This systematic study aimed to critically review the use of omeprazole in the Pediatric population. This drug is well known and widely used but remains difficult to use in this population due to formulation and administration issues. On the one hand, this study aimed to provide an overview of the physicochemical, pharmacokinetic and pharmacological aspects of omeprazole and the issues related to extemporaneously prepared formulations, especially instability issues. On the other hand, a review of published Pediatric formulations containing this active pharmaceutical ingredient (API) was also carried out to explore how researchers have tried to solve these problems and whether they have considered stability issues. In conclusion, it seemed clear from our investigation that the necessary gastro-resistance is not always accounted for in formulations and that stability is highly dependent on specific factors, such as pH and humidity.

Keywords: Omeprazole, Pediatrics, Pharmacokinetics, Pharmacology and Stability

INTRODUCTION

Currently, children are still considered to be therapeutic orphans due to the lack of pharmaceutical options that are adapted to the needs of pediatric patients. These patients constitute a heteromorphic population that is characterized by constant changes throughout the maturation process. Therefore, a large number of pediatric pathologies are treated with drugs that have not been studied for their potential therapeutic use in the pediatric population. However, in recent decades, there has been a great amount of interest in the development of oral medicines for pediatric use, both for rare and common diseases [1,2]. According to the European Medicines Agency (EMA) [3,4], pediatric investigation plans should include measures to adapt the formulation of the medicinal product to be age-appropriate for the different subsets of the pediatric population. There are several aspects to consider when deciding whether the pharmaceutical design of a pediatric medicinal product is appropriate, including the following:

• The minimum age, relevant developmental physiology and age characteristics of children in the target age groups
• The condition to be treated and its characteristics in the pediatric population
• The appropriate dose (considering the pharmacodynamic response curve and/or therapeutic margin) and dosage regimen (i.e., dose calculation, dose titration, dose flexibility, etc.)
• The maximum duration of therapy and dosing frequency
• The setting where the product is likely to be used (e.g., hospitals, community pharmacies, etc.)
• The stability of the compound formulations

In addition, all studies on pediatric medicinal products must be in line with the WHO criteria, as well as the WHO’s “Make medicines child-sized” campaign and 2009 “Better Medicines for Children” initiative, to ensure that medicines for children are appropriate, safe and effective [5,6]. At the same time, the EMA also emphasizes the development of pediatric medicines that meet the abovementioned requirements, which can be found in the pediatric regulation section of the EMA website [7] and pediatric investigation plans [8].

Typically, the lack of marketed pediatric medicines affects hospital pharmacy services, where magistral formulations are used to meet the needs of special patients (i.e., pediatric, geriatric or swallowing-impaired patients). Regarding pediatric patients, oral liquid formulations are often the most suitable preparations because they allow for safe and easy dosage adjustment (according to body weight or body surface area, etc.) and avoid the need to swallow tablets or capsules. Obviously, liquid preparations that are formulated in hospital pharmacies must also be tested for quality and stability as medicinal and commercially available products. However, in practice, reliance is placed on official published information (i.e., information from the National Formulary, drug regulatory agencies, web-based bibliographies, etc.) because hospital centers do not have the capacity or resources to carry out stability or exhaustive quality controls as in the pharmaceutical industry. Thus, this lack of stability and quality studies limits the use of many medicines in special patients [2,9].

According to data provided by the Hospital Materno Infantil del Vall de Hebrón (Barcelona, Spain), omeprazole is one of the most widely used active pharmaceutical ingredients in magistral formulations for the treatment of gastrointestinal diseases in the pediatric population, a fact that has been corroborated by other international hospitals, including hospitals in Thailand [10], Morocco [11] and France [12]. In addition, omeprazole formulations that are used for pediatric patients must meet the quality and safety requirements of the EMA, FDA and WHO [2,9] which is very difficult due to the chemical instability problems that are associated with omeprazole. For this reason, it is important to develop pediatric formulations of omeprazole that address these stability issues.

This study explored the characteristics of omeprazole that limit the development of adequate pediatric formulations. Additionally, a review of published pediatric formulations containing this API (from PubMed, SciFinderⁿ, Scopus and Web of Science) was conducted to see how researchers have tried to overcome the issues with omeprazole and how they have demonstrated its stability [5-8]. Finally, it was clear from the review of published studies that the administration of omeprazole in children is an important issue; although there have been studies on administration in pediatric patients, the appropriate doses are not well established and the drug information does not provide recommendations for use in the pediatric population [9].

PHARMACOLOGICAL CHARACTERISTICS AND MECHANISM OF ACTION OF OMEPRAZOLE

Omeprazole is a proton pump inhibitor (PPI) and is one of the most widely used antisecretory drugs due to its good efficacy and the lack of significant adverse effects [13,14]. It selectively and irreversibly inhibits the H⁺/K⁺-ATPase or proton pump, which is the final step in the acid secretory pathway. Its inhibitory capacity is independent from the stimulus that triggers acid production, i.e., it reduces both basal and stimulated gastric secretion [15-17].

Omeprazole is a substituted benzyl imidazole derivative and a racemic mixture of two enantiomers. It should be noted that omeprazole is a prodrug that is activated in acidic media. As a lipophilic weak base (pKa of 4,0), it is electrically uncharged and highly lipid soluble at approximately pH 7, which is why it can easily cross cell membranes [15,18]. It accumulates selectively in the acidic environments of the canaliculi of stimulated parietal cells. Once it reaches parietal cells, it crosses the cell membranes via passive diffusion. In the secretory canaliculi of these cells, omeprazole is in its active achiral form and is exposed to a pH of less than 2,0 (about 1). It is ionized through a protonation process, which transforms it into a sulphonamide (i.e., a stable molecule at acidic pH levels and not lipophilic). Its positive charge prevents it from crossing parietal cell membranes, leading to the accumulation and concentration of the drug in the canaliculi [18]. This accumulation is essential as it allows for a prolonged therapeutic effect despite the drug having a short plasma half-life (Figure 1) [15]. This sulphonamide reacts by forming covalent bonds with the sulfhydryl (thiol) groups of the cysteine radicals on the extracellular surfaces of its alpha-subunits and the H⁺/K⁺-ATPase, thereby irreversibly inhibiting the activity of this enzyme. Therefore, the reactivation of the secretory activity is only possible after the resynthesize of the inhibited enzyme, which has a half-life of about 18 h [18]. This need for de novo enzyme genesis enables a prolonged inhibitory effect on acid secretion [15,16,19].

Omeprazole was originally approved by the FDA in 1989 for the treatment of gastric acid-related disorders, such as gastro-esophageal reflux, peptic ulcer disease and other conditions that are characterized by excessive gastric acid secretion. Omeprazole is generally effective and well tolerated, which has promoted its common use in children and adults. It was the first clinically useful drug of its kind and its formulation was followed by the formulation of many other proton pump inhibitor drugs [13,19,21]. The most commonly used PPI drugs are omeprazole, lansoprazole, pantoprazole (in sodium salt form), rabeprazole and esomeprazole (which is an optical isomer of omeprazole) [13,17]. Omeprazole is a white or off-white crystalline powder, which melts at 155 ºC with decomposition, has a weak basic character and is freely soluble in lipids, ethanol and methanol, slightly soluble in acetone and isopropanol and very slightly soluble in water. Its stability is pH-dependent as it degrades rapidly in acidic media but remains practically stable in alkaline conditions [19,22-24].

PHARMACOKINETIC CHARACTERISTICS OF OMEPRAZOLE

In adults, omeprazole is administered orally in the form of capsules that contain enteric-coated (pH-sensitive) mini-granules or pellets in order to prevent ionization by acidic gastric environments and promote absorption in the duodenum (which increases its bioavailability by up to 50%). There are also buffered release forms of omeprazole and preparations for intravenous administration [13,15].

The absorption of omeprazole depends on the different formulations and therefore, its oral bioavailability is also varied. It should be noted that its bioavailability is the same whether administered orally or via a nasogastric tube [18,25].

After absorption in the small intestine, omeprazole passes from the blood into the parietal cells of the stomach and then into the canaliculi, where it exerts its therapeutic action [15]. It is metabolized in the liver by the cytochrome P450 enzyme complex, which is an enzyme that is absent in approximately 3% of white people and 20% of Asian people, hence why there may be more cases of intoxication when using the drug in the usual doses [15,26]. The CYP2C19 and CYP3A4 isoenzymes are responsible for most of its metabolism; therefore, changes in the maturation of this enzyme complex may affect the pharmacokinetic parameters of omeprazole. Cytochrome P450 activity is low at birth, reaches adult levels in early life and then increases and surpasses adult levels during childhood before recovering to adult levels after puberty [16]. Parietal cell immaturity and achlorhydria during the first 20-30 months of life are also maturation-dependent factors for the two isoenzymes that may prevent the transformation of omeprazole into its active form and, consequently, its accumulation in the intracellular canaliculi of parietal cells. Gastric emptying and intestinal transit are other age-varying factors that may affect the bioavailability of omeprazole in the pediatric population [16,27,28]. Thus, in order to determine the most appropriate dose for different age groups, safety and efficacy studies must be conducted.

As a consequence of the particular mechanism of action of omeprazole, the level of acid inhibition that is produced does not correlate with the plasma concentration but instead with the area under the plasma concentration versus time curve. This is because omeprazole forms covalent bonds with the proton pump stimulating enzyme, which means that the therapeutic effect of a single dose of the drug is maintained for more than 24 h even though its plasma half-life is 60 min [24]. The administration of food delays absorption and decreases the area under the plasma concentration versus time curve. Therefore, omeprazole should be administered on an empty stomach, preferably first thing in the morning, regardless of the time elapsed between the administration of the drug and the subsequent ingestion of food [13,18].

The initial bioavailability of omeprazole is low, so its maximum effect is not reached with the first dose but instead after 5-7 days of repeated administration. This gradual build-up could be due to the fact that gastric secretion is inhibited after the first few doses, leading to a decrease in the gastric degradation of successive doses. Alternatively, it may be due to reduced first-pass metabolism. Omeprazole is more than 90% bound to plasma proteins (mainly albumin and α1-acid glycoprotein), so its volume of distribution is low (0,3-0,4 L/kg). It can cross the blood–brain and placental barriers [13,15].

CLINICAL TRIALS ON THE PHARMACOKINETICS OF OMEPRAZOLE IN PEDIATRICS

The pharmacokinetics of omeprazole has been studied in children but mainly in those older than 2 years, so studies on younger children are still needed [29]. In a multicenter study by Andersson [30], the pharmacokinetics of orally administered omeprazole was evaluated in children from different age groups (1-16 years). The authors concluded that the pharmacokinetic parameters were mainly in the same range as those for adults, with the exception of the 1-6-year age group in which increased metabolic activity was observed. These results suggested an increase in metabolic activity as age decreased until the second year of life. This increased metabolic capacity in children aged 1-6 years is probably the main factor that explains the higher omeprazole dose requirements for young children compared to older children and adults.

In a subsequent study, also by Andersson et al., the pharmacokinetics of intravenously administered omeprazole was evaluated in new-born and infants requiring acid suppression [31]. The half-life and clearance of omeprazole in neonates (≤ 10 days) was found to be longer and lower than those in children aged 4,5-17 months. These values for the half-life and plasma clearance (expressed per body weight) could be explained by the low CYP2C19 and CYP3A4 enzyme activity that is present at birth. It is worth mentioning that these values were also close to the values of slow metabolizers with respect to the CYP2C19 enzyme. It was concluded that the new-born had a lower omeprazole metabolization rate than the other infants in the study, suggesting that their CYP2C19 and CYP3A4 enzymes were not yet fully mature.

It is worth highlighting that omeprazole is widely used for the treatment of gastric acid-mediated disorders. However, its pharmacokinetic and chemical instability does not allow for the synthesis of simple aqueous dosage formulations for the treatment of special patients (i.e., pediatric, geriatric or swallowing-impaired patients). Therefore, Karami [32] conducted a randomized parallel pilot study involving 34 pediatric patients with acid peptic disorder, who were treated with omeprazole. An omeprazole suspension was prepared by adding omeprazole powder to 8,4% sodium bicarbonate to obtain a final concentration of 2 mg/ml of omeprazole. Patients received either the suspension or granules. After oral administration, blood samples were collected and analyzed for omeprazole levels using a validated HPLC method. No significant differences were observed between the two dosage forms, both 2 h before and after the last dose. These results demonstrated that omeprazole suspensions are a suitable substitute for granules in the pediatric population [32].

In another prospective randomized clinical trial involving critically ill children who were at risk of gastrointestinal bleeding, Solana et al. studied the effects of two doses of intravenously administered omeprazole on gastric pH and the incidence of gastrointestinal bleeding. It was established that therapeutic efficacy was achieved when the gastric pH was above 4 and there was an absence of clinically significant gastrointestinal bleeding [33]. Between 24 and 48 h, a 1 mg/kg dose maintained gastric pH above 4 for a greater amount of time. The plasma levels of omeprazole were found to be higher after the 1 mg/kg dose. However, no correlations were found between omeprazole plasma levels and gastric pH levels. No toxic adverse effects were detected and there was no clinically significant bleeding [33].

Hassall [34] conducted an open multicenter study involving 57 children aged from 1 to 16 years old to determine the efficacy, safety and tolerability of omeprazole as a treatment for erosive esophagitis among this group of patients. For the curative dose of omeprazole, the investigators used a dose that corresponded to the treatment of acid reflux of less than 6% in a 24-hour intra-esophageal pH study. The dose correlated with the degree of esophagitis but not with age or underlying diseases. Of the 57 patients who completed the study, two thirds had grade 3 or 4 (0-4 scale) chronic esophagitis and about half had a neurological impairment or repaired esophageal atresia. It was concluded that omeprazole was well tolerated, effective and safe when used as a treatment for erosive esophagitis and gastro-esophageal reflux symptoms in children, including those for whom anti-reflux surgery or other treatment had failed. Reflux symptoms improved dramatically in almost all patients, including uncured patients. Additionally, the doses per Kg of omeprazole that were needed to cure erosive esophagitis in children were found to be higher than those needed in adults: 0,7-3,5 mg/kg/day in 44% of patients and 1,4 mg/kg/day in another 28% of patients.

A study by Strauss [35] investigated the effect of omeprazole on refractory histological esophagitis in pediatric patients. In total, 18 patients with histological esophagitis and recurrent symptoms who had been treated with H₂-receptor antagonists and prokinetic agents were prospectively treated with omeprazole. It was well tolerated in most patients and no short-term adverse reactions were observed. In patients with only histological evidence of esophagitis, omeprazole doses of approximately 0,5 ± 1,0 mg/kg/day were useful in controlling symptoms and improving esophageal histology. Those doses were similar to those used in adults with erosive esophagitis. Omeprazole did not produce prolonged symptomatic remission in children with recurrent esophagitis, even after the documented healing of esophagitis. No advantages were found for using omeprazole in patients whose symptoms were previously controlled by H₂-receptor antagonists. It was concluded that the treatment of symptoms with omeprazole could be advisable for patients without erosive esophagitis. However, the long-term progression of histological esophagitis could not be determined.

ADVERSE EFFECTS OF OMEPRAZOLE

The introduction PPIs in 1989 marked a turning point in the treatment of heartburn-related disorders. Due to their novel and effective mechanism of action and low side effects, these drugs rapidly displaced others (e.g., H2 antagonists), leading to an exponential increase in their prescription. However, this widespread use of PPIs has led to evidence of some previously undescribed adverse effects, particularly in the long term. Below is a summary table (Table 1) describing the adverse effects associated with the use of PPIs and investigated in recent decades.

Table 1. Adverse effects of omeprazole.

Although most researchers claim that more studies are needed, it seems clear that the most common side effects of omeprazole therapy are asthma [39], pneumonia [36,42] and acute gastroenteritis [42].

PEDIATRIC OMEPRAZOLE FORMULATIONS

It is important to note that there have not been many published studies concerning pediatric formulations of omeprazole, even though it is one of the most commonly prescribed APIs in the pediatric population.

With respect to the stability of omeprazole as a raw material, it is a substance that can be degraded by several factors, which have to be considered when developing formulations. Some of these factors are discussed in Table 2 [44-47]. It is clear that the formulation of this drug is not straightforward.

In order to facilitate our understanding of the current state of the subject, two summary tables (Tables 3 & 4) were drawn up following the literature search. Table 3 shows a list of published omeprazole formulations that are suitable for the pediatric population, although they are in the early stages of development. Most have undergone tentative quality controls to demonstrate the chemical validity of the product; however, most of the stability studies that have been carried out to demonstrate how long the proposed formulation is stable have not considered the gastro-resistance test. As mentioned previously, omeprazole is sensitive to acidic environments and needs to be protected from these environments so that it can pass through the cells of the intestine into the blood.

Table 2. External factors that affect omeprazole stability.

This is a key point in the development of omeprazole formulations. In Table 3, the formulations are grouped according to their pharmaceutical form: suspensions, syrups, mucoadhesive tablets, mucoadhesive films and suppositories. All of the formulations were considered to be good alternatives to the extemporaneous oral omeprazole preparations that are produced as officinal or compounding formulas in hospitals, most of which are made by manipulating commercial omeprazole drugs (capsules with pellets or mini-granules) or using omeprazole powder in sodium bicarbonate solutions. If these proposed alternatives are confirmed, they could improve the therapeutic efficacy and facilitate the administration of this active pharmaceutical ingredient in the pediatric population.

Further examples of stability studies on the liquid compounding formulas and extemporaneous preparations of omeprazole that are used in the pediatric population are presented in Table 3. Among the presented examples, the following parameters were generally studied: the shelf life of the preparations and the optimal storage temperature. It was observed that most preparations are best stored refrigerated rather than at ambient temperatures. It is noteworthy that only three of the studies (examples 3, 5 and 6 in Table 4) found that the solution turned yellow after 7 days, which is quite common when working with omeprazole [48-50]. More specifically, it is interesting to note that the recapitulated examples studied the stability of omeprazole suspensions at different concentrations [48,51]. In example 3, it was concluded that suspensions comprising sodium bicarbonate and 0,6-4 mg/mL of omeprazole could be stored at 4ºC in the dark for up to 28 days [48]. Other parameters, such as viscosity (example 3) and pH (examples 5 and 6), were also studied [48-50]. None of the examples studied the gastro-resistance required for omeprazole in depth or how the preparation of an alkaline liquid affects the protection of omeprazole once it reaches the stomach. For example, if the patient is able to drink, a common practice is to administer pellets with an acidic drink (e.g., fruit juice) to avoid the action of gastric juice with a pH of less than 5.3 [18]. This practice is also not discussed in the various studies collected.

Table 3. Examples of pediatric omeprazole formulations.

Table 4. Examples of stability studies on the liquid compounding formulas and extemporaneous preparations of omeprazole that are used in pediatrics

DISCUSSION

Omeprazole is widely used for the treatment of gastric disorders in the pediatric population. However, as previously mentioned in this review, the main problem with this active pharmaceutical ingredient (API) is its degradation in acidic environments [32,58]. This point is crucial because gastro-resistant excipients are not recommended for the pediatric population unless their use is completely justified [2]. Furthermore, omeprazole doses are not well established for pediatric population and the drug information does not include any recommendations for children [9]. Thus, hospitals do not have any guidelines for the administration of this medicine in pediatric patients.

Regarding the instability of omeprazole in acidic media, formulators are used to ensure the release of the API in the small intestine, thereby protecting omeprazole from gastric pH levels. One alternative that healthcare professionals apply to administer omeprazole to the pediatric population is the use of nasogastric tubes, which deliver the API directly to the small intestine [18,25]. Another common practice is the administration of omeprazole powder with sodium bicarbonate to promote alkaline pH levels [63]. However, this strategy seems to degrade the API (i.e., the solutions turn yellow) and the release of omeprazole in the small intestine has not been demonstrated. The third most widely used strategy is the preparation of liquid formulations that incorporate gastro-resistant pellets from commercialized capsules in acidic drinks (i.e., fruit juices). The acid pH levels of those drinks prevent the release of omeprazole in the liquid formulation. However, none of these preparations and strategies have shown the same quality or stability parameters as commercial products. Indeed, there is a lack of information about their stability [2,9]. There have only been a few studies describing the stability of some of these preparations. For example, there have been studies demonstrating that alkali solutions with gastro-resistant pellets are stable for 7-32 days [48,49,61,62] or 28 days [58] at room temperature.

In this study, a review of articles describing pediatric formulations of omeprazole was performed. Examples of various dosages and forms that are suitable for use in the pediatric population were collected, including suspensions, syrups, oral tablets, mucoadhesive films and suppositories. These examples could be good alternatives to the current officinal or extemporaneous preparations of omeprazole. Nevertheless, most of these works did not demonstrate the gastro-resistance of the proposed formulations (the only work that did discuss this point was the study by Del Gaudio et al. [59]). Furthermore, the stability problems were not fully resolved in these studies. Indeed, most of the proposed preparations had to be stored refrigerated [52,53,63] and were only stable for 2-4 weeks. The formulation that demonstrated the longest stability (1 year) was the suppository developed by Bestebreurtje [60]. Thus, more research is needed to solve the gastro-resistance and stability issues of omeprazole formulations.

In recent years, multiparticulate and orally disintegrating tablet (ODT) formulations have attracted interest, along with liquid formulations [64]. However, the aim is to develop final dosage forms without compromising the pharmaceutical efficacy of the drug [64]. Another interesting approach is the development of microspheres [59] or nanoparticles [54] that can encapsulate the API. However, studies on these drug delivery vehicles have not demonstrated the gastro-resistance of the developed formulations. Currently, new technologies (such as additive manufacturing (AM), commonly known as 3D printing (3DP)) are opening new frontiers in pharmaceutical applications. For example, 3DP is a tool that enables the manufacture of formulations with intricate structure designs, customized dosing and drug combinations and controlled release. Hence, 3DP allows for the customization of medicines, which could revolutionize pharmaceutical practice and provide personalized medicines for the pediatric population [65].

CONCLUSION

Omeprazole is a drug that has demonstrated its efficacy and security in adult patients over the last 30 years. However, the safe administration of omeprazole in children has not yet been fully resolved; although it has been studied at the clinical level and its therapeutic usefulness for the pediatric population has been validated. Nevertheless, the problems of its stability in acidic media and the need to adapt the dose according to the weight of the patient are barriers to its routine use. Different extemporaneous preparations are normally used but they do not solve the stability issue, as reported in this review. Clearly, much more investment and effort are required to assess all of the critical points during the development stage and more clinical trials are needed, including trials involving the pediatric population.

FUNDING

We acknowledge the financial support of the Department de Recerca i Universitats de la Generalitat de Catalunya (AGAUR 2021 SGR 01068).

      García PM (2019) Pediatric pharmacology. 1.a ed. Ciudad Autónoma de Buenos Aires: Journal.

2. Rouaz K, Chiclana BR, Nardi AR, Suñé MP, Mercadé DF, et al. (2021) Excipients in the Pediatric population: A Review. Pharmaceutics 13(3): 387.
3. European Medicines Agency (2013) Committee for Medicinal Products for Human Use (CHMP) Pediatric Committee (PDCO) Guideline on pharmaceutical development of medicines for pediatric use Guideline on pharmaceutical development of medicines for pediatric use. Accessed on: September 08, 2022. Available online at: www.ema.europa.eu
4. European Medicines Agency (2021) European Network of Pediatric Research at the European Medicines Agency (Enpr-EMA). Accessed on: September 08, 2022. Available online at: https://www.ema.europa.eu/en/partners-networks/networks/european-network-paediatric-research-european-medicines-agency-enpr-ema
5. WHO (2008) Measuring medicine prices, availability, affordability and price components. 2008. Accessed on: September 08, 2022. Available online at: https://apps.who.int/iris/handle/10665/70013
6. Chen Z, Li S, Choonara I, Zeng L, Jia ZJ, et al. (2022) Accessibility of Essential Medicines for Children in Sichuan Province of China: A Cross-Sectional Study. Front Pharmacol 13: 828152.
7. European Medicines Agency (2021) Pediatric Regulation. Accessed on: September 12, 2022. Available online at: https://www.ema.europa.eu/en/human-regulatory/overview/paediatric-medicines/paediatric-regulation
8. European Medicines Agency (2021) Pediatric investigation plans. Accessed on: September 12, 2022. Available online at: https://www.ema.europa.eu/en/human-regulatory/research-development/paediatric-medicines/paediatric-investigation-plans
9. Ramírez CC, Palomo GM, García-Palop B, Poy CMJ (2018) Formulación magistral y excipientes en pediatría Correspondencia. El Farmacéutico Hospitales 213: 22-28.
10. Tiengkate P, Lallemant M, Charoenkwan P, Angkurawaranon C, Kanjanarat P, et al. (2022) Gaps in Accessibility of Pediatric Formulations: A Cross-Sectional Observational Study of a Teaching Hospital in Northern Thailand. Children 9(3): 301.
11. Yafout M, Ousaid A, Lachguer K, Khayati Y, Said AHA (2022) Medication use in children: A survey among hospital pediatricians in Morocco. Le Pharmacien Clinicien 57(3): 227-233.
12. Yang S, Trinh NTH, Chalumeau M, Kaguelidou F, Ruemmele FM, et al. (2022) Pediatric Prescriptions of Proton Pump Inhibitors in France (2009-2019): A Time-Series Analysis of Trends and Practice Guidelines Impact. J Pediatr 245: 158-164.e4.
13. Flórez J, Esplugues JV, Martí-Cabrera M (2014) Farmacología Humana. 6^a ed. Elsevier España SL, editor. pp: 708-722.
14. Ward RM, Kearns GL (2013) Proton pump inhibitors in pediatrics: Mechanism of action, pharmacokinetics, pharmacogenetics, and pharmacodynamics. Paediatr Drugs 15(2): 119-131.
15. Rang H, Dale M (2020) Farmacología. 10^a ed. Elsevier España SLU, editor. pp: 395-407.
16. Carcelén AJ, Barroso PC, Fábrega BC, Feal CB, Gallego LV, et al. (2005) Inhibidores de la bomba de protones en pediatría. Farm Hosp 29: 43-54.
17. Litalien C, Théorêt Y, Faure C (2005) Pharmacokinetics of proton pump inhibitors in children. Clin Pharmacokinet 44(5): 441-466.
18. Molero GR, de Lama SMP, Arranz LC, Bafalluy MI, Manzano SMS, et al. (1997) Utilización Terapéutica del Omeprazol. Farm Hosp 21(5): 243-256.
19. Strand DS, Kim D, Peura DA (2017) 25 years of proton pump inhibitors: A comprehensive review. Gut Liver 11(1): 27-37.
20. Esplugues JV, Martí-Cabrera M, Flórez J (2014) Farmacología de la secreción gastrointestinal y de la ulceración mucosa digestiva. Elsevier España SL, editor. Farmacología Humana. 6^th ed. pp: 708-722.
21. Sachs G, Shin JM, Howden CW (2006) Review article: The clinical pharmacology of proton pump inhibitors. Aliment Pharmacol Ther 23(s2): 2-8.
22. RFE (2013) Omeprazol BOE. Accessed on: April 02, 2020. Available online at: https://extranet.boe.es/farmacopea/doc.php?id=0942
23. USP-NF (2020) Omeprazole. Accessed on: April 02, 2020. Available online at: https://online.uspnf.com/uspnf/document/1_GUID-45A0B885-E02A-4B1B-B5BF13822B829856_4_enUS?source=Search%20Results&highlight=omeprazole%20
24. European Pharmacopoeia 10.6. Omeprazole. Accessed on: April 08, 2022. Available online at: https://pheur.edqm.eu/app/106/content/106/0942E.htm?highlight=on&terms=omeprazole
25. Andersson T, Röhss K, Bredberg E, Hassan-Alin M (2001) Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole. Aliment Pharmacol Ther 15(10): 1563-1569.
26. Covarrubias J, Varea V (2009) Ensayos clínicos y práctica clínica. Uso de omeprazol en pediatría. A Pediatr Contin. 7(3): 161-164.
27. Gibbons TE, Gold BD (2003) The use of proton pump inhibitors in children: A comprehensive review. Paediatr Drugs 5(1): 25-40.
28. Raidal SL, Andrews FM, Nielsen SG, Trope G (2017) Pharmacokinetic and pharmacodynamic effects of two omeprazole formulations on stomach pH and gastric ulcer scores. Equine Vet J 49(6): 802-809.
29. Solana MJ, López-Herce J (2009) Pharmacokinetics of intravenous omeprazole in critically ill pediatric patients. Eur J Clin Pharmacol 66(4): 323-330.
30. Andersson T, Hassall E, Lundborg P, Shepherd R, Radke M, et al. (2000) Pharmacokinetics of orally administered omeprazole in children. International Pediatric Omeprazole Pharmacokinetic Group. Am J Gastroenterol 95(11): 3101-3106.
31. Andersson T, Göthberg G, Friberg L, Gatzinsky V, Lundborg P, et al. (2001) Pharmacokinetics of intravenous omeprazole in neonates and infants. J Pediatr Gastroenterol Nutr 33(3): 416-425.
32. Karami S, Dehghanzadeh G, Haghighat M, Mirzaei R, Rahimi HR (2016) Pharmacokinetic Comparison of Omeprazole Granule and Suspension Forms in Children: A Randomized, Parallel Pilot Trial. Drug Res (Stuttg) 66(3): 165-168.
33. Solana MJ, López-Herce J, Sánchez A, Sánchez C, Urbano J, et al. (2013) 0.5 mg/kg versus 1 mg/kg of intravenous omeprazole for the prophylaxis of gastrointestinal bleeding in critically Ill children: A randomized study. J Paediatrics 162(4): 776-782.
34. Hassall E, Israel D, Shepherd R, Radke M, Dalväg A, et al. (2000) Omeprazole for treatment of chronic erosive esophagitis in children: a multicenter study of efficacy, safety, tolerability and dose requirements. International Pediatric Omeprazole Study Group. J Pediatr 137(6): 800-807.
35. Strauss RS, Calenda KA, Dayal Y, Mo Bassaleh M (1999) Histological Esophagitis (Clinical and Histological Response to Omeprazole in Children). Dig Dis Sci 44: 134-139.
36. Yibirin M, De Oliveira D, Valera R, Plitt AE, Lutgen S (2021) Adverse Effects Associated with Proton Pump Inhibitor Use. Cureus 13(1): e12759.
37. Forgerini M, Mieli S, Mastroianni PC (2018) Safety assessment of omeprazole use: A review. Sao Paulo Med J 136(6): 557-570.
38. Canani RB, Cirillo P, Roggero P, Romano C, Malamisura B, et al. (2006) Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Paediatrics 117(5): e817-e820.
39. Wang YH, Svanström H, Wintzell V, Ludvigsson JF, Pasternak B (2022) Association between proton pump inhibitor use and risk of pneumonia in children: Nationwide self-controlled case series study in Sweden. BMJ Open 12: 60778.
40. Wang YH, Wintzell V, Ludvigsson JF, Svanström H, Pasternak B (2021) Association Between Proton Pump Inhibitor Use and Risk of Asthma in Children. JAMA Pediatr 175(4): 394-403.
41. Wang YH, Wintzell V, Ludvigsson JF, Svanström H, Pasternak B, et al. (2022) Proton pump inhibitor use and risk of depression and anxiety in children: Nationwide cohort study. Clin Transl Sci 15: 1112-1122.
42. Lewis SJ, Franco S, Young G, O’Keefe SJD (1996) Altered bowel function and duodenal bacterial overgrowth in patients treated with omeprazole. Aliment Pharmacol Ther 10(4): 557-561.
43. Pashankar DS, Israel DM, Jevon GP, Buchan AM (2001) Effect of long-term omeprazole treatment on antral G and D cells in children. J Pediatr Gastroenterol Nutr 33(5): 537-542.
44. Aparici DM (1997) Estudio de estabilidad de cápsulas de omeoprazol reenvasadas en dosis unitarias para su uso hospitalario. Universitat de Barcelona. Accessed on: October 06, 2022. Available online at: http://diposit.ub.edu/dspace/handle/2445/181586
45. Harald K (2018) Omeprazole Formulations. Switzerland. 16187705.5. Mar 14. Accessed on: November 15, 2022. Available online at: https://patentimages.storage.googleapis.com/ee/2a/a4/2e719a4636229f/EP3292862A1.pdf
46. Ruiz MMA, Gallardo VL, Sierra JS (2008) Suspensión extemporánea de omeprazol para vía oral. España. 2283172. Available online at: https://patentimages.storage.googleapis.com/6f/a7/fd/b32609bd267c3c/ES2283172A1.pdf
47. Pérez S, Alcocer CA (2013) Composición farmacéutica de omeprazol. España. 2667402. Available online at: https://patentimages.storage.googleapis.com/38/cf/a9/cd780c6262c614/ES2667402T3.pdf
48. Burnett JE, Balkin ER (2006) Stability and viscosity of a flavored omeprazole oral suspension for pediatric use. Am J Health Syst Pharm 63(22): 2240-2247.
49. Graudins LV, Kivi NJ, Tattam BN (2008) Stability of omeprazole mixtures: Implications for pediatric prescribing. J Pharm Pract Res 38(4): 276-279.
50. Rouaz K, Chiclana BR, Nardi AR, Suñé MP, Mercadé DF, et al. (2021) Stability omeprazole 2 mg/mL suspension for use in pediatrics in different acidic media. RESCIFAR Revista Española de Ciencias Farmacéuticas 2(2): 236-237.
51. Low M, Singh S, Venkataya B, Pearson J, Ibrahim M, et al. (2022) Stability of omeprazole in a commercial calcium carbonate based oral suspension at 2, 5 and 10 mg/mL stored under refrigeration (4°C) for 70 days. J Pharm Pract Res 52(1): 34-41.
52. Corral CC, Rodríguez MG, Martínez JP, Alarcón-Payer C, López IM, et al. (2012) Elaboración y caracterización de una suspensión oleosa de omeprazol para su administración en pediatría. Ars Pharmaceutica 53(2): 29-35.
53. Cruz MRS, Pérez JIM, Rabasco AMA (2015) Preparation and characterization of an oily suspension of omeprazole for administration in pediatrics. Int J Pharm Sci Res 6(10): 4216-4225.
54. Diefenthaeler HS, Domingues MB, Souza MM, Livia JN, Tainara EB, et al. (2020) Omeprazole Bnanoparticles suspension: Development of a stable liquid formulation with a view to pediatric administration. Int J Pharm 589: 119818.
55. Ronchi F, Sereno A, Paide M, Sacré P, Guillaume G, et al. (2019) Development and evaluation of an omeprazole-based delayed-release liquid oral dosage form. Int J Pharm 567: 118416.
56. Choi HG, Kim CK (2000) Development of omeprazole buccal adhesive tablets with stability enhancement in human saliva. J Control Release 68(3): 397-404.
57. Khan S, Boateng JS, Mitchell J, Trivedi V (2015) Formulation, Characterization and Stabilization of Buccal Films for Pediatric Drug Delivery of Omeprazole. AAPS Pharma Sci Tech 16: 800-810.
58. Khan S, Boateng J (2018) Effects of Cyclodextrins (β and γ) and l-Arginine on Stability and Functional Properties of Mucoadhesive Buccal Films Loaded with Omeprazole for Pediatric Patients. Polymers (Basel) 10(2): 157.
59. Del Gaudio P, De Cicco F, Sansone F, Aquino RP, Adami R, et al. (2015) Alginate beads as a carrier for omeprazole/SBA-15 inclusion compound: A step towards the development of personalized pediatric dosage forms. Carbohydr Polym 133: 464-472.
60. Bestebreurtje P, Roeleveld N, Knibbe CAJ, Van Sorge AA, Plötz FB, et al. (2020) Development and Stability Study of an Omeprazole Suppository for Infants. Eur J Drug Metab Pharmacokinet 45(5): 627-633.
61. Boscolo O, Perra F, Salvo L, Buontempo F, Lucangioli S (2020) Formulation and Stability Study of Omeprazole Oral Liquid Suspension for Pediatric Patients. Hosp Pharm 55(5): 314.
62. Makeen HA, Pancholi SS, Ali MS, Alam MI, Alam MS, et al. (2018) Shelf-life study of extemporaneously prepared omeprazole oral suspension. Saudi J Health Sci 7: 28-32.
63. Johnson CE, Cober MP, Ludwig JL (2007) Stability of partial doses of omeprazole-sodium bicarbonate oral suspension. Ann Pharmacother 41(12): 1954-1961.
64. Kaneria NS, Tuleu C, Ernest T (2022) Opportunities for enteral drug delivery for neonates, infants, and toddlers: A critical exploration. Expert Opin Drug Deliv 19(5): 475-519.
65. Anwar-Fadzil AF bin, Yuan Y, Wang L, Kochhar JS, Kachouie NN, et al. (2022) Recent progress in three-dimensionally-printed dosage forms from a pharmacist perspective. J Pharm Pharmacol 74(10): 1367-1390.