Formulation and Evaluation of Meclizine Hcl Orally Dispersible Tablets by using Natural Super Disintegrants

The present study is on Meclizine HCL orally disintegrating tablets. meclizine HCL is used for the treatment of many different types of bacterial infections such as bronchitis, sinusitis, tonsillitis, ear infections, skin infections, gonorrhea, and urinary tract infections. meclizine HCL is a β-lactam type antibiotic. More specifically, it is a second-generation cephalosporin. Natural super disintegrates like xanthum gum and algenic acid are added to the formula to increase its disintegration, Orodispersible tablets of Meclizine Hcl were formulated by the Natural Superdisintegrant addition method by direct compression technique. All the formulations were evaluated for disintegration time, hardness and friability, this Superdisintegrant addition method exhibits the lowest disintegration time 29 sec, hence it is ranked as the best among the methods. All the formulations were evaluated for weight variation 226.3, hardness 5.1 , friability0.29, drug content uniformity 99.5, wetting time 28 sec for in-vitro dissolution study. Among all the formulations containing naturally super disintegrates like algenic acid and xanthumgum was considered to be the best formulation, which release up to 99.6% of the drug in 20 mints. 53 Introduction Drug delivery systems (DDS) are a strategic tool for expanding markets/indications, extending product life cycles and generating opportunities. The DDS makes a significant contribution to global pharmaceutical sales through market segmentation, and are moving rapidly. Drug delivery systems are becoming increasingly sophisticated as pharmaceutical scientists acquire a better understanding of the physicochemical and biochemical parameters pertinent to their performance. 1 Oral drug delivery has been known for decades as the most widely utilized routes of the administered among all the routes that have been employed for the systemic delivery of drug via various pharmaceutical products of different dosage forms. The reasons that the oral route achieved such popularity may be in part attributed to its ease of administration1. It has been reported that Dysphagia (difficulty in swallowing) is common among all age groups and more specific with pediatric, geriatric population along with institutionalized patients and patients with nausea, vomiting, and motion sickness complications. ODTs with good taste and increase the flavor acceptability of bitter drugs by various groups of population. Orally disintegrating tablets are also called as orodispersible tablets, quick disintegrating tablets, mouth dissolving tablets, fast disintegrating tablets, fast dissolving tablets, rapid dissolving tablets, porous tablets, and rapimelts. However, of all the above terms, United States pharmacopoeia (USP) approved these dosage forms as ODTs. Recently, European Pharmacopoeia has used the term orodispersible tablet for tablets that disperses readily and within 3 min in mouth before swallowing. Despite of tremendous advancements in drug delivery, the oral route remains the perfect route for the administration of therapeutic agents because the low cost of therapy, ease of administration lead to high levels of patient compliance. M. Vinod Kumar, IJPSR 2016, 2:1 International Journal of Pharma Sciences and Scientific Research Volume 2 Issue 1, April 2016 2 54 It is always the aim of a scientist or a dosage form designed to enhance the safety of a drug molecule while maintaining its therapeutic efficacy. Recent advances in NDDS aim for the same by formulating a dosage form, convenient to be administered so as to achieve better patient compliance. Mouth Dissolving Tablet (MDT) is one among such approaches. Improved patient compliance has achieved enormous demand. Consequently the demand for their technologies is also increasing many folds. To develop a chemical entity, a lot of money, hard work and time are required. So the focus is rather being laid on the development of new drug delivery systems for already existing drugs, with enhanced efficacy and bioavailability, thus reducing the dose and dosing frequency to minimize the side effects. The oral route of administration is the most preferred route due to its many advantages like ease of administration, accurate dosage, self-medication, pain avoidance, versatility and patient compliance. Tablets and capsules are the most popular dosage forms.2,3 But one important drawback of such dosage forms is dysplasia or difficulty in swallowing. This is seen to afflict nearly 35% of the general population. This disorder is also associated with a number of pathological conditions, including stroke, Parkinson’s disease, neurological disorders, AIDS etc.. 2,3 • Parkinsonism • Motion sickness • Unconsciousness • Elderly patients • Children • Mentally disabled persons M. Vinod Kumar, IJPSR 2016, 2:1 M. Vinod Kumar, IJPSR 2016, 2:1 International Journal of Pharma Sciences and Scientific Research Volume 2 Issue 1, April 2016 3 55 • Ideal Properties of ODTs: 4,5,6 The performance of ODTs depends on the technology used during their manufacture. The necessary property of such tablets is the ability to disintegrate rapidly and disperse or dissolve in saliva, thereby obviating the need for water. Various technologies have been developed that enable ODT to perform this unique function. An ideal ODT should meet the following criteria: • Does not require water for oral administration yet disintegrates and dissolves in oral cavity within a few seconds • Has sufficient strength to withstand the rigors of the manufacturing process and post-manufacturing handling • Allow high drug loading • Has a pleasant mouth feel • Is insensitive to environmental conditions such as humidity and temperature is adaptable and amenable to existing processes and packaging machineries. 1.2 Advantages of Orodispersible tablet:4,5,6 1. No need of water to swallow the tablet. • Can be easily administered to pediatric, elderly and mentally disabled patients. • Accurate dosing as compared to liquids. • Dissolution and absorption of drug are fast, offering a rapid onset of action. • Bioavailability of drugs is increased as some drugs are absorbed from mouth, pharynx and esophagus through saliva, passing down into the stomach. • Advantageous over liquid medication in terms of administration as well as transportation. • First pass metabolism is reduced, thus offering improved bioavailability and thus reduced dose and side effects. • Free of the risk of suffocation due to physical obstruction when swallowed, thus offering improved safety. • Suitable for sustained/controlled release actives. • Unavailability of water To solve the above-mentioned problems, pharmaceutical technologists have put in their best efforts to develop a Fast dissolving drug delivery, i.e. Oro dispersible tablet that disintegrates and dissolves rapidly in the patient’s mouth, within a 15 Sec-3 min without the need for drinking water or chewing. Most of the ODTs include certain super disintegrates and taste masking agents. M. Vinod Kumar, IJPSR 2016, 2:1 International Journal of Pharma Sciences and Scientific Research Volume 2 Issue 1, April 2016 4 56 Figure 1: Figures showing Advantages of Orodispersible tablet 1.2.The need for development of ODT: 7,8,9 The need for non-invasive delivery systems persists due to patients’ poor acceptance of, and compliance with, existing delivery regimes, limited market size for drug companies and drug uses, coupled with the high cost of disease management. 1.2.1. Patient Factors: Orally disintegrating dosage forms are particularly suitable for patients, who for one reason or the other; find it inconvenient to swallow traditional tablets and capsules with an 8-Oz glass of water. These include the following • Pediatric and geriatric patients who have difficulty in swallowing or chewing solid dosage forms • Patients who are unwilling to take solid preparation due to fear of choking • Very elderly patients who may not be able to swallow a daily dose of antidepressant. • An eighty year old with allergies who desires a more convenient dosage form than antihistamine syrup. • A middle-aged woman undergoing radiation therapy for breast cancer may be too nauseous to swallow her H2blocker. • A schizophrenic patient in an institutional setting who may try to hide a conventional tablet under his or her tongue to avoid their daily dose of a typical antipsychotic. • A patient with persistent nausea, who may be journeying, or has little or no access to water. 1.2.2. Effectiveness Factor: Increased bioavailability and faster onset of action are a major claim of these formulations. Dispersion in saliva in oral cavity causes pregastric absorption from some formulations in those cases where drug dissolves quickly. Buccal, pharyngeal and gastric regions are all areas of absorption of many drugs. Any pregastric absorption avoids first pass metabolism and can be a great advantage in drugs that undergo a great deal of hepatic metabolism. Furthermore, safety profiles may be improved for drugs that produce significant amounts of toxic metabolites mediated by first-pass liver metabolism and gastric metabolism, and for drugs that have a substantial fraction of absorption in the oral cavity and pregastric segments of GIT. 1.2.3. Manufacturing and Marketing Factors: Developing new drug delivery technologies and utilizing them in product development is critical for pharmaceutical industries to survive, regardless of their size. As a drug nears the end of its patent life, it is common for pharmaceutical manufacturers to develop a given drug entity in a new and improved dosage form. A new dosage form allows a manufacturer to extend market exclusivity, product line extension, and extend patent protection, while offering its patient population a more convenient dosage form. This leads to increased revenue, while also targeting underserved and under-treated patient populations. As examples, Eisai Inc. Launched Aricept ODT, a line extension of donepezil for Alzheimer’s disease, in Japan in 2004 and in the U.S. in 2005 in response to a generic challenge filed in the U.S. by Ranbaxy. Merck’s Japanese subsidiary launched Lipola M (simvastatin ODT), a line extension of its blockbuster, Zocor®, a cholesterollowering drug, in response to seventeen generic registrations of simvastatin applied for in Japan in 200424. Marketers build a better brand and company image when they offer a unique, easyto-take form that satisfies the need of an underserved patient population. 1.3. Significance:10,11 Orally disintegrating tablets offer all advantages of solid dosage forms and liquid dosage forms along with special advantages, which include: M. Vinod Kumar, IJPSR 2016, 2:1 M. Vinod Kumar, IJPSR 2016, 2:1 International Journal of Pharma Sciences and Scientific Research Volume 2 Issue 1, April 2016 5 57 • As ODTs are unit solid dosage forms, they provide good stability, accurate dosing, easy manufacturing, small pack size, and easy to handle by patients. • No risk of obstruction of dosage forms, which is beneficial for traveling patients who do not have access to water. • Easy to administer for pediatric, geriatric, and institutionalized patients (especially for mentally retarded and psychiatric patients) • The rapid disintegration of tablet results in quick dissolution and rapid absorption, which provide rapid onset of action. • Medication as “bitter pill” has changed by excellent mouth feel property produced by use of flavors and sweeteners in ODTs. • Bioavailability of drugs that are absorbed from the mouth, pharynx, and esophagus is increased. 3 • Pregastric absorption of drugs avoids hepatic metabolism, which reduces the dose and increase the bioavailability. 1.4. Challenges in Formulating ODTs: 10,11 1.4.1. Palatability: As most drugs are unpalatable, orally disintegrating drug delivery systems usually contain the medicament in a tastemasked form. Delivery systems disintegrate or dissolve in the patient’s oral cavity, thus releasing the active ingredients which come in contact with the taste buds; hence, taste-masking of the drugs becomes critical to patient compliance. 1.4.2. Mechanical strength: In order to allow ODTs to disintegrate in the oral cavity, they are made of either very porous and soft-molded matrices or compression force, which makes the tablets friable and/or brittle, difficult to handle, and often requiring specialized peel-off blister packing that may add to the cost. Only few technologies can produce tablets that are sufficiently hard and durable to allow them to be packaged in multidose bottles, such as Wowtab® by Yamanouchi-Shaklee, and Durasolv® by CIMA labs. 1.4.3. Hygroscopicity: Several orally disintegrating dosage forms are hygroscopic and cannot maintain physical integrity under normal conditions of temperature and humidity. Hence, they need protection from humidity which calls for specialized product packaging. 1.4.4. Amount of drug: The application of technologies used for ODTs is limited by the amount of drug that can be incorporated into each unit dose. For lyophilized dosage forms, the drug dose must be lower than 400 mg for insoluble drugs and less than 60 mg for soluble drugs. This parameter is particularly challenging when formulating a fast-dissolving oral films or wafers. 1.4.5. Aqueous solubility: Water-soluble drugs pose various formulation challenges because they form eutectic mixtures, which result in freezingpoint depression and the formation of a glassy solid that may collapse upon drying because of the loss of supporting structure during the sublimation process. Such collapse sometimes can be prevented by using various matrix-forming excipients such as mannitol than can induce crystallinity and hence, impart rigidity to the amorphous composite. 1.4.6 Size of tablet: The degree of ease when taking a tablet depends on its size. It has been reported that the easiest size of the tablet to swallow is 7-8 mm while the easiest size to handle was one larger than 8 mm. Therefore, the tablet size that is both easy to take and easy to handle is difficult to achieve. 1.5 Criteria for Fast dissolving Drug Delivery System:12 The tablets should: • Not require water to swallow, but it should dissolve or disintegrate in the mouth in a matter of seconds. • Be compatible with taste masking. • Be portable without fragility concern. • Have a pleasant mouth feel. • Leave minimum or no residue in the mouth after oral administration. • Exhibit low sensitive to environmental condition as temperature and humidity. • Allow the manufacture of the tablet using conventional processing and packaging equipments at low cost. • 1.6 Salient Feature of Orodispersible Drug Delivery System:13 • Ease of Administration for the patient who cannot swallow, such as the elderly, stroke victims, bedridden patients, patient affected by renal failure and patient who refuse to swallow such as pediatric, geriatric & psychiatric patients. • No need of water to swallow the dosage form, which is highly convenient feature for patients who are traveling and do not have immediate access to water. • Rapid dissolution and absorption 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. • Pre-gastric absorption can result in improved bioavailability and as a result of reduced dosage; improve clinical performance through a reduction of unwanted effects. • Good mouth feel property helps to change the perception of medication as the bitter pill particularly in the pediatric patient. • The risk of choking or suffocation during oral administration of conventional formulation due to physical obstruction is avoided, thus providing improved safety. • New business opportunity like product differentiation, product promotion, patent extensions and life cycle management. M. Vinod Kumar, IJPSR 2016, 2:1 International Journal of Pharma Sciences and Scientific Research Volume 2 Issue 1, April 2016 6 58 • 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, particularly in cases of insoluble and hydrophobic drugs, due to rapid disintegration and dissolution of these tablets. • Stability for longer duration of time, since the drug remains in solid dosage form till it is consumed. So, it combines advantages of solid dosage form in terms of stability and liquid dosage form in terms of bioavailability. 1.7 Main ingredients used in preparation of Orodispersible tablets: 14 Important ingredients that are used in the formulation of Orodispersible tablet should allow quick release of the drug, resulting in faster dissolution. This includes both the actives and the excipients. Excipients balance the properties of the actives in Orodispersible tablets. This demands a thorough understanding of the chemistry of these excipients to prevent interaction with the actives. Determining the cost of these ingredients is another issue that needs to be addressed by formulators. The role of excipients is important in the formulation of fast-melting tablets. These inactive food-grade ingredients, when incorporated in the formulation, impart the desired organoleptic properties and product efficacy. Excipients are general and can be used for a broad range of actives, except some actives that require masking agents 1.7.1. Super disintegrates: Use of disintegrate is the basic approach in development of mouth dissolving tablets. Disintegrants play a major role in the disintegration and dissolution of ODT. It is essential to choose a suitable disintegrant, in an optimum concentration so as to ensure quick disintegration and high dissolution rates. Super disintegrates provide quick disintegration due to the combined effect of swelling and water absorption of the formulation. Due to swelling of superdisintegrants, the wetted surface of the carrier increases, which promotes the wettability and dispersibility of the system, thus enhancing the disintegration and dissolutio The optimum concentration of the superdisintegrant can be selected according to the critical concentration of disintegrant. Below this concentration, the tablet disintegration time is inversely proportional to the concentration of the superdisintegrant, whereas if concentration of superdisintegrant is above critical concentration, the disintegration time remains almost constant or even increases Sodium starch glycolate, Ac-di-sol (crosscaremellose sodium), crosspovidone, microcrystalline cellulose, pregelatinised starch are some of the examples of disintegrates. 1.7.2. Sugar based excipients: Sugar based excipients are used for taste masking and as bulking agents. Most of the drugs are having an unpleasant or bitter taste. And the basic requirement for designing ODTs is that the drug should not have a disagreeable taste. So taste masking is necessary in most of the cases. Sorbitol, Mannitol, Xylitol, dextrose, fructose, etc. Are mainly used. Indion-234 and Tulsion-335 were also utilized. Aqueous solubility and sweetness impart a pleasing mouth feel and good taste masking. But not all sugar-based materials have fast dissolution rate and good compressibility or compatibility. However technologies are developed to make use of the sugar based excipients on the design of Oro dispersible tablets. Other ingredients commonly used are water soluble diluents, lubricants, antistatic agents, plasticizers, colors and flavors. 1.8. Mechanism of action of disintegrates: The tablet breaks into primary particles of one or more of the mechanisms listed below: M. Vinod Kumar, IJPSR 2016, 2:1 M. Vinod Kumar, IJPSR 2016, 2:1 International Journal of Pharma Sciences and Scientific Research Volume 2 Issue 1, April 2016 7 59 Figure 2: Mechanism of fast-dissolving tablets: 1.8.1 By capillary action: Disintegration by capillary action is always the first step. When we put the tablet in suitable aqueous medium, the medium penetrates into the tablet and replaces the air adsorbed on the particles, which weakens the intermolecular bond and breaks the tablet into fine particles. Water uptake by tablet depends upon hydrophilicity of the drug /excipient and on tabulating conditions. For these types of disintegrants maintenance of porous structure and low interfacial tension towards aqueous fluid is necessary which helps in disintegration by creating a hydrophilic network around the drug particles.