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Objective To explore the acceptance of uncoated drug-free mini-tablets 2 mm in diameter in children aged 0.5-6 years and their ability to swallow the mini-tablets. Methods 60 children aged 0.5-6 years (10 subjects per year of life) were enrolled in our prospective, open random, two-way cross-over exploratory pilot study. The children were administered either an uncoated drug-free mini-tablet 2 mm in diameter with a beverage of their choice or 3 ml of glucose syrup 15% followed by the other formulation. Deglutition was visually assessed for the two different dosage forms using a predefined criteria list. Results The study hypothesis was that children would accept the liquid formulation better than the solid mini-tablets. Surprisingly, the authors found that the acceptance of the mini-tablets, defined as immediate swallowing or chewing first with subsequent swallowing, was higher or at least equal to that of the syrup. Very young children (6-12 months) were fully capable of swallowing the mini-tablets and may even accept them better than the sweet liquid formulation. Some children aged between 2 and 4 years chewed the tablets before swallowing, but still accepted them quite well. The acceptance rate of the mini-tablets in the different age groups was much higher than expected. Conclusions Uncoated mini-tablets seem to be a very promising alternative to liquid formulations and could be used at an earlier age in paediatric drug therapy than previously anticipated. [ABSTRACT FROM AUTHOR]

Physico-chemical interactions between drugs and plant extracts can result in the formation of nanoparticles, microparticles and precipitates. The extraction method may have an influence on the components of the plant preparations and the interactions between drugs and plant extracts. In this study the particle formation in different drug-containing preparations of Hypericum perforatum L. was compared. The formation of nanoparticles was investigated by PCS and scanning electron microscopy. Precipitates were separated from nanoparticles by centrifugation or filtration. The particle formation in drug-containing infusions and recon-stituted methanolic extracts of Hypericum perforatum L. was different. In reconstituted dry extracts 21.5% 17 α-ethinylestradiol and 36.6% levonorgestrel was bound to precipitates, in aqueous Hypericum infusions less than 4% of the hormones was bound. In infusions containing desipramine nanoparticles were formed while the formation of nanoparticles in desipramine-containing reconstituted extracts was negligible. Up to 10% of desipramine was bound to precipitates in reconstituted extracts, but only 4% was associated with the pre-cipitate of infusions. The interactions between extracts of Hypericum perforatum L. and drugs depended on the extraction method. Reconstituted methanolic extracts showed a more intensive binding with oral contraceptives than aqueous infusions. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The MUTZ-3 cell line is a surrogate for Langerhans cells (LCs) employed in New Approach Methodologies for assessing the skin sensitizing potential of chemicals. However, MUTZ-3 cells must first be differentiated to achieve the LC-typical phenotype. As all protocols use high fetal calf serum (FCS) concentrations, we aimed at reducing, or even replacing FCS, while maintaining MUTZ-LC characteristics. Additionally, we assessed the impact of the poorly defined 5637-conditioned medium (5637CM) on MUTZ-LC differentiation. With reducing the FCS content by 75 %, the desired differentiation status was achieved after 7 instead of 14 days, identified by elevated CD207 and CD1a expression. Culture with Ultroser G, a synthetic surrogate for FCS, resulted in an insufficient number of MUTZ-LCs. 5 % FCS-differentiated MUTZ-LCs could be activated with DNCB, an extreme sensitizer, as demonstrated by increased CD83 expression. 5637CM did not affect MUTZ-LC differentiation and is therefore not needed as a supplement. For their intended role in an immunocompetent skin model to assess the sensitizing potential of chemicals, MUTZ-LCs were successfully integrated into the Phenion® Full-Thickness skin model, as demonstrated by CD1a expression. These results are important steps towards medium standardization and the generation of an immunocompetent skin model according to the 3R principles., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Karsten R. Mewes reports financial support was provided by German Federal Ministry of Food and Agriculture (BMEL), Project No. 281A308B18. Patricia Boettcher reports financial support was provided by German Federal Ministry of Food and Agriculture (BMEL), Project No. 281A308B18. Laura Steinmeyer reports financial support was provided by German Federal Ministry of Food and Agriculture (BMEL), Project No. 281A308B18. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

In this study, deep UV resonance Raman spectroscopy (DUV-RRS) was coupled with high performance liquid chromatography (HPLC) to be applied in the field of pharmaceutical analysis. Naproxen, Metformin and Epirubicin were employed as active pharmaceutical ingredients (APIs) covering different areas of the pharmacological spectrum. Raman signals were successfully generated and attributed to the test substances, even in the presence of the dominant solvent bands of the mobile phase. To increase sensitivity, a low-flow method was developed to extend the exposure time of the sample. This approach enabled the use of a deep UV pulse laser with a low average power of 0.5 mW. Compared to previous studies, where energy-intensive argon ion lasers were commonly used, we were able to achieve similar detection limits with our setup. Using affordable lasers with low operating costs may facilitate the transfer of the results of this study into practical applications., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Bjoern Fischer reports financial support was provided by Federal Ministry for Economic Affairs and Climate Action. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Recently, APV organized in collaboration with Fette Compacting GmbH a course on current use and future opportunities of minitablets. The course including a workshop was attended by 30 participants and focused on the manufacturing, packaging, characterization and medical use of minitablets. It took place at the Headquarter of Fette Compacting GmbH in Schwarzenbek. This article provides an overview on the topics presented and discussed during the course., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Purpose: Neuropathic pain affects up to 10% of the global population and is caused by an injury or a disease affecting the somatosensory, peripheral, or central nervous system. NP is characterized by chronic, severe and opioid-resistant properties. Therefore, its clinical management remains very challenging. The N-type voltage-gated calcium channel, Ca v 2.2, is a validated target for therapeutic intervention in chronic and neuropathic pain. The conotoxin ziconotide (Prialt®) is an FDA-approved drug that blocks Ca v 2.2 channel but needs to be administered intrathecally. Thus, although being principally efficient, the required application route is very much in disfavour., Experimental Approach and Key Results: Here, we describe an orally available drug candidate, RD2, which competes with ziconotide binding to Ca v 2.2 at nanomolar concentrations and inhibits Ca v 2.2 almost completely reversible. Other voltage-gated calcium channel subtypes, like Ca v 1.2 and Ca v 3.2, were affected by RD2 only at concentrations higher than 10 μM. Data from sciatic inflammatory neuritis rat model demonstrated the in vivo proof of concept, as low-dose RD2 (5 mg·kg -1 ) administered orally alleviated neuropathic pain compared with vehicle controls. High-dose RD2 (50 mg·kg -1 ) was necessary to reduce pain sensation in acute thermal response assessed by the tail flick test., Conclusions and Implications: Taken together, these results demonstrate that RD2 has antiallodynic properties. RD2 is orally available, which is the most convenient application form for patients and caregivers. The surprising and novel result from standard receptor screens opens the room for further optimization into new promising drug candidates, which address an unmet medical need., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

External lubrication is an alternative to internal lubrication and its related detrimental effects on properties of tablets like tensile strength (TS). However, to date there are hardly any systematic investigations on external lubrication of mini-tablets on rotary tablet presses. Aim of this study was the systematic investigation of the impact of parameters tableting pressure, tableting speed, dosing rate and air pressure on the TS of mini-tablets. Both studies, the Central Composite Design (CCD) with SMCC 90 and the subsequently executed D-optimal design with SMCC 50, exhibited that tableting pressure had the highest positive effect on TS. Tableting speed and dosing rate in the CCD presumably did not seem to influence the TS, air pressure represented a positive coefficient. An additional temporal factor seemed to impact the results, deduced from the negative effect of the experimental order on TS in the CCD and from the negative correlation along the execution order in the residual plots. Additional long runs support findings of a non-linear decrease of TS over time. An interplay between dosing rate level and performance of the dust extraction collector is assumed, making more magnesium stearate available in the tablet press and potentially causing gradual contamination of the powder over time., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

In recent years, the application of fixed dose combinations of antiretroviral drugs in HIV therapy has been established. Despite numerous therapeutic benefits, this approach poses several challenges for the formulation development especially when poorly soluble drugs are considered. Amorphous solid dispersions (ASD) thereby have gained considerable interest in the pharmaceutical field, however, mainly including binary systems containing only one drug and a polymer. The co -formulation of two amorphous drugs can be accompanied by an immense increase in the complexity of the system as exemplarily reported for ritonavir and lopinavir embedded in a composite polymer matrix of PVPVA. The present study aims to present a new formulation approach to overcome the well-documented interaction during dissolution. Two different polymers, PVPVA and HPMCAS were used to produce ASDs for both drugs individually via hot-melt extrusion. The embedding of lopinavir in the slower dissolving polymer HPMCAS, while using PVPVA for ritonavir was found to significantly improve the overall dissolution performance compared to the individual use of PVPVA as well as to the commercial product Kaletra®. In addition, the use of different grades of HPMCAS demonstrated the possibility to further modify the dissolution profile. For a preliminary biorelevant assessment, the selected formulations were tested in a biphasic dissolution setup., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

The aim of this study was to evaluate the suitability of a non-disruptive Raman spectroscopic method to quantify drug concentrations below 5 w% within a polymer matrix produced by hot-melt extrusion (HME). For calibration, praziquantel (PZQ)-polyvinylpyrrolidone-vinylacetat-copolymer (PVP-VA) mixtures were extruded. By focusing the laser light of the Raman probe to a diameter of 1 mm and implementing a self-constructed filament holder, the signal-to-noise (S/N) ratio could be reduced considerably. The obtained Raman spectra show quite high fluorescence, which is likely to be caused by dissolved pharmaceutical active ingredient (API) in the polymer matrix. For content determination, HPLC analysis was conducted as a reference method using the same filament segments. A partial least squares (PLS) model, regressing the PZQ concentrations from HPLC method analysis versus the off-line collected Raman spectra, was developed. The linear correlation for a suitable extrusion run for the production of low-dosed filaments (extrusion 1, two kneading zones) is acceptable (R 2 = 0.9915) while the correlation for a extrusion set-up with low miscibility (extrusion 2; without kneading zone) is unacceptable (R 2 = 0.5349). The predictive performance of the calibration model from extrusion 1 is rated by the root mean square error of estimation (RMSEE), which was 0.08%. This calibration can now be used to validate the content of low-dosed filaments during HME.

The online coupling of size exclusion chromatography (SEC) to capillary enhanced Raman spectroscopy (CERS) based on a liquid core waveguide (LCW) flow cell was applied for the first time to assess the higher-order structure of different proteins. This setup allows recording of Raman spectra of the monomeric protein within complex mixtures, since SEC enables the separation of the monomeric protein from matrix components such as excipients of a biopharmaceutical product and higher molecular weight species (e.g., aggregates). The acquired Raman spectra were used for structural elucidation of well characterized proteins such as bovine serum albumin, hen egg white lysozyme, and β-lactoglobulin and of the monoclonal antibody rituximab in a medicinal product. Additionally, the CERS detection of the disaccharide sucrose, which is used as a stabilizing excipient, was quantified to achieve a limit of detection (LOD) of 120 μg and a limit of quantification (LOQ) of 363 μg injected on the column.

Mini-tablets (MTs) with losartan potassium were developed to treat the rare disease Epidermolysis Bullosa. The focus was placed on transfer and scale-up of a direct compressible formulation from the compaction simulator STYL'One Evo (CS) to the rotary tablet press Korsch XM 12 (RP). Transfer of tabletability and compactibility profiles from CS to RP did not show good agreement, e.g. at a tableting pressure of 125 MPa mean tensile strengths (TS) of 4 MPa on CS and 1-1.5 MPa on RP were reached. These results highlight the impact of the feed frame on final product qualities depending on process and material factors. In the scale-up studies the critical quality attributes (CQAs) mass variation, content uniformity, TS and disintegration time were investigated. After an appropriate run-up time, most CQAs reached a plateau, after reaching a balance between influx, efflux and distribution of lubricant in the feed frame. TS values of 1-2 MPa, disintegration times of max. 50 s, mass variation of 0.9-2.2 % (CV) and acceptance values below 15.0 were reached depending on chosen process parameters., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: Drug treatment of children is often limited to liquid formulations or manipulation of adult solid oral dosage forms because of the lack of age-appropriate formulations, concerns around particle aspiration and paediatric acceptability. Recent research revealed that the administration of mini-tablets has substantial advantages in improving dose accuracy and avoiding issues related to drug stability, storage conditions, potentially toxic excipients and taste masking (especially effective when the mini-tablets are coated). Most trials were performed with single and multiple uncoated mini-tablets. This study here aimed to investigate young children's acceptability and swallowability of multiple coated placebo mini-tablets compared with glucose syrup., Design: This clinical trial was conducted as a single-centre randomised cross-over study., Setting: Prospective cross-over study performed at the Children's University Hospital Düsseldorf., Patients: This study was conducted on 50 children in five age groups from 1 to <6 years., Interventions: An age-adapted amount of 16-28 mini-tablets and 3-6 mL syrup was administered in randomised order., Main Outcome Measures: Acceptability and swallowability of multiple coated mini-tablets and syrup., Results: In all age groups, administration of multiple coated mini-tablets and syrup showed good acceptability (mini-tablets 80%-100%, syrup 90%-100%) and swallowability (mini-tablets 30%-70%, syrup 20%-80%) without any clinically meaningful difference. This is consistent with results from large studies with uncoated mini-tablets., Conclusion: Multiple coated mini-tablets are a suitable age-appropriate alternative to liquid formulations in the paediatric population. No safety concerns with the use of coated mini-tablets were observed in the study., Trial Registration Number: DRKS00010395., Competing Interests: Competing interests: MH is a full-time employee of Novartis. THL, YK and FC were full-time employees of Novartis at the time of study conduct and eligible to receive Novartis stocks. THL is now employed at Ethris, Planegg, Germany; YK is now a consultant for MYRA Life Science Services, Rosenau, France; and FC is now employed at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. VK and HMB are full-time employees of University Hospital Düsseldorf, Germany, where the trial took place. University Hospital Düsseldorf, Germany, received a fee for conducting the study., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Dissolvable microneedle array patches offer the possibility to deliver active pharmaceutical ingredients bypassing the gastrointestinal tract by piercing the stratum corneum. Usually, microneedles are produced by micromolding but this often results in a waste of active pharmaceutical ingredient. In this study, inkjet printing was investigated as a manufacturing technology for dissolvable microneedle array patches. A suitable ink for the printing process was developed for lisinopril as a peptidomimetic model drug. The printing process was optimized. Povidone was found to be a promising polymer for the precise and smooth production of dissolvable microneedles. Different patterns of microneedles and blank spaces were successfully printed into one microneedle array patch. It was possible to exactly define the cavities to be filled. The amount of lisinopril was precisely adjusted between 95.14 and 99.26 % of the target dose. The applied method demonstrated the precise dosage opportunities of the inkjet printing methodology for customization and drug waste reduction. Inkjet printing could be used as a precise manufacturing method for personalized microneedle array patches as well as to combine incompatible drug substances in a single patch., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The 6th APV (Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnologie e.V., The International Association for Pharmaceutical Technology) Winter Conference took place in Salzburg (Austria) from January 19-20, 2023. This conference was dedicated to advance patient-centric drug development across all dosage forms, indications and patient populations and was organized by the APV PaCeMe IN Task Force. The topic was chosen due to emerging evidence and increasing regulatory requirements to consider patient needs and capabilities in drug product development. It is well acknowledged that acceptability of a drug product and its dosage form is a fundamental aspect of patient centric drug product design which can directly impact adherence and intended use, hence effectiveness and safety. Despite the requirement to proof acceptability within the drug development program, respective methods to determine and compare the degree of acceptability of different dosage forms and drug product designs are still limited., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Hot-melt extrusion (HME) and subsequent FDM 3D printing offer great potential opportunities in the formulation development and production of customized oral dosage forms with poorly soluble drugs. However, thermal stress within these processes can be challenging for thermo-sensitive drugs. In this work, three different formulations were prepared to investigate the degradation and the solid state of the thermo-sensitive and poorly soluble drug escitalopram oxalate (ESC-OX) during the two heat-intensive processes HME and FDM 3D printing. For this purpose, hydroxypropyl methyl cellulose (HPMC) and basic butylated methacrylate copolymer (bPMMA) were chosen as polymers. DSC and XRD measurements revealed that ESC-OX is amorphous in the HPMC based formulations in both, extrudates and 3D printed tablets. In contrast, in-situ amorphization of the drug from crystalline state in bPMMA filaments was observed during FDM 3D printing. With regard to the content, it was found that degradation of ESC-OX in extrudates with bPMMA could be avoided and in 3D printed tablets almost fully reduced. Furthermore, a possible conversion into the R-enantiomer in the formulation with bPMMA could be excluded using a chiral column. Compared to the commercial product Cipralex®, drug release from extrudates and tablets with bPMMA was slower but still qualified as immediate drug release., (Copyright © 2023. Published by Elsevier B.V.)

Amorphous solid dispersions (ASD) have been a successful formulation strategy to overcome the poor aqueous solubility of many novel drugs, but the development of pediatric formulations presents a special challenge due to variable gastrointestinal conditions in children. It was the aim of this work to design and apply a staged biopharmaceutical test protocol for the in vitro assessment of ASD-based pediatric formulations. Ritonavir was used as a model drug with poor aqueous solubility. Based on the commercial ASD powder formulation, a mini-tablet and a conventional tablet formulation were prepared. Drug release from the three formulations was studied in different biorelevant in vitro assays (i.e. MicroDiss, two-stage, transfer model, tiny-TIM) to consider different aspects of human GI physiology. Data from the two-stage and transfer model tests indicated that by controlled disintegration and dissolution excessive primary precipitation can be prevented. However, this advantage of the mini-tablet and tablet formulation did not translate into better performance in tiny-TIM. Here, the in vitro bioaccessibility was comparable for all three formulations. In the future, the staged biopharmaceutical action plan established herein will support the development of ASD-based pediatric formulations by improving the mechanistic understanding so that formulations are developed for which drug release is robust against variable physiological conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)