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Propylene glycol (PG) is a pharmaceutical excipient which is generally regarded as safe (GRAS), though clinical toxicity has been reported. PG toxicity has been attributed to accumulation due to saturation of the alcohol dehydrogenase (ADH)‐mediated clearance pathway. This study aims to explore the impact of the saturation of ADH‐mediated PG metabolism on its developmental clearance in adults and neonates and assess the impact of a range of doses on PG clearance saturation and toxicity. Physiologically based pharmacokinetic (PBPK) models for PG in adults and term neonates were developed using maximum velocity (Vmax) and Michaelis–Menten's constant (Km) of ADH‐mediated metabolism determined in vitro in human liver cytosol, published physicochemical, drug‐related and ADH ontogeny parameters. The models were validated and used to determine the impact of dosing regimen on PG clearance saturation and toxicity in adults and neonates. The Vmax and Km of PG in human liver cytosol were 1.57 nmol/min/mg protein and 25.1 mM, respectively. The PG PBPK model adequately described PG PK profiles in adults and neonates. The PG dosing regimens associated with saturation and toxicity were dependent on both dose amount and cumulative in standard dosing frequencies. Doses resulting in saturation were higher than those associated with clinically observed toxicity. In individuals without impaired clearance or when PG exposure is through formulations that contain excipients with possible interaction with PG, a total daily dose of 100–200 mg/kg/day in adults and 25–50 mg/kg/day in neonates is unlikely to result in toxic PG levels or PG clearance saturation. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) remains one of the most aggressive and treatment-resistant forms of brain cancer, with a notoriously poor prognosis. A major hurdle in effectively targeting GBM is the presence of the blood-brain barrier (BBB), a highly selective barrier that impedes the delivery of therapeutic agents to the tumor site. This review examines the potential of permeable macromolecules as a novel approach for targeted therapy in GBM treatment. We explore the design and function of these macromolecules, which are engineered to traverse the BBB and deliver therapeutic agents directly to the tumor, thereby enhancing treatment efficacy and minimizing systemic toxicity. The review highlights various types of permeable macromolecules, including their mechanisms of BBB penetration, and the strategies employed to optimize their therapeutic payload. We also address the challenges in the development and clinical translation of these macromolecules, including issues related to biocompatibility, pharmacokinetics, and targeted delivery. Additionally, we discuss the potential of these macromolecules in overcoming drug resistance and preventing tumor recurrence, key concerns in GBM treatment. This review underscores the promising future of permeable macromolecules in GBM therapy, offering insights into their role in advancing personalized and targeted treatment strategies. With continued research and development, these macromolecules hold the potential to significantly improve outcomes for patients suffering from this devastating disease. [ABSTRACT FROM AUTHOR]

A critical measure of the quality of pharmaceutical proteins is the preservation of native conformations of the active pharmaceutical ingredients. Denaturation of the active proteins in any step before administration into patients could lead to loss of potency and/or aggregation, which is associated with an increased risk of immunogenicity of the products. Interfacial stress enhances protein instability as their adsorption to the air‐liquid and liquid–solid interfaces are implicated in the formation of denatured proteins and aggregates. While excipients in protein formulations have been employed to reduce the risk of aggregation, the roles of albumin as a stabilizer have not been reviewed from practical and theoretical standpoints. The amphiphilic nature of albumin makes it accumulate at the interfaces. In this review, we aim to bridge the knowledge gap between interfacial instability and the influence of albumin as a surface‐active excipient in the context of reducing the immunogenicity risk of protein formulations. [ABSTRACT FROM AUTHOR]

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]

Protein biotherapeutics typically require expensive cold‐chain storage to maintain their fold and function. Packaging proteins in the dry state via lyophilization can reduce these cold‐chain requirements. However, formulating proteins for lyophilization often requires extensive optimization of excipients that both maintain the protein folded state during freezing and drying (i.e., "cryoprotection" and "lyoprotection"), and form a cake to carry the dehydrated protein. Here we show that sweet corn phytoglycogens, which are glucose dendrimers, can act as both a protein lyoprotectant and a cake‐forming agent. Phytoglycogen (PG) dendrimers from 16 different maize sources (PG1‐16) were extracted via ethanol precipitation. PG size was generally consistent at ~70–100 nm for all variants, whereas the colloidal stability in water, protein contaminant level, and maximum density of cytocompatibility varied for PG1‐16. 10 mg/mL PG1, 2, 9, 13, 15, and 16 maintained the activity of various proteins, including green fluorescent protein, lysozyme, β‐galactosidase, and horseradish peroxidase, over a broad range of concentrations, through multiple rounds of lyophilization. PG13 was identified as the lead excipient candidate as it demonstrated narrow dispersity, colloidal stability in phosphate‐buffered saline, low protein contaminants, and cytocompatibility up to 10 mg/mL in NIH3T3 cell cultures. All dry protein‐PG13 mixtures had a cake‐like appearance and all frozen protein‐PG13 mixtures had a Tg' of ~ −26°C. The lyoprotection and cake‐forming properties of PG13 were density‐dependent, requiring a minimum density of 5 mg/mL for maximum activity. Collectively these data establish PG dendrimers as a new class of excipient to formulate proteins in the dry state. [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]

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Although biopharmaceuticals constitute around 10% of the drug landscape, eight of the ten top-selling products were biopharmaceuticals in 2023. This study did a comprehensive analysis of the FDA’s Purple Book database. Firstly, our research uncovered market trends and provided insights into biologics distributions. According to the investigation, although biotechnology has advanced and legislative shifts have made the approval process faster, there are still challenges to overcome, such as molecular instability and formulation design. Moreover, our research comprehensively analyzed biological formulations, pointing out significant strategies regarding administration routes, dosage forms, product packaging, and excipients. In conjunction with biologics, the widespread integration of innovative delivery strategies will be implemented to confront the evolving challenges in healthcare and meet an expanding array of treatment needs. [ABSTRACT FROM AUTHOR]

Titanium dioxide (TiO2) is used primarily as an opacifier in solid dosage forms and is present in the majority of tablet and capsule dosage forms on the market. The IQ* TiO2 Working Group has previously shown that titanium dioxide has unique properties which are necessary for its function in these formulations and noted that, as the potential replacements lack the semi-conductor properties, high refractive index and whiteness of E171, it might be hard to replicate these properties with alternative materials. In this paper we detail the results of readiness surveys and practical assessments that have been conducted with alternative materials by IQ member companies. A range of technical challenges and regulatory hurdles were identified which mean that, in the short term, it may be difficult to replace titanium dioxide with the currently available alternative materials while readily achieving the same drug product quality attributes, especially for some of the marketed formulations that titanium dioxide is currently used for. We note the higher technical complexity, due to the variability, color fading and identified scale up risk, of E171 free film coatings and the likely impact on development costs and timelines. We also highlight several regulatory hurdles that would have to be overcome if a titanium dioxide replacement was required for some markets but was not mandated by others. [ABSTRACT FROM AUTHOR]

Excipients are important components of pharmaceutical preparations that affect their quality, safety, and efficacy. Macrocyclic receptors are a family of supramolecular excipients with several advantages, including molecular-level protection, small sizes, fast kinetics of host-guest recognition, and modular construction. With the continuous advances in the medical field, personalized and precision medicine requires the development of excipients with low dosages, integrated modifying effects, universality, and controlled release. To meet these requirements, we have developed a new family of macrocyclic excipients based on calixarenes by integrating their covalent (broad chemical design space) and noncovalent (wide range of substrates) advantages. Accordingly, azocalixarenes (AzoCAs) were designed, showing high binding affinities to a broad spectrum of active pharmaceutical ingredients (APIs), selectivity to interferents, and responsiveness to hypoxic microenvironments. Due to their highly efficient and controllable recognition, AzoCAs serve as low-dose excipients for 30 APIs. Molecular encapsulation by AzoCAs results in the integrated modification of the physicochemical properties of APIs, including solubility, stability, bioavailability, and biocompatibility. Moreover, AzoCAs can be reduced by azoreductases overexpressed in hypoxic microenvironments, leading to the controlled release of APIs. Collectively, AzoCA excipients have broad application prospects for a series of diseases such as enteritis, arthritis, stroke, cancer, bacterial infection and kidney injury, with diverse therapeutic modalities, including chemotherapy, photodynamic therapy, photothermal therapy, immunotherapy, boron neutron capture therapy, radiotherapy, fluorescence imaging, and their combinations. [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]

Psoriasis is a chronic inflammatory skin disease. Topical medicines are the preferred treatment for mild to moderate psoriasis, but the effect of excipients used in semi‐solid preparations on psoriasis‐like skin inflammation is not fully understood. In the present study, we investigated the effect of stearyl alcohol, a commonly used excipient, on imiquimod (IMQ)‐induced psoriasis‐like skin inflammation in mice. Psoriasis‐like skin inflammation was induced by topical IMQ treatment on the back of mice. Skin lesion severity was evaluated by using psoriasis area and severity index (PASI) scores. The skin sections were stained by haematoxylin–eosin and immunohistochemistry. Stearyl alcohol (20% in vaseline) treatment significantly reduced the IMQ‐induced increase of PASI scores and epidermal thickness in mice. IMQ treatment increased the number of Ki67‐ and proliferating cell nuclear antigen (PCNA)‐positive cells in the skin, and the increases were inhibited by stearyl alcohol (20% in vaseline) treatment. Stearyl alcohol treatment (1%, 5%, 10% in vaseline) dose‐dependently ameliorated IMQ‐induced increase of PASI scores and epidermal thickness in mice. Hexadecanol (20% in vaseline), stearic acid (20% in vaseline) and vaseline treatment had no significant effect on IMQ‐induced psoriasis‐like skin inflammation in mice. In conclusion, stearyl alcohol has the effect of improving IMQ‐induced psoriasis‐like skin inflammation in mice. [ABSTRACT FROM AUTHOR]

Orbital shaking in a glass vial is a commonly used forced degradation test to evaluate protein propensity for agitation-induced aggregation. Vial shaking in horizontal orientation has been widely recommended to maximize the air-liquid interface area while ensuring solution contact with the stopper. We evaluated the impact of shaking orbit diameter and frequency, and glass vial orientation (horizontal versus vertical) on the aggregation of three proteins prepared in surfactant-free formulation buffers. As soon as an orbit-specific frequency threshold was reached, an increase in turbidity was observed for the three proteins in vertical orientation only when using a 3 mm agitation orbit, and in horizontal orientation only when using a 30 mm agitation orbit. Orthogonal analyses confirmed turbidity was linked to protein aggregation. The most turbid samples had a visually more homogeneous appearance in vertical than in horizontal orientation, in line with the predicted dispersion of air and liquid phases obtained from computational fluid dynamics agitation simulations. Both shaking orbits were used to assess the performance of nonionic surfactants. We show that the propensity of a protein to aggregate in a vial agitated in horizontal or vertical orientation depends on the shaking orbit, and confirm that Brij® 58 and FM1000 prevent proteins from agitation-induced aggregation at lower concentrations than polysorbate 80. [Display omitted] • Protein propensity for aggregation in a vial agitated in horizontal or vertical orientation depends on the shaking orbit. • Computational fluid dynamics agitation simulations reflect the visual homogeneity of aggregated samples. • Brij® 58 and FM1000 prevent proteins from agitation-induced aggregation at lower concentrations than polysorbate 80. [ABSTRACT FROM AUTHOR]

Introduction: Potentially harmful excipients (PHEs) for children have been reported and the need for information collection has been advocated. However, studies on the actual occurrence of adverse events are limited. This study investigated the quantitative exposure of PHEs via injection and their association with adverse events in children under 2 years of age. Materials and Methods: As a single-center observational study, children aged 0–23 months received injectable drugs from April 1, 2018, to March 31, 2023 were included. Information on PHE exposure and adverse events after administration were extracted from medical records. Sodium benzoate, benzyl alcohol, ethanol, glycerol, lactose, polyethylene glycol paraben, polysorbate, propylene glycol, sorbitol, sucrose, sulfite, and thimerosal were selected as PHEs. Results and Discussion: 6265 cases, 333,694 prescriptions, and 368 drugs (264 ingredients) were analyzed. The median age was 0.63 years (interquartile range [IQR] 0.1–1.1). 72,133 prescriptions, 132 drugs and 99 ingredients contained PHE; 2,961 cases exposed to PHE and 1825 cases exceeding permitted daily exposure. The drug with the highest number of exposure cases was hydroxyzine, and the highest number of prescriptions was heparin (both drugs contain benzyl alcohol). In association between adverse events and PHE exposure, higher doses in cases of adverse event occurrence were found in benzyl alcohol, glycerol, polyethylene glycol, and polysorbate exposed cases. Among thimerosal-exposed cases, "developmental delay" was more frequent in exposed cases, but the causal relationship was unknown. Further investigation is needed to clarify the relationship between adverse events and PHE exposure. Additionally, more precise information on PDE for pediatrics including neonates is necessary. [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]

[Display omitted] This study discusses the lubricant properties of magnesium stearate solid lipid nanoparticles (MgSt-SLN) and their effect on the tabletability, mechanical properties, disintegration, and acetaminophen-model dissolution time of microcrystalline cellulose (MCC) tablets prepared by direct compression. The behavior of MgSt-SLN was compared to reference material (RM) to identify advantages and drawbacks. The nanoprecipitation/ion exchange method was employed to prepare the MgSt-SLN. Particle size, zeta potential, specific surface area, morphology, and true density were measured to characterize the nanosystem. The MgSt-SLN particle sizes obtained were 240 ± 5 nm with a specific surface area of 12.2 m2/g. The MCC tablets with MgSt-SLN presented a reduction greater than 20 % in their ejection force, good tabletability, higher tensile strength, lower disintegration delay, and marked differences in acetaminophen dissolution when compared to the RM. The reduced particle size of the magnesium stearate seems to offer a promising technological advantage as an efficient lubricant process that does not affect the properties of tablets. [ABSTRACT FROM AUTHOR]

Excipients are essential components within drug products that contribute significantly to their overall quality, effectiveness, and safety. There is a lack of global, harmonized guidance relating to the non-clinical testing of novel excipients which is perceived to create uncertainty and strategic risk, potentially hindering innovation and disincentivizing their use. To test these perceptions, the IQ Novel Excipient Working Group surveyed member companies regarding their main concerns and prior experience regarding the non-clinical evaluation of excipients. Of the 19 respondents, 13 provided, collectively, 33 non-clinical program examples supporting the development of novel excipients. Programs were distributed across a range of therapeutic areas and included a variety of drug modalities and administration routes. Package designs were variable, but where possible, employed the use of existing data, supplemented with new toxicology studies as appropriate. Of the programs which had submitted data to regional health authorities, only three received feedback requesting additional studies or that demonstrated differences in regional opinion. In addition, companies provided recommendations on how the current (or new) guidance related to non-clinical excipient evaluation (and other areas, such as Chemistry, Manufacturing, and Controls and databases) may be improved. [ABSTRACT FROM AUTHOR]

• Preclinical studies in rats show rapid absorption and elimination of caffeine with no effect from co-administered model mAb. • Caffeine does not affect PK profiles and SQ bioavailability of the model mAb. • SQ injection of caffeine at the tested dose levels shows no safety concern. • Current studies ensure further development of caffeine as a viscosity reducing excipient for high concentration mAb formulations. Caffeine is a novel excipient that effectively reduces viscosity of high concentration mAb formulations intended for subcutaneous (SQ) delivery. Two preclinical studies were conducted in rats to evaluate pharmacokinetic (PK) parameters of caffeine as well as its effects on the PK profile of a model mAb, namely ipilimumab. Results show that SQ absorption and elimination of caffeine was rapid, with the average T max of 0.4 h and T 1/2 of 1.6 h, administered with or without ipilimumab. Furthermore, caffeine did not affect ipilimumab SQ PK profiles. Independent of caffeine concentration, ipilimumab serum T 1/2 was between 2 and 3 days, T max was between 3 and 4 days and SQ bioavailability was about 64%. In addition, SQ injection of caffeine at different dose levels showed no irritation at the injection site or adverse effects. Results from the current PK studies warrant further development of caffeine as a viscosity reducing excipient for mAb SQ formulations. [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]

[Display omitted] Pharmaceutical excipients are an important part of biological products. However, few attempts have been made to distinguish between the risk of inflammation associated with the biological products themselves and that associated with excipients. The analysis of early immune response risk associated with excipients added to biological products is an important step in exploring the complex mechanism of side effects in susceptible patients. In this study, nanoparticle impurities (NPIs) were extracted from trehalose and characterized. A mouse popliteal lymph node cell (PLNA) model, a mouse spleen lymphocyte model, a human peripheral blood mononuclear cell cytokine release model, and a macrophage complement activation model were established to comprehensively evaluate the early immune risk related to impurities in the trehalose excipient. Although popliteal lymph node cell counts in mice did not show significant differences, all other models indicated possible immune risk. In the PLNA model, NPIs caused significant toe thickening in mice, whereby the content of IgE and MCP-1 increased significantly. NPIs significantly increased the proliferation and differentiation of spleen lymphocytes according to the CCK-8 assay and flow cytometry. After treatment with NPIs, the release of IgE and a variety of cytokines (MIP-1α, IFN-γ, IL-2, IL-8, TNF-α, IL-6, IL-1α) in human peripheral blood cells was significantly increased according to ELISA, while a concomitant increase of C3a/C5a as well as C4a/Bb proved that NPIs activated the complement system. NPIs from trehalose elicited an immune response in vitro, and the immune response to trehalose may be related to NPIs and not the excipient itself. Different batches of trehalose showed different immune response effects. The currents research suggests that when trehalose is applied in high-risk administration routes, NPIs should be assessed and reasonably controlled. [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.

This article discusses a case report of a 64-year-old female patient who experienced a delayed-type hypersensitivity reaction after taking a tablet of fosfomycin trometamol for a urinary tract infection. The patient had previously experienced a similar reaction after receiving an iodinated contrast agent. Skin tests and a lymphocyte transformation test confirmed a sensitization to trometamol. Trometamol is commonly used as a buffer in various medications and cosmetic products. This case highlights the importance of considering excipients, such as trometamol, in allergy workups and the potential consequences for patients who may encounter this ingredient in multiple medications and treatments. [Extracted from the article]

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]

In this paper, ten samples containing promestriene (PRMS) were investigated, namely the pure active pharmaceutical ingredient (API) and nine binary mixtures prepared with commonly used excipients in solid pharmaceutical formulations. The necessity of such study is represented by the fact that the physicochemical screening of PRMS is not reported in the literature. Also, as convergent arguments for the necessity of this study, it can be mentioned that on Romanian pharmaceutical market, promestriene containing formulations are no longer commercialized since 2015, creating health problems to a large category of patients. As such, this study can serve as a starting point for the adequate selection of ingredients used in magistral preparations, with increased stability and bioavailability. The study revealed that PRMS is compatible with all of the selected excipients, namely methyl 2-hydroxyethyl cellulose (tylose), methyl cellulose (MethocelTM), starch, mannitol, magnesium stearate, magnesium citrate, Talc, colloidal SiO2 (aerosil) and polyvinylpyrrolidone K-30 (PVPK30), as confirmed by universal attenuated total reflectance Fourier transform infrared (UATR-FTIR) spectroscopy, powder X-ray diffraction patterns and thermal analysis. [ABSTRACT FROM AUTHOR]

N -nitrosamines are genotoxic compounds which can be found as impurities in drug substances and drug products used in the pharmaceutical industry. To date, several possible nitrosamine sources in drug products have been reported and this study aims to illuminate another one. A case of afatinib drug product was investigated, in which up to 50 ppb N -nitrosodimethylamine (NDMA) traces were detected. Afatinib was found to degrade to the secondary amine dimethylamine (DMA), forming NDMA with traces of nitrite in crospovidone. Two series of film-coated tablets were prepared with crospovidone from two different manufacturers, containing different levels of nitrites. Tablets were subjected to an accelerated stability study (40 °C/75% relative humidity) or stored at room temperature and levels of NDMA, DMA and nitrite in tablets were monitored. NDMA and nitrite were found on ppb levels, whereas DMA was detected on ppm levels. NDMA formation in the drug product was found to be time, temperature and nitrite dependent and it was emphasized that DMA and nitrite should be reduced. The accelerated stability study proved to be a useful tool for predicting nitrosamine formation in the drug product. [Display omitted] [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.

BACKGROUND: Two-drug regimens antiretroviral therapies are increasingly prescribed to HIV patients, as they are recommended by international guidelines, and they show an excellent efficacy, safety, and tolerability profile. Regimens administered as single tablets (STRs) are usually preferred by patients and they are associated with higher adherence. CASE REPORT: We report two cases of drug-induced hypersensitivity (DIH) that occurred after switching from dolutegravir (DTG) plus rilpivirine (RPV) in separate pills to a fixed dose combination containing the same molecules (DTG/RPV; Juluca®). Following the DIH event, DTG/RPV coformulation was discontinued. At symptomatic resolution, they continued to receive DTG plus RPV in separate pills uneventfully. The component present only in the DTG/RPV coformulation was iron oxide red (E172), contained in the film-coating. Iron oxide red is an approved colorant, used as drug excipient. Patch test with DTG/RV coformulation performed several months after the DIH event was negative. Drug allergy to excipients remains underappreciated and underreported and frequently leads to inappropriate medication discontinuation. CONCLUSION: Our case underscores the role of meticulous medication allergy history in differentiating true medication allergy from excipient allergy. This observation may be useful in the era of antiretroviral simplification to two-drug regimens. [ABSTRACT FROM AUTHOR]

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]

Objective: During drug preformulation studies, thermal analysis and spectroscopic techniques are used to detect physical or chemical incompatibilities between the active compound and the excipients in the formulation, and to demonstrate the safety and/or efficacy of the final product. It has revolutionized erectile dysfunction with the development of a selective cyclic guanosine monophosphate-specific PDE-5 inhibitors. Tadalafil is one of these inhibitors. Excipients are included in dosage forms to assist in manufacture, absorption or application. Although considered to be pharmacologically inert, the drug active compound may impair effectiveness. Material and Method: DSC, TGA, and FTIR, were used in the work. Ascorbic acid, butylated hydroxyanisole, calcium phosphate dibasic, cellulose, magnesium stearate, mannitol, sodium carboxymethyl cellulose, sucrose, talc, starch, primojel, and citric acid exhibit interaction with Tadalafil. Binary mixtures of drug:excipient have been analyzed. Results: Based on spectroscopic and thermal results; Tadalafil is incompatible with magnesium stearate, mannitol, sucrose, and ascorbic acid. Conclusion: Studies to investigate drug-excipient compatibility are an important step in drug development studies. Thermal and spectroscopic techniques are widely used in such studies. [ABSTRACT FROM AUTHOR]

Objective: The aim of the research study is to compare the effects of excipient and pH and to develop a stable pharmaceutical product of desloratadine syrup formulation. For this stability study, 7 different formulation trial studies were prepared. In this study, different excipients were used and in this way different pH values were obtained to improve the product. Methods: To improve the stability of desloratadine, 7 different formulations (F1-F7) were evaluated as different excipients, pH and impurities of desloratadine during the stability period. Each trial formulation was compared with pH and impurity results at different stability conditions at initial, 3rd month, 6th month. Results: The most stable formulation study was evaluated within the pharmacopeia limits determined by comparing the stability results with each other in 7 different trial studies. According to the evaluation results, the F7 formulation was chosen as the most stable and best formulation in the studies. Conclusion: According to the evaluation results, the F7 formulation was chosen as the most stable and best formulation in the studies. [ABSTRACT FROM AUTHOR]