Proton Pump Inhibitors, also known as PPIs, belong to a group of antisecretory drugs. Since their introduction to pharmacotherapy, PPIs have been widely used in the treatment of numerous diseases manifested by excessive secretion of gastric acid. There are still unmet needs regarding their availability for patients of all age groups. Their poor stability hinders the development of formulations in which dose can be easily adjusted.
Proton Pump Inhibitors, also known as PPIs, belong to a group of antisecretory drugs. Since their introduction to pharmacotherapy, PPIs have been widely used in the treatment of numerous diseases manifested by excessive secretion of gastric acid. Despite that, there are still unmet needs regarding their availability for patients of all age groups. Their poor stability hinders the development of formulations in which dose can be easily adjusted.
Proton pump inhibitors have been found to be very effective in suppressing gastric acid secretion. They share the same mechanism of action, although there are slight differences in their chemical structure [1]. PPIs inhibit the activity of the enzyme H+/K+-ATPase, also named gastric proton pump, located in the parietal cells of the stomach. Proton pump inhibitors are inactive compounds (often simply but incorrectly called ‘prodrugs’), which require activation in the low pH of parietal cells, to suppress the activity of the proton pump. Therefore, to avoid premature activation in the stomach after oral administration, they must be protected from gastric acid, e.g., with enteric coating [2].
PPIs are administered by two different routes: oral or intravenous. Currently manufactured dosage forms for oral administration include enteric-coated capsules, enteric coated tablets, multiple-unit pellet system (MUPS), and suspensions with microparticulates. For intravenous administration, PPIs are available as lyophilized powders for reconstitution [25]. There are a large number of manufactured brand and generic products, among which are:
In vivo antiulcer activity (rats) | |||||
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Pantoprazole | In vitro |
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In vitro |
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Pantoprazole + Aceclofenac | In vitro In vivo (rats) |
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In vivo PK and bioavailability studies (rabbits) | |||||
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Omeprazole + clarithromycin | In vitro |
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Pantoprazole | In vitro |
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In vitro |
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In vitro |
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In vitro |
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In vitro |
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In vitro |
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In vitro In vivo antiulcer activity (rats) |
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In vitro In vivo antiulcer activity (rats) |
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In vitro In vivo antiulcer activity (rats) |
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In vitro In vivo antiulcer activity (rats) |
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In vitro |
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In vitro |
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In vivo bioavailability study (dogs) |
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In vitro In vivo antiulcer activity (rats) |
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Pantoprazole | |||||
In vitro |
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Pellets | Omeprazole | In vitro In vivo PK and gastro-resistance studies (dogs/rats) |
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In vitro In vivo PK and bioequivalence studies (rabbits) |
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In vitro In silico (ANN, modelling tablet properties) |
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In vitro |
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In vitro |
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Pantoprazole | In vitro |
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Lansoprazole | In vitro |
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In vitro |
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In vitro |
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In vitro In vivo PK study (dogs) |
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In vitro |
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In vitro In vivo bioavailability study (dogs) |
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Rabeprazole | In vitro |
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In vitro |
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In vitro |
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Esomeprazole | In vitro In vivo PK study (rats) IVIVC |
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In vitro In silico (ANN, coating process) |
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Tablets | Omeprazole | In vitro |
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In vitro |
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In vitro |
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Omeprazole + domperidone | In vitro |
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Pantoprazole | In vitro |
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In vitro In vivo antiulcer activity (rats) |
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In vitro |
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In vitro |
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In vitro |
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Lansoprazole | In vitro |
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In vitro |
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In vitro In vivo absorption studies (dogs), disintegration time in the mouth (human) |
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In vitro | |||||
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In vitro | |||||
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Rabeprazole | In vitro In vivo pharmacokinetic and antiulcer activity studies (rats) |
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Hydrogel formulations | Pantoprazole | In vitro |
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In vitro |
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In vitro In vivo studies on hydrogel gastro-retention (mice) |
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Rabeprazole | In vitro |
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Mucoadhesive tablets | Omeprazole | In vitro |
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In vitro In vivo studies on absorption from the oral cavity and tablets adhesion to the oral mucosa (human) |
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In vitro In vivo pharmacokinetic studies (hamsters) |
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In vitro In vivo pharmacokinetic studies (hamster), mucoadhesive force measurement (human) |
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In vitro |
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It is worth mentioning, that proton pump inhibitors can be administered to adult and pediatric patients who require enteral nutrition via a feeding tube. However, factors such as the risk of clogging the tube or adhering the drug to the walls of the tube or the possibility of drug degradation should be carefully considered before administration . The most convenient dosage forms for application via feeding tube are those composed of pellets or granules that can be easily dispersed in water or other vehicles. These include tablets or capsules containing delayed-release pellets, as well as granules for oral suspensions [28]. PPIs should be administered via feeding tube only in accordance with the manufacturer’s recommendations.
Proton pump inhibitors have been marketed worldwide for more than 30 years [29][30]. At this time, many pharmaceutical solutions have been proposed to improve their acceptability, stability, safety, and efficacy. The most popular route of administration of PPIs is oral, which is the most common for all medicinal products. Formulations with PPIs include numerous dosage forms, starting from simple enteric-coated tablets or pellets encapsulated in hard gelatine capsules, through the other novel form of tablets, and ending with many different forms of micro- or nanoparticulates. There have also been some approaches to the administration of PPIs through alternative routes of administration, such as transdermal or rectal.
The detailed information on PPIs’ formulations described in the literature have been collected in table 1.
Formulation | PPI | Development Stage | Description | ||
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Nanoparticles | Omeprazole | In vitro In vivo antiulcer activity (rats) |
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In vitro | |||||
Lansoprazole | In vitro |
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In vitro |
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In vitro |
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In vitro |
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Lansoprazole + curcumin | In vitro |
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Esomeprazole | In vitro Ex vivo permeability study In vivo PK and PD studies (rats) |
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Microparticles | Omeprazole | In vitro In vivo PK study (rabbits) |
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In vitro |
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In vitro |
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In vitro |
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In vitro |
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Omeprazole + piperine | |||||
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In vitro | |||||
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Lansoprazole | In vitro In vivo PK and antiulcer activity studies (rats) |
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In vitro |
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In vitro |
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In vitro |
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In vitro |
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In vitro |
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In vitro |
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In vitro |
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Rabeprazole | In vitro In vivo antiulcer activity (rats) |
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In vitro |
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In vitro In vivo floating study (rabbits) |
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Rabeprazole + amoxicillin | In vitro In vivo antiulcer activity and radiographic study (rats) |
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Esomeprazole | In vitro |
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Minitablets | Omeprazole | In vitro |
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In vivo (human) | |||||
Clinical trials | |||||
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In vivo (human) |
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In vivo bioequivalence studies (human) |
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In vitro In vivo (human) |
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In vitro |
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Rabeprazole | In vitro In vivo PK studies (beagle dogs) |
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In vitro |
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In vitro |
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In vitro |
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In vitro |
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In vitro |
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Esomeprazole | In vitro |
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In vitro |
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In vitro Ex vivo permeation studies (porcine mucosa) In vivo pharmacokinetics studies (rats) |
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In vitro |
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In vitro |
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Dexlansoprazole | In vitro |
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Tenatoprazole | In vitro |
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In vitro |
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Ilaprazole | In vitro |
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In vitro |
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Fixed-dose combination products | Esomeprazole + naproxen | In vitro |
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Bilayer tablets | Lansoprazole + amoxycillin | In vitro |
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Esomeprazole + aceclofenac | In vitro |
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Esomeprazole + clarithromycin | In vitro |
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Esomeprazole + levosulpiride | In vitro |
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Floating tablets | Pantoprazole | In vitro |
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In vitro |
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Lansoprazole | In vitro |
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Pantoprazole | |||||
In vitro | |||||
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Oral liquid suspensions | Omeprazole | In vitro |
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In vitro |
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In vitro In vivo preliminary toxicity and antiulcer activity studies (mice) |
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Transdermal delivery | Omeprazole | In vivo PK study (human) |
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Lansoprazole | Ex vivo penetration study (pigs) In vivo PK study (rats) |
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Rabeprazole | Ex vivo penetration study (snake) |
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Suppositories | Omeprazole | In vitro |
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Clinical trial (efficacy, PK) |
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Intravenous formulations | Omeprazole | In vitro |
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In vitro |
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