gastroretentive drug delivery systems 1/59. contents 2/59 introduction approaches evaluation...
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GASTRORETENTIVE DRUG DELIVERY SYSTEMS
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CONTENTS
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• INTRODUCTION• APPROACHES• EVALUATION• CONCLUSION• REFERENCES
INTRODUCTION
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• The control of gastrointestinal transit of orally administered dosage forms using gastroretentive drug delivery systems (GRDDS) can improve the bioavailability of drugs that exhibit site-specific absorption.
To overcome physiological adversities, such as short gastric residence times (GRT) and unpredictable gastric emptying times (GET).
This dosage forms will be very much useful to deliver ‘narrow absorption window’ drugs.
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• Need for gastroretentive drug delivery system
• A controlled drug delivery system with prolonged residence time in the stomach is of particular interest for drugs
Are locally active in the stomach (misoprostol, antacids antibiotics against H.pylori).
Have an absorption window in stomach or in the upper small intestine (L-dopa, P-aminobenzoic acid, furosemide).
Are unstable in the intestine or colonic environment (captopril).
Exhibit low solubility at high pH values (diazepam, verapamil).
Alter normal flora of the colon (antibiotics). Absorbed by transporter mechanism (paclitaxel).
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• Advantages
• Improved drug absorption, because of increased GRT and more time spent by the dosage form at its absorption site.
• Controlled delivery of drugs.
• Delivery of drugs for local action in the stomach.
• Minimizing mucosal irritation by drugs, by drug releasing slowly at a controlled rate.
• Treatment of gastrointestinal disorders such as gastro-esophageal reflux.
• Ease of administration and better patient compliance.
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• Gastric emptying
• The process of gastric emptying occurs both during fasting and fed state.
• In fasted state, the process of gastric emptying is characterized by an interdigestive motility pattern that is commonly called migrating motor complex (MMC).
• This is a series of events that cycle through the stomach and small intestine every 1.2 to 2hrs.
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• In the fed state, the gastric emptying rate is slowed down because the onset of MMC is delayed, i.e., the feeding state results in a lag time prior to onset of gastric emptying.
FACTORS CONTROLLING THE GASTRIC RETENTION TIME OF DOSAGE FORM
• Density of dosage form.• Size of dosage form.• Food intake and nature of food.• Effects of gender, posture, and age.
APPROACHES
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• High density system• Floating systems• Expandable systems• Superporous hydrogels• Mucoadhesive or bioadhesive systems• Magnetic systems
High density systems
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Gastric contents have a density close to water (~1.004).
A density close to 2.5g cm-3 is necessary for significant prolongation of gastric residence time.
The commonly used excipients in high density system includes barium sulphate, zinc oxide, iron powder, and titanium dioxide.
The major drawback with such systems is that it is technically difficult to manufacture them with a large amount of drug (>50%) and to achieve the required density of 2.4-2.8g/cm3.
Floating Systems
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• Single-unit floating dosage system1. Noneffervescent systems
2. Effervescent (gas-generating) systems
• Multiple-unit floating dosage system1. Noneffervescent systems2. Effervescent (gas-generating) systems3. Hollow microspheres
• Raft-forming systems
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• Single-Unit Floating Dosage System
• Noneffervescent Systems
These systems contain one or more hydrocolloids and are made into a single unit along with drug and other additives.
When coming in contact with water, the hydrocolloids at the surface of the system swell and facilitate floating.
The coating forms a viscous barrier, and the inner polymer slowly gets hydrated as well, facilitating the controlled drug release. Such systems are called “hydrodynamically balanced systems (HBS)”.
The polymers used in this system includes hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, agar, carrageenans, and alginic acid.
Hydrodynamically balanced system
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A.1 – FLOATING – NON EFFERVESCENT
MONOLITHIC SYSTEMS
MATRIX TABLET
Single Layer Tablet Bilayer Tablet
Loading Dose
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A.1 – FLOATING – NON EFFERVESCENT
MONOLITHIC SYSTEMS
TABLET with AGAR & MINERAL OIL
Drug +Mineral Oil
mix
Pour inTablet Mold
Cool
Warm AgarGel Solution
2% Agar per Tablet
Air Entrapped in Agar gel
Escape of Air – prevent by OIL
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Polypropylene Foam
Hydrophobic Powder
Open-cell Structure
Highly Porous
Low Inherent Density
TABLET with FOAM
Glyceryl Monooleate
Swells in Water
Converted to Liquid Crystals - Cubic Shape
Melted And Molded
TABLET with LIPID
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TABLETS IN CYLINDER
A I R
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polypropylene
The device consisting of two drug-loaded HPMC matrix tablets, which are placed within an impermeable, hollow polypropylene cylinder (open at both ends). Each matrix tablet closed one of the cylinder’s ends so that an air-filled space was created in between, providing a low total system density. The device remained floating until at least one of the tablets is dissolved.
HPMC matrix tablets
HPMC matrix tablets
MICROPOROUSRESERVIOR
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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
A.1 – FLOATING – NON EFFERVESCENT
MULTIPLE UNITS
CALCIUM ALGINATE/PECTINATE BEADS
Sodium Alginate Solution
Add
to
Calcium Chloride Solution
Spherical Gel
Beads
Separate,Freeze Dried (-
40oC)
IONOTROPIC GELATION METHOD
Calcium Pectinate Gel Beads
Calcium-Alginate-Pectinate Gel Beads
Calcium Alginate + Chitosan Gel Beads18/59
ALGINATE BEADS withAIR COMPARTMENT
Alginate Beadin Solution,
before Drying
Coating before Drying
After Drying Shrinkage of Bead
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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
A.1 – FLOATING – NON EFFERVESCENT
MULTIPLE UNITS
OIL ENTRAPPED GEL BEADS
Oil – Light weight and Hydrophobic
Pectin has some Emulsification propertyAqueous
Solution ofPectin
mixEmulsion
EdibleVeg. OIL
Add
to
Calcium Chloride Solution
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A.1 – FLOATING – NON EFFERVESCENT
MULTIPLE UNITS
CASEIN – GELATIN BEADS
Casein has Emulsification property- Entraps Air Bubbles
Casein GelatinSolution (60oC)
mixEmulsion
PreheatedMineral Oil
RapidCooling
Add to CooledAcetone
Separatedand
Dried
At Reduced Pressure – NO AIR – Non Floating Beads
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HOLLOWMICROSPHERE
MICROBALLOON
MULTIPLE UNITS
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Mechanism of formation of microballoon
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A.1 – FLOATING – NON EFFERVESCENT
MULTIPLE UNITS
FOAM Containing MICROPARTICLES
Drug,Polymer
FOAM
OrganicSolvent
Dissolved
Dispersed
Add
to
AqueousPVA
Solution
Solvent Evaporation Method
OnlyFOAM
FOAMMicroparticle
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A.1 – FLOATING – NON EFFERVESCENT
MULTIPLE UNITS
CALCIUM SILICATEAs FLOATING CARRIER
GELUCIRE® GRANULES
Highly Porous
Large Pore Volume
Low Inherent Density
Granules DrugHPMCCa-Silicate
Hydrophobic Lipid
Diff. Grades – 39/01 43/01
Low Inherent Density
Granulation
SR of Highly Soluble Drug
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• Gas-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.
• An alternative is incorporation of matrix containing portions of liquid, which produce gas that evaporates at body temperature.
The main drawback of single unit dosage systems are high variability of gastrointestinal transit time when orally administered because of all-or-nothing nature of their gastric emptying.
A.2 – FLOATING – EFFERVESCENT
MONOLITHIC SYSTEM
MATRIX TABLETMATRIX TABLETwith CARBOPOL
Bicarbonate + Polymer
Single Layer Tablet
Bilayer Tablet
Triple Layer Tablet
pH dependent Gelling
Only Carbopol - NO GELLING
Bicarbonate + Carbopol- GELLING
due to Alkaline MICROENVIRONMENT
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Triple-layer system
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• Multiple-Unit Floating Systems
• Hollow Microspheres
• Hollow microspheres possess the unique advantages of multiple-unit systems and better floating properties as a result of the central hollow space inside the microsphere.
• The general techniques involved in their preparation include simple solvent evaporation and solvent diffusion and evaporation.
• The drug release and better floating properties mainly depend on the type of polymer, plasticizer, and solvent employed for the preparation.
• Polymers such as polycarbonate, Eudragit S, and cellulose acetate were used in the preparation of hollow microspheres.
A.2 – FLOATING – EFFERVESCENT
MULTIPLE UNITS
POROUS ALGINATE BEADS
Na-Alginate Solution
mix
CaCl2Solution
NaHCO3
AceticAcid
- Simultaneous Generation of CO2 & Gelling of Beads
- Escape of CO2 creates Pores in Beads
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A.2 – FLOATING – EFFERVESCENT
MULTIPLE UNITS
FLOATING PILLS
DRUG
NaHCO3
Tartaric Acid
Swellable Polymer
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A.2 – FLOATING – EFFERVESCENT
MULTIPLE UNITS
ION EXCHANGE RESIN BEADS
ResinHCO3
HCO3
HCO3
DRUG
DRUG
H+ Cl
H+ Cl
H+ ClH+ Cl
H+ Cl
Uncoated Beads – No Floating – Escape of CO232/59
This system consists of mainly two different part attached with each other, one is floating part and other is osmotic controlled part
Floating part made up of deformable polymeric bag containing liquid that gasify at body temperature.Osmotic pressure controlling part consists of two part, drug reservoir & osmotically active compartment.
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Osmotically controlled DDS
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• Raft-Forming Systems
• 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, wherein each portion of the liquid swells, forming a continuous layer called raft.
• This raft floats in gastric fluids because of the low bulk density created by the formation of CO2.
• Usually the system contains a gel-forming agent and alkaline bicarbonates or carbonates responsible for the formation of CO2 to make the system less dense and more apt to float on the gastric fluids.
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• Expandable systems
• These systems include Unfoldable and Swellable systems.
• Unfoldable systems are made of biodegradable polymers. The concept is to make a carrier, such as a capsule, incorporating a compressed system which extends in the stomach.
• Swellable systems are retained because of their mechanical properties. The swelling is usually results from osmotic absorption of water.
• The dosage form is small enough to be swallowed, and swells in gastric liquids. The bulk enables gastric retention and maintain the stomach in fed state, suppressing housekeeper waves.
• The whole system is coated by an elastic outer polymeric membrane which was permeable to both drug and body fluids and could control the drug release.
• The device gradually decreases in volume and rigidity as a result depletion of drug and expanding agent and/or bioreosion of polymer layer, enabling its elimination.
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Different geometric forms of unfoldable systems
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• Prior to administration(A) Drug reservoir (B) Swellable expanding agent (C) and the whole enclosed by elastic outer polymeric envelope. Post administration Pressure of the expanding agent (B) swells the elastic polymer (C). Drug is released from the dosage form through the elastic polymeric envelope (C) as indicated by the arrow
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• Superporous hydrogels
• Swellable agents with pore size ranging between 10nm and 10µm, absorption of water by conventional hydrogel is very slow process and several hours may be needed to reach as equilibrium state during which premature evacuation of the dosage form may occur.
• Superporous hydrogels swell to equilibrium size with in a minute, due to rapid water uptake by capillary wetting through numerous interconnected open pores.
• They swell to large size and are intended to have sufficient mechanical strength to withstand pressure by the gastric contraction.
• This is achieved by co-formulation of a hydrophilic particulate material, Ac-Di-Sol.
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• Mucoadhesive or bioadhedive system
• The technique involves coating of microcapsules with bioadhesive polymer, which enables them to adhere to intestinal mucosa and remain for longer time period in the GI while the active drug is released from the device matrix.
• The cationic chitosan polymers are pharmaceutically acceptable to be used in the preparation of bioadhesive formulations owing to their known ability to bind well to gastric mucosa.
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• Magnetic systems
• This system is based on a simple idea: the dosage form contains a small internal magnet, and a magnet placed on the abdomen over the position of the stomach.
• Although these systems seem to work, the external magnet must be positioned with a degree of precision that might compromise patient compliance.
EVALUATION OF GRDDS
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• For Single Unit Dosage Forms (ex: tablets) (i)Floating lag time: It is the time taken by the tablet to emerge
onto the surface of dissolution medium and is expressed in seconds or minutes.
(ii) Invitro drug release and duration of floating: This is determined by using USP II apparatus (paddle) stirring at a speed of 50 or 100 rpm at 37 ± 0.2 °c in simulated gastric fluid (pH 1.2 without pepsin). Aliquots of the samples are collected and analysed for the drug content. The time (hrs) for which the tablets remain buoyant on the surface of the dissolution medium is the duration of floating and is visually observed.
(iii) In vivo evaluation for gastro-retention: This is carried out by means of X-ray or Gamma scintigraphic monitoring of the dosage form transition in the GIT. The tablets are also evaluated for hardness, weight variation, etc.
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For swelling system
1)Swelling Index
2)Water Uptake / Weight Gain
3)Penetration Rate
WU = (Wt – Wo) * 100 / Wo
PR = Water UptakePer Unit TimeX
2 r2
Water Density
Wilhemy’s plate technique
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For mucoadhesive
This involves the use of a microtensiometer and a microforce balance and is specific, yielding both contact sngle and surface tension. The mucous membrane is placed in a small mobile chamber with both pH and physiological temperature controlled. A unique microsphere is attached by a thread to the stationary microbalance. The chamber with the mucous membrane is raised until it comes into contact with the microsphere and, after contact time, is lowered back to the initial position
B. For Multiple Unit Dosage Forms (ex: microspheres)
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Apart from the In vitro release, duration of floating and in vivo gastro-retention tests, the multiple unit dosage forms are also evaluated for – (i) Morphological and dimensional analysis with the aid of scanning electron microscopy (SEM). The size can also be measured using an optical microscope. (ii) % yield of microspheres: This is calculated from weight of microspheres obtained ×100 total weight of drug and polymer
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(iii)Entrapment efficiency: The drug is extracted by a suitable method, analysed and is calculated from
Practical amount of drug present ×100 Theoretical drug content (iv) In vitro floating ability (Buoyancy %): A known quantity of microspheres are spread over the
surface of a USP (Type II) dissolution apparatus filled with 900 ml of 0.1 N HCl containing 0.002% v/v Tween 80 and agitated at 100 rpm for 12 hours. After 12 hours, the loating and settled layers are seperated, dried in a dessicator and weighed. The buoyancy is calculated from the following formula.
Buoyancy (%) = Wf / ( Wf + Ws) * 100 where Wf and Ws are the weights of floating and settled
microspheres respectively.
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(v) Drug-excipient (DE) interactions: This is done
using FTIR. Appearance of a new peak, and/or disappearance of original drug or excipient
peak indicates the DE interaction.
Apart from the above mentioned evaluation parameters, granules (ex:Gelucire 43/01) are also evaluated for the effect of ageing with the help of Differential Scanning Calorimeter or Hot stage polarizing microscopy.
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• Methods to measure gastroretentivity of GRDFs
• Magnetic Resonance Imaging• It is a noninvasive technique and allow observation of total
anatomical structure in relatively high resolution. • The visualization of GI tract by MRI has to be further improved
by the administration of contrast media.• For solid DFs, the incorporation of a superparamagnetic
compound such as ferrous oxide enables their visualization by MRI.
• Radiology (X-Ray)• In this technique a radio-opaque material has to be
incorporated in the DF, and its location is tracked by X-ray picture.
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• ɣ-Scintigraphy
• Gamma scintigraphy relies on the administration of a DF containing a small amount of radioisotope, e.g.,152Sm,which is a gamma ray emitter with a relatively short half life.
• Gastroscopy
• Gastroscopy is commonly used for the diagnosis and monitoring of the GI tract.
• This technique utilizes a fiberoptic or video system and can be easily applied for monitoring and locating GRDFs in the stomach.
Ultrasonography
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In this technique, ultrasonic waves are reflected at substantially different acoustic impedances across an interface, enabling the imaging . By transmission of ultrasonic waves, the acoustic mismatch is traced out across the interface between dosage form and physiological surface. However, this method is not popular due to lack of ultrasound traceability at the intestine. Another drawback of this method is some of the dosage forms may not exhibit a sharp acoustic mismatch.
13 C octanoic acid breath test
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Octanoic acid is a medium chain fatty acid absorbed by the upper part of the small intestine, rapidly transported to the liver and immediately oxidised by mitochondria to form CO 2, which is exhaled out in the breath. In this method, 13 C octanoic acid is incorporated into the GRDDS.The carbon atom of octanoic acid which essentially forms CO 2 is replaced with the 13 C isotope. After ingestion of the dosage form, the time duration after which 13 CO 2 gas is observed in the breath indicates the transfer of the dosage form from the stomach to the upper part of the small intestine, which may be considered as the gastric retention time of the dosage form
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• LimitationsFloating system They require a sufficiently high level of fluids in
the stomach for the drug delivery buoyancy, to float therein and to work efficiently.
Drugs which are well absorbed along the entire GI tract and which undergoes significant first- pass metabolism, may not be desirable candidates for GRDDS since the slow gastric emptying may lead to reduced systemic bioavailability.
.
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Drugs Unstable in Stomach / Acidic pH Very Low Soluble / insoluble Causes irritation Adhesive High Turn Over Rate of MUCUS LAYER Thick Mucus Layer Presence of Soluble Mucin Swelling Exit before Swells – Slow Swelling Rate Capable to Resist House Keeper Waves
Recent work
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Formulation and Evaluation of an Oral Floating Tablet of Cephalexin
Indian J.Pharm. Educ. Res. 44(3), Jul-Sep, 2010
Development and Evaluation of Rosiglitazone
Maleate Floating Tablets using Natural Gums
International Journal of PharmTech Research July-Sept 2010
Development of Floating Drug Delivery System with Biphasic Release for Verapamil Hydrochloride: In vitro and In Vivo EvaluationJournal of Pharmaceutical Science and Technology Vol. 2 (11), 2010,361-367
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Formulation and Evaluation of Effervescent Floating Tablet of Famotidine
International Journal of PharmTech Research July-Sept 2009
Formulation and Evaluation of Glipizide Floating-
Bioadhesive Tablets Vol.53, n. 5: pp.1073-1085, September-
October 2010
Brand Name Drug (dose) Company
Madopar® Levodopa (100 mg), Benserazide (25 mg) Roche, USA
Valrelease® Diazepam (15 mg)Hoffman LaRoche, USA
Liquid Gaviscon® Al(OH)3 + MgCO3GlaxoSmithKlein, India
Topalkan® Liquid Al – Mg antacid
Pierre Fabre Drug, France
Almagate Flotcoat® Al – Mg antacid
Conviron® Ferrous sulfate Ranbaxy, India
Cifran OD® Ciprofloxacin (1 g) Ranbaxy, India
Cytotec® Misoprostal (100/200 g) Pharmacia, USA
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S.No Type of formulation Patent no . Ref
1 Gastro retentive dosage form
U.S-7,413,752 Devane et al., 2008.
2 Multiple unit floating dosage form
European patent (EP) 10697
Vanderbist et al., 2007
3 Bilayer tablet EP-002445 Lohray et al., 2004
4 Floating Tablet U.S-66,352279 Kolter et al., 2003.
5 3-layer tablet U.S-5780057 Conte et al., 1998
6 Floating capsules U.S-4126672 Sheth et al., 1978
7 Foams (or) hollow bodies U.S-5626876 Muller et al., 1997
REFERENCES
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• Bardonnet PL, Faivre V, Pugh WJ, Piffaretti JC, Falson F. Gatroretentive dosage forms: Overview and special case of Helicobacter pylori. J Control Release. 2006;111:1-18.
• Ecyclopedia of Pharmaceutical Technology.• Hari Vardhan Reddy L and Murthy RSR. Floating
Dosage Systems in Drug Delivery. Critical Revises in Therapeutic Drug Carrier Systems. 2002;19(6):553-585.
• Julan UD. Floating Drug Delivery Dystem: An Approach to Gastroretension. Latest Reviews. 2007;5(1).
• Shweta A, Javed A, Alka A, Roop K, and Sanjula B. Floating drug delivery systems: a review. AAPS PharmSciTech. 2005;6 (3) Article 47.
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• Rouge N, Buri P, Doelker E. Drug absorption sites in the gastrointestinal tract and dosage forms for site specific delivery. Int J Pharm. 1996; 136:117-139.
• Wilson C.G, Washington N., Physiological Pharmaceutics: Biological Barriers to Drug Absorption, Horwood Ellis, Chichester, 1989; 47-70.
• Groning R, Heun G. Oral dosage forms with controlled gastrointestinal transit. Drug Dev Ind Pharm. 1984; 10: 527-539.
• Deshpande A.A., Shah N.H., Rhodes C.T., Malick W., Development of a novel controlled release system for gastric retention, Pharm. Res. 1997; 14: 815-819.
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