Development of Circular Drug Delivery Device for the Treatment of Fungal Keratitis

Thus, the rings hold the necessary amount of drug when in contact with voriconazole while maintaining its shape. His competent guidance and support helped me a lot during the research and writing of the thesis.

Introduction

Justification of the study

Modern treatment methods are usually ineffective for several reasons: poor bioavailability of the drug due to low corneal permeability, drug resistance and insensitivity to fungi, as well as problems with sustained release of the drug [5]. It is worth noting that it has a short period of activity, since only 1-10% of the drug volume reaches the damaged target areas, since most of the dosage of voriconazole is removed by the movement of the eyelids (blinking and flowing of tear fluid) [ 5 ].

Thesis organization and objectives

It is also worth mentioning that under clinical conditions it is difficult to follow and control the method, since frequent high daily doses of voriconazole may result in some side effects mentioned earlier.

Research hypothesis

Literature review

Antimicrobials used in the treatment of keratitis

• Bacterial keratitis
• Fungal keratitis

In a study by Muller [14], natamycin showed superiority over azole antifungals. Note: “Off-label” means that the drug was used in a way that is not specified on the FDA-approved label.

Limitations of topical drug application

• Anatomy of the eye: corneal epithelium and conjunctiva
• Nasolacrimal drainage system

Therefore, the drug has a short residence time of about 2 minutes on the surface of the eye, and only about 5-10%. Also, as the tear drains into the nasolacrimal duct, the drug can be absorbed into the bloodstream.

Figure 2.1. Nasolacrimal system anatomy (taken from [25])

Drug delivery approaches

• Nanoparticles
• Polymeric nanoparticles
• Solid lipid nanoparticles
• Contact lenses
• Soaking method
• Molecular imprinting …
• Coating
• In Situ forming gels

Nanoparticles for drug delivery for the treatment of keratitis (application of different drugs and different models where they have been used successfully). In vitro tests showed a controlled release of the drug over 8 hours compared to 2 hours release of commercially available econazole. The simple method of soaking commercially available contact lenses in a medicinal solution has shown limited success due to the fact that the drug is rapidly released from this device without demonstrating sustained release.

Most of the drug was released in the first 10 minutes, demonstrating that conventional contact lenses cannot be used as drug delivery devices [42]. Another strategy to obtain a prolonged and sustained release of the drug is to coat the contact lens with another material. Drug delivery contact lenses for the treatment of keratitis (application of different drugs and different models where they have been used successfully).

Hydrogels for the delivery of drugs for the treatment of keratitis (application of different drugs and different models where they have been successfully used). In this work, the method of soaking contact lenses in a medicinal solution was considered and additionally modified, namely the contact lenses were redesigned. 44], and Busin and Spitznas [45], soaked commercially available contact lenses in a drug solution so that the drug crystals were deposited only on the surface of the lens.

Table 2.2. Nanoparticles for the drug delivery to treat keratitis (application of various drugs and different models where they have been used successfully)

Materials and Methods

• Materials
• Preparation of drug delivery device
• Hydrogel formulation
• Preparation of molds for hydrogel rings
• Synthesis of hydrogel rings
• Characterization of hydrogel rings
• Morphological analysis
• In-vitro drug release …
• Spectrophotometric method for voriconazole determination in drug delivery device
• Determination of optical characteristics of voriconazole
• Determination of voriconazole concentration in hydrogel rings

Teflon was chosen as a material of choice for the molds as the hydrogel rings will not adhere to the surface of the mold after the polymerization reaction. A small incision (1 cm) near the circular cavity on Teflon molds was made to easily remove hydrogel rings without causing any damage to them. Note: A small incision (1 cm) near the circular cavity on Teflon forms is made to easily remove hydrogel rings without causing any damage to them.

Then, the hydrogel rings were carefully removed using a small needle and placed in the vial with water. After this period, the hydrogel rings were washed again 7–10 times with 20 mL of distilled water and left on the bench to dry at room temperature for 24 hours. As a result, two groups of hydrogel rings with different sizes were formed, namely rings with and without voriconazole in them (Table 3.3).

Specification of hydrogel rings obtained after the polymerization reaction Outer diameter. ID), mm Height (H), mm Voriconazole group A. XPS spectroscopy was used to analyze the chemical composition of hydrogel rings (ie, the elements present on the top surface). To measure the concentration of voriconazole in hydrogel rings and measure the release kinetics, two methods were proposed.

Figure 3.1. Schematic representation of Teflon mold.

Results and Discussion

Preparation of hydrogel rings

This happens due to the fact that PEG, which was initially present in the structure of the hydrogel, exchanged with water molecules during the washing procedure. The same explanation can be found in the study carried out by Bartolo [58], where they synthesized hydrogel from cyanoethyl acrylate, PEG 300 and PEG-DA in the ratio 9:10:1. The opacity of this device may create some difficulties during the clinical testing on a human model, as it would interfere with the patient's vision.

Regarding the size of the rings, the hydrogels had the same dimensions before washing with water, namely the following dimensions: OD = 10 mm, ID = 6 mm, and H = 0.8 mm. However, after immersing the hydrogel rings in water for 24 hours, the diameter was slightly increased by approximately 0.5 - 1 mm (Figure 4.1, B). This observation can be explained by the fact that hydrogels have the favorable property of swelling in the presence of a thermodynamically compatible solvent, in this case water.

Figure 4.1 demonstrates the hydrogel rings obtained after NVP polymerization

Morphological analysis

• Surface characterization: X-Ray Photoelectron Spectroscopy
• Surface characterization: Scanning Electron Microscopy
• Pore size distribution: Mercury porosimetry analysis

XPS spectra of hydrogel rings with loaded voriconazole (group A). peak at 531 eV demonstrates the C=O bond. The hydrogel rings have two surfaces (top and bottom) with different morphological structures as they were exposed to the different environments during polymerization reaction: the upper surface was exposed to ambient air and the lower surface was in contact with Teflon surface (Figure 4.7). From both figures, it can be stated that the morphology of the upper and lower surface of hydrogels is slightly different in terms of its pore size and volume.

For example, the upper surface of the hydrogel was in contact with the atmosphere, while the lower part was in contact with the Teflon mold. Therefore, the upper surface of the hydrogel ring must be placed on the surface of the eye, since only from there can the drug be released more efficiently. SEM images of hydrogel rings without voriconazole loading: bottom surface (left column) and top surface (right column) at x5K and x20K magnification.

SEM images of voriconazole-loaded hydrogel rings: bottom surface (left column) and top surface (right column) at x2K, x5K and x20K magnification. The presence of pores in the material of the polymer rings was verified by SEM;. 𝑉𝑡 , where Vv is the void volume and Vt is the total volume of a hydrogel.

Figure 4.3. Chemical structure of voriconazole

Determination the presence of voriconazole in hydrogel rings

In the case of the group B hydrogel ring, which was not loaded with voriconazole, it shows no fluorescence under UV light. In combination with any SEM images, EDS is thus useful to obtain a basic analysis of the area of ​​interest. Since the chemical structure of voriconazole consists of carbon, hydrogen and fluorine atoms, the latter indicates the presence of the drug on the SEM-EDS image.

Figures 4.12 and 4.13 demonstrate the EDS analysis of the top and bottom surface of the hydrogel ring, which was loaded with voriconazole (group A). Regions colored red, green and pink illustrate the presence of fluorine, oxygen and Figures 4.14 and 4.15 demonstrate the ring analysis of the hydrogel from group B (control group), which did not come into contact with voriconazole.

Note: Regions colored red, green, and pink illustrate the presence of fluorine, oxygen, and carbon atoms in the hydrogel matrix, respectively. Regions colored red and pink illustrate the presence of oxygen and carbon atoms in the hydrogel matrix, respectively. Regions colored red and pink illustrate the presence of oxygen and carbon atoms in the hydrogel matrix, respectively.

Figure 4.11. The hydrogel rings under UV light: group A (left ring) and group B (right ring) Note: group A = “drug-loaded”, group B = “unloaded” hydrogel rings

In-vitro drug release

The concentration values, as well as their corresponding absorbance, were plotted to find all the necessary parameters required to identify the concentration of voriconazole in the hydrogel rings (Figure 4.18). First, the determination of cumulative drug release was based on measuring absorbance values ​​at 256 nm for five days and fitting these values ​​into the equation from Figure 4.18. So the drug-loaded ring will deliver approximately 800 µg of the drug to the surface of the eye, while an eye drop delivers approximately 500 µg of the drug to the surface of the eye.

Drug molecules released from the epithelial-contacting surface and the inner ring surface will be able to diffuse to the site of the infection, causing a therapeutic effect. Complications can arise due to high local concentrations of the drug, especially at the epithelial-touching surface of the device. It is clear that the ring obstructs the flow in the direction of the upper and lower canaliculi.

In addition, it is expected that there will be virtually no flow in the inner circle of the ring. All this implies that much further research and development work involving representative models of the tear flow at the ocular surface is needed. Suresh, Nanosuspension: a novel vehicle for enhancing drug delivery to the ocular surface.

Release studies

• Determination of optical characteristics UV extinction of voriconazole
• Determination of voriconazole concentration in hydrogel rings

Conclusion

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