pulsatile drug delivery systems .....final

PULSATILE DRUG DELIVERY SYSTEMS”

Dissertation submitted in the partial fulfillment of the

Requirement for the award of the Degree of

BACHELOR OF PHARMACYIN

HEMCHANDRACHARYANORTH GUJARAT UNIVERSITY,

PATAN

GUIDE SUBMITTED BYMr. ASHOK MAHAJAN Mr.JITENDRA AMRUTIYA

A.P.M.C. COLLEGE OF PHARMACEUTICALEDUCATION AND RESEARCH

Motipura, Himmatnagar- 383001APRIL--2010

1APMCCPER HIMMATNAGAR

“PULSATILE DRUG DELIVERY SYSTEMS”

Dissertation submitted in the partial fulfillment of the

Requirement for the award of the Degree of

BACHELOR OF PHARMACYIN

HEMCHANDRACHARYANORTH GUJARAT UNIVERSITY,

PATAN

GUIDE SUBMITTED BYMr. ASHOK MAHAJAN Mr. JITENDRA

AMRUTIYA

A.P.M.C. COLLEGE OF PHARMACEUTICALEDUCATION AND RESEARCH

Motipura, Himmatnagar- 383001APRIL--2010


CERTIFICATE

This is to certify that the dissertation

entitled “Pulsatile drug delivery systems”

submitted by Jitendra G.Amrutiya in partial

fulfillment of the degree of Bachelor of Pharmacy

in Hemchandracharya North Gujarat

University, Patan, at APMC College of

Pharmaceutical Education and Research,

Himmatnagar is carried out by her under my

guidance and supervision during the academic

year 2009-2010.

Principal GuideDr. Dushyant A. Shah Mr. Ashok MahajanM.Pharm, Ph.D. M.PharmAPMCCPER Lecturer,

Department of Pharmaceutics, APMCCPER, Himmatnagar.

A.P.M.C. College of Pharmaceutical Education and Research


College Campus, Motipura, Himmatnagar-383001http:// www.apmccper.org, [email protected]

+91-2772-229674

ACKNOWLEDGEMENT

It affords me an immerse pleasure to acknowledge with gratitude

the help, guidance and encouragement rendered to me by all those

person to whom I owe a great deal for successful completion of this

project work.

It is my pleasant duty to express my deep sense of gratitude

and in deftness to my guide Mr. ASHOK MAHAJAN, M.Pharm, in

department of Pharmaceutics, APMC College of Pharmaceutical

Education and Research, for his excellent and memorable guidance,

constant inspiration and consideration which endlessly helped me in

the completion of this project work successfully.

With due respect I express my profound indulge and praise to

my most honored Principle Dr. DUSHYANT A. SHAH M.Pharm

(Ph.D) , APMC College of Pharmaceutical Education and Research

for his encouragement to carry out and complete work.

I also acknowledge the encouragement and help rendered to

me by all teaching and non-teaching staff members specially

ANAND BHANDARI SIR & DHAVAL PATEL SIR, APMC College of

Pharmaceutical Education and Research for their help during my

project work.

Last but not least , I specially thankfully to my dearest

friends DIMENDRA,VRAJ, RAKESH, HARDIK, DHARMENDRAAGHARA,

ANAND&BHAVESH(MBA) and also to my dearest cousin NIKHIL

PATEL who helped me a lot in the completion of my project work

successfully.


mailto:[email protected]

http://www.apmccper.org/

SR. NO

PARTICULARS PAGE NO

1 INTRODUCTION 1

2 ADVANTAGES 43 DISADVANTAGES 54 IMPORTANCE OF PULSATILE DRUG

DELIVERY SYSTEMS6

5 TYPES OF PULSATILE SYSTEMS 85.1 SINGLE UNIT SYSTEMS 85.2 MULTIPARTICULATE SYSTEMS 326 MARKETED TECHNOLOGIES 417 CONCLUSION 428 REFERENCES 43

INDEX


DEDICATEDTO

MY PARENTS,FRIENDS

&MY GUIDE


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

display constancy over a time 1. 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


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

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.


2. ADVANTAGES

Predictable, reproducible and short gastric residence time

Less inter- and intra-subject variability

Improve bioavailability

Reduced adverse effects and improved tolerability

Limited risk of local irritation

No risk of dose dumping

Flexibility in design

Ease of combining pellets with different compositions or release patterns.

Improve stability

Improve patient comfort and compliance

Achieve a unique release pattern

Extend patent protection, globalize product, overcome competition


3. DISADVANTAGES

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


4. IMPORTANCE OF PULSATILE DRUG DELIVERY SYSTEM

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

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. 12Dethlefsan 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.

All of these conditions demand for a time-programmed therapeutic scheme releasing

the right amount of drug at the right time. This requirement is fulfilled by Pulsatile

Drug Delivery Systems. A pulsatile drug delivery system is characterized by a lag

time that is an interval of no drug release followed by rapid drug release.

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


5. TYPES 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. 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.

.

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)

5.1(A). TIME CONTROLLED PULSATILE RELEASE

Time-dependent dosage forms are formulated to release their

drug load after a predetermined lag time. To achieve a drug release

that is independent of the environment (e.g. pH, enzymatic activity,

intestinal motility) and/or other stimuli, the lag time prior to the

release of the drug has to be controlled primarily by the delivery


system. The release mechanisms employed include bulk erosion of

polymers in which drug release by diffusion is restricted, surface

erosion of layered devices composed of alternating drug-containing

and drug-free layers, and osmotically controlled rupture.

(1) PULSATILE DRUG DELIVERY BY ERODIBLE/SOLUBLE/SWELLABLE

POLYMER COATINGS

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

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.

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

II. TIME CLOCK SYSTEM

.

The Time Clock system was proposed for oral dosage form, which should

enable fast and complete release of drug after a predetermined lag time. A tablet

containing the drug molecule and bulking agents [lactose, polyvinyl-pyrolidone

(PVP), corn starch and magnesium stearate] was prepared. This core was coated with

a hydrophobic dispersion of carnauba wax, beeswax, poly (oxyethylene) sorbitan

monooleate and HPMC in water. The lag time could be proportionally modulated by


altering the thickness of the coating. In vitro results indicated rapid release after

certain lag time for the Time Clock system with a hydrophobic coating. This approach

may also be used to control the release onset time.Becausetherugcore is formulated

with soluble ingredients; shell dissolution/disintegration becomes the key factor in

controlling the lag time. Furthermore, drug release is independent of normal

physiological conditions, such as pH, digestive state and anatomical position at the

timeofrelease.

(C ) HYDROPHILIC SANDWICH (HS) CAPSULE

It is a manually assembled delivery system based on capsule within a capsule, in

which the inter capsular space is filled with a layer of hydrophilic polymer (HPMC).

This effectively creates a hydrophilic sandwich between the two gelatin capsules.

When the outer capsule dissolves, the sandwich of HPMC forms a gel barrier layer

that provides a time delay before fluid could enter the inner capsule and cause drug

release.

(2) PULSATILE DRUG DELIVERY BY RUPTURABLE POLYMER

COATINGS

These systems consist of an outer release controlling water insoluble but

permeable coating subject to mechanically induced rupture phenomenon. Recently

different systems based on hard gelatin capsules and tablet core were described, all

coated by inner swellable and outer rutpurable layer. The film rupture may be attained

by including swelling, osmotic or effervescent additives in the reservoir. By

optimizing the system, drug release can be obtained at specific time interval.

Sungthongjeen et al developed a tablet system consisting of core coated with

two layers of swelling and rupturable coatings wherein they used spray dried lactose

and microcrystalline cellulose in drug core and then core was coated with swelling

polymer croscarmellose sodium and an outer rupturable layer of ethylcellulose.

Further Thombre et al developed osmotic drug delivery using swellablecore

technology wherein formulations consists of a core tablet containing the drug and a

water swellable component, and one or more delivery ports.


(3)CAPSULAR SHAPED SYSTEMS

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.

THE PULSINCAP SYSTEM:

It is consisted of a water-insoluble body (hard gelatin capsule coated with

polyvinyl chloride), filled with the drug formulation. 21,22The capsule half was closed

at the open end with a swellable hydro gel plug. Upon contact with dissolution media

or gastrointestinal fluids, the plug swelled and pushed itself out of the capsule after a

lag time, followed by a rapid release of the capsule content (Fig. ). The lag time prior

to the drug release was controlled by the dimension and the position of the plug. In

order to assure a rapid release of the drug content, effervescent agents or disintegrants

could be included in the drug formulation, in particular, with water insoluble drugs.

Studies in animals and healthy volunteers proved the tolerability of the formulation

(e.g., absence of gastrointestinal irritation).23 In order to overcome the potential problem of variable gastric residence time of a

single unit dosage form, the Pulsincap_ system was coated with an enteric layer,

which dissolved upon reaching the higher pH regions of the small intestine. This

allowed a more precise control of the drug release after passage of the stomach,

because the transit time in the intestinal tract is less variable. 24,25 The major

drawbacks of the Pulsincap_ system, which led to the withdrawal of commercial

activities with this system, were the complicated manufacturing process,

reproducibility problems, and the use of a plug material, a cross-linked polyethylene

glycol based polymer, which has not been approved in pharmaceutical products. As


an alternative to swellable, cross-linked plugs, erodible plugs have been investigated

for Pulsincap like systems (Fig.).


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.

The tablet-shaped plugs can be produced by compression of a water-soluble,

swellable polymer, such as HPMC, PVA, or polyethylene oxide. 26 After contact with

gastrointestinal fluids, the polymer plugs swelled quickly, forming a gel, followed by

a transition into a sol and a subsequent period of erosion. The swelling polymer could

also be combined with soluble low-molecular weight excipients, e.g., lactose, to

reduce the lag time. 27In general, the lag time was adjusted by the choice of the

molecular weight of the erodible polymer and by the thickness of the plug. Plug

degradation could also be achieved by enzymes being directly incorporated into the

plug. 28 In an example, plugs containing pectin, a natural polysaccharide, were

degraded by pectinolytic enzymes, where by the lag time of the system was controlled

by the ratio of pectin to enzymes . Besides compression, erodible plugs were formed

by a congealing method with melts of saturated polyglycolyted glycerides (Gelucire_)

or glyceryl monooleate (Myverol_).


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.


Special equipment and several manufacturing steps are necessary to combine all

components.

(4)PULSATILE DRUG DELIVERY BY OSMOTICALLY CONTROLLED

CAPSULAR SYSTEM BASED ON OSMOSIS

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

3). 35 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

correlation in lag times of in-vitro and in-vivo experiments in humans. 36 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


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.

A. SYSTEM BASED ON EXPANDABLE ORIFICE

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

expanding osmotic layer after the barrier layer is dissolved. 38 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


the barrier layer and that of semipermeable membrane, 38 and a capsule designed for

implantation can deliver drug intermittently at intervals of 6 hours for 2 days.

B .DELIVERY BY A SERIES OF STOPS:

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

C. PULSATILE DELIVERY BY SOLUBILITY MODULATION:

Such systems contain a solubility modulator for pulsed delivery of variety of

drugs. The system was especially developed for delivery of salbutamol sulphate. The

compositions contain the drug (salbutamol sulphate) and a modulating agent (sodium

chloride, NaCl). The amount of NaCl was such that it was less than the amount

needed to maintain saturation in a fluid that enters the osmotic device. The pulsed

delivery is based on drug solubility. Salbutamol has solubility of 275 mg/ml in water

and 16 mg/ml in saturated solution of NaCl, while NaCl has solubility of 321 mg/ml

in water, and its saturation solubility is 320 mg/ml. These values show that the

solubility of the drug is function of the modulator concentration, while the

modulator's solubility is largely independent of drug concentration. The modulating

agent can be a solid organic acid, inorganic salt, or organic salt. In order to control

zero-order release period and commencement of pulsed release, ratio of

drug/modulator can be varied. After the period of zero-order release, the drug is

delivered as one large pulse. A similar system is described for delivery of terbutaline


and oxprenolol. 42 However, in general, the large-scale manufacturing of these

systems is complicated and calls for special equipments and several manufacturing

steps.

5.1. (B) SITE SPECIFIC RELEASE

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.

(1). pH CONTROLLED 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


and complete disintegration of the coating and subsequently causes instant release of

the drug at the target site.

Specific delivery of drugs to a selected location/segment in the GI tract is

desired for the treatment of a wide variety of diseases and conditions. It is especially

desirable to be able to deliver drugs so that they are targeted to specific regions of the

GI tract. Targeting drugs to specific regions along the GI tract provides the ability to

locally treat GI diseases, thus reducing side effects of drugs or inconvenient and

painful direct delivery of drugs. Such specific delivery also potentially increases the

efficiency of the drug and enables a reduction of the minimum effective dose of the

drug. Furthermore, targeted delivery to certain parts in the GI tract may be

advantageous when the absorption of a drug into the systemic circulation is limited to

only a part of the GI tract. In such cases the absorption may be increased when the

drug is delivered in a pulsatile and complete way within the GI absorption window,

since it would increase the driving force for absorption at the site where it is

specifically needed.

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.


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.

Enteric polymers currently used to coat oral pharmaceutical dosage forms

include cellulose, vinyl, and acrylic derivatives. The most common enteric coatings

are methacrylic acid copolymers (Eudragits), cellulose acetate phthalate, cellulose

acetate succinate, and styrol maleic acid co-polymers .To obtains site specific delivery

to certain parts in the gastro-intestinal tract several strategies exist. Time-response

delivery systems are characterized by the fact that the drug is released after a certain

period following the moment that the system has got in contact with water

(swallowing of the system). However, the reliability of these systems is rather limited

by the significant variations that occur in the orocaecal transit time (OCTT).

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.

However, an important limitation of this technique is the fact that the

dissolution of the pH sensitive coating materials at pH values that are only slightly


above their setpoint pH is rather slow. Since intestinal pH variations may lead to a

situation in which the environmental pH is hardly above the setpoint pH at the target

site, the dissolution/disintegration of the coating is often slow. As a consequence, the

kinetics of drug release at the desired target location often displays a lag time of up to

several hours or the drug will be released slowly over a period of several hours. Given

the physiologically limited residence time at the target site, this lag time or low drug

release severely limits the amount of drug that is effectively delivered at the target

site. Furthermore, the GI motility pattern can vary widely in individual patients and in

different disease states. In combination with the lag time or slow drug release, the site

of drug release is hard to control. For instance, it may occur in an area ranging form

ileum to deep in the colon.

A pulsatile pH-controlled release system (PPRS) as provided herein allowing

for the pulsatile release of a substance in response to a change in pH, comprising a

core surrounded by a coating layer, wherein said core comprises the active substance.

Also, mixtures of two or more active substances can be used. The coating layer can be

applied directly onto the core such that the outer surface of the core is in contact with

the inner surface of the coating layer. It is however also possible that one or more

layer(s) are present which separate the outer surface of the core from the inner surface

of the coating layer.

In a preferred embodiment, the active substance surrounded by a pH-sensitive

coating layer is a drug, e.g. a drug for the treatment or prevention of disease.

However, the active substance can also be a diagnostic substance, such as a traceable

molecule e.g. a stable isotope. The core comprising the active substance is for

example a capsule or tablet. The solid core comprising the substance and optionally

additional materials can be covered with a coating suspension of the invention. The

additional materials that can be employed in making drug-containing cores are any of

those commonly used in pharmaceutics and should be selected on the basis of

compatibility with the active drug and the physicochemical properties of the core.

Included are binders, disintegrating agents, filling agents, surfactants, stabilizers and

lubricants.


5.1. (C) OPEN-LOOP DELIVERY SYSTEMS (EXTERNALLY

REGULATED)

Open-loop delivery systems are not self-regulating, but instead require

externally generated environmental changes to initiate drug delivery. These can

include

o Magnetic fields

o Ultrasound

o Electric field

o Temperature

o Light

o Mechanical force.

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


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:

Ultrasound is mostly used as an enhancer for the improvement of drug

permeation through biological barriers, such as skin, lungs, intestinal wall and blood

vessels. There are several reports describing the effect of ultrasound on controlled

drug delivery. Kost et al. described an ultrasound-enhanced polymer degradation

system. During polymer degradation incorporated drug molecules were released by

repeated ultrasonic exposure. As degradation of biodegradable matrix was enhanced

by ultrasonic exposure, the rate of drug release also increased. Thus, pulsed drug

delivery was achieved by the on-off application of ultrasound. Supersaxo et al. also

reported macromolecular drug release from biodegradable poly (lactic acid)

microspheres. Drug release from porous poly (lactic acid) microspheres showed an

initial burst followed by a sustained release for over several months. When ultrasound

was applied to this release system, pulsatile and reversible drug release was observed.

Authors speculated that ultrasonic exposure resulted in the enhancement of water

permeation within microspheres of the polymer matrix, inducing drug dissolution into

the releasing media.

Miyazaki et al. used ultrasound to achieve up to a 27-fold increase in the

release of 5-fluorouracil from an ethylene and vinyl acetate (EVAc) matrix.

Increasing the strength of the ultrasound resulted in a proportional increase in the

amount of 5-fluorouracil released.

Increase in the rate of p-nitro aniline delivery from a polyanhydride matrix

during ultrasonic irradiation is reported. The authors noted that the increase in drug

delivery was greater than the increase in matrix erosion when the ultrasound

triggering was active. Thus it was hypothesized that acoustic cavitation by ultrasonic

irradiation was responsible for the modulated delivery of p-nitro aniline


3. TEMPERATURE:

Temperature is the most widely utilized triggering signal for a variety of

triggered or pulsatile drug delivery systems. The use of temperature as a signal has

been justified by the fact that the body temperature often deviates from the

physiological temperature (37º) in the presence of pathogens or pyrogens. This

deviation sometimes can be a useful stimulus that activates the release of therapeutic

agents from various temperature-responsive drug delivery systems for disease

accompanying fever. Thermal stimuli-regulated pulsed drug release is established

through the design of drug delivery devices such as hydrogels and micelles.

Thermo-responsive hydrogel systems use hydrogels that undergo reversible volume

changes in response to changes in temperature. These gels shrink at a transition

temperature that is related to the lower critical solution temperature (LCST) of the

linear polymer from which the gel is made. Thermo-sensitive hydrogels have a certain

affinity for water, and thus swell at temperatures below the transition temperature,

whereas they expel water and thus shrink or "deswell" at temperatures above the

transition temperature. Thermally-responsive hydrogels and membranes have been

extensively evaluated as platforms for the pulsatile delivery of drugs.


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

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) .

Kaneka and co-workers developed a new method to accelerate gel

swelling/deswelling kinetics based on molecular design of gel structure. Free mobile

linear PIPAAm chains were grafted within the cross-linked PIPAAm hydrogels


[Figure]. These gels had the same transition temperature as conventional PIPAAm

gels and existed in the swollen state below the transition temperature, while above this

temperature they shrank. PIPAAm grafted gels showed rapid deswelling kinetics

without formation of skin layer on surface. This is probably due to rapid dehydration

of graft chains formed by hydrophobic aggregation on the three-dimensional cross-

linked chains. A similar rapid deswelling phase was achieved by incorporating

poly(ethylene glycol) graft chains in PIPAAm cross linked hydrogels .

Thermo-responsive polymeric micelle systems constitute polymeric micelles

whose properties and biological interests make them a most noteworthy candidate as

drug carrier for the treatment of cancer. The polymeric micelle is composed of

amphiphilic block copolymers exhibiting a hydrophobic core with a hydrophilic

corona. Due to these unique characteristics, polymer micelles exhibit stealth

characteristics and are not detected by the body defense system (reticuloendothelial

system). Thus passive targeting could be achieved through enhanced permeation

retention (EPR) effect of tumor sites. Okano and coworkers used an end

functionalized PIPAAm to prepare block copolymers. Hydrophobic polymers, such as

poly(butyl methacrylate) (PBMA), polystyrene (PSt) , poly(lactic acid) (PLA) were

used. Block copolymers formed micellar structure (with core-shell structure) in

aqueous solution below PIPAAm's transition temperature. The shell was made from

thermo-responsive PIPAAm, while the core consisted of hydrophobic polymer

aggregates of poly (butyl methacrylate) (PBMA). The hydrated PIPAAm corona acted

as an inert material towards all biological entities below PIPAAm's LCST. However,

upon temperature increase above 32° hydrated PIPAAm chains became hydrophobic,

due to dehydration of polymer chains, thus resulting in aggregation and precipitation.

The hydrophobic anticancer drug, andriamycin, was incorporated in to PBMA micelle

cores. At temperatures below PIPAAm's low crystalline solution temperature (LCST),

drug release was at a minimum, with a value less than 10%. However upon

temperature increase above PIPAAm's LCST, accelerated release of andriamycin.

4. ELECTRIC FIELD:


An electric field as an external stimulus has advantages such as availability of

equipment, which allows precise control with regards to the magnitude of the current,

duration of electric pulses, interval between pulses etc. Electrically responsive

delivery systems are prepared from polyelectrolytes (polymers which contain

relatively high concentration of ionisable groups along the backbone chain) and are

thus pH-responsive as well as electro responsive.

Under the influence of electric field, electro responsive hydrogels generally

deswell, swell or erode. The mechanisms of drug release include ejection of drug

from the gel as the fluid phase synereses out, drug diffusion along a concentration

gradient, and electrophoresis of charged drug towards an oppositely charged electrode

and liberation of the entrapped drug as the gel complex erodes. Synthetic as well as

naturally occurring polymers, separately or in combinations, have been used for this

purpose.

Examples of naturally occurring polymers include

Hyaluronic acid,

Chondrotin sulphate,

Agarose,

Carbomer,

Xanthan gum and

Calcium alginate.

The synthetic polymers are generally

Acrylate and

Methacrylate derivatives such as partially

Hydrolysed polyacrylamide,

Polydimethylaminopropylacylamide. .


Poly (2-acrlamide-2-methylpropanesulfonic acid-co-butyl methacrylate) (P (AMPS-

co-BMA) hydrogels were used for electric stimuli-induced drug delivery system.

Positively charged edrophonium chloride was incorporated as drug molecule within

negatively charged P (AMPS-co-BMA) hydrogels. By applying an electric field, ion

exchange between edrophonium ions and protons commenced at cathode, resulting in

rapid drug release from hydrogels. This rapid drug release was attributed to the

electrostatic force, squeezing effect, and electro-osmosis of the gel. Complete on-off

drug release was achieved, as no drug release was apparent without the application of

the electric current.

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:

Drug delivery can also be initiated by mechanical stimulation of an implant.

Alginate hydrogels that release vascular endothelial growth factor in response to

compressive forces of varying strain amplitudes were developed. Free drug that is

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.


5.1. (D) SELF REGULATED OR CLOSE LOOP DRUG

DELIVERY

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

There has been much interest in the development of stimuli-sensitive delivery

systems that release a therapeutic agent in presence of specific enzyme or protein.

One prominent application of this technology has been development of a system that

can autonomously release insulin in response to elevated blood glucose levels. Several

existing strategies that may be feasible for glucose-responsive drug delivery are

discussed below.

PH-dependent systems for Glucose stimulated drug delivery are based on the

reaction that glucose oxidase catalyses oxidation of glucose to gluconic acid. This

reaction can be used to drive the swelling of pH-dependent membrane. A dual

membrane system was formed. In the first membrane, glucose oxidase was

immobilized on cross linked polyacrylamide and this was referred to as glucose

sensing membrane. Co-polymer membrane composed of N,N-diethylaminoethyl

methacrylate and 2-hydroxypropyl methacrylate (DEA-HPMA) formed the barrier

membrane and worked as an interface between insulin reservoir and sensing

membrane. .

As shown in [Figure] - , gluconic acid formed by the interaction of glucose and

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]. .

B. INFLAMMATION-INDUCED PULSATILE RELEASE

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.

C. DRUG RELEASE FROM INTELLIGENT GELS RESPONDING TO

ANTIBODY CONCENTRATION.

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.


5.2 MULTIPARTICULATE PULSATILE DRUG

DELIVERY SYSTEM

The purpose of designing multiparticulate dosage form is to

develop a reliable formulation that has all the advantages of a

single unit formulation and yet devoid of the danger of alteration in

drug release profile and formulation behavior due to unit to unit

variation. The expected drug-release mechanism and corresponding

target bimodal plasma concentration profile of the above designed

multiparticulate pulsatile system is depicted in Fig. 1B.

In the following sections; recent innovations in multiparticulate

systems for pulsatile delivery have been reviewed. The major

mechanism by which the drug is released from pellets depends on

the type of coating; insoluble coating under all physiological

conditions, pH-dependent coating whose solubility changes

dramatically at some point in GI tract and slowly erodible coating.

The method of application and processing conditions may influence

the porosity of the coating and consequently the release

mechanism. Less obvious but also important to the kinetics of

release are the influences of the core formulation, in terms of both

the physical properties and amounts of the drug and excipient

materials present, and the physiological environment to which the

drug is released.


.

Fig... Hypothetical design and plasma drug profile of a

multiparticulate pulsatile system. A. Design of a pelletwithmultiple

coatings, and B. Predicted bi-modal plasma concentration profile.

(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

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.

Dittigen et al. 48 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

environment within the system, can be admixtured. This type of system 49where 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.

TIME- CONTROLLED EXPLOSION SYSTEMS (TES)

Ueda et al. 51–53 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

drawbacks associated with TES, two approaches have been proposed [55, 56]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

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

(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.

(3). SYSTEMS WITH CHANGED MEMBRANE PERMEABILITY

Sigmoidal release pattern is therapeutically beneficial for timed release and

colonic drug delivery, and is observed in coated systems. A sigmoidal release pattern

is reported based on the permeability and water uptake of Eudragit RS or RL,

influenced by the presence of different counter-ions in the release medium.

Based on this Narisawa et al. have developed a device capable of pulse release

depending on the change in diffusion properties of Eudragit RS. They found that a


core of theophylline coated with Eudragit RS showed very slow release rates in pure

water but significant increase in the release rate was found when the microcapsules

were immersed in an organic acid solution containing succinic, acetic, glutaric,

tartaric,malic, or citric acid. This was due to higher hydration of the film containing

quaternary ammonium groups on interaction with the acids. The drug release rate

from the beads coated with Eudragit NE 30D, which has no quaternary ammonium

groups in the polymer chain, was not affected by succinic acid, suggesting that the

quaternary ammonium groups of Eudragit RS are essential to produce the unique drug

release profile of the SRS. When succinic acid was incorporated into the core of

Eudragit RS-coated theophylline beads, the drug release profile showed a typical

sigmoidal pattern. Similar results were also obtained for acetaminophen contained in

the same system. Acetaminophen-containing beads with different coating thickness

were orally administered to beagle dogs and similar lag times were observed after

both in vivo and in vitro. In another similar system, theophylline and sodium acetate,

acting as the permeability modifying salt, were layered on sugar pellets, followed by

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.

(4). LOW DENSITY FLOATING MULTIPARTICULATE PULSATILE

SYSTEMS

Conventional multiparticulate pulsatile release dosage forms mentioned above are

having longer residence time in the gastrointestinal tract and due to highly variable

nature of gastric emptying process, may resulted in in vivo variability and

bioavailability problems. In contrary, low density floating multiparticulate pulsatile

dosage forms reside in stomach only and not affected by variability of pH, local


environment or gastric emptying rate. These dosage forms are also specifically

advantageous for drugs either absorbed from the stomach or requiring local delivery

in stomach.

Overall, these considerations led to the development of multiparticulate pulsatile

release dosage forms possessing gastric retention capabilities. A multiparticulate

floating-pulsatile drug delivery system was developed using porous calcium silicate

(Florite RE) and sodiumalginate, for time and site specific drug release of meloxicam

for chronopharmacotherapy of rheumatoid arthritis . Meloxicam wasadsorbed on the

Florite RE (FLR) by fast evaporation of solvent from drug solution containing

dispersed FLR. Drug adsorbed FLR powder was used to prepare calcium alginate

beads by ionotropic gelation method, using 3(2) factorial designs. The floating time

for this system was controlled by density of beads and hydrophobic character of drug.

Polysaccharides are widely used in oral drug delivery systems because of the

simplicity to obtain the desired drug delivery systemand drug release profile, by the

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.


6. MARKETED TECHNOLOGIES OF MULTIPARTICULATE

PULSATILE DRUG DELIVERY

Presently marketed multiparticulate pulsatile drug delivery systems are listed.

In 1998, Elan Drug Technologies got FDA approval for their chronotherapeutic

technology, CODAS® as multiparticulate pH dependent system, for delivery of

Verapamil HCl (Verelan® PM) in form of extended release capsule This was

followed by the FDA approval of DIFFUCAPS®, a multiparticulate technology by

Reliant Pharmaceuticals LLC, for chronotherapeutic delivery of a combination of two

drugs, Verapamil HCl and Propanolol HCl, as an extended release tablet (Innopran®).

But the biggest breakthrough in multiparticulate pulsatile technology was

achieved when MiddleBrook™ Pharmaceuticals, Inc. (earlier known as Advancis

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

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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