Mouth Dissolving Tablet Containing Solid Dispersion Biology

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Oral drug delivery is the simplest and easiest way of administering drugs. Due to greater stability, smaller bulk, accurate dose and easy production, solid oral dosages forms have many advantages over other types of oral dosage forms. Therefore, most of the new chemical entities (NCE) under development these days are intended to be used as a solid dosage form. Moreover the most promising NCEs, despite their high permeability, are generally only absorbed in the upper small intestine, absorption being reduced significantly after the ileum, showing, therefore, that there is a small absorption window. Consequently, if these drugs are not completely released in this gastrointestinal area, they will have a low bioavailability. Therefore, one of the major current challenges of the pharmaceutical industry is related to strategies that improve the water solubility of drugs. Drug release is a crucial and limiting step for oral drug bioavailability, particularly for drugs with low gastrointestinal solubility and high permeability (BCS class II drugs) (Mooter et al., 2006). By improving the solubility of these drugs, it is possible to enhance their bioavailability and reduce the dose. Solid dispersions are one of the most successful strategies to improve drug release of poorly soluble drugs (Leuner et al., 2000).

Solid Dispersion: A solid dispersion is a pharmaceutical formulation which may be defined as "a dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by melting the two (fusion), dissolving them in a solvent, or a combination of approaches, i.e. a melting solvent method" (Costa et al., 2007).

According to the Biopharmaceutics Classification System (BCS), the drug substances are classified as follows:

Class I - High Permeability, High Solubility: Those compounds are well absorbed and their absorption rate is usually higher than excretion. Example: Metoprolol, Atenolol.

Class II - High Permeability, Low Solubility: The bioavailability of those products is limited by their solvation rate. Example: Itraconazole, Nifedipine.

Class III - Low Permeability, High Solubility: The absorption of drug is limited by the permeation rate but the drug is solvated very fast. Example: Cimetidine, Ranitidine

Class IV - Low Permeability, Low Solubility: Those compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and high variability in bioavailability is expected. Example: Hydrochlorothiazide

Solid dispersion technologies are promising for improving the oral absorption and bioavailability of BCS-II drugs (Nehal et al., 2004).

Methods of preparation of solid dispersion

The methods mainly used for the manufacturing of solid dispersions are the fusion and solvent evaporation methods. Combinations of these methods have also been used (Sunada et al., 1998).

Melting or Fusion Method.

Solvent evaporation method.

Hot-melt extrusion.

Melt agglomeration.

Freeze drying.

Spray drying.

Supercritical Fluid Process (Ambiek et al, 2005).

(1) Fusion method:

A physical mixture of an active agent and a water soluble carrier is heated until it is melted. The melt is solidified rapidly in an ice bath under vigorous stirring to obtain the solid dispersion.

(2) Solvent evaporation method:

In this method the drug and the carrier is dissolve in an organic solvent. The solvent is usually removed by evaporation under reduced pressure at varying temperatures. The solvent evaporation method consists of the solubilization of the drug and carrier in volatile solvent/solvents. The solvent is later removed to obtain solid dispersion. In this method, the thermal decomposition of drugs or carriers can be prevented (Craig et al., 2002).

Classification of solid dispersion:

(1) Simple eutectic mixtures: Solid eutectic mixtures are usually prepared by rapid cooling of a comelt of the two compounds in order to obtain a physical mixture of very fine crystals of the two components. When a mixture with a particular composition consisting of a slightly soluble drug and an inert, highly water soluble carrier, is dissolved in an aqueous medium, the carrier will dissolve rapidly, releasing very fine crystals of the drug.

(2) Solid solutions: Solid solutions are comparable to liquid solutions consisting of just on phase irrespective of the number of components. In the case of solid solutions, the drug's particle reduced to its absolute minimum, the molecular dimensions and the dissolution rate is determined by the dissolution rate of carrier. (3) Glass solutions and glass suspensions: A glass solution is a homogenous, glassy system in which a solute dissolves in a glassy solvent. The glassy or vitreous state is usually obtained by an abrupt quenching of the melt. It is characterized by transparency and brittleness below the glass transition temperature. On heating, it softens progressively and continuously without a sharp melting point.

(4) Amorphous precipitations in a crystalline carrier: In amorphous solid solution, the solute molecules are dispersed molecularly but irregularly within the amorphous solvent. Polymer carriers are particularly likely to form amorphous solid solutions as the polymer itself is often present in the form of an amorphous polymer chain network (Karanth et al., 2006).

Reasons for improving solubility by solid dispersion:

(1) Solubilization effect.

(2) Metastable forms.

(3) Particles with reduced particle size.

(4) Particles with improved wet ability.

(5) Particles with higher porosity (Dong et al., 2008).

Mouth Dissolving Tablet:

Mouth dissolving tablets (MDT) are that solid dosage form which disintegrate or dissolve within a minute in the oral cavity. According to British Pharmacopoeia 2009 MDT are defined as "A solid dosage form containing medicinal substances or active ingredient which disintegrates rapidly usually within seconds when placed on the tongue" (British Pharmacopoeia. 2009).

ADVANTAGES OF MOUTH DISSOLVING TABLETS:

No need of water.

Fast dissolution and disintegration time.

Improved patient compliance.

Ideal for pediatric and geriatric patients.

Beneficial for travelling patients.

Rapid onset of action.

Minimise First pass metabolism.

Improved drug absorption.

Techniques for preparing Mouth Dissolving Tablets:

There are many techniques that have been reported for the formulation of Mouth dissolving tablets.

Freeze drying / lyophilization

Freeze drying is the process in which water is sublimed from the product after it is frozen. This technique creates an amorphous porous structure that can dissolve rapidly. A typical procedure involved in the manufacturing of mouth tablets using this technique is mentioned here. The active drug is dissolved or dispersed in an aqueous solution of a carrier/polymer. 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. Finally the blisters are packaged and shipped.

Tablet moulding

The tablet moulding process is of two types i.e. solvent method and heat method. The 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 posses a porous structure that hastens dissolution. 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 30â-‹C under vacuum.

(3) Spray drying

In this technique, gelatin can be used as a supporting agent and as a matrix, mannitol as a bulking agent and sodium starch glycolate or crosscarmellose or crospovidone are used as superdisintegrants. Tablets manufactured from the spray-dried powder have been reported to disintegrate in less than 20 seconds in aqueous medium. The formulation contained bulking agent like mannitol and lactose, a superdisintegrant like sodium starch glycolate & croscarmellose sodium and acidic ingredient (citric acid) and/or alkaline ingredients (e.g. sodium bicarbonate). This spray-dried powder, which compressed into tablets showed rapid disintegration and enhanced dissolution.

(4) Sublimation

The sublimation process consist of generation a porous matrix, volatile ingredients are incorporated in the formulation that is later subjected to a process of sublimation. Highly volatile ingredients like ammonium bicarbonate, ammonium carbonate, benzoic acid, camphor, naphthalene, urea, urethane and phthalic anhydride may be compressed along with other excipients into a tablet. 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 seconds. Even some solvents like cyclohexane; benzene can be used as pore forming agents.

(5) Direct compression

The direct compression represents the simplest and most cost effective tablet manufacturing technique. This technique can be applied to preparation of orodispersible tablets because of the availability of improved excipients especially superdisintegrants and sugar based excipients.

(6) Mass extrusion

This technology involves softening the active blend using the solvent mixture of water soluble polyethylene glycol and methanol and subsequent expulsion of softened mass through the extruder or syringe to get a cylinder of the product into even segments using heated blade to form tablet. The dried cylinder can also be used to coat granules for bitter drugs and thereby achieve taste masking.

Drug:Carvedilol

Carvedilol is a nonselective -adrenergic blocking agent with -blocking activity. It is used mainly in the treatment of:

Angina pectoris

Hypertension

Cardiac arrhythmia

Congestive heart failure

Its IUPAC name is 1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy) ethyl] amino]-2-propanol. It is a racemic mixture. Drugs bioavailability is very limited (25-30%) orally, since it is practically insoluble in water and its dissolution is rate limiting for its absorption from the gastrointestinal tract.

Chemical formula : C24H26N2O4

Molecular weight : 406.5 g/mol

Melting point : 113-1140C

Half life : 2.3-3hrs

Bioavailability : 90% absorbed from GIT with 10-20 % bioavailability

Solubility : Freely soluble in dimethylsulfoxide, sparingly

soluble in 95% ethyl alcohol and isopropanol,

practically insoluble in water, gastric fluids (simulated and

pH1.1) and intestinal fluid (simulated and pH 7.5)

Metabolism

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