Formulation and In-Vitro Characterization of Ketorolac Tromethamine Ophthalmic Inserts

S.N. Kothawade*, S.T. Deshpande, A.S. Lunkad, P.A. Dighe

SCSSS’s Sitabai Thite College of Pharmacy, Shirur (Ghodnadi). Dist: Pune- 412210

ABSTRACT:

Ophthalmic inserts are sterile, solid preparations containing drug as dispersion or as solution in the polymeric support. Ketorolac Tromethamine is a nonsteroidal anti- inflammatory drug (NSAID) has a pronounced analgesic, antipyretic and anti-inflammatory action. It is a pyrrole derivative and very effective against disorders of eye. In this study, ophthalmic inserts of Ketorolac Tromethamine were prepared using polymers such as Hydroxypropyl methyl cellulose (HPMC) and Methyl cellulose (MC), and plasticizer such as Polyethylene glycol 400 (PEG) by solvent casting method. The ophthalmic inserts were evaluated for uniformity of thickness, weight, drug content and swelling index. In vitro drug release studies of formulated ocuserts were performed by studying the diffusion through the artificial membrane (prehydrated cellophane). IR spectral studies were performed to confirm the interaction of drug in formulation using KBr disc method. Out of eight formulations prepared, the formulation containing HPMC (1:2) showed complete and prolonged release with 99.91% at the end of 7 hrs.

KEYWORDS: Ketorolac Tromethamine, ophthalmic inserts, HPMC, MC, In-vitro release.

INTRODUCTION:

Ophthalmic drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientist. The conventional method of ophthalmic drug administration is instillation of drug solution or suspension into the cul-de-sac. But this may leads to less systemic absorption of drug because of drainage through nasolacrimal duct. An effective way to achieve slow and prolonged absorption in ophthalmic practice is to incorporate a drug into a polymeric film, which when placed in the cul-de-sac of the eye exhibits a prolonged local release for drug action on tissue in the immediate vicinity. The main objective of the ophthalmic inserts is to increase the contact time between the preparation and the conjunctival tissue to ensure a sustained release suited to topical or systemic treatment.¹

Ketorolac Tromethamine, a nonsteroidal anti-inflammatory drug (NSAID) has a pronounced analgesic, antipyretic and anti-inflammatory action. It is a pyrrole derivative and very effective against disorders of eye.²

The prostaglandin inhibitory action of Ketorolac Tromethamine has been shown to be useful in the relief of pain. It is available in the conventional ocular drug delivery system as 1% eye drops. It is administered at dosing interval of 1 drop every 4 hrs for a treatment of muscular oedema and other ocular inflammatory conditions.

Table No.1. The formula for different formulations

Ingredients

Ketorolac Tromethamine (g)

H.P.M.C. (g)

Methyl cellulose (g)

PEG400 (30%) (ml)

Water (ml)

0.46

0.23

0.1

0.46

0.2

0.46

0.69

0.3

0.46

0.92

0.4

0.46

0.057

0.02

0.46

0.115

0.05

0.46

0.172

0.07

0.46

0.230

0.09

The eye drop dosage form is convenient to use but most of the drug is diluted by tear and rapidly washed out of the sac by constant tear flow which can be avoided by using inserts by which the therapeutic efficiency of ophthalmic drug can greatly improved.³

In the present work an attempt was made to formulate Ketorolac Tromethamine ophthalmic inserts using hydroxy propyl methyl cellulose and methyl cellulose as polymers by solvent casting method with aim of increasing the contact time, achieving controlled release, reduction in frequency of administration, improving patient compliance and greater therapeutic efficacy.

MATERIALS AND METHODS:

Materials

Ketorolac Tromethamine was obtained as gift sample from Wockhardt, Aurangabad. Hydroxy propyl methyl cellulose, Methyl cellulose and Polyethylene glycol 400 were purchased from Research Lab Fine Chem, Mumbai. Cellophane membrane is purchased from Himedia Private Laboratories Ltd, Mumbai.

Method of preparation of films

Solvent casting method- The required quantity of the polymer was weighed and dissolved in 10 ml of distilled water by gentle stirring. The required amount of polyethylene glycol 400 was added as plasticizer to above solution under stirring condition. The weighed amount of Ketorolac Tromethamine (passed through sieve 40) was added and stirred for 12 hrs to get uniform dispersion. After complete mixing the casting solution (5 ml) was poured in clean petriplate. Then the petriplate was dried at room temperature for 24 hrs. The dried films thus obtained were cut into required size (8 mm diameter) consisting of 2 mg of drug by cork borer and stored. The formula for different formulations are shown in the Table no.1.

Evaluation of the prepared formulations⁴

Uniformity of thickness

Five films were taken from each batch and their thickness was measured by using micrometer screw gauge. The mean thickness was calculated.

Uniformity of drug content

Five films were taken from each batch and dissolved or crushed in 10 ml of methanol in a beaker and were filtered into the 25 ml of volumetric flask and the volume was made up to 25 ml. Each 1 ml of above solution was withdrawn and the absorbance was measured by UV-Visible spectrophotometer at 238 nm after suitable dilutions.

Swelling index study

Three films were weighed and placed separately in beaker containing 4 ml of phosphate buffer solution. At regular intervals of time (every 5 min), the films were removed and the excess solution on their surface was removed using a filter paper and then again weighed. The procedure was continued till there was no increase in the weight. The swelling index was then calculated by dividing the increase in weight by the original weight and was expressed as percentage.

In-vitro diffusion studies

The In-vitro diffusion of drug from the different ophthalmic inserts was studied using the diffusion cell in the laboratory. A simple modification of a glass tube of 15 mm internal diameter and 100 mm height. The diffusion cell membrane was tied to one end of open cylinder, which acted as a donor compartment. An ophthalmic insert was placed inside this compartment. The diffusion cell membrane acted as corneal epithelium. The entire surface of the membrane was in contact with the receptor compartment containing 25 ml of phosphate buffer pH 7.4 in 100 ml of beaker. The content of receptor compartment was stirred continuously using a magnetic stirrer and temperature was maintained at 37⁰± 0.5⁰C.

At specific intervals of time, 1 ml of the sample solution was withdrawn from the receptor compartment and replaced with fresh buffer solution. The sample was analyzed for the drug content using UV-Visible spectrophotometer at 238 nm after appropriate dilutions against reference using phosphate buffer pH 7.4 as a blank.

Drug excipient compatibility studies

The compatibility between drug and the formulations components were confirmed by Infrared spectrophotometer using KBr disk method.

Table No. 2: Physicochemical data of ophthalmic inserts

Product code	Weight in (mg)	Thickness in (µm)	Drug content in (mg)	% Drug content	Swelling index
F1	8.16	123.33	1.953	99.09	1.348
F2	9.75	132.66	1.971	99.35	1.436
F3	8.00	136.00	1.967	99.29	1.750
F4	8.36	143.66	1.971	99.91	2.153
F5	8.26	88.00	1.953	97.12	1.089
F6	7.93	90.00	1.971	99.76	1.387
F7	9.65	95.00	1.934	99.07	1.554
F8	8.10	97.00	1.967	96.90	1.728

RESULTS AND DISCUSSION:

Ophthalmic inserts were prepared by using polymers such as hydroxypropyl methyl cellulose and methyl cellulose. The physicochemical evaluation data presented in Table No. 2 indicates that thickness of the formulations varied between 88.00 µm to 144 µm. The result showed that the thickness was uniform. The weight of formulations was ranging from 7.93 to 9.75 mg. The drug content of the formulations was determined according to procedure described in methods. The drug content in all formulations was found to contain 95.80% to 99.91% of Ketorolac Tromethamine. The HPMC and MC are hydrophilic polymers and are soluble in water. Due to its hydrophilic nature the polymers can expect to absorb water. So to verify this, a swelling index test was carried out. The result showed that there was no significant variation in the water absorption properties of formulations.

Figure No. 1: In vitro diffusion of Ketorolac Tromethamine from formulationsF1-F4

In vitro diffusion study

The release profile of the formulation is shown in the figure no. 1 and figure no. 2. The ophthalmic inserts prepared with HPMC releases the drug completely in 5 to 7 hrs. The release of the drug from the formulation F1, F2, F3 & F4 were found to be 99.09%, 99.35%, 99.29%, 99.91% respectively. The formulation with methyl cellulose showed complete release in 5-6 hrs. The release of drug from the formulations F5, F6, F7& F8 were found to be 97.12%, 99.76%, 99.07%, and 96.90% respectively.

Figure No. 2: In vitro diffusion of Ketorolac Tromethamine from formulationsF5-F8

Drug excipient compatibility studies

The drug excipient compatibility studies are done by Infrared spectrophotometer using KBr disc method. Figure No. 3 shows IR Spectra of pure drug and Figure No. 4 shows IR Spectra of optimized formulation with Drug: HPMC (1:2). The spectrum shows no interaction between drug and polymer.

CONCLUSION:

The formulation of ophthalmic inserts prepared by using various polymers like HPMC and MC. The formulation containing Ketorolac Tromethamine and HPMC (1:2) was promising and an in vitro study reveals the retention of drug for longer period than other formulations.

ACKNOWLEDGMENT:

Author thanks to Principal Mr. D. G. Baheti and Management of college for providing the necessary facilities to carry out the research work.

REFERENCES:

1. K.D. Tripathi., Essentials of Medical Pharmacology, Jaypee Publisher, 5^thedition, 2003; 167.

2. Jain, N. K., Controlled and novel drug delivery, C.B.S. Publisher and distributer, 2004; 88.

3. Manvi FV, Soppimath KS and Gadad AP. Development and evaluation of timolol maleate ocular inserts. Indian drugs 1997; 34:264-8.

4. Murthy SN. Biodegradable polymers matrix based ocuserts of diclofenac sodium. Indian drugs 1997; 34: 336-8.

Received on 18.07.2013

Modified on 17.08.2013

Accepted on 23.08.2013

Research Journal of Pharmaceutical Dosage Forms and Technology. 5(6): November-December, 2013, 311-314