Albumin­bilirubin grade is an independent prognostic factor for small lung cell cancer.

Albumin-bilirubin (ALBI) grade was first described in 2015 as an indicator of liver dysfunction in patients with hepatocellular carcinoma. ALBI grade has been reported to have prognostic value in several malignancies including non-small cell lung cancer (NSCLC). The present study aimed to explore the prognostic impact of ALBI grade in patients with small cell lung cancer (SCLC). It retrospectively analyzed 135 patients with SCLC treated at Hebei General Hospital between April 2015 and August 2021. Patients were divided into two groups according to the cutoff point of ALBI grade determined by the receiver operating characteristic (ROC) curve: Group 1 with pre-treatment ALBI grade ≤-2.55 for an improved hepatic reserve and group 2 with ALBI grade >-2.55. Kaplan-Meier and Cox regression analysis were performed to assess the potential prognostic factors associated with progression free survival (PFS) and overall survival (OS). Propensity score matching (PSM) was applied to eliminate the influence of confounding factors. PFS and OS (P<0.001) were significantly improved in group 1 compared with in group 2. Multivariate analysis revealed that sex (P=0.024), surgery (P=0.050), lactate dehydrogenase (LDH; P=0.038), chemotherapy (P=0.038) and ALBI grade (P=0.028) are independent risk factors for PFS and that surgery (P=0.013), LDH (P=0.039), chemotherapy (P=0.009) and ALBI grade (P=0.013) are independent risk factors for OS. After PSM, ALBI grade is an independent prognostic factor of PFS (P=0.039) and OS (P=0.007). It was concluded that ALBI grade was an independent prognostic factor in SCLC.

Polymyxin B-Modified Fosfomycin Liposomes Target Gram-Negative Bacteria and Exert Synergistic Antibacterial Effect.

Bacterial infection has always been one of the most serious threats faced by humans. Bacterial targeting is a promising strategy to enhance treatment efficacy and reduce the emergence of drug resistance. However, the traditional antibiotic targeting efficiency is poor, and it is challenging to achieve therapeutic concentrations of both drugs simultaneously in the same tissue due to differences in drug metabolism. This study aims to construct bacteria-targeted liposomes to enhance antibiotic delivery. In this study, anionic liposomes were constructed using the thin-film dispersion method, and the cationic antimicrobial peptide polymyxin B (PMB) was adsorbed onto the liposome surface through anionic-cationic electrostatic interaction as a carrier for fosfomycin (FOS), enabling bacteria-targeted drug delivery. The targeted effect of polymyxin B liposomes (PMB-Lipo) on Acinetobacter baumannii was evaluated in vitro and in vivo. The bactericidal activity of polymyxin B adsorbed fosfomycin liposomes (PMB-FOS-Lipo) in vitro and in vivo was compared with PMB and FOS mixture solution (PMB-FOS-Solution), and the anti-infection and anti-inflammatory effects were assessed. We also explored the issue of PMB nephrotoxicity using a series of biochemical indicators in mice. In vitro and in vivo experiments showed that PMB-Lipo effectively targeted Acinetobacter baumannii. PMB-FOS-Lipo exhibited better therapeutic efficacy compared to free PMB and FOS. Finally, adsorbing polymyxin B onto the liposome surface significantly reduced its severe nephrotoxicity. PMB-Lipo can effectively target Acinetobacter baumannii, and the encapsulated fosfomycin in liposomes synergizes with polymyxin B, enhancing antibacterial efficacy and reducing adverse drug reactions. We believe this antibacterial strategy can provide new insights into bacteria-targeted treatment.

Active DHEA uptake in the prostate gland correlates with aggressive prostate cancer.

Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3ßHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease. Genetic and transcriptomic features associated with the potency of prostatic DHEA utilization were analyzed to generate clinically accessible approaches for patient stratification. UBE3D, by regulating 3ßHSD1 homeostasis, was discovered to be a regulator of patient metabolic heterogeneity. Equilin suppressed DHEA utilization and inhibited tumor growth as a potent 3ßHSD1 antagonist, providing a promising strategy for the early treatment of aggressive prostate cancer. Overall, our findings indicate that patients with active prostatic DHEA utilization might benefit from 3ßHSD1 inhibitors as early intervention.

The Evaluation and Exploration of Piezoelectric Parameter Optimization for Droplet Ejection in Binder Jet 3D Printing Drugs.

Since the first three-dimensional (3D) printed drug was approved by the Food and Drug Administration in 2015, there has been a growing interest in using binder jet 3D printing (BJ-3DP) technology for pharmaceuticals. However, most studies are still at an exploratory stage, lacking micromechanism research, such as the droplet ejection mechanism, the effect of printhead piezoelectric parameters on inkjet smoothness and preparation formability. In this study, based on the inkjet printing and observation platform, the Epson I3200-A1 piezoelectric printhead matched to the self-developed BJ-3DP was selected to analyze the droplet ejection state of self-developed ink at the microlevel with different piezoelectric pulse parameters. The results showed that there was a stable inkjet state with an inkjet pulse width of 3.5 µs, an ink supply pulse width of 4.5 µs, and a jet frequency in the range of 5000-19,000 Hz, ensuring both better droplet pattern and print accuracy, as well as high ejection efficiency. In conclusion, we performed a systematic evaluation of the inkjet behavior under different piezoelectric pulse parameters and provided a good idea and case study for the optimization of printhead piezoelectric parameters when BJ-3DP technology was used in pharmaceuticals.

3D Printing Technology Based on Versatile Gelatin-Carrageenan Gel System for Drug Formulations.

Currently, there is a shortage of pediatric medicines on the market, and 3D printing technology can more flexibly produce personalized medicines to meet individual needs. The study developed a child-friendly composite gel ink (carrageenan-gelatin), created 3D models by computer-aided design technology, then produced personalized medicines using 3D printing to improve the safety and accuracy of medication for pediatric patients. An in-depth understanding of the printability of different formulations was obtained by analyzing the rheological and textural properties of different gel inks and observing the microstructure of different gel inks, which guided the formulation optimization. Through formulation optimization, the printability and thermal stability of gel ink were improved, and F6 formulation (carrageenan: 0.65%; gelatin: 12%) was selected as the 3D printing inks. Additionally, a personalized dose linear model was established with the F6 formulation for the production of 3D printed personalized tablets. Moreover, the dissolution tests showed that the 3D printed tablets were able to dissolve more than 85% within 30 min and had similar dissolution profiles to the commercially available tablets. This study demonstrates that 3D printing is an effective manufacturing technique that allows for flexible, rapid, and automated production of personalized formulations.

Methods and Characteristics of Drug Extraction from Ion-Exchange-Resin-Mediated Preparations: Influences, Thermodynamics, and Kinetics.

Since the discovery of ion-exchange resins, they have been used in many fields, including pharmacy. Ion-exchange resin-mediated preparations can realize a series of functions, such as taste masking and regulating release. However, it is very difficult to extract the drug completely from the drug-resin complex because of the specific combination of the drug and resin. In this study, methylphenidate hydrochloride extended-release chewable tablets compounded by methylphenidate hydrochloride and ion-exchange resin were selected for a drug extraction study. The efficiency of drug extraction by dissociating with the addition of counterions was found to be higher than other physical extraction methods. Then, the factors affecting the dissociation process were studied to completely extract the drug from the methylphenidate hydrochloride extended-release chewable tablets. Furthermore, the thermodynamic and kinetic study of the dissociation process showed that the dissociation process obeys the second-order kinetic process, and it is nonspontaneous, entropy-decreasing, and endothermic. Meanwhile, the reaction rate was confirmed by the Boyd model, and the film diffusion and matrix diffusion were both shown to be rate-limiting steps. In conclusion, this study aims to provide technological and theoretical support for establishing a quality assessment and control system of ion-exchange resin-mediated preparations, promoting the applications of ion-exchange resins in the field of drug preparation.

A Review of 3D Printing Technology in Pharmaceutics: Technology and Applications, Now and Future.

Three-dimensional printing technology, also called additive manufacturing technology, is used to prepare personalized 3D-printed drugs through computer-aided model design. In recent years, the use of 3D printing technology in the pharmaceutical field has become increasingly sophisticated. In addition to the successful commercialization of Spritam® in 2015, there has been a succession of Triastek's 3D-printed drug applications that have received investigational new drug (IND) approval from the Food and Drug Administration (FDA). Compared with traditional drug preparation processes, 3D printing technology has significant advantages in personalized drug manufacturing, allowing easy manufacturing of preparations with complex structures or drug release behaviors and rapid manufacturing of small batches of drugs. This review summaries the mechanisms of the most commonly used 3D printing technologies, describes their characteristics, advantages, disadvantages, and applications in the pharmaceutical industry, analyzes the progress of global commercialization of 3D printed drugs and their problems and challenges, reflects the development trends of the 3D printed drug industry, and guides researchers engaged in 3D printed drugs.

The Application and Challenge of Binder Jet 3D Printing Technology in Pharmaceutical Manufacturing.

Three-dimensional (3D) printing is an additive manufacturing technique that creates objects under computer control. Owing to the rapid advancement of science and technology, 3D printing technology has been widely utilized in processing and manufacturing but rarely used in the pharmaceutical field. The first commercial form of Spritam® immediate-release tablet was approved by FDA in 2015, which promoted the advancement of 3D printing technology in pharmaceutical development. Three-dimensional printing technology is able to meet individual treatment demands with customized size, shape, and release rate, which overcomes the difficulties of traditional pharmaceutical technology. This paper intends to discuss the critical process parameters of binder jet 3D printing technology, list its application in pharmaceutical manufacturing in recent years, summarize the still-open questions, and demonstrate its great potential in the pharmaceutical industry.

Semisolid Extrusion 3D Printing of Propranolol Hydrochloride Gummy Chewable Tablets: an Innovative Approach to Prepare Personalized Medicine for Pediatrics.

The demand for personalized medicine has received extensive attention, especially in pediatric preparations. An emerging technology, extrusion-based 3D printing, is highly attractive in the field of personalized medicine. In this study, we prepared propranolol hydrochloride (PR) gummy chewable tablets tailored for children by semisolid extrusion (SSE) 3D printing technology to meet personalized medicine needs in pediatrics. In this study, the effects of critical formulation variables on the rheological properties and printability of gum materials were investigated by constructing a full-factorial design. In addition, the masticatory properties, thermal stability, and disintegration time of the preparations were evaluated. Bitterness inhibitors were used to mask the bitterness of the preparations. The results of the full-factorial design showed that the amount of gelatin and carrageenan were the key factors in the formulation. Gelatin can improve printability and masticatory properties, carrageenan can improve thermal stability, and accelerate the disintegration of preparations; therefore, a reasonable combination of both could satisfactorily meet the demand for high-quality 3D printing. γ-Aminobutyric acid can reduce the bitterness of gummy chewable tablets to improve medication compliance and the determined formulation (F7) met the quality requirements. In conclusion, the gum material has excellent potential as an extrusion material for 3D printing. The dosage can be adjusted flexibly by the model shape and size. 3D printing has broad prospects in pediatric preparations.

Review of nanosuspension formulation and process analysis in wet media milling using microhydrodynamic model and emerging characterization methods.

Wet media milling is a popular technology used to prepare nanosuspensions. However, the theories and methods to guide the research on the formulation and process affecting wet media milling remain limited. The research on wet media milling follows a "black box" approach to a certain extent. This review focuses on exploring the formulation and process parameters factors in wet media milling. The formulation factors include the concentration, hydrophilicity/hydrophobicity, and structure of the drug and stabilizer, whereas the milling process parameters include the milling speed, milling time, and material, size, and filling volume of milling beads. Contrary to other reviews, this review attempts to quantify and visualize these factors by combining a microhydrodynamic model with emerging characterization methods to provide a scientific basis for the selection of nanosuspension formulations and process parameters, as opposed to the conventional trial-and-error approach.

Comparison of Paliperidone Palmitate from Different Crystallization Processes and Effect on Formulations In Vitro and In Vivo.

The quality of active pharmaceutical ingredients (APIs) is an important factor which can affect the safety and efficacy of pharmaceuticals. This study was designed to investigate the nature of paliperidone palmitate (PP) obtained by different crystallization processes, then compare the characteristics between test formulations which prepared PP of different crystallization and reference formulations (Invega Sustenna®) in vitro and in vivo. Two different PPs, namely PP-1 and PP-2, were prepared by different crystallization methods. Contact angle, morphology, and crystallinity of the PPs were characterized. Taking the particle sizes and distribution of Invega Sustenna® as reference, test formulations were prepared by the wet milling method using either a PP-1 or PP-2 sample. Their release behavior, stability in vitro, and pharmacokinetics in vivo were subsequently investigated. The results indicated that PP-2 had a higher surface free energy (SFE). More small particles were attached to the PP-1 surface under the influence of crystallization temperature. Different crystallization processes did not change the crystal of PP, but changed the crystallinity of PP. There was no obvious difference in in vitro releases between test formulations. However, the stability and state of formulation containing PP-2 were better compared to formulations containing PP-1, indicated by differences in crystallinity and SFE. Meanwhile, pharmacokinetic in vivo results demonstrated that the pharmacokinetic profiles and parameters of formulation containing PP-2 and Invega Sustenna® tended to be consistent, but those of formulations containing PP-1 were significantly different from those of formulations containing PP-2 or Invega Sustenna®, and there was burst release phenomenon of formulations containing PP-1 in rats. PP made by different crystallization processes could induce changes in appearance, SFE, and crystallinity, and further affect the stability, state, and pharmacokinetic in vivo formulation.

The Study of Cyclosporin A Nanocrystals Uptake and Transport across an Intestinal Epithelial Cell Model.

Cyclosporin A nanocrystals (CsA-NCs) interaction with Caco-2 cells were investigated in this study, including cellular uptake and transport across Caco-2 cell monolayers. CsA-NCs of 165 nm, 240 nm and 450 nm were formulated. The dissolution of CsA-NCs was investigated by paddle method. The effect of size, concentration and incubation time on cellular uptake and dissolution kinetics of CsA-NCs in cells were studied. Uptake mechanisms were also evaluated using endocytotic inhibitors and low temperature (4 °C). The cell monolayers were incubated with each diameter CsA-NCs to evaluate the effect of size on the permeation characteristics of CsA across the intestinal mucosa. The results of dissolution study showed that 165 nm CsA-NC had the highest dissolution rate followed by 240 CsA-NC and finally 450 nm CsA-NC. The saturation of cell uptake of CsA-NCs was observed with the increase of incubation concentration and time. 240 nm and 450 nm CsA-NCs had the lowest and highest uptake efficiency at different time and drug concentration, respectively. The uptake of all three-sized CsA-NCs declined significantly in some different degree after the pre-treatment with different endocytosis inhibitors. 165 nm CsA-NC showed a highest transport capacity across monolayers at the same concentration and time. The results suggest that the size of CsA-NCs can not only affect the efficiency of cellular uptake, but also the type of endocytosis. Decreasing particle size of CsA-NCs can improve transport capacity of CsA through cell monolayer.

The Effect of Particle Size on the Absorption of Cyclosporin A Nanosuspensions.

Background: Cyclosporin A (CsA) is a hydrophobic drug widely used as an immunosuppressant and anti-rejection drug in solid organ transplantation. On the market, there are two oral CsA formulations available containing polyoxyethylene castor oil, which can cause serious allergic reactions and nephrotoxicity. In order to eliminate polyoxyethylene castor oil, CsA was formulated into a nanosuspension. This study aimed to design an oral cyclosporin A nanosuspensions (CsA-NSs) and investigate the effect of particle size on absorption of CsA-NSs. Methods: CsA-NSs were prepared using a wet bead milling method. Particle size, morphology and crystallinity state of CsA-NSs were characterized. The in vitro dissolution, the intestinal absorption properties and pharmacokinetic study of CsA-NSs were investigated. Results: CsA-NSs with sizes of 280 nm, 522 nm and 2967 nm were prepared. The shape of CsA-NSs with smaller size was similar to that of spheres. The crystallinity of CsA in nanocrystals was reduced. The dissolution rate of CsA-NSs (280 nm) was greater than that of CsA-NSs (522 nm) and CsA-NSs (2967 nm). CsA-NSs (280 nm) showed higher absorption rate constants (Kα ) and effective permeability coefficients (Peff ) of different intestinal segments compared with that of CsA-NSs (522 nm) and CsA-NSs (2967 nm). AUC0-48h of 280 nm CsA-NSs was about 1.12-fold of that of 522 nm CsA-NSs, and about 1.51-fold of that of 2967 nm CsA-NSs. In particular, the particle size of CsA-NSs was nanoscale, and their bioavailability was bioequivalent with marked self-microemulsion (Sandimmun Neoral®). Conclusion: It is feasible to prepare CsA-NSs. The dissolution rate, gastrointestinal transport properties and the oral absorption of CsA-NSs were promoted by reducing size. Considering the cost, efficiency and energy consumption, there should be an optimal particle size range in industrial production.

Preparation of Azithromycin Amorphous Solid Dispersion by Hot-Melt Extrusion: An Advantageous Technology with Taste Masking and Solubilization Effects.

Azithromycin (AZI) is one of the most commonly used macrolide antibiotics in children, but has the disadvantages of a heavy bitter taste and poor solubility. In order to solve these problems, hot-melt extrusion (HME) was used to prepare azithromycin amorphous solid dispersion. Preliminary selection of a polymer for HME was conducted by calculating Hansen solubility parameter to predict the miscibility of the drug and polymer. Eudragit® RL PO was chosen as the polymer due to its combination of taste-masking effect and dissolution. Moreover, the solubility was improved with this polymer. Design of experiments (DoE) was used to optimize the formulation and process, with screw speed, extrusion temperature, and drug percentage as independent variables, and content, dissolution, and extrudates diameter as dependent variables. The optimal extrusion parameters were obtained as follows: temperature-150 °C; screw speed-75 rpm; and drug percentage-25%. Differential scanning calorimetry (DSC) and Powder X-ray Diffraction (PXRD) studies of the powdered solid dispersions showed that the crystalline AZI transformed into the amorphous form. Fourier transform infrared spectroscopy (FTIR) results indicated that the formation of a hydrogen bond between AZI and the polymer led to the stabilization of AZI in its amorphous form. In conclusion, this work illustrated the importance of HME for the preparation of amorphous solid dispersion of AZI, which can solve the problems of bitterness and low solubility. It is also of great significance for the development of compliant pediatric AZI preparation.

Feasibility of developing hospital preparation by semisolid extrusion 3D printing: personalized amlodipine besylate chewable tablets.

Semisolid extrusion (SSE) 3D printing is an emerging technology in personalized medicine. To address clinical multi-dose requirements, SSE has been explored to manufacture new preparations. In this study, amlodipine besylate (AMB) was the model drug, and SSE was the pharmaceutical strategy. We developed semisolids suitable for SSE and AMB chewable tablets with six strengths (1.5-5 mg) to meet the needs of 2-16-year-old patients. First, the semisolid extrudability was evaluated by texture analyzer, and then the amounts of carboxymethyl cellulose sodium, sodium starch glycolate, and glycerin were optimized by full factorial design. Then, rheological tests were performed to evaluate the properties of the semisolid and the effect of starch sodium glycolate on printability. Finally, the amount of corrigents was optimized using the electronic tongue. Laboratory amplified semisolids and 3D printed tablets can be stored for a few months, and the whole SSE process had no effect on crystal type. This study validated the feasibility of SSE 3D printing, and tablets with appropriate taste and cartoon appearance can meet or even exceed the traditional preparations. Our study provides a new strategy for multi-dose solid preparations and effectively meet the need for personalized amlodipine medicine.

Study on the Complexation and Release Mechanism of Methylphenidate Hydrochloride Ion Exchange Resin Complex.

Since the advent of ion exchange resin, it has been widely used in many fields, including drug delivery systems. The drug binds to the resin through an exchange reaction to form a drug-resin complex, which can gradually release drugs through the exchange of physiological ions in the gastrointestinal tract, to realize functions such as taste masking and regulating release. In this study, the complexes of methylphenidate hydrochloride and Amberlite IRP69 were prepared and evaluated to explore the mechanism of complexation, influencing factors and release mechanism at a molecular level. Firstly, with the properties of the selected complexes, molecular dynamics simulation was innovatively used to find that the intermolecular interaction between drug molecules and ion exchange resin molecules is mainly caused by the stacking effect of π and salt bridges. Secondly, with the drug loading status as an indicator, the factors affecting the compounding process of the drug and resin were explored. Finally, the release mechanism of the drug-resin complex was studied by mathematical model fitting. In summary, a variety of methods were used to study the mechanism of complexation and release between drug and resin, providing a theoretical basis for promoting the marketing of ion-exchange resin-mediated oral preparations.

Optimization of Personalized Amlodipine Dosing Strategies for Children Based on Pharmacokinetic Data from Chinese Male Adults and PBPK Modeling.

For children, a special population who are continuously developing, a reasonable dosing strategy is the key to clinical therapy. Accurate dose predictions can help maximize efficacy and minimize pain in pediatrics. Methods: This study collected amlodipine pharmacokinetics (PK) data from 236 Chinese male adults and established a physiological pharmacokinetic (PBPK) model for adults using GastroPlus™. A PBPK model of pediatrics is constructed based on hepatic-to-body size and enzyme metabolism, used similar to the AUC0-∞ to deduce the optimal dosage of amlodipine for children aged 1-16 years. A curve of continuous administration for 2-, 6-, 12-, 16-, and 25-year-olds and a personalized administration program for 6-year-olds were developed. Results: The results show that children could not establish uniform allometric amplification rules. The optimal doses were 0.10 mg·kg-1 for ages 2-6 years and -0.0028 × Age + 0.1148 (mg/kg) for ages 7-16 years, r = 0.9941. The trend for continuous administration was consistent among different groups. In a 6-year-old child, a maintenance dose of 2.30 mg was used to increase the initial dose by 2.00 mg and the treatment dose by 1.00 mg to maintain stable plasma concentrations. Conclusions: A PBPK model based on enzyme metabolism can accurately predict the changes in the pharmacokinetic parameters of amlodipine in pediatrics. It can be used to support the optimization of clinical treatment plans in pediatrics.

Binder Jet 3D Printing of Compound LEV-PN Dispersible Tablets: An Innovative Approach for Fabricating Drug Systems with Multicompartmental Structures.

Three-dimensional (3D) printing is an emerging technology that has high application potential for individualized medicines and complex solid dosage forms. This study is designed to explore binder jet 3D printing (BJ-3DP) for the development of high-precision and repeatable compound levetiracetam-pyridoxine hydrochloride (LEV-PN) multicompartmental structure dispersible tablets. PN was dissolved in printing ink directly and accurately jetted into the middle, nested layer of the tablet, and precise control of the drug dose was achieved through the design of printing layers. With modification of the drying method, the "coffee ring" effect caused by drug migration during the curing and molding of the tablets was overcome. Furthermore, 3D topography showed that the tablets have a promising surface morphology. Scanning electron microscopy and porosity results indicated that the tablets have a loose interior and tight exterior, which would ensure good mechanical properties while enabling the tablet to disintegrate quickly in the mouth and achieve rapid release of the two drugs. This study used BJ-3DP technology to prepare personalized multicompartmental structures of drug systems and provides a basis for the development of complex preparations.