Impact of Food and Drink Administration Vehicles on Paediatric Formulation Performance Part 2: Dissolution of Montelukast Sodium and Mesalazine Formulations

Abstract Paediatric medicines are not always age-appropriate, causing problems with dosing, acceptability and adherence. The use of food and drinks as vehicles for medicine co-administration is common practice, yet the impact on drug bioavailability, safety and efficacy remains unaddressed. The aim of this study was to use in vitro dissolution testing, under infant simulating conditions, to evaluate the effect of co-administration with vehicles on the dissolution performance of two poorly soluble paediatric drugs. Dissolution studies of mesalazine and montelukast formulations were conducted with mini-paddle apparatus on a two-stage approach: simulated gastric fluid followed by addition of simulated intestinal fluid. The testing scenarios were designed to reflect daily administration practices: direct administration of formulation; formulation co-administered with food and drinks, both immediately after mixing and 4 h after mixing. Drug dissolution was significantly affected by medicine co-administration with vehicles, compared to the direct administration of formulation. Furthermore, differences were observed on drug dissolution when the formulations were mixed with different vehicles of the same subtype. The time between preparation and testing of the drug-vehicle mixture also impacted dissolution behaviour. Drug dissolution was shown to be significantly affected by the physicochemical properties and composition of the vehicles, drug solubility in each vehicle and drug/formulation characteristics. Ultimately, in this study, we show the potential of age-appropriate in vitro dissolution testing as a useful biopharmaceutical tool for estimating drug dissolution in conditions relevant to the paediatric population. The setup developed has potential to evaluate the impact of medicine co-administration with vehicles on paediatric formulation performance.

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In Vivo Predictive Dissolution Testing of Montelukast Sodium Formulations Administered with Drinks and Soft Foods to Infants

AAPS PharmSciTech ◽

10.1208/s12249-020-01825-7 ◽

2020 ◽

Vol 21 (7) ◽

Author(s):

J. Martir ◽

T. Flanagan ◽

J. Mann ◽

N. Fotaki

Keyword(s):

Drug Product ◽

Drug Dissolution ◽

Simulated Gastric Fluid ◽

Dissolution Testing ◽

Fed State ◽

Fasted State ◽

Direct Administration ◽

The Impact

Abstract In vitro dissolution testing conditions that reflect and predict in vivo drug product performance are advantageous, especially for the development of paediatric medicines, as clinical testing in this population is hindered by ethical and technical considerations. The aim of this study was to develop an in vivo predictive dissolution test in order to investigate the impact of medicine co-administration with soft food and drinks on the dissolution performance of a poorly soluble compound. Relevant in vitro dissolution conditions simulating the in vivo gastrointestinal environment of infants were used to establish in vitro-in vivo relationships with corresponding in vivo data. Dissolution studies of montelukast formulations were conducted with mini-paddle apparatus on a two-stage approach: infant fasted-state simulated gastric fluid (Pi-FaSSGF; for 1 h) followed by either infant fasted-state or infant fed-state simulated intestinal fluid (FaSSIF-V2 or Pi-FeSSIF, respectively; for 3 h). The dosing scenarios tested reflected in vivo paediatric administration practices: (i.) direct administration of formulation; (ii.) formulation co-administered with vehicles (formula, milk or applesauce). Drug dissolution was significantly affected by co-administration of the formulation with vehicles compared with after direct administration of the formulation. Montelukast dissolution from the granules was significantly higher under fed-state simulated intestinal conditions in comparison with the fasted state and was predictive of the in vivo performance when the granules are co-administered with milk. This study supports the potential utility of the in vitro biorelevant dissolution approach proposed to predict in vivo formulation performance after co-administration with vehicles, in the paediatric population.

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Crushed Tablets: Does the Administration of Food Vehicles and Thickened Fluids to Aid Medication Swallowing Alter Drug Release?

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j39w3v ◽

2014 ◽

Vol 17 (2) ◽

pp. 207 ◽

Cited By ~ 26

Author(s):

Yady Juliana Manrique-Torres ◽

Danielle J Lee ◽

Faiza Islam ◽

Lisa M Nissen ◽

Julie A.Y. Cichero ◽

...

Keyword(s):

Drug Release ◽

Orange Juice ◽

Immediate Release ◽

Drug Dissolution ◽

In Vitro Dissolution ◽

Simulated Gastric Fluid ◽

Drug Bioavailability ◽

Thickening Agents

Purpose. To evaluate the influence of co-administered vehicles on in vitro dissolution in simulated gastric fluid of crushed immediate release tablets as an indicator for potential drug bioavailability compromise. Methods. Release and dissolution of crushed amlodipine, atenolol, carbamazepine and warfarin tablets were tested with six foods and drinks that are frequently used in the clinical setting as mixers for crushed medications (water, orange juice, honey, yoghurt, strawberry jam and water thickened with Easythick powder) in comparison to whole tablets. Five commercial thickening agents (Easythick Advanced, Janbak F, Karicare, Nutilis, Viscaid) at three thickness levels were tested for their effect on the dissolution of crushed atenolol tablets. Results. Atenolol dissolution was unaffected by mixing crushed tablets with thin fluids or food mixers in comparison to whole tablets or crushed tablets in water, but amlodipine was delayed by mixing with jam. Mixing crushed warfarin and carbamazepine tablets with honey, jam or yoghurt caused them to resemble the slow dissolution of whole tablets rather than the faster dissolution of crushed tablets in water or orange juice. Crushing and mixing any of the four medications with thickened water caused a significant delay in dissolution. When tested with atenolol, all types of thickening agents at the greatest thickness significantly restricted dissolution, and products that are primarily based on xanthan gum also delayed dissolution at the intermediate thickness level. Conclusions. Dissolution testing, while simplistic, is a widely used and accepted method for comparing drug release from different formulations as an indicator for in vivo bioavailability. Thickened fluids have the potential to retard drug dissolution when used at the thickest levels. These findings highlight potential clinical implications of the addition of these agents to medications for the purpose of dose delivery and indicate that further investigation of thickened fluids and their potential to influence therapeutic outcomes is warranted. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Performance Evaluation of Montelukast Pediatric Formulations: Part II — a PBPK Modelling Approach

The AAPS Journal ◽

10.1208/s12248-021-00662-1 ◽

2022 ◽

Vol 24 (1) ◽

Author(s):

Mariana Guimarães ◽

Maria Vertzoni ◽

Nikoletta Fotaki

Keyword(s):

Case Studies ◽

Pediatric Patients ◽

Pbpk Model ◽

Drug Dissolution ◽

Age Appropriate ◽

Adults And Children ◽

The Impact

AbstractThis study aimed to build a physiologically based pharmacokinetic (PBPK) model coupled with age-appropriate in vitro dissolution data to describe drug performance in adults and pediatric patients. Montelukast sodium was chosen as a model drug. Two case studies were investigated: case study 1 focused on the description of formulation performance from adults to children; case study 2 focused on the description of the impact of medicine co-administration with vehicles on drug exposure in infants. The PBPK model for adults and pediatric patients was developed in Simcyp® v18.2 informed by age-appropriate in vitro dissolution results obtained in a previous study. Oral administration of montelukast was simulated with the ADAM™ model. For case study 1, the developed PBPK model accurately described montelukast exposure in adults and children populations after the administration of montelukast chewable tablets. Two-stage dissolution testing in simulated fasted gastric to intestinal conditions resulted in the best description of in vivo drug performance in adults and children. For case study 2, a good description of in vivo drug performance in infants after medicine co-administration with vehicles was achieved by incorporating in vitro drug dissolution (under simulated fasted gastric to fed intestinal conditions) into a fed state PBPK model with consideration of the in vivo dosing conditions (mixing of formulation with applesauce or formula). The case studies presented demonstrate how a PBPK absorption modelling strategy can facilitate the description of drug performance in the pediatric population to support decision-making and biopharmaceutics understanding during pediatric drug development. Graphical abstract

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Intranasal Niosomal In Situ Gel as a Promising Approach for Enhancing Flibanserin Bioavailability and Brain Delivery: In Vitro Optimization and Ex Vivo/In Vivo Evaluation

Pharmaceutics ◽

10.3390/pharmaceutics12060485 ◽

2020 ◽

Vol 12 (6) ◽

pp. 485 ◽

Cited By ~ 3

Author(s):

Usama A. Fahmy ◽

Shaimaa M. Badr-Eldin ◽

Osama A. A. Ahmed ◽

Hibah M. Aldawsari ◽

Singkome Tima ◽

...

Keyword(s):

Ex Vivo ◽

Oral Treatment ◽

Drug Dissolution ◽

Nasal Administration ◽

Brain Delivery ◽

Drug Bioavailability ◽

In Vivo Evaluation ◽

In Situ Gel ◽

The Impact

Flibanserin (FLB) is a multifunctional serotonergic agent that was recently approved by the FDA for the oral treatment of premenopausal women with hypoactive sexual desire disorder. FLB is a centrally acting drug that has a low oral bioavailability of 33% owing to its exposure to the hepatic first-pass effect, as well as its pH-dependent solubility, which could be an obstacle hindering the drug dissolution and absorption via mucosal barriers. Thus, this work aimed at overcoming the aforementioned drawbacks and promoting the nose-to-brain delivery of FLB via the formulation of an intra-nasal in situ niosomal gel. The Box–Behnken design was employed to study the impact of Span® 85 concentration (X1), hydration time (X2), and pH of the hydrating buffer (X3) on the vesicle size and drug entrapment. The optimized formulation exhibited a spherical shape with a vesicular size of 46.35 nm and entrapment efficiency of 92.48%. The optimized FLB niosomes integrated into gellan gum-based in situ gel exhibited enhanced ex vivo permeation and improved plasma and brain concentrations after nasal administration in rats compared to raw FLB. These findings highlight the capability of the proposed intra-nasal FLB niosomal in situ gel to boost the drug bioavailability and to promote its direct delivery to the brain.

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Effects of Hydrophilic Carriers on Structural Transitions and In Vitro Properties of Solid Self-Microemulsifying Drug Delivery Systems

Pharmaceutics ◽

10.3390/pharmaceutics11060267 ◽

2019 ◽

Vol 11 (6) ◽

pp. 267 ◽

Cited By ~ 5

Author(s):

Tao Yi ◽

Jifen Zhang

Keyword(s):

Drug Delivery ◽

Drug Delivery Systems ◽

Delivery Systems ◽

Water Soluble ◽

Drug Dissolution ◽

Commercial Application ◽

Simulated Gastric Fluid ◽

Structural Transitions

Self-microemulsifying drug delivery systems (SMEDDS) offer potential for improving the oral bioavailability of poorly water-soluble drugs. However, their susceptibilities during long term storage and in vivo precipitation issues limit their successful commercial application. To overcome these limitations, SMEDDS can be solidified with solid carriers, thus producing solid self-microemulsifying drug delivery systems (S-SMEDDS). In this study, effects of various hydrophilic carriers on structural transitions and in vitro properties of S-SMEDDS were investigated in order to set up in vitro methods for screening out appropriate carriers for S-SMEDDS. Liquid SMEDDS was prepared and characterized using nimodipine as a model drug. The effects of various hydrophilic carriers on internal microstructure and solubilization of SMEDDS were investigated by conductivity measurement and in vitro dispersion test. The results showed that hydrophilic carriers including dextran 40, maltodextrin and PVP K30 seemed to delay the percolation transition of SMEDDS, allowing it to maintain a microstructure that was more conducive to drug dissolution, thus significantly increasing the solubilization of nimodipine in the self-microemulsifying system and decreasing drug precipitation when dispersed in simulated gastric fluid. S-SMEDDS of nimodipine were prepared by using spray drying with hydrophilic carriers. The effects of various hydrophilic carriers on in vitro properties of S-SMEDDS were investigated by using SEM, DSC, PXRD and in vitro dissolution. The results showed that properties of hydrophilic carriers, especially relative molecular mass of carriers, had obvious influences on surface morphologies of S-SMEDDS, reconstitution of microemulsion and physical state of nimodipine in S-SMEDDS. Considering that in vitro properties of S-SMEDDS are closely related to their pharmacokinetic properties in vivo, the simple and economical in vitro evaluation methods established in this paper can be used to screen solid carriers of S-SMEDDS well.

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Gastrin and Nitric Oxide Production in Cultured Gastric Antral Mucosa Are Altered in Response to a Gastric Digest of a Dietary Supplement

Frontiers in Veterinary Science ◽

10.3389/fvets.2021.684203 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jennifer L. MacNicol ◽

Wendy Pearson

Keyword(s):

Nitric Oxide ◽

Cell Viability ◽

Dietary Supplement ◽

Culture Media ◽

Gastric Fluid ◽

Simulated Gastric Fluid ◽

Antral Mucosa ◽

The Impact

In vitro organ culture can provide insight into isolated mucosal responses to particular environmental stimuli. The objective of the present study was to investigate the impact of a prolonged culturing time as well as the addition of acidic gastric fluid into the in vitro environment of cultured gastric antral tissue to evaluate how altering the commonly used neutral environment impacted tissue. Furthermore, we aimed to investigate the impact of G's Formula, a dietary supplement for horses, on the secretion of gastrin, interleukin1-beta (IL-1β), and nitric oxide (NO). These biomarkers are of interest due to their effects on gastric motility and mucosal activity. Gastric mucosal tissue explants from porcine stomachs were cultured in the presence of a simulated gastric fluid (BL, n = 14), simulated gastric fluid containing the dietary supplement G's Formula (DF, n = 12), or an equal volume of phosphate buffered saline (CO, n = 14). At 48 and 60 h, 10−5 M carbachol was used to stimulate gastrin secretion. Cell viability was assessed at 72 h using calcein and ethidium-homodimer 1 staining. Media was analyzed for gastrin, IL-1β, and NO at 48, 60, and 72 h. There were no effects of treatment or carbachol stimulation on explant cell viability. Carbachol resulted in a significant increase in gastrin concentration in CO and DF treatments, but not in BL. NO was higher in CO than in BL, and NO increased in the CO and DF treatments but not in BL. In conclusion, the addition of carbachol and gastric digests to culture media did not impact cell viability. The use of an acidic gastric digest (BL) reduced the effect of cholinergic stimulation with carbachol at a concentration of 10−5 M and reduced NO secretion. The addition of the dietary supplement to the gastric digest (DF) appeared to mediate these effects within this model. Further research is required to evaluate the specific effects of this dietary supplement on direct markers of mucosal activity and the functional relevance of these results in vivo.

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Sex-Dependence in the Effect of Pharmaceutical Excipients: Polyoxyethylated Solubilising Excipients Increase Oral Drug Bioavailability in Male but Not Female Rats

Pharmaceutics ◽

10.3390/pharmaceutics11050228 ◽

2019 ◽

Vol 11 (5) ◽

pp. 228 ◽

Cited By ~ 7

Author(s):

Yang Mai ◽

Liu Dou ◽

Christine M. Madla ◽

Sudaxshina Murdan ◽

Abdul W. Basit

Keyword(s):

Ussing Chamber ◽

Drug Formulation ◽

Female Rats ◽

Oral Drug ◽

Dependent Manner ◽

Drug Bioavailability ◽

Pharmaceutical Excipients ◽

Males And Females

It is known that males and females respond differently to medicines and that differences in drug behaviour are due to inter-individual variability and sex specificity. In this work, we have examined the influence of pharmaceutical excipients on drug bioavailability in males and females. Using a rat model, we report that a portfolio of polyoxyethylated solubilising excipients (polyethylene glycol 2000, Cremophor RH 40, Poloxamer 188 and Tween 80) increase ranitidine bioavailability in males but not in females. The in vivo sex and excipient effects were reflected in vitro in intestinal permeability experiments using an Ussing chamber system. The mechanism of such an effect on drug bioavailability is suggested to be due to the interaction between the excipients and the efflux membrane transporter P-glycoprotein (P-gp), whose expression in terms of gene and protein levels were inhibited by the solubilising agents in male but not in female rats. In contrast, the non-polyoxyethylated excipient, Span 20, significantly increased ranitidine bioavailability in both males and females in a non-sex-dependent manner. These findings have significant implications for the use of polyoxyethylated solubilising excipients in drug formulation in light of their sex-specific modulation on the bioavailability of drugs that are P-gp substrates. As such, pharmaceutical research is required to retract from a ‘one size fits all’ approach and to, instead, evaluate the potential impact of the interplay between excipients and sex on drug effect to ensure effective pharmacotherapy.

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Optimally Predictive In Vitro Drug Dissolution Testing for In Vitro Bioavailability

Journal of Pharmaceutical Sciences ◽

10.1002/jps.2600651207 ◽

1976 ◽

Vol 65 (12) ◽

pp. 1718-1724 ◽

Cited By ~ 6

Author(s):

Victor F. Smolen ◽

William A. Weigand

Keyword(s):

Drug Dissolution ◽

Dissolution Testing

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Use of a Round-Bottom Resin Kettle for in vitro Dissolution Testing

Journal of AOAC INTERNATIONAL ◽

10.1093/jaoac/59.2.367 ◽

1976 ◽

Vol 59 (2) ◽

pp. 367-367

Author(s):

Ross D Kirchhoefer

Keyword(s):

In Vitro Dissolution ◽

Dissolution Testing ◽

Drug Bioavailability ◽

Dissolution Properties ◽

Dissolution Tests

Abstract Dissolution tests are used to assist in the evaluation of drug bioavailability. A piece of glassware has been designed which allows one to take advantage of the dissolution properties of a 3-neck round-bottom flask and is compatible with and easier to use than existing stirring and bath equipment.

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