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MULTIPARTICULATE DRUG DELIVERY SYSTEMMULTIPARTICULATE DRUG DELIVERY SYSTEM
BY
Miss. JASMIN M. JAIN
(T. Y. B. Pharm)
GUIDE
Mr. HEMANT H. GANGURDE
(M. Pharm)
DEPARTMENT OF PHARMACEUTICS
S. N. J. B.S S.S.D.J COLLEGE OF PHARMACY, CHANDWAD.
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DRUGDRUG DELIVERYDELIVERY SYSTEMSYSTEM
Drug delivery is the method or process of administering a pharmaceutical
compound to achieve a therapeutic effect in humans or animals. Most common
routes of administration include the preferred non-invasive peroral (through the
mouth), topical (skin), transmucosal (nasal, buccal/sublingual, vaginal, ocular and
rectal) and inhalation routes.
The choice of the route, however, depends on
a) Physical & chemical characters of the drugs
b) Effect desired
c) Urgency and seriousness of the condition.
Local delivery
If the target receptor is external or easily accessed then local delivery of the
medication can be a feasible and effective approach.
Systemic delivery
When the target receptor cannot be easily accessed systemic
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MULTIPARTICULATE DRUG DELIVERY SYSTEM (MPDDS)MULTIPARTICULATE DRUG DELIVERY SYSTEM (MPDDS)
Multiparticulate dosage forms are pharmaceutical formulations in which the active
substance is present as a number of small independent subunits with diameter of
0.05-2.00 mm. They provide many advantages over single unit systems because of
their small size. Multiparticulate drug delivery is less dependent on gastric
emptying, resulting in less inter and intra subject variability in GI transit time.
MPDDS applies specially to multiple particles such as pellets, beads, microspheres,
microcapsules.
OBJECTIVEOBJECTIVE OFOF MPDDSMPDDS
Sustain release or prolong release medication Taste masking
Improve stability
Increase solubility or dispersability
Increase therapeutic efficiency
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ADVANTAGES OF MPDDSADVANTAGES OF MPDDS
It minimizes the risk of local irritation.
It results in shorter lag time for Floating Drug Delivery Sysyem
It avoids fortuitous (all or none) emptying process.
It reduces patient-to patient variability i.e. inter-subject variability.
It provides greater flexibility to the formulators.
It spreads more evenly in the GIT, thus improving the therapeutic
efficacy of the medicinal agents.
Lower Tendency of Dose Dumping
Greater stability of Chemically incompatible drugs
Ease of Design of Controlled Released Formulation containing more than
one drug
Improved Elegance, Product identification, & Patient compliance
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DISADVANTAGE OF MPDDSDISADVANTAGE OF MPDDS
Low drug loading
Proportionally higher need for excipients
Lack of manufacturing reproducibility and efficacy
Large number of process variables
Multiple formulation steps
Higher cost of production
Need of advanced technology
Trained/skilled personal needed for manufacturing
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MechanismMechanism ofof DrugDrug ReleaseRelease fromfrom MPDDSMPDDS
Three delivery systems dominate todays market of oral CR products: matrix,
reservoir, and osmotic systems. Release mechanisms from these dosage forms
have been the subjects of extensive studies. The mechanism of drug release
from MPDDS can be occurring in the following ways:
1. Diffusion
a. Matrix system
b. Reservoir system
2. Erosion
3. Osmosis
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11.. DiffusionDiffusion :
In these types of systems, the rate-controlling step is not the dissolution rate but
the diffusion of dissolved drug through a polymeric barrier. The process of
dissolution of solid particles in a liquid, in the absence of reactive or chemicalforces, consists of two consecutive steps:
a. Solution of the solid to form a thin film or layer at the solid liquid interface
called as the Stagnant film or diffusion layer which is saturated with the
drug; this step is usually rapid
b. Diffusion of the soluble solute from the stagnant layer to the bulk of the
solution; this step is slower & is therefore the rate determining step in drug
dissolution
The 2 types of diffusion controlled systems are:
a. Matrix System
b. Reservoir System
a. Matrix System
A matrix system consists of active and inactive ingredients that are
homogeneously mixed in the dosage form. We divide matrix systems into two
categories, based on rate-controlling materials like Hydrophobic and
Hydrophilic
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Hydrophobic matrix systems
As the term suggests, the primary rate controlling components of a hydrophobic
matrix are water insoluble in nature. Eg: waxes, glycerides, fatty acids, ethyl-
cellulose & methacrylate copolymers.
Hydrophilic matrix systems
The primary rate-controlling ingredients of a hydrophilic matrix are polymers
that would swell on contact with the aqueous solution and form a gel layer on the
surface of the system. Eg: HPMC ,polyethylene oxide , HPC, xantham gum.
Marketed products of Matrix SystemMarketed products of Matrix System
Products Active ingredient(s) Manufacturer
OPANA ER tab Oxymorphone HCL Endo
Seroquel XR tab Quetiapine fumarate Astrazeneca
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b. Reservoir System
A typical reservoir system consists of a core (the reservoir) and a coating
membrane (the diffusion barrier). The core contains the active ingredients and
excipients, whereas the membrane is made primarily of rate-controlling polymer(s).
Marketed Products:Marketed Products:
Metadate CD and Ritaline LA
22.. ErosionErosion
In this system, drug is dispersed throughout the polymer, and the rate of drug
release depends on the erosion rate of the polymer. However, some diffusion of the
drug from the polymer may also occur. In a surface eroding system, the drug
release rate is proportional to the polymer erosion rate and can be controlled by
changing the system thickness and total drug content. Surface erosion eliminates
the possibility of dose dumping, thus improving device safety.
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3. OsmosisOsmosis
The system is composed of a core tablet surrounded by a semipermeable
membrane coating having a 0.4mm diameter hole. The core tablet has 2 layers,
one containing the drug (the active layer) & the other containing a polymeric
osmotic. agent (a push layer). The rate of inflow of water & function of the tablet
depends on an osmotic gradient between the contents of the two-layer core & the
fluid in the GIT.
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CLASSIFICATIONCLASSIFICATION OFOF MPDDSMPDDS
Depending upon its size and structure MPDDS are classified as follows:
1. Drug crystals
2. Minitablets
3. Microcapsules
4. Nanoparticles
5. Microsphere
a. Spheronised granules (pellets)
i. Extrusion
ii. Spheronization
iii. Melt extrusion
b. Drug-loaded Non-pariels (pellets)/Drug layering
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11.. DRUGDRUG CRYSTALSCRYSTALS
Drug Crystals, of appropriate size and shape can be coated directly with a
modified release film coating.
22.. MINIMINI TABLETSTABLETS
Minitabs are small tablets with a diameter typically equal to or less than 3mm that
are typically filled into a capsule, or occasionally, further compressed into larger
tablets. The minitablets may have any shape convenient to the skilled person for
designing tablets i.e.Spherical, Cylindrical, Biconvex round, Flat-faced round. The
minitablets may be uncoated, or coated with one or more layers of coating.
Figure 1: Minitablet delivered as a tablet (a) or a capsule (b).
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33.. MICROCAPSULESMICROCAPSULES
In this the drug is centrally located within the polymeric shell of finite thickness
and release may be controlled by dissolution, diffusion or both. Steroids, peptides
and anti-neoplastics have been successfully administered parenterally by use of
controlled release microcapcules.
4. NANOPARTICLES4. NANOPARTICLES
The National Cancer Institute, under the National Nanotechnology Initiative
Program, recently defined nano-sized drug carriers as those which are typically
300 nm or smaller in size. The nanoparticles are also called as Nanospheres or
Nanocapcules depending upon whether the drug is in a polymer matrix or
encapsulated in a shell. The main objective of developing nanosized drug carriers
is to enhance the therapeutic potential of drugs so that they are less toxic and more
effective.
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55.. MICROSPHERESMICROSPHERES
Microspheres are small discrete spherical particles, with
diameters in the micrometer range(typically 1m to1000m(1mm).Microsphere are sometimes referred to as microparticles.
Polyethylene and polystyrene microspheres are two most common types of
polymer microspheres.
i. Spheronized Granules(Pellets)
Pellets are agglomerates of fine powders or granules of bulk drugs and excipients.
They consist of small, free-flowing, spherical or semi spherical solid units,
typically from about 0.5mm to 1.5 mm, and are intended usually for oral
administration. Implants of small, sterile cylinders formed by compression from
medicated masses are also defined as pellets in pharmacy.
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Mechanism of granule formation
Different theories have been postulated related to the mechanism of formation
and growth of pellets. The mechanism of pellet formation and growth, the
following steps were proposed:
nucleation, coalescence, and layering and abrasion transfer.
Figure 2: Pellet growth mechanisms (1) Nucleation, (2) coalescence,
(3) layering and abrasion transfer
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MethodsMethods forfor preparingpreparing pelletspellets
Compaction and drug layering are the most widely used pelletisation
techniques in pharmaceutical industry, extrusion and spheronization is the
most of the compaction techniques popular method.
Some of the methods used are:
i. Extrusion- technique
ii. Spheronization-technique
iii. Hot-melt extrusion
i. Extrusion Technique
Extrusion is a multiple step compaction process comprising dry mixing of the
ingredients with excipients, wet granulation of the mass, extrusion of the
wetted mass, charging the extrudates into the spheroniser to produce aspherical shape, drying the wet pellets in a dryer and, finally, screening to
achieve the required size distribution.
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Equipments used in Extrusion technique (Extruders):
A variety of extruders are currently in the market, differing in design features
and Operational principles. These can be classified as
1. Screw-fed extruders
2. Gravity-fed extruder
3. Rotary-cylinder extruders
4. RAM extruders
ii. Spheronizer Technique
A spheronizer, known as Marumizer, consists of a static cylinder or stator and
a rotating friction plate at the base. The stator can be jacketed for temperature
control.
iii. Hot Melt Extrusion (HME):
Melt extrusion is the process which can be clubbed under extrusion
spheronization whereby a drug substance and excipients are converted into a
molten or semi molten state and subsequently shaped using appropriate
equipment to provide solid spheres or pellets.
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The HME offers some advantage over a wet mass extrusion and
spheronization method:
1. It is a simple, efficient and continuous process requires.
2. It does not require a lengthy drying stage3. The absence of water may prevent drug degradation
4. It produces a spherical shape pellets with narrow range particle size
distribution.
a) Reduce the loss of coating material
ii. DrugDrug--loadedloaded NonNon--pareilspareils (pellets)(pellets)Spherical particles about 1mm in diameter consisting primarily of sucrose
and starch called non-pareils which are available in the market. Following
techniques can be used to get drug loaded non pareils. The different methods
used for preparation of Drug loaded Non-pareils (pellets) are:
1. Drug layering2. Miscellaneous methods
a.Balling
b.Compression
c.Cryopellitization
d.Globulation.
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EvaluationEvaluation && characterizationcharacterization ofof MultiparticulatesMultiparticulates
A. Size distribution
B. Shape and surface roughness
C. Surface area
D. Porosity
E. Density
F. Friability
G. Content Uniformity
H. Tensile strength
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MPDDS TECHNOLOGIES WITH EXAMPLESMPDDS TECHNOLOGIES WITH EXAMPLES
TECHNOLOGIES COMPANIES MECHANISM / PRINCIPLE
OF RELEASE
Diffucaps
Orbexa
Eurand SR and Pulsatile Release
Film diffusion via polymer
coating
SODAS / CODAS Elan Sustained and/or Pulsatile
Release
SDD Bend Research Spray-dried dispersion beads /
Enteric Release
MARKETED FORMULATIONSMARKETED FORMULATIONS
DRUG BRAND COMPANIES
Morphine sulfate Avinza King
Carbamazepie Carbatrol Shire,US
Equetro ER Validus
Carvedilol Coreg CR GSK
Dexmethylphenidate Focalin XR Novartis
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REFERENCESREFERENCES
a) Sahoo SK, Jain TK, Reddy MK, and Labhasetwar V. Nano-Sized Carriers for
Drug Delivery, NanoBioTechonology: Bio-Inspired Devices and Materials ofthe Future: 329
b) Jain KK. Drug Delivery System. 1st Edition, Basel: Jain Pharma Biotech
Publications. Switzerland: 30-31
c) Aulton ME. Pharmaceutics, The science of dosage form design. 2nd edition.
Edinburgh: Churchill Livingstone.2002: 374-379
d) Florence AT and Attwood D. Physicochemical principles of pharmacy. 4th
edition. London: Pharmaceutical Press. 2006
e) Patrick GL. An Introduction to Medicinal Chemistry. 3rd edition, Oxford:
Oxford University Press. 2005
f) Laila FA, Chandran S. Multiparticulate Formulation Approach to colon
specific drug delivery: current perspectives. J. Pharm Sci, 2006, 9(3): 327-38g) Shah NH. Multi-Particulate Dosage Form for Oral Controlled Release:
Development Considerations. Hoffmann La-Roche. In
h) Shaji J, Chadawar V, Talwalkar P. Multiparticulate Drug Delivery System.
The Indian Pharmacist. June 2007, 6(60): 21-28.
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