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Chapter 7
Summary
CHAPTER-VII
SUMMARY
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. The PPIs
are highly effective, irreversible inhibitors of H+/K+ ATPase, the final step in gastric
acid secretion. 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.
Limitations to enteric-coated PPI formulations 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 adeno-carcinoma. Individuals with nocturnal heartburn
also report less satisfaction with PPIs and a diminished quality of life in terms of both
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mental and physical components, compared with GERD patients, who do not
experience nocturnal heartburn.
Acid labile drugs such as the proton pump inhibitors (PPI) tend to be unstable
at acidic pH and therefore 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 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.
Although significant progress has been made in treating acid related disorders,
patients would benefit from advances in PPI therapy. Literature reports reveal that to
overcome the problems of enteric coating; the concept of immediate release was
developed; specifically, an acid- suppressing agent that shows more rapid absorption;
that can be administered orally, that provides better nocturnal acid control; and that
sustains gastric pH above a critical threshold. More rapid absorption has been
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associated with more rapid onset of suppression of gastric acidity compared with
delayed-release formulations.
There is a need for a stable and robust composition of an immediate release
composition for acid labile drugs, that is not enteric coated, uses minimal amount of
buffer and it is not susceptible to degradation by acid. The existing immediate release
composition of omeprazole contains a large quantity of alkalizing agents to protect
the drug from degradation by the stomach acid and utilizes the concept of
microenvironment pH which requires more quantity of alkalizing agents.
The research work entitled "Design and Development of a Novel concept for
immediate release of Pantoprazole" was undertaken with the following objective.
The objective of this study was 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. The
immediate release formulation will maintain an intragastric pH above 4 for more than
18 hours, which will reduce the dose needed and decrease the risk of adverse side
effects.
The study has been presented in 8 chapters with introduction in chapter 1,
followed by literature review in chapter 2. The Drug and polymer profile was
discussed in chapter 3. The objectives of the study were briefed in chapter 4 and
elaborate methodology in chapter 5. Results and discussion was made in chapter 6.
Summary was presented in chapter 7. Conclusion was finally presented in chapter 8
with up to date bibliography till 2010 related to the study at the end.
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Based on acid neutralizing capacity and titration studies, MgO and MgOH2
are potent buffers with a good acid neutralizing capacity. These are insoluble buffers.
The buffer which gives an immediate rise in pH and maintained a pH above 6.0 at the
excess secretion of acid was appropriate. Soluble buffers when added to the SGF
gives an initial pH rise above 6.0, but upon addition of excess acid, they were not able
to maintain the pH above 6.0 with time. Insoluble buffers like heavy magnesium
oxide and magnesium hydroxide gives a steep rise in pH gradually. Since they are
insoluble in stomach medium, they are combined with soluble buffers like sodium
bicarbonate, calcium carbonate, trisodium phosphate and tromethamine (TRIS) which
dissolves and gives a rapid rise in pH initially followed by the synergistic effect of
MgO or MgOH2 which maintains the pH above 6.0 for a period of 1 hr. A
combination of soluble and insoluble buffers was selected to neutralize the stomach
acid and to sustain the pH.
Stress testing studies by visual observation, IR spectroscopy, Differential
scanning Calorimetry (DSC) and HPLC was employed to evaluate the drug excipient
compatibility. Some drug-excipient interaction was observed with MCC PH102,
ludipress, lactose, dicalcium phosphate, klucel EXF, Povidone K30 and Colloidal
silicon dioxide. However, further evaluation of these incompatible excipients by
HPLC method showed that some of these excipients were compatible with
Pantoprazole. HPLC method was, thus, of help in interpreting results and excluding
all relevant pharmaceutical incompatibilities. IR spectrum of Pantoprazole and
excipients mixture showed the presence of bands corresponding to Pantoprazole. No
extra bands were present in the IR spectrum, which confirmed that there is no
chemical incompatibility between Pantoprazole and excipients. There was only little
change in the drug content after storage of drug-excipient blends under stressed
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conditions except the case of MCC pH102. Stress testing studies by HPLC ruled out
any degradation and it was concluded that most of the excipients were chemically
compatible with the drug except a few.
The compacted buffer granules compressed into tablets did not disintegrate
within 10 minutes and formed lumps when exposed to acid medium which resulted in
poor acid neutralization; and that may lead to degradation of the active. In order to
solve this problem, formulations were prepared with several disintegrants such as the
croscarmellose sodium, sodium starch glycolate and crospovidone and subjected to
disintegration studies to enhance the release of buffering agents. But the
disintegration results showed that the release rate of buffering agents was retarded
when compared to the formulations that do not contain any superdisintegrant which
might be associated with formation of gel like mass in acid medium. To enhance the
disintegration rate of the buffering agents, soluble sugars such as mannitol and
sucrose were added to the composition and tested for disintegration. This resulted in
an immediate disintegration of buffers in acid medium which ultimately lead to attain
the pH sufficient to protect the active from degradation.
The buffer combination which gave an immediate rise in pH and able to
sustain pH of the medium above 6.0 with time, compatibility of buffer with drug and
minimum quantity of buffer required to neutralize the stomach acid are important
attributes of the buffer selection. A combination of MgO /TSP and MgOH2/TSP
proved to be promising.
The release profile of the API with MgO /TSP buffer was tested against API
without buffers. The API without buffers when added to the dissolution vessel
containing simulated gastric fluid, the dissolution medium turned yellow immediately
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indicating a possible degradation of the active ingredient. When the API and required
amount of buffer, as determined by titration, was added simultaneously to the
dissolution vessel containing SGF, the dissolution medium turned slightly yellow
with time indicating a partial degradation of the active ingredient which proved that
the microenvironment created by the buffers was not sufficient to protect the drug.
This phenomenon lead to the concept of creating an alkaline environment for the
drug which was achieved by adding the required amount of buffers to the medium
initially and neutralized for 2 minutes followed by the addition of accurately weighed
amount of API that did not result in any color change of the solution and thereby no
degradation.
The above findings indicate that the microenvironment pH is not sufficient to
protect the drug from degradation. The present research focuses on the direct pH
neutralization of the stomach acid by the rapid release of the buffers in the stomach
creating a safe high pH environment, followed by the release of the active and thus
protecting the active from degradation by the stomach acid.
To achieve this, three formulation designs were developed namely core tablet
filled in a capsule containing buffers, core tablet sandwiched between buffer core and
pellets filled in a capsule containing buffers. In an in-vitro model, the capsule
disintegrates in the simulated gastric fluid and releases the buffer which rapidly
increases the pH of the medium to greater than 6.0 within two minutes and sustains
this pH environment for about 1 hour. This is followed by the release the active PPI
and attains 100 % release within 30 minutes. This pharmacological synergy of the
buffers protects the active PPI from gastric acid degradation, allows it to be rapidly
absorbed, and eliminates the need for an enteric coating.
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To evaluate the formulations, a stability indicating HPLC method was
developed and validated. The drug content and related impurities of different
formulations (F1 to F12) containing different combination of buffers were determined
by the developed method.
The selected formulation was evaluated for the effect of change in rpm,
volume of medium and increasing the content of acid. The effect on drug release by
changing rpm from 100 to 75 was evaluated to depict the variation in gastric motility
between different individuals; The effect on drug release by changing volume of
medium was evaluated to depict the variation in volume of gastric fluid between
different individuals; The effect on drug release by increasing the content of acid was
evaluated to depict the condition of extremely acidic patients. The proposed
immediate release formulation releases 95% of the active in 15 minutes and 100% in
30 minutes whereas the delayed release formulation releases only 90% at the end of 3
h.
The formula (F1) was prepared as per the microenvironment pH concept (the
API and excipients were granulated and filled into capsules) and added to the
dissolution vessel containing SGF, the color of the medium changed immediately and
did not give an initial rise in pH thereby leading to partial degradation of the API in
the medium which indicates that the microenvironment pH was too low to protect the
drug from degradation. But on the other hand when the same formula (F1) was
prepared as per the macroenvironment pH concept and added to the dissolution vessel
containing SGF, a pH raise in the medium was observed within 4 minutes and as a
result the API did not degrade. It is evident from the data that the micro environment
pH concept retards the release of the drug and generates more impurities in contrary
to the macro environment pH concept.
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The stability results of formulations F1, F5 & F9 shows that the product is
stable at both long term (30°C/65% RH) and accelerated (40°C/75% RH) storage
conditions in terms of assay, related impurities and dissolution of the dosage forms.
Since the product is highly sensitive to moisture the samples were packaged in
aluminum-aluminum blisters. The stability results were promising with fewer
amounts of related substances and a good release pattern which is comparable with
RT results.
The results of this pilot study showed that the immediate release product had
relative bioavailability of 81.552% AUC ratio. The ratio of Cmax was also more than
80%.The idea of Immediate release was proved in this study by the fact that the
maximum concentration for the immediate release product was at 0.75 hour compared
to 2.63 hours for the delayed release product.
There were wide inter-individual variations in Tmax of delayed release
formulation varying between 1.75-4.50 h, whereas the Tmax of immediate release
formulation was significantly shorter at about 0.73 h based on 12 subjects. 11 of the
12 subjects showed a uniform Tmax of 0.75 h after the oral administration of
immediate release formulation. The elimination half-life (t1/2) following delayed
release administration was shorter and more variable than immediate release
administration but the difference was not significant. This proves that the immediate
release formulation is advantageous over the delayed release formulation.
The results obtained from this study showed a significant difference in Tmax as
compared to delayed release formulations. The wide variability in Tmax in the delayed
release formulations could be due to non-uniform and incomplete disruption of
enteric coating. The immediate release formulation of the present study contains
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potent alkalizing agents like magnesium oxide and trisodium phosphate in
combination and is designed in such a way that it forms a macroenvironment of
buffers in the stomach acid followed by the release of the active ingredient in a safe
high pH environment. This protects the active component and does not undergo
degradation before being absorbed. The uniform Tmax as observed in the immediate
release formulation will reduce inter individual variability drastically. The
formulation will also maintain a high intragastric pH in the presence of potent
buffering agents. As a conclusion, the immediate release product of Pantoprazole
achieved its goal in providing Pantoprazole a significantly shorter time and at the
same time the relative bioavailability was more than 80%.
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