Floating Drug Delivery System: - an approach to …sphinxsai.com/2012/oct-dec/Pharmpdf/PT=63(1812-1826)OD12.pdf · Floating Drug Delivery System – An Approach To Oral Controlled

International Journal of PharmTech ResearchCODEN (USA): IJPRIF ISSN : 0974-4304Vol.4, No.4, pp 1812-1826, Oct-Dec 2012

Floating Drug Delivery System – An Approach ToOral Controlled Drug Delivery

Chikhalikar S.S.*, Wakade R.B.

Department OfPharmaceutics SudhakarraoNaik Institute OF Pharmacy, Pusad-445204 Dist: Yavatmal(M.H.),India.

*Corres.author: [email protected].

Abstract: The design of oral controlled drug delivery systems (CDDS) should primarily aimed at achievingmore predictable and increased bioavailability of drugs. Placing of DDS in specific region of the GIT offersnumerous advantages, specially the drugs having narrow absorption window in GIT, primary absorption inthe stomach, stability problem in the intestine, poor solubility at alkaline pH, local activity in stomach, andproperty to degrade in colonRecent scientific and patent literature has shown increased interest in noveldosage forms that can be retained in the stomach for a prolonged and predictable period of time.GRDFs aredesigned on the basis of one of the several approaches like formulating low density dosage form that remainbuoyant above gastric fluid (Floating Dosage Form) or high density dosage form that is retained at bottomof the stomach, imparting bio-adhesion to the stomach mucosa, reducing motility of the GIT by concomitantadministration of drugs or pharmaceutical excipients, expanding the dosage form by swelling or unfoldingto a large size which limits the emptying of the dosage form through the polymeric sphincter , utilizing ion –exchange resin which adheres to mucosa , or using modified shape system. This review article focuses onthe current technological development in FDDS with special emphasis on its potential for oral controlleddrug delivery.Keywords:Bioavailability, absorption window, floating, bio-adhesion,ion–exchange,modified shape.

INTRODUCTION[1, 2]

Oral controlled release (CR) dosage forms(DFs) have been developed over the past threedecades due to their considerable therapeuticadvantages such as ease of administration, patientcompliance and flexibility in formulation. Thedesign of oral controlled drug delivery systems(CDDS) should primarily aimed at achieving morepredictable and increased bioavailability of drugs.However the developmental process is precludedby several physiological difficulties such asinability to restrain & locate the CDDS within thedesired regions of GIT due to various gastricemptying & motility. The gastric emptying processcan vary from a few minutes to 12 hrs. This

mainly lead to unpredictable time for peak plasmalevels & bioavailability, therefore CRDFs notsuitable for various important drugs and ischaracterized by a narrow absorption window inthe upper part of GIT which is a relatively shorttransit time of DFs in this anatomical segments inperiod of less than 6 hrs. Such drugs leave theupper part of GIT and reaches non-absorbing distalsegment.

Furthermore, the relative gastric emptyingtime (GET) which is normally 2 to 3 hrs. Throughthe major absorption zone (stomach or upper partof intestine), and can result in incomplete drugreleased from the DDS leading to diminishedefficacy of the administered dose. Therefore

Chikhalikar S.S.et al /Int.J.PharmTech Res.2012,4(4) 1813

placing of DDS in specific region of the GIToffers numerous advantages, specially the drugshaving narrow absorption window in GIT, primaryabsorption in the stomach, stability problem in theintestine, poor solubility at alkaline pH, localactivity in stomach, and property to degrade incolon[1].

Recent scientific and patent literature hasshown increased interest in novel dosage formsthat can be retained in the stomach for a prolongedand predictable period of time. One of the mostfeasible approaches for this in the GIT is to controlgastric residence time (GRT) using gastroretentivedosage forms (GRDFs) that will provide us withnew and important therapeutic options.GRDFs aredesigned on the basis of one of the severalapproaches like formulating low density dosageform that remain buoyant above gastric fluid(Floating Dosage Form) or high density dosageform that is retained at bottom of the stomach,imparting bio-adhesion to the stomach mucosa,reducing motility of the GIT by concomitantadministration of drugs or pharmaceuticalexcipients, expanding the dosage form by swellingor unfolding to a large size which limits theemptying of the dosage form through thepolymeric sphincter , utilizing ion – exchangeresin which adheres to mucosa , or using modifiedshape system.

From the formulation and technologicalpoint of view, floating drug delivery system(FDDS) is considerably easy and logical approachin development of GRDFs. Hence, this reviewarticle focuses on the current technological

development in FDDS with special emphasis on itspotential for oral controlled drug delivery.

BASIC GASTROINTESTINAL TRACTPHYSIOLOGY[3,4]:-

Anatomically the stomach is divided in tothree regions: Fundus, Body and Antrum(pylorus).The proximal part made of fundus andbody acts as a reservoir for undigested materials,whereas the antrum is the main site for mixingmotions and acts as a pump for gastric emptyingby propelling actions. Gastric emptying occurs inboth the fasting and fed states. During the fastingstate an interdigestive series of electrical eventstake place which cycle both through stomach andintestine every 2-3 hrs which is called asinterdigestive myoelectric cycle or migratingmyoelectric cycle (MMC) which is further dividedin to four phases After the ingestion of a mixedmeal, the pattern of contractions changes fromfasted to that of fed state which is also termed asdigestive motility pattern.

1. Phase 1-(Basic phase)-last from 30-60 minuteswith rare contractions.

2. Phase 2-(Preburst phase)-last for 20-40minutes with intermittent action potential andcontractions.

3. Phase 3-(Burst phase)- last for 10-20 minuteswhich includes intense and regularcontractions for short periodalso known ashousekeeper wave .

4. Phase 4-last for 0-5 minutes and occursbetween phase 3 and phase 1of 2 consecutivecycles.(Period of transition).

Fig. 1: Motility pattern in GIT


FACTORS AFFECTING THEGASTRORETENTIVE SYSTEM [5,6]

Various attempts have been made to retain thedosage form in the stomach as a way of increasingthe retention time. These attempts include use offloating dosage forms (gas-generating systems andswelling or expanding systems), mucoadhesivesystems, high-density systems, modified shapesystems, gastric emptying delaying devices andco-administration of gastric-emptying delayingdrugs. Most of these approaches are influenced bya number of factors that affect their bioavailabilityand efficacy of the gastro retentive system. Density – Gastric retention time (GRT) is a

function of dosage form buoyancy that isdependent on the density.

Size – Dosage form units with a diameter ofmore than 7.5 mm are reported to have anincreased GRT compared with those with adiameter of 9.9 mm.

Shape of dosage form – Tetrahedron and ringshaped devices with a flexural modulus of 48and 22.5 kilo pounds per square inch (KSI) arereported to have better GRT 90% to 100%retention at 24 hours compared with othershapes.

Single or multiple unit formulation –Multiple unit formulations show a morepredictable release profile and insignificantimpairing of performance due to failure ofunits, allow co-administration of units withdifferent release profiles or containingincompatible substances and permit a largermargin of safety against dosage form failurecompared with single unit dosage forms.

Fed or unfed state – Under fastingconditions, the GI motility is characterized byperiods of strong motor activity or themigrating myoelectric complex (MMC) thatoccurs every 1.5 to 2 hours. The MMC sweepsundigested material from the stomach and, ifthe timing of administration of the formulationcoincides with that of the MMC, the GRT ofthe unit can be expected to be very short.However, in the fed state, MMC is delayedand GRT is considerably longer. (Caldwell etal., 1998; Murthy et al., 2000).

Nature of meal – Feeding of indigestiblepolymers or fatty acid salts can change themotility pattern of the stomach to a fed state,thus decreasing the gastric emptying rate andprolonging drug release.

Caloric content – GRT can be increased by 4to10 hours with a meal that is high in proteins

and fats (Marvola et al., 1989) (Mojaverian etal., 1988).

Frequency of feed – The GRT can increaseby over 400 minutes when successive mealsare given compared with a single meal due tothe low frequency of MMC.

Gender – Mean ambulatory GRT in males(3.4±0.6 hours) is less compared with their ageand race matched female counterparts (4.6±1.2hours), regardless of the weight, height andbody surface.

Age – Elderly people, especially those over70, have a significantly longer GRT.

Posture – GRT can vary between supine andupright ambulatory states of the patient.

Concomitant drug administration –Anticholinergics like atropine andpropantheline, opiates like codeine andprokinetic agents like metoclopramide andcisapride can affect floating time.

Biological factors – Diabetes and Crohn’sdisease, etc.

APPROACHES TO DESIGN FLOATINGDOSAGE FORMS[7]:-

The following approaches have been usedfor the design of floating dosage forms of single-and multiple-unit systems.

Single-Unit Dosage Forms:-

In Low-density approach the globularshells apparently having lower density than that ofgastric fluid can be used as a carrier for drug for itscontrolled release. A buoyant dosage form canalso be obtained by using a fluid-filled system thatfloats in the stomach. In coated shells24 popcorn,poprice, and polystyrol have been exploited asdrug carriers. Sugarpolymeric materials such asmethacrylic polymer and cellulose acetatephthalate have been used to undercoat these shells.These are further coated with a drug-polymermixture.

The polymer of choice can be eitherethylcellulose or hydroxypropyl cellulosedepending on the type of release desired. Finally,the product floats on the gastric fluid whilereleasing the drug gradually over a prolongedduration.

Fluid- filled floating chamber type ofdosage forms includes incorporation of a gas-filledfloatation chamber into a microporous componentthat houses a drug reservoir.


Apertures or openings are present along the topand bottom walls through which thegastrointestinal tract fluid enters to dissolve thedrug. The other two walls in contact withthe fluidare sealed so that the undissolved drug remainstherein. The fluid present could be air, underpartial vacuum or any other suitable gas, liquid, orsolid having an appropriate specific gravity and aninert behavior. The device is of swallowable size,remains afloat within the stomach for a prolongedtime, and after the complete release the shelldisintegrates, passes off to the intestine, and iseliminated.

Hydrodynamically balanced systems(HBS) are designed to prolong the stay of thedosage form in the gastro intestinal tract and aid inenhancing the absorption. Such systems are bestsuited for drugs having a better solubility in acidicenvironment and also for the drugs having specificsite of absorption in the upper part of the smallintestine. To remain in the stomach for aprolonged period of time the dosage form musthave a bulk density of less than 1. It should stay inthe stomach, maintain its structural integrity, andrelease drug constantly from the dosage form. Thesuccess of HBS capsule as a better system is bestexemplified with chlordiazeopoxidehydrochloride. The drug is a classical example of asolubility problem wherein it exhibits a 4000-folddifference in solubility going from pH 3 to 6 (thesolubility of chlordiazepoxide hydrochloride is150 mg/mL and is ~0.1 mg/mL at neutral pH).

The 3-layer principle has been improvedby development of an asymmetric configurationdrug delivery system in order to modulate therelease extent and achieve zero-order releasekinetics by initially maintaining a constant area atthe diffusing front with subsequentdissolution/erosion toward the completion of therelease process. The system was designed in sucha manner that it floated to prolong gastricresidence time in vivo, resulting in longer totaltransit time within the gastrointestinal tractenvironment with maximum absorptive capacityand consequently greater bioavailability. Thisparticular characteristic would be applicable todrugs that have pH-dependent solubility, a narrowwindow of absorption, and are absorbed by activetransport from either the proximal or distal portionof the small intestine.

Multiple-Unit Dosage Forms[7,8]:-The purpose of designing multiple-unit

dosage form is to develop a reliable formulationthat has all the advantages of a single-unit formand also is devoid of any of the disadvantages ofsingle-unit formulations.Single unit formulationsare associated with problems such as stickingtogether or being obstructed in gastrointestinaltract, which may have a potential danger ofprodanger of producing irritation.Multiple unitsystems avoid the “all-or-none” gastric emptyingnature of single unit systems. It reduces theintersubject variability in absorption and theprobability for dose dumping is lower In pursuit ofthis endeavour many multiple-unit floatabledosage forms have been designed. Microsphereshave high loading capacity and many polymershave been used such as albumin, gelatin, starch,polymethacrylate, polyacrylamine, andpolyalkylcyanoacrylate. Spherical polymericmicrosponges, also referred to as “microballoons,”have been prepared. Microspheres have acharacteristic internal hollow structure and showan excellent in vitro floatability. InCarbondioxide–generating multiple-unit oral formulationsseveral devices with features that extend, unfold,or are inflated by carbon dioxide generated in thedevices after administration have been describedin the recent patent literature. These dosage formsare excluded from the passage of the pyloricsphincter if a diameter of ~12 to 18 mm in theirexpanded state is exceeded.

CLASSIFICATION OF FLOATING DRUGDELIVERY SYSTEMS (FDDS)

(A) Non-effervescent systems

i. Colloidal gel barrier systems [9]:-

Hydrodynamically balanced system(HBS), which contains drugs with gel forminghydrocolloids, was first designed by Sheth andTossounian in 1975. These systems incorporate ahigh level (20-75%w/w) of one or more gelforming, highly swellable, cellulose typehydrocolloids, polysaccharides and matrix formingpolymers. On coming in contact with gastric fluid,the hydrocolloids in the system hydrate and form acolloidal gel barrier around its surface. This gelbarrier controls the rate of fluid penetration intothe device and consequentrelease of the drug.


Fig.2: Hydrodynamically balanced system (HBS).

ii. Micro porous compartment systems [10]:-This technology is based on the

encapsulation of a drug reservoir inside a microporous compartment with apertures along its topand bottom walls. The peripheral walls of the drugreservoir compartment are completely sealed toprevent any direct contact of the gastric mucosalsurface with the undissolved drug.

Fig.3: Gas filled floatation chamber

iii. Multiparticulate system: Floating Beads[10]

Multi-particulate drug delivery systemsare mainly oral dosage forms consisting of amultiplicity of small discrete units, each exhibitingsome desired characteristics. In these systems, thedosage of the drug substances is divided on aplurality of subunit,typically consisting ofthousands of spherical particles with diameter of0.05-2.00mm. Thus multiparticulate dosageforms are pharmaceutical formulations in whichthe active substance is present as a number ofsmall independent subunits. To deliver therecommended total dose, these subunits are filledinto a sachet.iv. Microballoons[10]:-

There are various approaches in deliveringsubstances to the target site in a controlledreleasefashion. One such approach is usingpolymeric 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 graphical studies proved that microballoonsorally administered to human were dispersed in theupper part of stomach andretained there for threehr against peristaltic movements.

Fig.4: Floating hollow microsphere ormicroballoon

(B) Effervescent systems:A drug delivery system can be made to

float in the stomach by incorporating a floatingchamber, which may be filled with vacuum, air orinert gas.i. Volatile liquid containing systems [9]:-

These have an inflatable chamber whichcontains a liquid e.g. ether, cyclopentane, thatgasifies at body temperature to cause the inflationof the chamber in the stomach. These systems areosmotically controlled floating systems containinga hollow deformable unit There are two chambersin the system first contains the drug and the secondchamber contains the volatile liquid.


Fig.5: Intragastric osmotic controlled drug delivery system

ii. Gas generating systems[9, 10]:-These buoyant delivery systems utilizeseffervescent reaction betweenCarbonate/bicarbonate salts and citric/tartaric acid to liberateCO2, which gets entrapped inthe jellifiedhydrocolloid layer of the system, thus decreasingits specific gravity and making it float over chime.These are formulated by intimately mixing theCO2 generating agents and the drug within thematrix tablet. These have a bulk density lower thangastric fluids and therefore remain floating in thestomach unflattering the gastric emptying rate fora prolonged period. The drug is slowly released ata desired rate from the floating system and afterthe complete release the residual system isexpelled from the stomach. This leads to anincrease in the GRT and a better control overfluctuations in plasma drug concentration.

Figure 6: Gas generating system: schematicmonolayer drug delivery system

RECENT WORK ON FLOATING DRUGDELIVERYSYSTEM:- Sandra Strubing et alstudied the mechanism

of floating and drug release behaviour ofpoly(vinyl acetate)-based floating tablets withmembrane controlled drug delivery ofPropranolol HCl containing tablets withKollidon_ SR as an excipient fordirectcompression and different Kollicoat_ SR30 D/Kollicoat_ IR coats. The drug releasewas delayed efficiently within a time intervalof 24 h by showing linear drug releasecharacteristicsand remained afloat until theend of the monitored 24 h time interval.

Srisagul S et aldeveloped multiple-unitfloating drug delivery system based on gasformation technique in order to prolong thegastric residence time and to increase theoverall bioavailability of the dosage form ofanhydrous theophylline. Drug-containing corepellets prepared by extrusion–spheronizationprocesses, which are coated with double layersof an inner effervescent layer (sodiumbicarbonate) and an outer gas-entrappedpolymeric membrane of an aqueous colloidalpolymer dispersion (Eudragit® RL 30D, RS30D, NE 30D).The optimum system floatedcompletely within 3 min and maintained thebuoyancy over a period of 24 h.

P.S. Rajinikanthet aldeveloped a new intra-gastric floating in situ gelling system forcontrolled delivery of amoxicillin for thetreatment of peptic ulcer disease caused byHelicobacter pylori (H. pylori). Gellan basedamoxicillin floating in situ gelling systems(AFIG) were prepared by dissolving varyingconcentrations of gellan gum in deionizedwater. The results substantiated that theprepared AFIG has feasibility of forming rigid


gels in the gastric environment and eradicatedH. pylori from the gastrointestinal tract moreeffectively than amoxicillin suspensionbecause of the prolonged gastrointestinalresidence time of the formulation. The in situgelling systemfloated completely within 2 minand maintained the buoyancy over a period of>24 h.

Praneeth Kumar Siripuramet alformulatedfloating sustained-release matrices ofmetoprolol succinate using Gelucire 43/01 andGelucire 44/14 by a melt-solidificationtechnique. The in vitro and in vivocharacteristics of the prepared matrices wereevaluated. The in vitro drug release studiesperformed in 0.1 N HCl revealed aproportional increase in drug release patternwith increased concentration of Gelucire44/14.The in vitrofloating characteristics ofGelucirematrices were greater than 12 h withgood in vivo gastric retention

J Josephine LJet alprepared and evaluated thefloating microspheres ofstavudine as a modeldrug byemulsion solventdiffusion methodusing Eudragit RS 100 as a rate controllingpolymer for prolongation of gastric retentiontime for oral delivery.The preparedmicrospheres were found to be spherical andfree flowing and remain buoyant for more than12 hrs.

Frances Stops et alstudied was the in vivobehavior of the radio-labelledcalcium alginatebeads when they were administeredunderfasting conditions with either water or anaqueous solution of citric acid, a potential guttransit delaying substance.The study wasperformed inhealthy male volunteers whoswallowed the radio-labelled calcium alginatebeads after a 10 h overnight fast. Gammascintigraphy monitored the movement of thecalcium alginate beads.Prolonged gastricretention was achieved when the dosage formwas administered with the citric acid solutionwhencompared to retention in the absence ofcitric acid.

MahalaxmiRathnanand et al formulated andevaluated (in vitro) floating-pulsatile tabletsof Nizatidine, a H2 receptor antagonist, whichconceptualizes a specific technology, basedoncombining principles of both the floatingand pulsatile principles to deliver a

programmed dose of drug from the developeddelivery system anticipated for chronotherapyof excessively secretedgastric acid and forpromoting healing of duodenal ulcers.Thefloating behavior of optimized formulationwhich was found to befloating for more thanfive hours.

Mukhopadhyay S et alformulated floating-bioadhesive tablets to increase the stay periodof drug in its absorption area of Ciprofloxacinhydrochloride. The effervescent base wasprepared by using 1:1 ratio of sodiumbicarbonate and citric acid. Increasing theeffervescent base of tablets from 5% to10%significantly lower the lag time of floatingas well as floating duration. Floating-bioadhesivetablets of ciprofloxacinhydrochloride increased thegastric residencetime as well as bioavailability.

J. Gooleet al developed and the in vitroevaluated sustained-release minitablets(MT), prepared by melt granulation andsubsequent compression, which were designedto float over an extended period of time.Theimportance of the composition andmanufacturing parameters of the MT on theirfloating and dissolution properties wasexamined.The investigation showedthat MTcomposition and MT diameter had the greatestinfluence on drug release, which was sustainedfor more than 8 h.

ADVANTAGES OF FLOATING DRUGDELIVERY[11]:- Enhanced bioavailability Sustained drug delivery/reduced frequency

of dosing Targeted therapy for local ailments in the

upper GIT Reduced fluctuations of drug

concentration Improved receptor activation selectivity Reduced counter-activity of the body Extended time over critical (effective)

concentration Minimized adverse activity at the colon Site specific drug delivery


LIMITATIONS[12]

These systems require a high level of fluid inthe stomach for drug delivery to float andwork efficiently.

Not suitable for drugs that have solubility orstability problem in GIT.

Drugs such as nifedipine which is wellabsorbed along the entire GIT and whichundergoes first pass metabolism, may not bedesirable.

Drugs which are irritant to gastric mucosa arealso not suitable.

The drug substances that are unstable in theacidic environment of the stomach are notsuitable candidates to be incorporated in thesystems.

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

These systems are not advantageous over theconventional dosage forms for those drugs,which are absorbed throughout thegastrointestinal tract.

EVALUATION OF FLOATING DRUGDELIVERY SYSTEMS:-

Various parameters that need to beevaluated ingastroretentive formulations includefloating duration, dissolution profiles, specificgravity, content uniformity, hardness, andfriability in case of solid dosage forms. In the caseof multiparticulate drug delivery systems,differential scanning calorimetry (DSC), particlesize analysis, flow properties, surface morphology,andmechanical properties are also performed.1. Buoyancy / Floating Test [13,14]:-

The test for buoyancy is usuallydetermined in 900 mL of simulated gastric(HCl/NaClwith 0.02% Tween 80, pH 1.2) orintestinal fluids (KH2PO4/NaOH buffer with0.02% Tween 80, pH 7.4) maintained at 370Cusing the USP dissolution apparatus. These fluidssimulate the surface tension of human gastric juice(35–50 mN/m2).The amount of time the dosageform floats is termed the floating time. In the caseof floating microparticles, the number of floatingparticles and the time during which they remainbuoyant on the test solution can be determined.The floating process depends on the balancebetween the weight and volume of the dosageform. An increase in the buoyancy force caused bythe increased volume causes a resultant weightincrease and leads to dosage-form flotation.

2. SwellingStudy[13,14]:-The swelling behavior of a dosage form

wasmeasured by studying its weight gain orwateruptake. The dimensional changes couldbemeasured in terms of the increase in tablet

diameterand/or thickness over time. Water uptakewasmeasured in terms of percent weight gain, asgivenby the equation.WU = (W1 – W0) x 100

W0

Wt= Weight of dosage form at time t.W0 = Initial weight of dosage form

3. In Vitro Drug Release Studies[13,14,15]:-The test for buoyancy and in vitrodrug

releasestudies are usually carried out in simulatedgastricand intestinal fluids maintained at 37oC. Inpractice, floating time is determined by using theUSPdissolution apparatus containing 900ml of 0.1HClas a testing medium maintained at 37oC. Thetimerequired to float the HBS dosage form isnoted asfloating (or floatation) time.

Dissolution tests are performed using theUSPdissolution apparatus. Samples arewithdrawnperiodically from the dissolutionmedium, replenished with the same volume offresh mediumeach time, and then analyzed fortheir drug contentsafter an appropriate dilution.

Recently Gohel et al proposed a morerelevant in vitro dissolution method to evaluate afloating drug delivery system (for tablet dosageform). A 100-mL glass beaker was modified byadding a side arm at the bottom of the beaker sothat the beaker can hold 70 ml of 0.1 mole/lit HCldissolution medium and allow collection ofsamples. A burette was mounted above the beakerto deliver the dissolution medium at a flow rate of2 ml/min to mimic gastric acid secretion rate.

The performance of the modifieddissolution apparatus was compared with USPdissolution Apparatus 2 (Paddle). The problem ofadherence of the tablet to the shaft of the paddlewas observed with the USP dissolution apparatus.The tablet did not stick to the agitating device inthe proposed dissolution method. The drug releasefollowed zero-order kinetics in the proposedmethod. Similarity of dissolution curves wasobserved between the USP method and theproposed method at 10% difference level. Theproposed test may show good in vitro-in vivocorrelation since an attempt is made to mimic thein vivo conditions such as gastric volume, gastricemptying, and gastric acid secretion rate.


Fig.7: In vitro dissolution method

4. Resultant weight test[13,14]:-An in vitro measuring apparatus has been

conceived to determine the real floatingcapabilities of buoyant dosage forms as a functionof time. It operates by measuring the forceequivalent to the force F required to keep theobject totally submerged in the fluid.

This force determines the resultant weightof the object when immersed and may be used toquantify its floating ornon-floating capabilities.The magnitude and directionof the force and theresultant weight corresponds to thevectorial sumof buoyancy (F buoy) and gravity (F grav) forcesacting on the object as shown in the equationF = F buoy – F grav

F = d f gV – d s gV = (d f - d s) GvF = (df – M / V) gVin which F is the total vertical force (resultantweight ofthe object), g is acceleration due togravity, d f is the fluiddensity, d s is the objectdensity, M is the object mass,and V is the volumeof the object .

By convention, a positive resultant weightsignifies thatthe force F is exerted upward and thatthe object is ableto float, whereas a negativeresultant weight means thatthe force F actsdownward and that the object sinks.

Fig.8: Effect of various forces on floatingsystem

Apart from the In vitro release, duration offloating and invivo gastro-retention tests, the

multiple unit dosage formsare also evaluatedfor[16]:-(i) Morphological and dimensional analysis withtheaid of scanning electron microscopy (SEM).The size can also be measured using anopticalmicroscope.

(ii)% yield of microspheres:This is calculated from

Weight of microspheres obtained ×100

Total weight of drug and polymer

(iii) Entrapment efficiency:The drug is extracted by a suitable

method, analyzed and is calculated from:Practical amount of drug present ×100

Theoretical drug content

In vivo methods:-1) X-Ray method/gamma-Scintigraphy[15, 16]:-X-Ray/Gamma Scintigraphy is a very popularevaluation parameter for floating dosage form nowa day40. It helps to locate dosage form in the g.i.t.and by which one can predict and correlate thegastric emptying time and the passage of dosageform in the GIT. Here the inclusion of a radio-opaque material into a solid dosage form enables itto be visualized by X-rays. Similarly, the inclusionof a γ-emitting radio-nucelide in a formulationallows indirect external observation using a γ-camera or scintiscanner41. In case of γ-scintigraphy, the γ-rays emitted by the radio-nuclide are focused on a camera, which helps tomonitor the location of the dosage form in the GItract.2) Pharmacokinetic studies [17]:

Pharmacokinetic studies are the integralpart of the in vivo studies and several works hasbeen on that. Sawicki studied thepharmacokinetics of verapamil, from the floatingpellets containing drug, filled into a capsule, andcompared with the conventional verapamil tabletsof similar dose (40 mg). The tmax and AUC (0-infinity) values (3.75 h and 364.65 ng.ml-1hrespectively) for floating pellets werecomparatively higher than those obtained for theconventional verapamil tablets. (tmaxvalue 1.21 h,and AUC value 224.22 ng.ml-1h). No muchdifference was found between the Cmax values ofboth the formulations, suggesting the improvedbioavailability of the floating pellets compared tothe conventional tablets. An improvement inbioavailability has also been observed with


piroxicam in hollow polycarbonate microspheresadministered in rabbits.

The microspheres showed about 1.4 timesmore bioavailability, and the elimination half-lifewas increased by about three times than the freedrug.

APPLICATIONS[9]:-1. Sustained Drug Delivery:-HBS systems can remain in the stomach for longperiods and hence can release the drug over aprolonged period of time. The problem of shortgastric residence time encountered with an oral CRformulation hence can be overcome with thesesystems. These systems have a bulk density of <1as a result of which they can float on the gastriccontents. These systems are relatively large in sizeand passing from the pyloric opening is prohibited.2. Site-Specific Drug Delivery:-These systems are particularly advantageous fordrugs that are specifically absorbed from stomachor the proximal part of the small intestine, e.g.,riboflavin and furosemide.

3. Absorption Enhancement:-Drugs that have poor bioavailability because ofsite specific absorption from the upper part of thegastrointestinal tract are potential candidates to beformulated as floating drug delivery systems,thereby maximizing their absorption.

RECENT ADVANCEMENT IN FDDS:-1. Osmotic Regulated systems [9]

It is comprised of osmotic pressure controlled drugdelivery device and an inflatable floating supportin a bioerodible capsule. In the stomach thecapsule quickly disintegrates to release theintragastricosmotically controlled drug deliverydevice. The inflatable support inside from adeformable hollow polymeric bag that contains aliquid that gasifies at body temperature to beinflates the bag. The osmotic controlled drugdelivery device consists of two components – drugreservoir compartment and osmotic ally activecompartment

2. PVA-PVP Spray Dried Tablets [16]

These tablets shows immediate floating withalmost no lag time, floating for 24 hr and do notsink. No swelling and erosion takes place in theGIT, so the release does not depend uponosmolarity of the medium. Buoyancy in suchsystem is due to high porosity in the tablet. Theexceptionally good compressibility of spray driedPVA-PVP combination makes it possible to

produce mechanically stable oral DF, even withextremely low pressure

3. Ion exchange resins Beads [19]

A coated ion exchange resin bead formulationhas been shown to have gastric retention propertieswhich were loaded with bicarbonates. Ionexchange resins were loaded with bicarbonate anda negatively charged drug is bound to the resin.The resulted beads were then encapsulated in asemi-permeable membrane to overcome the rapidloss of carbon dioxide. Upon arrival in the acidicenvironment of stomach, an exchange of chlorideand bicarbonate ions take place. As a result of thisreaction carbon dioxide was released and trappedin the membrane thereby carrying beads towardsthe top of gastric content and producing a floatinglayer of resin beads in contrast to uncoated beads,which will sink quickly.

.4. Micro particles[20]

This approach is based on low-density foampowder. This system is advantageous because ofits zero to negligible lag time before starting offloatation. These floating microcapsules preparedby emulsion solvent evaporation technique,contain polypropylene foam powder, polymers andmodel drug. Drug release increases ratesignificantly increases with different types ofpolymers.

5. Lipid based sustained release matrixsystems[21,22]

Floating glycerol monooleate single-unit lipidmatrix containing high drug: excipients ratioachieved sustained drug release. Hydrophobiclipid, gelucire 43/01 can be considered as aneffective carrier for design of multiple –unit FDDSof highly water-soluble drugs.

6. Chitosan granules/Microcapsules[23]

These are prepared by de-acidification process.When added to acidic and neutral media thesegranules were immediately buoyant and provide acontrolled release of the drug. Laminatedpreparations can be prepared by coating withchitosan granule layer with chitosan membrane.These preparations buoyant and provide sustainedrelease.

7. Floating Rafts[4, 24]

Floating Rafts are used in the treatment ofgastric oesophageal reflux. This raft formulationbased on an alginate biopolymer. On ingestion,this formulation reacts with gastric acid to formfloating raft structure, which impedes the reflux ofacid and food by acting as a physical barrier. Theraft has a pH value higher than that of the stomach


contents so that in the event of gastric reflux, thewall of the oesophagus is not subjected to irritationby HCl. Such formulation on entering the stomachforms a colloidal gel. Sodium alginate solutionreacting with gastric acid and this gel floats on thesurface of the gastric contents due to CO2

generation by gas generating excipients impedingreflux of acid into the oesophagus.

Fig.9: Barrier formed by a raft-forming system

7. Multiple unit floating pill[25]

The system consisted of sustained- releasepills as seeds surrounded by double layers. Theinner layer was an effervescent layer containingboth sodium bicarbonate and tartaric acid. Theouter layer was a swellable membrane containingmainly polyvinyl acetate and purified shellac.Moreover, the effervescent layer was divided andfinally air-dried. The results into two sublayerstoavoid direct contact between sodium bicarbonateand tartaric acid. Sodium bicarbonate wascontained in the inner sublayer and of tartaric acidwas in the outer layer. When the system wasimmersed in a buffer solution at 370C, it sank atonce in the solution and formed swollen pills, likeballoons, with a density much lower than 1 g/ ml.The reaction was due to carbon dioxide generatedby neutralization in the inner effervescent layerswith the diffusion of water through the outerswellable membrane layers. The system floatcompletely within 10 min and approximately 80%remained floating over a period of 5hr.

Figure 10: A) Multiple unit floating pill B) Mechanism of floatation via CO2 generation

Table.1 Patents on GRDDS[13]

Sr.No. US Patent NO YEAR Patent Title1 20100015224 2010 Programmable buoyant delivery technology.2 20100286660 2010 Gastroretentive duodenal pill4 20090324694 2009 GRDDS comprising an extruded hydratable Polymer5 20080220060 2008 Gastroretentive formulations & manufacturing process6 20060013876 2006 Novel floating dosage form


Marketed Products of FDDS[13]

Table 2: Generally Manufactured Marketed Product

S.No BRAND NAME DRUG (DOSE) COMPANY, COUNTRY REMARKS1. Modapar® Levodopa(100mg),

Benserazide(25 mg)Roche Products,USA

Floating CR capsule

2 CifranOD® Ciprofloxacin(1 gm)

Ranbaxy,India

Gas generatingFloating tablet

3 Valrelease® Diazepam (15 mg) Hoffmann-LaRoche, USA

Floating Capsule

5 LiquidGavison®

Al hydroxide (95mg), Mg carbonate(358 mg)

GlaxoSmithKline, India

Effervescent floatingLiquid alginatepreparation

6 Cytotec® Misoprostal(100 mcg/200 mcg)

Pharmacia,USA

Bilayer floatingcapsule

7 Topalkan® Al-Mgantacid

Pierre FabreDrug, France

Floating liquidAlginate preparation

Table 3. List of Drugs Formulated as Single and Multiple Unit Forms ofFloating Drug Delivery Systems[33]

Tablets Chlorpheniramine maleate Theophylline Furosemide Ciprofolxacin Pentoxyfillin Captopril Acetylsalicylic acid Nimodipine Amoxycillintrihydrate Verapamil HCl Isosorbide dinitrate Sotalol Atenolol Isosorbide mononitrate Acetaminophen Ampicillin Cinnarazine Diltiazem Florouracil Piretanide Prednisolone Riboflavin- 5' Phosphate

Capsules Nicardipine L-Dopaandbenserazide Chlordiazepoxide HCl Furosemide Misoprostal Diazepam Propranlol Urodeoxycholic acid

Microspheres Verapamil


Aspirin, griseofulvin, and p-nitroaniline Ketoprofen Tranilast Iboprufen Terfenadine

Granules Indomathacin Diclofenac sodium

Films Cinnarizinei

CONCLUSION:

Floating drug delivery systems haveplenty of advantages over the other drug deliverysystem. As floating drug delivery system providesa dosage form which is stable and provides asustained release.The principle ofhydrodynamically balanced systems preparationoffers a simple and practical approach to achieveincreased gastric residence time for the dosageform and sustained drug release. The mostimportant criteria which has to be looked into forthe productions of a floating drug delivery system

is that the density of the dosage form should beless than that of gastric fluid and so, it was seenthat FDDS serve the best in the treatment ofdiseases related to the GIT and for extracting aprolonged action from a drug with a short half-life.FDDS promises to be a potential approach forgastric retention.Although there are number ofdifficulties to be worked out to achieve prolongedgastric retention, a large number of companies arefocusing toward commercializing thistechnique.Day after day the FDDS shows morepromise for a bright future.

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