ArchiveThe purpose of this paper is to provide reference for improving the incentive policies of innovative drug research and development in China. Taking Takeda Pharmaceutical Co., Ltd. as an empirical research object, and on the basis of combing Japan's innovative drug R&D incentive policies in terms of R&D support, registration review and approval, intellectual property rights and drug pricing, this paper analyzes how relevant policies encourage enterprises to innovate and develop from the aspects of mechanism and implementation effect. The results show that Takeda Pharmaceutical has achieved innovation transformation under a series of supports of innovative drug research and development incentive policies in Japan. In order to improve the related incentive policy in China, our country should learn from Japan's experience and take incentive measures, such as enhancing the commercial development of scientific research achievements, perfecting the intellectual property financing system, establishing and perfecting the drug data protection system and perfecting the price formation mechanism of innovative drugs.
Traditional clinical trials that are randomized and controlled have exposed some deficiencies in the process of long-term use, prompting a growing number of researchers to look at real-world evidence (RWE). As an important basis of real-world study (RWS), real-world data (RWD) determine whether the RWS is qualified for supervision and review of institutions with reliable RWE. There are some problems about RWD, including unstructured and fragmented data, poor accessibility, lack of standards to standardize data, research design that is not rigorous, failure to control the applicability of RWD, etc. These problems will greatly affect the quality of RWD. Aiming to resolve the above problems, this paper provides six suggestions in order to provide a reference to improve the quality of RWD, including strengthening the management of RWD in medical institutions, improving RWD sharing mechanism, standardizing RWD according to data standards in RWS, collecting RWD according to rigorous research design, defining the responsibilities of personnel related to RWD quality and strictly controlling the applicability of RWD.
Generic drug has made a large contribution to our medical security system; however, the pharmaceutical industry starts late in China and there still exists a wide gap between generic drugs and original drugs. Given this situation, the generic drug consistency evaluation is extremely meaningful to ensure the efficacy and safety of generic drugs, and it is impressive for improving the integral level of pharmaceutical industry. This article discusses the relevant policies of the generic drug consistency evaluation in China, such as ensuring the consistency between generic drugs and original drugs, establishment of the strict review and supervision system, etc. At the same time, this article also outlines the relevant drug policies and their development process in US Food and Drug Administration (FDA) and Japan Pharmaceuticals and Medical Devices Agency (PMDA). We expect that the comparison and analysis would be benefit to the generic drug consistency evaluation in our country.
To explore the potential hepatocarcinogenic effect of aristolochic acid I (AAI) on 2-week-old C3H/HeN suckling mice and its possible mechanism.
Two-week-old C3H/HeN suckling mice were randomly divided into 3 groups, i.e., the vehicle control group (0.5% CMC-Na), the liver cancer positive agent model group (DEN 20 mg·kg-1) and the AAI group (AAI 10 mg·kg-1). After 9 months of observation after a single administration, the organs were taken for gross pathological and histopathological examination, and the levels of serum biochemical indicators such as ALT, AST and AFP in mice were detected. At the same time, the contents of IL-1β and IL-6, the expression of Ki67, CK19, NF-κB P65, Ras, Raf, and caspase-3 in mouse liver were detected.
In this experiment, AAI caused liver cancer in C3H/HeN suckling mice. The incidence of liver cancer in male and female mice were 78.57% and 41.67%, respectively. Compared with the vehicle control group, the levels of ALT, AST, AFP, IL-1β and IL-6 in the AAI group were significantly increased, and the expression of Ki67 and CK19 in liver were positive. The results of Western blot showed that AAI significantly increased the expression of NF-κB P65, P-AKT, Ras, C-Jun, C-Fos, C-MYC and Bcl-2, and significantly decreased the expression of IKBα, Bax and Caspase-3.
In this experiment, AAI caused liver cancer in 2-week-old C3H/HeN suckling mice. The mechanism may be related to the activation of PI3K/AKT inflammatory pathway in hepatocytes, Ras/AP1/C-MYC proliferation pathway and the inhibition of Bax/Bcl-2/Caspase-3 Mitochondrial apoptosis pathway.
Taking major components of conjugated estrogen (CE), sodium equilin sulfate (EqS) and sodium estrone sulfate (ES), as examples to investigate their absorption characteristics in the rat intestine, and to evaluate two intestinal models.
Determination method of EqS and ES using atenolol as an internal standard by HPLC was delevloped. Models of in situ single-pass intestinal perfusions (SPIP) and Ussing Chamber rat intestine were applied for this study. The samples of intestinal sac fluid and receiving fluid at different time points after dosages of EqS+ES and atenolol. The parameters of effective permeability (Peff) and apparent permeability (Papp) were calculated and compared with that of atenolol.
The linearity of the HPLC analysis methods for the two intestinal models is well correlated within a certain concentration range (r>0.999), the intra-day and inter-day precisions are both below 15%, the accuracy is between 85%~115%, and the recovery is greater than 70%. In SPIP rat model, no statistical difference was found between the Peff of EqS+ES (jejunum: 0.22±0.07×10-4, cm·s-1; ileum: 0.24±0.08×10-4, cm·s-1) and atenolol (jejunum: 0.18±0.11×10-4, cm·s-1; ileum: 0.32±0.15×10-4, cm·s-1) in jejunum and ileum (P空=0.373; P回=0.128). In Ussing Chamber rat intestine model, EqS+ES and atenolol were absorbed in all intestinal segments of rats (duodenum: 1.83±0.77×10-6, cm·s-1, 5.46±0.80×10-6, cm·s-1; jejunum: 6.93±1.43×10-6, cm·s-1, 10.04±1.16×10-6, cm·s-1; ileum: 6.96±1.28×10-6, cm·s-1, 6.28±0.82×10-6; colon: 10.03±2.07×10-6, cm·s-1, 11.09±1.08×10-6, cm·s-1). There was no statistical difference between Papp of EqS+ES and atenolol in the ileum and colon (Pileum=0.251; Pcolon=0.263). Atenolol is a alkaline compound, the permeability of which in ileum was higher than that in Jejunum theoretically. The in vitro model differs from the theory.
CE can be considered as a drug with moderate permeability. SPIP rat model among the two models seems more accurate and reliable.
Glucagon-like peptide-1 (GLP-1), considered as an effective peptide for the treatment of diabetes, can stimulate insulin secretion in response to rising glucose. Moreover, the novel peptide is becoming a new choice to treat type II diabetes. Nevertheless, the half-life of GLP-1 (approximately 1~2 min) is short, limiting its clinical application in diabetes. GLP-1-loaded PLGA microspheres have drawn more attentions in recent years. In this article, we introduces the preparation methods for encapsulation of GLP-1 in preparing PLGA microspheres. In order to solve the shortcomings of large burst release and drug degradation of traditional microspheres, some novel microsphere formulations (double-wall microspheres, self-healing microspheres and other new formulations of microspheres) are summarized. The new formulations effectively enhance protein stability and long-acting efficiency is achieved, providing new strategies for developing protein-loaded microspheres.
Universal CAR-T cell technology belongs to the universal T cell technology based on gene editing in general CAR-T. It knocks out the signal receptor factor of T cell through gene editing, and produces CAR-T cell by using modified T cell from healthy volunteers; therefore it will not cause immune rejection such as graft versus host disease (GvHD) and host versus graft reaction (HvGR) after infusion. In animal experiments and early clinical trials, UCAR-T technology shows significant anti-tumor effect, wide applicability and tremendous application potentials. In terms of industrialization, UCAR-T cell technology is expected to solve the problems of high cost in designing and culturing autologous CAR-T preparations, of long preparation cycle, difficult quality control, insufficient cell quantity and expansion capacity, because of its unique features such as quality controllable, off-the-shelf, and easy for large-scale preparation, etc. This paper introduces the current research progress and existing problems of UCAR-T cells, and conducts a preliminary analysis of the existing problems, providing a reference for the fundamental research and clinical trials of UCAR-T cells.
Poly ADP ribose polymerase (PARP) inhibitors are anti-tumor drugs targeting PARP enzymes. They have been approved by the US Food and Drug Administration (FDA) for the treatment of ovarian cancer, breast cancer, prostate cancer and pancreatic cancer. Additionally, National Medical Products Administration of China has also approved them for ovarian cancer. So far, PARP inhibitors have changed the traditional treatment mode for ovarian cancer. This article conducts literature review for PARP inhibitors in aspects of mechanisms of action, indications, pharmacokinetics, clinical application, and key points for pharmaceutical care, so as to provide reference to clinicians for rational use in clinical and pharmacy service for PARP inhibitors.
Andrographolide (AG) has been found extensively pharmacological activities such as anti-inflammatory, anti-tumor, anti-virus, anti-HIV, hepatic protection, etc. However, the poor solubility with low oral bioavailability of AG limits the clinical application. New formulations of AG using advanced techniques have been developed to improve these disadvantages. In this review, we summarizes the recent advancement of AG formulation studies, providing references on novel formulation development and clinic translation of AG.
Acorus calamus was first published in “Shen Nong's Materia Medica”. It is a traditional Chinese medicine for resuscitation and is widely used in prescriptions for the treatment of closed syndrome. In view of the exact clinical efficacy of calamus and the continuous discovery of new pharmacological activities and effective ingredients, in recent years, it has attracted wide attention in China and abroad and has become one of the hot research Chinese medicine varieties. However, the current edition of “Chinese Pharmacopoeia” stipulates the traditional physical and chemical identification of calamus and the determination of the total content of volatile oil. It is still difficult to reflect and directly relate the characteristics of calamus's multiple clinical functions with multiple complex components. The current quality markers of traditional Chinese medicine have pointed out the development direction and research ideas for the establishment of quality standards in line with the characteristics of traditional Chinese medicine. This article summarizes and analyzes the chemical components and pharmacological effects of calamus by consulting literature, and based on the definition of quality markers: The “five elements” of validity, uniqueness, transmission and traceability, measurability and prescription compatibility are used to predict and analyze the quality markers of calamus. The literature review found that the volatile components of Acorus calamus, especially the asarone components, can be used as the quality markers of this drug, providing a scientific basis for its complete quality control.
To combine the chemotherapy and photodynamic therapy in one system, the micelles (ID-M) that co-loaded the photosensitizer indocyanine green (ICG) and the chemotherapeutic drug doxorubicin (DOX) were prepared and characterized. The anti-tumor effects of ID-M in vitro were further investigated.
An ultrasound dialysis method was used to prepare the micelles containing ICG and DOX (ID-M), while the single-encapsulated ICG micelles (I-M) and the single-encapsulated DOX micelles (D-M) were prepared using the same method as the controls. The particle size, Zeta potential, encapsulation efficiency and drug release behaviors of the micelles were measured. In addition, the anti-tumor effects and mechanism of ID-M in 4T1 cells were investigated.
The average hydrated diameter of ID-M particles was 80.4 nm with negative charge, and the coefficient of the particle size dispersion was 0.252 (<0.3). The encapsulation efficiency of ICG and DOX in ID-M were 92.5% and 96.8%, respectively. The results of the temperature warming testing under irradiation of ID-M solution reached (36.5±1.1) ℃. The release experiment of ID-M in vitro showed a significant sustained-release effect. Cell experiment proved that the uptake of 4T1 cells for ID-M was nearly 2 times higher than that for free drugs. The IC50 of ID-M inhibiting the growth of 4T1 cells with irradiation was 0.72 μg·mL-1, which was 3.6-fold lower than that of free ICG/DOX. Before light exposure, ID-M was mainly located in the lysosome. However, after light exposure, the ROS levels in the cells were increased due to the existence of ICG in ID-M, which damaged the lysosomal membrane and made DOX in ID-M enter to the nucleus to play a chemotherapeutic effect.
In this study, the micelles (ID-M) with synergistic antitumor effects of phototherapy and chemotherapy were successfully prepared.
To establish the UPLC fingerprints and multi-components content determination method of Cistanches herba formula granules and ultrafine granular power, and to provide a basis for their quality evaluation.
The separation was achieved by using a ACQUITY UPLC BEH C18 (100 mm×2.1 mm, 1.7 μm) column via gradient elution with the mobile phase consisting acetonitrile and 0.1% phosphoric acid water. The flow rate was 0.3 mL·min-1 and the detection wavelength was set at 235 nm; the column temperature was 35 ℃ and the injection volume was 1 μL.
The UPLC fingerprints of Cistanches herba formula granules and ultrafine granular power were established, in which 10 common peaks were determined, and 6 components of geniposidic acid, caffeic acid, echinacoside, acteoside, tubuloside A, and isoacteoside were identified. The contents of these 6 components were determined. Using the developed method, the components were well separated, and had wide linear ranges with good linear relationships. The stability, repeatability and recovery rate met the requirements. Using cluster analysis and principal component analysis methods, Cistanches herba formula granules and ultrafine granular power can be distinguighed and identified.
The UPLC fingerprints combined with multi-components content determination method are simple, accurate, and reproducible. It can quickly identify the formula granules and ultrafine granular power of Cistanches herba and evaluate their internal quality, providing a method reference for improving the quality control of formula granules and ultrafine granular power of Cistanches herba.
To establish a liquid chromatography-tandem mass spectrometry method (LC-MS/MS method) for determination the contents of 5-methyl isoquinoline sulfonic acid (impurity A) and 5-ethyl isoquinoline sulfonic acid (impurity C) which are genotoxic impurities in fashudil hydrochloride.
The LC-MS/MS method was achieved by a Waters Symmetry C18(100 mm×3 mm, 3.5 μm) column utilizing a mobile phase of 0.1% formic acid aqueous solution-acetonitrile with gradient elution at a flow rate of 0.5 mL·min-1. The column temperature was set at 30 ℃, the injection volume was 10 μL. The electrospray was operated with the source ESI under positive ionization scanning mode, and data were collected and analyzed.
Standard curves of impurity A and impurity C have a good linear relationship in the linear range. The limits of detection were 0.2 and 0.02 ng·mL-1, respectively, and the average recovery range was 93.0%~98.0%, RSD<4.67%(n=9). The RSDs of precision, accuracy, stability and durability tests were all less than 10.0%. Impurities A and C in the 3 batches of fashudil hydrochloride were not detected.
The established method was fast, accurate and reproducible, which could be used for the control of genotoxic impurities A and C in fashudil hydrochloride.
Ranibizumab prevents the formation of new blood vessels and reduces blood vessel permeability via inhibiting vascular endothelia growth factor (VEGF). In clinical, it is mainly used to treat wet age-related macular degeneration (wAMD). In this study, the safety, effectiveness and economics of ranibizumab in the treatment of wAMD were evaluated in order to provide an evidence-based basis for clinical rational use.
Databases were systematically searched, including Pubmed, Ovid, the Cochrane Library, CNKI, Wanfang and CMB, according to the inclusion and exclusion criteria. The literatures were screened, the data were extracted, and then qualitative analysis on the results was conducted by 2 researchers separately.
17 Meta-analyses and 27 pharmacoeconomic studies were included. The results showed that the clinical effectiveness of ranibizumab in the treatment of wAMD was similar to bevacizumab, conbercept and aflibercept. However, compared with the combination of photodynamic therapy (PDT), the single use of ranibizumab had more benefit in improving patients' vision, especially on BCVA. In terms of safety, ranibizumab is safer than bevacizumab. Ranibizumab appeared significantly more cost-effective than the usual treatments, pegaptanib and PDT, while it is not cost-effective compared with bevacizumab, aflibercept and conbercept.
In the treatment of wAMD, ranibizumab has no significant advantage over other clinically available drugs in effectiveness, but higher safety than bevacizumab, and lower economical than bevacizumab, aflibercept and conbercept.
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