Taste evaluation of a novel midazolam tablet for pediatric patients: In vitro drug dissolution, in vivo animal taste aversion and clinical taste perception profiles

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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In Vivo and In Vitro Taste Assessment of Artesunate-Mefloquine, Praziquantel, and Benznidazole Drugs for Neglected Tropical Diseases and Pediatric Patients

AAPS PharmSciTech ◽

10.1208/s12249-021-02162-z ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Janine Boniatti ◽

Marcelo R. R. Tappin ◽

Rafaela G. da S Teixeira ◽

Tamires de A V Gandos ◽

Luis P. S. Rios ◽

...

Keyword(s):

Pediatric Patients ◽

Neglected Tropical Diseases ◽

Tropical Diseases ◽

Taste Assessment

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QUALITY BY DESIGN (QBD) AS A TOOL FOR THE OPTIMIZATION OF INDOMETHACIN FREEZE-DRIED SUBLINGUAL TABLETS: IN VITRO AND IN VIVO EVALUATION

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2021v13i5.42216 ◽

2021 ◽

pp. 160-171

Author(s):

MERVAT SHAFIK IBRAHIM ◽

NIHAL MOHAMED ELMAHDY ELSAYYAD ◽

ABEER SALAMA ◽

SHEREEN H. NOSHI

Keyword(s):

Response Surface ◽

Quality By Design ◽

Drug Dissolution ◽

Disintegration Time ◽

Optimization Study ◽

Freeze Dried ◽

Screening Study ◽

Wetting Time

Objective: This study aims to prepare and optimize indomethacin freeze-dried sublingual tablets (IND-FDST) by utilizing a quality by design (QbD) approach to achieve rapid drug dissolution and simultaneously bypassing the GIT for better patient tolerability. Methods: A screening study was utilized to determine the most significant factors which the quality attributes, namely disintegration time and % friability. Then an optimization study was conducted using a full response surface design to determine the optimized formula by varying the amount of the matrix-forming polymer (gelatin) and super disintegrant (croscarmellose sodium (CCS)). The variables' effect on the % friability, disintegration time, wetting time, and amount of drug release after 10 min (%Q10) was studied. The optimized formula was tested for compatibility, morphology as well as stability studies under accelerated conditions in addition to the in vivo pharmacodynamics in rats. QbD was adopted by utilizing a screening study to identify the significant formulation factors followed by a response surface optimization study to determine the optimized IND-FDST formulation. Results: Optimized IND-FDST comprised of gelatin/CCS combination in a ratio of 1:1 possessed adequate %friability (0.73±0.03%), disintegration time (25.40±1.21 seconds), wetting time (3.49±0.68 seconds), and % Q10 (100.99±5.29%) as well as good stability under accelerated conditions. IND-FDST also showed significant inhibition of edema, tumour necrosis factor-alpha, and interleukin-6 release in vivo compared to the oral market product by 70%, 42%, and 65%, respectively. Conclusion: QbD presents a successful approach in the optimization of a successful IND-FDST formula that showed superior in vivo and in vitro characteristics.

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Developing a new formulation of sodium phenylbutyrate

Archives of Disease in Childhood ◽

10.1136/archdischild-2012-302398 ◽

2012 ◽

Vol 97 (12) ◽

pp. 1081-1085 ◽

Cited By ~ 25

Author(s):

Nathalie Guffon ◽

Yves Kibleur ◽

William Copalu ◽

C Tissen ◽

Joerg Breitkreutz

Keyword(s):

Plasma Concentration ◽

Healthy Adult ◽

Taste Perception ◽

In Vitro Dissolution ◽

Time Curve ◽

New Formulation ◽

Adult Volunteers ◽

Sodium Phenylbutyrate

BackgroundSodium phenylbutyrate (NaPB) is used as a treatment for urea cycle disorders (UCD). However, the available, licensed granule form has an extremely bad taste, which can compromise compliance and metabolic control.ObjectivesA new, taste-masked, coated-granule formulation (Luc 01) under development was characterised for its in vitro taste characteristics, dissolution profiles and bioequivalence compared with the commercial product. Taste, safety and tolerability were also compared in healthy adult volunteers.ResultsThe in vitro taste profile of NaPB indicated a highly salty and bitter tasting molecule, but Luc 01 released NaPB only after a lag time of ∼10 s followed by a slow release over a few minutes. In contrast, the licensed granules released NaPB immediately. The pharmacokinetic study demonstrated the bioequivalence of a single 5 g dose of the two products in 13 healthy adult volunteers. No statistical difference was seen either for maximal plasma concentration (Cmax) or for area under the plasma concentration–time curve (AUC). CI for Cmax and AUC0–inf of NaPB were included in the bioequivalence range of 0.80–1.25. One withdrawal for vomiting and five reports of loss of taste perception (ageusia) were related to the licensed product. Acceptability, bitterness and saltiness assessed immediately after administration indicated a significant preference for Luc 01 (p<0.01), confirming the results of the taste prediction derived from in vitro measurements.ConclusionsIn vitro dissolution, in vitro and in vivo taste profiles support the view that the newly developed granules can be swallowed before release of the bitter active substance, thus avoiding stimulation of taste receptors. Moreover, Luc 01 was shown to be bioequivalent to the licensed product. The availability of a taste-masked form should improve compliance which is critical to the efficacy of NaPB treatment in patients with UCD.

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In Vitro and In Vivo Evaluation of Olmesartan Medoxomil Microcrystals and Nanocrystals: Preparation, Characterization, and Pharmacokinetic Comparison in Beagle Dogs

Current Drug Delivery ◽

10.2174/1567201816666190627143214 ◽

2019 ◽

Vol 16 (6) ◽

pp. 500-510

Author(s):

Rong Chai ◽

Hailing Gao ◽

Zhihui Ma ◽

Meng Guo ◽

Qiang Fu ◽

...

Keyword(s):

Particle Size ◽

Oral Bioavailability ◽

Olmesartan Medoxomil ◽

Water Soluble ◽

Size Reduction ◽

Drug Dissolution ◽

Beagle Dogs ◽

Enhanced Solubility

Background: Olmesartan medoxomil (OLM) is a promising prodrug hydrolyzed to olmesartan (OL) during absorption from the gastrointestinal tract. OL is a selective angiotensin II receptor antagonist, with high drug resistance and low drug interaction. However, OLM has low solubility and low bioavailability. Therefore, it is extremely urgent to reduce the drug particle size to improve its biological bioavailability. Objective: The aim of the study was to improve the oral bioavailability of poorly water-soluble olmesartan medoxomil (OLM) by using different particle size-reduction strategies. Method: Raw drug material was micronized or nanosized by either jet or wet milling processes, respectively. The particle sizes of the prepared nanocrystals (100-300 nm) and microcrystals (0.5-16 μm) were characterized by DLS, SEM, and TEM techniques. Solid state characterization by XPRD and DSC was used to confirm the crystalline state of OLM after the milling processes. Results: We demonstrated that OLM nanocrystals enhanced solubility and dissolution in the non-sink condition in which high sensitivity was found in purified water. After 1 h, 65.4% of OLM was dissolved from nanocrystals, while microcrystals and OLMETEC® only showed 37.8% and 31.9% of drug dissolution, respectively. In the pharmacokinetic study using Beagle dogs, an increase in Cmax (～2 fold) and AUC (～1.6 fold) was observed after oral administration of OLM nanocrystals when compared to microcrystals and reference tablets, OLMETEC®. In contrast, OLM microcrystals failed to improve the oral bioavailability of the drugs. Conclusion: Particles size reduction to nano-scale by means of nanocrystals technology significantly increased in vitro dissolution rate and in vivo oral bioavailability of OLM.

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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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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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From Bedside To Bench: Molecular Benchmarking Of An Fc-Optimized CD19 Antibody Used In Treatment Of Relapsed and Refractory Pediatric B-Lineage Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v122.21.3905.3905 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3905-3905 ◽

Cited By ~ 1

Author(s):

Ursula J.E. Seidel ◽

Ludger Grosse-Hovest ◽

Patrick Schlegel ◽

Martin Hofmann ◽

Friedhelm R. Schuster ◽

...

Keyword(s):

Pediatric Patients ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Compassionate Use ◽

Effector Cells ◽

Cytotoxicity Assays ◽

Healthy Donors ◽

B Lineage

Abstract B-lineage acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although this disease can be curatively treated in 80% of patients by chemotherapy, prognosis for primary refractory or relapsed patients is very poor. Even after allogeneic stem cell transplantation (SCT), relapse rates are considerable and correlate significantly with persistent minimal residual disease (MRD) prior to or after SCT. Since a MRD constellation represents favorable effector-target ratios it is well suited for immunotherapy with therapeutic antibodies. We developed and produced a third-generation CD19-specific monoclonal antibody (mAb) (4G7SDIE) in clinical-grade quality at a university-owned production unit. This high affinity Fc-optimized chimerized CD19-specific mAb mediates enhanced antibody-dependent cellular cytotoxicity (ADCC) by NK cells through its improved capability to recruit FcγRIIIa bearing effector cells. In this study, 4G7SDIE was applied within the scope of a compassionate use program in pediatric patients with relapsed or refractory B-lineage ALL and characterized in vitro and in vivo. Firstly, it was confirmed that CD19 is commonly and stably expressed in pediatric B-lineage ALL by quantitative flow cytometry analysis of primary leukemic blasts (mean expression: 1.4x104 CD19 molecules/cell; range 4.5x103-2.4x104; n = 18). Hence CD19 is a well suited target for immunotherapy of pediatric B-lineage ALL. Half-saturating concentrations of 4G7SDIE on primary leukemic blasts and cell line NALM-16 were reached at EC50= 85 ng/ml (± 29). Half-maximal target cell lysis was reached at EC50 = 25 ng/ml. Furthermore, lysis of primary B-lineage ALL blasts by PBMC of 4 healthy donors could be significantly increased by 22% when adding 1 µg/ml 4G7SDIE to donor serum in 2 h-cytotoxicity assays (n = 9; p = 0.03). 4G7SDIE was applied in 11 pediatric patients with relapsed or refractory B-lineage ALL in order to reduce or eradicate MRD and thus prevent relapse in these high-risk pre- and post-transplant patients. Especially, in a post-transplant context, with a high number of allogeneic NK effector cells available, use of an ADCC-mediating mAb shows potential. In 6/9 treated patients with detectable MRD, leukemic load was reduced by ≥ 1 log or pushed below detection limit (10-4) through immunotherapy with 4G7SDIE. Moreover, 2 further patients responded to 4G7SDIE treatment. However, they received additional therapy with tyrosine-kinase inhibitors. Five of the treated patients eventually relapsed, 5 other patients went into remission after 4G7SDIE application (range 27-597 days). Concomitant in vitro 2 h-cytotoxicity assays with donor-derived PBMC of 2 treated patients showed that NK-cell mediated lysis of autologous B-lineage ALL blasts was increased by 33%, when adding 1 µg/ml 4G7SDIE or by 22% when adding autologous patient serum taken after antibody treatment (n = 8; p = 0.02). Serum half-life of 4G7SDIE in the first treatment cycles ranged between 20 h and 43 h and after infusion of 20 mg/m2, saturating serum concentrations of ≥700 ng/ml were detectable for at least 13 days. In a standardized model with MCF7-CD19-transfectants, expressing various CD19 levels on the cell surface, a correlation between increasing CD19 molecules/cell and increasing specific lysis by PBMC of healthy donors coincubated with 4G7SDIE was shown (spearman r = 0.88; p = 0.01). Strikingly, in 3 patients with residual disease detectable by flow cytometry, a down-modulation of CD19 on leukemic blasts under 4G7SDIE therapy was observed. In one patient up-regulation of CD19 after discontinuation of 4G7SDIE treatment was observed. In vitro antigenic shift assays on primary leukemic blasts showed considerable but very heterogeneous shift of CD19 surface expression. These observations hint at in vivotumor escape mechanisms and furthermore indicate selective pressure exerted by immunotherapy with 4G7SDIE, underlining its therapeutic potential, but also delineating its limitations. In conclusion, promising antileukemic effects have been observed in vitro and in vivo in this compassionate use program. However, potential CD19 down-modulation upon immunotherapy should be taken into account and may indicate the relevance of optimized treatment schedules and dosage as well as specific patient selection. We are currently setting up a clinical trial. Disclosures: No relevant conflicts of interest to declare.

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Hydrophilic Sugars for Enhancing Dissolution Rate of Cilostazol: Effect of Wet Co-Processing

Pharmaceutical Sciences ◽

10.34172/ps.2020.64 ◽

2020 ◽

Vol 27 (1) ◽

pp. 111-120

Author(s):

Alaa Yosf Bazeed ◽

Ahmed Nouh ◽

Ebtessam Ahmed Essa ◽

Gamal El Maghraby

Keyword(s):

Aqueous Solubility ◽

Submicron Particles ◽

Drug Dissolution ◽

X Ray Diffraction ◽

Scanning Calorimetry ◽

X Ray ◽

Swallowing Difficulties ◽

Fast Disintegrating Tablets

Background: Cilostazol is an anti-platelets drug with considerable antithrombotic effects in vivo. Therefore, it is widely used by elderly patients. However, it suffers from poor bioavailability due to its low aqueous solubility. The objective of this work was to enhance the dissolution of cilostazol with the aim of formulating fast dissolving tablets for geriatrics and those of swallowing difficulties. Methods: Ethanol-assisted co-grinding of cilostazol with sugar-based excipients was adopted. Sucralose and mannitol were used for this purpose as hydrophilic excipient as well as taste improving agents. The obtained products were investigated regarding differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction, scanning electron microscope (SEM) and in vitro drug dissolution. Fast disintegrating tablets were prepared and evaluated. Results: Thermal behavior of the developed products reflected reduced crystallinity, it also suggested possible existence of new crystalline species with sucralose. Eutexia was also suggested for mannitol mixtures, that was supported by X-ray diffraction data. SEM indicated size reduction with the deposition of the drug as submicron particles over the excipient surface. Co-processing markedly improved cilostazol dissolution compared to unprocessed drug. The optimized formulations were successively formulated into fast disintegrating tablets. Conclusion: This investigation introduced the wet grinding strategy with sugar excipients as a platform for the formulation of easy to use tablets with optimum drug release.

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Preclinical Testing of Living Tissue-Engineered Heart Valves for Pediatric Patients, Challenges and Opportunities

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.707892 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ionela Movileanu ◽

Marius Harpa ◽

Hussam Al Hussein ◽

Lucian Harceaga ◽

Alexandru Chertes ◽

...

Keyword(s):

Stem Cells ◽

Endothelial Cells ◽

Cell Fate ◽

Heart Valve ◽

Pediatric Patients ◽

Living Tissue ◽

Congenital Diseases ◽

Challenges And Opportunities

Introduction: Pediatric patients with cardiac congenital diseases require heart valve implants that can grow with their natural somatic increase in size. Current artificial valves perform poorly in children and cannot grow; thus, living-tissue-engineered valves capable of sustaining matrix homeostasis could overcome the current drawbacks of artificial prostheses and minimize the need for repeat surgeries.Materials and Methods: To prepare living-tissue-engineered valves, we produced completely acellular ovine pulmonary valves by perfusion. We then collected autologous adipose tissue, isolated stem cells, and differentiated them into fibroblasts and separately into endothelial cells. We seeded the fibroblasts in the cusp interstitium and onto the root adventitia and the endothelial cells inside the lumen, conditioned the living valves in dedicated pulmonary heart valve bioreactors, and pursued orthotopic implantation of autologous cell-seeded valves with 6 months follow-up. Unseeded valves served as controls.Results: Perfusion decellularization yielded acellular pulmonary valves that were stable, no degradable in vivo, cell friendly and biocompatible, had excellent hemodynamics, were not immunogenic or inflammatory, non thrombogenic, did not calcify in juvenile sheep, and served as substrates for cell repopulation. Autologous adipose-derived stem cells were easy to isolate and differentiate into fibroblasts and endothelial-like cells. Cell-seeded valves exhibited preserved viability after progressive bioreactor conditioning and functioned well in vivo for 6 months. At explantation, the implants and anastomoses were intact, and the valve root was well integrated into host tissues; valve leaflets were unchanged in size, non fibrotic, supple, and functional. Numerous cells positive for a-smooth muscle cell actin were found mostly in the sinus, base, and the fibrosa of the leaflets, and most surfaces were covered by endothelial cells, indicating a strong potential for repopulation of the scaffold.Conclusions: Tissue-engineered living valves can be generated in vitro using the approach described here. The technology is not trivial and can provide numerous challenges and opportunities, which are discussed in detail in this paper. Overall, we concluded that cell seeding did not negatively affect tissue-engineered heart valve (TEHV) performance as they exhibited as good hemodynamic performance as acellular valves in this model. Further understanding of cell fate after implantation and the timeline of repopulation of acellular scaffolds will help us evaluate the translational potential of this technology.

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