Assessment of Patient Characteristics Influencing the Analgesic Effects of Ibuprofen Gargle After Mandibular Third Molar Extractions.

Introduction In our previous work, we investigated the analgesic effects of ibuprofen gargle after mandibular third molar extractions. However, a subsequent detailed review of individual patient data revealed variations in postoperative pain reduction among patients. Consequently, the present study was designed to conduct post-hoc subanalyses that identified factors contributing to variation in the analgesic response to ibuprofen gargle after third molar extractions. Materials and methods This study involved thirty-five Japanese patients from a prior randomized, double-blind, placebo-controlled, crossover study, which focused on the analgesic effects of ibuprofen gargle after mandibular third molar extractions. Participants were categorized as responders (n = 13) and non-responders (n = 22) based on the within-subject difference (ibuprofen-placebo, IP) of visual analog scale (VAS) changes. Baseline characteristics were compared, along with variables, such as age, sex, the reason for extraction, extraction site, Pell Gregory (space and depth) classification, Winter's classification, surgeon's experience, and surgery time. Baseline characteristics predicting responder status were examined using multivariate logistic regression. Results In the univariate analysis, variables such as age, sex, and baseline VAS scores with p-values <0.2 were evaluated using a stepwise approach. This analysis identified age (per -10 years) with an odds ratio of 4.163 (95% confidence interval (CI): 1.170-31.952, p = 0.0233) and sex (female) with an odds ratio of 9.977 (95% CI: 1.336-208.256, p = 0.0213) as significant predictors of responder status. Conclusions In young and female patients, ibuprofen gargle decreased postoperative pain after mandibular third molar extractions.

Changes in Tablet Color Due to Light Irradiation: Photodegradation of the Coating Polymer, Hypromellose, by Titanium Dioxide.

The color of the tablets and capsules produced by pharmaceutical companies is important from the perspectives of product branding and counterfeiting. According to some studies, light can change tablet color during storage. In this study, tablets comprising amlodipine besylate (AB), a well-known light-sensitive drug, were coated with commonly used coating materials and exposed to light. Compared to the tablets that were not exposed to light, the color of those exposed to light changed over time. In fact, a faster and more pronounced color change was observed in the tablets exposed to light; however, the amount of AB did not decrease significantly in these tablets. The coating materials and their amounts were varied to clarify the materials involved in the color change. Based on the results, titanium dioxide and hypromellose may be involved in the color change process. As titanium dioxide is a photocatalyst, it may induce or promote chemical changes in hypromellose upon light irradiation. Overall, care should be exercised during selection of the coating polymer because titanium dioxide may promote photodegradation of the coatings while protecting the tablet's active ingredient from light.

Investigating the efficacy of nasal administration for delivering magnetic nanoparticles into the brain for magnetic particle imaging.

This study explored the effectiveness of nasal administration in delivering magnetic nanoparticles into the brain for magnetic particle imaging of target regions. Successful delivery of iron oxide nanoparticles, which serve as contrast agents, to specific sites within the brain is crucial for achieving magnetic particle imaging. Nasal administration has gained attention as a method to bypass the blood-brain barrier and directly deliver therapeutics to the brain. In this study, we investigated surface modification techniques for administering magnetic nanoparticles into the nasal cavity, and provided experimental validation through in vivo studies. By compositing magnetic nanoparticles with gold nanoparticles, we enabled additional surface modification via AuS bonds without compromising their magnetic properties. The migration of the designed PEGylated magnetic nanoparticles into the brain following nasal administration was confirmed by magnetization measurements. Furthermore, we demonstrated the accumulation of these nanoparticles at specific target sites using probe molecules immobilized on the PEG terminus. Thus, the efficacy of delivering magnetic nanoparticles to the brain via nasal administration was demonstrated in this study. The findings of this research are expected to contribute significantly to the realization of magnetic particle imaging of target regions within the brain.

[Evaluation of Photostability of Small Molecular Compounds with Solid-state UV Spectra].

It is crucial to evaluate the photostability of drugs. However, it requires a longer period of time to evaluate the photodegradation of compounds because extended light exposure to the compound is required to detect photodegradation products with the help of the commonly utilized technique of chromatography. Therefore, a simple and easy approach to estimate the photostability of the compound is required particularly for the initial screening of the drug candidates. It was reported in our previous manuscript that, focusing on ultraviolet-visible (UV/vis) spectrometry, the area under the spectrum curve in the ultraviolet-A (UVA) range (AUSCUVA) are closely related to the photodegradation of indomethacin polymorphs. In this study, the solid-state UV/vis absorption spectra of compound A polymorphs, indomethacin complexes and some small molecule compounds were determined and analyzed to check the applicability of this method. AUSCUVA are closely related to the photodegradation of compound A polymorphs as well as indomethacin. On the contrary, no close relation was observed between AUSCUVA of indomethacin complexes and their photodegradation. Additionally, the result indicated that the differences in their solid-state UV/vis absorption spectra were observed between photosensitive and photostable compounds. Photosensitive compounds show absorption in UVA range, while photostable compounds exhibit less absorption. In conclusion, the solid-state UV/vis absorption spectra of small molecular compounds might provide the key information on the photosensitivity.

Phosphorylated Serine-Modified Polyamidoamine Dendrimer as an Osteoid Surface-Targeting Drug Carrier.

The aim of this study was to develop a polyethylene glycol (PEG)-conjugated third-generation polyamidoamine dendrimer (PAMAM) with phosphorylated serine as an osteoid surface-targeting drug carrier for the treatment of bone diseases. We conjugated PAMAM backbones to l-serine and obtained Ser-PAMAM. Then, phosphoric acid and PEG were covalently bound to the Ser-PAMAM to generate PEGylated phosphorylated Ser-PAMAM (PEG-phosSer-PAMAM). Using osteoblast-like cells (MC3T3-E1 cells) cultured in 3D collagen gels, we showed that phosSer-PAMAM adsorbed both the hydroxyapatite and type I collagen components of the bone matrix. Fourier transform infrared spectroscopy analysis indicated that the phosphoryl side chains of phosSer-PAMAM formed electrostatic interactions and hydrogen bonds with the anionic amino acid residues of type I collagen. Mice were intravenously injected with the foregoing molecules, and a tissue distribution study disclosed that the lower limb bone took up about twice as much 111In-labeled PEG-phosSer-PAMAM as 111In-labeled nonphosphorylated PEG-Ser-PAMAM or unmodified PAMAM. An intrabone distribution experiment showed that fluorescein isothiocyanate (FITC)-labeled PEG-phosSer-PAMAM accumulated on the osteoid surfaces, which is associated with bone pathogenesis such as skeletal dysplasias and osteoporosis to a far greater extent than nonphosphorylated PEG-Ser-PAMAM. Our findings indicated that PEG-phosSer-PAMAM is a promising carrier for efficient drug targeting to osteoid surfaces.

Topical Xerostomia Treatment with Hyaluronate Sheets Containing Pilocarpine.

Sjogren's syndrome and radiation therapy for head and neck cancers are often accompanied by xerostomia. Oral pilocarpine (PCP) to treat xerostomia produces systemic side effects, such as runny nose and lacrimation. To improve the therapeutic efficacy of PCP and reduce the aforementioned side effects, we developed a topical delivery system for PCP using freeze-dried sheets of hyaluronic acid (HA). The advantages of HA sheets over conventional oral formulations were examined through in vivo pharmacokinetic and pharmacodynamic studies after their application to oral tissues and salivary glands. The concentration of PCP in the submucosal tissue of the oral cavity was determined using the microdialysis (MD) method after buccal application of HA sheets containing PCP to hamsters. The concentration of PCP in the MD outflow was quite low after gastric administration, whereas the PCP concentration in plasma was high. In contrast, after buccal application of HA sheets containing PCP, the concentration of the drug in the MD outflow increased, despite the negligible concentration in plasma. These findings indicated that both enhancement of saliva secretion and the avoidance of systemic side effects could be achieved through buccal administration of PCP-loaded HA sheets. In addition, the pharmacodynamic study showed that when compared with intravenous and gastric administration, salivary application of HA sheets containing PCP resulted in similar volumes of saliva secretion and reduced lacrimal secretions. In conclusion, freeze-dried HA sheets allow for the development of a novel buccal delivery system with enhanced therapeutic efficacy and safety to treat xerostomia.

Simultaneous Determination of Active Pharmaceutical Ingredients and Water-Soluble Polymers: Analysis of Dissolution Profiles from Sustained-Release Formulations and Mechanisms Involved.

The dissolution behaviors of base excipients from sustained-release formulations have been investigated using various methodologies. However, the dissolution of polymers has not been fully evaluated because differences between formulations are still verified only by the release of active pharmaceutical ingredients (APIs). In our previous study, we proposed a quick and simultaneous analysis of dissolved APIs and water-soluble polymers by ultra HPLC using charged aerosol and photodiode array detectors. The purpose of this study was to verify whether the analysis system could be adapted to other water-soluble polymers. Dissolution tests were conducted using matrix model tablets prepared from three polymers and three APIs (propranolol, ranitidine, and cilostazol) with different solubilities. The dissolution profiles of the polymers and APIs were determined using the proposed analysis system and compared. The results clarified differences in the dissolution behaviors of the APIs and polymers. The polymers, especially hydroxypropyl cellulose, exhibited the dissolution properties characteristic of each model formulation. Propranolol and ranitidine showed the diffusion type, while cilostazol showed the erosion type release mechanism due to their different solubilities. The release of cilostazol was delayed in all models compared to the polymer, which may be due to the aggregation of cilostazol in the gel layer. This analytical method can be used to study the dissolution behavior (diffusion or erosion) of APIs from matrix tablets containing various polymers. This method will provide useful information on release control, which will make it easier and more efficient to design appropriate formulations and analyze the release mechanisms.

Quick and Simultaneous Analysis of Dissolved Active Pharmaceutical Ingredients and Formulation Excipients from the Dissolution Test Utilizing UHPLC and Charged Aerosol Detector.

The objective of the study is to develop a quick and simultaneous analysis system for the dissolution of the active pharmaceutical ingredient (API) and the formulation excipient in samples from the dissolution test by UHPLC using the charged aerosol and PDA detectors. The combination of two columns for size-exclusion chromatography (SEC) and the equipment of the charged aerosol detector allowed the quick determination of various water-soluble polymers. Three model sustained-release tablets, each containing a different API of different water solubility (propranolol (soluble), ranitidine (very soluble), and cilostazol (practically insoluble)), were prepared from polyethylene oxide (PEO) matrix to verify the applicability and utility of the analysis system. The dissolution of propranolol was the same as that of PEO, indicating that the diffusion rate of propranolol was consistent with the erosion rate of the PEO and that the dissolution of PRO was based on diffusion. Ranitidine was released faster than PEO, suggesting that ranitidine was diffused through the gel layer of PEO early upon contact with the dissolution medium and before PEO gel erosion. Cilostazol was released slower as compared to PEO, indicating that cilostazol dissolution was based on the polymer's erosion. These results suggested that the analysis system developed in this study is a precise and valid tool to study the dissolution behavior of both APIs and excipients. Optimization of the SEC column for the appropriate separation of APIs and excipients makes the analysis system more efficient and convenient to study the drug release mechanisms and to design formulations.

Direct Delivery of ANA-TA9, a Peptide Capable of Aß Hydrolysis, to the Brain by Intranasal Administration.

We have recently reported Catalytides (Catalytic peptides) JAL-TA9 (YKGSGFRMI) and ANA-TA9 (SKGQAYRMI), which are the first Catalytides found to cleave Aß42. Although the Catalytides must be delivered to the brain parenchyma to treat Alzheimer's disease, the blood-brain barrier (BBB) limits their entry into the brain from the systemic circulation. To avoid the BBB, the direct route from the nasal cavity to the brain was used in this study. The animal studies using rats and mice clarified that the plasma clearance of ANA-TA9 was more rapid than in vitro degradation in the plasma, whole blood, and the cerebrospinal fluid (CSF). The brain concentrations of ANA-TA9 were higher after nasal administration than those after intraperitoneal administration, despite a much lower plasma concentration after nasal administration, suggesting the direct delivery of ANA-TA9 to the brain from the nasal cavity. Similar findings were observed for its transport to CSF after nasal and intravenous administration. The concentration of ANA-TA9 in the olfactory bulb reached the peak at 5 min, whereas those in the frontal and occipital brains was 30 min, suggesting the sequential backward translocation of ANA-TA9 in the brain. In conclusion, ANA-TA9 was efficiently delivered to the brain by nasal application, as compared to other routes.

Evaluation of the Pharmacokinetics of Intranasal Drug Delivery for Targeting Cervical Lymph Nodes in Rats.

A well-developed lymphatic network is located under the nasal mucosa, and a few drugs that permeate the nasal mucosa are absorbed into the lymphatic capillaries. Lymph from the nasal cavity flows to the cervical lymph nodes (CLNs). In this study, we evaluated the pharmacokinetics of the direct transport of intranasally administered drugs to CLNs through the nasal mucosa of Wistar rats using methotrexate as a model drug. The drug targeting index, which was calculated based on the areas under the concentration-time curves after intravenous and intranasal administration, was 3.78, indicating the benefits of nasal delivery of methotrexate to target CLNs. The direct transport percentage, which was indicative of the contribution of the direct nose-CLN pathway of methotrexate after intranasal administration, was 74.3%. The rate constant of methotrexate from the nasal cavity to CLNs was 0.0047 ± 0.0013 min-1, while that from systemic circulation to CLNs was 0.0021 ± 0.0009 min-1. Through pharmacokinetic analysis, this study demonstrated that the direct nasal-CLN pathway contributed more to the transport of methotrexate to the CLNs than the direct blood-CLN pathway.

Amyloid beta cleavage by ANA-TA9, a synthetic peptide from the ANA/BTG3 Box A region.

INTRODUCTION: We recently discovered a short synthetic peptide derived from the ANA/BTG3 protein Box A region called ANA-TA9 (SKGQAYRMI), which possesses catalytic activity. Herein we demonstrated the proteolytic activity of ANA-TA9 against amyloid beta 42 (Aß42). METHODS: The proteolytic activity of ANA-TA9 against both the authentic soluble form Aß42 (a-Aß42) and the solid insoluble form Aß42 (s-Aß42) was analyzed by high-performance liquid chromatography and mass spectrometry. Plasma clearance, brain uptake, and cell viability were examined. RESULTS: ANA-TA9 cleaved not only a-Aß42 but also s-Aß42. Proteolytic activity was partially inhibited by 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride, a serine protease inhibitor. Plasma clearance was very rapid, and the brain concentration indicated efficient brain delivery of ANA-TA9 via nasal application. Cell viability analysis indicated that ANA-TA9 did not display toxicity. DISCUSSION: ANA-TA9 is an attractive potential candidate for the development of novel peptide drugs in Alzheimer's disease treatment.

Sunitinib decreases the expression of KRT6A and SERPINB1 in 3D human epidermal models.

Hand-foot skin reaction (HFSR) is a common side effect caused by several tyrosine kinase inhibitors, including sunitinib. However, the nature of the cornifying factors related to the molecular biological mechanisms underlying HFSR remains poorly understood. We used human keratinocyte models to investigate the key cornifying factors for dermatological and biological abnormalities induced by sunitinib. On the basis of the results of microarray analysis using the three-dimensional (3D) human epidermal model, keratin (KRT)6A, serine protease inhibitor (SERPIN)B1, KRT5, and SERPIN Kazal-type 6 were selected as candidate genes related to HFSR. Sunitinib treatment significantly decreased the expression of SERPINB1 and KRT6A in the immunohistochemical staining of the 3D epidermal model. In PSVK1 cells, but not in normal human epidermal keratinocyte cells, both of which are human normal keratinocyte cell lines, sunitinib decreased the expression of KRT6A with a concomitant decrease in levels of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated p38 mitogen-activated protein kinase (MAPK). Inhibitors of the ERK and p38 MAPK signal pathways also significantly decreased KRT6A expression. Sunitinib-induced decrease in KRT6A expression was suppressed by the inhibition of glycogen synthase kinase-3ß by enhancing ERK1/2 and p38 MAPK phosphorylation. Thus, sunitinib reduces the expression of KRT6A and SERPINB1 by inhibiting the ERK1/2 and p38 MAPK signalling pathways in the skin model. These changes in expression contribute to the pathology of HFSR.

Anticancer drug-loaded mesenchymal stem cells for targeted cancer therapy.

Mesenchymal stem cells (MSCs) have a tumor-homing ability-they accumulate inside tumors after systemic injection, and may thus be useful as carriers for tumor-targeting therapy. To use MSCs effectively as an anti-cancer therapy, they must first be functionalized with a large amount of anti-cancer drugs without causing any significant changes to their tumor-tropism. In the present study, we attempted to modify the cell surface of MSCs with doxorubicin-loaded liposomes (DOX-Lips), using the avidin-biotin complex method, and evaluated delivery efficiency and anti-tumor efficacy of DOX-Lip-modified MSCs. The amount of DOX in DOX-Lip-modified C3H10T1/2 cells, a murine mesenchymal stem cell line, was approximately 21.5 pg per cell, with no significant changes to the tumor-tropism of C3H10T1/2 cells. Notably, DOX-Lip-modified C3H10T1/2 cells significantly suppressed the proliferation of firefly luciferase-expressing murine colon adenocarcinoma colon26/fluc cells, compared to DOX-Lips alone. Fluorescent DOX accumulated at the cell contact surface and inside green fluorescence protein-expressing colon26 (colon26/GFP) in co-cultures of DOX-Lip-modified C3H10T1/2 and colon26/GFP cells. This localized distribution was not observed when only DOX-Lips was added to colon26/GFP cells. These results suggest that DOX-Lips are efficiently delivered from DOX-Lip-modified C3H10T1/2 cells to the neighboring colon26 cells. Furthermore, DOX-Lip-modified C3H10T1/2 cells suppressed tumor growth in subcutaneous tumor-bearing mice, and in a lung metastasis mouse model. Taken together, these results indicate that the intercellular delivery of DOX may be enhanced using DOX-Lip-modified MSCs as an efficient carrier system for targeted tumor therapy.

Brain and Nasal Cavity Anatomy of the Cynomolgus Monkey: Species Differences from the Viewpoint of Direct Delivery from the Nose to the Brain.

Based on structural data on the nasal cavity and brain of the cynomolgus monkey, species differences in the olfactory bulb and cribriform plate were discussed from the viewpoint of direct delivery from the nose to the brain. Structural 3D data on the cynomolgus monkey skull were obtained using X-ray computed tomography. The dimensions of the nasal cavity of the cynomolgus monkey were 5 mm width × 20 mm height × 60 mm depth. The nasal cavity was very narrow and the olfactory region was far from the nostrils, similar to rats and humans. The weight and size of the monkey brain were 70 g and 55 mm width × 40 mm height × 70 mm depth. The olfactory bulb of monkeys is plate-like, while that of humans and rats is bulbar, suggesting that the olfactory area connected with the brain of monkeys is narrow. Although the structure of the monkey nasal cavity is similar to that of humans, the size and shape of the olfactory bulb are different, which is likely to result in low estimation of direct delivery from the nose to the brain in monkeys.

Dendrimer-based micelles with highly potent targeting to sites of active bone turnover for the treatment of bone metastasis.

Bone-drug targeting therapies using nanoparticles based on targeting ligands remain challenging due to their uptake clearance at non-target sites such as the liver, kidney, and spleen. Furthermore, the distribution sites of nanoparticles in bones have not been fully investigated, thus halting the development of more effective bone metastasis treatment strategies. In this study, we developed nanoparticles self-assembled from cholesterol-terminated, polyethylene glycol-conjugated, aspartic acid (Asp)-modified polyamidoamine dendrimer (Asp-PAMAM-Micelles) with targeting to active bone turnover sites associated with bone metastasis pathogenesis. On analysis through whole-body single photon emission computed tomography/computed tomography (SPECT/CT) imaging, 111In-Asp-PAMAM-Micelles showed high specificity to active bone turnover sites (especially the joints in the lower limbs, shoulder, and pelvis) after intravenous injection in mice. The lower limb bone uptake clearance for 111In-Asp-PAMAM-Micelles encapsulating paclitaxel (PTX) was 3.5-fold higher than that for 111In-unmodified PAMAM-Micelles (PTX). 3H-PTX encapsulated Asp-PAMAM-Micelles effectively accumulated in the lower limb bones in a similar manner as the 111In-Asp-PAMAM-Micelles (PTX). In a bone metastatic tumor mouse model, the tumor growth in the lower limb bones was significantly inhibited by injection of Asp-PAMAM-Micelles (PTX) compared to unmodified PAMAM-Micelles (PTX). Our results demonstrate that Asp-PAMAM-Micelles are sophisticated drug delivery systems for highly potent targeting to active bone turnover sites.

Effect of Cerebrospinal Fluid Circulation on Nose-to-Brain Direct Delivery and Distribution of Caffeine in Rats.

Direct drug delivery from nose to brain has drawn much attention as an effective strategy for the treatment of central nervous system diseases. After intranasal administration, drug molecules can be directly delivered from the nose to the brain. However, the detailed mechanism for this direct delivery to the brain has not been elucidated. In the present study, the effect of the activation of the cerebral fluid circulation (the glymphatic system) on the efficacy of direct delivery from nose to brain was investigated. Because the glymphatic system is activated by some anesthetic regimens, the differences in brain delivery and the pharmacokinetics under anesthetic and conscious conditions were compared in rats. Under urethane anesthesia, direct delivery from the nose to the brain was facilitated, whereas the brain uptake from the systemic circulation via the blood-brain barrier was decreased. In addition, both the brain uptake of caffeine injected into the subarachnoid cerebrospinal fluid (CSF) and the extracerebral clearance of caffeine after intrastriatal injection were enhanced under anesthesia. For intranasal administration, caffeine was transported directly from the nose to the CSF and then delivered into the brain parenchyma by the CSF circulation. The results obtained in the present study clarified that the direct delivery from nose to brain could be facilitated by anesthesia. These findings suggest that fluid circulation in the brain can contribute to a wider cerebral distribution of the drug after direct delivery from nose to brain.

A chemically stable peptide agonist to neuromedin U receptor type 2.

Neuromedin U (NMU) is a peptide with appetite suppressive activity and other physiological activities via activation of the NMU receptors NMUR1 and NMUR2. In 2014, we reported the first NMUR2 selective agonist, 3-cyclohexylpropionyl-Leu-Leu-Dap-Pro-Arg-Asn-NH2 (CPN-116). However, we found that CPN-116 in phosphate buffer is unstable because of Nα-to-Nß acyl migration at the Dap residue. In this study, the chemical stability of CPN-116 was evaluated under various conditions, and it was found to be relatively stable in buffers such as HEPES and MES. We also performed a structure-activity relationship study to obtain an NMUR2-selective agonist with improved chemical stability. Consequently, CPN-219 bearing a Dab residue in place of Dap emerged as a next-generation hexapeptidic NMUR2 agonist.

Quantitative estimation of drug permeation through nasal mucosa using in vitro membrane permeability across Calu-3 cell layers for predicting in vivo bioavailability after intranasal administration to rats.

For establishing a precise system for predicting in vivo bioavailability following intranasal (IN) administration, the relationships among membrane permeability of drugs across Calu-3 cells, in situ nasal mucosal drug permeation rate, and in vivo drug absorption following IN administration were quantified. The membrane permeability coefficient (Papp) was determined for sixteen model drugs by in vitro permeation studies in Calu-3 cells. The drug permeation rate constant through the nasal mucosa (kn) was calculated from the in situ nasal perfusion of the drug solutions in rats. Bioavailability following IN administration of six model drugs with different membrane permeabilities were determined by in vivo drug absorption studies in rats. The correlations among in vitro membrane permeability properties, in situ nasal mucosal drug permeation rate, and in vivo drug absorption following IN administration, were assessed. The significant correlation between the in vitro Calu-3 cell permeability and nasal mucosal drug permeation rate (r2 = 0.812, p < 0.001) indicated that nasal mucosal drug permeability is estimable from in vitro membrane permeability. Furthermore, bioavailability following IN administration significantly correlated with the in vitro Papp across Calu-3 cells (r2 = 0.984, p < 0.001), suggesting that in vivo drug absorption following IN administration can be predicted from in vitro Calu-3 membrane permeability.

Comparison of Various Cell Lines and Three-Dimensional Mucociliary Tissue Model Systems to Estimate Drug Permeability Using an In Vitro Transport Study to Predict Nasal Drug Absorption in Rats.

Recently, various types of cultured cells have been used to research the mechanisms of transport and metabolism of drugs. Although many studies using cultured cell systems have been published, a comparison of different cultured cell systems has never been reported. In this study, Caco-2, Calu-3, Madin-Darby canine kidney (MDCK), EpiAirway and MucilAir were used as popular in vitro cell culture systems, and the permeability of model compounds across these cell systems was evaluated to compare barrier characteristics and to clarify their usefulness as an estimation system for nasal drug absorption in rats. MDCK unexpectedly showed the best correlation (r = 0.949) with the fractional absorption (Fn) in rats. Secondly, a high correlation was observed in Calu-3 (r = 0.898). Also, Caco-2 (r = 0.787) and MucilAir (r = 0.750) showed a relatively good correlation with Fn. The correlation between Fn and permeability to EpiAirway was the poorest (r = 0.550). Because EpiAirway forms leakier tight junctions than other cell culture systems, the paracellular permeability was likely overestimated with this system. On the other hand, because MDCK formed such tight cellular junctions that compounds of paracellular model were less likely permeated, the paracellular permeability could be underestimated. Calu-3, Caco-2 and MucilAir form suitable cellular junctions and barriers, indicating that those cell systems enable the precise estimation of nasal drug absorption.

Transnasal Delivery of the Peptide Agonist Specific to Neuromedin-U Receptor 2 to the Brain for the Treatment of Obesity.

Obesity and metabolic syndrome are threats to the health of large population worldwide as they are associated with high mortality, mainly linked to cardiovascular diseases. Recently, CPN-116 (CPN), which is an agonist peptide specific to neuromedin-U receptor 2 (NMUR2) that is expressed predominantly in the brain, has been developed as a new therapeutic candidate for the treatment of obesity and metabolic syndrome. However, treatment with CPN poses a challenge due to the limited delivery of CPN to the brain. Recent studies have clarified that the direct anatomical connection of the nasal cavity with brain allows delivery of several drugs to the brain. In this study, we confirm the nasal cavity as a promising CPN delivery route to the brain for the treatment of obesity and metabolic syndrome. According to the pharmacokinetic study, the clearance of CPN from the blood was very rapid with a half-life of 3 min. In vitro study on its stability in the serum and cerebrospinal fluid (CSF) indicates that CPN was more stable in the CSF than in the blood. The concentration of CPN in the brain was higher after nasal administration, despite its lower concentrations in the plasma than that after intravenous administration. The study on its pharmacological potency suggests the effective suppression of increased body weight in mice in a dose-dependent manner due to the direct activation of NMUR2 by CPN. This results from the higher concentration of corticosterone in blood after nasal administration of CPN as compared to nasal application of saline. In conclusion, the above findings indicate that the nasal cavity is a promising CPN delivery route to the brain to treat obesity and metabolic syndrome.