A Fast and Non-destructive Terahertz Dissolution Assay for Immediate Release Tablets

There is a clear need for a robust process analytical technology tool that can be used for on-line/in-line prediction of dissolution and disintegration characteristics of pharmaceutical tablets during manufacture. Tablet porosity is a reliable and fundamental critical quality attribute which controls key mass transport mechanisms that govern disintegration and dissolution behavior. A measurement protocol was developed to measure the total porosity of a large number of tablets in transmission without the need for any sample preparation. By using this fast and non-destructive terahertz spectroscopy method it is possible to predict the disintegration and dissolution of drug from a tablet in less than a second per sample without the need of a chemometric model. The validity of the terahertz porosity method was established across a range of immediate release (IR) formulations of ibuprofen and indomethacin tablets of varying geometries as well as with and without debossing. Excellent correlation was observed between the measured terahertz porosity, dissolution characteristics (time to release 50% drug content) and disintegration time for all samples. These promising results and considering the robustness of the terahertz method pave the way for a fully automated at-line/on-line porosity sensor for real time release testing of IR tablets dissolution.     

Efficient Prediction of In Vitro Piroxicam Release and Diffusion From Topical Films Based on Biopolymers Using Deep Learning Models and Generative Adversarial Networks

The purpose of this study was to simultaneously predict the drug release and skin permeation of Piroxicam (PX) topical films based on Chitosan (CTS), Xanthan gum (XG) and its Carboxymethyl derivatives (CMXs) as matrix systems. These films were prepared by the solvent casting method, using Tween 80 (T80) as a permeation enhancer. All of the prepared films were assessed for their physicochemical parameters, their in vitro drug release and ex vivo skin permeation studies. Moreover, deep learning models and machine learning models were applied to predict the drug release and permeation rates. The results indicated that all of the films exhibited good consistency and physicochemical properties. Furthermore, it was noticed that when T80 was used in the optimal formulation (F8) based on CTS-CMX3, a satisfactory drug release pattern was found where 99.97% of PX was released and an amount of 1.18 mg/cm² was permeated after 48 h. Moreover, Generative Adversarial Network (GAN) efficiently enhanced the performance of deep learning models and DNN was chosen as the best predictive approach with MSE values equal to 0.00098 and 0.00182 for the drug release and permeation kinetics, respectively. DNN precisely predicted PX dissolution profiles with f₂ values equal to 99.99 for all the formulations.     

小粒径氟尿嘧啶羧甲基壳聚糖微球制备工艺初探

目的初步探讨氟尿嘧啶羧甲基壳聚糖（FU-CMCS）微球制备工艺及体外释药特性。方法以羧甲基壳聚糖（CMCS）为载体材料。采用乳化交联法制备氟尿嘧啶羧甲基壳聚糖（FU-CMCS）微球。考察投药方式、交联剂、超声乳化作用等因素对微球粒径、体外释药的影响。结果该方法制得FU-CMCS微球平均粒径1．6μm,球形圆整、流动性良好,人工肠液释药长迭15d。结论该制备工艺方法简单,制得FU—CMCS微球粒径小,分布窄,在体外具有缓释作用。     

Poly Lactic Acid Based Injectable Delivery Systems for Controlled Release of a Model Protein,Lysozyme

The objective of this study was to evaluate the critical formulation parameters (i.e., polymer concentration, polymer molecular weight, and solvent nature) affecting the controlled delivery of a model protein, lysozyme, from injectable polymeric implants. The conformational stability and biological activity of the released lysozyme were also investigated. Three formulations containing 10%, 20%, and 30% (w/v) poly lactic acid (PLA) in triacetin were investigated. It was found that increasing polymer concentration in the formulations led to a lower burst effect and a slower release rate. Formulation with a high molecular weight polymer showed a greater burst effect as compared to those containing low molecular weight. Conformational stability and biological activity of released samples were studied by differential scanning calorimeter and enzyme activity assay, respectively. The released samples had significantly (P < 0.05) greater conformational stability and biological activity in comparison to the control (lysozyme in buffer solution kept at same conditions). Increasing polymer concentration increased both the conformational stability and the biological activity of released lysozyme. In conclusion, phase sensitive polymer-based delivery systems were able to deliver a model protein, lysozyme, in a conformationally stable and biologically active form at a controlled rate over an extended period.     

Drug Release from Ammonio–Methacrylate-Coated Diltiazem Particles: Influence of the Reservoir on Membrane Behavior

Drug-layered sugar spheres 15, 45, and 64% potent were made such that each had the same particle size distribution. The particles were coated to the same coat thickness with an ammonio polymethacrylate formulation, and drug release was measured in two media. The products exhibited a sigmoidal release pattern, where a lag time was followed by relatively rapid drug release. Lag time depended on the applied polymer amount, the media used, and the sugar content, where an increase in sugar content caused greater expansion before drug release. Lag times were related to expansion. Expansion of coated sugar spheres was measured.     

In Vitro Release—In Vivo Microbiological and Toxicological Studies on Ketoconazole Lipid Granules

In some multidrug therapy programs, ketoconazole (KTZ) may be administered with some antacids that could modify its dissolution rate and reduce its absorption, thus leading to therapeutic failures. The primary aim of this study was to evaluate the influence of Compritol HD5 ATO and Compritol 888 ATO on this interaction in comparison with commercial KTZ tablets. The second aim was to prepare lipid granules of KTZ that could be an alternative to the commercial formulation. Therefore, six KTZ sustained-release granules were prepared with different lipid concentrations, because they were found to be more suitable than tablets that are dissolved only in gastric medium. The results confirmed that the dissolution rate of KTZ granules was significantly reduced in the presence of antacids. The ideal formulation was selected as granules including 5% of Compritol lipids in relation to the suitability of the target profile. Therapeutic effects of orally administered, ideal KTZ granule formulations, and commercial tablets were evaluated in vivo by the experimental model of murine vulvo-vaginal candidiasis (VVC) with and without antacids. It was found that formulations were very effective on VVC, and the therapeutic effect decreased significantly in the presence of antacids. Histopathological studies were carried out for vagina, stomach, and liver tissues and hepatoxicity was also examined. The levels of reduced glutathione (GSH) were measured to assess the oxidative stress induced by KTZ and function of the liver. It was observed that orally administered formulations of KTZ were successful in treating candidiasis in mice without irritancy in stomach. However, liver tissues were damaged. The decreased GSH levels indicated toxicity in our study. This study suggested that in vitro release and in vivo microbiological-toxicological properties of KTZ were affected by antacids and drug-excipient interactions. Lipid granules of KTZ prepared with Compritol 888 ATO could be proposed as a new KTZ solid dosage form with optimum dissolution and therapeutic characteristics.     

Role of glutamate receptors and nitric oxide on the effects of glufosinate ammonium,an organophosphate pesticide,on in vivo dopamine release in rat striatum

The purpose of the present work was to assess the possible role of glutamatergic receptors and nitric oxide (NO) production on effects of glufosinate ammonium (GLA), an organophosphate pesticide structurally related to glutamate, on in vivo striatal dopamine release in awake and freely moving rats. For this, we used antagonists of NMDA (MK-801 and AP5) or AMPA/kainate (CNQX) receptors, or nitric oxide synthase (NOS) inhibitors (l-NAME and 7-NI), to study the effects of GLA on release of dopamine from rat striatum. So, intrastriatal infusion of 10 mM GLA significantly increased dopamine levels (1035 ± 140%, compared with basal levels) and administration of GLA to MK-801 (250 μM) or AP5 (650 μM) pretreated animals, produced increases in dopamine overflow that were ∼40% and ∼90% smaller than those observed in animals not pretreated with MK-801 or AP5. Administration of GLA to CNQX (500 μM) pretreated animals produced an effect that was not significantly different from the one produced in animals not pretreated with CNQX. On the other hand, administration of GLA to l-NAME (100 μM) or 7-NI (100 μM) pretreated animals, produced increases in dopamine overflow that were ∼80% and ∼75% smaller than those observed in animals not pretreated with these inhibitors. In summary, GLA appears to act, at least in part, through an overstimulation of NMDA (and not AMPA/kainate) receptors with possible NO production to induce in vivo dopamine release. Administration of NMDA receptor antagonists and NOS inhibitors partially blocks the release of dopamine from rat striatum.     

Preparation of honokiol-loaded chitosan microparticles via spray-drying method intended for pulmonary delivery

It has been demonstrated that spray-drying is a powerful method to prepare dry powders for pulmonary delivery. This paper prepared dispersible dry powders based on chitosan and mannitol containing honokiol nanoparticles as model drug. The results showed that the prepared microparticles are almost spherical and have appropriate aerodynamic properties for pulmonary delivery (aerodynamic diameters was between 2.8–3.3 μm and tapped density ranging from 0.14–0.?18?g/cm³). Moreover, surface morphology and aerodynamic properties of the powders were strongly affected by the content of mannitol. Fourier transform infra-red (FTIR) spectrum of powders indicated that the honokiol nanoparticles were successfully incorporated into microparticles. In vitro drug release profile was also observed. The content of mannitol in powders significantly influenced the release rate of honokiol from matrices.     

Design and in vitro evaluation of formulations with pH and transit time controlled sigmoidal release profile for colon-specific delivery

The primary objective of the study was to develop a pH and transit time controlled sigmoidal release polymeric matrix for colon-specific delivery of indomethacin. Tablet matrices were prepared using a combination of hydrophilic polymers (polycarbophil or carbopol) having pH sensitive swelling properties with hydrophobic polymer ethyl cellulose. The prepared matrices were characterized for physical properties and in vitro release kinetics. The presence of ethyl cellulose in a hydrophilic polymer matrix resulted in a sigmoidal in vitro drug release pattern with negligible to very low drug release in the initial phase (0–6?h) followed by controlled release for 14–16?h. The retardation in initial release can be attributed to the presence of ethyl cellulose that reduced swelling of hydrophilic polymer(s) while in the later portion, polymer relaxation at alkaline pH due to the ionization of acrylic acid units on carbopol and polycarbophil resulted in enhanced drug release. Thus, a sigmoidal release pattern was obtained that could be ideal for colonic delivery of indomethacin in the potential treatment of colon cancer.     

Controlled release study of 5-fluorouracil-loaded chitosan/polyethylene glycol microparticles

The aim of this research is to reduce the frequency of taking therapeutic drugs. Thus, anti-cancer drug [5-fluorourical (5-FU)] loaded chitosan/polyethylene glycol microparticles were prepared by a phase-inversion technique with tripolyphosphate (TPP) used as a cross-linking agent. The relationships between 5-FU release behavior/encapsulation efficiencies and chitosan concentrations, TPP concentrations, as well as cross-linking time were studied to identify better/superior conditions (3.5 wt% chitosan, 3 wt% TPP, and cross-linking time?=?4?h) for preparing 5-FU-loaded microparticles. Furthermore, in order to ascertain the influence of their physical properties on 5-FU release performance, 5-FU-loaded microparticles were evaluated by swelling tests and scanning electron microscopy.