GASTRO RETENTIVE DRUG DELIVERY SYSTEM.pptx

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1. GASTRO RETENTIVE DRUG DELIVERY SYSTEM 1 Ms. Harshada . R . Bafna

2. CONTENTS INTRODUCTION IDEAL CANDIDATE DRUGS FOR GRDDS ADVANTAGES LIMITATIONS APPROACHES EVALUATION REFERENCES 2 15-Feb-24 HRB 2

3. INTRODUCTION 3 Oral drug delivery is widely used in pharmaceutical field to treat the diseases. Some drugs are absorbed at specific site only, these require release at that specific site. Definition: Gastroretentive drug delivery is an approach to prolong gastric residence time, thereby targeting site- specific drug release at controlled manner in the upper gastrointestinal tract (GIT) for local or systemic effects. 15-Feb-24 HRB 3

4. Review of Stomach & GIT A tube about nine meters long that runs through the middle of the body from the mouth to the anus and includes ; ▫ throat (pharynx), ▫ esophagus, ▫ stomach, ▫ small intestine duodenum jejunum ileum ▫ large intestine . Fig.no- 1 15-Feb-24 HRB 4

5. Gastrointestinal dynamics These are the four motility phases within the stomach during fasting stage. The dosage form should be capable of withstanding the housekeeping action of phase III. This cyclic events are known as MMC (Migrating Motor Complex) Fig.no- 2 15-Feb-24 HRB 5

6. Factors Controlling The Gastric Retention Time of Dosage Form Density: GRT is a function of dosage form buoyancy that is dependent on the density. Size: Dosage form units with a diameter of more than 7.5mm are reported to have an increased GRT compared with those with a diameter of 9.9mm. Shape of dosage form: Tetrahedron and ring shaped devices. 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. Caloric content: GRT can be increased by 4 to 10 hours with a meal that is high in proteins and fats. 15-Feb-24 HRB 6

7. 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. 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. Age: Elderly people, especially those over 70, have a significantly longer GRT. Posture: GRT can vary between supine and upright ambulatory states of the patient. 15-Feb-24 HRB 7

8. Fig.no- 3 15-Feb-24 HRB 8

9. IDEAL CANDIDATE DRUGS FOR GRDDS 9 1. Drugs acting locally in the stomach. E.g. Antacids and drugs for H. Pylori viz., Misoprostol. 2. Drugs that are primarily absorbed in the stomach. E.g. Amoxicillin 3. Drugs that is poorly soluble at alkaline pH. E.g. Furosamide, Diazepam, Verapamil, etc. 4. Drugs with a narrow absorption window. E.g. Cyclosporine, , Levodopa, Methotrexate etc. 15-Feb-24 HRB 9

10. 10 5. Drugs which are absorbed rapidly from the GI tract. E.g. Metronidazole, tetracycline. 6. Drugs that degrade in the colon. E.g. Ranitidine, Metformin. 7. Drugs that disturb normal colonic microbes E.g. antibiotics against Helicobacter pylori. 15-Feb-24 HRB 10

11. ADVANTAGES 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 selectivity in receptor activation Reduced counter- activity of the body Extended effective concentration. Minimized adverse activity at the colon. 15-Feb-24 HRB 11

12. LIMITATIONS 12 The drug substances that are unstable in the acidic environment of the stomach are not suitable candidates to be incorporated in the systems. These systems require a high level of fluid in the stomach for drug delivery to float and work efficiently. Not suitable for drugs that have solubility or stability problem in GIT. Drugs which are irritant to gastric mucosa are also not suitable. These systems do not offer significant advantages over the conventional dosage forms for drugs, which are absorbed throughout GIT. 15-Feb-24 HRB 12

13. APPROACHES FOR PROLONGING THE GASTRIC RESIDENCE TIME High- density systems. (HDS) F S HD S S S 13 Floating systems. (FS) Swelling and expanding systems. (SS) Mucoadhesive & Bioadhesive systems. (AS) 15-Feb-24 HRB 13

14. HIGH DENSITY SYSTEMS FLOATING SYSTEMS HYDRODYNAMICA LLY BALANCED SYSTEMS HBS GAS-GENERATING SYSTEMS VOLATILE LIQUID / VACUUM CONTAINING SYSTEMS INTRAGATRIC FLOATING GASTROINTESTINAL DRUG DELIVERY SYSTEM INFLATABLE GASTROINTESTINAL DELIVERY SYSTEMS INTRAGASTRIC OSMOTICALLY CONTROLLED DRUG DELIVERY SYSTEM MATRIX TABLETS RAFT- FORMING CLASSIFICATION 14 GRDDS APPROACHES SYSTEMS HOLLOW MICROSPHERES ALGINATE BEADS SUPER POROUS HYDROGELS EXPANDING SYSTEMS SWELLING SYSTEMS UNFOLDABLE SYSTEMS BIO/MUCOADHESI VE SYSTEM MAGNETIC SYSTEMS 15-Feb-24 HRB 14

15. HIGH DENSITY SYSTEM 15 Gastric contents have a density close to water (1.004 g cm −3 ). When the patient take high- density pellets, they sink to the bottom of the stomach where they become entrapped in the folds of the antrum and withstand the peristaltic waves of the stomach wall. A density close to 2.5 g cm −3 seems necessary for significant prolongation of gastric residence time. Barium sulphate, zinc oxide, iron powder, and titanium dioxide are examples for excipients used. 15-Feb-24 HRB 15

16. Drawbacks of high density system The major drawback with such systems is that it is technically difficult to manufacture them with a large amount of drug (>50%) and to achieve the required density. It is unpredictable; whether the dosage form will stand peristaltic movement or not. 15-Feb-24 HRB 16

17. FLOATING DRUG DELIVERY These have a bulk density lower than the gastric content. They remain buoyant in the stomach for a prolonged period of time, with the potential for continuous release of drug. They include: Hydrodynamically balanced systems (HBS) Gas- generating systems Volatile liquid/ vacuum containing systems Raft- forming systems Low- density systems 17 15-Feb-24 HRB 17

18. 18 EFFERVESCENT SYSTEMS 15-Feb-24 HRB 18

19. GAS GENERATING SYSTEMS Carbonates or bicarbonates, which react with gastric acid or any other acid (e.g., citric or tartaric) present in the formulation to produce CO 2 , are usually incorporated in the dosage form, thus reducing the density of the system and making it float on the media. 19 15-Feb-24 HRB 19

20. MATRIX TABLETS Single layer matrix tablet is prepared by incorporating bicarbonates in matrix forming hydrocolloid gelling agent like HPMC, chitosan, alginate or other polymers and drug. Bilayer tablet can also be prepared by gas generating matrix in one layer and second layer with drug for its SR effect. Triple layer tablet also prepared having first swellable floating layer with bicarbonates, second sustained release layer of drug and third rapid dissolving layer of bismuth salt. 20 15-Feb-24 HRB 20

21. INFLATABLE GASTROINTESTINAL DELIVERY System is incorporated with an inflatable chamber which contains liquid ether- gasifies at body temperature to cause the chamber to inflate in stomach. Inflatable chamber is loaded with a drug reservoir which can be a drug, impregnated polymeric then encapsulated in a gelatin capsule. 21 15-Feb-24 HRB 21

22. INTRAGASTRIC OSMOTICALLY CONTROLLED DDS Comprised of both an osmotic pressure controlled drug delivery device and an inflatable floating support in a biodegradable capsule. In stomach, the capsule quickly disintegrates and release the intragastric osmotically controlled drug delivery device . Inflatable support forms a deformable hollow polymeric bag containing liquid that gasifies at body temperature to inflate the bag. 22 15-Feb-24 HRB 22

23. 23 Consists of 2 compartments : Drug reservoir Osmotically active compartment. 15-Feb-24 HRB 23

24. 24 NON- EFFERVESCENT SYSTEMS 15-Feb-24 HRB 24

25. INTRA- GASTRIC FLOATING GASTROINTESTINAL DRUG DELIVERY SYSTEMS System can be float by means of flotation chamber, which may be vacuum or filled with air or a harmless gas Drug reservoir is encapsulated inside a microporous compartment 25 15-Feb-24 HRB 25

26. HYDRODYNAMICALLY BALANCED SYSTEMS Prepared by incorporating a high level (20- 75%w/w) gel-forming hydrocolloids. E.g.:- HEC, HPC, HPMC & Sod. CMC into the formulation and then compressing these granules into a tablets or capsules. It maintains the bulk density less than 1. 26 15-Feb-24 HRB 26

27. RAFT FORMING This system is used for delivery of antacids and drug delivery for treatment of gastrointestinal infections and disorders. The mechanism involved in this system includes the formation of a viscous cohesive gel in contact with gastric fluids, forming a continuous layer called raft . 27 15-Feb-24 HRB 27

28. HOLLOW MICROSPHERES 28 Polymers used commonly: Polycarbonates, Cellulose acetate, Calcium alginate, Eudragit S, agar and methoxylated pectin etc. Microballoons / Hollow microspheres loaded with drugs prepared by solvent evaporation or solvent diffusion / evaporation methods. Buoyancy and drug release depends on quantity of polymers, plasticizer and solvents used. The microballoons floated continuously over the surface of an acidic dissolution media containing surfactant for >12 hours. Are the best because they combine the advantages of multiple- unit system and good floating. E.g. ethanol- dichloromethane solution of drug poured in aqueous solution of PVA 15-Feb-24 HRB 28

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30. SUPERPOROUS HYDROGELS ALGINATE BEADS Prepared by dropping sodium alginate solution into aqueous solution of calcium chloride, causing the precipitation of calcium alginate Freeze dried in liquid nitrogen at - 40 o C for 24h. Beads- spherical and 2.5 mm in Swellable agents have pore size ranging between 10nm to 10µm. Superporous hydrogels will swell more than the swelling ratio 100,This is achieved by co- formulation of a hydrophilic particulate 30 diameter. material, and Ac-Di- Sol (crosscarmellose). 15-Feb-24 HRB 30

31. EXPANDABLE SYSTEMS 1.UNFOLDED SYSTEMS SWELLABLE SYSTEMS The swelling is usually results from osmotic absorption of water. The device gradually decreases in volume and rigidity as a result depletion of drug and expanding agent and/or bioerosion of polymer layer, enabling its elimination. 31 15-Feb-24 HRB 31

32. MUCOADHESIVE SYSTEMS 32 The basis of mucoadhesion is that a dosage form can stick to the mucosal surface by different mechanisms. Examples for Materials commonly used for bioadhesion are poly(acrylic acid), chitosan, cholestyramine, tragacanth, sodium alginate . 15-Feb-24 HRB 32

33. Drawbacks: Continuous production of mucous may limit muco adhesion. Bio adhesion may cause local irritation. 15-Feb-24 HRB 33

34. MAGNETIC SYSTEM Based upon the principle that dosage form contains a small internal magnet, and a magnet placed on the abdomen over the position of stomach can enhance the GRT. Drawbacks: Although these systems seem to work, the external magnet must be positioned with a degree of precision that might compromise patient compliance. 34 15-Feb-24 HRB 34

35. EVALUATION OF GRDDS : A. FLOATING SYSTEM FLOATING TIME : Test for buoyancy It is performed in simulated gastric & intestinal fluid maintain at 37 C. The floating time is determined using USP dissolution apparatus containing 900 ml of testing medium. The time for which the dosage form float is termed as FLOATING or FLOATING TIME. DISSOLUTION TESTING : It is performed same as that conventional dosage form except that only acidic buffer is used. 15-Feb-24 HRB 35

36. B. BIO/MUCOADHESIVE SYSTEM : BIOADHESIVE STRENGTH : Bioadhesive strength of a polymer can be determined by the measurement of force required to separate the polymer specimen sandwiched between the layers of either an artificial (e.g. cellophane) or biological (rabbit stomach tissue) membrane. This force can be measured by using either a modified precision balance or an automated texture analyzer. 15-Feb-24 HRB 36

37. Bioadhesion strength measurement Force measuring device Upper jaw Polymer Lower jaw Membrane Fig.no- 9 15-Feb-24 HRB 37

38. 38 C. SWELLING SYSTEMS : 1. WEIGHT GAIN AND WATER UPTAKE : The swelling behavior of dosage unit can be measured either by studying it’s dimensional changes, weight gain or water uptake. The study is done by immersing the dosage form in the simulated gastric fluid at 37 C and determining the factor at regular interval. Dimensional changes can be measured in terms of increase in the tablet diameter or thickness with time. Water uptake is measured in terms of % weight gain as given below : WU = ( Wt – Wo ) * 1OO/Wo. WU= Water uptake. Wt = Weight of dosage form at time t. Wo = Weight of dosage form initially. 15-Feb-24 HRB 38

39. 39 2. SPECIFIC GRAVITY / DENSITY Density can be determined by the displacement method using Benzene as displacement medium GASTRORETENTION : The in- vivo gastro retention of dosage form can be evaluated by inclusion of a radio- opaque material into a solid dosage form which can be observed by using X- rays. Similarly, the inclusion of a γ - emiting radio nuclide in a formulation allows external observation using γ - camera or scintiscanner which helps to monitor the location of the dosage form in the GI tract. 15-Feb-24 HRB 39

40. Methods to measure gastroretentivity of GRDFs Magnetic Resonance Imaging (MRI) It is a noninvasive technique and allow observation of total anatomical structure in relatively high resolution. The visualization of GI tract by MRI has to be further improved by the administration of contrast media. For solid dosage forms, the incorporation of a super- paramagnetic compound such as ferrous oxide enables their visualization by MRI. Radiology (X-Ray) In this technique a radio- opaque material has to be incorporated in the dosage forms, and its location is tracked by X- ray picture. 15-Feb-24 HRB 40

41. ɣ -Scintigraphy Gamma scintigraphy relies on the administration of a dosage forms containing a small amount of radioisotope, e.g., 152 Sm,which is a gamma ray emitter with a relatively short half life. Gastroscopy Gastroscopy is commonly used for the diagnosis and monitoring of the GI tract. This technique utilizes a fiber optic or video system and can be easily applied for monitoring and locating GRDFs in the stomach. 15-Feb-24 HRB 41

42. Ultrasonography Used sometimes, not used generally because it is not traceable at intestine. 13 C octanoic acid breath test After ingestion of the dosage form, the time duration after which 13C octanoic acid gas is observed in the breath indicates the transfer of the dosage form from the stomach to the upper part of the small intestine, which may be considered as the gastric retention time of the dosage form. 15-Feb-24 HRB 42

43. 43 Marketed Products of GRDDS Brand name Delivery system Drug (dose) Company name Valrelease® Floating capsule Diazepam (15mg) Hoffmann- LaRoche, USA Madopar® HBS (Prolopa® HBS) Floating, CR capsule Benserazide (25mg) and L- dopa (100mg) Roche Products, USA Liquid Gaviscon® Effervescent Floating liquid alginate preparations Al hydroxide (95 mg), Mg Carbonate (358 mg) GlaxoSmithkline, India Topalkan® Floating liquid alginate Preparation Al – Mg antacid Pierre Fabre Drug, France Conviron® Colloidal gel forming FDDS Ferrous sulphate Ranbaxy, India Cytotech® Bilayer floating capsule Misoprostol (100μg/200μg) Pharmacia, USA Cifran OD® Gas- generating floating form Ciprofloxacin (1gm) Ranbaxy, India 15-Feb-24 HRB 43

44. REFERENCE 44 N K Jain. Gastroretentive drug delivery systems: Garima Chawla, Piyush Gupta and Aravind K. Bansal, editors. Progress in controlled and novel drug delivery systems.New delhi. S.P.vyas, roop K.khar controlled drug delivery concepts and advances page no.196-217. 15-Feb-24 HRB 44

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