FORMULATION AND EVALUATION OF AMOXICILLIN TRIHYDRATE MODIFIED RELEASE DOSAGE FORMS
*1 Patel Dimpalben Girishkumar, 2 Mr.K.H.Shah, 3 Rohit K Patel, 3Yatish Shukla, 3 Modi B, 3 Nilesh Patel
1 Dharmaj Degree Pharmacy College,
Dist- Anand, Dharmaj -388430, Gujarat
2 Professor, IPCPRC, Dharmaj, Gujarat
3 KAPTAB Pharmaceuticals
The aim of the current investigation is to design oral once daily modified release dosage forms of amoxicillin trihydrate for treatment of pharyngitis/tonsilitis, which release the drug for 24 hours and match with theoretical drug release profile. The tablets and capsules were prepared by the different method using different polymers in different concentrations. The interference of the polymers was ruled out by FT-IR spectroscopy studies. The powder-blends of tablets and drug were evaluated for their physical properties like angle of repose, bulk density, compressibility index, and Hausner ratio and found to be satisfactory. The manufactured tablets were evaluated for in process and finished product quality control tests including appearance, thickness, weight variation, hardness, friability, drug content, and in vitro drug release. All formulations showed appearance, thickness, weight variation, hardness, friability and drug content in specified limit. All formulations showed acceptable pharmacotechnical properties and complied with in-house specifications for tested parameters. The results of dissolution studies indicated that formulation containing 50% ethyl cellulose and 50% methocel was the most successful formulation which was evidenced by similarity (f2) and dissimilarity (f1) factors. The formulated amoxicillin trihydrate tablets followed zero order release kinetics and Higuchi diffusion was the dominant mechanism of drug release, resulting in regulated and complete release within 24 hours. Formulations were subjected to short term stability studies as per ICH guidelines and were found stable. Capsule formulations 16 were evaluated for weight uniformity, drug content and in vitro drug release. The results of dissolution studies indicated that drug release from capsule not extend up to 24hrs. All formulations of capsule failed in in-vitro drug release test. In comparison of tablet and capsule formulations, tablet found to be successful dosage form.
REFERENCE ID: PHARMATUTOR-ART-1483
Conventional dosage forms, which are prompt release in nature, have been used from decades as antibiotics for different infection. To maintain drug concentration within the therapeutically effective range, it is necessary to take these types of dosage forms several times a day and which results in the fluctuations in drug levels. Recently, several technical advancements have been made which results in new techniques for drug delivery. These techniques are capable of controlling the rate of drug delivery, extending the duration of therapeutic activity and / or targeting the delivery of drug to a tissue. Modified release pharmaceutical dosage forms may offer one or more advantages over conventional dosage forms of the same drug. Modified release dosage forms continue to draw attention in the search for improved patient compliance and decreased incidences of adverse drug reactions and decrease total dose of drug. Ideally, a extended release dosage form will provide a therapeutic concentration of the drug in te blood that is maintained throughout the dosing interval with a reduction in a peak concentration ratio. One of the least complicated approaches is to form a tablet and capsule. Various types of polymers used for modified release of drug from dosage form and their modeling aspects have been reviewed. It contained general concepts and requirements for modified release drug delivery system. Classification, advantages and disadvantages of oral extended release drug delivery systems, ideal characteristics of extended release formulations, concept of tablet and capsule, and overview about antibiotic and disease were discussed.
The objectives of the research work undertaken are;
1) To prepare different modified release dosage form of amoxicillin for the treatment of pharyngitis/tonsillitis.
2) To study the Preformulation factors such as melting point, drug-excipients interaction, angle of repose, carr’s index, drug property etc.
3) To characterize manufactured tablets for hardness, thickness, content uniformity, weight uniformity, dimensions, etc. and capsule for weight uniformity, content uniformity, appearance.
4) To study in vitro drug release study comparison of different dosage form like tablet, capsule.
5) To study in vitro drug release study of different dosage form with marketed product in US or with the ideal theoretical drug release profile.
6) To carry out short term accelerated stability studies on the most satisfactory formulation as per ICH guidelines.
In the present investigation, efforts were made to develop modified release tablets and capsule of amoxicillin trihydrate for treatment of Pharyngitis/Tonsilitis, which will provide similar in vitro release profiles to that of developed theoretical drug release profiles which can be confirmed by calculating f1 (difference factor) and f2 (similarity factor) values.
1.1 MODIFIED RELEASE DOSAGE FORM
Modified preparations where the rate and/or place of release of the active ingredient are different from that of the conventional dosage form administered by the same route. This deliberate modification is achieved by special formulation design and/or manufacturing method. Modified release dosage forms include prolonged release, delayed release, pulsatile release and accelerated release dosage forms.1
Modified release dosage form is the dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form. Modified release solid oral dosage forms include both delayed and extended release drug products.2
Drug products designed to reduce the frequency of dosing by modifying the rate of drug absorption have been available for many years. Early modified-release products were often intramuscular/subcutaneous injections of suspensions of insoluble drug complexes, e.g. procaine penicillin, protamine zinc insulin. Advances in technology have resulted in novel oral modified-release dosage forms. Many terms are used to describe modified-release products including extended-release, prolonged-release, controlled-release, controlled-delivery, slow-release and sustained-release. These preparations, by definition, have a reduced rate of release of active substance.3
Oral solid dosage forms are the preferred route for many drugs and are still the most widely used formulations for new and existing modified release (MR) products.
Over many years, approaches and technologies in the area of MR oral drug delivery have been developed to:
* Extend the release of drug over a number of hours, an effect accomplished either by combining the drug with release-retardant materials to form a matrix core, or applying release-modifying film coatings to cores containing the drug.
* Delay the release of drug for a period of time, usually through the application of an externally applied enteric coating.
Technologies are available for the formulation, development and production of MR tablets and multiparticulates such as drug-loaded pellets and granules, mini-tablets and drug crystals.
Over the last decade, the approach to MR oral drug delivery systems has changed from a line extension strategy to a clinically superior approach for marketed drugs as well as for new chemical entities. The benefits offered by MR systems include reduced dosing frequency with improved patient compliance, better and more uniform clinical effects with lower incidence of side effects and possible enhanced bioavailability. The rational design of MR systems, where biological, physicochemical and physicomechanical considerations have been taken into account during formulation of MR dosage form, has alleviated the risk of ‘dose dumping’ in vivo. In addition to the pharmacological and patient benefits, MR dosage forms offer commercial opportunity through intellectual property, brand differentiation and recognition, plus the potential to license technologies to other companies.
The United States Pharmacopoeia definition of an MR system is that: “the drug release characteristics of time, course and/orlocation are chosen to accomplish therapeutic orconvenience objectives not offered by conventionaldosage forms...”
This includes technologies that modify the site of drug delivery. The successful formulation of an MR device requires a comprehensive understanding of the mechanisms of drug release from the macroscopic effects of size, shape and structure through to chemistry and molecular interactions. Multiparticulate dosage forms have been shown to be less prone to food effects than monolithics1 and are often the preferred formulation for extended and/or delayed release. Film coating is an ideal process for the production of extended release multiparticulate dosage forms. For application in extended release delivery systems, film coats with well-characterised permeability properties are essential.
An important MR technology is delayed release through application of gastro-resistant coatings. In this case, a coating layer is applied to the dosage form, either multiparticulate or monolithic, providing protection to the stomach from the drug or protecting the drug from exposure to acidic gastric fluids. The majority of modern enteric coatings rely on polymers containing carboxylic acid groups as the functional moiety. These groups remain unionised in the low pH environment of the stomach but start to ionise as the dosage form passes into the small intestine. As the pH level rises above the point of dissolution, the polymer is ionised and the drug is released. In the past, enteric coating systems have required the use of non-aqueous solvents for application; however, the majority of new enteric coating developments are based on aqueous enteric polymeric systems.4
1.1.1 IMMEDIATE RELEASE
The term “immediate release” pharmaceutical formulation includes any formulation in which the rate of release of drug from the formulation and/or the absorption of drug, is neither appreciably, nor intentionally, retarded by galenic manipulations. In the present case, immediate release may be provided for by way of an appropriate pharmaceutically acceptable diluent or carrier, which diluent or carrier does not prolong, to an appreciable extent, the rate of drug release and/or absorption.5
1.1.2 EXTENDED RELEASE
Extended release is designed to slow the rate of release of the active ingredient(s) in the gastrointestinal tract.Some extended-release medications have the letters "XL" or "LA" or "XR" in their name.Extended-release medications have special coatings or ingredients that control how fast the drug is released from the dosage form into body. This may allow you to take certain medications only once a day, instead of more often.
The extended release formulations are the type of formulations which will improves the therapeutic index of drug concentration. This formulation makes the drug available over extended time period after oral administration.6
* Sustained Blood Levels:
The size and frequency of dosing is determined by the pharmacodynamics and pharmacokinetic properties of the drug. The slower the rate of absorption, the less the blood concentrations fluctuate within a dosing interval. This enables higher doses to be given less frequently. For drugs with relatively short half-lives, the use of extended release products may maintain therapeutic concentrations over prolonged periods.
* Attenuation of adverse effects:
With conventional dosage forms, high peak blood concentrations may be reached soon after administration. With possible adverse effects related to the transiently high concentration. An example is hypotension in patients taking rapid-release nifedipine products. The use of an extended-release product avoids the high initial blood concentrations which cause the sudden reduction in blood pressure and other significant hemodynamic changes such as reflex tachycardia. Anotherexamples are the transient nausea at sub-toxic concentration of some conventional release products such as throphylline.
* Improved Patient Compliance:
Drugs with short half-lives often need to be given at frequent intervals to maintain blood concentrations within the therapeutic range. There is an inverse correlation between the frequency of dosing and patient compliance. A reduction in the number of daily doses offered by extended-release products has the potential to improve compliance. However, this advantage probably only occurs when conventional formulations need to be given three or more times a day.
* The extended release formulations may maintain therapeutic concentrations over prolonged periods.
* The use of extended release formulations avoids the high blood concentration.
* Extended release formulations have the potential to improve the patient compliance.
* Reduce the toxicity by slowing drug absorption.
* Increase the stability by protecting the drug from hydrolysis or other degradative changes in gastrointestinal tract.
* Minimize the local and systemic side effects.
* Improvement in treatment efficacy.
* Minimize drug accumulation with chronic dosing.
* Usage of less total drug.
* Improvement the bioavailability of some drugs.
* Improvement of the ability to provide special effects. E.g.: Morning relief of arthritis through bed time dosing.
* High cost of preparation.
* The release rates are affected by various factors such as, food and the rate transit through the gut.
* Some differences in the release rate from one dose to another dose but these have been minimized by modern formulations.
* Extended release formulation contains a higher drug load and thus any loss of integrity of the release characteristics of the dosage form.
* The larger size of extended release products may cause difficulties in ingestion or transit through gut.
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