Hajare and Rachh, IJPSR, 2020; Vol. 11(3): 1075-1083.

E-ISSN: 0975-8232; P-ISSN: 2320-5148

IJPSR (2020), Volume 11, Issue 3 (Review Article)

Received on 14 June 2019; received in revised form, 30 September 2019; accepted, 03 February 2020; published 01 March 2020

GASTRORETENTIVE MICROBALLOONS: A NOVEL APPROACH FOR DRUG DELIVERY

Pranit P. Hajare * 1 and Punit R. Rachh 2
Department of Pharmaceutics 1, Dr. Vithalrao Vikhe Patil College of Pharmacy, Vilad Ghat, Ahmednagar -
414111, Maharashtra, India.
Department of Pharmaceutical Sciences 2, Bhagwant University, Ajmer - 305004, Rajasthan, India.
Keywords: ABSTRACT: Hollow microballoons (microspheres) are spherical empty
Floating microballoons, Gastro- particles without core. Microballoons (Hollow microsphere) are a drug
retentive drug delivery system, delivery system that promises to be a potential approach for gastric
Characterizations and formulation retention. Microballoons drug-delivery systems are based on a non-
aspects effervescent system containing empty particles of spherical shape without
Correspondence to Author: core ideally having a size less than 200 micrometers. Microballoons drug
Pranit P. Hajare delivery systems have shown to be of better significance in controlling
Assistant Professor, the release rate for drugs having site-specific absorption. The floating
Department of Pharmaceutics, microballoons showed gastro retentive controlled release delivery with
Dr. Vithalrao Vikhe Patil College of efficient means of enhancing the bioavailability and promises to be a
Pharmacy, Vilad Ghat, Ahmednagar -
potential approach for gastric retention. Optimized hollow microspheres
414111, Maharashtra, India.
will find the central place in novel drug delivery, particularly in safe,
E-mail: [email protected] targeted and effective in-vivo delivery promises to be a potential approach
for gastric retention. They are gastro retentive drug-delivery systems,
which provide controlled release properties. The advantages, limitations,
methods of preparation of hollow microsphere, applications, polymers
used in hollow microspheres, characterizations of microballoons and
formulation aspects with various evaluation techniques and marketed
products are covered in detail.
INTRODUCTION: Oral administration of drug is These microspheres are characteristically free-
most preferred type of route of drug administration flowing powders comprising of proteins or
1
. In-vivo performance of drug delivery systems can synthetic polymers, ideally having a size less than
be affected by gastric emptying and frequent 200 micrometers 6.
dosing of these drugs is required to achieve suitable To overcome the impact of gastric emptying a
therapeutic activity 2. Microballoons are gastro controlled drug delivery system with prolonged
retentive drug-delivery systems with the non- residence time in the stomach can be of importance
effervescent approach. Microballoons (Hollow for drugs with an absorption window in the upper
microsphere) are in a strict sense, empty particles small intestine 3. Gastro retentive drug delivery is
of spherical shape without a core. an approach to prolong gastric residence time,
QUICK RESPONSE CODE thereby targeting site-specific drug release in the
DOI:
10.13040/IJPSR.0975-8232.11(3).1075-83 upper gastrointestinal tract (GIT) for local or
systemic effects. Gastroretentive dosage forms can
remain in the gastric region for long periods and
This article can be accessed online on
www.ijpsr.com hence significantly prolong the gastric retention
time (GRT) of drugs. Floating Drug Delivery
DOI link: http://dx.doi.org/10.13040/IJPSR.0975-8232.11(3).1075-83 Systems (FDDS) or hydrodynamically balanced

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systems are among the several approaches that gastric contents, the drug is released slowly at a
have been developed in order to increase the gastric desired rate from the system. After the release of
residence time of dosage forms. FDDS is useful for the drug, the residual system is emptied from the
drugs acting locally in the proximal gastrointestinal stomach. This results in an increase in gastric
tract and it has a bulk density lower than gastric retention time and better control of fluctuations in
fluids and thus remains buoyant in the stomach for plasma drug concentrations. The systems are also
a prolonged period of time, without affecting the used for poorly soluble drugs or unstable in
gastric emptying rate. While the system floats on intestinal fluids 4.
TABLE 1: VARIOUS APPROACHES FOR GASTRORETENTIVE DRUG DELIVERY 39, 40, 41, 42
S. no. System Description
1 High density / sinking These systems formulated by coating the drug on a heavy core or mixing it with inert
system materials, density exhibited higher than the density of gastric content. GI transit time of pellets
can be enhanced by this method
2 Swelling system Systems which upon swallowing undergo swelling up to an extent which prevents their exit
from the pylorus. Due to this, the formulation can be retained for a prolonged period of time
3 Magnetic system In this type of dosage form, it comprises a smaller magnetic material and another magnet is
applied on the abdomen over the position of the stomach.
4 Bioadhesive / Gastric retention increased by adhering the bioadhesive system to the gastric mucosal
Mucoadhesive system membrane, thus improving the bioavailability
5 Expandable system A formulation could withstand the gastric emptying when it is larger in size than the pyloric
sphincter. For achieving this, three configurations are required: one for oral administration, an
expandable gastric form and a part enabling gastric evacuation following complete drug
release. Thus, gastro retention can be increased via a combination of substantial dimensions
with high rigidity of formulations and mechanical contractions of the stomach
6 Unfoldable system These systems when swallowed undergo unfolding and enlarge in size, remain lodged at
sphincter avoiding its exit from the stomach
7 Low density/ floating These systems are formulated with Less density than gastric fluids and so remain buoyant in
system the stomach without affecting gastric emptying rate flora prolonged period
a. Effervescent Comprises of the swellable polymers like chitosan, and effervescent agents like sodium
bicarbonate, disodium glycine carbonate, cytroglycine, citric acid, and tartaric acid
b. Non-effervescent Formulated using highly swellable or gel-forming cellulose type hydrocolloids, matrix-forming
polymers, and polysaccharides
c. Microporous In these formulations Drug reservoir encapsulated within the microporous compartment
containing pores. The floating chamber comprising entrapped air provides the delivery system
the ability to remain buoyant over the gastric content. The gastric fluid penetrates through the
aperture, dissolves the drug and carries the dissolved drug for absorption in the stomach and
upper part of the small intestine
d. Microballoons/hollow These systems when coming in contact with the gastric fluid, the gel formers
Microspheres (polysaccharides/polymers) hydrate to form a colloidal gel barrier that controls the rate of fluid
penetration into the microballoons and consequently the drug release. The air entrapped in
microballoon cavity confers buoyancy to the microparticles. However, minimal gastric content
is needed to maintain buoyancy
8 Ion-exchange resin In order to achieve gastroprotection, ion-exchange beads are treated with bicarbonate and the
system negatively charged drug is then bound to the resin. To prevent the loss of carbon dioxide, the
beads are entrapped in a semipermeable membrane. On oral administration, the exchange of
bicarbonate and chloride occurs in the stomach
9 Raft system Raft-forming system is one of the most extensively used systems due to the advantage of
prolonged and predictable drug delivery provided by this system. This system is effective in
releasing the drug in a sustained manner. Raft forming systems are hydrogels at room
temperature and undergo gelation on contact with body fluids or with a change in pH. The
main objective behind the development of this system is to minimize the dosing frequency and
to enhance the efficacy of drug via localization at the desired site of action

There are various approaches designed and systems, expandable, unfoldable and swellable
developed by various researchers like high density systems, super porous hydrogel systems and
(sinking) system or non- floating system, non- magnetic systems to achieve gastro retentive drug
effervescent systems, microballoons / hollow delivery 4, 5. Floating or hydrodynamically
microspheres, microporous compartment system, controlled drug delivery systems are useful and
bioadhesive or mucoadhesive drug delivery most popular in such applications. Various

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gastroretentive dosage forms are available, inner core. The drug and an enteric acrylic polymer
including tablets, capsules, pills, laminated films, mixture is dissolved in ethanol/dichloromethane
floating microballoons, granules and powders. solution and it is poured into an agitated solution of
Floating microballoons have been gaining attention Poly Vinyl Alcohol (PVA) that as thermally
due to the uniform distribution of these multiple- controlled at 40 ºC. After the formation of stable
unit dosage forms in the stomach, which results in emulsion, the organic solvent is evaporated from
more reproducible drug absorption and reduced risk the emulsion by increasing the temperature under
of local irritation. Such systems have more pressure or by continuous stirring. The gas phase is
advantages over the single-unit dosage forms. generated in the droplet of the dispersed polymer
by the evaporation of dichloromethane and thus
Microballoons are considered as one of the most formed the hollow internal cavity in the
favorable buoyant systems with the unique microsphere of the polymer with the drug.
advantages of multiple unit systems as well as The micro balloon continuously floats over the
better floating properties, because of central hollow surface of an acidic dissolution media containing
space inside the microsphere. The novel techniques surfactant for more than 12 h 7. Once formulated
involved in their preparation include simple solvent these microballoons are generally characterized for
evaporation method, emulsion-solvent diffusion its quality and efficacy by using different methods
method, single emulsion technique, double including, percentage yield, compatibility studies,
emulsion technique, phase separation coacervation micromeritic properties, in-vitro buoyancy,
technique, polymerization technique, spray drying scanning electron microscopy, in-vitro drug release
and spray congealing method and hot melt studies, data analysis of release studies, swelling
encapsulation method. The slow release of drugs at studies, in-vivo studies and entrapment efficiency
the desired rate and better-floating properties etc.
mainly depend on the type of polymer, plasticizer
and the solvents employed for the preparation. Mechanism of Drug Release: Microballoon
Polymers such as polylactic acid, Eudragit® S and comes in contact with gastric fluid the gel formers,
hydroxypropyl methylcellulose, cellulose acetate polysaccharides and polymers hydrate to form a
are used in the formulation of hollow microspheres, colloidal gel barrier that controls the rate of fluid
and the release of the drug can be modulated by penetration into the device and consequent drug
optimizing polymer concentration and the polymer release. As the exterior surface of the dosage form
-plasticizer ratio 5. dissolves, the gel layer is maintained by the
hydration of the adjacent hydrocolloid layer. The
Hollow microspheres / microballoons loaded with air trapped by the swollen polymer lowers the
the drug in their outer polymer shell are prepared density and confers buoyancy to the microspheres/
by a novel method such as solvent evaporation or microballoon.
solvent diffusion/evaporation to create a hollow
TABLE 2: EXAMPLE OF VARIOUS AGENTS USED FOR FORMULATION OF MICROBALLOON
Drugs as Microballoon Polymers Solvents Processing Surfactant Cross linking
formulation Medium agents
Nizatidine 8 Cellulose acetate, Ethanol, Paraffin, Tween 80, Formaldehyde,
Metformin 9, 10 Chitosan, eudragit, Dichloromethane Polyvinyl Span 80, Glutaraldehyde
Itopride 11 Acrycoat, methocil, (DCM), alcohol, SLS
Famotidine 12 Polyacrylates, Acetonitrile, Water
Rabeprazole and Polyvinyl acetate, Acetone,
Amoxicillin 13 Carbopol, Isopropyl Alcohol
Glipizide 14 Agar, polyethylene (IPA),
Pantoprazole 15 oxide, Dimethyl
Propanolol 16 Polycarbonates, formamide (DMF)23
17
Cinnarizine Acrylic resins,
Celecoxib 18 Polyethylene 22
Captopril 19
Stavudine 20
Orlistat 21

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However, minimal gastric content needed to allow organic solvent and an aqueous solvent. The drug is
proper achievement of buoyancy. Micro-balloon of dissolved in the organic solvent and the solution is
acrylic resins, eudragit, polyethylene oxide and dispersed in the aqueous solvent producing the
cellulose acetate; polystyrene floatable shells; emulsion droplets even though the organic solvent
polycarbonate floating balloons and gelucire is miscible. The organic solvent diffuses gradually
floating granules are the recent developments. out of the emulsion droplets into the surrounding
aqueous phase and the aqueous phase diffuse into
Methods of Preparation of Microballoons: the droplets by which drug crystallizes. The
A. Solvent Evaporation Method: In this method, mixture of drug-polymer is dissolved in the
a polymer is dissolved in an organic solvent and the solution of ethanol: dichloromethane and this
drug is either dissolved or dispersed in the polymer mixture are adding dropwise to polyvinyl alcohol
solution. The solution containing the drug is then solution. This solution is stirred at 1500 rpm for 1 h
emulsified into an aqueous phase containing and at different temperature ranges. By changing
suitable additive (surfactants/polymer) to form oil the polymer concentration in the co-solvent and the
in water emulsion after the formation of a stable ratio of ethanol to dichloromethane, it is possible to
emulsion, the organic solvent is evaporated either prepare microballoons with various drug contents
by increasing the temperature under pressure or by 25
.
continuous stirring. The solvent removal leads to
polymer precipitation at the oil/water interface of
droplets, forming cavity and thus making them
hollow to impart the floating properties. The
polymers for the development of such systems
include Eudragit, HPMC K4M and ethyl cellulose
etc. Polymers are mixed with drugs and further this
mixture is dissolved in the solution of ethanol,
acetone or dichloromethane either alone or in
combination to get homogenous polymer solution.
FIG. 2: SOLVENT DIFFUSION METHOD
The resulting solution is poured into 100 mL of
liquid paraffin rotating at 1500 rpm. The emulsion C. Solvent Diffusion-Evaporation Technique:
is formed and heated at 35 ºC temperature for 3hr. This technique is with a slight modification of both
After the formation of a stable emulsion, the the emulsion solvent evaporation method and the
acetone or dichloromethane is completely emulsion solvent diffusion method. Drugs,
evaporated and resulting solidified microballoons polymers and 0.1% of a surfactant such as PEG are
are filtered using Whatman filter paper. This mixed in the solution of ethanol: dichloromethane
hollow microballoons imparts the floating and (1:1) at room temperature. This solution is slowly
sustained properties 24. introduced into 80 ml of 0.46% w/w of polyvinyl
alcohol as an emulsifier. This is stirred using
propeller agitator for 1 h for evaporation of organic
solvents and then filtered it 26.

FIG. 1: SOLVENT EVAPORATION METHOD

B. Emulsion Solvent Diffusion Method: In the

solvent diffusion method the affinity between the FIG. 3: SOLVENT DIFFUSION-EVAPORATION
METHOD
drug and organic solvent is stronger than that of

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D. Spray Drying: Spray drying is the most widely Characterization and Evaluation parameters for
employed industrial process for particle formation hollow Microballoons:
and drying. It is an ideal process where the required 1. Percentage Yield: The percentage yield of the
particle size distribution, bulk density and particle hollow microspheres is determined for drug and is
shape can be obtained in a single step 27. calculated using the following equation.
Yield = M/Mo × 100

Where M = weight of beads

Mo = total expected weight of drug and polymer.

2. Micromeritic Properties: 10 Microballoons are

evaluated by their micrometric properties such as
particle shape and size, bulk density, tapped
density, Hausner’s ratio and flow properties which
are determined by Carr’s index, porosity and angle
FIG. 4: SPRAY DRYING METHOD of repose.
TABLE 3: DETAILS OF MICROMETRICS PROPERTIES
S. no. Name of Property Descriptions
1 Bulk density It is defined as the mass of particles of the material divided by the total volume they
occupy. It is calculated by using the formula,
Bulk Density = Mass / Volume
2 Tapped density The tapped density is an increased bulk density attained after mechanically tapping a
container containing the powder sample. The tapped density is obtained by
mechanically tapping a graduated measuring cylinder or vessel containing the powder
sample. After observing the initial powder volume or mass, the measuring cylinder or
vessel is mechanically tapped, and volume or mass readings are taken until little
further volume or mass change is observed.
Tapped Density = Mass / Change in Volume after tapping
3 Hausner’s ratio The Hausner ratio is a number that is correlated to the flowability of a powder or
granular material. It is named after the engineer Henry H. Hausner (1900–1995) The
Hausner’s ratio is calculated by the formula,
Hausner Ratio (HR) = Tapped Density / Bulk Density
4 Carr’s index The Carr index is an indication of the compressibility of a powder. It is named after
the scientist Ralph J. Carr, Jr. The Carr index is frequently used in pharmaceutics as an
indication of the flowability of a powder. In a free-flowing powder, the bulk density
and tapped density would be close in value, therefore, the Carr index would be small.
It is Calculated using the formula,
Carr’s Index (CI) = Tapped Density - Bulk Density × 100 / Tapped Density
5 Angle of repose The angle of repose of a granular material is the steepest angle of descent relative to
the horizontal plane to which a material can be piled without slumping. When bulk
granular materials are poured onto a horizontal surface, a conical pile will form. The
internal angle between the surface of the pile and the horizontal surface is known as
the angle of repose and is related to the density, surface area and shapes of the
particles, and the coefficient of friction of the material. It is calculated using formula,
Angle of repose (θ) = tan-1(h/r)
Where h = Height of Pile and r = radius of Pile

3. Compatibility Studies: Infrared spectrum of the 10 h in the dissolution apparatus. After 8 to 10 h,

drug, drug-loaded microballoons, blank micro- the layers of buoyant microspheres are pipetted and
balloons, physical mixture and empty separated by filtration particle which lies in the
microballoons are recorded using FTIR 28. layer of sinking particulate are separated by
filtration. Particles of both types (buoyant
4. In-vitro Buoyancy: 29 Appropriate quantity of microspheres and settled microspheres) are dried in
hollow/empty microspheres are placed in 900 ml of a desiccator until a constant weight is achieved.
0.1N HCl. The mixture is stirred at 100 rpm for 8-

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Both the fractions of empty/hollow microspheres and Hixon-Crowell release equations are applied to
are weighed and in-vitro buoyancy is determined process the in-vitro release data to find the equation
by the weight ratio of floating microspheres to the with the best fit using PCP Disso v3 software.
sum of floating and sinking microspheres.
8. Swelling Studies: 32 Swelling studies are
Buoyancy (%) = {Wf / (Wf + Ws)} × 100 performed to calculate molecular parameters of
swollen polymers. Swelling studies are determined
Where Wf and Ws are the weights of the floating by using dissolution apparatus, optical microscopy
and settled microspheres and other sophisticated techniques, which include
5. Scanning Electron Microscopy: 8 Dry hollow H1NMR imaging, Confocal laser scanning
microspheres are placed on an electron microscope microscopy (CLSM), Cryogenic scanning electron
brass stub a coated with gold in an ion sputter. microscopy (Cryo-SEM), Light scattering imaging
Then pictures of microsphere are taken by Spectro (LSI), etc. The swelling studies by using
random scanning of the stub. The microspheres are Dissolution apparatus (USP dissolution apparatus
viewed at an accelerating voltage of 20KV. USP-24) lab India disso 2000) is calculated as per
Scanning electron microscopy was performed to the following formula
characterize the surface of formed microspheres. Swelling ratio = Weight of wet formulation / Weight of
The samples for SEM were prepared by lightly formulations
sprinkling the microballoons on a double-adhesive
tape stuck to an aluminum stub. The stubs were 9. In-vivo Studies: The in-vivo studies are
then coated with gold to a thickness of about 300 Å performed on suitable animal models example such
under argon atmosphere using a gold sputter as a rat, beagle dogs, etc. The floating behavior can
module in a high-vacuum evaporator. The samples be investigated by radiographical studies using
were then randomly scanned using a Scanning barium sulphate microballoons.33
Electron Microscope and photomicrographs were
10. Entrapment Efficiency: Microballoons
captured.
containing drug equivalent to 100 mg are digested
6. In-vitro Drug Release Studies: 30 The release in a 10 mL mixture of dichloromethane and
rate of hollow microspheres is determined in a methanol (1:1 v/v). The mixture is to be placed in
United States Pharmacopoeia (USP) basket type the centrifuge at 3000 rpm for 3 min and 1 ml of
dissolution apparatus. A weighted amount of supernatant is then withdrawn and after suitable
floating microballoons equivalent to 75 mg of the dilution, with distilled water, it is assayed
drug is placed in screening medium having smaller spectrophotometrically. The percentage drug
mesh size than the microballoons. The mesh is then entrapment is calculated from the equation given
tied with a nylon thread to avoid the escape of any below.
microballoons and a glass bead used in the mesh to Entrapment Efficiency = Amount of drug actually present ×
induce the sinking of microballoons in the 100 / Theoretical drug load expected
dissolution medium. The dissolution test was
performed in 900 mL medium at 100 rpm; at Advantages of Floating Microballoons: 34
specified time intervals, aliquots are to be
withdrawn, filter, dilute with the same medium and 1. Improved patient compliance due to a
assay using a UV double-beam spectrophotometer. reduction in the dosing frequency.

7. Data Analysis of Release Studies: 31 Five 2. Improvement in bioavailability due to better

kinetic models including the zero-order drug utilization.
(cumulative percentage of drug release versus 3. Reduction in the incidence or intensity of
time), first-order (log cumulative percentage of adverse effects due to avoidance of
drug remaining versus time), Higuchi matrix fluctuation in plasma drug concentration.
(cumulative percentage of drug release versus
square root of time), Peppas Korsmeyer (log 4. Maintenance of a desirable plasma drug
cumulative percent drug release versus log of time) concentration by continuous drug release.

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5. Hollow microspheres are used to decrease local drug release. Thus, eradicating
material density and Gastric retention time is Helicobacter pylori from sub-mucosal tissue
increased because of buoyancy. of the stomach is useful in the treatment of
peptic ulcers, chronic gastritis,
6. Enhanced absorption of drugs that solubilize gastroesophageal reflux diseases etc. Floating
only in the stomach. bio-adhesive microspheres of aceto-
hydroxamic acid are formulated for the
7. Release of the drug in a controlled manner
treatment of Helicobacter pylori infection.
for a prolonged period.
Hollow microspheres of Ranitidine HCl are
8. Site-specific drug delivery to the stomach can also developed for the treatment of gastric
be achieved. ulcers.

9. Avoidance of gastric irritation, because of 4. Floating microspheres are especially effective

sustained-release effect. in the delivery of sparingly soluble and
insoluble drugs. It is known that as the
Limitation of Floating Microballoons: 34 solubility of a drug decreases, the time
available for drug dissolution becomes less
1. The release rate of the controlled release adequate and thus the transit time becomes a
dosage form may vary from a variety of significant factor affecting drug absorption.
factors like food and the rate of transit For weakly basic drugs that are poorly
through the gut. soluble at an alkaline pH, hollow
2. Differences in the release rate from one dose microspheres may avoid the chance for
to another. solubility to become the rate-limiting step in
a release by restricting such drugs to the
3. Controlled release formulations generally stomach. The positioned gastric release is
contain a higher drug load and thus, any loss useful for drugs efficiently absorbed through
of integrity of the release characteristics of the stomach. The gastro-retentive floating
the dosage form may lead to potential microspheres will alter beneficially the
toxicity. absorption profile of the active agent, thus
enhancing its bioavailability.
4. Dosage forms of this kind should not be
crushed or chewed. 5. The floating microspheres can be used as
carriers for drugs with so-called absorption
Applications of Floating Microballoons: windows, these substances, for example,
Microballoons/hollow microspheres generally vary antiviral, antifungal and antibiotic agents are
in density and therefore, used for different taken up only from very specific sites of the
applications. Hollow microspheres are typically used GI mucosa.
as additives to lower the density of a material. Solid
microspheres have numerous applications like 34 6. Hollow microspheres of non-steroidal anti-
inflammatory drugs are very effective for
1. Hollow microspheres can greatly improve the controlled release as well as it reduces the
pharmacotherapy of the stomach through major side effect of gastric irritation; for
local drug release, leading to high drug example, floating microspheres of
concentrations at the gastric mucosa. Indomethacin are quiet beneficial for
rheumatic patients.
2. It provides sustained drug release behavior
and releases the drug over a prolonged period Recent Advancement: Recently development in
of time. They are mainly fabricated as a hollow microspheres as follow,
floating controlled drug delivery system.
1. Yuning Huo et al., have developed hollow
3. They can greatly improve the CdS-TiO2 microspheres with enhanced
pharmacotherapy of the stomach through visible-light photocatalytic activity 35.

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How to cite this article:

Hajare PP and Rachh PR: Gastroretentive microballoons: a novel approach for drug delivery. Int J Pharm Sci & Res 2020; 11(3): 1075-83.
doi: 10.13040/IJPSR.0975-8232.11(3).1075-83.
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