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FORMULATION AND EVALUATION OF ESOMEPRAZOLE MAGNESIUM DELAYED RELEASE TABLETS 40 MG

 

Clinical courses

ABOUT AUTHORS:
*1MR.B.Ashok, 2Dr.K.S.Manjunatha Shetty, 3Dr. Manikanta kumar, Chandra Shekar
1Master of Pharmacy in Pharmaceutics
2Ph.D Professor and Principal
3Ph.D, Associate Professor
Jawaharlal Nehru Technological University, Hyderabad
Srinivasa Pharmaceutical Institute And Center For Research Burugupally, Vikarabad, R.R Dist, A.P.
ashok.belde@gmail.com

ABSTRACT
The present study was an attempt to formulate and evaluate enteric coated tablets for esomeprazole magnesium dihydrate. Different core tablets were prepared and formulation was selected for further enteric coating, based on the disintegration time. Seal coating was applied to achieve 3% weight gain. Enteric coating was carried out using different polymers like hydroxyl propyl methylcellulose phthalate to achieve 5% weight gain. Disintegration studies showed that the formulations failed in 0.1 N HCl media. Hence the quantity of enteric coating was increased to 8% w/w. In vitro analysis of the developed tablets was carried out. Results from disintegration time and dissolution rate studies indicate that all the esomeprazole enteric tablets prepared possess good integrity, desirable for enteric coated tablets.

REFERENCE ID: PHARMATUTOR-ART-2030

INTRODUCTION1,4,6
Esomeprazoleis a proton pump inhibitor which reduces acid secretion through inhibition of the H+ / K+ ATP ase in gastric parietal cells. By inhibiting the functioning of this transporter, the drug prevents formation of gastric acid.


It is used in the treatment of dyspepsia, peptic ulcer disease(PUD), gastro esophageal reflux disease(GORD/GERD) and Zollinger-Ellison syndrome. Esomeprazole is the S-enantiomer of omeprazole.

Fig: 1.1 Esomeprazole


Application:            

A proton pump inhibitor

   

Purity                   :             

≥98%

Molecular Weight  :

749.15

Molecular Formula:

C34H36MgN6O6S2 2H2O

Description:
A leading proton pumps inhibitor.

Technical Information

Appearance           :

Powder

PhysicalState        :

Solid

Solubility               :

Soluble in DMSO: 5 mg/mL

Storage                 :

Desiccate at 4° C

Medical use
The primary uses of esomeprazole are gastroesophageal reflux disease, treatment of duodenal ulcers caused by H. pylori, preventing of gastric ulcers in those on chronic NSAID therapy, and treatment of gastrointestinal ulcers associated with Crohn's disease.

Gastroesophageal reflux disease
Gastroesophageal Reflux Disease (GERD) is a condition in which the digestive acid in the stomach comes in contact with the esophagus(food pipe). The irritation caused by this disorder is known as heartburn. Long term contact between the acid and esophagus can cause permanent damage to the esophagus. Esomeprazole reduces the production of digestives acids, thus minimizing their effect on the esophagus.

Duodenal ulcers
Esomeprazole is combined with the antibiotics clarithromycin and amoxicillin(or metronidazole in penicillin-hypersensitive patients) in the 7-14 day eradication triple therapy for Helicobacter pylori. Infection by H. pylori is the causative factor in the majority of peptic and duodenal ulcers.

Adverse effects
Common side effects include headache, diarrhea, nausea, flatulence, decreased appetite, constipation, dry mouth, and abdominal pain. More severe side effects are severe allergic reactions, chest pain, dark urine, fast heartbeat, fever, paresthesia, persistent sore throat, severe stomach pain, unusual bruising or bleeding, unusual tiredness, and yellowing of the eyes or skin. Proton pump inhibitors may be associated with a greater risk of hip fractures and clostridium difficile-associated diarrhea. By suppressing acid-mediated break down of proteins, antacid preparations such as esomeprazole lead to an elevated risk of developing food and drug allergies. This happens due to undigested proteins then passing into the gastrointestinal tract where sensitisation occurs. It is unclear whether this risk occurs with only long-term use or with short-term use as well. Patients are frequently administered the drugs in intensive care as a protective measure against ulcers, but this use is also associated with a 30% increase in occurrence of pneumonia.

Interactions
Esomeprazole is a competitive inhibitor of the enzymes CYP2C19 and CYP2C9, and may therefore interact with drugs that depend on them for metabolism, such as diazepamand warfarin; the concentrations of these drugs may increase if they are used concomitantly with esomeprazole. Conversely, Clopidogrel(Plavix) is an inactive prodrug that partially depends on CYP2C19 for conversion to its active form; inhibition of CYP2C19 blocks the activation of clopidogrel, thus reducing its effects.

Drugs that depend on stomach pH for absorption may interact with omeprazole; drugs that depend on an acidic environment (such as ketoconazoleor atazanavir) will be poorly absorbed, whereas drugs that are broken down in acidic environments (such as erythromycin) will be absorbed to a greater extent than normal.

Pharmacokinetics
Single 20–40 mg oral doses generally give rise to peak plasma esomeprazole concentrations of 0.5-1.0 mg/L within 1–4 hours, but after several days of once-daily administration these levels may increase by about 50%. A 30 minute intravenous infusion of a similar dose usually produces peak plasma levels on the order of 1–3 mg/L. The drug is rapidly cleared from the body, largely by urinary excretion of pharmacologically-inactive metabolites such as 5-hydroxymethylesomeprazole and 5-carboxyesomeprazole. Esomeprazole and its metabolites are analytically indistinguishable from omeprazole and the corresponding omeprazole metabolites unless chiral techniques are employed.

Dosage forms
Esomeprazole is available as delayed-release capsules in the United States or as delayed release tablets in Australia, the United Kingdom and Canada (containing esomeprazole magnesium) in strengths of 20 mg and 40 mg; and as esomeprazole sodium for intravenous injection/infusion. Oral esomeprazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic conditions of the stomach. This is achieved by formulating capsules using the multiple-unit pellet system.

Multiple unit pellet system
Esomeprazole capsules are formulated as a "multiple unit pellet system" (MUPS). Essentially, the capsule consists of extremely small enteric-coated granules (pellets) of the esomeprazole formulation inside an outer shell. When the capsule is immersed in an aqueous solution, as happens when the capsule reaches the stomach, water enters the capsule by osmosis. The contents swell from water absorption causing the shell to burst, releasing the enteric-coated granules. For most patients, the multiple-unit pellet system is of no advantage over conventional enteric-coated preparations. Patients for which the formulation is of benefit include those requiring nasogastric tube feed and those with difficulty swallowing.

Controversy3
There has been some controversy about AstraZeneca's behaviour in creating, patenting and marketing of the drug. Esomeprazole's successful predecessor omeprazole is a mixture of two mirror-imaged molecules (esomeprazole which is the S-enantiomer, and R-omeprazole); critics said that the company was trying to "evergreen" its omeprazole patent by patenting the pure esomeprazole and aggressively marketing to doctors that it is more effective than the mixture, claiming that omeprazole has no beneficial effects on the patient. In the acidic environment of the parietal cells, both esomeprazole and omeprazole are converted to the same active drug which stops the gastric acid production.

Marcia Angell, former Editor-in-Chief of the New England Journal of Medicine, spoke at Harvard Medical School to a German magazine on August 16, 2007, and said that AstraZeneca's scientists deceptively doctored their comparative studies such that the difference from omeprazole would look larger, providing a marketing advantage. Thomas A. Scully, head of the Centers for Medicare and Medicaid Services, also criticized AstraZeneca for their aggressive marketing of Nexium. At a conference of the American Medical Association he said that Astra was using the new drug to overcharge consumers and insurance companies. "You should be embarrassed if you prescribe Nexium," he claimed, "because you're screwing your patients and you're screwing the taxpayers." An AstraZeneca sponsored study showed that 40 mg of esomeprazole provided more effective acid control than 40 mg of omeprazole.

esmoperazole.Gastro-esophageal reflux (GERD) is defined as the reflux of gastric contents into the esophagus leading to reflux symptoms sufficient to affect patient well-being and/or cause complications. Population-based studies suggest that heartburn is a very common symptom in the general population with a prevalence of 10%–20% in the Western world but far from all are consulters. However, in Asia the prevalence of GERD-like symptoms is lower and has been reported to be less than 5%. When traditional endoscopy is used, GERD can be subdivided into reflux esophagitis (or erosive GERD) and endoscopy-negative reflux disease (or non-erosive reflux disease, NERD). About 50% of patients with the disease have a normal endoscopy in referral centers, but in primary care the occurrence of esophagitis is lower. Erosive GERD has been associated with complications such as esophageal strictures and Barrett’s esophagus.

The proton pump inhibitors (PPIs) are substituted benzimidazoles administered as enteric-coated tablets or capsules that pass through the stomach and are absorbed in the duodenum. They act on the proton pump molecule on the luminal surface of gastric parietal cells, resulting in inhibition of acid secretion. Esomeprazole is the latest PPI and was developed as the S-isomer of omeprazole as an improvement in its pharmacokinetic properties. PPIs are the drugs of choice in the treatment of GERD.

Esomeprazole is considered to have a somewhat higher potency in acid inhibition than other PPIs. However, previous reports have reported variable results in comparing its efficacy in healing erosive GERD, in maintenance therapy of healed erosive GERD, and in therapy of NERD compared with other PPIs. Some systematic reviews and meta-analyses have been published on the efficacy of esomeprazole in the therapy of erosive GERD. The aim of the current systematic review was to provide an update on the efficacy of esomeprazole in acid suppression, in the acute and maintenance therapy of erosive GERD and NERD as well as in improving health-related quality of life (QoL) in GERD. Comparison with other PPIs in this context was also undertaken.

Delayed release dosage form is the best formulations which are used for drugs that are destroyed in gastric fluids, or cause gastric irritation or absorbed preferentially in the intestine. Such preparations contain an alkaline core material comprising the active substance, a separating layer and enteric coating layer.1 Esomeprazole, the new S-isomer of omeprazole, is introduced to reduce gastric acid secretion more efficiently. esomeprazole exhibits significantly higher bioavailability, leading to the greater inhibition of gastric acid secretion compared to Omeprazole.2 Esomeprazole, the stereospecific S-isomer of Omeprazole, is the first proton pump inhibitor (PPI) to be developed as a single isomer for use in the treatment of acid-related diseases.3 The intragastric pH-monitoring data for esomeprazole, 20 mg once daily, show improvement over omeprazole, 20 mg once daily, but the esomeprazole, 40 mg once daily, intragastric pH data show a further convincing gain in control of gastric pH.

Early studies have shown Esomeprazole achieves 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.

Additionally, a recent crossover study demonstrated that Esomeprazole at a standard dose of 40 mg once daily provides more effective control of gastric acid at steady state than standard doses of Pantoprazole, Lansoprazole and Rabeprazole in patients with symptomatic gastroesophageal reflux disease (GERD).

AIMS AND OBJECTIVES5, 7
To formulation and evaluation of esomeprazole magnesium delayed release tablets40 mg.

Objective of present investigation is to design and evaluation of esomeprazole magnesium delayed release tablet.For the past two decades, there has been enhanced demand for more patient compliance dosage forms. As a result, the demand for their technologies has been increasing three-fold annually. Since the development cost of a new chemical entity is very high, the pharmaceutical companies are focusing on the development of new drug delivery systems for existing drug with an improved efficacy and bioavailability together with reduced dosing frequency to minimize side effects. The present experiment is to formulate and evaluate the esomeprazole magnesium delayed release of tablet by Wet granulation method.These formulations are then evaluated to check whether the drug and polymer are compatible for this we use analytical methods such as HPLC was also used to determine the percentage drug release. After the analytical results are obtained we go for punching, followed by pre compression studies, post compression studies.

LITERATURE REVIEW1,6,4
Proton-pump inhibitors (PPIs) are the drugs of choice for the treatment of gastroesophageal reflux disease (GERD). Esomeprazole is the latest PPI and was developed as the S-isomer of omeprazole as an attempt to improve its pharmacokinetic properties. Esomeprazole has been reported to have a somewhat higher potency in acid inhibition than other PPIs. Despite some controversy, data from clinical trials and meta-analyses indicate that esomeprazole 40 mg od for up to 8 weeks provided higher rates of healing of erosive GERD and a greater proportion of patients with sustained resolution of heartburn, than omeprazole 20 mg, lansoprazole 30 mg, or pantoprazole 40 mg od. Esomeprazole 20 mg od has also been shown to be more effective in maintaining healing of erosive GERD compared with lansoprazole 15 mg od or pantoprazole 20 mg od. However, it is not clear whether these statistically significant differences are of major clinical importance. Esomeprazole 20 mg od is superior to placebo for treatment of non-erosive reflux disease (NERD) but clinical trials have not shown any significant differences in efficacy between esomeprazole 20 mg and omeprazole 20 mg or pantoprazole 20 mg od. Lastly, although esomeprazole treatment in GERD has been reported to result in improvement of health-related quality of life (QoL) indices, no clinical trials have evaluated the possible differential effects of different PPIs on QoL in GERD.

Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, Global Consensus Group:17 Gastro-esophageal reflux (GERD) is defined as the reflux of gastric contents into the esophagus leading to reflux symptoms sufficient to affect patient well-being and/or cause complications.

Dent J, El-Serag HB, Wallander MA, Johansson S:18Population-based studies suggest that heartburn is a very common symptom in the general population with a prevalence of 10%–20% in the Western world but far from all are consulters. However, in Asia the prevalence of GERD-like symptoms is lower and has been reported to be less than 5% . When traditional endoscopy is used, GERD can be subdivided into reflux esophagitis (or erosive GERD) and endoscopy-negative reflux disease (or non-erosive reflux disease, NERD). About 50% of patients with the disease have a normal endoscopy in referral centers, but in primary care the occurrence of esophagitis is lower. Erosive GERD has been associated with complications such as esophageal strictures and Barrett’s esophagus.

Hatlebakk:19 The proton pump inhibitors (PPIs) are substituted benzimidazoles administered as enteric-coated tablets or capsules that pass through the stomach and are absorbed in the duodenum. They act on the proton pump molecule on the luminal surface of gastric parietal cells, resulting in inhibition of acid secretion. Esomeprazole is the latest PPI and was developed as the S-isomer of omeprazole as an improvement in its pharmacokinetic properties. PPIs are the drugs of choice in the treatment of GERD.

Esomeprazole is considered to have a somewhat higher potency in acid inhibition than other PPIs. However, previous reports have reported variable results in comparing its efficacy in healing erosive GERD, in maintenance therapy of healed erosive GERD, and in therapy of NERD compared with other PPIs. Some systematic reviews and meta-analyses have been published on the efficacy of esomeprazole in the therapy of erosive GERD

Edwards SJ, Lind T, Lundell :20 The aim of the current systematic review was to provide an update on the efficacy of esomeprazole in acid suppression, in the acute and maintenance therapy of erosive GERD and NERD as well as in improving health-related quality of life (QoL) in GERD. Comparison with other PPIs in this context was also undertaken.

Data selection
Randomized clinical trials from 2000 to 2006 comparing esomeprazole vs alternative PPIs in the treatment of GERD. The bibliography of systematic reviews and meta-analyses performed comparing the efficacy of esomeprazole vs other PPIs in GERD was searched manually for references not found by the strategy described above. Abstracts from presentations at conferences, animal studies, or data from the manufacturers not published as full-text articles were not included. A review of the literature on esomeprazole and Barrett’s esophagus or extra esophageal manifestations of GERD was beyond the scope of this article.

Acid suppression

Bell NJ, Burget D, Howden CW, Wilkinson J, Hunt RH:21 Although investigators agree that GERD is associated with dysmotility and results from an imbalance between normal defensive factors such as esophageal clearance, lower esophageal sphincter tone, and aggressive factors such as acid and pepsin, it has become increasingly clear that the key to controlling symptoms and to healing esophagitis is decreasing the duration of exposure to the acidic refluxate. The duration of esophageal exposure to a refluxate with a pH of 4.0 or less has been shown to be correlated to mucosal injury and to a reduced ability of the injured mucosa to proliferate and heal. Controlling GERD symptoms and healing erosive GERD can be best achieved by increasing the gastric pH to 4.0 or above for as long a duration as possible. Furthermore, it has been suggested that in patients with more severe grades of esophagitis, there are abnormally high levels of nocturnal acid exposure. Also, ulcerative esophagitis, esophageal strictures, and Barrett’s esophagus are characterized by high levels of supine nocturnal percentage acid reflux time, indicating that control of nocturnal acid secretion is important.

Hellstrom PM, Vitols S:16 PPIs reduce gastric acid secretion by inhibiting activity of the gastric H+/K+-ATPase. They are protonated in the acidic gastric environment to active forms, which irreversibly bind to the H+/K+-ATPase and inactivate. As PPIs block the last step in the pathway to gastric acid secretion, they are effective in both basal and stimulated acid secretion.

The effects of esomeprazole on gastric acidity

Miehlke S, Madisch A, Kirsch C, Lindner F, Kuhlisch E, Laass M, Knoth H, Morgner A, Labenz:22Recently, acid control with esomeprazole has been compared with that of other PPIs in several cross-over studies in either patients with GERD or in healthy individuals., all studies showed that esomeprazole 40 mg od was more effective in maintaining intragastric pH at 4.0 or lower compared with all other PPIs given at standard doses. The same studies demonstrated that esomeprazole 40 mg od is superior to all other PPIs at standard doses in terms of achieving higher 24-hour median intragastric pH and in terms of the number of patients achieving intragastric pH ≥4.0 for at least 12 hours per day. Nocturnal pH was measured in one of these studies, comparing esomeprazole 40 mg with pantoprazole 40 mg bd. During night-time the proportion of time with intragastric pH >4.0 was 85.4% with esomeprazole and 63.6% with pantoprazole (p = 0.0001). Nocturnal acid breakthrough, defined as intragastric pH <4.0 for at least one consecutive hour between 10 pm and 6 am, was observed in 26.7% of subjects receiving esomeprazole and in 73.3% of those receiving pantoprazole (p = 0.009). Data on the effect of esomeprazole on nocturnal pH in comparison with other PPIs are otherwise largely lacking.

In certain situations, it is reasonable to use higher than approved doses of PPIs, often divided in two doses. These include a diagnostic trial for noncardiac chest pain, empiric treatment trial for supraesophageal symptoms of GERD, cases of partial response to standard dose therapy, cases with breakthrough symptoms, GERD patients with severe esophageal dysmotility, and Barrett’s esophagus. A recent double-blind, randomized, cross-over study investigated the 24-hour intragastric pH profile of esomeprazole 40 mg bd vs 20 mg bd vs 40 mg od in 25 healthy volunteers. Esomeprazole 40 mg bd provided a mean time of 19.2 hours with intragastric pH >4.0 (80.1% of a 24-hour time period, 95% confidence interval (CI) 74.5%–85.7%) vs 14.2 hours with 40 mg od (59.2%, 95% CI 53.7%–64.7%) and 17.5 hours with 20 mg bd (73.0%, 95% CI 67.4%–78.5%). The percentage of time of a 24-hour period that pH remained >4.0 was significantly higher with the esomeprazole bd dosing regimens compared to the 40 mh od regimen during the supine (sleeping) portion of the monitoring period (83.7% (95% CI 74.9%–92.4%) for esomeprazole 40 mg bd vs 79.2% (95% CI 70.5%–87.9%) for esomeprazole 20 mg bd vs 57.9% (95% CI 49.0%–66.9%) for esomeprazole 40 mg od. Esomeprazole 40 mg bd has also been shown to be superior to pantoprazole 40 mg bd and lansoprazole 30 mg bd in maintaining intragastric pH at 4.0 or lower. These data indicate that twice-daily dosing of omeprazole provides significantly greater acid suppression than once-daily dosing and may, therefore, be a reasonable consideration for patients requiring greater acid-suppression for GERD.

The effects of esomeprazole on esophageal acidity
Two studies have assessed the effect of esomeprazole on intraesophageal pH profiles compared to other PPIs. In a double-blind, randomized, cross-over study in 35 patients with GERD symptoms, esomeprazole 40 mg od was compared with pantoprazole 40 mg od as to their effects on intraesophageal pH. At baseline the median percentage of total time with pH <4.0 was 20.1% in the esomeprazole and 21.3% in the pantoprazole group. After 7 days of repeated administration, this time was reduced to 0.9% and 2.6% respectively, and the mean within-subject differences in mean 24-hour pH values between pre- and post-treatment values were 19.2% and 18.7% respectively. The Hodges-Lehmann estimate for the mean within-subjects differences in mean 24-hour pH between pre- and post-treatment values for the two PPIs was 2.86% and the corresponding 90% CI was within the equivalence range set at ± 10% (90% CI −2.27; 7.07). In another open-label randomized study, esomeprazole 40 mg od was compared with lansoprazole 30 mg od in 30 patients with complicated GERD. Normalization of total and supine nocturnal esophageal acid exposure was achieved in 75% vs 28% (p = 0.026) and 93% vs 50% (p = 0.012) of patients in the esomeprazole and the lansoprazole group, respectively.

Erosive GERD
Randomized trials evaluating the role of esomeprazole in healing of erosive GERD or maintenance therapy of healed erosive GERD were reviewed.

Healing of erosive GERD
Gillessen A, Beil W, Modlin IM, Gatz G, Hole U
:23 Several clinical trials have compared esomeprazole with other PPIs in healing of erosive GERD.  Similar double-blind, randomized design; they included intention-to-treat analyses of healing rates, and, as a secondary endpoint, evaluation of therapy effect on GERD symptoms. Also, all studies included patients who had endoscopy-confirmed erosive GERD at baseline. Follow-up endoscopy was performed at 4 weeks and at 8 weeks, except for one study in which patients underwent first follow-up endoscopy at 4 or 6 weeks and second follow-up endoscopy at 8 or 10 weeks. Although at least two randomized studies comparing esomeprazole with each of the other PPIs were identified, no comparative studies of esomeprazole vs rabeprazole in erosive GERD could be found.

Five out of 8 studies showed that esomeprazole 40 mg od achieves better healing rates of erosive esophagitis after 4 and 8 weeks of treatment compared with omeprazole 20 mg, lansoprazole 30 mg, or pantoprazole 40 mg od. In these trials a total of 13,797 patients with erosive GERD were included. The greater efficacy of esomeprazole over omeprazole, lansoprazole, or pantoprazole was consistent when adjusted for baseline severity of esophagitis according to the Los-Angeles classification. Furthermore, all of these studies showed that esomeprazole 40 mg od is more effective than omeprazole 20 mg, lansoprazole 30 mg, or pantoprazole 40 mg od in providing resolution of GERD-associated symptoms. Interestingly, all these studies were supported by the manufacturer of esomeprazole.

Fennerty MB, Johanson JF, Hwang C, Sostek M:24
However, 3/8 comparative studies, in which a total of 1659 patients were included, showed that there were no statistically significant differences in 4- or 8-week healing rates between esomeprazole 40 mg od and omeprazole 20 mg, lansoprazole 30 mg, or pantoprazole 40 mg od. One of these studies showed that healing rates with esomeprazole were significantly higher than those with omeprazole at weeks 4 (60.8% vs 47.9%, p = 0.02) and 8 (88.4% vs 77.5%, p = 0.007) in patients with moderate to severe (Los Angeles grade C or D) erosive esophagitis at baseline but were not significantly different for patients with mild (Los Angeles grade A or B) erosive esophagitis. These studies reported similar efficacy of esomeprazole compared to omeprazole, lansoprazole, or pantoprazole in GERD-related symptoms. One out of three of these studies was supported by the manufacturer of esomeprazole, showing some benefits of esomeprazole for patients with more severe esophagitis. The other two were supported by the manufacturers of lansoprazole, showing no difference between lansoprazole and esomeprazole, and by the manufacturer of pantoprazole, showing no difference between pantoprazole and esomeprazole. Equivalence of esomeprazole 40 mg and pantoprazole 40 mg od in treating GERD-related symptoms in patients with erosive GERD was also reported in a double-blind randomized study in which 217 patients with esophagitis were included. In this trial no follow-up endoscopic evaluation was performed and, thus, no data on healing rates could be calculated.

Helicobacter pyloriinfection has been shown to elevate the intragastric pH achieved by PPIs. In a study with pantoprazole, it has also been proposed that this increased efficacy of PPIs in H. pylori-infected patients may be associated with improved symptom control and more rapid healing of the esophagitis. Furthermore, H. pylori eradication has been reported to be a predictor of failure in the treatment of GERD with omeprazole 20 mg od but this finding was not reproduced in another study. A recent review on this topic concluded that at present it is unclear whether H. pylori should be eradicated in GERD patients. In all of the studies reviewed here H. pylori status was evaluated in the patients included. A significant effect of H. pylori infection was shown in one of the studies comparing esomeprazole 40 mg with pantoprazole 40 mg od with H. pylori-negative patients experiencing lower healing rates than in H. pylori-positive patients. No difference was observed in the efficacy of esomeprazole between H. pylori-negative and H. pylori-positive GERD patients in the studies where this was investigated. However, it should be taken into consideration that the effect of H. pylori status on healing of erosive esophagitis was only a secondary endpoint in these studies.

Five meta-analyses on the effect of different PPIs were identified, three of which focused on the effect of different PPIs (including esomeprazole) in healing erosive esophagitis. In a recent meta-analysis comparing the efficacy of PPIs in short-term use, two studies evaluating healing rates with esomeprazole 40 mg vs omeprazole 20 mg od were included. The authors concluded that esomeprazole was superior to omeprazole (relative risk, 1.18; 95% CI 1.14–1.23). Another meta-analysis comparing the efficacy of PPIs in the management of GERD and peptic ulcer disease included three studies comparing esomeprazole 40 mg od with either omeprazole 20 mg od or lansoprazole 30 mg od. The authors concluded that esomeprazole was superior to both the PPIs with which it was compared in healing of erosive esophagitis and in speed of symptom relief. In a meta-analysis of the efficacy of PPIs in acute treatment of reflux esophagitis, three studies comparing esomeprazole 40 mg with omeprazole 20 mg od were included. Two of these were taken into consideration in the current review as well but also used data on file from the manufacturer of esomeprazole. They concluded that esomeprazole demonstrated higher healing rates than omeprazole at 4 weeks (relative risk 1.14; 95% CI 1.10–1.18) and 8 weeks (relative risk 1.08: 95% CI 1.05, 1.10). Another meta-analysis by the same investigators comparing esomeprazole with other PPIs for the healing of erosive esophagitis included all the randomized trials summarized in. The authors concluded that esomeprazole demonstrated higher healing rates compared with standard dose PPIs at 4 weeks (relative risk 0.92; 95% CI 0.90,0.94; p < 0.00001) and at 8 weeks (relative risk 0.95; 95% CI 0.94.0.97; p < 0.00001). Lastly, a meta-analysis of randomized clinical trials comparing esomeprazole with other PPIs in healing erosive esophagitis included 7 out of the 8 randomized studies summarized in as well as data from the manufacturer of esomeprazole included in the product information (esomeprazole vs omeprazole 20 mg od) and a study published in abstract form (esomeprazole 40 mg vs omeprazole 40 mg od). The last two mentioned studies have not been published and could therefore potentially create a bias in this context. In comparing healing rates of erosive esophagitis at 4 and 8 weeks, the authors found a 10% (relative risk 1.10; 95% CI 1.05–1.15) and 5% (relative risk 1.05; 95% CI 1.02–1.08) relative increase in the probability of healing, respectively, with esomeprazole vs alternative PPIs. Also, the authors found that esomeprazole conferred an 8% (relative risk 1.08; 95% CI 1.05–1.11) relative increase in the probability of GERD symptom relief at 4 weeks. In this meta-analysis, the calculated numbers needed to treat (NNT) by Los Angeles grade of erosive esophagitis (grades A–D) were 50, 33, 14, and 8. This suggests that the benefit of esomeprazole might be important in more severe erosive disease as indicated by the decreasing NNTs with increasing Los Angeles grade. It is at the present time not entirely clear if these statistically significant differences are clinically significant.

Maintenance therapy of healed erosive GERD
Moayyedi P,Talley NJ
:25GERD usually relapses once drug therapy is discontinued, with about 80% having erosive GERD relapse after 6–12 months. Thus, many patients with GERD require long-term, possibly life-long, PPI therapy. However, a recent study on discontinuation of PPIs in long-term users found that 20% of GERD patients were able to discontinue their PPIs without development of symptoms. Two double-blind, randomized studies have shown superiority of esomeprazole 40 mg, 20 mg, or 10 mg od to placebo in maintenance therapy of healed erosive GERD. The primary endpoint of both studies was endoscopically maintained healing 6 months after inclusion. In one of these, 375 patients with endoscopically healed esophagitis were randomized to receive esomeprazole 40 mg, 20 mg, 10 mg, or placebo od. After 6 months, significantly (p < 0.001) more patients remained healed with esomeprazole 40 mg (87.9%), 20 mg (78.7%), or 10 mg (54.2%) than with placebo (29.1%) at endoscopy. In the other placebo-controlled study, 318 patients with endoscopically confirmed healing of erosive GERD were randomized to receive esomeprazole 40 mg, 20 mg, 10 mg, or placebo od. After 6 months, healing was maintained in 93.6% of patients treated with esomeprazole 40 mg, 93.2% treated with esomeprazole 20 mg, and 57.1% treated with esomeprazole 10 mg; p < 0.001 vs 29.1% treated with placebo. Both of these studies reported that patients treated with esomeprazole had less severe heartburn than those treated with placebo. However, symptom maintenance data from these studies should be interpreted with caution as only those patients who maintained healing at the previous visit continued to the subsequent visits during the 6-month study period.

Three clinical trials have compared esomeprazole with other PPIs as a maintenance therapy in GERD patients with healed erosive esophagitis. had a similar double-blind, randomized design and they included intention-to-treat analyses of endoscopy and symptom maintenance rates. Also, all three studies included patients who had endoscopy-confirmed healing of their erosive GERD at baseline and follow-up endoscopy was performed at 3 and 6 months. The primary endpoint was endoscopic and symptom maintenance at 6 months. Secondary endpoints were separate endoscopic and symptom maintenance rates at 6 months. No comparative studies of esomeprazole vs omeprazole or rabeprazole in maintenance therapy of healed erosive GERD could be found.

All three studies showed superiority of esomeprazole 20 mg to lansoprazole 15 mg or pantoprazole 20 mg od in the primary endpoint. Furthermore, these studies showed superiority of esomeprazole 20 mg to lansoprazole 15 mg (endoscopic maintenance rate: 84% vs 76%, p < 0.0002; 84.5% vs 75.9%, p < 0.0001 or pantoprazole 20 mg (88.1% vs 76.6%, p < 0.0001 od in maintaining endoscopic remission at 6 months. As regards maintenance of symptomatic remission only, one of these studies reported that esomeprazole 20 mg was more effective than lansoprazole 15 mg od (symptomatic remission maintenance rate: 78% vs 71%, p < 0.001 and another that esomeprazole 20 mg was more effective than pantoprazole 20 mg od (94.5% vs 90.5%, p < 0.0001. However, the third study could not show any statistically significant difference between esomeprazole and lansoprazole 15 mg od in maintaining symptomatic remission (76.4% vs 73%, p > 0.05). Lastly, studies comparing esomeprazole with lansoprazole showed that esomeprazole had consistently higher remission maintenance rates when patients were stratified according to initial severity of erosive GERD. However, the study comparing esomeprazole 20 mg with pantoprazole 20 mg od reported that although esomeprazole had higher remission maintenance remission rates in patients with erosive GERD Los Angeles A–C, differences were not significant in patients with Los Angeles D.

Although these data indicate superiority of esomeprazole compared with lansoprazole or pantoprazole in maintenance therapy of healed erosive GERD, there is a need for new clinical trials comparing esomeprazole with omeprazole and rabeprazole before definite conclusions can be drawn.

Non-erosive GERD
Patients with NERD may exhibit similar symptom severity to those with erosive GERD but as many as half of them may have a normal esophageal pH testing demonstrating pH values within the normal range of healthy subjects. Although PPIs have been shown to be effective in patients with NERD, symptom improvement is lower compared with patients with erosive GERD .Three papers on clinical trials comparing continuous esomeprazole with other PPIs as therapy in NERD patients were identified. They all had a similar double-blind, randomized design, patients had a normal baseline endoscopy, intention-to-treat analysis of data was performed, and study duration was 4 weeks. No study comparing continuous esomeprazole with lansoprazole therapy in NERD was identified.

In one of these papers, three studies were reported comparing A (n = 1282) esomeprazole 40 mg, esomeprazole 20 mg, or omeprazole 20 mg od; B (n = 693) esomeprazole 40 mg or omeprazole 20 mg od; and C (n = 670) esomeprazole 20 mg or omeprazole 20 mg od. Resolution of heartburn at 4 weeks (no heartburn symptoms during the last 7 days) was achieved in similar proportions of patients in each treatment arm in study A (esomeprazole 40 mg, 56.7%; esomeprazole 20 mg, 60.5%; omeprazole 20 mg, 58.1%), study B (esomeprazole 40 mg 70.3%; omeprazole 20 mg 67.9%), and study C (esomeprazole 20 mg 61.9%; omeprazole 20 mg, 59.6%).

MATERIALS AND METHODOLOGY

Materials
Esomeprazole magnesium dihydrate, hydroxypropyl methyl cellulose phthalate and cellulose acetate phthalate and other additives were procured commercially. All the reagents and solvents used were of analytical gradeIn vitro analysis of the prepared tablets was carried out as per the requirements of enteric coated tablets as specified in official pharmacopoeia.

Drug excipient interaction study
Active drug blended with individual excipients were taken in 1:1 ratio, filled in closed vials and placed in

stability chambers at 35°C } 2°C / 60% } 5% RH for a period of 4 weeks. Samples were analyzed by IR

Table no: 4.1

Master Formula: For 2000 tablets:

Sr no

Ingredients

Quantity/Unit[mg]

Quantity/ Batch[gm]

1

Esomeprazole magnesium dihydrate

43.5

0.087

2

Anhydrous lactose

52.1

0.105

3

Starch

13.9

0.027

4

HPC

2

0.004

5

CCS

3

0.006

6

Magnesium carbonate[light]

15

0.030

7

Meglumine

3

0.006

8

Povidone

6.5

0.013

9

IPA

54.95

0.110

Extra-granular ingredients:

10

Magnesium stearate

2

0.004

11

CCS

2.5

0.005

12

Crospovidone

5

0.010

13

Colloidal anhydrous silica

1.5

0.003

core tablet weight              

150.00

0.300

MANUFACTURING INSTRUCTIONS:

Sifting:

1. Check the integrity of sieve before use.

2. Sift
Esomeprazole Magnesium Dihydrate
Anhydrous Lactose
Starch
Hydroxy Propyl Cellulose
Crosscarmellose Sodium
Magnesium Carbonate [light]
Meglumine
Through sieve no #40 on vibratory sifter and collect in clean separate prelabeled double poly bag.

3. Check the integrity of the sieve after use.

GRANULATION AND DRYING:

Dry mixing:

  1. Load the sifted material in to RMG.
  2. Mix the material for 20 min with mixer at slow speed.

Preparation of binder solution:
Stir isopropyl alcohol in a pre labeled paste vessel to form a vortex without drawing air in to the liquid. Add steadily povidone to the vortex to get clear solution.

Wet mixing:

  1. Add prepared binder solution in to the RMG over a period of 2-3 minutes while mixing at slow speed.
  2. Mix the wet mass 1-2 minutes mixer at high speed. if  required  add extra quantity of iso      propyl  alcohol, while mixing with mixer at slow speed with regular interval checking for suitable granules formation.

Note: the granulation end point is judged   completed when a portion of wet mass taken in hand and observed.

End point by physical observation: confirmed/not confirmed.

3. Transfer the wet granular mass into a clean pre-labeled suitable container and transfer to drying area.

Drying:

1.   Transfer the wet mass in ti bowl of fbd

2.   Air- dry the wet mass until there is no perceptible smell of isopropyl alcohol to get LOD NMT 4.0% w/w at 105°C , by auto mode using IR moisture analyzer.

General & safety precautions:

  • Follow secondary gowning  procedure as per SOP
  • Snood for entire face covering
  • Hand gloves
  • Nose mask for respiratory protection (3M mask)
  • Air stream helmets
  • Goggles for eye protection.

Equipment safety precautions (Cadmach compression m/c 10th station):

Check & ensure the following points before starting the activity:

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