Layered Tablets: A Novel Oral Solid Dosage Form

Abstract

Oral solid dosage forms hold a predominant position in the drug delivery system. Tablets are the most widely used and convenient dosage form. Due to their ease of manufacturing, the minimum cost of production, easy handling and storage, and better stability, tablets are most preferred. Patients who are prescribed more than one drug are in a situation to consume multiple tablets. To minimize the counts, one or more drugs are cast into layers to form a single tablet, thus called layered tablets. Layered tablets tend to improve patient compliance and reduce the cost of production by half. Layers can be of multiple drugs or the same drug at different doses or drugs with release enhancers or drugs with fillers. Layered tablets hold a greater potential with better patient outcomes as well as stay production-friendly.

1. Introduction

A particular route of administration is conferred to a drug therapy based on its intended site of action, physicochemical properties, targeting aspects, the convenience of administration, stability, duration and onset of action, and many others. All these parameters help in building a stable, efficient, and therapeutically sound product. The most commonly used routes of administration include oral, IV, IM, and transdermal.

Since the era of drug delivery, the oral dosage is retaining an unbeatable position in drug administration. A drug delivery system aims at improving the efficiency of the treatment and various parameters like handling, administration, storage, etc. The oral route of drug administration is one of the oldest choices and has been consistently dominating the world of drug delivery. It comes with enormous merits like improved patient compliance, a simple manufacturing process, less complex requirements, easy storage and handling, and so on. Despite hindrances like first-pass metabolism, slow onset of action compared to IV/IM, and recent advances in novel drug delivery, the oral solid dosage form has still not lost its dominance.

The oral route is the most widely accepted and marketed route of administration. Besides convenience, it gives the advantage of enhanced absorption. The gastrointestinal tract has a larger surface area conferring to increased absorption of drugs. The intestinal epithelial wall is composed of villi, a micro- erective structure, that increases the absorptive surface area in the gastrointestinal tract up to 300–400 m² [1]. Pharmaceutical active ingredients are mostly weak acids or weak bases. The absorption of drugs is based on pH and dissociation constant. Drugs exhibit various degrees of absorption at differing pH. GIT offers a wide range of pH from highly acidic to highly basic nature (0.8–8). This enables absorption of both acidic and basic drugs. The stomach is a primary organ for the absorption of acidic drugs. The intestine has a grading basic pH enhancing the absorption of basic drugs [2, 3].

The oral dosage form denotes systems administered by the oral route. Being the most anticipated route, many formulations are available in the market. They can be solids, liquids, and semi-solids. One of the major factors to be considered for developing a formulation is its pharmaceutical stability. Solids showcase high mechanical, microbial, and chemical stability. An added advantage of oral solids is they do not require sterile manufacturing needs. No much sophistication is needed for manufacturing. Simple instruments are sufficient to produce large quantities of oral solids.

Commonly seen oral solids are tablets, capsules, and pellets. Oral solids are non-invasive and stand out due to its higher compliance and accepted for long term therapy. Production cost of oral solids are lower with retail price remains affordable too. Mechanical strength makes it easier to handle, transport and store. They can also provide modified release of drug enabling sustained, controlled and immediate release.

Despite all these advantages, oral solids bear some disadvantages. Solids are not a preferred dosage form for geriatric and pediatric patients. Dysphagic patients find it difficult to swallow solids and it is not an option for unconscious patient. Even with immediate release mechanism, it takes a lag time to disintegrate, dissolve and reach systemic circulation. It may take some to initiate onset of action, making it not an option for emergency conditions. One unavoidable hinderance is first pass metabolism. GIT is a high degradative pathway conferring to presence to enzymes, acid secretions and altering transit time. Recent advancements like oro-dispersible tablets and sublingual tablets are available, but still oral solids are not comparable to parenteral.

2. Tablets

Tablets are popularly denoted as unit dosage form is an which contains active ingredient(s) and excipients, compressed into a compact solid. It is available in various shapes like, circular, cylindrical, triangular. They are mostly circular, with convex ends and blunt edges. Tablets are manufactured by compressing the actives and other ingredients by use of punches and dies. Tablets may carry break line, break marks and symbols for breaking and identification. They are usually swallowed with liquids, may be chewable, oral disintegrating, etc.….

Tablets are unit dosage form that offers accurate dosing at an affordable price. With increased consumption, simple large-scale production makes it more feasible. Other advantages include easy and cost-effective handling, and ease of identification, as tablets come in various shapes, sizes and colors.

Tableting may be affected by due to the poor compressibility and flow properties of powders which is a major compression parameter. The minimum dose also plays a role in compression. Unacceptable taste and odour make it difficult to devise formulation. Physical instability is a serious drawback that can affect the formulation which could be overcome by encapsulation.

In order to classify the tablets representatively, a schematic flow chart is shown in Figure 1.

Figure 1.

Flow chart of types of tablets.

3. Layered tablets

The layered tablet is a combination of one or more APIs (Active Pharmaceutical Ingredients) along with excipients, cast in two or more layers to form a single unit dosage form. Formulating a combination of drugs in a single dosage form is appreciated in the case of long-term therapy like parkinsonism [4]. The noticeable feature is that the drug is released without any pharmacokinetic interactions with individual release rate [5]. It can greatly help in minimizing the dosing frequency and can also add to the synergistic effect [6].

The ideal properties expected for a layered tablet include sufficient mechanical strength, better chemical, and physical stability, and no interaction between the layers. The layered tablets exhibit increased patient compliance as the dosing burden is reduced [7]. Layers of the tablet can provide multiple release kinetics of the same or different drugs of the same or different physicochemical properties and showcase different release control mechanisms [8]. Generally, when two or more drugs are co-administered, they might possess the ability to enhance the effect of each other. The layered tablets are the potential in offering such a synergistic effect [6, 9]. These layered tablets also confer high product identification, as the layers are usually of different colours and enable patients to identify the tablets at ease. This also contributes to the attractive appearance of the dosage form.

The bigger advantage is that dual release profiles are obtained in a single unit dosage form. One layer can promote immediate release while the other may contribute to controlled or sustained release [10]. It is very much possible to avoid active-active, active – excipient and excipient - excipient interactions. The cost of production is reduced to a greater extent as the production of two or more tablets is merged into one. It is time-saving and production-friendly.

Accurate dosing and minimized inter-unit variability make it a potential candidate. Low production cost helps in reducing health care expenditure. Ease of packing and handling are added advantages. For a patient under multiple drug regimens, it is easier to carry a single unit compared to multiple units. For drugs with bitter/ obnoxious taste, the oral route may be less preferred. This can be overcome by adapting various taste-masking techniques. Incompatibility is a serious issue when various drugs are administered together. Two incompatible drugs can be administered together by adding an inert layer between the active layers [8]. Fillers constitute a majority of a tablet. When two or more drugs are administered in a single dosage form, there is a possible reduction in the use of excipients like fillers. Layered tablets are very much preferred in case of multiple drug therapy and long-term care.

When it comes to the disadvantages, the weight of the tablet remains a major concern. With all the fillers and inert separating layers, weight adjustment of each layer during a continuous batch is difficult. The layers should have sufficient binding capacity to hold the formulation together. This requires high throughput planning and pre-formulation. Lack of binding of two or more layers and separation of layers. High labor input and equipment sophistication are necessary. Based on the active ingredients, layered tablets are classified as bi-layered tablets with a single active ingredient or bi-layered with two different active ingredients. Tri-layered tablets have three different active ingredients. Based on formulation type, bi-layered tablets may contain one immediate release and another sustained-release layer; two immediate layers; one sustained release and another inert supporting layer; one sustained-release and another inert protecting layer.

4. Release aspect

These bi-layered to multi-layered tablets are formulated to achieve desired release kinetics such as immediate-release, controlled release based on time, pH and related factors, zero-order sustained release, etc. [11, 12]. Bi-layered tablets comprise an immediate-release layer and another extended-release layer. The immediate-release layer disintegrates immediately on reaching the GIT and releases a loading dose. While the other layer stays for a longer period in GIT and maintains drug plasma concentration. The hydrophobic/hydrophilic polymer matrix layer in layered tablets is used in controlling the drug release pattern by hydrophobic polymer coating over the hydrophilic matrix to attain sustained release, whereas one-sided coating aid in controlled release of the drug. In the case of a combined release strategy, initial rapid release followed by prolonged drug release is required to maintain stable plasma concentration. Bimodal release tablets show an initial rapid drug release, followed by slow release of the drug substance, then a third phase of rapid drug release, i.e., tablets exhibit sigmoidal release profiles [11, 13, 14, 15].

5. Manufacturing technology

In the past decades, layered tablets have been gaining attention, thus increasing the requirement for the development of newer formulation techniques and technologies. However, most of the techniques are the same as that of a conventional tablet, some variations in compression are necessary. It is important to analyze physio-chemical properties, cohesive properties, compression, and compaction profiles of all the layers used individually before the production of layered tablets. The ultimate objective is to produce stable layered tablets, that remain in a single unit, without layer separation and reduce the bulk of the tablet [5, 16, 17].

5.1 OROS® push-pull technology

The system comprises two or more layers in which one or more layers contain active ingredients and others are push layers (Figure 2). The drug layer can be made of single or multi-components. Mostly poorly soluble drugs are incorporated. The drug release can be aided by the addition of suspending or osmotic agent. The tablet core can be surrounded by a semi-permeable membrane.

Figure 2.

Bilayer OROS push pull technology.

5.2 L-OROS tm Technology

This is used in the case of poorly soluble and insoluble drugs. By this technique a lipid soft gel product which holds the drug in a dissolved state is initially produced, then it is coated with a barrier membrane followed by an osmotic push layer and semipermeable membrane, as shown in Figure 3. An exit orifice is drilled at the end.

Figure 3.

L-OROS tm technology.

5.3 EN SO TROL technology

It is an integrated method to deliver the drug to enhance solubility and incorporate enhancers to achieve controlled drug release from the dosage form. A wicking agent is generally used.

6. DUREDAS™ technology

It is a dual drug delivery form consisting of two layers where one provides immediate release and sustained release of the same drug (Figure 4). An immediate-release layer is composed of granules with a matrix layer for the modified release of the drug. One or more hydrophilic polymers are used in such cases.

Figure 4.

Dual drug delivery dosage form.

6.1 RoTab bilayer compression

It is one of the dynamic and widely trusted equipments used in compression on mono and bilayer tablets. It comes with software, which makes it easy to use. Due to various controllable parameters and flexibility, it is of greater utility in R&D. Switching between mono and bilayer makes an impact on its desirability.

7. Challenges in manufacturing layered tablets

Apart from the common tableting problems, there are several other challenges that are more dominant in the case of layered tablets.

7.1 Weight variation, sequence

Weight variation is generally studied in the case of solid unit dosage forms. The weight variation can be subjected to variation between units and also between the layers. Each layer should possess the predetermined weight without any major deviation in range. Individual layer weight [18]. It is preferable for the layers to have similar weight so that it aids produce required strength, weight distribution, appearance, and similar compression profiles.

7.2 Mechanical strength

It is noted that excipients play important role in producing a high-quality layered tablet. Excipients that confer brittleness to the formulation are preferred to provide sufficient mechanical strength to layered tablets such that they can withstand mechanical pressure during production, packing, and transportation [19, 20].

7.3 Lubrication

It is studied that increase in lubricant concentration, decreases the strength of interfacial bonding and can deteriorate the interfacial interaction between the layers [21, 22].

7.4 Adhesion strength

The major challenge is holding the layers together which is dependent on interlayer adhesion strength between two or more layers used. In the production of layered tablets, initially, a central core is prepared by pre-compression, then the upper and lower layers are compressed around the central core. Necessary interlayer adhesion strength is required to hold these layers together as a single unit. Low compression force for the core and high compression force for layers can help in attaining adequate adhesion [23, 24, 25].

7.5 Interlayer cross-contamination

There is a high possibility of cross-contamination between the adjacent layers. To overcome this, scraper plates are placed around the die fill to remove residual powder [26]. In some cases, suction and dust removers are also being used.

7.6 Long term integrity and storage

The layered tablets should display a long-term physical and chemical integrity throughout the shelf life of the dosage form [28]. Temperature and humidity changes during storage have a greater impact on interlayer adhesion [27, 28].

7.7 Size of the tablet

Attention has to be given to the size of the tablet, as multiple layers can lead to an increase in size, making it difficult to swallow. This can be handled by minimizing the separation layers. It is difficult to accommodate two drugs in high doses.

8. Evaluation of layered tablets

Most of the pre and post-compression evaluations are the same as that of a conventional tablet.

8.1 Pre-compression evaluations

Before the compression, the API and other excipients are evaluated to study the powder characteristics and micromeritics. The powder particle size is determined using a laser diffractometer. Various other powder properties like Hausner’s ratio, Carr’s index, and angle of repose are also determined before manufacturing a tablet. The moisture content of the powders is evaluated thermogravimetrically.

8.2 Post compression evaluations

8.2.1 Weight uniformity

The formulation should have a uniform weight within the batch. It is a major quality control test in the formulation of tablets. It is necessary to ensure that all tablets have weights within the tolerated limits to ensure intra and inter-batch uniformity data. About 20 tablets from each batch are evaluated for weight uniformity by determining individual weights.

8.2.2 Thickness

One serious drawback of layered tablets is the increased thickness. It should possess sufficient thickness to accommodate multiple layers of drug and inert materials. It should also be ensured that it lies within the swallowable limits. The thickness of the tablet is determined by the vernier caliper. It ensures that the tablet lies within the desired range, enabling easy swallowing.

8.2.3 Friability and hardness

To test tablets to withstand mechanical damage during processing, transport, and storage, friability and hardness are evaluated. About 10 tablets are weighed and loaded into the rotating drum of friability apparatus set at 100 rotations. Then the tablets are reweighed to calculate the weight lost. Hardness is the measure of the maximum pressure that a tablet can withstand. It is measured using instruments like Pfizer/Monsanto hardness tester.

8.2.4 Content uniformity

In order to assure that each tablet contains a labeled amount of API, they are evaluated using UV Visible spectrophotometer. Tablets are dissolved in suitable solvents and evaluated under a specific wavelength. In the case of more than one API, the simultaneous equation method is generally used.

8.2.5 Disintegration time

Time taken for a tablet to break down directly confers to the absorption. Faster disintegration promotes faster dissolution and absorption. The disintegration apparatus consists of disintegration vessels made up of mesh, immersed in a disintegration medium, which moves at specified cycles at the rate of 28-32 strokes per minute. The disintegration time is calculated as the time at which the tablet completely disintegrates.

8.2.6 In-vitro drug release

It is determined using dissolution apparatus to study the release profile and dissolution profile of the tablets. It directly influences the rate of absorption. Since it possesses more than one API, the simultaneous equation method is used to calculate the drug concentration in the sample by UV Visible spectrophotometer [29]. Tablets are dropped into the dissolution medium of 900 ml volume, maintained at 37 ± 0.5 ºC. Based on the requirement Type I or II dissolution apparatus is selected. The paddle/basket is rotated at 25-100 rpm. Samples are withdrawn at a specific time period and evaluated UV spectroscopically.

8.2.7 Drug release kinetic

It is necessary to evaluate the kinetics of drug release as multiple layers may exhibit various release rates, which can confer to its profile. Each layer may exhibit a different release rate, characterizing sustain release and immediate release pattern is necessary.

8.2.8 Stability studies

It is one such star test common for all pharmaceutical products. Here stability of all the layers is studied. Layers may display different degrees of degradation. Shelf life is determined based on each layer’s characteristics.

8.2.9 Morphology analysis

Physical qualities can be examined by visualization. The morphology of layered tablets can be visualized by Scanning Electron Microscopy using cross-section samples [30].

8.2.10 Thermal analysis

Thermal analysis is of greater interest in detecting drug-excipient, drug-drug, and excipient-excipient interactions in the formulation. Using Differential Scanning Calorimetry, molecular dispersion of drug substance in tablet matrix system can be identified [30].

8.2.11 Crystallinity

The crystalline and amorphous nature of drugs has a direct influence on their stability, solubility, and various other Physico-chemical properties. The crystal nature of drug substances in various layers is evaluated by using X-Ray Diffractometer (XRD). Possible transformation of drug nature from crystalline to amorphous form or vice versa during processing or storage can be studied [31].

9. Conclusion

The oral dosage form has gained its prominent position at the top of the chain. Even after decades of advancements and novel drug delivery approaches, oral tablets make up most of the pharmaceutics. Oral tablets are not only popular but also are most stable with a high degree of patient compliance. Speaking about enhancing oral tablets, layered tablets are an add-on. By weighing several parameters, layered tablets can be a vital approach in oral solid dosage forms. The layered tablets are gaining a lot of attention. Devising oral tablets using multiple layers makes it convenient over delivering multiple tablets. It enhances compliance and also offers a low capital investment and cost-effective production. From the perspective of manufacturers, clinicians, and patients, layered tablets remain preferable. Thus, greater focus can be shown on such technology in the future to explore more in this dosage form.

Acknowledgments

The authors are thankful to KMCH College of Pharmacy, Coimbatore, for their constant support.

Conflict of interest

The authors declare no conflict of interest.