ISSN: 2455-281X

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ASIO Journal of Pharmaceutical & Herbal Medicines Research (ASIO-JPHMR)

Volume 3, Issue 1, 2017, 01-06

Doi: 10.2016-19146535; doi link: http://doi-ds.org/doilink/03.2017-19982562/

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PROTON PUMP INHIBITOR: A MAJOR TOOL TOWARDS GASTRO ESOPHAGEAL

REFLUX DISEASE

Pritam Roy

Bengal College of Pharmaceutical Sciences and Research, Durgapur, West Bengal, India.

ARTICLE INFO ABSTRACT

Review Article History Received: 17th January, 2017 Accepted: 25th March, 2017

Corresponding Author: † Pritam Roy

Department of Pharmaceutical

Science, Bengal College of

Pharmaceutical Sciences and

Research, Durgapur, West

Bengal, India.

Enteric coatings prevent the release of medication before it reaches the small intestine. The enteric coated polymers remain unionized at low pH, and therefore remain insoluble. But as the pH increases in the GIT, the acidic functional groups are capable of ionization, and the polymer swells or becomes soluble in the intestinal fluid (above pH 5.5). Proton pump inhibitors reduce the production of acid in the stomach. This leaves little acid in the stomach juice so that if stomach juice backs up into the esophagus, it is less irritating. This allows the esophagus to heal. Proton pump inhibitors also work to help symptoms of GERD. Proton pump inhibitors act by irreversibly blocking the hydrogen/ potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase or more commonly, the gastric proton pump) of the gastric parietal cells. The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion.

Keywords: enteric coating, gastric parital cells, gastric lumen.

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1. INTRODUCTION

A tablet is a pharmaceutical dosage form comprising a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose. The excipients can include glidants (flow aids), diluents, binders or granulating agents and lubricants to ensure efficient tableting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive. A polymer coating is often applied to enhance the tablet's appearance or to make the tablet smoother and easier to swallow and to control the release rate of the active ingredient, to make it more resistant to the environment (extending its shelf life) [1].

Another systematic that can be used to differentiate drug delivery systems is according to the way the drug is released. Broadly, one can differentiate as follows [1-3]:

Immediate release – drug is released immediately after administration Modified release – drug release only occurs some time after the administration or for a prolonged period of time or to a specific target in the body. Modified release systems can be further classified as- – Delayed release: drug is released only at some point after the initial administration.

– Extended release: prolongs the release to reduce dosing frequency.

Whilst immediate-release dosage forms are designed to give a fast onset of drug action, modifications in drug release are often desirable to increase the stability, safety and efficacy of the drug, to improve the therapeutic outcome of the drug treatment and/or to increase patient compliance and convenience of administration.

Figure 1: Drug level versus time profile showing the relationship between sustained release and conventional release

Pritam Roy / ASIO Journal of Pharmaceutical & Herbal Medicines Research (ASIO-JPHMR), 2017, 3(1): 01-06

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Modified release

Dosage forms can be designed to modify the release of the drug over a given time or after the dosage form reaches the required location.

Delayed release

Delayed-release dosage forms can be defined as systems which are formulated to release the active ingredient at a time other than immediately after administration. Delayed release from oral dosage forms can control where the drug is released, e.g. when the dosage form reaches the small intestine (enteric-coated dosage forms) or the colon (colon-specific dosage forms).

Delayed-release systems can be used to protect the drug from degradation in the low pH environment of the stomach or to protect the stomach from irritation by the drug. In these cases drug release should be delayed until the dosage form has reached the small intestine. Often polymers are used to achieve this aim. The dosage form (for example, a tablet or the granules before tableting) can be coated with a suitable polymer. The polymer dissolves as a function of pH, so when the dosage forms travel from the low-pH environment of the stomach to the higher-pH environment of the small intestine, the polymer coat dissolves and the drug can be released. Once this occurs, the release is again immediate and the resulting plasma concentration versus time curve is similar to the one for immediate release dosage forms [1-3].

Extended release

Extended-release systems allow for the drug to be released over prolonged time periods. By extending the release profile of a drug, the frequency of dosing can be reduced. For immediate-release dosage forms the time interval the plasma concentration is in the therapeutic range of the drug can be quite short. Therefore frequent dosing, with its associated compliance problems, is required. This is especially an issue in chronic diseases when patients need to take the medicine for prolonged periods of time, often for the rest of their life. Extended release can be achieved using sustained- or controlled-release dosage forms [1-2].

TABLET COATING

Coating is a process by which an essentially dry, outer layer of coating material is applied to the surface of a dosage form in order to confer specific benefits that broadly ranges from facilitating product identification to modifying the drug release from the dosage form [1-3]. Coating may be applied to multiple range of oral solid dosage form, including tablets, capsules, multi-particulates and drug crystals. When coating composition is applied to a batch of tablets in a coating pan, the tablet surfaces become covered with a tacky polymeric film. Before the tablet surface dries, the applied coating changes from a sticky liquid to tacky semisolid and eventually to a non-sticky dry surface pans. The entire coating process is conducted in a series of mechanically operated acorn-shaped coating pans of galvanized iron stainless steel or copper. The smaller pans are used for experimental, developmental, and pilot plant operations, the larger pans for industrial production [2-3].

Primary components involved in tablet coating [2-3]

Tablet properties Coating process Coating equipments Parameters of the coating process Facility and ancillary equipments Automation in coating processes

Coating Process Design & Control [1-7]

The coating process is usually a batch operating task consisting of the following phases: Identification of batch and Recipe selection (film or sugar coating) Loading/Dispensing (accurate dosing of all required raw materials) Pre-Warming Spraying (Both application and rolling are carried out simultaneously) Drying/Curing Cooling Unloading

Coating equipment

A modern tablet coating system combines several components: A coating pan A spraying system with Compressed air system A air handling unit A dust collector A PLC embedded with a programmer

Advantages of tablet coating

To control the release of drug from the tablet. To protect the drug from the gastric environment of the stomach with acid resistant enteric coating. To incorporate another drug/formula adjuvant in coating to avoid chemical incompatibility and sequential drug release. Coatings are necessary for tablets for giving a smoother finish, thus making larger tablets easier to swallow and also to mask the unpleasant taste.

Disadvantages of tablet coating

Limitations of sugar coating such as relatively high cost, long coating time and high bulk have led to the use of other coating materials. However the process of coating is tedious and time-consuming and it requires the expertise of highly skilled technician. Various solvent systems are required. May cause environment harm. Problem of disposal issue may also arise.

ENTERIC COATING [3-5] The word “enteric” indicates “small intestine; therefore enteric coatings prevent release of medication before it reaches the small intestine. The enteric coated polymers remain unionize at low pH, and therefore remain insoluble. But as the pH increases in the GIT, the acidic functional groups are capable of ionization, and the polymer swells or becomes soluble in the intestinal fluid (above pH 5.5).

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Materials used for enteric coatings include Methacrylic acid copolymers, Cellulose acetate phthalate (CAP), Cellulose acetate trimellitate (CAT), polyvinyl acetate phthalate (PVAP) and Hydroxypropyl methyl cellulose phthalate (HPMCP), fatty acids, waxes, shellac, plastics and plant fibers.

There are four reasons for putting such a coating on a tablet:

Protection of active pharmaceutical ingredients, from the acidic environment of the stomach (e.g. enzymes and certain antibiotics). To prevent gastric distress or nausea from a drug due to irritation (e.g. sodium salicylate, sodium aminosalicylate, Diclofenac). For the delivery of drugs that are optimally absorbed in the small intestine to their primary absorption site in their most concentrated form. To provide a delayed-release component for repeat action. Required for minimizing first pass metabolism of drugs The choice of the polymer and the thickness of the coated layer are critical to control the pH solubility profile and for proper/desired release of the medicaments of the enteric coated dosage form [8].

Ideal properties of Enteric Coating material

Resistance to gastric fluids Susceptible/permeable to intestinal fluid Compatibility with most coating solution components and the drug substrate Formation of continuous film Nontoxic, cheap and ease of application Ability to be readily printed [3-5].

Limitations

The reliability and delivery efficiency is doubtful due to presence of wide range of pH values and different enzymes present in the GI tract which is encountered by the drugs before reaching the target site [9, 10].

PROTON PUMP INHIBITORS (PPI) [11]

Proton pump inhibitors reduce the production of acid in the stomach. This leaves little acid in the stomach juice so that if stomach juice backs up into the esophagus, it is less irritating. This allows the esophagus to heal. Proton pump inhibitors are usually used: To prevent GERD symptoms. To heal inflammation of the esophagus (esophagitis). To prevent esophagitis from coming back after the esophagus is healed (maintenance therapy) and to prevent complications of gastroesophageal reflux disease (GERD). People with Barrett's esophagus are often treated with proton pump inhibitors. Proton pump inhibitors also work to help symptoms of GERD. But the number of people who take PPIs and who have no GERD symptoms is usually less than 5 out of 10 people. That means that of the people taking PPIs, more than 5 out of 10 still have some GERD symptoms. Proton pump inhibitors work best when they are taken 30 minutes before your first meal (for example, breakfast).

Mechanism of action of PPIs

Proton pump inhibitors act by irreversibly blocking the hydrogen/ potassium adenosine tri phosphatase enzyme system (the H+/K+ ATPase, or, more commonly, the gastric proton pump) of the gastric parietal cells. The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion. Targeting the terminal step in acid production, as well as the irreversible nature of the inhibition, results in a class of drugs that are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%. Decreasing the acid in the stomach can aid the healing of duodenal ulcers and reduce the pain from indigestion and heartburn. Stomach acids are needed however to digest proteins, vitamin B12, calcium, and other nutrients. Too little stomach acid causes the condition hypochlorhydria. The PPIs are given in an inactive form, which is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like the parietal cell canaliculus) with acidic environments. In an acid environment, the inactive drug is protonated and rearranges into its active form. As described before, the active form will covalently and irreversibly bind to the gastric proton pump, deactivating it [12].

The gastric H,K-ATPase is the primary target for the treatment of acid-related diseases. Proton pump inhibitors (PPIs) are weak bases composed of two moieties, a substituted pyridine with a primary pKa of about 4.0, which allows selective accumulation in the secretory canaliculus of the parietal cell, and a benzimidazole with a second pKa of about 1.0. PPIs are acid-activated prodrugs that convert to sulfenic acids or sulfenamides that react covalently with one or more cysteines accessible from the luminal surface of the ATPase. Because of covalent binding, their inhibitory effects last much longer than their plasma half-life. However, the short half-life of the drug in the blood and the requirement for acid activation impair their efficacy in acid suppression, particularly at night. PPIs with longer half-life promise to improve acid suppression. All PPIs give excellent healing of peptic ulcers and produce good results in reflux esophagitis. PPIs combined with antibiotics eradicate Helicobacter pylori [13].

Figure 2: Main stimulators (green) and inhibitors (red) involved in acid secretion leading to either activation or inhibition of the proton pump (H+, K+ ATPase).

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2. REVIEW OF LITERATURE

Ghebre Sellassie, John Twist et al. [14], developed an enteric coating formulation & process of tablets primarily composed of a highly water soluble, organic acid. Dissolution results revealed that all enteric coat tablets inhibited drug release for two hours in 0.1N HCL & tablets without a seal coat failed the USP disintegration test.

Mitesh P. Modi and Abin Abraham [15], prepared enteric coated time release press-coated tablets (ETP) by coating enteric polymer on timed release press-coated tablets containing diltiazem HCl as model drug. The results of the in vitro dissolution test in pH 1.2 & pH 6.8 showed both acid resistance and timed release.

Haitham F. Mostafa et al. [16], assessed Pantoprazole sodium sesquihydrate (PSS) coated tablets in 2 local markets relative to the innovator product (pantozol). Uniformity of dosage unit, disintegration and in vitro drug release were determined using United States pharmacopeia for delayed release tablets. The similarity factor (f2) was assessed using the FDA recommended approach (f2 similarity factor).

Murat Turkoglu, et al. [17], fluidized-bed manufactured enteric-coated omeprazole pellets were compressed into tablets. It was found that enteric-coated omeprazole pellets could be compressed into quickly disintegrating tablets using microcrystalline cellulose granules as the pressure absorbing matrix. The ANN, using the multilayer perceptron model, predicted that there was a positive correlation between tablet crushing strength and microcrystalline cellulose concentration.

R. Pohlmann et al. [18], studied the gastro resistant microparticles containing sodium pantoprazole, stability studies and in vivo antiulcer activity. These loaded microparticles are prepared by spray drying in pilot scale using eudragit s 100 as polymer. Studies showed that microparticles had acceptable stability under accelerated condition and were efficient in protecting the stomach against ulceration caused by ethanol.

Nykanen P et al. [19], studied about enteric coated tablets can be made from enteric coated matrix granules and drug release targeted to the colon. The author reports that citric acid retarded the drug release in in-vitro studies, the effect of acid was more if added in tablet matrix & the effect was weak if added in granule cores.

P. Suresh Kumar et al. [20], the main purpose of this work was to develop delayed release stable tablet formulation of Rabeprazole sodium by direct compression and wet granulation method and enteric coating of tablets. All enteric coated tablets are delayed release tablets but all delayed release tablets are not enteric coated tablets. The present work aims to avoid degradation of drug in acidic environment of stomach.

R.P. Raffin et al. [21], prepared and characterized gastro-resistant pantoprazole-loaded microparticles using an O/O emulsification/solvent evaporation technique. DSC and IR analyses showed that pantoprazole was physically and molecularly dispersed in the polymer.

S. Bozdag et al. [22], studied that Omeprazole, a substituted Benzimidazole, is a specific and non-

competitive inhibitor of the enzyme H +/K+-ATPase, known as the gastric proton pump. It is unstable in conditions of low pH and must be protected from the effects of gastric acid when given orally; thus, it is administered in the form of enteric-coated dosage forms.

Mohamed Nasr et al. [23], the objective of this study was to evaluate the bioequivalence of two commonly prescribed Enteric Coated Formulations of 20 mg Omeprazole, Omez(test) and Losec (reference). In-vitro studies were adopted to determine and compare the dissolution behaviour of both products.

Ann D et al. [24], studied about the influence of formulation and compression parameters on the properties of tablets, containing enteric coated pellets & on the integrity of the enteric polymer of the individual pellets after compression.

Anroop B Nair et al. [25], studied the formulation and evaluation of enteric coated tablet of proton pump inhibitor for esomeprazole trihydrate with different polymers like Eudragit L-30 D-55, HPMC Phthalate, celluloseacetate Phthalate. The tablet showed good integrity, desirable for enteric coated tablets. Dissolution studies showed better dissolution for Methacrylic polymer than cellulose polymers.

A. Mukharya, S.A. et al. [26], studied the Stable and Bioequivalent Formulation Development of Highly Acid Labile Proton Pump Inhibitor. The main challenge in the formulation of Rabeprazole tablets was the degradation of Rabeprazole upon exposure to acidic environment. Thus, to prevent exposure of Rabeprazole in gastric acidic environment enteric coating was done and to prevent interaction between Rabeprazole and acidic enteric coating material, seal coating was done over the core tablet. They have reported that the formulation did not release Rabeprazole in gastric acidic pH and released 91% of Rabeprazole in 45 minutes at intestinal alkaline pH.

J Williams et al. [27], studied that on a randomised single blind crossover study in children with cystic fibrosis and pancreatic insufficiency, two enteric coated microsphere preparations of pancreatin were compared on a capsule for capsule basis, by measuring the coefficient of fat absorption, nitrogen excretion, weight change, and symptom scores after four weeks treatment with each preparation. Thirty nine subjects were randomly allocated to receive pancrease followed by Creon or vice versa. Each individual subject received the same number of capsules per day in each study period. Data from 27 children (Pancrease/Creon, n=13 and Creon/Pancrease, n=14) were suitable for analysis. Results showed no significant differences between the two preparations in any variable studied. We conclude that there is no significant difference between Pancrease and Creon when compared on a capsule for capsule basis.

K. L. Senthil Kumar et al. [28], enteric coated tablets of Didanosine were developed to get resistance from Gastric juice when it presents in stomach, because Didanosine is incompatible with gastric juice. The tablets are prepared by using wet granulation technique using polymer Ethyl Cellulose STD 100 FP, Ethyl Cellulose MED 70 P, Ethyl Cellulose Med 50 P and other excipients are Povidone Micro Crystalline Cellulose in different ratios. These

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polymers and excipients are used for sustained the drug release.

Dhruba Sankar Goswami et al. [29], the objective of the study was to formulate and optimize an Enteric Coated Sustained Release Mucoadhesive Tablet of Metronidazole. Metronidazole is an antibacterial, widely recommended in the treatment of Amoebiasis infections, Diarrhoea, Trichomoniasis infections, and Giardiasis infections.

Devraj and D. C. Bhatt [30], studied on enteric coated sustained timed-release tablets of Metronidazole. The present article deals with an oral dosage form proposed for the attainment of timed release drug delivery of Metronidazole. Metronidazole containing matrix tablets coated with 3, 4, 5 & 6% w/v Cellulose Acetate Phthalate in Acetone examined for applicability as timed release tablets with a predetermined lag time of 4-5 hrs.

Abebe Endale et al. [31], the purpose of this research was to improve the hygroscopicity and poor flow properties of the crude dry extract of the seeds of Glinus lotoides and improve the disintegration time of the core-tablets for enteric coated formulation.

Rabia Bushra et al. [32], developed Enteric coating of ibuprofen tablets (200 mg) using an aqueous dispersion system. Ibuprofen is a propionic acid derivative that belongs to the class NSAIDs. Major adverse reactions associated with Ibuprofen are related to GIT and include peptic and mucosal ulcers, dyspepsia and severe gastric pain and bleeding, that results in excessive treatment failure. The goal of this study was to develop enteric coated ibuprofen tablets in order to avoid gastric mucosal irritation, diffusion of drug across mucosal lining and to let active ingredient be absorbed easily in small intestine.

CONCLUSION

Coating may be applied to multiple range of oral solid dosage forms, including tablets, capsules, multiparticulates and drug crystals. Enteric coatings prevent release of medication before it reaches the small intestine. Materials used for enteric coatings include Methacrylic acid copolymers, Cellulose acetate phthalate (CAP), Cellulose acetate trimellitate (CAT), polyvinyl acetate phthalate (PVAP) and Hydroxypropyl methyl cellulose phthalate (HPMCP), fatty acids, waxes, shellac, plastics and plant fibers. Proton pump inhibitors are usually used to prevent GERD symptoms, to heal inflammation of the esophagus (esophagitis) to prevent esophagitis from coming back after the esophagus is healed (maintenance therapy) and to prevent complications of gastroesophageal reflux disease (GERD). Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or, more commonly, the gastric proton pump) of the gastric parietal cells.

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