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10 | P a g e International Standard Serial Number (ISSN): 2319-8141

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International Journal of Universal Pharmacy and Bio Sciences 5(1): January-February 2016

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.093***

ICV 5.13***

Pharmaceutical Sciences REVIEW ARTICLE …………!!!

“PULSATILE DRUG DELIVERY SYSTEMS: A NEWER TECHNIQUE FOR

EFFECTIVE MANAGEMENT OF ASTHMA”

Isha Thakur*, Nimrata Seth

Department of Pharmaceutics, Rayat Institute of Pharmacy, Railmajra, SBS Nagar (Pb.).

KEYWORDS:

Asthma, chronotherapy

of asthma, lag time,

PDDS, classification of

PDDS and marketed

formulation.

For Correspondence:

Isha Thakur*

Address:

Department of

Pharmaceutics, Rayat

Institute of Pharmacy,

Railmajra, SBS Nagar

(Pb.).

ABSTRACT

Asthma is the most common disease with the largest circadian variation. It

is a chronic condition where airways are hyperreactive to certain irritants

which can constrict them and so making difficulty in breathing.

Approximately 80% of severe asthmatic attacks occur especially around 4

am. Asthma is currently controlled by taking either a long acting β2

agonists like salmetrol inhalers, sustained release theophylline. All the

current sustained release formulation has shortcomings of inability to

maintain high blood levels during most vulnerable period. This may make

the patient unprotected against the worse events of asthma. Thus, a smart

drug delivery system that is administered before sleep and maintains high

blood levels for longer period (from midnight to 4 am in the morning)

could be very much beneficial for proper management of asthma. Pulsatile

drug delivery systems are gaining a lot of interest as they deliver the drug

at the right place at the right time and in the right amount, thus providing

spatial and temporal delivery and increasing patient compliance. PDDS is

useful in the treatment of disease, in which drug availability is timed to

match rhythm of disease, in order to optimize therapeutic effect and

minimize side effects. This review article discusses the currently available

medications of asthma, their merits-demerits and the applicability of newer

concept of chronotherapeutics for effective management of asthma. The

articles also describe the development of pulsatile drug delivery system,

advantages and future scope.



INTRODUCTION:

Asthma is a common respiratory disease among both adult and children whose prevalence is

increasing worldwide; affecting 15-20 million Indians.[1]

It is a chronic inflammatory disease

associated with airway hyperresponsiveness (an exaggerated airway-narrowing response to triggers,

such as allergens and exercise) that leads to recurrent symptoms like wheezing, coughing, shortness

of breath, chest tightness. Symptom episodes are generally associated with widespread but variable

and reversible airflow obstruction within the lungs.[2]

Asthma leads to significant degrees of

morbidity and mortality. It is reported that 70% of sudden deaths and 80% of cases of respiratory

arrest in active asthma occurs during sleep related hours.[3]

The worsening of asthma at night is

commonly referred to as nocturnal asthma (NA). Nocturnal asthma is a variable exacerbation of the

underlying asthma condition associated with increase in symptoms, need for medication, airway

responsiveness and/or worsening of lung function.[4]

SIGN AND SYMPTOMS OF ASTHMA

Asthma symptoms can range from mild to severe. An asthma attack is a sudden worsening of

asthma symptoms caused by the tightening of muscles around the airways (bronchospasm). During

the asthma attack, the lining of the airways also becomes swollen or inflamed and thicker mucus

more than the normal is produced. All of these factors bronchospasm, inflammation and mucus

production cause symptoms of asthma attack such as difficulty in breathing, wheezing, coughing,

shortness of breath, chest tightness and difficulty performing normal daily activities.[5]

CAUSES OF ASTHMA

Asthma is caused by a combination of complex and incompletely understood environmental and

genetic interactions. These factors influence both its severity and responsiveness to treatment. It is

believed that the recent increased rates of asthma are due to changing epigenetics (heritable factors)

other than those related to the DNA sequence and changing living environment.[6]

Person who has

genetic or epigenetic changes in their genes makes them have a bigger chance of getting asthma

(genetic predisposition).[7]

An overly sensitive immune system makes airways (bronchial tubes)

inflamed and swollen when you exposed to certain triggers. Asthma triggers vary from person to

person. Common asthma attack triggers include:[8]

Allergens such as pollen and mold

Air pollutants

Smoking and second hand smoke

Exercise

Cold air or dry air

Upper respiratory infections



PRESENT AVAILABLE DRUG DELIVERY SYSTEMS FOR ASTHMA

There is no permanent cure for asthma; however, the disorder can be adequately controlled with

drugs. The optimal asthma control would include minimal chronic symptoms and minimal

exacerbations. Assessment of severity is important before treatment is initiated and patient should

be placed in the highest category of severity based on any of the clinical features or lung function

tests.

Asthma is treated with two types of medicines: long term control medicines and quick relief

medicines. Long term control medicines help to reduce airways inflammation and prevent asthma

symptoms. Quick relief medicines relieve asthma symptoms that may flare up.[9,10]

Present available

medication for asthma include mainly oral, injectable and inhalational medications.

CONVENTIONAL RELEASE DOSAGE FORM: A conventional release dosage form is a

preparation showing a release of the active substance which is not deliberately modified by a

special formulation design or manufacturing method. Equivalent term: immediate release dosage

form. Eg. Zyflo

CONTROLLED RELEASE DOSAGE FORM: The controlled release system is to deliver a

constant supply of the active ingredient, usually at a zero order rate, by continuously releasing, for a

certain period of time, an amount of the drug equivalent to the eliminated by the body. An ideal

controlled drug delivery system is the one, which delivers the drugs at a predetermined rate, locally

or systematically, for a specific period of time.[22]

Eg. Proventil Repetabs.

Orally asthma medications:

Orally asthma medications are used for asthma control to prevent asthma flare ups and not used to

relieve immediate symptoms. They are taken daily even when a person does not have any

symptoms of asthma. The following oral medications are frequently prescribed for the management

of asthma

Theophylline: A long term controller medication taken by mouth and used alone or together with

inhaled corticosteroids to treat asthma.

Oral corticosteroids: Oral corticosteroids are used in the combination with short acting beta

agonist (also called bronchodilators) to treat moderate to severe asthma flare ups.

Leukotriene modifiers: Also called leukotriene receptor antagonist. Medicines used for long term

control and preventions of asthma symptoms.

Example of orally asthma medication: Emlucast, Brethex, Ascoril.

Injectable asthma medication: Omalizumab (xolair) is a medicine used to treat moderate to

severe, persistent allergic asthma not adequately controlled with inhaled steroids. Omalizumab



(xolair) is a medicine called an IgE blocker. By blocking the IgE, Omalizumab can reduce those

reactions. In studies, long term treatment in people with allergic asthma showed a decrease in

asthma flare ups and corticosteroids usage. Omalizumab is only effective as long as the injections

continue.[11]

Example of injectable asthma medication: Esmasol, Salsol.

Table 1: Marketed formulation for orally and injectable asthma medication

Brand name Manufacturers Type

Asthalin Cipla limited Tablet

Ascoril Glenmark Pharmaceutical Ltd Tablet

Brethex Sapco Laboratories Tablet

Salsol Kee pharma Ltd Injection

Esmasol Obsurge Biotech Limited Injection

Theochron Sustained release tablet

Vospire ER Extended release tablet

Proventil Repetabs Controlled release tablet

Volumax Extended release tablets

ZYFLO CR Extended release tablet

Inhaled asthma medication: An inhaler or puffer is a medical device used for medication via the

lungs. It is mainly used in the treatment of asthma and chronic obstructive pulmonary disease

(COPD).[12]

Example of inhaled asthma medication: Asthalin inhaler, Salbutamol.

There are different types of inhalers for asthma medicines.[12-15]

Table 2: Types of inhalers for asthma

Parameters Metered dose inhaler

(MDI)

Dry powder inhaler

(DPI)

Nebulizers

Properties A MDI is a device that

delivers a specific amount

of drug to the lungs, in the

form of a short burst of

aerosolized medicine that is

usually self administered by

the patient via inhalation.

DPI release a metered

dose of powdered

medication that is

inhaled through

device. Used in

patients under five

years of age.

Nebulizers deliver

drug in the form of an

aqueous formulation.

Nebulizers are most

commonly used for

beta - 2 agonists and

ipratropium bromide.

Advantages Portable and compact.

Short treatment time.

Suitable for emergency

situation.

Short treatment time.

Less patient

coordination required.

Suitable for

emergency situation.

It requires no hand

breath coordination on

the patient’s part.

Disadvantages It deposits more than 80%

of the medication in the

mouth.

Coordination of breathing

and actuation is necessary.

All medications are

not available in dry

powder inhaler form.

Medication is lost if

accidently exhaled

into the devices.

The process takes

longer time than MDI

and DPI.

It is more expensive

than MDI and DPI.



CHRONOPHARMACOTHERAPY

Recent studies have revealed that diseases have predictable cyclic rhythms and that the timing of

medication regimens can improve outcome in selected chronic conditions. ―Chronopharmaceutics‖

consist of two words chronobiology and pharmaceutics. Chronobiology is the study of biological

rhythms and their mechanisms.[16]

There are three types of mechanical rhythms in our body. They are:

Ultradian: Cycles shorter than a day. For example, the milliseconds, it takes for a neuron to fire, or

a 90 minute sleep cycle.

Infradian: Referring to cycles longer than 24 hours. For example, monthly menstruation.

Circadian rhythm: Biological rhythm within a single day is termed as circadian rhythm. Here, the

oscillation time is 24 hours. Human circadian rhythm is based on sleep – activity cycle, is

influenced by our genetic makeup and hence, affects the body’s function day and night (24 hrs

Period).[17]

The dependence of body’s functions in certain diseased states on circadian rhythm is well known.

Chronobiological studies have established circadian rhythm for almost all body functions, e.g.

Heart rate, blood pressure, body temperature, plasma concentration of various hormones, gastric pH

and renal function.[18]

The disease recently targeted for chronotherapy are those which have enough scientific background

to justify chronopharmaceutical drug delivery system compared to conventional drug

administration. These include asthma, arthiritis, duodenal ulcer, cancer, cardiovascular disease,

diabetes and neurological disorders as shown in figure 1.[19]

Treatment of such disease requires a

drug delivery system that releases the drug after lag time at the time of the need of disease.

Figure 1: Diagram Showing the Circadian Pattern of Disease



BRONCHIAL ASTHMA AND CHRONOTHERAPY: The role of circadian rhythms in

pathogenesis and treatment of asthma indicates that airway resistance increases progressively at

night in asthmatic patients. The circadian changes are seen in normal lung function, which reaches

at low point in the early morning hours.[20]

. The incidence of asthma attacks are more than 100

times greater during night time sleep, especially around 4 am. For example cortisol (an anti-

inflammatory substance) levels were highest at the time of awakening and lowest in the middle of

the night and histamine (a mediator of bronchoconstriction) concentrations peaked at a level that

coincided with the greatest degree of bronchoconstriction at 4 am. Chronotherapy for asthma is

aimed at getting maximal effect from bronchodilator medications during the early morning hours.

In one study use of timed – release formulation of theophylline achieved therapeutic drug

concentrations during the night and avoid toxic levels during the day when the dose was ingested

at morning hours. A drug delivery system administered at bedtime but releasing drug during

morning hours would be ideal in this case. One example is the bronchodilator Uniphyl, a long

acting theophylline preparation manufactured by purdue Frederick Co. of Norwalk, Conn, and

approved by FDA in 1989. Uniphyl causes theophylline blood levels to reach their peak and

improve lung function during the difficult early morning hours.[21]

PULSATILE DRUG DELIVERY SYSTEM

Among chronotherapeutic drug delivery systems, pulsatile drug delivery systems are gaining a lot

of interest as they deliver the drug at the right time and in the right amount, thus increasing patient

compliance. PDDS is defined as the rapid and transient release of certain amount of molecules

within a short time period immediately after a predetermined off – released period, i.e, lag time, or

these systems has a peculiar mechanism of delivering the drug rapidly and completely after a lag

time, i.e, a period of no drug release. The lag time of PDDS depends upon the nature of disease to

be treated.[22]

Various drug release profiles exhibited by pulsatile drug delivery system are

deplicated in figure 2.[23]



Figure 2: Drug Release Profile of Pulsatile Drug Delivery Systems

Advantages of PDDS[22]

Extended day time and night time activity.

Reduced side effects.

Reduction in first pass metabolism due to rapid release of drug causing saturation of

metabolic enzymes.

Reduction in dose size.

Improved patient compliance.

Drug targeting to specific site is possible.

Disadvantages of PDDS[24]

Higher cost of production.

Batch manufacturing process.

Need of advanced technology.

CLASSIFICATION OF PULSATILE DRUG DELIVERY SYSTEM

A. Time controlled pulsatile release

I. Single unit system

i. Capsular system

ii. Port system

iii. Delivery by solubility modulation

iv. Delivery by reservoir systems with erodible barrier coatings



II. Multi-particulate system

i. Pulsatile system based on rupturable coating

ii. Time controlled expulsion system

iii. Pulsatile delivery by change in membrane permeability

iv. Sigmoidal release system

B. Stimuli induced

I. Internal stimuli induced pulsatile system

i. Temperature induced system

ii. Chemical stimuli induced system

iii. pH sensitive drug delivery system

II. External stimuli induced system

i. Electrically stimulated pulsatile system

ii. Magnetically stimulated pulsatile system

iii. Ultrasonically stimulated pulsatile system

A. Time controlled pulsatile release

I. Single unit system

i. Capsular system: Single unit systems are developed in capsule form. The lag time is controlled

by a plug, which gets pushed away by swelling or erosion, and the drug is released as a ―pulse‖

from the insoluble capsule body as shown in figure 3.[25]

The lag time can be controlled by

manipulating the dimension and the position of the plug. Polymers used for designing of the

hydrogel plug are Polymethacrylates, Hydroxypropylmethyl cellulose, poly vinyl alcohol,

polyethylene oxide, saturated polyglycolated glyceride, Pectine.[26]

Figure 3: Schematic Diagram of Capsular System



ii. Port system: Port system consists of a gelatin capsule coated with a semi permeble membrane

(e.g. cellulose acetate) housing an insoluble plug (e.g. lipidic) and an osmotically agent along

with the drug formulation. When in contact with the aqueous medium, it results in increased

inner pressure that ejects the plug after a lag time.[27]

iii. Pulsatile delivery by solubility modulation: Such system contains 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). 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.[28]

Figure 4: Drug Release Mechanism From Port Capsule

Step 1: Caps dissolves immediately and modified release dose is release.

Step 2: Energy source is activated by controlled permeation of GI fluid.

Step 3: Time release plug is expelled.

Step 4: Pulse or sustained release of second dose.

iv. Pulsatile system with erodible barrier coatings:

The chronotropic system: The chronotropic system consists of a drug containing core coated by

hydrophilic swellable hydroxypropylmethyl cellulose (HPMC), which is responsible for a lag phase

in the onset of release. In addition, through the application of an outer gastric – resistance enteric

film, the variability in gastric emptying time can be overcome, and a colon specific release can be

obtained, relying on the relative reproducibility of small intestinal transit time.[29]

The lag time can be controlled by the thickness and the viscosity of various grades of HPMC. The

system is suitable for both tablet and capsules.

„TIME CLOCK‟ System: The time clock system is a delivery device based on solid dosage form

that is coated by an aqueous dispersion. The core is coated at 70°C with aqueous dispersion of a



hydrophobic surfactant layer (Beeswax, Carnaubawax). The lag time could be controlled by

varying the thickness of the film. After the lag time, i.e., Time required for rehydration, the core

immediately releases the drug. This system has shown reproducible results in-vitro and in-vivo.[30]

v. Multiparticulate system

i. Pulsatile system based on rupturable coating: These systems depend on th disintegration of

coating for the release of drug. The pressure necessary for the rupture of the coating can be

achieved by the effervescent excipients, swelling agents, or osmotic pressure. An effervescent

mixtue of citric acid and sodium bicarbonate was incorporated in a tablet core coated with ethyl

cellulose. The carbon dioxide developed after penetration of water into the core resulted in a

pulsatile release of drug after rupture of the coating.

ii. Time controlled explosion system: This is a multiparticulate system in which drug is coated on

non-pareil sugar seeds followed by a swellable layer and an insoluble top layer. The swelling agents

used include super disintegrants like sodium carboxymethyl cellulose, sodium starch glycollate, L

hydroxypropyl cellulose and polymers include polyvinyl acetate, poly acrylic acid, poly ethylene

glycol, etc.[31]

Figure 5: Time Controlled Explosion System (TCES)

iii. 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. 48 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.

iv. Sigmoidal release system: Sigmoidal release pattern is therapeutically beneficial for time

release, colonic drug delivery and 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.[32]



B. Stimuli induced

I. Internal stimuli induced pulsatile system

i. 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. Y.H. bae et al

developed indomethacin pulsatile release pattern in the temperature ranges between 200°C and

300°C by using reversible swelling properties of copolymers of N-isopropylacrylamide and

butyrylacrylamide.

ii. Chemical stimuli induced system

(a) Glucose-responsive insulin release devices: In case of Diabetes mellitus, there is rhythmic

increase in the level of glucose in the body, requiring injection of the insulin at proper time.[33]

Several systems have been developed which are able to respond to changes in glucose

concentration. One such system includes pH sensitive hydrogel containing glucose oxidase

immobilized in the hydrogel. When glucose concentration in the blood increases glucose oxidase

converts glucose into gluconic acid which changes the pH of the system. Example of pH

sensitive polymers include N,N-dimethylaminoethyl methacrylate, chitosan, polyol etc.

(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. 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.

iii. 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 systems advantage has been taken of

the fact that there exists different pH environment at different parts of the gastrointestinal

tract.[34]

By selecting the pH dependent polymers, drug release at specific location can be

obtained. Example of pH dependent polymers includes cellulose acetate phthalate, polyacrylates,

sodium carboxymethylcellulose.

II. External induced pulsatile system

i. Electrically stimulated pulsatile system: These systems are prepared by using

polyelectrolytes (polymers which contain relatively high concentration of ionisable groups along

the backbone chain) pH responsive as well as electro-responsive hydrogels generally bend,

depending on the shape of the gel which lies parallel to the electrodes where as deswelling

occurs when the hydrogel lies perpendicular to the electrodes.[35]



ii. Magnetically stimulated pulsatile system: Magnetic carriers receive their magnetic

response to a magnetic field from incorporated materials such as magnetite, iron, nickle, cobalt

etc. A magnetic hydrogels (Ferrogels) was fabricated by mixing PVA hydrogels and Fe3O4

magnetic particles through freezing thawing cycles. Although the external direct current

magnetic field was applied to the ferrogel, the drug got accumulated around the ferrogel, but the

accumulated drug spurt to the environment instantly when the magnetic fields instantly switched

―off‖.

iii. Ultrasonically stimulated pulsatile system: Ultrasound is mostly used as an enhancer for

the improvement of drug permeation through biological barriers, such as skin. The interactions

of ultrasound with biological tissues are divided into two broad categories: thermal and non

thermal effects. Thermal effects are associated with the absorption of acoustic energy by the

fluids or tissues. Non thermal bio-effects are generally associated with oscillating or cavitating

bubbles, but also include noncavitation effects such as radiaton pressure, radiation torque and

acoustic streaming.[36]

Table 3: Patented technologies for PDDS[37]

Technolgy Mechanism Proprietary

name and

dosage form

API Disease

CODAS Multiparticuate

pH dependent

system

Veralan PM;XL

release capsule

Verapamil HCL Hypertension

Three

dimensional

Externally

regulated system

Theirform Diclofenac

Sodium

Inflammation

CONTIN Extended release

tablet

Uniphyl Theophylline Asthma

CEFORM Extended release

tablet

Cardiazem LA Diltiazem HCL Hypertension

Physico-chemical

modification of

API

Tablet Pepcid Famotidine Ulcer

PROCARDIA XL Sustained release Procardia XL Nifedipine Hypertension



CONCLUSION

Circadian rhythm of the body is an important concept for understanding the optimum need of drug

in the body. There is a constant need for new delivery systems that can provide increased

therapeutic benefits to the patients. Pulsatile drug delivery is one such system that, by delivering

drug at the right time, right place and in right amounts, holds good promises of benefit to the

patients suffering from chronic problems like asthma, hypertension and arthritis etc. Thus designing

of proper pulsatile drug delivery will enhances the patient compliance, optimum drug delivery to

the target site and minimizes the undesired effects. PDDS in future is certainly going to gain

popularity. Chronopharmaceutics will certainly improve patient outcome and optimize disease

management in the future.

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