A REVIEW: PULSINCAP A NOVEL DRUG DELIVERY SYSTEM. RPA1415019015.pdf · Pulsatile drug delivery...

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International Journal of Universal Pharmacy and Bio Sciences 3(2): March-April 2014

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Pharmaceutical Sciences REVIEW ARTICLE……!!!

A REVIEW: PULSINCAP A NOVEL DRUG DELIVERY SYSTEM

1Ruchi Joshi,

1 Ashutosh Badola,

2 Preeti Kothiyal

Department of 1 pharmaceutics &

2pharmacology,Division of pharmaceutical sciences,Shri Guru

Ram Rai Institute Of Technology & science, Patel Nagar dehradun,248001.

KEYWORDS:

Pulsincap, circadian

rhythm, hydrogel,

polymers.

For Correspondence:

Ruchi Joshi*

Address: Department of 1

pharmaceutics, Division

of pharmaceutical

sciences,Shri Guru Ram

Rai Institute Of

Technology & science,

Patel Nagar

dehradun,248001.

E-mail:

[email protected]

m

ABSTRACT

Pulsincap is a special dosage form comprising a water insoluble capsule

body enclosing a drug reservoir. The body is closed at the open end

with a swellable hydrogel plug, which consists of insoluble, but

permeable and swellable polymers. Pulsatile systems are gaining a lot

of interest as they deliver the drug at the right site of action at the right

time and in the right amount, thus providing spatial and temporal

delivery and increasing patient compliance. These systems are designed

according to the circadian rhythm of the body. The principle rationale

for the use of pulsatile release is for the drugs where a constant drug

release, i.e., a zero-order release is not desired. The ability of the

modified Pulsincap to provide colon-specific drug delivery was

assessed by in vitro drug release studies in buffer pH 1.2 for 2 h, pH 7.4

for 3 h and pH 6.8 for 7 h. The lag time of the drug release decreased

by increasing the inner swelling layer and increased by increasing the

rupturing layer level. These systems are beneficial for the drugs having

chronopharmacological behaviour where night time dosing is required

and for the drugs having high first-pass effect and having specific site

of absorption in GIT.Products available as once-a-daily formulation

based on Pulsatile release like Pulsincap, Ritalin, and Pulsys.

mailto:[email protected]

mailto:[email protected]



INTRODUCTION:

With the advancement of the pharmaceutical field, novel drug delivery systems have drawn an increasing

attention in the last few decades. Now, the emphasis of pharmaceutical research is turned towards the

development of more efficacious drug delivery systems with already existing, molecule rather going for

new drug discovery. (1-2)

Controlled drug delivery systems have acquired very important role in pharmaceutical Research and

Development (R&D) business. Such systems offer control over the release of drug and grant a new lease on

life to a drug molecule in terms of patentability. These dosage forms offer many advantages over the

conventional drug delivery systems; such advantages include nearly constant drug level at the site of

action, prevention of peak-valley fluctuations, reduction in dose of drug, reduced dosage frequency,

avoidance of side effects, and improved patient compliance.(3)

In recent years considerable attention has been focused on the development of pulsatile drug delivery

system. Pulsatile drug delivery system is defined as the rapid and completely release the drug after a lag

time, thus provide spatial & temporal delivery and increasing patient compliance.(4-5)

Pulsatile drug

delivery system has gained increasing importance not just for the treatment of diseases that are influenced

by the circadian rhythm of the body, but also for the potential it holds to prevent the down regulation of

drug receptors and to achieve efficient therapeutic effects. Pulsatile drug delivery systems release active

ingredient completely and rapidly after a defined lag time,(6)

Pulsatile systems are designed in a manner

that the drug is available at the site of action at the right time in the right amount. These systems are

beneficial for drugs having high first-pass effect; drugs administered for diseases that follow

chronopharmacological behaviour; drugs having specific absorption site in GIT, targeting to colon; and

cases where night time dosing is required.(7)

The pulsatile effect, i.e., the release of drug as a “pulse” after a lag time has to be designed in such a way

that a complete and rapid drug release should follow the lag time (fig. 1). Such systems are also called

time-controlled as the drug released is independent of the environment These systems have a peculiar

mechanism of delivering the drug rapidly and completely after a “lag time,” i.e., a period of “no drug

release.” Though most delivery systems are designed for constant drug release over a prolonged period of

time, pulsatile delivery systems are characterized by aprogrammed drug release, as constant blood levels of

adrug may not always be desirable.(8)



Drug release profiles from pulsatile drug delivery system

a = release of drug as a “pulse” after a lag time,

b = delivering the drug rapidly and completely after a “lag time” and

c = constant drug release over a prolonged period of time after a “lag time”.(8)

Pulsincap System

R. R. Scherer (International Corporation, Michigan, US) developed Pulsincap. This system comprises of a

water-insoluble capsule enclosing the drug reservoir. Seal the drug contents into the capsule body, a swell

able hydrogel plug was used. It swelled, when this capsule came in contact with the dissolution fluid and

after a lag time, the plug pushed itself outside the capsule and rapidly released the drug.

A various polymers used for designing of the hydrogel plug were various viscosity grades of hydroxyl

propyl methyl cellulose, polymethyl methacrylates, poly vinyl acetate and poly ethylene oxide. The length

of the plug and its point of insertion into the capsule controlled the lag time. Pulsincap was studied in

human volunteers and was reported to be well tolerated. As the swelling hydrogel polymer plug replaced

the erodible tablet, the dependence of the dimensional accuracy between the plug and the capsule for the

pulling mechanism of the plug from the capsule was also overcome. A release profile is characterized by a



period during which no release followed by rapid and complete drug release. Release using this system was

found to be reproducible in-vitro and in-vivo. When gastrointestinal transit of the formulations was carried

out by gamma scintigraphy, it was found that in six of the eight subjects that the device reached the colon

before drug was released. The formulation had been administered with the subjects in a fasting state.

Effects of food and gastric retention time were not investigated. In later scintigraphic studies, it was found

that the site of release of drug in the gastrointestinal tract varied. In one subject, the formulation even

remained in the stomach for a long time and drug was also released in the stomach. Ross et. al. used low

substituted hydroxylpropyl cellulose for the expulsion system for the release of propanolol over a time

period of 2-10 hr. This could be controlled using compressed erodible tablets made of lactose and HPMC.

Krogel and Bodmeier studied the release of Chlorpheniramine utilizing the erodible plugs(9-10)

Advantages and drawbacks of Pulsatile drug delivery systems:

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

Improve stability

Improve patient comfort and compliance

Achieve a unique release pattern

Extend patent protection, globalize product, and overcome competition.

Drawbacks

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.(11)



Diseases requiring Pulsatile Drug Delivery(12)

Disease Chronological behavior Drugs used

Peptic ulcer Acid secretion is high in the afternoon and at

night

H2 blockers

Asthma Precipitation of attacks during night or at early

morning hour

β2 agonist,

Antihistaminics

Cardiovascular

diseases

BP is at its lowest during the sleep cycle and

rises steeply during the early morning

awakening period

Nitroglycerin,

Calcium channel

blocker, ACE

inhibitors etc.

Arthritis

Pain in the morning and more pain at night

NSAIDs,

Glucocorticoids

Diabetes mellitus

Increase in the blood sugar level after meal

Sulfonylurea,

Insulin, Biguanide

Attention deficit

syndrome

Increase in DOPA level in afternoon Methylphenidate

Hypercholesteroleia Cholesterol synthesis is generally higher during

night than during day time

HMG CoA

reductase inhibitors

Classification Of Pulsatile Drug Delivery System.(13)

I. Time controlled pulsatile release

A.Single unit system

B. Multi-particulate system

II. Stimuli induced

A.Thermo-Responsive Pulsatile release

B.Chemical stimuli induced Pulsatile systems

III. External stimuli pulsatile release

A.Electro responsive pulsatile release

B. Magnetically induced pulsatile release

IV. Pulsatile release systems for vaccine and hormone products

I. TIME CONTROLLED SYSTEM

In this system pulsatile release is obtained after a particular time interval in order to mimic the circadian

rhythm. Such type of pulsatile drug delivery system contains two gears: one is of immediate release type



and other one is a pulsed release type (14)

These time-controlled systems can be classified as single unit

(e.g., tablet or capsule) or multiple unit systems. (15)

A. Single Unit System (16)

Capsular Systems

Capsular System Based on Osmosis

Pulsatile system with erodible or soluble barrier coating

Pulsatile system with rupturable coatings

i. Capsular System:

The general structure of this system consists of an insoluble capsule body containing a drug and a plug,

which is erodible, swelling or soluble after a predetermined lag time. (17)

Eg.Pulsincap system: It consists of a water insoluble capsule body filled with drug formulation. The

capsule body is closed at the open end with a swellable hydrogel plug(18)

Upon contact with the GI fluids,

the plug swells and after a lag time, pushes itself out of the capsule. This leads to drug release as a pulse.

The lag time can be controlled by changing the dimensions and the position of the plug. The plug material

consists of insoluble but permeable and soluble polymers, e.g. Polymethacrylates, erodible compressed

polymers, e.g. HPMC, congealed melted polymers, eg. Glyceryl monooleate, enzymatically controlled

erodible polymers, e.g. Agar, pectin(19)

Design Of Pulsincap System

ii. Capsular System Based On Osmosis(Port System):

The Port

system was developed by Therapeutic system research laboratory Ann Arbor, Michigan,

USA(20)

This system consists of a gelatin capsule coated with a semi permeable membrane (cellulose

acetate). Inside the capsule is an insoluble plug, an osmotically active agent along with the drug



formulation(21)

When this cap comes into contact with GI fluids, water diffuses across the semi permeable

membrane, resulting in increased pressure inside that ejects the plug after a predetermined lag time. The lag

time is controlled by the thickness of the coating. E.g. Ritalin (methyl phenidate) used in the treatment of

attention deficit hyper active disorder (ADHD) in children, is formulated as PORT system. The use of this

system avoided second time dosing which is beneficial for school children. (22)

iii) Pulsatile System With Erodible Or Soluble Barrier Coating:

Most of the pulsatile drug delivery systems are reservoir devices coated with a barrier layer. Thisbarrier

erodes or dissolves after a specific lag period, and the drug is subsequently released rapidly. The time lag

depends on the thickness of the coating layer(23)

This system consists of a solid dosage form coated with

lipidic barriers containing carnauba wax and bees wax along with surfactants (spans). After a lag time

proportional to the thickness of the film, the coat erodes or emulsifies in the aqueous environment and then

the core is available for Dispersion(24)

Delivery System With Erodible Coating Layer (25)

The Chronotropic System:

The Chronotropic system consists of a drug containing core coated by hydroxypropylmethyl cellulose

(HPMC), a hydrophilic swellable polymer, which is responsible for a lag phase in the onset of release. The

lag time is controlled by the thickness and viscosity grades of HPMC.



Colon- specific release can be obtained by coating the system by an enteric polymer such as Cellulose

Acetate Pthallate(26)

An additional enteric-coated film is given outside this layer to overcome intra-subject

variability in gastric emptying rates(27)

Time Clock System:

The time clock system is a delivery device based on solid dosage form that is coated by an aqueous

dispersion(28)

It consists of a solid dosage form coated with lipidic barriers containing carnauba wax and

bees’ wax along with surfactants, such as span 80. After a lag time proportional to the thickness of the film,

this coat erodes or emulsifies in the aqueous environment, and the core is then available for dispersion (29)

iii. Pulsatile System With Ruputurable Coatings:

In contrast to the swellable or erodible coating systems, these systems depend on the disintegration of the

coating for the release of drug(30)

Similar to single-unit system, the rupturing effect is achieved by coating the individual units with

effervescent or swelling agents. Drug delivery was controlled by the rupture of the membrane The timing

of release was controlled by the thickness of coating and the amount of water-soluble polymer to achieve

the pulsed release. The individual particles had the same composition of internal core, but the thickness of

the external coating layer varied(31)

Delivery System With Rupturable Layers(32)

iv) Multi Particulate System:

Multi-particulate drug delivery systems are mainly oral dosage forms consisting of a multiplicity of small

discrete units, in which the active substance is present as a number of small independent subunits(33)

The

drugcarrying capacity of multiple systems is lower due to presence of higher quantity of excipients. Such

systems are invariably a reservoir type with either rupturable or altered permeability coating(34)



i. Pulsatile system based on rupturable coating:

The drug is coated on sugar beads and then the beads are further coated with insoluble and swellable top

layer(35)

The swelling agents used include superdisintegrants like sodium carboxymethyl cellulose,sodium

starch glycollate, L-hydroxypropyl cellulose, etc. Upon absorption of water, the swellable layer expands,

resulting in rupture of film with subsequent rapid drug release. The lag time can be varied by varying

coating thickness or adding high amounts of lipophilic plasticizer in the outermost layer(36)

ii) Osmotic-based rupturable coating systems:

This system is based on a combination of osmotic and swelling effect(37)

The core containing the drug, a

low bulk density solid and/or liquid lipid material (eg, mineral oil) and a disintegrant was prepared. This

core was then coated with cellulose acetate. Upon immersion in aqueous medium, water penetrates the core

displacing lipid material. After the depletion of lipid material, internal pressure increases until a critical

stress is reached, which results in rupture of coating. The use of osmotically active agents that do not

undergo swelling was reported by Schultz and Kleinebudde(38)

ii. Pulsatile Delivery by Change in Membrane Permeability:

The permeability and water uptake of acrylic polymers with quaternary ammonium groups can be

influenced by the presence of different counter-ions in the medium(39)

Several delivery systems based on

this ion exchange have been developed. Eudragit RS 30D is reported to be a polymer of choice for this

purpose(40)

It typically contains positively polarized quaternary ammonium group in the polymer side chain,

which is always accompanied by negative hydrochloride counter-ions. The ammonium group being

hydrophilic it facilitates the interaction of polymer with water, thereby changing its permeability and

allowing water to permeate the active core in a controlled manner.(41)

iii. Sigmoidal Release System:

This consists of pellet cores comprising drug and succinic acid coated with ammonio-methacrylate

copolymer USP/NF type B. The lag time is controlled by the rate of water influx through the polymer

membrane. The water dissolves succinic acid, and the drug in the core and the acid solution in turn

increases permeability of the hydrated polymer film. In addition to succinic acid, acetic acid, glutaric acid,

tartaric acid, malic acid, or citric acid can be used. The increased permeability can be explainedby

improved hydration of film, which increases free volume(42-43)

iv. 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 result in



in vivo variability and bioavailability problems. In contrary, low density floating multiparticulate pulsatile

dosage forms reside only in stomach 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(44)

II. STIMULI BASED PULSATILE RELEASE:

Several polymeric delivery systems undergo phase transitions and demonstrate marked swelling-deswelling

changes in response to environmental changes including solvent composition, ionic strength, temperature,

electric fields, and light(45)

The mechanisms of drug release include ejection of the drug from the gel as the

fluid phase synerges out, drug diffusion along a concentration gradient, electrophoresis of charged drugs

towards an oppositely charged electrode and liberation of the entrapped drug as the gel or micelle complex

erodes(46)

1. Thermo-responsive Pulsatile release:

Temperature Induced System

Thermo-responsive hydrogel systems have been developed for pulsatile release. In these systems the

polymer undergoes swelling or deswelling phase in response to the temperature which modulate drug

release in swollen state(47)

Kataoka et al developed the thermosensitive polymeric micelles as drug carrier

to treat the cancer. They used end functionalized poly (N-isopropylacrylamide) (PIPAAm) to prepare

corona of the micelle which showed hydration and dehydration behavior with changing temperature(48)

2. Chemical stimuli induced Pulsatile 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(49)

Glucose-responsive insulin release devices

Self-regulating insulin-delivery devices depend on theconcentration of glucose in the blood to

control the release of insulin. Ishihara et al(1983) prepared one gel membrane system to regulate the

insulin permeability. Thesystem proposed immobilizing glucose oxidase (an enzyme) to a pH-

responsivepolymeric hydrogel, which encloses a saturated insulin solution. At high glucoselevels,

glucose is catalyzed by glucose oxidase and converts it to gluconic acid, thuslowering the pH. This

decrease in pH causes the membrane to swell, forcing the insulinout of the device.(50)

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(51)

Drug release from responding to antibody concentration intelligent gels

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(52)

pH sensitive drug delivery system

Such type of pulsatile drug delivery system contains two components one is of immediate release

type and other one is pulsed release which releases the drug in response to change in pH. In case of

pH dependent system advantage has been taken of the fact that there exists different pH

environment at different parts of the gastrointestinal tract. By selecting the pH dependent polymers

drug release at specific location can be obtained. Examples of pH dependent polymers include

cellulose acetate phthalate, polyacrylates, and sodium carboxymethylcellulose. These polymers are

used as enteric coating materials so as to provide release of drug in the small intestine(53)

III. EXTERNAL STIMULI PULSATILE RELEASE:

For releasing the drug in a pulsatile manner, another way can be the externally regulated systems in which

drug release is programmed by external stimuli like magnetism, ultrasound, electrical effect and

irradiation(54)

Magnetically Induced Pulsatile Release

The use of an oscillating magnetic field to modulate the rates of drug release from polymer matrix was

one of the old methodologies. Magnetic carriers receive their magnetic response to a magnetic field



from incorporated materials such as Magnetite, Iron, Nickel, Cobalt etc. For biomedical applications,

magnetic carriers must be water-based, biocompatible, non-toxic and non-immunogenic mechanistic

approach based on magnetic attraction is the slowing down of oral drugs in the gastrointestinal system.

This is possible by filling an additional magnetic component into capsules or tablets. The speed of

travel through the stomach and intestines can then positions by an external magnet, thus changing the

timing and/or extent of drug absorption into stomach or intestines be slowed down at specific (55)

Electro Responsive Pulsatile Release

Electrically responsive delivery systems are prepared from polyelectrolyte’s (polymers which contain

relatively high concentration of ionisable groups along the backbone chain) and are thus, pH responsive

as well as electro-responsive. Examples of naturally occurring polymers include hyaluronic acid,

chondroitin sulphate, agarose, carbomer, xanthan gum and calcium alginate. The synthetic polymers are

generally acrylate and methacrylate derivatives such as partially hydrolyzed polyacrylamide,

polydimethylaminopropyl acryl amide(56)

IV. Pulsatile Release Systems For Vaccine And Hormone Products:

Vaccines are traditionally administered as an initial shot of an antigen followed by repeated booster shots

to produce protective immunity (57)

The frequency of the booster shots, and hence the exact immunisation

schedule is antigen dependent. Also, co-administration of vaccine adjuvant is often required to enhance the

immune response to achieve protective immunity. PDDS offer the possibility of single-shot vaccines if

initial booster release of the antigen can be achieved from one system in which timing of booster release is

controlled. Vizcarra et al. found in nutritionally anoestrous cows, GnRH administered in pulses of 2 mg

over 5 min every hour for 13 days produced a higher frequency of luteal activity by 13th day than cows

given continuous infusions or pulses every 4 Hr(58)

MARKETED TECHNOLOGIES OF PULSATILE DELIVERY(59)

Technology Mechanism Proprietary name and

dosage form API Disease

OROS Osmotic

mechanism

Covera-HS; XL tablet Verapamil HCl Hypertension

Three dimensional

printing

Externally regulated system

Their Form Diclofenac Sodium

Inflammation

DIFFUCAPS Multiparticulate Innopran; XL tablets Verapamil

HCL,

Hypertension

PulsincapTM Rupturable system PulsincapTM Propranolol

HCL Dofetilide

Hypertension

CODAS Multiparticular pH

dependent system

Verelan PM; XL release

capsule

Verapamil HCl Hypertension



CONCLUSION:

It can be concluded that pulsatile drug delivery systems offer a solution for delivery of drugs exhibiting

chrono pharmacological behavior, extensive first pass metabolism, necessity of night time dosing, etc. so, a

variety of systems based on single or multiple units are being developed for pulsatile release of the drug.

Pulsatile drug delivery is one system that holds good promises of benefits to patients suffering from

chronic problems like Arthritis, Asthma, Hypertension, etc. by delivering the drug at the right time, the

right place and in the right amounts. Further, research is being carried out to develop a pulsatile release

dosage form for Diabetes.

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