INTRODUCTION:

Indomethacin is a non-steroid anti-inflammatory drug (NSAID) that blocks prostaglandin biosynthesis by inhibiting cyclooxygenase. Indomethacin is used in ocular drug delivery system for the prevention of uveitis, cystoid macular oedema and other ocular inflammatory conditions and prevention of surgically induced miosis. It has a plasma half life of 2-5 hours.

Topical application of ophthalmically active drugs is the most prescribed route of administration for treatment of various ocular disorders. It is generally agreed that the intraocular bioavailability of topically applied drugs is extremely poor. This is mainly due to drainage of excess fluid by the nasolacrimal duct as well as dilution and elimination of the solution by tear turnover. Ocular bioavailability of drugs is an important parameter influencing the efficacy of ophthalmic preparation^1-3.

Several approaches have been reported and numerous novel ophthalmic drug delivery systems were developed to achieve a higher bioavailability. of drugs. Among these formulations are in situ gel polymers,^4-7 microspheres,^8-12 nanoparticles,^13-16 Liposomes,^17-20 and ocular inserts.^21-25 The advantages of ocular inserts, which are solid devices placed in cul-de-sac of eye, in comparison with liquid formulation are numerous. Because of the prolonged retention of the device and a controlled release, the effective drug concentration in the eye can be ensured over an extended time period. Dosing of the drugs is also more accurate and the risk of systemic side-effects is decreased. Furthermore, solid devices have an increased shelf life and the presence of additives such as preservatives is not required. Nevertheless, despite all these advantages one major drawback of these solid devices that they may cause irritation in the eye due to the film thickness. The modified ocular insert of Indomethacin were prepared with the major objective of reducing the thickness of ocular insert by formulating this ocular insert as a single film instead of tri film (two rate controlling film around the single drug reservoir film).^{26, 27} It has been observed that due to its lesser thickness, this modified insert is better retained in the cul-de-sac of the eye because retention of ocular insert is a function of size and shape.

MATERIAL AND METHODS:

Materials:

Indomethacin was generously gifted by Jagsonpal Pharmaceutical Ltd., Delhi, India. Eudragit RS 100 was purchased from Rohm Pharma, Germany. Ethyl cellulose and Dibutyl phthalate were obtained from Loba Chemie Pvt. Ltd. Mumbai, India. Anhydrous calcium chloride, Sodium hydroxide and Potassium dihydrogen ortho phosphate were procured from S.d. fine chemicals. Ltd, Mumbai, India. Dichloromethane was obtained from Merck Pvt Ltd, Mumbai, India. The microbiological media was purchased from Hi-media, Mumbai, India. All the reagents used were of analytical grade.

Methods:

Fabrication of modified ocular insert:

The modified ocular insert was prepared by solvent casting method.^{26, 27} In this method the polymers Ethyl cellulose and Eudragit RS 100 were dissolved in dichloromethane by continuous stirring and calculated quantity of Indomethacin was incorporated into it (Table -1), followed by further stirring and then sonicating for 30 seconds in a bath sonicator.²⁷ The above solution was stirred at 500 rpm for 5 minutes and during stirring 30% of plasticizer (dibutyl phthalate) was added. The resultant homogenous solution was casted on leveled glass moulds. The solvent was allowed to evaporate for 3 hours at room temperature. Afterwards the films were removed and elliptical inserts of 0.5 cm² were punched out with a sharp punch, wrapped in a aluminium foil and stored in amber colored glass vials in a desiccator till further use.

TABLE-1: COMPOSITION OF MODIFIED OCULAR INSERTS

Formulation code	Drug (mg)	Polymer( %)		Plasticizer (%w/w)
Formulation code	Drug (mg)	Ethyl cellulose	Eutragit RS 100	Dibutyl phthalate
F1	76.8	4.0	-	30
F2	76.8	5.0	-	30
F3	76.8	6.0	-	30
F4	76.8	4.0	0.5	30
F5	76.8	4.0	1.0	30
F6	76.8	4.0	1.5	30
F7	76.8	4.0	2.0	30
F8	76.8	4.0	2.5	30

Characterization of Fabricated Inserts:

Interaction studies

Interaction studies were conducted on the formulation F7 by comparing it with the pure drug on the basis of ATR-FTIR and FT-IR.

The FT-IR spectrum of pure Indomethacin and Physical mixture of Indomethacin, ERS and EC were analyzed for compatibility study.

ATR-FTIR was used for interaction studies by comparing the formulation F7 with the pure drug. Attenuated total reflectance (ATR) is a sampling technique used in conjunction with IR which enables ocular insert to be examined directly without further preparation (in contrast to KBr method).^28,29 The ATR-FTIR and FT-IR absorption spectra of the pure drug and medicated ocular insert were taken in the range of 400-4000 cm^-1.

Physico-chemical Parameters

The modified ocular inserts of Indomethacin were evaluated for physico-chemical parameters such as thickness, weight variation, percentage elongation at break, tensile strength and moisture vapor transmission. The above films were evaluated for the thickness using a Digimatic caliper with a sensitivity 0.01 mm. The thickness was measured at five different places and the mean value was calculated.^30-31

The inserts were subjected to weight variation by individual weighing of 5 randomly selected inserts and mean was calculated.^30,
31

Pulley based tensile strength apparatus fabricated in the laboratory was used to measure the percentage of elongation at break and tensile strength of films.³²

Percent elongation at break = 100 ×(I_b– I₀)/ I₀

Tensile strength = break force. (1 + ΔL/L)/( a.b)

where I₀is original length of film, I_bis length of film at break when stress was applied, a is width of the film, b is thickness of the film, L is length of the film, ΔL is elongation at break and break force is the weight required to break the film. Quantity of moisture transmitted through unit area of film in unit time is defined as Moisture vapor transmission (MVT). Glass cells were filled with 2g of anhydrous calcium chloride and a film of specified area (0.50 cm²) was affixed on the rim of cell. The assembly was accurately weighed and placed in a humidity chamber (80±5% RH) at 25±2^oC for 24 h. The glass cells were weighed at intervals times and MVT was calculated.³⁰

Drug content uniformity- The inserts were weighed individually and dissolved in 50 ml of 0.2 M phosphate buffer pH 7.4 by stirring for 6 h. The solution was then filtered through G2 glass filter and an aliquot of the filtrate was diluted suitably and analyzed spectrophotometrically (Elico SL 164, Mumbai.) at 319.5 nm for Indomethacin content.²⁷

Sterility testing

The ocular inserts were sterilized by UV radiation and direct inoculation method was used to test sterility of ocular inserts.³³ The sterilized ocular insert was placed aseptically in a culture tube containing 10 ml of sterile Soya bean-casein digest media. The mouth of the tube was closed tightly with a cotton plug, which was wrapped with aluminum foil. It was incubated at 25±2°C for 7 days. The tubes were examined visually for sign of any microbial growth during the incubation period. Positive and negative controls were also employed in order to support the test.

Five film units of each formulation were dissolved in 10 ml of Alternate Thioglycolate fluid (ATF) of pH 7.4 in separate volumetric flasks. The resulting solutions were filtered through a 0.45μ membrane, diluted suitably and analyzed for indomethacin spectro-photometrically at 319.5 nm.

In vitro release study

The in vitro release studies were carried out using bi-chambered donar-receptor compartment model using commercial semi-permeable membrane. Membrane was tied at one end of the open - end cylinder which is acted as the donar compartment containing 0.7ml of pH 7.4 isotonic phosphate buffer. This membrane was used to simulate ocular in vivo conditions like corneal epithelial barrier. The surface of the membrane is in contact with receptor compartment, which contain 25ml of pH 7.4 isotonic phosphate buffer and stirred continuously using a magnetic stirrer. Samples were withdrawn from the receptor compartment at periodic intervals and replaced with equal volume of pH 7.4 isotonic phosphate buffer. The drug content was analysed in UV Spectrophotometer at 319.5 nm against reference standard using phosphate buffer pH 7.4 as blank.³⁴

Ocular irritation test:

Draize technique was employed to perform the ocular irritation test. Assessment of ocular irritation potential of ophthalmic formulations is an extremely important

step in the development of any ophthalmic formulation. The test has been standardized at the international level. e.g. using the OECD guideline no. 405. ‘Acute eye irritation and corrosion’ is the most widely used test for classifying and labeling chemicals according to their ocular safety. Formulation was tested on six rabbits by placing the inserts in the cul-de-sac of the left eye. The sterile preparations were placed once a day for a period of 21 days and the potential ocular irritation and/ or damaging effects of the ocuserts under test were evaluated by observing them for any redness, inflammation and/or increased tear production.³⁵

In vivo release study:

The in vivo study was performed on male albino rabbits (n=5), weighing 2.5-3.0 kg and about 10-12 weeks old. They were housed in cages in animal house under controlled conditions of temperature (27±2^oC) and light. They were fed with standard laboratory diet; and water was provided ad libitum. They were treated as prescribed in the publication ‘Guide for the care and use of laboratory animals’ (NIH Publication No. 92-93, revised 1985). Ethical clearance for the handling of experimental animals was obtained from the institutional animal ethical committee (IAEC) constituted for the purpose. All experiments were carried out under veterinary supervision.

Un-anesthetized rabbits were kept in a prone position on a wooden plate with no restriction of head or eye movement. The ophthalmic inserts (F₇) were carefully placed in the cul-de-sac of the right eye and similarly a blank film was placed in the left eye to serve as control. Utmost care was taken during placing the ocular insert in the eye so that the sensitive tissues of the eye do not get damaged. An attempt was made to collect the tear fluid of rabbit’s eye but the modified ocular insert having a single film do not cause any irritation in the rabbit’s eye so there is no expulsion of tear fluid hence it was not possible to analyse the drug in the tear fluid. Instead at regular time intervals, the ocular inserts were removed carefully at 2, 4, 6, 8, 12 and 24 hours and analyzed for the residual drug content spectrophotometrically at 319.5 nm.. The drug content obtained was subtracted from the initial drug content in the ocular inserts, to give the amount of drug released in the rabbit’s eye.^{36, 37}

FIGURE-1. ATR-FTIR OF INDOMETHACIN

FIGURE-2. ATR-FTIR OF MODIFIED OCULAR INSERT

FIGURE -3. FT-IR OF INDOMETHACIN

Kinetic Analysis

The in vitro and in vivo data were analyzed by a zero order kinetics equation as well as Higuchi’s and Korsmeyer-Peppa’s equation to understand the release profile and release mechanism. When a graph of the cumulative percentage of the drug released from the matrix against time is plotted, zero order release is linear, indicating that the release rate is independent of concentration. The rate of release of the drug can be described mathematically as follows:

Rate of release = (dC_s/t) = k

Where, C_s = concentration of the drug present in the matrix, k = rate constant and t = time. Since C_s is a constant, and x = amount of drug released described as dx/dt = k, integration of the equation yields x = kt + constant. A plot of x versus t results in a straight line with the slope = k. The value of k indicates the amount of the drug released per unit of time and the intercept of the line at time zero is equal to the constant in the equation. The curves plotted may have different slopes, and hence it becomes difficult to exactly pin-point which curve follows perfect zero order release kinetics. Therefore, to confirm the kinetics of drug re-lease, data’s were also analyzed using Korsemeyer’s equation. Korsemeyer et al. used a simple empirical equation to describe general solute release behavior from controlled release polymer matrices:

M_t/M_= atⁿ

Where M_t/M_ = fraction of drug released, a = kinetic constant, t = release time and n = the diffusional exponent for drug release.

The slope of the linear curve gives the ‘n’ value. Peppas stated that the above equation could adequately describe the release of solutes from slabs, spheres, cy-linders and discs, regardless of the release mechanism. The value of ‘n’ gives an indication of the release mechanism. When n = 1, the release rate is independent of time (zero order) (case II transport); n = 0.5 for Fickian diffusion; and when 0.5 < n < 1, diffusion and non-Fickian transport are implicated. Lastly, when n > 1.0 super case II transport is apparent. ‘n’ is the slope value of log Mt/M_ versus log time curve.^38-40

FIGURE- 4. FT-IR OF PHYSICAL MIXTURE OF DRUG AND POLYMERS

RESULTS AND DISCUSSION:

Solvent casting method is used as the method of choice for preparing the modified ocular insert of indomethacin and these modified inserts were designed with main aim of reducing the thickness and weight as much as possible to ensure patient acceptability and compliance. The inserts were characterized on the basis of interaction studies, physico-chemical characteristics, stability studies, sterility studies, ocular irritation studies, in vitro and in vivo studies.

Interaction studies were carried out to ascertain any kind of interaction of the drug with the excipients used in the formulations of ocular inserts. For this purpose, the formulation F7 and the pure drug were subjected to ATR-FTIR and FT-IR analysis. The IR spectra of the formulations exhibited absorption peaks similar to those of the pure drug sample.

The IR spectra of the formulation showed characteristic peaks at wave numbers 1692.42, 1716 cm^-1 (carbonyl group); 1029 cm^-1 (aryl alkyl ether);1223 cm^-1 (C-O-C asymmetrical stretching); 1479,752 cm^-1 (bands for aromatic rings) which were similar to those of the pure drug ( Figure-1-4). The results of IR analysis indicated that there was no chemical interaction between the drug and the excipients in the ocular insert.

The modified ocular insert of indomethacin were flexible and elastic. As the delivery system was designed to release the drug in controlled manner and minimize the irritation, the batches were formulated to have minimum thickness and the patches were found to have thickness in the range of 0.11±0.004 to 0.14±0.005 mm (when polymer EC was used) and the thickness was found to be in the range of 0.12±0.005 to 0.15±0.008 mm (when both polymers EC and ERS were used). This indicated that as the concentration of the polymers increased, there was increase in the thickness of the ocular inserts (Table-2). The weight of modified ocular insert varies between 5.76±0.01 to 8.38±0.06 mg (Table-2). The minimum standard deviation values revealed that the process is reproducible in its capability of giving films of uniform magnitude. Reliability of the process in the purview of getting uniform drug loading was confirmed by drug content analysis data and it was between 1.542±0.011 to 1.572±0.017 mg (Table-2).

MVT study was performed at 25±2^oC (80±5% RH) for a period of 24 h. The MVT varies between 0.226±0.001 and 0.201±0.002 (when polymer EC was used) and the MVT varies between 0.296±0.003 and 0.251±0.004 (when both polymers EC and ERS were used). It was found from the above data that the MVT was reduced by increase in insert thickness probably due to increase in diffusion path length (Table-2).

Tensile strength and the percent elongation at break were measured using the instrument as described by Seth et al.³² The maximum tensile strength and maximum elongation at break was observed with F8 whereas the least value was found with F1. By using combination of polymers ERS and EC the films do not break easily and hence it is concluded that the properties of the inserts was influenced by the molecular weight distribution or viscosity of the polymers (Table-2).

UV radiation was used to sterilize the ocular inserts and sterility testing was carried out under aseptic conditions. There was no growth of microorganisms in the samples under test, confirming the sterility of ocular inserts; therefore, the sterilized inserts were considered suitable for in vivo studies.

The different models, viz.-zero-order, Higuchi’s eq. and Korsmeyer-Peppa’s eq. were used to study the in vitro release of the modified ocular insert.^38-40 The zero order plot of formulations were found to be fairly linear as indicated by their high regressional values (Figure-5). Therefore, it was ascertained that the drug release from modified ocular inserts followed either near zero or zero order kinetics. . The zero order curves alone are not sufficient to predict zero order since each curve, albeit straight, has a different slope. Hence to confirm the exact mechanism of drug release from the films, the data were computed and graphed according to Higuchi’s eq. and Korsemeyer’s Peppas equation.: Regressional values of Higuchi’s plot revealed that the mechanism of drug release was diffusion (Figure-6) The in-vitro kinetic data is subjected to log time-log drug release transformation plot (Korsmeyer-Peppas plot),all the slope values ranges from 1.16893 to1.396967 (n>1) revealed the fact that the drug release follows super case II transport diffusion (Figure-7).

The two polymers used in the modified ocular inserts were actually compensates each other on their release rates and on property of deforming ocular inserts. From the in-vitro release study it was found that as the concentration of ERS is increased keeping the concentration of EC constant, there is increase in the release rate (Table-3). This is probably because the ERS reduces the resistance offered by the EC film alone, and by increasing pores and/or their diameter the drug diffuses with less resistance. The inherent problems encountered with ERS are the rapid penetration of the lachrymal fluid into the device, the blurred vision caused by the solubilization of ocular insert⁴¹ where as Ethyl cellulose, a hydrophobic polymer, can be used to decrease the deformation of the insert and thus to prevent blurred vision.^23,36

Polymeric ocular inserts appeared to be devoid of any irritant effect on cornea, iris, and conjunctiva during ocular irritation test, which probably suggest its suitability for ophthalmic drug delivery. The overall irritation was found to be 2 out of 110 on the scale of scores for reading the severity of ocular lesions given by the OECD guidelines no. 405.

The best Formulation F7 was subjected to in vivo studies in the rabbit eye. The drug release at the end of the 24 hrs was found to be 97.759 % and the release characteristics were similar to those obtained from in vitro studies. The in vitro and in vivo release profiles of the insert, F7 containing Indomethacin indicated that there were no significant differences between the amounts of drug released at the end of 24 h. The difference between the indomethacin released from ocular inserts during in vitro and in vivo studies for formulation F7 was found to be insignificant.. An attempt was made to correlate in vitro and in vivo release (Figure-8). A linear correlation was obtained, as it was evident from the regression value of 0.998837 for F7.

CONCLUSION:

Modified ocular inserts of Indomethacin were formulated as a single film instead of tri-film by using solvent casting method. The advantage of this ocular insert is that it reduces the thickness and weight as well as is better retained in the cul-de-sac of the eye and hence improves patient acceptability and compliance.

The formulation F7 formulated as a single film was found to give best release with 94.13% at the end of 24 hours in concentration independent manner.

The formulation was found to be smooth, transparent and flexible. Thickness was fairly uniform as indicated by its coefficient of variation.

In vitro release studies revealed that the ocular inserts followed zero-order release kinetics. Higuchi’s plot and Korsmeyer-Peppas plot revealed that the mechanism of drug release involved in all the formulations was super case II transport diffusion. There was a good correlation between in vitro and in vivo release data indicated correctness of the in-vitro method followed and adoptability of the delivery system to the biological system, where it released the drug in concentration independent manner.

The modified ocular insert achieved controlled release of indomethacin for a period of 24 hours. These inserts have the potential to form the basis of a once-daily therapy of ocular inflammation and may improve patient compliance and acceptability by reducing irritation as well as is better retained in the cul-de-sac of the eye. However further work is in progress to establish the therapeutic utility of these systems by pharmacokinetic and pharmacodyanamic studies in human beings.

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Received on 24.03.2008 Modified on 06.05.2008

Research J. Pharm. and Tech. 1(2): April-June. 2008;Page 93-99

Formulation Code	Thickness (µm)	Weight Variation (mg)	Drug content (mg)	Elongation at break(%)	Tensile Strength (kg/mm²)	MVT in 24 h (g.cm^-2h^-1)
F1	0.11±0.004	5.76±0.01	1.542±0.011	15.64±0.13	0.193±0.002	0.226±0.001
F2	0.13±0.005	6.80±0.003	1.538±0.015	16.21±0.14	0.198±0.003	0.211±0.002
F3	0.14±0.005	7.86±0.08	1.534±0.010	18.84±0.20	0.211±0.003	0.201±0.002
F4	0.12±0.005	6.31±0.04	1.532±0.013	18.91±0.12	0.218±0.004	0.296±0.003
F5	0.13±0.005	6.82±0.005	1.551±0.010	19.21±0.13	0.225±0.003	0.283±0.004
F6	0.13±0.004	7.34±0.06	1.588±0.013	20.12±0.15	0.234±0.003	0.271±0.004
F7	0.14±0.008	7.86±0.003	1.541±0.010	21.89±0.12	0.239±0.004	0.260±0.003
F8	0.15±0.008	8.38±0.06	1.572±0.017	21.98±0.15	0.245±0.003	0.251±0.004

Formulation code	Zero order		Higuchi’s		Peppa`s
Formulation code	n	R²	n	R²	n	R²
F1	1.255714	0.998792	6.514885	0.94837	1.16893	0.990519
F2	1.033967	0.995613	5.303147	0.934553	1.090293	0.99006
F3	0.901253	0.982156	4.51744	0.900975	1.073728	0.963697
F4	2.134733	0.996593	10.97715	0.937886	1.194939	0.997999
F5	2.567411	0.998297	13.530501	0.962863	1.232995	0.991631
F6	2.888788	0.998651	15.16626	0.959539	1.242217	0.989922
F7	3.81413	0.994362	19.59264	0.934821	1.306235	0.990224
F8	4.659352	0.992058	22.45492	0.920213	1.396967	0.993162