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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.

Opalescence is a problem concerned with the stability of an antibody solution. It occurs when a high concentration of a protein is present. Arginine (Arg) is a versatile aggregation suppressor of proteins, which is among the candidates that suppress opalescence in antibody solutions. Here, we investigated the effect of various types of small molecular additives on opalescence to reveal the mechanism of Arg in preventing opalescence in antibody solution. As expected, Arg suppressed the opalescence of the immunoglobulin G (IgG) solution. Arg also concentration dependently inhibited the formation of microstructures in IgG molecules. Interestingly, the intrinsic fluorescence spectra of highly concentrated IgG solutions differed from those having low concentrations, even though IgG retained a distinct tertiary structure. Arginine ethylester was more effective in suppressing the opalescence of IgG solutions than Arg, whereas lysine and γ-guanidinobutyric acid were less effective. These results indicated that positively charged groups of both α-amine and guanidinium actively influence Arg as an additive for suppressing opalescence. Diols, which are the suppressors of the liquid–liquid phase separation of proteins were also effective in suppressing the opalescence. These results therefore provide insight into the control of opalescence of antibody solutions at high concentrations using solution additives. [ABSTRACT FROM AUTHOR]

The encapsulation of proteins into core-shell structures is a widely utilised strategy for controlling protein stability, delivery and release. Despite the recognised utility of these microstructures, however, core-shell fabrication routes are often too costly or poorly scalable to allow for industrial translation. Furthermore, many scalable routes rely upon emulsion-techniques implicating denaturing or environmentally harmful organic solvents. Herein, we investigate core-shell protein encapsulation through single-feed, aqueous spray drying: a cheap, industrially ubiquitous particle-formation technology in the absence of organic solvents. We show that an excipient's preference for the surface of the spray dried particle is well-predicted by its hydrodynamic diameter (D h ) under relevant feed buffer conditions (pH and ionic strength) and that the predictive power of D h is improved when measured at the spray dryer outlet temperature compared to room temperature ( R 2 = 0.64 vs. 0.59). Lastly, we leverage these findings to propose an adaptable design framework for fabricating core-shell protein encapsulates by single-feed aqueous spray drying. [ABSTRACT FROM AUTHOR]

A liquid chromatography-mass spectrometry (LC–MS) method was developed to provide a fingerprint of polysorbate 80 (PS80) subspecies that enables identification of PS80 degradation pathway. The developed method demonstrates unique monoester peak profile of PS80 from different vendors, attributed by differences in relative abundance of the fatty acid monoesters. The LC–MS method was also applied to examine the susceptibility of PS80, at different grades, to auto-oxidation and hydrolysis. PS80 oxidative degradation induced by iron or occurred in open bottle without nitrogen overlay was found to follow the same pathway, but at a much faster rate in the former scenario. The oxidation preferentially occurs at the double bond of fatty acid chains, thus providing explanation on the faster degradation observed in PS80 at Chinese Pharmacopia (ChP) grade than at multi-compendial (MC) grade. In contrast, the difference in susceptibility of MC and ChP grade PS80 against esterase-induced hydrolysis in placebo was not pronounced. The method was also able to provide a fingerprint to identify both PS80 hydrolysis and oxidation in mAb drug product stability samples, but it required a solid phase extraction step to remove protein prior to the analysis. [ABSTRACT FROM AUTHOR]

The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. In particular, sugar alcohols have been identified as potential absorption-modifying excipients. These biowaivers and excipient risks are discussed here. [ABSTRACT FROM AUTHOR]

Abstract Background Pharmaceutical excipient development is an extensive process requiring a series of pre-formulation studies to evaluate their performance. The present study compares the conventional compaction and compression pre-formulation studies with artificial intelligence (AI) modeling to predict the performances of thermally and chemically modified starches obtained from Livingstone potato. Results The native starch was modified by three methods, and we obtained the following starches; pregelatinized starch (PS), ethanol dehydrated pregelatinized starch (ES), and acid hydrolyzed starch (AS). Microcrystalline cellulose (Avicel® PH101) was employed as a reference since its use in tablet direct compression has been established. The role of compaction pressure on the degree of volume reduction of the tablets was studied using Kawakita and Heckel models which highlighted that when the starch is modified by pregelatinization followed by ethanol dehydration, and/and or acid hydrolysis modification, a directly compressible starch can be obtained that can plastically deform. The data-intelligence results indicated the reliability of the AI-based models over the linear models. Hence, the comparative results demonstrated that the Adaptive neuro-fuzzy inference system (ANFIS) outperformed the other two models in modeling the performance of all of the four excipients with considerable performance accuracy. Conclusion The compressibility indices have shown matching characteristics of AS and ES to Avicel® PH101 in terms of direct compressibility potential than PS. Moreover, the data intelligence modeling demonstrates the reliability and satisfactory of ANFIS as a hybrid model over the other two models with increased performance skills in modeling the compaction properties of these novel pharmaceutical excipients.

The objective of present work was to isolate the mucilage as polysaccharide from the seeds of Cassia obtustifolia and to modify the isolated polysaccharide chemically by thiolation and carboxymethylation to develop novel excipient for drug delivery application. The attempts were made to enhance mucoadhesive potential of Cassia obtustifolia seed mucilage by thiolation and to reduce the disintegration time in prepared tablets by carboxymethylation. Thiolation of Cassia obtustifolia seed mucilage was achieved by esterification with thioglycolic acid and thiol group content was measured by using Ellman's reagent, whereas carboxymethylation was archived by etherification of Cassia obtusifolia seed mucilage with monochloroacetic acid and the degree of carboxymethyl substitution was determined by titrimetric method. Thiolation and carboxymethylation of Cassia mucilage was confirmed by, Fourier transform infrared spectroscopy (FT-IR), 1H NMR spectroscopy, differential scanning calorimeter (DSC thermogram) and by Zeta potential measurement. The findings demonstrated that there is significant improvement in bioadhesive and disintegration property via respective chemical modifications such as thiolation and carboxymethylation. [ABSTRACT FROM AUTHOR]

[Objectives] To optimize the forming process of Yi medicine Tongfeng Granules. [Methods] The forming process of Yi medicine Tongfeng Granules was optimized, with paste density, ethanol volume fraction, and type and proportion of excipient as inffuencing factors, and granule formability, solubility, moisture absorption, and angle of repose as evaluation indicators. Critical relative humidity (CRH) was investigated to select optimal storage conditions. [Results] Maltodextrin was selected as the excipient, and the best procees parameters was the ratio of drug to excipient at 1 : 2 ( g/g), under which the forming rate, solubility, moisture absorption rate, and angle of repose were 81.38%, 98.90%, 8. 81%, and 27.5°, respectively. The critical relative humidity was 72%. [Conclusions] The forming procees adopted is reasonable and feasible, and can provide a reference for large-scale production of Yi medicine Tongfeng Granules. [ABSTRACT FROM AUTHOR]

Soy polysaccharides represent a multipurpose class of chemicals that include both therapeutical and technological properties. Since they have been first time introduced in the pharmaceutical field, Soy polysaccharides were used in two different pharmaceutical formulations; sublingual tablets and in colon drug delivery. For the sublingual tablets, Soy polysaccharides under the brand name of Emcosoy© - were used as a superdisintegrant in concentrations between 4-8% showing comparable results with the artificial superdisintegrants (sodium starch glycolate, sodium croscarmellose, and polyvinylpyrrolidone). The second technological field where Soy polysaccharides were used is represented by colon drug delivery where it was used in combination with ethylcellulose showing a prolonged lag time compared to the results found in the literature. The medicinal effect of these polysaccharides consists of treating diarrhea. As it will be presented in the article, these chemical compounds tend to decrease the aqueous stool time in patients with diarrhea and to conduct to a softer stool in healthy patients. In conclusion, these polysaccharides present multiple purposes possessing a medicinal effect and also the possibility of being used as a double-faceted pharmaceutical excipient. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Objectives: The physicochemical characteristics of bran of cassava starch flour and bran of cassava flour (viz. organoleptic characteristics, pH value, moisture content, total ashes, lipid, protein, starch and fiber contents) and biopharmacotechnical parameters (viz. granulometry, flow capacity, angle at rest, outflow time and apparent density) were evaluated aiming at assessing their potential use as tablet excipients. Methodos: Three tablet formulations of venlafaxine hydrochloride were proposed, having as excipients bran of cassava flour, bran of cassava starch flour and Starch 1500®. The tablets were produced using two different pressures (98±5 MPa and 32±6 Mpa) and their mechanical (hardness and friability) and dissolubility characteristics were evaluated. Results and Conclusions: The tablets produced with both cassava flours, using higher pressures, presented similar physicochemical characteristics to those obtained with the excipient Starch1500®, thus indicating that cassava flours possess the potential to be used as disintegrating agents in tablets.

Excipients are inactive substances that are included in pharmaceutical formulations alongside active ingredients. These substances are added to pharmaceutical products for various purposes, including improving stability, enhancing bioavailability, aiding in the manufacturing process, enhancing the appearance or taste, and facilitating administration or delivery of the active ingredient. We summarized a recent study published in science. This work suggests a systematic method to identify such active “inactive ingredients,” including the detection of allergenic and immunogenic properties. The examined excipient activity by combining large-scale computational screening with targeted experimental testing. They identified 38 excipients with activities against 44 targets. Although most excipients deserve their status as inert, many approved excipients may directly modulate physiologically relevant targets. This review increases our understanding of the relationship between drug excipients and active sites and provides more comprehensive theoretical support for future excipient selection.

Introduction. The article deals with the aspects of the use of Medical Clays in Pharmaceutical Technology. A review of the traditional areas of application of Medical Clay, as well as highlighting new directions.Text. One of the main problems of domestic industrial pharmacy is a narrow nomenclature of active pharmaceutical substances and excipients. Replenishment of the nomenclature occurs in two ways-through the synthesis of new chemical compounds or through the processing of natural raw materials of animal, plant or mineral origin. In the process of purification and processing of mineral raw materials, Medical Clays are obtained, which are now widely used as active pharmaceutical substances for the production of Enterosorbents, as well as auxiliary substances.Conclusion. A review of perspectives and areas of use of Medicinal Clays have shown that at present, Medical Clays used in the three traditional areas: cutaneous application, application per os, application in pharmaceutical and food technology. A promising direction is the use of Medical Clays as transport drug systems. The study of this information array and its generalization has undoubted practical and scientific significance in modern pharmaceutical technology.

Drying protein-based drugs, usually via lyophilization, can facilitate storage at ambient temperature and improve accessibility but many proteins cannot withstand drying and must be formulated with protective additives called excipients. However, mechanisms of protection are poorly understood, precluding rational formulation design. To better understand dry proteins and their protection, we examine Escherichia coli adenylate kinase (AdK) lyophilized alone and with the additives trehalose, maltose, bovine serum albumin, cytosolic abundant heat soluble protein D, histidine, and arginine. We apply liquid-observed vapor exchange NMR to interrogate the residue-level structure in the presence and absence of additives. We pair these observations with differential scanning calorimetry data of lyophilized samples and AdK activity assays with and without heating. We show that the amino acids do not preserve the native structure as well as sugars or proteins and that after heating the most stable additives protect activity best.

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.

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.

Drug-coated balloon (DCB) therapy is a promising endovascular treatment for obstructive arterial disease. The goal of DCB therapy is restoration of lumen patency in a stenotic vessel, whereby balloon deployment both mechanically compresses the offending lesion and locally delivers an antiproliferative drug, most commonly paclitaxel (PTX) or derivative compounds, to the arterial wall. Favorable long-term outcomes of DCB therapy thus require predictable and adequate PTX delivery, a process facilitated by coating excipients that promotes rapid drug transfer during the inflation period. While a variety of excipients have been considered in DCB design, there is a lack of understanding about the coating-specific biophysical determinants of essential device function, namely, acute drug transfer. We consider two hydrophilic excipients for PTX delivery, urea (UR) and poly(ethylene glycol) (PEG), and examine how compositional and preparational variables in the balloon surface spray-coating process impact resultant coating microstructure and in turn acute PTX transfer to the arterial wall. Specifically, we use scanning electron image analyses to quantify how coating microstructure is altered by excipient solid content and balloon-to-nozzle spray distance during the coating procedure and correlate obtained microstructural descriptors of coating aggregation to the efficiency of acute PTX transfer in a one-dimensional ex vivo model of DCB deployment. Experimental results suggest that despite the qualitatively different coating surface microstructures and apparent PTX transfer mechanisms exhibited with these excipients, the drug delivery efficiency is generally enhanced by coating aggregation on the balloon surface. We illustrate this microstructure-function relation with a finite element-based computational model of DCB deployment, which along with our experimental findings suggests a general design principle to increase drug delivery efficiency across a broad range of DCB designs.

The processing steps involved in converting from a powder to a tablet entail numerous operations in a which the coamorphous system is recrystallized and dissociated easily. This research focused on (i) a single-step preparation of a coamorphous tablet during injection molding (IM) from the bulk powder, and (ii) a mechanistic characterization of the coamorphous formulation. We selected several organic acids [citric acid, succinic acid, tartaric acid, and malic acid] in an effort to compound with basic loratadine (a poorly water-soluble drug). Loratadine–acids coamorphous tablets were produced via an IM process, and the dissolution was more enhanced than in the pure loratadine amorphous. The interaction was analyzed by FT-IR and terahertz spectroscopies. Each tablet was stored at 40 °C/75%RH, and then XRD patterns were acquired at the desired timepoints. In summary, loratadine exhibited ionic interaction with each acid, and the physical stability of the coamorphous tablet was in proportion to the loratadine–acids interaction strength. Terahertz spectra detected the molecular mobility, which plays an important role in the crystallization propensity of a coamorphous system. This understanding offers a framework for robust coamorphous tablet formulation using the IM methodology. [Display omitted] [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

ABSTRACT Dimethyl sulfoxide (DMSO) and polyethylene glycols (PEGs) are frequently used as potent excipients in pharmaceutical formulations. However, these agents also have an interesting antimicrobial and anti-inflammatory profile that could interfere with the efficacy testing of anti-infective compounds when the latter are solubilized in DMSO or PEGs. Here, we demonstrate the antimicrobial and anti-inflammatory effects of DMSO-PEG400 in a murine Pseudomonas aeruginosa infection model, aiming to draw attention to the appropriate selection of solvents for difficult-to-solubilize anti-infectives. IMPORTANCE Our study demonstrates the antimicrobial and anti-inflammatory effects of the combination of DMSO and PEG400 against Pseudomonas aeruginosa in vitro and in vivo in a murine infection model of heightened intestinal permeability. The aim of this study is to draw attention to the appropriate selection of solvents for difficult-to-solubilize anti-infective compounds, to avoid interference with the assay or system tested. This is an extremely important consideration, since potential antimicrobial and anti-inflammatory effects of the solvent vehicle are detrimental to research studies on the efficacy of new anti-infective agents, given that the vehicle effect can mask the effect of the tested compounds. Our results can therefore be of great value to the scientific community, as they can guide researchers in the future to avoid this significant pitfall that can cost substantial amounts of money and valuable time during investigations of the effects of novel, difficult-to-solubilize antimicrobial compounds.

Background: Aim of the present study was to put forth certain modifications in Quality by design approach to predict the in-vivo performance of dosage form based on in-vivo performance parameter simulation using in-vitro experimentations. Materials and Methods: One factor design was used with prime focus on impact of Mucuna pruriens seed mucilage as excipient on dosage form functionality and applicability. During product development stage, apart from manufacturing variables other impacting parameters considered were GI pH, alterations in body temperature and GI motility. Factors considered were simulated pH, Temperature and RPM (Rotations per minutes) variations. Process flow worksheet was developed. QTPP (Quality target product profile) and CQA (Critical Quality Attributes) data was generated. Results: Risk assessment and Ishikawa diagram (Cause and effect analysis) were found to be helpful to generate the results predicting in vivo performance of dosage from. The process capability indices helped for judging product/process performance. The study design could be helpful to analyze the alterations in in-vivo performance based on excipient behavior in simulated conditions tested in-vitro. Conclusion: The present research work has successfully used Quality by design approach to predict the in-vivo performance of Tablet dosage form based on in-vitro data simulation. It can be concluded that study design with more number of simulating variables could be helpful pattern to come up with in-vivo performance predictions. [ABSTRACT FROM AUTHOR]

Background: A multicenter investigation of neonate exposure to potentially harmful excipients (PHEs) in neonatal intensive care units (NICUs) in Japan has not been conducted. Methods: A multicenter nationwide observational study was conducted. Neonate patient demographic data and information on all medicines prescribed and administered during hospitalization on 1 day between November 2019 and March 2021 were extracted from the medical records. Nine PHEs, paraben, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol, benzalkonium chloride, and aspartame, were selected. PHEs were identified from the package insert and the Interview Form. The quantitative daily exposure was calculated if quantitative data were available for each product containing the PHE. Results: Prescription data was collected from 22 NICUs in Japan. In total, 343 neonates received 2360 prescriptions for 426 products containing 228 active pharmaceutical ingredients. PHEs were found in 52 (12.2%) products in 646 (27.4%) prescriptions for 282 (82.2%) neonates. Benzyl alcohol, sodium benzoates, and parabens were the most common PHEs in parenteral, enteral, and topical formulations, respectively. Quantitative analysis showed that 10 (10%), 38 (42.2%), 37 (94.9%), and 9 (39.1%) neonates received doses exceeding the acceptable daily intake of benzyl alcohol, polysorbate 80, propylene glycol, and sorbitol, respectively. However, due to the lack of quantitative information for all enteral and topical products, accurate daily PHE exposure could not be quantified. Conclusions: Neonates admitted to NICUs in Japan were exposed to PHEs, and several of the most commonly prescribed medicines in daily clinical practice in NICUs contained PHEs. Neonate PHE exposure could be reduced by replacing these medicines with available PHE-free alternatives. [ABSTRACT FROM AUTHOR]

Synthetic amorphous silica (SAS) nanomaterial – consisting of aggregates and agglomerates of primary silicon dioxide (SiO2) particles in the nanorange (<100 nm) – is commonly used as excipient in pharmaceuticals, in cosmetics and as food additive (E551). The available data suggest that SAS nanoparticles (NP) after intravenous (IV) exposure persist in liver and spleen; however, insufficient data exist to verify whether SAS may also induce adverse effects. The aim of the present study was to verify the potential long-term effects of SAS NP (NM-203) on spleen and liver as target organs following short-term exposure. Adult male and female Sprague-Dawley rats were treated by IV injection in the tail vein with a single (1-day) dose (SD) and repeated (5-day) doses (RD) of 20 mg/kg bw per day of SAS dispersed in sterile saline solution as vehicle. Histopathological examinations of target organs were performed after 90 days. Tissue biodistribution and full characterization of NM-203, primary particle size 13–45 nm, was performed within the framework of the Nanogenotox project. No mortality or general toxicity occurred; histopathological analysis showed splenomegaly in the RD group accompanied by inflammatory granulomas in both sexes. Granulomas were also present in liver parenchyma in the RD (both sexes) and SD groups (male only). The histopathological results indicated that SAS NP have the potential to persist and induce sex-specific chronic inflammatory lesions in spleen and liver upon short-term treatment. Overall, the data showed that the widespread use of silica in drugs might elicit chronic reactions in spleen and liver prompting to the need of further investigations on the safety of SAS NP. [ABSTRACT FROM AUTHOR]

Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS‐CoV‐2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti‐inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy. [ABSTRACT FROM AUTHOR]

Polysorbates (PS) are used in biopharmaceuticals to stabilize therapeutic proteins. Oxidative degradation of (poly)unsaturated fatty acids (PUFAs) contained in PS was shown to lead to α,β-unsaturated carbonyls. The n-6-PUFA linoleic acid accounts for up to 18% of all FAs contained in multi-compendial grade PS80. 4-Hydroxynonenal (HNE) is highly reactive towards nucleophilic amino acids, potentially leading to covalent protein modifications. This study tests whether HNE may be a pharmaceutically relevant PS80 peroxidation product. Since HNE was not directly detectable in the PS80 matrix by UV and MS, a new quantification method was established. After derivatization with 2,4-dinitrophenyl hydrazine (DNPH) and extraction of the formed hydrazone with a salting-out assisted liquid-liquid extraction, the HNE-DNPH adduct was analyzed by multiple reaction monitoring. Kinetic oxidation studies were conducted incubating PS80 in presence and absence of the antioxidant butylhydroxytoluene (BHT). HNE was confirmed as PS80 degradant in oxidatively stressed samples. BHT was shown to prevent its formation. HNE is a detectable PS80 degradation product raising questions about the potential impact on critical quality attributes of biopharmaceuticals formulated with PS80. Addition of BHT prevented HNE formation under oxidative stress. Consequently, BHT might be a valuable additive in PS used in biopharmaceuticals. [ABSTRACT FROM AUTHOR]

[Display omitted] The stability of lactate dehydrogenase (LDH) and β-galactosidase (β-gal), incorporated in arginine/pullulan (A/P) mixtures at various weight ratios by lyophilization, was determined. The physicochemical characteristics of various A/P mixtures were assessed. With decreasing A/P ratios, the glass transition temperature of the formulations increased. Furthermore, arginine crystallization due to high relative humidity (RH) exposure was prevented at an A/P weight ratio of 4/6 or less. When stored at 0 % RH / 60 °C for 4 weeks, arginine was superior to pullulan as stabilizer. During storage at 43 % RH / 30 ℃ for 4 weeks, the enzymatic activity of LDH was best retained at an A/P weight ratio of 2/8, while β-gal activity was relatively well-retained at A/P weight ratios of both 8/2 and 2/8. LDH seemed to be more prone to degradation in the rubbery state. In the glassy state, β-gal degraded faster than LDH. Solid-state nuclear magnetic resonance spectroscopy showed that (labeled) arginine experienced a different interaction in the two protein samples, reflecting a modulation of long-range correlations of the arginine side chain nitrogen atoms (Nε, Nη). In summary, LDH stabilization in the A/P matrix requires vitrification. Further stabilization difference between LDH and β-gal may be dependent on the interaction with arginine. [ABSTRACT FROM AUTHOR]

• MS detection improves dynamic range and sensitivity compared to ELSD and CAD. • Raw material impurities can transfer to drug substances in lipid nanoparticle therapies. • Hydrazone derivatization increases assay sensitivity for detection of aldehydes. • Aldehyde impurities above regulatory thresholds pose a risk to mRNA payloads. Lipid nanoparticles (LNPs) are designed to protect and transport sensitive payloads or active pharmaceutical ingredients as part of new therapeutic modalities. As a multi-component particle, a high degree of quality control is necessary to ensure raw materials are free of critical impurities that could adversely impact the drug product. In this study, we demonstrate a reversed phase liquid chromatography method hyphenated with a single quadrupole mass spectrometer (RPLC-MS) as an alternative platform to methods that incorporate evaporative light scattering or charged aerosol detectors in the detection and quantitation of critical impurities associated with LNPs. The proposed RPLC-MS method offers an increase of up to 2 orders of magnitude in dynamic range and 3 orders of magnitude in sensitivity in the analysis of impurities associated with LNPs compared to conventional detectors. Access to complementary mass data enabled the detection and identification of stability indicating impurities as part of stress studies carried out on an ionizable lipid. In addition to confirmation of peak identity, complementary mass data was also used to assess residual aldehydes in raw material and formulated LNPs in accordance with regulatory guidance. Following derivatization using 2,4-dinitrophenylhydrazine, aldehyde content in the ionizable lipid raw material was determined to exceed the reporting threshold of 0.05% in 30% of the test cases. The experimental findings observed in this study demonstrate the utility of the proposed RPLC-MS method in the identification and monitoring of stability-indicating attributes associated with LNPs as part of current Good Manufacturing Practices for improved consumer safety in drug products. [ABSTRACT FROM AUTHOR]

The article presents theoretical analysis and practical experience of the production of premixes (P) by different technologies of preparation of the filler. Their advantages and disadvantages are stated. The classification of premix fillers is presented and the distribution of biologically active substances in the premix composition, which is made on different fillers, is schematically presented. The technology of production of a complex filler premixes (CFP) in the form is theoretically and practically substantiated. Various methods of forming depending on the composition of the complex filler are considered, as well as the technological scheme of their production is presented. The results of industrial approbation of technologies of forming (granulation, briquetting, rolling, extrusion) of fillers and ready premixes in the production conditions of TG "VBA" "Izvestnyaki" are presented. The physical indicators of the formed complex fillers / premixes were investigated, and on the basis of the analysis of the obtaineddata it was found that granulation and briquetting can be subjected to CFP consisting of 75… 50% wheat bran and 25… 50% limestone flour. The pellet is a CFP consisting of 85% wheat bran and 15% limestone flour. Optimal technological modes of forming KNP and P in different ways have been established, as a result of which it is possible to obtain particles of P, which, upon further mixing with the feed components, ensure a high homogeneity of the finished feed. The results of the study of microbiological parameters are presented, it is established that the formation of CFP or P reduces the bacterial flora and improves the conditions during their storage. The proposed technological methods of preparation of CFP can eliminate the stratification and stabilize its composition during transportation and storage.

Information on the toxicological and pharmacological characteristics of the main excipients used in the formulation of torasemide (sodium croscarmellose, microcrystalline cellulose, magnesium stearate, pregelatinized corn starch, silica, mannitol) is presented in the article.

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.

Designing an antibody with the desired affinity to the antigen is challenging, often achieved by lengthening the hydrophobic CDRs, which can lead to aggregation and cause major hindrance to the development of successful biopharmaceutical products. Aggregation can cause immunogenicity, viscosity and stability issues affecting both the safety and quality of the product. As the hydrophobic residues on the CDR are required for direct binding to antigens, it is not always possible to substitute these residues for aggregation-reduction purposes. Therefore, discovery of specific excipients to prevent aggregation is highly desirable for formulation development. Here, we used a combination of in silico screening methods to identify aggregation-prone regions on an aggregation-prone therapeutic antibody. The most aggregation-prone region on the antibody was selected to conduct virtual screening of compounds that can bind to such regions and act as an aggregation breaker. The most promising excipient candidate was further studied alongside plain buffer formulations and formulations with trehalose using coarse-grained molecular dynamics (CGMD) simulations with MARTINI force field. Mean interaction value between two antibody molecules in each formulation was calculated based on 1024 replicates of 512 ns of such CGMD simulations. Corresponding formulations with an excipient:antibody ratio of 1:5 were compared experimentally by measuring the diffusion interaction parameter kD and accelerated stability studies. Although the compound with the highest affinity score did not show any additional protective effects compared with trehalose, this study proved using a combination of in silico tools can aid excipient design and formulation development.

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.

The recent growing interest in lactose intolerance has resulted in the proliferation of lactose-free products by food manufacturing companies. Since updated papers about lactose and its uses are missing, the main purpose of this review is to investigate this sugar comprehensively. Firstly, its chemical and physical characteristics were studied, following its employment in the food and drug industries. The positive and negative health-related effects of lactose are reported, focusing on the condition of lactose intolerance, for which an adequate lactose-free diet has to be followed to avoid symptoms that impairs quality of life. Considering that EU legislation on lactose-free product labelling is still controversial, suitable options for producing and identifying lactose-free products are suggested, in order to meet lactose-intolerant people’s needs.

Therapies for autoimmune diseases such as multiple sclerosis and diabetes are not curative and cause significant challenges for patients. These include frequent, continued treatments required throughout the lifetime of the patient, as well as increased vulnerability to infection due to the non-specific action of therapies. Biomaterials have enabled progress in antigen-specific immunotherapies as carriers and delivery vehicles for immunomodulatory cargo. However, most of this work is in the preclinical stage, where small dosing requirements allow for on-demand preparation of immunotherapies. For clinical translation of these potential immunotherapies, manufacturing, preservation, storage, and stability are critical parameters that require greater attention. Here, we tested the stabilizing effects of excipients on the lyophilization of polymeric microparticles (MPs) designed for autoimmune therapy; these MPs are loaded with peptide self-antigen and a small molecule immunomodulator. We synthesized and lyophilized particles with three clinically relevant excipients: mannitol, trehalose, and sucrose. The biophysical properties of the formulations were assessed as a function of excipient formulation and stage of addition, then formulations were evaluated in primary immune cell culture. From a manufacturing perspective, excipients improved caking of lyophilized product, enabled more complete resuspension, increased product recovery, and led to smaller changes in MP size and size distribution over time. Cocultures of antigen-presenting cells and self-reactive T cells revealed that MPs lyophilized with excipients maintained tolerance-inducing function, even after significant storage times without refrigeration. These data demonstrate that excipients can be selected to drive favorable manufacturing properties without impacting the immunologic properties of the tolerogenic MPs.

The development of orally administered protein drugs is challenging due to their intrinsic unfavourable features, including large molecular size and poor chemical stability, both of which limit gastrointestinal (GI) absorption efficiency. Nanoparticles can overcome the GI barriers effectively and improve the oral bioavailability of proteins in the GI tract. They possess large surface area to volume ratio, and can facilitate the GI absorption of nanoparticles via the paracellular and transcellular routes. Nanoparticles can be prepared by various fabrication techniques that can encapsulate the fragile therapeutic proteins via hydrophobic bonding and electrostatic interaction. A desirable technique should involve minimal harsh conditions and encapsulate therapeutic proteins with preserved functionalities. The current review examines the characteristics of each preparation technique, and illustrates the examples of insulin-loaded nanoparticles that have been developed in each fabrication method. The following techniques, which include nanoprecipitation, hydrophobic conjugation, flash nanocomplexation, double emulsion, ionotropic gelation, and layer-by-layer adsorption, have been used to formulate ligand-modified nanoparticles for targeted delivery of insulin. Other techniques, including reduction, complex coacervation (polyelectrolyte complexation), hydrophobic ion pairing and emulsion solvent diffusion method, and sol-gel technology, were also discussed in the latter part of the review due to their extensive use in fabrication of insulin nanoparticles. This review also discusses the strategies that have been utilised during the formulation process to improve the stability and bioactivity of therapeutic proteins. [ABSTRACT FROM AUTHOR]

Developing ultra-high concentration biotherapeutics drug products can be challenging due to increased viscosity, processing, and stability issues. Excipients used to alleviate these concerns are traditionally evaluated at lower protein concentrations. This study investigates whether classically known modulators of stability and viscosity at low (<50 mg/mL) to high (>50 – 150 mg/mL) protein concentrations are beneficial in ultra-high (>150 mg/mL) concentration protein formulations and drug products. This study evaluates the effect of arginine monohydrochloride, proline, and lysine monohydrochloride on viscosity and concentratability at different high and ultra-high protein concentrations using a monoclonal antibody, mAbN, formulation as a candidate protein system. The effect of excipients on the viscosity and concentratability (rate and extent) was different at high versus ultra-high protein concentrations. These results highlight that classical excipients in literature known to modulate protein interactions at low protein concentrations and reduce viscosity at high protein concentrations may need to be evaluated at target protein concentrations in a product-specific manner while developing ultra-high concentration biologics drug products. [ABSTRACT FROM AUTHOR]

Formulation of protein-based therapeutics employ advanced formulation and analytical technologies for screening various parameters such as buffer, pH, and excipients. At a molecular level, physico-chemical properties of a protein formulation depend on self-interaction between protein molecules, protein-solvent and protein-excipient interactions. This work describes a novel in silico approach, SILCS-Biologics, for structure-based modeling of protein formulations. SILCS Biologics is based on the Site-Identification by Ligand Competitive Saturation (SILCS) technology and enables modeling of interactions among different components of a formulation at an atomistic level while accounting for protein flexibility. It predicts potential hotspot regions on the protein surface for protein-protein and protein-excipient interactions. Here we apply SILCS-Biologics on a Fab domain of a monoclonal antibody (mAbN) to model Fab-Fab interactions and interactions with three amino acid excipients, namely, arginine HCl, proline and lysine HCl. Experiments on 100 mg/ml formulations of mAbN showed that arginine increased, lysine reduced, and proline did not impact viscosity. We use SILCS-Biologics modeling to explore a structure-based hypothesis for the viscosity modulating effect of these excipients. Current efforts are aimed at further validation of this novel computational framework and expanding the scope to model full mAb and other protein therapeutics. [ABSTRACT FROM AUTHOR]

The rapid growth in technological advances and quantity of scientific data over the past decade has led to several challenges including data storage and analysis. Accurate models of complex datasets were previously difficult to develop and interpret. However, improvements in machine learning algorithms have since enabled unparalleled classification and prediction capabilities. The application of machine learning can be seen throughout diverse industries due to their ease of use and interpretability. In this review, we describe popular machine learning algorithms and highlight their application in pharmaceutical protein development. Machine learning models have now been applied to better understand the nonlinear concentration dependent viscosity of protein solutions, predict protein oxidation and deamidation rates, classify sub-visible particles and compare the physical stability of proteins. We also applied several machine learning algorithms using previously published data and describe models with improved predictions and classification. The authors hope that this review can be used as a resource to others and encourage continued application of machine learning algorithms to problems in pharmaceutical protein development. [ABSTRACT FROM AUTHOR]

Development of an effective male contraceptive agent remains a challenge. The present study evaluates the potential of N, N-Dimethylacetamide (DMA), a FDA approved excipient as a male contraceptive agent. Male Sprague Dawley rats injected with DMA for a period of 8 weeks (one injection per week) showed a significant alteration of reproductive parameters. Furthermore, DMA treated animals showed complete infertility in a dose dependent manner, as no pups were born despite proper mating between females and DMA treated males. However, stopping the DMA treatment for a period of 8 weeks (after the initial treatment) restored the reproductive parameters to normal. Moreover, the fertility was resumed to normal as pups were born in the groups where DMA treatment was halted after initial DMA treatment. All these changes had no effect on the level of reproductive hormones FSH, LH and testosterone. Taken together, our results indicate that DMA acts in a reversible and non-hormonal manner to achieve contraception in rats. Therefore, repurposing the use of DMA could lead in a short time to an inexpensive and safer male contraceptive option.

Citric acid, a tricarboxylic acid, has found wide application in the chemical and pharmaceutical industry due to its biocompatibility, versatility, and green, environmentally friendly chemistry. This review emphasizes the pharmaceutical uses of citric acid as a strategic ingredient in drug formulation while focusing on the impact of its physicochemical properties. The functionality of citric acid is due to its three carboxylic groups and one hydroxyl group. These allow it to be used in many ways, including its ability to be used as a crosslinker to form biodegradable polymers and as a co-former in co-amorphous and co-crystal applications. This paper also analyzes the effect of citric acid in physiological processes and how this effect can be used to enhance the attributes of pharmaceutical preparations, as well as providing a critical discussion on the issues that may arise out of the presence of citric acid in formulations.

The encapsulation of proteins into core-shell structures is a widely utilised strategy for controlling protein stability, delivery and release. Despite the recognised utility of these microstructures, however, core-shell fabrication routes are often too costly or poorly scalable to allow for industrial translation. Furthermore, many scalable routes rely upon emulsion-techniques implicating denaturing or environmentally harmful organic solvents. Herein, we investigate core-shell protein encapsulation through single-feed, aqueous spray drying: a cheap, industrially ubiquitous particle-formation technology in the absence of organic solvents. We show that an excipient’s preference for the surface of the spray dried particle is well-predicted by its hydrodynamic diameter (Dh) under relevant feed buffer conditions (pH and ionic strength) and that the predictive power of Dh is improved when measured at the spray dryer outlet temperature compared to room temperature (R2 = 0.64 vs. 0.59). Lastly, we leverage these findings to propose an adaptable design framework for fabricating core-shell protein encapsulates by single-feed aqueous spray drying.

From the perspective of depression-like behavior and muscle inflammatory response, the curative effect of curcumin in two excipient carriers of cocoa butter and peanut oil on chronic stress rats was studied. Curcumin preparations were prepared with cocoa butter and peanut oil as excipients respectively, and 50 male SD rats were randomly divided into blank control group, model control group, curcumin cocoa butter group, curcumin peanut oil group, and positive control group. Except for the blank control group, each group used the methods of restraint, noise and sound stimulation, ice water bath stimulation, tail pain stimulation, etc. for 6 weeks to establish a chronic stress rat model. Each was given various design drugs based on maintaining the model stimulation conditions. After 7 days of continuous medication, the behavioral changes of the tail suspension struggling time, mechanical pain threshold, and sugar water preference of model animals in each group were investigated, and then use the Elisa kit method to detect the content of 5-HT and DA in the brain of each group of rats. Make HE-stained rat masseter tissue sections, observe the pathological changes of muscles, and detecte the levels of HMGB-1, IL-1茁, IL-6, and TNF-琢in masseter muscle. Compared with the model group, both curcumin preparations can significantly reduce the depression-like behavior of stress rats and improve the content of 5-HT and DA in the brain. Compared with the positive control group, the two curcumin in the masseter muscle pathology section group can significantly reduce the inflammatory response around the masseter muscle vessels in stress rats. The two curcumin can significantly reduce the levels of IL-1茁, IL-6 and TNF-琢in masseter muscle tissue (P<0.05), and the curcumin cocoa butter group had the most obvious effect.Both curcumin preparations have a therapeutic effect against depression-like symptoms in chronic stress rats, and can reduce the levels of inflammatory factors HMGB-1, IL-1茁, IL-6, and TNF-琢in masseter muscle. Cocoa butter has a significant effect when used as an excipient, and it has good development potential in the research of curcumin's antidepressant preparations. [ABSTRACT FROM AUTHOR]

Acceptable palatability of an oral dosage form is crucial to patient compliance. Excipients can be utilised within a formulation to mask the bitterness of a drug. One such category is the bitter-blockers. This term is used inconsistently within the literature and has historically been used to describe any additive which alters the taste of an unpleasant compound. This review defines a bitter-blocker as a compound which interacts with the molecular pathway of bitterness at a taste-cell level and compiles data obtained from publication screening of such compounds. Here, a novel scoring system is created to assess their potential utility in a medicinal product using factors such as usability, safety, efficacy and quality of evidence to understand their taste-masking ability. Sodium acetate, sodium gluconate and adenosine 5′monophophate each have a good usability and safety profile and are generally regarded as safe and have shown evidence of bitter-blocking in human sensory panels. These compounds could offer a much needed option to taste-mask particularly aversive medicines where traditional methods alone are insufficient. [ABSTRACT FROM AUTHOR]

Cocoa butter (CB) is an essential component of chocolates, which was used up to 40% as maximum. Cocoa butter has been used as a food flavour, cosmetics, suppositories additive and various biomedical applications for a longer period. Application of cocoa products as pharmaceutical excipient expanded in recent times in pharmaceutical product development. Particularly cocoa butter's melting and lubricant activity gained attention from researchers for developing oral disintegrating tablets (ODTs) or fast melting tablets (FMTs). Fast melting tablets are oral tablets formulations without the need for chewing or swallowing it with or without water. This dosage form helps to solve the limitations of dysphagia in all populations but especially for geriatrics and paediatrics. Cocoa butter is a readily available lipid that melts at body temperature 37°C. Cocoa butter has many polymorphisms and form V cocoa butter is the preferred stable form. This review explored the application of cocoa butter in pharmaceutical tablet dosage form development and its approved patent. [ABSTRACT FROM AUTHOR]

Background: Vitamin B 12 (Vit B 12 ) deficiency affects approximately 20% of those above the age of 60 years in the United Kingdom and United States. If untreated, it leads to detrimental health outcomes., Objective: To investigate a cohort of patients with Vit B 12 hypersensitivity (VB12H) referred to 3 UK allergy centers and design a pathway for the investigation of VB12H., Methods: A total of 29 patients seen between 2014 and 2022 underwent skin prick testing (1 mg/mL) with cyanocobalamin (CC) and hydroxycobalamin (HC) and intradermal testing (0.1 and 0.01 mg/mL). Patients with negative skin tests underwent a Vit B 12 drug provocation test (DPT) with either the index or the alternative drug., Results: Of 29 patients, 18 (62%) presented with immediate VB12H. Eight experienced anaphylaxis (4 to HC and 4 to CC) and had positive skin tests to the index drug. One patient reacted to oral and 7 patients to injectable Vit B 12 . Seven patients sensitized to one form of Vit B 12 -tolerated DPT with an alternative Vit B 12 . One patient with immediate VB12H reacted to polyethylene glycol (PEG) in oral cobalamin. Of 29 patients, 8 presented with delayed hypersensitivity reaction; 4 patients tolerated the intramuscular index formulation, whereas 2 patients tolerated the per oral formulation. One patient presented with symptoms consistent with symmetrical drug-related intertriginous and flexural exanthema. Three patients were referred because of cobalt allergy., Conclusion: Confirmed VB12H is rare. We propose a comprehensive evaluation protocol that includes Vit B 12 skin tests and considers PEG allergy in patients presenting with VB12H., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)