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Chapter 4 Objectives of the Study CHAPTER-IV OBJECTIVES OF THE STUDY 4.1. BACKGROUND Acid-related disorders encompass a wide variety of diagnoses; including the extremely prevalent gastroesophageal reflux disease (GERD), which affects an estimated 25 million Americans, duodenal and gastric ulceration, stress related mucosal disease and acute upper gastrointestinal bleeding, a common medical emergency resulting in approximately 300,000 hospitalizations annually. During the last three decades, the management of these disorders has been revolutionized by the introduction of histamine- 2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs). Currently, the PPIs are available as delayed release formulations. These PPI’s are highly effective, irreversible inhibitors of H+/K+ ATPase, the final step in gastric acid secretion. The indications for PPIs have expanded to include a variety of gastric acid-related diseases, including peptic ulcer disease (PUD), NSAID-induced ulcer prevention, Zollinger–Ellison syndrome, and adjunctive therapy for Helicobacter pylori eradication. Although these agents form the therapeutic cornerstone of management for a variety of acid-related disorders, there is still room for improvement because of the serious drawbacks of delayed release formulations. All proton pump inhibitors (PPI) are weak bases and acid labile that tend to be unstable at acidic pH and are rapidly degraded, usually within minutes, in the acidic environment of the stomach. Therefore, they have to be formulated as enteric-coated dosage forms to prevent acid degradation. The coating protects the active ingredient from degradation by gastric acid, but it also delays absorption, so Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 124 Chapter 4 Objectives of the Study that the peak plasma concentration (Cmax) is not typically attained for up to five hours after oral administration of these formulations. Due to their pH-dependent attributes and the uncertainty of gastric retention time, in-vivo performances as well as inter and intra subject variability are very high; making it an uncertain method. After ingestion, an enteric-coated dosage form resides in the low pH environment of the stomach before moving into the duodenum. During this time, the enteric-coating may begin to dissolve, or imperfections or cracks in the coating may develop, allowing gastric acid to penetrate the coating and prematurely release drug into the stomach rather than in the small intestine. In the absence of buffering agent, an acid-labile drug that is exposed to this gastric acid is rapidly degraded and rendered therapeutically ineffective. In addition, patients must not chew or crush the tablets or the enteric coated granules. Limitations to enteric-coated PPI formulations also include the potential for nocturnal acid breakthrough (NAB), defined as an intragastric pH below 4 for at least one hour during the night with PPI therapy. NAB occurs in up to 70% of patients with GERD. Despite adequate therapeutic dosing (including twice-daily administration), patients taking enteric coated, delayed-release PPIs may experience nocturnal gastric acidity, whether or not the agent is taken before breakfast, before dinner, or twice daily and may have night time symptoms of heartburn. Patients with nocturnal GERD may have a higher potential for severe reflux induced complications such as esophagitis, Barrett’s esophagus, esophageal motility disorder, esophageal stricture formation, and esophageal adenocarcinoma. Individuals with nocturnal heartburn also report less satisfaction with delayed release PPIs and a diminished quality of life in terms of both mental and physical components, compared with GERD patients, who do not experience nocturnal heartburn. Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 125 Chapter 4 Objectives of the Study Strategies for managing nocturnal gastric acidity include increasing PPI administration from once to twice daily, increasing the dose, switching to another PPI, or adding an H2RA at bedtime. Although this strategy may provide shortterm efficacy, its clinical utility may be limited by the potential for the development of tolerance to H2RAs as well as by the additional cost of therapy. Although significant progress has been made in treating acid related disorders, patients would still benefit from advances in PPI therapy. In order to fulfil the advancement in PPI therapy, where most of them suffer from the drawbacks of delayed release formulations, it is desirable to have immediaterelease drug delivery systems to improve the overall therapeutic benefit and to achieve an ideal therapy. By immediate delivery, it is possible to achieve more rapid absorption; provide a better nocturnal acid control; and sustain a gastric pH above a critical threshold. More rapid absorption will result in more rapid onset of suppression of gastric acidity compared with delayed-release formulations. It is also possible to minimize inter individual variability, achieve an effective therapy with low dosage of the drug, to reduce the frequency of medication and thus improve patient compliance. Literature reports reveal that the existing immediate release composition of omeprazole contains a large quantity of sodium bicarbonate to protect the drug from degradation by the stomach acid and utilizes the concept of microenvironment pH. This surface pH requires a large quantity of alkalizing agents to neutralize the stomach acid and to maintain a desired pH of the system so as to protect the active that is prone to acid degradation. While using this concept, the amount of buffer depends on the pKa of the drug used. The amount of buffer required to make an immediate release composition of Pantoprazole or Rabeprazole, may be more than that required for Omeprazole. Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 126 Chapter 4 Objectives of the Study The administration of large amounts of sodium bicarbonate as an alkalizing agent can produce significant adverse effects, which can dramatically reduce the efficacy of the therapy in patients and reduce the overall health of the patients. Sodium bicarbonate is usually neutralized in the stomach or is absorbed, such that belching results, patients with gastroesophageal reflux may exacerbate or worsen their reflux disease as the belching can cause upward movement of stomach acid (Brunton, 1990). Patients with conditions such as hypertension or heart failure are advised to avoid the intake of excessive sodium as it can cause aggravation or exacerbation of their hypertensive conditions. Also patients with numerous conditions that typically accompany critical illness should avoid the intake of excessive sodium bicarbonate as it can cause metabolic alkalosis that can result in a serious worsening of the patient's condition. Excessive antacid intake (such as sodium bicarbonate) can result in drug interactions that produce serious adverse effects. For example, by altering gastric and urinary pH, antacids can alter rates of drug dissolution and absorption, bioavailability, and renal elimination. Moreover, sodium bicarbonate used in the composition has poor stability properties and decomposes by converting to carbonate and such; the decomposition is accelerated by agitation or heat. Hence, such compositions comprising large amount of sodium bicarbonate are not suitable for long term usage. Findings indicate that sodium bicarbonate transiently buffers postprandial intragastric contents. Therefore, sodium bicarbonate fails to reconstitute the protein buffer of the meal effectively, and the observations suggest that it leaves the stomach rapidly with the liquid phase of the meal. However, the water insoluble, aluminum-magnesium antacid has a longer duration of buffering, probably because it leaves the stomach more slowly, largely with the solid portion of the meal. Other drawbacks of the existing immediate release composition include poor patient compliance, poor stability and inter individual variability. Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 127 Chapter 4 Objectives of the Study Therefore, there is a need for a stable and robust composition of an immediate release acid labile drug, that is not enteric coated, uses minimal amount of buffer and it is not susceptible to degradation by acid. Current attempts to overcome the drawbacks of existing immediate release formulation include the development of a novel concept of creating a macroenvironment of alkalizing agents in the stomach followed by the release of the active in the safe high pH environment, which requires a minimal quantity of potent alkalizing agents, irrespective of the pKa of the drug being used, to design the immediate release formulation. Hence in this work an attempt was made • To formulate and optimize an immediate release formulation of Pantoprazole to counteract the disadvantages of enteric coating. • To use minimal quantity of alkalizing agents and thus a better patient compliance. • To improve the Tmax and reduce inter and intra subject variability. • To reduce the dose needed and frequency of administration and thus decrease the risk of adverse side effects. 4.2. 4.2.1. RATIONALE BEHIND SELECTION OF RESEARCH TOPIC Reason for choice of Acid related disorders as the disease for drug delivery development Millions of people are suffering from acid reflux or heartburn problems worldwide. This is a health disorder which can affect any age group of people. Acid-related disorders are common conditions that negatively impact quality of life for a significant number of people worldwide. Acid-related disorders Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 128 Chapter 4 Objectives of the Study encompass a wide variety of diagnoses; including the extremely prevalent gastroesophageal reflux disease (GERD), which affects an estimated 25 million Americans, duodenal and gastric ulceration, stress related mucosal disease and acute upper gastrointestinal bleeding, a common medical emergency resulting in approximately 300,000 hospitalizations annually. The pathology of these conditions involves an imbalance between acid secretion by gastric parietal cells and the ability of upper GI tract mucosa to defend against the effects of the acid. Therefore, therapy is targeted at elevating gastric pH. PPIs are used to control the effects of excessive acid secretion. This class of drugs has a unique mechanism of action that inhibits the final pathway to gastric acid secretion — the parietal cell proton pump. During the last three decades, the management of these disorders has been revolutionized by the introduction of histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs). 4.2.2. Reason for choice of Immediate release drug delivery system Currently, the PPIs are available as delayed release formulations. These PPI’s are highly effective, irreversible inhibitors of H+/K+ ATPase, the final step in gastric acid secretion. The indications for PPIs have expanded to include a variety of gastric acid-related diseases, including peptic ulcer disease (PUD), NSAID-induced ulcer prevention, Zollinger–Ellison syndrome, and adjunctive therapy for Helicobacter pylori eradication. Although these agents form the therapeutic cornerstone of management for a variety of acid-related disorders, there is still room for improvement because of the serious drawbacks of delayed release formulations. The Cmax of the delayed release formulation is not typically attained for up to four to five hours after oral administration of these formulations. Due to their Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 129 Chapter 4 Objectives of the Study pH-dependent attributes and the uncertainty of gastric retention time, in-vivo performances as well as inter and intra subject variability are very high. 4.2.3. Reason for development of a novel concept for immediate release of the PPI Literature reports reveal that the existing immediate release composition of omeprazole contains a large quantity of sodium bicarbonate to protect the drug from degradation by the stomach acid and utilizes the concept of microenvironment pH. This surface pH requires a large quantity of alkalizing agents to neutralize the stomach acid and to maintain a desired pH of the system so as to protect the active that is prone to acid degradation. While using this concept, the amount of buffer required may vary to a large extent depending on the pKa of the drug being used. This virtual membrane pH determines the extent of drug ionization and hence drug dissolution and absorption. Thus the concept of microenvironment pH questions the basics of pH partition hypothesis. It has been demonstrated that the pH of the diffusion layer at the surface of the dosage form resembles that of a saturated solution of drug and excipients in a dissolution media and represents the microenvironment pH of the system. During dissolution, medium that may eventually penetrate into the core, or during storage, moisture may penetrate into the core resulting in a saturated solution of drug and excipients. If the microenvironment pH is low, it will lead to ultimate degradation of the drug. Hence; it is seen that the compositions of acid labile drugs of prior art either use an enteric coating or high concentration of buffers or are liable to degradation in the microenvironment pH. Moreover, the administration of large amounts of sodium bicarbonate as an alkalizing agent can produce significant adverse effects, which can dramatically reduce the efficacy of the therapy in patients and reduce Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 130 Chapter 4 Objectives of the Study the overall health of the patients. Other drawbacks of the existing immediate release composition include poor patient compliance, poor stability and inter individual variability. 4.2.4. Reason for choice of Pantoprazole as the candidate for immediate drug delivery Initially, Pantoprazole was approved for treatment and maintenance of erosive esophagitis (40 mg/day for 8 to 16 weeks). Later in 2001, Pantoprazole iv was approved for short-term treatment (7 to 10 days) of GERD patients and a history of erosive esophagitis (40 mg/day) who are unable to tolerate oral pantoprazole. Since then, the indications for Pantoprazole have expanded to include a variety of gastric acid-related diseases, including peptic ulcer disease (PUD), NSAID-induced ulcer prevention, Zollinger–Ellison syndrome, and adjunctive therapy for Helicobacter pylori eradication. In-vitro studies have shown that Pantoprazole may actually have a longer duration of action than other PPIs because it is the only PPI to bind both cysteine 813 and cysteine 882, the more distal residue of the proton pump. Numerous multicenter randomized control studies have shown pantoprazole to be more efficacious than histamine-2 receptor antagonists (H2RAs) as the first-line drug for both treatment and maintenance therapy of erosive esophagitis associated with GERD. When compared to other PPIs, pantoprazole has similarly efficacy in both the initial treatment and maintenance therapy of GERD. Although the efficacy seems to be relatively similar when comparing pantoprazole to other PPIs, limited data indicate that pantoprazole has a faster onset of symptom relief in patients with mild GERD. Pantoprazole is currently the only PPI that is FDA approved to treat night time symptoms of GERD. Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 131 Chapter 4 4.3. Objectives of the Study PLAN OF WORK PHASE - 1: Preformulation studies Analytical Method Development and Validation Analytical investigation of Pantoprazole and systematic excipient selection o pH Stability analysis of Pantoprazole in different buffers o Drug excipient compatibility studies o Determination of acid neutralizing capacity of different buffers o Selection of buffers based on acid neutralizing capacity Evaluation of disintegration and dissolution of buffers in simulated gastric fluid Dissolution of active in SGF with and without buffers Evaluation and Comparison of Physicomechanical characteristics of gelatin and hypromellose capsules PHASE-2: Design And Development of Stable Immediate Release Formulations for Acid-Labile Compound: Dosage Form Design and Performance Evaluation for a model drug, Pantoprazole Design Strategy Formulation and Evaluation of Pantoprazole Tablet Cores Formulation Design using Macroenvironment pH concept o Core tablet filled in capsule containing buffers o Core tablet embedded inside the buffer core o Pellets and buffer granules filled into capsule Evaluation of Immediate Release Formulations o Drug content and related impurities o In-vitro release by dissolution o Effect on Invitro release by varying dissolution parameters Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 132 Chapter 4 Objectives of the Study o pH profile of Pantoprazole Immediate Release Formulations in SGF o Comparative in-vitro release of delayed release and immediate release formulations o Effect on in-vitro release by illustrating microenvironment and macroenvironment pH concept PHASE-3: Comparative bioavailability studies of delayed release and immediate release formulations in healthy human volunteers PHASE-4: Stability studies Physical stability Assessing drug content and related impurities Dissolution Performance of various IR formulations upon Storage Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 133