Development and Optimization of a New UPLC-UV/MS Method through DoE and MLR for Detecting Substandard Drug Products to Treat Tuberculosis.

Drug products used for treating tuberculosis are one of the most widely reported medicines to be classified as falsified or substandard in low- and middle-income countries, representing a major hazard to health. The aim of this study was, firstly, to develop an ultra-performance liquid chromatography (UPLC) method which is able to analyze fixed combination tablets with up to four active pharmaceutical ingredients, including isoniazid, pyrazinamide, rifampicin, and ethambutol. Secondly, we aimed to optimize it through the design of experiments and multi-linear regression based on a central composite design and to validate it according to the guidelines of the International Conference on Harmonization. The application of this tools enabled the identification of the influential factors (flow rate, formic acid, and temperature) and their effects on the studied responses (retention factor and percentage for each drug) as part of the quality by design approach. The method proved to be to be linear in the range from 5.0 to 15 µg/mL for isoniazid, pyrazinamide, and rifampicin, being precise (<1%) and accurate (97−101%). In addition, the method validated for ethambutol proved to be linear from 1.4 to 4.2 µg/mL, as well as precise (0.54%) and accurate (97.3%). The method was stability indicated for all the active pharmaceutical ingredients studied and was able to detect two substandard formulations sampled on the African market.

Design and optimization of a child-friendly dispersible tablet containing isoniazid, pyrazinamide, and rifampicin for treating tuberculosis in pediatrics.

Objective: Develop a child-friendly Fixed Dose Combination (FDC) water-dispersible tablet for Tuberculosis (TB) treatment, with 50, 150, and 75 mg of isoniazid, pyrazinamide and rifampicin respectively. This new formulation must contain the lowest number of excipients accepted for pediatrics and fulfill all the pharmacopeia requirements.Significance: At present, there is no adequate market dosage form available for children. There is, however, one in a prequalification phase by the World Health Organization but its composition contains excipients which may not be suitable for pediatrics. Therefore, this new formulation would cover this therapeutic gap.Methods: A factorial design, based on three quantitative factors (compression force and concentration of AcDiSol® and Explosol®) at three levels each, was performed to elucidate their influence over disintegration time and friability. In addition, the influence of the press speed on disintegration time, friability, tensile strength, fineness of dispersion and content uniformity over the target tablet was tested. A stability test was done following ICH guideline for accelerated conditions.Results: Tablets developed with 9% w/w of Explosol® and a compression force of 16 kN disintegrated in less than 3 min and showed a friability below 1% when 15-mm punches were used. The tableting process could be done up to 25 and 50 cycles/minute ensuring good quality attributes when 15 and 12-mm punches were used, respectively. All APIs remained inside the limit of ± 5% of drug content till 6 months of storage.Conclusion: A high-quality child-friendly FDC water-dispersible tablet was developed improving the treatment of TB in pediatric.

A High-Demanding Strategy to Ensure the Highest Quality Standards of Oral Liquid Individualized Medicines for Pediatric Use.

Individualized medicines for pediatrics are a useful alternative if there is no correct dosage marketed for this segment (easy to swallow, adequate volume and content, correct composition for pediatrics, good organoleptic properties, etc.). Its validation process must ensure quality testing: its content uniformity, physical (homogeneity after shaking), chemical, and microbiological stability. Some of these attributes are checked by the recommendations of European Pharmacopoeia (Ph. Eur.), International Conference of Harmonization (ICH), and National Formularies but others are not. The aim of this study is to develop a general high-demanding strategy to ensure the final quality of liquid dosage forms testing and developing standard operating processes (SOPs) for the elaboration of individualized oral liquid medicines for pediatric use. Furosemide was used as an example of the validation of an individualized liquid solution for pediatric use. Three SOPs were selected according to their composition and the recommendations of liquid dosage forms for pediatric use. Quality attributes according to National Formularies, Ph. Eur., and ICH were tested: pH, organoleptic properties, uniformity of mass of delivered dose from multidose containers, and chemical stability. In this study, a general high-demanding strategy was elaborated to validate oral liquid dosage forms, including validation of the analytical method used to test their quality. A second part focuses on the elaboration of liquid formulations for pediatrics with the highest standards of quality taking into account CQAs that were not contemplated by official compendial such as content uniformity and physical stability.

Development of a novel physico-chemically and microbiologically stable oral solution of flecainide for pediatrics.

There is as yet no commercialized preparation for oral administration of flecainide acetate (FA) to children. In such cases, manipulation of commercial tablets is the usual practice in pharmacy services of hospitals and compounding pharmacies, to provide a suitable dosage form for this vulnerable pediatric population group. In this study, we have formulated FA as an oral solution, as an alternative to the suspension elaborated from commercial tablets. Due to this sensitivity of young patients, we have used the pure active pharmaceutical ingredient (API) and the lowest permitted levels of pediatric excipients. Despite being a highly soluble API, only one of the formulations appears as a transparent solution due to complete FA solubilization. The proposed formulation is physico-chemically and microbiologically stable and the mass and dose uniformity is appropriate for 30 days' storage at 25 °C.

Formulation design of oral pediatric Acetazolamide suspension: dose uniformity and physico-chemical stability study.

CONTEXT: The formulation of an active pharmaceutical ingredient (API) as oral solution or suspension in pediatrics is a habitual practice, due to the non-existence of many commercialized medicines in pediatric doses. It is also the simplest way to prepare and administer them to this vulnerable population. The design of a formulation that assures the dose and the system stability depends on the physico-chemical properties of the API. OBJECTIVE: In this study, we formulate a class IV API, Acetazolamide (AZM) as suspension for oral administration to pediatric population. The suspension must comply attributes of quality, safety and efficacy for this route of administration. MATERIALS AND METHODS: We use simple compounding procedures, as well as fewer pure excipients, as recommended for children. Mass and uniformity content assays and physical and chemical stability studies were performed. To quantify the API an UPLC method was used. RESULTS AND DISCUSSION: We verified the physico-chemical stability of the suspensions and that they passed the mass test of the European Pharmacopeia (EP), but not the dose uniformity test. CONCLUSIONS: This reveals that AZM must be formulated as liquid forms with a more complex system of excipients (not usually indicated in pediatrics), or otherwise solid forms capable of assuring uniformity of mass and dose for every dosage unit.

Revolutionizing Three-Dimensional Printing: Enhancing Quality Assurance and Point-of-Care Integration through Instrumentation.

Three-dimensional printing in the field of additive manufacturing shows potential for customized medicines and solving gaps in paediatric formulations. Despite successful clinical trials, 3D printing use in pharmaceutical point-of-care is limited by regulatory loopholes and a lack of Pharmacopoeia guidelines to ensure quality. Semi-solid extrusion is a 3D printing technology that stands out for its versatility, but understanding the fluid dynamics of the semi-solid mass is critical. The aim of this research is to look into the advantages of instrumenting a 3D printer with a semi-solid extrusion motor-driven printhead, which is able to record the printing pressure over time, for in situ characterization of the semi-solid mass and quality evaluation of dosage forms. Four formulations using hydrochlorothiazide as the active pharmaceutical ingredient and several excipients were used. Their flow properties were studied at different printing speeds and temperatures using traditional techniques (rheometer and Texture Analyzer) and the proposed semi-solid extrusion motor-driven printhead incorporated into a printing platform. In addition, the influence of printing speed in the printing process was also evaluated by the study of printing pressure and printlet quality. The results demonstrated the similarities between the use of a Texture Analyzer and the semi-solid extrusion motor-driven. However, the latter enables temperature selection and printing speed in accordance with the printing process which are critical printing parameters. In addition, due to the incorporation of a sensor, it was possible to conclude, for the first time, that there is a link between changes in essential printing parameters like printing speed or formulations and variations in printing pressure and printlet quality attributes such as the energy require to obtain a single dosage unit, weight or diameter. This breakthrough holds a lot of potential for assuring the quality of 3D printing dosage forms and paving the way for their future incorporation into point-of-care settings.

Quality assessment of oral antimalarial and antiretroviral medicines used by public health systems in Sahel countries.

Malaria and Human Immunodeficiency Virus infections are among the top 10 causes of death in low income countries. Furthermore, many medicines used in these treatment areas are substandard, which contributes to the high death rate. Using a monitoring system to identify substandard and falsified medicines, the study aims to evaluate the quality of antimalarial and antiretroviral medicines in Sahel countries, assessing site conditions, compliance of medicines with pharmacopoeia tests, formulation equivalence with a reference medicine, and the influence of climate on quality attributes. Ultra Performance Liquid Chromatography methods for eight active pharmaceutical ingredients were validated following the International Conference for Harmonization guideline for its detection and quantification. Quality control consists of visual inspections to detect any misinformation or imperfections and pharmacopeial testing to determine the quality of pharmaceutical products. Medicines which complied with uniformity dosage units and dissolution tests were stored under accelerated conditions for 6 months. Artemether/Lumefantrine and Lopinavir/Ritonavir formulations failed uniformity dosage units and disintegration tests respectively, detecting a total of 28.6% substandard medicines. After 6 months stored under accelerated conditions (40 °C // 75% relative humidity) simulating climatic conditions in Sahel countries, some medicines failed pharmacopeia tests. It demonstrated the influence of these two factors in their quality attributes. This study emphasizes the need of certified quality control laboratories as well as the need for regulatory systems to maintain standards in pharmaceutical manufacturing and distribution in these countries, especially when medicines are transported to rural areas where these climatic conditions are harsher.

The Design of Novel 3D-Printed, Moulded, and Oral Viscous Budesonide Formulations for Paediatrics: A Comparative Evaluation of Their Mucoadhesive Properties.

BACKGROUND/OBJECTIVES: Paediatric eosinophilic oesophagitis (EoE) treatment is challenging due to the limited number of age-appropriate formulations. This study aims to develop and evaluate oral viscous suspensions and solid formulations of budesonide (BUD), focusing on their in vitro mucoadhesive properties, to enhance drug delivery and therapeutic outcomes in paediatric EoE. METHODS: This study encompasses the development of oral viscous suspensions and orodispersible solid formulations (moulded tablets and 3D-printed dosage forms) containing BUD. The formulations underwent quality control tests as per the European Pharmacopoeia, chemical stability assessments, and an in vitro evaluation of their mucoadhesiveness properties. RESULTS: A validated analytical method enabled accurate BUD quantification and efficient extraction, and all developed formulations demonstrated chemical stability for 30 days, meeting Ph. Eur. quality standards. Three-dimensional printing using SSE successfully produced 1 mg and 0.5 mg BUD printlets, complying with quality tests for conventional tablets. Formulations containing xanthan gum (L2-XG and P1-0.5-XG) exhibited superior mucoadhesive properties. L2-XG showed significantly higher mucoadhesion than L1-MC. Among the solid formulations, P1-0.5-XG demonstrated the highest mucoadhesive properties. CONCLUSIONS: This is the first study to develop solid oral dosage forms of BUD at a very low dose, specifically for paediatric use. The results highlight the potential of 3D printing for developing individualised orodispersible BUD formulations with improved bioadhesion for paediatric EoE treatment. The L2-XG formulation and the XG-containing printlets are the most promising formulations in terms of increasing contact time with the oesophageal mucosa, which could translate into improved therapeutic efficacy in this patient population.

Characterization and Validation of a New 3D Printing Ink for Reducing Therapeutic Gap in Pediatrics through Individualized Medicines.

3D printing technology can be used to develop individualized medicines in hospitals and pharmacies, allowing a high degree of personalization and the possibility to adjust the dose of the API based on the quantity of material extruded. The main goal of incorporating this technology is to have a stock of API-load print cartridges that could be used at different storage times and for different patients. However, it is necessary to study the extrudability, stability, and buildability of these print cartridges during storage time. A paste-like formulation containing hydrochlorothiazide as a model drug was prepared and distributed in five print cartridges, each of which was studied for different storage times (0 h-72 h) and conditions, for repeated use on different days. For each print cartridge, an extrudability analysis was performed, and subsequently, 100 unit forms of 10 mg hydrochlorothiazide were printed. Finally, various dosage units containing different doses were printed, taking into account the optimized printing parameters based on the results of the extrudability analysis carried out previously. An appropriate methodology for the rapid development of appropriate SSE 3DP inks for pediatrics was established and evaluated. The extrudability analysis and several parameters allowed the detection of changes in the mechanical behavior of the printing inks, the pressure interval of the steady flow, and the selection of the volume of ink to be extruded to obtain each of the required doses. The print cartridges were stable for up to 72 h after processing, and orodispersible printlets containing 6 mg to 24 mg of hydrochlorothiazide can be produced using the same print cartridge and during the same printing process with guaranteed content and chemical stability. The proposed workflow for the development of new printing inks containing APIs will allow the optimization of feedstock material and human resources in pharmacy or hospital pharmacy services, thus speeding up their development and reducing costs.

A pharmaceutical monitoring system to assess the quality of antituberculosis drug products used in Mauritania.

The quality of drug products may be affected from manufacture to dispensing, particularly at high temperature and humidity as in Mauritania. This country is not included in the World Health Organization reports on poor quality products due to the lack of a qualified laboratory and monitoring system. Ensuring the quality of medicine is even more relevant in the case of diseases such as Tuberculosis, due to its high prevalence, complex treatment and continuous bacterial resistance. The aim was to develop a monitoring system to assess the quality of antituberculosis drugs products, by the substandard detection based on European and United States Pharmacopeial recommendations regarding quality control. In addition to studying the influence of accelerated storage conditions (40 ± 2°C/75 ± 5% relative humidity) on their qualities and comparing the dissolution profiles to contrast the quality. 18 antituberculosis drug products were taken from Europe and Mauritania, and quality was studied through visual inspection and according to the compliance of the mass uniformity, uniformity of dosage units, dissolution, disintegration and friability pharmacopeial tests. Furthermore, a dissolution profile comparison was carried out to examine quality. A stability study was conducted to assess the influence of climatic conditions on the content and the dissolved amount of the active pharmaceutical ingredients, which were determined by an ultra-performance liquid chromatography system. As result, 69.3% of 13 Mauritanian formulations had a substandard quality mainly due to non-compliance with the test for friability or content uniformity of these medicines. All European drug products complied with pharmacopeia specifications. In addition, storage conditions affected the dissolution rate of ethambutol and the uniformity of the 4 antituberculosis combination drug products.

Supercritical CO2 technology for one-pot foaming and sterilization of polymeric scaffolds for bone regeneration.

Sterilization is a quite challenging step in the development of novel polymeric scaffolds for regenerative medicine since conventional sterilization techniques may significantly alter their morphological and physicochemical properties. Supercritical (sc) sterilization, i.e. the use of scCO2 as a sterilizing agent, emerges as a promising sterilization method due to the mild operational conditions and excellent penetration capability. In this work, a scCO2 protocol was implemented for the one-pot preparation and sterilization of poly(ε-caprolactone) (PCL)/poly(lactic-co-glycolic acid) (PLGA) scaffolds. The sterilization conditions were established after screening against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) vegetative bacteria and spores of Bacillus stearothermophilus, Bacillus pumilus and Bacillus atrophaeus. The transition from the sterilization conditions (140 bar, 39 °C) to the compressed foaming (60 bar, 26 °C) was performed through controlled depressurization (3.2 bar/min) and CO2 liquid flow. Controlled depressurization/pressurization cycles were subsequently applied. Using this scCO2 technology toolbox, sterile scaffolds of well-controlled pore architecture were obtained. This sterilization procedure successfully achieved not only SAL-6 against well-known resistant bacteria endospores but also improved the scaffold morphologies compared to standard gamma radiation sterilization procedures.

Influence of the carbon source on the properties of poly-(3)-hydroxybutyrate produced by Paraburkholderia xenovorans LB400 and its electrospun fibers.

Poly-3-hydroxybutyrate (PHB) is a biocompatible polymer produced by a wide variety of bacteria from different carbon sources. However, the carbon source effects on PHB properties are largely unknown. This study aimed to characterize PHB produced by Paraburkholderia xenovorans LB400 supplied with glucose (PHBg), mannitol (PHBm), or xylose (PHBx) as sole carbon sources and to evaluate their potential application as the main component of scaffolds obtained by electrospinning. The PHBs produced by strain LB400 had different molecular weights; the largest value corresponded to PHBm. The XRD-spectra revealed that PHB produced by strain LB400 from the three carbon sources are less crystalline than the commercially available polymer (PHBc). Moreover, the electrospinning process decreases even further their degree of crystallinity, which could lead to an improvement in the mechanical properties of the polymers. Relevantly, PHBx-microfibers exhibited mechanical characteristics similar to those of human skin. None of the scaffolds made of PHBs from strain LB400 grown in different carbon sources showed adverse effects on fibroblast cell growth. Thus, modifying the sugar used as the carbon source may be useful to tune the structural properties of PHB and its performance as a component of electrospun scaffolds, which may better fit specific biomedical applications.

Stability Study of Isoniazid and Rifampicin Oral Solutions Using Hydroxypropyl-Β-Cyclodextrin to Treat Tuberculosis in Paediatrics.

(1) Background: First-line antituberculosis treatment in paediatrics entails the administration of Isoniazid, Pyrazinamide, and Rifampicin. This study examines the possibility of developing a combined dose liquid formulation for oral use that would facilitate dose adjustment and adherence to treatment for younger children. (2) Methods: The active pharmaceutical ingredients stability under in vitro paediatric digestive pH conditions have been checked. The samples were studied as individual or fixed combined paediatric dosages to determine the pH of maximum stability. The use of hydroxypropyl-ß-cyclodextrin to improve Rifampicin solubility and the use of ascorbic acid to increase the stability of the formulation have been studied. (3) Results: Maximum stability of combined doses was determined at pH 7.4, and maximum complexation at pH 8.0. Taking this into account, formulations presented the minimum dose of two active pharmaceutical ingredients dissolved. The addition of ascorbic acid at 0.1% w/v enables the detection of a higher remaining quantity of both drugs after three days of storage at 5 °C. (4) Conclusions: a formulation which combines the minimum paediatric dosages dissolved recommended by WHO for Isoniazid and Rifampicin has been developed. Future assays are needed to prolong the stability of the formulation with the aim of incorporating Pyrazinamide to the solution.

Effectiveness of Antimicrobial Preservation of Extemporaneous Diluted Simple Syrup Vehicles for Pediatrics.

OBJECTIVES: Extemporaneous or magistral formulation of active pharmaceutical ingredients using traditional compounding techniques is a common practice when no commercial form is available for pediatrics. For this vulnerable group of patients, the formulation must be prepared with the minimum quantity and lowest proportion of excipients approved for pediatrics, avoiding the use of preservatives. Often the vehicles used for these preparations are dilutions of simple syrup with water. The objective of this study is to assess the effectiveness of antimicrobial preservation in simple syrup diluted with aqua conservans (conserved water), without propylene glycol or with a reduced proportion of parabens. METHODS: The European Pharmacopoeia test of efficacy of antimicrobial preservation was applied to 5 trial vehicles prepared with simple syrup diluted with water. RESULTS: Simple syrup is stable during 14 days. Vehicles prepared with simple syrup diluted with purified water did not meet the microbiological quality criteria, but when they are diluted with water that incorporates propylene glycol and parabens (aqua conservans), then they meet the criteria. In addition, if the water is prepared with parabens and without propylene glycol, the criteria for the dilution are met. Nevertheless, if the dilution is done with water prepared with an insufficient proportion of parabens to act as preservatives, the dilution does not meet the pharmacopoeia microbiological criteria. CONCLUSIONS: Dilution of simple syrup (50:50 v/v) to prepare a vehicle for extemporaneous or magistral preparation is microbiologically safe when water with methylparaben and propylparaben is used in a proportion of 0.08% and 0.02% (w/w), respectively, avoiding the use of propylene glycol as a solvent and thus its toxic effects in pediatrics.

Concepciones de los maestros sobre la creatividad y su enseñanza / Teachers’ concept about creativity and its teaching

Esta investigación tuvo como objetivo general comprender las concepciones de seis maestros de un colegio de la ciudad de Barranquilla (Colombia) sobre la creatividad y su enseñanza y la manera como éstas se reflejan en su práctica pedagógica. Para ello se desarrolló una investigación de carácter cualitativo dentro de un diseño interpretativo-explicativo, que no sólo dio cuenta de las teorías implícitas que los maestros tenían sobre la creatividad y su enseñanza, sino que igualmente permitió comprender por qué se dan. Para ello, en primer lugar se establecieron y describieron las concepciones de un «Grupo de referencia¼ sobre la creatividad y su enseñanza; en segundo lugar se comprendieron las concepciones de los casos de estudio sobre el fenómeno de estudio; en tercer lugar se compararon las concepciones de los casos con las concepciones del Grupo de referencia, y finalmente se contrastó la práctica pedagógica de los casos (en su fase interactiva) con las concepciones que éstos tenían de la creatividad y su enseñanza. De las conclusiones de la investigación se destacan las siguientes: la evaluación de la creatividad se realiza a través de los productos concretos del estudiante; independiente del área de conocimiento se comparten concepciones generales sobre el fenómeno de la creatividad; no hay una enseñanza única para cada concepción de la creatividad; las concepciones sobre la creatividad y su enseñanza inciden en la forma como los sujetos desarrollan su práctica de aula y cada concepción de los casos tiene sus propias características que la hacen única.

This research aimed at understanding the general concepts on creativity and its teaching of six teachers from a school in the city of Barranquilla and how these concepts are reflected in their teaching practice. A qualitative research was developed within an interpretative- explanatory design was developed and it not only accounted for the implicit theories on creativity and its teaching on the part of the teachers, but it also allowed the understanding of the reason why they exist. As an initial step, the conceptions of a "reference group" were established and described. Secondly, the conceptions of the case study individuals concerning this subject were understood. Thirdly, the conceptions of the cases studied were compared with those of the "reference group" and finally, the teaching practice (in its interactive phase) of the cases was contrasted with the conceptions they had on creativity and its teaching. From the findings of this research we can conclude that: creativity is assessed through the concrete products of the students. General concepts on the creativity issue are shared independently of the area of knowledge; there is not a unique teaching for each conception of creativity; The conceptions on creativity and its teaching do have an influence on the way subjects develop their classroom teaching and each conception of the subjects has its own characteristics that make it unique.