Formulation Development and Optimization of Effervescent Systems for Histamine Antagonists

Abstract

In dysphagia, patient exhibits a problem in throat or esophagus which causes difficulty in swallowing. In dysphagia, muscles and nerves which help in movement of food toward stomach cannot work properly which may be due to the injury in brain, problem in nervous system, esophageal spasm etc. Although the likelihood of occurrence of this disease is for all age groups, elderly patients and children feel more discomfort in swallowing of medications. Chronic administration of drugs leads to poor patient compliance.To overcome the problems of dysphasia, several dosage forms have been developed which include oral dispersible tablets (ODT), lozenges, chewing gum, effervescent products (tablets, granules and pellets). These formulations provide ease of swallowing and also helps in achieving faster onset of action. These formulations come in liquid state in oral cavity or need to disperse in vehicle prior to administration. Successful adoption of such formulations is reflected in various marketed products based on these technologies.Formulations which dissolve/disperse in oral cavity (ODT, lozenges and chewing gum) require sweeteners and flavors to mask the bitter taste of drugs. Thus, increasein number of excipients results in increase in chances of incompatibilities with the active ingredients. These formulations may exhibit “cheeking problem” (retention of drug particles in oral cavity) which may cause after effects of bitter taste in oral cavity. Also, these formulations are not suitable for drugs with larger dose of API.Effervescent products helps in overcoming such drawbacks. Effervescence generated after dispersing the formulation in water not only helps in masking the bitter taste of API but also helps in increasing absorption of drugs from GIT. It can be applicable for both small dose of API (in the form of tablet or pellets) and larger dose of API (in the form of granules). These formulations are dissolved in water for administration which reduces gastric irritation due to reduced localization of drug. It also provides buffering actions and prevents degradation of acid labile drugs. These formulations provide advantages of liquid dosage form along with reduction of transportation cost and stability which is major issues of liquid dosage forms. Diseases likes allergic disorders, pruritides, common cold, cough, motion sickness, vertigo, different types of ulcer and Gastroesophageal reflux disease (GERD) require faster onset of action. If the patient is suffering from dysphagia, than it is difficult to give the medication. Thus, in these casesparenteral administration will be first choice of treatment. Effervescent formulation can be the alternative treatment. Quick relief may be achieved by administering oral effervescent formulation of H1 antagonist in such conditions which may also help in avoiding invasive parenteral route.Thus, taking into consideration of the advantages of effervescent formulations, the aim of present investigations was to develop and optimize effervescent formulations, tablets and pellets, for various drugs, Chlorpheniramine Maleate, Promethazine and Diphenhydramine, belonging to antihistamineclass using concept of DOE. The characteristics of formulations which were taken in consideration for selection of optimized formulations were amount of carbon dioxide release, shape and size (in pellets), morphology, disintegration time as well as drug dissolution. The optimized formulations were evaluated using in-vivorabbit model and pharmacokinetic parameters were compared with the pure drug dispersion. Effervescent tablet was formulated using direct compression method. Pellets were made using meltable binder in extrusion shperonization methods. Effervescent formulation of CPM, PMZ & DPH was made successfully and evaluated for morphological characterization, disintegration time, amount of carbon dioxide, drug release and other pharmacopoeial evaluation parameters. The in-vivo study was carried out using rabbit model. The pharmacokinetic study showed faster tmax of effervescent formulation with compared to reference standard. The bitterness of optimized formulation was very less compared to quinine hydrochloride. The short term stability study of optimized formulation of tablet and pellet shown all parameterswithin acceptable limits However, Effervescent pellets gave fast disintegration than effervescent tablet. The study proved that developed formulations are advantageous in improving onset of action compared to conventional formulations.