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  2. 2. Various NDDS….Bio/Muco Adhesive DDSColon Targeted DDSIntelligent Controlled Release DDSNanotechnology & Liposomal DDSPulmonary DDS (MD inhalers)Microspheres & Microcapsules DDSTransdermal DDSOcular DDSOsmotic DDSGastro Retentive DDSMarch 22, 2013 DrLDP 2
  3. 3. GASTRO RETENTIVE DRUG DELIVERY SYSTEM (GRDDS)PresentationOutline:IntroductionMeritsStomach Physiology GRDDSGR TechnologiesFactors affectingGRDDSEvaluation of GRDDSDemeritsMarch 22, 2013 DrLDP 3
  4. 4. . The Introduction oral route is the mostpromising route of drug delivery.Effective oral drug delivery maydepend upon - gastric emptying process, - GI transit & residence time, - drug release from DF and - site of absorption of drug.. Conventional oral dosage formspossess several physiologicallimitations like - variable gastric emptying, - variable GI transit & shorter residencetime, March 22, 2013 DrLDP 4 - incomplete drug release
  5. 5. Introduction….• It may lead to incomplete & non uniform absorption of the drugs having absorption window in upper part of GIT as once the DF passes down the absorption site, the remaining quantity goes unabsorbed.• Hence, a beneficial DDS would be one which exhibits the ability to control & prolong the gastric emptying time and can deliver drug in maximum conc. at the absorption site (i.e. upper part of the small intestine). March 22, 2013 DrLDP 5
  6. 6. Introduction...• Gastro Retentive Drug Delivery System (GRDDS) is one of the site specific delivery for the delivery of drugs either in stomach or intestine . This can be obtained by retaining dosage form into stomach and drug is released in controlled manner to specific site either in stomach, duodenum or/and intestine. AbsorptionMarch 22, 2013 DrLDP window 6
  7. 7. Different from SR… Sustained Release Absorption GRDDSMarch 22, 2013 window DrLDP 7
  8. 8. Merits of GRDDS• Deliver the drugs with narrow absorption window in small intestine. e.g Furosemide, L. Dopa.• Efficient delivery for local action in upper part of small intestine due to longer residence time in stomach. e.g. treatment of peptic ulcer.• Improved bio-availability for drugs that are absorbed readily upon release in GIT.• Better patient compliance by once a day therapy.March 22, 2013 DrLDP 8
  9. 9. Beneficiary Drugs by GRDDS• Drugs that act locally in stomach. e.g. Antacids.• Drugs that disturb colonic microbes . e.g. against Helicobacter Pylori, Misoprostol.• Drugs that are principally absorbed in the stomach. e.g. amoxycillin.• Drugs that are poorly soluble at alkaline pH. e.g. diazepam, chlordiazepoxide, verapamil.• Drugs absorbed readily throughout GIT. e.g. metronidazole, tetracycline.• Drugs that are unstable in the colon. e.g. captopril, ranitidine, metformin.• Drugs with a narrow absorption window in GIT. e.g. L-DOPA, para aminobenzoic acid, furosemide, riboflavin. March 22, 2013 DrLDP 9
  10. 10. Drugs unsuitable for GRDDS - Drugs unstable in gastric environment. e.g. erythromycin. - Drugs intended for selective release in colon. e.g. 5-aminosalicylic acid, corticosteroids. - Drugs having limited acid solubility. e.g. phynytoin. - Drugs in enteric coated systems.March 22, 2013 DrLDP 10
  11. 11. Physiology of stomachUnder fasting conditions, stomach is likea collapsed bag with a residual volumeof 50 ml.The pH is 1-3 in fastedstate.Normal GR time is1.5-3 hrs.Diameter of pyloricsphincter is 12 ± 7mm.March 22, 2013 DrLDP 11
  12. 12. Cont… GIT exhibits continuous motility of two modes: Interdigestive &Digestive motility pattern. The interdigestive motility pattern is called as “Migrating Motor Complex” (MMC) . It is divided in four phases and repeated at every 2-Phase I: Basal phase 3 hrs.- Silent, no contractionsPhase II: Pre-burst phase- Contraction increasesPhase III: Burst phase- intense & large regular contractions- efficient evacuation of contentsPhase IV: Transition phase- Contraction dissipate betw the last partof phase III & quiescence of phase I. March 22, 2013 DrLDP 12
  15. 15. A)LOW DENSITY SYSTEMS (FLOATING DRUG DELIVERY) Widely used approach. Due to inherent low density of dosage form, it floats onto gastric fluids. It is known as “Hydro - Dynamically Balanced System (HBS)”March 22, 2013 DrLDP 15
  16. 16. Floating systemsa) Non-effervescent b) EffervescentSingle Multiple units Single Multiple unitsunit (i-ix) unit (i-ii)(Monolithi (Monolithic c System)system) (i-vii)(i-x) March 22, 2013 DrLDP 16
  17. 17. a) Floating Non- effervescent Systems – Monolithic (i-x)HBSTM CapsuleIt consists of Drug +Highly swellable gelformingHydrocolloids (20-75%) like HPMC,HEC, Na-CMC, etc. DrLDPMarch 22, 2013 17
  18. 18. Cont… i) Matrix TabletSingle layer Tablet Bi-layer Tablet Bilayer matrix tablet prepared using polymers responsible for floating in one layer + drug loaded in other layer. Other type of bilayer tablet: prepared by incorporating a loading dose of drug in one layer + remaining drug in other layer with hydrocolloid for its sustained release effect. Such tablets will float & remain in March 22, 2013 stomach. DrLDP 18
  19. 19. ii) Non-Matrix Bi-layer system Bi-Layer Capsule Bi-Layer TabletMarch 22, 2013 DrLDP 19
  20. 20. iii) Tablet with agar & mineral oil Drug + Mineral Oil Mix Pour into Cool tablet mouldWarm Agar gel solution Air is entrapped in Agar gel. Escape of air is prevented by oil. The tablet contains approx 2% agar. March 22, 2013 DrLDP 20
  21. 21. v) Tablet with foam• Polypropylene Foam• Hydrophobic Powder• Open-cell Structure• Highly Porous• Low Inherent DensityMarch 22, 2013 DrLDP 21
  22. 22. vi) Tablet with lipidGlyceryl Mono-oleate• Swells in water• Amphiphilic water insoluble lipid• Converted to liquid crystals (cubic shape)It is usually melted & mouldedMarch 22, 2013 DrLDP 22
  23. 23. vii) Tablets in cylinder viii) Coated Hollow globular shell AIR AIR March 22, 2013 DrLDP 23
  24. 24. ix) Multi-Layer FilmIt Sealing at periphery films which are sealed consists of twotogether along their periphery in such a way asto entrap some air between them & make airpocket to impart floating.One film is carrier film made up of waterinsoluble polymer matrix having drugdispersed/dissolved therein.Other film is barrier film overlaying the carrierfilm. Barrier film consists of copolymer of waterinsoluble & water and drug permeable polymer.Floating time & drug release rate can bemodulated by appropriate selection of polymer March 22, 2013 DrLDP 24
  25. 25. x) Micro-porous reservoir Floating chamber Drug reservoir Microporous wallIt comprised of a drug reservoir encapsulatedin microporous compartment having pores onits surface.A floating chamber was attached at onesurface which gives buoyancy to entire device.Drug slowly dissolves out via micro pores.March 22, 2013 DrLDP 25
  26. 26. a) Floating Non- effervescent system - Multiple units (i-ix)i) Calcium alginate / Pectinate / chotosan beads IONOTROPIC GELATION METHOD Drug + CaCl2 solution Na alginate solution Separated & freeze dried Spherical gel beadsFreeze dried calcium alginate beads produced bydropping Na alginate solution into CaCl 2 solution.Due to chemical reaction named as Ionotropicgelation, gelation take place and forms solidspherical gel beads , which are separated fromsolution and they are freeze dried at - 40oC for 24hours. 2013 March 22, The resultant weight of beads is less DrLDP 26giving buoyancy up to 12 hours.
  27. 27. ii) Coated Alginate beads with air compartmentCoating before drying Alginate bead in solution before dryingDue to shrinkage of internal core bead duringdrying, it produces the air compartment whichimparts buoyancy.March 22, 2013 DrLDP 27
  28. 28. iii) Floating powder Drug + Sodium/Potassium Alginate + HPMC/HPC + Binder Floating powder can be filled in capsule or compressed to tabletMarch 22, 2013 DrLDP 28
  29. 29. iv) Oil entrapped gel beadsVegetable oil is used as floating carrier as it is light weight &hydrophobic. It is incorporated into gel matrix of beads. Oilentrapped beads are prepared by both calcium alginate beadand calcium pectinate bead. March 22, 2013 DrLDP 29
  30. 30. v) Hollow Microspherevi) Microbaloon Emulsion solvent Solvent Evaporation diffusion method MethodMarch 22, 2013 DrLDP 30
  31. 31. vii) Foam containing Micro- particles Drug Polymer Dissolved Only foam Organic Aqueous PVA Solvent solution Dispersed Foam Micro-particle Foam Foam Micro-particlesMarch 22, 2013 DrLDP 31
  32. 32. viii) CalciumSilicate asfloatingcarrierHighly porous ix) GELUCIRE ®Large pore volume GranulesLow inherentdensityGranules Hydrophobic Lipidcontaining Diff. Grades –39/01,Drug, HPMC & Ca 43/01Silicate. Low Inherent DensityMarch 22, 2013 Melt Granulation DrLDP 32 SR of Highly Soluble
  33. 33. b) Floating effervescent systems - Monolithic (i-vii)i) Matrix Tablet ii) Matrix tabletBicarbonate + Polymer with Carbopol pH dependent GellingSingle Layer TabletBilayer Tablet Only CarbopolTriple Layer Tablet - No gelling (at acidic pH) Triple layer tablet prepared having Bicarbonate + Carbopol first swellable floating layer, second - Gelling due to Alkaline sustained release layer of 2 drugs pH Carbopol gives swelling & gelling. (Metronidazole & Tetracycline) and But this system do not remain intact third rapid dissolving layer of for long time. Hence, it can be bismuth salt. This tablet is used as coated with permeable elastic single dosage form for Triple polymer like Eudragit to support Therapy of H. Pylori. March 22, 2013 integrity of core. DrLDP 33
  34. 34. iii) Floating pills It consists drug pill surrounded by double layers Swellable polymer coat. Inner layer, effervescentTartaric acid NaHCO 3 layer, contains two sub- layers to avoid direct contact of NaHCO3 & tartaric acid. Outer layer, swellable permeable layer, is made up DRUG of PVA and shellac.As CO2 gas can not go out from outermembrane makes a balloon like system whichcan float upto 5 hrs irrespective of pH &viscosity22, 2013 March of medium. DrLDP 34
  35. 35. iv) Coated effervescent core v) Multiple film NaHCO3 Drug March 22, 2013 DrLDP 35
  36. 36. vi) Programmable drug delivery CO2 Fluid in Drug release vii) Osmotically controlled DDSMarch 22, 2013 DrLDP 36
  37. 37. b) Floating effervescent systems - Multiple units (i-ii)i) Porous Alginate beads CaCl 2 NaHCO 3 Na-Alginate Acetic Solution Solution Acid Simultaneous generation of CO 2 and gelling of beads. Escape of CO 2 creates pores in beads.March 22, 2013 DrLDP 37
  38. 38. ii) Ion exchange resin beads H+ Cl H+ Cl HCO3 HCO3 Resin UG H+ Cl DR DR HCO3 UG H+ Cl H+ ClThis system comprised of ion exchange resin beads loadedwith bicarbonate and a negatively charged drug tagged toresin. The beads were encapsulated in a semi permeablemembrane. Upon contact with gastric fluid, Cl - ion of HCl isexchanged with bicarbonate and produce CO 2 gas, whichcan not escape due to semi permeable membrane. Hence, March 22, 2013 DrLDP 38it floats. Uncoated beads don’t show floating due to
  39. 39. B) EXPANDABLE SYSTEMSAlso called ‘ PLUGSYSTEM’Size of the formulationgreater than PyloricsphincterSmaller in size for oralintakeShould expand/swell forgastric retentionShould be collapsed afterMarch 22, 2013 DrLDP 39
  40. 40. EXPANDABLE APPROACHa)Swelling systems b) Unfolding systems (i-ii) (i-iv)Superporous hydrogel in its dry (a) & water-swollen (b) state. On the right, schematicillustration of the transit of superporous hydrogel. March 22, 2013 DrLDP 40
  41. 41. a) Swellingi) systems Polymeric envelope reservoir (A) It consist of drug in center surrounded by swellable material (B) are placed in elastic polymeric envelope type system (C). The polymeric envelope is permeable to drug and fluids. This system gets swollen in gastric fluid and integrity is retained by elastic polymeric envelope and drug is released in controlled manner. March 22, 2013 DrLDP 41
  42. 42. Swelling systemsii) Tiny pills in matrix Tiny pills containing drug are incorporated intohydrogel matrix and coated with wax to givestrength to wall. It works by plugging pylorussphincter. It keeps the stomach in fed state andthus delays house keeper waves which comes infasted state.After administration, it achieves high volume andtiny pills are released slowly out from matrix andgives GR to drug. i) The dosage from side-view ii) The cross-sectional view which comprises of A) Waxy wall B) Hydrogel Matrix March 22, 2013 DrLDP 42 C) Tiny pills
  43. 43. b) Unfolding systems a capsule It is (A) containing 2i) Obstructing means reservoirs (C) attached together with hydrophilic/hydrophobic strips (B). The flexible strips get enlarge and get sufficient strength and becomes rigid to achieve gastro retention. March 22, 2013 DrLDP 43
  44. 44. b) Unfolding systemsii) Multilayer films Gelatin band/Strip (C)It consists of one erodiblepolymeric film containingdrug (A) which is adheredon another non-erodiblecarrier polymeric film (B) .This bilayer sheet is folded Beforeand gelatin bands/strips (C)are used to maintainfolded. The system isplaced in capsule. AfterIn stomach, capsule andgelatin band dissolves togive unfolded system. Drug (A)March 22, 2013 Drug Erodible Polymer film (B) DrLDP 44
  45. 45. b) Unfolding systemsii) Multilayer films Intec Pharma Drug Delivery system produced by Virtual PointMarch 22, 2013 DrLDP 45
  46. 46. iii) Geometric configurations iv) Recaptacle meansMarch 22, 2013 DrLDP 46
  47. 47. C) BIO/MUCO-ADHESIVE SYSTEMS Drug is incorporated with bio /muco adhesive agents, enabling the device to adhere to stomach wall, thus resisting gastric emptying. The mucus on the walls of stomach is in a state of constant renewal, resulting in unpredictable adherence.March 22, 2013 Hence, this approach is not DrLDP 47
  48. 48. Bio-Muco-AdhesiveMarch 22, 2013 DrLDP 48
  49. 49. D) HIGH DENSITY SYSTEMS- SEDIMENTATION Density greater than stomach content i.e. 1.004 g/cm3. When the patient is upright, small high-density pellets sink to the bottom of stomach where they are entrapped in the folds of antrum & thus withstand peristaltic motion of stomach. Prepared by coating or mixing drug with heavy (>3g/cm3) inert material like BaSO4, ZnO, iron powder, TiO2.March 22, 2013 DrLDP 49
  50. 50. E) RAFT FORMING SYSTEMSRAFT (Continuous viscous gel layer) Raft forming system contains alginates & alkaline bicarbonates or carbonates. Upon reaction with the gastric acid, causes the bubbles to form & thus enables floating. Generally used for antacids.March 22, 2013 DrLDP 50
  51. 51. Factors affecting the performance of GRDDSFormulation factors Idiosyncratic factors• Density of DF • Food intake, nature <1 for floating of food, caloric• Size of DF content & frequency. > size of DF, > • Effect of gender,GR time posture, age, sleep & disease state. March 22, 2013 DrLDP 51
  52. 52. Evaluation of GRDDS In-vitro evaluation 1) For floating systems 2) For swelling systems 3) Penetration rate 4) DissolutionMarch 22, 2013 DrLDP 52
  53. 53. 1) For floating system• Buoyancy lag time : Time taken by DF to float on top of the dissolution medium.• Floating time : Time for which DF continuously floats on the dissolution medium.• Specific gravity/ density• Resultant weight : Density changes with change in F resultant – Fgrav as Df.g.V – Ds.g.V = (Df – Ds).g.V = (Df – = Fbuoy weight = a function of time. M/V).g.V, F=Resultant weight of object, Df=Density of Fluid, Ds=Density of object, g=Gravitational force, M=Mass of dosage form, V=Volume of DF March 22, 2013 DrLDP 53
  54. 54. 2) For swelling systemi) Swelling Index: dimensional changes aremeasured in terms of increase in tablet thickness /diameter with time.ii) Water uptake/Weight gain: Water uptake= Wu= (Wt –Wo).100/Wo, Wt = weight of dosage form attime t,iii) Penetration Wo = initial weight of dosageformrate: March 22, 2013 DrLDP 54
  55. 55. Swelling systemContinuous monitoring of Penetration rate BALANCE HEATERMarch 22, 2013 DrLDP 55
  56. 56. In-vitro dissolution HEATER Modified Rossett- Rice TestMarch 22, 2013 DrLDP 56
  57. 57. In-vivo evaluation • Radiology ∀ γ-Scintigraphy • Gastroscopy • Magnetic Marker Monitoring • Ultrasonography • 13C Octanoic Acid Breath TestMarch 22, 2013 DrLDP 57
  58. 58. Demerits…- GRDDS is not preferred for drugs which are unstable at acidic pH, insoluble drugs & drugs causing gastric irritation.- For floating, high level of fluid in stomach is required. Sleeping condition is not favorable for the better results as DF may swept away.- Food is an important factor . Presence of food delays emptying time of DF. So presence of food is preferable.- Adhesive systems can not prevail longer due to high turn-over rate of mucus layer and presence of soluble mucin.- For swelling systems, it is necessary that it should not exit before appropriate swelling. March 22, 2013 DrLDP 58
  59. 59. Conclusions• In the field of GR, there are many obstacles that need to be overcome in order to able to claim true gastric retention.• Considering the advantages for improved delivery of drugs, some mfgers have undertaken the herculious task of developing such devices, some with success and some with failure ended due to un-predictability of GIT.• However, the scientists are as close as ever been to seeing a greater transition of GR devices from a developmental level to the manufacturing & commercial. March 22, 2013 DrLDP 59
  60. 60. Marketed Products Brand Drug (dose) Company Name Levodopa (100 mg),Madopar® Roche, USA Benserazide (25 mg) Hoffman LaRoche,Valrelease® Diazepam (15 mg) USALiquid Al(OH)3 + MgCO3 GlaxoSmithKlein,Gaviscon® IndiaTopalkan® Pierre Fabre Drug, Al – Mg antacidLiquid FranceConviron® Ferrous sulfate Ranbaxy, IndiaCifran OD® Ciprofloxacin (1 g) Ranbaxy, IndiaCytotec®March 22, 2013 Misoprostal (100/200µg) DrLDP Pharmacia, USA 60
  61. 61. References• S. P. Vyas, Roop K. Khar, CONTROLLED DRUG DELIVERY – Concepts & Advances, Vallabh Prakashan, page no. 196-217• N. K. Jain, Progress in Controlled & Novel Drug Delivery Systems, 1st edition 2004, CBS Publishers, page no.76-97• G. Chawla, P. Gupta, V. Koradia, A. K. Bansal, Pharmaceutical Technology, July 2003, 50-68• Drs Jose Gutieerez-Rocca, Hossein Omedian, Khalid Shah, Progresses in Gastro-retentive drug delivery system-A report. Business briefing, Pharmtech 2003, 152-156.• S.R.Parakh, A.V.Gothoskar, M.T.Karad, Pharmaceutical Technology, MAY 2003, 40-48• M. C. Gohel, P. R. Mehta, R. K. Dave, N. H. Bariya, Dissolution Technologies, November 2004.• S. T. Prajapati, L. D. Patel, D. M. Patel, Formulation and In vitro Evaluation of floating Matrix Tablets of domperidone: Influence of Combination of Hydrophilic and Hydrophobic Matrix Formers, J. Pharmacy and Chemistry, Vol. 2, Issue 1, 54-59, January-March 2008.• S. T. Prajapati, L. D. Patel, D. M. Patel, Gastric floating matrix tablets: Design and optimization using combination of polymers, Acta Pharmaceutica, 58 (2), 221-229, 2008.• Tejas B. Patel, L. D. Patel, Timir B. Patel, Kirit A. Patel, Tushar R. Patel, Sunil H. Makwana, Design and Development of gastric Floating drug delivery system Using Factorial Design, Pharma Buzz, Vol. 3, No. 6, 21-27, June 2008. March 22, 2013 DrLDP 61
  62. 62. THANK YOU ALL for your participation! Dr. L. D. PatelSr. Lecturer, L.M. College of Pharmacy, AhmedabadMarch 22, 2013 DrLDP 62 (Gujarat)
  63. 63. BEST WISHES…. L. D. Patel Dr. Principal & Professor SAL Institute of Pharmacy, Ahmedabad (Gujarat) Dr. L. D. Patel Dean & Professor Faculty of Pharmacy,D.D. University, Nadiad – 387001 (Gujarat)March 22, 2013 DrLDP 63
  64. 64. QUESTIONS - -Lachoo College ofPharmacy, Jodhpur on 7 thJune 2012 DR. L.D. PATEL DIRECTOR & PROFESSOR C.U. SHAH COLLEGE OF PHARMACY & RESEARCH March 22, 2013 DrLDP 64 WADHWAN-363030, DIST: SURENDRANAGAR