Development and optimization of guaifenesin sustained release mini-tablets for adult and geriatric patients.

Aim: The main aim of this study was to formulate and optimize sustained release mini-tablets of guaifenesin.Materials & methods: Guaifenesin granules were successfully prepared using different blend ratios of carnauba wax to drug by melt granulation method. The properties of granules were further modified by combining them with ethyl cellulose. The obtained granules were then mixed and compressed into mini-tablets using a tablet press machine. The resulting mini-tablets were characterized in terms of weight, thickness, hardness, drug content and in vitro drug release.Results: Mini-tablets with 1:6 carnauba wax to drug ratio showed superior physicochemical characteristics, releasing about 100.03% of guaifenesin over 8 h. Ethyl cellulose offers a great potential to accurately control drug release from mini-tablets.Conclusion: The prepared mini-tablets seem to be a very promising alternative to guaifenesin conventional formulations and can be used in adults and elderly people.

[Box: see text].

Validity of the Tablet-Based Digital Cognitive Test (SCST) in Identifying Different Degrees of Cognitive Impairment.

BACKGROUND: As society ages, the incidence of Alzheimer's disease and other dementias has surged, highlighting the importance of early dementia diagnosis. The Seoul Cognitive Status Test (SCST), a digital neuropsychological test, is designed for the early detection of cognitive impairment and has been standardized to establish reliability and validity. This study aims to verify whether the SCST effectively discriminates between groups based on three cognitive statuses (subjective cognitive decline [SCD], mild cognitive impairment [MCI], Dementia) in a large sample. We also seek to determine whether the SCST discriminates between individuals with three different cognitive statuses as defined by the Cognitive Dementia Rating (CDR). METHODS: We enrolled 254 participants from a dementia clinic who underwent a comprehensive neuropsychological battery (Seoul Neuropsychological Screening Battery-II) during the dementia evaluation by experienced neurologists (55 with SCD, 126 with MCI, 73 with dementia). In addition, the degree of cognitive decline in participants was classified by CDR level (186 with CDR 0.5, 52 with CDR 1, 15 with CDR 2). One-way analysis of variance was used to compare SCST scores according to each of the three cognitive status groups and CDR levels. RESULTS: The SCST total score, cognitive domain scores (attention, language, visuospatial function, memory, executive function), and most of the subtest scores decreased significantly in the order of SCD, MCI and dementia. Likewise, the differences in SCST scores between CDR levels were significant, particularly in distinguishing between CDR 0.5 and CDR 1. CONCLUSION: This study reaffirmed that the SCST can significantly discriminate between groups of individuals with SCD, MCI, and dementia based on a large sample. Furthermore, differences in SCT scores were found across the levels of CDR, confirming the clinical utility of the SCST. These findings suggest that the SCST is an efficient and useful neuropsychological test for the sensitive detection of early cognitive impairment.

Socio-demographic and other factors contributing to excessive leisure screen time in preadolescent children.

OBJECTIVES: Excessive screen use in early school age is associated with worsened health habits and negative child development in later age. We aimed to assess the time spent on modern and traditional screen-based devices and examine its associations with socio-demographic characteristics. METHODS: This population-based cross-sectional observation study was conducted in Czechia, Slovakia and Finland between April and June 2021. Participants (N = 1,915) were parents/caregivers of children attending elementary school grades 1 to 3, selected by stratified random sampling. Children's daily leisure screen time (LST) based on parental reports was the main outcome. Descriptive statistics, mean comparison and linear regression analysis were used for the analysis. RESULTS: The average daily LST was found to be as high as 3.5 hours and significantly associated with most socio-demographic variables. Eighty percent of children exceeded the threshold of two hours of LST per day, which was formerly introduced by the American Academy of Pediatrics. The most important predictor of LST in children was having their screen-based device(s) for their exclusive personal use (EPU). Linear regression with all predictors assessed together confirmed the significant effect of the screen-based devices' EPU, the child's sex and grade, the child's birth order and the parent's education, even when controlled for media parenting practices. CONCLUSIONS: Given the widespread availability of smartphones for exclusive personal use among young children, the regulation of EPU and the reinforcement of effective media parenting practices, particularly in families with lower education and income, are critical public health strategies to mitigate the negative impact of excessive screen time on child development and overall well-being.

Siwu tablet attenuates high fructose-induced glomerular podocyte senescence in rats through increasing Nup155 to promote INO80 mRNA nuclear export.

ETHNOPHARMACOLOGICAL RELEVANCE: Siwu tablet (SWT), derived from a traditional Chinese medicinal formula named Siwu decoction, is widely used for blood deficiency syndrome. Siwu decoction and its derived formulas have been proven to improve renal anemia and prevent senescence. Whether SWT prevents glomerular podocyte senescence and the underlying molecular mechanism remains unknow. AIM OF THE STUDY: To elucidate the protective effect and possible mechanism of SWT on glomerular podocyte senescence. MATERIAL AND METHODS: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to characterize components of SWT. Male Sprague-Dawley rats were given 10% fructose drinking water for 16 weeks. SWT (810 and 1620 mg/kg) was administered orally for the last 8 weeks. The assays of senescence-associated beta-galactosidase (SA-ß-gal) staining, immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot as well as enzyme linked immunosorbent assay were performed to evaluate rat glomerular podocyte senescence. The mRNA and protein levels of nucleoporin 155 (Nup155) and inositol requiring mutant 80 (INO80) in rat glomeruli were detected by qRT-PCR, Western blot and immunofluorescence. Foot processes and nuclear pore complexes (NPCs) of rat glomerular podocytes were visualized by transmission electron microscopy. RESULTS: One hundred and fifty-nine components were preliminarily identified in SWT. The results of animal experiments showed that SWT decreased the activity of SA-ß-gal, protein levels of p16, p21, p53 and phosphorylated histone H2AX (γ-H2AX), and mRNA levels of interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor-α (TNF-α) in glomeruli of high fructose-fed rats. As expected, SWT increased renal cortex erythropoietin mRNA expression and serum erythropoietin concentration in this animal model. SWT reduced urine albumin-to-creatinine ratio and serum levels of uric acid, creatinine and blood urea nitrogen, and recovered glomerular structure injury in high fructose-fed rats. It up-regulated mRNA and protein levels of Nup155 and the number of podocyte NPCs, and subsequently reinforced mRNA nuclear export and protein expression of INO80 in rat glomeruli under high fructose stimulation. CONCLUSIONS: SWT ameliorates glomerular podocyte senescence in high fructose-fed rats possibly by increasing Nup155 to promote INO80 mRNA nuclear export.

Bioinformatics-based drug repositioning and prediction of the main active ingredients and potential mechanisms of action for the efficacy of Dan-Lou tablet.

Drug repositioning is gaining attention as a method for developing new drugs due to its low cost, short cycle time, and high success rate. One important approach is to explore new uses for already marketed drugs. In this study, we utilized the strategy of drug repositioning, focusing on the Dan-Lou tablet. We predicted the efficacy of Dan-Lou tablet against non-small cell lung cancer based on gene expression similarity and verified it by in vitro experiments. Next, we performed further analysis and validation using network pharmacology, molecular docking and molecular dynamics. Based on the results, it was concluded that Dan-Lou tablet mainly acted through nine compounds, Quercetin, Luteolin, Scoparone, Isorhamnetin, Eugenol, Genistein, Coumestrol, Hederagenin, Succinic Acid, and mainly targeted CCL2, FEN1, TPI1, RMI2 by six pathways. This discovery not only provides a new idea for the development of Dan-Lou tablet but also provides useful predictive information for clinical treatment. The method we adopted has great development prospects as a way to predict the efficacy of new drugs and their main mechanisms of action, and it has a positive impact on the research and development of new drugs using drug repositioning and the modernization of traditional Chinese medicine.

Efficacy of Danlou tablets in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a multicenter prospective cohort study.

Background: Danlou tablets (DLTs) have been widely used to treat coronary heart disease in China. However, the benefits associated with DLT for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) in routine practice require further investigation. Purpose: To investigate the effectiveness of DLT in patients with ACS undergoing PCI. Methods: This multicenter prospective cohort study for patients with ACS undergoing PCI was conducted in 40 centers in mainland China from February 2012 to December 2018. This trial is registered under ChiCTR-OOC-14005552. Patients were assigned to either the DLT group or the conventional medicine (CM) group based on whether they used DLT prior to enrollment. The duration of DLT use (1.5 g, three times a day) was 12 months. The primary endpoint comprised of cardiac death, non-fatal myocardial infarction, and urgent revascularization. Secondary endpoint included rehospitalization owing to ACS, heart failure, stroke, and other thrombotic events. The Seattle Angina Questionnaire (SAQ) was used to assess quality of life (QOL). Primary and secondary endpoints were followed up for 36 months, and the SAQ was followed up for 12 months. The Cox proportional hazards regression model was used to analyze the independent effect of DLT on primary and secondary endpoints. Propensity score matching (PSM) analyses were performed to mitigate bias. Survival estimation was performed using Kaplan-Meier survival curves and log-rank tests in the PSM cohort, and landmark analyses were used for further evaluation of primary and secondary endpoints. Subgroup analyses and interactions confirmed the robustness of the findings. Linear mixed effects models were used to assess the QOL. Results: Overall, 936 patients were enrolled in this cohort study, of whom 875 completed follow-up. The primary and secondary endpoints had no significantly difference between the DLT and CM groups after Cox proportional hazards models. Kaplan-Meier survival curves and log-rank tests performed in the PSM cohort also found no significant differences between the two groups on primary and secondary endpoints. However, landmark analysis showed significant benefit in the primary endpoint for the DLT group after 200 days (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.22-0.93, P = 0.03). Landmark analysis also showed a significant benefit in the secondary endpoint in the DLT group within 200 days (HR 0.33, 95% CI 0.15-0.73, P = 0.006). Moreover, DLT improves the SAQ summary score, and scores in the physical limitation, treatment satisfaction, and disease perception domains for patients with ACS undergoing PCI. Conclusions: DLT combined with conventional treatment reduced the risk of the primary endpoint after 200 days and the secondary endpoint within 200 days during the 3-year follow-up. Additionally, DLT can improve the QOL without adverse effects.

Integrating network pharmacology and transcriptomics to study the potential mechanism of Jingzhi Niuhuang Jiedu tablet in rats with accumulation of heat in the lungs and stomach.

ETHNOPHARMACOLOGICAL RELEVANCE: Accumulation of heat in the lungs and stomach (AHLS) is an important syndrome within the realm of traditional Chinese medicine (TCM). It is the fundamental reason behind numerous illnesses, including mouth ulcers, dermatological conditions, acne, and pharyngitis. Jingzhi Niuhuang Jiedu tablet (JN) serves as the representative prescription for treatment of AHLS clinically. However, the effective components and mechanism of JN's impact on AHLS remain unexplored. AIM OF THE STUDY: The objective of this research was to analyze the effective components of JN and investigate the therapeutic effect and potential mechanism of JN on AHLS. MATERIALS AND METHODS: The effective compounds of JN extract were analyzed and identified using UHPLC-Q-Exactive/HRMS. Utilizing network pharmacology to investigate JN's multi-target, multi-pathway process in treating AHLS. Subsequently, anti-inflammatory activities of JN extract were evaluated in the RAW264.7 cells stimulated by lipopolysaccharide (LPS). In addition, a rat AHLS model induced by LPS and dried ginger was established. Pathological changes in rat lung and stomach tissues observed by HE staining and Masson's trichrome staining. Additionally, the expression of TNF-α, IL-6, and IL-1ß in bronchoalveolar lavage fluid (BALF) was identified through the ELISA assay. For a deeper understanding of how JN might affect AHLS, transcriptomics was utilized to examine differential genes and their underlying mechanisms. Concurrently, techniques like quantitative polymerase chain reaction (q-PCR), immunofluorescence, and western blotting (WB) were employed to confirm various mRNA and protein expression, including Il17ra, Il17re, IL-17A, IL-1ß, IL-6, PPARγ, PGC1-α and UCP1. RESULTS: We identified 178 potential effective components in the JN extract. Network pharmacology analysis showed that the 144 components in JN act on 200 key targets for the treatment of AHLS by suppressing inflammation, regulating energy metabolism, and gastric function. In addition, JN suppressed the LPS-stimulated generation of NO, TNF-α, IL-1ß, and IL-6 in RAW264.7 cells. And JN treatment effectively alleviated lung and stomach injury and reduced inflammation in rats. Analysis of RNA-seq from lung tissues revealed JN's substantial control over crucial genes in the IL-17 signaling pathway, including Il1b and Il17ra. Likewise, RNA sequencing of stomach tissues revealed that JN markedly decreased crucial genes in the Thermogenesis pathway, including Ppargc1a and Ppara. Additional experimental findings confirmed that treatment with JN significantly reduced the expression levels of mRNA (Il17ra, Il17re, Il1b, Ppargc1a and Ucp1), and the expression levels of protein (IL-17A, IL-1ß, IL-6, PPARγ, PGC1-α and UCP1). CONCLUSION: This study not only analyzes the effective components of JN but also reveals that JN could effectively ameliorate AHLS by inhibiting IL-17 signaling pathway and Thermogenesis pathway, which provides evidence for subsequent clinical studies and drug development.

Exploring the role of Yuxuebi tablet in neuropathic pain with the method of similarity research of drug pharmacological effects based on unsupervised machine learning.

Introduction: Having multiple pharmacological effects is a characteristic of Traditional Chinese Medicine (TCM). Currently, there is a lack of suitable methods to explore and discover modern diseases suitable for TCM treatment using this characteristic. Unsupervised machine learning technology is an efficient strategy to predict the pharmacological activity of drugs. This study takes Yuxuebi Tablet (YXB) as the research object. Using the unsupervised machine learning technology of drug cell functional fingerprint similarity research, the potential pharmacological effects of YXB were discovered and verified. Methods: LC-MS combined with the in vitro intestinal absorption method was used to identify components of YXB that could be absorbed by the intestinal tract of rats. Unsupervised learning hierarchical clustering was used to calculate the degree of similarity of cellular functional fingerprints between these components and 121 marketed Western drugs whose indications are diseases and symptoms that YXB is commonly used to treat. Then, based on the Library of Integrated Network-based Cellular Signatures database, pathway analysis was performed for selected Western drugs with high similarity in cellular functional fingerprints with the components of YXB to discover the potential pharmacological effects of YXB, which were validated by animal experiments. Results: We identified 40 intestinally absorbed components of YXB. Through predictive studies, we found that they have pharmacological effects very similar to non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. In addition, we found that they have very similar pharmacological effects to anti-neuropathic pain medications (such as gabapentin, duloxetine, and pethidine) and may inhibit the NF-κB signaling pathway and biological processes related to pain perception. Therefore, YXB may have an antinociceptive effect on neuropathic pain. Finally, we demonstrated that YXB significantly reduced neuropathic pain in a rat model of sciatic nerve chronic constriction injury (CCI). Transcriptome analysis further revealed that YXB regulates the expression of multiple genes involved in nerve injury repair, signal transduction, ion channels, and inflammatory response, with key regulatory targets including Sgk1, Sst, Isl1, and Shh. Conclusion: This study successfully identified and confirmed the previously unknown pharmacological activity of YXB against neuropathic pain through unsupervised learning prediction and experimental verification.

Investigating the Effects of Formulation Variables on the Disintegration of Spray Dried Amorphous Solid Dispersion Tablets.

Amorphous solid dispersion (ASD) tablets based on hydrophilic polymer carriers may encounter disintegration challenges. In this work, the effect of different formulation composition variables on the ASD tablet disintegration performance was systematically studied. GDC-0334: copovidone (PVPVA) 60: 40 ASD prepared by spray drying was selected as the model ASD system. The effects of ASD loading, filler type and ratio, disintegrant type and level were then investigated using tablets made by direct compression process. Tablet disintegration time increased with the increase of ASD loading, especially when ASD loading exceeded 50%. At the same tablet solid fraction, when lactose was used as the soluble filler, faster tablet disintegration time was observed compared to the tablets with mannitol as the soluble filler. Among the three tested disintegrants, croscarmellose sodium performed the best in facilitating the ASD tablet disintegration, followed by sodium starch glycolate, and crospovidone was the poorest. When croscarmellose sodium was used as the disintegrant, 5% level was sufficient to enable ASD tablet disintegration at 60% ASD loading and further increase of croscarmellose sodium level to 8% did not provide additional benefit. Water uptake experiments were performed on selected tablets and the results demonstrated a positive correlation with tablet disintegration time, indicating water penetration is a major contributing step for the disintegration of our ASD tablets. Overall, this work provides a rationale for excipient selection and insights into building a platform formulation approach for developing immediate-release ASD tablets.

Repurposing prescribed hydromorphone: Alternative uses of safer supply and tablet-injectable opioid agonist treatment to meet unaddressed health needs.

BACKGROUND: In response to the ongoing overdose crisis in Canada, a number of opioid agonist treatment and safer supply programs provide people at high overdose risk with daily-dispensed tablet hydromorphone, with some requiring witnessed ingestion and others providing take-away doses. While these programs are intended to reduce overdose events by limiting people's use of the contaminated drug supply, the experiences of people receiving hydromorphone vary. In this article we explore the ways people repurpose hydromorphone to address unmet needs. METHODS: This article draws on in-depth qualitative interviews from two studies evaluating hydromorphone tablet distribution programs in British Columbia, Canada. We used thematic analysis to identify themes related to repurposing hydromorphone. We compared themes across the two studies to identify any similarities or differences in relation to the ways study participants discussed repurposing hydromorphone tablets. We utilize vignettes - snapshots of participant experiences - to analyse and represent the data. RESULTS: Four vignettes demonstrate how hydromorphone tablets are often being used to address and resolve unmet needs of people who use drugs. While most participants reported reducing their use of illicit drugs, a variety of instrumental uses of tablet hydromorphone were also discussed, including reducing anxiety, addressing sleep issues, withdrawal management, and managing chronic pain. CONCLUSION: Our findings demonstrate how people who use drugs are maximizing the benefits of tablet hydromorphone distribution to address unmet needs. Hydromorphone distribution programs represent a public health and harm reduction intervention that is usefully addressing experiences related to structural vulnerabilities (such as inadequate pain management), which are often overlooked amongst stigmatized groups.

In-line porosity and hardness monitoring of tablets by means of optical coherence tomography.

In-line monitoring of critical quality attributes (CQAs) during a tableting process is an essential step toward a real-time release strategy. Such CQAs can be the tablet mass, the API content, dissolution, hardness and tensile strength. Since dissolution testing is laborious and time-consuming and cannot be performed in-line, it is desirable to replace dissolution testing with predictive models based on other CQAs that affect the dissolution characteristics, such as the tablet porosity and hardness. Traditionally, porosity is determined offline via gas adsorption methods or other techniques, such as Terahertz spectroscopy or gas in scattering media absorption spectroscopy. Tablet hardness is typically established using a hardness tester. While these destructive tests can readily be performed at-line, they have limited applicability in in-line settings for a high-percentage inspection. Optical coherence tomography (OCT) has recently been proposed as a possible tool for determining quality attributes. This work describes the first application of OCT for the prediction of tablet porosity and hardness. OCT measurements of tablets produced in a ConsiGma 25™ tableting line and a Stylcam 200R compaction simulator in several compaction force settings were made and correlated with the porosity and hardness. It was demonstrated that OCT can easily be installed in-line and provide real-time information about critical material attributes. These insights confirm the applicability of OCT as a real-time quality control tool and its potential to replace time-consuming and destructive offline measurements.

Optimization and characterization of a dose-controllable orodispersible dexamethasone film for personalized medicine.

Decadron® tablets are commercially available in 0.5 and 4 mg formulations, often requiring the use of multiple tablets or fractional doses when the required dosage is unavailable. This practice can lead to inaccuracies and handling difficulties associated with tablet splitting and crushing tablets into powder. This study aimed to develop an orodispersible dexamethasone film that would allow precise dose control and overcome these challenges. The film formulation was optimized by dissolving varying amounts of hypromellose, glycerol, and dexamethasone in ethanolic solutions. These solutions were cast and dried at different thicknesses. Statistical optimization using the design of experiments was used to determine the ideal film composition. The optimized films met pharmaceutical standards, with a mass variation ≦ 2 %, thickness variation ≦ 2.5 %, and disintegration time ≦ 20 s. The uniform distribution of dexamethasone within the film enabled easy content control based on the film area. Dissolution testing indicated that the dissolution behavior of the film formulation behaved similarly to commercial tablets for up to 90 min. In conclusion, the developed orodispersible film offers precise dexamethasone dose control and addresses the limitations of tablet splitting, positioning it as a promising candidate for personalized medicine applications.

Material-Sparing Approach to Predict Tablet Capping Under Processing Compression Conditions Based on Mechanical and Molecular Properties Derived from Compaction Simulation and Crystal Structural Analysis.

Present study evaluates the usability of compaction simulation-based mechanical models as a material-sparing approach to predict tablet capping under processing compression conditions using Acetaminophen (APAP) and Ibuprofen (IBU). Measured mechanical properties were evaluated using principal component analysis (PCA) and principal component regression (PCR) models. PCR models were then utilized to predict the capping score (CS) from compression pressure (CP). APAP formulations displayed a quadratic correlation between CS and CP, with CS rank order following CP of 200MPa < 300MPa < 100MPa, indicating threshold compression pressure (TCP) limit between 200 and 300 MPa, resulting in higher CS at 300 than 200 MPa regardless of increased CP. IBU formulations displayed a linear correlation between CS and CP, with CS rank order following CP of 100MPa < 200MPa < 300MPa, indicating TCP limit between 100 and 200 MPa, resulting in higher CS at 200 and 300 than 100 MPa regardless of increased CP. Molecular models were developed as validation methods to predict capping from CP. Measured XRPD patterns of compressed tablets were linked with calculated Eatt and d-spacing of slip planes and analyzed using variable component least square methods to predict TCP triggering cleavage in slip planes and leading to capping. In APAP and IBU, TCP values were predicted at 245 and 175 MPa, meaning capped tablets above these TCP limits regardless of increased CP. A similar trend was observed in CS predictions from mechanical assessment, confirming that compaction simulation-based mechanical models can predict capping risk under desired compression conditions rapidly and accurately.

Kids are not just small adults: An attempt to validate pediatric tablet-based digits in noise testing.

Objective: The objective of this study is to investigate whether conductive hearing loss (CHL) can be differentiated from sensorineural hearing loss in children ages 3-18 using a diotic and antiphasic digits-in-noise (DIN) tablet-based test using existing adult cut-off criteria. Methods: A blinded multi-institutional prospective cohort of 64 children aged 3-18 scheduled for an audiometric soundbooth evaluation with a pediatric audiologist and a same-day otolaryngologist examination were recruited for the study. Following a conventional audiogram, the subjects underwent diotic (same-phased stimuli) and antiphasic (out-of-phase stimuli) DIN testing on a HearX Samsung Galaxy tablet with over-the-ear headphones, for a total of 128 measurements. DIN test results were compared with soundbooth audiometry using known adult "cut off criteria." Results: A logistic regression analysis adjusted for demographics (age, sex) and race was performed to compare CHL determination from DIN testing to CHL determination with soundbooth audiometry. The results showed 50% agreement with a p-value of .753. The determinations based on combined DIN testing agreed with each other 33% of the time and had a p-value of .373. Otologic pathology and age were not predictive of outcome. Conclusion: This preliminary analysis of DIN testing indicated that DIN and audiometric testing completed in a soundbooth were not significantly predictive of one another in the population of children aged 3-18 when using the adult cut-off criteria for CHL differentiation. Given these findings, further testing is required in children to determine pediatric specific cut-off values.

Characterization of 2-((4-(chloromethyl)benzoyl)oxy)benzoate acid for analgesic tablet dosage form formulation.

The 2-((4-(chloromethyl)benzoyl)oxy)benzoic acid (4CH2Cl) is a potential analgesic compound derived from salicylic acid and 4-chloromethyl benzoyl chloride. Characterization required 4CH2Cl for the formulation of tablet dosage forms. This study aims investigate the effect of SSG, PVP-K30, and the combination of SSG*PVP K-30 on the formulation of 4CH2Cl tablets. Additionally, this study aimed to obtain the optimum 4CH2Cl tablet composition. The experiment followed the two-factor simplex lattice design and direct compression method. The analgesic activity of 4CH2Cl in the optimal tablet was investigated using the hot-plate methods. The ANOVA of linear models is acceptable and the polynomial coefficients of quadratic models are similar to those of linear models. The coefficient of the linear model shows that SSG and PVP K-30 increase the Carr index (16.26; 20.61), Hausner ratio (1.19; 1.29), hardness (4.19; 9.39), friability (0.48; 0.67), disintegration time (0.34; 7.50), and drug release (85.29; 97.69). The coefficient of the quadratic model shows that SSG*PVP K-30 increased the Carr index (1.90), Hausner ratio (0.04), hardness (1.88), friability (0.06), and drug release (4.56), and decreased disintegration time (-0.30). SSG and PVP K-30 increased Carr index, Hausner ratio, hardness, friability, disintegration time, and drug release. The combination of SSG*PVP K-30 has the same effect, except that the disintegration time decreased. The optimum tablet formula is 4CH2Cl (300 mg), Ne (75 mg), SSG (33.60 mg), PVP K-30 (22.40 mg), MCC (40 mg), and SDL (up to 800 mg). 4CH2Cl tablets can be a candidate and choice for new analgesic drugs in the future.

Statistical-Based Optimization of Modified Mangifera indica Fruit Starch as Substituent for Pharmaceutical Tableting Excipient.

This study aimed to optimize modified starch from Mangifera indica (mango) fruit using acid hydrolysis and pre-gelatinization via computer-assisted techniques as a substituent for pharmaceutical tableting excipients. The hydrolysis and microwave-assisted pre-gelatinization time and temperature were optimized using a three-level factorial design. The modified starches were characterized for flowability, compressibility, and swelling properties. It was found that all parameters fit a quadratic model, which can be used to predict the properties of the modified starch. The optimized hydrolysis reaction was 3.8 h at 56.4 °C, while the pre-gelatinization reaction was 3 min at 150 °C. Structural changes were found, ascertaining that starch modification was successful. The optimized hydrolyzed starch showed superior properties in relative to unmodified M. indica fruit starch and comparable characteristics to conventional excipients. The optimized pre-gelatinized starch presented an excellent enhancement in the flow and compression properties, with %swelling greatly augmented 3.95-fold and 1.24-fold compared to unmodified starch and SSG, respectively. Additionally, the pre-gelatinized starch presented comparable binding effect, while the hydrolyzed powder had reduced binding capacity due to shorter chains. The findings revealed that the use of software-assisted design of experiment facilitated a data-driven approach to optimize the modifications. The optimized modified mango starch demonstrated potential as a multifunctional excipient, capable of functioning as binder, disintegrant, and diluent.

Pharmacometrics to Evaluate Dosing of the Patient-Friendly Ivermectin CHILD-IVITAB in Children ≥ 15 kg and <15 kg.

The antiparasitic drug ivermectin is approved for persons > 15 kg in the US and EU. A pharmacometric (PMX) population model with clinical PK data was developed (i) to characterize the effect of the patient-friendly ivermectin formulation CHILD-IVITAB on the absorption process and (ii) to evaluate dosing for studies in children < 15 kg. Simulations were performed to identify dosing with CHILD-IVITAB associated with similar exposure coverage in children ≥ 15 kg and < 15 kg as observed in adults receiving the reference formulation STROMECTOL®. A total of 448 ivermectin concentrations were available from 16 healthy adults. The absorption rate constant was 2.41 h-1 (CV 19%) for CHILD-IVITAB vs. 1.56 h-1 (CV 43%) for STROMECTOL®. Simulations indicated that 250 µg/kg of CHILD-IVITAB is associated with exposure coverage in children < 15 kg consistent with that observed in children ≥ 15 kg and adults receiving 200 µg/kg of STROMECTOL®. Performed analysis confirmed that CHILD-IVITAB is associated with faster and more controlled absorption than STROMECTOL®. Simulations indicate that 250 µg/kg of CHILD-IVITAB achieves equivalent ivermectin exposure coverage in children < 15 kg as seen in children ≥ 15 kg and adults.

An economic model to understand the cost-effectiveness of olanzapine orally dispersible tablets (ODT) and olanzapine film coated tablets as a group compared with other oral atypical antipsychotics for treating schizophrenia in Morocco.

BACKGROUND: Antipsychotic medications are the primary treatment for schizophrenia, with olanzapine being an effective medication for schizophrenia. The economic cost for each individual with schizophrenia is high, with antipsychotic medication being a major expense. This study aims to develop an economic decision model that compares different treatment options for schizophrenia patients, including olanzapine Orally Dispersible Tablets (ODT), olanzapine [ODT + Standard Oral Tablet (SOT)], risperidone (ODT + SOT), and aripiprazole (ODT + SOT), to determine their cost-effectiveness with an objective to optimize healthcare resource allocation in Morocco. METHODS: The study used published medical literature and a clinical expert panel to develop a decision analytic model. This model was designed to capture parameters such as adherence levels, treatment discontinuation, relapse with and without hospitalization, quality-adjusted life years (QALYs), treatment-related adverse events, healthcare resource utilization, and associated costs. The main outcomes of interest included the total annual direct cost per treatment, QALYs, and incremental cost-effectiveness ratio (ICER) per 1 QALY gained. One-way and probabilistic sensitivity analyses were employed to account for parameter uncertainty. RESULTS: According to the simulation model, the ODT and ODT + SOT as a group form of olanzapine was the most effective treatment option in terms of the lowest percentages of inpatient relapse, and patients who remained stable (11% and 79% respectively) than risperidone (19% and 62% respectively) and aripiprazole ODT (26% and 50% respectively) and ODT + SOT formulation groups. Olanzapine (ODT + SOT) therapy group was cost-effective when compared to the combined group of ODT + SOT forms of risperidone [ICER: Moroccan Dirham (MAD) 103,907], and aripiprazole (ICER: MAD 65,047). Additionally, olanzapine ODT was found to be cost-effective compared to olanzapine SOT with an ICER of MAD 3921, risperidone ODT with an ICER of MAD 1,02,298, risperidone SOT with an ICER of MAD 31,088, and aripiprazole ODT or SOT formulations. All the above ICERs fall under the willingness-to-pay threshold in Morocco of MAD 250,832.40. Sensitivity analyses confirmed the reliability of the findings. CONCLUSIONS: The model concluded that olanzapine ODT is the most cost-effective first-line treatment option for schizophrenia in Morocco when compared to other atypical antipsychotic medications in ODT and SOT formulations.

Virtual screening of drug materials for pharmaceutical tablet manufacturability with reference to sticking.

The manufacturing of pharmaceutical solid dosage forms, such as tablets involves a large number of successive processing operations including crystallisation of the drug substance, granulation, drying, milling, mixing of the formulation, and compaction. Each step is fraught with manufacturing problems. Undesired adhesion of powders to the surface of the compaction tooling, known as sticking, is a frequent and highly disruptive problem that occurs at the very end of the process chain when the tablet is formed. As an alternative to the mechanistic approaches to address sticking, we introduce two different machine learning strategies to predict sticking directly from the chemical formula of the drug substance, represented by molecular descriptors. An empirical database for sticking behaviour was developed and used to train the machine learning (ML) algorithms to predict sticking properties from molecular descriptors. The ML model has successfully classified sticking/non-sticking behaviour of powders with 100% separation. Predictions were made for materials in the handbook of Pharmaceutical Excipients and a subset of molecules included in the ChemBL database, demonstrating the potential use of machine learning approaches to screen for sticking propensity early at drug discovery and development stages. This is the first-time molecular descriptors and machine learning were used to predict and screen for sticking behaviour. The method has potential to transform the development of medicines by providing manufacturability information at drug screening stage and is potentially applicable to other manufacturing problems controlled by the chemistry of the drug substance.

A discovery in traditional Chinese medicine compatibility: Cinnabaris suppresses the Strychni Semen-induced neurotoxicity in Shang-Ke-Jie-Gu tablet.

BACKGROUND: Cinnabaris, as a commonly used mineral drugs, is a classic sedative medicine. Shang-Ke-Jie-Gu tablet is a famous Chinese patent medicine with Cinnabaris, However, the function of Cin in the prescription hasn't been clarified. PURPOSE: Our study evaluated the toxicity of Shang-Ke-Jie-Gu tablet (SK) with or without Cinnabaris, and illuminate the related mechanisms that why cinnabaris is necessary. METHODS: The toxicity of SK and Cin free Shang-Ke-Jie-Gu tablet (CFSK) was evaluated by physical and behavioral tests and histological examinations. The detoxificaion mechanism of Cin on Strychni Semen (SS)-induced neurotoxicity in SK was performed based on the analysis of intestinal absorption, liver metabolism, serum metabolomics, and gut microbiota. The mercury accumulation of SK was assayed using human hair by ICP-MS. RESULTS: Cin was found to inhibit the neurotoxicity of SS in SK. Our study shows that Cin could inhibit SS's absorption in small intestine and promote its metabolism in the liver. A serum metabolomics study showed that taurine and hypotaurine metabolism and retrograde endocannabinoid signaling pathway were associated with Cin attenuation. Association analysis with gut microbiota suggested that Cin could downregulate four key metabolites, including 12­hydroxy arachidonic acid, GM4(d18:1/18:0), C16 sphinganine, and LysoPC(18:1(11Z)/0:0), by downregulating Lachnospiraceae_NK4A136 and upregulating Prevotella to inhibit the toxic effects of SS. In addition, the danger of mercury poisoning in a longer time administration of SK was evaluated using human hair, and no visible increase in mercury was observed. CONCLUSION: As a new discovery in compatibility, Cin was proved to be capable of inhibiting the neurotoxicity not only in SK but also in Cin-SS combination, displaying vital roles in Traditional Chinese Medicines.