Gastro-retentive Drug Delivery System (GRDDS)

Gastro-retentive Drug Delivery System

Session Objectives

By the end of this session, students will be able to:

       Explain various gastro-retentive strategies for drug absorption

       Elaborate various factors to be considered in the design of GRDDS

       Explain the significance of various processes involved in preformulation of GRDDS

       Formulate a suitable gastro-retentive dosage form based on the need and drug characteristics

Limitations of GRDDS

  Retention in the stomach is not desirable for drugs that cause gastric lesions (e.g. Non- steroidal anti-inflammatory drugs NSAIDs).

  Drugs that are degraded in acidic environment of stomach (e.g. Insulin).

  Drugs that undergo a significant first-pass metabolism (e.g.  Nifedipine).

  Drugs that have very limited acid solubility (e.g. Phenytoin).

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

-          duodenu

-          jejunum

-          ileum

  Large intestine.

Approaches

  Approaches

  Floating drug delivery systems

  Mucoadhesive system

  Swellable Systems

  High density systems.

Floating DDS

  These are low density systems.

  Have ability to float over gastric contents.

  The drug is must have sufficient structure to form a cohesive gel barrier.

  It must maintain an overall specific gravity lower than that of gastric contents (1.004 – 1.010).

  Eased from the system at desired rate.

Techniques for floatation

Effervescent

  Volatile liquid containing systems

  Gas generating systems

Non-Effervescent

  Colloidal gel barrier systems

  Alginate beads

  Hollow Microspheres

  Microporous Compartment System

1. Effervescent systems

Gas generating systems

  Effervescence is there.

  Utilizes effervescent reactions between carbonate/bicarbonate salts and citric/tartaric acid.

  CO2 is released in presence of H2O.

  When tablet is put in beaker it will sink

  2NaHCO3+C4H6O6 à C4H4Na2O6+2CO2+2H2O

  With production of gas it rises up and floats.

Volatile liquid containing systems

  Incorporates 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 PVA, Polyethylene, 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 from the stomach.

  These systems are very less used as the gas generating systems are safer.

2. Non-effervescent systems

q  This type of system, after swallowing, swells unrestrained via imbibition of gastric fluid to an extent that it prevents their exit from the stomach.

q  One of the formulation methods of such dosage forms involves the mixing of the drug with a gel, which swells in contact with gastric fluid after oral administration.

a) Colloidal gel barrier systems

  Such systems contains drug with gel forming hydrocolloids meant to remain buoyant on stomach contents.

  These systems incorporate a high level of one or more gel forming highly Swellable cellulose type hydrocolloids. 

  e.g.HEC, HPMC, NaCMC.

  On coming in contact with gastric fluids forms a viscous core.

  Incorporates H2O and entraps air.

  Density of system falls below 1gm/cm3. Then it starts floating

The air trapped by the swollen polymer confers buoyancy to these dosage forms.

Excipients used most commonly in these systems include

1.       Hydroxypropyl methyl cellulose (HPMC)

2.       Polyacrylate polymers

3.       Polyvinyl acetate

4.       Carbopol

5.       Agar

6.       Sodium alginate

7.       Calcium chloride

8.       Polyethylene oxide

9.       Polycarbonates

b). Microporous membrane systems

  Based on the encapsulation of drug reservoir inside a Microporous compartment.

  The peripheral walls of the drug reservoir compartment are completely sealed to prevent any direct contact of the gastric mucosal surface with the undissolved drug.

  In stomach the floatation chamber containing entrapped air causes the delivery system to float over the gastric contents.

  Gastric fluid enters through the apertures, dissolves the drug, and carries the dissolve drug for absorption.

c) Alginate Beads

  Spherical beads of approximately 2.5 mm in diameter can be prepared by dropping a sodium alginate solution in to aqueous solutions of calcium chloride, causing precipitation of calcium alginate.

  Sodium alginate+ Calcium chloride à Calcium alginate+  NaCl

  The beads are then separated snap and frozen in liquid nitrogen, and freeze dried at -40°C for 24 hours, leading to the formation of porous system.

  Maintain a floating force of over 12 hours.

d) Hollow microspheres

  Microballoons / hollow microspheres loaded with drugs are prepared by simple solvent evaporation method.

  Commonly used polymers to develop these systems are polycarbonate,              cellulose acetate, calcium alginate, Eudragit S, agar and pectin etc.

  These systems have capacity to float on acidic dissolution media containing surfactant for about 12 hours invitro.

Mucoadhesive systems

  Involves the use of bioadhesive polymers, which can adhere to the epithelial surface in the stomach.

  Dosage form can stick to mucosal surface by following  mechanisms:

  1. The wetting theory
  2. The diffusion theory
  3. The absorption theory
  4. The electron theory

Swellable Systems

  A dosage form in the stomach will withstand gastric transit if it bigger than pyloric sphincter, but should be small enough to be swallowed.

  These systems swells many times its original size.

  Cross linking should be optimum highly cross linked don’t swell.

  Chitosan, HPMC, sodium starch glycolate, carbopol are used.

  Diclofenac, Ciprofloxacin, Furosemide are reported with these systems.

  These have density greater than that of  gastric fluids (1.4g/cc).

  Above 1.6g/cc is preferable, tend to withstand peristaltic movements of stomach.

  Zinc oxide, Iron oxide, Titanium dioxide, barium sulfate are used as inert heavy core.

Osmotic Drug Delivery System

Osmosis

       Osmosis can be defined as the net movement of water across a selectively permeable membrane driven by a difference in osmotic pressure across the membrane.

       It is driven by a difference in solute concentrations across the membrane that allows passage of water, but rejects most solute molecules or ions.

       Osmotic pressure is the pressure which, if applied to the more concentrated solution, would prevent transport of water across the semipermeable membrane.

Osmotic Drug Delivery System

Osmotically controlled drug delivery systems utilize osmotic pressure for controlled delivery of active agent.

Osmotic pressure: It is colligative property of solution in which a non-volatile solute is dissolved in a volatile solvent.

It has no water chamber, and the device is activated by water imbibed from the surrounding environment.

The pump is activated when it is swallowed or implanted in the body.

This pump consists of a rigid housing, and the semipermeable membrane is supported on a perforated frame.

It has a salt chamber containing a fluid solution with excess solid salt. Recent modification in Higuchi-Leeper pump accommodated pulsatile drug delivery.

Further simplified variant of Rose-Nelson pump was developed by Higuchi and Theeuwes

Mechanism of drug release

It involves osmosis of gastrointestinal fluid across the semi permeable membrane at a controlled rate.

Dissolution of drug & osmotic agent to produce a saturated drug solution within a tablet core.

As the no. of molecules in solution increases, the osmotic pressure within a tablet core increases.

Outer coating (semi permeable membrane) is rigid.

Therefore to reduce the osmotic pressure within the tablet, saturated drug solution is emitted from a tablet core through orifice.

The major formulation components of a typical osmotic delivery system include:

  1. Drug
  2. Osmotic agents
  3. Semi permeable membrane

Osmotic agents

Osmotic components usually are ionic compounds consisting of either inorganic salts or hydrophilic polymers.

These materials maintain a concentration gradient across the membrane.

They also generate a driving force for the uptake of water and assist in maintaining drug uniformity in the hydrated formulation.

Osmotic pressure of saturated solution of common pharmaceutical solutes

Compound or Mixture

Osmotic pressure (atm)

Sodium chloride

356

Fructose

355

Potassium chloride

245

Sucrose

150

Dextrose

82

Potassium sulphate

39

Mannitol

38

Sodium phosphate tribasic

36

Semi permeable membrane

Semi permeable membrane has important role in controlling drug release.

 Membrane must meet several performance criteria-:

1.       Polymer must exhibit sufficient wet strength and water permeability so as to attain water flux rate in the desired range.

2.       Reflection coefficient (leakage of solute through membrane) should approach the limiting value of 1.

3.       Membrane should be biocompatible.

e.g. Cellulose esters like cellulose acetate, cellulose acetate butyrate, cellulose triacetate and ethyl cellulose and Eudragits.

Wicking agents -:

 - It has ability to draw water in to the porous network of a delivery device

 - E.g. colloidal silicon dioxide, kaolin, titanium dioxide, SLS, low molecular weight (PVP).

Pore forming agents -:

- These agents are particularly used in the pumps developed for poorly water soluble drugs and in the development of controlled porosity osmotic pumps.

- These pore forming agents cause the formation of micro porous membrane.

- alkaline metal salts such as sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, etc.

Classification of ODDS

       Implantable osmotic pump.

       Oral osmotic pump.

Implantable systems further classified as-:

  1.  For experimental use
  2.  For human use

Oral osmotic pump.

These systems can be further classified as-:

Single chamber osmotic system:

 - Elementary osmotic pump

Multi-chamber osmotic systems:

 - Push-pull osmotic pump

Miscellaneous:

- Controlled porosity osmotic pumps

- Osmotic bursting osmotic pump

- Effervescent activity-based osmotic systems

- OROS- CT,-  L-OROS

Single chamber osmotic system

Elementary osmotic pump -:

It consist of an osmotic core containing drug & if required osmotic agent, which is coated with semi permeable membrane.

When core imbibes water osmotically at a controlled rate through semi permeable membrane, forming a saturated drug solution.

The system delivers, via orifice, saturated drug solution.

Factors affecting drug release rate

       Orifice size

       Solubility

       Osmotic Pressure

Orifice size

The size of the orifice must be larger than a minimum size (600µ), to minimize hydrostatic pressure.

This is necessary step in achieving zero order drug release.

The size of the orifice must be smaller than a maximum size (1 mm) , to minimize diffusional contribution to delivery rate.
Solubility

The release rate depends on the solubility of the solute inside the drug delivery system.

Therefore, drugs should have sufficient solubility to be delivered by osmotic delivery.

Various solubility modifying approaches include: 

    - Use of swellable polymers

     - Use of wicking agents

     - Use of effervescent mixtures

     - Use of cyclodextrin derivatives

     - Use of alternative salt form

Advantages

       There is no requirement for the system to disintegrate for the release of drug to occur.

       Delivery of drugs takes place in solution form, which is ready for absorption.

       Delivery rate is independent of pH and outside agitation.

       The in vivo delivery rate of drug is expected to be same as that in vitro.

       Due to its zero order release profile it is used in early stages of drug research, such as drug screening, animal toxicology.

Limitations

       Special equipment is required for making an orifice in the system.

       If the coating process is not well controlled there is a risk of film defects, which results in dose dumping.

       Residence time of the system in the body varies with the gastric motility and food intake.

       It may cause irritation or ulcer due to release of saturated solution of drug.

Elementary osmotic pump

Brand Name

API

Efidac 24

Chlorpheniramine

Acutrim

Phenylpropanolamine

Sudafed 24

Pseudoephedrine

Push-pull osmotic systems

Brand Name

API

Ditropan XL ®

Oxybutynin chloride

Procardia XL®

Nifedipine

 

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