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Adisa et al

Tropical Journal of Pharmaceutical Research, September 2008; 7 (3): 1067-1075


© Pharmacotherapy Group,
Faculty of Pharmacy, University of Benin,
Benin City, 300001 Nigeria.
.
All rights reserved

Available online at http://www.tjpr.org


Review Article

Multiparticulate Drug Delivery Systems for Controlled


Release

NS Dey*, S Majumdar and MEB Rao


Department of Pharmaceutics, Roland Institute of Pharmaceutical Sciences, Khodasinghi, Berhampur,
Orissa760010, India

Abstract
Pharmaceutical invention and research are increasingly focusing on delivery systems which enhance
desirable therapeutic objectives while minimising side effects. Recent trends indicate that
multiparticulate drug delivery systems are especially suitable for achieving controlled or delayed release
oral formulations with low risk of dose dumping, flexibility of blending to attain different release patterns
as well as reproducible and short gastric residence time. The release of drug from microparticles
depends on a variety of factors including the carrier used to form the multiparticles and the amount of
drug contained in them. Consequently, multiparticulate drug delivery systems provide tremendous
opportunities for designing new controlled and delayed release oral formulations, thus extending the
frontier of future pharmaceutical development.

Keywords: Dose dumping, Microparticles, Multiparticulate delivery system, Delayed release

*Corresponding author: Email: niladrisekhar111@gmail.com Phone no: +91-09861352986

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Dey et al

INTRODUCTION Drug safety may also be increased by using


Multi-particulate drug delivery systems are multiparticulate dosage forms, particularly for
mainly oral dosage forms consisting of a modified release systems. For example, if the
multiplicity of small discrete units, each film coat of a single-unit (monolithic) enteric
exhibiting some desired characteristics. In coated tablet is damaged, the complete dose
these systems, the dosage of the drug will be released into the stomach where it may
substances is divided on a plurality of subunit, cause pain or ulceration or reduced efficacy,
typically consisting of thousands of spherical depending on the reason for choosing the
particles with diameter of 0.05-2.00mm1. Thus protection of the enteric coating. Equally, if
multiparticulate dosage forms are there is damage to the film coating of a
pharmaceutical formulations in which the monolithic tablet with a sustained release
active substance is present as a number of formulation, this can lead to “dose dumping”
small independent subunits. To deliver the and result in dramatic side effects. By
recommended total dose, these subunits are contrast, in multiparticulate formulation, the
filled into a sachet and encapsulated or release characteristics are incorporated into
compressed into a tablet4. Multiparticulates every single subunit and any damage only
are discrete particles that make up a multiple- affects the release behavior of the subunit
unit system. They provide many advantages involved, which represents a small part of the
over single-unit systems because of their total dose, reducing the likelihood of safety
small size. Multiparticulates are less problems4.
dependent on gastric empty ting, resulting in
less inter and intra-subject variability in SOME APPROACHES TO
gastrointestinal transit time. They are also MULTIPARTICULATE FORMULATION
better distributed and less likely to cause local A multiparticulate floating–pulsatile drug
irritation 2. Recently much emphasis is being delivery system was developed using porous
laid on the development of multiparticulate calcium silicate [RE(R)] and sodium alginate,
dosage forms in preference to single unit for time and site specific drug release of
systems because of their potential benefits meloxicam5.
such as increased bioavailability, reduced risk An oral controlled onset extended release
of systemic toxicity, reduced risk of local dosage form intended to approximate the
irritation and predictable gastric emptying3. chronobiology of rheumatoid arthritis was
There are many reasons for formulating a proposed for site specific release to the colon.
drug as a multiparticulate system for example, The multiparticulate system consisting of drug
to facilitate disintegration in the stomach, or to loaded cellulose acetate cores encapsulated
provide a convenient, fast disintegrating tablet within Eudragit S-100 microcapsules was
that dissolves in water before swallowing designed for chronotherapeutic delivery of
which can aid compliance in older patients ketoprofen6. The site-specific delivery of drugs
and children. Multiparticulate systems show to the colon has implications in a number of
better reproducible pharmacokinetic behavior therapeutic areas, which include topical
than conventional (monolithic) formulations. treatment of colonic disorders such as Crohn’s
After disintegration which occurs within a few disease, ulcerative colitis, constipation,
minutes often even within seconds, the colorectal cancer, spastic colon and irritable
individual subunit particles pass rapidly bowel syndrome7.
through the GI tract. If these subunits have Multiparticulates approaches tried for colonic
diameters of less than 2mm, they are able to delivery includes formulations in the form of
leave the stomach continuously, even if the pellets, granules, microparticles and
pylorus is closed. These results in lower intra nanoparticles. Because of their smaller
and inter individual variability in plasma levels particle size compared to single unit dosage
and bioavailability. forms these systems are capable of passing
through the GI tract easily, leading to low inter

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and -intra subject variability. Moreover, release system based on coated pellets
multiparticulate systems are to be more containing an osmotic active ingredient has
uniformly dispersed in the GI tract and also been prepared. The coating consisted of a
3
ensure more uniform drug absorption . A semi permeable membrane of cellulose
multiparticulate system of chitosan hydrogel acetate. Following ingestion water penetrates
beads has been investigated for colon-specific into the core and forms a saturated solution of
delivery of macromolecules using fluorescein the soluble components. The osmotic
is othiocyanate-labeled bovine serum albumin pressure gradient induces a water influx
as a model protein8. resulting in a rapid expansion of the
Multiparticulates may be prepared by several membrane leading to the formation of pores.
methods. Different methods require different The osmotic ingredient and the drug are
processing conditions and produce released through these pores according to
multiparticulates of distinct qualities. Some of zero order kinetics. In comparison with the
these methods may be broadly classified as sodium chloride free formulation the inclusion
pelletization, granulation, spray drying, and of the osmotically active ingredient results in a
spray congealing. Drug particles may be completely different dissolution behavior. Lag
entrapped within the multiparticulates or time and dissolution rate were dependent on
layered around them. Subsequently, these the coating level and the osmotic properties of
multiparticulates may be modified in many the dissolution medium10.
ways to achieve the desired drug release
profile. MECHANISM OF DRUG RELEASE FROM
One approach to the modification of drug MULTI-PARTICULATES
release profile in multiparticulates is to coat The mechanism of drug release from
them. Reasons for the application of coating multiparticulates can be occur in the following
onto maltiparticulates are to obtain functional ways:
coats, provide chemical stability, improve
Diffusion
physical characteristics and enhance patient
acceptance. Coats are formed from various On contact with aqueous fluids in the
polymeric coating materials broadly classified gastrointestinal tract (GIT), water diffuses into
as aqueous polymer dispersions, polymer the interior of the particle. Drug dissolution
solutions, molten polymers and dry powders. occurs and the drug solutions diffuse across
Depending on the type of coating material the release coat to the exterior.
used, functions such as sustained release
Erosion
(SR), targeted release, delayed release, and
pulsatile release can be achieved. Some coatings can be designed to erode
The most common method used for the gradually with time, thereby releasing the drug
application of coating onto multiparticulates is contained within the particle.
air suspension coating. Other methods include
compression coating, solvent evaporation, Osmosis
coacervation, and interfacial complexation. It In allowing water to enter under the right
is also possible to form coated circumstances, an osmotic pressure can be
multiparticulates by spray drying and spray built up within the interior of the particle. The
2
congealing . A multiparticulate composition drug is forced out of the particle into the
may allow controlled release of the drug over exterior through the coating 1.
a wide range of release rates, and permit the
release rate to be set at a predetermined rate, DESIGN OF MULTIPARTICULATE DRUG
such a formulation may be formed using a DELIVERY SYSTEMS
melt-congeal process which maintains the The purpose of designing multiparticulate
crystallinity of the drug during the melt- dosage form is to develop a reliable
congeal process 9. A multiparticulate delayed formulation that has all the advantages of a

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Dey et al

Fig 1: Intestinal Protective Drug Absorption System Fig 2: Spheroidal Oral Drug Absorption System

Fig 3: Programmable Oral Drug Absorption System Fig 4: Diffucaps

Fig 5: Minitab

single unit formulations and yet devoid of the out through the length of the intestine cause
danger of alteration in drug release profile and less irritation, enjoy a slower transit through
formulation behavior due to unit to unit the colon and give a more reproducible drug
variation, change in gastro –luminal pH and release. As in the case of single unit dosage
enzyme population. A generally accepted view forms, for the purpose of the designing
is that multiparticulate systems perform better multiparticulate colon specific drug delivery
in vivo than single unit system, as they spread system, the presence of specific bacterial

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populations in the colon and increasing pH the drug in the stomach which subsequently
gradient have been extensively explored as pass into the duodenum and along the
triggering mechanism in order to initiate colon gastrointestinal tract in a controlled and
specific drug release. gradual manner, independent of the feeding
state. Release of active ingredient from the
Multiparticulate crystalline drug
multiparticulates occurs through a process of
compositions
diffusion either through the polymeric
A multiparticulate for controlled release of a
membrane and /or the micro matrix of the
drug comprises a crystalline drug, a glyceride
polymer/active ingredient formed in the
having at least one alkylate substituent of not
extruded/spheronized multiparticulates. The
less than 16 carbon atoms, and a poloxamer,
intestinal protection of IPDAS is by virtue of
wherein at least 70 wt % of the drug in the
the multiparticulate nature of the formulation
multiparticulate is crystalline. The
which ensures wide dispersion of irritant drug
multiparticulate comprises crystalline drug
throughout the gastrointestinal tract.
particles embedded in the glyceride/
Naprelan®, which is marketed in the United
poloxamer mixture. The poloxamer 16 is
States, employs IPDAS technology. This
substantially homogeneously distributed
innovative formulation of naproxen sodium is
throughout the glyceride 14 and is present as
a unique controlled release formulation
a separate phase from the glyceride 1411.
indicated both for acute and chronic pain1,12.
Multiparticulates as NDDS
Spheroidal oral drug absorption systems
Incorporating an existing medicine into a novel
Spheroidal Oral Drug Absorption System
drug delivery system (NDDS) can significantly
(SODAS) (Figure 2) is a multiparticulate
improve its performance in terms of efficacy,
technology that enables the production of
safety and improved patient compliance. In
customized dosage forms and responds
the form of a NDDS, an existing drug
directly to individual drug candidate needs. It
molecule can get new life, thereby increasing
can provide a number of tailored drugs
its market value and competitiveness and
release profiles including immediate release of
even extending patent life1.
drug followed by sustained release to give rise
Intestinal Protective Drug Absorption to a fast onset of action which is mainted for
System 24 hours. Alternatively, the opposite scenario
Intestinal protective drug absorption system can be achieved where drug release is
(IPDAS) (Figure 1) is a multiparticulate tablet delayed for a number of hours1,13.
technology that has been developed to
Programmable Oral Drug Absorption
enhance the gastric tolerability of potentially
System
irritant or ulcerogenic drugs such as the
Programmable Oral Drug Absorption System
NSAIDs. It consists of high density controlled
(PRODAS) (Figure 3) is presented as a
release beads that are compressed into a
number of mini tablets contained in hard
tablet form. The beads may be manufactured
gelatin capsule. It thus combines the benefits
by techniques such as extrusion
of tableting technology within a capsule. It is
spheronization and controlled release can be
possible to incorporate many different
achieved with the use of different polymer
minitablets, each one formulated individually
systems to coat the resultant beads.
and programmed to release drug at different
Alternatively, the drug can also be coated into
sites within the GIT. These combinations may
on an inert carrier such as non-pareil seeds to
include immediate release, delayed release,
produce instant release multiparticulates.
and/or controlled release mini tablets. It is also
Controlled release can be achieved by the
possible to incorporate mini tablets of different
formation of a polymeric membrane onto
sizes so that high drug loading is possible.
these instant release multparticulates. Once
Their size ranges usually from 1.5 – 4 mm in
an IPDAS tablet is ingested, it rapidly
diameter 1, 14.
disintegrates and disperses beads containing

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Diffucaps As a result, combination products can be


In this multiparticulate system, drug profiles developed to allow for two or more release
are created by layering an active drug onto a profiles within a single capsule. Eurand
neutral core such as sugar spheres, crystals minitabs offer high drug loading, the ability to
or granules followed by the application of a fine tune release rates for targeted delivery
rate-controlling, functional membrane (Figure and content uniformity for more accurate
4). The coating materials can be water dosing. Eurand Minitabs offer high drug
soluble, pH dependent or independent or loading, a wide range of release rate designs,
water insoluble depending on the individual and fine tuning of these release rates. The
needs of compound. The resultant beads are capsules can be opened and the contents
small in size approximately 1mm or less in used as a "sprinkle" formulation 1, 16.
diameter. By incorporating beads of differing
Stabilized Pellet Delivery System
drug release profiles into hard gelatin
Stabilized pellet delivery system technology
capsules, combination release profiles can be
uses functional polymers or a combination of
achieved. It is possible to customize any
functional polymers and specific additives,
combination of sustained release, pulsatile
such as composite polymeric materials to
release and immediate release profiles
deliver a drug to a site of optimal absorption
depending on the specific needs of the
along the intestinal tract. The active drug is
product.
incorporated in multiparticulate dosage forms
The drug layering process can be conducted
such as DIFFUCAPS or Eurand MINITABS,
either from aqueous or solvent based drug
which are then subsequently coated with pH
solutions. Eurand has also developed a
dependent/independent polymeric
formulation technology that combines the
membranes that will deliver the drug to the
customized drug release offered by Diffucaps
desired site. These are then filled into hard
with technologies that enhance the solubility
gelatin capsules. This technology is designed
of insoluble drugs in the gastrointestinal tract.
specifically for unstable drugs and
Eurand is using this technology to provide a
incorporates a pellet core of drug and
degree of delivery control that goes beyond
protective polymer outer layer(s) 1.
that of single technology systems.
Diffucaps beads are small in size, Pelletized Delivery System
approximately 1mm in diameter, and are filled Pelletized Delivery System (PDS) is a
into a capsule to create the final dosage sustained release system using pellets or
form. Beads of differing drug release profiles beads manufactured using marumerization/
can be easily combined in a single capsule pheronization/pelletization techniques or by
providing high levels of control over release layering powders or solutions on nonpareil
profiles. Diffucaps beads of different drugs seeds. Release modulating polymers are
can be combined to make convenient single sprayed on the beads using various coating
dose units for combination therapies 1, 15. techniques. The coated beads are filled in to
hard gelatin capsules. Drug release occurs by
Minitabs
diffusion associated with bioerosion or by
The Eurand MINITABS technology (Figure 5)
osmosis via the surface membrane. The
is unique in that it offers the advantages of a
release mechanism can be pH-activated or
tablet combined with those of a
pH-independent. The beads can be
multiparticulate drug form. Eurand MINITABS
formulated to produce first order or zero order
are tiny (2mm x 2mm) tablets containing gel- 1
release .
forming excipients that control drug release
rate. Additional membranes may be added to Pelletised tablet
®
further control release rate. The small size of Pelletised tablet (Peltab ) system utilizes
Eurand minitabs means that they can be filled polymer-coated drug pellets or drug crystals,
into capsules as a final dosage form. which are compressed into tablets. In order to
provide a controlled release, a water insoluble

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polymer is used to coat discrete drug pellets KV/24


or crystals, which then can resist the action of KV/24 is a patented, multiparticulate drug
fluids in the GIT. This technology incorporates delivery technology that encapsulates one or
a strong polymer coating enabling the coated more drug compounds to achieve release in a
pellets to be compressed into tablets without pre-determined fashion over a 24-hour period
1
significant breakage . after oral administration. KV/24 technology is
based upon coating a neutral core (non-
Multiparticle Drug Dispersing Shuttle pareiled bead) with a drug substance, then
Multiparticle drug dispersing shuttle sequentially coating with one or more
(Multipart®) consists of a tablet carrier for the polymers to achieve a once-a day release
delivery of controlled release beads or pellets profile. The drug can either be combined with
through the GIT which preserves the integrity the neutral core or incorporated into the
and release properties of the beads. The coating process 1.
distribution of the beads is triggered by the
disintegration of the tablet carrier in the Flashtab
stomach. Drug release from the beads is Flashtab technology is a fast
triggered by super disintegration of the tablets. dissolving/disintegrating oral tablet
It can be pH-activated or pH-independent and formulation. It is a combination of taste
can occur by disintegration or osmosis. The masked multiparticulate active drug
beads can be formulated to produce first or substances with specific excipients
zero order release 1. compressed into tablets. A disintegrating
agent and a swelling agent are used in
Macrocap® combination with coated drug particles in this
Macrocap® consists of immediate release formulation to produce a tablet that
beads made by extrusion/ spheronization/ disintegrates in the mouth in less than one
pelletization techniques or by layering minute. These oro-dispersible tablets disperse
powders or solutions on nonpareil seeds. rapidly before the patient swallow them 1.
Release modulating polymers are sprayed on
InnoHerb
the beads using various coating techniques.
This technology is used coating the pellets
The coated beads are filled in hard gelatin
inside of the capsule, InnoHerb
capsules. Drug release occurs by diffusion
Phytogranules. The multiparticulate is made
associated with bioerosion or by osmosis via
up of many micropellets or small beads
the surface membrane. The release
containing active herbal compounds. The
mechanism can be pH-activated or pH-
special coating for each plant extract contains
independent. The beads can be formulated to
top quality standardised dried extracts which
produce first or zero order release 1.
assures efficacy and safety of the semi-
permeable membrane, improves stability,
Orbexa®
® mask taste/smell and affords gastro-protection
Orbexa technology is a multiparticulate
as well as promote controlled release of
system that enables high drug loading and is
actives, optimal availability and better
suitable for products that require granulation. 17
absorption .
This technology produces beads that are of
controlled size and density using granulation,
Layering process for multiparticulate
extrusion and spheronization techniques. This
dosage form
process is unique in that it allows for higher
Layering processes involve loading solid inert
drug loading than other systems, is flexible
cores with drugs and/or excipients. Inert
and is suitable for use with sensitive materials
cores, placed in a suitable vessel such as a
such as enzymes 1.
coating pan or a fluid bed, may be layered
according to different methods. Some
methods consist of spraying onto the cores a

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solution/suspension containing both drug and include an inert core, such as a carbohydrate
binding agent. Others are based on layering sphere, a layer of IL-11 and an enteric coat.
the drug directly in powdery form where drug The enteric coat can include, e.g., a pH
loading occurs by gravity and adhesion is dependent polymer, a plasticizer, and an
ensured by a liquid binder sprayed onto the antisticking agent/glidant. Preferred polymers
cores. include e.g., methacrylic acid copolymer,
The layering process is particularly suitable for cellulose acetate phthalate, hydroxyl propyl
production of small drug loaded units, methylcellulose phthalate, polyvinyl acetate
multiples of which are placed into capsules for phthalate, shellac, hydroxylpropyl
patient delivery. In the case of spherical inert methylcellulose acetate succinate and
cores such as non-pareils, the layering carboxymethylcellulose. Preferably, an inert
techniques from solution/suspensions produce seal coat is present in the composition as a
homogeneous drug loaded particles, which barrier between the IL-11 layer and enteric
retain an approximately spherical shape. They coat. The inert seal coat can be e.g. hydroxyl
are therefore particularly suitable for propyl methyl cellulose, povidone,
successively film coating to build up the hydroxylpropyl cellulose or another
particle with the aim of providing a desired pharmaceutically acceptable binder.
drug release profile 18. Suitable sustained release polymers include,
e.g., amino methacrylate copolymers
Delayed release oral polypeptides (Eudragit RL, Eudragit RS), ethylcellulose or
In one embodiment, the composition further hydroxypropyl methylcellulose. In some
includes an inert core. The inert core can be, embodiments, the methacrylic acid copolymer
e.g., a pellet, sphere or bead made up of is a pH dependent anionic polymer solubilizing
sugar, starch, microcrystalline cellulose or any above pH 5.5. The methacrylic acid copolymer
other pharmaceutically acceptable inert can be provided as a dispersion and be
excipient. A preferred inert core is a present in the composition at a concentration
carbohydrate, such as a monosaccharide, of 10-20% wt/wt. A preferred methacrylic acid
disaccharide, or polysaccharide, i.e., a copolymer Eudragit® L30D-55 19.
polymer including three or more sugar
Multiparticulate mucoadhesive
molecules. An example of a suitable
formulations
carbohydrate is sucrose. In some embodi-
In a preferred embodiment, illustrated by way
ents, the sucrose is present in the composition
of example, there is provided a supply of gas-
at a concentration of 60-75%.
developing components as well as a number
When the bioactive polypeptide is IL-11, the
of film-like, stacked individual particles which
IL-11 layer is preferentially provided with a
consist of a mucoadhesive, active substance-
stabilizer such as methionine, glycine,
containing layer and of a backing layer
polysorbate 80 and phosphate buffer, and/or a
controlling the direction of active substance
pharmaceutically acceptable binder, such as
release, these components being located
hydroxypropyl methylcellulose, povidone or
within a polymer enclosure which is resistant
hydroxypropyl ‘cellulose. The composition can
to gastric juice but permeable to intestinal
additionally include one or more
juice. Here, the active substance may be
pharmaceutical excipients. Such pharmaceu-
present embedded in the film-like component.
ical excipients include, e.g., binders,
The process for the production of a gastric
disintegrants, fillers, plasticizers, lubricants,
juice-resistant device, consisting of at least
glidants, coatings and suspending/ ispersing
one active substance in the form of a
agents. In some embodiments, the
multiparticulate preparation with muco-
composition is provided as a multiparticulate
adhesive properties, and of a blowing agent
system that includes a plurality of enteric
which on contact with liquid produces gas
coated, IL-11 layered pellets in a capsule
individual particles being enclosed by a gastric
dosage form. The enteric coated IL-11 pellets
juice-resistant, intestinal juice-soluble polymer

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enclosure, is as follows: (a) transfer of a release multiparticulate systems for


chronotherapeutic delivery of ketoprofen,
polymer material in web form to a moulding
Indian journal of Pharmaceutical Science 2006,
board provided with bores, and applying a 68(1): 76-82.
vacuum to form the compartments of the 7. Chourasia M.K., Jain S.K., Design and development
polymer enclosure; (b)alternately filling-in the of multiparticulate systems for targeted drug
delivery to colon, Drug Delivery 2004, 11(3):
active substance-containing preparation and 201-207(7).
the blowing agent-containing preparation; (c) 8. Zhang H., Alsarra I.A., Neau S.H., An in vitro
superposing a second polymer web, and evaluation of a chitosan-containing
closing the compartments by sealing with multiparticulate system for macromolecule, In J
of Pharm, 2002, 239(1):197-205.
application of heat and pressure; and (d)
9. Peter S., Peter K., New multiparticulate delayed
separating the individual devices by punching release system, J of Controlled Rel, 1997,
20
or cutting . 147(2):181-189.
10. Verma R.K., Garg S., Current status of drug delivery
technologies and future directions, Pharm
CONCLUSION
Technol, 2001, 25 (2), 1-14.
The market for drug delivery system has come 11. Multiparticulate crystalline drug compositions having
a long way and will continue to grow at an controlled release profiles. United States
impressive rate. Today’s drug delivery Patent 20050181062,
www.freepatentsonline.com
technologies enable the incorporation of drug 12. Intestinal protective drug absorption system, Elan
molecules into a new delivery system, thus Corporation, U.S.Patent 75111480, Nov 4,
providing numerous therapeutic and 1997.
commercial advantages. Multiparticulate drug 13. Spheroidal oral drug absorption system, Elan
Corporation, U.S.Patent 73700314, Nov21,
delivery systems provide several all the
1989.
advantages including greater flexibility and 14. Programmable oral drug absorption system, Elan
adaptability of microparticulate dosage forms Corporation, U.S.Patent 75283262, Jun27,
which gives clinicians and those engaged in 2000.
15. Diffucaps in multiparticulate drug delivery, Eurand
product development powerful new tools to
S.P.A. Corporation, U.S. Patent 72329344,
optimize therapy. It is little wonder therefore, Feb29, 1972.
that such systems are growing rapidly in 16. Minitabs in multiparticulate drug delivery, Eurand
popularity. S.P.A. Corporation, U.S. Patent 75843477,
June 17, 2003.
17. Alam S., Ehsan S.D., Pharma niaga marketing,
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