INTRODUCTION:

Ocular drug delivery is considered one of the most challenging affairs for pharmaceutical scientists because of the complex and unique structure of the human eye that makes it highly resistant to foreign substances, including drugs^1,2. Currently, anterior eye segment diseases are commonly managed by eye drops which consist more than 90% of the marketed ophthalmic formulations³. However, these dosage forms have many limitations including poor bioavailability⁴, high dose requirements⁵, undesirable side effects⁶, frequent instillation⁷, and low patient compliance⁵.

To overcome the disadvantages of eyedrop formulation, novel ocular drug delivery devices have been explored involving soft contact lenses which appear a natural choice, because millions of people safely use contact lenses⁸. The use of soft contact lenses as a drug-carrier has succeeded in receiving a lot of attention in recent years due to their ability to sustain the release of drugs with the advantage of > 50% bioavailability, leading to an increase in therapeutic efficacy and compliance. This benefit makes contact lenses a promising ocular drug delivery system in the treatment of various ophthalmic diseases especially the chronic ones that require a constant therapeutic level of the drug in the eye for effective control of the disease, as is the case of glaucoma⁹.

Glaucoma is a common cause of blindness in the world¹⁰. It is an irreversible condition resulting from the increase in intraocular pressure; which leads to permanent loss of vision with the destruction of retinal ganglion cells¹¹. Many beta-blockers are used to lower this pressure like carteolol, timolol, levobunolol, and betoxalol as eyedrops¹², which need to be instilled twice daily¹³. Noncompliance to the strict therapeutic regimen is considered one of the major problems associated with this disease¹⁴, and this issue can be managed by the usage of contact lenses as they can provide a sustained release of medication¹⁵.

First recorded attempts to use contact lenses for the treatment of glaucoma come back to the 1970s. These experiments depended on submerging the lens in a drug solution followed by releasing it to the post lens tear film⁹. However, the conventional soaking method showed limitation like low drug uptake and high burst release¹⁶. Drug release from soaked contact lenses occurs rapidly, with complete release from the lens in a few hours¹⁶. To achieve extended drug delivery, studies have successfully tested different methods to modify commercial lenses, for example through the addition of vitamin E diffusion barriers¹⁷, nanoparticles¹⁸, microemulsion¹⁹, supercritical solvent impregnation method²⁰.

One study reported the ability of oleic acid to both extending release durations of cationic drugs and accelerating anionic drug release durations from commercial silicone contact lenses, and the result was attributed to the electrostatic interactions between the anionic oleate and the charged drugs²¹.

Several publications chose timolol maleate as an active ingredient^{17,19,20,22,23}. Timolol maleate - a representative sympathetic β blocker - possesses a good intraocular pressure-lowering effect but it shows decreased tear due to its local anesthetic effect and possesses toxicity to the surface of the cornea and conjunctiva²⁴. On the other hand, while the ophthalmic formulation of CRT belongs in the same category of sympathetic β blockers, it shows less effect on the corneal perception and causes less disorder of the cornea²⁴. That was the reason to choose CRT in this work, as anti-glaucoma ophthalmic preparations are required to show not only intraocular pressure-lowering effects but also fewer adverse reactions because they are often used for long term²⁴. And to our knowledge, there is no study on extending CRT release from contact lenses before, although CRT is the second most commonly prescribed topical beta-blocker with an intrinsic sympathomimetic action¹².

In this paper, “soak and release” method was applied after the incorporation of oleic acid into the lenses in an attempt to improve CRT uptake from CRT-soaking solution and to retard its diffusion from contact lenses for sustained release. We expect a result matched to the result mentioned above as CRT pKa is 9.76 and it is hypothesized to obtain a cationic charge in physiological pH²⁵.

The oleic acid modified lenses were characterized to explore drug release profiles and some of other lenses properties such as transparency, water content, diameter and tensile modulus.

MATERIALS AND METHODS:

Materials:

One type of commercial silicone hydrogel contact lenses (diopter −6) (AIR OPTIX^®). The detailed information of these lenses is described in Table 1. Carteolol hydrochloride (CRT) was kindly provided by Rama Pharma (Rama Pharma, Syria). Oleic acid (OA) (97%) was purchased from PROLABO (France). Ethanol (≥99.5%) was purchased from Chem-Lab (Belgium). Di-sodium hydrogen orthophosphate, Potassium dihydrogen orthophosphate were purchased from TM Media (India). Sodium chloride was purchased from HiMedia (India). Potassium Chloride was purchased from Qualikems (India). These salts were used to prepare the phosphate-buffered saline (PBS).

Table 1. Characteristics of the contact lenses used in the current work.

Commercial name	AIR OPTIX^®
Material	Silicone Hydrogel, lotrafilcon B
Water Content (%)	33
Center thickness (mm @-3.00D)	0.08
Wearing Schedule	Daily wear and up to 6 nights extended wear
Base Curve (mm)	8.6
Diameter (mm)	14.2
Color	Light Blue Visitint^®
Manufacturer	Alcon^® a Novartis company
Main monomers	DMA;TRIS; siloxane macromer
Tensile Modulus (MPa)²⁶	1.2

DMA: N,Dimethylacetamide; TRIS: propyltris(trimethylsiloxy)silane.

Data collected from manufacturers and FDA reports.

Methods:

Oleic acid loading into contact lenses:

The protocol of oleic acid loading described by Torres-Luna et al. was followed in this study with some modifications²¹. AIR OPTIX^® contact lenses were rinsed with distilled water for an hour and then air-dried for a day before use. Lenses were soaked in 4 ml of 35 mg/ml or 60 mg/ml of oleic acid in ethanol for 24 hr at room temperature. Following the loading step, the contact lenses were taken out and excess oleic acid–ethanol solution was blotted from the lens surface. Lenses were washed in distilled water for 1 hr and subsequently air-dried overnight. To determine the loading amount of OA, dry lenses were weighed before and after the fatty acid loading process.

CRT loading into contact lenses:

CRT was loaded into the rinsed and dried lenses and into the oleic acid loaded lenses by soaking these lenses in 15 ml of a CRT-PBS solution according to the method described by Torres-Luna et al.²¹. The drug loading concentration was 2mg/ml and the soaking duration was 24 hr at room temperature. After the CRT loading step, lenses were gently blotted with a filter paper to remove the excess solution from the surface and immediately immersed in the release medium for in vitro release experiments.

In vitro CRT release experiments:

The drug release experiments were performed by soaking the lenses in 2ml of PBS at pH 7.4 and at room temperature without agitation. During the release process, 0.6ml of release sample was removed and substituted by 0.6ml of fresh PBS at predetermined time intervals (3, 6, 12, 24, 48, 96, 144, 192, 264, 360hr). The absorbance of released CRT was measured using a UV-Spectrophotometer (UV–vis Spectrophotometer, JASCO, model V-530, Japan) at wavelength of 251nm against suitable blank lenses, then the released amount of CRT was calculated using a previously determined calibration curve²¹. The drug release experiments were carried out in triplicate for each time point. The release profile of the drug was evaluated by plotting different graphs: cumulative CRT release versus time (days), percentage cumulative CRT release versus time (days) and release rate (µg/hr) versus time (days).

Characterization of prepared contact lenses:

a) Transmittance analysis:

The clarity of the lenses was evaluated using a UV–visible spectrophotometer (UV–vis Spectrophotometer, JASCO, model V-530, Japan). Contact lenses were cut into stripes and mounted on the outer surface of a quartz cuvette²². The cuvette was placed in the spectrophotometer and the transmittance spectra was obtained at wavelengths ranging from 400nm to 700 nm²¹. The experiment was performed in triplicate.

b) Water content:

Contact lens were removed from the soaking solutions, gently blotted to remove the excess liquid from the surface, and the wet lens weight was recorded. Dried weights were recorded after drying the lenses at room temperature overnight. The experiment was repeated three times, and the following equation was used to calculate the % water content²¹:

Water content (%) = (Weight_wet – Weight_dry) *100 / Weight_wet

c) Lens diameter:

A vernier caliper was used to investigate the lens diameter changes²⁷. The diameter was determined in hydrated state in triplicate.

d) Mechanical properties:

Hydrated lenses were cut into 5 * 16 mm² strips. Tensile test was then carried out in triplicate using a Series IX Automated Materials Testing System (Instron Corp.) with a crosshead speed of 20 mm*min^-1 at room temperature and a relative humidity of 50%²⁸.

RESULTS AND DISCUSSION:

Oleic acid loading into contact lenses:

Fig. 1 shows the oleic acid loadings into commercial lenses for different concentrations of loading solutions. A linear dependency was found between oleic acid loading and concentration of the loading solution²¹. In this study, we explored two different loadings of oleic acid for AIR OPTIX^®. We chose oleic acid soaking concentrations of 35mg/ml and 60 mg/ml for the in vitro release experiments, which correspond to loadings of 14.6% and 24% respectively.

Fig. 1. Correlation of oleic acid loading and concentration of soaking solutions for AIR OPTIX^® lens. The R² of the fitted linear line is 0.9931. Data are presented as mean ± standard deviation (n = 3).

Determination of CRT loading duration for in vitro release experiments:

Pure lenses and 24% oleic acid-loaded lenses were soaked in 15ml of 0.4mg/ml drug-PBS solutions for 1 day and 6 days. After the drug loading step, drug release experiments for 14 days were performed. The total amount of the released drug was found to be the same for both control and modified lenses (P>0.05). (results not shown). Torres-Luna et al. reported that one day of drug loading duration is sufficient to establish cationic drug equilibrium in both control and oleic acid modified lenses²¹. Thus, according to their result and to the result of this study, one day of soaking in drug loading solution is assumed to be sufficient to achieve carteolol hydrochloride – a cationic drug - equilibrium.

In vitro CRT release experiments:

The cumulative CRT release in PBS from lenses incorporated with oleic acid is shown in Fig. 2. As indicated in Fig. 2, the presence of OA significantly increased the amount of released drug at each measured point, and enhanced the total amount of released drug from 70.9±1.9μg for 0% OA to 725.6±40.8μg and 1289.3±26.8μg for 14.6% OA and 24% OA, respectively.

Fig. 2. CRT cumulative release profiles from contact lenses loaded with oleic acid. Data are presented as mean ± standard deviation (n = 3).

The cumulative release % of drug is shown in fig. 3, and calculated by dividing the amount of drug released at a defined time by the total amount of drug released for each lens. From Fig. 3. Oleic acid prolonged drug release from commercial lenses. More than 90% of the loaded CRT released in the first 3 hr, which indicated a rapid drug release. After using 35mg/mL OA- loading solution, the release time (90% drug release) increased by a factor of 12, corresponding to 1.5 days. For 60 mg/mL OA–loading solution, the release time increased by 56 fold, corresponding to 7 days.

Fig. 3. CRT cumulative release % profiles from contact lenses loaded with oleic acid. Data are presented as mean ± standard deviation (n = 3).

In this experiment, a burst release was obtained by all lenses, which can be due to low molecular weight²⁹ and high aqueous solubility³⁰ of CRT. Then, sustained release was achieved due to oleic acid incorporation. However, Oleic acid could significantly reduce the burst release. Using 35mg/mL and 60 mg/mL of OA solution, 69% and 51% of CRT were released in the first 3 hr respectively, whereas 90% was released at the same time in the absence of OA.These results show that oleic acid incorporation increased the drug release duration from AIR OPTIX^® lenses but not as important as from ACUVUE^®OASYS^® and ACUVUE^® TruEye^® lenses in Torres-Luna research work²¹, likely due to the lower AIR OPTIX^® water content (33%) compared with 38% and 46% for ACUVUE^®OASYS^® and ACUVUE^® TruEye^®, respectively, as the higher water content means higher content of aqueous pores and a consequently higher disposition of interfacial oleate ions²¹.

CRT release rate for therapeutic use:

The prescribed dose of Teoptic^® eye drop (1 % w/v solution of carteolol hydrochloride) is 1 drop 2 times daily for glaucoma therapy¹³. Thus, a 25 µL eye drop³¹ administered twice a day would yield 500 μg of CRT per day. Assuming 50% bioavailability for contact lenses¹⁶, and just about 1% or less for eye drops³², the lenses require a release of about 10 μg/day or 0.4 μg/hr. The release rate of CRT is plotted as a function of time in Fig. 4 and compared to the therapeutic level to evaluate the clinical significance of the oleic acid-based contact lenses.

Fig. 4. CRT release rate (μg/hr) from contact lenses loaded with oleic acid. Data are presented as mean ± standard deviation (n = 3). The therapeutic level (green dotted line) is calculated based on an eye drop bioavailability of 1%, contact lens bioavailability of 50%, and 2 eye drops being administered every day.

As shown in Fig. 4, control lenses maintain CRT release rate above the therapeutic level for less than 10 hr. On the other hand, 14.6% and 24% OA-loaded lenses maintain the release rate above the desired therapeutic level for about 3days and 11 days, respectively. AIR OPTIX^® is an approved contact lens for extended wear up to 6 nights only, thus a better clinical significance is expected if an appropriate lower drug loading concentration is used with 24% OA-loaded lenses. Further experiments are needed to confirm this prediction.

Characterization of modified contact lenses:

Transmittance analysis:

Contact lenses are optical devices designed to cover the cornea³³. Therefore, they must be optically transparent. An optical transparency above 90% is acceptable for commercial contact lenses²³. From Fig. 5, All silicone hydrogel lenses exhibit above 90% transmittance in the visible range.

Water content:

The water content of silicone hydrogel lenses is expected to decrease on incorporation of oleic acid due to its hydrophobic nature²¹. Surprisingly, T-test indicates that there is no statistically significant difference (P>0.05) between the water content of loaded lenses compared with the control (Table 2).

Fig. 5. Visible light transmittance of loaded lenses. Data are presented as mean ± standard deviation (n = 3).

Lens diameter:

The diameters of modified commercial lenses were measured in the hydrated state (Table 2). Increasing of oleic acid concentration resulted in statistically significant increases in lens diameter. 4.6%, 8.9% changes were found with 14.6%, 24% oleic acid loaded lenses, respectively. Increases are tolerable by the eye until 7%, where the power of the lens could be maintained³⁴, but in larger cases, listed power of the lens should be adjusted²².

Mechanical analysis:

Mechanical properties are an important consideration when selecting hydrogels for pharmaceutical applications to ensure the integrity of the prepared system³⁵. Tensile modulus of oleic acid loaded lenses decreased with increasing oleic acid content. This can be attributed to the plasticizing effect of the fatty acid, which increases the flexibility of the lens matrix. However, from table 2. all lenses possessed a tensile modulus in the range adequate for extended wear comparable to existing commercial silicone contact lenses (e.g. Acuvue Oasys^® tensile modulus is 0.7 MPa)²⁶.

CONCLUSION:

The use of soft contact lenses for drug delivery represents a potential alternative to topical eye drops. Studies have successfully tested different methods to load lenses with drugs. In this study, CRT binding amount and release time from one type of commercial silicone-based contact lens were improved by using oleic acid. The 90% drug release time was increased from 3 to 36 and 168 hr after soaking in concentrations of 35 and 60 mg/ml oleic acid solution. Changes in visible light transmittance, water content, diameter, tensile modulus for modified lenses were acceptable and no serious effects were found except a change in lens power should be considered with 24% OA-loaded lenses. The outcomes of this study are promising but further experiments are needed to investigate changes in other key parameters of contact lenses such as wettability, ion and oxygen permeability of lenses loaded with fatty acid in addition to in vivo studies and clinical trials which are necessary to evaluate the efficiency of oleic acid in CRT delivery from commercial silicone contact lenses.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 20.07.2021 Modified on 15.08.2021

Research J. Pharm. and Tech. 2022; 15(5):2135-2140.

DOI: 10.52711/0974-360X.2022.00354

	Oleic acid soaking concentration (mg/ml)	Oleic acid loading % (weight of oleic acid/weight of dry lens)	Water content (%) Listed (33%)	Wet Diameter (mm) Listed (14.2mm)	Tensile modulus (MPa) Listed (1.2 MPa)
AIR OPTIX^®	0	0	32.79 ± 0.51	14.17 ± 0.08	1.201 ± 0.08
	35	14.58 ± 0.80	32.32 ± 0.82	14.83 ± 0.06	1.085 ± 0.031
	60	24.03 ± 0.90	32.11 ± 0.68	15.43 ± 0.07	1.069 ± 0.043