INTRODUCTION:

Rheumatoid arthritis is an autoimmune disorder. It causes chronic joint inflammation, inflammation of the synovial membrane and associated pain causing a severe disability. This condition might affects any joint of the body however it mainly affects proximal inter-phalangeal, metacarpophalangeal, and metatarsophalangeal joints of wrists and knees. It is more prevalent in adult age peoples ageing 30 to 50 years of age. It is more prevalent in women as compare to men^1-4.

The NSAIDs are widely used in the management of rheumatoid arthritis. They are most preferred because of their analgesic and anti-inflammatory action. They also help in improving the arthritic condition by reducing the skeleton muscular pain and acute pain. NSAIDs act by reacting with the cyclooxygenase enzyme which is involved in the conversion of arachidonic acid to prostaglandins. There are two different types of COX inhibitor COX-I and COX-II. Some may react with both ^5,6.

Zaltoprofen is one of novel NSAID, which can be used in the treatment of rheumatoid arthritis, osteoarthritis and to relive pain. It is water insoluble drug. It is mainly COX 2 inhibitor.^7,8.

There are many limitations of conventional drug delivery systems such as poor bioavailability because of low solubility and permeability, first pass metabolism, more doses of drug and GI degradation. To overcome these limitations several new strategies have been proposed. These newer strategies are called as novel drug delivery system approach which increase the bioavailability, reduces dose and toxicity of drug. Different novel drug delivery system approaches such as SMEDDS, nanoparticles, nanoemulsion, liposomes, dendrimers are developed. These systems can overcome the limitations of conventional system and increases drug bioavailability.^9,10

Delivery systems with a pulsatile-release pattern are receiving increasing interest for the development of drugs for which conventional controlled drug-release systems with a continuous release are not ideal. The drugs which have a high first-pass effect or special chronopharmacological needs can be formulated as pulsatile delivery system A pulsatile-release profile is characterized by a time period of no release (lag time) followed by a rapid and complete drug release. Pulsatile systems are designed in a manner that the drug is available at the site of action at the right time in the right amount, thus providing spatial and temporal delivery and increasing patient compliance. In the field of modified release, there has been a growing interest in pulsatile delivery, which generally refers to the liberation of drugs following a programmable lag phase from the time of administration. In particular, the recent literature reports on a variety of pulsatile release systems intended for the oral route, which have been recognized as potentially beneficial to the chronotherapy of widespread diseases, such as rheumatoid arthritis, hypertension, bronchial asthma and angina pectoris, with mainly night or early morning symptoms^11-13.

The objective of the present study was to develop a novel “Film coated pulsatile release tablet” providing programmed delivery of zaltoprofen in pulsatile release manner for the treatment of rheumatoid arthritis.

MATERIAL AND METHOD:

Material:

Zaltoprofen obtained from IPCA labs, Mumbai as gift sample, Eudragit L100 from Evonik industries. All other chemicals are of reagent grade obtained from Research Lab, Mumbai.

Formulation of Self emulsifying core tablet:

Fast disintegrating tablet of zaltoprofen was formulated with different concentration of superdisintegrants. Solid self emulsifying formulation was used to formulate core tablet of zaltoprofen. Tablets were prepared by direct compression technique.

Formulation of film coated tablet:

Coating Process^14,15:

The core tablets prepared as fast disintegrating tablets were coated in a coating machine (R&D Coater) by spray coating process, using 3” coating pan. The coating process parameters were optimized with respect to pan speed, inlet air temperature, atomizing air pressure and spray rate. Coating process was started once the required bed temperature was attained. During the coating few tablets were taken out randomly and their % weight gain was determined and the coating was continued until the desired weight gain was obtained on the core tablets.

After completion of coating, tablets were allowed to dry (curing) at 45-50°C in the coating pan itself for 10 min and then kept in oven at 40⁰C for 12 Hr.

Formulation of film coated tablet of zaltoprofen based on SNEDDS ^{16, 17}:

Based on the trial batches, nine different formulations with different coating composition on core tablet were prepared. Ethyl cellulose and eudragit L100 were used in 3:1, 1:1 and 1:3 ratios with 4%, 5% and 6% coating level. All the formulations were evaluated for various parameters including rupture time and in vitro dissolution study. The composition of film coated tablet of zaltoprofen is shown in Table 1.

Evaluation of film coated tablet:

Tablet thickness and diameter:

Thickness and diameter of coated tablets were measured using digital vernier callipers. Uniform thickness and diameter of tablet assures the uniformity of coating.

Tablet hardness:

Hardness is the crushing strength of tablet. Film coated tablet should have sufficient hardness. The hardness of tablet of each formulation was measured by Pfizer hardness tester.

Weight variation:

Weight variation test was performed on film coated tablet as per IP. Uniformity in tablet weight assures uniform weight gain on core tablet. Twenty tablets from each formulation were weighed individually using an electronic balance. The average weight was determined and compared with the individual weight of the tablet.

Drug content:

Weighed and powdered three film coated tablets of zaltoprofen. Accurately weighed and transferred a quantity of powder equivalent to 10mg of zaltoprofen in 100ml volumetric flask and volume was made with methanol. 1ml of the above solution again diluted to 10 ml with methanol. The absorbance was measured using UV spectrophotometer. Amount of drug present in each tablet was calculated at 340nm.

Table 1: Coating composition for film coated tablet of zaltoprofen

Ingredients	P-1	P-2	P-3	P-4	P-5	P-6	P-7	P-8	P-9
2% Polymer- ethyl cellulose: eudragit L100 Ratio	3:1	1:1	1:3	3:1	1:1	1:3	3:1	1:1	1:3
Dibutyl phthalate (ml)	0.2	0.2	0.2	0.2	0.2	0.2	0.l	0.2	0.2
Magnesium stearate (mg)	200	200	200	200	200	200	200	200	200
Ethyl alcohol q.s. to make (ml)	100	100	100	100	100	100	100	100	100
Coating Level	4%	4%	4%	5%	5%	5%	6%	6%	6%

Rupture time:¹⁸

Rupture time is indicative of lag time from pulsatile release tablet. As core tablet contains superdisintegrant after a particular time based on coating level film gets ruptured, and can be noted as ruptured time based on visual observation. USP dissolution type II apparatus was used to perform this test with paddle speed 50 RPM and in 900ml of 0.1 M HCl for two hours followed by pH 6.8 phosphate buffer as media maintained at 37⁰C.

In vitro dissolution study:

In vitro dissolution study of film coated pulsatile release tablets were performed using USP type II paddle apparatus. Initially 900ml of 0.1 M HCl for first two hours and later 900ml of phosphate buffer pH 6.8 was used as dissolution medium maintained at 37±0.5⁰C. The 5 ml of aliquots were withdrawn at time interval of 1, 2, 3, 4, 5, 6, 6.5, 7, 7.5 and 8 hours, properly diluted and filtered through Whatman filter paper no. 1. Zaltoprofen dissolution aliquots were analyzed at 340nm on UV spectrophotometer. An equal volume of fresh dissolution medium maintained at the same temperature was added after withdrawing each sample to maintain the volume.

RESULT AND DISCUSSION:

Formulation of Self emulsifying core tablet:

A self-emulsifying fast disintegrating tablet of zaltoprofen was prepared using solid self-emulsifying formulation of zaltoprofen equivalent to 80 mg of zaltoprofen. A core tablet to get pulse release was prepared using crosspovidone as superdisintegrant. Core tablets was formulated by direct compression technique and used for formulation of film coated tablet.

Formulation of film coated tablet of zaltoprofen based on SNEDDS:

Coating variables in the formulation of film coated tablet of zaltoprofen using particular coating composition were optimized as mentioned below in Table 2. Coating was continued till the required weight gains were obtained. Coated tablets were kept for curing and then evaluated.

Table 2: Operating conditions for coating

Operating parameters	Conditions used
Coating pan speed	12-16 rpm
Inlet air temperature	41-45°C (Inlet)
Atomizing air pressure	0.2 bar
Spray gun speed	1-2 RPM

Evaluation of film coated tablet of zaltoprofen:

All nine formulations of film coated tablet were evaluated for various parameters. The results of evaluation parameters are shown in Table 3

Table 3: Evaluation of Film coated Tablet

Formulation	Hardness (Kg/cm²)	Drug Content (%)	Rupture Time (Min.)	% C.R. at 8 Hr.
P-1	4.4±0.2	96.18	389	80.14
P-2	4.4±0.16	97.12	223	91.5
P-3	4.5±0.5	99.3	192	96.28
P-4	5.3±0.19	96.15	367	91.27
P-5	5.5±0.24	94.12	402	75.16
P-6	5.6±0.31	96.11	310	80.74
P-7	5.5±0.18	91.15	408	56.41
P-8	5.8±0.45	92.45	382	59.09
P-9	5.9±0.22	94.19	258	76.7

In vitro drug release profile for formulation:

These core formulations were coated with three different coating levels to study the effect of coating level on lag time. As expected, the rupture time increased with higher coating level because of the increased mechanical strength of the coating and the reduced medium permeation rate at higher coating thickness. The results are shown in Fig. 1.

Fig. 1: In vitro drug release from film coated tablet of zaltoprofen

In the case when eudragit L100 concentration is increase in combination with ethyl cellulose (P-3) the drug release before lag time was found to be more as drug release occurs due to diffusion as well as erosion, hence desired pulsatile effect was not observed in this case.

P-4 Formulation has given best release profile with desired lag time. P-4 formulation contains 3:1 ratio of ethyl cellulose and eudragit L100 with 5 % coating level.

CONCLUSION:

A new pulsatile release film coated tablet of self-emulsifying formulation of zaltoprofen was successfully developed. Coating process was optimized for different process variables. Coating compositions with combination of time and pH dependent polymers given desired lag time with pulsed release profile. P-4 Formulation has given best release profile with desired lag time. P-4 formulation contains 3:1 ratio of ethyl cellulose and eudragit L100 with 5% coating level. A water insoluble zaltoprofen in self emulsifying film coated tablet can be used for the treatment of chronopharmacological disorder, Rheumatoid arthritis.

ACKNOWLEDGEMENT:

We are thankful to School of Pharmacy, SRTMU, Nanded and Shri D.D. Vispute College of Pharmacy and Research Center, Panvel for assistance in the research work.

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Received on 25.03.2020 Modified on 22.06.2020

Research J. Pharm. and Tech. 2021; 14(8):4287-4290.

DOI: 10.52711/0974-360X.2021.00745