethasone.

[0028] The release profile of dexamethasone (initial amount: 0.023 mg) from the fabricated nanofibers was evaluated in phosphate-buffered saline (PBS, pH 7.4) at 37 °C. Complete release (100%) of dexamethasone from uniaxial nanofibers occurred within 24 hours. In contrast, only 57% of the drug was released from the coaxial nanofibers within the same period, with full release observed by day 7.

[0029] Zeta potential and diffusion coefficient analyses of the nanofibers were conducted using a dynamic light scattering (DLS) instrument. The zeta potential of uniaxial nanofibers was measured as -5.7 ± 0.8 mV on day 1 and -3.3 ± 0.1 mV on day 8. The zeta potential of coaxial nanofibers was significantly more negative, recorded as -46.8 ± 3.2 mV on day 1 and -4.2 ± 0.1 mV on day 8.

[0030] The diffusion coefficient of uniaxial nanofibers was 0.124 ± 0.022 pm2 / s on day 1, decreasing to 0.055 ± 0.003 pm2 / s by day 8. The diffusion coefficient of coaxial nanofibers was 0.177 ± 0.035 pm2 / s on day 1 and 0.074 ± 0.006 pm2 / s on day 8.

Claims

CLAIMS1. A method for producing an ocular implant, wherein dexamethasone, used for the treatment of retinal vein occlusion (RVO), is encapsulated within a nanofibrous structure via electrospinning and said nanofibers are coated onto contact lenses, characterized in that it comprises the steps• preparing a feed solution by adding undiluted dexamethasone to a gelatin solution prepared in dilute acetic acid;• forming uniaxial or coaxial nanofibers from the feed solution using the electrospinning technique;• directly depositing the drug-loaded nanofibers onto contact lenses temporarily placed on the collector plate during the electrospinning process.

2. The method according to claim 1, characterized in that following the formation of nanofibers, the dexamethasone-loaded nanofibers are dispersed in phosphate- buffered saline (PBS) or physiological saline at room temperature, and the contact lenses are immersed in this dispersion to achieve coating with the nanofibers.

3. The method according to claim 1, characterized in that coaxial nanofibers are formed by electrospinning two separate feed solutions, wherein the inner solution comprises dexamethasone and the outer solution comprises a gelatin solution prepared in dilute acetic acid, such that the resulting nanofibers encapsulate dexamethasone in the core and gelatin in the shell.

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