Pulsatile Drug Delivery System: Drugs used in the Pulsatile
Formulations
Haribansh Narayan Singh1*, Shivangi Saxena1, Sunil Singh2, Ajit Kumar Yadav1
1Department
of Pharmaceutics, Invertis Institute of Pharmacy, Invertis University, Bareilly, U.P.
2Department of Pharmaceutical Chemistry, Invertis Institute of Pharmacy, Invertis
University, Bareilly, U.P
ABSTRACT:
Pulsatile drug delivery systems are developed to deliver drug in a
programmed manner according to circadian behavior of diseases resulting in
improved therapeutic efficacy as well as patient compliance These systems are
designed for diseases showing chronopharmacological
behavior and where the drug dose is
required for extended day time or night time activity or for the drugs having
high first pass effect or having site specific absorption in GIT, or for drugs
with high risk of toxicity. Diseases wherein Pulsatile drug
delivery system are likely to be successful for diseases such as asthma, peptic
ulcer, cardiovascular diseases, arthritis, hypertension, and
hypercholesterolemia. The current article focuses on the review of literature
concerning the disease requiring Pulsatile drug
delivery system and the drugs used in the pulsatile
formulations to target diseases.
KEYWORDS:
INTRODUCTION:
Oral drug delivery due to its obvious
advantages covers the largest portion of the total drug delivery market. It
aims to maintain plasma drug concentration within the therapeutic window for
long period of time[1] and offer other advantages like prevention of peak valley,
reduced dosage frequency and improved patient compliance.[2]However, there are
certain conditions like in some diseases for which such a release pattern is
not suitable. For example, due to ‘first pass effect’ there will be reduction
in the bioavailability of the drug because gradual release can result in
greater degradation[3] also drugs with short half-life need to be administered
repeatedly which results in patient non-compliance and in case of a chronic
treatment, when the drug is given in sustained release dosage form, continuous
exposure of the drug to body may lead to adverse effects At this time drug
delivery should be such that there is complete drug release after a lag time. Lag
time is defined as the time between when a dosage form is placed into an
aqueous environment and the time at which the active ingredient begins to get
released from the dosage form.[4] The drug should not release during its initial period of
administration, followed by a rapid and complete release (pulse release) of
drug which is called Pulsatile drug delivery system.
Pulsatile drug delivery system targets to
release drugs in a programmed manner i.e. at appropriate time and/or at a
suitable site of action as per the pathophysiological
need of the disease, resulting in improved patient therapeutic efficacy and
compliance and is designed for chronopharmacotherapy (timed
drug therapy) which is based on circadian rhythm.
Control release systems for 12 or 24 hr drug release
are not suitable for diseases, which follow circadian variation and in such
conditions there is requirement for time or pulsatile
drug delivery system.
Researchers account that some medications may work better if their
administration is coordinated with day-night patterns and biological rhythms.
Human circadian rhythm is based on sleep activity cycle, is influenced
by our genetic makeup and hence, affects the body’s functions day and night
(24-hour period) [5].
In
1729, the first known experiment on biological rhythms was conducted by French
astronomer Jean Jacques d’Ortous deMairan.[6]Biological
rhythms not only impact the function of physiology, but the pathophysiology
of diseases [7].If symptoms of a disease became worse during the
night or in the early morning the timing of drug administration and nature of
the drug delivery system need careful consideration.[8].For example, in an
asthmatic patient circadian changes are seen in normal lung function,
and in cardiovascular diseases, several functions (e.g. Blood pressure, heart
rate, stroke volume, cardiac output, blood flow) of the cardiovascular system
are subject to circadian rhythms where pulsatile drug
delivery system can be useful.
Fig. 1: Drug release profile of
pulsatile drug delivery systems
Advantages of the Pulsatile drug delivery systems[9, 10]:
There are numerous advantages of the pulsatile drug delivery systems such as:
1.
These systems can be used for extended day
time or night time activity.
2.
They reduce the dose frequency, dose size
and cost, which ultimately reduces side effects, thereby improving patient
compliance.
3.
Hormones such as renin,
aldosterone, and cortisol
etc their levels in blood may alter with circadian rhythms therefore, drug
delivery through this system suits circadian rhythms of body functions or
diseases.
4.
Drug targeting to a specific site, like
the colon (in case of ulcerative colitis) can be achieved.
5.
This system helps to prevent the
continuous presence of some drugs (e.g. salbutamol
sulphate) that produce biological tolerance and thus they increase their
therapeutic effect.
6.
These systems are beneficial for the drugs having chronopharmacological behavior where night time dosing is
required and for the drugs having high first-pass effect.
7.
They provide constant drug levels at the
site of action and prevent the peak-valley fluctuations.
8.
Protection from gastric environment is essential for drugs that
cause gastric irritation (e.g. NSAIDS) or get degraded in gastric medium (e.g.
peptide drugs) so enteric coated Pulsatile drug
delivery system can be the best option for it.
Limitations [11]:
1. Multiple manufacturing steps in
case of Multiparticulate drug delivery system.
2. Low drug loading capacity and
incomplete release of drug.
3. In vivo variability in single
unit pulsatile drug delivery system.
4. Drug dose manipulation in case
of child and elder patients is not possible.
5. Immediate withdrawal of drug is
not possible.
Pulsatile systems arebasically time controlled
drug delivery systems in which the system controls the lag time independent of
environmental factors like pH, enzymes & gastric motility. They are
classified as:
1. Single Unit Systems:
i.
Capsular Systems
ii.
Port Systems (osmosis based capsular systems)
iii.
Systems with erodible/ soluble barrier coatings
iv.
Systems with rupturable coatings
2. Multiple Unit Systems:
i.
Multiple unit pulsatile systems
ii. Pulsatile system based on change in membrane permeability
iii. Pulsatile systems with rupturable
coating:
This review covers the detail outlook on a
variety of pulsatile release systems intended for the
oral route, which have been recognized as potentially beneficial to the chronotherapy of widespread diseases like Asthma, arthritis
and cardiovascular diseases (including hypertension, myocardial infarction
etc...) that are promising to be treated by pulsatile
drug delivery.
Fig
2.Schematic diagram of Capsule shaped system provided with release controlling
plug
Cardiovascular
Diseases:
Cardiovascular
diseases, several functions (e.g. BP,heart rate,
stroke volume, cardiac output, blood flow) of the cardiovascular system are subject
to circadian rhythms.For instance, capillary
resistance and vascular reactivity are higher in the morning and decrease later
in the day whereas Platelet aggregation is increased and fibrinolytic
activity is decreased in the morning, leading to a state of relative hypercoagulability of the blood. [12]Careful analysis of
trials illustrate that myocardial infarction (MI), stroke, ventricular ectopy, and sudden cardiac death occur between 6 am and
noon. The peak blood pressure is between 6 am and noon, with activation of the
sympathetic nervous system prior to awakening, blood pressure begins to
increase with the heart rate. These changes in blood pressure corresponds the
morning activation in catecholamines, renin, and angiotensin. Commonly
used drugs are- Nitroglycerin, Calcium
channel blocker, ACE inhibitors etc.
Bajpai et al[13] have prepared the compression coated pulsatile release tablets of losartan potassium for the treatment of hypertension. The prepared system
consisted of a core tablet coated with versatile polymers such as Hydroxypropyl methyl cellulose. Hydroxypropyl
cellulose, sodium carboxy methylcellulose along with
the effervescent agent to produce burst release after predetermined lag time.
The results revealed that objective of producing lag time of 6-7 hours and then
fast release of drugs was achieved.
Monica
Rao et al[14] have prepared Pulsatile Release from Tablet and Capsule Dosage Forms
of Metoprolol tartarate
used in the treatment of hypertension and myocardial infarction. It was concluded
that capsule dosage formshowed a lag time (period of
no drug release) followed by better pulsatile release
whereas, tablet dosage form showed a lag time in which 10-20% of the drug was
released during the lag time followed by a pulsatile
release.
Prashant A. Borgaonkar et al[15] have prepared Pulsatile
Drug Delivery System of Metoprolol tartarate Using Core in Cup Tablet. The core tablet contained metoprolol tartarate, cellulose
acetate propionate is used as impermeable membrane and sodium alginate 500 cps
and sodium alginate 2000 cps used as soluble hydrophilic polymer layer. The
results revealed that lag time of 5 hrs was achieved suggesting that this
system a pulsatile drug delivery system can be
prepared to increase the therapeutic effectiveness of the drug.
K Latha et al [16]
developed an optimized Losartan Potassium
Press-Coated Tablets for Chronotherapeutic Drug Delivery.The inner core were prepared by
compression-coating with HPMC 100KM alone and admixed with MCC as the outer
layer in different ratios.The lag time was from 0.5
to 18.5 h and could be modulated as it decreased as the amount of MCC inthe outer layer increased.
R. Archana et al[17]
prepared a Programmable
‘Tablet-In-Capsule’ Drug Delivery Device for Oral Administration of Propranolol
Hydrochloride using a swellable hydrophilic polymer Hydroxypropylmethylcellulose
K 15 (HPMC K 15) as a plug material for chronotherapeutic
delivery . The results showed that this device can be used for chronotherapeutic drug delivery of propranolol
hydrochloride for preventing early morning heart stroke.
BasawarajS.Patil et al [18] have developed time controlled pulsatile release Lisinopril tablets based on a press coated
tablet, where a core tablet surrounded coating material.The
coating materials consisted of hydrophobic polymer of ethyl cellulose and
hydrophilic materials (HPMC 15 CPS) were used in different concentration. The
results revealed that it is a promising formulation technique for chronotherapeutic management of hypertension.
Swati C. Jagdale et al[19] have designed a Enteric Press - Coated
Tablet for Pulsatile Delivery of Atenolol. A novel colon targeted tablet
formulation was developed by press coating rapidly disintegrating tablet of Atenolol with guar gum and Eudragit
L-100 as barrier layer. Different ratios of polymers were selected to achieve
suitable lag time for the treatment of angina pectoris.
Jain,
D. K et al[20] have formulated Pulsatile Drug
Delivery System Containing Losartan Potassium
and Hydrochlorothiazide. The results indicate that press-coated tablets
achieve a burst release after 4 h lag time which is applicable pulsatile drug delivery for hypertension.
Patil AS et al[21] developed chronomodulated pulsatile drug delivery system of captopril for the treatment of hypertension. The core containing captopril as a bioactive compound were prepared by direct
compression method and then coated sequentially with an inner swelling layer
containing hydrocolloid HPMC E5 and an outer rupturable
layer consisted of Eudragit RL/RS (1:1). The system
was found to be satisfactory in terms of release of the drug after the lag time
of 6 hours.
Mukesh C. Gohel et al[22] have done modulation
of diltiazem hydrochloride release from a novel
‘tablet in capsule system’ containing an effervescentblend.
Drug release having lag time of 4 hours was achieved through the system.
Arthritis:
In
case of arthritis there is a circadian rhythm in the plasma concentration of C-
reactive protein and interleukin-6 of patients with rheumatoid arthritis [23]. Chronobiological patterns associated with the arthritis
have been observed with morning stiffness and arthritic pain inpatients. The
people who suffer from osteoarthritis tend to have less pain in the morning and
more at night but in rheumatoid arthritis the pain mostly increases at morning and
decreases as the day goes on. The new cyclooxygenase-2inhibitors effectively
relieve the osteoarthritis symptoms when taken in the morning and better
results are obtained in rheumatoid arthritis when small part of the dose is
taken in the evening[24].
Dharmarajsingh chauhan et al[25] have formulated pulsatile drug
delivery system of aceclofenac for treatment
of rheumatoid arthritis, combination of Eudragit L-100 and S-100
with core. The concentration of the plugging material was found sufficient to
maintain the lag period for a minimum period of 4 hrs.
Kinjal T. Patel et al [26]
had developed a formulation of chronotherapeutics
dosage of aceclofenac. The formulation achieved the desired pulsed
release profile after a programmed lag time.
J. Kausalya et al [27] had
designed and developed Pulsatile Drug Delivery of flurbiprofen microspheres. The multiparticulate
system consisted of drug loaded cellulose acetate cores encapsulated within Eudragit S-100 microspheres. The formulation showed drug
release at the 12th hour.
Abhijit Moon et al [28]
had formulated press -coated Indomethacin
tablets for pulsatile drug delivery system. The release profile of the
press-coated tablet exhibited a time period without drug release (time lag
around 4-8 hrs) followed by a rapid and complete release phase.
Jain Sheetal et al [29] had formulated floating pulsatile drug delivery system of lornoxicam for chronotherapy of rheumatoid arthritis. The system consisted
of drug containing core tablets, which were coated with pH- dependent polymer Eudragit S100 and outer effervescent layer of polymers. The
formulation had shown promising results with no drug release for 6-7 hrs
followed by rapid and burst release of drug from Floating Pulsatile
Tablets.
Bin
Li, JiaBi Zhu et al [32] have designed a three-pulse diclofenac sodium release based on “tablets in
capsule” device for the treatment of rheumatoid arthritis. Sodium alginate and hydroxy-propyl methyl cellulose (HPMC E5) were chosen as
the candidate modulating barrier material. The lag time of 7 hours was observed
with about 60% sodium alginate concentration.
A.Meena et al [33] have developed
Pulsatile drug delivery system of lornoxicam.
Lornoxicam microcapsules were prepared by solvent
evaporation method using Eudragit L/S 100. The system
was found to be effective for the chronotherapy of
rheumatoid arthritis.
Asthma is a chronic inflammatory disease of the airways, characterized
by hyper responsiveness to a variety of stimuli [34]. Disease like Asthma
results in increased airway responsiveness & worsening of lung function.
From extensive studies it has been concluded that the role of circadian rhythms
in the pathogenesis and treatment of asthma indicates that airway resistance increases
progressively at night in asthmatic patients, and later reaches a low point in
the early morning hours. These symptoms typically occur between midnight &
especially around 4 am. For example, cortisol (an
anti-inflammatory substance) levels are 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 4:00 am [35].
Bailpattar Padmaxi et al [36] have developed a one pulse drug delivery system based on a
press-coated tablet preparation of montekulast sodium
for treating asthma. The programmable time controlled release was achieved from
a press-coated tablet over a period of 5 hr and burst release was obtained
after a lag time, which is consistent with the demands of chronotherapeutic
drug delivery.
Sadaphal K.P et al [37]
have formulated Pulsatile drug delivery system of Theophylline for treating Asthma. A combination of Isopropyl Alcohol (70%)
and Acetone (30%) was used as solvent for Eudragit
S100 coating. The system was found to be satisfactory in terms of release of
the drug which was after a predetermined lag time of 6 h and thus the dosage
forms can be taken at bedtime so that the content will be released in the
morning hours.
J. Ali et al [38] have developed a Chronomodulated
Drug Delivery System of Salbutamol Sulphate for the Treatment of Nocturnal Asthma. They have designed a rupturable pulsatile drug
delivery system that consisted of a core (made up of microcrystalline
cellulose, sodium chloride) a drug containing reservoir, inner or intermediate
swelling layer (hydroxypropyl methyl cellulose (HPMC
E5) and an outer water insoluble
but permeable coating. The system
was found to be satisfactory in terms of release of the drug after a lag time
of 6 h.
Vinayak D. Kadam et al [39] have
developed a colon targeted multiparticulate pulsatile drug delivery system of theophylline for treating
nocturnal asthma. Fast release enteric-coated pellets of theophylline
were prepared for a pulsatile drug delivery. A
significant lag phase of 5 h was seen.
Mahajan AN et al [40]
have developed a timed delayed capsule device for chronotherapeuitc
delivery of terbutaline sulphate
for the therapy of asthma the lag time criterion of 5 hrs was achieved.
Janugade B. U et al [41]
have prepared a formulation of press-coated Montelukast
sodium tablets for pulsatile Drug delivery
system. The tablets were prepared by both dry and wet granulation methods. As compared to dry mixed blend method wet
granulation method gives less lag time.
Table 1.Various Pulsatile drug delivery system for the diseases
|
Disease |
Drug used |
Type of system |
References |
|
Hypertension |
Losartan potassium |
Press-coated tablets |
16 |
|
Hypertension |
captopril |
Rupturable coating method |
21 |
|
Nocturnal asthma |
Montekulast sodium |
Time controlled press-coated tablets |
36 |
|
Rheumatoid arthritis |
Flurbiprofen |
microspheres |
27 |
|
Rheumatoid arthritis |
Indomethacin |
Time controlled press-coated tablets |
28 |
|
Rheumatoid arthritis |
Lornoxicam |
Floating pulsatile tablets |
29 |
|
Hypertension |
Propranolol hydrochloride |
Tablet – In – capsule device |
17 |
|
Asthma |
Theophylline |
Time controlled press-coated tablets |
37 |
|
Nocturnal asthma |
Theophylline |
Fast release enteric coated tablets |
39 |
|
Nocturnal asthma |
Salbutamol sulphate |
Single unit rupturable pulsatile drug delivery system |
38 |
|
Asthma |
Terbutaline sulphate |
Time delayed capsule device |
40 |
|
Angina pectoris |
Atenolol |
Enteric press coated tablet |
19 |
|
Arthritis |
Aceclofenac |
Floating pulsatile drug delivery
system |
26 |
|
Hypertension |
Lisinopril |
Time controlled press coated tablets |
18 |
|
Hypertension and myocardial infarction |
Metoprolol tartarate |
Pulsatile tablet and pulsatile
capsule |
14 |
|
Hypertension |
Metoprolol tartarate |
Core in cup tablet |
15 |
|
Hypertension, Rheumatoid arthritis |
Diltiazem hydrochloride |
Tablet – In - capsule device |
22 |
|
Hypertension |
Losartan potassium and hydrochlorthiazide |
Time controlled press coated tablets |
20 |
|
arthritis |
meloxicam |
Low density multiparticulate
system |
31 |
|
Rheumatoid arthritis |
Diclofenac sodium |
Multi-layered tablets for three pulse tablet in capsule
device |
32 |
|
Rheumatoid arthritis |
Lornoxicam |
Microcapsules for pulsincap
system |
33 |
|
Rheumatoid arthritis |
aceclofenac |
Time controlled press coated tablets |
25 |
CONCLUSION:
Circadian rhythm of the body is an
essential concept for understanding the optimum need of drug in the body. Pulsatile drug delivery is one such system that, by
delivering drug at the right time, right place and in right amounts, provides
promising benefits for the patients
suffering from chronic problems like arthritis, asthma, hypertension etc. A significant
progress has been made towards designing Pulsatile
drug delivery system that can effectively treat diseases with non-constant
dosing therapies and thus, enhance the patient compliance, optimum drug
delivery to the target site while minimizing the undesired effects.
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Received on 30.04.2013
Modified on 20.05.2013
Accepted on 26.05.2013
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