GRDDS improves bioavailability of drugs by sute specfic absorption

1. K.B.H SS TRUST’S INSTITUTE OF PHARMACY
MALEGAON,NASHIK
GRDDS: MODULATION OF GI TRANSIT, APPROACHES
AND FLOATING DRUG DELIVERY SYSTEM
Presented By:
Osama Tauseef
M.Pharm 1st semester
Guided By:
Dr. A. B. Gangurde
Head of Department
Department of pharmaceutics
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2. Contents
• Introduction
• Modulation of GI transit time
• Approaches to extend GI transit
• Floating drug delivery system
• Classifications
• Formulation
• Evaluations
• Advantages and Disadvantages
• Applications
• Marketed products
• Bibliography
2

3. INTRODUCTION:
Gastrointestinal Transit:
 Gastrointestinal transit: The time taken by food to leave the stomach and travel through the
intestines.
 The transit time for the mouth to anus: Depend upon object ingested and physiological
condition of the tract.
 Factors affect transit time:
 diet
 medication
 gender
 level of physical activity
 stress level that affect GI tract.
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4. MAODULATION OF GI TRANSIT TIME:
Successful modulation of Gi transit time of drug delivery involves study
of following GI Parts
 Anatomy of GI tract
 Dynamics of GI tract
 GI transit
 Ileocecal junction
 Colon and Gut flora
 GI Mucus
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5. Anatomy of GI tract:
GI tract: A group of organs joined in a long tube divided into several sections, each have
a specific function.
The tract begins with oral cavity and follows to
o pharynx
o esophagus
o stomach
o small intestine
o large intestine
o ending with rectum to anus part.
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6. DIGESTIVE TRACT
GI TRACT
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7. GI layers:
• inner mucosa
• Submucosa
• muscularis externa
• serosa
Stomach serves the most primarily mixing area and a reservoir that secretes:
• pepsinogen
• gastric lipase
• hydrochloric acid
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8.  Stomach section of the GI tract is normally impermeable for absorption of most materials into
the blood except water, ions, alcohol, and certain drugs such as aspirin. The human stomach
is capable of absorbing most acidic drugs and the very weakly basic drugs. Salicylic acid,
aspirin, thiopental, secobarbital and antipyrine, which are undissociated in the acidic gastric
contents, were readily absorbed.
 Small intestine, the major digestive and absorptive site of the GI tract, providing an extended
surface area.
 The last part of the GI tract is the large intestine extending from the ileum to the anus with 1.5
m long and 6.35 cm in diameter that’s work for water absorptive roles.
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9. GI tract is always in a state of continuous motility mainly there are 2 types of motility
patterns
 Digestive mode
 Inter digestive mode
 This mode consist of four distinct phases:
I. Period of no contraction
II. Period of intermittent contractions
III. Period of regular contractions at maximal frequency
IV. Period of transition between phase 3 and phase I
Average duration of these 4 phases is 90-120 min, this can be influenced under diseases
states.
Phase 3 serves a role of clearing all indigestible materials from stomach and intestine.
Dynamics of GI tract:
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10. GI transit:
o The transit of food through the stomach, small intestine and colon for digestion and
absorption of nutrients.
o The fasted state emptying of liquid Is independent of presence of any indigestible solid in stomach.
o The suggested DDS should be administered with small volume of liquid for prolongation
GI emptying time.
GI TRANSIT TIME 10

11. Colon and Gut flora:
 The high water absorption capacity of the colon.
 The availability of most drugs to the absorptive membrane is low.
 The human colon has over 400 distinct species of bacteria as resident flora.
 Reactions carried out by gut flora are azoreduction and enzymatic cleavage.
 These metabolic processes may be responsible for the metabolism of many
drugs and may also be applied to colon-targeted drug delivery.
Ileocecal junction:
This serves mainly to ensure the unidirectional flow of luminal contents from small to large
intestine.
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12. GI MUCUS:
 Mucus is continuously secreted by goblet cells located throughout GIT.
 Fresh mucous is very thick and becomes diluted and less thick near lumen, thickness
varies upon various region in GIT.
 Main function is to protect surface Mucosal cell from gastric acid. Chemical
composition is glycoproteins.
 Presence of mucus in GIT that is prolong transit time by application of bio (muco)
adhesive polymers.
GI MUCOSA 12

13. APPROACHES TO EXTEND GASTRICTRANSIT TIME:
Prolonged gastric retention time in the stomach could be advantageous for local action in the
upper part of the small intestine
Eg : Treatment of peptic ulcer In the few decades several stomach specific and gastro
retentive approaches being designed and developed including
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14. 14

15. Floating Drug Delivery Systems (FDDS)
 Floating Oral Drug Delivery System (FDDS) are retained are useful for drugs that
are poorly soluble or unstable in intestinal fluids.
 Floating drug delivery system (FDDS) have a bulk density less than gastric fluids and
so remain buoyant in the stomach.
 without affecting the gastric emptying rate for a prolonged period of time.
 While the system is floating on the gastric contents, the drug is released slowly at the
desired rate from the system.
 release of drug, the residual system is emptied from the stomach.
 This results in an increased GRT and a better control fluctuations in plasma drug
concentration.
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16. CLASSIFICATION OF FLOATING DRUG DELIVERY
SYSTEM:
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17. 1) Effervescent Floating Dosage Forms:
A drug delivery system can be made to float in the stomach by incorporating a floating chamber
, which may be filled with vacuum, air or inert gas.
Volatile liquid containing system Gas generating systems
These have an inflatable chamber contains a
liquid e.g. ether, cyclopentane
These buoyant delivery systems utilizes effervescent reaction
between carbonate/bicarbonate salts and citric acid to liberate CO2
gasifies at body temperature to cause the
inflation of the chamber in the stomach
which gets entrapped in the jellified hydrocolloid layer of the system,
thus decreasing its specific gravity and making it float over chime.
For floating contain a hollow deformable
unit
The system consists of a sustained release (SR) pill as seed,
surrounded by double layers
Two chamber system: first contains the
drug and the second chamber contains the
volatile liquid.
The inner layer is an effervescent layer containing sodium
bicarbonate and tartaric acid. The outer layer is of a swell able
membrane layer containing PVA, shellac etc.
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18. 2) Non-effervescent systems:
1) Colloidal gel barrier systems / Single Layer Floating Tablets:
Hydrodynamically balanced system (HBS), which contains drugs with gel forming hydrocolloids.
These systems incorporate one or more gel forming, highly swellable, cellulose type hydrocolloids,
polysaccharides and matrix forming polymers.
On coming in contact with gastric fluid, the hydrocolloids in the system hydrate and form a
colloidal gel barrier around its surface. This gel barrier controls the rate of fluid penetration into the
device and consequent release of the drug.
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19. • This technology is based on the encapsulation of a drug reservoir
• Inside a micro porous compartment with apertures along its top and bottom walls.
• 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.
2) Micro porous compartment systems
• A bi-layer tablet contain two layer one immediate release layer which
releases initial dose from system.
• the another sustained release layer absorbs gastric fluid.
• forming an impermeable colloidal gel barrier on its surface,
• And maintain a bulk density of less than unity and thereby it remains buoyant in
the stomach.
3) Bi-layer floating tablets:
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20. • Multiple unit floating dosage forms have been developed from freeze-dried calcium alginate.
• 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.
• 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, which can maintain a floating force over 12 hours.
Alginate beads:
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21.  There are various approaches in delivering substances to the target site in a controlled release fashion.
 One such approach is using polymeric micro balloons as carrier for drugs.
 Hollow microspheres are known as the micro balloons.
 Micro balloons were floatable invitro for 12 hrs., when immersed in aqueous media.
 Radio graphical studies proved that micro balloons orally administered to human were dispersed in the upper
part of stomach and retained there for three hrs.
 Against peristaltic movements.
Micro balloons / Hollow Microspheres
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22. formulation:
Polymers and other ingredients used in preparations 0f floating drugs:
ingredients Examples
Polymers HPMC , Calcium alginate, ethyl cellulose, CMC, Polyethylene
glycol, polycarbonate, PVA, Sodium alginate, PVP and Carbopol.
Inert fatty materials Beeswax, fatty acids, long chain fatty alcohols.
Effervescent agents Sodium bicarbonate, citric acid, tartaric acid, CG (Citro glycine)
Release rate accelerants lactose, mannitol.
Release rate retardants Dicalcium phosphate, talc, magnesium stearate.
Low density material Polypropylene
Buoyancy increasing
agents
Ethyl cellulose
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23. Preparation of floating tablets:
Floating tablets were prepared by both wet granulation and direct compression method.
 In the wet granulation method:
granules were prepared using absolute ethanol as granulating agent.
Lubricants and glidants were added one after to the granules and mixed each time by tumbling
process in a dry bottle.
Accurately weighed amount of granules (containing 240 mg of drug and polymers) were
placed on the die cavity and a preparatory pressing was made.
suitable compression force such that the tablet hardness was 2, 4 and 8 kg/cm2 .
 In the direct compression method:
the powders after passing through appropriate sieves were mixed and compressed directly in a
similar method mentioned above. The amount of polymers was optimized to obtain
formulations that would afford 90% release of the drug in 12 hrs.
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24. A. In Vitro Methods
1) Floating lag time and floating time:
• The test for floating time measurement is usually performed in stimulated gastric fluid or 0.1 N HCl
maintained at 37 0C.
• It is determined by using USP dissolution apparatus. The time taken by the dosage form to float is
termed as floating lag time.
• . The system to check continuous floating behavior contains a stainless steel basket connected to a metal
string and suspended from a Sartorius electronic balance.
• spread sheet could automatically pick up the reading on the balances.
• data was collected at 30 sec interval.
• baseline was recorded and subtracted from each measurement.
Evaluations
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25. 2) Dissolution study
 A 100-ml glass beaker was modified by adding a side arm at the bottom of the beaker.
 The dissolution medium and allow collection of samples.
 A burette was mounted above the beaker to deliver the dissolution medium at a flow rate of 2
ml/min to mimic gastric acid secretion rate.
 The drug release followed zero-order kinetics in the proposed method.
3) Swelling index:
 An in vitro measuring apparatus has been conceived to determine the real floating capabilities of
buoyant dosage forms as a function of time.
 It operates by measuring the force equivalent to the force in the fluid.
 This force determines the resultant weight of the object.
 when immersed and may be used to quantify its floating or non floating capabilities.
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26. B. In vivo method
1) X-Ray method:
X-Ray is a very popular evaluation parameter for floating dosage form now a day.
It helps to locate dosage form in the GIT and by which one can predict and correlate the gastric
emptying time and the passage of dosage form in the GIT.
2) gamma-Scintigraphy:
Gamma -Emitting radio isotopes compounded the state-of-art for evaluation of gastro retentive formulation
in healthy volunteers.
A small amount of a stable isotope .
The main drawbacks of gamma - scintigraphy are the associated ionizing radiation for the patient.
the limited topographic information, low resolution inherent to the technique and the complicated and
expensive preparation of radiopharmaceuticals.
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27. 3) Gastroscopy:
 It comprises of peroral endoscopy, used with a fiberoptic and video systems.
 It is suggested that gastroscopy may be used to inspect visually the effect of prolonged stay in
stomach on the FDDS.
 Alternatively, FDDS may be drawn out of the stomach for more detailed evaluation.
4) Ultrasonography:
Ultrasonic waves reflected substantially different acoustic impedances across interface enable the
imaging of some abdominal organs. Most do not have sharp acoustic mismatches across their
interface with the physiologically. Therefore, Ultrasonography is not routinely used for the
evaluation of FDDS. The characterization included assessment of intragastric location of the
hydrogels, solvent penetration into the gel and interactions between gastric wall and FDDS
during peristalsis.
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28. Advantages disadvantages
Drug complete absorption is achieved. The drug which is unstable in the acidic
environment
Targeted therapy for the local site in the stomach
part can be achieved.
solubility and stability problem in the stomach.
Drug concentration fluctuation problem is reduced
in case of FDDS.
Drugs which undergoes first pass metabolism – not
suitable.
Floating system shows improved selectivity in
receptor activation
Drugs which make irritation to gastric mucosa.
Reduced counter activity of the body is achieved Dosage form required minimum 200 to 250ml of
water for administration.
Extended effective concentration is showed. Floating tablet has not having significant advantage
over the conventional dosage form.
At the colon, junction minimized adverse activity is
achieved.
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29. Application of floating drug delivery system:
 Enhanced bioavailability
The bioavailability of the drug is increased significantly enhanced when comparison to the
administration of non floating type of system polymeric formulations.
 Sustained Drug Delivery
Hydro Dynamically Balanced System which overcomes the gastric residence problem by retaining
in the stomach for longer period due to having bulk density <1 as a result it floats in gastric
contents.
 Site-Specific Drug Delivery
These systems are more advantageous particularly for drugs that are specifically absorbed from stomach
or proximal part of the small intestine, e.g., furosemide.
Furosemide absorbed primarily from stomach then by the duodenum.
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30.  Bioavailability or Absorption Enhancement:
Drugs which are absorbed from the upper part of the gastrointestinal tract are have poor
bioavailability,
because of site specific absorption hence potential candidates are formulated as a floating drug
delivery systems and maximizing their absorption.
Marketed product
1. Madopar: levodopa and benserzide
2. Valrelase: diazepam
3. Liquid gavison: alginic acid and sodium bicarbonate
4. Topalkan: aluminum magnesium antacid
5. Almagate flatcoat: antacid
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31. Bibliography
 Hirtz J. The GIT absorption of drugs in man: a review of current concepts and methods of
investigation. Br J Clin Pharmacol. 1985;19:77SY83S.
 Desai S. A Novel Floating Controlled Release Drug Delivery System Based on a Dried Gel Matrix
Network [master’s thesis]. 1984 Jamaica, NY, St John’s University.
 Singh BN, Kim KH. Floating drug delivery systems: an approach to oral controlled drug delivery
via gastric retention. J Control Release. 2000;63:235Y259.
 Soppimath KS, Kulkarni AR, Rudzinski WE, Aminabhavi TM. Microspheres as floating drug
delivery system to increase the gastric residence of drugs. Drug Metab Rev. 2001;33:149Y160.
 Atyabi F.,Sharma H.L., Mohammad H. AH. and Fell J. T., Controlled drug release from coated
floating ion exchange resin beads. Journal of Controlled Release.1996;42: 25- 28.
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