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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.
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.
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.
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.
Carvedilol is a nonselective ¢-adrenergic blocking agent with ¡-blocking activity. It is used mainly in the treatment of:
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 : Carvedilol is extensively metabolized in liver (USP).
REVIEW OF LITERATURE
Pokharkar et al. (2009) studied solubility and dissolution rate of carvedilol by forming a ternary complex with beta-cyclodextrin and citric acid and to formulate its mouth-dissolving tablets. Phase solubility studies revealed the ability of Î² cyclodextrin and citric acid to complex with carvedilol and significantly increase its solubility. Ternary complexation of carvedilol was carried out with Î² -cyclodextrin and citric acid by physical mixing, kneading and spray drying methods and the prepared complexes were characterized by Fourier transform infra red spectroscopy, differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy and complexation efficiency. The complex obtained by the spray drying method resulted in highest complexation efficiency and a 110-fold increase in the solubility of carvedilol. In the stability study, no significant changes were recorded with respect to XRD, DSC, drug content, disintegration and dissolution over a period of 3 months, indicating a stable complex. The in vitro dissolution studies of the tablets prepared from the ternary complex of carvedilol obtained by spray drying showed 71% release in 5 minutes.
Deshpande et al. (2009) prepared the mouth disintegrating tablet of clonazepam. Solid dispersion of drug and PVP K30 was prepared by solvent evaporation method. Different combinations of superdisintegrants such as crosscarmellose sodium, sodium starch glycolate, crospovidone were used. The tablets were prepared by direct compression technique on rotary tablet machine. The tablets were evaluated for hardness, friability, weight variation, wetting time, dispersion time and uniformity of content. All the tablets had hardness 3-3.5 kg/cm2 and friability of all formulations was less than 1, weight variation and drug content were within official limit. Amongst all formulations, formulation prepared by drug:PVP-K30 (1:4) ratio and combination of 5% w/w crosscarmellose sodium and 5% w/w of sodium starch glycolate showed least dispersion time of 8seconds and faster dissolution.
Dehghan et al. (2006) investigated the effect of different types of carriers on in vitro dissolution of Meloxicam. Meloxicam solid dispersions were prepared by physical mixing, co-grinding and solvent evaporation methods with polyethylene glycol (PEG) 6000. The effect of solubilization by sodium lauryl sulphate (SLS) was also studied. The increased in dissolution rate of meloxicam by solid dispersion technique may be due to increase wet ability and hydrophilic nature of carrier. It can be concluded that maximum in vitro dissolution was observed for solid dispersion containing PEG 6000 (350 mg), SLS (75 mg), and Meloxicam (150 mg) containing 3 g of lactose and microcrystalline cellulose (4:1) as additives and prepared by solvent evaporation method.
Swami et al., (2008) prepared orodispersible tablets of carbamazepine with a view to enhance patient compliance by direct compression method using 3² full factorial designs. They used Crospovidone (2-10 % w/w) as superdisintegrant and microcrystallinecellulose (0-30 % w/w) was used as diluent, along with directly compressible mannitol to enhance mouth feel. The tablets were evaluated for hardness, friability, thickness, drug content uniformity, in vitro dispersion time, wetting time and water absorption ratio. Based on in vitro dispersion time (approximately 10 seconds); the formulation containing 2 % w/w crospovidone and 30%w/w microcrystalline cellulose was found to be promising and tested for in vitro drug release pattern (in pH 6.8 phosphate buffer), short-term stability (at 40°C /75 % RH for 3 months ) and drug-excipient interaction. The formulation showed four-fold faster drug release compared to the conventional commercial tablet formulation.
Bhalerao et al., (2009) developed fast disintegrating tablets of Clonazepam which offers a new range of product having desired characteristics and intended benefits. The drug is poorly water soluble therefore to enhance the solubility and release of drug, solid dispersion of drug and PVP-K30 was prepared by solvent evaporation method. Different combinations of superdisintegrants such as crosscarmellose sodium, sodium starch glycolate, crospovidone were used. Directly compressible mannitol, and aspartame were used to enhance the mouth feel and taste. Lactose was used as diluents. The tablets were evaluated for hardness, friability, weight variation, wetting time, dispersion time and content uniformity. Optimized formulations were evaluated by in vitro dissolution test. All the tablets had hardness 3-3.5 kg/cm2 and friability of all formulations was less than 1, weight variation and drug content were within official limit. Amongst all formulations, formulation prepared by drug:PVP-K 30 (1:4) ratio and combination of 5% w/w crosscarmellose sodium and 5% w/w of sodium starch glycolate showed least dispersion time of 8 seconds and faster dissolution.
Selection of carrier for solid dispersion
A carrier should meet the following criteria to be suitable for solid dispersion of a drug. A carrier should be:
Hydrophilic in nature.
Non-toxic and pharmacologically inert.
Soluble in various solvents.
Carriers used for solid dispersion:
Sugars: Dextrose, mannitol.
Acids: Acrylic acids, polyacrylic acids.
Polymeric materials: Polyvinyl pyrrolidone (PVP), polyethylene glycols (PEGs).
Insoluble or enteric polymers: Eudragit.
Surfactants: Poloxamer, Tweens, Spans (Mahmoud et al., 2009).
AIM AND OBJECTIVES
Formulation and evaluation of mouth dissolving tablets containing Carvedilol solid dispersion.
Preparation of solid dispersions using different polymers and their combinations and selection of optimum concentration of polymers using different methods of solid dispersion
Formulation of mouth dissolving tablets using optimized solid dispersion prepared in step 2.
Carvedilol is a BCS class II with poor water solubility. We have selected solid dispersion technique to enhance drug dissolution. As the biological half life of the drug is very short (2.2 hrs) and it is 90% absorbed from GIT, but its bioavailability is only 10-20% indicating extensive first pass metabolism in liver. Due to substantial first pass effect and its shorter plasma half life, mouth dissolving tablets will be prepared. Mouth dissolving tablets are also good for those patients who have difficulty to swallow oral dosage forms, especially the elderly and children patients. These tablets are also suitable for the mentally ill, the patients with persistent nausea, who are travelling, and who do not have easy access to water.
Preparation of standard curves:
In 0.1N HCl
In Phosphate buffer pH 6.8
Preparation of standard curve in 0.1N HCl
100 mg of Carvedilol was dissolved in 100 ml of methanol; 10 ml of this solution was taken and diluted to 100 ml with 0.1N HCl to get 100 µg/ml as a stock solution. From this stock solution, 1ml solution was withdrawn and transferred to 10 ml volumetric flask and volume was made up to 10 ml with 0.1N HCl. From these solution aliquots of 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml were withdrawn and transferred to 10 ml volumetric flask and volume was made upto10 ml with 0.1N HCl. The absorbance of these solutions was measured at 240 nm against blank as 0.1N HCl.
Preparation of standard curve in phosphate buffer pH 6.8 100 mg of Carvedilol was dissolved in 100 ml of methanol; 10 ml of this solution was taken and diluted to 100 ml with phosphate buffer pH 6.8 to get 100 µg/ml as a stock solution. From this stock solution, 1ml solution was withdrawn and transferred to 10 ml volumetric flask and volume was made upto10 ml phosphate buffer pH 6.8. From these solution aliquots of 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml and 9 ml were withdrawn and transferred to 10 ml volumetric flask and volume was made upto10 ml with phosphate buffer pH 6.8. The absorbance of these solutions was measured at 240 nm against blank as in phosphate buffer pH 6.8.
Table No. 2