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BACHELOR OF PHARMACY
IN
HEMCHANDRACHARYA
NORTH GUJARAT UNIVERSITY,
PATAN
GUIDE SUBMITTED BY
Mr. ASHOK MAHAJAN Mr.JITENDRA AMRUTIYA
1
APMCCPER HIMMATNAGAR
“PULSATILE DRUG DELIVERY SYSTEMS”
BACHELOR OF PHARMACY
IN
HEMCHANDRACHARYA
NORTH GUJARAT UNIVERSITY,
PATAN
GUIDE SUBMITTED BY
Mr. ASHOK MAHAJAN Mr. JITENDRA
AMRUTIYA
2
APMCCPER HIMMATNAGAR
CERTIFICATE
Principal Guide
Dr. Dushyant A. Shah Mr. Ashok Mahajan
M.Pharm, Ph.D. M.Pharm
APMCCPER Lecturer,
Department of Pharmaceutics,
APMCCPER, Himmatnagar.
ACKNOWLEDGEMENT
whom I owe a great deal for successful completion of this project work.
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SR. PARTICULARS PAGE
NO NO
1 INTRODUCTION 1
2 ADVANTAGES 4
3 DISADVANTAGES 5
4 IMPORTANCE OF PULSATILE DRUG 6
DELIVERY SYSTEMS
5 TYPES OF PULSATILE SYSTEMS 8
5.1 SINGLE UNIT SYSTEMS 8
5.2 MULTIPARTICULATE SYSTEMS 32
6 MARKETED TECHNOLOGIES 41
7 CONCLUSION 42
8 REFERENCES 43
INDEX
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DEDICATED
TO
MY PARENTS,
FRIENDS
&
MY GUIDE
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APMCCPER HIMMATNAGAR
1. INTRODUCTION
Over the past three decades, advances in research aiming towards underlying
principles to bring both commercial and therapeutic values to health care products, are
contributing to novel drug delivery systems. These new and/or improved delivery
systems work on various principles by providing variable/constant drug amounts over
a particular time period in our body based on the fact that physiologic parameters
1.
display constancy over a time However, a new concept which belie this popular
belief, termed as chronotherapy has been introduced.
Chronotherapeutics refers to a clinical practice of synchronizing drug delivery in
a manner consistent with the body's circadian rhythm including disease states to
produce maximum health benefit and minimum harmful effects. The dependence of
several diseases and body function on circadian rhythm is well known. A genetic
control of a “master clock” located in the nucleus suprachiasmaticus has been recently
proposed 2 Numerous studies conducted, suggest that pharmacokinetics, drug efficacy
and side effects can be modified by following therapy matching the biological
rhythm. Specificity in delivering higher amount of drug in a burst at circadian timings
correlated with specific pathological disorder is a key factor to achieve maximum
drug effect 3–6.
Particular rhythms in the onset and extent of symptoms were observed in diseases
such as,
o Bronchial asthma,
o Myocardial infarction,
o Angina pectoris,
o Rheumatic disease,
o Ulcer, diabetes,
o Attention deficit syndrome,
o Hypercholesterolemia,
o Hypertension 7
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All these acted as a push for the development of “Pulsatile Drug Delivery Systems”
.In these systems; there is rapid and transient release of a certain amount of drug
molecules within a short time-period immediately after a predetermined off-release
period 8
Various techniques are available for the pulsatile delivery, broadly classified as,
Single-unit and Multiple-unit systems. Overall, they work on same basic principles of
erosion or dissolution; swelling and rupturing; and system based on change in
membrane permeability. However, single unit pulsatile drug delivery system may
suffer from the disadvantage of unintentional disintegration of the formulation due to
manufacturing deficiency or unusual gastric physiology that may lead to drastically
compromised systemic drug bioavailability or loss of local therapeutic action. In
recent pharmaceutical applications involving pulsatile delivery, multiparticulate
dosage forms are gaining much favor over single-unit dosage forms 9
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The potential benefits include increased bioavailability; predictable, reproducible
and generally short gastric residence time; no risk of dose dumping; reduced risk of
local irritation; and the flexibility to blend pellets with different compositions or
release patterns. Because of their smaller particle size these systems are capable of
passing through the GI tract easily, leading to less inter- and intra-subject variability.
However, potential drug loading of a multiparticulate system is lower because of the
proportionally higher need for excipients (e.g., sugar cores). Although several
technologies for the production of microparticulate Systems have been designed; thus
far the mainstream technologies are still based on spray-drying, spheronization, and
film-coating technology. Limitation of process variables caused by multiple
formulation steps can act as technical hurdles in manufacturing reproducibility and
lack of safety and efficacy, true reservoir devices have not yet succeeded.
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2. ADVANTAGES
Improve bioavailability
Flexibility in design
Improve stability
3. DISADVANTAGES
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Proportionally higher need for excipients
However, there are certain conditions for which such a release pattern is not suitable.
These conditions demand release of drug after a lag time. In other words, it is required
that the drug should not be released at all during the initial phase of dosage form
administration. Such a release pattern is known as pulsatile release. The conditions
that demand such release include:
Much body functions that follow circadian rhythm, i.e., their activity waxes
and wanes with time. A number of hormones like rennin, aldosterone, and
cortisol show daily fluctuations in their blood levels.10 Circadian effects are
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also observed in case of pH and acid secretion in stomach, gastric emptying,
and gastrointestinal blood transfusion.11
Diseases like bronchial asthma, myocardial infarction, angina pectoris,
rheumatic disease, ulcer, and hypertension display time dependence.
12
Dethlefsan and Repges 13 reported sharp increase in asthmatic attacks during
early morning hours. Such a condition demands considerations of diurnal
progress of the disease rather than maintaining constant plasma drug level. A
drug delivery system administered at bedtime, but releasing drug well after the
time of administration (during morning hours), would be ideal in this case.
Same is true for preventing heart attacks in the middle of the night and the
morning stiffness typical of people suffering from arthritis.
Drugs that produce biological tolerance demand for a system that will prevent
their continuous presence at the bio phase as this tends to reduce their
therapeutic effect.14
The lag time is essential for the drugs that undergo degradation in gastric
acidic medium (e.g., peptide drugs) irritate the gastric mucosa or induce
nausea and vomiting. These conditions can be satisfactorily handled by enteric
coating, 15and in this sense; enteric coating can be considered as a pulsatile
drug delivery system.
Targeting a drug to distal organs of gastro-intestinal tract (GIT) like the colon
requires that the drug release is prevented in the upper two-third portion of the
GIT. 16
The drugs that undergo extensive first-pass metabolism (b blockers) and those
that are characterized by idiosyncratic pharmacokinetics or
pharmacodynamics resulting in reduced bioavailability, altered
drug/metabolite ratios, altered steady state levels of drug and metabolite, and
potential food-drug interactions require delayed release of the drug to the
extent possible.
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The first pulsed delivery formulation that released the active substance at a precisely
defined time point was developed in the early 1990s. In this context, the aim of the
research was to achieve a so-called sigmoidal release pattern. The characteristic
feature of the formulation was a defined lag time followed by a drug pulse with the
enclosed active quantity being released at once. 17
Thus, the major challenge in the development of pulsatile drug delivery system is to
achieve a rapid drug release after the lag time. Often, the drug is released over an
extended period of time
In these systems, there is rapid and transient release of a certain amount of drug
molecules within a short time-period immediately after a predetermined off-release
period. Various techniques are available for the pulsatile delivery, broadly classified
as,
• Single-unit
• Multiple-unit (Multiparticulate) systems.
Overall, they work on same basic principles of erosion or dissolution; swelling and
rupturing; and system based on change in membrane permeability.
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.
5.1 SINGLE UNIT SYSTEMS
There are various approaches, are used to formulate single unit pulsatile drug delivery
system, including
o Time controlled release
o Site specific release
o Externally regulated (non self regulated or open loop delivery)
o Self- regulated ( close loop delivery)
Most pulsatile systems are reservoir devices coated with a barrier layer. In this
drug delivery system, drug release occurs through barrier or polymer coatings, which
dissolves or erodes after a specific lag period, following which the drug is released
rapidly from the reservoir core.
I. CHRONOTROPIC SYSTEM
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System consists of a drug containing core and an HPMC layer, optionally coated
with an outer enteric coating. The lag time prior to drug release was controlled by the
o Thickness and
o Viscosity grade of the HPMC layer.
After erosion of the rubbery HPMC layer, a distinct pulse was observed. To avoide
retarding effects in the drug release phase, the thickness as well as the viscosity grade
of the HPMC layer should be limited. The system probably worked best for poorly
water-soluble drugs, because highly water-soluble drugs could diffuse through the
swollen HPMC layer prior to complete erosion. This system is not particularly well
suited for the applications to multiparticulate systems, because relatively thick barrier
layers were needed and the resulting drug loading of the system, often more critical in
multidose systems, could be further decreased.
A release pattern with two pulses was obtained from three-layer tablet consisting of
two drug-containing layers, separated by a drug-free gellable polymeric barrier layer.
The three-layer tablet was coated on three sides with an impermeable coating (ethyl
cellulose) and the top side of the tablet remained uncoated. Upon contact with
dissolution fluids, the initial dose incorporated into the top layer was released rapidly
from the uncoated surface of the tablet. The second pulse was obtained from the
bottom layer after the gelled barrier layer (HPMC) has been eroded and dissolved.
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FIG: Theoretical pulsatile release of a drug from surface-eroding polymeric
systems. The time between initial release and booster release is determined by
the erosion of the drug-free layer
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timeofrelease.
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Several single unit pulsatile dosage forms with a capsular design have been
developed. Most of them consist of an insoluble capsule body, which contains the
drug, and a plug, which prevents drug release during the lag phase. Mechanisms of
plug removal include dissolution, erosion, or induced pushing-out of the plug by
swelling or osmotic pressure.
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Fig. . Capsular-shaped pulsatile drug delivery system, consisting of
an impermeable capsule body and (A) a swellable,Insoluble coated
plug and (B) an erodible plug.
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CHRONSET_ SYSTEM:
In this system the driving force for the drug release was an osmotically active
layer in the semi permeable vessel, which pushed the cap out off the impermeable
vessel after a predetermined time interval.31 The complete release of the drug, often
problematic in capsular-shaped dosage forms, was ensured by an expanding layer at
the bottom of the capsule body.
Chronset system
Even more sophisticated were insoluble high frequency (HF) capsules, which released
the drug in a pulsed fashion after a high-frequency signal was applied externally to the
human body.32,33 These HF capsules were used to evaluate the absorption of drugs
from distinct regions within the digestive tract. A similar capsule activated by an
oscillating magnetic field has been published recently, which ejected an active
compound or a radioactive marker to localize the position of the dosage form in the
gastrointestinal tract.34 In general, the large-scale manufacturing of the above
mentioned capsular-shaped pulsatile drug delivery systems appears to be complicated.
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Special equipment and several manufacturing steps are necessary to combine all
components.
(4)PULSATILE DRUG DELIVERY BY OSMOTICALLY CONTROLLED
The Port® System (Port Systems, LLC) consists of a gelatin capsule coated
with a semi permeable membrane (eg, cellulose acetate) housing an insoluble plug
(eg, lipidic) and an osmotically active agent along with the drug formulation (Figure
35
3). When in contact with the aqueous medium, water diffuses across the semi
permeable membrane, resulting in increased inner pressure that ejects the plug after a
lag time. The lag time is controlled by coating thickness. The system showed good
36
correlation in lag times of in-vitro and in-vivo experiments in humans. The system
was proposed to deliver methylphenidate for the treatment of attention deficit
hyperactivity disorder (ADHD) in school-age children. Such a system avoids a second
daily dose that otherwise would have been administered by a nurse during school
hours. 37
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F
IG: Theoretical pulsatile release of a drug from an osmotically driven system. The
time until the booster release is determined by the influx of water into and swelling of
the tablet core. Gray region indicates the pore formation and subsequent uptake of
water occurs through these pores.
To deliver the drug in liquid form, an osmotically driven capsular system was
developed in which the liquid drug is absorbed into highly porous particles, which
release the drug through an orifice of a semi permeable capsule supported by an
38
expanding osmotic layer after the barrier layer is dissolved. The capsular system
delivers drug by the capsule's osmotic infusion of moisture from the body. The
capsule wall is made up of an elastic material and possesses an orifice. As the osmosis
proceeds, the pressure within the capsule rises, causing the wall to stretch. The orifice
is small enough so that when the elastic wall relaxes, the flow of the drug through the
orifice essentially stops, but when the elastic wall is distended beyond threshold
value, the orifice expands sufficiently to allow drug release at a required rate.
Elastomers, such as styrene-butadiene copolymer have been suggested.39,40 Pulsatile
release was achieved after lag times of 1 to 10 hours, depending on the thickness of
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38
the barrier layer and that of semipermeable membrane, and a capsule designed for
implantation can deliver drug intermittently at intervals of 6 hours for 2 days.
This system is described for implantable capsules. The capsule contains a drug and
a water-absorptive osmotic engine that are placed in compartments separated by a
movable partition. The pulsatile delivery is achieved by a series of stops along the
inner wall of the capsule. These stops obstruct the movement of the partition but are
overcome in succession as the osmotic pressure rises above a threshold level. The
number of stops and the longitudinal placements of the stops along the length of the
capsule dictate the number and frequency of the pulses, and the configuration of the
partition controls the pulse intensity. This system was used to deliver porcine
somatotropin . 41
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42
and oxprenolol. However, in general, the large-scale manufacturing of these
systems is complicated and calls for special equipments and several manufacturing
steps.
Site specific DDS release the drug at the desired site within the intestinal
tract .the release is usually controlled by environmental factors, such as the presence
of pH or enzymes in the intestinal tract. The simple pulsatile drug delivery system is
an enteric coated dosage form, which releases the drug rapidly after dissolution of the
enteric coating. The lag time prior to the release depends primarily on the type and
coating level of enteric polymer and the residence time in the stomach. Longer lag
time can be achieved with polymers, which dissolves at a higher pH, and at higher
coating levels. The lag time under in vivo conditions are, however, quite variable,
especially with single unit systems.
The invention relates to delivery systems that allows for the pulsatile release of a
substance, such as a drug, in response to a change in pH. More specifically, it relates
to drug administration to the gastrointestinal (GI) tract, in particular to site-specific
intestinal drug delivery via the oral route. Provided is a pH-controlled release system
that allows for a rapid release of a drug in response to the pH of intestinal fluids. The
drug delivery system has the capability of complete loss of integrity in a very short
period of time, allowing delivery of virtually all of the drug contained therein at the
desired location/segment. This is achieved by surrounding the drug with a layer of pH
sensitive coating material in which a swellable agent is embedded. The structure of
the coating is such that the swellable agent is embedded in a continuous matrix of the
pH sensitive coating polymer in a concentration below the percolation threshold. As
soon as the outer layer of enteric coating material starts to erode upon a change in pH,
GI fluid can reach the swellable agent, which swells enough to accelerate the further
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and complete disintegration of the coating and subsequently causes instant release of
the drug at the target site.
Significant variations in the pH occur in the GI tract with values ranging from
approximately 1 in the stomach, 6.6 in the proximal small intestine and a peak of
about 7.5 in the distal small intestine.
The pH differential between the stomach and small intestine has historically been
exploited to orally deliver drugs to the intestinal tract by way of pH-sensitive
polymeric coatings. Delivery of drugs to sites beyond the stomach is especially
desirable for drugs that are destroyed by the acid conditions or enzymes of the
stomach, or for drugs that cause adverse events by local activity in the stomach. The
low stomach pH and presence of gastric enzymes have led to the development of oral
drug dosage forms in which the drug is provided with an enteric coating.
Enteric coating materials exhibit resistance to acidic gastric fluids yet are
readily soluble or permeable in intestinal fluid. Enteric polymeric materials are
primarily weak acids containing acidic functional groups, which are capable of
ionization at elevated pH. In the low pH of the stomach, the enteric polymers are
protonized, and therefore, insoluble. As the pH increases in the intestinal tract, these
functional groups ionize, and the polymer becomes soluble in the intestinal fluids.
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Thus, an enteric polymeric film coating allows the coated solid, e.g. a capsule
comprising a drug, to pass intact through the stomach to the small intestine, where the
drug is then released in a pH-controlled fashion. The drug can become available for
absorption to the systemic circulation or locally in the GI-tract where it can exert its
pharmacologic effects.
When the transit is faster or slower than expected the drug may be released at the
wrong site or outside the absorption window of the drug. A second strategy exploits
the differences that occur in environmental conditions at different sites in the GI-tract,
thereby circumventing problems that may arise from variations in the OCTT. Two
different sub-strategies exist; systems that respond to bacterial enzymes may be used
to target the colon whereas systems that respond to pH variations may be used to
target different sites in the g-i tract. The bacterial-enzyme dependent systems suffer
from two major limitations in their performance. First of all the bacterial flora may
vary from individual to individual, if the required bacteria are not present in a patient
the drug may not be released at all. Furthermore, the release from these systems is in
general very slow and pulsatile release is difficult to obtain. A pH-controlled drug
delivery system has the advantage that it is site-specific. Just as bacterial-enzyme-
dependent controlled formulations. It is largely independent of the orocaecal transit
time (OCTT), which may vary between individuals. Furthermore, it is independent of
the presence of bacteria. Finally, pH-sensitive polymers that allow for a site-specific
release are readily commercially available.
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5.1. (C) OPEN-LOOP DELIVERY SYSTEMS (EXTERNALLY
REGULATED)
1. MAGNETIC FIELD:
Use of an oscillating magnetic field to modulate the rates of drug delivery from a
polymer matrix was one of the first methodologies investigated to achieve an
externally controlled drug delivery system. Magnetic carriers can receive their
magnetic response to a magnetic field from incorporated materials such as magnetite,
iron, nickel, cobalt and steel. .
Magnetic steel beads were embedded in an ethylene and vinyl acetate (EVAc)
copolymer matrix that was loaded with bovine serum albumin as a model drug.
Authors demonstrated increased rates of drug release in the presence of an oscillating
magnetic field . During exposure to the magnetic field, the beads oscillate within the
matrix, alternatively creating compressive and tensile forces. This in turn acts as a
pump to push an increased amount of the drug molecule out of the matrix. Co-
polymers with a higher Young's modulus were more resistant to the induced motion
of steel beads, and consequently the magnetic field has less effect on the rate of drug
release from these materials.
Saslawski et al. developed different formulations for in vitro magnetically
triggered delivery of insulin based on alginate spheres. In an experiment, ferrite
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microparticles (1 mm) and insulin powder were dispersed in sodium alginate aqueous
solution. The ferrite-insulin alginate suspension was later dropped in aqueous calcium
chloride solution which causes the formation of cross linked alginate spheres, which
were further cross linked with aqueous solution of poly(L-lysine) or poly(ethylene
imine). They described that the magnetic field characteristics due to the ferrite
microparticles and the mechanical properties of the polymer matrices could play role
in controlling the release rates of insulin from the system.
2. ULTRASOUND:
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Special attention has been given to the thermally responsive poly(N-
isopropylacrylamide) and its derivative hydrogels. Poly (N-isopropyl acryl amide)
(PIPAAm) cross-linked gels have shown thermo responsive, discontinuous
swelling/deswelling phases: swelling for example, at temperatures below 32°, while
shrinking above this temperature. A sudden temperature increase above the transition
temperature of these gels resulted in formation of a dense, shrunken layer on the gel
surface (skin layer), which hindered water permeation from inside the gel into the
environment. Drug release from the PIPAAm hydrogels at temperature below 32° was
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governed by diffusion, while above this temperature drug release was stopped
completely, due to the 'skin layer' formation on the gel surface (on-off drug release
regulation) .
4. ELECTRIC FIELD:
Hyaluronic acid,
Chondrotin sulphate,
Agarose,
Carbomer,
Calcium alginate.
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Acrylate and
Hydrolysed polyacrylamide,
Polydimethylaminopropylacylamide. .
5. LIGHT
The interaction between light and material can be used to modulate drug delivery.
This can be accomplished by combining a material that absorbs light at a desired
wavelength and a material that uses energy from the absorbed light to modulate drug
delivery. Gold nanoshells are a new class of optically active nanoparticles that consist
of a thin layer of gold surrounding a core. The optical properties of the nanoshells can
be tuned over the visible and near IR spectrum. Embedding the nanoshells in a
NIPAAm-co-AAM hydrogel formed the required composite material. When exposed
to near-infrared light, nanoshells absorb the light and convert it to heat, raising the
temperature of composite hydrogel above its LCST. The hydrogel collapses and this
results in an increased rate of release of soluble drug held with in the matrix …
6.MECHANICAL FORCE:
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held with in the polymer matrix is released during compression; once the strain is
removed hydrogel returns to its original volume. This concept is essentially similar to
squeezing the drug out of a sponge.
Closed-loop delivery systems are those that are self-regulating. They are similar
to the programmed delivery devices in that they do not depend on an external signal
to initiate drug delivery. However, they are not restricted to releasing their contents at
predetermined times. Instead, they respond to changes in local environment, such as
the presence or absence of a specific molecule.
A. GLUCOSE-SENSITIVE SYSTEMS
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glucose oxidase, caused the tertiary amine groups in the barrier membrane to
protonate and induce a swelling response in the membrane. Insulin in the reservoir
was able to diffuse across the swollen barrier membrane. When the glucose
concentration decreased, the pH of the barrier membrane increased and it returned to a
more collapsed and impermeable state.
Another glucose - sensitive delivery system is based on the competitive binding of
concanavalin (con A), which is a glucose binding lectin. Obaidat and Park prepared a
copolymer of acrylamide and allyl glucose. The side chain glucose units in the
copolymer were bound to con A. These hydrogel showed a glucose-responsive, sol-
gel phase transition, depending on the external glucose concentration due to the
competition between free glucose and con A. Con A acts as cross linker for the
polymer chains due to the presence of four glucose-binding sites on the molecule, but
competitive binding with glucose disrupts these cross links, making the material more
permeable and thus increasing the rate of drug delivery [Figure]..
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On receiving any physical or chemical stress, such as injury, fracture etc.,
inflammation take place at the injured sites. During inflammation, hydroxyl radicals
are produced from these inflammation-responsive cells. Yui and co-workers focused
on the inflammatory induced hydroxyl radicals and designed drug delivery systems,
which responded to the hydroxyl radicals and degraded in a limited manner. They
used hyaluronic acid (HA) which is specifically degraded by the hyaluronidase or free
radicals. Degradation of HA via the hyaluronidase is very low in a normal state of
health. Degradation via hydroxyl radicals however, is usually dominant and rapid
when HA is injected at inflammatory sites. Thus, it is possible to treat patients with
inflammatory diseases like rheumatoid arthritis; using anti-inflammatory drug
incorporated HA gels as new implantable drug delivery systems.
There are numerous kinds of bioactive compounds which exist in the body.
Recently, novel gels were developed which responded to the change in concentration
of bioactive compounds to alter their swelling/deswelling characteristics. Special
attention was given to antigen-antibody complex formation as the cross-linking units
in the gel, since such interactions are very specific. Utilizing the difference in
association constants between polymerized antibodies and naturally derived
antibodies towards specific antigens, reversible gel swelling/deswelling and drug
permeation changes occurs.
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5.2 MULTIPARTICULATE PULSATILE DRUG
DELIVERY SYSTEM
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.
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(1). RESERVOIR SYSTEMS WITH SOLUBLE OR ERODING POLYMER
COATINGS
One class of reservoir-type multiparticulate pulsatile systems is based on soluble /
erodible layers in place of rupturable coatings. The barrier dissolves or erodes after a
specific lag time followed by burst release of drug from the reservoir core. In general,
for this kind of systems, the lag time prior to drug release can be controlled by the
thickness of the coating layer. However, since from these systems release mechanism
is dissolution, a higher ratio of drug solubility relative to the dosing amount is
essential for rapid release of drug after the lag period. The lag times delayed by the
hydration of various thicknesses of Eudragit RS films were studied in an attempt to
deliver drugs to various sites in the gastrointestinal (GI) tract 45
Diltiazem hydrochloride was selected as a model drug with high and pH
independent water solubility. In a theoretical simulation, it was found that the lag time
could be controlled by varying the thickness of the coated polymer, which was
equivalent to the amount of the dry polymer in coating. The relationship between the
lag time and the square of the amount of polymer coated, as well as that between the
release rate at steady state and the inverse of the amount of polymer coated was well
predicted. Traditionally, the coatings that have been employed because of their large
increase in solubility at some point in the GI tract have been those that are pH
sensitive. This sensitivity has been utilized to prevent release in the stomach affording
complete release in intestine. A formulation dependent on the slow dissolution
behavior of high viscosity polymers is described by Gazzaniga et al. 46. It consists of
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FIG: Theoretical pulsatile release of a drug from a bulk eroding polymer system.
The time between initial release and booster release is determined by the period
of bulk erosion to reach a molecular weight that causes porosity in the matrix.
MW is molecular weight.
Mini-tablets with there in dispersed a drug substance which is coated with a high
viscosity polymer (HPMC 4000) and an outer enteric coating. The outer film protects
the system from the fluids in the stomach and dissolves on entering the small
intestine. HPMC layer delays the release of drug for 3–4 h when the system is
transported through small intestine. A pH sensitive multi-particulate system,
comprising of Eudragit S-100 coated pellets was designed for chronotherapeutic
delivery of diltiazem hydrochloride for treating angina pectoris 47.
The drug loaded pellets were produced by aqueous extrusion spheronization
technique using microcrystalline cellulose as a spheronizing aid and PVP K 30 as a
binder. Different coat weights of Eudragit S-100 were applied to the drug loaded
pellets to produce the pH sensitive pellets. In vitro dissolution studies of the
coated pellets performed following pH progression method showed that the drug
release depended on the coat weights applied and pH of the dissolution media. A
single dosage form which can able to release its components at different time and site
of gastrointestinal tract can be a very useful approach.
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48
Dittigen et al. have developed such formulation comprises of four compressed
compositions filled in a capsule, each with a different coating compositions and
soluble at different pH throughout the gastrointestinal tract. This system can provide
widely varying pharmaceutically required release profile of effective ingredients or
effective ingredient combination defined by their release profile.
Most of the time-controlled systems or delayed release systems suffers from the
disadvantage that they are not suitable for delivering weakly basic, since the basic
drugs are insoluble at intestinal pH. To overcome the problem of pH-dependent
solubility of weakly basic drugs, pH adjusters, which can provide local acidic
49
environment within the system, can be admixtured. This type of system where a
capsule containing a multitude of multicoated particulates is expected to deliver
therapeutic agents into the body in a time-controlled controlled pulsatile release
fashion was described. One of the coating membranes is an enteric polymer and the
second membrane barrier is a mixture of a water-insoluble polymer and an enteric
polymer. An organic acid, such as fumaric acid, citric acid, succinic acid, tartaric acid
or malic acid, or a maleic-acid-containing membrane may be provided between the
first and second membrane layers to provide for the time-separated pulses. The acids
in between the membranes may delay the dissolution of the enteric polymer in the
inner layer, thereby increasing the lag time as well as decreasing the rate of release of
the active ingredient from the coated micro particulates.
.
(2). RESERVOIR SYSTEMS WITH RUPTURABLE POLYMERIC
COATINGS
Most multiparticulate pulsatile delivery systems are reservoir devices coated with
a rupturable polymeric layer. Upon water ingress, drug is released from the core after
rupturing of the surrounding polymer layer, due to pressure build-up within the
system. The pressure necessary to rupture the coating can be achieved with swelling
agents, gas producing effervescent excipients or increased osmotic pressure. Water
permeation and mechanical resistance of the outer membrane are major factors
affecting the lag time.
Water soluble drugs are mainly released by diffusion; while for water insoluble drug,
the release is dependent on dissolution of drug.
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TIME- CONTROLLED EXPLOSION SYSTEMS (TES)
51–53
Ueda et al. have discovered a Time-controlled explosion system (TES),
where drug is released by a quite novel mechanism which is neither diffusion control
nor dissolution control, but by explosion of the outer membrane. This mechanism is
especially useful with water insoluble drugs in which those prior art delay
mechanisms related to diffusion of the drug through a permeable coating would not be
effective. TES were developed for both single and multiple unit dosage forms. In both
cases, a core contains drug plus an inert osmotic agent and suitable disintegrants.
Individual units can be coated by a protective layer and then by a semi permeable
layer, which is the rate controlling membrane for the influx of water into the osmotic
core. Build up of the osmotic pressure by water ingress, the core ultimately explodes,
with immediate release of the drug. The explosion of formulation can also be
achieved through use of swelling agents.
With the change of the form of TES, different release pattern can be achieved; as
in form of tablet, drug is released quickly after the explosion of the outer membrane,
while in case of TES in form of beads or granules, drug is released with zero order
pattern after a definite lag time because of the time variance of the explosion of the
outer membrane in each bead or granule. Drug release is time-controlled by the
rupturing of the external water-insoluble membrane caused by explosive swelling
effect of swelling agents. The lag time increased with increasing coating level and
higher amounts of talc or lipophilic plasticizer in the coating. A four layered time-
controlled explosion system was developed where, drug was layered on an inner core
(polystyrene balls or non-pareil sucrose beads), followed by a swellable layer (e.g.,
hydroxypropyl cellulose) and an insoluble polymeric top layer (e.g., ethylcellulose).
The release from TES systems was described to be complete, independent of the
environmental pH and drug solubility. However, these systems has the drawback of
failing to release the drug if the swelling agents fail to rupture the water insoluble
coating and having limited flexibility in the release patterns and also maximum lag
times of approximately four h was reported by the authors. To overcome the
[55, 56]
drawbacks associated with TES, two approaches have been proposed to have
bettercontrol over release pattern, incorporation of water soluble polymer in insoluble
polymeric membrane of TES has been suggested. This water soluble polymer is of the
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enteric coating polymer type in which the polymer becomes soluble only at pH values
above certain specific values. This prevents dissolving of the polymer in the stomach.
When the pellet reaches the elevated pH of the intestine, the polymer begins to
dissolve and weaken the membrane coating, so that explosion of the weakened
membrane can be assured after a predetermined time of exposure to the intestinal
environment.
By varying the proportion of soluble and insoluble material in the coating as well
as the coating thickness, the time delay before explosion can be prolonged with better
control and reliability, with eventual disintegration of the coating ensuring release of
the drug. However, the disadvantage of a water-soluble polymer to regulate time
release is that, once the portions of water-soluble polymers are dissolved, active agent
may start leaching out, leading to premature drug release and inconsistent drug
efficacy. Increase in the lag time of the TES systems can be achieved by incorporating
water impermeable materials in coating. By reducing the rate of influx of water into
the interior of the pellet containing the swelling agent, the rate of swelling can be
reduced and the time to explosion can be prolonged and controlled. In the similar line,
a drug delivery system comprises of plurality of particles with outer coating of water
insoluble, water permeable polymer, and water-permeation adjusting agents for
dispensing single or multiple precisely timed pulsed releases has been investigated
The plurality of particles are divided into several delivery units, with each group
having its own unique inner structured active core and specific external coatings.
These particles contain a polymer-blend hydrogel for the controlled-release matrix
layer delivering controlled prolonged pulsed doses, and a swelling agent for the rapid-
release layer delivering recurring short pulsed doses. The controlled-release layer and
the swelling rapid-release layer can each contain one or more active agents for single
or multiple therapeutic regimes. Super-disintegrants are substances with a high
swelling potential and can be used to form the swelling layer of rupturable systems.
Dashevsky et al. developed a rupturable pulsatile multiparticulate drug delivery
system consists of a drug core; a swelling layer, comprising a superdisintegrant and a
binder; and an insoluble, water-permeable polymeric coating Aquacoat® ECD. Lag
time was shorter for theophylline layered on sugar cores, compared to cores of 100%
theophylline. A fast and complete release after lag time was achieved with crosslinked
carboxymethyl cellulose (AcDiSol®), in comparison to a sustained release pattern
with low-substituted hydroxypropyl cellulose (L-HPC) and sodium starch glycolate
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(Explotab®) as swelling agents. Lag time was controlled by the coating level of the
outer membrane which was brittle and ruptured sufficiently to ensure fast drug
release. Addition of talc increased the brittleness of membrane. Upon water ingress,
the swellable layer expands, resulting in the rupturing of outer membrane with
subsequent rapid drug release. Later, they performed the in vitro and in vivo
evaluation of the above system to investigate its drug release performance, with
acetaminophen as a model drug Overcoming the pH and transit time differences
between the animals and humans are necessary to obtain good correlation between the
pharmacokinetic data for sustained release-pulsatile drug delivery systems.
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coating with Eudragit RS . The lag time increased with increasing thickness of the
outer membrane. However, the slope of the drug release phase was independent of the
thickness but was influenced by the amount of the salt in the system, indicated that the
release mechanism is depend on the amount of the salt or permeability modifier.
The release profile of systems based on permeability changes depend strongly
on the physicochemical properties of the drug and its interaction with the membrane.
Therefore, with this system a pulsatile release profile may be obtained for some
particular drug molecules in a specific formulation but cannot be generally applied to
all drugs.
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control of cross-linking, insolubility of crosslinked beads in gastric environment and
broad regulatory acceptance.
Badve et al s devlophollow calcium pectinate beads for floating-pulsatile release of
diclofenac sodium intended for chronopharmacotherapy. To overcome limitations of
various approaches for imparting buoyancy, hollow/porous calcium pectinate beads
were prepared by simple process of acid-base reaction during ionotropic crosslinking.
The floating beads provided two-phase release pattern with initial lag time during
floating in acidic medium followed by rapid pulse release in phosphate buffer. This
approach suggested the use of hollow calcium pectinate microparticles as promising
floating-pulsatile drug delivery system for site- and timespecific release of drugs for
chronotherapy of diseases. Further, combined floating and pulsatile principles were
achieved using a specific technology, in which low density microporous
polypropylene, Accurel MP 1000, were used as a multiparticulate carrier for
ibuprofen.
Ibuprofen was adsorbed on the polymer by solvent evaporation technique; a single
step method resulted in to different porous particles. This drug delivery system
showed distinct behaviour from other approaches in chronotherapy with desired low
drug release in acidic medium, reduced time consumption due to single step process,
and even overcame the limitations of process variables caused by multiple
formulation steps.
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Pharmaceutical) got the green signal from FDA in 2008 for its proprietary, once-a-day
pulsatile delivery technology called PULSYS™, which enables the delivery of
antibiotic amoxicillin in regular concomitant pulses. MiddleBrook™ is developing a
broad portfolio of drugs based on the novel biological finding that bacteria exposed to
antibiotics in front-loaded, sequential bursts, or pulses, are killed more efficiently and
effectively than those exposed to standard antibiotic treatment regimens.
When an immediate release antibiotic is administered, bacteria respond to it by
going into a dormant stage, while the administration of a pulsatile system in such a
case is more effective because the regular release of increased pulses of antibiotic
does not let the defense system of the bacteria to go into a dormant stage. By
examining the resistance patterns of microorganisms and applying its improved
technologies, MiddleBrook™ has redefined microbial infection treatment
significantly improving drug efficacy, shortening length of therapy, and reducing the
emergence of antibiotic resistance.
.
7. CONCLUSION
Experts forecast a continuously rising demand for dosage forms with pulsatile drug
release, since circadian rhythms have been extensively described for many diseases.
Thus, more and more attempts are being made to adjust drug delivery systems
accurately to patient requirements, both in terms of therapeutic efficacy and
compliance. Multiparticulate pulsed-release formulations are smart drug delivery
systems specially suited to satisfying these needs, and may offer interesting options
for intelligent life-cycle management.
However, despite of their potential therapeutic benefits, the lack of manufacturing
reproducibility and efficacy and large number of process variables due to multiple
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formulation steps still limits the number of marketed products of these kinds. We are
sure that with increase in technological advancement and better design parameters
these hurdles can be overcome in the near future and more number of patients will be
greatly benefited by these systems. Further, multiple-unit pulsatile systems like
microspheres and nanoparticles can provide a platform for spatial delivery of
candidates like peptides, proteins, oligo nucleotides and vaccines.
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