Pharmaceutical Materials Research Articles

Sulforaphene Attenuates Cutibacterium acnes-Induced Inflammation.

Acne is a chronic inflammatory disease of the sebaceous gland attached to the hair follicles. Cutibacterium acnes is a major cause of inflammation caused by acne. It is well known that C. acnes secretes a lipolytic enzyme to break down lipids in sebum, and free fatty acids produced at this time accelerate the inflammatory reaction. There are several drugs used to treat acne; however, each one has various side effects. According to previous studies, sulforaphene (SFEN) has several functions associated with lipid metabolism, brain function, and antibacterial and anti-inflammatory activities. In this study, we examined the effects of SFEN on bacterial growth and inflammatory cytokine production induced by C. acnes. The results revealed that SFEN reduced the growth of C. acnes and inhibited proinflammatory cytokines in C. acnes-treated HaCaT keratinocytes through inhibiting NF-κB-related pathways. In addition, SFEN regulated the expression level of IL-1α, a representative pro-inflammatory cytokine expressed in co-cultured HaCaT keratinocytes and THP-1 monocytes induced by C. acnes. In conclusion, SFEN showed antibacterial activity against C. acnes and controlled the inflammatory response on keratinocytes and monocytes. This finding means that SFEN has potential as both a cosmetic material for acne prevention and a pharmaceutical material for acne treatment.

COVID-19: Accrual Earnings Management Practices in Pharmaceutical Companies in Indonesia

The COVID-19 pandemic has disrupted the supply chain of domestic pharmaceutical raw materials, where 95% of the fulfillment of raw materials relies on imports. Amid difficulties in meeting raw materials, the pharmaceutical sub-sector companies have become one of the sectors of choice for investors throughout 2020, in line with the sentiment of the COVID-19 pandemic. As one of the prima donnas’ sectors during pandemic, financial reports presented by pharmaceutical sector should report the actual condition of the company. This study aims to empirically examine the differences in accrual earnings management before and after the COVID-19 pandemic in pharmaceutical sub-sector companies in Indonesia. To evaluate changes in accrual earnings management in the period before the COVID-19 pandemic, namely in 2019 and after the COVID-19 pandemic, namely in 2020, the Paired Sample T-test was used. The findings of this study show that there is no average difference between accrual earnings management before COVID-19 (Pre-test) and after COVID-19 (Post-test), indicating that COVID-19 has no impact on earnings management practices in the pharmaceutical sub-sector companies in Indonesia. The deteriorating global economic conditions caused by the COVID-19 pandemic do not necessarily encourage managers to carry out aggressive earnings management. The pharmaceutical sub-sector companies that have become the center of attention of investors during this pandemic, as a result the company’s performance shown in the financial statements does not make managers aggressively try to manipulate their financial statements.

Quantifying Micromolar Crystallinity in Pharmaceutical Materials Utilizing 19F Solid-State NMR.

Quantifying low-level components in solid-state analysis presents a significant challenge for most thermal, diffractometric, vibrational, and spectroscopic techniques. In pharmaceutical analysis, identifying and quantifying the physical form of the drug substance in solid dosages is a critical task to ensure the quality of drug products. For example, recrystallization of active pharmaceutical ingredients in amorphous solid dispersions can compromise the stability and bioavailability of drug products. Herein, we have developed and demonstrated fluorine-19 solid-state nuclear magnetic resonance (19F ssNMR) methods and pushed the boundary to quantify minor crystalline contents in amorphous pharmaceuticals. Calibration curves suggest that 19F direct polarization and 1H-19F cross-polarization ssNMR can readily quantify 0.1% w/w crystalline compound I, a commercial fluorinated drug molecule developed by Merck & Co., Inc., Rahway, NJ, U.S.A., in its amorphous formulation. 1H-19F multiple cross-polarization (MultiCP) has been implemented, for the first time, and compared with conventional cross-polarization methods. Most importantly, a relaxation-filtered 19F ssNMR method was utilized to unambiguously identify and quantify as low as 0.04% w/w crystalline components, that is, 6 μmol in a 100 mg tablet at 25% drug loading, by suppressing the signal from the amorphous counterpart. Such a low level of detection offers high confidence and sensitivity to quantify trace amounts of phase change in pharmaceutical amorphous materials in the solid state, which can facilitate formulation development as well as quality control.

Biopolymer-Based Films Reinforced with FexOy-Nanoparticles.

Nowadays, natural polymer-based films are considered potentially environmentally friendly alternatives to conventional plastic films, due to many advantageous properties, including their easy processability, high flexibility, non-toxicity, low cost, high availability, and environmental safety. However, they are limited in their application by a number of shortcomings, including their high water solubility and vapor permeability as well as their poor opacity and low mechanical resistance. Thus, nanoparticles, such as green FexOy-NPs, can be used to overcome the drawbacks associated with these materials. Therefore, the aim of this study was to develop three different polymer-based films (gelatin-based, cellulose acetate-based and chitosan-based films) containing green synthesized FexOy-NPs (1.0% w/w of the initial polymer weight) as an additive to improve film properties. This was accomplished by preparing the different films using the casting method and examining their physicochemical, mechanical, microstructural, and functional characteristics. The results show that the incorporation of FexOy-NPs into the different films significantly enhanced their physicochemical, mechanical, and morphological properties as well as their antioxidant characteristics. Consequently, it was possible to produce suitable natural polymer-based films with potential applications across a wide range of industries, including functional packaging for food, antioxidants, and antimicrobial additives for pharmaceutical and biomedical materials as well as pesticides for agriculture.

Fermentative effects by probiotic Lactobacillus brevis B7 on antioxidant and anti-inflammatory properties of hydroponic ginseng.

Soil-cultivation presents environmental limitations and requires considerable labor, space, and water supply. Alternatively, hydroponically-cultured ginseng (HG) was improved its productivity, availability, and functionality. Improvement of bio-functionality by probiotic fermentation also has been studied. Therefore, in this study, HG was fermented using probiotics to enhance antioxidant and anti-inflammatory activities. Soil-cultivated ginseng (SG), 1 and 2-year HG (HG1, HG2) were extracted using 70% ethanol and fermented by Lactobacillus brevis B7. After fermentation, the phenolic and flavonoid contents, and antioxidant and NO scavenging activities were increased, and HG showed higher bioactivities than SG. Particularly, fermented HG2 showed the highest antioxidant and anti-inflammatory activities and significantly decreased the level of inflammatory mediators. Furthermore, fermented HG2 also effectively inhibited NF-κB signaling pathway. These results suggested that fermented HG significantly enhanced functionality compared to SG and non-fermented HG. This suggests that fermented HG is a potentially useful ingredient for developing health-functional foods or pharmaceutical materials.

Classification of scanning electron microscope images of pharmaceutical excipients using deep convolutional neural networks with transfer learning

Convolutional Neural Networks (CNNs) are image analysis techniques that have been applied to image classification in various fields. In this study, we applied a CNN to classify scanning electron microscopy (SEM) images of pharmaceutical raw material powders to determine if a CNN can evaluate particle morphology. We tested 10 pharmaceutical excipients with widely different particle morphologies. SEM images for each excipient were acquired and divided into training, validation, and test sets. Classification models were constructed by applying transfer learning to pretrained CNN models such as VGG16 and ResNet50. The results of a 5-fold cross-validation showed that the classification accuracy of the CNN model was sufficiently high using either pretrained model and that the type of excipient could be classified with high accuracy. The results suggest that the CNN model can detect differences in particle morphology, such as particle size, shape, and surface condition. By applying Grad-CAM to the constructed CNN model, we succeeded in finding particularly important regions in the particle image of the excipients. CNNs have been found to have the potential to be applied to the identification and characterization of raw material powders for pharmaceutical development.

(Sensor Division Outstanding Achievement Award) Micro/Nano Sensors and Drug Delivery

Our research center of excellence ‘IDUN’ combines research in nanosensors/centrifugal microfluidics and microfabricated devices for oral drug delivery. This allows us to explore the synergy between sensor development and search for new pharmaceutical delivery tools and materials. I will show examples of recent findings and results within drug/polymer characterization, microdevices for drug delivery and diagnostics. Also, new applications within therapeutic drug monitoring using Surface Enhanced Raman Scattering will be presented as well as sensor integration with centrifugal microfluidics platforms. In the future our vision is to combine sensing and delivery, to be able to perform e.g. personalized medication.

Sunset Yellow: physical, thermal and bioactive properties of the widely employed food, pharmaceutical and cosmetic orange azo-dye material

Sunset Yellow: physical, thermal and bioactive properties of the widely employed food, pharmaceutical and cosmetic orange azo-dye material

Recent progress in three-dimensionally-printed dosage forms from a pharmacist perspective.

Additive manufacturing (AM), commonly known as 3D printing (3DP), has opened new frontiers in pharmaceutical applications. This review is aimed to summarise the recent development of 3D-printed dosage forms, from a pharmacists' perspective. Keywords including additive manufacturing, 3D printing and drug delivery were used for literature search in PubMed, Excerpta Medica Database (EMBASE) and Web of Science, to identify articles published in the year 2020. For each 3DP study, the active pharmaceutical ingredients, 3D printers and materials used for the printing were tabulated and discussed. 3DP has found its applications in various dosage forms for oral delivery, transdermal delivery, rectal delivery, vaginal delivery, implant and bone scaffolding. Several topics were discussed in detail, namely patient-specific dosing, customisable drug administration, multidrug approach, varying drug release, compounding pharmacy, regulatory progress and future perspectives. AM is expected to become a common tool in compounding pharmacies to make polypills and personalised medications. 3DP is an enabling tool to fabricate dosage forms with intricate structure designs, tailored dosing, drug combinations and controlled release, all of which lend it to be highly conducive to personalisation, thereby revolutionising the future of pharmacy practice.

Agro-Morphological and Cytogenetic Characterization of Colchicine-Induced Tetraploid Plants of Polemonium caeruleum L. (Polemoniaceae).

Polemonium caeruleum L. (Polemoniaceae) is a valuable medicinal herb with a wide spectrum of biological activities. Under natural conditions, the productivity of this species is rather low. In this study, colchicine-induced tetraploid plants (2n = 4x = 36) of P. caeruleum were obtained, and for the first time, their morphological and cytogenetic characterization was performed. In the tetraploid plants, raw material productivity and also the content of triterpene saponins were significantly higher than in the control diploids. The analysis of chromosome behavior at meiosis and FISH chromosome mapping of 45S and 5S rDNA generally demonstrated stability of both genomes in the tetraploid plants. Based on chromosome morphology and distribution patterns of the studied molecular cytogenetic markers, all chromosome pairs in karyotypes were identified, and chromosome karyograms and idiograms of P. caeruleum were constructed. The revealed specific microdiagnostic characteristics of P. caeruleum (strongly sinuous cells and anomocytic stomata of the leaf epidermis, and also glandular hairs along the veins) could be useful for raw material identification. In the obtained tetraploids, the predominance of large stomata on the lower leaf epidermis was determined. The studied tetraploids can be used in various breeding programs to obtain high-quality pharmaceutical raw materials of P. caeruleum.

Semi-rational engineering membrane binding domain of L-amino acid deaminase from Proteus vulgaris for enhanced α-ketoisocaproate

α-Keto acids are important raw materials for pharmaceuticals and functional foods, which could be produced from cheap feed stock by whole cell biocatalysts containing L-amino acid deaminases (L-AADs). However, the production capacity is limited by the low activity of L-AADs. The L-AAD mediated redox reaction employs the electron transport chain to transfer electrons from the reduced FADH2 to O2, implying that the interaction between L-AAD and the cell membrane affects its catalytic activity. To improve the catalytic activity of L-AAD from Proteus vulgaris, we redesigned the membrane-bound hydrophobic insertion sequences (INS, residues 325–375) by saturation mutagenesis and high-throughput screening. Mutants D340N and L363N exhibited higher affinity and catalytic efficiency for L-leucine, with half-life 1.62-fold and 1.28-fold longer than that of wild-type L-AAD. D340N catalyzed L-leucine to produce 81.21 g⋅L–1 α-ketoisocaproate, with a bioconversion rate of 89.06%, which was 17.57% higher than that of the wild-type. It is predicted that the mutations enhanced the interaction between the protein and the cell membrane.

Mucoadhesive brinzolamide-loaded nanofibers for alternative glaucoma treatment

Despite the advances in the field of pharmaceutical materials and technology, topical administration remains a method of choice for the treatment of eye diseases such as glaucoma, with eye drops being a leading dosage form. Their main disadvantage is a very short drug residence time and thus poor drug bioavailability, leading to the necessity of continuous repeated dosing. Mucoadhesive electrospun nanofibers are promising candidates for overcoming these challenges, while still benefiting from topical ocular administration. As an alternative for eye drops, a nanofibrous drug delivery system (DDS) for the delivery of brinzolamide (BRZ), based on β-cyclodextrin (β-CD), hydroxypropyl cellulose (HPC) and polycaprolactone (PCL), was designed. The results showed β-CD/BRZ guest–host interactions, successful drug incorporation into the nanofibers, and the possibility of more accurate dosing in comparison with the control eye drops. Drug permeation through sheep corneas was almost linear in time, achieving therapeutic concentrations in the receptor medium, and mucoadhesion to sheep eye mucosa was relatively high in case of formulations with high HPC content. All formulations were biocompatible, their mechanical properties were sufficient to handle them without caution and UV irradiation was suitable to reduce bioburden of the fibers matrix, yet no antibacterial properties of BRZ were observed.

Cell-Size Space Regulates the Behavior of Confined Polymers: From Nano- and Micromaterials Science to Biology.

Polymer micromaterials in a liquid or gel phase covered with a surfactant membrane are widely used materials in pharmaceuticals, cosmetics, and foods. In particular, cell-sized micromaterials of biopolymer solutions covered with a lipid membrane have been studied as artificial cells to understand cells from a physicochemical perspective. The characteristics and phase transitions of polymers confined to a microscopic space often differ from those in bulk systems. The effect that causes this difference is referred to as the cell-size space effect (CSE), but the specific physicochemical factors remain unclear. This study introduces the analysis of CSE on molecular diffusion, nanostructure transition, and phase separation and presents their main factors, i.e., short- and long-range interactions with the membrane surface and small volume (finite element nature). This serves as a guide for determining the dominant factors of CSE. Furthermore, we also introduce other factors of CSE such as spatial closure and the relationships among space size, the characteristic length of periodicity, the structure size, and many others produced by biomolecular assemblies through the analysis of protein reaction-diffusion systems and biochemical reactions.

Effects of Rosa roxburghii Tratt glycosides and quercetin on D-galactose-induced aging mice model.

To investigate the effects of RRT (Rosa roxburghii Tratt) glucosides and quercetin on oxidative stress and chronic inflammation in D-galactose-induced aging mice, 90 mice (8 weeks old) were randomly divided into the normal group (NC), aging model group (D-gal), isoquercitrin group (D-gal+isoquercitrin), quercitrin group (D-gal+quercitrin), quercetin group (D-gal+quercetin) and positive control group (D-gal+Metformin). The aging model was established by subcutaneous injection of D-galactose (100 mg/kg). After 42 days of the administration, antioxidant and inflammatory indexes were measured, HE staining was used to investigate pathological changes in liver and brain tissue, and Western blot was used to determine the protein abundance of nuclear factor E2-related factor (Nrf2) and heme oxygenase (HO-1) in the brain. The results showed that, when compared to the NC group, the D-gal group had a significantly lower brain, liver, kidney, and spleen indexes; the contents of MDA, L-1β, IL-6, and TNF-α in serum, liver, and brain were significantly higher, but the levels of CAT, SOD, and GSH-Px were significantly lower. Isoquercitrin, quercitrin, and quercetin significantly increased organ indexes and activities of CAT, SOD, and GSH-Px while decreasing MDA, IL-1β, IL-6, and TNF-α levels in serum, liver, and brain tissues compared to the D-gal group. The morphological changes in the brain and liver tissue were significantly restored by glycosides and quercetin, as observed in HE staining. Furthermore, Western blot results revealed that glycosides and quercetin increased the protein levels of Nrf2, HO-1, and NQO1. Finally, the antioxidant and anti-inflammatory effects of RRT glycoside and quercetin in aging may be attributed to an activated Nrf2/HO-1 signaling pathway. PRACTICAL APPLICATIONS: Aging is characterized by physical changes and dysfunction of numerous biological systems caused by a variety of factors. The oxidative stress and inflammatory effects of RRT glycosides and quercetin on D-galactose-induced aging mice were investigated in this study. RRT glycosides and quercetin were found to protect organ atrophy, liver, and brain tissue in aging mice by regulating oxidative stress and chronic inflammation. It served as the theoretical foundation for the investigation of Rosa roxburghii Tratt as a health product and pharmaceutical raw material.

Dissociation and Recombination Processes in Lactose Monohydrate Detected by THz Time-Domain Spectroscopy

The terahertz (THz) region has much appeal for differentiating between hydrate systems and for physically characterizing pharmaceutical drug materials. The present study employs THz absorption spectroscopy to investigate the effect of heating on dehydration and hydration in α-lactose monohydrate. Distinctive THz absorption spectra were observed following various heating durations. The THz absorption spectra for α-lactose monohydrate and anhydrous α-lactose exhibit clear differences. Pure α-lactose monohydrate displays clear absorption peaks at 0.53, 1.05, 1.11, 1.33, and 1.56 THz. The complete dehydration of α-lactose monohydrate takes only 15 mins at 145°C (418 K). Moreover, the THz refractive index of α-lactose monohydrate decreases during dehydration. The dehydration of α-lactose monohydrate was also studied using Beer–Lambert law to compare THz absorption spectra as functions of the heating time. The absorption coefficient spectra recorded at 0.53 and 1.35 THz for α-lactose monohydrate after different dehydration times vary linearly with the remaining water content.

An extended 3-compartment model for describing step change experiments in pharmaceutical twin-screw feeders at different refill regimes

Residence time distributions (RTDs) are a valuable tool for product tracking in the unit operations of a continuous line for manufacturing pharmaceutical oral solid dosage (OSD) and the integrated system itself. The first unit operation in such a continuous line in which extended intermixing can occur, is typically a feeder. The RTD of a feeder can be obtained by performing tracer experiments with a tracer material. A physical interpretation can be given to the observed tracer concentration responses by fitting a tanks-in-series (TIS) or compartmental model to it. Consequently, the internal mixing behaviour inside the feeder hopper can be rationalized. However, typically, a constant volume is assumed for the tanks or compartments in these models. This has led to several publications where the experimental set-up does not violate the constant volume assumption, i.e. one performs refills at a high hopper fill level. Here, we step away from this assumption and develop a set of differential equations for a 3-compartment model in order to account for a non-constant volume of the compartments. Moreover, the model distinguishes between a bypass trajectory formed by the agitator inside the feeder and an inner mixing volume, in which the tracer concentration lags on the tracer concentration in the bypass volume. This compartmentalization was inspired by the results obtained in a previous study using a spatial sampling method to assess the tracer concentration throughout the feeder hopper for different experimental runtimes. The developed model successfully describes the step responses for different refill regimes: the standard smooth first order plus dead time response (FOPDT) for a high refill regime and the more complex step response, including dips in the rising phase of the curve, for the low refill regime. As a consequence, a more thorough understanding of the complex mixing behaviour inside the feeder is obtained, which allows for an improved traceability. Next to that, the model delivers enhanced knowledge on the interaction between the residence time and the refill regime. The developed model was fitted to a data set, containing step change experiments for different pharmaceutical materials (Tablettose 80 (T80), Microcelac 100 (MCL), and Avicel PH101 (MCC)), different mass flow rates, and refill regimes. The experimentally observed phenomena could be reliably described by the proposed model. The model showed an improved transferability compared to typical TIS models.

LOGISTIC DEVELOPMENT STRATEGY FOR PHARMACEUTICAL INDUSTRY FOLLOWING LEAN PERSPECTIVE: THE CASE STUDY OF PAKISTAN

Pharmaceutical strategies are typically unseen to patients but have a direct impact on how well healthcare is managed. This study focuses on creating a new strategy to further develop the coordinated elements supporting the pharmaceutical divisions. The study focuses on the administration and network of stores for pharmaceutical materials used in this sector in Pakistan. This study investigates previous studies to develop an improvement strategy to computerise the systems used in the distribution center and outbuildings. The study explores the impact of the disagreements between pharmaceutical organizations on the business and their commitment to the development of strategies along with recognizing the best-known strategies of pharmaceutical development and their benefits. It also offers best practices and develops a structure of understanding with respect to the pharmaceutical companies in Pakistan. The study finds that the pharmaceuticaldevelopment and its situation in Pakistan is exceptionally unique and rapidly evolving. The study formulates new strategic proposals within the broader political context of Pakistan and its pharmaceutical industry.

Spectrofluorimetric determination of selected genotoxic impurities in pharmaceutical raw materials and final products

A green spectrofluorimetric method was introduced for the determination of selected genotoxic impurities; 2-aminopyridine and 3-aminopyridine in different pharmaceutical raw materials and dosage forms. The method relied on the native fluorescence of these impurities in acidic medium. The experimental conditions were carefully studied and optimized, and the method was validated according to International Council on Harmonisation (ICH) guidelines. The linear range for both analytes was 2.50–100 ng/mL with good determination coefficients of 0.9995 and 0.9992 and detection limits of 0.62 ng/mL and 0.74 ng/mL for 2-aminopyridine and 3-aminopyridine, respectively. The method was successfully applied for determination of 2-aminopyridine and 3-aminopyridine in four active pharmaceutical ingredients and nine dosage forms with satisfactory percentage recoveries and without interference from co-formulated excipients. Analytical performance of the proposed method was comparable to that of the reported methods; hence, the proposed method can be used as a simple and low-cost alternative in quality control laboratories.

Operando X‐ray Powder Diffraction Study of Mechanochemical Activation Tested for the CO Oxidation over Au@Fe2O3 as Model Reaction

AbstractMechanochemistry has proven to be an excellent green synthesis method for preparing organic, pharmaceutical, and inorganic materials. Mechanocatalysis, inducing a catalytic reaction by mechanical forces, is an emerging field because neither external temperature nor pressure inputs are required. Previous studies reported enhanced catalytic activity during the mechanical treatment of supported gold catalysts for CO oxidation. So far, the processes inside the milling vessel during mechanocatalysis could not be monitored. In this work, the results of high‐energy operando X‐ray powder diffraction experiments and online gas analysis will be reported. A specific milling setup with a custom‐made vessel and gas dosing system was developed. To prove the feasibility of the experimental setup for operando diffraction studies during mechanocatalysis, the CO oxidation with Au@Fe2O3 as a catalyst was selected as a well‐known model reaction. The operando studies enabled monitoring morphology changes of the support as well as changes in the crystallite size of the gold catalyst. The change of the crystal size is directly correlated to changes in the active surface area and thus to the CO2 yield. The studies confirm the successful implementation of the operando setup, and its potential to be applied to other catalytic reactions.

Identification and quantification of extractables and leachables in laminated film and pouches for pharmaceutical packaging

Extractables and leachables from pharmaceutical packaging material can potentially be detrimental, which may affect the safety of the drug products. In this study, two compounds were found to be the possible extractables from the secondary packaging material. A strategy combining high performance liquid chromatography (HPLC), fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and nuclear magnetic resonance (NMR) spectroscopy was utilized for identification of the two compounds. Afterwards, a simple and sensitive HPLC method was developed and validated for the simultaneous quantification of both. The results indicated that this method was suitable for quantificating the two extractables in the pharmaceutical packaging material.