Mouth Dissolving Tablets: A Modern Approach to Delivery of Drug

 

Prevesh Kumar¹*, Md. Rageeb Md. Usman², Aditya Sharma¹, Diskha¹, Munesh Mani¹,

Pawan Singh¹, Navneet Verma¹

¹Faculty of Pharmacy, IFTM University, Lodhipur Rajput, Moradabad, U. P., India

²Department of Pharmacognosy, Smt. S. S. Patil College of Pharmacy, Chopda, India

 

ABSTRACT:

Recently pharmaceutical preparations used for elderly patients have been investigated to improve the treatment compliances and quality of life of patients. Recent advances in Novel Drug Delivery System (NDDS) aims to enhance safety and efficacy of drug molecule by formulating a convenient dosage form for administration and to achieve better patient compliance. One such approach is "Mouth Dissolving Tablet" are disintegrates instantaneously when placed on tongue, releasing the drug that dissolves or disperses in the saliva. Mouth Dissolving Drug Delivery System emerged from the desire to provide patient with conventional mean of taking their medication. Difficulty in swallowing (Dysphagia) is a common problem of all age groups, especially elderly and pediatrics, because of physiological changes associated with these groups of patients.  The saliva containing the dissolved or dispersed medicament is then swallowed and the drug is absorbed in the normal way. Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach & it may produce rapid onset of action. Bioavailability of drug is significantly greater than those observed from conventional tablet dosage form.

 

 

INTRODUCTION:

Oral routes of drug administration have wide acceptance up to 50-60% of total dosage forms. Solid dosage forms are popular because of ease of administration, accurate dosage, self-medication, pain avoidance and most importantly the patient compliance. The most popular solid dosage forms are being tablets and capsules; one important drawback of this dosage forms for some patients, is the difficulty to swallow. Drinking water plays an important role in the swallowing of oral dosage forms. For these reason, tablets that can rapidly dissolve or disintegrate in the oral cavity have attracted a great deal of attention Or dispersible tablets are not only indicated for people who have swallowing difficulties. United States Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER)

 

define orally disintegrating tablets in the ‘Orange Book’ as “A solid dosage form which contain a medicinal substance or active ingredient which disintegrates rapidly within a matter of seconds when placed upon a tongue”. Mouth dissolving drug delivery systems are a new generation of formulations which combine the advantages of both liquid and conventional tablet formulations and at the same time, offer added advantages over both the traditional dosage forms, which can be seen in (Fig. 1). MDT offers the luxury of much more accurate dosing than the primary alternative oral liquids. Dysphagia or difficulty in swallowing is common among all age groups. Dysphagia is common in about 35% of the general population, well as an additional 30–40% of elderly institutionalized patients and 18–22% of all persons in long-term care facilities. Preparation of mouth dissolving tablet can be manufactured by several techniques such as Freeze drying or Lyophilization, Spray Drying, Direct Compression, Sublimation, Cotton Candy Process, Mass Extrusion, Molding, Nanonization, Fast Dissolving Films, Phase transition process, Melt granulation.

 

Fig. 1: Mouth dissolving tablets

 

Requirements for mouth dissolving drug:^[3-6]

The tablets should-

·       Not require water to swallow, but it should dissolve or disintegrate in the mouth within seconds.

·       Be compatible with taste masking.

·       Have a pleasant mouth feel and leave no residue in the mouth after oral administration.

·       Less friable and have sufficient hardness.

·       Exhibit low sensitive to environmental condition as temperature and humidity.

·       Allow the manufacture of the tablet using conventional processing at low cost.

·       Ease of Administration to the patient who cannot swallow easily such as the pediatric, geriatric & psychiatric patients.

·       Rapid disintegration of the drug, which will produce quick onset of action.

·       Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach. In such cases bioavailability of drug is increased and improve clinical performance through a reduction of unwanted effects.

·       Good mouth feel property helps to change the perception of medication as bitter pill particularly in pediatric patient.

·       Beneficial in cases such as motion sickness, sudden episodes of allergic attack or coughing, where an ultra-rapid onset of action required.

·       An increased bioavailability for insoluble and hydrophobic drugs.^{[4, 14]}

 

Choice of drug candidate: ^{[7, 8]}

·       No bitter taste.

·       Good stability in water and saliva.

·       Dose should be low as possible.

·       Unsuitable drug candidate for orally disintegrating tablet should include:-

·       Short half-life and frequent dosing.

·       Drug having very bitter taste.

·       Required controlled or sustained release.

 

API Properties- Biopharmaceutical Classification Scheme:^{[7, 8]}

Class I - high solubility, high permeability

-        Rapid absorption, good bioavailability

Eg:- Propanolol, Metoprolol

Class II - low solubility, high permeability

-        Particle size effects on bioavailability

Eg:- ketoprofen, carbamazepine

Class III - high solubility, low permeability

-        As dissolve rapidly and poorly absorbed

-        Require fast dissolution to maximize absorption

-        Particle size reduction

Eg:- ranitidine, atenolol

Class IV - low solubility, low permeability

-        Challenging molecules, likely to exhibit low bioavailability

Eg hydrochlorothiazide, furosemide,

-        Option to increase permeability - modify as ‘Prodrugs

 

Advantages:^[9]

·       Quick onset of action and improved bioavailability.

·       Useful for patients who cannot swallow the dosage forms.

·       Improved patient compliance.

·       Frequently administered when water is not available.

·       Accurate dose can be given as compared to oral liquids. And also allows high drug loading.

·       Pleasant mouth feel of the tablet helps to change the perception of medication as bitter pill particularly in pediatric patients.

·       Stability of drug is improved as compared to oral dosage forms like suspension.

·       Suitable for controlled/sustained release actives

·       Ability to provide advantages of liquid medication in the form of solid preparation.

·       Cost‐ effective, lower production, packaging and distribution costs compared to current commercially available products.

·       The technology is versatile and suitable for the development of enhanced products for veterinary medicines, OTC, Rx medicines & line extensions.^[15]

 

Key ingredients to use:^{[7, 8]}

·       Should allow quick release of drug

·       Should not impart bitter taste

·       Temperature preferred for the excipients should be between 30-35 ºC

 

Technology for Mouth dissolving Tablets:

Conventional Techniques:

·       Freeze drying or Lyophilization

·       Spray Drying

·       Direct Compression

·       Sublimation

·       Mass Extrusion

·       Molding

·       Nanonization

·       Fast Dissolving Films

·       Phase transition process

·       Cotton Candy Process

·       Melt granulation

 

Freeze drying or Lyophilization^{7, 8,10}:

Freeze drying is the process of drying at low temperature in which water is sublimed from the product after it is frozen.  This technique creates an amorphous porous structure that can dissolve rapidly. Lyophilization technique is shown in (Fig. 2). Drug in a water soluble matrix which is then freeze dried to give highly porous structure. The mixture is done by weight and poured in the walls of the preformed blister packs. The trays holding the blister packs are passed through liquid nitrogen freezing tunnel to freeze the drug solution or dispersion. Then the frozen blister packs are placed in refrigerated cabinets to continue the freeze-drying. After freeze-drying the aluminum foil backing is applied on a blister-sealing machine. The tablets prepared by lyophilization disintegrate rapidly in less than 5 seconds due to quick penetration of saliva in pores when placed in the oral cavity. Lyophilization is useful for heat sensitive drugs i.e. thermo-labile substances. The major disadvantages of lyophilization technique are that it is expensive and time consuming; fragility makes conventional packaging unsuitable for these products and poor stability under stressed conditions.

 

Spray Drying^7,8:

Spray drying can produce highly porous and fine powders that dissolve rapidly. This technique is based on a particulate support matrix, which is prepared by spray drying an aqueous composition containing support matrix and other components to form a highly porous and fine powder. This then mixed with active Ingredients and compressed into tablets. Tablets manufactured from the spray-dried technique are shown in (Fig. 3) and have been reported to disintegrate in less than 20 seconds in aqueous medium. The formulation contained supporting matrix such as gelatin, bulking agent like mannitol and lactose, superdisintegrants like sodium starch glycolate & croscarmellose sodium and acidic ingredient (citric acid) and/or alkaline ingredients (e.g. sodium bicarbonate).

 

Fig. 2: Freeze drying or Lyophilization

 

Fig. 3: Spray drying technique

 

Fig. 4: Direct compression technique

 

Direct Compression^{7, 8,11-13}:

This is most popular technique because of its easy implementation and cost-effectiveness. The basic principle involves addition of superdisintegrants and/or water-soluble excipients and/or effervescent agents. Superdisintegrant in optimum concentration (about 2- 5%) are mostly used so as to achieve rapid disintegration along with the good mouth feel. Direct Compression techniques are shown in (Fig. 4).

 

a)    Super-disintegrants:

The addition of superdisintegrants affects rate of disintegration and hence the dissolution.

 

b)    Sugar based excipients:

The sugar based excipients which are commonly used are especially bulking agents (like dextrose, fructose, lactilol, maltilol, maltose, mannitol, sorbitol, starch hydrolysate, polydextrose and xylitol) which display high aqueous solubility and sweetness, and hence impart taste masking property and provide pleasing mouth feel.

 

This method complete within 3 steps i.e.

a)    Milling of drug and excipients

b)    Mixing of drug and excipients

c)     Tablet compression

 

Sublimation^7,8:

This technique is based on the use of volatile ingredients (e.g. camphor, ammonium bicarbonate, naphthalene, urea, urethane etc.) to other tablet excipients and the mixture is then compressed into tablets and techniques are shown in (Fig. 5).  This volatile material is then removed by sublimation leaving behind a highly porous matrix. Tablets manufactured by this technique have reported to usually disintegrate in 10-20 sec. Even solvents like cyclohexane; benzene can be used as pore forming agents.

 

Fig. 5: Sublimation technique

 

Mass Extrusion:^{[7, 8]}

Involves softening the active blend using the solvent mixture of water soluble polyethylene glycol, methanol and expulsion of softened mass through the extruder or syringe to get a cylindrical shape of the product into even segments using heated blade to form tablets.

Characteristics: 

The dried product can be used to coat granules of bitter tasting drugs and thereby masking their bitter taste.

 

Molding:^[6]

Water-soluble ingredients with a hydro-alcoholic solvent is used and is molded into tablets under pressure  lower than that used in conventional tablet compression.

 

Characteristics:

Molded tablets  are  very  less  compact than compressed  tablet  porous  structure  that  enhances disintegration/dissolution and finally absorption increased.

Molding process is of two types

a)    Solvent method

b)    Heat method

 

a)    Solvent method:

Involves moistening the powder blend with a hydro alcoholic solvent followed by compression at low pressures in molded plates to form a wetted mass (compression molding). The solvent is then removed by air-drying. The tablets manufactured in this manner are less compact than compressed tablets and possess a porous structure that hastens dissolution.

 

b)    The heat molding:

Process involves preparation of a suspension that contains a drug, agar and sugar (e.g. mannitol or lactose) and pouring the suspension in the blister packaging wells, solidifying the agar at the room temperature to form a jelly and drying at 30ºC under vacuum.

 

Nanonization:^{[21, 22]}

involves  size  reduction  of  drug  to  nanosize  by  milling  the  drug  using  a  proprietary  wet-milling  technique.  The nano-crystals of the drug are stabilized against agglomeration by surface adsorption on selected stabilizers, which are then incorporated into FDTs.

 

Characteristics:

It is used for poorly water soluble drugs. It leads to higher bioavailability and reduction in dose, cost effective manufacturing process, conventional packaging due to exceptional durability and wide range of doses (up to 200mg of drug per unit).

 

Fast Dissolving Films:^[10-14]

In this technique, a non-aqueous solution is prepared containing water soluble film forming polymer (Pullulan, Carboxy Methyl Cellulose, Hydroxypropyl Methyl Cellulose, Hydroxyl Ethyl Cellulose, Hydroxyl Propyl Cellulose, Polyvinyl Pyrrolidone, Polyvinyl Alcohol or Sodium Alginate, etc.), drug and other taste masking ingredients, which is allowed to form a film after evaporation of solvent. In case of a bitter drug, resin adsorbate or coated microparticles of the drug can be incorporated into the film. This film, when placed in mouth, melts or dissolves rapidly, releasing the drug in solution or suspension form. The features of this system include paper thin films of size less than 2X2 inches, dissolution in 5 sec, instant drug delivery and flavored after taste.

 

Phase transition process:^[13]

It is concluded that a combination of low and high melting point sugar alcohols, as well as a phase transition in the manufacturing process, are important for making FDTs without any special apparatus. FDT were produced by compressing powder containing erythritol (melting point: 122°C) and xylitol (melting point: 93-95°C), and then heating at about 93°C for 15 min. After heating, the median pore size of the tablets was increased and tablet hardness was also increased. The increase of tablet hardness with heating and storage did not depend on the crystal state of the lower melting point sugar alcohol.

 

Cotton Candy Process:

The FLASHDOSE® is a MDDDS manufactured using Shearform™ technology in association with Ceform TI™ technology to eliminate the bitter taste of the medicament.^[14,15] The Shearform technology is employed in the preparation of a matrix known as ‘floss’, made from a combination of excipients, either alone or with drugs. The floss is a fibrous material similar to cotton-candy fibers, commonly made of saccharides such as sucrose, dextrose, lactose and fructose at temperatures ranging between 180–266 °F^[16]. However, other polysaccharides such as polymaltodextrins and polydextrose can be transformed into fibers at 30–40% lower temperature than sucrose. This modification permits the safe incorporation of thermolabile drugs into the formulation^[17]. The tablets manufactured by this process are highly porous in nature and offer very pleasant mouth feel due to fast solubilization of sugars in presence of saliva. The manufacturing process can be divided into four steps as detailed below.

 

a)    Floss Blend:

In this step, 80% sucrose in combination with mannitol/dextrose and 1% surfactant is blended to form the floss mix. The surfactant acts as a crystallization enhancer in maintaining the structural integrity of the floss fibers. It also helps in the conversion of amorphous sugar into crystalline form from an outer portion of amorphous sugar mass and subsequently converting the remaining portion of the mass to complete crystalline structure. This process helps to retain the dispersed drug in the matrix, thereby minimizing migration out of the mixture.^[29]

 

b)    Floss Processing:

The floss formation machine uses flash heat and flash flow processes to produce matrix from the carrier material. The machine is similar to that used in ‘cotton-candy’ formation which consists of a spinning head and heating elements. In the flash heat process, the heat induces an internal flow condition of the carrier material. This is followed by its exit through the spinning head (2000-3600 rpm) that flings the floss under centrifugal force into long and thin floss fibers, which are usually amorphous in nature.^{[30, 31]}

 

c)     Floss Chopping and Conditioning:

This step involves the conversion of fibers into smaller particles in a high shear mixer granulator. The conditioning is performed by partial crystallization through an ethanol treatment (1%) which is sprayed onto the floss and subsequently evaporated to impart improved flow and cohesive properties to the floss.^[28]

 

d)    Blending and Compression:

Finally, the chopped and conditioned floss fibers are blended with the drug along with other required excipients and compressed into tablets. In order to improve the mechanical strength of the tablets, a curing step is also carried out which involves the exposure of the dosage forms to elevated temperature and humidity conditions, (40°C and 85% RH for 15 min). This is expected to cause crystallization of the floss material that results in binding and bridging to improve the structural strength of the dosage form. ^[32]

 

Melt Granulation:^[18]

Melt granulation technique is a process by which pharmaceutical powders are efficiently agglomerated by a melt able binder. The advantage of this technique compared to a conventional granulation is that no water or organic solvents is needed. Because there is no drying step, the process is less time consuming and uses less energy than wet granulation. It is a useful technique to enhance the dissolution rate of poorly water-soluble drugs, such as griseofulvin. This approach to prepare FDT with sufficient mechanical integrity, involves the use of a hydrophilic waxy binder. Superpolystate is a waxy material with a melting point of 33–37°C and a HLB value of 9. So it will not only act as a binder and increase the physical resistance of tablets but will also help the disintegration of the tablets as it melts in the mouth and solublises rapidly leaving no residues.

 

Role of disintegrants in mouth dissolving tablets: ^[27]

Three main type of disintegrants used-

a)    Effervescent disintegrating agents

b)    Non Effervescent disintegrating agents

c)     Modern approach-Superdisintegrants.

 

a)    Effervescent Disintegrating Agents:

When these agents come in contact with water they absorb water and disintegrate very quickly and impart fast dissolving property to the tablets. The major disadvantages are that the excipients shows inability to prevent moisture absorption (Controlled manufacturing environment). The cost of ODTs is higher than the cost of standard tablets made by direct compression.

 

b)    Non Effervescent disintegrating agents:

They have their own property which makes them enable to cause disintegration of tablets. Directly compressible starches (such as starch 1500) modified starches (such as carboxy methyl starches and sodium starch glycolate) Starch derivatives (such as amylose).

 

c)     Modern Approach- Superdisintegrants:

Superdisintegrants are generally used at a low level in the solid dosage form, typically 1–10% by weight relative to the total weight of the dosage unit. Examples: Crospovidone A1, Crospovidone A2, Crospovidone B Sodium starch glycolate croscarmellose sodium.

 

Superdisintegrants:^[23-26]

Superdisintegrants (table no 1) which provide improved compressibility compared to prior art superdisintegrants and which does not negatively impact the compressibility of formulations which include high-dose drugs, and methods for obtaining the same are disclosed. The superdisintegrants include a particulate agglomerate of co-processed starch or cellulose and a sufficient amount of an augmenting agent to increase the compactibility of the superdisintegrants. The augmented superdisintegrants provides a fast disintegration of a solid dosage form when incorporated in sufficient quantity therein, without untowardly affecting the compactibility of the solid dosage form (relative to the solid dosage form without the superdisintegrants).

 

They all should possess the following characteristics: ^{[23, 24]}

·       Poor water solubility with good hydration capacity

·       Poor gel formation

·       Good flow properties

·       Good compressibility

·       Inert

·       Non-toxic

·       Requirement of least quantity

 

METHOD OF INCORPORATION:

The incorporation of superdisintegrants in the dosage forms are mainly of three types

 

Intragranular or during granulation:

In this process the superdisintegrants are blend with other powders and granulation is carried out. Thus the superdisintegrants are incorporated within the granules.

 

Extragranular or prior to compression:

In this process, the superdisintegrants are mixed with prepared granules before compression.

 

Incorporation of superdisintegrants at intra and extra granulation steps:

In this process part of superdisintegrants are added to intragranular and a part to extragranulers. This method usually produces better results and more complete disintegration than type I and type II.

 

Table 1:  Various Disintegrants and Superdisintegrants and Their Properties

 

Evaluation test:^{[19, 20]}.

1.     Weight variation:

20 tablets were selected randomly from the lot and weighted individually to check for weight variation according to table no (2). Weight variation is given by the formula.

 

% Weight variation =   Individual weight – Average weight/Average weight × 100

 

Table 2: Weight Variation Specification as per IP

 

2.     Hardness:

Hardness or tablet crushing strength (fc), the force required to break a tablet in a diametric compression was measured using Monsanto tablet hardness tester. It is expressed in kg/cm². ^[1]

 

3.     Friability (F):

Friability of the tablet determined using Roche friabilator. This device subjects the tablet to the combined effect of abrasion and shock in a plastic chamber revolving at 25 rpm and dropping a tablet at a height of 6 inches in each revolution. Pre-weighted sample of tablets was placed in the friabilator and were subjected to the 100 revolutions. Tablets were dusted using a soft muslin cloth and reweighed. The friability (F) is given by the formula.

 

F   =    W initial – W final × 100 / W initial

 

4.     In vitro dispersion time:

Tablet was placed in 10 ml phosphate buffer solution, pH 6.8±0.5°C. Time required for complete dispersion of a tablet was measured.

 

5.     In-vitro disintegration time:

The process of breakdown of a tablet into smaller particles is called as disintegration. The in-vitro disintegration time of a tablet was determined using disintegration test apparatus as per I.P. specifications. One tablet was placed in each of the 6 tubes of the basket. Add a disc to each tube and run the apparatus using pH 6.8 (simulated saliva fluid) maintained at 37±20C as the immersion liquid. The assembly should be raised and lowered between 30 cycles per minute in the pH 6.8 maintained at 37±20C. The time in seconds taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured and recorded.

 

6.     Thickness:

Tablet thickness can be measured using a simple procedure. 5 tablets were taken and their thickness was measured using Varnier calipers.

 

7.     Accelerated Stability study:

The Orally disintegrating tablets are packed in suitable packaging and stored under the following conditions for a period as prescribed by ICH guidelines for accelerated studies. (i) 40 ± 1 °C (ii) 50 ± 1°c (iii) 37 ±1 ° C and Relative Humidity= 75% ± 5% The tablets were withdrawn after a period of 15 days and analyzed for physical characterization (Visual defects, Hardness, Friability, Disintegrations, and Dissolution etc.) and drug content. The data obtained is fitted into first order equations to determine the kinetics of degradation. Accelerated stability data are plotting according Arrhenius equation to determine the shelf life at 25°C.

 

8.     General appearance:

Mainly it includes the visual identity, elegance, consumer acceptance and the size and shape of the tablet.

9.     Size and Shape:

The size and shape of the tablet can be dimensionally described, monitored and controlled.^[8]

 

10. In vitro Dissolution test:

The development of dissolution methods for MDTs is comparable to the approach taken for conventional tablets and is practically identical. Dissolution conditions for drugs listed in a pharmacopoeia monograph, is a good place to start with scouting runs fora bioequivalent FDT. Other media such as 0.1 M HCl and buffer (pH 4.5 and 6.8) should be evaluated for MDT much in the same way as their ordinary tablet counterparts. It has been suggested that USP 2 paddle apparatus is the most suitable and common choice for orally disintegrating tablets, with a paddle speed of 50 rpm commonly used.

 

Table no 3: List of marketed mouth dissolving drug

 

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Accepted on 14.11.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(6): 2943-2950.