INTRODUCTION:

Oral administration^1,2 of drugs has been the most common and preferred route of delivery of most therapeutic agents due to good patient acceptance, ease of administration, examples Tablets, capsules, liquid solutions, etc. The absorption rate varies from the stomach to the intestine owing to the increased surface area (about 4500cm²), the intestinal mucosa and greater blood flow (1000 ml/min) through the intestinal capillaries compared to the gastric capillaries. It is also known that some drugs possessing pH dependent stability which are not stable in acidic environment (Stomach). Various techniques have been developed to overcome this stability problem. One out of them is development of enteric coated products. These enteric coated dosage forms resist the acidic environment of the stomach and allow disintegration in the higher pH environment of the intestinal fluid. The enteric coating on a solid dosage form can also be used for site-specific drug delivery of a therapeutic agent to the intestinal region.

Modified release systems^2,3designed to reduce the frequency of dosing by modifying the rate of drug absorption have been available from many years. Intestinal release systems: A drug may be enteric coated for intestinal release for several known reasons such as to prevent gastric irritation, prevent destabilization in gastric pH, etc. Colonic release systems: Drugs are poorly absorbed through colon but may be delivered to such a site for two reasons- Local action in the treatment of ulcerative colitis and Systemic absorption of protein and peptide drugs.

The most advantages of pelletization are improved appearance of the product and the core is pharmaceutically elegant. Pelletization^3,4offers flexibility in dosage form design and development. Pellets are less susceptible to dose dumping. It reduces localized concentration of irritative drugs. It improves safety and efficacy of a drug. Pellets offer reduced variation in gastric emptying rate and transit time. Pellets disperse freely in G.I.T. and invariably maximize drug absorption and also reduce peak plasma fluctuation. Pellets ensure improved flow properties in formulation development. Coating of pellets can be done with different polymers to enable controlled release of the drug. In case of immediate Release Products larger surface area of pellets enables better distribution. Chemically incompatible products can be formed into pellets & delivered in a single dose by encapsulating them. Varied applications are possible in the pellet form. eg: sustained release. Pellets ensure improved flow properties, and flexibility in formulation development and manufacture. Pellets may have varied applications in varied industries. It just requires an innovative bend to use it to derive maximum profitability. The smooth surface & the uniform size of the pellets allow uniform coating not only for each pellet but also to whole batch itself.

Omeprazole^5,6is a highly effective inhibitor of gastric acid secretion used in the therapy of stomach ulcers and Zollinger-Ellison syndrome. Omeprazole belongs to a class of anti- secretory compounds, the substituted benzimidazoles that suppresses gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the surface of the gastric parietal cell.

MATERIALS AND METHODOLOGY:

List of materials:

Omeprazole, Mannitol, sucrose, sodium lauryl sulphate, Disodium hydrogen phosphate, Calcium carbonate, HPMC E5, HPMC P-55, Titanium dioxide, Sodium methyl paraben, Sodium propyl paraben, PEG-6000, Purified water.

Method of Formulation^7,8

Omeprazole enteric coated pellets were prepared by Spheronization method and are enteric coated using aqueous enteric coating solution.

Preparation of Omeprazole enteric coated pellets:

Drug loading: Specified quantity of non-pareil seeds were accurately weighed and dispensed. 500ml of purified water is taken in a beaker and kept for stirring under a mechanical stirrer. Specified quantities of mannitol, sucrose (diluent), di-sodium hydrogen phosphate were added slowly to form a uniform suspension. Specified quantity of Omeprazole is added and stirring is continued further. To this suspension, sodium lauryl sulfate and calcium carbonate are added followed by sodium methyl paraben and sodium propyl paraben. The non pareil seeds were coated using coating pan. The pellets are dried and the dried pellets were collected.

a) Sub coating stage: 500ml of purified water is taken in a beaker and kept for stirring under a mechanical stirrer. Specified quantity of HPMC E5 was added slowly to form a uniform suspension. Drug loaded pellets were coated with the above suspension using Fluidized bed coater (FBC). The dried pellets were then collected.

b) Enteric coating stage: 500ml of purified water was taken in a beaker and kept for stirring under a mechanical stirrer. Specified quantities of enteric polymer i.e., HPMCP-55 and plasticizer i.e., PEG-6000 were added slowly to form a uniform suspension. Stirring was continued until the suspension is completely formed. Barrier coated pellets were coated with this prepared suspension using Fluidized bed coater. Dried pellets were collected and evaluated.

Aqueous enteric coating solution preparation⁹

Table no 1. List of ingredients

S.no	Ingredients	Quantity
1.	HPMCP-55	60gm (6%)
2.	Ammonia	Quantity sufficient
3.	Water	1000ml

Evaluation Parameters

The following evaluation tests were performed to the formulated pellets.

Moisture content (or) Water content by KF:

Take around 50ml of methanol in titration vessel of Karl Fischer titrator and titrate with Karl Fischer reagent to end point. In a dry motor grind the pellets to fine powder. Weigh accurately about 0.5g of the sample, transfer quickly to the titration vessel, stir to dissolve and titrate with Karl Fischer reagent to end point.

Calculation:

Moisture content = V*F*100/weight of sample in mg

Where, F = factor of Karl Fischer reagent, V = volume in ml of Karl Fischer reagent consumed for sample titration.

Assay:

Standard preparation:

Weigh accurately about 20mg of Omeprazole working standard into a 50ml volumetric flask and add 50ml of 0.1N NaoH. Shake well and make up the volume with 0.1N NaoH. Pipette out 3ml of this solution into a 100ml volumetric flask, dilute it to volume with 0.1N NaoH and mix well.

Sample preparation:

Weigh accurately 20mg drug equivalent pellets in a 100ml volumetric flask, add 0.1N NaoH and make up the volume. Filter the solution through Whatman filter paper. Pipette out 5ml of the filtrate into a 50ml volumetric flask. Dilute to volume with 0.1N NaOH.

Procedure: Scan the solution of both standard and sample preparation against blank preparation between 200-400 nm and measure the absorbance for both standard and sample at 302nm.

Calculation¹⁰:

A = At/As*Ws/50*3/100*50/Wt*100/3*100

Where, At = Absorbance of the sample preparation, As = Absorbance of the standard preparation

Ws = Weight of the standard taken in mg, Wt = Weight of the sample taken in mg

In-vitro Dissolution¹¹

Procedure:

Dissolution studies for gastric resistance: Transfer 900ml of 0.1N HCl in each vessel of the dissolution apparatus and adjust the temperature to 37°C + 0.5°C.Weigh and transfer the pellets equivalent to 20mg of Omeprazole individually in each of the 6 dissolution flasks, containing 900ml of 0.1N HCl, Note the time. After two hours, collect the pellets sample from each vessel and 0.1N NaOH is added for neutralization. Filter the solution through filter media. Pipette out 5ml in a 50ml volumetric flask and make up the volume with 0.1N NaOH. The samples were analyzed using UV-Spectrophotometer at 302nm.

Dissolution studies in phosphate buffer¹² p^H6.8: Transfer 900ml of phosphate buffer P^H6.8in each vessel of the dissolution apparatus and adjust the temperature to 37°C + 0.5°C. Transfer the pellets which were previously tested for gastric resistance into the vessels. Run the apparatus for 45 minutes. After 45 minutes, draw 10ml of the sample from each vessel, filter the sample. Analyze the samples using UV-Spectrophotometer at 302nm.

Calculation:The percentage drug release can be calculated by the following equation,

Percentage drug release = At/As*W/Ws*100/Assay*P

Where, At = Absorbance of sample, As = Absorbance of standard, W = weight of standard

Ws = weight of sample, P = potency

Table no. 2: Formulation:

S.No	F1	F2	F3	F4	F5	F6
HMPCP-55	6%	6%	6%	6%	6%	6%
Ammonia	15ml	13ml	12ml	11ml	10ml	9ml
Water(ml)	1000	1000	1000	1000	1000	1000
PEG-6000	6.5g	6.5g	6.5g	6.5g	6.5g	6.5g

Six formulations of pellets were prepared and from that formulation F5 was selected, as its results were found to be convincing compared to all other formulations

Table no. 3: Physical properties of enteric coated pellets

Parameters	F1	F2	F3	F4	F5	F6
Bulk density (gm/cm³)	0.82	0.84	0.87	0.92	0.8	0.81
Moisture content (%)	1.94	1.96	1.94	1.92	1.9	1.93

Table no. 4: Dissolution studies:

Time	F1	F2	F3	F4	F5	F6
0	0	0	0	0	0	0
15min	3.15%	2.73%	2.57%	1.25%	0.85%	0.92%
30min	5.12%	3.85%	3.26%	2.52%	2.18%	2.02%
1 Hr	6.95%	5.84%	5.68%	3.48%	3.05%	2.98%
2Hr (0.1N HCl)	9.01%	7.66%	7.31%	4.43%	4.21%	4.24%
2Hr 45min (buffer)	81.40%	83.28%	84.24%	94.28%	95.81%	94.98%

The release kinetics was evaluated for F5 formulation using linear regression method. The best fit model was observed to be Korsemeyer-Peppas. The value of n was found to be 0.92, indicating super case II transport drug release.

Table no.5:release kinetics of formulation F5

Formulation	Zero order	First order	Higuchi	Peppas	Best fit model
F5	0.45	0.42	0.37	0.92	Peppas

Stability Studies:

Stability Studies were carried out at 40°C ± 2°C / 75% ± 5% RH for f5 formulation for 3 months.

Results of stability studies:

There was no change observed. So the prepared f5 formulation was stable.

Table no.6 : Stability studies of formulation F5

Time	Dissolution (0.1N HCl)	Dissolution (Phosphate buffer)
0 month	4.21%	95.81%
1 month	4.19%	95.74%
2 months	4.19%	95.65%
3 months	4.15%	95.27%

CONCLUSION:

In the present study, Omeprazole enteric coated pellets were prepared using enteric coating polymer like hydroxyl propyl methyl cellulose phthalate. From this study it can be concluded that Omeprazole enteric coated pellets prepared by HPMCP-55 showed better performance than the pellets prepared using other enteric polymers like CAP, HPMC, etc. The formulation F5 was considered optimum because it showed negligible drug release in acidic medium and the drug release in the phosphate buffer (pH 6.8) was found to be almost complete. The stability studies of the selected formulation showed that the product was stable throughout the study period (3months).

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Received on 13.10.2015 Modified on 10.12.2015

Res. J. Pharm. Dosage Form. & Tech. 8(1): Jan.-Mar. 2016; Page 01-04

DOI: 10.5958/0975-4377.2016.00002.1