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Journal of Drug Delivery & Therapeutics; 2012, 2(3): 12-21

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REVIEW ARTICLE ADVANCEMENTS IN CONTROLLED RELEASE GASTRORETENTIVE DRUG DELIVERY SYSTEM: A REVIEW
* 1

Makwana Ami 1; S ameja Krunal 1; Parekh Hejal 1; Pandya Yogi 2

Department of Pharmaceutics, C.U.Shah College of pharmacy and Research Opp: IBP Petrol Pump, Surendranagar-Ahmedabad Highway, Wadhwan-363030
2

Arihant School of Pharmacy & Bio Research Institute, Uvarsad, Gandhinagar-382421 E mail:krunalsameja@gmail.com

Received 19 April 2012; Revised 28 April 2012; Accepted 02 M ay 2012, Available online 15 M ay 2012 ABS TRACT: Oral delivery of the drug is by far the most preferable route of drug delivery due to the ease of administration, patient compliance and flexibility in the formulations but has a drawback of non-site specificity and short gastric resident time. In order to overcome the drawbacks of conventional oral drug delivery syst ems, several technical advancements have led to the development of gastro retentive drug delivery system that could revolutionize method of medication and provide a number of therapeutic benefits. In order to understand various physiological difficulties t o achieve gastric retention, we have summarized important factors controlling gastric retention. Afterwards, we have reviewed various gastroretentive approaches designed and developed until now, i.e. floating drug delivery system(FDDS), bio- or mucoadhesive system, expandable, unfoldable system, high density system, raft forming system, super porous hydrogel system and magnetic systems. Among these systems, FDDS have been most commonly used. Finally, advantages, disadvantages, evaluation, marketed preparation and future potential of gastro retentive drug delivery systems were covered. KEY WORDS : Gastroretentive drug delivery system, Gastric retention time, Gastric emptying time, Floating system, M igrating myloelectric cycle.

INTRODUCTION: The major objective of oral controlled drug delivery system is todeliver drugs for longer period of time to achieve betterbioavailability, wh ich should be predictable and reproducible.But this is difficult due to number of physiological problems such as fluctuation in the gastric emptying process, narrowabsorption window and stability problem in the intestine. An Ideal drug delivery system should possess two main properties: (1) It should be a single dose for the whole duration of the treatment. (2) It should deliver the active drug directly at the site of action 1 . Gastroretentive drug delivery system (GRDDS) is one of the novel approach in this area.Oral controlled release dosage forms are the mostcommonly formu lated but still offer highest attentionin the area of novel drug delivery systems 2 . Drugs that areeasily absorbed from gastrointestinal tract (GIT) and have short half-lives are eliminated quickly fro m the systemic circu lation. Frequent dosingof these drugs is required to achieve suitabletherapeutic activity. To avoid this limitation,the development of oral sustained-controlledrelease formulat ions is an attempt to release thedrug slowly into the GIT and maintain an effective drug concentration inthe systemic circulat ion for a long time. Afteroral administration, such a drug delivery wouldbe retained in the stomach and release the drugin a controlled manner, so that the drug could besupplied continuously to its absorption sites in the GIT.3 Poor absorption of many drugs in the lower GIT necessitates controlled release dosage forms to be maintained in the upper GI tract, particularly the stomach 2011, JDDT. All Rights Reserved and upper small intestine.4 These drugdelivery systems suffer fro m main ly twoadversities: the short gastric retention time(GRT) and unpredictable short gastric emptyingtime (GET), which can result in inco mplete drugrelease from the dosage form in the absorptionzon e (stomach or upper part of small intestine)leading to dimin ished efficacy of ad ministered dose.5 To formulate a site-specific orallyad min istered controlled release dosage form, itis desirable to achieve a prolong gastricresidence time by the drug delivery.

Figure 1: (a) Conventional Dosage Form and (b) Gastric Retentive Drug Delivery S ystem (ref. https://data.epo.org/)

GRDDS are thus beneficial for such drugs by imp roving their bioavailability, therapeutics efficacy and possible reduction of the dose and improves the drug solubility that is less soluble in a high pH environment.6 Apart of these advantages, these systems offer various pharmacokinetics advantages like maintenance of constant therapeutic levels over a prolonged period and thus reduction in fluctuation in the therapeutic levels.7 Gastric retention will provide ISSN: 2250 -1177 CODEN: JDDTAO

Makwana et al Journal of Drug Delivery & Therapeutics; 2012, 2(3): 12-21 advantages such as the delivery of drugs with narrow 3. Drugs that is poorly soluble at alkaline p H, e.g. absorption windows in the s mall intestinal reg ion. Also Furosemide, Diazepam, Verapamil HCL, prolonged gastric retention time in the stomach could be Chlord iazepo xide etc. advantageous for localaction in the upper part of the small 4. Drugs with a narrow window of absorption in GIT, e.g. intestine. Riboflavin, ParaAminobenzoic Acid, Cyclos porine, PHYS IOLOGY OF STOMACH: Methotrexate, Levodopa etc. 5. Drugs which are absorbed rapidly fro m the GI tract. e.g. Metonidazole, tetracycline. 6. Drugs that degrade or unstable in the colon. e.g. Captopril, Ranit idine HCL, Metronidazol, Metformin HCl. 7. Drugs that disturb normal colonic microbes , e.g. Amo xicillin Trihydrate, antibiotics against Helicobacter pylori. UNS UITAB LE DRUGS FOR GRDDS
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Figure 2: Physiology of stomach (ref http:// www.zuni v.net/ physiolog y/ book/chapter22.html ) The stomach is an organ with a capacity for storage and mixing. Anatomically the stomach is divided into three regions: Fundus, Body and antrum (pylorus). The pro ximal part made up of fundus and body which acts as a reservoir for undigested material, whereas the antrum is the main site for mixing motions and act as a pump for gastric emptying by propelling actions.8 Under fasting conditions, the stomach is a collapsed bag with a residual volume of approximately 50ml and contains a small amount of gastric flu id (pH 1 3) and air. The mucus spreads and covers the mucosal surface of the stomach as well as the rest of the GI tract. The GI tract is in a state of continuous motility consisting of two modes, interdigestive motility pattern and digestive motility pattern. The former is dominant in the fasted state with a primary function of clean ing up the residual content of the upper GIT. The interdigestive motility pattern is commonly called the migrat ing motor complex (MM C) and is organised in cycles of activity and quiescence.9 NEEDS FOR GAS TRO RETENTION 11 Drugs that are absorbed fro m the pro ximal part of the gastrointestinal tract (GIT). Drugs that are less soluble or are degraded by the alkaline pH they encounters at the lower part of GIT. Drugs that are absorbed due to variable gastric emptying time. Local or sustained drug delivery to the stomach and proximal Small intestine to treat certain conditions. Part icularly useful for the treatment of peptic ulcers caused by H. Pylo ri Infections. IDEAL DRUG CHARACTERIS TICS FOR GRDDS
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1. Drugs that have very limited acid solubility. e.g. phenytoin etc. 2.Drugs that suffer instability in the gastric environ ment. e.g. erythromycin etc. 3.Drugs intended for selective release in the colon. e.g. 5amino salicylic acid and corticosteroids etc. FACTORS CONTROLLING GRDDS The stomach anatomy and physiology contain parameters to be considered in the development of gastroretentive dosage forms. To pass through the pyloric valve in to the small intestine the particle size should be in the range of 1 to 2 mm.13 The most important parameters controlling the GRT of oral dosage forms include : density, size, shape of the dosage form, food intake and its nature, caloric content, frequency of intake, posture, gender, age, sex, sleep, body mass index, physical activ ity, diseased states of the individual ( e.g. chronic disease, diabetes etc.) and administration of drugs with impact on GI transit time.for example drugs acting as anticholinergic agents ( e.g. atropine, propantheline), Opiates ( e.g. codeine) and prokinetic agents ( e.g. metclopramide, cisapride.) 14 . The mo lecular weight and lipophilicity of the drug depending on its ionizat ion state are also important parameters. 15 A. Dosage form related factors Density of dosage forms: Dosage forms having a density lower than the gastric contents can float to the surface, while high density systems sink to bottom of the stomach.16 Both positions may isolate the dosage system fro m the pylorus. A density of < 1.0 g m/ cm3 is required to exhibit floating property.17 However; the floating tendency of the dosage form usually decreases as a function of time, as the dosage form gets immersed into the fluid, as a result of the development of hydrodynamic equilibriu m. 18 Size of the dosage form: The mean GRT of nonfloating dosage forms are highly variable and greatly dependent on their size, wh ich may be large, mediu m and small units. 19 In most cases, the larger the dosage form the greater will be the GRT due to the larger size of the dosage form would not allow this to quickly pass through the pyloric antrum into the intestine 20 . Dosage forms having a diameter of more than 7.5 mm show a better gastric residence time co mpared with one having 9.9 mm 17 . Thus the size of the dosage form appearsto be an important factor affecting gastric retention. 20 ISSN: 2250 -1177 CODEN: JDDTAO

1. Drugs acting locally in the stomach, e.g. Antacids and drugs for H. Pylori viz., M isoprostol 2. Drugs that are primarily absorbed in the stomach and upper part of GI, e.g. A mo xicillin, Calciu m Supplements, Chlord iazepo xide and Cinnarazine 2011, JDDT. All Rights Reserved

Makwana et al Journal of Drug Delivery & Therapeutics; 2012, 2(3): 12-21 14 Shape of the dosage form: Ring-shaped and tetrahedronofthe gastric contents and remained for a longer time, shaped devices have a better gastric residence time as showing prolonged GRT. But the non-floating unitssettled compared with other shapes 21 . to the lower part of the stomach andunderwent faster emptying as a result of peristaltic contractions and the Single or multi ple unit formul ation: Mu ltiple unit floating units remained awayfro m the pylorus. However, in formulat ions show a more predictable releaseprofile and supine position, thefloating units are emptied faster than insignificant impairing of performancedue to failu re of non-floatingunits of similar size. units, allow co-ad min istration ofunits with different release profiles or containingincompatible substances and permit a Concomi tant drug admi nistration largermargin of safety against dosage form anticholinergics like atropine and propantheline, opiates failureco mpared with single unit dosage forms. like codeine and prokinetic agents like metoclopramide B. Food intake and its nature and cisapride. Thepresence or absence of food in the GIT influences the GRT of the dosage form.Usually the presence offood in the GIT imp roves the GRT of the dosage form andthus, the drugs absorption increases by allowing itsstay at the absorption site for a longer period.Again, increase in acidity and caloric value showsdown gastric emptying time and improve the gastric retention of dosage forms 22 . Food habits affect the GRT in the fo llo wing ways 23 . Fed or unfed state under fasting conditions, theGI motility is characterized byperiods of the migrat ingmyoelectric comp lex (MM C) that occursevery 1.5 to 2 hours. The MMC sweeps undigestedmaterial fro m the stomach and, if thetiming of ad min istration of the formulat ioncoincides with that of the MMC, the GRT of theunit can be expected to be very short. However, inthe fed state, MMC is delayed and GRT isconsiderably longer. It was concluded that as mealswere given at the time when the previous digestivephase had not completed, the floating form buoyantin the stomach could retain its position for anotherdigestive phase as it was carried by the peristalticwaves in the upper part of the stomach. Nature of meal feeding of indigestible poly mersor fatty acid salts can change themotility pattern of the stomach to a fed state, thusdecreasing the gastric emptying rate andprolonging drug release. Cal oric content GRT can be increased by four to10 hours with a meal that is high inproteins and fats. Frequency of feed the GRT can increase by over400 minutes when successive mealsare g iven compared with a single meal due to thelow frequency of MMC. C. Patient related factors Gender : Generally femalesshowed comparatively shorter mean a mbulatory GRT than males, and the gastric emptying in wo men was slower than in men.24 Age: In case of elder persons, gastric emptying is slowed down, especially those over 70, have a significantly longer GRT; Posture: GRT can vary between supine and upright ambulatory states of the patient; the floating and nonfloating systems behaved differently. In the uprightposition, the floating systems floated to the top D. Disease states: Gastric ulcer, diabetes, hypothyroidism increase GRT. Hyperthyroidism, duodenal ulcers decrease GRT. E. Volume of GI flui d: The resting volume of the stomach is 25 to 50 ml. When volume is large, the emptying is faster. Flu ids taken at body temperature leave the stomach faster than colder of warmer flu ids. F. Effect of buoyancy On comparison of floating and nonfloating units, it wasconcluded that regardless of their sizes the floating units remained buoyant on thegastric contents throughout their residence in the GIT, wh ile the non-floating units sank and remained in the lower part of thestomach. Floating units away from the gastro-duodenal junction were protected fro m theperistaltic waves during digestive phase while then on floating forms stayed close to the pylorus andwere subjected to propelling and retropelling waves of the digestive phase.25 TYPES OF DOSAGE FORM FOR GRDDS: A) FLOATING DRUG DELIV ERY (FDDS) AND ITS MECHANIS M: S YSTEMS

FDDS is one of the important approaches to achieve gastric retention to obtain sufficient drug bioavailability 26 . This system is desirable for drugs with anabsorption window in the stomach or in the uppersmall intestine 27 . This have a less density then gastric fluids and so remain buoyant in thestomach without affecting gastric emptying rate fora pro longed period and the drug is released slowlyas a desired rate fro m the system. After release ofdrug, the residual system is emptied fro m thestomach. This results in an increased GRT and a better control of the fluctuation in plas ma drugconcentration. The major requirements for FDDS are 28 : It should release contents slowly to serve as a reservoir. It must maintain specific g ravity lower than gastric contents (1.004 1.01 g m/cm3). It must form a cohesive gel barrier

2011, JDDT. All Rights Reserved

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Journal of Drug Delivery & Therapeutics; 2012, 2(3): 12-21

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Figure 3: Mechanism of floating systems, GF= Gastric flui d (ref. http:// www.pharmainfo.net/ pharma-studentmagazine/comprehensive-review-floating-tablets) The inherent low density can be provided by theentrapment of air (e.g . hollo w chambers)29 or bythe incorporation of low density materials (e.g. fattymaterials or oils, or foam powder)30-32 . Thesefollowing approaches have been used for the designof floating dosage forms of single and multip le-unitsystems. Recently a single-unit floating system was proposed consisting of polypropylene foam powder, matrix fo rming polymers, drug and filler33 . The good floating behaviour of systems could besuccessfully combined with accurate control of theresulting drug release patterns. Single-unit dosageforms are associated with problems such as stickingtogether or being obstructed in the GIT wh ich may produce irritation. On theother hand multip le-unit floating systems may be anattractive alternative since they have been shown to reduce inter and intra- subject availabilit ies indrug absorption as well as to lower the possibility of dose dumping. Various mult iple-unit floatingsystem like air compart ment mult iple-unit system, hollo w microspheres (microballoons) preparedby the emulsion solvent diffusion method 34 , micropart icles based on low density foam powder31 , beads prepared by emulsion gelatin method 35 etc. can be distributed widely throughout the GIT, providing the possibility of achieving a longerlasting and more reliable release of drugs.Based onthe mechanism of buoyancyFDDS can be div ided as below: I. Effervescent S ystems The first chamber contains the drug and the second chamber contains the volatile liquid. TheGRT of a drug delivery system can be sustained by incorporating an inflatable chamber, which contains a liquid e.g. ether, cyclopentane, that gasifies at body temperature to cause the inflatation of the chamber in the stomach. The device may also consist of a bioerodible plug made up of Poly vinyl alcohol, Po lyethylene, etc. that gradually dissolves causing the inflatable chamber to release gas and collapse after a predetermined time to permit the spontaneous ejection of the inflatable systems fro m the stomach 36 . The device inflates, and the drug iscontinuously released from the reservoir into the gastric flu id.

These buoyant systems utilize matrices prepared with swellable poly mers such as methocel, polysaccharides (e.g., ch itosan), effervescentcomponents (e.g., sodium bicarbonate, citric acidor tartaric acid). The system is so prepared thatupon arrival in the stomach, CO2 isreleased, causing the formu lation to float in thestomach. Other approaches and materials that havebeen reported are a mixtu re of sodium alginate andsodium bicarbonate 17 ,multip le unit floating pills that generate CO2 when ingested, floating min icapsules witha core of sodium bicarbonate, lactose and poly vinyl pyrrolidone coated with hydro xyl propyl methyl cellulose (HPM C), and floating systemsbased on ion exchange resin technology, etc. a. Volatile li qui d containing systems This type of system consists of two chambers separated by an impermeab le, pressure-responsive, movable bladder. 2011, JDDT. All Rights Reserved

Figure 4: Volatile liquid containing system (ref. http://www.sciencedirect.com/science/article/pii/S0168365999002047)

b. Gas generating systemsThese buoyant delivery systems utilize effervescentreaction between carbonate/bicarbonate salts andcitric/tartaric acid to liberate CO2 , which getsentrapped in the gellified hydrocollo id layer of thesystems, thus decreasing its specific gravity andmaking it float over chyme36,37 . The optimal stoicheometric ratioof cit ric acid and sodium bicarbonate for gasgeneration is reported to be 0.76: 1.

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Makwana et al

Journal of Drug Delivery & Therapeutics; 2012, 2(3): 12-21 16 cellu lose, sodiumcarbo xy methyl cellu lose, polycarbophil,polyacrylate, polystyrene, agar, carrageenans oralginic acid are used 40, 41 .

Figure 5: a) Floating pill b) Principle mechanism of floating by CO2 gas releasing method (ref.www.pharmastuff.blogspot.com)

A new multip le type of floating dosage system composed of effervescent layers and swellable membrane layers coated on sustained release pills. The inner layer of effervescent agents containing sodium b icarbonate and tartaric acid was divided into two sublayers to avoid direct contact between the two agents. These sublayers were surrounded by a swellable poly mer membrane containing polyvinyl acetate and purified shellac. When this system was immersed in the buffer at 37C, it settled down and the solution permeated into the effervescent layer through the outer swellab le membrane. CO2 was generated by the neutralization reaction between the two effervescent agents, producing swollen pills (like balloons) with a density less than 1.0 g/ ml. It was found that the system had good floating ability independent of pH and viscosity and the drug (Paraamino benzoic acid) released in a sustained manner as shown in Fig.537 . II. Non-Effervescent FDDS

Figure 6: Working pri nci ple of hydrodynamically balanced system (ref. www.sciencedirect.com) The polymer is mixed with drugs and usually administered in HB-capsule. Thecapsule shell dissolves in contact with water andmixture swells to form a gelat inous barrier, whichimparts buoyancy to dosage form in gastric juice fora long period. Because, continuous erosion of the surface allows water penetration to the inner layers maintaining surface hydration and buoyancy to dosage form41 . Incorporation of fatty excip ients gives low-density formulat ions reducing theerosion. Madopar LP, based on the system wasmarketed during the 1980s 43 . Effective drugdeliveries depend on the balance of drug loadingand the effect of poly mer on its release profile.Several strategies have been tried and investigatedto improve efficiencies of the floating hydro dynamically balanced systems 41,42 . b. Microporous compartment system

Non-effervescent FDDS are normally prepared fro m gelforming or highly swellable cellulose type hydrocolloids, polysaccharides or matrix fo rming polymers like polyacrylate, polycarbonate, polystyrene and polymethacrylate. In one approach, intimate mixing of drug with a gel forming hydrocolloid wh ich results in contact with gastric flu id after oral ad ministration and maintain a relative integrity of shape and a bulk density less than unity within the gastric environment 38 . The air trapped by the swollen polymer confers buoyancy to these dosage forms. Excip ients used most commonly in these systems includeHPMC polyacry lates, polyvinyl acetate, carbopol, agar, sodium alg inate, calciu m chloride, polyethylene oxide and polycarbonates. This system can be further divided into the sub-types: a. Hydrodynamically balanced systems OR Colloi dal Gel B arrier System:

Thesesystems contains drug with gel-forming hydrocolloids meant to remain buoyant on the stomach content. This prolongsGRT and maximizes the amount of drug that reaches its absorption sites in the solution form forready absorption.These are single-unit dosageform, containing one or more gel-forminghydrophilic polymers 39 . HPMC, hydroxethyl cellu lose, hydroxypropyl 2011, JDDT. All Rights Reserved

Thistechnology is based on the encapsulation of a drugreservoir inside a microporous compart ment with pores along its top and bottom walls. Theperipheral walls of the drug reservoir compart mentare co mpletely sealed to prevent any direct contactof gastric surface with the undissolved drug. In thestomach, the floatation chamber containingentrapped air causes the delivery system to floatover the gastric content. Gastric flu id entersthrough the aperture dissolves the drug and carriesthe dissolved drug for continuous transport acrossthe intestine for absorption 43 . c. Alginate beads

Multi-unit floatingdosage forms have been developed from freezedriedcalciu m alg inate. Spherical beads ofapproximately 2.5 mm in dia meter can be preparedby dropping sodium alginate solution into aqueoussolution of ISSN: 2250 -1177 CODEN: JDDTAO

Makwana et al Journal of Drug Delivery & Therapeutics; 2012, 2(3): 12-21 17 calciu m chlo ride, causing theprecipitation of calciu m d. Microballoons or Hollow Micros pheres alginate. The beads arethen separated, snap-frozen in Microballoons / hollow microspheres loaded withdrugs in liquid nitrogen, andfreeze-dried at -40C for 24 hours, their other polymer shelf were prepared bysimp le solvent leading to theformat ion of a porous system, which can evaporation or solvent diffusion method to prolong the maintain afloating force for over 12 hours. These GRT of the dosage form. floatingbeads gave a prolonged residence time of morethan 44 5.5 hours.

Figure 7: Formulation of floating hollow microsphere or microballoon (ref. www.pharmainfo.net) Co mmonly used polymers to develop these systems are polycarbonate, cellulose acetate, calciumalginate, Eudragit S, agar and low methoxy lated pectin etc. Buoyancy and drug release fro m dosageform are dependent on quantity of polymers, theplasticizer polymer ratio and the solvent used forformu lation. These microballoons floated continuously over the surface of an acidic dissolution media containing surfactant for >12 hours. At present hollow microspheres are considered to be one of the most promising buoyantsystems because they combine the advantages ofmu ltip le-unit system and good floating 45 . B. BIO/ MUCO ADHES IVE S YSTEMS : Bioadhesive drug delivery systems (BDDS) are used as a delivery device within the lumen toenhance drug absorption in a site specific manner. This approach involves the use of bioadhesive polymers, which can adhere to the epithelial cell surface o r mucin in the stomach. It increases the GRT by increasing the intimacy and duration of contact between the dosage form and the biological membrane. The adherence to the gastric wall increases residence time at a part icular site, thereby improving bioavailab ility 46 . Gastric mucoadhesion does not tend to be strongenough to impart to dosage forms the ability toresist the strong propulsion forces of the stomachwall. The continuous production of mucous by thegastric mucosa to replace the mucous that is lostthrough peristaltic contractions and the dilution ofthe stomach content also seem to limit the potentialof mucoadhesion as a gastroretentive force. Someof the most promising excip ients that have been used are polycarbophil, carbopol, lectins, chitosan andgliadin, etc. BDDS are used as a delivery device within the hu man to enhance drugabsorption in a site-specific manner47 . The basis of adhesion in that a dosageform can stick to the mucosal surface by different mechanism. These mechanis ms [43,49 are: 1) The wetting theory, which is basd on the abilityof bioadhesive polymers to spread and developintimate contact with the mucous layers. 2) The diffusion theory which proposes physical entanglement of mucin strands the flexible poly mer chains, or an interpenetration of mucinstrands into the porous structure of the polymersubstrate. 3) The absorption theory, suggests that bioadhesion due to secondary forces such as Vander Waalforces and hydrogen bonding. 4) The electron theory, which proposes attractiveelectrostatic forces between the glycoprotein mucin network and the bio adhesive material. Binding of polymers to the mucin/epithelial surface can be divided into three categories: a. Hydrati on mediated adhesion-Certainhydrophilic polymers have the tendency to imb ibelarge amount of water and become sticky, therebyacquiring b ioadhesive properties. The prolonged gastroretention of the bio/mucoadhesive delivery system is further controlled by the dissolution rateof the polymer. b. Bonding mediated adhesion- The adhesion of polymers to a mucus or epithelial cell surface involves various bonding mechanis ms including physical, mechanical and chemical bonding.Physical ormechanical bonds can result from deposition andinclusion of the adhesive material in the crevices ofthe mucusa. Chemical bonds may be either covalent (primary) or ionic (secondary) in nature. Secondary chemical bonds consist of dispersive interactions (i.e. VanderWaals interactions) and stronger specific interactions such as hydrogen bonds. The hydrophilic functional groups responsible for fo rming hydrogen bonds are the hydroxyl and carbo xylic groups 50 . c. Receptor mediated adhesion- Certainpoly mers have the ability to bind to specificreceptor sites on the cell surface. The receptormed iated events serves as a potential approach inbio/muco- adhesion, hence enhancing the gastricretention of dosage forms. Certain plant lectins, like ISSN: 2250 -1177 CODEN: JDDTAO

Figure 8: Bio-adhesion System (ref. www.sciencedirect.com) 2011, JDDT. All Rights Reserved

Makwana et al Journal of Drug Delivery & Therapeutics; 2012, 2(3): 12-21 18 tomato lectins, interact specifically with the sugar groups D. HIGH DENS ITY S YSTEMS present in mucus or on the glycocalyx51 . Gastric contents have a density close to water (1.004 C. EXPANDAB LE, UNFOLDAB LE AND g/cm3 ). When high density pellets is given to the patient, it SWELLAB LE S YSTEMS will sink to the bottom of the stomach and are entrapped in the folds of the antrum and withstand the peristaltic waves A dosage form in the stomach will withstand gastrictransit of the stomach wall. Sedimentation has been emp loyed as if it bigger than pyloric sphincter. However,the dosage a retentionmechanism for pellets that are small enough to form must be small enough to beswallowed, and must not beretained in the rugae or folds of the stomach body near cause gastric obstructioneither singly or by accumulation. the pyloric region, which is the part of theorgan with the Thus, theirconfigurations 52,53 are required to develop lowest position in an uprightposture. Dense pellets anexpandable system to prolong GRT: (approximately 3g/cm3 ) trapped in rugae also tend to withstand theperistaltic movements of the stomach wall. 1) A s mall configuration for oral intake, Withpellets, the GI transit time can be extended fro m 2) An expanded gastroretentive form, and anaverage of 5.825 hours, depending more ondensity than on the diameter of the pellets27.Co mmonly used 3) A final s mall form enabling evacuation followingdrug excip ients are barium sulphate,zinc o xide, titaniu m dio xide release fro m the device. and iron powder, etc.These materials increase density by Thus, gastro-retention is improved by thecombination of up to 1.5 2.4g/cm3 . The only majo r drawbacks with this substantial dimension with highrigidity of dosage form to systems is that it is technically d ifficult to manufacture withstand peristalsis andmechanical contractility of the them with a large amount of drug (>50%) and to achieve stomach. the required density of 2.4-2.8 g/cm3 E. MAGNETIC S YS TEMS This approach toenhance the GRT is basedon the simple principle that the dosage formcontains a small internal magnet, and a magnetplaced on the abdomen over the position of thestomach. Although magnetic system seems towork, the external magnet must be positioned with adegree of precision that might co mpro misepatient compliance.The technological approach in rabbits with bioadhesive granules containing ultra-fine ferrite. They guided them to oesophagus with an external magnet for the initial 2 minutes and almost all the granules were retained in the region after 2hours 56 . F. RAFT FORMING S YSTEM

Figure 9: Unfol dable and s wellable systems (ref. www.sciencedirect.com) Unfoldable and swellable systems have been investigated andrecently tried to develop an effective GRDDS. Unfoldable systems are made ofbiodegradable polymers. They are available indifferent geometric forms like tetrahedron, ring orplanner membrane (4 - label disc or 4 limbed crossform) of bioerodible poly mer co mpressed withinacapsule which extends in the stomach 54,55 . Swellab le systems are also retained in the GIT due to their mechanicalproperties. The swelling is usually results from osmotic absorption of water. Expandable systems have somedrawbacks like problematical storage of mucheasily hydrolysable, biodegradable polymersrelatively short-lived mechanical shape memory forthe unfolding system most difficult to industrialize and not cost effective. Again, permanent retentionof rigid, large single-unit expandable drug deliverydosage forms may cause brief obstruction, intestinaladhesion and gastropathy. 2011, JDDT. All Rights Reserved

Raft System incorporate alg inate gels these have a carbonate component and, upon reaction with gastric acid, bubbles form in the gel, enabling floating 57 . Raft forming systems have received much attention for the drug delivery for GI infections and disorders. Themechanism includes the formation ofviscous cohesive gel in contact with gastric fluids, wherein eachportion of the liquid swells forming a continuous layer called a raft.Th is raft floats on gastric fluids because of low bulk density createdby the formation of CO2 . Usually, the system ingredients includes agel forming agent and alkaline bicarbonates or carbonatesresponsible for the format ion of CO2 to make the system less denseand float on the gastric flu ids

Figure 3: S chematic illustration of the barrier formed by a raft-forming system. (ref.

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Makwana et al Journal of Drug Delivery & Therapeutics; 2012, 2(3): 12-21 19 An antacid raft forming floating system contains a gel absorption and transit of the drug in the GIT that act forming agent (e.g. sodium alginate), sodiu mbicarbonate concomitantly to influence the magnitude of drug and acid neutralizer, which forms a foaming absorption 63 . sodiumalginate gel (raft), which when comes in contact 2) In a similar fashion to the increased efficacy of active with gastric flu ids,the raft floats on the gastric flu ids and transporters exhibit ing capacity limited activity, the prevents the reflu x of thegastric contents (i.e. gastric acid) pre-systemic metabolis m of the tested compound may into the esophagus by acting as abarrier between the be considerably increased when the drug is presented stomach and esophagus58 . to the metabolic enzy mes (cytochrome P450, in particular CYP3A 4) in a sustained manner, rather than G. SUPER POROUS HYDROGEL S YS TEMS by a bolus input. These swellab le systems differ sufficiently fro m 3) For drugs with relatively short half life, sustained release may result in a flip-flop pharmacokinetics and theconventional types to warrant separateclassification. also enable reduced frequency of dosing with Super porous hydrogel that expand dramat ically (hundreds of times their dehydrated form within a matter of seconds) improved patientcompliance. 4) They also have an advantage over their conventional when immersed in water. With pore size ranging, 10n m to system as it can be used to overcome the adversities of 10m, absorption window by conventional hydrogel is a very slow process and several hours may be needed to the GRT as well as the GET. As these systems are expected to remain buoyant on the gastric fluid reach an equilibriu m state during which parameter without affecting the intrinsic rate of emp loying evacuation of the dosage form may occur59 . In this approach to improve GRT super porous hydrogel of because of low density. 5) GRDDS can produce prolong and sustain release of average pore size less than 100m, swell toequilibriu m drugs from dosage forms which avail local therapy in size within a minute due to rapid wateruptake by capillary wetting through numerousinterconnected open pores 60 . the stomach and small intestine. Hence they are useful in the treatment of disorders related to stomach and They swell to a largesize (swelling ratio : 100 or mo re) and small intestine. are intendedto have sufficient mechanical strength to withstandpressure by gastric contraction. This is advised 6) The controlled, slow delivery of drug form GRDF provides sufficient local action at the diseased site, byco-formu lation of hydrophilic particu late material61 . thus minimizing or eliminating systemic exposure of H. SWELLING S YSTEMS drugs. This site-specific drug delivery reduces undesirable effects of side effects. These are the dosage forms, which after swallowing; swell 7) Continuous input of the drug following CR-GRDF at an extent that prevents their exit fro m the pylorus. As a administration produces blood drug concentrations result, the dosage form is retained in the stomach for a within a narrower range compared to the IR dosage long period of time. These systems may be named as plug forms. Thus, GRDF min imize the fluctuation of drug type systems, since they exhib it the tendency to remain concentrations and effects.Therefore, concentration lodged at the pyloric sphincter. The formu lation is dependent adverse effects that are associated with designed for gastric retention and controlled delivery of peak concentrations can be presented. This feature is the drug into the gastric cavity. Such poly meric matrices of special importance for drug with a narrow remain in the gastric cavity for several hours even in the therapeutic index 64 . fed state. Sustained and controlled drug release may be 8) Retention of the drug in the GRDF at the stomach achieved by selection of proper molecular weight polymer, minimizes the amount of drug that reaches the colon. and swelling of the poly mer retards the drug release. On Thus, undesirable activities of the drug in colon may coming in contact with gastric fluid, the polymer imb ibes be prevented. water and swells. The extensive of these polymers is due to 9) In many cases, the pharmacological response which the presence of physical/chemical cross -links in the intervenes with the natural physiologic processes hydrophilic poly mer network. provokes a rebound activity of the body that minimizes drug activity. Thus Slow input of the drug into the body was shown that gastroretentive drug delivery system can minimize the counter activity of the body leading to higher drug efficiency. 10) Reduction of fluctuation in drug concentration makes it possible to obtain improved selectivity in receptor activation. 11) The sustained mode of drug release from gastroretentive dosage form enables extension of the time over a critical concentration and thus enhances Figure 41: S wellable tablet in stomach(ref.www.pharmainfo.net) the pharmacological effects and improves the chemical outcomes. ADVANTAGES OF GAS TRORET ENTIVE DRUG DELIVERY S YS TEMS LIMITATIONS OF GASTRORET ENTIVE DRUG 1) The bioavailability of therapeutic agents can be significantly enhanced especially for those which get metabolized in the upper GIT by thisGRDDS in comparison to the admin istration of nonGRDDS62 .There are several different factors related to 2011, JDDT. All Rights Reserved DELIVERY S YS TEMS GRDDS have potential in imp roving BA of drugsexhibiting absorption window. Ho wever theyhave certain limitations. One of the majordisadvantages of the ISSN: 2250 -1177 CODEN: JDDTAO

Makwana et al Journal of Drug Delivery & Therapeutics; 2012, 2(3): 12-21 floating system is therequirement of h igh levels of fluids in Table 1: Some marketed preparati ons of GRDDS the stomachfor the delivery system to float and work available i n the Market69 65 efficiently. 1) 2) Require a higher level o f fluids in the stomach. Not suitable for drugs that may cause gastric lesions e.g. Non- steroidal anti inflammatory drugs. Drugs that are unstable in the strong acidic environment, these systems do not offer significant advantages over the conventional dosage forms fo r drugs that are absorbed throughout the GIT. Drugs intended for selective release in the colon E.g. 5- amino salicylic acid and cort icosteroids etc. The floating systems in patients with achlorhydria can be questionable in case of swellab le system. Retention of high density systems in the antrum part under the migrating waves of the stomach is questionable. The mucus on the walls of the stomach is in a state of constant renewal, resulting in unpredictable adherence. Bioadhesion in the acidic environment and high turnover of mucus may raise questions about the effectiveness of this technique. Similarly retention of high density systems in the antrum part under the migrat ing waves of the stomach is questionable. In all the above systems the physical integrity of the system is very impo rtant and primary requirement. The residence time in the stomach depends upon the digestive state. Hence FDDS should be administered after the meal. [4 The ability to float relies on the hydration state of the dosage form, In order to keep these tablets floating in vivo, intermittent admin istration of water (a tumbler full, every 2 hours) is beneficial.4 The ability of the drug to remain in the stomach depends upon the subject being positioned upright. 66 Nifedipin like drug cant be candidate for FDDS since the slow gastric emptying may lead to the reduced systemic bio -availab ility.67
Drug Diazepam Floating capsule Benserazide and L-Dopa Aluminium M agnesium antacid Antacid preparation Ciprofloxacin M etformin HCL M isoprostal Aluminium Hydroxide Ferrous sulphate Brand name Valrelease M adopar Topalkan AlmagateFlot-Coat Cifran OD Glumetza GRTM Cyotec Liquid Gavison Conviron

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3) 4) 5)

CONCLUS IONS: Controlled release gastroretentive dosage forms (CRGRDF) enable prolonged and continuous input of the drug to the upper parts of the gastrointestinal (GI) tract and improve the bioavailability of medicat ions that are characterized by a narrow absorption window. Based on the literature surveyed, it may be concluded that gastroretentive drug delivery offers various potential advantages for drug with poor bioavailability due their absorption is restricted to the upper gastrointestinal tract (GIT) and they can be delivered efficiently thereby maximizing their absorption and enhancing absolute bioavailability. And hence, it can be concluded that these dosage forms serve the best in the treatment of diseases related to the GIT and for extracting a prolonged action fro m a drug with a short half-life. FUTUR E POTENTIAL FOR GRDDS: While the control of drug release profiles has been a major aim o f pharmaceutical research and development in the past two decades, the control of GI transit profiles could be the focus of the next two decades and might result in the availability of new products with new therapeutic possibilit ies and substantial benefits for patients. Soon, the so-called once-a-day formulat ions may be rep laced by novel gastroretentive products with release and absorption phases of approximately 24 hours.

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