ArchiveDuring the past ten years, the research and development of new drugs for skin diseases have boomed. The new drugs including biologics and small molecules have rapidly developed and greatly improved the treatment of common inflammatory/immunological skin diseases. More than 200 clinical trials have been performed and many new drugs was approved in China, bringing the dermatological treatment to a new era. In this paper, recent progress was reviewed in new drug development on psoriasis, atopic dermatitis, alopecia areata and androgenetic alopecia in China.
Since the reform of the drug review and approval system, with the support of a series of policies and technology that encourages innovation, a large number of clinical trial application of new drugs for skin disease has been approved. In addition, innovative drugs, high-quality generic drugs, and biosimilar products have been accelerately approved, which meets the availability and accessibility of drugs to a certain extent. In order to guide innovation and scientific development of new drugs for skin disease, this article reviews the reform of drug review and approval system, the continuous improvement of the drug regulatory system, and the progress in development, evaluation and approval of new drugs for skin disease in China. We focus on the challenges, opportunities, and improvement measures faced in the development, evaluation, and regulation of drugs in this field. With multiple measures simultaneously taken, the goal is to meet the urgent clinical medication needs of patients with skin disease, so that effective and safe drugs can benefit patients as soon as possible.
Focusing on the specialty of locally applied locally acting drugs, we discuss and explain the special considerations in its design and evaluation of clinical trials.
The technical guidelines on the research and development of locally applied locally acting drugs issued by domestic and foreign regulatory agencies and related literature were extensively investigated. The relevant drug research and development situation and review practice were combed. Combined with case analysis and expert discussion opinions, the technical standards for clinical research and development of local drugs under different registration types were discussed.
The sponsor should formulate the corresponding research and development strategy based on the clinical medication needs and developmental background. For the innovative drugs, in addition to following the general consideration of clinical trials of innovative drugs, specific studies should also be carried out at the same time considering the characteristics of drug dosage forms, the routes of administration, and application sites, etc. Meanwhile, due to the technical and ethical difficulties of sampling in local pharmacokinetics and pharmacodynamics research, pharmaceutical quality research and comprehensive non-clinical research are particularly important. Some necessary exploratory and confirmatory clinical trials should be carried out combining the clinical data of the original active ingredient to prove the clinical advantages in safety and effectiveness etc. of the improved drug. For generic drugs that is locally administered and locally acting, beside pharmacy and non-clinical comparative studies with the original reference preparations, the sponsors may also need to carry out necessary human pharmacokinetics, pharmacodynamics, and even clinical equivalence trials to prove the consistency of quality and efficacy of generic drugs and reference preparations.
To explore the consideration on the key techniques of clinical trial design of drugs for the treatment of atopic dermatitis.
By summarizing the clinical research status of drugs for the treatment of atopic dermatitis, and investigating the progress of technical guidelines for the drugs in China and abroad in recent years, relevant technical considerations are proposed based on the China's experience in Drug R&D and the process of review.
The design of whole clinical trial of drugs treating atopic dermatitis should be based on the characteristics of the disease and investigational drug, the purpose of the study. Clinical trials for pediatric patients should be conducted as early as possible under the premise of prior research evidence and ensuring the safety of subjects. The appropriate study population should be selected, and a series of key elements, such as control drugs, efficacy and safety indicators, study period, etc., should be reasonably set up in the clinical trial design, in order to assist the scientific research and the development of the drugs. The positioning of the study population should be based on the drug action mechanism and drug effect intensity, and the patients with corresponding severity should be selected. The efficacy of the study should be comprehensively evaluated to assess the improvement of skin lesions, symptoms, quality of life, etc., and attention should be paid to the efficacy and safety of the study when used in pediatric patients as well as in long-term treatment.
To discuss the scientific considerations on the design of drug therapeutic efficacy indicators for the treatment of atopic dermatitis.
By investigating the progress of global clinical trials of new drugs, relevant guidelines and the literatures, the scientific design of efficacy indicators in clinical trials of atopic dermatitis was discussed.
Generally, the design of drug efficacy indicators for the treatment of atopic dermatitis should comprehensively evaluate the symptoms, signs, quality of life and long-term control of the disease. The main efficacy indicators should reflect the clinical benefits and remain consistent with the treatment objectives. The design, validation and application of patient-centered assessment scale are crucial, and are still challenging in the scientific evaluation of drug efficacy.
To explore the key technical elements of clinical trial design for the treatment of plaque psoriasis vulgaris.
By searching both relevant domestic and international literature, and combined with research and evaluation practices in China, scientific considerations on innovative drug clinical trial design for the treatment of psoriasis are summarized and proposed.
The overall design of clinical trials for the treatment of psoriasis vulgaris should be based on the characteristics of the disease's pathophysiology and drug action mechanisms, with a reasonable selection of control and population, as well as the design of trial duration, efficacy, and safety indicators. To comprehensively evaluate the effectiveness and safety of drugs, attention should be paid to the improvement of patients' quality of life, relapse or rebound after drug withdrawal, and long-term medication while evaluating the improvement of psoriasis symptoms and signs after drug treatment.
Taking the development of dermatology drugs as an example, proposals are provided after analysis by summarizing the common clinical questions about drugs development encountered in communication, in order to provide reference for the same problems and improve the efficiency and quality in communication system.
The clinical improvement questions were collected and classified regarding dermatology drugs' communication applications in the communication subsystem of the Center for Drug Evaluation of National Medical Products Administration drug technical review system. The common questions were analyzed and regulatory considerations for improvement were elaborated.
Efficient communication system can promote the interaction between research and regulation, solve more individual problems, satisfy the needs in drug developments; however, developers and regulators need to work together to improve the quality and efficiency of communication.
Model-informed drug development (MIDD) is a major shift of new mode of drug development based on the establishment of PK-PD model using blood concentration- (i.e., exposure, PK) and efficacy/safety (i.e., response, PD)-corresponding data, in order to analyze exposure-response relationship, replace dose-response relationship that is difficult to obtain, and establish the chain of evidence on drug safety and efficacy. The above model can integrate data from in vitro and in vivo, animals and human beings, adults and children, literature and trials, original and new dosage forms, domestic and foreign trials, and other sources to solve a wide range of key clinical problems. It is particularly important to transform the exploration paradigm of new drug development into a model verification mode. Therefore, MIDD is not only related to the change of technical means, but also the integration of multidisciplinary research, as well as a change of research and development strategy and scientific regulatory. It greatly improves the efficiency and success rate of new drug research and development. Based on the summary of MIDD success cases, this paper tries to clarify the basic principle, concept and method, implementation path, and takes anti-psoriasis monoantibody as an example to establish a complete MIDD working mode.
Autoimmune skin diseases are a kind of diseases caused by the immune response to self-antigens, resulting in damages to skin with or without to other tissues and organs. The traditional immunosuppressants exert their curative effect, but accompanied by a wide range of adverse reactions. In-depth understanding of pathogenesis facilitated the development of various cytokine-based therapies or drugs targeting the signaling pathways, which has significantly improved the patient's condition. However, these therapies often require long-term maintenance treatment, and the targeting pathways of many autoimmune skin diseases are still not quite clear. Therefore, emerging therapeutic strategies and innovative drugs are still in need to balance the homeostasis of the immune system and induce the long-term remission of the disease, providing new hope for the treatment of autoimmune skin diseases. This review discusses the development of drugs treating autoimmune skin diseases according to different mechanisms of action and targets.
Atopic dermatitis is a chronic inflammatory disease of skin that is commonly seen and easy to relapse. Treatments nowadays still have many drawbacks and adverse effects, thus cannot meet the needs of clinicians and patients. In recent years, our expanding knowledge of the complex pathomechanisms of atopic dermatitis has given rise to new interventions of targeted therapy, which will help clinicians better treat and manage the atopic dermatitis. This review summarizes the advances in new medications for pediatric atopic dermatitis.
Psoriasis is a chronic immune-mediated inflammatory skin disease. A growing understanding of the mechanism has led to the advent of biological agents that specifically target the cytokines which are involved in the pathogenesis. Because of the significant efficacy with high safety shown in the treatment of psoriasis, biologic agents have becoming more and more usual in clinical practice. Rapid progress in biotechnology allows the development of an increasing number of novel biologic agents, such as biologics targeting existing and promising inflammatory mediators, bispecific agents targeting multiple different antigens and agents including nanobodies and peptides. This review summarizes the current application of biologic agents in clinical practice, new drugs that are under study, potential targets and novel technology of biologics.
Vitiligo is a kind of refractory depigmentation skin disease, which seriously affects the appearance and psychology of patients. At present, the pathogenesis of vitiligo includes heredity, oxidative stress, autoimmunity and environmental factors. The treatment includes systematic application of glucocorticoid, local application of glucocorticoid or calcineurin inhibitor, phototherapy and melanocyte transplantation. In this article, we reviewed the commonly used therapeutic drugs for vitiligo in the past and summarized the new progress of therapeutic drugs for the treatment of vitiligo. The emergence of new small-molecule targeted drugs, such as Janus kinase inhibitor baricitinib, has brought hope for vitiligo.
As a sensor of environment-cell interaction, aryl hydrocarbon receptor (AhR) plays an important role in maintaining barrier function, immune system and antioxidant process of the skin. AhR regulates the expression of many genes that are related to basic skin functions. It is expressed in all types of skin cells and involved in the progression of a variety of inflammatory skin diseases, including atopic dermatitis and psoriasis. Due to the complexity of the AhR protein structure, its crystal structure has not been successfully resolved until researchers obtained the crystal structure of indirubin binding to HSP90-XAP2-AhR complex recently. Clinical studies have shown that activation of the AhR pathway by ligands is of significance to the treatment of inflammatory skin diseases, as demonstrated by the clinical success of an AhR agonist, Benvitimod, for the treatment of psoriasis. This article presents a brief review on the role of AhR in inflammatory skin diseases and the current progress in drug development.
The study aims to prepare human immunoglobulin by chromatography combined with low-temperature ethanol, detect the effect of impurities removal in the preparation process and the effect of chromatography on product quality.
Human immunoglobulin (pH 4) was prepared by one-step anion-exchange chromatography from FII precipitated from healthy human plasma. It was further separated and purified by low-temperature ethanol-protein separation. The distribution of molecular size, IgA content, IgG content and IgG subclasses distribution, protein secondary structure of IgG were determined and analyzed. The effect of IgA and IgM removal of intravenous human immunoglobulin (pH 4) prepared by low-temperature ethanol protein separation and anion exchange purification was compared.
The precipitation of component II was dissolved by 5-fold volume of water for injection, and the dissolution rate of IgG was higher after stirring for 2 h. The content of IgA in intravenous human immunoglobulin (pH 4) prepared by anion exchange chromatography combined with low-temperature ethanol was controlled below 100 μg·mL-1, consistent with the distribution of molecular size and IgG isoforms of commercial products. The virus inactivation flux of nanofilms (20 nm) was increased.
Anion exchange chromatography can reduce the residual amount of IgA, IgM and other impurities in IVIG products, improve the permeability of nano-film (20 nm), and has no significant effect on the key quality of IVIG products.
This study used "microneedles" as the keyword to search for relevant literature in CNKI and PubMed databases from 2017 to 2022. This article reviews the research progress of the carriers of microneedles based on structures, preparation methods, pharmacodynamics and clinical applications. A total of 1 040 valid kinds of literature were retrieved from the two databases. The structure of microneedles can be divided into solid microneedles, coated microneedles, dissolve microneedles, hydrogel microneedles, and hollow microneedles. The microneedles preparation methods involve microcasting, drawing lithography, and 3D printing methods. Some microneedle carrier pharmacodynamics studies include the treatment of skin, metabolic diseases, immune system diseases, and eye diseases. The microneedles' clinical application researches include vaccine, radiofrequency therapy and biological diagnosis. The main direction of future microneedle research is to develop a new transdermal microneedle drug delivery system, which is combined with the new pharmaceutical preparation technology. This study provides reference for further development of microneedle transdermal delivery formulations. The authors expect to provide a reference for the related research on microneedles.
To establish the method of simultaneous determination of 12 major chemical components (such as berberine, magnolflorine and curcumin) in Tibetan medicine Ji-Ni De-Xie.
The separation was achieved on a WondaSil C18-WR column. High performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-QqQ-MS) was used with the mobile phase 0.1% formic acid solution (A)-methanol (B) under gradient elution. The temperature of Electron Spray Ionization (ESI) was 300 ℃. The charged ions were scanned in positive and negative ion modes at the same time with multiple reaction monitoring. The contents of 12 components in 5 batches of samples were calculated according to the linear equation of 12 reference substances.
The 12 components of the Ji-Ni De-Xie have a good linear relationship within the detection range. The average contents of magnolflorine, jatrorrhizine, berberine, curcumin, demethoxycurcumin, gallic acid, chebulagic acid, ferulic acid 4-O-β-D-glucopyranoside, hydroxysafflor yellow A, rutin, ferulic acid, and ellagic acid are 3.18, 0.20, 1.71, 0.52, 0.22, 15.93, 7.56, 3.29, 0.07, 0.20, 1.47, 2.89 mg·g-1, respectively.
The established analytical method is highly selective with high sensitivity. providing reference for the quality control of the Tibetan medicine Ji-Ni De-Xie.
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