Chapter 1. Introduction

Transcription

1 Chapter 1 Introduction

2 Controlled drug delivery systems, which are intended to deliver drugs at predetermined rates for predefined periods of time, have been used to overcome the shortcomings of conventional drug formulations. Although, significant progress has been made in the controlled drug delivery area, more advances are yet to be made for treating many clinical disorders, such as diabetes, hypertension and rhythmic heart disorders. In these cases, the drug has to be delivered in response to ph in the body. In fact, it would be most desirable if the drugs could be administered in a manner that precisely matches physiological needs at proper times (temporal modulation) and/or at the proper site (site-specific targeting). In addition, the controlled drug delivery area needs further development of techniques for delivery of peptide and protein drugs. In the body, the appearance of numerous bioactive peptides is tightly controlled to maintain a normal metabolic balance via a feedback system called homeostasis 1. Natural and synthetic polymers have been used to fabricate different types of particles that vary in shape, size (micro- or nano-sized), degradability, and type of surface groups 2. These particles have been routinely used as vehicles for delivery of therapeutic agents as they protect the encapsulated drug coupled with their ease of fabrication, tunable degradation kinetics, and high surface to volume ratio, which allows the display of a large number of targeting agents and/or imaging probes 3-5. The first generation of polymeric particles released the encapsulated drug via degradation of the polymer matrix regardless of where these particles are located within the body 6. However, there is significant interest in delivering therapeutic drug molecules selectively to diseased tissues by utilizing certain cues that are specific to the targeted tissue/cell to trigger the release of the encapsulated drug from the particulate carriers. This need catalyzed the development of smart particles, which are fabricated using stimuli-sensitive polymers that can sense and respond to small 1

3 changes in environment conditions such as ph, temperature, light, and ionic strength 7. We are particularly interested in ph-sensitive polymers, which are characterized by their unique ability to sense small changes in environment ph that trigger a corresponding change in the polymer s physical properties such as size, shape, hydrophobicity and/or degradation rate. The ph range of fluids in various segments of the gastrointestinal tract may provide environmental stimuli for responsive drug release. Studies by several research groups have been performed on polymers containing weakly acidic or basic groups in the polymeric backbone. The charge density of the polymers depends on ph and ionic composition of the outer solution (the solution into which the polymer is exposed). Altering the ph of the solution will cause swelling or deswelling of the polymer. Thus, drug release from devices made from these polymers will display release rates that are ph sensitive. Polyacidic polymers will be unswollen at low ph, because the acidic groups will be protonated and hence unionized. With an increase in ph, polyacidic polymers will swell. The opposite holds for polybasic polymers, because the ionization of the basic groups will increase with decreasing ph found the swelling properties of the polybasic gels are influenced also by buffer composition (concentration and pka). A practical consequence proposed is that these systems may not reliably mediate ph sensitive swelling controlled release in oral applications, because the levels of buffer acids in the stomach (where swelling and release are expected to occur) generally cannot be controlled. However, the system may be useful as mediators of ph-triggered release when precise rate control is of secondary importance. This approach utilizes the existence of the ph gradient in the GIT that increases progressively from the stomach (ph ) and small intestine (ph ) to the colon ( ). The most commonly used ph-sensitive polymers are 2

4 derivatives of acrylic acid and cellulose. By combining the knowledge of polymers and their solubility at different ph environments, delivery systems have been designed to release drugs at the target site

5 Need for the study The research and development of the pharmaceutical companies is not as productive as it used to be. In addition, the cost of new drug development is expensive, and costs more than Rupees 500 crores. While there is no doubt that new drugs are the most important component in drug formulations, drug delivery technologies are also important in producing products on the market. In recent years, considerable attention has been focused on the development of novel drug delivery systems. In the form of novel drug delivery systems, an existing drug molecule can get a new life, thereby increasing its market value, competitiveness, and product patent life. Among the various novel drug delivery systems available in the market, the oral route release systems hold a major share because of their ease of administration and better patient compliance. The main goal of an oral sustained release product is to maintain the therapeutic blood level over an extended period of time. An attempt has been made in this study to formulate ph dependent drug delivery systems to release the drug for specific purposes such as gradient release drug delivery systems to release the drug all along the GIT, gastroretentive drug delivery systems and site specific drug delivery systems. 4

6 Why ph dependent gradient release drug delivery system was developed? Lercanidipine HCl is a dihydropyridine calcium antagonist used in the treatment of hypertension. Lercanidipine and its salts, such as the hydrochloride salt, is practically insoluble in water displaying an aqueous solubility of about 5µg/ml. The solubility of lercanidipine is marginally greater in acidic mediums; however, even at ph 5 it is less than 20 µg/ml. The solubility of lercanidipine at a ph greater than 5 is essentially less than 5µg/ml. Thus, lercanidipine is essentially insoluble in gastrointestinal ph range of 1 to 8. Lercanidipine also shows low experimental permeability and is classified as a low permeable drug, as defined by the BCS classification. Additionally, when administered to patients, lercanidipine displays extensive presystemic first pass elimination as a result of it being a substrate for cytochrome P450 IIIA4 isoenzyme. The combination of poor water solubility, low permeability and considerable first pass metabolism results in low and highly variable bioavailability. In the present investigation, an attempt was made to deliver Lercanidipine HCl via ph dependent gradient drug delivery system to overcome drawback of poor oral bioavailability and erratic oral absorption. The advantage of ph gradient release drug delivery system is that bioavailability of the poorly water soluble drugs could be enhanced by releasing the drug throughout the GIT. 5

7 Why mucoadhesive ph dependent microspheres as intestinal drug delivery system were developed? Esomeprazole magnesium trihydrate is a classical example of proton pump inhibitor and is approved by FDA for the treatment of Zollinger-Ellison syndrome. Esomeprazole, the stereo specific S-isomer of omeprazole, is the first proton pump inhibitor (PPI) to be developed as a single isomer for use in the treatment of acidrelated diseases. This optical isomer is subject to less first-pass metabolism and lower plasma clearance than omeprazole, thereby offering higher systemic bioavailability. Earlier studies have shown that esomeprazole achieved greater and more sustained acid control than omeprazole, with a similar tolerability and safety profile. Furthermore, esomeprazole shows a more rapid onset of acid-suppression effect than omeprazole and less inter-individual variation in acid control. In addition, esomeprazole treatment yields higher erosive esophagitis healing rates and provides sustained resolution of heartburn in more patients than any other currently available proton pump inhibitors. It has a plasma elimination half life of 1.5 h. The stability of esomeprazole magnesium decreases with a corresponding decrease in the ph of the media. Hence, the exposure of esomeprazole magnesium to the acidic contents of the stomach would lead to significant degradation of the drug and would result in reduced bioavailability. To bypass the ph of the stomach and reach the duodenum for absorption, several approaches have been attempted and reported during the last decade to develop new methodologies for site-specific drug release, including ph dependent drug release. ph dependent mucoadhesive drug delivery systems are used to immobilize a drug delivery device on a specific site for targeted release and optimal drug delivery due to intimacy and duration of contact. 6

8 Why ph dependent superporous hydrogels as gastroretentive dosage form? One of the most feasible approaches for achieving a prolonged and predictable drug delivery profile in the GI tract is to control the gastric residence time. To achieve gastric retention, the dosage form must be able to withstand the forces caused by peristaltic waves in the stomach and the constant contractions and grinding and churning mechanisms. To function as a gastric retention device, it must also resist premature gastric emptying. Dosage forms that can be retained in the stomach are called gastroretentive drug delivery systems (GRDDS). After oral administration, such a dosage form would be retained in the stomach and release the drug there in a controlled and prolonged manner, so that the drug could be supplied continuously to its absorption sites in the upper gastrointestinal tract. The various gastroretentive drug delivery systems are floating drug delivery systems/ hydrodynamically balanced systems (HBS), expandable, unfoldable and swellable systems, bioadhesive or mucoadhesive drug delivery systems, effervescent (gas generating) systems, microporous compartment system, microballoons/hollow microspheres, non-effervescent systems, low density systems and high density systems. A new type of challenging dosage form is superporous hydrogel (SPH). Interpenetrating polymer networks (IPNs) are defined as a combination of two polymers in network form, at least one of which is synthesized and/or crosslinked in the immediate presence of the other. If only one of the polymers is crosslinked, then it is known as semi-ipn. Losartan Potassium is an orally active non-peptide angiotensin II receptor (type AT1) antagonist used in the treatment of hypertension due to mainly blockade of AT1 receptors. It is readily absorbed from the stomach and upper part of small intestine. The main limitation of low therapeutic effectiveness is due to narrow 7

9 absorption window, poor bioavailability (25-35 %), and short biological half life (1.5-2 h). Therefore, Losartan Potassium was selected as a suitable drug for the design of a gastroretentive drug delivery system based on SPH. 8