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@#Acute myeloid leukemia (AML) is a disease caused by abnormal cloning of hematopoietic stem cells in the bone marrow, which leads to accumulation of a large number of abnormally differentiated myeloid cells. It is difficult to cure by traditional treatment. The successful application of chimeric antigen receptor T cell (CAR-T) immunotherapy indicates that the treatment of hematological tumors has entered a new stage of precision immunotherapy. However, CAR-T immunotherapy has been found to have many problems in clinical applications, including long treatment cycle, expensive prices, off-target effects, cytokine release syndrome, etc. Therefore, it is necessary to expand the application of CAR or adopt improved measures to enhance the therapeutic effect. This article reviews the new strategies for genetic engineering modification of CAR immune cells and the research progress and application of in situ programming to generate CAR-T, and besides, briefly introduces the new methods about the delivery of gene drugs in vivo, aiming to provide new ideas and theoretical basis for expanding and improving the application of precision immunotherapy in AML.
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@#Abstract: To investigate the in vitro release, in vivo pharmacokinetics, and the in vitro-in vivo correlation of progesterone suspension injection, self-made progesterone suspension injection was taken as an example. The in vitro release curves of three different particle sizes of progesterone suspension injections were measured using paddle method and dialysis bag method. The in vivo pharmacokinetic characteristics of self-made progesterone suspension injection was studied on SD rats. The plasma concentration of self-made progesterone preparation was detected after intramuscular injection, and correlated with the in vitro release profiles obtained by the dialysis bag method after processing by Wagner-Nelson method. The results showed that when the in vitro release of three different particle sizes of progesterone suspension injections was measured by the paddle method, more than 85% was rapidly released within 20 min, while 85% cumulative release was reached at 40 h, 84 h and 120 h by dialysis bag method, respectively. The release rate obtained by the dialysis bag method was basically consistent with the in vivo release trend, with a correlation coefficient of >0.95, indicating a strong in vivo and in vitro correlation. This study provides some reference for the establishment of the in vitro and in vivo correlation of long-acting suspension injection.
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@#Long-acting injectables(LAIs) play an important role in the field of drug preparation research because they can control drug release for a long time and decrease dosing frequency. In this review, two types of LAIs, including injectable microspheres and in situ forming gel implants, were used as the breakthrough point to analyze the strategies and technologies used in the formulation and process to achieve long-acting drug release.At the same time, in view of the common burst release phenomenon, the relevant coping strategies in the current research were summarized, which provides some reference for the design, development and optimization of such long-acting preparations.
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@#The physiologically based pharmacokinetic (PBPK) modeling strategy was adopted to predict the pharmacokinetic behavior of crystal forms I and II of rifampicin in humans, which was used to determine whether the two were bioequivalent.After conducting studies in vitro of the two crystal forms, a rat PBPK model was established based on the pharmacokinetic data of intravenous administration in rats.The model was optimized by the pharmacokinetic data of oral administration in rats.Species were extrapolated to healthy humans, and the extrapolation model was used to predict such pharmacokinetic behaviors as the drug-time curve, absorption site, and absorption amount of the two crystal forms of rifampicin in healthy humans.The prediction results of the healthy human model showed that the cmax of form I and form II rifampicin were 8.42 and 10.35 μg/mL, tmax were 0.40 and 0.32 h,and AUC0-t were both 62.90 μg·h/mL.According to the prediction results of absorption, neither crystal form I nor crystal form II rifampicin was absorbed in the stomach, yet both were completely absorbed in the intestinal tract, with both the absorption site and the absorption amount were basically the same.The pharmacokinetic parameters of both crystal forms I and II of rifampicin were very close, which could indicate bioequivalence.
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@#Non-alcoholic fatty liver disease (NAFLD) is a series of chronic liver diseases strongly associated with the metabolic disorder with an increasing rate of worldwide prevalence.Due to its complicated pathogenesis, only Saroglitazar has been approved by Indian Drug Controller General (DCGI) as a PPAR-α/γ dual agonist to treat non-cirrhotic non-alcoholic steatohepatitis.Combination therapy, which can target same or different signaling pathways of NAFLD pathogenesis, has been developed to achieve synergistic therapeutic efficacy.Currently, small-molecule drug combination, RNAi combination therapy, and chemogene therapy are proposed as promising strategies in NAFLD treatment.In addition, designing a smart, safe and effective drug delivery system is key to realizing the druggability, clinical translation and industrialization of small molecule drugs and gene drugs.This review summarizes the research status and delivery system of small-molecule drug combination, RNAi combination therapy, and chemogene therapy, in the hope of providing some novel insight for the treatment of NAFLD.
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@#Remdesivir-loaded liposomes for inhalation were prepared and the in vitro properties were evaluated. Firstly, preparation methods of remdesivir-loaded liposomes were screened, and single-factor experiments were conducted to optimize the prescription and preparation process. Then the physical property, deposition ratio and aerodynamic particle size distribution of remdesivir-loaded liposomes suspension for inhalation were comprehensively evaluated. As a result, the optimal liposomes were prepared by the thin-film dispersion method with pH 6.5 phosphate-buffered saline as the hydration medium. In the prescription, the ratio of drug to DPPC was 1∶20; the cholesterol accounted for 10% of total lipids; and 20% DSPE-mPEG 2000 was added as stabilizer.4% trehalose was added as lyoprotectant when lyophilizing to obtain ideal appearance, good stability and a small particle size change after reconstitution. Remdesivir-loaded liposomes were spherical with smooth surface and uniform particle size distribution under transmission electron microscope. In vitro release tests showed no significant change for release curves of remdesivir-loaded liposomes suspension before and after nebulization. Deposition experiments indicated that the fine particles fraction of liposomes was 51.4%, and the mass median aerodynamic diameter was less than 5 μm measured by next generation impactor. To sum up, remdesivir-loaded liposomes for inhalation with high encapsulation efficiency and stability can achieve a suitable particle size distribution to effectively deposit in the lung after nebulization, which provides a new approach for the treatment of COVID-19.
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@#In this study, ivabradine hydrochloride (IVB) was prepared as elementary osmotic pump tablets whose administration frequency was reduced to once daily. The dissolution method was developed, and effects on drug release profiles were evaluated by single factor analysis involving suspending agents, osmotic active agents and aging process. Orthogonal test was carried out at 3 levels on 3 factors including the amount of polyoxyethylene (PEO) in the core, polyethylene glycol (PEG) percentage and weight increase of controlled-release film coatings. The final formulation consisted of IVB (16.25 mg), PEO N80 (60 mg), hypromellose E5 (10 mg), lactose (111.75 mg), magnesium stearate (2 mg); and the film coatings consisted of PEG (15%), cellulose acetate (85%), with a weight increase of 7.5%. In vitro drug release behaviors were investigated. Prepared tablets exhibited similar release profiles in different pH dissolution media, with no risk of dose dumping in 40% ethanol solutions. The osmotic pressure differences inside and outside the membrane drove drug release. IVB osmotic pump tablets could reduce the frequency of administration and improve patients'' compliance, thus with better application values.
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Invasive fungal infections (IFIs) represent a growing public concern for clinicians to manage in many medical settings, with substantial associated morbidities and mortalities. Among many current therapeutic options for the treatment of IFIs, amphotericin B (AmB) is the most frequently used drug. AmB is considered as a first-line drug in the clinic that has strong antifungal activity and less resistance. In this review, we summarized the most promising research efforts on nanocarriers for AmB delivery and highlighted their efficacy and safety for treating IFIs. We have also discussed the mechanism of actions of AmB, rationale for treating IFIs, and recent advances in formulating AmB for clinical use. Finally, this review discusses some practical considerations and provides recommendations for future studies in applying AmB for combating IFIs.
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Co-delivery of chemotherapeutics and immunostimulant or chemoimmunotherapy is an emerging strategy in cancer therapy. The precise control of the targeting and release of agents is critical in this methodology. This article proposes the asynchronous release of the chemotherapeutic agents and immunostimulants to realize the synergistic effect between chemotherapy and immunotherapy. To obtain a proof-of-concept, a co-delivery system was prepared
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@#Efficient and safe delivery of drugs, proteins or genes to the targeted sites has been the focus of pharmaceutical research. Inorganic nanomaterials are ideal materials for drug delivery systems due to their good stability, excellent biocompatibility and high drug loading capacity.Inorganic nanomaterials are ideal materials for drug delivery systems due to their good stability, high biocompatibility and excellent drug loading capacity. In this review, we started with reported researches and clinical trials to discuss the researches and clinical transformation of these inorganic nanoparticles in application of drug delivery, including carbon nanomaterials, silica nanoparticles, calcium nanomaterials, gold nanoparticles, magnetic nanoparticles, upconversion nanoparticles and quantum dots, providing theoretical reference for application of inorganic drug delivery carriers in the development of new drugs, looking to the prospects of inorganic nanomaterials in clinical application.
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@#Recently,an increasing number of studies have found that matrix metalloproteinase (MMPs) are closely related to the severity,diagnosis and prognosis of a variety of diseases. MMPs have therefore also gained increasing attention as a potential biomarker. In this paper,the application of MMPs in the diagnosis of tumors,cardiovascular diseases,inflammatory diseases and neurodegenerative diseases was summarized,and three types of detection methods based on RNA level,protein level and hydrolase activity of MMPs were introduced,which aims to provide some theoretical reference for the study of clinical application of MMPs detection.
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@#Atherosclerosis is an inflammatory disease which mediated by the immune system of the arterial wall. Specific and non-specific immune systems of arterial wall showed positive immunore action with many endogenous and exogenous antigens.Studies have shown that the immune system promotes atherosclerosis on the one hand and delays atherosclerosis on the other. Therefore,the progress of atherosclerosis can be regulated through activating immune regulation. In this review,the double effects of specific and non-specific immune systems on the process of atherosclerosis were discussed. The studies of those antigen which have been made into vaccines and successfully delayed the process of atherosclerosis in laboratory models were introduced. And the prospects and challenges for future clinical application of atherosclerosis vaccines were discussed in this review.
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@#In this study, pregabalin controlled porosity osmotic pump tablets which are taken once a day were prepared. Single-factor tests were carried out to investigate the influence of excipients and manufacturing process. The formulation was optimized through orthogonal experiment on three levels of three significant factors including the amount of sodium citrate, and polyethylene glycol 400 and coating weight gain. On the basis of the results of the single-factor tests and the orthogonal experiment, optimal formulation and manufacturing process were obtained. The final tablet formulation contained pregabalin(82. 5 mg), microcrystalline cellulose(40%), sodium citrate(27. 5%), magnesium stearate(0. 5%)and 5% povidone K30 solution as the tablet binder; the coating formulation consisted of cellulose acetrate and 60% of polyethylene glycol 400 as a porogen; the coating weight gain was 3%. In vitro drug release kinetic study suggested that the drug release from controlled porosity osmotic pump tablets was mainly driven by osmotic pressure, which was barely affected by the pH of the release medium. The drug release behavior of the tablets within 12 hours complied with zero-order release rule and the linear correlation coefficient was 0. 991 6. The obtained porosity osmotic pump tablets could effectively slow the drug release rate, reduce concentration fluctuation and improve the safety and convenience for the patients, hence with broad prospects.
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@#To prepare tacrolimus solid dispersion to increase the solubility and bioavailability of tacrolimus. Tacrolimus solid dispersions were prepared by different water-soluble carriers, which were evaluated by in vitro drug dissolutions to select the optimal formulation. The optimal tacrolimus solid dispersion was evaluated by scanning electron microscopy(SEM), X-ray diffraction(XRD)and differential scanning calorimetry(DSC), and its gastrointestinal absorption kinetics was studied in rats. The results showed that tacrolimus solid dispersion with HPMC E3 as carrier had the fastest dissolution rate. SEM, XRD and DSC studies indicated that tacrolimus was distributed within the carrier HPMC E3 in amorphous form. Gastrointestinal absorption experiments in rats demonstrated that the optimal formulation remarkably increased oral absorption of tacrolimus. These results demonstrate that a novel tacrolimus solid dispersion with HPMC E3 as carrier may be an advantageous dosage form of tacrolimus, boosting the solubility and absorption in gastrointestinal tract.
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Objective To investigate the preparation technique and optimal formulation of diammonium glycyrrhizinate sustained-release tablets and study the release mechanism of diammonium glycyrrhizi-nate release from the tablet.Methods Using HPMCk4m,Compritol 888 as skeleton material to prepare the diammonium glycyrrhizinate sustained-release tablet.To optimize the formulations by Box-Behnken design,and use Design Expert program for statistical analysis of experimental results.Release mechanism of diammonium glycyrrhizinate from sustained release tablets was established by equation fitting.ResultsThe average accumulate release rates of diammonium glycyrrhizinate sustained-release tablets in 2,4,8,and 12 h were 32.55%,49.94%,73.88%,and 97.89%.And the release of diammonium glycyrrhizinate could be controlled by diffusion associated with erosion.Conclusion Box-Behnken design could be successfully used to optimize the sustained-release tablet of diammonium glycyrrhizinate.