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Journal of Pharmacy Research V ol.11 Issue 2 February 2017 Raghavendra Kumar Gunda et al. / Journal of Pharmacy Research 2017112167-178 167-178 Review Article ISSN: 0974-6943 Available online through http://jprsolutions.info Corresponding author. Mr.Raghavendra Kumar Gunda M.Pharm Research Scholar School of Pharmaceutical Sciences VISTAS V els University Pallavaram Chennai Tamilnadu India- 600117. Formulation Development and Evaluation of Gastro Retentive Drug Delivery Systems- A Review Raghavendra Kumar Gunda 1 A.V ijayalakshmi 2 1 Research Scholar School of Pharmaceutical Sciences VISTAS V els University Pallavaram Chennai Tamilnadu India- 600117. 2 School of Pharmaceutical Sciences VISTAS V els University Pallavaram Chennai Tamilnadu India- 600117. Received on:12-01-2017 Revised on: 19-02-2017 Accepted on: 27-02-2017 ABSTRACT In recent years many advancement has been made in research and development of Oral Drug Delivery System. Concept of Novel Drug Delivery System arose to overcome the certain aspect related to physicochemical properties of drug molecule and the related formulations. Purpose of this review is to compile the recent literature with special focus on Gastro Retentive Drug Delivery Systems to give an update on pharmaceutical approaches used in enhancing the Gastric Residence Time GRT. V arious approaches are currently used including Gastro Retentive Floating Drug Delivery SystemsGRFDDSswelling and expanding system polymeric bioadhesive systems modified- shape systems high density system and other delayed gastric emptying devices. These systems are very helpful to different problem solve during the formulation of different dosage form. The present work also focuses on the polymers used in floating drug delivery systems mostly from natural origin. Floating drug delivery systems are less dense than gastric fluids hence remain buoyant in the upper GIT for a prolonged period releasing the drug at the desired/ predeterminedrate. This review article focuses on the recent technological development in floating drug delivery systems with special emphasis on the principal mechanism of floatation and advantages of achieving gastric retention brief collection on various polymers employed for floating drug delivery systems etc. In addition this review also summarizes the In –Vitro and In -Vivo studies to evaluate their performance and also their future potential. KEY WORDS: Controlled release Floating lag time Floating duration/ Gastric residence time Gastro retentive drug delivery systems Natural gums Bioadhesive. INTRODUCTION Oral administration is the most convenient andpreferred means of any drug delivery to thesystemic circulation.The effective oral drugdelivery practice depends on various factors like gastricemptying process gastrointestinal transit time of dosageform drug release from dosage form and site ofabsorption of drug 1-3 . Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control the emptying time is a valuable asset for dosage forms which reside in the stomach for a longer period of time than conventional dosage forms.It has been frequently observed thatmany drugs which are easily absorbed at uppergastrointestinal tract GIT eliminated quickly in to lowerGIT because of the peristaltic movement. So it leads toincomplete absorption of drugs from upper part of GIT. To overcome this limitation the development of oralgastro retentive sustained or controlled releaseformulations is an attempt to release the drug slowly atupper GIT to maintain effective drug concentration insystemic circulation for a prolonged period 3 . Several difficulties are faced in designing controlled release systems for better absorption and enhanced bioavailability 4 . Gastroretentive systems 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 for drugs that are less soluble in a high pH environment. It has applications also for local drug delivery to the stomach and proximal small intestines.Gastric retention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits for patients. The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion flotation

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Journal of Pharmacy Research V ol.11 Issue 2 February 2017 Raghavendra Kumar Gunda et al. / Journal of Pharmacy Research 2017112167-178 167-178 sedimentation High density expansion modified shape systems or by the simultaneous administration of pharmacological agents that delay gastric emptying.Several recent examples have been reported showing the efficiency of such systems for drugs with bioavailability problems 4-6 . Approaches to increase gastric residence time include  High-density systems  Bioadhesive or Mucoadhesive systems  Swelling and Expanding Systems  Superporous Hydrogels  Ion Exchange Resins  Bioadhesive Liposomal Systems  Raft-forming systems  Gas-generating systems  Low-density systems Floating systems / Hydrodynamically Balanced Systems Floating Drug Delivery Systems GRFDDS These are the low density systems having their density lesser than the gastric fluid 1.004 gm/cm 3 and thus remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period. GRFDDS are classified into two major categories 7-13 . Effervescent systems/ Gas generating systems In this system floatability can be achieved by the generation of gas bubbles. They are formulated in such a way that when in contact with the acidic gastric contents CO 2 is liberated and gets entrapped in swollen hydrocolloids which provides buoyancy to the dosage forms. In vitro the lag time before the unit floats is l minute and buoyancy is prolonged for 8-10 hours. Bilayer or multilayer systems have also been designed in which drug and excipients can be formulated independently and the gas generating unit can be incorporated into any of the layers of multiple unit systems which avoids the ‘all-or-nothing’ emptying process encountered in single unit systems 14-15 . It must form a cohesive gel barrier. It should release contents slowly to serve as a reservoir 16 . Gas-generating Effervescent systems.a Bilayer gas-generating systems with c or without b semi permeable membrane. Hydrodynamically balance systems are best suited for drugs having a better solubility in acidic environment and also for the drugs having specific site of absorption in the upper part of the small intestine. To remain in the stomach for a prolonged period of time the dosage form must have a bulk density of less than 1. It should stay in the stomach maintain its structural integrity and release drug constantly from the dosage form. HBS are single-unit dosage form containing one or more gel-forming hydrophilic polymers. Hydroxypropyl methylcellulose HPMC hydroxethyl cellulose HEC hydroxypropyl cellulose HPC sodium carboxymethyl cellulose NaCMC polycarbophil polyacrylate polystyrene agar carrageenans or alginic acid are commonly used excipients to develop these systems 17-18 . The polymer is mixed with drug and usually administered in a gelatin capsule. The capsule rapidly dissolves in the gastric fluid at body temperature and hydration. Table 1:Polymers and other ingredients used for increasing GRT 19 Polymers and other ingredients Example Hydrocolloids 20-75 Acacia Pectin Chitosan Agar Casein Bentonite Veegum HPMC K4M K100M and K15M Gellan gum Sodium CMC MC Calcium alginate Eudragit S100 Eudragit RL Propylene foam Eudragit RSethyl cellulose Polyethylene oxide β Cyclodextrin CMC Polyethylene glycol polycarbonate PVA Sodium alginate HPC-L CP 934P HPC Eudragit S Metolose S.M. 100 PVP HPC-H HPC-M HPMC K15 Acrylic polymer E4 M and Carbopol. Inert fatty materials 5- 75 Beeswax fatty acids long chain fatty alcohols Gelucires® 39/01 and 43/01. Effervescent agents Sodium bicarbonate citric acid tartaric acid Di- SGC Di-Sodium Glycine Carbonate CG Citroglycine. Release rate accelerants 5-60 Lactose Mannitol Release rate retardants 5-60 Dicalcium phosphate Talc Magnesium stearate Buoyancy increasing agents upto80 Ethyl cellulose Low density material Polypropylene foam powder Accurel MP 1000®. Effervesant Layers Inner and outer sublayer Conventional sustain release pills Swelable membrane layer H 2 O A B A Multiple-unit oral floating drug delivery system. B Working principle of effervescent floating drug delivery

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Journal of Pharmacy Research V ol.11 Issue 2 February 2017 Raghavendra Kumar Gunda et al. / Journal of Pharmacy Research 2017112167-178 167-178 High-density systems These systems which have a density of 3 g/cm 3 are retained in the rugae of the stomach and are capable of withstanding its peristaltic movements. Above a threshold density of 2.4–2.8 g/cm 3 such systems can be retained in the lower part of the stomach. 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 which is the part of the organ with the lowest position in an upright posture. 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 the diameter of the pellets. A density close to threshold density seems necessary for significant prolongation of gastric residence time. Commonly used excipients are barium sulphate zinc oxide titanium dioxide and iron powder etc. These materials increase density by up to 1.5–2.4g/cm 3 20-23 . Swelling and Expanding Systems Swelling and expanding systems are dosage forms that after swallowing swell to an extent that prevents their exit from the pylorus 24 . As a result the dosage form is retained in the stomach for a long period. These systems may be called ‘plug type systems’ since they exhibit a tendency to be logged at the pyloric sphincter. Swelling and controlled release of the drug may be achieved on contact of the drug delivery system with gastric fluid the polymer imbibes water and swells. Extensive swelling of the polymer is the result of the presence of physical-chemical crosslinks in the hydrophilic polymer network. The bulk enables gastric retention and maintains the stomach in a ‘fed’ state suppressing housekeeper waves 2526 . Medicated polymer sheets or swelling balloon hydrogels are examples of such delivery systems. A balance between the rate and extent of swelling and the rate of erosion of the polymer is crucial to achieve optimum benefit and to avoid adverse effects. They are explained as follows Non-Effervescent systems 27 . Colloidal gel barrier systems These systems incorporate a high level 20-75 w/w of one or more gel forming highly swellablecellulose type hydrocolloids polysaccharides and matrix forming polymers. On coming in contact withgastric fluid the hydrocolloids in the system hydrate and form a colloidal gel barrier around its surface.This gel barrier controls the rate of fluid penetration into the device and consequent release of the drug 27 . inside a micro-porous compartment with apertures along its top and bottom walls. The peripheral walls of the drug reservoir compartment are completelysealed to prevent any direct contact of the gastric mucosal surface with the undissolved drug. Multiparticulate system Floating Beads In these systems the dosage of the drug substances is divided on a plurality of subunit typically consisting ofthousands of spherical particles with diameter of 0.05-2.00 mm. Thus multi particulate dosage forms arepharmaceutical formulations in which the active substance is present as a number of small independent subunits.To deliver the recommended total dose these subunits are filled into a sachet. Microballons various approaches are made in delivering substances to the target site in a controlled release fashion. Oneof such approach is using polymeric microballoons as carrier for drugs. Hollow microspheres are known as themicroballoons. Microballoons were floatable in vitro for 12 hrs when immersed in aqueous media. Radio graphicalstudies proved that microballoons orally administered to human were dispersed in the upper part of stomach andretained there for three hr against peristaltic movements. Super porous Hydrogels In this approach to improve gastric retention time GR T super porous hydrogels of average pore size 100 micro meter swell to equilibrium size within a minute due to rapid water uptake by capillary wetting through numerous interconnected open pores. They swell to a large size swelling ratio: 100 or more and are intended to have sufficient mechanical strength to withstand pressure by gastric contraction. This is achieved by co-processing with a hydrophilic particulate material croscarmellose sodium. Which forms a dispersed phase within the continuous polymer matrix during the synthesis ‘superporous hydrogel composites’. The superporous hydrogel composites stay in the upper GIT for 24 hours. Recent advances in the field have led to “superporous hydrogel hybrids” which are prepared by adding a hydrophillic or water dispersible polymer that can be cross-linked after the superporous hydrogel is formed. Examples of hybrid agents include polysaccharides such as sodium alginate pectin and chitosan 28-30 . Ion-Exchange Resins A coated ion exchange resin bead formulation has been shown to have gastric retentive properties which was loaded with bicarbonates. Ion exchange resins are loaded with bicarbonate and a negatively charged drug is bound to the resin resultant beads were then This technology is based on the encapsulation of a drug reservoir Micro porous compartment systems

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Journal of Pharmacy Research V ol.11 Issue 2 February 2017 Raghavendra Kumar Gunda et al. / Journal of Pharmacy Research 2017112167-178 167-178 encapsulated in a semipermeable membrane to overcome the rapid loss of carbon dioxide. Upon arrival in the acidic environment of the stomach and exchange of chloride and bicarbonate ions take place. As a result of this reaction carbon dioxide was released and trapped in a membrane thereby carrying beads towards the top of gastric content and producing a floating layer of resin beads in contrast the uncoated beads which will sink quickly 31-34 . Bioadhesive or Mucoadhesive Systems The term “mucoadhesion” is commonly used to describe an interaction between the mucin layer that lines the entire GIT and a bioadhesive polymer. Bioadhesive drug delivery systems BDDS are used as a delivery device within the lumen to enhance drugabsorption in a site specific manner. This approach involves the use of bioadhesive polymers which can adhere to the epithelial surface in the stomach. Thus they prolong the gastric retention time 35-36 . Bioadhesion can be explained by 37-38  The absorption theory  The electron theory  The wetting theory  The diffusion theory Bioadhesive mechanism Bioadhesive liposomal Systems Mucoadhesive liposomal systems are formulated by coating a polymer to facilitate enteral absorption of poorly absorbed drugs. Liposomes are generally coated with mucoadhesivepolymers such as chitosan carbopol Carboxymethyl chitin and carboxymethyl chitosan. The mucoadhesion of the resultant liposomes leads to an enhanced GRT of the dosage forms 39-40 . Raft forming systems Raft forming systems have received much attention for the drug delivery for gastrointestinal infections and disorders. Floating Rafts have been used in the treatment of Gastric esophageal reflux disease GERD. The mechanism involved in the raft formation includes the formation of viscous cohesive gel in contact with gastric fluids where in each portion of the liquid swells forming a continuous layer called a raft. This raft floats on gastric fluids because of low bulk density created by the formation of CO 2 . Usually the system ingredients includes a gel forming agent and alkaline bicarbonates or carbonates responsible for the formation of CO2 to make the system less dense and float on the gastric fluids . Jorgen et al described an antacid raft forming floating system. The system contains a gel forming agent e.g. sodium alginate sodium bicarbonate and acid neutralizer which forms a foaming sodium alginate gel raft which when comes in contact with gastric fluids the raft floats on the gastric fluids and prevents the reflux of the gastric contents i.e. gastric acid into the esophagus by acting as a barrier between the stomach and esophagus 41-42 . FACTORS AFFECTING Gastro Retention Time of Floating Drug Delivery Systems The various factors which influence the efficacy of Gastro Retentive Drug Formulation‘s as a gastro-retentive systems are: Formulation Factors and Idiosyncratic Factors 2743 Formulation Factors Density GRT is a function of dosage form buoyancy that is dependent on the density . The density of a dosage form also affects the gastric emptying rate. A buoyant dosage form having a density of less than that of the gastric fluids floats. Since it is away from the pyloric sphincter the dosage unit is retained in the stomach for a prolonged period. Drug floatation is a function of time and it could least until hydrodynamic equilibrium is achieved. Dosage forms having larger density then the gastric content sink at the bottom of the atrium where they settle and release the active compound in a controlled manner over a prolonged period of time. Size Dosage form units with a diameter of more than 7.5 mm are reported to have an increased GRT compared with those with a diameter of 9.9 mm. Larger dosage forms tend to have longer gastric retention time than smaller ones because they are emptied in the digestive phase weaker MMC and also because their passage through the pyloric sphincter into the small intestine is hindered. Shape of dosage form: Tetrahedron and ring shaped devices with a flexural modulus of 48 and 22.5 kilo pounds per square inch KSI are reported to have

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Journal of Pharmacy Research V ol.11 Issue 2 February 2017 Raghavendra Kumar Gunda et al. / Journal of Pharmacy Research 2017112167-178 167-178 better GR T 90 to100 retention at 24 hours compared with other shapes. Under fasting conditions the GI motility is characterized by periods of strong motor activity or the MMC that occurs every 1.5 to 2 hours. The MMC sweeps undigested material from the stomach and if the timing of administration of the formulation coincides with that of the MMC the GRT of the unit can be expected to be very short. However in the fed state MMC is delayed and GRT is considerably longer. Viscosity Grade of Polymer: Drug release and floating properties of GRFDDS are greatly affected by viscosityof polymers and their interaction. Low viscosity polymers e.g. HPMC K100 LV were found to be morebeneficial than high viscosity polymers e.g. HPMC K4M in improving floating properties. In addition adecrease in the release rate was observed with an increase in polymer viscosity. Nature of meal Feeding of indigestible polymers or fatty acids salts can change the motility pattern of the stomach to a fed state thus decreasing the gastric emptying rate and prolonging drug release. Type of meal and its caloric content volume viscosity and co-administered drugs affect gastric secretions and gastric emptying time. The rate of emptying primarily depends on caloric contents of the ingested meal. It does not differ for proteins fats and carbohydrates as longas their caloric contents are the same. Generally gastric emptying is slowed down because of increased acidity osmolarity and calorific values.Gastric residence time increases in the presence of food leading to increased drug dissolution of the dosage form at the most favorable site of absorption. A GRT of 4-10 hours has been reported after a meal of fats and proteins. Frequency of feed The GRT can be increased by over 400 minutes when successive meals are given compared with a single meal due to the low frequency of MMC. Idiosyncratic Factors Idiosyncrasy is genetically determined abnormality to a chemical. The drug interacts with some unique feature of theindividual not found in majority of subjects and produces the uncharacteristic reaction. The type of reaction isrestricted to individuals with a particular genotype. It may also depends on- Gender their age and race matched female counterparts 4.6±1.2 hours regardless of theweight height and body surface.Mean ambulatory GRT in males 3.4 ± 0.6 hours is less compared with their age and race matched female counter parts 4.6 ± 1.2 hours regardless of the weight height and body surface. Age Low gastric emptying time is observed in elderly than do in younger subjects. Intra subject and inter subjectvariations also are observed in gastric and intestinal transit time. Elderly people especially those over 70 years havea significantly longer GRT. Elderly people especially those above 70 have a significantly longer GRT. Posture GRT can vary between supine and upright ambulatory states of the patient Upright Position: An upright position protects floating forms against postprandial emptying because the floatingform remains above the gastric contents irrespective of its size. Floating dosage forms show prolonged and morereproducible GRTs while the conventional dosage form sink to the lower part of the distal stomach from wherethey are expelled through the pylorus by astral peristaltic movements. Supine Position: This position offers no reliable protection against early and erratic emptying. In supine subjectslarge dosage forms both conventional and floating experience prolonged retention. The gastric retention offloating forms appear to remain buoyant anywhere between the lesser and greater curvature of the stomach. On moving distally these units may be swept away by the peristaltic movements that propel the gastric contentstowards the pylorus leading to significant reduction in GRT compared with upright subjects. Concomitant Intake of Drugs: Drugs such as prokinetic agents e.g. metoclopramide and cisapride anticholinergics e.g. atropine or propantheline opiates e.g. codeine may affect the performance of GRFDDS. The co- administration of GI-motility decreasing drugs can increase gastric emptying time. Biological factors Diseases like gastroenteritis gastric ulcer pyloric stenosis diabetes and hypothyroidism retard gastric emptying. Partial or total gastrectomy duodenal ulcer and hypothyroidism promote gastric emptying rate. Women have slower gastric emptying time than men. Mean ambulatory GRT in meals 3.4±0.4 hours is less as compared with

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Journal of Pharmacy Research V ol.11 Issue 2 February 2017 Raghavendra Kumar Gunda et al. / Journal of Pharmacy Research 2017112167-178 167-178 Advantages of GRFDDS Increasing the GRT with either of the approaches offers several advantages such as:  Acidic drug substances like aspirin cause irritation on the stomach wall when come in to contact with it. Hence HBS formulation may be useful for the administration of aspirin and other similar drugs.  The Floating systems are advantageous for drugs meant for local action in the stomach. e.g. antacids.  The GRFDDS are advantageous for drugs absorbed through the stomach ex: Ferrous salts Antacids. Improved drug absorption because of increased GRT and more time spent by the dosage form at its absorption site.  Controlled delivery of drugs.Minimizing the mucosal irritation due to drugs by drug releasing slowly at controlled rate.The controlled slow delivery of drug to the stomach provides sufficient local therapeutic levels and limits the systemic exposure to the drug. This reduces side effects that are caused by the drug in the blood circulation. In addition the prolonged gastric availability from a site directed delivery system may also reduce the dosing frequency.  Administration of prolongs release floating dosage forms tablet or capsules will results in dissolution of the drug in the gastric fluid. They dissolve in the gastric fluid would be available for absorption in the small intestine after emptying of the stomach contents. It is therefore expected that a drug will be fully absorbed from the floating dosage forms if it remains in the solution form even at the alkaline pH of the intestine.  When there is vigorous intestinal movement and a shorted transit time as might occur in certain type of diarrhea poor absorption is expected. Under such circumstances it may be advantageous to keep the drug in floating condition in stomach to get a relatively better response.  As sustained release systems floating dosage forms offer various potential advantages. Drugs that have poor bioavailability because their absorption is limited to upper GI tract can be delivered efficiently thereby maximizing their absorption and improving their absolute bioavailability.  Floating dosage forms with SR characteristics can also be expected to reduce the variability in transit performance. In addition it might provide a beneficial strategy for gastric and duodenal cancer treatment. The concept of GRFDDS has also been utilized in the development of various anti- reflux formulations Disadvantages/Limitations of GRFDDS:  Floating system is not feasible for those drugs that have solubility or stability problem in G .I. tract.  These systems require a high level of fluid in the stomach for drug delivery to float and work efficiently.  Drugs showing absorption window at stomach region are only considered to be better candidates.  Drugs such as Nifedipine which is well absorbed along the entire GI tract and also undergo significant first-pass metabolism may not be suitable candidates for increasing the GRT since the slow gastric emptying may lead to reduced systemic bioavailability. Also there are limitations to the applicability of GRFDDS for drugs that are irritant to gastric mucosa.  The dosage form should be administered with a full glass of water 200-250 ml.  These systems do not offer significant advantages over the conventional dosage forms for drugs which are absorbed throughout the gastrointestinal tract.  The use of large single-unit dosage forms sometimes poses a problem of permanent retention of rigid large-sized single- unit forms especially in patients with bowel obstruction intestinal adhesion gastropathy or a narrow pyloric opening mean resting pyloric diameter 12.8 ± 7.0 mm POTENTIAL DRUG CANDIDA TE FOR GRFDDS GRFDDS is beneficial for drug candidate which have stability problems at alkaline pH captopril ranitidine HCl metronidazole Drugs having narrow absorption window in stomach or upper part of small intestine L-DOPA p- aminobenzoic acid furosemide riboflavin

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Journal of Pharmacy Research V ol.11 Issue 2 February 2017 Raghavendra Kumar Gunda et al. / Journal of Pharmacy Research 2017112167-178 167-178 Drugs those are locally active in the stomach misroprostol antacids Drugs that exhibit low solubility at high pH values e.g. diazepam chlordiazepoxide verapamil Drugs that disturb normal colonic microbes e.g. antibiotics used for the eradication of Helicobacter pylori suchas tetracycline clarithromycin amoxicillin Table 2: The Potential Candidates for GRFDDS Formulation Drug candidates Floating microspheres Aspirin Griseofulvin p-nitroaniline Ibuprofen Ketoprofen Piroxicam Verapamil Cholestyramine Theophylline Nifedipine Nicardipine Dipyridamol Tranilast and Terfinadine Floating granules Diclofenac sodium Indomethacin and Prednisolone Films Cinnarizine Albendazole Floating tablets and PillsAcetaminophen Acetylsalicylic acid Ampicillin Amoxycillintrihydrate Atenolol Fluorouracil Isosorbide mononitrate Para- aminobenzoic acid Piretanide Theophylline Verapamil hydrochloride Chlorpheniramine maleate Aspirin Calcium Carbonate Fluorouracil Prednisolone Sotalol pentoxyfilline and DiltiazemHCl Atenolol ciprofloxacin. Floating Capsules Chlordiazepoxide hydrogen chloride Diazepam Furosemide Misoprostol L- Dopa Benserazide Ursodeoxycholic acid and Pepstatin and Propranolol Formulation of Floating Dosage Form The following types of the ingredients can be incorporated in to GRFDDS Hydrocolloids Inert fatty materials Release rate accelerants Release rate retardant Buoyancy increasing agents Miscellaneous Hydrocolloids: Suitable hydrocolloids are synthetic anionic or non-ionic like hydrophilic gums modifiedcellulose derivatives. e.g. Acacia pectin agar alginates gelatin casein bentonite veegum MC HPC HEC and SCMC can be used. The hydrocolloids must hydrate in acidic medium i.e. gastric fluid is having pH 1.2.Althoughthe bulk density of the formulation may initially be more than one but when gastric fluid is enter in the system itshould be hydro-dynamically balanced to have a bulk density of less than one to assure buoyancy. Table 3: Polymers and their Applications in GRFDDS 1927 Name of Pharmaceutical A Application in GRFDDS the polymer pplications Pec tin Adsorbent Pectin gel beads have been emulsifying agent shown to be an effective Gelling agent medium for controlling the thickening agent release of a drug within the stabilizing agent. gastrointestinal GI tract. Acacia Emulsifying and Used in novel tablet suspending agent formulations and modified binder viscosity- release tablets enhancer Agar Emulsifying agent It has been investigated in a stabilizing agent number of experimental suppository base pharmaceutical applications suspending agent including as a Sustained tablet binder release agent in gels beads thickening agent microspheres and tablets. viscosity-increasing agent Gelatin Coating agent Low-molecular-weight film-former gelatin has been investigated Gelling agent for its ability to enhance the suspending agent dissolution of orally tablet binder ingested drugs. Ibuprofen– viscosity-increasing gelatin micro pellets have agent. been prepared for the controlled release of the drug. Alginic Acid Stabilizing agent Alginate gel beads capable suspending agent of floating in the gastric sustained release cavity have been prepared adjuvant tablet binder the release properties of tablet disintegrant which were reported to be Viscosity increasing applicable for sustained agent release of drugs and for targeting the gastric mucosa. C hito s an Coating agent Chitosan has been processed disintegrant into several pharmaceutical filmformer forms including gels films mucoadhesive binder beads microspheres tablets viscosity-increasing and coatings for liposomes. agent. Ethylcellulose Coating agent Studies have also suggested flavoring fixative ethylcellulose for use in Tablet binder floating microparticles tablet filler viscosity- Based on low-density foam Increasing agent. powder for gastro retentive drug delivery systems Polycarbophil Adsorbent Floating-bioadhesive bioadhesive microspheres coated with Controlled release poly carbophil have been tablet binder found to be a useful gastro emulsifying agent retentive drug delivery thickening agent system for the treatment of suspending agent. Helicobacter pylori. Sodium Alkalizing agent Sodium bicarbonate has bicarbonate therapeutic agent. been used as a gas-forming agent in alginate raft systems and in floating controlled-release oral dosage forms of furosemide and cisapride. Inert fatty materials: Edible pharmaceutical inert fatty material having a specific gravity

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Journal of Pharmacy Research V ol.11 Issue 2 February 2017 Raghavendra Kumar Gunda et al. / Journal of Pharmacy Research 2017112167-178 167-178 less than one can beadded to the formulation to decrease the hydrophilic property of formulation and hence increases the buoyancy e.g.Purified grades of beeswax fatty acids long chain alcohols glycerides and mineral oils can be used. Release rate accelerant: The release rate of the medicament from the formulation can be modified by includingexcipient like lactose and/or mannitol. These may be present from about 5-60 by weight. Super Disintegrant Release rate retardants: Insoluble substances such as di-calcium phosphate talc magnesium stearate decreases thesolubility and hence retard the release of medicaments. Buoyancy Increasing agents: Materials like ethyl cellulose which has bulk density less than one can be used forenhancing the buoyancy of the formulation. It may be adapted up to 80 by weight. Table 4: List of Marketed Products with increased GRT 44 Brand name Drug dose Company country Dosage form Madopar® Levodopal00mg benserazide25mg Roche Products US Floating controlled release capsule Valrelease® Diazepam 15mg Hoffmann-La Roche US Floating capsule Liquid Gaviscon® Al. hydroxide 95mg Mg. carbonate 358mg GlaxoSmithKline India Raft-forming liquid alginate preparation Topalkan® Aluminium-magnesium antacid Pierre Fabre Drug France Floating liquid alginate preparation Conviron® Ferrous sulphate Ranbaxy India gel-forming floating system Cifran OD® Ciprofioxacin 500mg 1g Ranbaxy India Gas-generating floating tablet Oflin OD® Ofloxacin 400mg Ranbaxy India Gas-generating floating tablet Cytotec® Misoprostol 100ng Pharmacia US Bilayer floating capsule Miscellaneous: Pharmaceutically acceptable adjuvant like preservatives stabilizers and lubricants can beincorporates in the dosage forms as per the requirements. They do not adversely affect the hydrodynamic balance of the systems. A list of Polymers and their Applications in GRFDDS are given in Table 3. Evaluation of Floating Drug Delivery System: Evaluation of a formulation and parameters to be evaluated is a critical aspect in formulation technology. Aschematic on evaluation of GRFDDS is shown as in Schematic Diagram. Evaluation of Powder Blend as per general Pharmacopoeial specifications such as Angle of Repose Bulk Density Tapped Density Hausners Ratio Compressibility Index etc. Evaluation of Floating Tablets Pharmacopoeial Tests Hardness 46 The hardness of the tablets was tested by diametric compression using a Monsanto Hardness Tester. A tablet hardness of about 2-4 Kg/cm 2 is considered adequate for mechanical stability. Friability 46 The friability of the tablets was measured in a Roche Friabilator. 20 Tablets were taken Weighed and Initial weight was noted W 0 are dedusted in a drum for a fixed time 100 Freefalls in a Roche Friabilator and weighed W again. Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss should not be more than 1 Friability Initial weight- Final weight / Initial weight x 100 Content Uniformity 46 In this test 20 tablets were randomly selected and the percent drug content was determined the tablets contained not less than 85 or not more than 115 100±15 of the labeled drug content can be considered as the test was passed. Schematic Diagram of Evaluation of Floating Drug Delivery System

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Journal of Pharmacy Research V ol.11 Issue 2 February 2017 Raghavendra Kumar Gunda et al. / Journal of Pharmacy Research 2017112167-178 167-178 Assay 47 The drug content in each formulation was determined by triturating 20 tablets and powder equivalent to average weight was dissolved in 100ml of 0.1N Hydrochloric acid by sonication for 30 min. The solution was filtered through a 0.45μ membrane filter diluted suitably and the absorbance of resultant solution was measured spectrophotometrically at λmax of API nm using 0.1 N Hydrochloric acid as blank . Thickness 46 Thickness of the all tablet formulations were measured using verniercalipers by placing tablet between two arms of the verniercalipers. In-Vitro Buoyancy Studies 48-49 The tablets were placed in a 100-mL beaker containing 0.1N HCl. The time required for the tablet to rise to the surface and float was determined as floating lag time. Buoyancy W f /W f +W s 100 Where W f and W s are the weights of floating and settled microspheres respectively. In-Vitro Dissolution Study 50-51 The In-vitro dissolution study for the Floating tablets were carried out in USP XXIII type-II dissolution test apparatus Paddle type using 900 ml of 0.1 N HCl as dissolution medium at 50 rpm and temperature 37±0.5°C. At predetermined time intervals 5 ml of the samples were withdrawn by means of a syringe fitted with a pre-filter the volume withdrawn at each interval was replaced with same quantity of fresh dissolution medium. The resultant samples were analyzed for the presence of the drug release by measuring the absorbance at λmax of API nm using UV Visible spectrophotometer after suitable dilutions. The determinations were performed in triplicate n3 Kinetic modelling of drug release 52-57 The dissolution profile of all the formulations was fitted in to zero- order first-order Higuchi and Korsmeyer-peppas models to ascertain the kinetic modelling of drug release. In-Vivo Evaluation for Gastro-Retention: X-ray/ Gamma Scintigraphy: X ray/Gamma Scintigraphy is a very popular evaluation parameter for floatingdosage form nowadays. It helps to locate dosage form in the gastrointestinal tract GIT by which one can predictand correlate the gastric emptying time and the passage of dosage form in the GIT. Here the inclusion of aradio opaque material into a solid dosage form enables it to be visualized by X rays. Similarly the inclusion of a  emitting radionuclide in a formulation allows indirect external observation using a  camera or scintiscanner. Incase of  scintigraphy the  rays emitted by the radionuclide are focused on a camera which helps to monitor thelocation of the dosage form in the GIT. TheFormulated Tablets TranilastEudragit S BaSO4 Isardipine HPMC systemand for In-Vivo studies two healthy male volunteers administered hard gelatin capsules packed with microballons 1000 mg with 100 mL water. X-ray photographs at suitable intervals were taken 58-60 . Two phases: Phase I fasted conditions: Five healthy volunteers 3 males and 2 females in an open randomized crossover design capsules ingested in sitting position with 100 mL of tap water. Phase II fed states: Four subjects received normal or MR capsules in a crossover design after standard breakfast. V enous blood samples were taken in heparinized tubes at predetermined time intervals after dosing. In-Vivo behavior of coated and uncoated beads prepared floating beads was monitored using a single channel analyzing study in 12 healthy human volunteers of mean age 34 yrs by Gamma scintigraphy 31 . Tablet density Tablet density is an important parameter for floating tablets. The tablet would floats only when its density is less than that of gastric fluid 1.004. The density is determined using following relationship 61 V r 2 hd m/v v volume of tablet cc r radius of tablet cm h crown thickness of tablet g/cc m mass of tablet FOR MUL TIPLE UNIT DOSAGE FORMS MICROSPHERES/ MICROBALLONS 60 In case of multiparticulate drug delivery systems differential scanning calorimeter DSC particle size analysis flow properties surface morphology mechanical properties and x-ray diffraction studies are performed. Size and shape evaluation The particle size and shape plays a major role in determining solubility rate of the drugs and thus potentially its bioavailability. The particle size of the formulation can be determined using Sieve analysis Air elutriation analysis Photo analysis Optical microscope Electro

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Journal of Pharmacy Research V ol.11 Issue 2 February 2017 Raghavendra Kumar Gunda et al. / Journal of Pharmacy Research 2017112167-178 167-178 résistance counting methods Sedimentation techniques Laser diffraction methods 3162 . Morphology and surface topography The surface topography and structures were determined using scanning electron microscope SEM operated with an acceleration voltage of 10k.v Contact angle meter Atomic force microscopy AFM Contact profiliometer 62 . Percentage drug entrapment Percentage entrapment efficiency was reliable for quantifying the phase distribution of drug in the pre-pared formulations. The drug is extracted by a suitable method analyzed and is calculated from: PDE Practical Drug Loading /Theoretical Drug Loading 100 FUTURE POTENTIAL AND CONCLUSION The development of GRFDDS products is currently one of the most important challenges in pharmaceutical research. From the above review we conclude that GRFDDS products by virtue of formulation and product design provide drug release in a modified form distinct from that of the conventional dosage forms mainly at stomach region aptly applicably to drugs showing absorption at stomach site. The physicochemical properties of the drug polymer and the drug to polymer ratio govern the release of drug from the formulation. The use of one kind of polymer or another can affect the release kinetics the presence of burst effect and the mechanisms involved in the release. Natural polymers have been used significantly in designing and synthesis of novel drug delivery systems because of their biodegradable biocompatible ecofriendly nature and vast availability. Hence these natural polymers will expand the scope of new drug delivery systems in the future. With proper selection of natural polymers and their blending with other polymers better floating dosage forms with improved floating lag time floating duration and drug release can be achieved. The use of Natural Polymers can be a good replacement for synthetic polymers in the Formulation development of controlled release floating dosage forms Formulations prepared by such renewable and eco-friendly plant resources can be considered as promising floating matrix forming agents to bring about sustained release action with site specific delivery for improved bioavailability. FDDS approach may be used for various potential active agents with narrow absorption window e.g. antiviral antifungal and antibiotic agents sulphonamides quinolones penicillins cephalosporins aminoglycosides and tetracyclines. The kinetic study of drug release helps in obtaining meaningful parameters which are employed for comparative purposes and relating the release parameter with important parameters such as bioavailability which further aids in studying the influence of formulation factors on the drug release for optimization. RE FER ENC ES 1. Praveen N Mahant S Sharma D Floating systems: A novel approach towards gastro retentive drug delivery systems Int J Pharm PharmSci 22 2010 3-15. 2. Sonia D Singh TG Kumar AR Sood S Arora S Gastro retentive: controlled release drug delivery system Asian J Pharm Clin Res41 2011 5-13. 3. Satyajit Panda NeerajaSukanyaSailada Bandaru Devi SnigdhaPattnaik LaxmidharMaharana. Design of Floating Drug Delivery Systems: An Update on Polymeric Advancements with Special Reference from Natural Origin. Int. J. Pharm. Sci. Rev . Res. 391 July – August 2016 Article No. 26 Pages: 125-132. 4. Hirtz J. The git absorption of drugs in man: a review of current concepts and methods of investigation. Br J ClinPharmacol. 1985 19: 77-83. 5. Arora S. Ali J. Ahuja A. Khar R.K. Baboota S. Floating drug delivery systems: A Review AAPS Pharmscitech 2005 372-390. 6. Jain S. K. Agrawal G . P . Jain N. K. Floating microspheres as drug delivery system: Newer Approaches evaluation of porous carrier-based floating or list at microspheres for gastric delivery AAPS Pharmascitech 2006 7 54-62. 7. Kumar AJ Senthilanthan B Ravichandiran V A review article on different types of floating drug delivery systems Int J PharmPharmSci 41 2012 45-50. 8. Arunachalam A Karthikeyan K Kishore K Prasad PH Sethuraman S Ashuthoshkumar S Manidipa S Floating drug delivery systems: A review Int J Res Pharm Sci 21 2011 76-83. 9. Yeole PG Khan S Patel VF Floating drug delivery systems: Need and development Indian J Pharm Sci 673 2005 265- 272. 10. Pattan SR Wani NP Shelar MU Nirmal SA Chaudhari PD Gude RS Scope and significance of floating drug delivery system Indian Drugs 4910 2012 5-12. 11. Shweta A Ali J Ahuja A Khar RK Baboota S Floating drug delivery systems: Review AAPS PharmSciTech 63 2005 E372- E390. 12. Shah SH Patel JK Patel NV Stomach specific floating drug delivery system: A review Int J PharmTech Res 1 2009 623–33.

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Journal of Pharmacy Research V ol.11 Issue 2 February 2017 Raghavendra Kumar Gunda et al. / Journal of Pharmacy Research 2017112167-178 167-178 13. Prasad G Rao GC Studies on development and characterization of gastro retentive drug delivery system for antibiotics: Cefdinir J Pharm Res 6 2013 836-844. 14. Hasim H. Li W.P. A. Improving the release characteristics of water-soluble drugs from hydrophilic sustained release matrices by in situ gas generation. Inl J Pharm. 1987 35 201-206. 15. Krogel I. Bodlmeier R. Floating or pulsatile drug delivery systems based on coated effervescent cores. Int J Pharm. 1999 1872 175-184. 16. Srikanth MV V anitha A Weeliang PH Dharmalingam SR Ravi S Adinarayana G Preparation and in vitro characterization of noneffervescent floating drug delivery system of poorly soluble drugcarvedilol phosphate Acta Pharm 64 2014 485-494. 17. Sato Y . Kawashima Y . Takeuchi H. In vitro and in vivo evaluation of riboflavin-containing microballoons for a floating controlled drug delivery systems in healthy humans. Int J Pharm. 2004 275 97-107. 18. Kawashima Y. Niwa T. Takeuchi H. Hino T. Itoh Y . Hollow microspheres: for use as a floating controlled drug delivery system in the stomach J Pharm Sci 1992 81 135- 140. 19. Reddy LH Murthy RS. Floating dosage system in drug delivery . Crit Rev Ther Drug Carrier Syst 2002 196: 553- 85. 20. Peppas N. A. Bures P. Leobandung W. Hydrogel in pharmaceutical formulations. Eur J Pharm Sci. 2000 50 27- 46. 21. Oarke G. M. Newton J. M. Shon M. B. Comparative gastrointestinal transit of pellet systems of varying density. Int J Pharm. I995 114 1 1-11. 22. Riner J. L. Byford R. L. Stratton L. G . Influence of density and location on degradation of sustained-release boluses given to cattle. Am J V et Res. 1982 43ll 2028-2030. 23. Seth P .R. Tossounian J. The hydrodynamically balanced system: a novel drug delivery system for oral use Drug Dev Ind Pharm 1984 10 313-339. 24. Wang K He Z Alginate konjacglucomannan chitosan beads as controlled release matrix Inter J Pharm 2441-2 2002 117-126. 25. Gupia P .Vermani K. Garg S. Hydrogels from controlled release to pH-responsive drug delivery . Drug Discov Today. 2002 10 369-379. 26. Klausner E. A. Lavy E. Friedman M. Expandable gastroretentive dosage forms. J Cont Rel. 2003: 90 14-62. 27. P . N. Murthy Anjan K. Mahapatra Tapan Kumar Nayak and DiptanuDey. Formulation characterization and drug release kinetics of floating drug delivery systems. J. Chem. Pharm. Res. 2015 76:781-792. 28. Chen J. Blevins W. E. Park H. Gastric retention properties of Superporous hydrogel composites. J Cont Rel. 2000 64 39-51. 29. Chen J. Park K. Synthesis and characterization of superporous hydrogel composites. J Cont Rel. 2000 65 1- 2 73-82. 30. Chavda H Patel C Chitosan super porous hydrogel compositebased floating drug delivery system: A newer formulation approach J Pharm BioalliedSci 22 2010 124– 131. 31. Atyabi F. Sharma H. L. Mohammad H. A. H. In vivo evaluation of a novel gastric retentive formulation ba.sed on ion exchange resins. J Cont Rel. 1996 42 2 105-113. 32. Spandana ADS Neelofar SS Sabiya SS Ramana BV Nagarajan G Formulation and evaluation of bilayer floating tablets of simvastatin and lovastatin J Chem Pharm Res 612 2014 186- 197. 33. Shaheen S Sushma T Devender S Ahmad R V enu M Aseem B Ahmad FJ An approach for lacidipine loaded gastro retentive formulation prepared by different methods for gastroparesis in diabetic patients Saudi Pharm J 21 2013 293-304. 34. Mina IT Controlled-release effervescent floating matrix tablets of ciprofloxacin hydrochloride: Development optimization and in vitro–in vivo evaluation in healthy human volunteers Europ J Pharm Biopharm 74 2010 332- 339. 35. Harrigan R.M. Drug delivery device for preventing contact of un-dissolved drug with the stomach lining US Patent 41977 055 178. 36. Rajamma AJ Yoogesh HN Sateesha SB Natural gums as sustained release carriers: development of gastro retentive drug delivery system of ziprasidone HCl DARU J Pharm Sci 201 2012 58. 37. Lehr C. M. Hass J. Development in the area of bio adhesive drug delivery systems. Expert OpinBiolTher. 2002 2 287- 98. 38. Ponchel G. Irache J. M. Specific and non-specific bioadhesive particulate systems for oral delivery to the gastrointestinal tract. Adv Drug Del Rev. 1998 34 191-219. 39. Takeucbi H. Yamamoio H. Niwa T. Mucoadhesion of polymer-coated liposomes to rat intestine in vitro. Chem Pharm Bull. 1999 42 1954-1956.

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