Gastro retentive drug delivery system (GRDDS)

gastro retentive drug delivery system topic include
1. introduction
2.advantages
3.technology
4.evaluation
5.disadvantages
6. matrix tablet
and other relative information regarding the topic

1. Gastro-retentive drug delivery system Ravish Yadav

2. Content Introduction Advantages Gastro-retentive technologies Evaluation of GRDDS Disadvantages References

3. Introduction Conventional oral drug delivery system (DDS) is complicated by limited gastric residence time (GRT) . Rapid GI transit can prevent complete drug release in absorption zone & reduce the efficacy of the administered dose since the majority of drugs are absorbed in stomach or the upper part of small intestine.

4. To overcome these limitations, various approaches have been proposed to increase gastric residence of drug delivery systems in the upper part of GIT includes gastro retentive drug delivery system (GRDDS). Among the GRDDS, floating drug delivery system (FDDS) have been the most commonly used.

5. Gastro-retentive delivery is one of the site specific delivery of the drugs at stomach. It is obtained by retaining dosage form into stomach and drug is being released at sustained manner to specific site either in stomach or intestine. What is GRDDS??????

6. Differ from Conventional Release… Conventional Release GRDDS Absorption window

7. Delivery of drugs with narrow absorption window in the small intestine region. Longer residence time in the stomach could be advantageous for local action in stomach, for example treatment of peptic ulcer disease. Bio-availability can be improved. Advantages…

8. Reduced Frequency of Dosing with improved patient compliance Minimize the Fluctuation of drug concentrations Site specific drug delivery Enhances the Pharmacological effects

9. LIMITATIONS They require a sufficiently high level of fluids in the stomach for the drug delivery buoyancy, to float therein and to work efficiently. Floating systems are not feasible for those drugs that have solubility or stability problems in gastric fluid. Drugs which are well absorbed along the entire GI tract and which undergoes significant first- pass metabolism, may not be desirable candidates for GRDDS since the slow gastric emptying may lead to reduced systemic bioavailability. Drugs that are irritant to gastric mucosa are not suitable for GRDDS.

10. Gastric emptying The process of gastric emptying occurs both during fasting and fed state. In fasted state , the process of gastric emptying is characterized by an inter digestive motility pattern that is commonly called migrating motor complex (MMC)(migrating myloelectric cycle) This is a series of events that cycle through the stomach and small intestine every 1.2 to 2hrs.

11. In fed state , the gastric emptying rate slowed down because the onset of Migration Motor Complex (MMC) is delayed the feeding state results in a lag time prior to the onset of gastric emptying It is thought that the sieving efficiency of the stomach is enhanced by the fed pattern or by the presence of food.

12. Salient Features Of Upper Gastrointestinal Tract Length (m) Transit time (hr) pH Absorbing surface area (m2) Absorption pathway Stomach 0.2 Variable 1-4 0.1 P,C,A Small Intestine 6-10 3±1 5-7.5 120-200 P,C,A F,I,E,CM P –  Passive diffusion                            C – Aqueous channel transport A –  Active transport                             F – Facilitated transport I –   Ion-pair transport                          E –  Entero -or pinocytosis CM – Carrier mediated transport

13. FACTORS CONTROLLING THE GASTRIC RETENTION TIME OF DOSAGE FORM 1.Density:  GRT is a function of dosage form buoyancy. 2. Size 3. Shape of dosage form: Tetrahedron and ring shaped devices. 4. Fed or unfed state: If the timing of administration of the formulation coincides with MMC, the GRT of the unit can be expected to be very short. However, in the fed state, MMC is delayed and GRT is considerably longer. 5. Caloric content: GRT can be increased by 4 to 10 hours with a meal that is high in proteins and fats.

14. 6. Frequency of feed: The GRT can increase by over 400 minutes, when successive meals are given compared with a single meal due to the low frequency of MMC. 7. Gender: Mean ambulatory GRT in males (3.4±0.6 hours) is less compared with their age and race matched female counterparts (4.6±1.2 hours), regardless of the weight, height and body surface. 8. Age: Elderly people, especially those over 70, have a significantly longer GRT. 9. Posture: GRT can vary between supine and upright ambulatory states of the patient.

15. Candidates for GRDDS Drugs acting locally in the stomach E.g. Antacids Drugs that are principally absorbed in the stomach Drugs that are poorly soluble at the alkaline pH Drugs with a narrow window of absorption E.g. Furosemide Drugs absorbed readily from the GI tract Drugs that degrade in the colon Drugs with variable Bioavailability Drugs with less half life

16. Approaches STOMACH Esophagus Cardia Body Pyloric Sphinctor Duodenum Fundus Pylorus Pyloric Antrum 1 2 4 3 1- Floating System 2- Bioadhesive System 3- Swellable System 4- High Density System

17. Classification of gastro retentive drug delivery systems.

18. Swellable System Also called ‘ PLUG SYSTEM’ Size of the formulation more than Pyloric sphincter It should expand for gastric retention Should be Collapsed after lag time

19. High degree of Cross-linking Low degree of Cross-linking Gastric Fluid Time

20. Picture of tablet in Dry and Wetted state

21. Disadvantages of Swelling System The Dosage form must maintain a size larger than pyloric sphincter The Dosage form must resist premature gastric emptying

22. Bio/ Muco Adhesive System Here, the drug is incorporated with bio/ Muco -adhesive agents, enabling the Device to adhere to the stomach walls, Thus resisting gastric emptying. However, the mucus on the walls of the Stomach is in a state of constant renewal, Resulting in unpredictable adherence. Thus, this approach is not widely used.

23. Bio/ Muco Adhesive Polymers Chitosan Polyacrylic acid Carbopol 934P, 971P, 980 Sodium alginate HPMC K4M, K15M, K100M Hydroxypropylcellulose (HPC) Cholestyramine

24. Problem of Muco -adhesive System Rapid removal of mucus. We are not sure weather the DF will adhere to the mucus or epithelial cell layer DF may adhere to esophagus resulting in drug induced injuries

25. High Density Approach Density should be more then stomach content i.e. 3 g/cm3 Capable to withstand with peristaltic movement of stomach Prepared by coating or mixing drug with heavy inert material

26. Diluents such as… barium sulphate (density = 4.9), zinc oxide, titanium dioxide, iron powder must be used to manufacture such high-density formulations.

27. Problem with High Density Approach Higher amount of drug require The dosage form must stand with peristaltic movement of stomach

28. Low Density Approach (Floating Drug Delivery) Retained in stomach Useful for poorly water soluble OR unstable in intestinal Fluid Bulk density : Less than gastric fluid, so remain buoyant in the stomach without affecting gastric emptying rate for prolonged period of time So drug release slowly at the desired rate from system

29. Advantages of Low Density Approach OR Floating Drug Delivery Drugs those are... Primarily absorbed in the stomach Poorly soluble at an alkaline pH Narrow window of absorption Degrade in colon

30. When there is a vigorous intestinal movement and a short transit time as might occur in certain type of diarrhoea, poor absorption is expected. Under such circumstances it may be advantageous to keep the drug in floating condition in stomach to get a relatively better response.

31. Disadvantages of Low Density Approach OR Floating Drug Delivery Not feasible for those drugs that have solubility OR stability problem in GIT Require high level of fluid in stomach The drugs that may irritate the stomach lining OR are unstable in acidic environment The dosage form should be administered with a full glass of water (200-250 ml)

32. Classification: Noneffervescent systems Single-unit floating dosage system Multiple unit floating dosage system Effervescent (gas-generating) systems Single-unit floating dosage system Multiple unit floating dosage system Raft-forming systems

33. Non effervescent Systems Single unit Floating tablets( MATRIX TABLET) Floating capsules(HBS capsules) Tablets with hollow cylinder Microporous reservior Multilayer flexible film

34. 1.MATRIX TABLET Incorporating gel forming hydrocolloids HPMC, which is the most commonly used polymer for floating. Out of various grades of HPMC, low viscosity grade are used for floating purpose. Mixture of alginate and HPMC also prepared for floating tablet.

35. Single Layer Tablet Bilayer Tablet Loading Dose

36. 2.Floating capsules: HBS Capsules: It is Hydrodynamically Balanced System. It is a hard gelatin capsule containing drug with high level of one or more highly swellable gel forming hydrocolloids (20-75%) like HPMC, HPC, HEC, Na-CMC etc. When coming in contact with water, the hydrocolloids at the surface of the system swell and facilitate floating. Gel structure controls rate of diffusion of fluid-in and drug- out making “ Receding Boundary ”. After exterior surface dissolves/erodes, the immediate adjacent hydrocolloid layer is hydrated and process continues to give floating for extended period of time.

37. 1. hbs capsules

38. 3.TABLETS IN CYLINDER A I R polypropylene The device consisting of two drug-loaded HPMC matrix tablets, which are placed within an impermeable, hollow polypropylene cylinder (open at both ends). Each matrix tablet closed one of the cylinder’s ends so that an air-filled space was created in between, providing a low total system density. The device remained floating until at least one of the tablets is dissolved. HPMC matrix tablet HPMC matrix tablet

39. 4.MICROPOROUS RESERVIOR D rug reservoir encapsulated in microporous compartment having pores on its top and bottom walls Peripheral walls are sealed,to prevent direct contact with gastric fluid A floating chamber was attached at one surface which gives buoyancy to entire device. Drug slowly dissolves out via micro pores

40. 5.Multi-layer flexible film: The device consist of two films which are sealed together along their periphery and in such a way as to entrap some air between two films and so make air pocket which imparts buoyancy.

41. Multiple unit: Reduce the inter subject variability in absorption Lower the probability of dose dumping. Available as Beads, Micro-spheres, Micro-balloons, Carrier system.

42. A. Beads 1.CALCIUM ALGINATE/PECTINATE BEADS 2.ALGINATE BEADS with AIR COMPARTMENT 3.OIL ENTRAPPED GEL BEADS 4.CASEIN – GELATIN BEADS

43. 1.CALCIUM ALGINATE/PECTINATE BEADS Sodium Alginate Solution Dropped to Calcium Chloride Solution Spherical Gel Beads(2.5mm) Separate, Freeze Dried (-40 o C) 24hrs IONOTROPIC GELATION METHOD Calcium Pectinate Gel Beads Calcium-Alginate- Pectinate Gel beads(fasten drug release) Calcium Alginate + Chitosan Gel Beads(air entrapement gives Better buoyancy) porous beads with about 12 hrs buoyancy period & residence time of 5.5 hrs

44. 2.ALGINATE BEADS with AIR COMPARTMENT Alginate Bead in Solution, before Drying Coating before Drying After Drying Shrinkage of Bead During the preparation of calcium alginate beads before drying process the beads are coated with the coating solution which may be calcium alginate or mixture of calcium alginate and PVA(water soluble additive in coating composition which increase membrane permeability), and then they are dried

45. 3.OIL ENTRAPPED GEL BEADS Oil – Light weight and Hydrophobic Pectin has some Emulsification property Aqueous Solution of Pectin homogenization Emulsion Edible Veg. OIL extruded to Calcium Chloride Solution

46. 4.CASEIN – GELATIN BEADS Casein has Emulsification property- Entraps Air Bubbles Biodegradable beads Casein Gelatin Solution (60 o C) Rapidly stirred Emulsion Preheated Mineral Oil Rapid Cooling (5c o ) Add to Cooled Acetone Separated and Dried At Reduced Pressure – NO AIR – Non Floating Beads

47. B.HOLLOW MICROSPHERE Or MICROBALLOON Emulsion-solvent diffusion method Agitate solution of PVA and thermally control at 40 degree Celsius. Ethanol-dichloromethane solution of drug and polymer was poured into it. Polymers such as polycarbonate and cellulose acetate were used in the preparation of hollow microspheres.

48. Mechanism of drug release: When microspheres come in contact with gastric fluid the polymer forms a colloidal gel barrier that controls the rate of fluid penetration into the device and consequent drug release.

49. d) Carrier systems CALCIUM SILICATE AS FLOATING CARRIER Highly Porous Large Pore Volume Low Inherent Density Granules of calcium silicate as a floating carrier , which has a characteristically porous structure . Air trapped in the pores of calcium silicate when they were coated with polymer(HPC).

50. Effervescent systems: Gas generating system Matrix tablets Single layer tablets Bilayer tablets Multi unit floating pills Floating based on ion exchange resin Volatile liquid containing system Deformable unit with inflatable chamber Osmotically controlled DDS

51. 1.Gas generating system Effervescent reaction between carbonate/ bicarbonate salts and citric/tartaric acid to liberate CO2,which get enrtapped in the gellified hydrocolloid layer of the system,decreasing its bulk density and making it float over chyme . Matrix tablets: Single layer: CO2 generating components intimately mixed within tablet matrix.( HPMC,Chitosan,alginate ) Bilayer tablets: Gas generating components comprssed in one hydrocolloid containing layer and drug in other formulated for SR.

52. FLOATING PILLS DRUG NaHCO 3 Tartaric Acid Swellable Polymer (PVA and shellac)

53. ION EXCHANGE RESIN BEADS Resin HCO 3 HCO 3 HCO 3 DRUG DRUG H + Cl H + Cl H + Cl H + Cl H + Cl Uncoated Beads – No Floating – Escape of CO 2

54. This system consists of mainly two different part attached with each other, one is floating part and other is osmotic controlled part Floating part made up of deformable polymeric bag containing liquid that gasify at body temperature.Osmotic pressure controlling part consists of two part, drug reservoir & osmotically active compartment. 1. Osmotically controlled DDS Volatile liquid containing system:

55. 2.Deformable unit with inflatable chamber These type of systems consist of two chambers separated by an impermeable, pressure- responsive,movable bladder. The first chamber contains the drug impregnated polymeric matrix and the second chamber contains the volatile liquid(ether). Both enclosed in gelatin shell. The device inflates, and the drug is continuously released from the reservoir into the gastric fluid.

56. Raft-Forming Systems T his system is used for delivery of antacids and drug delivery for treatment of gastrointestinal infections and disorders. These are liquid preparations having gel forming agent( alginic acid),Na-bicarbonates and drug, which forms foaming Na-alginate gel, while reacting with gastric acids. This raft floats in gastric fluids because of the low bulk density created by the formation of CO 2 The raft has pH value higher than that of stomach contents so that in gastric reflux the wall of oesophagus is not subjected to irritation by HCl .

57. Evaluation of GRDDS GRDDS Hardness Friability Drug Content Diameter Weight Variation

58. Evaluation of GRDDS Dissolution medium : 0.1 N HCl Temp. : 37 ± 0.5°C RPM : 50-100 Sample analysis : UV Dissolution Study

59. Evaluation of GRDDS In-vitro Mucoadhesion Apparatus : USP type VI (rotating cylinder apparatus) Medium : 0.1 N HCl Temp. : 37 ± 0.5°C RPM : 100

60. Evaluation of GRDDS Lag time : Measurement : 0.1 N HCl at pH 1.2 Temp. : 37 ± 0.5°C Apparatus : USP Type II dissolution apparatus A tablet is placed in a beaker containing 100 – 200 ml dissolution medium & the time for a tablet to emerge on to the surface of the dissolution medium is known as lag time .

61. Evaluation of GRDDS Floating Time After achieving lag time, the time taken for a tablet to remain float on the surface of the dissolution medium is called floating time.

62. Evaluation of GRDDS Water uptake : Apparatus : USP type II dissolution apparatus Medium : Water Temp. : 37 ± 0.5°C RPM : 50 WU (%) = Wt. of swollen tab. – Initial wt. of tab. Initial wt. of tab. × 100

63. Evaluation of GRDDS In vitro Mucoadhesive strength

64. Limitation of GRDDS It is not recommended for drugs which are unstable at gastric/acidic pH, insoluble or very low soluble drugs and drugs which causes gastric irritation. For floating, high level of fluid is required in GIT. Also sleeping condition is favorable for the better results of GRDDS.

65. Limitation of GRDDS Bioadhesive systems, cannot prevail longer due to high turn-over rate of mucus layer and presence of soluble mucin For swelling systems, it is necessary that the formulation should not exit before the appropriate swelling For High density systems, High amount of drug is require

66. References Doshi S.M., Tank H.M., Gastro Retention – An Innovation over Conventional poorly Soluble Drugs : A review, International Journal of Pharmaceutical and chemcal Sciences, 2012;1(2):859-866. 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