Development of a physiologically relevant dripping analytical method using simulated nasal mucus for nasal spray formulation analysis

Current methods for nasal spray formulations have been elementary evaluating the dripping characteristics of a formulation and have not assessed the behavior of the nasal formulation in the presence of varying types of mucus depending on the indication or diseased state. This research investigated the effects of nasal mucus on the dripping behavior of nasal formulations and focused on developing an improved in vitro analytical test method that is more physiologically relevant in characterizing nasal formulation dripping behavior. Method development was performed using simulated nasal mucus preparations for both healthy and diseased states as coatings for the dripping experiment representing a wide range of viscosity. Factors evaluated during development of this in vitro test method included amount of mucus, application of mucus, drying times, and compatibility of the mucus on a C18 Thin Layer Chromatography(TLC) substrate. The dripping behavior of nasal formulations containing a range of 1%Avicel to 3.5% Avicel was assessed by actuating the nasal spray on a perpendicular TLC plate coated with either healthy or diseased simulated nasal mucus. After actuation of the nasal spray, the dripping of the formulation on the coated TLC plate was measured after the plate was repositioned vertically. The method that was developed generated reproducible results on the dripping behavior of nasal formulations and provided critical information about the compatibility of the formulation with the nasal mucus for different diseased states, aiding in nasal spray formulation development and physical characterization of the nasal spray.

Septoplasty and Decongestant Improve Distribution of Nasal Spray

This study prospectively examined the intranasal distribution of nasal spray after nasal septal correction and decongestant administration. A cohort of 20 patients was assessed for the distribution of nasal spray before and after nasal septum surgery. Sprays were dyed and administered one puff per nostril when patients hold their head up in an upright position. Before and after decongestant admini-stration, the intranasal distribution was semi-quantitatively determined by nasal endoscopy. The results showed that the dyed drug was preferentially sprayed onto the nasal vestibule, the head of the inferior turbinate, the anterior part of septum and nasal floor. As far as the anterior-inferior segment of the nasal cavity was concerned, the distribution was found to be influenced neither by the decongestant nor by the surgery （P〉0.05）. However, both the decongestant and surgery expanded the distribution to the anatomical structures in the superior and posterior nasal cavity such as olfactory fissure, middle turbinate head and middle nasal meatus. No distribution was observed in the sphenoethmoidal recess, posterior septum, tail of inferior turbinate and nasopharynx. It was concluded that nasal septum surgery and decongestant administration significantly improves nasal spray distribution in the nasal cavity.

Quantitative analysis of glutamate compounds in the swine brain following central analgesics nasal spray using proton magnetic resonance spectroscopy and linear combination model

BACKGROUND： In localized brain proton magnetic resonance spectroscopy （^1H-MRS）, metabolite levels are often expressed as ratios, rather than absolute concentrations. Frequently, the denominator is creatine, which is assumed to be stable in normal, as well as many pathological, states. However, in vivo creatine levels do not remain constant. Therefore, absolute metabolite measurements, which provide the precise concentrations of certain chemical compounds, are superior to metabolite ratios for determining pathological and evolutional changes. OBJECTIVE： To investigate the feasibility of quantification analysis of brain metabolite changes caused by central analgesics nasal spray using the ^1H-MRS and linear combination model （LCModel） methods. DESIGN, TIME AND SETTING： This neuroimaging, observational, animal study was performed at the Laboratory of the Department of Medical Imaging, Second Affiliated Hospital, Medical College, Shantou University, China from July to December 2007. MATERIALS： Butorphanol tartrate nasal spray, as a mixed agonist-antagonist opioid analgesic, was purchased from Shanghai Hengrui Pharmacy, China. A General Electric Signa 1.5T System （General Electric Medical Systems, Milwaukee, WI, USA） and LCModel software （Stephen Provencher, Oakville, Ontario, Canada） were used in this study. METHODS： MRS images were acquired in ten healthy swine aged 2 weeks using single-voxel point-resolved spectroscopic sequence. A region of interest （2 cm × 2 cm × 2 cm） was placed in the image centers of maximum brain parenchyma. Repeated MRS scanning was performed 15-20 minutes after intranasal administration of 1 mg of butorphanol tartrate. Three settings of repetition time/echo time were selected before and after nasal spray administration 3 000 ms/30 ms,1 500 ms/30 ms, and 3 000 ms/50 ms. Metabolite concentrations were estimated by LCModel software. MAIN OUTCOME MEASURES： ^1H-MRS spectra was obtained using various repetition time/echo time settings. Concentrations of glutamate compounds （glutamate ＋ glutamine）, N-acetyl aspartate, and choline were detected in swine brain prior to and following nasal spray treatment. RESULTS： The glutamate compounds curve was consistent with original spectra, when a repetition time/echo time of 3 000 ms/30 ms was adopted. Concentrations of glutamate compounds, N-acetyl aspartate, and choline decreased following administration. The most significant reduction was observed in glutamate compound concentrations from （9.28 ± 0.54） mmol/kg to （7.28 ± 0.54） mmol/kg （P 〈 0.05）. CONCLUSION： ^1H-MRS and LCModel software were effectively utilized to quantitatively analyze and measure brain metabolites. Glutamate compounds might be an important neurotransmitter in central analgesia.

Intranasal Delivery of Two Benzodiazepines, Midazolam and Diazepam, by a Microemulsion System

Nasal application of benzodiazepines might be an alternative to intravenous administration in acute clinical situations such as seizures emergencies. However, irritation and pain as well as symptoms like teary eyes, dizziness, discomfort, nasal drainage and bad taste usually accompany subject received midazolam and diazepam via the nasal route. The purpose of this study was to evaluate the use of a new alcohol-free microemulsion system as a carrier for diazepam or midazolam given intranasally. Midazolam (base) or diazepam was solubilized in the microemulsion to obtain a high drug concentration of 25 mg/g (2.5% by weight), to provide 2.5 mg drug in 100 μl spray (d ≈ 1.00 g/ml). The nasal absorption of both drugs from the same microemulsion formulation (containing 20% aqueous phase) was found to be fairly rapid after administration of 0.4 mg/kg to rabbits. The absolute bioavailability of diazepam after intranasal administration using this formulation was 33.45% ± 12.36% and the tmax was 18.33 ± 23.09 min, which was twice longer than the tmax obtained after midazolam administration, 9.25 ± 6.75 min. The pharmacokinetic parameters of midazolam in W/O (20% water) microemulsion and their comparison with midazolam in O/W (50% water) microemulsion have shown that both formulations resulted in a relatively short time to reach the peak plasma level (tmax), that is, 9.25 ± 6.75 min and 6.75 ± 5.67 min, respectively. However, the peak plasma levels (Cmax) and the absolute bioavailability (FA) of midazolam were significantly higher after administration of the W/O formulation than those obtained after application of O/W formulation, i.e., 46.62 ± 17.38 μg/ml vs. 15.44 ± 4.00 μg/ml, and 35.19% ± 11.83% vs. 19.83% ± 16.32%, respectively. Our results suggest that the new microemulsion system may be useful for getting rapid-onset of midazolam and diazepam following intranasal administration, resulting in reasonable peak plasma levels and bioavailability, but most importantly, providing a high measure of tolerability and comfort.

曲安奈德鼻喷雾剂联合桉柠蒎肠溶胶囊治疗分泌性中耳炎

分泌性中耳炎（secretory otitis media,SOM）主要以传导性聋及鼓室积液为主要特征的中耳炎症,儿童和成人发生率均较高,治疗方法 主要为药物和鼓膜穿刺、切开置管术等,如何尽量减少有创治疗一直是临床医师探讨的问题。本研究用曲安奈德鼻喷雾剂（triamcinolone acetonide nasal spray,TANS）喷鼻加桉柠蒎肠溶胶囊（eucalyptol,limonene and pinene enteric soft capsules,ELPESC）治疗SOM取得了较好的临床治疗效果,

Effects of Desloratadine Citrate Disodium combined with Budesonide suspension on serum IgE, EOS and inflammatory factors in patients with CRS after endoscopic sinus surgery

Objective: To observe the clinical application of Desloratadine Citrate Disodium combined with Budesonide suspension in patients with chronic rhinosinusitis CRS after endoscopic sinus surgery, and analyze the change of serum immunoglobulin E (IgE), eosinophils (EOS) and inflammatory factors level in patients. Method: A total of 90 cases of patients with CRS were randomly divided into control group (n=45) and observation group (n=45) according to the lottery method. Both groups were treated with endoscopic sinus surgery. On the basis of this, control group was given Budesonide suspension and observation group was treated with Desloratadine Citrate Disodium combined with Budesonide suspension. The change of serum IgE, EOS and inflammatory factors were measured before and after operation in all subjects. Results: There was no significant difference in IgE and EOS levels between control group and observation group before treatment. After treatment, the levels of serum IgE and EOS in the two groups were significantly lower than those before treatment. Moreover, after treatment, observation group was lower than control group, and the difference was significant. There was no significant difference in inflammatory factors level between control group and observation group before treatment. After treatment, the levels of serum IL-6, IL-8, TNF-α and hs-CRP were significantly lower than those before treatment. After treatment, observation group was lower than the control group in the same period, the difference was significant. Conclusion:Combined Desloratadine Citrate Disodium treatment for CRS patients on the basis of endoscopic sinus surgery and Budesonide Nasal Spray treatment, it can more effectively reduce serum IgE and EOS levels, decrease the inflammatory response. Therefore it was a potential effective treatment for patients with CRS.

Preliminary Clinical Observation on Treatment of Chronic Simple and Hypertrophic Rhinitis with Rhinitis Spray

Objective: To investigate the clinical effect of Rhinitis Spray (RS) in treating chronic simple and hypertrophic rhinitis.Methods: Eighty patients with chronic rhinitis were divided into three groups and treated with RS, ephedrine and normal saline respectively.Results: The short-term effective rate in the three groups was 89.3%, 66.7% and 8.0% respectively. RS was effective in alleviating symptoms, increasing IgG level in nasal discharge, improving ventilatory function of nasal cavity and transfer function of nasal muosa cilia obviously.Conclusion: The therapeutic effect of RS in treating chronic rhinitis is satisfactory.