nisarg grdds

GASTRO RETENTIVE DRUG DELIVERY SYSTEM

PRESENT BY :- PATEL NISARG (2nd

semester M.pharm)

Department of Pharmaceutics

GUIDED BY :- DR. ANURADHA PATEL

CONTENTS

INTRODUCTION APPROPRIATE CANDIDATE DRUGS FOR GRDDS ADVANTAGES & DISADVANTAGES LIMITATIONS FORMULATION FACTORS AFFECTING GASTRIC RETENTION TIME APPROACHES CONCLUSION REFERENCES

Smt.B.N.B.Swaminarayan Pharmacy College, Salvav ,Vapi.

3INTRODUCTION

• 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.

• Gastro retentive drug delivery(GRDDS) is one of the site specific drug delivery for the delivery of the drugs at stomach.

• It is obtained by retaining dosage form into stomach and drug is being released at controlled manner at specific site


4APPROPRIATE CANDIDATE DRUGS FOR GRDDS

Drugs acting locally in the stomach. E.g. Antacids and drugs for H. Pylori viz., Misoprostol. Drugs that are primarily absorbed in the stomach. E.g. Amoxicillin Drugs that is poorly soluble at alkaline pH. E.g. Furosamide, Diazepam, Verapamil, etc. Drugs with a narrow absorption window. E.g. Cyclosporine, , Levodopa, Methotrexate etc. Drugs which are absorbed rapidly from the GI tract. E.g. Metronidazole, tetracycline. Drugs that degrade in the colon. E.g. Ranitidine, Metformin. Drugs that disturb normal colonic microbes E.g. antibiotics against Helicobacter pylori.


5ADVANTAGES OF GRDDS

Enhanced bioavailability Sustained drug delivery/reduced frequency of Dosing Targeted therapy for local action 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.


6DISADVANTAGES OF GRDDS Floating systems has limitation, that they require high level of fluids in stomach for floating

and working efficiently. So more water intake is prescribed with such dosage form. In supine posture (like sleeping), floating dosage form may swept away (if not of larger size)

by contractile waves. So patient should not take floating dosage form just before going to bed. Food is also an important factor. Presence of food delays emptying time of food and dosage

form. So presence of food is preferable. Drugs having stability problem in high acidic environment, having very low solubility in

acidic environment and drugs causing irritation to gastric mucosa can not be incorporated into GRDDS.

Bio/mucoadhesives systems have problem of high turn over rate of mucus layer, thick mucus layer & soluble mucus related limitations.

Swellable dosage form must be capable to swell fast before its exit from stomach & achieve size larger than pylorus aperture. It must be capable to resist the housekeeper waves of Phase III of MMC.


7LIMITATIONS

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.


8FORMULATION DRUG HPMC-K-100M SODIUM BICARBONATE CITRIC ACID TARTRIC ACID CROSS CARMELOSS SODIUM XANTHUM GUM MCC PVP-K-30 MAGNESIUM STERATE TALC


9FACTORS AFFECTING GASTRIC RETENTION TIME OF THE DOSAGE FORM

Density: it 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 with a flexural modulus of 48

and 22.5 kilo pounds per square inch (KSI) are reported to have better GRT 90% to 100% retention at 24 hours compared with other shapes.

Nature of meal: Feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release.

Caloric content: GRT can be increased by 4 to 10 hours with a meal that is high in proteins and fats.


10

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. Concomitant drug administration: Anticholinergics like atropine and

propantheline, opiates like codeine and prokinetic agents like metoclopramide and cisapride.

Biological factors: Diabetes and Crohn’s disease.


11APPROACHES TO GASTRIC RETENTION

• High-density systems. (HDS)

• Floating systems. (FS)

• Swelling and expanding systems. (SS)

• Mucoadhesive & Bioadhesive systems. (AS)


12ClassificationG

RD

DS

APP

RO

AC

HE

S

HIGH DENSITY SYSTEMS

FLOATING SYSTEMS

HYDRODYNAMICALLY 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 SYSTEMMATRIX TABLETS

RAFT-FORMING SYSTEMS

HOLLOW MICROSPHERES

ALGINATE BEADS

SUPER POROUS HYDROGELS

EXPANDING SYSTEMS

SWELLING SYSTEMS

UNFOLDABLE SYSTEMSBIO/

MUCOADHESIVE SYSTEM

MAGNETIC SYSTEMS Smt.B.N.B.Swaminarayan Pharmacy College, Salvav ,Vapi.

13HIGH DENSITY SYSTEM• 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.


14FLOATING DRUG DELIVERY

These have a bulk density lower than the gastric content. They remain float 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 systemsRaft-forming systems Low-density systems


15HYDRODYNAMICALLY BALANCED SYSYTEMS

Prepared by incorporating a high level(20-75%w/w) gel-forming hydrocolloids. E.g.:- Hydoxyethylcellulose, hydroxypropylcellulose, HPMC & Sod. CMC into the formulation and then compressing these granules into a tablets or capsules.

It maintains the bulk density less than 1.


16GAS 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 CO2 , are usually incorporated in the dosage form, thus reducing the density of the system and making it float on the media.


17MATRIX TABLETS

Single layer matrix tablet is prepared by incorporating bicarbonates in matrix forming hydrocolloid gelling agent like HPMC, chitosin, 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.


18INFLATABLE 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.


19INTRAGASTRIC 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.

Consists of 2 compartments:• Drug reservoir • Osmotically active compartment.


20MICRO POROUS RESERVOIR SYSTEM

System can be float by flotation chamber, which may be vacuum or filled with air or a harmless gas

This device comprised of a drug reservoir encapsulated in microporous compartment having pores on its surface.

A floating chamber was attached at one surface which gives buoyancy to entire device. Drug is slowly dissolves out via micro pores.


21RAFT 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.

This raft floats on gastric fluids because of a low density created by the formation of CO2. Usually this contains a gel-forming agent and alkaline bicarbonates or carbonates responsible for the formation of CO2 to make the system less dense to float on the gastric fluids.


22HOLLOW MICROSPHERES Hollow (porous) microsphere using polymers like polycarbonates have been

prepared using solvent evaporation technique. After preparation of microsphere, organic solvent evaporates from it creating holes inside microsphere. A high (50%) drug loading can be achieved.

Polymers used commonly: Polycarbonates, Cellulose acetate, Calcium alginate, Eudragit S, agar and methoxylated pectin etc.


23ALGINATE BEADS

• Prepared by dropping sodium alginate solution into aqueous solution of calcium chloride, causing the precipitation of calcium alginate

• Freeze dry in liquid nitrogen at -40oc for 24h.

• Beads-spherical and 2.5 mm in diameter.

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 material, and Ac-Di-Sol (crosscarmellose).


SUPERPOROUS HYDROGELS

24 EXPANDABLE SYSTEMS

1.UNFOLDED SYSTEMS 2.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.


• Unfolding systems are systems which are actually of larger size but they are folded to decrease size and kept in capsules. In stomach these systems comes out of capsules and unfolds to larger size.

• The important factor for unfolding system is shape memory. They should have sufficient shape memory such that they retain their unfolded (expanded) shape in stomach against gastric motility and not get folded again and escape out till the desired time interval.

MUCOADHESIVE SYSTEMS • 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) (Carbopol®, polycarbophil), chitosin, Gantrez® (Polymethyl vinyl ether/maleic anhydride copolymers), cholestyramine, tragacanth, sodium alginate


25

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.


26

27EVALUATION

A) IN-VITRO EVALUATION i) Floating systems a) Buoyancy Lag Time It is determined in order to assess the time taken by the dosage form to

float on the top of the dissolution medium, after it is placed in the medium. These parameters can be measured as a part of the dissolution test.

b) Floating Time Test for buoyancy is usually performed in SGF-Simulated Gastric Fluid

maintained at 370C. The time for which the dosage form continuously floats on the dissolution media is termed as floating time.

c) Specific Gravity / Density Density can be determined by the displacement method using Benzene as

displacement medium.


28 ii) Swelling systems a) Swelling Index After immersion of swelling dosage form into SGF at 370C, dosage form is

removed out at regular interval and dimensional changes are measured in terms of increase in tablet thickness / diameter with time.

b) Water Uptake It is an indirect measurement of swelling property of swellable matrix. Here

dosage form is removed out at regular interval and weight changes are determined with respect to time. So it is also termed as Weight Gain.

Tablet Water uptake = WU = (Wt – Wo) * 100 / Wo Where, Wt = weight of dosage form at time t Wo = initial weight of dosage form While we remove dosage form out and measure dimensions, the outer gel

layer is disturbed which can create a problem. So new idea came into picture by which swelling index and water uptake can be measured without disturbing tablet.


29 B) IN-VITRO DISSOLUTION TESTS A. In vitro dissolution test is generally done by using USP apparatus with paddle and

GRDDS is placed normally as for other conventional tablets. But sometimes as the vessel is large and paddles are at bottom, there is much lesser paddle force acts on floating dosage form which generally floats on surface. As floating dosage form not rotates may not give proper result and also not reproducible results. Similar problem occur with swellable dosage form, as they are hydrogel may stick to surface of vessel or paddle and gives irreproducible results.

In order to prevent such problems, various types of modification in dissolution assembly made are as follows.

B. To prevent sticking at vessel or paddle and to improve movement of dosage form, method suggested is to keep paddle at surface and not too deep inside dissolution medium.

C. Floating unit can be made fully submerged, by attaching some small, loose, non- reacting material, such as few turns of wire helix, around dosage form. However this method can inhibit three dimensional swelling of some dosage form and also affects drug release.

D. Other modification is to make floating unit fully submerged under ring or mesh assembly and paddle is just over ring that gives better force for movement of unit.

E. Other method suggests placing dosage form between 2 ring/meshes.


30


31 F. In previous methods unit have very small area, which can inhibit 3D swelling of swellable units, another method suggest the change in dissolution vessel that is indented at some above place from bottom and mesh is place on indented protrusions, this gives more area for dosage form.

G. Inspite of the various modifications done to get the reproducible results, none of them showed co-relation with the in-vivo conditions. So a novel dissolution test apparatus with modification of Rossett-Rice test Apparatus was proposed.

Rossett-Rice test is used for predicting in-vitro evaluation of directly acting antacid (action by chemical neutralization of acid), where HCl is added gradually to mimic the secretion rate of acid from the stomach.

In this modified apparatus as shown in figure, it has side arm from bottom of beaker such that it maintains volume of 70ml in beaker and fresh SGF is added from burette at 2 ml/min rate. Thus sink condition is maintained

along with easy sampling. Stirring is done by magnetic stirrer at 70-75 RPM. Thus this apparatus mimics in-vivo condition for GRDDS.


32 C) IN-VIVO EVALUATION a) Radiology X-ray is widely used for examination of internal body systems.. Barium Sulphate is widely used Radio Opaque

Marker. So, BaSO4 is incorporated inside dosage form and X-ray images are taken at various intervals to view GR. b) -Scintilography Similar to X-ray, -emitting materials are incorporated into dosage form and then images are taken by

scintigraphy. Widely used -emitting material is 99Tc. c) Gastroscopy Gastroscopy is peroral endoscopy used with fiber optics or video systems. Gastroscopy is used to inspect visually

the effect of prolongation in stomach. It can also give the detailed evaluation of GRDDS. d) Magnetic Marker Monitoring In this technique, dosage form is magnetically marked with incorporating iron powder inside, and images can be

taken by very sensitive bio-magnetic measurement equipment. Advantage of this method is that it is radiation less and so not hazardous.

e) Ultrasonography Used sometimes, not used generally because it is not traceable at intestine. f) 13C Octanoic Acid Breath Test 13C Octanoic acid is incorporated into GRDDS. In stomach due to chemical reaction, octanoic acid liberates CO2

gas which comes out in breath. The important Carbon atom which will come in CO2 is replaced with 13C isotope. So time upto which 13CO2 gas is observed in breath can be considered as gastric retention time of dosage form. As the dosage form moves to intestine, there is no reaction and no CO2 release. So this method is cheaper than other.

Smt.B.N.B.Swam

inarayan Pharmacy College, Salvav

,Vapi.

33Commonly used drugs in formulation of

gastroretentive dosages forms Floating tablets

Floating capsules

Floating microspheres

Floating granules

Powders Films

Acetaminophen, Acetylsalicylic acid, Ampicillin, Amoxicillin trihydrate, Atenolol, Captopril. Chlorpheniramine maleate, Cipro. Diltiazem, Fluorouracil, Isosorbide dinitrate and mononitrate, PABA, Prednisolone,

Theophylline, Verapamil Diazepam, Furosemide, L-DOPA Nicardipine, Misoprostol, Propranolol,

Aspirin, Griseofulvin, p-nitro aniline, Ibuprofen, Terfenadine Diclofenac sodium, Indomethacin, Prednisolone Several basic drugs Cinnerzine

Marketed Products of GRDDSBrand name Delivery system Drug (dose) Company

nameValrelease® 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), MgCarbonate (358 mg)

GlaxoSmithkline,India

Topalkan® Floating liquid alginatePreparation

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


34

Smt.B.N.B.Swam


,Vapi.

35OTHE APPROCHES FOR FLOATING SYSTEMS

CLASSIFICATION OF THE FLOATING SYSTEMS:

i) Non-effervescent systems Single unit Multiple units ii) Effervescent systems Single unit Multiple units

Smt.B.N.B.Swam


,Vapi.

36NON EFFERVESENT SINGLE UNIT SYSTEMS a) Floating tablet It’s a matrix tablet with single layered or bi-layered. Matrix tablet were prepared by incorporating gel forming

hydrocolloids like HPMC, which the most commonly used polymer for floating. Out of various grades of HPMC, low viscosity grade are use for floating purpose. Mixture of alginate and HPMC also prepared for floating tablet.

BILAYER CAPSULE Capsule is filled with non compressed bilayer formulation. One layer

is drug releasing layer and other is floating layer. Both the layer consists of hydrocolloid gelling layer such as HPMC, gums, polysaccharides and gelatin

37MULTIPLE UNIT ALGINATE BEADS WITH AIR

COMPARTMENT These are also calcium alginate beads but the

difference is that the calcium alginate core is separated by air compartment from a coating membrane calcium alginate or mixture of calcium alginate and PVA.

During the preparation of calcium alginate beads before drying process the beads are coated with the coating solution which may be calcium alginate or mixture of calcium alginate and PVA, and then they are dried.

38OIL ENTRAPPED GEL BEADS

Vegetable oil is use as floating carrier as they are light weight and hydrophobic used for floating by incorporating it into gel matrix of beads. Oil entrapped beads are prepared by both calcium alginate bead and calcium pectinate beads. Pectin has some emulsification property, so aqueous solution of pectin is mix edible oil. Emulsion is obtained by homogenization. And this emulsion is extruded into calcium chloride solution to form beads which are separated, washed and dried.

39MICROBALLOON

Microballoons are the hollow microspheres which are completely hollow from inside forming cavity inside and drug loaded in their outer shells are prepared by an emulsion solvent diffusion method. Organic phase of drug and polymer in ethanol/dichloromethane is poured on to aqueous solution of PVA maintained at 40oC. So gas phase of organic solvent is generated in dispersed polymer droplet, goes out by creating internal cavity which is responsible for floating

40Floating powder

Floating powder which can be filled in capsule or compress to tablet was made up of drug, pH dependent polymer - which was a water soluble salt of alginic acid (such as a sodium or potassium alginate) and a pH independent hydrocolloid gelling agent (such as HPMC, HPC, MC) and binder.

Smt.B.N.B.Swam


,Vapi.

41QUESTIONS…. WHAT IS GRDDS ? HOW IT CAN BE ACHIVED ? WRITE A NOTE ON FDDS? ADVANTAGES OF GRDDS? FORMULATION OF FLOATING MICROSPHERE? EXPLAIN HIGH DENSITY APPROCH? DESCRIBE EFFERVESENT BASED FLOATING DRUG DELIVARY SYSTEM. IN-

VITRO EVALUATION OF GRDDS? DESCRIBE CONCEPT OF GRDDS. MENTION DIFFERENT APPROCHES TO GET

GESTRORETNTION AND DESCRIBE ANY ONE APPROCH. DISCUSS THE CONCEPT OF IN-VITRO DISSOLUTION.STUDY FOR FLOATING

DRUG DELIVARY SYSTEM. ENUMERATE ON NON-EFFERVESENT TYPE OF SINGLE & MULTIPLE FLOATING

GDDS. DESCRIBE FORMULATION ASPECTS ,EXCIPIENTS USED IN MFG &

EVALUTION PARAMETER OF EFFERVESENT ANTACID GRANULES. VARIOUS MECHANISM FOR FLOATING FORMULATION.

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