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Raghavendra Rao et al. World Journal of Pharmaceutical research
NOVEL TECHNOLOGIES IN FORMULATIONS: AN OVERVIEW
Mohd Abdul Hadi1, Raghavendra Rao NG2*.
1Dept of Pharmaceutics, Bhaskar Pharmacy College, Moinabad, R.R District, Hyderabad -
500075, AP, India. 2Dept of Pharmaceutics, Jyothishmathi Institute of Pharmaceutical Science, Karimnagar -
505481, AP, India.
ABSTRACT
Significant advances have been attained in developing and
commercializing oral controlled release products. Many platforms are
available for delivering small molecule drugs with good aqueous
solubility in prolonged or delayed release forms. On the other hand, the
continuous improvement of current delivery technologies is also
important when it comes to decreasing cost and increasing efficiency.
Those advancements include novel excipient, processes, and
equipment as new tools formulation scientists can use to develop oral
controlled-release formulations. In the present review article, the novel
methods of preparing controlled or extended release formulations
which can be successfully used in chronotherapy have been mentioned.
These techniques also applied for drugs that require modification of
drug release, masking of bitter taste, and protection of volatile
substances. These technologies have also been found useful for timed-
release dosage forms, as timing release tablets, time clock system and delayed-release tablets.
This article emphasis on the novel technologies such as capsule-in-a-capsule technology,
tablet-in-a-tablet technology and tablet-in-a-capsule technology.
Key words: Oral controlled-release formulations, Chronotherapy, Capsule-in-a-capsule
technology, tablet-in-a-tablet technology, tablet-in-a-capsule technology.
World Journal of Pharmaceutical research
Volume 1, Issue 3, 415-431. Review Article ISSN 2277 – 7105
Article Received on 4 May 2012, Revised on 20 May 2012, Accepted on 25 May 2012
*Correspondence for
Author:
*Dr. N. G. Raghavendra Rao
Dept of Pharmaceutics, Jyothishmathi Institute of Pharmaceutical Science, Karimnagar - 505481, AP, India. [email protected]
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INTRODUCTION
The oral route of administration is considered as the most widely accepted route because of
its convenience of self administration, compactness and easy manufacturing [1-2].
Nevertheless, it is probable that at least 90% of all drugs used to produce systemic effects are
administered by oral route (see Fig 1). Of drugs that are administered orally, solid oral
dosage forms represent the preferred class of product [3].
Fig 1: Global drug delivery market by administration mode.
Over recent years, controlled release combination products have become increasingly popular
within the pharmaceutical industry. A number of products have reached global markets and
several high-profile brands have generated considerable revenues. Significant advances have
been attained in developing and commercializing oral controlled release products. Many
platforms are available for delivering small molecule drugs with good aqueous solubility in
prolonged or delayed release forms. Those unmet technology needs create great opportunities
for research, development, and innovation. On the other hand, the continuous improvement
of current delivery technologies is also important when it comes to decreasing cost and
increasing efficiency. Those advancements include novel excipients, processes, and
equipment as new tools formulation scientists can use to develop oral controlled-release
formulations [4].
Delayed drug delivery system (DDS), zero-order DDS, and site-specific DDS are focuses of
oral controlled-release solid dosage forms for researchers. Oral delayed DDS, which releases
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Raghavendra Rao et al. World Journal of Pharmaceutical research
drugs after a programmable period of time, is intended for the therapy of diseases that depend
on circadian rhythms. The system consists of a core and a coating. The core is coated with
different polymeric barriers by film or compression, and the coating prevents drug release
from the core until the polymeric shell is completely swollen or eroded. Better patient
compliance and large surface area in the gastrointestinal tract are the two most important
advantages of oral drug delivery systems [5]. Assuming that physiological processes and
biological functions display constancy over time, much effort had been devoted in the past in
developing the drug delivery systems that maintain a flatter plasma level for an extended
period of time. However, chronobiological studies believe this concept [6].
Chronotherapy coordinates drug delivery with human biological rhythms and holds huge
promise in areas of pain management, treatment of asthma, heart disease and cancer. The
coordination of medical treatment and drug delivery with such biological clocks and rhythms
is termed chronotherapy. The goal of chronotherapeutic is to synchronize the timing of
treatment with the intrinsic timing of illness. In contrast, many side effects can be minimized
if a drug is not given when it is not needed. A major objective of chronotherapy in the
treatment of several diseases is to deliver the drug in higher concentrations during the time of
greatest need according to the circadian onset of the disease or syndrome. The chronotherapy
of a medication may be accomplished by the judicious timing of conventionally formulated
tablets and capsules [7-10].
Circadian rhythms and their implications
Circadian rhythms are self-sustaining, endogenous oscillation, exhibiting periodicities of
about one day or 24 hrs. Normally, circadian rhythms are synchronized according to the
body’s pacemaker clock, located in the suprachiasmic nucleus of the hypothalamus.
The physiology and biochemistry of human being is not constant during the 24 hrs, but
variable in a predictable manner as defined by the timing of the peak and through of each of
the body’s circadian processes and functions. The peak in the rhythms of basal gastric and
secretion, white blood cells (WBC), lymphocytes, prolactin, melatonin, eosinophils, adrenal
corticotrophic hormone (ACTH), follicle stimulating hormone (FSH), and leuteinizing
hormone (LH), is manifested at specific times during the nocturnal sleep span. The peak in
serum cortisol, aldosterone, testosterone plus platelet adhesiveness and blood viscosity
follows later during the initial hours of diurnal activity. Hematocrit is the greatest and airway
caliber the best around the middle and afternoon hours, platelet numbers and uric acid peak
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later during the day and evening. Hence, several physiological processes in humans vary in a
rhythmic manner, in synchrony with the internal biological clock (see Fig 2 and 3)[7,8].
Fig 2: A 24-hrs clock diagram of the peak time of selected human circadian rhythms with reference to the day-night cycle
Fig 3: A 24-hrs clock diagram of the peak time of selected human circadian rhythms with reference to the day-night cycle
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Examples of some of the diseases are shown in Table.
Circadian rhythm and manifestation of clinical diseases
Disease or syndrome Circadian rhythmicity
Allergic Rhinitis Worse in the morning/upon rising
Asthma Exacerbation more common during the sleep period
Rheumatoid Arthritis Symptoms more common during the sleep period
Osteoarthritis Symptoms worse in the middle/later portion of the day
Angina Pectoris Chest pain and ECG changes more common in early morning
Myocardial Infraction Incidence greatest in early morning
Stroke Incidence higher in the morning
Sudden cardiac death Incidence higher in the morning after awakening
Peptic ulcer disease Worse in late evening and early morning hours
Time controlled drug delivery system based on chronotherapy or chronopharmacology have
been investigated together with release rate controlled system for the treatment of diseases
such as chemotherapy, neurological disorders, ischemic heart disease, asthma and arthritis.
Drug for treatment of such diseases should be administered so as to maintain a therapeutic
blood level only at the required time, at the required time, and hence the drug release
behavior should be controlled by rate. For this purpose, various system and sigmoidal release
system have been discussed using various techniques and functional polymers or additives.
These technologies have the unique characteristic that a drug is released from the formulation
after a predetermined lag time[10-15]. Hence, they can be successfully used as a
chronotherapeutic drug delivery system.
Modified release drug delivery system
The term MR drug product is used to describe products that alter the timing and/ or the rate of
release of the drug substance.
Types of Modified release drug delivery systems
Extended release dosage forms: A dosage that allows at least a two fold reduction in dosage
frequency as compared to that drug presented as an immediate release form.
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Example: Control release, sustained release.
Sustained release: It includes any drug delivery system that achieves slow release of drugs
over an extended period of time not particularly at a predetermined rate. Sustained release
dosage forms to complement the pharmaceutical activity of the medicament in order to
achieve better selectivity and longer duration of action. Sustained release products are helpful
to reduce the dose frequency and side effects of drugs and improve patient convenience.
Controlled release: It includes any drug delivery system from which the drug is delivered at
a pre-determined rate over a long period.
Delayed release dosage forms: A dosage form releases a discrete portion of drug at a time or
times other than promptly after administration although one portion may be released
immediately after administration. Ex. Enteric coated dosage forms.
Targeted release dosage forms: A Dosage forms that release drug at /or near the intended
physiological site of action. Targeted release dosage forms may have extended release
characteristics.
Repeat action dosage forms: It is a type of modified release drug product that is designed to
release one dose or drug initially followed by a second dose of drug at a latter time.
Prolonged action dosage forms: It is designed to release drug slowly to provide a
continuous supply of drug over an extended period.
Extended release dosage forms are formulated in such manner as to make the contained drug
available over an extended period of time following administration. Expressions such as
controlled release, prolonged action, repeat action and sustain-release have also been used to
describe such dosage forms. A typical controlled release system is designed to provide
constant or constant drug levels in plasma via reduce fluctuations via slow release over an
extended period of time [16].
Most of the drugs are incompatible due to severe degradation in presence of each other.
Because due to the chemical incompatibility of the combined drugs which causes mutual
decomposition and leads to stability problems. This poses a challenge to the formulating
scientist while presenting the combination of the two drugs in a single dosage form. The
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objective of formulating a single dosage form is improved patient compliance resulting in
decreased possibility of recurrence or developing resistance [17].
SOME OF THE TECHNOLOGIES WHICH CAN BE USED ARE
1. Capsule-in-a-capsule technology
2. Tablet-in-a-tablet technology
3. Tablets-in-a-capsule technology
4. Granules and Tablets-in-a capsule technology [Biphasic delivery system]
1. Capsule-in-a-capsule technology
Single oral capsule dosage units comprising capsule-in-a-capsule technology (See Fig 4)
offer a broad range of therapeutic applications. This method allows the insertion of a pre-
filled, smaller capsule into a larger, liquid-filled capsule. The smaller, inner capsule may
contain either a liquid or semi-solid formulation and, according to the formulation or product
requirements, either or both capsules may be of gelatin or HPMC composition and can be
coated, if necessary. The inner and outer capsules may contain the same active drug,
providing multiple release profiles from the dosage unit for example, an immediate release
formulation from the outer capsule and a controlled release formulation from the inner
capsule. In addition to modifying release profiles, it is also possible to target the inner and
outer capsule to different areas of the GI tract (small intestine or colon) with an appropriate
coating. Alternatively, the inner and outer capsules may contain different actives for use with
combination therapies or actives that are incompatible. Inner-capsule contains liquid, semi-
solid or powder formulation or outer capsule contains liquid or semi-solid formulation. This
method is suited for both pharmaceutical and nutraceutical use. It is a simplified drug
regimen.
Fig 4: Capsule-in-a-capsule technology- Examples of various fills: liquid/ liquid;
liquid/ semisolid; liquid/ beads.
Combination therapies are currently of significant interest, as demonstrated by the
recent launches of Combodart™ (GSK) and Vimovo™ (Pozen, AstraZeneca). This interest in
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combination therapies is being driven by an increasing acceptance by regulators, and a desire
on the part of pharmaceutical companies to develop life cycle products that provide increased
patient convenience and compliance. Currently only nutraceutical companies have progressed
this technology to a commercial product; however, various pharmaceutical companies have
products in development [18].
Advantages of Capsule-in-capsule technology [19]
1. Provides both controlled and multi-phase release for single or combination prescription
and over the counter medicines.
2. Comprising of two independent compartments in one single oral dosage unit.
3. Patient convenience & compliance and cost effective therapy can be achieved.
4. Delivering of incompatible APIs are possible.
5. Sustained, pulsed or delayed release profiles can be achieved.
6. Drug delivery can be targeted to two different regions of the GI tract.
7. Broad therapeutic applications can be achieved.
2. Tablet-in-a-tablet technology
Tablets are indeed the most popular solid dosage form for oral administration. One category
of tablet formulations that has gained remarkable importance in drug therapeutics owing to
various benefits it offers is controlled or modified release formulations [20].
Although less popular, tablet-in-a-tablet technology (see Fig 5) gained increased interest in
the recent years for creating modified released products. It involves the compaction of
granular materials around a preformed tablet core using specially designed tableting
equipment. Compression coating is a dry process. This type of tablet (compression coated
tablet) has two parts, internal core and surrounding coat. The core is small porous tablet and
prepared on one turret. After tablet core manufacture it is transferred (centrally positioned) to
another slightly larger die that is partially filled with coating powder. More coating powder is
filled on the top of the core and compressed again resulting in tablet with in tablet.
Mechanically, it is a complex process, as the tablet may be tilted when transferred to the
second die cavity. Mostly, the coat is water soluble and disintegrates easily after swallowing,
in order to achieve immediate release product. This tablet readily lend itself in to a repeat
action tablet as the outer layer provides the initial dose while the inner core release the drug
later on. But, when the core quickly releases the drug, entirely different blood level is
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achieved with the risk of over dose toxicity. To avoid immediate release of both the layers,
the core tablet is coated with enteric polymer so that it will not release the drug in stomach
while, the first dose is added in outer sugar coating. Even so, coating operation requires
interpretation while manufacturing and dawdling the manufacturing process. Sometimes,
inner core may be of liquid formulation to provide immediate release of core after the coat
gets dissolved.
Fig 5: Tablet-in-a-tablet technology
Advantages of tablet-in-a-tablet technology
1. It is simple and inexpensive.
2. It is used to separate incompatible materials (one in the core and the other in the coat).
3. May be used to create modified-release products such as Delayed Release (Release in
intestinal).
4. It is not hazardous to the environment since it does not require the use of high amounts
of organic solvents.
5. CCT can also be used to avoid pharmacokinetic drug–drug interactions between
concomitantly administered medications, creating a time interval between their releases
into the gastrointestinal tract [21-25].
3. Tablets-in-a-capsule technology
Controlled release capsules often containing plurality of coated pellets is yet another category
of solid oral formulation that offers analogous therapeutic benefits. A relatively more recent
approach that has come into existence is the one that combines the features of both controlled
release tablets and modified release capsules in one dosage form [20].
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Drugs are usually encapsulated in one way or another within a barrier material, which is
composed of an erodible or biodegradable polymer. Depending on the barrier material
structure and thickness, different release lag times can be achieved. After the barrier material
is dissolved, eroded or degraded, drugs are rapidly released from the inner reservoir core.
Based on the concept that a formulation given once a time daily, a multifunctional and
multiple unit system for oral use can be developed by filling versatile tablets in a hard
capsule. This can be developed by preparing Rapid-release Mini-Tablets (RMTs), Sustained-
release Mini-Tablets (SMTs), Pulsatile Mini-Tablets (PMTs), and Delayed-onset Sustained-
release Mini-Tablets (DSMTs), each with various lag times of release. Based on the
combinations of mini-tablets, multiplied pulsatile drug delivery system (DDS), site-specific
DDS, slow/quick DDS, quick/slow DDS, and zero-order DDS could be obtained. This system
can be used for achieving the selective delivery of drugs at appropriate time, which is a
chronopharmaceutical approach for the better treatment of disease with circadian rhythms.
This novel system is a so-called “tablets in capsule device”. (see Fig 6 and 7). The designed
capsule device consists of an impermeable capsule body and a soluble cap. The multi-layered
tablets formulation prepared is filled within the capsule body and sealed with the water-
soluble cap [6, 26-29].
In this technology we can reduce the size of the tablet such that it could be enclosed in a
capsule, and then deploy tablets with different release properties, within one single dosage
form. This technology may be achieved by fast/slow delivery system. The proposed fast/slow
delivery devices show a wide flexibility in the modulation of the delivery program. The two
different release phases can be easily adjusted in a wide range of values of both delivery rate
and ratio of the dose fractions, on the basis of the pharmacokinetics and therapeutic needs, to
perform the desired in-vivo profile [30,31].
The concept of this technology is characterised by the fact that the dose is administered as a
number of subunits, each one containing the drug. The dose is then the sum of the quantity of
the drug in each subunit and the functionality of the entire dose is directly correlated to the
functionality of the individual subunits [32].
Multi-particulate (MP) modified release drug delivery systems have several performance
advantages vs. single unit dosage forms. After ingestion, MP units are released from the
capsule in the stomach, predictably transit to the small intestine and spread along the gastro-
intestinal tract resulting in a consistent drug release with reduced risk of local irritation. MP
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formulations generally have a more reliable in-vivo dissolution performance when compared
to a single unit dosage form, resulting in more uniform bioavailability and clinical effect [33-
35].
Fig 6: Tablets-in-a-capsule technology
Fig 7: Tablets-in-a-capsule technology
Advantages of tablets-in-a-capsule technology
1. It causes significant savings, lower treatment failure rate & lower case-fatality ratios.
2. Provides both controlled and multi-phase release for single or combination
prescription and over the counter medicines.
3. Patient convenience & compliance and cost effective therapy can be achieved.
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4. Delivering of incompatible APIs are possible.
5. Sustained, pulsed or delayed release profiles can be achieved.
6. Drug delivery can be targeted to two different regions of the GI tract.
7. It has higher colonic residence time, more predictable gastric emptying and
consequently less money needed for the development of new products in long-term
therapy.
8. It offer high drug loading, a wide range of release rate designs, and fine tuning of
these release rates. It has less risk of dose dumping, less inter- and intra- subject
variability, high degree of dispersion in the digestive tract thus minimizing the risks of
high local drug concentrations.
9. Broad therapeutic applications can be achieved [26-35].
4. Granules and Tablets-in-a capsule technology
Biphasic delivery systems are designed to release a drug at two different rates or in two
different periods of time: they are either quick/slow or slow/quick. A quick/slow release
system provides an initial burst of drug release followed by a constant rate (ideally) of
release over a defined period of time and in slow/quick release system provides release vice
versa [36]. (see Fig 8).
Fig 8: Granules and Tablets-in-a capsule technology
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Biphasic release system is used primarily when maximum relief needs to be achieved
quickly, and it is followed by a sustained release phase to avoid repeated administration.
Suitable candidate drugs for this type of administration include non-steroidal anti-
inflammatory drugs (NSAIDs) antihypertensive, antihistaminic, and anti-allergic agents[37].
Generally, conventional controlled dosage forms delay the release of therapeutic systemic
levels and do not provide a rapid onset of action. While immediate release granules give fast
release to provide rapid onset of action, but fails to provide longer duration of action. A
relatively constant plasma level of a drug is often preferred to maintain the drug
concentration within the therapeutic window. However, it is difficult to achieve, especially
for once-daily dosage forms, partly because the environment for drug diffusion and/or
absorption varies along the gastrointestinal (GI) tract [38]. On the basis of these
considerations, we have proposed a new oral delivery device, in the form of a double-
component tablet and granules, in which the one portion is formulated to obtain a prompt
release of the drug, with the aim of reaching a high serum concentration in a short period of
time. The second portion is a sustain release matrix, which is designed to maintain an
effective plasma level for a prolonged period of time [39]. This concept can be used to
produce a biphasic delivery system combining a fast release together with the slow release
period of the drug, provided that the excipients powder that fills The void spaces between
the mini-tablets incorporate a part of the total drug dose. This system can produce a rapid
rise in the plasmatic concentrations for some drugs (such as analgesic, anti-inflammatory,
anti hypertensive and antihistaminic agents) that are requested to promptly exercise the
therapeutic effect, followed by an extended release phase in order to avoid repeated
administrations [40].
Compressed mini-tablets systems are presented as a biphasic delivery system. The outer
layer that fills the void spaces between the mini-tablets was formulated to release the drug in
a very short time (fast release), while the mini-tablets provided a sustained release. Fast
releasing component comprises superdisintegrant crospovidone, while mini-tablet was
formulated using different concentration of HPMC and Ethyl cellulose. The In-vitro
performance of these systems showed the desired biphasic behavior [41]. Prepared immediate
release granules and sustained release mini tablets are filled in the capsule. The drug
contained in the fast releasing phase (Granular powder) dissolved within the first 5 min,
whereas the drug contained in the mini-tablets was released at different rates, depending
upon composition of mini tablets [42, 43].
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CONCLUSION
Over the past two decades there has been a growing appreciation on the importance of
circadian rhythms on GIT physiology and on disease states, together with the realization of
the significance of time-of-day of drug administration on resultant pharmacodynamic and
pharmacokinetic parameters. The significance of these day-night variation has not been
overlooked from the drug delivery perspective and pharmaceutical scientist has displayed
considerable intenuity in the development of time delayed drug delivery system to address
emerging chronotherapeutic formulation. Thus, the above mentioned technologies have
potential advantages over conventional dosage forms, with improved patient compliance,
convenience, bioavailability, delivering of incompatible APIs and rapid onset of action are
possible. Along with this, prolonged multiple release profiles can be achieved and hence can
be successfully used in chronotherapy.
ACKNOWLEDGEMENT
The authors express their thanks to Bhasker Pharmacy College, R. R. District, Hyderabad and
Jyothishmathi Institute of Pharmaceutical Science, Karimnagar for supporting us to make this
review article. Based on the outcome results of those published research work it has been
possible for us to publish this review article.
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