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OBJECTIVE To study the pharmacokinetics of Esketamine hydrochloride nasal spray in rats and ciliary toxicity to maxillary mucosa of bullfrog. METHODS The plasma concentration of esketamine hydrochloride in rats was determined by LC-MS/ MS after intravenous injection of esketamine hydrochloride solution and nasal administration of esketamine hydrochloride； the pharmacokinetic parameters were calculated by using Phoenix WinNonlin 8.1.0 software. Using the maxillary mucosa of isolated bullfrog as a model， the morphological changes of maxillary mucosa were investigated， and the duration and recovery of ciliary oscillation were recorded after nasal administration of esketamine hydrochloride. RESULTS The peak of blood concentration occurred 2 min after nasal administration of esketamine hydrochloride； cmax was （814.58±418.80） ng/mL， AUC0－∞ was （203.75± 92.76） ng·h/mL， and the absolute bioavailability was 60.68%. After nasal administration of esketamine hydrochloride， it was observed that the cilia of bullfrog were arranged neatly， the edges were clear， the cilia tissue structure was complete and the cilia moved actively. The cilia movement time was （178.17±13.30） min for the first time， and after the cilia moved again， the ciliary movement time measured again was （24.50±9.19）min with a relative movement percentage of 53.56%. CONCLUSIONS Esketamine hydrochloride nasal spray has a rapid onset of action， high bioavailability， and low ciliary toxicity.
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Objective To prepare asenapine maleate microemulsion gel(ASPM-Emulgel)and evaluate its brain targeting by nasal administration.Methods The prescription composition and dosage of asenapine maleate microemulsion(ASPM-Emul)was determined according to the equilibrium solubility of asenapine maleate(ASPM)in different oils,emulsifiers,co-emulsifiers and the compatibility results of excipients,and ASPM-Emul was prepared into a gel with carbomer 940 as the gel matrix.The particle size distribution and microstructure of ASPM-Emul were investigated.The in vitro release rates and permeability in sheep nasal mucosa of ASPM-Emul and ASPM Emulgel were compared using the Franz diffusion cell method.The nasal ciliary toxicity of ASPM-Emulgel was investigated using the in vivo toad maxillary model method.Brain targeting of ASPM-Emulgel by nasal administration in rats was evaluated.Results According to the results of equilibrium solubility and compatibility,Maisine 35-1,Tween 80 and Transcutol P were selected as the oil phase,emulsifier and co-emulsifier of ASPM-Emul,respectively,with the ratio of 4 ∶ 4 ∶ 2.ASPM-Emul was a light blue semi-transparent microemulsion with a particle size of(73.6±7.4)nm.The microemulsion was regularly spherical and uniformly dispersed under transmission electron microscopy.The results of in vitro release and permeation showed that the release rate of ASPM-Emul was relatively fast,while the release rate of ASPM-Emulgel remained stable.However,the permeability of the two formulations in sheep nasal mucosa was basically similar.ASPM-Emul and ASPM-Emulgel showed no significant toxicity to nasal cilia of toad.Compared with the tail vein ASPM group,the drug content in the brain of ASPM-Emul and ASPM-Emulgel significantly increased after nasal administration,both exhibiting significant brain targeting,and the drug targeting efficiency(DTE)of ASPM-Emulgel was higher.Conclusion The preparation of ASPM into microemulsion gel can significantly improve the brain targeting after nasal administration,and is expected to improve the clinical therapeutic effect of ASPM.
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Abstract Objective This study was designed to investigate the effect of butorphanol-soaked nasal packing on analgesia and sleep quality in patients undergoing bilateral endoscopic nasal surgery. Methods Sixty-six patients were enrolled and randomly allocated into three groups: group B1 (butorphanol 0.03 mg/kg), group B2 (butorphanol 0.04 mg/kg) and group N (control group). The primary outcome was postoperative pain scores evaluated by a Visual Analogue Scale (VAS) at 2 h (T1), 8 h (T2), 24 h (T3) and 48 h (T4) after surgery. Secondary outcome was postoperative sleep quality measured using Subjective Sleep Quality Value (SSQV). Results Postoperative VAS scores of butorphanol groups were significantly lower than the control group at T2, T3 and T4. VAS scores at each time point did not differ between groups B1 and B2. On the first and second nights after surgery, SSQV was higher in butorphanol groups than in the control group. There were no significant differences in SSQV1 and SSQV2 between group B1 and group B2. The incidence of respiratory depression, dizziness, agitation and rescue analgesic use did not show difference among three groups. Conclusions Butorphanol-soaked nasal packing can reduce pain and improve sleep quality after bilateral endoscopic nasal surgery without increasing adverse effects. A concentration of 0.03 mg/kg may be appropriate for clinical application. Level of Evidence Level 1B.
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Nasal preparations have unique advantages in drug delivery and are widely used in the treatment of local and systemic diseases. Nasal administration of traditional Chinese medicine （TCM） has a long history in China. In recent years， nasal preparations of TCM have attracted wide attention. Based on the information about nasal preparations of TCM from the database of National Medical Products Administration （NMPA）， Yaozh.com and China National Knowledge Internet （CNKI） in the recent 30 years， the formulation， the listed products， commonly used TCM， pharmaceutical excipients， clinical application and safety research of modern nasal preparations of TCM were summarized and expounded. Focusing on many problems in the development of modern nasal preparations of TCM， such as inaccurate dosage of some products， incomplete quality standard system of pharmaceutical excipients， imperfect safety evaluation， lack of research and development of nasal drug delivery devices and so on， the possible solutions and prospects were put forward from the aspects of optimizing the extraction and separation process of TCM， the quality control and application method of pharmaceutical excipients， the development of new dosage forms， the safety evaluation of nasal administration of TCM， and the design and development of nasal administration devices. The aim is to provide ideas for the development of nasal preparations of TCM and provide scientific basis for its sustainable utilization.
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Abstract Nociceptive and inflammatory orofacial pain is highly prevalent in the population, which justifies the search for safer analgesics. There is increasing evidence of the analgesic and anxiolytic potential of Lavandula angustifolia essential oil (LAV EO), which may represent, when administered through inhalation, may represent a safer alternative for pain treatment. Objective to evaluate whether LAV EO has antinociceptive effect in the formalin test, and anti-hyperalgesic and anxiolytic-like effects in rats subjected to a model of orofacial postoperative pain. Methodology Female Wistar rats were exposed to LAV EO (5%) by inhalation for 30 minutes. After exposure, animals were injected with formalin (2.5%, 50 μL) or saline into the hind paw or upper lip and the number of flinches or facial grooming time, respectively, were evaluated. Likewise, on day 3 after intraoral mucosa incision, the animals were exposed to LAV EO and facial mechanical, and heat hyperalgesia were assessed. The influence of LAV EO inhalation on anxiety-like behavior was assessed in operated rats by testing them on the open field (OF) and elevated plus maze (EPM). Results LAV EO reduced the phase II of the paw formalin test and both phases of the orofacial formalin test. On day three post-incision, LAV EO reduced heat and mechanical hyperalgesia, from 30 minutes up to three hours, and reduced the anxiety-like behavior in operated rats without causing locomotor deficit. Conclusion LAV EO inhalation results in antinociceptive and anxiolytic-like effects in orofacial pain models, which encourages further studies on LAV EO indications and effectiveness on orofacial pain conditions.
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Coronavirus disease-2019 (COVID-19) belongs to the epidemic diseases of traditional Chinese medicine (TCM), which is infected by the air with disease and the initial stage of the disease is in upper energizer. TCM holds that the nose is the orifice of the lung and the gateway of the breath. WU Shang-xian, the famous external doctor in Qing dynasty, discussed in Liyue Pianwen that "for the disease in upper energizer, the most effective method is to use the medicine powder via nasal administration and sneeze to disperse". For thousands of years, ancient Chinese medical practitioners had explored and developed the TCM nasal administration method in the struggle against epidemics. Qingkailing is the basic formula for heat-clearing and detoxifying, and researches have clarified its therapeutic effect on upper respiratory tract infections. Therefore, based on TCM nasal administration, this article took Qingkailing as an example to study the feasibility of its nasal preparations for the treatment of COVID-19. On the one hand, it is helpful for the rapid development of Qingkailing nasal preparations for COVID-19. On the other hand, it can broaden the new thinking of TCM in treating epidemic diseases, and give full play to the advantages of TCM in treating epidemic diseases.
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In order to better evaluate the transport effect of nanoparticles through the nasal mucosa, an nasal cavity-mimic model was designed based on M cells. The differentiation of M cells was induced by co-culture of Calu-3 and Raji cells in invert model. The ZO-1 protein staining and the transport of fluorescein sodium and dexamethasone showed that the inverted co-culture model formed a dense monolayer and possessed the transport ability. The differentiation of M cells was observed by up-regulated expression of Sialyl Lewis A antigen (SLAA) and integrin 1, and down-regulated activity of alkaline phosphatase. After targeting M cells with iRGD peptide (cRGDKGPDC), the transport of nanoparticles increased. , the co-administration of iRGD could result in the increase of nanoparticles transported to the brain through the nasal cavity after intranasal administration. In the evaluation of immune effect , the nasal administration of OVA-PLGA/iRGD led to more release of IgG, IFN-, IL-2 and secretory IgA (sIgA) compared with OVA@PLGA group. Collectively, the study constructed M cell model, and proved the enhanced effect of targeting towards M cell with iRGD on improving nasal immunity.
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The traditional systemic treatment of post-traumatic stress disorder (PTSD) requires a long time period for an effect and has obvious side effects. In this study, tetrandrine temperature-sensitive gel (TTG) was prepared for treatment of PTSD in mice by nasal administration. TTG was prepared with poloxamer as matrix, the gelation temperature was suitable (<32 ℃) and the gelation time was short (1.32 min). Rheology experiments demonstrated that TTG has temperature sensitivity. In vivo imaging system of small animals proved that TTG nasal cavity retention time was so long. The cilia toxic test of toad showed that the formulation was safe. Animal experiments were approved by the Ethics Committee of Beijing Institute of Radiation Medicine, Academy of Military Medical Sciences and the experiments were conducted in accordance with relevant guidelines and regulations. The mice were randomly assigned into healthy group, model group and TTG group. The PTSD model of mice was established by single prolonged stress (SPS) and foot-shock method to generate anxiety and fear behavior. On the day 0 of TTG administration, SPS model mice were evaluated by the elevated plus maze (EPM). Percentages of open arm entries number (OE), latency of open arm entries (OL) and the residence time of open arm entries (OT) all indicated that the SPS model was successfully established. On the 7th day of TTG administration, TTG increased the OE and OT, decreased the OL of SPS mice. The feard behavior of mice in the foot-shock model was tested using conditioned fear box, 7 days of TTG treatment can reduce the freezing time of the mice obviously. The pathological changes of hippocampus, prefrontal cortex and amygdala were observed by H&E histological sections and c-fos immunohistochemical expression. The main influenced areas of PTSD were revealed to be the CA1 of hippocampus, prefrontal cortex and amygdala. All of the above indicated that TTG is a convenient, safe and effective drug for PTSD treatment, and will provide a new choice for clinical management of PTSD.
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Objective To study the metabolic process of ginkgolides in rats with cerebral ischemic injury based on pharmacokinetic- pharmacodynamics (PK-PD) binding model. Methods The middle cerebral artery occlusion (MCAO) model was established by the suture method. After reperfusion, rats were randomly assigned to nasal administration, ig administration, and iv administration group.The orbital blood was taken at different time points of 0.25, 0.33, 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 4.0, 6.0, 9.0, and 12.0 h after the administration of the ginkgolides solution. The drug-time curve of ginkgolide B in plasma were drawn according to the concentration measured by LC-MS. The time-effect curve of superoxide dismutase (SOD) and malondialdehyde (MDA) were drawn based on the value measured by the kit. The pharmacokinetic parameters were calculated by DAS 2.0 software to fit the PK-PD binding model. Results The t1/2 of ginkgolide B of the rats in the administration group was smaller than that in the MCAO model group. The area under the curve (AUC) of nasal administration was significantly higher than intragastric administration and intravenous administration. Conclusion Ginkgolide B has a good protective and mitigating effect on ischemic stroke. The pharmacokinetics of nasal administration is better than iv and ig administration, which can provide reference for the development of nasal administration of ginkgolide B.
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Objective To explore the protective effect of erythropoietin(EPO) administrated by intranasal on cerebral ischemia reperfusion in rats with acute cerebral infarction reperfusion.Methods Total of 100 SD rats were divided into model control group,sham operation group,intraperitoneal administration group ([PEPO group),nasal saline group (INNS group) group,and nasal drug delivery group (INEPO group) with 20 in each group.The middle cerebral artery occlusion model of rat was established by thread embolism method and the NSS method was used to evaluate the neural behavior of rats.The expression of EPO in peripheral blood,cerebrospinal fluid and brain regions of rats were detected by Elisa.The vascular endothelial growth factor(VEGF) in brain was detected by immunofluorescence and then the density of newborn blood vessels in the brain was measured.Results Fifteen days after the operation,the NSS score of INEPO group(3.80± 1.61) was significantly lower than that of IPEPO group (11.53±2.11),and the difference was statistically significant(P＜0.01).And the levels of EPO in blood,cerebrospinal fluid and different brain regions of rats in INEPO group were higher than that of INNS group(all P＜0.01).Compared with IPE-PO group,the level of EPO cerebrospinal fluid and different brain regions of rats in INEPO group increased obviously,the difference was statistically significant (all P＜0.01),and the EPO concentration of the olfactory bulb was the most obvious (INEPO group:(1 456.90 ± 128.22) pg/ml,IPEPO group:(426.11 ± 36.68)pg/ml,P＜0.01).Seventy-two hours after operation,the expression of CD31 in ischemic penumbra of rats of model control group (18.21 ± 3.45),INNS group (18.54 ± 2.58),IPEPO group (27.01 ± 2.13) and INEPO group(35.52±2.79)was increased compared with sham operation group (5.14± 1.28),and the difference was statistically significant (all P＜0.05).The expression of CD31 in IPEPO group and INEPO group was significantly higher than that in INNS group (P＜0.05).In INEPO group,the expression of CD31 increased significantly compared with that of IPEPO group (P＜0.05).Conclusion Nasal administration of EPO can effectively improve the neurological function of rats with ischemia-reperfusion,and increase the expression of CD31 in the brain tissue of rats.The effect of nasal administration is better than that of intraperitoneal administration.
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OBJECTIVE:To study the pharmacokinetics and brain targeting of Toutongning nasal spray in rats in vivo. METH-ODS:84 SD rats were divided into nasal administration group and vein administration group,42 in each group,with dose of 1.2 mL/kg. 5 mL sample blood was taken in abdominal aorta after 5,10,15,30,60,90,120 min of administration,and brain tissue was taken (6 rats in each time point). HPLC-MS was adopted to determine the concentration of prim-o-glucosylcimifugin and 5-O-methylvisammioside in plasma and brain tissue of rats in each group,and DAS 2.0 software was used to calculate the pharma-cokinetic parameters and brain targeting indexes. RESULTS:The cmax of prim-o-glucosylcimifugin and 5-O-methylvisammioside in plasma of rats in nasal administration group were(0.2024±0.0158),(0.3738±0.0857)μg/mL;tmax were(10.0000±0.0000) min;and AUC0-∞ were (16.5429 ± 2.1103),(27.4527 ± 5.5721)μg·h/mL,respectively. The cmax of prim-o-glucosylcimifugin and 5-O-methylvisammioside in brain tissue of rats were (0.1802 ± 0.0384),(0.3204 ± 0.0277)μg/g;tmax were (10.0000 ± 0.0000)min;and AUC0-∞ were(17.1053±2.4329),(24.5416±3.7534)μg·h/g,respectively. The cmax of prim-o-glucosylcimi-fugin and 5-O-methylvisammioside in plasma of rats in vein administration group were (0.3002 ± 0.0161),(0.5267 ± 0.0441)μg/mL;tmax were(10.0000±0.0000)min;and AUC0-∞ were(28.0105±4.1128),(60.2941±11.2902)μg·h/mL,respective-ly. The cmax of prim-o-glucosylcimifugin and 5-O-methylvisammioside in brain tissue of rats were(0.1498±0.0315),(0.1998± 0.0401)μg/g;tmax were(15.0000±0.0000)min;and AUC0-∞were(22.6434±2.8831),(36.7218±14.8856)μg·h/g,respec-tively. The brain targeting indexes of prim-o-glucosylcimifugin and 5-O-methylvisammioside were 2.3870 and 2.1761,respective-ly. CONCLUSIONS:After nasal administration of Toutongning nasal spray,parts of drugs can directly transport to the brian by na-sal absorption. It is scientific and reasonable to make nasal spray.
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@#Reduning nasal sprays were prepared from Reduning injection to explore the pharmacokinetics of its nasal administration in rabbits. Healthy rabbits were divided into three groups: blank group, nasal administration group, and intravenous injection group. Plasma samples were pretreated using acetonitrite to precipitate proteins. High-performance liquid chromatography(HPLC)was performed for the detection of chlorogenic acid. The results showed that chlorogenic acid was detected in the plasma samples of nasal administration group with the highest concentration occurring in 2-5 min after administration, which indicated that Reduning nasal sprays could be successfully absorbed from nasal mucosa and could rapidly metabolize in blood. Compared with intravenous injection group, nasal administration group had lower concentration of active ingredients, revealing that the transdermal absorption rate of Reduning nasal sprays requires further improvement.
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Objective: To optimize the preparation technology of geniposide ethosome spray (GES) and to evaluate the regulation of its nasal mucosa permeability in vitro and nasal ciliotoxicity. Methods: Geniposide ethosomes were prepared by ethanol injection method. An central composite design-response surface method was used to optimize the related factors and technical parameters in the preparation of geniposide ethosomes with entrapment efficiency as evaluation index. Their physical properties were evaluated by the transmission electron microscope and photon correlation spectrometer. The isolated pig nasal mucosa was used to investigate the regulation of GES nasal mucosa permeability in vitro. The accumulated permeation amounts of geniposide aqueous solution, geniposide liposomes, and geniposide ethosomes were compared. In situ toad palate model was established to evaluate the effects of geniposide ethosomes on persistent vibration duration of toad palate cilia, so as to evaluate the cililary toxicity. Results: The average encapsulation percentage, particle size, drug loading, and Zeta potential of geniposide ethosomes were (65.80 ± 2.53)%, (173.40 ± 71.02) nm, (5.25 ± 0.15)%, and (-42.50 ± 8.27) mV, respectively. The accumulative permeation amount of geniposide ethosomes in 300 min was 23.39 μg/cm2, which was about 2.17 times of liposomes and 11.03 times of geniposide aqueous solution. Furthermore, the GES showed less mucociliary toxicity. Conclusion: The optimized formulation and preparation technology of geniposide ethosomes are rational. GES could significantly increase the mucosa permeability of geniposide and could be used for nasal administration.
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OBJECTIVE: To investigate the distribution of baicalin-phospholipid solution after unilateral nasal administration in rat blood and left olfactory, right olfactory bulb, left brain, right brain, and the cerebellum, and to evaluate its brain targeting effect. METHODS: After intravenous and unilateral nasal administration of baicalin-phospholipid solution, the concentrations of baicalin-phospholipid in the plasma and the brain tissues of the rats were determined by HPLC. RESULTS: After administration by left nasal cavity, the drug concentration was maximum in the left olfactory bulb, followed by the right olfactory bulb, left brain, right brain, and finally the cerebellum. The olfactory propotion was 100%, 100%, 75.06%, 62.39% and 65.11%, respectively. CONCLUSION: Baicalin can distribute into brain by "nose-brain" transport pathway after intranasal administration of baicalin-phospholipid. Copyright 2012 by the Chinese Pharmaceutical Association.
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[Objective] To investigate the possibility of [poly(lactic-co-glycolic acid) ,PLGA] nanoparticles (NP) as a new kind of protein drug carrier for nasal administration. [Method] CNT-PLGA-NP was prepared by double emulsification solvent evaporation. Its morphology was examined by transmission electronmicroscope (TEM). In the use of photon correlation spectroscopy(PCS) and laser Doppler anemometry(LDA),its Zeta potential and mean particle size were estimated .Also, the entrapment efficiency of CNT-PLGA-NP and its pharmacokinetics in rats through nasal administration were studied. [Result] The Zeta potential, mean particle size, entrapment efficiency of CNT-PLGA-NP were-13.4mV, 320.20nm and 45% respectively .Its vitro CNT release from CNT-PLGA-NP appeared to consisting of two components with initial rapid release followed by a exponential stage.The AUC and t1/2(?) of CNT, CNT-PLGA-Np and CNT-PLGA-NP(B+T)were 1.14, 8.37, 7.12?g?h/mL and 20.06, 44.14, 34.82h respectively. [Conclusion]PLGA-NP might be a potential new drug carrier for CNT.Polysorbate 80 and borneol might be good absorption enhancers.