Development of a novel UPLC approach to co-prediction of four active compounds in a multi-component pharmaceutical preparation.

In this work, a new ultra-performance liquid chromatography method based on photodiode array detection (UPLC-PDA) was first developed for the quantitative analysis of the quaternary mixture of ascorbic acid (AA), paracetamol (PAR), caffeine (CAF) and chlorpheniramine maleate (CPA) in a commercial dosage form. The developed UPLC-PDA method offered a new possibility for the co-determination of four active ingredients in a drug combination with short run time and simple sample preparation. The successful chromatographic separation of the four drugs was performed using a Waters Acquity UPLC BEH C18 column (1.7 µm 2.1 × 100 mm) (Mildford, USA) and a mobile phase consisting of water (12 %), acetonitrile (13 %) and 0.1 M H3PO4 (75 %) at a flow rate of 0.25 mL/min. The validation of the proposed UPLC-PDA approach was verified by analyzing synthetic mixtures, inter- and intra-day experiments, and commercial powder samples and provided satisfactory results.

Electrosprayed Eudragit RL100 nanoparticles with Janus polyvinylpyrrolidone patches for multiphase release of paracetamol.

Advanced nanotechniques and the corresponding complex nanostructures they produce represent some of the most powerful tools for developing novel drug delivery systems (DDSs). In this study, a side-by-side electrospraying process was developed for creating double-chamber nanoparticles in which Janus soluble polyvinylpyrrolidone (PVP) patches were added to the sides of Eudragit RL100 (RL100) particles. Both sides were loaded with the poorly water-soluble drug paracetamol (PAR). Scanning electron microscope results demonstrated that the electrosprayed nanoparticles had an integrated Janus nanostructure. Combined with observations of the working processes, the microformation mechanism for creating the Janus PVP patches was proposed. XRD, DSC, and ATR-FTIR experiments verified that the PAR drug was present in the Janus particles in an amorphous state due to its fine compatibility with the polymeric matrices. In vitro dissolution tests verified that the Janus nanoparticles were able to provide a typical biphasic drug release profile, with the PVP patches providing 43.8 ± 5.4% drug release in the first phase in a pulsatile manner. In vivo animal experiments indicated that the Janus particles, on one hand, could provide a faster therapeutic effect than the electrosprayed sustained-release RL100 nanoparticles. On the other hand, they could maintain a therapeutic blood drug concentration for a longer period. The controlled release mechanism of the drug was proposed. The protocols reported here pioneer a new process-structure-performance relationship for developing Janus-structure-based advanced nano-DDSs.

Studies in Solid Solution Formation between Acetaminophen and Povidone and Mouth-dissolving Strip Formulation.

INTRODUCTION: This invention reports the solubilization of Acetaminophen (ACM) within the Povidone (PVP K30) in the solid state for the first time. METHODS: First-generation solid dispersions (SDs) were attempted with a different ratio of PVP K:30:ACM. SDs prepared were transparent, suggesting a solid solution (SS) formation, which was a serendipitous discovery. A minimum ratio of 1.25:1 PVP K30: ACM was required to form stable SS, suggesting discontinuous SS. A computational complex prediction tool, fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) confirmed the SS formation. RESULTS: The oral strip formulation was developed from the PVP K30: ACM SS using Polyvinyl alcohol as a film-former found to be optimum concerning physicochemical properties, offering rapid drug dissolution and taste masking. CONCLUSION: The designed strip is suitable for delivering a child's dose (100-150 mg). However, the developed SS can be formulated as tablets, capsules, or oral dissolving tablets to deliver adult doses with improved therapeutic benefits and patient compliance.

Detection of Distinct Distributions of Acetaminophen and Acetaminophen-Cysteine in Kidneys up to 10 µm Resolution and Identification of a Novel Acetaminophen Metabolite Using an AP-MALDI Imaging Mass Microscope.

Drug distribution studies in tissue are crucial for understanding the pharmacokinetics and potential toxicity of drugs. Recently, matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) has gained attention for drug distribution studies due to its high sensitivity, label-free nature, and ability to distinguish between parent drugs, their metabolites, and endogenous molecules. Despite these advantages, achieving high spatial resolution in drug imaging is challenging. Importantly, many drugs and metabolites are rarely detectable by conventional vacuum MALDI-MSI because of their poor ionization efficiency. It has been reported that acetaminophen (APAP) and one of its major metabolites, APAP-Cysteine (APAP-CYS), cannot be detected by vacuum MALDI-MSI without derivatization. In this context, we showed the distribution of both APAP and APAP-CYS in kidneys at high spatial resolution (25 and 10 µm) by employing an atmospheric pressure-MALDI imaging mass microscope without derivatization. APAP was highly accumulated in the renal pelvis 1 h after drug administration, while APAP-CYS exhibited characteristic distributions in the outer medulla and renal pelvis at both 30 min and 1 h after administration. Interestingly, cluster-like distributions of APAP and APAP-CYS were observed in the renal pelvis at 10 µm spatial resolution. Additionally, a novel APAP metabolite, tentatively coined as APAP-butyl sulfate (APAP-BS), was identified in the kidney, brain, and liver by combining MSI and tandem MSI. For the first time, our study revealed differential distributions of APAP, APAP-CYS (in kidneys), and APAP-BS (in kidney, brain, and liver) and is believed to enhance the understanding of the pharmacokinetics and potential nephrotoxicity of this drug.

Deep Eutectic Solvent-Assisted Synthesis of a Strontium Tungstate Bifunctional Catalyst: Investigation on the Electrocatalytic Determination and Photocatalytic Degradation of Acetaminophen and Metformin Drugs.

In this work, we propose a modified solid-state approach for the sustainable preparation of a SrWO4 bifunctional catalyst using thymol-menthol-based natural deep eutectic green solvents (NADESs). Various spectroscopic and morphological techniques analyzed the as-synthesized SrWO4 particles. Acetaminophen (ATP) and metformin (MTF) were selected as the model drug compounds. The electrochemical detection and photocatalytic degradation of ATP and MTF upon ultraviolet-visible (UV-vis) light irradiation in the presence of as-prepared SrWO4 particles as an active catalyst are examined. The present study displayed that the proposed catalyst SrWO4 has enhanced catalytic activity in achieving the optimum experimental conditions, and linear ranges of ATP = 0.01-25.90 µM and MTF = 0.01-25.90 µM, a lower limit of detection (LOD) value (ATP = 0.0031 µM and MTF = 0.008 µM), and higher sensitivity toward ATP and MTF determination were obtained. Similarly, the rate constant was found to be k = ATP = 0.0082 min-1 and MTF = 0.0296 min-1 according to the Langmuir-Hinshelwood model, benefitting from the excellent synergistic impact of the SrWO4 catalyst toward the photocatalytic degradation of the drug molecule. Hence, this work offers innovative insights into the applicability of the as-prepared SrWO4 bifunctional catalyst as an excellent functional material for the remediation of emerging pollutants in water bodies with a recovery range of 98.2-99.75%.

Molten-salts assisted preparation of iron-nitrogen-carbon catalyst for efficient degradation of acetaminophen by periodate activation.

Highly efficient and stable heterogeneous catalysts were desired to activate periodate (PI) for sustainable pollution control. Herein, iron-nitrogen-carbon catalyst was synthesized using a facile molten-salts mediated pyrolysis strategy (denoted as FeNC-MS) and employed to activate PI for the degradation of acetaminophen (ACE). Compared with iron-nitrogen-carbon catalyst prepared by direct pyrolysis method (marked as FeNC), FeNC-MS exhibited superior catalytic activity due to its large specific surface area (1600 m2 g-1) and the abundance of FeNx sites. The batch experiments revealed that FeNC/PI process achieved 37 % ACE removal within 20 min, while ACE removal in FeNC-MS/PI process was 98 % under the identical conditions. Integrated with electron paramagnetic resonance tests, quenching experiments, chemical probe identification, and electrochemical experiments, we demonstrated that FeNC-MS-PI complexes-mediated electron transfer was the predominant mechanism for the oxidation of ACE. Further analysis disclosed that FeNx sites in FeNC-MS were the main active sites for the activation of PI. Additionally, FeNC-MS/PI process exhibited significant resistance to humic acid and background electrolyte, and avoided the secondary pollution imposed by Fe leaching. The possible degradation pathways of ACE were proposed. The germination experiments of lettuce seeds showed that the ecotoxicity of ACE solution was significantly reduced after treatment with FeNC-MS/PI process. Overall, this study provided a facile strategy for the synthesis of efficient iron-nitrogen-carbon catalysts and gained fundamental insight into the mechanism of PI activation by iron-nitrogen-carbon catalysts for pollutants degradation.

Simultaneous Quantitation of Paracetamol and Lornoxicam in the Presence of Five Related Substances and Toxic Impurities by a Selective HPLC-DAD Method.

OBJECTIVE: This research describes the simultaneous quantitation of paracetamol (PRM) and lornoxicam (LRX) with five of their related substances and toxic impurities, including, 4-nitrophenol (NTP), 4-aminophenol (AMP), 4-chloroacetanilide (CAC), N-phenylacetamide (NPA), and 2-aminopyridine (APD) using a specific HPLC-diode array detector (DAD) method. METHODS: The chromatographic separation involves the use of a XTerra C18 column as the stationary phase and a mobile phase consisting of acetonitrile and 0.025 M phosphate buffer (pH 6). The separation was performed using gradient elution mode at 1.0 mL/min flow rate and detection at 260 nm for the determination of PRM and LRX. For detecting PRM and LRX in the presence of their toxic impurities, 270 nm was used. Validation of the suggested HPLC method was accomplished with regard to linearity, ranges, detection and quantitation limits, robustness, accuracy, precision, and specificity. RESULTS: Excellent resolution of the mixture components was accomplished at retention times 4.2, 4.8, 7.4, 11.1, 13.5, 14.7, and 15.3 min for APD, AMP, PRM, NPA, LRX, NTP, and CAC, respectively. Linearity was established for PRM and LRX within concentration ranges of 10-100 and 10-60 µg/mL, respectively. The correlation coefficients obtained were >0.9997. The suggested method was confirmed to be a specific stability-indicating through the selective separation of PRM and LRX from their related substances, degradants, and impurities. CONCLUSION: The proposed method was successfully utilized for the sensitive and selective determination of PRM and LRX in their pharmaceutical formulation. HIGHLIGHTS: To the best of our knowledge, this is the first impurity profiling assay method for this combination in the presence of five of their toxic related substances and impurities. Taking into consideration that at least two of the studied impurities (AMP and APD) are actually reported degradation products for the main drugs, the suggested method can be considered stability-indicating as well.

Formulation and Cost-Effectiveness of Fluid Gels as an Age-Appropriate Dosage Form for Older Adults with Dysphagia.

Dysphagia is associated with increased dependency and treatment costs, whereby patients resort to extemporaneous compounding that may further increase the number of adverse events and medical errors. In the management of dysphagia, increasing the bolus viscosity of medication such as fluid gels can be practiced. This study aimed to prepare and characterize the fluid gels as well as to estimate the cost of using fluid gels and compare it to the conventional practice of extemporaneous preparation of thickened liquid. Fluid gels were formulated using gellan gum and determined for physicochemical characteristics and in vitro drug release profile. The cost-based price of the fluid gel was estimated and compared to the cost of administering standard medication as well as administering thickened liquid using thickening powder. Fluid gels exhibited good physicochemical properties with the viscosity within nectar and honey consistency. A similar dissolution profile to the reference was observed for the 0.5% w/v gellan gum fluid gel and exhibiting the Higuchi release model. The price for 100 mL unit of 50 mg/mL paracetamol/acetaminophen and 20 mg/mL ibuprofen fluid gel was estimated to be about USD2.30 and USD2.37, respectively. A dose of 1000 mg paracetamol and 400 mg ibuprofen fluid gel was estimated to be about USD0.46 and USD0.47, respectively, which is lower than the cost of administering the same dose using extemporaneous thickened liquid. Fluid gels could be a cost-effective formulation for delivering medication in patients with dysphagia and can be developed on a profitable scale.

Ultra-Fast Insulin-Pramlintide Co-Formulation for Improved Glucose Management in Diabetic Rats.

Dual-hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co-secretion. Here, amphiphilic acrylamide copolymers are used to create a stable co-formulation of monomeric insulin and amylin analogues (lispro and pramlintide) with synchronous pharmacokinetics and ultra-rapid action. The co-formulation is stable for over 16 h under stressed aging conditions, whereas commercial insulin lispro (Humalog) aggregates in 8 h. The faster pharmacokinetics of monomeric insulin in this co-formulation result in increased insulin-pramlintide overlap of 75 ± 6% compared to only 47 ± 7% for separate injections. The co-formulation results in similar delay in gastric emptying compared to pramlintide delivered separately. In a glucose challenge, in rats, the co-formulation reduces deviation from baseline glucose compared to insulin only, or separate insulin and pramlintide administrations. Further, comparison of interspecies pharmacokinetics of monomeric pramlintide suggests that pharmacokinetics observed for the co-formulation will be well preserved in future translation to humans. Together these results suggest that the co-formulation has the potential to improve mealtime glucose management and reduce patient burden in the treatment of diabetes.

Sub-100-micron calcium-alginate microspheres: Preparation by nitrogen flow focusing, dependence of spherical shape on gas streams and a drug carrier using acetaminophen as a model drug.

We developed a miniature gas-liquid coaxial flow device using glass capillaries, aiming to produce sub-100-µm Ca-alginate microspheres. Depending on collecting distance and the flow rates of nitrogen gas and alginate solution, however, Ca-alginate microparticles of different shapes were obtained. Spherical, monodisperse microparticles (microspheres) could only be obtained at certain gas flow rates and within a corresponding range of collecting distance. The result suggests that, for particles of this size, the gas flow rate and collecting distance are crucial for the formation of the spherical shape. We evaluated, as an example of its applications, the microsphere as a drug carrier using acetaminophen as a model drug. Large (~150 µm) and small (~70 µm) drug-loaded microspheres were prepared using two respective devices. Specifically, the drug-loaded microspheres were complexed with chitosan of different molecular weights. The dependence of in vitro drug release on the microsphere size and the chitosan molecular weight was examined. CHEMICAL COMPOUNDS STUDIED IN THIS ARTICLE: Alginic acid sodium salt (PubChem CID: 5102882); Chitosan (PubChem CID: 71853); Calcium chloride (PubChem CID: 5284359); Sodium chloride (PubChem CID: 5234); Acetaminophen (PubChem CID: 1983); Polydimethylsiloxane (PubChem CID: 24771); n-Octadecyltrimethoxysilane (PubChem CID: 76486).

Preparation and Optimization of PEGylated Nano Graphene Oxide-Based Delivery System for Drugs with Different Molecular Structures Using Design of Experiment (DoE).

Graphene oxide (GO), due to its 2D planar structure and favorable physical and chemical properties, has been used in different fields including drug delivery. This study aimed to investigate the impact of different process parameters on the average size of drug-loaded PEGylated nano graphene oxide (NGO-PEG) particles using design of experiment (DoE) and the loading of drugs with different molecular structures on an NGO-PEG-based delivery system. GO was prepared from graphite, processed using a sonication method, and functionalized using PEG 6000. Acetaminophen (AMP), diclofenac (DIC), and methotrexate (MTX) were loaded onto NGO-PEG particles. Drug-loaded NGO-PEG was then characterized using dynamic light scattering (DLS), Fourier transform infrared (FTIR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), XRD. The DLS data showed that the drug-loaded NGO-PEG suspensions were in the size range of 200 nm-1.3 µm. The sonication time and the stirring rate were found to be the major process parameters which affected the average size of the drug-loaded NGO-PEG. FTIR, DSC, XRD, and SEM demonstrated that the functionalization or coating of the NGO occurred through physical interaction using PEG 6000. Methotrexate (MTX), with the highest number of aromatic rings, showed the highest loading efficiency of 95.6% compared to drugs with fewer aromatic rings (diclofenac (DIC) 70.5% and acetaminophen (AMP) 65.5%). This study suggests that GO-based nano delivery systems can be used to deliver drugs with multiple aromatic rings with a low water solubility and targeted delivery (e.g., cancer).

Lyophilized Drug-Loaded Solid Lipid Nanoparticles Formulated with Beeswax and Theobroma Oil.

Solid lipid nanoparticles (SLNs) have the potential to enhance the systemic availability of an active pharmaceutical ingredient (API) or reduce its toxicity through uptake of the SLNs from the gastrointestinal tract or controlled release of the API, respectively. In both aspects, the responses of the lipid matrix to external challenges is crucial. Here, we evaluate the effects of lyophilization on key responses of 1:1 beeswax-theobroma oil matrix SLNs using three model drugs: amphotericin B (AMB), paracetamol (PAR), and sulfasalazine (SSZ). Fresh SLNs were stable with sizes ranging between 206.5-236.9 nm. Lyophilization and storage for 24 months (4-8 °C) caused a 1.6- and 1.5-fold increase in size, respectively, in all three SLNs. Zeta potential was >60 mV in fresh, stored, and lyophilized SLNs, indicating good colloidal stability. Drug release was not significantly affected by lyophilization up to 8 h. Drug release percentages at end time were 11.8 ± 0.4, 65.9 ± 0.04, and 31.4 ± 1.95% from fresh AMB-SLNs, PAR-SLNs, and SSZ-SLNs, respectively, and 11.4 ± 0.4, 76.04 ± 0.21, and 31.6 ± 0.33% from lyophilized SLNs, respectively. Thus, rate of release is dependent on API solubility (AMB < SSZ < PAR). Drug release from each matrix followed the Higuchi model and was not affected by lyophilization. The above SLNs show potential for use in delivering hydrophilic and lipophilic drugs.

Cytochrome P450 2E1 and its roles in disease.

Cytochrome P450 (P450) 2E1 is the major P450 enzyme involved in ethanol metabolism. That role is shared with two other enzymes that oxidize ethanol, alcohol dehydrogenase and catalase. P450 2E1 is also involved in the bioactivation of a number of low molecular weight cancer suspects, as validated in vivo in mouse models where cancers could be attenuated by deletion of Cyp2e1. P450 2E1 does not have a role in global production of reactive oxygen species but localized roles are possible, e.g. in mitochondria. The structures, conformations, and catalytic mechanisms of P450 2E1 have some unusual features among P450s. The concentration of hepatic P450 varies ≥10-fold among humans, possibly in part due to single nucleotide variants. The level of P450 2E1 may have relevance in the rates of oxidation of drugs, particularly acetaminophen and anesthetics.

Preparation and evaluation of orally disintegrating tablets containing taste masked microparticles of acetaminophen.

In the present work, taste masked particles of acetaminophen (AAP), a highly soluble bitter tasting drug, were developed and ODT containing the taste masked particles were prepared. Taste masked particles of AAP were prepared using different amounts of tetraglycerol polyricinoleate (TGPR) and Eudragit ®E100. Although the drug content ratio and drug recovery decreased with increasing TGPR, drug release from AAP-CR100 particles containing a large amount of TGPR was mostly suppressed for 2 min. Hence, AAP-CR100 was incorporated into ODT as taste masked particles for AAP. Three major disintegrants were used for ODT, and it was confirmed that the tensile strength of all formulations showed applicable hardness for handling. The AAP-CR100-CP(40) formulation containing crospovidone showed the shortest disintegration time and the drug release from AAP-CR100-CP(40) into pH 6.8 test solution was suppressed compared with commercial AAP tablets. Because the drug release from AAP-CR100-CP(40) into the pH 1.2 test solution was rapid, it was suggested that drug release from AAP-CR100-CP(40) is suppressed in the oral cavity, and the drug is released promptly in the stomach. Thus AAP-CR100-CP(40) may be useful as an ODT in which the dissolution of AAP in the oral cavity is suppressed.

Establishment of the experimental procedure for prediction of conjugation capacity in mutant UGT1A1.

UDP-glucuronosyltransferase 1A1 (UGT1A1) is an enzyme that is found in the endoplasmic reticulum membrane and can reportedly have a large number of amino acid substitutions that result in the reduction of glucuronidation capacity. For example, adverse drug reactions when patients receive CPT-11 (irinotecan) such as in cancer chemotherapy are caused by amino acid substitutions in UGT1A1. We previously found that the extent of the docking when the hydroxyl residue of bilirubin was oriented toward UDP-glucuronic acid correlated with in vitro conjugation capacity. In this study, we analyzed the conformation of mutant UGT1A1s by means of structural optimization with water and lipid bilayers instead of the optimization in vacuo that we used in our previous study. We then derived a mathematical model that can predict the conjugation capacities of mutant UGT1A1s by using results of substrate docking in silico and results of in vitro analysis of glucuronidation of acetaminophen and 17ß-estradiol by UGT1A1s. This experimental procedure showed that the in silico conjugation capacities of other mutant UGT1A1s with bilirubin or SN-38 were similar to reported in vitro conjugation capacities. Our results suggest that this experimental procedure described herein can correctly predict the conjugation capacities of mutant UGT1A1s and any substrate.

Hydrophilic excipients in digital light processing (DLP) printing of sustained release tablets: Impact on internal structure and drug dissolution rate.

Three-dimensional (3D) printing enables the production of different objects adjusted for the specific application, which has particular importance of providing personalized therapy, whereby the challenge is to apply pharmaceutical materials into 3D printing technology. In this study, effect of poly(ethylene glycol) 400 (PEG 400), sodium chloride (NaCl), and mannitol, as hydrophilic excipients, was investigated in order to overcome very slow and incomplete drug release from tablets (printlets) fabricated by photopolymerization using digital light processing (DLP) technology. Paracetamol (acetaminophen) was used as a model drug, while polyethylene glycol diacrylate (PEGDA) was used as a photopolymer and diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide as a photoinitiator in photoreactive mixtures. Most of printlet formulations exhibit sustained release over 8 h, wherein drug release kinetics is the best described with Korsmeyer-Peppas kinetics. Variation in the content of photopolymer and excipients had an influence on the dissolution rate, mechanical characteristics, and internal structure of the investigated samples. The addition of hydrophilic polymers increased drug release rate, while PEGDA had the greatest influence on the tensile strength of printlets. The results indicate the possibility of implementation of traditional excipients into different formulations for photopolymerization based 3D printing for the production of small batches of tablets with tailored drug release.

Precision Printing of Customized Cylindrical Capsules with Multifunctional Layers for Oral Drug Delivery.

Advances in personalized medicine will require custom drug formulations and delivery mechanisms. Herein, we demonstrate a new type of personalized capsule comprising of printed concentric cylindrical layers with each layer having a distinctive functional drug component. Poly ε-caprolactone (PCL) with paracetamol (APAP) and chlorpheniramine maleate (CM), synergistic drugs commonly used to alleviate influenza symptoms, are printed as an inner layer and outer layer, respectively, via microscaled electrohydrodynamic (EHD) printing. Polyvinylpyrrolidone (PVP) nanofibers are embedded as interlayers between the two printed PCL-drug layers using electrospinning (ES) techniques. The complete concentric cylindrical capsule with a 6 mm inner diameter and 15 mm length can be swallowed for oral drug delivery. After dissolution of the PVP interlayer, the capsule separates in two, with inner and outer capsules for continuous drug dosing and targeting. Imaging was achieved using a 3T MRI system which allowed temporal observations of the targeted release through the incorporation of nanoparticles (Fe3O4). The morphology and structure, chemical composition, mechanical properties, and biocompatibility of the capsules were studied in vitro. In summary, this new type of custom printed and electrospun capsule that enabled component separation, targeted drug release may advance personalized medicine via multidrug oral delivery.

Temperature-dependent toxicity of acetaminophen in Japanese medaka larvae.

Because of its analgesic properties, acetaminophen (AAP) is widely used to relieve headache. AAP is generally considered safe for humans, but its effects on aquatic organisms are not well known. Here, we have hypothesis that effects of AAP on aquatic organisms would be environmental temperature dependent, because their physiological function depend on the temperature. To test this hypothesis, we used medaka (Oryzias latipes) as a model, because they can live at a wide range of temperatures (0-40 °C). We exposed medaka larvae to 0 (control), 50, or 150 mg/L of AAP at 15, 25 (optimal temperature), or 30 °C for 4 days. Egg yolk absorption was accelerated with raising temperature at any AAP dose. AAP exposure did not have biologically significant effects on survival ratio and body length of larvae at any tested temperature or dose, but heart rate decreased as the dose of AAP and environmental temperature increased. In addition, as the temperature increased, amount of ATP in individual larvae increased in control group, but decreased in AAP exposed group. Subsequently, exposure to 150 mg/L of AAP at 30 °C decreased the number of red blood cells in the gills; we used 150 mg/L of AAP in subsequent hematological and histological analyses. Hematological analysis showed that rising temperature increased the proportion of morphologically abnormal red blood cells in AAP-exposed larvae, suggesting that AAP induced anemia-like signs in larvae. Histological observation of the kidney, which is a hematopoietic organ in fish, revealed no abnormalities. However, in the liver, which is responsible for drug metabolism, the proportion of vacuoles increased with increasing temperature. Although the exposure concentration we tested was higher than environmentally relevant concentrations, our data indicated that rising temperature enhances the toxicity of AAP to medaka larvae, suggesting an ecological risk of AAP due to global warming.

Paracetamol-Galactose Conjugate: A Novel Prodrug for an Old Analgesic Drug.

Paracetamol has been one of the most commonly used and prescribed analgesic drugs for more than a hundred years. Despite being generally well tolerated, it can result in high liver toxicity when administered in specific conditions, such as overdose, or in vulnerable individuals. We have synthesized and characterized a paracetamol galactosylated prodrug (PARgal) with the aim of improving both the pharmacodynamic and pharmacological profile of paracetamol. PARgal shows a range of physicochemical properties, solubility, lipophilicity, and chemical stability at differing physiological pH values and in human serum. PARgal could still be preclinically detected 2 h after administration, meaning that it displays reduced hepatic metabolism compared to paracetamol. In overdose conditions, PARgal has not shown any cytotoxic effect in in vitro analyses performed on human liver cells. Furthermore, when tested in an animal pain model, PARgal demonstrated a sustained analgesic effect up to the 12th hour after oral administration. These findings support the use of galactose as a suitable carrier in the development of prodrugs for analgesic treatment.

Comparison of Linear and 4-Arm Star Poly(vinyl pyrrolidone) for Aqueous Binder Jetting Additive Manufacturing of Personalized Dosage Tablets.

Fabrication of personalized dosage oral pharmaceuticals using additive manufacturing (AM) provides patients with customizable, locally manufactured, and cost-efficient tablets, while reducing the probability of side effects. Binder jetting AM has potential for fabrication of customized dosage tablets, but the resulting products lack in strength due to solely relying on the binder to produce structural integrity. The selection of polymeric binders is also limited due to viscosity restraints, which limits molecular weight and concentration. To investigate and ameliorate these limitations, this article reports a comprehensive study of linear and 4-arm star poly(vinyl pyrrolidone) (PVP) over a range of molecular weights as polymeric binders for binder jetting AM and their effect on physical tablet properties. Formulation of varying molecular weights and concentrations of linear and 4-arm star PVP in deionized water and subsequent jetting revealed relationships between the critical overlap concentrations (C*) and jettability on binder jetting systems with thermal inkjet printheads. After printing with a commercially available ZCorp Spectrum Z510 printer with an HP11 printhead with a lactose and powdered sugar powder bed, subsequent measurement of compressive strength, compressive modulus, and porosity revealed structure-property relationships between molecular weight, polymer concentration, and linear and 4-arm star architectures with physical properties of binder jetted tablets. This study elucidated that the dominating factor to increase compressive strength of a tablet is dependent on the weight percent of the polymer in the binder, which filled interstitial voids between powder particles. Because 4-arm star polymers have lower solution viscosities compared to linear analogues at the same molecular weights, they were jettable at higher concentrations, thus producing the strongest tablets at a compressive strength of 1.2 MPa. Finally, the inclusion of an active pharmaceutical ingredient (API), acetaminophen, revealed maintenance of the tablet physical properties across 5-50 total wt % API in each tablet.