INTRODUCTION:

Glaucoma is a group of disease of the eye characterized by damage to the ganglion cells and the optic nerve. Increased intraocular pressure (IOP) remains the most important risk factor for the development of glaucoma¹. Glaucoma is the leading cause of irreversible blindness worldwide (if left untreated) and it is associated with a reduced quality of life².

Beta blockers are beta adrenergic receptor antagonist which reduces IOP. They are classified into two categories i.e. non selective beta blockers (timolol, levobunolol, etc.) and selective beta blockers (betaxolol). After the approval of the first beta blocker for the treatment of intra ocular pressure reduction by US-FDA, timolol became the first choice of the treatment of glaucoma³.

Timolol presumably exerts a direct action on the beta-2 adrenergic receptors in the ciliary processes to decrease aqueous humor secretion⁴. It is used as eye drops for treatment of open-angle glaucoma⁵.

Eye being a unique and complex organ the access of exogenous substances to the ocular tissues are restricted by its physiology and defense mechanism⁶. Thus, the eye is very difficult to study from a drug delivery point of view⁷.

Although most of the conventional formulation already exist in the market like eye drops (90% of ocular drug products), suspensions and ointments which have found wide applications in the therapy for disorders affecting anterior segment of eye. However, these conventional formulations have certain limitations like rapid washout due to tearing, nasolacrimal drainage, nonproductive absorption, low ocular bioavailability, systemic toxicity. Additionally, due to anatomical ocular barrier, only less than 5% of drug is typically bioavailable to the ocular tissues, requiring the frequent administration of drops with high drug concentrations to maintain target drug concentration within the therapeutic window and patient noncompliance⁸^,⁹.

Additionally, eye drops deliver drug to the eye in a high frequency, pulsatile fashion with a peak drug concentration followed by a valley before the next dose is administered the same day or the following day.

Perhaps a better alternative would be continuous drug delivery and the associated sustained suppression of IOP⁷.

So, there is a need for sustained release drug delivery system such as implants, gels, or particles. Of these, implant like systems, commonly referred to as inserts, were previously approved for clinical use⁸.

Ocular inserts was firstly developed in 1975 by 'Alza Corporation, in the United State of America⁷. They are defined as flexible preparations with a solid or semisolid consistency, whose size and shape are especially designed for ophthalmic application (i.e., rods or shields). These inserts are placed in the lower fornix and, less frequently, in the upper fornix or on the cornea. They are usually composed of a polymeric vehicle containing the drug and are mainly used for topical therapy¹⁰.

Ocular inserts have been developed in which the drug is delivered on the basis of diffusion mechanism. Such a solid dosage form delivers an ophthalmic drug at near constant rate, minimizing side effect by avoiding absorption peaks⁷.

Besides sustained release, other potential advantages of the controlled release delivery systems over conventional ophthalmic dosage forms are: reduced total dose and lower or slower systemic exposure, which reduces the risk of systemic side effects⁸, increased ocular contact time and thus improved drug bioavailability, administration of an accurate dose in the eye gives better therapy, better patient compliance by reduction of the number of administered dose, increased possibility of internal ocular tissue targeting, increased shelf life with respect to standard formulation due to the absence of water⁷.

Ophthalmic inserts are classified based upon their solubility behavior into: insoluble (reservoir systems and matrix systems), soluble (based on natural or synthetic polymers) and bio-erodible (such as SODI and collagen shields)¹¹.

Nowadays, ocuserts of different ophthalmic drugs are available in market such as antibiotics, non-steroidal anti-inflammatory and beta blockers⁷.

MATERIALS AND METHODS:

Materials:

Timolol maleate (TM) was supplied by Gangwal Chemicals Pvt. Ltd., India, Methylcellulose was supplied by Otto Chemie Pvt. Ltd., India, Hydroxypropyl methylcellulose 15000 was supplied by Nellu medicare, New delhi, Eudragit RL100 was supplied by EVONIK, Germany, Polyvinyl pyrrolidone k90 was supplied by BASF, Germany, Ethyl cellulose was supplied by Sigma-Aldrich, Germany, Polyvinyl pyrrolidone k30 was supplied by S. D. Fine Chemicals, India.

Methods:

Spectrophotometric analysis:

a) Determination of lambda max of Timolol maleate:

A solution containing 10μg/ml of drug in phosphate buffer (pH 7.4) was prepared and scanned over the wavelength range of 250nm to 400nm against phosphate buffer as a blank using double beam UV spectrophotometer. The plot of absorbance vs. wavelength was recorded¹².

b) Calibration Curve for Timolol maleate:

100mg of Timolol maleate was accurately weighed and was dissolved in 100ml of phosphate buffer (pH 7.4) to generate a stock solution having concentration of 1mg/ml. Stock solution (5ml) was further diluted to 100 ml to produce standard solution having concentration of 50μg/ml. The standard solution was serially diluted with phosphate buffer (pH 7.4) to get working standard solutions having concentration of 10, 20, 30, 40, 50 μg/ml. The absorbance of the solutions was measured at 294nm using UV visible spectrophotometer against phosphate buffer (pH 7.4) as a blank. The plot of absorbance vs. concentration (μg/ml) was plotted and data was subjected to linear regression analysis in Microsoft Excel¹³.

Preparation of ocular inserts (films):

The ocular inserts were prepared by solvent casting method¹⁰with (Timolol maleate) as the active pharmaceutical ingredient.

Initially, accurately weighed amount of the film forming agent (polymer) was taken and dispersed in known quantity of solvent and this was stirred using a magnetic stirrer at 300rpm for about 30 minutes at room temperature for uniform dispersion. Following that, the employed plasticizer (Glycerin, PEG 400 or Dibutyl phthalate) and Timolol maleate amounts were carefully added into the viscous solution and stirred at 300rpm for about 10 minutes. Then the mixture was put in a water-bath sonicator until getting rid of all air bubbles. The resultant clear solution was poured in a suitable dish previously lubricated. A glass funnel with a cotton plug closed into its stem was placed in an inverted manner over the dish to ensure uniform evaporation of solvent. The whole arrangement was located inside a hot air oven adjusted at 60 ± 2°C for 24-48 h to facilitate evaporation of the solvent slowly. After that, the dried films were removed and cut into sections of medicated films¹⁴^,¹⁵ Table (1).

Evaluation of ocular inserts:

The prepared ocular inserts were evaluated for the following parameters as described below.

a) Physical appearance:

All the ocular inserts were visually observed for color, clarity and smoothness of its surface by visual inspection¹³^,¹⁶.

b) Weight variation:

As weight variation between the formulated films can lead to difference in drug content and in vitro behavior, a study was carried out using an electronic balance by weighing 5 films from each formula. The mean value was calculated, and the standard deviations of weight variation were computed from the mean value¹⁷^,¹⁸.

c) Thickness:

Thickness of the film is an important factor while considering its drug release from ocular delivery systems. If thickness varies from one film to another, the drug's release from the film also varies. So, it is must to keep the thickness of the film uniform to get reproducible results¹⁹. The films were evaluated for the thickness using a digital thickness meter (digiNax^®). The thickness was measured at five different places and the mean value was calculated as well as the standard deviation²⁰.

d) Surface pH:

Surface pH of the prepared formulas was detected using a calibrated pH meter by allowing them to swell in a closed petri dish at room temperature for 30 min in 0.1 mL of distilled water. The tip of pH meter was gently placed over the swollen devices and the surface pH was determined¹³^,²¹.

e) Folding endurance:

The folding endurance is expressed as the no of folds (number of times the insert is folded at same place) either to break specimen or to develop visible cracks. This test is important to check the efficiency of the plasticizer, the strength of the patch (prepared using varying ratios of the polymers) and the ability of sample to withstand folding. This can also give an indication of brittleness. The specimen was folded in center, between the fingers and thumbs and then opened. This was termed as 1 folding. This process was repeated till the insert showed breakage and cracks in center of insert. The total folding operation was named as folding endurance value¹⁸^,²².

f) Percentage moisture absorption:

The percentage moisture absorption test was carried out to check physical stability or integrity of the inserts maintaining high humidity²³. Three inserts were weighed individually from each batch and placed in desiccators, which maintained high relative humidity (RH) at about 75±5% RH using an excess amount of salt in solution. After 3 d the inserts were taken out and reweighed. The percentage moisture absorption was calculated using this equation:

Percentage moisture absorption =

(final weight – final weight) × 100/initial weight

g) Percentage moisture loss:

The percentage moisture loss was carried out to check integrity of the film at dry condition. Three inserts from each formula were taken for the study. Inserts were weighed individually and kept in a desiccator containing anhydrous calcium chloride. After 3 d, the inserts were taken out and reweighed. The percentage moisture loss was calculated using this equation:

Percentage moisture loss =

(initial weight – final weight) × 100/initial weight²⁴

h) Drug content uniformity:

Medicated ocular inserts were dissolved individually in 10ml of the solvent of choice for 24h under occasional shaking. Then required volume of solution was taken out and filtered through filter paper and further dilutions were made with phosphate buffer (pH 7.4).

The drug content was determined at 294nm using a UV spectrophotometer against blank solution which was prepared by dissolving a placebo insert in the same solvent and the same volume used with medicated insert to prevent polymer or plasticizer interference. Drug content was determined using slope of standard curve. This experiment was repeated to three inserts of each formula and the results were obtained¹⁵^,²⁵^,²⁶^,²⁷.

i) In-vitro drug release study:

No official method was reported to resemble the eye to study the in-vitro release of drug from the ocular inserts, a simple method was used to differentiate between the release patterns of the prepared inserts. A modified Franz diffusion cell with a donor compartment and receptor compartment was fabricated to study the in-vitro Timolol maleate release profile from the ocular inserts under investigation.

For this study, the inserts (1.77 cm²) were stuck to a diffusion membrane (prehydrated by soaking in phosphate buffer pH 7.4, for 24 h). The diffusion membrane simulates the corneal epithelium and its entire surface was in contact with the receptor compartment [comprising 12ml of phosphate buffer (pH 7.4) placed in a water bath]. The content of receptor compartment was shaken continuously using a magnetic stirrer at constant temperature (37±2°C). At definite time intervals, 2ml of the receptor fluid was withdrawn from the receptor compartment and immediately replaced with fresh phosphate buffer (pH 7.4) solution to maintain constant volume. To determine the percentage of drug released, the removed fluid was analyzed using UV spectrophotometer at wavelength 294nm for the drug content after appropriate dilutions against phosphate buffer (pH 7.4) as blank and concentration was observed from Timolol maleate calibration curve¹⁵^,²⁸.

j) Mechanism and kinetics of drug release from ocular inserts:

To determine the mechanism of drug release from these formulas, the data were treated cumulatively % of the drug released vs. time represented zero order, log cumulative % of drug remaining vs. time represented First order, cumulative % of the drug released vs. Square root of time representing Highuchi model and finally, representing Korsmeyer-Peppas model by plotting log cumulative % of drug released vs. log time by using special computer program¹⁵.

k) Drug-polymer interaction:

FTIR:

Fourier Transform Infrared Spectroscopy (FTIR) was used to assess any potential interactions between the drug and polymers using (ALPHA BRUKER^®)²⁹.

The procedure consisted of placing a sample (drug alone, each polymer by itself and mixtures of drug with polymers) in light path and spectrum was recorded over a frequency range of 4000–500 cm^–1³⁰.

RESULTS AND DISCUSSION:

Spectrophotometric analysis:

Figure 1. Lambda max of Timolol maleate

Figure 2. Calibration graph for Timolol maleate in phosphate buffer (pH 7.4)

Figure (1) shows the estimated λ max of Timolol maleate in phosphate buffer (pH= 7.4) which is 294 nm and that's agreed with the reported values.

Figure (2) shows the calibration curve within the involved media which indicates a good linearity with a correlation coefficient of 0.9991.

Evaluation of the ocular inserts:

Table 2. Results of physical appearance test of prepared ocular inserts:

Formula code	physical appearance
F1	Sticky and breakable. This composition was observed unsuitable for the formulation of desired film
F2	Good appearance; transparent, thin and flexible with smooth surface. This concentration was further used for formulation
F3	Good appearance; transparent and flexible with a smooth and glossy surface. These concentrations were further used for formulation
F4
F5	Good appearance; transparent, thin and flexible with a glossy and smooth surface. This concentration was further used for formulation
F6	Good appearance; semi-transparent, thin and flexible with a smooth surface. These concentrations were further used for formulation
F7
F8

Table (2) shows the results of evaluating the physical appearance of the prepared films, the films were described and evaluated in term of color, transparency, continuity, and surface smoothness.

Most prepared ocular inserts had a good appearance with smooth, transparent or semi-transparent, with uniform surface.

Breaking and cracking of film surface occur in formula (F1) could be due to unsuitable plasticizer percentage or unsuitable temperature/duration of drying. Hence, this batch was discarded and remaining batches (F2 to F8) were considered for further study.

Table 3. Evaluation of Timolol maleate loaded ocular inserts:

Formula code	(mg)Weight	Thickness (mm)	Surface pH	Folding endurance
F2	1.262 ± 0.031	0.140 ± 0.055	5.020 ± 0.092	≥150
F3	12.940 ± 0.785	0.440 ± 0.055	4.850 ± 0.991	≥150
F4	15.426 ± 0.324	0.720 ± 0.110	5.157 ± 0.456	≥150
F5	14.124 ± 0.884	0.250 ± 0.071	4.933 ± 0.370	≥150
F6	6.818 ± 0.457	0.220 ± 0.142	5.347 ± 0.050	≥150
F7	6.825 ± 0.686	0.300 ± 0.071	5.067 ± 0.115	≥150
F8	7.738 ± 0.981	0.440 ± 0.035	4.899 ± 0.123	≥150

Table 3. Contd.

Formula code	Moisture absorption (%)	Moisture loss (%)	Drug content (%)
F2	13.484 ± 0.906	11.159 ± 0.389	91.065 ± 0.491
F3	3.667 ± 0.752	5.791 ± 0.912	100.217 ± 0.960
F4	5.491 ± 0.221	5.023 ± 0.102	94.542 ± 0.777
F5	9.665 ± 0.152	8.096 ± 0.284	93.312 ± 0.307
F6	3.027 ± 0.370	1.691 ± 0.215	93.204 ± 0.020
F7	4.917 ± 0.817	2.199 ± 0.337	95.485 ± 0.335
F8	5.221 ± 0.252	2.786 ± 0.114	92.873 ± 0.930

(Presented values: Mean ± Standard deviation "SD")

Table (3) shows the results of physical tests for the prepared films.

The average weight of ocuserts range from 1.262±0.031 mg (F2) to 15.426±0.324mg (F4). It was found to have a good weight uniformity in all formulas indicating an even distribution of drug in the polymer matrix prepared by solvent casting technique.

The mean thickness and standard deviation were calculated. The low standard deviation of all formulations indicates uniform thickness of the prepared films. Thickness was found to be in the range of 0.140± 0.055mm (F2) to 0.720±0.110mm (F4).

It was found that the inserts' weight and thickness have increased by increasing the total polymer concentration.

the surface pH of the prepared ocuserts were found to be between 4.850±0.991 to 5.347±0.050. The results showed that nearly all formulations were slightly acidic. This could be attributed to the presence of Timolol maleate.

Generally, ophthalmic formulations must be in the pH range between 4.5 and 11.5²⁷. According to this range the ocuserts were not showing irritation potential and safe to be used in the eye.

The recorded folding endurance was ≥ 150. This indicates the flexibility of the prepared films and confirmed the usage of suitable plasticizers and in appropriate quantities to give it the required strength.

The percentage moisture absorption was calculated for all formulas and the mean of three replicates. According to the results obtained, formula (F2) showed maximum moisture absorption 13.484±0.906%, this may be due to that both polymers (MC and HPMC) and plasticizer (Glycerin) are hydrophilic in nature and expected to absorb water. All other formulations which contain hydrophobic polymers (ERL 100 or EC) had lower moisture absorption.

The percentage moisture content was high (˃ 10%) in the case of hydrophilic polymers (HPMC and MC), while it was low in the hydrophobic formulas (which contain ERL 100 or EC).

The moisture content was found to increase slightly with increasing concentration of the hydrophilic polymer PVP in the films (F6, F7 and F8).

The moisture present in the matrix aided in preventing drying and brittleness of the films.

The low moisture uptake protects the films from bacterial contamination, and the low moisture content preserves them from absolute drying out.

Good drug content uniformity among the batches was observed for all the formulations (91.065%-100.217%) indicating that the drug was homogenously dispersed in the matrix films.

In-vitro drug release studies from Timolol maleate ocuserts in phosphate buffer (pH 7.4), were carried out in triplicate. For different time interval samples were withdrawn and cumulative percentage drug release was calculated.

Formula (F2) gave burst effect, which is a rapid release of the drug substance from the matrix (more than 90% in about 60 minutes), so it doesn't meet the goal of our study. This effect may be attributed to the fact that the polymers in it are hydrophilic, so when they come into contact with the receptor fluid, they will absorb a large amount of water, which leads to the hydration of the polymer and the rapid dissolution of the drug molecules.

Figure 3. In-vitro drug release profile of Timolol maleate from the formulas F3, F3, and F5 (n=3)

Figure 4. In-vitro drug release profile of Timolol maleate from the formulas F6, F7, and F8 (n=3)

Figure (3) and Figure (4) show plot of cumulative percentage drug release as a function of time for all the six (F3 to F8) formulas of TM ocular inserts.

Formulas F3 and F4 released (96.8%) and (95.33%) within 6 h and 8 h, respectively. Therefore, the increase of hydrophobic polymer concentration leads to a delay in the release of the drug due to the obstruction formed by the polymer to the drug's molecules.

Formula F5 shows a maximum cumulative percentage drug release (98.37%) at the end of 6 h, Thus, this formula gave a similar release to formula F3 despite it contains a hydrophilic polymer (PVP k90), this may be due to the high molecular weight of PVP k90, which gave high viscosity that delayed the release of the drug.

By comparing the release profile of formulas F6 and F7, we noticed that formula F7 gave a higher percentage of release, due to the increase in the concentration of PVP k30, which attracts water to the matrix and forms pores, which facilitates the release of the drug into the dissolution medium.

As for formula (F8), despite the increase in PVP k30 concentration, a decrease in the released amount of the drug was observed at all time intervals - even lower than F6 - and the reason for this is that this large increase in polymer concentration resulted in leads to an increase in tortuosity, i.e. an increase in the length of the diffusion path (compared to the straight distance between the two ends of the flow), which leads to a decrease in the release of the drug, as the distance that molecules must travel within this three-dimensional network is inversely proportional to the speed of diffusion, and as the polymer is a dynamic structure, so increasing its concentration significantly leads to an increase in the interactions between its molecules, thus increasing the viscosity of the polymer matrix and decreasing the release of the drug.

In general, formulas containing Ethyl cellulose gave a very slow release (<30% at the end of 24 hours) due to the extreme hydrophobicity of EC.

Table 4. Correlation Coefficients and release components derived from four different kinetic models:

Formula	Zero order	First order	Higuchi	Korsmeyer-Peppas		Mechanism of drug release
Formula	R²	R²	R²	R²	n	Mechanism of drug release
F3	0.934	0.973	0.988	0.994	0.186	Diffusion
F4	0.851	0.989	0.953	0.992	0.211
F5	0.847	0.739	0.821	0.839	0.258
F6	0.954	0.965	0.986	0.951	0.277
F7	0.945	0.96	0.975	0.932	0.31
F8	0.686	0.701	0.889	0.926	0.649	Diffusion and erosion

Table (4) shows the value of correlation coefficient (R²) for the release models of zero order, first order, Higuchi and Korsmeyer-Peppas.

Formulas (F3, F4 and F8) gave a release from Korsmeyer-Peppas model, formula (F5) gave a release from Zero order model, and formulas (F6 and F7) gave a release from Higuchi model, where the values of the correlation coefficient (R²) were the highest.

The value of the exponential coefficient (n) was calculated, it was less than 0.45 (F3 to F7), this indicates that the release follows Fickian diffusion's first law, meaning that the mechanism of diffusion controls the release of the drug through the used polymers.

While it was between 0.45-0.89 (F8), this indicates so release does not follow Fick's law. Anomalous (Non-Fickian) diffusion, that is, the drug is delivered in a controlled manner by the mechanisms of diffusion and erosion.

The results of the drug compatibility studies revealed that there were no major differences in the IR spectra of pure drug and its physical mixtures with the used polymers, indicating that there were no chemical interactions between the drug and excipients in the ocular inserts.

Figure 5. FTIR spctra of pure Timolol maleate and it physical mixtures with polymers (a), (b), (c) and (d)

CONCLUSION:

1. In the present study an attempt was made to develop various batches of Timolol maleate ocuserts by using the solvent casting method.

2. The formulation of Timolol maleate loaded ocuserts were prepared with the objectives of increase contact time, prolonged drug release, decreased dose frequency and administration, improving therapeutic efficacy and thus may enhancing patient compliance.

3. Hydrophilic and hydrophobic polymers such as MC, HPMC, ERL100, PVP k90, PVP k30 and Ethyl cellulose were used as film forming agents.

4. Glycerin, PEG 400 and Dibutyl phthalate were used as plasticizers.

5. Eight different ocular inserts were prepared and evaluated for their physio-chemical properties.

6. Polymers were easily dissolved in solvents, then the drug was added with continuous stirring to get a uniform distribution of drug within the matrix.

7. Plasticizers were used in different ratios (20-30% w/w) of polymer weight to obtain ocuserts with suitable flexibility.

8. MC formula (F1) needs further modifications in order to obtain a film with acceptable physical specifications.

9. All results showed that (F2 to F8) ocuserts are compatible with the eye and does not produce any inflammation or redness in the eye.

10. Formula (F2) gave burst effect, which may be due to the hydrophobicity of polymers in it (MC and HPMC).

11. The other formulas (F3-F8) gave sustained release.

12. In the FTIR analysis, there were no apparent chemical interactions between the drug and the excipients.

REFERENCES:

1. Darwhekar G, et al. Development and Optimization of Dorzolamide Hydrochloride and Timolol Maleate in Situ Gel for Glaucoma Treatment. Asian J. of Pharm. Ana. 2011 Oct-Dec 1(4):93-97.

2. Allison K, et al. Epidemiology of Glaucoma: The Past, Present, and Predictions for the Future. Cureus. 2020 12(11). doi:10.7759/cureus.11686

3. Yadav KS, et al. Glaucoma: Current treatment and impact of advanced drug delivery systems. Life Sci. 2019 Feb 221:362-376. doi:10.1016/j.lfs.2019.02.029

4. Venkateswaran J, Venkataraman S. Pre-formulation study on API characterization of Brimonidine Tartrate, Timolol maleate and Dorzolamide Hydrochloride in Anti-glaucoma drugs. Research Journal of Pharmaceutical, Biological and Chemical Sciences. 2017 Jul-Aug 8(4):920-932.

5. Mandour AA, et al. Review on analytical studies of some pharmaceutical compounds containing heterocyclic rings: brinzolamide, timolol maleate, flumethasone pivalate, and clioquinol. Futur J Pharm Sci. 2020 6(1). doi:10.1186/s43094-020-00068-4

6. Mythili L, et al. Ocular Drug Delivery System – An Update Review. Research J. Pharm. and Tech. 2019 May 12(5). doi:10.5958/0974-360X.2019.00426.8

7. Parveen N, Joshi H. Ocuserts: A Novel Formulation Approach in Drug Delivery System. Saudi J Med Pharm Sci. 2020 4929:420-425. doi:10.36348/sjmps.2020.v06i05.005

8. Kompella UB, et al. Extraocular, periocular, and intraocular routes for sustained drug delivery for glaucoma. Progress in Retinal Eye Research. 2021 Sep 82. doi:10.1016/j.preteyeres.2020.100901

9. Suresh PK, et al. Ocular implants as drug delivery device in opthalmic therapeutics: An overview. Research J. Pharm. and Tech. 2014 Jun 7(6):665-676.

10. Kumar N, Sharma S. Design, formulation and evaluation of sustained ophthalmic delivery of ciprofloxacin from ocular inserts. Research J. Pharm. and Tech. 2013 6(3):285-286.

11. Beena K. Ocular drug delivery system: Approaches to improve ocular bioavailability. GSC Biological and Pharmaceutical Sciences. 2019 6(3):1-10.

12. Rathore KS, et al. Preparation and Characterization of Timolol Maleate Ocular Films. Int. J. PharmTech Res. 2010 2(3):1995-2000.

13. Nair RV, et al. Ocular insert of Timolol Maleate using naturally occurring biodegradable polymer. J. Chem. Pharm. Res. 2015 7(7):476-485.

14. Girish PK, Sreenivasa RM. Formulation and evaluation of extended release ocular inserts prepared from synthetic and natural biodegradable - biocompatible polymers. Research J. Pharm. and Tech. 2014 Jan 7(1):48-51.

15. Dawaba HM, Dawaba AM. Development and evaluation of extended release ciprofloxacin HCl ocular inserts employing natural and synthetic film forming agents. J Pharm Investig. 2018 Jun. doi:10.1007/s40005-018-0400-x

16. Jagdale S, et al. Optimization of Thermoreversible in Situ Nasal Gel of Timolol Maleate. Scientifica 2016. doi:10.1155/2016/6401267

17. Karthikeyan D, et al. Design and Evaluation of Ofloxacin Extended Release Ocular Inserts For Once a Day Therapy. Research J. Pharm. and Tech. 2008 Oct-Dec 1(4):460-468.

18. Dhaka M, et al. Preparation and assessment of ocular inserts containing sulbactum for controlled drug delivery. Journal of Drug Delivery & Therapeutics. 2020 10(1):66-71.

19. Mujoriya RZ, Kshirsagar MD. Evaluation Study of Sustained Release Ocular Insert of Brimonidine Tartrate and Timolol. Res. J. Pharm. Dosage Form. & Tech. 2016 Oct-Dec 8(4)1-6.

20. Karthikeyan D, et al. Development and Characterization of Modified Ocular Inserts with Improved Ocular Compatibility. Research J. Pharm. and Tech. 2008 Apr-Jun 1(2):93-99.

21. Al-Juboori ZA, et al. Formulation and evaluation of ocular in-situ gelling system containing ciprofloxacin and naproxen sodium. Research J. Pharm. and Tech. 2021 14(1):91-95. doi:10.5958/0974-360X.2021.00017.2

22. Shivhare UD. Effect of Combination of Hydrophilic an Hydrophobic Polymers on Trandermal Drug Delivery Systems Properties. Res. J. Pharm. Dosage Form. & Tech. 2011 3(5):203-209.

23. Gajanan GV, et al. Methods for Evaluation of Ocular Insert with Classification and Uses in Various Eye Diseases - A Review. Asian J. Pharm. Tech. 2017 7(4):261-267. doi: 10.5958/2231-5713.2017.00038.1

24. Gorle AP, Gattani SG. Design and Evaluation of Polymeric Ocular Drug Delivery System. Chem. Pharm. Bull. 2009 57(9):914-919.

25. Valarmathi S, et al. In Vivo studies of Ophthalmic Ocular Insert Containing Aciclovir. Research J. Pharm. and Tech. 2017 10(7):2139-2142. doi: 10.5958/0974-360X.2017.00376.6

26. Mohabe V, et al. Preparation and evaluation of captopril transdermal patches. Bull Pharm Res. 2011 1(2):47-52.

27. Shafie A, Rady H. In vitro and In vivo Evaluation of Timolol Maleate Ocular Inserts Using Different Polymers. J Clin Exp Ophthalmo. 2012 3(8). doi:10.4172/2155-9570.1000246

28. Al-Samman HB, Al-Laham A. Transdermal drug delivery system of sodium cromoglycate. Int. J. Pharm. Sci. Rev. Res. 2016 36(2):1-7.

29. Mehta P, et al. Development and characterisation of electrospun timolol maleate-loaded polymeric contact lens coatings containing various permeation enhancers. International Journal of Pharmaceutics. 2017 532(1):408-420. doi:10.1016/j.ijpharm.2017.09.029

30. Thakkar V, et al. Formulation and in Vitro - in Vivo Evaluations of Timolol Maleate Viscous Eye Drops for the Treatment of Glaucoma. Eur J Biomed Pharmaceu. 2016 Sep 3(9):573-585.

Received on 14.06.2022 Modified on 18.07.2022

Research J. Pharm. and Tech 2023; 16(3):1259-1266.

DOI: 10.52711/0974-360X.2023.00208

Formula code*	MC (mg)	HPMC 15000 (mg)	ERL 100 (mg)	PVP k90 (mg)	EC (mg)	PVP k30 (mg)	Plasticizer	Solvent
								(10 ml)
F1	100	-	-	-	-	-	Glycerin (20%)	D.W
F2	50	50	-	-	-	-	PEG 400 (30%)	D.W
F3	-	-	500	-	-	-	PEG 400 (30%)	Isopropanol:
								Dichloromethane
								60:40:00
F4	-	-	1000	-	-	-	PEG 400 (30%)	Isopropanol:
								Dichloromethane
								60:40:00
F5	-	-	300	50	-	-	PEG 400 (20%)	Isopropanol:
								Ethanol 95%
								50:50:00
F6	-	-	-	-	300	50	Dibutyl Phthalate (30%)	Chloroform
F7	-	-	-	-	300	100	Dibutyl Phthalate (30%)	Chloroform
F8	-	-	-	-	300	200	Dibutyl Phthalate (30%)	Chloroform