gastroretentive drug delivery system: a review - wjpps

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES Kumbhar et al.

World Journal of Pharmacy and Pharmaceutical Sciences SJIF Impact Factor 6.041

Volume 5, Issue 9, 1049-1067

Review Article

ISSN 2278 – 4357

GASTRORETENTIVE DRUG DELIVERY SYSTEM: A REVIEW *Ravindra B. Kumbhar, Pramod J. Shirote, Dhanashree S. Chavan, Sachin A. Pishawikar, Harinath N. More, Suresh G. Killedar Pacific Academy of higher Education and Research University, Udaipur, India.

Article Received on 15 July 2016,

ABSTRACT Drug absorption form gastrointestinal tract is a complex procedure and

Revised on 05 August 2016, Accepted on 24 August 2016

is subject to many variables. The extent of drug absorbed from

DOI: 10.20959/wjpps20169-7664

gastrointestinal tract is related to its contact time. The real challenge in the development of an oral controlled release drug delivery system is,

*Corresponding Author

not only to sustain the drug release but also to prolong the presence of

Ravindra B. Kumbhar

dosage form within gastrointestinal tract. This will help the entire drug

Pacific Academy of higher

to get completely released in desired time at the desired site leading to

Education and Research University, Udaipur, India.

maximum absorption and increased bioavailability. Gastroretentive systems such as mucoadhesive, high-density, expandable and floating

systems have been developed for drug that have better absorption form GIT but show reduced bioavailability due to lesser contact time. These systems provide controlled drug delivery with prolonged gastric residence time. KEYWORDS: Gastroretantive, MMC, low density, Bioadhesive Systems, floating drug delivery system. INTRODUCTION The oral route is considered as the most promising route of drug delivery, due to ease of administration, low cost, patient compliance and flexibility in formulation. The real challenge in the development of an oral controlled release drug delivery system is, not only to sustain the drug release but also prolong the presence of dosage form within gastrointestinal tract till entire drug gets completely released in desired time at the desired site leading to maximum absorption. Drug absorption form GIT is a complex process subject to many variables. The extent of drug absorbed from GI tract is related to its contact time. Small GI transit time is one of the major

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World Journal of Pharmacy and Pharmaceutical Sciences

parameter for drugs that are incompletely absorbed leading to lesser bioavailability. Gastric emptying of dosage form is an extremely variable process. Prolonging emptying time can be an important asset for dosage forms that reside in the stomach than conventional dosage forms. Basic human physiology with the details of gastric emptying, motility pattern, physiological and formulation variables affecting the cosmic emptying are few of the important features which can be considered in designing of gastroretantive formulations.Gastroretentive formulations will remain in the gastric region longer time, which in turn should lead to improvement in bioavailability, reduces drug waste, and improve solubility for drugs that are less soluble in a high pH environment. This type of system will have a better therapeutic capability with good patient compliance, which invariably should be the prerequisites in design of any formulations. Development of floating tablet formulation is one such example. FLOATING DRUG DELIVERY SYSTEMS DEFINITION Floating systems or dynamically controlled systems are low density systems that have sufficient buoyancy to float over the gastric content and remain buoyant in the stomach without affecting gastric emptying rate for a prolonged period of time. This results in an increased gastric retention time and a better control of the fluctuations in the plasma drug concentration for those compounds which are actively absorbed from stomach region. CRITERIA FOR SUITABILITY OF DRUG CANDIDATES 

Drugs with narrow absorption window in GI tract.

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e.g. Para amino benzoic acid, furosemide, riboflavin and Levodopa.

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Drugs which are primarily absorbed from stomach and upper part of GIT.

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e.g. Calcium supplements, Chlordiazepoxide and Scinnarazine.

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Drugs that act locally in the stomach.

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e.g. Antacids and Misoprostol.

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Drugs that degrade in the colon.

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e.g. Ranitidine HCl and Metronidazole.

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Drugs that disturb normal colonic bacteria.

e.g. Amoxicillin trihydrate.

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PHYSIOLOGY OF GI TRACT AND ITS IMPORTANCE IN DESIGN OF GASTRORETENTIVE DRUG DELIVERY SYSTEM

Figure: 1 Anatomy of Stomach The stomach is a j-shaped organ, with two openings. One just at the end of oesophagus called the oesophageal end and the rare end which opens in the intestine called duodenal end. The total stomach region can be divided into four regions- the cardia, fundus, body and pylorus. Each region performs different functions; the fundus collects digestive gases, the body secretes pepsinogen and hydrochloric acid, and the pylorus is responsible for mucus, gastrin and pepsinogen secretion. It act as a pump for gastric emptying by propelling actions. Gastric emptying occurs in two states one when fasting and another when fed, but with different motility pattern. During the fasting state an interdigestive series of electrical events occur called as myoelectric or migrating myoletric cycle (MMC). It has four phases as shown in figure; 2.

GI MOTILITY PATTERN

Figure: 2

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FACTORS AFFECTING GASTRIC RETENTION The gastric retention time (GRT) of dosage form is affected by several factors affect their efficacy as a gastroretentive system, 

Density: GRT is a function of dosage form buoyancy which is dependent on the density.



Size: The dosage form with a diameter of more than 9.5 mm, is reported to show increased GRT.

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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 better GRT.

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Single or multiple unit formulation: Multiple unit formulations show a more predictable release profile and insignificant impairing of performance due to failure of units. Also allow co-administration of units with different release profiles or containing incompatible drugs.

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Fed or unfed state: Under fasting conditions, the GI motility is characterized by strong motor activity or the migrating myoelectric cycle (MMC) that occurs every 1.5 to 2 hours. The MMC sweeps undigested material from the stomach and, if the time of administration of the formulation coincides with MMC, the GRT of the formulation get affected. However, in the fed state, MMC is delayed and GRT is considerably longer.

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Nature of meal: Feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release.

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Caloric content: GRT can be increased by four to 10 hours with a meal that is high in proteins and fats.

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Frequency of feed: The GRT can increase by over 400 minutes when successive meals are given compared with a single meal due to the low frequency of MMC.

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Gender: Mean ambulatory GRT in males is less compared with their age and racematched female counterparts, regardless of the weight, height and body surface.

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Age: Elderly people, especially those over 70, have a significantly longer GRT.

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APPROACHES IN GASTRIC RETENTION To make the drug remain in stomach for a prolong period of time and to improve bioavailability the approaches shown in figure 3 can be utilized to design Gastroretentive formulations,

Figure: 3 Low Density Approach These systems are also known as hydro dynamically balanced systems (HBS) or floating drug delivery systems (FDDS). They have a bulk density lower than density of gastric fluid, i.e. their bulk density is less than 1. The specific gravity of gastric fluid is nearly1.0041.01g/cm3, thus FDDS remains buoyant in stomach without affecting gastric emptying rate for prolonged period of time, releasing the drug slowly at desired rate.

Fig. 4: Low density system (< 1 g / cm3)

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High Density Approach High density formulations have a density greater than that of stomach contents which is achieved by coating the drug with some heavy inert material such as barium sulphate, zinc oxide, tisstanium dioxide or iron powder.

Fig. 5: Low density system (> 1 g / cm3) Swelling and Expanding Systems These systems are such that after administration they swell to the extent, which prevents their exit from stomach through pyloric sphincter. As a result the dosage form is retained in stomach for long period of time.

Figure: 6 Swelling system Bio-adhesive Systems These systems are used to localize a delivery device within the lumen and cavity of body. Various bioadhesive polymers are used for achieving bioadhesion with the help of form hydrogen and electrostatic bonds at the mucus membrane and polymer boundary. They enhance the drug absorption process in site specific manner.

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Fig. 6: Bio-adhesive system Modified Shape System These are non-disintegrating geometric shapes molded from plastic elastomer or extruded from polyethylene blends which extend the gastric retention depending on the size, shape and flexural modulus of drug delivery system. FLOATING DRUG DELIVERY SYSTEM

Figure: 7 Mechanism of floating system Floating drug delivery system have a bulk density less than gastric fluids and hence remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. This system floats on the gastric contents. The drug is released slowly at the desired rate from the system. After complete release of drug, the residual system is emptied from the stomach. ADVANTAGES  Enhanced bioavailability. 

Enhanced first-pass biotransformation.

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

Sustained drug delivery/reduced frequency of dosing.

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Targeted therapy for local ailments in the upper GIT.

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Reduced fluctuations of drug concentration.

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Improved receptor activation selectivity.

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Reduced counter-activity of the body.

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Extended time over critical (effective) concentration.

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Minimized adverse activity at the colon.

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Site specific drug delivery.

DISADVANTAGES 

These systems require a high level of fluid in the stomach for drug delivery to float and work efficiently.



Not suitable for drugs that have solubility or stability problem in GIT.

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Drugs such as nifedipine which is well absorbed along the entire GIT and which undergoes first pass metabolism, may not be desirable.

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Drugs which are irritant to gastric mucosa are also not suitable.

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The drug substances that are unstable in the acidic environment of the stomach are not suitable candidates to be incorporated in the systems.



The dosage form should be administered with a full glass of water (200-250 ml).

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These systems are not advantageous over the conventional dosage forms for those drugs, which are absorbed throughout the gastrointestinal tract.

CLASSIFICATION

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SINGLE UNIT DOSAGE FORM Effervescent System Known as gas generating system. When carbonates such as sodium bicarbonate and acid either natural gastric fluid or citric acid or tartaric acid which is incorporated in single unit system such as tablet or capsule interact, the CO2 gas is released and entrapped in the gellified hydrocolloid layer of the systems reducing the density of the system, which remain buoyant in the stomach for a prolong period of time and releases the drug slowly at desired rate. The optimal stoichiometric ratio of citric acid to sodium bicarbonate for gas generation is considered to be 0.76:1.

Figure: 8 Gas generating system Non Effervescent The system works by mechanism of bioadhesion to mucosal layer in GI tract or swelling of polymer. The excipients commonly used in non effervescent FDDS are gel forming or highly swellable. In general hydrophilic gums, hydrocolloids, polysaccharides and matrix forming materials such as polymethacrylate, polystyrene, polycarbonate, polyacrylate are used along with bioadhesive polymers such as carbopol and Chitosan. These dosage form swells when come in contact with gastric fluids. A bulk density of < 1 is achieved. Buoyancy of the dosage form is due to the air entrapped within the swollen matrix. Multiple Unit Dosage Form This dosage forms may be an attractive alternate since they have been shown to reduce inter and intra subject variability in drug absorption as well as to lower the possibility of dose dumping.

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Double Layered Effervescent System The system consists of sustained release pills as ‘seeds’ surrounded by double layer. The inner layer made up of effervescent agents while the outer layer is of swellable material. When the system is immersed in dissolution medium at body temperature, it sinks at once and then forms swollen pills like balloons, which floats due to lower density due to generation and entrapment of CO2 within the system.

Figure: 9 Effervescent System Hydrodynamicaly Balanced System (HBS) HBS system consist of a homogeneous mixture of drug and the hydrocolloid in a capsule, upon contact with gastric fluid, it acquired and maintains a bulk density of less than 1 thereby being buoyant on the gastric contents of stomach until all the drug is released.

Figure: 10 Hydrodynamicaly balanced system Raft Forming System Raft formation is formation of viscous cohesive gel in contact with gastric fluid, wherein each portion of the liquid swells forming a continuous layer called a raft. Usually, the system contains a gel forming agent and alkaline bicarbonates or carbonates which generate CO2 www.wjpps.com

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making the system less dense and float on the gastric fluids. It prevent the reflux of gastric contents like HCl and enzymes into the esophagus.

Figure: 11 Raft forming system Hollow Microspheres Hollow microspheres are considered as one of the most promising buoyant systems.They pusses the unique advantages of multiple unit systems as well as better floating properties because of central hollow space inside them. They are generally prepared by techniques like solvent evaporation, solvent diffusion and evaporation.

Figure: 12 Hollow microsphere Polymers and Excipients Used in Preparation of Floating Drugs Delivery Systems: Natural Polymers Used in Floating Drug Delivery System Natural Polymer

Basic chain

Guar gum

β- D - mannopyranose

Pectin

α- (1,4)- linked D-galacturonic acid

Chitosan

Deacylated P-1, 4-N-acetyl-1-D-glucosamine

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Source Endosperm of the seed of cyamopsis tetragonolobus. Citrus peel, apple pomace, sugar beat, pulp etc. Shell of marine invertebrates 1059

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Xanthan gum

β- (1,4)- linked D-glucose

Psyllium husk starch

β- (1,4)- linked D xylopyranosyl α- (1,4)- linked D-glucose and α- (1,6)- linked D-glucose D-glucose, D-glucuronic acid and rhamnose in β-1,4 linkage

Gellan gum

1-4 linked β- D- mannuronic acid and α-Lglucuronic acid

Alginates

Fermentation of glucose by xanthomonas compestris Seed coats of Plantago ovate Pseudomonas elodea Laminaria hyperbola, Aschophyllum nodosum, Macrocystis pyrifera etc.

ADVANTAGES OF NATURAL POLYMERS 

Biodegradable: They are naturally available and produced by living organism.

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Biocompatible and Non toxic: Basically they are plant materials

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Low cost: Production cost is less compared to synthetic material.

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Environmental Friendly processing: There are many types of natural compounds obtained from different plant sources which are widely used in pharmaceutical industry and collected in large quantities because of simple production process involved.

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Local availability especially in developing countries: In India and other developing countries, there is promotion for the production of plants as a pharmaceutical excipients being done by government and it also provide the facilities for bulk production, like gum and mucilage because of their wide application in industries.

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Better patient tolerance and public acceptance: Less chance of side as well as adverse effect with natural material compared with synthetic one.

Other Semi Synthetic and Synthetic Polymers Used are HPMC K4 M, Calcium alginate, Eudragit S100, Eudragit RL Propylene foam, Eudragit RS, ethyl cellulose, poly methyl methacrylate, Methocel K4M, Polyethylene oxide, β Cyclodextrin, HPMC 4000, HPMC 100, CMC, Polyethylene glycol, polycarbonate, PVA, Polycarbo-nate, Sodium alginate, HPC-L, CP 934P, HPC, Eudragit S, HPMC, Metolose S.M. 100, PVP, HPC-H, HPC-M, HPMC K15, Polyox, HPMC K4, Acrylic polymer, E4 M and Carbopol. Inert Fatty Materials (5%-75%) Edible, inert fatty material having a specific gravity of less than one can be used to decrease the hydrophilic property of formulation and hence increase buoyancy. E.g. Beeswax, fatty acids, long chain fatty alcohols, Gelucires 39/01 and 43/01.

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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). IN VITRO AND IN VIVO EVALUATION PARAMETERS FOR STOMACH SPECIFIC FDDS Different studies reported in the literature indicate that pharmaceutical dosage forms exhibiting gastric residence in-vitro floating behaviour show prolonged gastric residence in vivo. Although, in-vitro floating behaviour alone is not sufficient proof for efficient gastric retention hence, in-vivo studies can provide definite proof that prolonged gastric residence is has been achieved. The following evaluation parameters have to be applied for success of FDDS formulations Hardness, Friability, Assay, Content Uniformity (Tablets) These tests are performed as per described in specified monographs. Floating Lag Time and Total Floating Time Determination The time between the introduction of the tablet into the medium, its rise to upper one third of the dissolution vessel is termed as floating lag time and the time for which the dosage form floats is termed as the floating or flotation time. These tests are usually performed in simulated gastric fluid or 0.1 mole.lit‐1 HCl maintained at 37oC, by using USP dissolution apparatus containing 900 ml of 0.1 molar HCl as the dissolution medium. Drug Release The test for in-vitro drug release studies are usually carried out in simulated gastric and intestinal fluids maintained at 370C. Dissolution tests are performed using the USP dissolution apparatus. Samples are withdrawn periodically, the volume of dissolution medium is replaced with the same volume of fresh medium each time. Analysis of the drug contents is done after an appropriate dilution. Recent methodology as described in USP XXIII states that the dosage unit is allowed to sink to the bottom of the vessel before rotation of blade is

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started. A small, loose piece of non reactive material such as not more than a few turns of wire helix may be attached to the dosage units that would otherwise float. However, standard dissolution methods based on the USP or British Pharmacopoeia (BP) have been shown to be poor predictors of in vitro performance for floating dosage forms. Drug

loading,

drug

entrapment

efficiency,

particle

size

analysis,

surface

characterization, micromeritics studies and percentage yield (for floating microspheres and beads) Drug loading is assessed by crushing accurately weighed sample of beads or microspheres in a mortar and added to the appropriate dissolution medium which is then centrifuged, filtered and analysed by various analytical methods like spectrophotometry. The percentage drug loading is calculated by dividing the amount of drug in the sample by the weight of total beads or microspheres. The particle size and the size distribution of beads or microspheres are determined in the dry state using the optical microscopy method. The external and cross‐sectional morphology (surface characterization) is done by scanning electron microscope (SEM). The measured weight of prepared microspheres was divided by total amount of all non‐volatile components used for the preparation of microspheres, which will give the total percentage yield of floating microspheres. Resultant Weight Determination Bulk density and floating duration have been the main parameters to describe the adequacy of a dosage form’s buoyancy, although single density determination does not predict the floating force evolution of the dosage form because the dry material of it is made progressively reacts or interacts with in the gastric fluid to release its drug contents. So to calculate real floating capabilities of dosage form as a function of time a novel method has been conceived. It operates by force equivalent to the force F required to keep the object totally submerged in the fluid. This force determines the resultant weight of the object when immersed and may be used to quantify its floating or non floating capabilities. The magnitude and direction of the force and the resultant weight corresponds to the Victoria sum of buoyancy (Fbuoy) and gravity (Fgrav) forces acting on the objects as shown in the equal. F = Fbuoy – Fgrav F = dfgV – dsgV = (df‐ds) gV F = (df – M/V) gV

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In which the F is total vertical force (resultant weight of the object), g is the acceleration due to gravity, df if the fluid density, ds is the object density is the object mass and V is the volume of the object. Weight Gain and Water Uptake (WU) Weight gain or water uptake can be studied by considering the swelling behaviour of Floating dosage form. The study is done by immersing the dosage form in simulated gastric fluid at 37oC and determining the dimensional changes like tablet diameter and/ or thickness at regular 1‐h time intervals until 24 h, the tablets were removed from beaker, and the excess surface liquid was removed carefully using the paper. The swollen tablets were then reweighed and WU is measured in the terms of percent weight gain, as given by Equation WU = (Wt – Wo) X 100 / Wo In which Wt and Wo are the weights of the dosage form at time t and initially, respectively. XRay/Gamma Scintigraphy For in vivo studies, X‐Ray/Gamma Scintigraphy is the main evaluation parameter for floating dosage form. In each experiment, the animals are allowed to fast overnight with free access to water, and a radiograph is done just before the administration of the floating tablet to ensure the absence of radio‐opaque material. Visualization of dosage form by X‐ray is due to the inclusion of a radio‐opaque material. The formulation is administered by natural swallowing followed by 50mL of water. The radiographic imaging is taken from each animal in a standing position and the distance between the source of X‐rays and the animal should kept constant for all imaging, so that the tablet movement could be easily noticed. Gastric radiography was done at 30‐min time intervals for a period of 5 h using an X‐ray machine. Gamma scintigraphy is a technique whereby the transit of a dosage form through its intended site of delivery can be non‐invasively imaged in vivo via the judicious introduction of an appropriate short lived gamma emitting radioisotope. The inclusion of a γ‐emitting radionuclides in a formulation allows indirect external observation using a γ‐camera or scintiscanner. But the main drawback of γ‐ scintigraphy are the associated ionizing radiation for the patient, the limited topographic information, low resolution inherent to the technique and the complicated and expensive preparation of radiopharmaceutical.

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Pharmacokinetic Studies Pharmacokinetic studies include AUC (Area under Curve), Cmax, and time to reach maximum plasma concentration (Tmax) were estimated using a computer. Statistical analyses were performed using a Student t test with p, 0.05 as the minimal level of significance. Specific Gravity Displacement method is used to determine the specific gravity of floating system using benzene as a displacing medium. Polymers and Excipients Used in Floating System Delivery system Excipients used Polymer: HPMC, Polyacrylate acid, polyvinyl acetate, carbapol, agar, sodium alginate, xanthan gum, polyvinyl pyrrolidone Effervescent system Effervescent agent: Sodium bicarbonate, citric acid, tartaric acid. Polymer: chitosan. Non effervescent system Polymer: polycarbonate, eudragit. Solvents: Polyvinyl alcohol, methanol, Hollow microsphere ethanol. Gel forming agent: Alginic acid. Effervescent agent: Sodium bicarbonate, citric acid. Raft forming system Sweetening agent: Mannitol. Marketed products of GDDS Brand name Delivery system

Drug (dose)

Valrelease®

Floating capsule

Madopar® HBS (Prolopa® HBS)

Floating, CR capsule

Liquid Gaviscon® Topalkan® Almagate Flot coat® Conviron® Cytotech® Cifran OD®

Diazepam (15mg)

Effervescent Floating liquid alginate preparations Floating liquid alginate preparation Floating dosage form Colloidal gel formingFDDS Bilayer floating capsule Gas-generating floating form

Benserazide (25mg) and L-Dopa (100mg) Al hydroxide (95 mg), Mg Carbonate (358 mg) Al – Mg antacid

Company name Hoffmann- LaRoche, USA Roche Products, USA GlaxoSmithkline, India Pierre Fabre Drug, France

Al – Mg antacid ----------Ferrous sulphate Ranbaxy, India Misoprostol(100μg/200μg) Pharmacia, USA Ciprofloxacin (1gm)

Ranbaxy, India

APPLICATION OF FLOATING DRUG DELIVERY SYSTEM Enhanced Bioavailability The bioavailability of riboflavin CR-GRDF is significantly enhanced in comparison to the administration of non-GRDF CR polymeric formulations. There are several different processes, related to absorption and transit of the drug in the gastrointestinal tract, that act concomitantly to influence the magnitude of drug absorption.

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Sustained Drug Delivery Oral CR formulations are encountered with problems such as gastric residence time in the GIT. These problems can be overcome with the HBS systems which can remain in the stomach for long periods and have a bulk density