“FORMULATION DEVELOPMENT AND EVALUATION OF FLOATING DRUG DELIVERY SYSTEM OF METOPROLOL SUCCINATE.”
DESSERTATION PROTOCOL
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE.
BY
SANGHOI KAUSHAL SHANTILAL
M.PHARM, PART-I
DEPARTMENT OF PHARMACEUTICS
NARGUND COLLEGE OF PHARMACY
BANGALORE-85, KARNATAKA
(2011-2013)
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / NAME OF THE CANDIDATEAND ADDRESS (IN BLOCK LETTERS) / SANGHOI KAUSHAL SHANTILAL
NARGUND COLLEGE OF PHARMACY,
DATTATREYANAGAR, II MAIN,
100 FT RING ROAD, BSK III STAGE,
BANGALORE-85
KARNATAKA.
2. /
NAME OF THE INSTITUTION
/ NARGUND COLLEGE OF PHARMACY,DATTATREYANAGAR, II MAIN,
100 FT RING ROAD, BSK III STAGE,
BANGALORE-85
KARNATAKA.
3. /
COURSE OF STUDY AND SUBJECT
/ MASTER OF PHARMACY IN PHARMACEUTICS4. / DATE OF ADMISSION OF COURSE / 27th JUNE 2011
5. /
TITLE OF TOPIC
/ “FORMULATION DEVELOPMENT AND EVALUATION OF FLOATING DRUG DELIVERY SYSTEM OF METOPROLOL SUCCINATE.”6.
7.
8. / BRIEF RESUME OF THE INTENDED WORK:
6.1 NEED FOR THE STUDY:
Hypertension is a chronic medical condition in which the blood pressure in the arteries is elevated. It is classified as either primary (essential) or secondary. About 90-95% of cases are termed "primary hypertension", which refers to high blood pressure for which no medical cause can be found and for the remaining fraction of cases the causes are known like hyperlipidemia etc. Hypertension affects almost all organs of the body like kidneys, arteries, heart, or endocrine system. Hence, there is growing need for development of suitable medication to treat or manage hypertension.
Anti-hypertensive are a class of drugs which are used to manage hypertension. There are various classes of drugs which are used as antihypertensive like beta blockers, calcium channel blockers, ACE inhibitors etc. Among all these, beta blockers are still being used as first line agents used for the management of hypertension.
One of the most feasible approaches for achieving a prolonged predictable drug delivery profile is floating drug delivery system (FDDS). which prolongs the gastric residence time and increases the overall bioavailability of the dosage form. Gastric floating drug delivery system can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability, reduces drug waste and improves solubility of drug that is less soluble in high pH environment. It is also suitable for local drug delivery in stomach and proximal small intestine.
A number of FDDS involving various technologies, carrying their own advantages and limitations were developed. such as, single and multiple unit hydrodynamically balanced systems (HBS), single and multiple unit gas generating systems, hollow microspheres and raft forming systems. Floating systems have low bulk density so, that they can float on the gastric juice in the stomach. The problem arises when the stomach is completely emptied of gastric fluid, in such a situation, there is nothing to float on.
Floating systems can be based on the following:
· Hydrodynamically balanced systems (HBS) – incorporated buoyant materials enable the device to float;
· Effervescent systems – gas-generating materials such as sodium bicarbonate or other carbonate salts are incorporated. These materials react with gastric acid and produce carbon dioxide, which entraps in the colloidal matrix and allows them to float;
· Low-density systems - have a density lower than that of the gastric fluid so they remain buoyant;
· Bioadhesive or mucoadhesive systems – these systems permit a given drug delivery system (DDS) to be incorporated with bio/mucoadhesive agents, enabling the device to adhere to the stomach (or other GI) walls, thus resisting gastric emptying. However, the mucus on the walls of the stomach is in a state of constant renewal, resulting in unpredictable adherence.
· High-density Systems - sedimentation has been employed as a retention mechanism for pellets that are small enough to be retained in the rugae or folds of the stomach body near the pyloric region. Dense pellets (approximately 3g/cm3) trapped in rugae also tend to withstand the peristaltic movements of the stomach wall. With pellets, the GI transit time can be extended from an average of 5.8–25 hours, depending more on density than on diameter of the pellets.
Metoprolol succinate is a beta1-selective (cardio selective) adrenergic receptor blocking agent. This preferential effect is not absolute, however, at higher plasma concentrations. Metoprolol succinate also inhibits beta 2-adrenoreceptors, chiefly located in the bronchial and vascular musculature. Metoprolol succinate has no intrinsic sympathomimetic activity and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for beta-blockade. Because of these desired pharmacodynamic properties, Metoprolol succinate is used popularly for management of hypertension.
Metoprolol succinate belongs to class I category in BCS classification system freely soluble & highly permeable. Because of good solubility and permeability, its bioavailability is more and half life is less. This results in multiple doses of Metoprolol succinate every day. Hence, continuous efforts are being made whereby number of doses of Metoprolol succinate can be minimized.
6.2 REVIEW OF LITERATURE :
Ø Sanjay P et al., developed and evaluated optimized gastroretentive drug delivery system of metoprolol succinate using novel combinations of sodium alginate (SA), sodium carboxymethylcellulose (NaCMC), magnesium alumino metasillicate. Tablets were studied for dissolution for 24 hours and found to exhibit controlled release of metoprolol succinate remaining buoyant for 16 hours. The release profile indicated first order kinetics and the release of the drug was diffusion controlled.1
Ø Rabi N et al., formulated and evaluated floating mucoadhesive tablets of metoprolol succinate were developed to prolong its release and improve bioavailability by avoidance of first pass metabolism during the treatment of chronic hypertension. Tablets were prepared by direct compression using directly compressible polymers such as HPMC K4M, HPMC K15M, sodium carboxy methyl cellulose and carbopol 940P and were evaluated for buoyancy test, mucoadhesion force, swelling study, drug content, ex-vivo mucoadhesion strength and in-vitro release profile. Results indicated that the release from the formulation containing 35 mg of HPMC K4M best fitted square root kinetics.2
Ø Patel A et al., formulated a novel gastro retentive controlled release drug delivery system of verapamil HCl to increase the gastric retention time of the dosage form and to control drug release. HPMC K4M, HPMC K15M, carbopol 934P, carbopol 940P and xanthan gum were incorporated for gel-forming properties. Buoyancy was achieved by adding an effervescent mixture of sodium bicarbonate and anhydrous citric acid. In vitro drug release studies were performed, and drug release kinetics was evaluated using the linear regression method. The optimized intragastric floating tablet composed of 3:2 of HPMC K4M to xanthan gum exhibited 95.39% drug release in 24h. while the buoyancy lag time was 36.2s, and the intragastric floating tablet remained buoyant for more than 24h.3
Ø Streuble A et al., formulated single unit dosage form which consist of polypropylene, matrix-forming polymer, foam powder, drug and filler. This system is based on low density foam powder and matrix-forming polymer like methylcellulose, polyacrylates, sodium alginate, corn starch, carrageenan, gum guar, and gum arabic. In vitro floating performance and the ability to control drug release over prolonged time have been demonstrated. The drug release patterns can effectively be adjusted by varying simple formulation parameters, such as the matrix-forming polymer/ foam powder ratio, initial drug loading, tablet height and diameter, type of matrix forming polymer, addition of water soluble and water insoluble fillers, and the use of polymer blends. Thus, desired release profiles adapted to the pharmacokinetic/ pharmacodynamic properties of the incorporated drug can easily be provided.4
Ø Srivastava AK et al., evaluated microspheres with cimetidine as a model drug for prolongation of gastric residence time. The microspheres were prepared by the solvent evaporation method using polymer HPMC and ethyl cellulose. The shape and surface morphology of the prepared microspheres were characterized by optical and scanning electronic microscope. In-vitro data obtained for floating microspheres of cimetidine showed excellent and prolonged drug release for approximately 8 hours. 5
Ø Patel VF et al., described the influence of content of polyethylene oxide and ratio of lactose to starch 1500 on dipyridamole release from self correcting floating matrix tablets using 32 full factorial design. Tablets were evaluated for in-vitro floating ability and drug release using USP 24 type II apparatus using 0.1N HCl at 100 rpm and temperature of 37±0.5º. All formulations floated within 2 min and had total floating time of more than 12 hours. As the content of the polymer increased, the release rate declined with increase in value of diffusion exponent giving anomalous drug release to zero order drug release. It was observed that above a certain threshold level of polymer content, further increase did not contribute significantly for percentage drug release. Lactose gave higher drug release with release mechanism toward zero order compared to starch 1500 which gave slower release with release mechanism towards diffusion based. Although both the factors significantly contributed for percentage drug release at different time point, the content of polymer dominated. It was observed that polymer content was a dominant controlling factor for drug release kinetics and it could be controlled by employing various blends of fillers.6
Ø Kumar R et al., developed and evaluated floating matrix tablets of metformin hydrochloride. Floating matrix tablets were formulated using gas generating agent (potassium bicarbonate) and hydrophilic gelling polymer HPMC 15000 cps (hypromellose) by wet granulation technique. Upon contact with gastric fluid, hydrogels formed that showed presence of porous structure in matrix granules. Formulations with high amount of HPMC 15000 cps (hypromellose) were found to float for a longer duration and provide more sustained release of drug.7
Ø Narendra C et al., developed an optimized gastric drug delivery system (GFDDS) containing metoprolol tartrate (MT) as a model drug. A 23 factorial design was employed in formulating the GFDDS with total polymer content to drug ratio (X1 ), polymer to polymer ratio(X2) and different viscosity grades of HPMC(X3) as independent variables. Four dependent variables were considered: percentage of MT release at 8 hours,T 50 %, diffusion coefficient and floating time. The results indicated that X 1 and X 2 significantly affected the floating time and release properties, but the effect of different viscosity grades of HPMC (K4M and K10M) was non-significant. Fickian release transport was confirmed as the release mechanism from optimized formulation.8
Ø Ali J et al., developed a hydrodynamically balanced system for celecoxib as single unit floating capsules using various grades of low density polymers for formulation of these capsules. The capsules were prepared by physical blending of celecoxib and polymer in varying ratio. Capsules prepared with polyethylene oxide 60K and Eudragit RL100 give the best in-vitro release of 78-79% in 8hrs in citrate phosphate buffer pH 3.0 with 1% sodium lauryl sulphate. The release of celecoxib from the matrix formulation followed zero order release kinetics.9
Ø Yang L et al., designed triple layer tablet with floating drug delivery system using HPMC K4M and polyethylene oxide as the major controlling polymeric excipients. The design was based on the swellable asymmetric approach, with floating features in order to prolong the gastric retention time of the delivery system. Tetracycline and metronidazole were incorporated into the core layer of triple layer matrix for controlled delivery, while bismuth salt was included in one of the outer layers for instant release. Here triple layer technology can be rationally designed for instant drug release as well as sustained delivery over 6-8 hours. The floating feature possibly prolonged the gastric retention time and maintained high localized concentrations of drug.10
Ø Gangadharappa HV et al., designed the controlled release floating tablet of Atenolol using Karya gum and HPMC K4M as matrix polymer based on gas formulation technique in order to develop prolong gastric residence time and to increase the overall bioavailability of the dosage form. Sodium bicarbonate was incorporated as a gas-generating agent. The floating tablets were prepared by direct compression technique. The tablet formulations of Atenolol were evaluated for weight variation, hardness, thickness, swelling index, in vitro floating capabilities, floating lag time, drug content uniformity, compatibility studies and in vitro drug release. The results showed the formulations had good floating capability, shorter floating lag time, and sustained drug release for 12 hours. The results showed that swelling increased with increase in the concentration of karaya gum. The sodium bicarbonate present in the tablet affected the floating lag time.11
Ø Havaldar VD et al., prepared floating matrix tablets using natural polymer like xanthan gum and semi synthetic polymer like HPMC K4M and HPMC K100M. Sodium bicarbonate was used as a gas generating agent and dicalcium phosphate (DCP) was used as a channelling agent. The prepared tablets were evaluated for physiochemical parameters such as hardness, floating properties, swelling studies, and drug content. They found that the prolonged floating duration can be achieved by using the polymer Xanthan gum and formulation containing Xanthan gum retarded the release of the drug as the polymer swelling is crucial in determining the release rate.12
Ø Sungthongjeen S et al., developed the multi-unit floating drug delivery system based on gas formation technique in order to prolong the gastric residence time and to increase the overall bioavailability of the dosage form. The system consists of the drug-containing core pellets prepared by extrusion-spheronization process, which are coated with double layers of an inner effervescent layer and an outer gas-entrapped polymeric membrane of an aqueous colloidal polymer dispersion like Eudragit RL 30D, RS 30D, NE 30D. Only the system using Eudragit RL 30D as a polymeric membrane had high water and low CO2-permeabilities with high flexibility. The system could float completely within 3 min and maintain the buoyancy over a period of 24 hours.13
6.3 OBJECTIVES OF THE STUDY:
The objectives of the present study is highlighted as given below;
ü Analytical method development for the Metoprolol succinate.
ü To evaluate compatibility between drug-polymers and other excipients.
ü To carry out pre-formulation studies.
ü To develop and formulate controlled release floating delivery system.
ü To evaluate post compression parameters like Weight variation, Hardness, Friability, Content uniformity, Floating time, Specific Gravity, In vitro buoyancy studies, Weight gain and water uptake etc.