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The treatment of several pediatric metabolic diseases involves vitamins supplementation. Among these, thiamine, riboflavin, pyridoxine and biotin can be prescribed and compounded as hard gelatin capsules. In compounding practice, a medication can be done extemporaneously, leading to a risk of error. However, a medication can also be done in advance, analytically controlled and stored. Such practice reduce the risk of error and decrease the cost, but also imposes the realization of stability studies to establish beyond-use-dates. Thiamine hydrochloride, riboflavin, pyridoxine hydrochloride, and biotin hard gelatin capsules chromatographic and microbiological methods were both validated and used to perform stability studies. Thiamine hydrochloride 50 mg hard gelatin capsules with microcrystalline cellulose and silica as excipients are stable for 6 months when stored at 25 ° C/ 60% RH protected from light. Riboflavin 50 mg with microcrystalline cellulose, pyridoxine hydrochloride 50 mg with microcrystalline cellulose and biotin 40 mg with microcrystalline cellulose/silica are stable for one year when stored at 25 ° C/ 60% RH protected from light. These results allow the compounding in advance of batches of 300 capsules controlled, stored, and quickly dispensed in case of an emergency, such decreasing the risk of error and/or iatrogenic event.

BackgroundNausea and vomiting of pregnancy (NVP) affect almost pregnancies. The only agent approved by the FDA and other countries for the management of NVP symptoms has been the delayed release combination of doxylamine and pyridoxine. This combination, formulated as a 10 mg/10 mg delayed release tablet, was approved by the FDA for the treatment of NVP in 2013 (Diclegis®).Due to its delayed release properties, Diclegis® begins to exert its antiemetic properties 6–8 hours after ingestion, and hence symptom relief may be delayed and necessitate the use of an immediate release medication.MethodsIn 2016 the FDA approved Bonjesta®, a novel, dual- release combination of doxylamine and pyridoxine, whereby a rapid release phase is followed by a delayed release phase, thus overcoming the time delay in action of Diclegis®. Bonjesta®, is a multilayer, extended-release tablet consisting of an enteric-coated core containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride, and an immediate-release coating of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride, delivering a total of 20 mg doxylamine succinate and 20 mg pyridoxine hydrochlorideResultsIn a single-and multiple dose study in 48 healthy, premenopausal women, one Bonjesta® (20 mg doxylamine succinate and 20 mg pyridoxine) was bioequivalent to two combination tablets of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochlorideBonjesta has shown an immediate peak concentrations, followed by a delayed release phase.ConclusionsThe combination of the immediate release with a delayed action is unique to Bonjesta® as it allows for the bedtime dose to be effective immediately and also provide with sustained control of NVP symptoms throughout the day.Disclosure(s)G Koren has been a consuntant for Duchesnay Inc.

The current study developed a method for quantifying four drugs—Sulfamethoxazole, Trimethoprim, Isoniazid, and Pyridoxine—in rabbit plasma. The method uses gradient liquid chromatography based on analytical quality by design. To achieve separation, a Eclip Plus C18 (250 mm × 5 mm, 4.6 µm) column with L1 packing was used, and analytes were detected at 254 nm at ambient temperature. The optimized mobile phase consisted of 50 mM potassium dihydrogen phosphate buffer (pH 6.5) and Methanol. The concentration of Methanol was 3% (0–5 min), 15% (5–15 min), 55% (15–27 min), and 3% Methanol until the end of the 30-min runtime, and the flow rate was set at 0.95 mL/min. Control Noise Experimentation was used to screen studies, revealing that flow rate, pH, and Methanol concentration significantly affected the analytical attributes. The study identified critical attributes (resolution and asymmetric factor) and developed a quality target method profile. A central composition design was used to optimize the essential parameters. The method developed for the drugs showed peaks at retention times of 6.990 min for Isoniazid, 7.880 min for Pyridoxine, 15.530 min for Sulfamethoxazole, and 26.890 min for Trimethoprim, respectively. The method was validated with linearity in the range of 10–640 ng ml −1 , with R 2 of 0.9993, 0.9987, 0.9993, and 0.9992 for Sulfamethoxazole, Trimethoprim, Isoniazid, and Pyridoxine, respectively.

The interactions of vitamin B6 (pyridoxine hydrochloride) with different concentrations of cationic compounds (cocarboxylase or thiamine pyrophosphate chloride) were investigated in an aqueous solution using UV-VIS absorption spectroscopy. The results depict a hyperchromic shift at 300 ± 1 nm, a hypochromic shift at 330 ± 1 nm with increasing concentration of carboxylase, and an isosbestic point at 312 nm. Hydrophilic-hydrophilic (hydrogen bonding) interaction is the dominating force for the association of two compounds. The binding constant (K b ) value has been determined by two cases of the Benesi-Hildbrand equation and the concept developed by Hashemi and Sun. The values of K b calculated from all three methods were in close agreement. Furthermore, the standard free energy change, ΔG o was detected from the computed values of K b .

The experience with Bendectin (doxylamine succinate and pyridoxine hydrochloride, for treating nausea and vomiting of pregnancy) reveals how non–science-based decisions may affect the availability of a drug product, with adverse public health consequences. In 1983, the combination-drug product Bendectin (Merrell Dow), consisting of 10 mg of doxylamine succinate and 10 mg of pyridoxine hydrochloride per tablet, was voluntarily withdrawn from the U.S. market by the manufacturer. For the next 30 years, there were no medications that had been approved by the Food and Drug Administration (FDA) for the treatment of nausea and vomiting of pregnancy. Recently, the FDA approved Diclegis (Duchesnay), a product with the same combination of doxylamine and pyridoxine that had been marketed as Bendectin. The Bendectin experience serves as an informative case study of how decisions that are not science-based . . .

Glutamate decarboxylase (GAD) catalyzes the irreversible decarboxylation of L-glutamate to the valuable food supplement γ-aminobutyric acid (GABA). In this study, GAD from Escherichia coli K12, a pyridoxal phosphate (PLP)-dependent enzyme, was overexpressed in E. coli. The GAD produced in media supplemented with 0.05 mM soluble vitamin B6 analog pyridoxine hydrochloride (GAD-V) activity was 154.8 U mL-1, 1.8-fold higher than that of GAD obtained without supplementation (GAD-C). Purified GAD-V exhibited increased activity (193.4 U mg-1, 1.5-fold higher than that of GAD-C), superior thermostability (2.8-fold greater than that of GAD-C), and higher kcat/Km (1.6-fold higher than that of GAD-C). Under optimal conditions in reactions mixtures lacking added PLP, crude GAD-V converted 500 g L-1 monosodium glutamate (MSG) to GABA with a yield of 100%, and 750 g L-1 MSG with a yield of 88.7%. These results establish the utility of pyridoxine supplementation and lay the foundation for large-scale enzymatic production of GABA.

Pyridoxine hydrochloride and magnesium sulfate (pyridoxine-Mg) have been used for the management of autism spectrum disorder (ASD). We present a case report of 2 children with ASD who were administered pyridoxine-Mg for 2 months. The Childhood Autism Rating Scale, Second Edition, was used to confirm the adverse reaction. The Naranjo Adverse Drug Reaction Probability Scale was used to assess causality. Children were reported by their parents as being hyperactive. Evaluation by the psychologist using the Childhood Autism Rating Scale, Second Edition, also confirmed the reaction. According to the Naranjo scale, hyperactivity had a possible and probable association with pyridoxine-Mg for child 1 and 2, respectively. A probable to possible association exists between hyperactivity and pyridoxine-Mg. Clinical Trial Registry–India identifier: CTRI/2019/07/020102.

A simple, rapid, sensitive and new RP-HPLC method was developed and validated concerning ICH guidelines for simultaneous assessment of doxylamine succinate (DOXY) and pyridoxine hydrochloride (PYRI) in bulk and combined dosage form. Isolation was performed on C18 column, using phosphate buffer (pH 4.0) and acetonitrile (70:30) as mobile phase, flow rate at 1ml/min. Retention times were 4.256 min and 2.400 min for DOXY and PYRI respectively. Linearity for both drugs were in the concentration range of 10-50µg/ml. Correlation coefficients were 0.999 and 0.999 for DOXY and PYRI respectively. Method was validated according to the parameters of ICH guidelines.The accelerated stability study was conducted as per the ICH guidelines. Study suggests that both the drugs were most stable in photolytic condition. DOXY was more susceptible in basic condition whereas in oxidation condition PYRI was more susceptible. Results obtained were quite satisfactory for this method and this method can be suitable for the estimation of DOXY and PYRI in any formulation along with degradation product.

Background: New treatment platforms that can prevent acute respiratory distress syndrome (ARDS) or reduce its mortality rate in high-risk coronavirus disease 2019 (COVID-19) patients, such as those with an underlying cancer, are urgently needed. Rejuveinix (RJX) is an intravenous formulation of anti-oxidants and anti-inflammatory agents. Its active ingredients include ascorbic acid, cyanocobalamin, thiamine hydrochloride, riboflavin 5′ phosphate, niacinamide, pyridoxine hydrochloride, and calcium D-pantothenate. RJX is being developed as an anti-inflammatory and anti-oxidant treatment platform for patients with sepsis, including COVID-19 patients with viral sepsis and ARDS. Here, we report its clinical safety profile in a phase 1 clinical study (ClinicalTrials.govIdentifier: NCT03680105) and its potent protective activity in the lipopolysaccharide galactosamine (LPS-GalN) mouse model of ARDS.Methods: A phase 1, double-blind, placebo-controlled, randomized, two-part, ascending dose-escalation study was performed in participating 76 healthy volunteer human subjects in compliance with the ICH (E6) good clinical practice guidelines to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of RJX (Protocol No. RPI003;ClinicalTrials.govIdentifier: NCT03680105). The ability of RJX to prevent fatal shock, ARDS, and multi-organ failure was examined in the well-established LPS-GalN mouse model of sepsis and ARDS. Standard methods were employed for the statistical analysis of data in both studies.Findings: In the phase 1 clinical study, no participant developed serious adverse events (SAEs) or Grade 3-Grade 4 adverse events (AEs) or prematurely discontinued participation in the study. In the non-clinical study, RJX exhibited potent and dose-dependent protective activity, decreased the inflammatory cytokine responses (interleukin-6, tumor necrosis factor alpha, transforming growth factor beta), and improved survival in the LPS-GalN mouse model of sepsis and ARDS. Histopathological examinations showed that RJX attenuated the LPS-GalN induced acute lung injury (ALI) and pulmonary edema as well as liver damage.Conclusion: RJX showed a very favorable safety profile and tolerability in human subjects. It shows potential to favorably affect the clinical course of high-risk COVID-19 by preventing ARDS and its complications.

Protein-based APIs represent a big group of modern therapeutics. Their characterization involves complex analytical protocols which require special methods, especially in the case when the protein drug is included into tablet dosage forms. Although the fluorescence polarization assay (FPA) is not currently regulated by many national Pharmacopeias, it represents a promising approach for protein drug standardization, considering their rapid, sensitive, and automatable detection suitable for high-throughput analysis and real-time quality control. To evaluate the applicability of FPA for the analysis of protein drugs in tablets, the quantifying of lysozyme in tablet dosage forms was studied by this method with the use of a fluorescently labeled synthetic chitooligosaccharide tracer. It was shown that this approach overcomes the limitations of the conventional turbidimetric assay of lysozyme determination, which is labor-intensive and relies on unstable reagents. Measurements were performed with both portable and stationary fluorescence polarization readers. Commercial tablets from five manufacturers containing lysozyme (20 mg) and pyridoxine hydrochloride (10 mg) together with other excipients were analyzed. The FPIA method showed a linear range of 5.0–70 µg/mL, with specificity confirmed by the absence of interference from excipients. Accuracy, evaluated by standard addition (10–20 mg), yielded recoveries of 100.2–106.0%. Placebo spiked with lysozyme at 80–120% of nominal content demonstrated recoveries of 98.0–100.1%, with RSD (n = 6) not exceeding 13.7%, indicating good precision. The developed method enables reliable lysozyme quantification in tablets, offering speed, simplicity, and robustness, and shows its suitability for the routine quality control of protein-containing dosage forms including the enzyme ones.