World Journal of Pharmaceutical Research et al. SJIF ... · 2) This is unit dosage form with...

www.wjpr.net Vol 7, Issue 13, 2018.

338

Bura et al. World Journal of Pharmaceutical Research

OPENING NOVEL WAYS IN THE DRUG DELIVERY SYSTEMS BY

BI-LAYER TABLET TECHNOLOGY

Abhishek R. Bura1*, Amit N. Chavan

2 and Gaurav Lodha

1

1Dr. Vithalrao Vikhe Patil Foundation’s College of Pharmacy, Vilad Ghat, Ahmednagar,

(MS), India, 414111.

2Department of Pharmaceutics Dr. Vithalrao Vikhe Patil Foundation’s College of Pharmacy,

Vilad Ghat, Ahmednagar, (MS), India, 414111.

ABSTRACT

For patent extension, few pharmaceutical companies are currently

developing the bi-layer tablets, addition in therapeutic efficacy etc. Bi-

layer tablet is a novel era for the unbeaten development of controlled

release formulation along by various features to provide a method of

successful drug delivery system and for separation of two incompatible

substances two drugs are used in combination for sequential release

and as initial dose sustained release tablet in which one layer is

immediate release and the second layer is maintenance dose. Bi-layer

tablets can be major option to avoid chemical incompatibilities among

APIs by physical separation and to allow the development of dissimilar

drug release profiles. The present article provides a review of the oral

drug delivery system, types of the tablets, Bilayer tablet developing, various type of tablet

presses use, quality and the GMP requirements for high production output and current

developments in the field of Bilayer technology and production of superiority bi-layer tablets

need to be carried out on the reason built tablet presses, such as layer parting, lacking in

hardness, incorrect individual layer weight control, cross-contamination among the layers and

reduced the yield.

KEYWORDS: Bilayer tablet, GMP requirements, DUROS Technology, tablet presses,

Trilayer tablets.

World Journal of Pharmaceutical Research SJIF Impact Factor 8.074

Volume 7, Issue 13, 338-351. Review Article ISSN 2277– 7105

Article Received on

12 May 2018,

Revised on 03 June 2018,

Accepted on 24 June 2018,

DOI: 10.20959/wjpr201813-12785

*Corresponding Author

Abhishek R. Bura

Dr. Vithalrao Vikhe Patil

Foundation’s College of

Pharmacy, Vilad Ghat,

Ahmednagar, (MS), India,

414111.


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INTRODUCTION

Oral intake has long been the most suitable and commonly employed route of the drug

delivery due to its simplicity of the administration. The conventional dosage form produces

the extensive variation in the drug concentration in the bloodstream and tissues with the

resulting unwanted toxicity and the poor efficiency. The aim in the designing sustained or the

controlled delivery systems are to reduce the frequency of the dosing or to raise efficacy of

the drug by the localization at the site of action, reducing the dose required. The main

purpose of sustained release drug delivery is to make sure the safety and to improve the

effectiveness of the drugs as well as patient compliance[7]

now a day’s various developed &

developing countries are a move towards combination therapy for the treatment of various

diseases & disorders requiring long-term therapy. There are some key advantages of bi-layer

tablets which are compared to conservative bi- tablets. for instance, by physical division, such

tablets are typically used to avoid chemical incompatibilities of formulation components.[9]

However, these drug delivery procedure is mechanically complicated to design/manufacture

and the harder to predict their long-term mechanical properties due to poor mechanical and

compression character of the component materials in the compacted next layers.

TYPES AND CLASSES OF TABLETS[3]

All over 90% of the tablets manufactured today are ingested in orally. Orally ingested tablets

are intended to be swallowed intact, with the omission of chewable tablets. Table-1

summarizes the classes for the dissimilar types of tablets.

Table 1: Various Types of Tablets.

A) Oral Tablets for Ingestion

1) Standard compressed tablets.

2) Multiple compressed tablets:-

a. Layered tablets.

b. Compression coated tablets.

c. Inlay tablets.

3) Modified release tablets.

4) Delayed action tablets.

5) Targeted tablets:-

a. Floating tablets.

b. Colon targeted tablets.


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6) Chewable tablets.

B) Tablets Used In the Oral Cavity

1) Buccal tablets.

2) Sublingual tablets.

3) Troches and lozenges.

4) Dental cones.

C) Tablets Administered By Other Routes

1) Implantation tablets

2) Vaginal tablets

D) Tablets Used To Prepare Solution

1) Effervescent tablets

2) Dispersible tablets

3) Hypodermic tablets

4) Tablet triturates

Table 2: Advantages and Disadvantages of Tablets.

ADVANTAGES

1) Ease of precise dosing and low content variability.

2) Good physical and chemical stability.

3) Competitive unit manufacture expenses.

4) High level of patient suitability.

5) High convenience.

6) Easy to packaging and the shipping.

7) Simple to identify.

8) The convenience of the self-administration.

DISADVANTAGES

1) Irritant effects on the gastrointestinal mucosa by some solids.

2) A possibility of bioavailability problems resulting from slow disintegration and

dissolution.

3) Some drugs resist compression into tablets.

4) Difficulty in swallowing in some patients; pediatrics and geriatrics.


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5) In emergency cases, intravenous or intramuscular injections are more effective.

BILAYER TABLETS

A multi-layered tablet is a tablet that has more than one separately compressed powder layers

within its final single body e.g. a bi-layered tablet consists of the two sequentially

compressed layers that form a single final coherent tablet body at the end of the compression

method. Multi-layered tablets are favored due to their controlled release profiles of the active

ingredients.[4]

The intention of any drug delivery system is to supply a therapeutic amount of

the drug to the appropriate site of the body to achieve rapid and or uphold the required drug

concentration. Combination therapy is more helpful as compared to mono-therapy because in

this we can reduce the dose-dependent on its side effects. Low dose combination of two

dissimilar drugs reduces the side effect of a single drug in high dose.[5]

Figure No. 1a: Single Layer Tablet.

Figure No. 1b: Bilayer Tablet.

Figure No. 1c: Multilayer Tablet.


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NEED OF BILAYER TABLET

1) To control the delivery rate of also single or two different API'S.

2) To modify the total shell area available for API layer either by sandwiching with one or

two inactive layers in order to get swellable/erodible barriers for controlled release.

ADVANTAGES OF BILAYER TABLETS.[6,7]

1) The chemical and the microbial stability is more than another oral dosage form.

2) This is unit dosage form with various capabilities for highest dose accuracy and least of

unpredictable content.

3) Easy to swallow with the fewer tendencies to hang-up.

4) It is appropriate for large-scale manufacturing.

5) The cost is low as compared to another oral dosage form.

6) The product identification is easy.

7) It maintains physical and chemical stability.

8) Patient expediency is improved because less daily doses are required compared to a

traditional delivery system.

9) The potential use of single entity feed granules.

DISADVANTAGES OF BILAYER TABLET DOSAGE FORM.[6]

1) The drug which resists the compression or the drug which is amorphous in nature or have

the low density, those drugs cannot be included into bi-layer tablet.

2) Bitter drugs, drugs which are sensitive to the oxygen or drugs which have an unpleasant

odor, they require the extra step of coating.

3) Trouble in swallowing of the table in the case of unconscious patients and children.

4) The drugs which have the poor wetting & the slowly dissolves in GIT.

GENERAL PROPERTIES OF BILAYER TABLETS.[8]

1) Bi-layer Tablet should be elegant with free from defect, cracks, discoloration, and

contamination.

2) It should have the sufficient potency to resist mechanical shock during the production,

packaging and the shipping.

3) It should be physically and chemically stable.

4) It has to release the drug in expected and reproducible manner.

5) It has to be chemically steady to resist of the modification of chemical nature of drug

substance in the shelf life.


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APPROACHES FOR LAYERED TABLETS

1) Multi-Layered tablets (two to three component systems.)

2) Compression coated tablets (tablet within a tablet.)

3) Inlay tablet (coat partially surrounding the core.)

1. Compression coated tablets.

The layer provides the initial dose while the inner core releases the drug later on. But, when

the core rapidly releases the drug, entirely different blood level is achieved with the risk of

overdose toxicity.

Figure No. 2: Core coated tablets.

2. Inlay tablets

By the coating, it’s a category of a layered tablet in which instead of the core tablets being

completely surrounded. Peak surface is completely covered. While preparation, the only

bottom of the die cavity is filled with the coating material and core is placed upon it. The

coating material is displaced to form the sides by applying compression force and compact

the entire tablet Under GMP conditions.[20]

Figure No. 3: Inlay tablets.


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BILAYER TABLETS QUALITY AND GMP REQUIREMENTS[8]

To create excellent bi-layer tablets it is important to choose Bilayer Tablet Press which are

accomplished of the following quality:

1) It should provide sufficient hardness to a tablet.

2) It should be preventing cross-contamination among two layers.

3) It should produce bi-layer tablet with distinct visual separation of two layers.

4) It should prevent capping and the separation of two layers.

5) It should be accurate and the individual weight control of both the layers.

6) It should be able to produce tablets with minimum weight variation.

CHALLENGES IN FORMULATION OF BILAYER TABLETS[7]

While development of bi-layer tablet various challenges is developed like, the first layer

tamping force, the elastic difference of the adjacent layers, an order of layer sequence and the

layer weight ratio. If these factors are not well controlled in one way or the other will affect

the bi-layer compression pressure and the quality attributes like mechanical strength and

individual layer weight control. Therefore the care must be taken to enable the design of a

vigorous product and the process. Some Challenges in the formulation of Bilayer Tablets are

as given follows:

1) The lamination i.e. layer separation is a major problem in the production of layered

tablets.

2) Mixing both the layers together i.e. Cross-contamination.

3) Lack of sufficient bonding and the adhesion at adjoining layers.

4) It’s difficult to maintain the integrity of the final Tablets.

5) The individual layer weight is difficult to control.

6) Lacking hardness.

7) The production yield of Bilayer tablet is very low compared to single layer tablet.

8) Bi-layer tablet is more expensive than single layer tablet.

TYPES OF BILAYER TABLET PRESS[14,15]

1) Single sided tablet press.

2) Double-sided tablet press.

3) Bilayer tablet press with displacement monitoring.


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1) Single Sided Tablet Press[10]

Every chamber is gravity or forced fed with dissimilar power, producing the two individual

layers of tablets. Then the whole tablet is compressed into one or two steps. The two layers in

the dye mix to some extent at their interface and in most cases bond properly so that no layer-

partition occurs when the tablet is formed

Figure No. 4: Single Sided Tablet Press.

Limitations of the single sided press[12,13]

No weight monitoring/control of the individual layers.

1. No separate visual division between the two layers.

2. Very short first layer dwell time due to the small compression roller, possibly resulting in

Poor desertion, capping and hardness troubles.

3. This will be corrected by reducing the turret revolving speed (to extend the dwell time)

but with the consequence of lower tablet output.

2) Double-sided tablet press[10]

In most double-sided tablet presses with computerized production control use compression

force to monitor and control tablet weight. The control system at main compression of the

layer is measured or each individual tablet by the successful peak compression force.


346


Figure No. 5: Double-sided tablet press.

Limitations of compression force controlled system

A compression force-controlled system requires a negligible compression force of various

hundreds of daN. However, lots of bi-layer formulations require a smaller amount than 100

daN to compress the first layer in order to keep the ability to bond with the second layer.

Above 100 daN, this ability may be lost; bonding between both the layers may not be enough,

resulting in a low hardness of the bi-layer tablet and division of the two layers. At superior

production speed, the risk of disconnection and capping increases but can be reduced by the

sufficient dwell time at Compression stages.

3) Bilayer tablet press with displacement monitoring[10]

This double-sided tablet press has been exclusively designed and developed for the

manufacture of good quality bi-layer tablets and provides:

1. Displacement of the weight monitoring/control for accurate and independent weight

control of the individual levels.

2. Low compression force exerted on the first layer to avoid the capping and the separation

of the two individual layers.

3. Maximum prevention of the cross-contamination among the two layers.

Figure No. 6: Bi-layer Tablet Press with Displacement.


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Figure 7: The process of bi-layer tablet compression.

(a) First layer fill; (b) First-layer tamping; (c) Upper punch with drawl;

(d) Second layer fill; (e) Main compression; (f) Ejection.

Ideal Properties of Bilayer Tablet Press

1. They should produce maximum yield and precise individual layer weight control.

2. It should produce clear visualization among two layers.

3. It should avoid the cross-contamination among two layers.

4. It should avoid capping and disconnection of two individual layers.

ROLE OF COMPRESSION FORCE CONTROL SYSTEM IN THE BILAYER

TABLET PREPARATION

Separation of the two layers of the bi-layer tablet is due to the insufficient bonding between

two layers. For the suitable bonding, the first layer is compressed at the low compression

force. It allows the first layer to interact with the second layer during the final compression of

the tablet. The controlling system is provided with the presses. It measures the effective peak

compression force exerted on each of the individual tablets.The rates at which the sensitivity

changes take place are dependent on the formulation or the powder characteristics. This

system is always based on measurement of the compression force at main compression and

not at pre-compression.[14]

It shows that the weight control system is based on the

compression force monitoring. The compression force controlled by the system requires a

small compression force of a number of hundreds of daN. An exchange is to the

“compression force measurement” is “Dislocation measurement”. It is advantageous because

of the accuracy in the increased with a decrease in the compression force. This system also

provides the increased dwell time with the good bonding between the two layers. A double-


348


sided press with the displacement measurement is the preferred presses for bi-layer tablet

manufacture.[15]

Figure No. 8: Double-sided tablet press.

VARIOUS TECHNIQUES FOR BILAYER TABLETS[17]

1. OROS® Push-Pull Technology

This system consists of mainly two or three layers between which the one or more layer is

necessary of the drug and the other layers are consist of push layer. There is promoting

addition of the suspending agent and the osmotic agent. A semi-permeable membrane

surrounds with the tablet core.

Figure No. 9: Bi-layer and Tri-layer OROS Push-pull technology.

2. L-OROS TM Technology

This system is mostly used for the solubility problem, where a lipid soft gel product

containing the drug in a dissolved state initially prepared and then coated with the barrier

membrane then osmotic push layer and then with semi-permeable membrane drilled with exit

orifice for the drug release.


349


Figure No. 10: L – OROS to technology.

3. DUROS Technology

The system consists of an outer cylindrical titanium alloy reservoir. It protects the drug

molecules from enzymes. These give a small drug dispensing system in the continues and

consistent which release little quantity of concentrated form.

Figure No. 11: DUROS Technology.

4. Duras Technology

The dual release drug absorption system utilizes in the bi-layer tableting technology. This is

specifically developed to give two dissimilar release rates or dual release of drug from a

single dosage form. The tablets are prepared as an immediate release layer and controlled

release layer within the single tablet.

5. Geminex Technology

It is dual drug delivery technology, which can deliver the one or more drugs at particular

times. This technology controls the release rate of the two drugs by maximizing their

individual therapeutic effect and minimizes the side-effects. The benefits of this technique are

that two dissimilar actives can be delivered at the different rates in the single tablet.


350


6. PRODAS

These are system is based on encapsulation of controlled release mini tablets in the size

ranging from the 1.3 to 4.5 mm diameter. This technology is a mixture of multiparticulate and

hydrophilic matrix technology thus shows benefits of both. These combinations may include

instant release, late release and or controlled release mini tablets.

CONCLUSION

Bilayer tablets present a good opportunity for manufacturers to split themselves from their

competitors. The bi-layer tablet excellence and GMP requirements vary broadly range. Lack

of accuracy at low compression forces required to safe interlayer bonding.

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