Formulation and Evaluation of Fast Dispersible Tablets

FORMULATION AND EVALUATION OF FAST DISPERSIBLE TABLETS

OF A MODEL ANTI-EMETIC DRUG USING NATURAL DISINTEGRANTS

M. Pharm Dissertation Protocol Submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore – 560 041

By

Mr. K. R. SHASHIDHAR, B.Pharm.

Under the Guidance of

Mr. ANUP KUMAR ROY, M.Pharm.

Asst. Professor

Department of Industrial Pharmacy,

Acharya & B.M. Reddy College of Pharmacy,

Soldevanahalli, Chikkabanavara (Post),

Hesaraghatta Main Road, Bangalore – 560 090

2009-2010

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE.

ANNEXURE - II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / Name of the Candidate
and Address / Mr. K. R. SHASHIDHAR
S/O Mr. K. R. Rajasekhar
“KASHYAP”,
#641, 13th Cross,
Chandralayout,
1st Stage, 1st Phase,
Bangalore-560072
2. /
Name of the Institution
/ ACHARYA & B.M. REDDY COLLEGE OF PHARMACY,
Soldevanahalli, Hesaraghatta Main Road,
Chikkabanavara Post.
Bangalore-560090
3. / Course of Study and Subject / M. Pharm
(Industrial Pharmacy)
4. /
Date of Admission
/
20th June 2009
5. TITLE OF THE PROJECT:-
FORMULATION & EVALUATION OF FAST DISPERSIBLE TABLETS OF
A MODEL ANTI-EMETIC DRUG USING NATURAL DISINTEGRANTS
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7.4 / BRIEF RESUME OF THE INTENDED WORK:
NEED FOR THE STUDY:
Among the different routes of administration, the oral route continues to be the most preferred route due to various advantages including ease of ingestion, avoidance of pain, versatility and most importantly patient compliance. The different dosage forms include tablets and capsules. The important drawback of these dosage forms for pediatric and geriatric patients is difficulty in swallowing.
Nearly 70% of general population, especially the elderly patients and children suffer from dysphagia or difficulty in swallowing, which results in high incidence of non-compliance and ineffective therapy. Other groups who may experience problems in swallowing conventional oral dosage forms are the patients with tremors of extremities, mentally ill, developmentally disabled, non co-operative patients and patients with reduced liquid intake plans or patients suffering from nausea. The swallowing problems are common in some cases such as patients with motion sickness, sudden episodes of allergic attack or coughing and due to lack of water.
To overcome these problems, formulators have considerably dedicated their effort to develop a novel type of tablet dosage form for oral administration, i.e., one, which disintegrates and dissolves rapidly in saliva without the need for drinking water. The tablet is placed in the mouth, allowed to disperse or dissolve in saliva. These tablets usually dissolve within 15 seconds to 2 minutes. The faster the drug goes into solution, the quicker the absorption and onset of clinical effect.
Less frequently they are designed to be absorbed through the buccal and oesophageal mucosa as the saliva passes into the stomach. In the latter case, the bioavailability of the drug from rapidly dispersible tablets may be even greater than that observed for other standard dosage forms.
The rapidly dispersible tablets also offer advantages over other oral dosage forms such as effervescent tablets, suspensions, chewing gums or chewing tablets, which are commonly used to enhance patient compliance. Effervescent tablets and suspensions require preparatory steps before administration of the drug. The elderly, who are often unable to chew large pieces of gum or tablets, sometimes experience unpleasant taste when bitter drugs are consumed.
The advantages of rapidly dispersible tablets are being recognized in both industry and academia. Their growing importance was underlined recently when the European Pharmacopoeia adopted the term Orodispersible tablet as a “tablet to be placed in the mouth where it disperses rapidly before swallowing.”
The ideal rapidly dispersible tablet technology should address the following:
Ø Requires no water for oral administration, yet dissolve or disintegrate in the mouth in a matter of seconds.
Ø Allow high drug loading.
Ø Bitter taste to be masked.
Ø Have a pleasant mouth feel.
Ø Leave minimal or no residue in the mouth after oral administration.
Ø Be portable without fragility concerns.
Ø Exhibit low sensitivity to environmental conditions such as humidity and temperature.
Ø Allows the manufacturing of tablets using conventional processing and packaging equipment at low costs. 15
Prochlorperazine maleate (PCZM) is a phenothiazine antiemetic and widely used in prevention and treatment of nausea, vomiting including that associated with migraine or drug-induced emesis. The concept of formulating fast dissolving tablets containing prochlorperazine maleate offers a suitable and practical approach in serving desired objective of faster disintegration and dissolution characteristics with increased bioavailability. Upon ingestion, the saliva serves to rapidly disperse/dissolve the dosage form. The saliva containing the dissolved/dispersed medicament is then swallowed and the drug is absorbed in the normal way. Some drugs are absorbed from mouth, pharynx and esophagus as the saliva passes down into the stomach. In such cases, bioavailability is significantly greater than those observed from conventional dosage form. 16
The biological half life of prochlorperazine maleate is 4 to 8 hours with protein binding of 91% to 99%.
Considering the advantages of prochlorperazine maleate, we are proposing to choose it as a model anti-emetic drug for the present study.
REVIEW OF LITERATURE :
The reviews of literatures revealed that number of studies have been carried out on fast dispersible tablets using different techniques.
·  Dispersible tablets of norfloxacin were prepared using natural substances as disintegrants such as ispaghula husk powder, cassia tora powder, cassia tora power (defatted) and cassia nodosa powder in different concentrations by direct compression methods. Formulations were evaluated for the standard of dispersible tablets and were compared with marketed products. It was observed that all the formulations were acceptable with reasonable limits of standard required for dispersible tablets. The study reveals that natural gums used as disintegrants were effective in low concentration. 14
·  Fast dissolving tablets of poorly soluble carbamazepine was formulated using direct compression technique with β-cyclodextrin complexes using various superdisintegrants like Indion-414, croscarmellose sodium, crospovidone and sodium starch glycolate. The prepared tablets were evaluated for hardness, friability, drug content, weight variation, disintegration time, wetting time, in vitro dissolution studies etc. The results revealed that fast dissolving tablets of poorly soluble drug, carbamazepine, showing enhanced dissolution and, hence, better patient compliance. ¹
·  Mouth dissolving tablets of fenofibrate were prepared by sublimation technique. The poor aqueous solubility of drug leads to variable dissolution rates. These tablets were prepared using different subliming agents like camphor, thymol, ammonium bicarbonate and different concentrations of menthol by direct compression method. This technique was carried out to increase the porosity of the tablets whereby subliming material was sublimed from the granules by exposing the granules to vacuum. The porous granules were then compressed into tablets. ²
·  Fast dissolving tablets of domperidone were prepared using avicel PH 102 and sodium starch glycolate by direct compression method. All formulations were evaluated for characteristics such as hardness, friability, disintegration time and dissolution rate. An effective, pleasant tasting formulation was found to have drug release comparable with the marketed dispersible tablet. ³
·  Ziprasidone hydrochloride fast disintegrating/ dissolving tablets were prepared. For enhancing solubility of drug, inclusion complexes of drug were prepared using βCD and HPβCD. To aid in faster disintegration of tablets, superdisintegrants in different proportions were used and their effect on disintegration was studied. The inclusion complexes with HPβCD prepared by microwave method exhibited highest enhancement in solubility (0.024g/100ml) and also showed fastest dissolution profile (100% drug release in 5 min.). So this complex was worked further for formulation of ziprasidone hydrochloride fast disintegrating/ dissolving tablets. 4
·  Fast dissolving tablets of granisetron hydrochloride were prepared using low compressible (mannitol) and high compressible saccarides (sorbitol 5-15%w/w) along with crospovidone, croscarmellose sodium and L-HPC as superdisintegrants in different ratios(2-8% w/w). In case of sorbitol, the presence of interlocking crystals that are generated using specific manufacturing conditions enables strong binding and result in a more robust tablet at low compression forces. In addition, mannitol provides the required dispersibility and mouth feel for a successful FDT formulation. In addition contributing to the robustness of the tablets, the sorbitol also imparts a sweet taste and unique textured to the mannitol, thereby improving the ODT formulations mouth feel. 5
·  The development of rapidly disintegrating fast release tablets of diazepam was done, which could provide rapid disintegration and immediate release of drug in oral cavity. Tablets were prepared by conventional wet granulation and direct compression methods. Diazepam was formulated with polyethylene glycol (PEG-6000) as a solid dispersion to increase aqueous solubility and dissolution of the drug. Croscarmellose sodium and aerolac® were used in tablet formulation to achieve rapid disintegration of tablets prepared respectively by wet granulation and direct compression methods. Tablets developed in this study disintegrated in 37 seconds (wet granulation) and 31 seconds (direct compression) and released 85% in about 21-22 minutes, which is much improved than available marketed product. 6
·  The factors affecting the characteristics of rapidly disintegrating tablets in the mouth prepared by crystalline transition of amorphous sucrose was studied. The effect of storage conditions and formulating ratio of amorphous sucrose on the characteristic changes (tensile strength, porosity and disintegration time) of the rapidly disintegrating tablets was studied. The faster crystalline transition resulted in a faster rate of increase in the tablet tensile strength the higher formulating ratio of amorphous sucrose provided the longer disintegration time in the mouth. Therefore the formulating ratio of 10 to 20 % of the amorphous sucrose in the tablet is suitable for the rapidly disintegrating tablet in the mouth when prepared by CTM. 7
·  The work assessed the potential of a natural polysaccharide, pectin to mask the bitter taste of ambroxol hydrochloride, by microencapsulation technique, and its possibility to formulate as a fast disintegrating dosage form. The prepared microspheres by emulsion solvent evaporation technique possessed good sphericity, smooth surface morphology, uniform and narrow size distribution (10-90 μm), when analyzed by scanning electron microscopy, laser diffraction and optical microscopy. Method of preparation had influenced the particle size and drug loading efficiency. The resulting granules were found to melt fast at body temperature, have smooth mouth feel and good physical stability. 8
·  The purpose of this investigation was to develop fast dissolving tablets of etoricoxib. Granules containing etoricoxib, menthol, crospovidone, aspartame and mannitol were prepared by wet granulation technique. Menthol was sublimed from the granules by exposing the granules to vacuum. The porous granules were then compressed into tablets. A 3² full factorial design was applied to investigate the combined effect of 2 formulation variables: amount of menthol and crospovidone. The results of multiple regression analysis indicated that for obtaining fast dissolving tablets; optimum amount of menthol and higher percentage of crospovidone should be used. 9
·  In view of enhancing bioavailability an attempt had been made to study two different methods direct compression and sublimation in formulation of mouth dissolving tablets of clozapine. Total four formulations using various superdisintegrants and subliming agents were prepared. All prepared formulations were evaluated for physico-chemical parameters. The formulations exhibited good disintegration properties with total disintegration time in the range of 25 to 35 seconds. Comparative evaluation of two methods showed direct compression method is a better alternative to sublimation method as its formulations rapidly disintegrate in oral cavity. In vitro cumulative percentage drug release for formulations prepared by direct compression with explotab superdisintegrants shows 99.79% while sublimation method using camphor 93.58% release in 12 min. Kinetic studies indicated that all the formulations followed first order release with diffusion mechanism. 10
·  Aceclofenac fast-dispersible tablets have been prepared by direct compression method. Effect of superdisintegrants (such as, croscarmellose sodium, sodium starch glycolate and crospovidone) on wetting time, disintegration time, drug content, in vitro release and stability parameters has been studied. Disintegration time and dissolution parameters (t 50% and t 80%) decreased with increase in the level of croscarmellose sodium whereas, disintegration time and dissolution parameters increased with increase in the level of sodium starch glycolate in tablets. However, the disintegration time values did not reflect in the dissolution parameter values of crospovidone tablets and release was dependent on the aggregate size in the dissolution medium. 11
·  Orodispersible tablets of pheniramine maleate were designed with a view to enhance patient compliance by effervescent method. In this method, mixture of sodium bicarbonate and tartaric acid (each of 12% w/w concentration) were used along with super disintegrants, i.e., pregelatinized starch, sodium starch glycolate, croscarmellose sodium and crospovidone. Among three promising formulations, formulation ECP4 containing 4% crospovidone and mixture of sodium bicarbonate and tartaric acid (each 12% w/w) emerged as the overall best formulation (t70%=1.65 min) based on the in vitro drug release characteristics compared to commercial conventional tablet formulation. 12
There is limited reference of the work done about the use of natural disintegrants in dispersible tablets using direct compression method. Thus, we are planning to employ this technique for prochlorperazine maleate as the model drug.
OBJECTIVE OF THE STUDY:-
The main objective of the present work is to formulate fast dispersible tablets of prochlorperazine maleate using natural disintegrants with an aim to improve the patient compliance for the treatment of nausea and vomiting. Thus increase in patient compliance also provides quicker onset of action.
·  The objectives of the present study are following:-
1.  To carry out pre-formulation studies.
2.  To design and develop fast dispersible tablets by direct compression method.
3.  To carry out in vitro release studies using U.S.P. II dissolution test apparatus.
4.  To evaluate in vitro disintegration time of the formulation.
5.  To carry out stability studies on the most satisfactory formulation as per ICH guidelines at 30 ± 2°C (65 ± 5 %RH) and 40 ± 2°C (75 ± 5 %RH).
MATERIALS AND METHODS:
SOURCE OF DATA:-
·  Review of literature from: