Gastroretentive Drug Delivery Systems (GRDDS) – Concepts, Mechanisms, and Applications

This presentation provides an in-depth overview of Gastroretentive Drug Delivery Systems (GRDDS) — an innovative approach to enhance the gastric residence time (GRT) of drugs, enabling controlled and site-specific drug release in the upper gastrointestinal tract. GRDDS is particularly useful for drugs absorbed primarily in the stomach or upper intestine, drugs with narrow absorption windows, or those unstable in intestinal pH.

The presentation covers the need, principles, advantages, disadvantages, and various approaches used to achieve gastric retention — including floating systems, bio/mucoadhesive systems, high-density systems, swelling/expanding systems, and osmotic-controlled systems. It also explains floating drug delivery mechanisms (FDDS), their types (effervescent and non-effervescent), and key evaluation methods used in research and formulation development.

Highlights:

Concept and need for gastroretentive drug delivery

Approaches to prolong gastric residence

Floating drug delivery systems (HBS, bilayer tablets, floating capsules)

Effervescent and non-effervescent mechanisms

Factors affecting gastric retention time (GRT)

In vitro and in vivo evaluation parameters

Useful for:

B.Pharm and M.Pharm students

Pharmaceutical formulation and R&D professionals

Educators preparing pharmaceutics lectures or seminars

Researchers in drug delivery and controlled-release systems

1. Gastroretentive Drug Delivery Systems (GRDDS) Presenter: Ms. Seema Uttam Shinde M. Pharm Ashokrao Mane Institute of Pharmacy , Ambap.

2. ​ Gastroretentive Drug Delivery Systems (GRDDS) Gastro retentive drug delivery is an approach to prolong gastric residence time, thereby targeting site-specific drug release in the upper gastrointestinal tract (GIT) for local or systemic effects. Gastro retentive dosage forms can remain in the gastric region for long periods and hence significantly prolong the gastric retention time (GRT) of drugs. Gastro-retentive drug delivery systems provide efficient means of enhancing the bioavailability and controlled delivery of many drugs. The concept involved in GRDDS is increasing the gastric retention time. Drugs which require increase in bioavailability and controlled delivery can be formulated by utilizing the novel concept GRDDS.

3. Need for gastro-retention: Drugs that are absorbed from the proximal part of the gastrointestinal tract (GIT). Drugs that are less soluble or that degrade at the alkaline pH. 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. Treatment of peptic ulcers caused by H.Pylori infections.

4. Potential Drug Candidates for Gastro-retentive Drug Delivery Systems: Drugs those are locally active in the stomach. Drugs that have narrow absorption window in gastrointestinal tract (GIT). Drugs those are unstable in the intestinal or colonic environment. Drugs that disturb normal colonic microbes Drugs that exhibit low solubility at high pH values.

5. Advantages This system offers improved bioavailability It reduces dose and dosing frequency. This system minimizes fluctuation of drug concentration in blood This system helps in targeting of drugs Local action can be achieved in GIT. Eg. Antacids This system reduces the side effect. Sustained release can be achieved. Safest route of administration It is economic and can be used for wide range of drugs.

6. ​ Disadvantages This system should be administered with plenty of water. Drugs with solubility or stability problem in GIT can’t be administered. Drugs, which undergoes first pass metabolism, are not suitable. e.g. Nifedipine. Drugs which are irritant to gastric mucosa are not suitable. E.g. Aspirin & NSAID. Drugs that absorb equally well through GIT. E.g. Isosorbide dinitrate, Nifidipine

7. Approaches to Achieving Gastric Retention

8. 1. Buoyant Systems (Floating Systems) ​ Principle:  These systems have a bulk density lower than the stomach fluid, causing them to float in the stomach. ​ Mechanism:  The drug is released at a controlled rate from the floating dosage form. This allows for a prolonged stay in the stomach without affecting the gastric emptying rate. ​ Types: ​ Effervescent Systems:  Gas-generating agents (e.g., sodium bicarbonate, citric acid) create gas bubbles that get trapped within the dosage form, causing it to float. ​ Non-effervescent Systems:  These include single-unit systems (e.g., hydrogels) that swell and float upon contact with stomach fluid, and multi-unit systems (e.g., beads, microspheres).

9. 2. ​Bio/Muco-Adhesive Systems:  Bio/mucoadhesive systems are those which bind to the gastric epithelial cell surface or mucin and serve as a potential means of extending the Gastro retention of drug delivery system (DDS) in the stomach by increasing the intimacy and duration of contact of drug with the biological membrane. 3. High-Density Systems (Sinking Systems) Principle:  These systems have a high density, allowing them to sink to the bottom of the stomach (antrum) and resist the passage of the pylorus. ​ Mechanism:  Their high density and size prevent them from being emptied along with stomach contents. They are retained in the antrum until they disintegrate.

10. ​4. Swelling and Expanding Systems ​ Principle:  These dosage forms swell to a large size after exiting the pylorus, preventing them from passing through the gastric outlet. ​ Mechanism:  They are small enough when ingested to pass easily, but they expand to a size of 12-18 mm in the stomach, which is larger than the pyloric sphincter. This prevents them from being emptied for several hours. ​5. Other Approaches ​ Ion Exchange Resins:  Coated ion-exchange beads that float on the stomach contents. ​ Incorporation of Passage Delaying Food Agents:  Using food excipients (e.g., fatty acids) to delay gastric emptying. ​ Osmotic Regulated Systems:  Pressure-controlled systems that inflate a balloon or bag to a larger size in the stomach, preventing passage through the pylorus.

11. FLOATING DRUG DELIVERY SYSTEMS (FDDS) FDDS have a  bulk density less than gastric fluids  and remain buoyant in the stomach, without affecting the gastric emptying rate for a prolonged period of time. Applications and Limitations of FDDS A. Applications Sustained drug delivery: Hydrodynamically Balanced System (HBS)  type dosage forms remain in the stomach for several hours, increasing the gastric residence time. Example:  Madopar HBS formulation has shown to release  levodopa  for up to 8 hours  in vitro , enhancing bioavailability.

12. Site specific drug delivery (FDDS): Particularly useful for drugs having specific absorption from stomach or proximal part of the small intestine. Examples :   Riboflavin ,  Furosemide , and  Captopril  (found to be site specific, improving bioavailability by prolonging the gastric residence time). Absorption enhancement: Drugs that have poor bioavailability because their absorption is restricted to the upper GIT can be delivered specifically. Example:  Floating dosage form of  captopril  is compared to commercially available tablet (Acetab-25), showing superior results.

13. Poorly Bioavailable Drugs: Relative bioavailability of floating dosage form is reduced as compared to conventional dosage form for  amoxicillin trihydrate  (reduced to 80.5% with conventional capsules). In cases of advanced Parkinson’s disease, reduction in bioavailability is compensated by the advantages offered by FDDS, such as better control of motor fluctuations by the HBS dosage form. Local Action (H. pylori): FDDS serve as an excellent drug delivery system for the eradication of  Helicobacter pylori  (causative bacterium for chronic gastritis and peptic ulcers). The floating dosage form allows the drug to remain within the gastric mucosa. Example:  Sustained liquid preparation of  ampicillin  developed using sodium alginate.

14. Acid Stable Drugs: Particularly useful for acid stable drugs which are poorly soluble or unstable in intestinal fluids. Example:  Floating system for  furosemide  may lead to potential treatment of Parkinson's disease. (drug absorbed 30% after oral administration). B. Limitations Fluid Requirement:  The major disadvantage is the requirement of a sufficient high level of fluids in the stomach for drug delivery. (This can be overcome by coating the dosage form with the help of  bio-adhesive polymers ). Drug Solubility/Stability:  Floating system is  not feasible  for those drugs that have  solubility or stability problem in gastric fluids .

15. Administration Volume:  The dosage form should be administered with a minimum of a full glass of water (200-250 ml ). First-Pass Metabolism:  Drugs absorbed throughout the gastro-intestinal tract which undergo first-pass metabolism are  not a desirable candidate . Examples:  Nifedipine, Propranolol . Gastric Irritation:  Some drugs present in the floating system cause  irritation to gastric mucosa .

16. F loating Drug Delivery Systems (FDDS) Definition:  Systems designed to be retained in the stomach for a prolonged period, leading to a sustained drug release. Classification:  Based on the mechanism of buoyancy, FDDS are generally divided into two main types: (A) Effervescent System (B) Non-Effervescent System Effervescent Floating Systems Mechanism:  These systems use  gas-generating agents  (e.g., Sodium bicarbonate, Citric acid, Tartaric acid) which react with the acidic fluid to produce  carbon dioxide

17. The entrapped gas reduces the density of the system , causing it to  float  on the gastric fluid. This prolonged gastric retention time (GRT) leads to: Sustained release of the drug. Better control over fluctuations in plasma drug concentration.

18. Types of Effervescent Systems Gas Generating System 1. Intra Gastric Single Layer Floating Tablets Also known as: Hydrodynamically Balanced System (HBS). Composition:  Drug and gas-generating agents are intimately mixed within a single  hydrocolloid   matrix (e.g., 20%-75% w/w). Mechanism : Upon contact with gastric fluid, the hydrocolloids swell, forming a  colloid gel barrier   around the tablet, which traps the and helps the tablet to float.

19.  2. Intra Gastric Bilayer Floating Tablets Structure Compressed tablet containing two distinct layers: ( i ) Immediate release layer:  Provides an initial therapeutic dose. (ii) Sustained release layer:  Contains hydrocolloids for buoyancy and sustained drug release.

20. 3. Multiple Unit Type Floating Pills Structure Sustained-release "seeds" surrounded by double layers: Inner sublayer:  Contains  effervescent agents . Outer sublayer:  A  swellable membrane layer .

21. Mechanism: Water penetrates and dissolves the effervescent agents. It is generated, and the outer membrane swells. The pill sinks and forms a balloon-like structure with entrapped (lower density), causing it to float.

22. 2. Volatile Liquid/Vacuum Containing Systems 1. Intra Gastric Floating Gastrointestinal Drug Delivery Systems . Principle:  These systems contain a pre-formed  flotation chamber  (may be a vacuum or filled with a harmless gas/air). Mechanism:  The drug reservoir is encapsulated inside a  microporous compartment  or a hollow structure that floats due to its lower density. Example : Intra Gastric Floating Gastrointestinal Drug Delivery Device

23. 2. Inflatable Gastrointestinal Delivery Systems Mechanism:  Incorporates an  inflatable chamber  containing a  liquid ether  that easily gasifies at body temperature. Administration:  The system is fabricated into a polymeric matrix with a drug reservoir, then encapsulated in a gelatin capsule.

24. In Stomach: The capsule dissolves. The drug reservoir and inflatable chamber are released. The liquid ether gasifies, causing the chamber to  inflate . The inflated system floats, releasing the drug continuously from the reservoir. A B io erodible polymer filament  may be included for eventual deflation and expulsion.

25. 3. Intragastric Osmotically Controlled Drug Delivery System Structure:  Comprised of two main parts: 1. Osmotic Pressure-Controlled Drug Delivery Device:  A drug reservoir and an osmotically active compartment. 2. Inflatable Floating Support:  A deformable hollow polymeric bag.

26. Mechanism: The system is released in the stomach. Water enters the  osmotically active compartment  through a semi-permeable membrane. The resulting osmotic pressure acts on a  collapsible bag , reducing its volume and forcing the drug solution out through the  drug delivery orifice . The  inflatable support  maintains flotation and contains a  bio-erodible plug  that erodes after a predetermined time to deflate the system, allowing for its expulsion.

27. TYPE FLOATING DRUG DELIVERY SYSTEMS 1. Single Layer Floating Tablets Formulated with a  gel-forming hydrocolloid  that swells in contact with gastric fluid. This forms a bulk with a  density less than unity , providing buoyancy. 2. Bilayer Floating Tablets Two layers: one for  immediate release  (initial dose) and another for  sustained release  that forms an  impermeable colloidal gel barrier  on its surface, maintaining buoyancy. 3. Alginate Beads Multi-unit floating dosage forms prepared by dropping a sodium alginate solution into aqueous , forming a  alginate layer. providing a prolonged residence time (e.g., more than  5.5 hours ). 4. Hollow Microspheres Micro-balloons  loaded with drug in the inner oily layer. The resulting microspheres providing a prolonged residence time (e.g., more than  12 hours in vitro ). Non-Effervescent Systems Based on swelling of polymer or bioadhesion to GI tract mucosal layer. Excipients are high molecular weight polymers like  hydroxypropyl methylcellulose (HPMC) ,  polyacrylate ,  polyethylene oxide ,  polyacrylamide ,  polystyrene , and bioadhesive polymers like  chitosan  and  carbopol .     

28. Factors Controlling Gastric Retention Time (GRT) – Dosage Form FACTORS CONTENT Density Size GRT is dependent on the density of the system. Dosage forms with a diameter of  more than 9.5 mm  are reported to have an  increased GRT . Shape of Dosage Form Tetrahedron  and  ring-shaped devices  with a flexible modulus of 48 and2.5kilo pounds/square inch are reported to have better GRT (  90% to100%  retention at 24hrs) compared with other shapes. Single or Multiple Unit Formulation Multiple unit formulations  show a more predictable release profile and a significantly  larger margin of safety  against dosage form failure compared with single unit systems.

29. FACTORS CONTENT Fed or Unfed State Under fasting, the GI motility is controlled by the  Migrating Motility Complex (MMC) , which sweeps the GI tract. The GRT of the unit can be expected to be  very short  in the  fasted state . Nature of Meal Feeding of  indigestible polymers  or  fatty acid salts  can change the motility pattern to a  fed state , thus  prolonging  the gastric emptying rate. Caloric Content GRT can be increased by  four to  10 hours  with a meal that is  high in proteins and fats . Frequency of Feed GRT can increase by over 400   minutes  when successive meals are given compared with a single meal. Factors Controlling GRT - Physiological & Caloric            

30. FACTORS CONTENT Gender Mean GRT in males ( 3.4+_0.6hours) is less compared with their age- and race-matched female counterparts ( 4.6+_1.2hours). 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. Concomitant Drug Administration Anticholinergics  (Atropine, Propantheline) and  Opiates  (Codeine, Prokinetic agents) like  Cisapride  affect GRT. Biological Factors Diseases like  Diabetes  and  Crohn’s disease  can alter GRT. Factors Controlling GRT - Biological & Excipient

31. Heading Evaluation of Gastroretentive Drug Delivery Systems 1. Floating Lag Time Time taken to emerge and float on the surface of the dissolution medium. Measured in  minutes or seconds . 2. In Vitro Drug Release/Dissolution Determined by using  Apparatus I (basket) or II (paddle) stirring at a speed of  50 or 100 rpm  at 37 o C in Ph 1.2 medium. 3. Water Uptake Study Done by immersing the dosage form in simulated gastric fluid at  and determining the  dimensional changes  (diameter) and  fluid uptake  in a suitable animal model. 4. In Vivo Evaluation (Gastric Retention) Analysis of the position of the dosage form in the GI tract using techniques like  γ -scintigraphy  or  X-ray . Other Evaluation like Gastroscopy ,  ultrasonography ,  per-oral endoscopy , and  video systems  are also used. 5. Drug-Excipient Interaction Detected by  and . Appearance of a new peak or disappearance of an original drug or excipient peaks indicates an interaction   Evaluation Methods (In Vitro & In Vivo)

32. Heading Physicochemical and Morphological Evaluation Tablet/Dosage Form Evaluation Hardness ,  friability ,  weight variation , and other conventional instant release tests. Morphological and Dimensional Analysis Performed with the aid of  scanning electron microscopy  and  optical microscope . Water Uptake Calculation WU=( W t -W o )*100/W o ( W t -W o ): Weight of the tablet after time  t: Initial weight of the tablet Entrapment Efficiency Percentage yield of microsphere. The drug is extracted by a suitable method and analyzed to find out the  amount of drug present . Valuation Methods (Testing & Entrapment)