OBJECTIVE To summarize the research requirements of Food and Drug Administration(FDA) on generic drugs of nasal preparations by reviewing product-specific guidances for nasal preparations issued by FDA, and to provide reference for the development and evaluation of generic drugs of nasal preparations in China. METHODS The relevant product-specific guidances of nasal preparations were selected from FDA's official website and summarized and analyzed. RESULTS There were currently 43 FDA product-specific guidances for nasal preparations. The recommended bioequivalence methods include in vitro bioequivalence studies, pharmacokinetic studies, comparative clinical endpoint studies, etc., which vary according to different drugs. Some of the product-specific guidances had included advanced in vitro detection techniques such as morphology-directed Raman spectroscopy(MDRS) in place of in vivo clinical trials. In this paper, the experimental design, main study endpoint and equivalence criteria of different types of bioequivalence tests were described. CONCLUSION This paper summarizes and analyzes the related product-specific guidances of nasal preparations issued by FDA, and provides reference for the development and evaluation of generic nasal formulations in China.

According to the differences in function and structure, the nasal cavity can be roughly divided into three regions:the vestibule, respiratory zone, and olfactory zone. The current mainstream of research believes that the process of drugs entering the brain through the nasal cavity mainly occurs in the latter two regions, with the olfactory zone being the primary area. To allow more effective ingredients to enter the brain or reach the above-mentioned delivery pathway targets quickly, when developing related drug products, it should be possible to deliver the drug to the upper nasal cavity, like the upper respiratory zone and olfactory zone. Therefore, special drug delivery devices that can target the upper nasal cavity play a key and core role in Nose-to-Brain delivery. It is nasal spray device Nose-to-Brain delivery products approved by FDA mainly use. The following are three main research directions of the Nose-to-Brain delivery devices. 1) In-depth assessment and research of critical quality attributes and their influencing factors. Many research institutions and enterprises have conducted extensive research on liquid or powder sprays aided by nasal spray devices, and it is currently agreed that spray pattern, plume geometry, and particle size are the critical quality attributes, which can be mainly affected by spray devices and content properties. A spray with a smaller angle can penetrate the nasal valve easier and deliver to the upper nasal cavity. 2) The study of delivery platforms for such complex drug-device combinations is also a key direction, such as Exhalation Delivery Systems (EDS), Precision Olfactory Delivery Systems (POD®), and Controlled Particle Dispersion Technology (CPD) platforms, etc., which are general technology platforms established by drug delivery device manufacturers to better achieve Nose-to-Brain delivery. They have indeed achieved more accurate drug delivery, more significant therapeutic effects, and more convenient use for patients. 3) Combining drug delivery devices with new technologies. For example, adding mucosal adsorbents and permeation enhancers to the prescription, and preparing medicinal products using nanoparticle formulation technology. It is new directions for future research and development which can further meet the needs of Nose-to-Brain delivery. Nose-to-Brain delivery bring new hope to a wide range of clinical needs for brain diseases due to its special advantages. In order to play the truly important role of Nose-to-Brain delivery, it is not only the industry make efforts in research and industrialization, but also regulatory aspects need scientific evaluation and reasonable regulation of emerging technologies. Here are our thoughts. First, we need to pay attention to the important role of regulatory science in the technical research and evaluation of Nose-to-Brain delivery products. Next, we need to pay attention to the interaction and collaboration between scientific researchers, industry, regulators, and users. Then, regulatory authorities needs to broaden its thinking flexibility and attach importance to the role of individual drug guidelines, summary key technical points and solutions from multiple cases. Finally, we need to pay attention to the design, research and development support, and industrialization security of domestic drug delivery devices.

Biologics are developing rapidly and have demonstrated their unique advantages in the treatment of many diseases. And with common administration, like oral and injection, biological products often have problems in instability, short half-life and poor utilization of the central nervous system, which limits the application scope and development of biological products. Intranasal biologics are promising strategy taking advantages in nasal administration that bypass the restrictions in vivo, like blood-brain-barrier, to improve the drug avalibility in the target site, which have potential to improve efficient delivery and the availability. According to published literature, clinical databases, industry guidelines around the world, this review highlighted the rescent progress in intranasal macromolecular drugs, intranasal vaccine and intranasal cell therapy, which were the main fields of intranasal biologics, offering perspectives suggestions for the further development of this field.

Due to the special structure of the nasal cavity, the addition of functional excipients in nasal drugs can improve the transmembrane absorption of the active pharmaceutical ingredient or reduce the clearance of nasal mucocilia, which plays an important role in maintaining the effective concentration of active pharmaceutical ingredient in the target area and promoting the absorption of nasal mucosa. In this paper, the excipients used in drug new approved by the United States Food and Drug Administration(FDA) in the past decade were summarized, and the current research advances and safety evaluation of excipients for nasal drug were reviewed, providing ideas and references for the selection of excipients for nasal drug development.

OBJECTIVE To investigate the effect of the concentration of the suspending aid Avicel® in a suspension nasal spray on the spray pattern, plume geometry and droplet size of nasal spray. METHODS Preparation of Fluticasone furoate nasal suspension with different concentration of Avicel®. Through SprayVIEW® spray test system to test the spray characteristic parameters of nasal spray, and Box-Behnken response surface method was used to analyze the influence of Avicel® concentration on the spray characteristics of nasal spray in vitro. At the same time, the influence of Avicel® concentration on the distribution of spray droplet size and the change of droplet size at different detection distances were investigated. RESULTS Increasing the concentration of the Avicel® would significantly reduce the spray area, spray angle and width(P<0.001), while increasing D50 and overall particle size. It was also found that increasing the actuation velocity would significantly increase the spray area, spray angle and width(P<0.05), and the influence of actuation acceleration on spray characteristics was far less than that of Avicel® concentration and actuation velocity. As the detection distance increased, the droplet size distribution become more concentrated and the span of droplet size distribution become smaller. CONCLUSION In this study, Box-Behnken response surface method is used to observe the antagonistic effects of Avicel® concentration and actuation velocity on spray characteristics, which provides a reference for the selection of Avicel® concentration for nasal sprays as well as the recommended actuation parameters for the device.

OBJECTIVE To systematically review the background of bioequivalence assessment of nasal sprays and nasal aerosols and the guiding considerations for the bioequivalence assessment of these complex drug-device combination products by regulatory authorities in the United States, the European Union(EU) and China. METHODS This article provided detailed explanations on the innovative weight of evidence assessment approach adopted by the US Food and Drug Administration(FDA), and the statistical rationale, methods and considerations for the bioequivalence assessment of nasal sprays and nasal aerosols. Using the calculation methods described in the draft guidance for budesonide inhalation suspension and the draft guidance for fluticasone nasal spray propionate issued by FDA, the statistical parameters of two-sided and one-sided population bioequivalence calculation were realized through R language programming, and pseudo-code for the population bioequivalence (PBE) calculation programs was provided. This article also presented a comprehensive review of published guidelines and summaries review principles of the EU and China for nasal sprays and nasal aerosols equivalence assessment. RESULTS & CONCLUSION Nasal sprays/nasal aerosols is the focus of innovative and generic drug development in recent years. This paper provided valuable considerations references for the research and development, quality control and bioequivalence evaluation of generic preparations of nasal sprays/nasal aerosols.

OBJECTIVE To investigate the effects of nasal administration of non-mitogenic acid fibroblast growth factor(NMFGF1) loaded nanoparticles(NMFGF1-NPs) on the improvement of cognitive function in vascular dementia(VD) mice and its mechanism. METHODS Nanoparticles containing NMFGF1(NMFGF1-NPs) were prepared by water-in-water emulsion technique and characterized. The mice were divided into sham group, VD model group, blank-NPs group, NMFGF1 solution group and NMFGF1-NPs group after repeated cerebral ischemia-reperfusion to establish VD test model, and then given the corresponding form of drug intervention by nasal cavity. After drug intervention, Morris water maze was used to evaluate the learning and memory function of the animals in each group from the perspective of behavior. Meanwhile, the morphology, arrangement and apoptosis index(AI) of hippocampal neurons in each group were evaluated by pathological methods such as HE staining, FJB staining and Tunel apoptosis staining. In addition, ELISA and Western blotting were used to investigate the molecular mechanism of NMFGF1-NPs improving VD by nasal administration. RESULTS The morphology of NMFGF1-NPs was round. The encapsulation rate of NMFGF1-NPs respectively was (87.76±5.89)%. Morris water maze results showed that the behavioral indexes of mice in VD model group were significantly different from those in sham operation group(P<0.01). At the same time, the pathological results showed that the neurons in the CA1 region of the hippocampus in the VD model group were disordered, the cells morphology and structure were missing, and the AI was significantly increased compared with that in the sham operation group(P<0.01). Meanwhile, compared with the VD model group, the NMFGF1-NPs treatment group showed significant improvement in various behavioral indexes, and the hippocampal neuron cells were intact and orderly, and the AI index was significantly decreased(P<0.01). ELISA and Western blotting analysis showed that compared with that of VD model group and other intervention groups, the content of MDA in the brain of NMFGF1-NPs treatment group was significantly decreased. While the content of SOD, NO and the expressions of Nrf2, SOD-1 and GSTO1/2 was significantly increased (P<0.01). CONCLUSION Nasal administration of NMFGF1-NPs can play the role of antioxidant stress damage by activating Nrf2/ARE signal pathway, and ultimately improve the learning and cognitive function of VD mice.

OBJECTIVE New inhaled formulations that act on the nose, mouth, respiratory tract, and whole body have received increasing attention. Meanwhile, the research and declaration of inhaled drugs have become hot spots amid infectious respiratory pandemic diseases worldwide. Due to the special anatomic structure of the nose, folds, grooves, and special structures may cause the specific uptake and deposition of inhaled substances. There are various epithelial tissues, glands, muscles, and cartilages in the vestibule, respiratory, and olfactory parts of the nose. Inhaled substances can generate irritating and toxic effects on various parts. The pathological diagnosis results from the preclinical safety evaluation of inhaled drugs are considered the gold standard for judging drug toxicology. The nose is composed of many bone components, and decalcification is required for the sectioning of hard bone tissues. Therefore, an efficient and high-quality decalcification method is the crucial pathological technique for evaluating inhaled drugs. METHODS In this study, 10% ethylenediamine tetraacetic acid(EDTA), 10% formic acid, and 5% nitric acid decalcification solutions were selected. Besides, the decalcification time and effect of these decalcification solutions for rat nasal tissues were compared and analyzed under static room temperature and microwave conditions. Moreover, the quality of pathological bone tissue sections prepared through different decalcification methods was comprehensively evaluated. RESULTS Compared with the decalcification method under normal temperature, the decalcification time under the treatment of KOS decreased significantly. The treatment with the EDTA decalcification solution had the longest decalcification time under normal temperature, while the treatment with the nitric acid decalcification solution had the shortest decalcification time under microwaves. During section evaluation, the EDTA decalcification solution had a higher quality score under normal temperature and microwaves, which indicated that the section quality was favorable. The nitric acid decalcification solution had a lower section quality score under microwaves, which indicated that the section quality was unfavorable. There was medium section quality for the formic acid decalcification solution under microwaves and normal temperature and for the nitric acid decalcification solution under normal temperature. The HE staining results suggested that there were incomplete nasal mucosa epithelia, fragmentation, and pink nasal bone tissues in the tissue sections treated by the nitric acid decalcification solution, presenting a peracid state. In the tissue sections treated by the formic acid decalcification solution and the EDTA decalcification solution, the nucleus of epithelial cells was blue-purple, the cytoplasm and interstitial components were pink, and the epithelial tissue structure of nasal mucosa was intact. The MASSON staining results suggested that in the tissue sections treated by the nitric acid decalcification solution, the whole section staining was red, the positive area was not obvious, and the epithelial cell differentiation was not prominent, with a fuzzy structure. In the tissue sections treated by the formic acid decalcification solution, the sections were slightly detached during staining, and slight cracks were observed in submucosa tissues. In the tissue sections treated by the EDTA decalcification solution, the structure of positive regions and epithelial mucosa regions was clear, and the nuclear and interstitial components were clearly distinguished. The immunohistochemical staining (Ki67) results suggested that in the tissue sections treated by the nitric acid decalcification solution, the staining of positive regions was uneven, and there were nonspecific negative reactions in some regions. In addition, local epithelial cells were unstained. In the tissue sections treated by the formic acid decalcification solution, the local regions were not clearly stained, and nonspecific negative and positive reactions appeared in some local regions. In the tissue sections treated by the EDTA decalcification solution, the positive regions were prominent, the boundaries between negative regions and positive ones were clear, and each region of the sections was stained evenly. CONCLUSION Among the three decalcification solutions in this study, the nitric acid decalcification solution had the shortest decalcification time while the poor section and staining quality. The decalcification time of nasal tissues through the EDTA decalcification solution combined with microwaves was significantly shorter than that through the EDTA decalcification solution at normal temperature. Furthermore, this decalcification method achieved favorable section and staining quality.

Intranasal administration has the advantages of quick onset, high bioavailability, potential delivery into brain, and non-invasive. However, the limitations of the complex nasal microenvironment, such as the mucosal barrier, ciliary movement, low pH mucous layer, and enzyme degradation, appear to be key challenges in nasal drug development. Although a large number of animal trials provide reference data for the development of nasal drugs, the species differences, high cost and long cycle make this approach more difficult to develop, especially in the high-throughput preclinical screening stage of new drugs. Therefore, it is critical to select a nasal model with good in vitro and in vivo correlation for preclinical drug research. Whether the targeting through the nasal into the brain or blood, the epithelial cell barrier directly determines the bioavailability and efficacy during the intranasal administration. Moreover, mucosal irritation is also one of the critical evaluations of the safety aspects during nasal drugs development, where cell model can be quite useful. Therefore, this review summarized the application of the in vitro nasal model based on nasal epithelial cells in the nasal drug development.

OBJECTIVE To analyze the current situation and characteristics of clinical trials of nasal spray registration in China in the past 10 years, and to discuss the future development trend of nasal spray drugs in China, taking into account the current situation of international research. METHODS By accessing the State Drug Administration's drug clinical trial registration and information disclosure platform(http://www.chinadrugtrials.org.cn/index.html), collected information on clinical trials of nasal spray drugs in China from the open registration date(November 1, 2012) to March 29, 2023, in terms of clinical trial status, analyzed the status and characteristics of clinical trials of nasal sprays in terms of clinical trial status, indications, geographical distribution and trial phases, and trial design types by Microsoft Office Excel. RESULTS A total of 80 clinical trials of nasal sprays were conducted in China, of which 24 (30.0%) were phase I, 15 (18.8%) were phase II, 13(16.3%) were phase III, 3(3.8%) were phase IV, 17(21.3%) were bioequivalence trials, and 8(10.0%) were other(pharmacokinetic/pharmacodynamic studies). The status of clinical trials included 13(16.3%) in progress(not yet enrolled), 7(8.8%) in progress (enrollment completed), 15(18.8%) in progress (enrollment in progress), 44(55.0%) completed, and 1(1.3%) voluntarily terminated. There were 56 phase I-IV clinical trials, including 41(73.2%) parallel group trials, 14(25.0%) crossover design trials, and 1(1.8%) single-arm trial. A total of 65(81.3%) were chemicals, 7(8.8%) were biologics and 8(10.0%) were traditional Chinese medicine/natural drugs. A total of 15 indications were identified, which included allergic rhinitis, sedation, dry eye, paroxysmal supraventricular tachycardia, etc. CONCLUSION The research and development of nasal sprays in China is still at an early stage, but it keeps up with the international and independent innovation ability is being strengthened, and more new clinical research directions and strategies of nasal sprays should be explored in the future to help the development of nasal sprays and meet the needs of more patients.