Transcript Gastroretentive Drug Delivery System
GASTRORETENTIVE DRUG DELIVERY SYSTEMS
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CONTENTS
INTRODUCTION APPROACHES EVALUATION CONCLUSION REFERENCES 2/59
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INTRODUCTION
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 . 3/59
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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 p H 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.
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APPROACHES
High density system Floating systems Expandable systems Superporous hydrogels Mucoadhesive or bioadhesive systems Magnetic systems 8/59
High density systems
Gastric contents have a density close to water (~1.004).
A density close to 2.5g cm residence time.
-3 is necessary for significant prolongation of gastric 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/cm 3 .
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2.
Floating Systems
Single-unit floating dosage system
Noneffervescent systems Effervescent (gas-generating) systems • • 1.
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3.
Multiple-unit floating dosage system
Noneffervescent systems Effervescent (gas-generating) systems Hollow microspheres
Raft-forming systems
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Single-Unit Floating Dosage System
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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 .
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12/59 Hydrodynamically balanced system
A.1 – FLOATING – NON EFFERVESCENT MONOLITHIC SYSTEMS
MATRIX TABLET
Single Layer Tablet
Loading Dose
Bilayer Tablet
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A.1 – FLOATING – NON EFFERVESCENT MONOLITHIC SYSTEMS TABLET with AGAR & MINERAL OIL
Drug + Mineral Oil mix Warm Agar Gel Solution Pour in Tablet Mold Air Entrapped in Agar gel Escape of Air – prevent by OIL 2% Agar per Tablet Cool 14/59
TABLET with FOAM
Polypropylene Foam Hydrophobic Powder Open-cell Structure Highly Porous Low Inherent Density
TABLET with LIPID Glyceryl Monooleate
Swells in Water Converted to Liquid Crystals - Cubic Shape
Melted And Molded
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TABLETS IN CYLINDER
HPMC matrix tablets polypropylene A I R HPMC matrix tablets
The two matrix device consisting drug-loaded of HPMC tablets, which are placed impermeable, within an hollow polypropylene cylinder (open at both ends). Each matrix tablet closed one of the cylinder’s ends so that an air filled space was between, providing created in a low total device system density. The remained
floating until at least one of the tablets is dissolved.
MICROPOROUS RESERVIOR
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 17/59
A.1 – FLOATING – NON EFFERVESCENT MULTIPLE UNITS CALCIUM ALGINATE/PECTINATE BEADS
IONOTROPIC GELATION METHOD
Sodium Alginate Solution Add to Calcium Chloride Solution Spherical Gel Beads Separate, Freeze Dried ( 40 o C) Calcium Pectinate Gel Beads Calcium-Alginate-Pectinate Gel Beads Calcium Alginate + Chitosan Gel Beads 18/59
ALGINATE BEADS with AIR COMPARTMENT
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
Alginate Bead in Solution, before Drying
19/59 Coating before Drying After Drying Shrinkage of Bead
A.1 – FLOATING – NON EFFERVESCENT MULTIPLE UNITS OIL ENTRAPPED GEL BEADS
Oil – Light weight and Hydrophobic Pectin has some Emulsification property Aqueous Solution of Pectin Edible Veg. OIL mix Emulsion Add to Calcium Chloride Solution 20/59
A.1 – FLOATING – NON EFFERVESCENT MULTIPLE UNITS CASEIN – GELATIN BEADS
Casein has Emulsification property- Entraps Air Bubbles
Casein Gelatin Solution (60 o C) mix
Rapid Cooling Emulsion Add to Cooled Acetone
Preheated Mineral Oil At Reduced Pressure – NO AIR – Non Floating Beads 21/59
Separated and Dried
MULTIPLE UNITS HOLLOW MICROSPHERE MICROBALLOON
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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
Dissolved
Solvent Evaporation Method
Organic Solvent
Add to Dispersed
Aqueous PVA Solution
Only FOAM FOAM Microparticle
FOAM
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A.1 – FLOATING – NON EFFERVESCENT MULTIPLE UNITS
CALCIUM SILICATE As FLOATING CARRIER GELUCIRE ® GRANULES
Highly Porous Large Pore Volume Low Inherent Density Granules Drug HPMC Ca-Silicate 25/59 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 CO 2 , 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.
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A.2 – FLOATING – EFFERVESCENT MONOLITHIC SYSTEM MATRIX TABLET MATRIX TABLET with 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 27/59
Triple-layer system
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Multiple-Unit Floating Systems
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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.
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A.2 – FLOATING – EFFERVESCENT MULTIPLE UNITS POROUS ALGINATE BEADS
NaHCO 3 Na-Alginate Solution CaCl 2 Solution mix - Simultaneous Generation of CO 2 & Gelling of Beads - Escape of CO 2 creates Pores in Beads 30/59 Acetic Acid
A.2 – FLOATING – EFFERVESCENT MULTIPLE UNITS FLOATING PILLS
NaHCO 3 Tartaric Acid
DRUG
Swellable Polymer 31/59
A.2 – FLOATING – EFFERVESCENT MULTIPLE UNITS ION EXCHANGE RESIN BEADS
H + Cl H + Cl HCO 3 HCO 3 Resin HCO 3 H H + Cl H + Cl Uncoated Beads – No Floating – Escape of CO 2 32/59 + Cl
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Osmotically controlled DDS
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 liquid that up deformable polymeric bag containing gasify at of body temperature.Osmotic
controlling part consists active compartment.
pressure of two part, drug reservoir & osmotically
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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 CO 2 . Usually the system contains a gel-forming agent and alkaline bicarbonates or carbonates responsible for the formation of CO fluids.
2 to make the system less dense and more apt to float on the gastric 34/59
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Expandable systems
These systems include Unfoldable and Swellable systems.
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36/59 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. 38/59
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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. 39/59
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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.
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EVALUATION OF GRDDS
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
variation, etc.
: 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 41/59
For swelling system 1)Swelling Index 2)Water Uptake / Weight Gain WU = (Wt – Wo) * 100 / Wo 3)Penetration Rate PR = Water Uptake Per Unit TimeX 2
r 2 Water Density
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For mucoadhesive Wilhemy’s plate technique
This involves microtensiometer the and use a of 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 43/59
B. For Multiple Unit Dosage Forms (ex: microspheres)
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
aid of scanning electron microscopy (SEM). The with 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 44/59
(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
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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.
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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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-Scintigraphy
• Gamma scintigraphy relies on the administration of a DF containing a small amount of radioisotope, e.g., 152 Sm,which is a gamma ray emitter with a relatively short half life .
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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.
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Ultrasonography
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.
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13 C octanoic acid breath test
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 50/59
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Limitations
Floating 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. . 51/59
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 52/59
Recent work
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 Evaluation
Journal of Pharmaceutical Science and Technology Vol. 2 (11), 2010,361-367 53/59
Formulation and Evaluation of Effervescent Floating Tablet of Famotidine International Journal of PharmTech Research July-Sept 2009
Formulation and Evaluation of Glipizide Floating BioadhesiveTablets
Vol.53, n. 5: pp.1073-1085, September-October 2010 54/59
Brand Name
Madopar ® Valrelease Liquid Gaviscon ® Topalkan Almagate Flotcoat Cytotec ® 55/59 ® ® ® Conviron ® Cifran OD ® Liquid
Drug (dose)
Levodopa (100 mg), Benserazide (25 mg) Diazepam (15 mg) Al(OH) 3 + MgCO Al – Mg antacid 3
Company
Roche, USA Hoffman LaRoche, USA GlaxoSmithKlein, India Pierre Fabre Drug, France Al – Mg antacid Ferrous sulfate Ciprofloxacin (1 g) Ranbaxy, India Ranbaxy, India Misoprostal (100/200 g) Pharmacia, USA
3 6 7 4 5 56/59
S.No
1
Type of formulation
Gastro retentive dosage form 2 Multiple unit floating dosage form Bilayer tablet Floating Tablet 3-layer tablet Floating capsules Foams (or) hollow bodies
Patent no
U.S-7,413,752 European patent (EP) 10697 EP-002445 U.S-66,352279 U.S-5780057 U.S-4126672 U.S-5626876
. Ref
Devane et al., 2008.
Vanderbist et al., 2007 Lohray et al., 2004 Kolter et al., 2003.
Conte et al., 1998 Sheth et al., 1978 Muller et al., 1997
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REFERENCES
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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