Chapter 2 Rationale and Objective

Transcription

1 Chapter 2 SPP School of Pharmacy & Technology Management, SVKM s NMIMS, Mumbai 44

2 2.0 Rationale Need for extended release drug delivery systems Over the past 50 years or so, substantial research in the human arena has been focused on the optimization of drug delivery. Traditionally, these delivery systems have been drug specific, revolving around a particular drug and its clinical application. However, the past two decades have witnessed the emergence of numerous drug delivery technologies that have developed independently of any specific compound or diseased condition 118 (Rathbone MJ et al, 2003). An ideal dosage regimen for the treatment of any disease is the one, which attains therapeutic concentration of a drug molecule in plasma and or at the site of action in predetermined time interval and is subsequently required to be maintained during treatment. Conventional dosage forms have many limitations like patient noncompliance, chances of missing the dose because of frequent administration, peak-valley concentration profile, fluctuating blood levels, gastro intestinal (GI) irritation, first pass metabolism, degradation in GI acidity etc. Extended release drug delivery systems can be used to overcome the above mentioned limitations. Extended release drug delivery systems are designed to deliver drugs specific target tissues at the right amount, at and for the right amount of time and with minimum of side effects. These systems help to achieve prolonged therapeutic effect by continuously releasing the drug over an extended period of time after administration of a single dose. The blood level oscillations by multiple dosing of conventional dosage forms are reduced as a more even and effective drug level is maintained. The safety margin of high potency drugs can be increased and incidence of both local and systemic side effects can be reduced in sensitive patients. Objective of Extended Release Drug Delivery systems The fundamental need and principles underlying the development and use of modified drug delivery systems for humans include. Improved clinical effectiveness. The relative efficiency of reduced dosing regimens (i.e. improved patient compliance). Improved patient handling (e.g. nursing or outpatient visits for repeat drug administration) and medical care (e.g. handling of adverse events or side effects). SPP School of Pharmacy & Technology Management, SVKM s NMIMS, Mumbai 45

3 Need for generic development Many diseases are still major culprits for morbidity and mortality. There are not enough effective and sufficient drugs to control these diseases. However, to launch new molecules as drugs is too costly a proposition. Hence to recover cost of development, new molecule is allowed to be patented for some time. After patent expiry, other companies may launch same molecule as generic version. To make drug therapy more cost effective, it is necessary to reduce cost of drug development while taking care of safety and efficacy of drug product. Thus, generic drugs have to pass limited clinical trial in the form of comparative bioavailability or bioequivalence study. This accelerates the process of development and takes care of safety issues. This view is also supported by regulatory authorities. This makes drug therapy more cost effective, while taking care of safety and efficacy of drug product. Gliclazide is a second generation hypoglycemic sulfonylurea mainly used in the treatment of type II Diabetes mellitus. It is drug of choice as it has good tolerance, low incidence of hypoglycemia, low rate of secondary failure, inhibits platelet aggregation and increases fibrinolysis. Gliclazide - Need for extended release formulation Gliclazide is usually marketed in the base form. Gliclazide has absorption in gastrointestinal tract. Its oral bioavailability is in the range of 40-60% and shows linear response with the dose increment. Drugs that have absorption limited to the gastrointestinal tract coupled with poor absorption in the large intestine and colon, such drugs are usually regarded as inappropriate candidates for formulation into oral controlled delivery systems. This limitation on absorption (for example, in the gastrointestinal tract) is referred to as the absorption window. The gastrointestinal tract functions to propel ingested material from the stomach (where digestion takes place) into the small intestine (where absorption principally occurs) and on to the large intestine (where water is absorbed/secreted as part of body fluid regulation processes). Residence time for non-digestible materials in the stomach depends on whether one is dealing with a fed or fasting subject. Typical gastric emptying times for particular material (greater than a few millimeters in diameter) vary from a few tens of minutes in the fasted state to a few hours in the fed state. Transit times through the small intestine are consistently of the order of 3-4 hours. Oral controlled release delivery systems function by releasing their payload of the drug over an extended period of time following short period in the regions of SPP School of Pharmacy & Technology Management, SVKM s NMIMS, Mumbai 46

4 the gastrointestinal tract where good absorption of certain drugs is poor or non-existent, still releasing its contained drug albeit with a significant percentage of its payload still to be delivered. Drug when released from the dosage form in the circumstances described will not be absorbed. Thus, administration of a drug subject to a window of absorption in a conventional controlled release delivery system can lead to sub therapeutic blood levels and ineffective treatment of the disease state for which the drug was invented. Maintained or even improved bioavailability from an extended release dosage form that releases gliclazide at a rate likely to provide the desired plasma levels of drug for an extended time period might, however, be possible from a dosage form that has extended residence time in the upper gastrointestinal tract, resisting mechanisms that promote normal transit time for solid materials. The distinct advantages of gliclazide if it is an extended release product is it reduces the number of daily doses and increases patient compliance. Gliclazide being an extended release preparation can also avoid loading dose. This commonly occurs with conventional oral formulations when large doses are given which may cause sudden release and absorption of a large amount of drug. Gliclazide is released in smaller doses, and hence ensures increased bioavailability and decreased side effects. In contrast, conventional gliclazide has less bioavailability since absorption decreases as it passes through the lower part of small intestine. Conventional gliclazide has an oral bioavailability of 40-60% and gastrointestinal absorption is apparently complete within 6 hours of ingestion. Plasma t 1/2 is 10 hours. Hence it has to be given 2-3 times a day, whereas gliclazide extended release tablet being a controlled release formulation is released in small quantities in intestine where drug has better absorption and has a prolonged duration of action. The bioavailability increases to almost 100%. As gliclazide is released slowly, side effects like flatulence, abdominal discomfort, are less unlike plain gliclazide tablets. An inverse relationship was observed between the dose ingested and elative absorption with therapeutic doses ranging from mg suggesting the involvement of an active, storable absorption process. Thus extended release formulation of gliclazide can not only optimize the daily requirement of gliclazide but can also reduce the need of a higher dose. SPP School of Pharmacy & Technology Management, SVKM s NMIMS, Mumbai 47

5 Objective The primary objective of the project is to develop a stable, non-infringing extended release formulation which can be marketed as a generic product in the regulated market. To develop and evaluate a stable gliclazide extended release tablet formulation using three different technologies: i. Matrix technology ii. Melt granulation technology iii. Multiparticulate unit dose technology To carry out bio-equivalence studies for the developed formulation in human subjects (fasting condition). Pharmacoeconomics of the developed formulation for the comparison of the cost of one drug formulated with different technologies. SPP School of Pharmacy & Technology Management, SVKM s NMIMS, Mumbai 48