4. •GRT; the time interval between the arrival of
the magnetic tablet in the stomach and its
gastric emptying
•GET: The gastric emptying rate is a measure of
the speed of delivery of gastric contents into
the duodenum.
• Gastric contents to be delivered include
liquids, digestible solids, and indigestible food
residues
15. DIFFERENT APPROACHES FOR
GASTRO RETENTIVE DRUG DELIVERY SYSTEM
4,9,24,31,37,40,59
GOVERNMENT PHARMACY COLLEGE
(SAJONG , EAST SIKKIM)
16.
17. GOVERNMENT PHARMACY COLLEGE
(SAJONG , EAST SIKKIM)
1. High density (sinking) system or non- floating drug delivery system :
• This approach involves formulation of dosage forms with the density that must
exceeds density of normal stomach content (~ 1.004 gm/cm3 ).
• These formulations are prepared by coating drug on a heavy core or mixed with
inert materials such as :
iron powder, barium sulphate, zinc oxide and titanium oxide etc .
• The materials increase density by up to 1.5- 2.4 gm/cm3 .
• A density close to 2.5 gm/cm3 seems necessary for significant prolongation of
gastric residence time. But, effectiveness of this system in human beings was not
observed and no system has been marketed.
18.
19.
20. GOVERNMENT PHARMACY COLLEGE
(SAJONG , EAST SIKKIM)
[BUOYANCY is an upward force exerted by a fluid that
opposes the weight of a partially or fully immersed
object.]
21. GOVERNMENT PHARMACY COLLEGE
(SAJONG , EAST SIKKIM)
2.Floating drug delivery systems :
• It is one of the important approaches to achieve gastric retention to obtain sufficient
drug bioavailability .
• This delivery systems is desirable for drugs with an absorption window in the stomach or
in the upper small intestine .
• This have a bulk density less then gastric fluids and so remain buoyant in the stomach
without affecting gastric emptying rate for a prolonged period and the drug is released
slowly .
• The major requirements for floating drug delivery system are
• It should release contents slowly to serve as a reservoir.
• It must maintain specific gravity lower than gastric contents (1.004 – 1.01 gm/cm3).
• It must form a cohesive gel barrier
34. • Incorporation of Passage delaying Food Agents : Fatty acids with chain length C10-C14 e.g. salts
of myristic acid modify the pattern of the stomach to a fed state thereby decreasing gastric
emptying rate and permitting considerable prolongation of release.
• Ion Exchange Resins: A coated ion exchange resin bead formulation has been shown to have
gastric retentive properties which was loaded with bicarbonates.
• Ion exchange resins are loaded with bicarbonates and negatively charged drug is bound to the
resin. The resultant beads were then encapsulated in a semi-permeable membrane to overcome
the rapid loss of CO2. upon arrival in the acidic environment of the stomach, an exchange of
chloride and bicarbonate ions takes place releasing CO2 which gets trapped in the membrane
thereby carrying beads towards the top of the gastric content and producing a floating layer of
resin beads in contrast to uncoated beads.
35. Osmotic Regulated System:
Osmotic pressure controlled drug delivery device (OPCDDD) and an inflatable floating support
in a bio-erodible capsule which disintegrates to release OPCDDD. The inflatable support
contains a liquid that gasify at body temperature to inflate the bag.
The OPCDDD consist of 2 compartments: 1. drug reservoir 2. osmotically active compartment.
36. 2,3,4,,6,8,9,10,17,18,27,38,39,44,51,52,53,56,59,60
• DENSITY : GRT is a function of dosage form buoyancy that
is dependent on the density.
• SIZE : unit > 9.5mm increases GRT
• SHAPE: Tetrahedron and ring shaped devices > GRT
• FED or UNFED STATE: GI motility is characterized by periods of strong motor
activity (peristaltic movement) or Migrating myoelectric complex (MMC) every
1.5-2 hrs. The MMC sweeps any undigested material from the stomach and if
the time of administration of formulation coincides with MMC during unfed
condition the GRT of unit is very short. In the Fed state MMC is delayed and
GRT is longer.
37. FACTORS CONTROLLING GASTRIC RETENTION TIME
OF DOSAGE FORM
• DENSITY : GRT is a function of dosage form buoyancy that
is dependent on the density.
• SIZE : unit > 9.5mm increases GRT
• SHAPE: Tetrahedron and ring shaped devices > GRT
• FED or UNFED STATE: GI motility is characterized by periods of strong motor
activity (peristaltic movement) or Migrating myoelectric complex (MMC) every
1.5-2 hrs. The MMC sweeps any undigested material from the stomach and if
the time of administration of formulation coincides with MMC during unfed
condition the GRT of unit is very short. In the Fed state MMC is delayed and
GRT is longer.
38. • SINGLE OR MULTI-UNIT FORMULATION: multiple unit formulations show a more
predictable release profile with larger margin of safety as compared with single
unit dosage form.
• NATURE OF MEAL: indigestible polymers or fatty acid salts can change the
motility pattern of the stomach to a fed state, thus decreasing the gastric
emptying rate.
• CALORIE CONTENT: GRT can be increased by 4-10 hr with a meal that is high in
proteins and fats.
• 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 GRT in males (3.4 ± 0.6hrs) is less compared with their age and
race matched female counterparts (4.6 ± 1.2hrs) regardless of weight, height and
body surface.
• AGE: Elderly people >70 years have significantly longer GRT.
• POSTURE: GRT can very b/w supine and upright state of patient.
• CONCOMITANT DRUG ADMINISTRATION: Anticholinergics like atropine, Opiates
like Codeine > GRT and Prokinetic agents like metaclopromide/Cisapride < GRT.
39.
40. TYPES OF FLOATING DRUG DELIVERY SYSTEMS
Based on the mechanism of buoyancy, two distinctly different technologies have
been utilized in development of FDDS which are:
1. Effervescent System
2. Non-Effervescent System
3. Effervescent System: includes use of gas generating agents such as carbonates
(sodium bicarbonate) and other organic acids (citric acid and tartaric acid)
present in the formulation to produce CO2 gas, thus reducing the density of the
system and making it to float on the gastric fluid.
An alternative is the incorporation of matrix containing portion of liquid, which
produces gas that evaporates at body temperature.
These effervescent systems further classified into two types:
1. Gas generating system
2. Volatile liquid/Vacuum containing system.
41. (I). GAS GENERATING SYSTEMS:
1. Intra gastric single layer floating tablets/ Hydrodynamically balanced system [HBS]
•These are formulated by mixing the CO2 generating agents and the drug with in the matrix
tablet.
• These have a bulk density lower than gastric fluids and therefore remain floating in the
stomach unflattering the gastric emptying rate for a prolonged period.
• The drug is slowly released at a desired rate from the floating system and after the complete
release, the residual system is expelled from the stomach.
• This leads to increase in GRT and better control over fluctuations in plasma drug
concentration.
d < 1
Hydrocolloids
20%-75% w/w
Colloidal Gel Barrier
Gastric Fluid (d > 1)
42. 2. Intra gastric Bilayer floating tablets
These are also compressed tablets and contain two layers ; immediate release layer and
sustained release layer.
d < 1
Sustained release
Hydrocolloids
Colloidal Gel Barrier
Gastric Fluid (d > 1)
Immediate release layer
Sustained release layer
43. 3. Multiple unit type floating pills:
These systems consist of sustained release pills as seeds surrounded by double
layers.
The inner layer consists of effervescent agents while the outer layer is of
swellable membrane layer.
When the system is immersed in dissolution medium at body temperature, it
sinks at once and then forms swollen pills like balloons which float as they have
lower density. This lower density is due to generation and entrapment of CO2
with in the system. Conventional
sustained release pill
Effervescent layer
Swellable
membrane
44. (II). Volatile Liquid/Vacuum Containing system:
1. Intragastric floating gastrointestinal drug delivery system: these systems can
be made to float in the system because of floatation chamber, which may be a
vacuum or filled with air or a harmless gas, while drug reservoir is encapsulated
inside a microporous compartment.
Flotation chamber
Drug Reservoir
Microporous wall
45. (II). Volatile Liquid/Vacuum Containing system:
1. Inflatable gastrointestinal Delivery system: in this system an inflatable
chamber is incorporated which contains liquid ether that gasify at body
temperature to cause the chamber to inflate in the stomach.
. These systems are fabricated by loading the inflatable chamber with the drug
reservoir which can be a drug impregnated polymeric matrix and encapsulated
in a gelatin capsule.
3. Intra gastric osmotically controlled drug delivery system
46. GOVERNMENT PHARMACY COLLEGE
(SAJONG , EAST SIKKIM)
3. Non-effervescent floating drug delivery systems :
•They are normally prepared from gel-forming or highly swellable cellulose type
hydrocolloids, polysaccharides or matrix forming polymers
like polyacrylate, polycarbonate, polystyrene and polymethacrylate.
• In one approach, intimate mixing of drug with a gel forming hydrocolloid which
results in contact with gastric fluid after oral administration and maintain a relative
integrity of shape and a bulk density less than unity within the gastric environment .
•The air trapped by the swollen polymer confers buoyancy to these dosage forms.
•Excipients used most commonly in these systems include:
Hydroxypropyl methylcellulose (HPMC) polyacrylates, polyvinyl acetate, carbopol, agar,
sodium alginate, calcium chloride, polyethylene oxide and polycarbonates .
47. Non-Effervescent Systems: these are based on mechanism of swelling of polymer or
bioadhesion to mucosal layer in GI tract.
•The most commonly used excipients in this system are gel forming or highly swellable cellulose type
hydrocolloids, polysaccharides and matrix forming material such as polycarbonate, polyacrylate,
polymethacrylate, polystyrene as well as bioadhesive polymer such as chitosan and Carbopol.
•These non-effervescent system can also be of various types such as:
1. Single layer Floating tablets
2. Bilayer floating tablets
3. Alignate beads
4. Hollow microsperes
48. EVALUATION PARAMETERS OF GRDDS
• Drug-excipient interaction: by performing FTIR/HPLC. Appearance of new peak
or disappearance of original peak indicates interaction.
• Floating Lag time: it is the time taken to emerge tablet onto the surface after it is
kept into the dissolution medium. It is measured in minutes or seconds.
• In vitro Drug Release and Duration of floating: it is determined by using USP II
apparatus (paddle) stirring at a speed of 50 or 100 rpm at 37 ± 2°C in simulated
gastric fluid of pH 1.2.
• Aliquots of the samples are collected and analysed for the drug content.
• The time for which the drug remains floating on the surface of the medium is the
duration of the floating time.
49. EVALUATION PARAMETERS OF GRDDS
• In vivo evaluation of gastric retention: analysis of the position of the dosage
form in the GIT involves imaging through γ-Scintigraphy and X-ray.
γ-Scintigraphy : small amount of stable isotope is compounded in the dosage form.
γ emmision is observed using Scinti scanner.
In X-ray : barium sulphate is used as a contrast medium.
Other methods : USG, Gastroscopy.
50. • Water Uptake Study: it is done by immersing the dosage form in simulated
gastric fluid at 37C and determining the dimensional changes, such as diameter
and thickness, at regular interval of time.
• After the stipulated period of time , the swollen tablets are weighed and water
uptake is measured in terms of percentage weight gain as given:
WU = (Wt-Wo) x 100/Wo
Where, Wt and Wo are the weight of the tablet after time t and initially.
51. The tablets are also evaluated for hardness, friability, weight variation, etc. which
are applicable for conventional instant release tablets.
• Entrapment efficiency: the drug is extracted by suitable method and analysed to
find the amount of drug present.
52. GOVERNMENT PHARMACY COLLEGE
(SAJONG , EAST SIKKIM)
Effervescent (gas generating) systems Floatability can be achieved by generation of gas bubbles. These buoyant
systems utilize matrices prepared with swellable polymers such as polysaccharides (e.g. chitosan), effervescent
components (e.g. sodium bicarbonate, citric acid or tartaric acid) .
The optimal stoicheometric ratio of citric acid and sodium bicarbonate for gas generation is reported to be 0.76: 1
In this system carbon dioxide is released and causes the formulation to float in the stomach . Other approaches
and materials that have been reported are a mixture of sodium alginate and sodium bicarbonate, multiple unit
floating dosage forms that generate gas (carbon dioxide) when ingested, floating mini capsules with a core of
sodium bicarbonate, lactose and polyvinyl pyrrolidone (PVP) coated with hydroxypropyl methylcellulose (HPMC),
and floating system based on ion exchange resin technology etc .
Bilayer or multilayer system has also been designed . Drugs and excipients can be formulated independently and
the gas generating material can be incorporated in to any of the layers. Further modifications involve coating of
the matrix with a polymer which is permeable to water, but not to carbon dioxide. The main difficulty of these
formulations is finding a good compromise between elasticity, plasticity and permeability of the polymers.
53. GOVERNMENT PHARMACY COLLEGE
(SAJONG , EAST SIKKIM)
Microballoons / Hollow microspheres: Microballoons / hollow microspheres loaded with drugs in their other polymer
shelf were prepared by simple solvent evaporation or solvent diffusion / evaporation methods to prolong the gastric
retention time (GRT) of the dosage form. Commonly used polymers to develop these systems are polycarbonate,
cellulose acetate, calcium alginate, Eudragit S, agar and low methoxylated pectin etc.
Buoyancy and drug release from dosage form are dependent on quantity of polymers, the plasticizer polymer ratio
and the solvent used for formulation.
The microballoons floated continuously over the surface of an acidic dissolution media containing surfactant for >12
hours .
At present hollow microspheres are considered to be one of the most promising buoyant systems because they
combine the advantages of multiple-unit system and good floating.
Alginate beads: Talukdar and Fassihi [32] recently developed a multiple-unit floating system based on cross-linked beads.
They were made by using Ca2+ and low methoxylated pectin (anionic polysaccharide) or Ca2+ low methoxylated pectin
and sodium alginate. In this approach, generally sodium alginate solution is dropped into aqueous solution of calcium
chloride and causes the precipitation of calcium alginate. These beads are then separated and dried by air convection
and freeze drying, leading to the formulation of a porous system, which can maintain a floating force for over 12 hrs.
These beads improve gastric retention time (GRT) more than 5.5 hrs [
54. GOVERNMENT PHARMACY COLLEGE
(SAJONG , EAST SIKKIM)
Hydrodynamically balanced systems:
Sheth and Tossounian first designated these ‘hydrodynamically balanced systems’.
These systems contains drug with gel-forming hydrocolloids meant to remain buoyant on the stomach content.
These are single-unit dosage form, containing one or more gel-forming hydrophilic polymers. Hydroxypropyl
methylcellulose (HPMC), hydroxethyl cellulose (HEC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose
(NaCMC), polycarbophil, polyacrylate, polystyrene, agar, carrageenans or alginic acid are commonly used excipients to
develop these systems .
The polymer is mixed with drugs and usually administered in hydrodynamically balanced system capsule.
The capsule shell dissolves in contact with water and mixture swells to form a gelatinous barrier, which imparts
buoyancy to dosage form in gastric juice for a long period. Because, continuous erosion of the surface allows water
penetration to the inner layers maintaining surface hydration and buoyancy to dosage form . Incorporation of fatty
excipients gives low-density formulations reducing the erosion. Madopar LP® , based on the system was marketed
during the 1980’s . Effective drug deliveries depend on the balance of drug loading and the effect of polymer on its
release profile.
