A new esomeprazole packet (sachet) formulation for suspension: in vitro characteristics and comparative pharmacokinetics versus intact capsules/tablets in healthy volunteers

doi:10.1016/j.clinthera.2007.03.014

Clinical Therapeutics

Volume 29, Issue 4, April 2007, Pages 640-649

https://doi.org/10.1016/j.clinthera.2007.03.014 Get rights and content

Abstract

Background:

A packet (sachet) formulation of esomeprazole for suspension has been developed for use in patients who have difficulty swallowing.

Objectives:

This article reports the in vitro characteristics of the new esomeprazole formulation, including stability in suspension and suitability for administration orally or via enteral tubes. It also describes the pharmacokinetic profile of the esomeprazole 40-mg packet compared with that of existing solid dosage forms (capsules and tablets) in a clinical bioequivalence study.

Methods:

The stability in suspension of the packet formulation was assessed after reconstitution at various strengths (2.5, 10, and 40 mg) and a different pH (3.4–5.0) in strength-appropriate volumes of water held at temperatures ranging from 5°C to 37°C for up to 60 minutes. Suitability for oral administration was examined in terms of reconstitution time and the actual dose delivered after simulated oral administration, as well as in terms of the actual dose delivered by enteral tubes ranging in diameter from 6 to 20 Fr. Chemical stability and suspension characteristics were also analyzed using alternative reconstitution vehicles (applesauce, apple juice, and orange juice). The comparative pharmacokinetics of the packet, capsule, and tablet formulations of esomeprazole were evaluated in a randomized, open-label, 3-way crossover study in healthy volunteers, who received single 40-mg doses of each formulation. Bioequivalence was assumed if the 90% CIs for the ratios of the geometric mean AUC and CmaX were between 0.80 and 1.25. Reversephase liquid chromatography with ultraviolet detection was used to assess the esomeprazole content and/or degradation products of esomeprazole in the tests for in-suspension stability, dose delivery, and acid resistance. Normal-phase liquid chromatography was used to assess the esomeprazole content of the plasma samples in the bioequivalence study.

Results:

At the pH and temperature ranges investigated, the packet formulation was stable for up to 60 minutes after reconstitution. Chemical degradation was low (<0.1%) for all reconstitution vehicles investigated. Reconstitution time was 2 minutes with water and 9 to 10 minutes with apple or orange juice. Dose delivery was ≥98% after simulated oral administration and was generally ≥96% after administration via enteral tubes. Ninety-six healthy volunteers (56 women, 40 men; mean age, 24.9 years; mean weight, 68.9 kg) participated in the randomized, crossover, comparative pharmacokinetic study of the packet and capsule/tablet formulations. The estimated ratios of the geometric mean AUC and C_max for the packet:capsule and packet: tablet formulations were 0.98 (90% CI, 0.93–1.03) and 0.99 (90% CI, 0.94–1.04), respectively.

Conclusions:

In these analyses, the packet (sachet) formulation of esomeprazole was chemically stable in suspension and when administered orally and via enteral tubes. The formulation had a short reconstitution time, remaining fully dispersed in water for at least 30 minutes, and was dispersed in applesauce, apple juice, or orange juice without compromising its stability or dispersion characteristics. The packet formulation met the regulatory definition for bioequivalence to the tablet and capsule formulations.

References (19)

WelageL.S. et al.
Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases
J Am Pharm Assoc (Wash)
(2000)
DeVaultK.R. et al.
Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease
Am J Gastroenterol
(2005)
WelageL.S.
Pharmacologic properties of proton pump inhibitors
Pharmacotherapy
(2003)
RobinsonM.
Proton pump inhibitors: Update on their role in acid-related gastrointestinal diseases
Int J Clin Pract.
(2005)
FrestonJ.W.
Therapeutic choices in reflux disease: Defining the criteria for selecting a proton pump inhibitor
Am J Med.
(2004)
JohnsonD.A.
Alternative dosing for PPI therapy: Rationale and options
Rev Gastroenterol Disord.
(2003)
AnderssonT. et al.
Esomeprazole 40 mg capsules are bioequivalent when administered intact or as the contents mixed with applesauce
Clin Drug Invest.
(2001)
JohnsonD.A. et al.
Stability of esomeprazole capsule contents after in vitro suspension in common soft foods and beverages
Pharmacotherapy
(2003)
MohiuddinM.A. et al.
Effective gastric acid suppression after oral administration of enteric-coated omeprazole granules
Dig Dis Sci.
(1997)

There are more references available in the full text version of this article.

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Citation Excerpt :
For example, the administration time restriction of instant jelly of paracetamol within 30 min for effective taste-masking because the paracetamol release from beads to jelly stayed below the bitterness threshold (2 mg/mL) during this time (Almurisi et al., 2020c; Hamed Almurisi et al., 2022). Likewise, the esomeprazole and lansoprazole sachets must be administered within 30 and 15 min, respectively due to stability matters (Bladh et al., 2007). Information on the impact of the co-administration of a small amount of food to aid palatability/administration of medicine upon drug efficacy and how this can be risk-assessed during product development is limited (Batchelor et al., 2018).
Taste refers to those sensations perceived through taste buds on the tongue and oral cavity. The unpleasant taste of drugs leads to the refusal of taking the medicine in the paediatric population. It is widely known that a pharmaceutical product's general acceptability is the result of numerous contributing components such as swallowability, palatability (taste, flavour, texture, and mouthfeel), appearance, ease of administration, and patient characteristics. Multiparticulate as a dosage form is a platform technology for overcoming paediatrics' incapacity to swallow monolithic dosage forms, masking many medications' inherent nasty taste, and overcoming the obstacles of manufacturing a commercially taste masked dosage form. This review will discuss the considerations that must be taken into account to prepare taste masked multiparticulate dosage forms in the best way for paediatric use.
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Since previously reported pharmacokinetic profiles of enteric coated PPI multiparticulate products do not provide gastric emptying values, an attempt is made to add the suggested average gastric emptying time to the t80 of drug release in pH 6.8 phosphate and mHanks buffer and compare to reported in vivo tmax values under fasting conditions. The reported in vivo tmax values for enteric coated esomeprazole multiparticulate preparations range from 1.3 to 2.0 h (Bladh et al., 2007; Sostek et al., 2003). The in vitro drug release t80 values (including a mean gastric emptying time of 40 min) of esomeprazole products are 1.1–1.4 and 1.7–1.9 h in pH 6.8 phosphate buffer and mHanks buffer, respectively.
Proton-pump inhibitor (PPI) products based on enteric coated multiparticulates are design to meet the needs of patients who cannot swallow tablets such as children and older adults. Enteric coated PPI preparations exhibit delays in in vivo absorption and onset of antisecretory effects, which is not reflected by the rapid in vitro dissolution in compendial pH 6.8 phosphate buffer commonly used for assessment of these products. A more representative and physiological medium, pH 6.8 mHanks bicarbonate buffer, was used in this study to evaluate the in vitro dissolution of enteric coated multiparticulate-based PPI products. Commercially available omeprazole, lansoprazole and esomeprazole products were subject to dissolution tests using USP-II apparatus in pH 4.5 phosphate buffer saline for 45 min (acid stage) followed by pH 6.8 phosphate buffer or pH 6.8 mHanks bicarbonate buffer. In pH 6.8 phosphate buffer, all nine tested products displayed rapid and comparable dissolution profiles meeting the pharmacopeia requirements for delayed release preparations. In pH 6.8 mHanks buffer, drug release was delayed and failed the pharmacopeia requirements from most enteric coated preparations. Despite that the same enteric polymer, methacrylic acid–ethyl acrylate copolymer (1:1), was applied to all commercial multiparticulate-based products, marked differences were observed between dissolution profiles of these preparations. The use of pH 6.8 physiological bicarbonate (mHanks) buffer can serve as a useful tool to provide realistic and discriminative in vitro release assessment of enteric coated PPI preparations and to assist rational formulation development of these products.
Randomized, Open-Label, Single-Dose, Crossover, Relative Bioavailability Study in Healthy Adults, Comparing the Pharmacokinetics of Rabeprazole Granules Administered Using Soft Food or Infant Formula as Dosing Vehicle Versus Suspension
2012, Clinical Therapeutics
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Exposure to rabeprazole thioether, the major metabolite of rabeprazole, was also comparable between all dosing vehicles. Similar results, suggesting that different dosing vehicles (suspension, juice, applesauce, yogurt, and cottage cheese) did not affect the bioavailability of granule formulations, have also been reported previously for other PPIs, including pantoprazole,11 lansoprazole,13–15 and esomeprazole.17,18 Several studies have also reported that PPI formulations designed for sprinkle administration have bioavailabilities (in particular AUC values) comparable to those of the tablet or capsule formulations.9,10,12,15,17,18
A sprinkle capsule formulation containing enteric-coated, delayed-release rabeprazole granules is being developed for the treatment of children with gastrointestinal reflux disease. The granules are designed to be mixed with vehicles that facilitate delivery to children, who may be unable to swallow solid formulations.
The primary objective of this study—conducted on the sponsor's initiative—was to compare the bioavailability of rabeprazole granules when mixed with various dosing vehicles (small amount of soft food or infant formula) with that of a rabeprazole suspension with inactive vehicle granules (reference), to determine which dosing vehicle can be used to deliver rabeprazole in children. Tolerability was also assessed.
This single-center, single-dose, randomized, open-label, 5-period crossover study was conducted in 35 healthy adult subjects. In a randomized sequence, fasting subjects received a single dose of 10-mg rabeprazole granules per treatment period, mixed with small amounts of 1 of 5 dosing vehicles (a strawberry-flavored suspension of rabeprazole granules with inactive vehicle granules reconstituted with water, yogurt [1 tablespoon], applesauce [1 tablespoon], or infant formula [5 mL], or a suspension of rabeprazole granules with inactive vehicle tablet reconstituted with water). Full plasma pharmacokinetic (PK) profiles of rabeprazole and its thioether metabolite were collected; concentrations were estimated via LC-MS/MS. PK properties were estimated using noncompartmental methods; 90% CIs around least squares mean test-to-reference ratios were calculated for C_max and AUC values. All treatment-emergent adverse events (TEAEs) were recorded and assessed for severity (mild, moderate, or severe) and relationship to study drug.
A total of 35 subjects were enrolled (mean age, 38 years; 54.3% female; 100% white; mean weight, 71.4 kg). Thirty-four subjects completed the study. Rabeprazole and rabeprazole thioether plasma PK properties were comparable between all of the dosing vehicles tested. Median T_max was 2.5 to 3.0 hours, and mean elimination half-life was 1.27 to 1.43 hours. The 90%CIs for the least squares mean ratios for rabeprazole and rabeprazole thioether exposure were within the 80% to 125% bioequivalence limits for all relevant comparisons. All TEAEs were of mild or moderate intensity, with headache being the most commonly reported; 21 subjects (60%) experienced TEAEs during the study. No deaths or serious AEs were reported during the study; 1 subject experienced a TEAE (urinary tract infection) that led to the discontinuation of treatment.
In these healthy adult subjects, the bioavailability of rabeprazole granules was comparable between all of the dosing vehicles tested, and rabeprazole was well tolerated. Soft food suitable for young children or infant formula may be appropriate for use as dosing vehicles for rabeprazole granules. ClinicalTrials.gov identifier: NCT01186497.
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2019, Revista de Gastroenterologia de Mexico
Los inhibidores de la bomba de protones (IBP) son el estándar de referencia para el tratamiento de las enfermedades relacionadas con el ácido. En la enfermedad por reflujo gastroesofágico (ERGE) la supresión ácida se asocia con una alta tasa de cicatrización de la mucosa; sin embargo, la respuesta sintomática difiere entre los fenotipos endoscópicos. Las manifestaciones extraesofágicas tienen buena respuesta clínica en quienes presentan una exposición anormal al ácido (prueba diagnóstica) en el esófago.
Los IBP han demostrado su efectividad para disminuir la intensidad sintomática en el reflujo nocturno y en los trastornos del sueño, mejorando la calidad de vida y la productividad laboral. Esto se logra, en ocasiones, mediante las modificaciones al fraccionar o aumentar la dosis, así como la galénica.
Estos fármacos no están exentos de aspectos controversiales en relación con los eventos adversos asociados. El desarrollo tecnológico está encaminado a mejorar el rendimiento del IBP mediante el incremento de la vida media, la concentración máxima y el área bajo la curva de las concentraciones plasmáticas mediante la galénica, y por otra parte a crear fármacos más seguros y tolerables.
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Proton pump inhibitors have shown their effectiveness for reducing symptom intensity in nighttime reflux and sleep disorders, improving quality of life and work productivity. That can sometimes be achieved through dose modifications by splitting or increasing the dose, or through galenic formulation.
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A new esomeprazole packet (sachet) formulation for suspension: in vitro characteristics and comparative pharmacokinetics versus intact capsules/tablets in healthy volunteers

Abstract

Background:

Objectives:

Methods:

Results:

Conclusions:

J Am Pharm Assoc (Wash)

Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease

Am J Gastroenterol

Pharmacologic properties of proton pump inhibitors

Pharmacotherapy

Proton pump inhibitors: Update on their role in acid-related gastrointestinal diseases

Int J Clin Pract.

Therapeutic choices in reflux disease: Defining the criteria for selecting a proton pump inhibitor

Am J Med.

Alternative dosing for PPI therapy: Rationale and options

Rev Gastroenterol Disord.

Esomeprazole 40 mg capsules are bioequivalent when administered intact or as the contents mixed with applesauce

Clin Drug Invest.

Stability of esomeprazole capsule contents after in vitro suspension in common soft foods and beverages

Pharmacotherapy

Effective gastric acid suppression after oral administration of enteric-coated omeprazole granules

Dig Dis Sci.