Development and preclinical safety testing of biodegradable Silica Eye Drop as an ophthalmic carrier matrix

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Akieh-Pirkanniemi, Aleksandra Poluianova, Pingping Su, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7880491/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Jan, 2026 Read the published version in Journal of Pharmaceutical Innovation → Version 1 posted You are reading this latest preprint version Abstract Purpose: Topical eye drops are common for treating eye diseases, often requiring multiple daily doses. Silica Matrix technology enables ophthalmic drug delivery systems that release drugs over time. This study aimed to develop and characterize a silica-based eye drop, as well as a 14-day tolerance and toxicity assessment to evaluate its potential as a drug carrier in ophthalmology. Methods: Silica Eye Drop is a silica-based composite containing silica microparticles, made via sol-gel chemistry and spray drying, along with silica hydrogel. The product was terminally sterilised by gamma irradiation and characterised by particle size, silica content, in vitro dissolution time, droplet size, applicability, microbiological purity, and short-term stability. Four New Zealand rabbits received one drop daily in one eye's conjunctival sac for 14 days, while the other eye served as a control. During the study, eye conditions, blood chemistry, and postmortem histology were monitored. Results: The final formulation contained 23% (w/w) silica microparticles (average diameter 3.21 µm) and 77% (w/w) silica hydrogel, with 18.2 wt% silica, dissolving in 24 hours. The average droplet volume was 31.3 ± 4.4 µl, easily dispensed manually from a single dose unit with acceptable size variability. A 2-month stability study showed no major changes in product properties. Finally, in the rabbit toxicity study, both the treated and untreated eyes showed similar tolerability levels. Conclusions: The Silica Eye Drop was successfully developed and manufactured. Easy to use with consistent quality, it demonstrated the safety and potential of silica platform technology for sustained drug release in topical ophthalmology. ~100 WORD SUMMARY In this study, a novel silica-based eye drop formulation for prolonged ocular drug delivery was developed and evaluated. Silica microparticles were synthesised and incorporated through a Fill and Finish process, followed by sterilization and characterization for particle size, silica content, dissolution, droplet size, microbiological purity, and short-term stability. In vivo tolerability was assessed in four New Zealand rabbits over 14 days with daily administration. The optimised formulation contained 23% (w/w) silica microparticles and 77% (w/w) silica hydrogel (18.2 wt% silica). Microparticles (D50 = 3.21 µm) fully dissolved within 24 hours. No adverse ocular effects occurred, confirming excellent safety, stability, and therapeutic potential. 25-30 WORD TEASER A novel Silica Eye Drop formulation was developed, showing sustained release, full dissolution in 24 hours, and good tolerability in rabbits, highlighting its promise for future ocular therapies. silica hydrogel GLP study eye drops silica matrix tolerability ophthalmology drug delivery system Figures Figure 1 Figure 2 Figure 3 Figure 4 1 INTRODUCTION Eye drops are non-invasive medications for the treatment of eye diseases. Topical delivery of drugs designed to address ophthalmological conditions often necessitates multiple daily administrations [ 1 ]. This requirement results from the limited residence time of the drug on the ocular surface following application, which can challenge patient adherence to treatment regimens [ 2 ]. The conjunctival sac naturally holds a limited volume of about 30 µl (non-blinking state) [ 3 ]. This small capacity, coupled with the eye’s protective mechanisms, decreases ocular bioavailability and increases the need for frequent dosing. Understanding this dynamic is crucial for optimizing treatment outcomes and ensuring that medications are effective. Sustaining drug concentration at the site of action for an extended period is necessary, as this can contribute to reduced application frequency, lowered dosage, increased absorption, improved drug efficacy, and patient compliance. To enhance ocular bioavailability, innovative drug delivery systems such as inserts, contact lenses, mucoadhesives, collagen shields, and penetration enhancers have been developed [ 4 , 5 ]. Additionally, vesicular systems like liposomes, niosomes, and nanoparticles, along with in situ forming gels, significantly improve ocular therapy outcomes [ 6 – 9 ]. Silica (silicon dioxide, SiO 2 ) gel matrices have been investigated as carrier materials for controlled and sustained delivery of active substances [ 10 – 14 ]. The adjustable biodegradation rate of silica and its nanosized pore structure, combined with mild and aqueous processing conditions of silica gel, make it an ideal material for controlled drug delivery. Its potential applications in ophthalmology open new possibilities for enhancing patient care. Silica matrix is a synthetic inorganic biodegradable polymer made from amorphous silicon dioxide, produced through a chemical process known as the sol-gel process. Silica microparticles are produced after spray drying of the silica sol. An active substance can be encapsulated in the silica microparticles. In contact with body fluids, the silica composite material dissolves over time, and the embedded active substance is released concomitantly. The dissolution of the Silica Matrix takes place mainly through a surface erosion mechanism [ 15 ]. Eroded silica is freely dispersed in tissue and excreted via urine in the form of a very weak inorganic acid, silicic acid. The biodegradation process does not change the pH within the silica gel nor in the surrounding tissue. The manufacturing process can be adjusted to vary the number of hydroxyl groups and the specific surface area of silica matrix, thereby influencing the rate of silica biodegradation and the release rate of the active substance [ 16 – 18 ]. The Silica Matrix technology can be utilised in ophthalmic drug delivery systems designed to release an embedded active substance for a prolonged period. Examples of active substances that can be incorporated in the silica matrix are many, including antibacterial, antiviral, anti-inflammatory, eye pressure-lowering, and many other pharmacologically active agents [ 19 – 22 ]. The aim of this study was to develop a Silica Eye Drop formulation and characterise the formulation as a promising drug carrier platform for the treatment of eye diseases. A 14-day topical ocular tolerance and toxicity study was run with Silica Eye Drop in rabbits. Silica composite material is a new excipient for eye drops and its ocular tolerance and safety has not been previously demonstrated. 2 MATERIALS AND METHODS 2.1. Reagents Reagent-grade (98%) tetraethyl orthosilicate (TEOS) and L (+)-tartaric acid were purchased from Aldrich Sigma. 0.1 M HCl and 0.1 M NaOH solutions were obtained from Merck. Silica standard solution (1000 µg/ml Si in H 2 O), isopropanol (IPA), and sodium peroxide pellets were sourced from VWR Chemicals. Nitric acid (67–70%) and Dimethyl sulfoxide (DMSO), bioreagent grade, were supplied by Fisher Chemicals. 4-amino-3-hydroxy-1-naphthalene sulfonic acid was from Alfa Aesar. Sodium bisulfite was from Acros Organics. Ethanol (≥ 99.5%, ETAX Aa) was from Anora Group Oyj. Deionised water (18.2 MΩ.cm) was prepared in-house using a Millipore Milli-Q system. All other chemicals and reagents used were of analytical grade and were used as received without further purification. 2.2 Materials 60-mL straight containers with screwed caps used in dissolution testing were purchased from Corning. The primary packaging materials for the eye drop were single-dose units (SDU) (Code/Ref: AA03898ABAAQ00C) produced by Lameplast Spa, Italy, while the secondary packaging was a LamiZip stand-up pouch (PET/LDPE/aluminum) purchased from DaklaPack. 2.3. Manufacture and characterisation of Silica Eye Drop Silica Eye Drop is a silica composite material that consists of silica microparticles embedded in silica hydrogel. Silica microparticles and hydrogel are used to control the dissolution rate and rheological properties, such as viscosity, of the composite. The silica microparticles can also act as a reservoir for an active pharmaceutical ingredient (API). However, in the current study, no active substance was incorporated into silica microparticles. The manufacturing of Silica Eye Drop is a three-step process, which includes the manufacturing of the silica microparticles, compounding silica microparticles with dilute silica sol, and packaging into SDUs. The product was terminally sterilised by gamma irradiation. A flow scheme of the manufacturing process is shown in Fig. 1 . The process for manufacturing silica microparticles began with the hydrolysis of the silica precursor, TEOS, in water. The reaction was catalysed by 0.1 M HCl at pH 2, where TEOS was hydrolysed completely (Fig. 2 ). The hydrolysed species form a nano-scale silica cluster-water suspension, known as silica sol. The silica sol was cooled down to 5–10°C and diluted with ethanol. The pH of the sol was adjusted with 0.1 M NaOH solution to 5.8–6.2 before spray drying. The sol was pumped into a spray dryer (Mobile Minor, PSD 1 from GEA, Denmark) via a tube reactor and spray dried to form silica microparticles. The following spray drying parameters were used: Inlet temperature 180°C, process flow rate for nitrogen gas 80 kg/h (3 bar), atomization flow rate for nitrogen gas 12 kg/h (1.5 bar), and pump feed rate 35 g/min. Silica microparticles were collected in a collection vessel of the pilot-scale spray dryer. Silica microparticles were manufactured in a class C clean room (EU-GMP certified facility). After the manufacture, silica microparticles were packed in a polyethylene bag and an aluminum laminated bag as a secondary package. They were stored at 5 ± 3°C prior to Fill and Finish manufacture. The Fill and Finish process was performed in an ISO 8 classified clean room. In the process, a diluted silica sol was prepared and mixed with silica microparticles. The pH of the sol was adjusted with 0.1 M NaOH solution to 6.0–6.5 prior to mixing with the silica microparticles. The suspension was transferred into pre-sealed SDUs by pipetting. The target filling volume was 0.8 ml per SDU, which represents a large overfill, as only one drop (0.03 ml) is used from each SDU. Each SDU was closed tightly with a Lameplast SDU cap. The filled and tightly closed SDUs were placed in a tube rotator to prevent particle sedimentation while the suspension contents were allowed to gel and stabilize at ambient temperature for approximately 24 hours. The filled SDUs were labelled and packed in labeled resealable aluminum pouches (secondary package). After the Fill and Finish manufacture, the SDUs in secondary packages were stored at 5 ± 3°C °C before sterilisation by gamma irradiation at 25 kGy. 2.4 Characterisation of Silica Eye Drop 2.4.1. Particle size analysis Silica microparticles present in the eye drop were controlled for their particle size distribution (PSD), which is determined using a validated laser diffraction method (Laser Helo Sympatec with cuvette and R3 lens). 20 mg of silica microparticles were suspended in 20 ml of ethanol. The suspension was added dropwise, under stirring, to a cuvette containing about 50 ml of ethanol until an optical density of 5% to 25% was achieved. The measurement was performed in triplicate. 2.4.2. In vitro dissolution test To establish the in vitro release kinetics of silica, a dissolution testing method with silica under sink conditions was used. Briefly, 25–35 mg of Silica Eye Drop were weighed into a dissolution vessel. 50 ml of dissolution buffer, 50 mM TRIS buffer (pH7.4 @37°ꓚ), was added, and the vessel was transferred to a shaking water bath at + 37°C and 60 strokes per minute. At specified time points (1h, 2h, 3h, 4h, 5h, 6h, 9h, and 24h), the sample was centrifuged at 4500 rpm for 5 minutes. Silica content in the supernatant was analysed while the pellets were resuspended in fresh 50 ml dissolution buffer. The dissolution vessel was returned to the water bath shaker (+ 37°C and 60 rpm). The cycle continued until the final dissolution time point. The silica concentration in the dissolution samples was measured with a spectrophotometer (Jenway 630, Cole-Parmer Ltd, UK). The method involves derivatisation, whereby a blue colour complex is formed in a reaction containing ammonium molybdate in an acidic environment [ 23 ]. The intensity of the blue color was measured spectrophotometrically at a wavelength of 820 nm and was directly proportional to the concentration of dissolved silica. Three parallel dissolution tests were carried out per batch. 2.4.3. Silica content analysis A sample of Silica Eye Drop (20–30 mg) was dissolved in 50 ml of 2% NaOH at 37°C and 60 rpm for 3 days in a water shaking bath. After complete dissolution of the sample, the sample solution was diluted 100 times in water. The same spectrophotometric method used for analysing the dissolution samples was used for the determination of total silica content. 2.4.4. Ethanol content analysis Silica microparticles contain some residual amount of ethanol. Ethanol was produced as a by-product in the sol-gel process and was also used for dilution of the sol prior to spray drying. Potentially, high ethanol content could cause irritation in the living eye. The determination of ethanol in Silica Eye Drop was carried out by headspace-gas chromatography using a flame ionisation detector (HS-GC-FID, Agilent G1888-6890N). Sample solution preparation involved dissolving 30–40 mg Silica Eye Drop in a 20 ml glass vial with 50 ml of 2% NaOH at 37°C and 60 rpm for 3 days in a water shaking bath. 20 µg/ml of isopropanol was used as an internal standard. The chromatographic separation was carried out on a DB-624, 30m x 0.53mm, 3 µm GC column (Agilent) with a gradient oven temperature ramp from 35°C, 20°C / min to 90°C, 50°C / min to 240°C hold for 5 min and nitrogen constant gas flow at 1.5 ml/min. The inlet temperature was 220°C, and the split ratio was 1:50 with a 4 mm deactivated glass liner. The headspace temperature conditions were set as follows: oven at 80°C, loop at 210°C, and transfer line at 220°C. 2.4.5 Endotoxin An endotoxin test was conducted on the EndoSafe NexGen PTS device. This device performed endotoxin testing according to Ph. Eur. 2.4.16/USP Method D chromogenic technique. The Detection limit of the method was < 0.176 EU/mg. 2.4.6. Sterility Sterility assurance level (SAL) of 10 − 6 was demonstrated by sterilization dose substantiation (gamma irradiation) using the VDmax 25 kGy method in accordance with the requirements in ISO 11137-2 [ 24 – 26 ]. The maximum allowable dose was determined to be 35 kGy. The VDmax 25 kGy method was used to establish 25 kGy as the sterilisation dose for products manufactured frequently or infrequently in large or small batches. For the validation of a single lot or infrequent production batches, 10 products were tested for bioburden, and then a dose audit was performed on 10 products irradiated at the verification dose. A SAL 10 − 6 was demonstrated by experimental evidence that the product bioburden was less resistant than a Standard Distribution of Resistances (SDR) for which a SAL of 10 − 6 was obtained at 25 kGy. The resistance to the sterilisation process was demonstrated by irradiation of the test items at a verification dose (VDmax) for which a SAL of 10 − 1 was obtained for the SDR. A SAL of 10 − 1 would result in 1 non-sterile sample per 10 items tested. Bioburden was determined using the validated most probable number method. The verification dose according to ISO 11137-2 was equal to 2.7 kGy. Sterility testing by a validated direct inoculation method for 10 test items irradiated at the verification dose was performed. A sterilisation dose of 25 kGy was established to obtain a SAL 10 − 6 since there was not more than one positive test of sterility out of the ten product items tested. 2.5. Stability study A stability study was conducted with Silica Eye Drop to test stability during storage and the preclinical in-use phase. The purpose of stability studies was to provide information on changes in the quality of the product over time because of environmental factors such as temperature, humidity, and light on the product. The following analyses were performed in the study at time points 0, 1 month, and 2 months: Visual inspection, silica content, ethanol content, in vitro dissolution testing, and pH. The storage conditions were based on ICH Q1 guidelines for stability testing of drug substances and drug products. The study was conducted at 5 ± 3°C and 25 ± 2°C/60 ± 5% relative humidity (RH). 2.6. GLP toxicity study in rabbits The study was conducted according to the EMA guideline on non-clinical local tolerance testing (2015), OECD Test No. 405 (2021), Directive 2010/63/EU on animal protection, the Finnish Animal Protection Act (497/2013) and Decree (564/2013), OECD guidance on humane endpoints (2000), and OECD Principles of Good Laboratory Practice (1998). The investigation has been approved by the National Laboratory Animal Board of Finland (Care and Use Committee) with license number ESAVI/26478/2019. The biocompatibility, safety, and tolerability of Silica Eye Drop were investigated in four female New Zealand White (NZW) rabbits in compliance with Good Laboratory Practice (GLP). One drop of Silica Eye Drop was administered daily for 14 days to the conjunctival sac of one (left) eye of four animals. One drop (approximately 0,05 ml) of sterile 0.9% NaCl was administered in the conjunctival sac of the other eye (right) as a control. The eyes were checked daily before applying the test items by a veterinarian. The degree of eye irritation/corrosion was repeatedly evaluated by scoring lesions of the conjunctiva, cornea, and iris. The veterinarian used fluorescein (Kunze Indopharm B.V., Netherlands) to detect any possible damage to the cornea on study Days 2, 8, and 15. The scoring was performed according to OECD/OCDE Test No. 405: Acute Eye Irritation/Corrosion. Intraocular pressure was repeatedly measured in both eyes on study Day − 5 (pre-test) and on study Days 1 (prior to the first dose), 2, 8, and 15. Measurements were done by the veterinarian using the Icare Tonovet Plus (Icare, Finland) device. The animals were restrained with a towel, and after approximately two minutes, the measurements were performed. Three acceptable subsequent results from both eyes were collected from each animal, and an average of these three measurements was calculated. Other possible effects on the eye and adverse systemic effects were also recorded to provide a complete evaluation of the effects. Clinical signs were observed twice daily, and blood sampling for hematological analyses, coagulation tests, and clinical chemistry was taken at baseline and termination. After 14 days of treatment (on study Day 15), the animals were sacrificed by exsanguination after inducing deep anesthesia using Medetomidine (Cepetor vet 1 mg/ml, CP-Pharma Handelsges. mbH, Germany) and Ketamine (Ketaminol vet 50 mg/ml, Intervet International B.V., Germany). Some animals were additionally given Euthasol 400 mg/ml (Produlab Pharma B.V., the Netherlands) intravenously to complete the euthanasia. Scheduled necropsy was performed in all animals, and all macroscopic changes were recorded. At necropsy, eyes with optic nerves, lids, conjunctivae, and nictitating membranes were collected from all animals into Davidson’s solution (both sides for paired organs). The tissues were kept in Davidson’s fixative for 24 to 27 hours, after which they were transferred into 70% ethanol. The fixed tissues were sent to AnaPath GmbH, Department AnaPath Services, Switzerland. Trimming, processing, embedding in paraffin wax, cutting, and staining by eosin and hematoxylin were performed at AnaPath GmbH, Department AnaPath Services, Switzerland. The sections were evaluated by a professional veterinary pathologist. 3 RESULTS AND DISCUSSION 3.1 Characterisation and stability of Silica Eye Drop The Silica Eye Drop formulation contained 23% (w/w) silica microparticles and 77% (w/w) silica hydrogel. By visual inspection, the eye drop was a white to nearly white homogeneous suspension. Figure 2 shows a photograph of the final eye drop product in its primary package. The silica microparticles in the eye drop exhibited a monomodal particle size distribution with D10 at 1.69 µm, D50 at 3.21 µm, and D90 at 5.78 µm. The amount of silica in the final eye drop product was measured to be 18.2 ± 0.65 wt%, the ethanol content was 3.9 wt%, and the pH was 6.1. Silica Eye Drop was shown to dissolve completely in 24 hours with an in-house in vitro in-sink dissolution testing method. Silica microparticles play a major role in controlling the dissolution rate of Silica Eye Drop. The dissolution rate of silica is influenced by several manufacturing parameters, including the precursor ratios (i.e., molar ratio of water to TEOS), aging of the silica sol, pH of the silica sol, nature of the diluent, and spray drying parameters. As mentioned above, silica microparticles are produced by the hydrolysis and condensation of TEOS via an acid-catalysed reaction. A lower water-to-TEOS molar ratio and ethanol as diluent in the manufacturing process resulted in silica microparticles with a fast dissolution rate. Unlike traditional mesoporous silica systems [ 27 ], which rely on the loading of drugs into pores, the silica matrix in this study is non-porous or nanoporous [ 28 ]. The dissolution of the matrix occurs through the surface erosion of the silica matrix in bodily fluids rather than through diffusion. Additionally, the rate of biodegradation can be finely tuned, enabling controlled release that can be tailored over a duration of days to months. The droplet size variation was determined by gravimetry from ten different SDUs. The average droplet weight was 33.8 ± 4.8 mg, corresponding to 31.3 ± 4.4 µl. The minimum and maximum weights were 29.1 mg and 39.1 mg, respectively. It was concluded that dispensing the droplet manually from the SDU results in droplets with acceptable variability in size. This was substantiated by the content uniformity test results, which conformed to the European pharmacopeia [Ph. Eur 2.9.40]. The application of a droplet was easy and required only a minimum amount of pressing force by fingers. The Silica Eye Drop formulation contained very low levels of endotoxin; the measured endotoxin content was below 0.2 EU/mg, which is the limit of quantitation of the method. Low endotoxin and bioburden (0.36 CFU/g) indicated a good control strategy for endotoxin and microbial contamination during the manufacturing process of the eye drop used in this study. The product was terminally sterilised by gamma irradiation at 25 kGy, and sterilisation dose substantiation confirmed that the irradiation dose of 25 kGy was adequate to reach SAL 10 − 6 level for the product. This study also demonstrated that the Silica Eye Drop formulation tolerates well gamma irradiation without any sign of loss of critical properties needed for an eye drop. A 2-month preliminary stability study was conducted with Silica Eye Drop to establish adequate stability of the product needed for the in vivo rabbit study. By visual inspection, the product looked the same, i.e., white to almost white homogenous suspension at all time points and both conditions. No changes were seen in silica or ethanol content over time. After 2 months, a slight decrease in pH from 6.1 to 5.9 and 5.7 was recorded at 5 ± 3°C and 25 ± 2°C / 60 ± 5%RH, respectively. Although the dissolution rate of silica was slower at 1 month and 2 months than at the 0-month timepoint (Fig. 3 ), all the silica dissolved within 24 hours at all conditions studied. In conclusion, Silica Eye Drop was stable for at least 2 months and can be stored for this period of time either at 25 ± 2°C / 60 ± 5%RH or 5 ± 3°C. 3.2 GLP toxicity study All animals gained weight normally during this study (data not shown). No unusual clinical signs were recorded in any of the animals. The clinical observations of the eyes recorded are summarised in Table 1 . A total of 4 left eyes that were treated and 4 right eyes that served as controls. No severe irritation or corrosion was observed in any of the animals. Scores of grades 1 to 2 of test item residues were observed in the conjunctival sac of the test eyes in two out of four animals during eye examinations on Days 3, 7, 8, 10, and 15. Eyelid swelling (chemosis) above normal was observed in both control and treated eyes of the animals. The Silica Eye Drop group had 8 observations on the test (left) eye and 4 on the control (right) eye. These changes were not persistent. There were no other reactions in the eyes. The results of the haematological analyses, coagulation tests, and clinical chemistry analyses were comparable between pre- and post-treatment. Histopathological evaluation revealed no treatment-related findings in the examined organs, tissues, or structures. Minimal (grade 1) mononuclear cell infiltrates in the nictitating membrane were observed in one eye treated with Silica Eye Drop. Focal mononuclear infiltrate, grade 2, was observed in the eyelid dermis of one control eye. The findings were considered incidental/background changes that sometimes occur in this type of study. IOP (intraocular pressure) values for treated and control eyes are shown in Fig. 4 . IOP values for all animals in this study remained within the normal reference range for laboratory animals despite showing a variation over 14 days (12–25 mmHg). This may be due to the fact that the IOP can be influenced by restraint techniques, animal stress, diurnal or circadian rhythm, eye position, sedation or anesthesia, corneal thickness, and several other variables [ 29 ]. Chemosis, which is the swelling of the conjunctiva, was observed in the test and control groups. In rabbits, these changes can be triggered by various factors, including environmental conditions often present in animal holding centers [ 30 ]. Additionally, stress resulting from the experiment may weaken a rabbit’s immune system, increasing its susceptibility to infections that can lead to conjunctival swelling. This explains the minor histological changes observed in the tissues of some animals in both study groups. After administering Silica Eye Drop, significant absorption of the main compounds of the medication into the eye structures or directly into the bloodstream is not expected due to their very low quantities and physicochemical properties. When the drop is in contact with tear fluid, the silica material begins to dissolve into silicic acid (SiA). This material may then be transported via the nasolacrimal duct. Additionally, some SiA could be absorbed directly into the bloodstream through the epithelium of the conjunctival sac and later excreted in the urine by the kidneys. Compared to other sources of silica and SiA, the amount contained in this material represents only trace levels of daily intake for humans [ 31 – 35 ]. Studies conducted with rabbits that used silica from various manufacturers show that this topic is highly relevant, indicating the need for additional experiments [ 36 – 39 ]. It was concluded that 14-day repeated daily dosing of Silica Eye Drop was well-tolerated and considered to be safe and non-irritant. Table 1. Summary of clinical observations of the eyes recorded in the rabbit GLP toxicity study (frequency of incidence) Silica Eye Drop Study day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 1. RESIDUE OF TEST ITEM IN THE EYE Left eye 0/4 0/4 1/4 0/4 0/4 0/4 1/4 1/4 0/4 1/4 0/4 0/4 0/4 0/4 1/4 Right eye 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 2. AMOUNT OF THE TEAR FLUID Left eye 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 Right eye 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 3. CONJUNCTIVAE Left eye 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 Right eye 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 1/4 0/4 0/4 0/4 0/4 4. CHEMOSIS Left eye 0/4 0/4 1/4 1/4 0/4 0/4 0/4 0/4 2/4 0/4 3/4 0/4 0/4 1/4 0/4 Right eye 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 2/4 0/4 1/4 0/4 0/4 1/4 0/4 5. IRIS Left eye 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 Right eye 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 6. CORNEA Left eye 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 Right eye 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 0/4 4 CONCLUSION The Silica Eye Drop formulation was designed with the following target product properties: a dissolution time of approximately 24 hours in the conjunctival sac and tear fluid, easy administration by the patient, a drop weight of around 33 mg (30 µl), and a sterile composition that is non-toxic and well-tolerated. The results in this study demonstrate that a silica composite eye drop formulation meeting these criteria was successfully developed. The eye drop formulation containing 23% (w/w) silica microparticles and 77% (w/w) silica hydrogel dissolved completely in 24 hours according to the in vitro dissolution results. Moreover, in the rabbit in vivo GLP study with daily dosing for 14 days, no residual silica material was detected before the next dosing in 9/10 cases. Additionally, no unusual clinical signs were observed during the experiment. At necropsy, no abnormalities were found in any of the animals. No pathological changes were observed in this study; the control and test groups showed similar results throughout the entire period without any statistically significant differences. IOP values for all animals in this study remained within the normal reference range for laboratory animals. The data show that Silica Eye Drop is safe and well-tolerated for once-a-day use for 14 days in NZW rabbits without causing any toxic effects in tissues and organs, either locally or systemically. The Silica Eye Drop formulation was easy to administer, and the average droplet weight was 33.8 ± 4.8 mg, corresponding to 31.3 ± 4.4 µl, which is in line with the target value. In conclusion, this study demonstrates the potential of the silica platform technology in sustained drug release applications in topical ophthalmology. Additional experiments are necessary, particularly those that involve combining the Silica Matrix with a drug, to evaluate clinical efficacy and pharmacokinetics of this technology. Abbreviations API Active Pharmaceutical Ingredient DMSO Dimethyl Sulfoxide EMA European Medicines Agency GLP Good Laboratory Practice HCl Hydrochloric Acid HS GCFID Headspace Gas Chromatography Flame Ionization Detector ICH International Council for Harmonisation IOP Intraocular Pressure IPA Isopropyl Alcohol NZW New Zealand White (rabbit) NaOH Sodium Hydroxide OECD Organisation for Economic Co operation and Development Ph Eur European Pharmacopoeia PSD Particle Size Distribution RH Relative Humidity Rpm Revolutions per Minute SAL Sterility Assurance Level SDR Spray Dried Residue SDU Single Dose Unit Si Silicon SiA Silicic Acid SiO 2 Silicon Dioxide TEOS Tetraethyl Orthosilicate TRIS Tris(hydroxymethyl)aminomethane VDmax Maximum Validated Dose w/w Weight per Weight wt% Weight Percent Declarations Competing Interests M.N. A-P., P.S. M.V., and H.A. are employees of DelSiTech Ltd., where the formulation development and physicochemical properties were analysed. However, in vivo tolerability and safety studies were conducted independently by a third party not affiliated with DelSiTech Ltd. The authors affirm that this separation of roles ensured that the objectivity and integrity of the tolerability data remained unaffected by the company. Author Contribution L. L. – сonceptualisation and study design, M. N. A-P., H. A. – supervision, M. N. A-P., P. S. – analytical development and stability studies (experiments), M. V., H. A. – formulation development and manufacturing (experiments), M. N. A-P., A. P., P. S., M. V., H. A. – data collection, analysis, and interpretation, M. N. A-P., A. P., P. S. – preparation of tables and figures, L. L., M. N. A-P., A. P. – manuscript writing. All authors reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work. Data Availability The data that support the findings of this study are available from the corresponding author upon reasonable request. 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EFSA Journal. 2009;7. https://doi.org/10.2903/j.efsa.2009.1132 Dekkers S, Krystek P, Peters RJB, Lankveld DPK, Bokkers BGH, van Hoeven-Arentzen PH, et al. Presence and risks of nanosilica in food products. Nanotoxicology. 2011;5:393–405. https://doi.org/10.3109/17435390.2010.519836 Alhowyan AA, Kalam MA, Iqbal M, Raish M, El-Toni AM, Alkholief M, et al. Mesoporous Silica Nanoparticles Coated with Carboxymethyl Chitosan for 5-Fluorouracil Ocular Delivery: Characterization, In Vitro and In Vivo Studies. Molecules. 2023;28:1260. https://doi.org/10.3390/molecules28031260 Swain R, Nandi S, Swain SS, Pattanaik KP, Mohapatra S, Panigrahi D, et al. Bentonite-in hypromellose-poloxamer sol-gel for corneal application of trimetazidine: Study of rheology and ocular anti inflammatory potential. Int J Biol Macromol. 2023;242:124628. https://doi.org/10.1016/j.ijbiomac.2023.124628 Kim S-N, Ko SA, Park CG, Lee SH, Huh BK, Park YH, et al. Amino-Functionalized Mesoporous Silica Particles for Ocular Delivery of Brimonidine. Mol Pharm. 2018;15:3143–52. https://doi.org/10.1021/acs.molpharmaceut.8b00215 Zaghloul N, El Hoffy NM, Mahmoud AA, Elkasabgy NA. Cyclodextrin Stabilized Freeze-Dried Silica/Chitosan Nanoparticles for Improved Terconazole Ocular Bioavailability. Pharmaceutics. 2022;14:470. https://doi.org/10.3390/pharmaceutics14030470 Additional Declarations Competing interest reported. M.N. A-P., P.S. M.V., and H.A. are employees of DelSiTech Ltd., where the formulation development and physicochemical properties were analysed. However, in vivo tolerability and safety studies were conducted independently by a third party not affiliated with DelSiTech Ltd. The authors affirm that this separation of roles ensured that the objectivity and integrity of the tolerability data remained unaffected by the company. Cite Share Download PDF Status: Published Journal Publication published 06 Jan, 2026 Read the published version in Journal of Pharmaceutical Innovation → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7880491","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":538780834,"identity":"c87ada11-9ad1-42b2-9ff4-392c74315ba4","order_by":0,"name":"Marceline N. 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16:12:07","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":123472,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7880491/v1/2b2e861752f72819220ea12d.html"},{"id":95042083,"identity":"d24b6a9c-c08a-4b48-a7e6-c7410d899a28","added_by":"auto","created_at":"2025-11-03 16:12:07","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":150588,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow charts for the manufacturing of Silica Eye Drop. The flow chart on the left illustrates the manufacture of silica microparticles by spray drying, while the flow chart on the right depicts the Fill and Finish of the final eye drop product\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7880491/v1/e9d66dffc07bf8f2ad6ebf61.png"},{"id":95222107,"identity":"f4d03841-0f02-43ec-af09-6f961d72a40d","added_by":"auto","created_at":"2025-11-05 16:20:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":135542,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA picture representation of the Silica Eye Drop product. Silica microparticles-silica hydrogel composite material inside single-dose units (SDU, primary package) and a drop of the product on a petri dish. The droplet weight is 33.8 ± 4.8 mg, corresponding to 31.3 ± 4.4 µl. Data are presented as mean ± SD\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7880491/v1/14428af0d3ac8596da772629.png"},{"id":95042084,"identity":"582c2e0b-4c77-4883-926a-de5132d3a1a0","added_by":"auto","created_at":"2025-11-03 16:12:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":69632,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDissolution curves for Silica Eye Drop at 5 ± 3 °C and 25°C/60%RH storage conditions for 0, 1, and 2 months. The data represent the average of three replicate dissolution tests per sample\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7880491/v1/f632307f89e700a18fa879c3.png"},{"id":95042085,"identity":"30edd770-e32d-49bf-9a89-d2baf9029937","added_by":"auto","created_at":"2025-11-03 16:12:07","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":27513,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIntraocular pressure values in control and treated eyes in the rabbit GLP toxicity study. Data are presented as mean ± SD; sample sizes of 4 are reported for each group\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7880491/v1/cfe4caaea6772f86e3705999.png"},{"id":100071066,"identity":"26516892-dd13-47b0-85bd-75ab9029a70c","added_by":"auto","created_at":"2026-01-12 16:19:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1589361,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7880491/v1/550378ed-17b7-4123-86d5-b2992c2dac1a.pdf"}],"financialInterests":"Competing interest reported. M.N. A-P., P.S. M.V., and H.A. are employees of DelSiTech Ltd., where the formulation development and physicochemical properties were analysed. However, in vivo tolerability and safety studies were conducted independently by a third party not affiliated with DelSiTech Ltd. The authors affirm that this separation of roles ensured that the objectivity and integrity of the tolerability data remained unaffected by the company.","formattedTitle":"Development and preclinical safety testing of biodegradable Silica Eye Drop as an ophthalmic carrier matrix","fulltext":[{"header":"1 INTRODUCTION","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eEye drops are non-invasive medications for the treatment of eye diseases. Topical delivery of drugs designed to address ophthalmological conditions often necessitates multiple daily administrations [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This requirement results from the limited residence time of the drug on the ocular surface following application, which can challenge patient adherence to treatment regimens [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The conjunctival sac naturally holds a limited volume of about 30 \u0026micro;l (non-blinking state) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This small capacity, coupled with the eye\u0026rsquo;s protective mechanisms, decreases ocular bioavailability and increases the need for frequent dosing. Understanding this dynamic is crucial for optimizing treatment outcomes and ensuring that medications are effective. Sustaining drug concentration at the site of action for an extended period is necessary, as this can contribute to reduced application frequency, lowered dosage, increased absorption, improved drug efficacy, and patient compliance. To enhance ocular bioavailability, innovative drug delivery systems such as inserts, contact lenses, mucoadhesives, collagen shields, and penetration enhancers have been developed [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Additionally, vesicular systems like liposomes, niosomes, and nanoparticles, along with in situ forming gels, significantly improve ocular therapy outcomes [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSilica (silicon dioxide, SiO\u003csub\u003e2\u003c/sub\u003e) gel matrices have been investigated as carrier materials for controlled and sustained delivery of active substances [\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The adjustable biodegradation rate of silica and its nanosized pore structure, combined with mild and aqueous processing conditions of silica gel, make it an ideal material for controlled drug delivery. Its potential applications in ophthalmology open new possibilities for enhancing patient care. Silica matrix is a synthetic inorganic biodegradable polymer made from amorphous silicon dioxide, produced through a chemical process known as the sol-gel process. Silica microparticles are produced after spray drying of the silica sol. An active substance can be encapsulated in the silica microparticles. In contact with body fluids, the silica composite material dissolves over time, and the embedded active substance is released concomitantly. The dissolution of the Silica Matrix takes place mainly through a surface erosion mechanism [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Eroded silica is freely dispersed in tissue and excreted via urine in the form of a very weak inorganic acid, silicic acid. The biodegradation process does not change the pH within the silica gel nor in the surrounding tissue. The manufacturing process can be adjusted to vary the number of hydroxyl groups and the specific surface area of silica matrix, thereby influencing the rate of silica biodegradation and the release rate of the active substance [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The Silica Matrix technology can be utilised in ophthalmic drug delivery systems designed to release an embedded active substance for a prolonged period. Examples of active substances that can be incorporated in the silica matrix are many, including antibacterial, antiviral, anti-inflammatory, eye pressure-lowering, and many other pharmacologically active agents [\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe aim of this study was to develop a Silica Eye Drop formulation and characterise the formulation as a promising drug carrier platform for the treatment of eye diseases. A 14-day topical ocular tolerance and toxicity study was run with Silica Eye Drop in rabbits. Silica composite material is a new excipient for eye drops and its ocular tolerance and safety has not been previously demonstrated.\u003c/p\u003e"},{"header":"2 MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Reagents\u003c/h2\u003e\u003cp\u003eReagent-grade (98%) tetraethyl orthosilicate (TEOS) and L (+)-tartaric acid were purchased from Aldrich Sigma. 0.1 M HCl and 0.1 M NaOH solutions were obtained from Merck. Silica standard solution (1000 \u0026micro;g/ml Si in H\u003csub\u003e2\u003c/sub\u003eO), isopropanol (IPA), and sodium peroxide pellets were sourced from VWR Chemicals. Nitric acid (67\u0026ndash;70%) and Dimethyl sulfoxide (DMSO), bioreagent grade, were supplied by Fisher Chemicals. 4-amino-3-hydroxy-1-naphthalene sulfonic acid was from Alfa Aesar. Sodium bisulfite was from Acros Organics. Ethanol (\u0026ge;\u0026thinsp;99.5%, ETAX Aa) was from Anora Group Oyj. Deionised water (18.2 MΩ.cm) was prepared in-house using a Millipore Milli-Q system. All other chemicals and reagents used were of analytical grade and were used as received without further purification.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Materials\u003c/h2\u003e\u003cp\u003e60-mL straight containers with screwed caps used in dissolution testing were purchased from Corning. The primary packaging materials for the eye drop were single-dose units (SDU) (Code/Ref: AA03898ABAAQ00C) produced by Lameplast Spa, Italy, while the secondary packaging was a LamiZip stand-up pouch (PET/LDPE/aluminum) purchased from DaklaPack.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Manufacture and characterisation of Silica Eye Drop\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eSilica Eye Drop is a silica composite material that consists of silica microparticles embedded in silica hydrogel. Silica microparticles and hydrogel are used to control the dissolution rate and rheological properties, such as viscosity, of the composite. The silica microparticles can also act as a reservoir for an active pharmaceutical ingredient (API). However, in the current study, no active substance was incorporated into silica microparticles. The manufacturing of Silica Eye Drop is a three-step process, which includes the manufacturing of the silica microparticles, compounding silica microparticles with dilute silica sol, and packaging into SDUs. The product was terminally sterilised by gamma irradiation. A flow scheme of the manufacturing process is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe process for manufacturing silica microparticles began with the hydrolysis of the silica precursor, TEOS, in water. The reaction was catalysed by 0.1 M HCl at pH 2, where TEOS was hydrolysed completely (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The hydrolysed species form a nano-scale silica cluster-water suspension, known as silica sol. The silica sol was cooled down to 5\u0026ndash;10\u0026deg;C and diluted with ethanol. The pH of the sol was adjusted with 0.1 M NaOH solution to 5.8\u0026ndash;6.2 before spray drying. The sol was pumped into a spray dryer (Mobile Minor, PSD 1 from GEA, Denmark) via a tube reactor and spray dried to form silica microparticles. The following spray drying parameters were used: Inlet temperature 180\u0026deg;C, process flow rate for nitrogen gas 80 kg/h (3 bar), atomization flow rate for nitrogen gas 12 kg/h (1.5 bar), and pump feed rate 35 g/min. Silica microparticles were collected in a collection vessel of the pilot-scale spray dryer. Silica microparticles were manufactured in a class C clean room (EU-GMP certified facility). After the manufacture, silica microparticles were packed in a polyethylene bag and an aluminum laminated bag as a secondary package. They were stored at 5\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u0026deg;C prior to Fill and Finish manufacture.\u003c/p\u003e\u003cp\u003eThe Fill and Finish process was performed in an ISO 8 classified clean room. In the process, a diluted silica sol was prepared and mixed with silica microparticles. The pH of the sol was adjusted with 0.1 M NaOH solution to 6.0\u0026ndash;6.5 prior to mixing with the silica microparticles. The suspension was transferred into pre-sealed SDUs by pipetting. The target filling volume was 0.8 ml per SDU, which represents a large overfill, as only one drop (0.03 ml) is used from each SDU. Each SDU was closed tightly with a Lameplast SDU cap. The filled and tightly closed SDUs were placed in a tube rotator to prevent particle sedimentation while the suspension contents were allowed to gel and stabilize at ambient temperature for approximately 24 hours. The filled SDUs were labelled and packed in labeled resealable aluminum pouches (secondary package). After the Fill and Finish manufacture, the SDUs in secondary packages were stored at 5\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u0026deg;C \u0026deg;C before sterilisation by gamma irradiation at 25 kGy.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Characterisation of Silica Eye Drop\u003c/h2\u003e\u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\u003ch2\u003e2.4.1. Particle size analysis\u003c/h2\u003e\u003cp\u003eSilica microparticles present in the eye drop were controlled for their particle size distribution (PSD), which is determined using a validated laser diffraction method (Laser Helo Sympatec with cuvette and R3 lens). 20 mg of silica microparticles were suspended in 20 ml of ethanol. The suspension was added dropwise, under stirring, to a cuvette containing about 50 ml of ethanol until an optical density of 5% to 25% was achieved. The measurement was performed in triplicate.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section3\"\u003e\u003ch2\u003e2.4.2. In vitro dissolution test\u003c/h2\u003e\u003cp\u003eTo establish the in vitro release kinetics of silica, a dissolution testing method with silica under sink conditions was used. Briefly, 25\u0026ndash;35 mg of Silica Eye Drop were weighed into a dissolution vessel. 50 ml of dissolution buffer, 50 mM TRIS buffer (pH7.4 @37\u0026deg;ꓚ), was added, and the vessel was transferred to a shaking water bath at +\u0026thinsp;37\u0026deg;C and 60 strokes per minute. At specified time points (1h, 2h, 3h, 4h, 5h, 6h, 9h, and 24h), the sample was centrifuged at 4500 rpm for 5 minutes. Silica content in the supernatant was analysed while the pellets were resuspended in fresh 50 ml dissolution buffer. The dissolution vessel was returned to the water bath shaker (+\u0026thinsp;37\u0026deg;C and 60 rpm). The cycle continued until the final dissolution time point. The silica concentration in the dissolution samples was measured with a spectrophotometer (Jenway 630, Cole-Parmer Ltd, UK). The method involves derivatisation, whereby a blue colour complex is formed in a reaction containing ammonium molybdate in an acidic environment [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The intensity of the blue color was measured spectrophotometrically at a wavelength of 820 nm and was directly proportional to the concentration of dissolved silica. Three parallel dissolution tests were carried out per batch.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\u003ch2\u003e2.4.3. Silica content analysis\u003c/h2\u003e\u003cp\u003eA sample of Silica Eye Drop (20\u0026ndash;30 mg) was dissolved in 50 ml of 2% NaOH at 37\u0026deg;C and 60 rpm for 3 days in a water shaking bath. After complete dissolution of the sample, the sample solution was diluted 100 times in water. The same spectrophotometric method used for analysing the dissolution samples was used for the determination of total silica content.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section3\"\u003e\u003ch2\u003e2.4.4. Ethanol content analysis\u003c/h2\u003e\u003cp\u003eSilica microparticles contain some residual amount of ethanol. Ethanol was produced as a by-product in the sol-gel process and was also used for dilution of the sol prior to spray drying. Potentially, high ethanol content could cause irritation in the living eye. The determination of ethanol in Silica Eye Drop was carried out by headspace-gas chromatography using a flame ionisation detector (HS-GC-FID, Agilent G1888-6890N). Sample solution preparation involved dissolving 30\u0026ndash;40 mg Silica Eye Drop in a 20 ml glass vial with 50 ml of 2% NaOH at 37\u0026deg;C and 60 rpm for 3 days in a water shaking bath. 20 \u0026micro;g/ml of isopropanol was used as an internal standard. The chromatographic separation was carried out on a DB-624, 30m x 0.53mm, 3 \u0026micro;m GC column (Agilent) with a gradient oven temperature ramp from 35\u0026deg;C, 20\u0026deg;C / min to 90\u0026deg;C, 50\u0026deg;C / min to 240\u0026deg;C hold for 5 min and nitrogen constant gas flow at 1.5 ml/min. The inlet temperature was 220\u0026deg;C, and the split ratio was 1:50 with a 4 mm deactivated glass liner. The headspace temperature conditions were set as follows: oven at 80\u0026deg;C, loop at 210\u0026deg;C, and transfer line at 220\u0026deg;C.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section3\"\u003e\u003ch2\u003e2.4.5 Endotoxin\u003c/h2\u003e\u003cp\u003eAn endotoxin test was conducted on the EndoSafe NexGen PTS device. This device performed endotoxin testing according to Ph. Eur. 2.4.16/USP\u0026thinsp;\u0026lt;\u0026thinsp;85\u0026thinsp;\u0026gt;\u0026thinsp;Method D chromogenic technique. The Detection limit of the method was \u0026lt;\u0026thinsp;0.176 EU/mg.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section3\"\u003e\u003ch2\u003e2.4.6. Sterility\u003c/h2\u003e\u003cp\u003eSterility assurance level (SAL) of 10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e was demonstrated by sterilization dose substantiation (gamma irradiation) using the VDmax 25 kGy method in accordance with the requirements in ISO 11137-2 [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The maximum allowable dose was determined to be 35 kGy. The VDmax 25 kGy method was used to establish 25 kGy as the sterilisation dose for products manufactured frequently or infrequently in large or small batches. For the validation of a single lot or infrequent production batches, 10 products were tested for bioburden, and then a dose audit was performed on 10 products irradiated at the verification dose. A SAL 10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e was demonstrated by experimental evidence that the product bioburden was less resistant than a Standard Distribution of Resistances (SDR) for which a SAL of 10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e was obtained at 25 kGy. The resistance to the sterilisation process was demonstrated by irradiation of the test items at a verification dose (VDmax) for which a SAL of 10\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e was obtained for the SDR. A SAL of 10\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e would result in 1 non-sterile sample per 10 items tested. Bioburden was determined using the validated most probable number method. The verification dose according to ISO 11137-2 was equal to 2.7 kGy. Sterility testing by a validated direct inoculation method for 10 test items irradiated at the verification dose was performed. A sterilisation dose of 25 kGy was established to obtain a SAL 10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e since there was not more than one positive test of sterility out of the ten product items tested.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e2.5. Stability study\u003c/h2\u003e\u003cp\u003eA stability study was conducted with Silica Eye Drop to test stability during storage and the preclinical in-use phase. The purpose of stability studies was to provide information on changes in the quality of the product over time because of environmental factors such as temperature, humidity, and light on the product. The following analyses were performed in the study at time points 0, 1 month, and 2 months: Visual inspection, silica content, ethanol content, in vitro dissolution testing, and pH. The storage conditions were based on ICH Q1 guidelines for stability testing of drug substances and drug products. The study was conducted at 5\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u0026deg;C and 25\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026deg;C/60\u0026thinsp;\u0026plusmn;\u0026thinsp;5% relative humidity (RH).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e2.6. GLP toxicity study in rabbits\u003c/h2\u003e\u003cp\u003eThe study was conducted according to the EMA guideline on non-clinical local tolerance testing (2015), OECD Test No. 405 (2021), Directive 2010/63/EU on animal protection, the Finnish Animal Protection Act (497/2013) and Decree (564/2013), OECD guidance on humane endpoints (2000), and OECD Principles of Good Laboratory Practice (1998). The investigation has been approved by the National Laboratory Animal Board of Finland (Care and Use Committee) with license number ESAVI/26478/2019.\u003c/p\u003e\u003cp\u003eThe biocompatibility, safety, and tolerability of Silica Eye Drop were investigated in four female New Zealand White (NZW) rabbits in compliance with Good Laboratory Practice (GLP). One drop of Silica Eye Drop was administered daily for 14 days to the conjunctival sac of one (left) eye of four animals. One drop (approximately 0,05 ml) of sterile 0.9% NaCl was administered in the conjunctival sac of the other eye (right) as a control. The eyes were checked daily before applying the test items by a veterinarian. The degree of eye irritation/corrosion was repeatedly evaluated by scoring lesions of the conjunctiva, cornea, and iris. The veterinarian used fluorescein (Kunze Indopharm B.V., Netherlands) to detect any possible damage to the cornea on study Days 2, 8, and 15. The scoring was performed according to OECD/OCDE Test No. 405: Acute Eye Irritation/Corrosion. Intraocular pressure was repeatedly measured in both eyes on study Day \u0026minus;\u0026thinsp;5 (pre-test) and on study Days 1 (prior to the first dose), 2, 8, and 15. Measurements were done by the veterinarian using the Icare Tonovet Plus (Icare, Finland) device. The animals were restrained with a towel, and after approximately two minutes, the measurements were performed. Three acceptable subsequent results from both eyes were collected from each animal, and an average of these three measurements was calculated. Other possible effects on the eye and adverse systemic effects were also recorded to provide a complete evaluation of the effects. Clinical signs were observed twice daily, and blood sampling for hematological analyses, coagulation tests, and clinical chemistry was taken at baseline and termination.\u003c/p\u003e\u003cp\u003eAfter 14 days of treatment (on study Day 15), the animals were sacrificed by exsanguination after inducing deep anesthesia using Medetomidine (Cepetor vet 1 mg/ml, CP-Pharma Handelsges. mbH, Germany) and Ketamine (Ketaminol vet 50 mg/ml, Intervet International B.V., Germany). Some animals were additionally given Euthasol 400 mg/ml (Produlab Pharma B.V., the Netherlands) intravenously to complete the euthanasia. Scheduled necropsy was performed in all animals, and all macroscopic changes were recorded. At necropsy, eyes with optic nerves, lids, conjunctivae, and nictitating membranes were collected from all animals into Davidson\u0026rsquo;s solution (both sides for paired organs). The tissues were kept in Davidson\u0026rsquo;s fixative for 24 to 27 hours, after which they were transferred into 70% ethanol. The fixed tissues were sent to AnaPath GmbH, Department AnaPath Services, Switzerland. Trimming, processing, embedding in paraffin wax, cutting, and staining by eosin and hematoxylin were performed at AnaPath GmbH, Department AnaPath Services, Switzerland. The sections were evaluated by a professional veterinary pathologist.\u003c/p\u003e\u003c/div\u003e"},{"header":"3 RESULTS AND DISCUSSION","content":"\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Characterisation and stability of Silica Eye Drop\u003c/h2\u003e\n \u003cp\u003eThe Silica Eye Drop formulation contained 23% (w/w) silica microparticles and 77% (w/w) silica hydrogel. By visual inspection, the eye drop was a white to nearly white homogeneous suspension. Figure \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e shows a photograph of the final eye drop product in its primary package. The silica microparticles in the eye drop exhibited a monomodal particle size distribution with D10 at 1.69 \u0026micro;m, D50 at 3.21 \u0026micro;m, and D90 at 5.78 \u0026micro;m. The amount of silica in the final eye drop product was measured to be 18.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.65 wt%, the ethanol content was 3.9 wt%, and the pH was 6.1. Silica Eye Drop was shown to dissolve completely in 24 hours with an in-house in vitro in-sink dissolution testing method. Silica microparticles play a major role in controlling the dissolution rate of Silica Eye Drop. The dissolution rate of silica is influenced by several manufacturing parameters, including the precursor ratios (i.e., molar ratio of water to TEOS), aging of the silica sol, pH of the silica sol, nature of the diluent, and spray drying parameters. As mentioned above, silica microparticles are produced by the hydrolysis and condensation of TEOS via an acid-catalysed reaction. A lower water-to-TEOS molar ratio and ethanol as diluent in the manufacturing process resulted in silica microparticles with a fast dissolution rate. Unlike traditional mesoporous silica systems [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], which rely on the loading of drugs into pores, the silica matrix in this study is non-porous or nanoporous [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. The dissolution of the matrix occurs through the surface erosion of the silica matrix in bodily fluids rather than through diffusion. Additionally, the rate of biodegradation can be finely tuned, enabling controlled release that can be tailored over a duration of days to months. The droplet size variation was determined by gravimetry from ten different SDUs. The average droplet weight was 33.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8 mg, corresponding to 31.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4 \u0026micro;l. The minimum and maximum weights were 29.1 mg and 39.1 mg, respectively. It was concluded that dispensing the droplet manually from the SDU results in droplets with acceptable variability in size. This was substantiated by the content uniformity test results, which conformed to the European pharmacopeia [Ph. Eur 2.9.40]. The application of a droplet was easy and required only a minimum amount of pressing force by fingers. The Silica Eye Drop formulation contained very low levels of endotoxin; the measured endotoxin content was below 0.2 EU/mg, which is the limit of quantitation of the method. Low endotoxin and bioburden (0.36 CFU/g) indicated a good control strategy for endotoxin and microbial contamination during the manufacturing process of the eye drop used in this study. The product was terminally sterilised by gamma irradiation at 25 kGy, and sterilisation dose substantiation confirmed that the irradiation dose of 25 kGy was adequate to reach SAL 10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e level for the product. This study also demonstrated that the Silica Eye Drop formulation tolerates well gamma irradiation without any sign of loss of critical properties needed for an eye drop.\u003c/p\u003e\n \u003cp\u003eA 2-month preliminary stability study was conducted with Silica Eye Drop to establish adequate stability of the product needed for the in vivo rabbit study. By visual inspection, the product looked the same, i.e., white to almost white homogenous suspension at all time points and both conditions. No changes were seen in silica or ethanol content over time. After 2 months, a slight decrease in pH from 6.1 to 5.9 and 5.7 was recorded at 5\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u0026deg;C and 25\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026deg;C / 60\u0026thinsp;\u0026plusmn;\u0026thinsp;5%RH, respectively. Although the dissolution rate of silica was slower at 1 month and 2 months than at the 0-month timepoint (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e), all the silica dissolved within 24 hours at all conditions studied. In conclusion, Silica Eye Drop was stable for at least 2 months and can be stored for this period of time either at 25\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026deg;C / 60\u0026thinsp;\u0026plusmn;\u0026thinsp;5%RH or 5\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u0026deg;C.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 GLP toxicity study\u003c/h2\u003e\n \u003cp\u003eAll animals gained weight normally during this study (data not shown). No unusual clinical signs were recorded in any of the animals. The clinical observations of the eyes recorded are summarised in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. A total of 4 left eyes that were treated and 4 right eyes that served as controls. No severe irritation or corrosion was observed in any of the animals. Scores of grades 1 to 2 of test item residues were observed in the conjunctival sac of the test eyes in two out of four animals during eye examinations on Days 3, 7, 8, 10, and 15. Eyelid swelling (chemosis) above normal was observed in both control and treated eyes of the animals. The Silica Eye Drop group had 8 observations on the test (left) eye and 4 on the control (right) eye. These changes were not persistent. There were no other reactions in the eyes. The results of the haematological analyses, coagulation tests, and clinical chemistry analyses were comparable between pre- and post-treatment. Histopathological evaluation revealed no treatment-related findings in the examined organs, tissues, or structures. Minimal (grade 1) mononuclear cell infiltrates in the nictitating membrane were observed in one eye treated with Silica Eye Drop. Focal mononuclear infiltrate, grade 2, was observed in the eyelid dermis of one control eye. The findings were considered incidental/background changes that sometimes occur in this type of study. IOP (intraocular pressure) values for treated and control eyes are shown in Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e. IOP values for all animals in this study remained within the normal reference range for laboratory animals despite showing a variation over 14 days (12\u0026ndash;25 mmHg). This may be due to the fact that the IOP can be influenced by restraint techniques, animal stress, diurnal or circadian rhythm, eye position, sedation or anesthesia, corneal thickness, and several other variables [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e]. Chemosis, which is the swelling of the conjunctiva, was observed in the test and control groups. In rabbits, these changes can be triggered by various factors, including environmental conditions often present in animal holding centers [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]. Additionally, stress resulting from the experiment may weaken a rabbit\u0026rsquo;s immune system, increasing its susceptibility to infections that can lead to conjunctival swelling. This explains the minor histological changes observed in the tissues of some animals in both study groups. After administering Silica Eye Drop, significant absorption of the main compounds of the medication into the eye structures or directly into the bloodstream is not expected due to their very low quantities and physicochemical properties. When the drop is in contact with tear fluid, the silica material begins to dissolve into silicic acid (SiA). This material may then be transported via the nasolacrimal duct. Additionally, some SiA could be absorbed directly into the bloodstream through the epithelium of the conjunctival sac and later excreted in the urine by the kidneys. Compared to other sources of silica and SiA, the amount contained in this material represents only trace levels of daily intake for humans [\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]. Studies conducted with rabbits that used silica from various manufacturers show that this topic is highly relevant, indicating the need for additional experiments [\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e]. It was concluded that 14-day repeated daily dosing of Silica Eye Drop was well-tolerated and considered to be safe and non-irritant.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eTable 1. Summary of clinical observations of the eyes recorded in the rabbit GLP toxicity study (frequency of incidence)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003ctable style=\"border: none;width:100.0%;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family: \"Times New Roman\",serif;color:black;'\u003eSilica Eye Drop\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.46%;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0cm 3.5pt;height: 14.15pt;vertical-align: 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3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003eLeft eye\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 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style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;border-top:none;background: #4C94D8;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e2. AMOUNT OF THE TEAR FLUID\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#F2F2F2;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"14\" style=\"width:57.6%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid black 1.0pt;background:#F2F2F2;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;border-top:none;padding: 0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003eLeft eye\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;border-top:none;padding: 0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003eRight eye\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;border-top:none;background: #4C94D8;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e3. CONJUNCTIVAE\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#F2F2F2;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"14\" style=\"width:57.6%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid black 1.0pt;background:#F2F2F2;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;border-top:none;padding: 0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003eLeft eye\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 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style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n 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style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;border-top:none;padding: 0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003eRight eye\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp 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3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 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style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;border-top:none;background: #4C94D8;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e4. CHEMOSIS\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#F2F2F2;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"14\" style=\"width:57.6%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid black 1.0pt;background:#F2F2F2;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;border-top:none;padding: 0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003eLeft eye\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#DBEAF8;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e1/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid 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style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#DBEAF8;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New 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style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e3/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#DBEAF8;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e1/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;border-top:none;padding: 0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003eRight eye\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 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3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e5. IRIS\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#F2F2F2;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"14\" style=\"width:57.6%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid black 1.0pt;background:#F2F2F2;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;border-top:none;padding: 0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003eLeft eye\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n 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Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;border-top:none;padding: 0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New 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style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n 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Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;border-top:none;background: #4C94D8;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e6. CORNEA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#F2F2F2;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"14\" style=\"width:57.6%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid black 1.0pt;background:#F2F2F2;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;border-top:none;padding: 0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003eLeft eye\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n 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style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:36.94%;border:solid windowtext 1.0pt;border-top:none;padding: 0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003eRight eye\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:5.46%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:4.12%;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;line-height:normal;font-size:16px;font-family:\"Aptos\",sans-serif;text-align:center;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;color:black;'\u003e0/4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"4 CONCLUSION","content":"\u003cp\u003eThe Silica Eye Drop formulation was designed with the following target product properties: a dissolution time of approximately 24 hours in the conjunctival sac and tear fluid, easy administration by the patient, a drop weight of around 33 mg (30 \u0026micro;l), and a sterile composition that is non-toxic and well-tolerated. The results in this study demonstrate that a silica composite eye drop formulation meeting these criteria was successfully developed. The eye drop formulation containing 23% (w/w) silica microparticles and 77% (w/w) silica hydrogel dissolved completely in 24 hours according to the in vitro dissolution results. Moreover, in the rabbit in vivo GLP study with daily dosing for 14 days, no residual silica material was detected before the next dosing in 9/10 cases. Additionally, no unusual clinical signs were observed during the experiment. At necropsy, no abnormalities were found in any of the animals. No pathological changes were observed in this study; the control and test groups showed similar results throughout the entire period without any statistically significant differences. IOP values for all animals in this study remained within the normal reference range for laboratory animals. The data show that Silica Eye Drop is safe and well-tolerated for once-a-day use for 14 days in NZW rabbits without causing any toxic effects in tissues and organs, either locally or systemically. The Silica Eye Drop formulation was easy to administer, and the average droplet weight was 33.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8 mg, corresponding to 31.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4 \u0026micro;l, which is in line with the target value. In conclusion, this study demonstrates the potential of the silica platform technology in sustained drug release applications in topical ophthalmology. Additional experiments are necessary, particularly those that involve combining the Silica Matrix with a drug, to evaluate clinical efficacy and pharmacokinetics of this technology.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eAPI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eActive Pharmaceutical Ingredient\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eDMSO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eDimethyl Sulfoxide\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eEMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eEuropean Medicines Agency\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eGLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eGood Laboratory Practice\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eHCl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eHydrochloric Acid\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eHS GCFID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eHeadspace Gas Chromatography Flame Ionization Detector\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eICH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eInternational Council for Harmonisation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eIOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eIntraocular Pressure\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eIPA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eIsopropyl Alcohol\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eNZW\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eNew Zealand White (rabbit)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eNaOH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eSodium Hydroxide\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eOECD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eOrganisation for Economic Co operation and Development\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003ePh Eur\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eEuropean Pharmacopoeia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003ePSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eParticle Size Distribution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eRH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eRelative Humidity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eRpm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eRevolutions per Minute\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eSAL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eSterility Assurance Level\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eSDR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eSpray Dried Residue\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eSDU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eSingle Dose Unit\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eSi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eSilicon\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eSiA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eSilicic Acid\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eSiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eSilicon Dioxide\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eTEOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eTetraethyl Orthosilicate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eTRIS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eTris(hydroxymethyl)aminomethane\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eVDmax\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eMaximum Validated Dose\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003ew/w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eWeight per Weight\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003ewt%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eWeight Percent\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eM.N. A-P., P.S. M.V., and H.A. are employees of DelSiTech Ltd., where the formulation development and physicochemical properties were analysed. However, in vivo tolerability and safety studies were conducted independently by a third party not affiliated with DelSiTech Ltd. The authors affirm that this separation of roles ensured that the objectivity and integrity of the tolerability data remained unaffected by the company.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eL. L. \u0026ndash; сonceptualisation and study design, M. N. A-P., H. A. \u0026ndash; supervision, M. N. A-P., P. S. \u0026ndash; analytical development and stability studies (experiments), M. V., H. A. \u0026ndash; formulation development and manufacturing (experiments), M. N. A-P., A. P., P. S., M. V., H. A. \u0026ndash; data collection, analysis, and interpretation, M. N. A-P., A. P., P. S. \u0026ndash; preparation of tables and figures, L. L., M. N. A-P., A. P. \u0026ndash; manuscript writing. All authors reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAli M, Byrne ME. Challenges and solutions in topical ocular drug-delivery systems. Expert Rev Clin Pharmacol. 2008;1:145\u0026ndash;61. https://doi.org/10.1586/17512433.1.1.145\u003c/li\u003e\n\u003cli\u003eGote V, Sikder S, Sicotte J, Pal D. Ocular Drug Delivery: Present Innovations and Future Challenges. Journal of Pharmacology and Experimental Therapeutics. 2019;370:602\u0026ndash;24. https://doi.org/10.1124/jpet.119.256933\u003c/li\u003e\n\u003cli\u003eForrester J V., Dick AD, McMenamin PG, Roberts F, Pearlman E. General and ocular pharmacology. The Eye. Elsevier; 2016. p. 338-369.e1. https://doi.org/10.1016/B978-0-7020-5554-6.00006-X\u003c/li\u003e\n\u003cli\u003eGaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular Drug Delivery. AAPS J. 2010;12:348\u0026ndash;60. https://doi.org/10.1208/s12248-010-9183-3\u003c/li\u003e\n\u003cli\u003eJumelle C, Gholizadeh S, Annabi N, Dana R. Advances and limitations of drug delivery systems formulated as eye drops. Journal of Controlled Release. 2020;321:1\u0026ndash;22. https://doi.org/10.1016/j.jconrel.2020.01.057\u003c/li\u003e\n\u003cli\u003eFedorchak M V., Conner IP, Schuman JS, Cugini A, Little SR. Long Term Glaucoma Drug Delivery Using a Topically Retained Gel/Microsphere Eye Drop. Sci Rep. 2017;7:8639. https://doi.org/10.1038/s41598-017-09379-8\u003c/li\u003e\n\u003cli\u003eAlmeida H, Amaral MH, Lob\u0026atilde;o P, Lobo JMS. In situ gelling systems: a strategy to improve the bioavailability of ophthalmic pharmaceutical formulations. Drug Discov Today. 2014;19:400\u0026ndash;12. https://doi.org/10.1016/j.drudis.2013.10.001\u003c/li\u003e\n\u003cli\u003eStefansson E, Loftsson T, Larsen M, Papp A, Kaarniranta K, Munk MR, et al. Topical treatment of diabetic macular edema using dexamethasone ophthalmic suspension: A randomized, double-masked, vehicle-controlled study. Acta Ophthalmol. 2023;101:22\u0026ndash;33. https://doi.org/10.1111/aos.15215\u003c/li\u003e\n\u003cli\u003eWang Y, Wang C. Novel Eye Drop Delivery Systems: Advance on Formulation Design Strategies Targeting Anterior and Posterior Segments of the Eye. Pharmaceutics. 2022;14. https://doi.org/10.3390/pharmaceutics14061150\u003c/li\u003e\n\u003cli\u003eForsback A-P, Noppari P, Viljanen J, Mikkola J, Jokinen M, Leino L, et al. Sustained In-Vivo Release of Triptorelin Acetate from a Biodegradable Silica Depot: Comparison to Pamorelin\u0026reg; LA. Nanomaterials. 2021;11:1578. https://doi.org/10.3390/nano11061578\u003c/li\u003e\n\u003cli\u003eMcGowan A, Gennemark P, Akieh-Pirkanniemi M, Wirman L, Davies N, Elebring M, et al. Injectable Biodegradable Silica Depot for Controlled Subcutaneous Delivery of Antisense Oligonucleotides with beyond Monthly Administration. Mol Pharm. 2024;21:143\u0026ndash;51. https://doi.org/10.1021/acs.molpharmaceut.3c00663\u003c/li\u003e\n\u003cli\u003eNoppari P, Forsback A-P, Terjung C, Marttila A, Leino L, Unger F, et al. Development of injectable long-acting controlled release intravitreal depot of BAY224 using biodegradable silica microparticle-silica hydrogel composite. Invest Ophthalmol Vis Sci. 2020;61:1357. \u003c/li\u003e\n\u003cli\u003eTyagi P, Koskinen M, Mikkola J, Leino L, Schwarz A. Silica microparticles for sustained zero-order release of an anti-CD40L antibody. Drug Deliv Transl Res. 2018;8:368\u0026ndash;74. https://doi.org/10.1007/s13346-017-0408-1\u003c/li\u003e\n\u003cli\u003eTyagi P, Koskinen M, Mikkola J, Sarkhel S, Leino L, Seth A, et al. Injectable Biodegradable Silica Depot: Two Months of Sustained Release of the Blood Glucose Lowering Peptide, Pramlintide. Pharmaceutics. 2022;14:553. https://doi.org/10.3390/pharmaceutics14030553\u003c/li\u003e\n\u003cli\u003eRosenholm JM, Sahlgren C, Lind\u0026eacute;n M. Towards multifunctional, targeted drug delivery systems using mesoporous silica nanoparticles \u0026ndash; opportunities \u0026amp;amp; challenges. Nanoscale. 2010;2:1870. https://doi.org/10.1039/c0nr00156b\u003c/li\u003e\n\u003cli\u003eJokinen M, Koskinen M, Areva S. Rationale of Using Conventional Sol-Gel Derived SiO\u0026amp;lt;sub\u0026amp;gt;2\u0026amp;lt;/sub\u0026amp;gt; for Delivery of Biologically Active Agents. 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J Cataract Refract Surg. 2020;46:1548\u0026ndash;53. https://doi.org/10.1097/j.jcrs.0000000000000366\u003c/li\u003e\n\u003cli\u003eHu C, Sun J, Zhang Y, Chen J, Lei Y, Sun X, et al. Local Delivery and Sustained‐Release of Nitric Oxide Donor Loaded in Mesoporous Silica Particles for Efficient Treatment of Primary Open‐Angle Glaucoma. Adv Healthc Mater. 2018;7. https://doi.org/10.1002/adhm.201801047\u003c/li\u003e\n\u003cli\u003eRadin S, Ducheyne P, Kamplain T, Tan BH. Silica sol-gel for the controlled release of antibiotics. I. Synthesis, characterization, andin vitro release. J Biomed Mater Res. 2001;57:313\u0026ndash;20. https://doi.org/10.1002/1097-4636(200111)57:2\u0026lt;313::AID-JBM1173\u0026gt;3.0.CO;2-E\u003c/li\u003e\n\u003cli\u003eAkimsheva EYu, Dolinina ES, Parfenyuk EV. Interactions of sol-gel encapsulated acyclovir with silica matrix. Colloids Surf B Biointerfaces. 2019;178:103\u0026ndash;10. https://doi.org/10.1016/j.colsurfb.2019.02.052\u003c/li\u003e\n\u003cli\u003eYang H, Li C, Wei C, Li M, Li X, Deng Z, et al. Molybdenum blue photometry method for the determination of colloidal silica and soluble silica in leaching solution. Analytical Methods. 2015;7:5462\u0026ndash;7. https://doi.org/10.1039/C5AY01306B\u003c/li\u003e\n\u003cli\u003eInternational Organization for Standardization. ISO 11737-2:2019 Sterilization of health care products \u0026mdash; Microbiological methods \u0026mdash; Part 2: Tests of sterility performed in the validation of a sterilization process. 2019. \u003c/li\u003e\n\u003cli\u003eInternational Organization for Standardization. ISO 11737-1:2018 Sterilization of health care products \u0026mdash; Microbiological methods \u0026mdash; Part 1: Determination of the population of microorganisms on products. 2018. \u003c/li\u003e\n\u003cli\u003eInternational Organization for Standardization. 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Cham: Springer International Publishing; 2018. https://doi.org/10.1007/978-3-319-78364-2\u003c/li\u003e\n\u003cli\u003eVarga M. Rabbit Basic Science. Textbook of Rabbit Medicine. Elsevier; 2014. p. 3\u0026ndash;108. https://doi.org/10.1016/B978-0-7020-4979-8.00001-7\u003c/li\u003e\n\u003cli\u003eJugdaohsingh R. Silicon and bone health. J Nutr Health Aging. 2007;11:99\u0026ndash;110. \u003c/li\u003e\n\u003cli\u003eJurkić LM, Cepanec I, Pavelić SK, Pavelić K. Biological and therapeutic effects of ortho-silicic acid and some ortho-silicic acid-releasing compounds: New perspectives for therapy. Nutr Metab (Lond). 2013;10:2. https://doi.org/10.1186/1743-7075-10-2\u003c/li\u003e\n\u003cli\u003eSripanyakorn S, Jugdaohsingh R, Elliott H, Walker C, Mehta P, Shoukru S, et al. The silicon content of beer and its bioavailability in healthy volunteers. British Journal of Nutrition. 2004;91:403\u0026ndash;9. https://doi.org/10.1079/BJN20031082\u003c/li\u003e\n\u003cli\u003eCalcium silicate and silicon dioxide/silicic acid gel added for nutritional purposes to food supplements. EFSA Journal. 2009;7. https://doi.org/10.2903/j.efsa.2009.1132\u003c/li\u003e\n\u003cli\u003eDekkers S, Krystek P, Peters RJB, Lankveld DPK, Bokkers BGH, van Hoeven-Arentzen PH, et al. Presence and risks of nanosilica in food products. Nanotoxicology. 2011;5:393\u0026ndash;405. https://doi.org/10.3109/17435390.2010.519836\u003c/li\u003e\n\u003cli\u003eAlhowyan AA, Kalam MA, Iqbal M, Raish M, El-Toni AM, Alkholief M, et al. Mesoporous Silica Nanoparticles Coated with Carboxymethyl Chitosan for 5-Fluorouracil Ocular Delivery: Characterization, In Vitro and In Vivo Studies. Molecules. 2023;28:1260. https://doi.org/10.3390/molecules28031260\u003c/li\u003e\n\u003cli\u003eSwain R, Nandi S, Swain SS, Pattanaik KP, Mohapatra S, Panigrahi D, et al. Bentonite-in hypromellose-poloxamer sol-gel for corneal application of trimetazidine: Study of rheology and ocular anti inflammatory potential. Int J Biol Macromol. 2023;242:124628. https://doi.org/10.1016/j.ijbiomac.2023.124628\u003c/li\u003e\n\u003cli\u003eKim S-N, Ko SA, Park CG, Lee SH, Huh BK, Park YH, et al. Amino-Functionalized Mesoporous Silica Particles for Ocular Delivery of Brimonidine. Mol Pharm. 2018;15:3143\u0026ndash;52. https://doi.org/10.1021/acs.molpharmaceut.8b00215\u003c/li\u003e\n\u003cli\u003eZaghloul N, El Hoffy NM, Mahmoud AA, Elkasabgy NA. Cyclodextrin Stabilized Freeze-Dried Silica/Chitosan Nanoparticles for Improved Terconazole Ocular Bioavailability. Pharmaceutics. 2022;14:470. https://doi.org/10.3390/pharmaceutics14030470\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"silica hydrogel, GLP study, eye drops, silica matrix, tolerability, ophthalmology, drug delivery system","lastPublishedDoi":"10.21203/rs.3.rs-7880491/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7880491/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eTopical eye drops are common for treating eye diseases, often requiring multiple daily doses. Silica Matrix technology enables ophthalmic drug delivery systems that release drugs over time. This study aimed to develop and characterize a silica-based eye drop, as well as a 14-day tolerance and toxicity assessment to evaluate its potential as a drug carrier in ophthalmology.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eSilica Eye Drop is a silica-based composite containing silica microparticles, made via sol-gel chemistry and spray drying, along with silica hydrogel.\u003cstrong\u003e \u003c/strong\u003eThe product was terminally sterilised by gamma irradiation and characterised by particle size, silica content, \u003cem\u003ein vitro\u003c/em\u003e dissolution time, droplet size, applicability, microbiological purity, and short-term stability.\u003cstrong\u003e \u003c/strong\u003eFour New Zealand rabbits received one drop daily in one eye's conjunctival sac for 14 days, while the other eye served as a control.\u003cstrong\u003e \u003c/strong\u003eDuring the study, eye conditions, blood chemistry, and postmortem histology were monitored.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe final formulation contained 23% (w/w) silica microparticles (average diameter 3.21 µm) and 77% (w/w) silica hydrogel, with 18.2 wt% silica, dissolving in 24 hours. The average droplet volume was 31.3 ± 4.4 µl, easily dispensed manually from a single dose unit with acceptable size variability. A 2-month stability study showed no major changes in product properties. Finally, in the rabbit toxicity study, both the treated and untreated eyes showed similar tolerability levels.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThe Silica Eye Drop was successfully developed and manufactured. Easy to use with consistent quality, it demonstrated the safety and potential of silica platform technology for sustained drug release in topical ophthalmology.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e~100 WORD SUMMARY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, a novel silica-based eye drop formulation for prolonged ocular drug delivery was developed and evaluated. Silica microparticles were synthesised and incorporated through a Fill and Finish process, followed by sterilization and characterization for particle size, silica content, dissolution, droplet size, microbiological purity, and short-term stability. \u003cem\u003eIn vivo\u003c/em\u003e tolerability was assessed in four New Zealand rabbits over 14 days with daily administration. The optimised formulation contained 23% (w/w) silica microparticles and 77% (w/w) silica hydrogel (18.2 wt% silica). Microparticles (D50 = 3.21 µm) fully dissolved within 24 hours. No adverse ocular effects occurred, confirming excellent safety, stability, and therapeutic potential.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e25-30 WORD TEASER\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA novel Silica Eye Drop formulation was developed, showing sustained release, full dissolution in 24 hours, and good tolerability in rabbits, highlighting its promise for future ocular therapies.\u003c/p\u003e","manuscriptTitle":"Development and preclinical safety testing of biodegradable Silica Eye Drop as an ophthalmic carrier matrix","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-03 16:12:03","doi":"10.21203/rs.3.rs-7880491/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d9b1f0d6-8c40-41f8-b366-56fa3d4dae75","owner":[],"postedDate":"November 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:18:05+00:00","versionOfRecord":{"articleIdentity":"rs-7880491","link":"https://doi.org/10.1007/s12247-025-10331-x","journal":{"identity":"journal-of-pharmaceutical-innovation","isVorOnly":false,"title":"Journal of Pharmaceutical Innovation"},"publishedOn":"2026-01-06 15:59:07","publishedOnDateReadable":"January 6th, 2026"},"versionCreatedAt":"2025-11-03 16:12:03","video":"","vorDoi":"10.1007/s12247-025-10331-x","vorDoiUrl":"https://doi.org/10.1007/s12247-025-10331-x","workflowStages":[]},"version":"v1","identity":"rs-7880491","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7880491","identity":"rs-7880491","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}