Current Advances in Technology of Proton Pump Inhibitor Formulations
Vilas Sonagre1*, Piyush Lulay2, Meka Lingam3, Srinivas Arutla3, Sachi Patel3 and Meghana Kulkarni4
1Sharad Pawar College of Pharmacy Wanadongri, Hingna Road, Nagpur-441110,
2Vels College of Pharmacy, Pallavaram, Chennai 600117,
3Dr. Reddy’s Laboratories, Hyderabad 500016,
4SVKM's NMIMS University, Mumbai 400056.
Corresponding author: vsonagre@rediffmail.com
ABSTRACT:
Since the identification of gastro erosive reflux disease and peptic ulcer in the early 1900’s, the line of treatment of the disease has evolved reasonably. The antisecretory agents used in the treatment regime have developed, beginning with the introduction of cimetidine in the mid-1970s to proton pump inhibitor (PPI) omeprazole in 1989 and subsequently dexlansoprazole dual delayed release in 2009. This development was done to address the unmet needs of patients suffering from severe esophagitis and nocturnal acid breakthrough (NAB). The available PPI formulations which had short plasma elimination half life of less than 2 hours could not inhibit the proton pumps synthesized in the nighttime hours. The inadequacy in symptom control and high prevalence of NAB in patients with more severe gastro esophageal disease still prevailed after medication. This was identified as the unmet needs of PPI formulations. Although novel formulations, including immediate release omeprazole may offer some advantages over existing formulations, it does not address many of the potential unmet needs of patients with these disorders. However, these needs are addressed by dual delayed release technology which delivers dose in a pulsatile manner and provides acid suppression for prolonged period of time.
KEYWORDS: Proton pump inhibitors; Dexlansoprazole; Unmet needs; Nocturnal acid breakthrough.
INTRODUCTION:
History of GERD:
Over a period of time gastro esophageal reflux disease (GERD) and peptic ulcer (PU) have evolved from rarely diagnosed to most frequently diagnosed diseases1. This increase is due to the sedentary lifestyles and improper eating habits. GERD is a clinical condition characterized by persistent retrograde movement of gastric contents into the esophagus that typically manifests as burning retrosternal pain and/or regurgitation (i.e., at least two heartburn episodes/week and/or complications). These symptoms are often mistaken with cardiac chest pain, prompting large numbers of emergency department visits2. Atypical symptoms of GERD have been described and include chronic cough, vocal hoarseness (laryngitis), chronic pharyngitis, waterbrash and throat pain3. The complications that are developed due to excessive exposures of esophagus to gastric contents are esophagitis, stricture, Barret’s esophagus (replacement of squamous epithelia by columnar metaplasia) and esophageal carcinoma. On endoscopic investigating, approximately one-third of patients with typical GERD symptoms, present evidence of mucosal damage.
The majority, however (two-thirds) have no abnormalities on endoscopy and are referred to as non-erosive reflux disease patients (NERD)4. It was observed that the lower esophageal sphincter (LES) prevented the reflux of gastric material back in to esophagus, thereby offering pleasant security from nauseating odors and highly disagreeable taste. Today the term GERD includes NERD as well as reflux esophagitis (as a complication of reflux disease), and it is generally accepted that the majority of patients presenting with reflux disease do not have endoscopically evident esophageal erosion5.
An increasing number of patients with Barrett's oesophagus are being identified and current medical therapy offers little to alter the natural history of this disease. It is known that the frequency of nocturnal reflux and heartburn give raise to potential complications such as severe erosive esophagitis, nocturnal aspiration which produce greater likelihood of Barrett's oesophagus. The awareness of sleep disorders and their association with GERD, the overall decrease in quality-of-life is seen with nocturnal reflux6. Gastric acid secretion is a physiologic process is controlled by a number of redundant second messenger pathways activated as a result of the binding of gastrin, acetylcholine, histamine, and prostaglandins to the specific receptors on the basolateral surface of parietal cells. The stimulatory effect of acetylcholine and gastrin is mediated by an increase in cytosolic calcium, whereas that of histamine is mediated by activation of adenylate cyclase and generation of cyclic AMP (cAMP). Strong potentiating between histamine and either gastrin or acetylcholine reflects post receptor interaction between the distinct pathways as well as the ability of acetylcholine and gastrin to release histamine from mucosal enterochromaffinlike (ECL) cells. The acid secretion, however, is the stimulation of the proton pump (H+, K+-ATPase) to secrete hydrogen ions into the gastric lumen in exchange for potassium ions (Fig. 1)7.
The ability of the parietal cell to secrete acid is restored when new proton pumps are converted from their inactive status in the tubulovesicle to their active form resulting in their location to the canalicular surface. Not all pumps are active at any given time, and it is thought that a single dose of a PPI will inhibit only 70–80% of active pumps. Thus, PPIs do not completely inhibit acid secretion. Because proton pumps are always in the process of regeneration, daily or more frequent dosing may be needed to achieve optimal antisecretory effect. Full restoration of antisecretory effect takes about 96 hours in healthy subjects. This acid secretion in unregulated state leads to GERD, nocturnal acid breakthrough, erosive esophagitis and esophageal carcinoma6.
Fig. 1. Main stimulatory (in green) and inhibitory (in brown) mediators of acid secretion together with their G protein-coupled receptors on the parietal cell. After mediatorreceptor coupling, intracellular pathways (i.e. cAMP formation or Ca2+ release) are activated or inhibited, leading to activation/inhibition of the proton pump (H+/K+-ATPase). Gi denotes inhibitory G proteins and AC adenylcyclase.
Nocturnal acid breakthrough (NAB):
NAB is the presence of gastric acid pH level below 4 for at least 1 hour during the night time. NAB is not synonymous with nighttime heartburn. Heartburn is a symptom, most frequently described as burning sensation behind the sternum that radiates up towards the throat. In contrast it is an exclusively gastric pH phenomenon. Normal gastric acid secretions follow a circadian rhythm. Immediately after meals, intragastric pH is elevated by the buffering effect of the food, but the meals also stimulate acid secretion, causing the intragastric pH to drop later (Fig.2). Gastric acid secretion is most pronounced in evening and early night, resulting in a surge of gastric acidity around 2 AM, with acid secretion decreasing towards the morning. Prolonged nocturnal esophageal acid exposure has been shown to contribute to the development of erosive esophagitis 8.
This phenomenon of NAB suggested that the medication available were unable to target it and provide relief.
Fig.2. Nocturnal acid breakthrough demonstrated on a 24- hr pH tracing.
Proton pump inhibitors (PPI):
The line of treatment of GERD and PU started with histamine -2 receptors antagonist (H2RA) cimetidine in 1977 and then shifted to more efficient class of drugs, proton pump inhibitors. The first PPI, omeprazole was available in 1989, followed by lansoprazole (1995), rabeprazole (1999), esomeprazole (2001), pantoprazole (2002) and dexlansoprazole (2009).The PPIs are considered for the effective and safe in treating GERD, peptic ulcer and other acid related disorders. They have influenced the management of acid-peptic disorders dramatically over the last few years. This development suggests that the initial PPI formulations had some unmet needs that were required to be addressed to make them clinically more efficient9.
PPIs are all substituted benzimidazole derivatives. They function as pro-drugs, accumulating within the parietal cell canaliculus where they are acid-catalysed conversion of the pro-drug to a tetracyclicplanar sulphenamide occurs. The sulphenamide binds covalently to key cysteine groups on proton pump to cause prolonged inhibition of gastric acid secretion. These agents selectively and irreversibly inhibit the gastric hydrogen/potassium adenosine triphosphate part of the proton pump that performs the final step on the acid secretory process9.
All PPIs undergo acid accumulation and acid activation, and inhibit the H+K+-ATPase via covalent binding. There are two pKa of the PPIs. The pKa for the first protonation leads to accumulation of PPIs in the parietal cell, pKa1, of PPIs ranges from 3.8 to 4.5. The selective accumulation of PPIs in the parietal cell occurs where the pH is below 4 relies on pKa1 of the pyridine ring. Substituents on a pyridine ring affect its tendency to undergo protonation and hence the level of protonation is at a given pH. The substituents on the pyridine ring which influence the pKa1 are similar among the PPIs10.
There is no large range in pKa1 values, but the differences in the pKa1 value among PPIs may have an effect on their activity. For example, lansoprazole and rabeprazole have the same benzimidazole group, which differs structurally in the substituents on their pyridine rings. In such a situation, a higher pKa1 (rabeprazole, 4.53) is associated with greater nucleophilicity of the pyridine moiety and hence faster conversion to the active form of the drug. However, when the benzimidazole moieties differ, the second step – protonation of the benzimidazole (or imidazopyridine in the case of tenatoprazole) – determines the rate of acid activation of a PPI in the parietal cell. The pKa value for this step (pKa2) is ≤1, such that the reaction occurs rapidly in the acidic space of the parietal cell or on the surface of the active, acid-producing H+K+-ATPase (pH ∼0.8). A comparison of lansoprazole and pantoprazole serves to illustrate the influence of pKa2 on the activation rate, as these two PPIs have a similar pKa1 (3.83). The pKa2 of lansoprazole (0.62) is higher than that of pantoprazole (0.11). The pKa1 does influence PPI activation and the maximum activation rate of current PPIs generally dependent on the second protonation, pKa2, particularly in acidic conditions. The selective accumulation of PPIs in the parietal cell (pKa1) and the requirement for acid activation (pKa2) ensure that covalent modification is specific to the active H+K+-ATPase in the highly acidic conditions generated when gastric acid secretion is stimulated. The pKa2, as the main determinant of the rate of activation, is also thought to affect the stability of inhibition of gastric acid secretion10.
Proton pump inhibitors inhibit the gastric H+/K+-ATPase via covalent binding to cysteine residues of the proton pump and cause prolonged inhibition of gastric acid secretion. All proton pump inhibitors must undergo acid accumulation in the parietal cell through protonation, followed by activation mediated by a second protonation at the active secretory canaliculus of the parietal cell10.
The ease with which these steps occur with different proton pump inhibitors underlies the differences in their rates of activation, which in turn influence the location of covalent binding and the stability of inhibition. Slow activation is associated with binding to a cysteine residue involved in proton transport that is located deep in the membrane. However, this is inaccessible to the endogenous reducing agents responsible for restoring H+/K+-ATPase activity, favouring a longer duration of gastric acid inhibition. Pantoprazole and tenatoprazole, a novel proton pump inhibitor which has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors, are activated more slowly than other proton pump inhibitors but their inhibition is resistant to reversal. In addition, tenatoprazole has a greatly extended plasma half-life in comparison with all other proton pump inhibitors10.
Pharmacokinetics of PPIs:
The maximal plasma drug concentration of PPIs varies widely depending on the rate of passage in the gastrointestinal tract, release of drug and intraduodenal pH11. PPIs are slow to achieve steady state inhibition of gastric acid and take almost 3 days to achieve maximum acid suppression10. The area under the plasma concentration time curve (AUC) does correlate well with acid suppression, and the area under the same curves for omeprazole 20mg and rabeprazole 20 mg or 40 mg are significantly lower than for pantoprazole 20mg or lansoprazole 30 mg. The PPIs have similar short plasma half-lives of elimination at approximately 1-2 hours and are therefore unlikely to accumulate even when clearance is significantly reduced. This short plasma half life allows rapid restoration of gastric acid secretion of uninhibited proton pumps. However, the duration of acid inhibition is relatively long (48-72 h) because of the irreversible binding of the sulphanilamide to the H+K+-ATPase. Rabeprazole has a shorter duration of action as it can dissociate to a greater extent than the other drugs (Table 1)11.
The oral bioavailibilites (BA) of the proton pump inhibitors differ significantly. The oral BA of omeprazole is initially low at approximately 35-40 % but increases to about 65 % on repeated dosing. This may reflect improved drug absorption associated with increase in gastric pH and reduced breakdown of the acid-labile drug in stomach. In contrast, pantoprazole has constant BA of 77 %, independent of dose. Lansoprazole also has a constant high BA of 80-91 % at therapeutic doses, although studies have shown that BA is reduced at doses lower than 20 mg/day. All PPIs are highly protein bound (>95 %), rapidly metabolized in the liver and have negligible renal clearance11, 12.
Table1. Comparison of the Pharmacokinetics of the PPIs
Pharmacokinetic parameters |
Omeprazole 20 mg |
Pantoprazole 40 mg |
Lansoprazole 30 mg |
Rabeprazole 20 mg |
Dexlansoprazole MR 60 mg |
AUC (µg.h/ml) |
0.2-1.2 |
2-5 |
1.7-5 |
0.8 |
6.533 |
Cmax (µg/ml) |
0.08-8 |
1.1-3.3 |
0.6-1.2 |
0.41 |
1.29 |
Tmax (h) |
1-3 |
2-4 |
1.3-2.2 |
3.1 |
5.03 |
t1/2 (h) |
0.6-1 |
0.9-1.9 |
0.9-1.6 |
1 |
1.49 |
Cl (L.h/kg) |
0.45 |
0.08-0.13 |
0.2-0.28 |
0.5 |
NA |
Vd (L/kg) |
0.31-0.34 |
0.13-0.17 |
0.30-0.46 |
NA |
NA |
BA (%) |
35-65 |
Constant |
Constant |
NA |
NA |
Protein binding% |
95 |
98 |
97-99 |
95-98 |
NA |
Dose linearity |
Non-linear |
Linear |
Linear |
Linear |
NA |
AUC, area under the curve concentration; Tmax ,time to maximum serum concentration; t1/2,elimination half life; Cl, drug clearance; Vd, apparent volume of distribution; BA, bioavailability; Cmax, maximum serum concentration. NA, Not applicable
Table 2. Comparison of General Effectiveness of PPIs
Generic Name and Dose Per Day |
Brand Name
|
Symptom Relief at 4 Weeks, Average Percentage of Patients (Range) % |
Esophageal Healing at 8 Weeks, Average Percentage of Patients (Range) % |
Relapse Prevention % |
Esomeprazole 20 mg |
Nexium |
NA |
87 (84-91) |
87 |
Esomeprazole 40 mg |
Nexium |
73 (65-82) |
90 (88-92) |
93 |
Lansoprazole 30 mg |
Prevacid |
70 (61-80) |
86 (83-90) |
91 |
Omeprazole 20 mg |
Prilosec |
65 (54-76) |
85 (81-88) |
86-92 |
Pantoprazole 20 mg |
Protonix |
77 (70-84) |
77 (65-88) |
86-92 |
Pantoprazole 40 mg |
Protonix |
72 (62-83) |
89 (86 to 92) |
78 |
Rabeprazole 20 mg |
Aciphex |
69 (52-86) |
82 (76-89) |
89 |
NA: Not Applicable
Efficacy of PPIs:
PPIs have proved to be clinically more efficient than the H2RA, which have a relatively short duration of action and depending on the individual agent and whether the patient is in a fed or fasting state, suppress acid for approximately 4–8 h13. A further shortcoming is that tolerance to standard H2-RAs generally develops within 2 weeks of repeated administration, resulting in a decline in acid suppression14. Tolerance to ranitidine, which develops within 5 days of continuous administration, is not explained by altered drug pharmacokinetics15. This tolerance to H2-RAs appears evident even when they are combined with twice daily PPI therapy in order to better control nocturnal acid secretion16. Even twice daily PPIs may not adequately control intragastric acidity during the nighttime hours. In a significant proportion of both healthy subjects and GERD patients NAB does occur17 has suggested the use of a bedtime dose of H2-RAs to improve acid control18. However, long-term use of these agents led to development of tolerance so that their effect on NAB is lessened with prolonged therapy (Table 2) 16, 19.
Safety of PPIs:
Taking into account all the available risk/benefit data, PPI use is strongly justified when clinically indicated. Potential adverse effects of this class of drugs are rare, largely dose-related and, in some instances, time-dependent. These compounds should therefore be used in those clinical conditions, where their benefit is proven (e.g. GERD) and given at the minimum effective dose. The duration of treatment will depend on the underlying acid-related disease and on the ability of PPIs to alter its natural history 20.
PPIs are often used to treat disorders associated with gastric hypersecretion in children, despite the lack of pediatric formulations and of formal indications. They are highly effective in the treatment of ulcers, GERD and hypersecretory diseases. They provide a high level of gastric acid inhibition with few adverse effects. The primary limitation to PPI use in children is related to the lack of comparative experimentation in terms of risks/costs/benefits versus anti-H2, particularly with regard to esophagitis reflux-related and H. pylori-negative peptic disease. The secondary limitation is associated with the definition of the safety profile in long-term therapies 21.
The long-term use of PPIs seems to have a high margin of safety but there have been potential risks after long-term use. Several studies have investigated the potential effect of PPI therapy on vitamin B12 absorption but a firm association is not established. There are relatively little data to indicate that PPI therapy causes iron deficiency. However, care should be taken in prescribing PPIs to patients who are already iron depleted, and adequate supplementation with iron should be considered. The studies examining the impact of PPIs on calcium absorption are limited by several factors, including the use of indirect methods to assess calcium and few have suggested an association with increased risk of fracture22.
In the geriatric patients due to their advanced age and multiple chronic diseases place they are at risk for polypharmacy and adverse drug reactions, clinicians should carefully determine whether PPI use is indicated and appropriate. In addition, clinicians should consider discontinuation of PPIs if the medication is no longer indicated23.
GERD is a very common complaint in pregnant females. This is due to decrease in lower esophageal sphincter tone induced by the hormonal changes of pregnancy, coupled with an increase in intra-abdominal pressure from and enlarging uterus and displaced abdominal organs24. The pregnant females with GERD are treated with life style modification, antacids, H2RA blockers and finally PPIs.
Acid control with PPIs:
Acid control by the PPIs is considered efficient if it provides, controls and maintains pH>4. A randomized, open label, comparative five way cross over study of esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg, and rabeprazole 20 mg in 34 helicobacter pylori- negative patients was performed. All five PPIs investigated provided gastric acid suppression (pH>4) for at least 10 hours. Esomeprazole suppressed acid production and maintained pH greater than 4 for a significantly greater time compared to other PPIs on day 5(Table 3) 25. However, the current available formulation in market are efficient to provide pH >4, but not for 24 hours, which is the unmet need of conventional PPIs. This maintenance of pH>4 should be evaluated for the day 1 post dosing.
Table3. Comparison of PPIs and their pH Suppressing Time
Standard Dose |
Time for maintaining pH greater than 4 after post dose in GERD |
Esomeprazole 40 mg once a day |
14.0 hrs |
Lansoprazole 30 mg once a day |
11.5 hrs |
Omeprazole 20 mg once a day |
11.8 hrs |
Pantoprazole 40 mg once a day |
10.1 hrs |
Rabeprazole 20 mg once a day |
12.1 hrs |
Unmet needs of PPIs:
A PPI can inhibit only actively secreting pump molecules at the surface of the secretory canaliculus of the parietal cell. Any pumps with covalently bound PPI will remain inactive unless inhibition is reversed by a cellular reducing agent such as glutathione. The pumps are newly synthesized or activated after the plasma concentration of the PPI has fallen below threshold. A short plasma half-life, thus allows rapid restoration of gastric acid secretion by uninhibited, restored or new pumps, such that the extension of PPI half-life is an obvious goal. A PPI with a longer half-life should induce more prolonged blockade of proton pumps and is likely to bring about greater suppression of gastric acid secretion. There is a general misconception that the PPIs are destroyed in gastric acid. If PPIs are exposed to acid prior to their delivery to the parietal cells, protonation occurs and the active moiety is formed. This in turn reduces the absorption and bioavailability12. To protect the PPI, formulations are made with several enteric coatings which protect it in stomach lumen26. This in turn provides a lag time until the drug is absorbed in the body. The absorption of PPIs usually takes place from duodenum onwards. If there is an urgent requirement of using PPIs, this delay in absorption is inconvenient for the patient. However, these delayed release formulations do not address the requirement of maintaining pH>4 for about 24 hrs with once dosing.
The new advances to satisfy the above mentioned need are the immediate release omeprazole formulation and Dexlansoprazole MR dual delayed release (DDR).
Immediate release formulations:
In 2004, FDA approved the immediate releasing (IR) formulation of omeprazole named Zegerid. The formulation includes unique properties that contribute to its immediate release profile and distinguish it from the delayed-release PPIs. There is absence of an enteric coating and the presence of 1680 mg of sodium bicarbonate (20 mEq acid neutralizing capacity), whose primary role is to protect the omeprazole from gastric acid degradation27.
The comparison between the PPIs to prove their efficiency in maintaining pH>4 shows us that IR omeprazole produces a reasonable advantage over other formulations (Table 4)28. So this formulation proves its potential for treating NAB, but also explains that the patient has to consume the capsule at the advent of NAB that is at around 2AM and in turn disturb the night sleep and cause inconvenience due to multiple dosing.
Extended release formulations:
The pharmaceutical companies are eyeing to make extended release (ER) formulations of PPIs to satisfy the clinical needs and benefit the patient. The ER formulations will be potential patron in the line of treatment of GERD and NAB. Since all the PPIs have a short half life, it does not block the proton pumps that are regenerated after the PPI attains subtherapeutic level, hence the idea of another dose to combat these regenerating proton pumps arise. This leads to multiple dosing of the formulation.
However, Dexlansoprazole MR that is a DDR formulation, developed by Takeda Pharmaceuticals solved these issues. The DDR formulation employed in delivering dexlansprazole is a formulation available in two dosage strengths, 30 and 60 mg, containing two types of enteric coated pellets. The design is in such a way that one part of pellets which are coated with a pH-dependant polymer provides the drug at proximal end of the intestine and the second part does it at the distal end. The second part is release at about 4 to 5 hours after capsule ingestion29. This gives two distinct release profiles of the formulation (Fig.3)30. The AUC of dexlansoprazole MR is 2-5 times higher and so the total exposure of drug to the parietal cells is more than other PPIs. This proves it clinical efficacy in the treatment on GERD.
The novel rabeprazole ER formulations were also developed which were prototype and contained single rabeprazole enteric coated tablet and multiple rabeprazole pulsatile release tablets. The rabeprazole enteric coated tablet was designed to release the drug in the proximal intestinal region and the pulsatile release tablets at the distal end. It produced prolonged acid suppression for 24 hours for once daily treatment for 5 days and demonstrated its advantage over esomeprazole 40 mg and rabeprazole 20 mg31.
Another novel PPI which provided prolonged suppression of gastric acidity was AGN 201904-Z. It is a new drug that is slowly absorbing and acid stable pro-PPI which rapidly gets converted to omeprazole in systemic circulation. It produced significantly greater acid suppression than esomeprazole. This drug is designed to provide chemically metered absorption of the pro-PPI throughout the length of small intestine in contrast to the rapid absorption of omeprazole in the upper part of gut32.
Table4. Comparison of Proton Pump Inhibitors in maintaining pH >4
Parameters |
IR- Omeprazole (Zegerid®) |
Esomeprazole (Nexium®) |
Lansoprazole (Prevacid®) |
Raberazole (Aciphex®) |
|||
40 mg |
20 mg |
40 mg |
20 mg |
30 mg |
15 mg |
20 mg |
|
Time in gastric pH>4 (hours) |
18.6 |
12.2 |
16.8 |
12.7 |
15.8 |
11.7 |
14.4 |
Percentage of time with gastric pH>4 |
77% |
51% |
70% |
53% |
66% |
49% |
60% |
Median gastric pH |
5.2 |
4.2 |
4.9* |
4.1* |
4.9* |
4.0* |
3.5 |
* Mean
Fig.3. Mean plasma dexlansoprazole concentration- time profile following oral administration of Dexilant on day 5 in healthy subjects
Advantage over conventional PPI formulations:
These ER formulations maintains prolonged plasma concentrations and releases drug over a longer period than the conventional delayed release PPIs and thereby requires high daily doses. The amount of drug released is sufficient to achieve therapeutic blood levels, as evidenced by elevated intragastric pH and percentage of time intragastric pH>4 over 24 hours33. Among the other ER formulations, the current technology in market, DDR, prolongs the mean residence time (MRT) of dexlansoprazole. The MRT of dexlansoprazole is 5.6 to 6.4 hours compared to 2.8 to 3.2 hours for single release lansoprazole demonstrating that the DDR formulation extends the duration of drug exposure by prolonging the mean absorption time34. It was also found that dexlansoprazole exhibited time-independent pharmacokinetics and the exposure on the day five was similar to day one33.
Thus the efficiency of dexlansoprazole MR produces more advantage over the conventional PPI formulations. The formulation fulfills the unmet needs of night time dosing, reduces multiple dosing and proves to provide extended gastric acid suppression.
CONCLUSION:
There is now a well documented evidence of the various PPI formulations with proven clinical efficacy. The key challenges of PPI therapy were to address GERD and prolonged acid suppression. Few targeted patient’s needs were addressed, but not for all. It is indicated that the DDR technology can prove clinically advantageous and make the PPI therapies more affordable. The pharmaceutical companies can use this technology as a delivery platform and attribute it to other PPIs to provide with generic formulated products and facilitate patient compliance
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Received on 30.09.2011 Modified on 20.10.2011
Accepted on 27.10.2011 © RJPT All right reserved
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