Design and development of floating In - Situ gel of pantoprazole

The present investigation deals with the formulation, optimization and evaluation of sodium alginate based floating oral In situ gel of Pantoprazole. Sodium alginate used as a polymer and Calcium carbonate was used as a crosslinking agent. In-situ forming polymeric formulation drug delivery systems is in sol form before administration in the body, but once administered, undergoes gelation in-situ to form a gel. The formulation of gel depends upon factors like temperature modulation, pH changes, presence of ions and ultraviolet irradiation from which drug gets released in sustained and controlled manner. The objective of this study was to develop a novel insitu gel system for sustained drug delivery using natural biodegradable polymer. The system utilizes polymers that exhibit sol-togel phase transition due to change in specific physicochemical parameters. In-situ gel was formed at a gastric p from designed set of experiments, it was evident that formulation containing 2 % of sodium alginate control the release of drug for longer duration. The in-situ gel exhibited the expected, viscosity, drug content, p, in vitro gelling capacity, in vitro floating ability and sustained drug release. The formulated in situ gel for Pantoprazole was found to be stable in situ gel. It was found to have better floating efficacy and in vitro release profile characteristics. Better efficiency and results of batch F-6 gives newer alternative use of natural biodegradable polymers in situ gel formulation. Key-words: Oral In-situ gel, Sustained Release, Sodium alginate, Calcium Carbonate, Pantoprazole. _____________________________________________________________________________________________ INTRODUCTION Peptic ulcers are open craters or sores that develop in the inner lining (mucosa) of the stomach or the duodenum (the first section of the small intestine). A coating of mucus and other chemicals normally shield the stomach and duodenum from digesting themselves. When these protective mechanisms are disrupted, powerful digestive acids can erode into the lining of these organs and cause peptic ulcers.[1] In situ is a Latin word which means in position. In situ gel formation of drug delivery systems can be defined as a liquid Formulation generating a solid or semisolid depot after administration. In-situ activated gel forming Systems are those which are when exposed to physiological conditions will shift to a gel phase. This new concept of producing a gel in situ was suggested for the first time in the early 1980s. Gelation occurs via the cross-linking of polymer chains that can be achieved by covalent bond formation (chemical cross-linking) or Non-covalent bond formation (physical cross-linking) [2].Floating drug delivery systems is one of the important approaches to achieve gastric retention to obtain sufficient drug bioavailability. This delivery systems is desirable for drugs with an Ramana B. V. et al Der Pharmacia Lettre, 2016, 8 (8):239-249 ______________________________________________________________________________ 240 Scholar Research Library absorption window in the stomach or in the upper small intestine6. This have a bulk density less then gastric fluids and so remain buoyant in the stomach without affecting gastric emptying rate for a prolonged period and the drug is released slowly as a desired rate from the system. After release of drug, the residual system is emptied from the stomach.[3]. Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by covalently binding to the (H, K)-ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect leads to inhibition of both basal and stimulated gastric acid secretion, irrespective of the stimulus. The binding to the (H, K)-ATPase results in a duration of antisecretory effect that persists longer than 24 hours for all doses tested (20 mg to 120 mg).[4] EXPERMINENTAL INVESTIGATIONS Materials: Pantoprazole(Ranbaxy Pharmaceuticals Ltd (India). Sodium Alginate (Lobachemie (P) Ltd.), Calcium carbonate (Central Drug House (P) Ltd.), Sodium citrate (Central Drug House (P) Ltd.), D-sorbitol (Central Drug House (P) Ltd.). All the other chemicals used were of Analytical grade. Methods: Preformulation Studies: Identification of Drug by FTIRCompatibility of Pantoprazole with gelling agent and other excipients was established by infrared spectral analysis IR Spectral analysis of samples (Ranitidine hydrochloride, Sodium Citrate, Sodium alginate, calcium carbonate, sorbitol) was carried out to investigate the changes in chemical composition of the drug[5] Preparation of Formulations Preparation of Pantoprazole in-situ gelling solutions – The polymeric dispersion was prepared by dispersing required quantity of gums and polymers in water using a magnetic stirrer and allowing it to swell overnight.SA (sodium alginate) Solutions were prepared in distilled water by heating to 60C under continuous stirring. After cooling below 40C ingredients including drug, gelling agent and other excipients were weighed accurately and formulations were prepared as per the table 3.The resulting six formulations (F1-F6) were finally stored in amber coloured bottles until further use. Table no.1 Composition of Floating in situ gel: Ingredients Formulation code & Quantities F1 F2 F3 F4 F5 F6 Pantoprazole 400mg 400mg 400mg 400mg 400mg 400mg Sodium Alginate 1gm 1.5 gm 2 gm 1 gm 1.5 gm 2 gm Sodium Citrate 250 mg 250 mg 250 mg 500 mg 500 mg 500 mg CaCo3 250 mg 250 mg 250 mg 500 mg 500 mg 500 mg D. sorbitol 1gm 2gm 3gm 1gm 2gm 3gm Distil Water q.s. q.s. q.s. q.s. q.s. q.s. Total Weight(ml) 100ml 100ml 100ml 100ml 100ml 100ml Physical Appearance and p:[6] All the prepare sodium alginate based in-situ solution were checked for their clarity and the type of the solution. After administration of the prepared solution in (0.1N HCL, p 1.2) also checked the time required for gel formation and type of gel formed. The p was measured in each of the solution of sodium alginate based in-situ solution using a calibrated digital p meter at 27C. The measurement of p of each data was in triplicate. Viscosity of in situ gelling solutions – The viscosity of formulations was determined by a Brookfield viscometer DV-III (Brookfield, USA) using spindle number 21 with cup and bob setting at 50 rpm. Floating behavior – The floating ability of the prepared formulations was evaluated in (0.1N HCl, pH 1.2) Solution. The floating time of the prepared formulation took to emerge on the medium surface (floating lag time) was found to be 60sec.The time the formulation constantly floated on the dissolution medium surface (duration of floating) was evaluated to be 12hrs resulting the formation of thick gel with good floating tendency. Ramana B. V. et al Der Pharmacia Lettre, 2016, 8 (8):239-249 ______________________________________________________________________________ 241 Scholar Research Library In-vitro gelling capacity To evaluate the formulations for their in-vitro gelling capacity by visual method, solutions of in-situ gel forming drug delivery system were prepared. The in-vitro gelling capacity of prepare formulations was measured by placing 5 ml of the gelation solution (0.1N HCL, p 1.2) in a 15 ml borosilicate glass test tube and maintained at 37±1oC temperature. One ml of formulation solution was added with the help of pipette. The formulation was transferred in such a way that places the pipette at surface of fluid in test tube and formulation was slowly released from the pipette. As the solution comes in contact with gelation solution, it was immediately converted into stiff gel like structure. The gelling capacity of solution was evaluated on the basis of stiffness of formed gel and time period for which the formed gel remains as such. The in-vitro gelling capacity was graded in three categories on the basis of gelation time and time period for which the formed gel remains. (+) Gels after few minutes, dispersed rapidly (++) Gelation immediate remains for 12 hours (+++) Gelation immediate remains for more than 12 hours. Drug content: Preparation of standard calibration curve of Pantoprazole: Pantoprazole (10 mg) was dissolved in (0.1 N HCl, p 1.2) and volume was made up to 100 ml in 100 ml volumetric flask. This solution (100 mcg/ml) was further diluted with (0.1 N HCl, p 1.2) to obtain solution of 10 to 100 mcg/ml. The absorbance of each solution was measured at 283.4 using UV spectrophotometer. The standard curve was obtained by plotting absorbance v/s. concentration (μg/ml) . Ten ml of the solution was added to 900 ml (0.1N HCl, p 1.2) Solution and stirred for 1 hr. on a magnetic stirrer. The solution was filtered, suitably diluted with (0.1N HCl, p 1.2) and the drug concentration was determined by using a UV-visible spectrophotometer a (Shimandzu UV 1700 Pharmaspec) at 284nm against a suitable blank solution. In-vitro release studies: An in-vitro release study was carried out using dissolution test apparatus USP Type II (Paddle Method). The following procedure was followed throughout the study that is shown in (table 2) to determine the in vitro dissolution rate for the formulations. The release of Pantoprazole from the formulations was determined using dissolution test apparatus USP Type II with a paddle stirrer at 50 rpm. The dissolution medium used 900 ml of (0.1N HCL, p 1.2) solution and temperature was maintained at 37 ± 0.2 °C. Ten ml of the formulation were placed into a Petri dish (4.5cm i.d.) which was kept in the dissolution vessel and 0.1N HCL solution was carefully added to the vessel avoiding any disturbance of the Petri dish. At each time interval, a precisely measured sample of the dissolution medium was pipette out and replenished with fresh medium. Pantoprazole concentration in the aliquot was determined spectrophotometrically.[6] Table: 2 Dissolution of Floating In Situ Gel Dissolution medium 900 ml of (0.1N HCL,1.2 pH) solution Temperature 37 C±0.2 C RPM 50 Volume withdrawn 10 ml every 1 hrs. λ max 284nm Sol. taken Ten ml sol. (Known drug content ) Evaluation of in-vitro release kinetics:[34] To study kinetics data obtained from in-vitro release were plotted in various kinetic models. Zero-order equation: %R = Kt This model represents an ideal release profile in order to achieve the pharmacological prolonged action. This is applicable to dosage forms like transdermal systems, coated forms, osmotic systems, as well as matrix tablets with low soluble drugs. Ramana B. V. et al Der Pharmacia Lettre, 2016, 8 (8):239-249 ______________________________________________________________________________ 242 Scholar Research Library First order equation: Log% unreleased = Kt / 2.303 This model is applicable to study hydrolysis kinetics and to study the release profiles of pharmaceutical dosageforms such as those containing water soluble drugs in porous matrices. Higuchi equation: %R=Kt0.5 This model is applicable to systems with drug dispersed in uniform swellable polymer matrix as in case of matrixtablets with water soluble drug. Hixson and Crowell equation: (%unreleased) 1/3 = Kt This expression applies to pharmaceutical dosage forms such as tablets, where the dissolution occurs in planes that are parallel to drug surface if the tablet dimensions diminish proportionality in such a manner that the initialgeometrical form keeps constant all the time. When this model is used, it is assumed that release rate is limitedby drug particles dissolution rate and not by diffusion that might occur through the polymeric matrix. Korsmeyer-Peppas equation: