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Plant gums are useful excipient materials for preparation of different health care formulations. Gums are generally carbohydrates, which consist of long chain polysaccharides. Traditionally, plant gums have been utilized for preparation of different drug delivery systems. A. nilotica seed has nutritional and ethnobotanical values, which has been traditionally used as food and folk medicine. Thus, the purpose of this study was separation of A. nilotica seed endosperm and isolation of endospermic gum for exploration of their physicochemical properties. Result revealed that isolated endospermic gum was amorphous in nature based on SEM and XRD analysis. Elements C, K and Mg were found to be attached on gum surface in EDS analysis pH, tapped and true density were found to be closer in seed endosperm and their isolated gum. Hygroscopicity, water holding capacity, porability, swelling index, angle of repose and porosity were enhanced in isolated gum. Tensile strength and viscosity of isolated gum i.e., 60.93 mN.m-1 and 5-200 cP respectively, were increased as compared to seed endosperm i.e., 55.73 mN.m-1 and 4-100 cP respectively. Thus, isolated endospermic gum was found to be suitable in terms of physicochemical properties and may be used as plant based safe, non-toxic and eco-friendly excipient material in pharmaceutical applications. [ABSTRACT FROM AUTHOR]

Abstract We applied computing-as-a-service to the unattended system-agnostic miscibility prediction of the pharmaceutical surfactants, Vitamin E TPGS and Tween 80, with Copovidone VA64 polymer at temperature relevant for the pharmaceutical hot melt extrusion process. The computations were performed in lieu of running exhaustive hot melt extrusion experiments to identify surfactant-polymer miscibility limits. The computing scheme involved a massively parallelized architecture for molecular dynamics and free energy perturbation from which binodal, spinodal, and mechanical mixture critical points were detected on molar Gibbs free energy profiles at 180 °C. We established tight agreement between the computed stability (miscibility) limits of 9.0 and 10.0 wt% vs. the experimental 7 and 9 wt% for the Vitamin E TPGS and Tween 80 systems, respectively, and identified different destabilizing mechanisms applicable to each system. This paradigm supports that computational stability prediction may serve as a physically meaningful, resource-efficient, and operationally sensible digital twin to experimental screening tests of pharmaceutical systems. This approach is also relevant to amorphous solid dispersion drug delivery systems, as it can identify critical stability points of active pharmaceutical ingredient/excipient mixtures.

Abstract Background The improvement in flowability and adhesion of starch powder (SP) is essential for using starch as an excipient for lactose intolerant patients. In this study, we attempted to evaluate the usefulness of hydroxypropylcellulose with molecular weight 80,000 (HPC-80) in the preparation of the starch granules (SG) as a substitute for excipient lactose. Methods Hydroxypropylcellulose with molecular weight 30,000 (HPC-30) and HPC-80 were used as binders to prepare the SG, and defined as HPC-30-SG and HPC-80-SG, respectively. Mean particle size (D50) was measured according to the Method, Optical Microscopy of Particle Size Determination in Japanese Pharmacopoeia, Eighteenth Edition, and storage stability were evaluated by measuring of the physical properties after vortexing the granules for 180 s (physical impact). The product loss rate was calculated from the weight change of the various excipients before and after the one dose packaging (ODP). Results The D50 of SP (30 µm) was smaller than that of the lactose powder (115 µm). The granulation with 0.75–3% HPC-30 and HPC-80 increased the particle size of SP, and the D50 in 1.5% HPC-30-SG (255 µm) and HPC-80-SG (220 µm) were higher than that of lactose. The excipient was removed from the heat seal of the ODP, and upon visual inspection, a large amount of starchy material was observed to be adhering to the paper in the SP. On the other hand, the low recovery rate in SP was attenuated by the granulation with HPC-30 and HPC-80. In the both HPC-30 and HPC-80, the improvement in recovery rate reached a plateau at 1.5%, and the levels of recovery rate was similar to that of lactose. The recovery rate in the 0.75–3% HPC-30-SG and 0.75% HPC-80-SG were decreased by the physical impact, however, the recovery rate and amount of 1.5% and 3% HPC-80-SG were not affected by the physical impact, and these levels were similar to that of lactose. Conclusions The use of HPC-80 as a binder of SG was found to produce a higher quality granule product than conventional HPC-based SG. This finding is useful in streamlining the preparation of starch-based powdered medicine in clinical applications.

We applied computing-as-a-service to the unattended system-agnostic miscibility prediction of the pharmaceutical surfactants, Vitamin E TPGS and Tween 80, with Copovidone VA64 polymer at temperature relevant for the pharmaceutical hot melt extrusion process. The computations were performed in lieu of running exhaustive hot melt extrusion experiments to identify surfactant-polymer miscibility limits. The computing scheme involved a massively parallelized architecture for molecular dynamics and free energy perturbation from which binodal, spinodal, and mechanical mixture critical points were detected on molar Gibbs free energy profiles at 180 °C. We established tight agreement between the computed stability (miscibility) limits of 9.0 and 10.0 wt% vs. the experimental 7 and 9 wt% for the Vitamin E TPGS and Tween 80 systems, respectively, and identified different destabilizing mechanisms applicable to each system. This paradigm supports that computational stability prediction may serve as a physically meaningful, resource-efficient, and operationally sensible digital twin to experimental screening tests of pharmaceutical systems. This approach is also relevant to amorphous solid dispersion drug delivery systems, as it can identify critical stability points of active pharmaceutical ingredient/excipient mixtures. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies require careful formulation due to their inherent stability limitations. Polysorbates are commonly used to stabilize mAbs, but they are prone to degradation, which results in unwanted impurities. KLEPTOSE® HPβCD (hydroxypropyl beta-cyclodextrin) has functioned as a stable stabilizer for protein formulations in our previous research. The current study investigates the collaborative impact of combining polysorbates and HPβCD as excipients in protein formulations. The introduction of HPβCD in formulations showed it considerably reduced aggregation in two model proteins, bevacizumab and ipilimumab, following exposure to various stress conditions. The diffusion interaction parameter revealed a reduction in protein–protein interactions by HPβCD. In bevacizumab formulations, the subvisible particle counts per 0.4 mL of samples in commercial formulations vs. formulations containing both HPβCD and polysorbates subjected to distinct stressors were as follows: agitation, 87,308 particles vs. 15,350 particles; light, 25,492 particles vs. 6765 particles; and heat, 1775 particles vs. 460 particles. Isothermal titration calorimetry (ITC) measurement indicated a weak interaction between PS 80 and HPβCD, with a KD value of 74.7 ± 7.5 µM and binding sites of 5 × 10–3. Surface tension measurements illustrated that HPβCD enhanced the surface activity of polysorbates. The study suggests that combining these excipients can improve mAb stability in formulations, offering an alternative for the biopharmaceutical industry. [ABSTRACT FROM AUTHOR]

Drug-coated balloons (DCBs) are effective tools for cardiovascular interventions, ensuring uniform drug delivery to occluded arteries. This research investigates the potential of Pluronic P123 (P123), a micelle-forming polymer, to solubilize and release Everolimus (EVE) from DCBs. Furthermore, it seeks to understand how the ratio of P123 to EVE affects release rates and micelle formation under physiological conditions. We tested three P123 to EVE ratios: 90:10, 75:25, and 50:50. Microscopy revealed that increasing EVE proportions resulted in more uniform coatings. Fourier-transform infrared spectroscopy (FTIR) analysis confirmed the successful incorporation of EVE into the P123 matrix without altering its chemical properties. Differential scanning calorimetry (DSC) studies showed that EVE incorporation affected the crystalline structure of P123, leading to more uniform coatings. In vitro release studies showed that all formulations had

Natural polysaccharides, which are described in this study, are some of the most extensively used biopolymers in food, pharmaceutical, and medical applications, because they are renewable and have a high level of biocompatibility and biodegradability. The fundamental understanding required to properly exploit polysaccharides potential in the biocomposite, nanoconjugate, and pharmaceutical industries depends on detailed research of these molecules. Polysaccharides are preferred over other polymers because of their biocompatibility, bioactivity, homogeneity, and bioadhesive properties. Natural polysaccharides have also been discovered to have excellent rheological and biomucoadhesive properties, which may be used to design and create a variety of useful and cost-effective drug delivery systems. Polysaccharide-based composites derived from natural sources have been widely exploited due to their multifunctional properties, particularly in drug delivery systems and biomedical applications. These materials have achieved global attention and are in great demand because to their biochemical properties, which mimic both human and animal cells. Although synthetic polymers account for a substantial amount of organic chemistry, natural polymers play a vital role in a range of industries, including biomedical, pharmaceutical, and construction. As a consequence, the current study will provide information on natural polymers, their biological uses, and food and pharmaceutical applications. [ABSTRACT FROM AUTHOR]

OBJECTIVES: In 2020, a list of Key Potentially Inappropriate Drugs in Pediatrics, known as the "KIDs List," was published. The objective of this analysis was to evaluate institutional compliance with the recommendations in this publication and identify areas for improvement. METHODS: Medications in the KIDs List were compared to the institutional formulary at a large academic medical center caring for pediatric and adult patients. Medications listed in the formulary were then evaluated for order comments and restrictions related to their use in pediatric patients. Oral liquid products and a group of commonly used intravenous (IV) medications were reviewed for potentially inappropriate excipients through available manufacturer information. The pediatric clinical specialists were then solicited to review and make recommendations for medications that had not been addressed. RESULTS: Of the 67 medications or classes listed in the KIDs List, 47 (70.1%) of the medications are listed in our formulary and available for use. Of these 47 medications, 4 (8.5%) included warnings related to their use in pediatric patients. Of the 270 oral liquid medications reviewed, 206 (76.3%) contained at least 1 potentially inappropriate excipient. Of the 20 commonly used IV medications, 3 (15%) contained at least 1 potentially inappropriate excipient. CONCLUSIONS: This review found that many medications listed in the KIDs List are included in our institution's formulary and that few have warnings for pediatric patients built into the institutional electronic health record. Further review of medications in the formulary will be conducted to determine the next steps to implementing KIDs List recommendations. [ABSTRACT FROM AUTHOR]

Abstract Introduction Corneal epithelial toxicity and delayed healing process have already been attributed to preservatives or some excipients. We study the effects of galenic components in antiglaucoma drugs such as benzalkonium chloride (BAC) or surfactants like macrogolglycerol hydroxystearate 40 (MGHS 40) on corneal toxicity in an ex vivo system mimicking chronic use. Methods Latanoprost-containing eyedrops are available with and without preservatives on the market. Unpreserved, they are available in different formulations with various excipients like MGHS at different concentrations (0%, 2.5%, and 5%). We studied these in the ex vivo bioreactor (EVEIT) on initially injured rabbit corneas. The drugs were applied six times daily for observation periods of 3 or 5 days. BAC, 5% MGHS 40 solution, and 0.18% hyaluronic acid served as controls. Macroscopic photographic, biochemical methods and corneal integrity quantification were used for evaluation. Toxicity was assessed by measuring wound healing and corneal fluorescein sodium permeability and was confirmed by histology studies. Results The BAC-preserved formulation resulted in high corneal toxicity, which was expected. Interestingly, the preservative-free (PF) formulation containing 5% MGHS 40, carbomer, macrogol 4000, and sorbitol showed the highest corneal toxicity, followed by the control formulation with equal MGHS 40 concentration, which presented significantly less damage. No toxicity was shown by eyedrops containing 2.5% MGHS 40 or salts only. Conclusion Our study demonstrates a significant corneal toxicity of certain formulations of PF antiglaucoma ophthalmic drugs containing 5% MGHS 40 with other excipients compared to other formulations with lower MGHS 40 concentrations (2.5% or 0%), or even compared to the solution containing 5% MGHS alone. This suggests a concentration-dependent toxicity of MGHS 40, especially in interaction with other excipients, which may increase its epithelial toxicity, and that has to be considered in clinical glaucoma therapy. Further single-component formulation trials are needed to support this interpretation.

BackgroundExcipient allergy is a rare, but potentially lethal, form of drug allergy. Diagnosing excipient allergy remains difficult in regions without mandatory drug ingredient disclosure and is a significant barrier to drug safety.ObjectiveTo investigate the feasibility of a drug allergy registry-based excipient database to identify potential excipient culprits in patients with history of drug allergy, using polyethylene glycol (PEG) as an example.MethodsAn excipient registry was created by compiling the excipient lists pertaining to all available formulations of the top 50 most reported drug allergy culprits in Hong Kong. Availability of excipient information, and its relationship with total number of formulations of individual drugs were analysed. All formulations were checked for the presence or absence of PEG.ResultsComplete excipient information was available for 36.5% (729/2,000) of all formulations of the top 50 reported drug allergy culprits in Hong Kong. The number of formulations for each drug was associated with proportion of available excipient information (ρ = 0.466, p = 0.001). Out of 729 formulations, 109 (15.0%) and 620 (85.0%) were confirmed to contain and not contain PEG, respectively. Excipient information was not available for the other 1,271 (63.6%) formulations. We were unable to confirm the presence or absence of PEG in any of the top 50 drug allergy culprits in Hong Kong.ConclusionIn countries without mandatory drug ingredient disclosure, excipient databases are unlikely able to identify potential excipient allergy in drug allergy patients. Legislations to enforce mandatory and universal ingredient disclosure are urgently needed.

Ocular drug delivery presents a unique set of challenges owing to the complex anatomy and physiology of the eye. Processed excipients have emerged as crucial components in overcoming these challenges and improving the efficacy and safety of ocular drug delivery systems. This comprehensive overview examines the opportunities that processed excipients offer in enhancing drug delivery to the eye. By analyzing the current landscape, this review highlights the successful applications of processed excipients, such as micro- and nano-formulations, sustained-release systems, and targeted delivery strategies. Furthermore, this article delves into the bottlenecks that have impeded the widespread adoption of these excipients, including formulation stability, biocompatibility, regulatory constraints, and cost-effectiveness. Through a critical evaluation of existing research and industry practices, this review aims to provide insights into the potential avenues for innovation and development in ocular drug delivery, with a focus on addressing the existing challenges associated with processed excipients. This synthesis contributes to a deeper understanding of the promising role of processed excipients in improving ocular drug delivery systems and encourages further research and development in this rapidly evolving field.

Introduction : Le but de la présente étude est de formuler et fabriquer des suppositoires antipaludiques à base des matières premières locales (poudre de feuilles et de tiges de Artemisia annua comme principe actif et beurre de karité amélioré utilisé comme excipient) afin d’améliorer la prise en charge du paludisme chez les enfants de moins de 5 ans. Méthodologie : Les plantules d’Artemisia annua utilisées ont été identifiées à l’HNC (Herbier National du Cameroun) sous le numéro Voucher 67472/HNC. Après transformation du matériel végétal (feuilles et tiges) en poudre, une série de contrôles a été effectué et exploité dans la suite. L’essai organoleptique consiste en la détermination du caractère macroscopique de la poudre des feuilles et tiges d’Artemisia annua. La mesure du volume en fonction du tassement a été effectuée à l’aide d’un voluménomètre. La compressibilité de la poudre a été évaluée à partir de divers indices tels que l’indice de Carr (ICarr), l’indice de Hausner (IHausner) et la quantité V10-V500. Le dosage de l’artémisinine s’est fait par la chromatographie sur couche mince (CCM)-densitométrie. En vue de la formulation galénique, connaissant le facteur de déplacement et la quantité de poudre de feuilles et tiges d’Artemisia annua par suppositoire, la masse exacte d’excipient à utiliser a été déterminé. M(g) de beurre de karité +4% de silice colloïdale et S(g) de poudre de feuilles et tiges d’Artemisia annua, quantités majorées à 10% pour couvrir les pertes, ont été utilisé pour préparer 6 suppositoires pesant chacun 2g selon le mode opératoire décrit dans la pharmacopée. Un contrôle de la qualité des suppositoires obtenus a également été effectués selon les prescriptions de la pharmacopée. Résultats : La poudre des feuilles et tiges d’Artemisia annua utilisée est de couleur grisâtre, de saveur amère et très odorante. L’humidité résiduelle moyenne de la poudre d’Artemisia annua est 12,69 % par séchage à l’infrarouge. Le chromatogramme de l’extrait d’Artemisia annua correspondant à six dépôts de concentration croissante. Le calcul du Rf de l’Artémisinine a donné la valeur de 0,35. Afin d’apprécier les résultats obtenus et par conséquent de valider la technique de dosage, nous avons procédé tour à tour à la vérification de la linéarité, de la répétabilité et à la détermination de la limite de détection et de quantification selon qu’indiqué dans le mode opératoire. Compte tenu des caractéristiques de la substance active (artemisinine), le beurre de karité additionné de 4% de silice colloïdale anhydre a été utilisé comme excipient. La formule obtenue pour un suppositoire consiste à additionner X mg de poudre de feuilles et tiges d’Artemisia annua à Y mg de beurre de karité. Le contrôle de la qualité des suppositoires obtenus a montré des résultats (organoleptiques, masse, point de fusion, temps de désagrégation, dosage principe actif) satisfaisants en accord avec la pharmacopée Européenne 11 e Edition. Conclusion : L’analyse granulométrique a montré que la poudre de feuilles et tiges d’Artémisia annua a une granulométrie allant de très fine à fine et un taux d’artemisinine conforme. La formule retenue dans le cadre de cette étude a consisté à additionner X mg de poudre de feuilles et tiges d’Artemisia annua à Y mg de beurre de karité additionné de 4% de silice colloïdale anhydre pour un suppositoire de 2 g. La forme galénique issue de cette formule pourrait présenter d’énormes avantages pour la qualité de prise en charge des enfants atteints de paludisme. Toutefois, des essais cliniques sont nécessaires en vue de déterminer la toxicité liée à leur utilisation

Introduction : La lutte contre les infections vaginales a connu des avancées significatives ces dernières années. Plusieurs méthodes préventives et curatives pour lutter contre les vaginoses ont été développées et regroupent l’utilisation des polyènes et des dérivés azolés. Le but de cet article est de vérifier l’aptitude du beurre de karité amélioré à être utilisé comme excipient pour la fabrication des ovules contenant comme principe actif l’association Métronidazole-Clotrimazole pour le traitement des infections génitales chez la femme. Méthodologie : Au laboratoire, nous avons formulé et fabriqué quelques échantillons d’ovules selon les normes de la pharmacopée Européenne 11e Ed. Le matériel utilisé est constitué essentiellement du beurre de karité brut de production locale amélioré à 4% de silice colloïdale ,500mg de la poudre de Métronidazole, 100mg de la poudre de Clotrimazole, un mortier avec son pilon, un réfrigérateur, une balance électrique de précision Explorer OHAUSS®, un bain-marie P Selecta®/Univeba, des moules pour ovules , un tube en U, puis un kit de verrerie de laboratoire et un appareil pour désintégration. Résultats : Pour le contrôle qualité des produits finis, l’ensemble des paramètres déterminés regroupe les paramètres organoleptiques (aspect, forme, couleur, tissus, homogénéité) et les paramètres pharmacotechniques (uniformité de masse, point de fusion et temps de désagrégation). Le contrôle pharmaceutique des ovules fabriqués a montré les valeurs des paramètres pharmacotechniques (uniformité masse, point de fusion et temps de désagrégation) et physicochimiques (couleur, odeur, texture) sont conformes aux valeurs standards indiquées par la pharmacopée Européenne. Conclusion : Nous avons formulé et fabriqué convenablement des ovules de l’association Métronidazole 500mg + Clotrimazole 100mg. Le contrôle qualité des ovules ainsi obtenus a donné des résultats satisfaisants comparativement aux valeurs standards indiquées par la pharmacopée européenne. Ces ovules ont présenté des résultats acceptables et pourraient être utilisés pour le traitement des infections génitales chez la femme.

Introduction: Corneal epithelial toxicity and delayed healing process have already been attributed to preservatives or some excipients. We study the effects of galenic components in antiglaucoma drugs such as benzalkonium chloride (BAC) or surfactants like macrogolglycerol hydroxystearate 40 (MGHS 40) on corneal toxicity in an ex vivo system mimicking chronic use. Methods: Latanoprost-containing eyedrops are available with and without preservatives on the market. Unpreserved, they are available in different formulations with various excipients like MGHS at different concentrations (0%, 2.5%, and 5%). We studied these in the ex vivo bioreactor (EVEIT) on initially injured rabbit corneas. The drugs were applied six times daily for observation periods of 3 or 5 days. BAC, 5% MGHS 40 solution, and 0.18% hyaluronic acid served as controls. Macroscopic photographic, biochemical methods and corneal integrity quantification were used for evaluation. Toxicity was assessed by measuring wound healing and corneal fluorescein sodium permeability and was confirmed by histology studies. Results: The BAC-preserved formulation resulted in high corneal toxicity, which was expected. Interestingly, the preservative-free (PF) formulation containing 5% MGHS 40, carbomer, macrogol 4000, and sorbitol showed the highest corneal toxicity, followed by the control formulation with equal MGHS 40 concentration, which presented significantly less damage. No toxicity was shown by eyedrops containing 2.5% MGHS 40 or salts only. Conclusion: Our study demonstrates a significant corneal toxicity of certain formulations of PF antiglaucoma ophthalmic drugs containing 5% MGHS 40 with other excipients compared to other formulations with lower MGHS 40 concentrations (2.5% or 0%), or even compared to the solution containing 5% MGHS alone. This suggests a concentration-dependent toxicity of MGHS 40, especially in interaction with other excipients, which may increase its epithelial toxicity, and that has to be considered in clinical glaucoma therapy. Further single-component formulation trials are needed to support this interpretation. [ABSTRACT FROM AUTHOR]

Propylene glycol (PG) and benzyl alcohol (BA) have been shown to inhibit the metabolizing enzyme for acetaminophen in the liver. Ethanol has unpredictable effects on acetaminophen metabolism. Critically ill neonates commonly receive drug formulations containing PG, BA, and ethanol as excipients. Until now, there have been no reports on the influence of BA, PG, and ethanol as excipients in patients undergoing concomitant acetaminophen therapy. We devised the present study to evaluate whether any significant differences in plasma acetaminophen concentrations, liver function tests, and serum creatinine exist between neonates receiving excipients containing drugs compared to those without. We included neonates that were administered intravenous acetaminophen with at least one concomitant drug containing either BA, PG, or ethanol as excipients. Plasma acetaminophen concentrations and levels of liver function were evaluated using tests. The doubling of alanine aminotransferase levels was considered to be a marker of hepatotoxicity. Elevation of serum creatinine >1.5 times higher than the baseline value was considered to be indicative of an acute kidney injury. Fifty-seven neonates were recruited in the study. No significant differences in the serum acetaminophen concentrations, liver and renal function tests, and rates of successful closure of ductus arteriosus were observed between the groups. No significant changes in the serum acetaminophen levels and the clinical outcomes were observed due to the presence of BA, PG, or ethanol in concomitant drugs as excipients. Probably, drugs containing these excipients can be safely administered, and even formulations containing these excipients with acetaminophen are likely to be safe for critically ill neonates.

Monoclonal antibodies require careful formulation due to their inherent stability limitations. Polysorbates are commonly used to stabilize mAbs, but they are prone to degradation, which results in unwanted impurities. KLEPTOSE® HPβCD (hydroxypropyl beta-cyclodextrin) has functioned as a stable stabilizer for protein formulations in our previous research. The current study investigates the collaborative impact of combining polysorbates and HPβCD as excipients in protein formulations. The introduction of HPβCD in formulations showed it considerably reduced aggregation in two model proteins, bevacizumab and ipilimumab, following exposure to various stress conditions. The diffusion interaction parameter revealed a reduction in protein–protein interactions by HPβCD. In bevacizumab formulations, the subvisible particle counts per 0.4 mL of samples in commercial formulations vs. formulations containing both HPβCD and polysorbates subjected to distinct stressors were as follows: agitation, 87,308 particles vs. 15,350 particles; light, 25,492 particles vs. 6765 particles; and heat, 1775 particles vs. 460 particles. Isothermal titration calorimetry (ITC) measurement indicated a weak interaction between PS 80 and HPβCD, with a KD value of 74.7 ± 7.5 µM and binding sites of 5 × 10–3. Surface tension measurements illustrated that HPβCD enhanced the surface activity of polysorbates. The study suggests that combining these excipients can improve mAb stability in formulations, offering an alternative for the biopharmaceutical industry.

Propylene glycol (PG) and benzyl alcohol (BA) have been shown to inhibit the metabolizing enzyme for acetaminophen in the liver. Ethanol has unpredictable effects on acetaminophen metabolism. Critically ill neonates commonly receive drug formulations containing PG, BA, and ethanol as excipients. Until now, there have been no reports on the influence of BA, PG, and ethanol as excipients in patients undergoing concomitant acetaminophen therapy. We devised the present study to evaluate whether any significant differences in plasma acetaminophen concentrations, liver function tests, and serum creatinine exist between neonates receiving excipients containing drugs compared to those without. We included neonates that were administered intravenous acetaminophen with at least one concomitant drug containing either BA, PG, or ethanol as excipients. Plasma acetaminophen concentrations and levels of liver function were evaluated using tests. The doubling of alanine aminotransferase levels was considered to be a marker of hepatotoxicity. Elevation of serum creatinine >1.5 times higher than the baseline value was considered to be indicative of an acute kidney injury. Fifty-seven neonates were recruited in the study. No significant differences in the serum acetaminophen concentrations, liver and renal function tests, and rates of successful closure of ductus arteriosus were observed between the groups. No significant changes in the serum acetaminophen levels and the clinical outcomes were observed due to the presence of BA, PG, or ethanol in concomitant drugs as excipients. Probably, drugs containing these excipients can be safely administered, and even formulations containing these excipients with acetaminophen are likely to be safe for critically ill neonates. [ABSTRACT FROM AUTHOR]

Solid dosage forms based on hypromellose (HPMC) with prolonged/extended drug release are very important from the research and industrial viewpoint. In the present research, the influence of selected excipients on carvedilol release performance from HPMC-based matrix tablets was studied. A comprehensive group of selected excipients was used within the same experimental setup, including different grades of excipients. Compression mixtures were directly compressed using constant compression speed and main compression force. LOESS modelling was used for a detailed comparison of carvedilol release profiles via estimating burst release, lag time, and times at which a certain % of carvedilol was released from the tablets. The overall similarity between obtained carvedilol release profiles was estimated using the bootstrapped similarity factor (f2). In the group of water-soluble carvedilol release modifying excipients, which produced relatively fast carvedilol release profiles, POLYOXᵀᴹ WSR N-80 and Polyglykol® 8000 P demonstrated the best carvedilol release control, and in the group of water-insoluble carvedilol release modifying excipients, which produced relatively slow carvedilol release profiles, AVICEL® PH-102 and AVICEL® PH-200 performed best. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (M.tb) has infected one-quarter of the world's population and led to the deaths of 1.6 million individuals in 2021 according to estimates from the World Health Organization. The rise in prevalence of multidrug-resistant and extensively drug-resistant M.tb strains coupled with insufficient therapies to treat such strains has motivated the development of more effective treatments and/or delivery modalities. Bedaquiline, a diarylquinoline antimycobacterial agent, effectively targets mycobacterial ATP synthase but may lead to systemic complications upon oral delivery. Targeted delivery of bedaquiline to the lungs represents an alternative strategy to harness the sterilizing benefits of the drug against M.tb while mitigating off-target side effects. Two pulmonary delivery modalities were developed herein, including dry powder inhalation and liquid instillation. Despite bedaquiline's poor water solubility, spray drying was performed in predominantly aqueous conditions (≥80%) to avoid a closed-loop, inert system. Aerosols of spray-dried bedaquiline with L-leucine excipient outperformed spray-dried bedaquiline alone, demonstrating superior fine particle fraction metrics (~89% of the emitted dose below <5 µm), suitable for inhalation therapies. Furthermore, the use of a 2-hydroxypropyl-β-cyclodextrin excipient allowed a molecular dispersion of bedaquiline in an aqueous solution for liquid instillation. Both delivery modalities were successfully administered to Hartley guinea pigs for pharmacokinetic analysis and were well-tolerated by the animals. Intrapulmonary liquid delivery of bedaquiline led to adequate serum absorption and appropriate peak serum concentrations of the drug. The liquid formulation was superior in systemic uptake compared to the powder formulation. The predominant route via which M.tb bacilli enter the body is aerosol droplets that are deposited onto airway surfaces. For this reason, we believe that further studies should focus on inhalation or intrapulmonary therapies that target the site of entry and primary site of infection for M.tb. [ABSTRACT FROM AUTHOR]

Mechanistic-understanding-based selection of excipients may improve formulation development strategies for generic drug products and potentially accelerate their approval. Our study aimed at investigating the effects of molecular excipients present in orally administered FDA-approved drug products on the intestinal efflux transporter, BCRP (ABCG2), which plays a critical role in drug absorption with potential implications on drug safety and efficacy. We determined the interactions of 136 oral molecular excipients with BCRP in isolated membrane vesicles and identified 26 excipients as BCRP inhibitors with IC50 values less than 5 μM using 3H-cholecystokinin octapeptide (3H-CCK8). These BCRP inhibitors belonged to three functional categories of excipients: dyes, surfactants, and flavoring agents. Compared with noninhibitors, BCRP inhibitors had significantly higher molecular weights and SLogP values. The inhibitory effects of excipients identified in membrane vesicles were also evaluated in BCRP-overexpressing HEK293 cells at similar concentrations. Only 1 of the 26 inhibitors of BCRP identified in vesicles inhibited BCRP-mediated 3H-oxypurinol uptake by more than 50%, consistent with the notion that BCRP inhibition depends on transmembrane or intracellular availability of the inhibitors. Collectively, the results of this study provide new information on excipient selection during the development of drug products with active pharmaceutical ingredients that are BCRP substrates.

Nucleic acid (NA)-based biopharmaceuticals have emerged as promising therapeutic modalities. NA therapeutics are a diverse class of RNA and DNA and include antisense oligonucleotides, siRNA, miRNA, mRNA, small activating RNA, and gene therapies. Meanwhile, NA therapeutics have posed significant stability and delivery challenges and are expensive. This article discusses the challenges and opportunities for achieving stable formulations of NAs with novel drug delivery systems (DDSs). Here we review the current progress in the stability issues and the significance of novel DDSs associated with NA-based biopharmaceuticals, as well as mRNA vaccines. We also highlight the European Medicines Agency (EMA) and US Food and Drug Administration (FDA)-approved NA-based therapeutics with their formulation profiles. NA therapeutics could impact future markets if the remaining challenges and requirements are addressed. Regardless of the limited information available for NA therapeutics, reviewing and collating the relevant facts and figures generates a precious resource for formulation experts familiar with the NA therapeutics' stability profile, their delivery challenges, and regulatory acceptance. [ABSTRACT FROM AUTHOR]

A majority of therapeutics are not available as suitable dosage forms for administration to pediatric patients. The first part of this review provides an overview of clinical and technological challenges and opportunities in the development of child-friendly dosage forms such as taste masking, tablet size, flexibility of dose administration, excipient safety and acceptability. In this context, developmental pharmacology, rapid onset of action in pediatric emergency situations, regulatory and socioeconomic aspects are also reviewed and illustrated with clinical case studies. The second part of this work discusses the example of Orally Dispersible Tablets (ODTs) as a child-friendly drug delivery strategy. Inorganic particulate drug carriers can thereby be used as multifunctional excipients offering a potential solution to address unique medical needs in infants and children while maintaining a favorable excipient safety and acceptability profile in these vulnerable patient populations. [ABSTRACT FROM AUTHOR]

Some pharmaceutical excipients are able to modify intestinal permeability, thus influencing drug absorption and bioavailability. The effect of four polyols (mannitol, maltitol, sorbitol and xylitol) on the permeability of seven active pharmaceutical ingredients (API), representing different BCS classes (furosemide, amiloride, atenolol, ranitidine, nadolol, L-thyroxine and acyclovir), was investigated using the Caco-2 cell permeability model. Analytical methods for the sensitive polyol and API quantification were developed using Ultra High Performance Liquid Chromatography coupled to triple-quadrupole Mass Spectrometry (UHPLC-QqQ). Apparent permeability coefficients (Papp) were calculated from the measured concentrations in the apical and basolateral compartments. The cell monolayer remained intact throughout the experiment in all trials, neither significant Lucifer Yellow (LY) passage, nor modification of the electrical resistance was detected, demonstrating that no active principle or excipient (or combinations thereof) modulated the paracellular transport. The Papp values for apical to basolateral and basolateral to apical directions of drug + excipient combinations were compared with the Papp values for the drug substance alone. Our results show that mannitol, maltitol, sorbitol and xylitol did not modify the permeability of furosemide, amiloride, atenolol, ranitidine, nadolol, acyclovir and L-thyroxine APIs. Moreover, the presence of polyols did not alter the efflux of the active principle (basolateral to apical). [ABSTRACT FROM AUTHOR]

Nanoscale medicine confers passive and active targeting potential. The development of nanomedicine is however met with processing, handling and administration hurdles. Excessive solid nanoparticle aggregation and caking result in low product yield, poor particle flowability and inefficient drug administration. These are overcome by converting the nanoparticles into a microscale dosage form via agglomeration or compaction techniques. Agglomeration and compaction nonetheless predispose the nanoparticles to risks of losing their nanogeometry, surface composition or chemistry being altered and negating biological performance. This study reviews risk factors faced during agglomeration and compaction that could result in these changes to nanoparticles. The potential risk factors pertain to materials choice in nanoparticle and microscale dosage form development, and their interplay effects with process temperature, physical forces and environmental stresses. To render the physicochemical and biological behaviour of the nanoparticles unaffected by agglomeration or compaction, modes to modulate the interplay effects of material and formulation with processing and environment variables are discussed. [ABSTRACT FROM AUTHOR]

Natural polysaccharides, which are described in this study, are some of the most extensively used biopolymers in food, pharmaceutical, and medical applications, because they are renewable and have a high level of biocompatibility and biodegradability. The fundamental understanding required to properly exploit polysaccharides potential in the biocomposite, nanoconjugate, and pharmaceutical industries depends on detailed research of these molecules. Polysaccharides are preferred over other polymers because of their biocompatibility, bioactivity, homogeneity, and bioadhesive properties. Natural polysaccharides have also been discovered to have excellent rheological and biomucoadhesive properties, which may be used to design and create a variety of useful and cost-effective drug delivery systems. Polysaccharide-based composites derived from natural sources have been widely exploited due to their multifunctional properties, particularly in drug delivery systems and biomedical applications. These materials have achieved global attention and are in great demand because to their biochemical properties, which mimic both human and animal cells. Although synthetic polymers account for a substantial amount of organic chemistry, natural polymers play a vital role in a range of industries, including biomedical, pharmaceutical, and construction. As a consequence, the current study will provide information on natural polymers, their biological uses, and food and pharmaceutical applications.

Nanoscale medicine confers passive and active targeting potential. The development of nanomedicine is however met with processing, handling and administration hurdles. Excessive solid nanoparticle aggregation and caking result in low product yield, poor particle flowability and inefficient drug administration. These are overcome by converting the nanoparticles into a microscale dosage form via agglomeration or compaction techniques. Agglomeration and compaction nonetheless predispose the nanoparticles to risks of losing their nanogeometry, surface composition or chemistry being altered and negating biological performance. This study reviews risk factors faced during agglomeration and compaction that could result in these changes to nanoparticles. The potential risk factors pertain to materials choice in nanoparticle and microscale dosage form development, and their interplay effects with process temperature, physical forces and environmental stresses. To render the physicochemical and biological behaviour of the nanoparticles unaffected by agglomeration or compaction, modes to modulate the interplay effects of material and formulation with processing and environment variables are discussed.

Polysorbate 80 is a non-ionic detergent derived from polyethoxylated sorbitan and oleic acid. It is widely used in pharmaceuticals, foods, and cosmetics as an emulsifier. Nav1.7 is a peripheral sodium channel that is highly expressed in sympathetic and sensory neurons, and it plays a critical role in determining the threshold of action potentials (APs). We found that 10 μg/mL polysorbate 80 either abolished APs or increased the threshold of the APs of dorsal root ganglions. We thus investigated whether polysorbate 80 inhibits Nav1.7 sodium current using a whole-cell patch-clamp recording technique. Polysorbate 80 decreased the Nav1.7 current in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50) of 250.4 μg/mL at a holding potential of −120 mV. However, the IC50 was 1.1 μg/mL at a holding potential of −90 mV and was estimated to be 0.9 μg/mL at the resting potentials of neurons, where most channels are inactivated. The activation rate and the voltage dependency of activation of Nav1.7 were not changed by polysorbate 80. However, polysorbate 80 caused hyperpolarizing shifts in the voltage dependency of the steady-state fast inactivation curve. The blocking of Nav1.7 currents by polysorbate 80 was not reversible at a holding potential of −90 mV but was completely reversible at −120 mV, where the channels were mostly in the closed state. Polysorbate 80 also slowed recovery from inactivation and induced robust use-dependent inhibition, indicating that it is likely to bind to and stabilize the inactivated state. Our results indicate that polysorbate 80 inhibits Nav1.7 current in concentration-, state-, and use-dependent manners when used even below commercial concentrations. This suggests that polysorbate 80 may be helpful in pain medicine as an excipient. In addition, in vitro experiments using polysorbate 80 with neurons should be conducted with caution. [ABSTRACT FROM AUTHOR]

A drug-excipient interaction impurity associated with the degradation process of pramipexole was isolated. The impurity was detected during the stability study of pramipexole extended-release tablets. It was found at a relative retention time of 0.88 with respect to pramipexole, using the pramipexole gradient HPLC-UV detection method described in the USP. The structure of the impurity was identified and fully characterized using high resolution mass spectrometry, IR and NMR techniques, as presented herein. The degradation impurity was identified as (S)-N2-(methoxymethyl)-N6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine. The drug-excipient interaction mechanism of its formation was proposed. An efficient and straightforward synthetic approach was developed to prepare the degradation impurity to confirm its proposed degradation pathway and structure. [ABSTRACT FROM AUTHOR]

Polysorbate 80 is a non-ionic detergent derived from polyethoxylated sorbitan and oleic acid. It is widely used in pharmaceuticals, foods, and cosmetics as an emulsifier. Nav1.7 is a peripheral sodium channel that is highly expressed in sympathetic and sensory neurons, and it plays a critical role in determining the threshold of action potentials (APs). We found that 10 µg/mL polysorbate 80 either abolished APs or increased the threshold of the APs of dorsal root ganglions. We thus investigated whether polysorbate 80 inhibits Nav1.7 sodium current using a whole-cell patch-clamp recording technique. Polysorbate 80 decreased the Nav1.7 current in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50) of 250.4 µg/mL at a holding potential of -120 mV. However, the IC50 was 1.1 µg/mL at a holding potential of -90 mV and was estimated to be 0.9 µg/mL at the resting potentials of neurons, where most channels are inactivated. The activation rate and the voltage dependency of activation of Nav1.7 were not changed by polysorbate 80. However, polysorbate 80 caused hyperpolarizing shifts in the voltage dependency of the steady-state fast inactivation curve. The blocking of Nav1.7 currents by polysorbate 80 was not reversible at a holding potential of -90 mV but was completely reversible at -120 mV, where the channels were mostly in the closed state. Polysorbate 80 also slowed recovery from inactivation and induced robust usedependent inhibition, indicating that it is likely to bind to and stabilize the inactivated state. Our results indicate that polysorbate 80 inhibits Nav1.7 current in concentration-, state-, and use-dependent manners when used even below commercial concentrations. This suggests that polysorbate 80 may be helpful in pain medicine as an excipient. In addition, in vitro experiments using polysorbate 80 with neurons should be conducted with caution. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the direct compression properties of a novel coprocessed excipient (CPE) generated by processing cow bone powder (CBP), maize starch (MS) and Khaya gum (KG) together to form a single composite excipient. Design of experiments (DoE) was employed to optimise the formulation of CPE. CPE was prepared by wet granulation using the optimised formulation of CBP (40%), MS (40%) and KG (20%) as recommended by DoE. Assessment of the organoleptic properties of CPE revealed an odourless, tasteless and coarse texture with a neutral pH of 7.3. CPE was found to be partly crystalline and partly amorphous and demonstrated compatibility between the three components of the formulation. The material in terms of flowability compared well with the flow parameters of StarLac, a reference co-processed excipient. Tablets of diclofenac produced by direct compression using CPE as the directly compressible excipient compared well with the hardness and disintegration time of tablets made using StarLac® as the directly compressible excipient. The study’s outcome shows that CPE can be used as a direct compression excipient in the formulation of tablets by direct compression. [ABSTRACT FROM AUTHOR]

Given their safety and efficiency in protecting protein integrity, polysorbates (PSs) have been the most widely used excipients for the stabilization of protein therapeutics for years. In recent decades, however, there have been numerous reports about visible or sub-visible particles in PS-containing biotherapeutic products, which is a major quality concern for parenteral drugs. Alternative excipients that are safe for parenteral administration, efficient in protecting different protein drugs against various stress conditions, effective in protein stabilization in high-concentrated liquid formulations, stable under the storage conditions for the duration of the product's shelf-life, and compatible with other formulation components and the primary packaging are highly sought after. The aim of this paper is to review potential alternative excipients from different families, including surfactants, carbohydrate- and amino acid-based excipients, synthetic amphiphilic polymers, and ionic liquids that enable protein stabilization. For each category, important characteristics such as the ability to stabilize proteins against thermal and mechanical stresses, current knowledge related to the safety profile for parenteral administration, potential interactions with other formulation components, and primary packaging are debated. Based on the provided information and the detailed discussion thereof, this paper may pave the way for the identification or development of efficient excipients for biotherapeutic protein stabilization. [ABSTRACT FROM AUTHOR]

In this study, Na-attapulgite was explored as an excipient to prepare domperidone sustained-release tablets and test them in accordance with United States Pharmacopoeia requirements. Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC) were employed to explore the compatibility between Na-attapulgite and domperidone. The XRD and DSC show no interaction between the drug and Na-attapulgite. The FTIR spectrum indicates a shift in the absorption of N-H in the drug molecule, which can be explained by the hydrogen bonding interaction between the N-H in the DOM molecule and the -OH on the surface of Na-ATP. The diameter, hardness, friability and drug content of the tablets were measured, and they all met the relevant requirements of the United States Pharmacopoeia. In addition, the tablets with Na-attapulgite as excipient exhibit a better release performance within the release time of 12 h. These results demonstrate that the domperidone sustained-release tablets have been successfully prepared by using Na-attapulgite as an excipient. The doping of Na-ATP in domperidone sustained-release tablets improves the cytocompatibility. Moreover, with the increase of Na-ATP content, cells proliferate remarkably and cell activity is significantly enhanced. [ABSTRACT FROM AUTHOR]

Freeze-drying, also known as lyophilization, significantly improves the storage, stability, shelf life, and clinical translation of biopharmaceuticals. On the downside, this process faces complex challenges, i.e., the presence of freezing and drying stresses for the active compounds, the uniformity and consistency of the final products, and the efficiency and safety of the reconstituted lyophilized formulations. All these requirements can be addressed by adding specific excipients that can protect and stabilize the active ingredient during lyophilization, assisting in the formation of solid structures without interfering with the biological and/or pharmaceutical action of the reconstituted products. However, these excipients, generally considered safe and inert, could play an active role in the formulation interacting with the biological cellular machinery and promoting toxicity. Any side effects should be carefully identified and characterized to better tune any treatments in terms of concentrations and administration times. In this work, various concentrations in the range of 1 to 100 mg/mL of cellobiose, lactose, sucrose, trehalose, isoleucine, glycine, methionine, dextran, mannitol, and (2-hydroxypropyl)-β-cyclodextrin were evaluated in terms of their ability to create uniform and solid lyophilized structures. The freeze-dried products were then reconstituted in the appropriate cell culture media to assess their in vitro cytotoxicity on both a healthy cell line (B-lymphocytes) and their tumoral lymphoid counterpart (Daudi). Results showed that at 10 mg/mL, all the excipients demonstrated suitable lyophilized solid structures and high tolerability by both cell lines, while dextran was the only excipient well-tolerated also up to 100 mg/mL. An interesting result was shown for methionine, which even at 10 mg/mL, selectively affected the viability of the cancerous cell line only, opening future perspectives for antitumoral applications. [ABSTRACT FROM AUTHOR]

Background & Aims: Drug excipient incompatibility evaluation is an important part of pre-formulation studies. Drug-excipient interaction may affect drug stability, bioavailability, therapeutic effects, efficacy, and safety. Therefore, development of a successful drug delivery systems or dosage forms depends on correct selection of excipients. The aim of this study is to evaluate of celecoxib-lactose incompatibility reactions at solid state using physicochemical methods. Materials & Methods: Celecoxib and lactose were blended in 1:1 mass ratios and added to 20% (v/w) water and stored in closed vials at 60°C (inside the oven). Also, pure drug and pure excipient were prepared. Celecoxib, celecoxib-lactose and lactose tablets prepared using direct compression method. Produced tablets were stored at 60 °C (inside the oven). Finally, celecoxib -lactose incompatibility in the solid state was investigated by Fourier transform infrared (FTIR) and differential scanning calorimetry (DSC) methods over four consecutive weeks. Results: the incompatibility of celecoxib with lactose was not observed using physicochemical methods including DSC, FTIR spectroscopy and also visual observation. Conclusion: It can be concluded that using lactose in celecoxib solid pharmaceutical preparations will not cause incompatibilities.

Abstract Background Excipients are widely used in pharmaceuticals, detergents, food, and drink because of their properties of low toxicity and hypoallergenicity. The excipient carboxymethylcellulose is used extensively as a thickener in foods such as baked goods, ice cream, gluten free, and reduced fat products, where it may be labeled as e-number E466. However, excipients can rarely cause type 1 hypersensitivity reactions. Several publications have described systemic allergy following carboxymethylcellulose exposure in pharmaceuticals, particularly systemic corticosteroids. Furthermore, there is one reported case in the literature of anaphylaxis following food containing carboxymethylcellulose. Case presentation We identify a case of anaphylaxis in a 45-year-old atopic Caucasian woman on receiving an injectable suspension of the corticosteroid triamcinolone acetonide containing carboxymethylcellulose, and subsequent allergic symptoms on reexposure to carboxymethylcellulose in a commercial drink. Diagnosis of carboxymethylcellulose excipient allergy was confirmed through skin prick testing using Celluvisc carmellose 0.5% eye drops, which contain carboxymethylcellulose as the active ingredient. Conclusion This case highlights the importance of identifying excipients such as carboxymethylcellulose as causes of allergy, to reduce burden of further hypersensitivity reactions, not just to drugs but to other consumables.

Objectives: This study aimed to characterize the tableting performance of maize and potato starches, when used in combination either as a disintegrant or binder in solid dosage form development. Materials and Methods: Wet granulation was used to process metronidazole granules incorporating either maize starch, potato starch, or a combination of the two starches as binders or disintegrant at 10% w/w. Granule analysis was carried out on the various formulations and subsequently compressed into tablets weighing approximately 500 mg following the addition of extragranular excipients. Tablet properties were assessed after 24 h of storage. Results: Analysis of granule properties did not reveal a wide variation across the formulations irrespective of the type and combination of starches used in the formulation either as binder or disintegrant. It was observed, however, that there were slight differences in particle size, bulk and tapped densities of granule formulations containing the combined starch as excipients compared to granule formulations containing individual starch as the excipient. Tablets prepared using the combined starches as binder had lower tensile strength and disintegration time compared to other formulations incorporating the individual starches as binders. However, when evaluated as disintegrant, the tablet formulation containing the combined starches produced tablets with relatively lower disintegration time compared to formulations containing the individual starches as disintegrant. Conclusion: The study concludes that the combination of maize and potato starches as excipients in tablet formulation influenced the outcome of granule and tablet properties. [ABSTRACT FROM AUTHOR]

Unintended immunogenicity can affect the safety and efficacy of therapeutic proteins and peptides, so accurate assessments of immunogenicity risk can aid in the selection, development, and regulation of biologics. Product- and processrelated impurities can act as adjuvants that activate the local or systemic innate immune response increasing the likelihood of product immunogenicity. Thus, assessing whether products have innate immune response modulating impurities (IIRMI) is a key component of immunogenicity risk assessments. Identifying trace levels of individual IIRMI can be difficult and testing individually for all potential impurities is not feasible. Therefore, to mitigate the risk, cell-based assays that use human blood cells or monocyte-macrophage reporter cell lines are being developed to detect minute quantities of impurities capable of eliciting innate immune activation. As these are cell-based assays, there is concern that excipients could blunt the cell responses, masking the presence of immunogenic IIRMI. Here, we explore the impact of frequently used excipients (non-ionic detergents, sugars, amino acids, bulking agents) on the sensitivity of reporter cell lines (THP-1- and RAW-Blue cells) and fresh human blood cells to detect purified TLR agonists as model IIRMI. We show that while excipients do notmodulate the innate immune response elicited by TLR agonists in vivo, they can impact on the sensitivity of cell-based IIRMI assays. Reduced sensitivity to detect LPS, FSL-1, and other model IIRMI was also evident when testing 3 different recombinant drug products, product A (a representative mAb), B (a representative growth factor), C (a representative peptide), and their corresponding formulations. These results indicate that product formulations need to be considered when developing and validating cell-based assays for assessing clinically relevant levels of IIRMI in therapeutic proteins. Optimization of reporter cells, culture conditions and drug product concentration appear to be critical to minimize the impact of excipients and attain sensitive and reproducible assays. [ABSTRACT FROM AUTHOR]

An excipient intended for direct compression in pharmaceutical tableting must show important features of flowability and compactibility. This study investigated pregelatinised sago starch as an excipient for direct compression tablets. Pregelatinised sago starch was prepared and characterised. Its powder bulk properties and performance in the tablet formulations with paracetamol as a model drug were compared against two commercial, directly compressible excipients, namely Avicel® PH 101 and Spress® B820. The results showed that pregelatinisation did not affect the chemical structure of sago starch, but its degree of crystallinity reduced, and X-ray diffraction pattern changed from C-type to A-type. Powder bulk properties of pregelatinised sago starch and Spress® B820 were comparable, exhibiting better flowability but lower compactibility than Avicel® PH 101. In the formulation of paracetamol tablets, pregelatinised sago starch and Spress® B820 performed equally well, followed by Avicel® PH 101 as indicated in Formulations 3, 2 and 1, respectively. [ABSTRACT FROM AUTHOR]

Wannada Laisuan,1 Chamard Wongsa,2 Chirawat Chiewchalermsri,3 Torpong Thongngarm,2 Ticha Rerkpattanapipat,1 Pansa Iamrahong,4 Chulapha Ruangwattanachok,4 Sira Nanthapisal,5 Mongkhon Sompornrattanaphan2 1Division of Allergy, Immunology and Rheumatology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 2Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; 3Department of Medicine, Panyananthaphikkhu Chonprathan Medical Center, Srinakharinwirot University, Nonthaburi, Thailand; 4Clinical Pharmacy Section, Pharmacy Division, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 5Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathum Thani, ThailandCorrespondence: Mongkhon SompornrattanaphanDivision of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandTel +66 2419 8263Fax +66 2419 8263Email mongkhon.som@mahidol.ac.thAbstract: Anaphylaxis to CoronaVac, an inactivated vaccine against COVID-19, is extremely rare. We report 12 cases of anaphylaxis after CoronaVac administration, focusing on clinical characteristics and management outcomes. Skin test and graded vaccine challenge were successfully performed in our cases and might be considered if an inactivated vaccine is the only remaining option.Keywords: anaphylaxis, COVID-19 vaccine, drug allergy, excipient, vaccine allergy, COVID-19, skin testing

Abstract Introduction Bentonitic clays from the Hammam Boughrara deposit in the Maghnia area (northwestern Algeria) were studied by mineralogical, chemical and physicochemical characterization to evaluate their potential suitability as raw and purified materials in pharmaceutical and cosmetic applications. Methodology Natural bentonite was purified by Na+ ion exchange treatment combined with sedimentation techniques. Before use in the pharmaceutical industry, bentonite samples must be safe and conform to recommendations and directives of pharmacopeia. A set of technological tests were investigated with the samples, such as cation exchange capacity (CEC), specific surface area (SSA), swelling capacity (SC),sedimentation volume (SV) and viscosity, and mineralogical, chemical and microbial properties were also identified by X-ray fluorescence (XRF), X-ray diffraction (XRD) and scanning electron microscopy (SEM). Results Mineralogical data proved that the raw bentonite is mainly composed of smectite and illite with small quantities of gangue minerals such quartz, feldspars (orthoclase and albite) and calcite. The purified bentonite matches the mineralogical properties of Wyoming bentonite as an international standard clay (deposits of high economic value). Quartz and feldspars were successfully eliminated in the absence of illite and calcite after beneficiation. Investigation of chemical analyses indicated that the contents of trace elements (particularly Pb and As) were below the more restrictive limits proposed by major pharmacopeias for raw and purified bentonite clay. For microbiological tests, the absence of Escherichia coli, Salmonella species, Staphylococcus aureus and Pseudomonas aeruginosa was confirmed. Moreover, we note that a high cation exchange capacity, large surface area, and good swelling capacity and sedimentation volume were also obtained for purified bentonite. Conclusion In view of the fundamentals of major pharmacopoeias for the use of bentonite in pharmacies and considering the results obtained, we identified a pharmaceutically acceptable designation for purified Algerian bentonite, which can be used as a pharmaceutical excipient and in cosmetic products such as creams, powders and emulsions.

Background: Excipients are used in the formulation of pharmaceutical dosage forms, but mayinteract with active pharmaceutical ingredients (APIs). Some of these interactions could alterthe physicochemical properties of the APIs which can affect the therapeutic efficacy and safety.Acarbose is an anti-diabetic drug used in this study as an API to investigate its compatibility withcommon excipients in order to development of pharmaceutical controlled release formulations. Methods: For this purpose, 15 different excipients were selected. Binary mixtures of drug witheach of the excipients (1:1 mass ratio) were prepared. Mixtures were analyzed immediately aftermixing and also after incubation at stress conditions (adding 20% water and incubated at 40°Cfor 2 months). The thermal analytical investigation like differential scanning calorimetry (DSC),Fourier transform infra-red spectroscopy (FTIR) and high-performance liquid chromatography(HPLC) were employed for physicochemical evaluations of the possible incompatibility.Photodiode-array (PDA) and mass studies were performed to ensure the peak purity of theHPLC peaks of API in stressed samples. Results: Incompatible excipients with acarbose were determined as EC (ethyl cellulose),Carbopol 934, Hydroxypropyl cellulose, PEG2000 (Polyethylene Glycol 2000), Mg Stearate, NaAlginate and Poloxamer. Conclusion: Results of this study would be used for the development of controlled releaseformulation of acarbose. It is recommended to avoid the use of incompatible excipients.

Excipients are important components of the final medicinal product. They perform many important functions as fillers, lubricants, disintegrating agents, stabilizers, emulsifiers, etc., and their presence in the formulation is essential. They facilitate the technological process and improve the drug bioavailability. Their proper selection is necessary to obtain the final product with appropriate physicochemical properties. The excipients are not inert compounds. They undergo many interactions with the drug. The occurrence of chemical interactions as a consequence of the chemical reaction of the active substance with the excipient or its impurities can lead to degradation of the drug (including the formation of toxic degradation products) or reduction of its therapeutic properties. Examples of chemical reactions are reactions with water molecules (including hydrolysis), oxidation, isomerization, and other complex chemical reactions such as Maillard reactions. Physical interactions involving changes in physicochemical parameters such as solubility, alteration in flavor, odor, or color lead to changes in the bioavailability of the drug. Physical drug-excipient interactions (adsorption or complex formation, etc.) are commonly used in the pharmaceutical industry e.g., to improve the solubility of lipophilic substances, thus achieving higher bioavailability. Sometimes they are unintentional, and the occurrence of these phenomena may have a detrimental effect on the final product (changes in color, odor, or flavor, difficult drug release from the excipient complex). Excipients may also affect the drug metabolism by enhancing or inhibiting the activity of cytochrome P450 and P-glycoprotein. In addition, they are also subject to a number of interactions with body fluids. The impurities of excipients are an important aspect of the formulation. The most common impurities are oxides, aldehydes, acids, and metals. Usually, these substances are highly reactive. Therefore, their presence is often the cause of incompatibility. In order to minimize the occurrence of interactions, so-called formulation compatibility tests are performed, and the most effective is the combination of thermoanalytical and non-thermoanalytical (spectroscopic, chromatographic) methods of analysis. Currently, there are no globally harmonized regulatory requirements for excipients, however, organizations such as IPEC are working towards harmonization.

Reducing injection-site pain (ISP) in patients with chronic conditions such as growth hormone deficiency is a valuable strategy to improve patient compliance and therapeutic efficiency. Thus understanding different aspects of pain induction following subcutaneous injection of biotherapeutics and identifying the responsible factors are vital. Here we have discussed the effects of formulation’s viscosity, concentration, osmolality, buffering agents, pH, and temperature as well as injection volume, dosing frequency, and different excipients on ISP following subcutaneous injection of commercially available recombinant human growth hormone products. Our literature review found limited available data on the effects of different components of parenteral rhGH products on ISP. This may be due to high cost associated with conducting various clinical trials to assess each excipient in the formulation or to determine the complex interactions of different components and its impact on ISP. Recently, conducting molecular dynamics simulation studies before formulation design has been recommended as an alternative and less-expensive approach. On the other hand, the observed inconsistencies in the available data is mainly due to different pain measurement approaches used in each study. Moreover, it is difficult to translate data obtained from animal studies to human subjects. Despite all these limitations, our investigation showed that components of parenteral rhGH products can significantly contribute to ISP. We suggest further investigation is required for development of long acting, buffer-free, preservative-free formulations. Besides, various excipients are currently being investigated for reducing ISP which can be used as alternatives for common buffers, surfactants or preservatives in designing future rhGH formulations.

Unintended immunogenicity can affect the safety and efficacy of therapeutic proteins and peptides, so accurate assessments of immunogenicity risk can aid in the selection, development, and regulation of biologics. Product- and process- related impurities can act as adjuvants that activate the local or systemic innate immune response increasing the likelihood of product immunogenicity. Thus, assessing whether products have innate immune response modulating impurities (IIRMI) is a key component of immunogenicity risk assessments. Identifying trace levels of individual IIRMI can be difficult and testing individually for all potential impurities is not feasible. Therefore, to mitigate the risk, cell-based assays that use human blood cells or monocyte-macrophage reporter cell lines are being developed to detect minute quantities of impurities capable of eliciting innate immune activation. As these are cell-based assays, there is concern that excipients could blunt the cell responses, masking the presence of immunogenic IIRMI. Here, we explore the impact of frequently used excipients (non-ionic detergents, sugars, amino acids, bulking agents) on the sensitivity of reporter cell lines (THP-1- and RAW-Blue cells) and fresh human blood cells to detect purified TLR agonists as model IIRMI. We show that while excipients do not modulate the innate immune response elicited by TLR agonists in vivo, they can impact on the sensitivity of cell-based IIRMI assays. Reduced sensitivity to detect LPS, FSL-1, and other model IIRMI was also evident when testing 3 different recombinant drug products, product A (a representative mAb), B (a representative growth factor), C (a representative peptide), and their corresponding formulations. These results indicate that product formulations need to be considered when developing and validating cell-based assays for assessing clinically relevant levels of IIRMI in therapeutic proteins. Optimization of reporter cells, culture conditions and drug product concentration appear to be critical to minimize the impact of excipients and attain sensitive and reproducible assays.

Abstract The objective of this study was to determine the influence of nonionic surfactants on the effectiveness of preservatives used in emulsions containing high surfactant content. Mixtures of different concentrations were prepared between polyethoxylated (40) hydrogenated castor oil (PHCO) and polyoxyethylene sorbitan monooleate (PSO), with methylparaben, phenoxyethanol, methylparaben, ethylparaben, propylparaben, and isobutylparaben (PMEPBI) blend, phenoxyethanol and benzoic acid (BP) blend, and phenoxyethanol and caprylyl glycol (PC) blend. Subsequently, the compatibility of the formulation ingredients and the effectiveness of the preservatives were evaluated by the challenge test. It was found that PHCO and PSO inactivated the antimicrobial action of methylparaben and PMEPBI. Paraben-free preservatives BP and PC had less influence on surfactants than systems containing parabens. When incorporated into microemulsions and nanoemulsions containing 40% and 20% surfactants, methylparaben and BP 0.2% and 0.5% were only effective against Aspergillus niger. The PMEPBI 0.2% was effective as a preservative in nanoemulsified formulations against A. niger, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. The results demonstrate that the efficacy of the preservative system in formulations containing nonionic surfactant excipients depends on the type of excipient, the components of the formulation, the preservative systems composition, the excipient to preservative ratio, and the availability in the formulation.

Mycobacterium tuberculosis (M.tb) has infected one-quarter of the world’s population and led to the deaths of 1.6 million individuals in 2021 according to estimates from the World Health Organization. The rise in prevalence of multidrug-resistant and extensively drug-resistant M.tb strains coupled with insufficient therapies to treat such strains has motivated the development of more effective treatments and/or delivery modalities. Bedaquiline, a diarylquinoline antimycobacterial agent, effectively targets mycobacterial ATP synthase but may lead to systemic complications upon oral delivery. Targeted delivery of bedaquiline to the lungs represents an alternative strategy to harness the sterilizing benefits of the drug against M.tb while mitigating off-target side effects. Two pulmonary delivery modalities were developed herein, including dry powder inhalation and liquid instillation. Despite bedaquiline’s poor water solubility, spray drying was performed in predominantly aqueous conditions (≥80%) to avoid a closed-loop, inert system. Aerosols of spray-dried bedaquiline with L-leucine excipient outperformed spray-dried bedaquiline alone, demonstrating superior fine particle fraction metrics (~89% of the emitted dose below M.tb bacilli enter the body is aerosol droplets that are deposited onto airway surfaces. For this reason, we believe that further studies should focus on inhalation or intrapulmonary therapies that target the site of entry and primary site of infection for M.tb.

Glucomannan (GM)—a polysaccharide generally extracted from the tuber of Amorphophallus konjac—has great potential as a filler–binder in direct compression, disintegrant in tablets, or gelling agent due to its strong hydrophilicity and extremely high viscosity. However, it has poor water resistance and low mechanical strength when used as an excipient in solid form. Several physical and chemical modifications have been carried out to improve these drawbacks. Chemical modification affects the characteristics of GM based on the DS. Carboxymethylation improves GM functionality by modifying its solubility and viscosity, which in turn allows it to bind water more efficiently and thus improve its elongation and gel homogeneity. Meanwhile, physical modification enhances functionality through combination with other excipients to improve mechanical properties and modify swelling ability and drug release from the matrix. This review discusses extraction of GM and its modification to enhance its applicability as an excipient in solid form. Modified GM is a novel excipient applicable in the pharmaceutical industry for direct compression, as a tablet disintegrant, a film-forming agent, and for encapsulation of macromolecular compounds or drug carriers for controlled release. [ABSTRACT FROM AUTHOR]

Tuberculosis is one of the most frequent causes of death in humans worldwide. One of the primary reasons tuberculosis remains a public health threat is that diagnosis can take weeks to months, is often not very sensitive and cannot be accomplished in many remote environments. A rapid, sensitive and inexpensive point-of-care (POC) diagnostic would have a major impact on tuberculosis eradication efforts. The tuberculosis diagnostic system REFtb is based on specific detection of the constitutively expressed β-lactamase (BlaC) in Mycobacterium tuberculosis using a custom fluorogenic substrate designated as CDG-3. REFtb has potential as a diagnostic for tuberculosis that could be very inexpensive (