NOVEL TECHNOLOGIES IN FORMULATIONS: AN OVERVIEW

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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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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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