Download Chapter 4 Objectives of the Study

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