[Development of Drug Delivery Systems Based on New Concepts].

This review is a partial summary of the author's 40 years of research and development at Otsuka Pharmaceutical Co., Ltd. and the Faculty of Pharmaceutical Sciences, Tokyo University of Science.

GLP-1 derivatives with functional sequences transit and migrate through trigeminal neurons.

Patients with dementia are increasing with the aging of the population, and dementia has become a disease with high unmet medical needs. Glucagon-like peptide-1 (GLP-1), a neuropeptide, has been reported to improve learning and memory following intracerebroventricular administration. We focused on intranasal administration, which can deliver drugs noninvasively and efficiently to the brain.

Characterization of a spontaneous mouse model of mild, accelerated aging via ECM degradation in emphysematous lungs.

Emphysema limits airflow and causes irreversible progression of chronic obstructive pulmonary disease (COPD). Strain differences must be considered when selecting mouse models of COPD, owing to disease complexity. We previously reported that a novel C57BL/6JJcl substrain, the Mayumi-Emphysema (ME) mouse, exhibits spontaneous emphysema; however, the other characteristics remain unknown.

Intracellular Drug Delivery Process of Am80-Encapsulated Lipid Nanoparticles Aiming for Alveolar Regeneration.

Chronic obstructive pulmonary disease (COPD) results in obstructive ventilatory impairment caused by emphysema, and current treatment is limited to symptomatic therapy or lung transplantation. Therefore, the development of new treatments to repair alveolar destruction is especially urgent. Our previous study revealed that 1.

Am80-Encapsulated Lipid Nanoparticles, Developed with the Aim of Achieving Alveolar Regeneration, Have an Improvement Effect on Pulmonary Emphysema.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis and emphysema, and current drug treatments target its symptoms. Thus, the development of a therapeutic drug to repair alveolar destruction is urgently needed. Our previous research revealed that the synthetic retinoic acid Am80 (1.

Involvement of trigeminal axons in nose-to-brain delivery of glucagon-like peptide-2 derivative.

In our previous study, we created a glucagon-like peptide-2 (GLP-2) derivative with the functional sequence PAS-CPP to achieve efficient uptake by the respiratory epithelium and trigeminal nerve. By using octaarginine for cell penetrating peptides (CPP) and FFLIPKG, a reverse sequence of a part of the cathepsin D sequence for the penetration accelerating sequence (PAS), we found that the derivative was taken up by the cells through macropinocytosis and efficiently escaped from the endosomes and exited the cells. Moreover, it showed drug effects by intranasal (in.

Intracerebroventricular administration of oxytocin and intranasal administration of the oxytocin derivative improve β-amyloid peptide (25-35)-induced memory impairment in mice.

Aim: We previously reported that oxytocin, a peptide hormone, can reverse the β-amyloid peptide (25-35) (Aβ )-induced impairments of the murine hippocampal synaptic plasticity. In this study, we examined the effects of oxytocin on the Aβ -induced impairment of cognitive behavior in murine in order to investigate the potential of oxytocin as a clinical treatment tool for Alzheimer's disease (AD).

Methods: The Y-maze and Morris water maze (MWM) tests were performed.

A Mouse Model for Tuberculosis Combined With Inhalable Imiquimod-PLGA Nanocomposite Particles Based on Macrophage Phenotype.

Background/aim: In vivo models of tuberculosis are effective tools for developing new drugs. The objective of this study was to prepare in vivo models for tuberculosis by utilizing nanocomposite particles (NCPs) containing imiquimod-loaded poly(lactic-co-glycolic acid) nanoparticles.

Materials And Methods: NCPs were prepared from dichloromethane with imiquimod and poly(lactic-co-glycolic acid) using a spray dryer.

Radiolabeling Method for Lyophilizate for Dry Powder Inhalation Formulations.

Human lung deposition data is non-mandatory for drug approval but very useful for the development of orally inhaled drug products. Lung deposition of inhaled drugs can be quantified by radionuclide imaging, for which one of the first considerations is the method used to radiolabel formulations. In this study, we report the development of a radiolabeling method for lyophilizate for dry powder inhalation (LDPI) formulations.

Induction of mucosal immunity by pulmonary administration of a cell-targeting nanoparticle.

We previously found that a nanoparticle constructed with an antigen, benzalkonium chloride (BK) and γ-polyglutamic acid (γ-PGA) showed high Th1 and Th2-type immune induction after subcutaneous administration. For prophylaxis of respiratory infections, however, mucosal immunity should be induced. In this study, we investigated the effect of pulmonary administration of a nanoparticle comprising ovalbumin (OVA) as a model antigen, BK, and γ-PGA on induction of mucosal immunity in the lungs and serum.

Usefulness of cell-penetrating peptides and penetration accelerating sequence for nose-to-brain delivery of glucagon-like peptide-2.

Neuropeptides are expected as therapeutic drug candidates for central nervous system (CNS) disorders. Intracerebroventricular (i.c.

Optimization of Very Low-Dose Formulation of Vitamin D3 with Lyophilizate for Dry Powder Inhalation System by Simple Method Based on Time-of-Flight Theory.

It has been previously reported that active vitamin D3 (VD3) is a candidate drug that can repair alveolar damage in chronic obstructive pulmonary disease at a very low dose. We herein report the optimization of a very low-dose formulation of VD3 for dry powder inhalation by a simple method based on time-of-flight (TOF) theory. As the preparation content of VD3 is very low, aerodynamic particle size distribution cannot be measured by pharmacopeial methods that require quantification of the main drug.

Systemic Delivery of hGhrelin Derivative by Lyophilizate for Dry Powder Inhalation System in Monkeys.

Ghrelin is the peptide that increases the hunger sensation and food intake and is expected to be clinically applied for treatment of diseases such as cachexia and anorexia nervosa. In the clinical application of ghrelin, injections are problematic in that they are invasive and inconvenient. Thus, we aimed to develop a formulation that can eliminate the need for injections and can be applied clinically.

Simple Method to Measure the Aerodynamic Size Distribution of Porous Particles Generated on Lyophilizate for Dry Powder Inhalation.

Recently, statistical techniques such as design of experiments are being applied for efficient optimization of oral formulations. To use these statistical techniques for inhalation formulations, efficient methods for rapid determination of the aerodynamic particle size distribution of many samples are needed. Therefore, we aimed to develop a simple method to measure aerodynamic particle size distribution that closely agrees with the results of inhalation characteristic tests.

Expression of clock gene in omental and mesenteric adipose tissue in patients with type 2 diabetes.

Introduction: We previously reported in ob/ob mice, one of animal models of human type 2 diabetes mellitus (DM2), that (i) acetylation of histone H3 lysine 9 (H3K9) at the promoter region of clock gene and DBP mRNA expression are reduced in epididymal adipose tissue, (ii) binding of DBP to the promoter region of peroxisome proliferator-activated receptor ( and mRNA expression of PPAR-γ1sv were decreased in preadipocytes and (iii) adiponectin secretion was decreased, leading to the impaired insulin sensitivity.

Research Design And Methods: The present study was undertaken to evaluate whether such the changes in visceral adipose tissue were detected in patients with DM2. We obtained omental and mesenteric adipose tissue during surgery of lymph node dissection for gastric and colorectal cancers, and investigated these variables in adipose tissue (omental from gastric cancer; 13 non-DM, 12 DM2: mesenteric from colorectal cancer; 12 non-DM, 11 DM2).

Development of a DNA Vaccine for Melanoma Metastasis by Inhalation Based on an Analysis of Transgene Expression Characteristics of Naked pDNA and a Ternary Complex in Mouse Lung Tissues.

The present study investigated a pulmonary delivery system of plasmid DNA (pDNA) and its application to melanoma DNA vaccines. pCMV-Luc, pEGFP-C1, and pZsGreen were used as a model pDNA to evaluate transfection efficacy after inhalation in mice. Naked pDNA and a ternary complex, consisting of pDNA, dendrigraft poly-l-lysine (DGL), and γ-polyglutamic acid (γ-PGA), both showed strong gene expression in the lungs after inhalation.

The effects of 1α,25-dihydroxyvitamin D3 on alveolar repair and bone mass in adiponectin-deficient mice.

Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide. However, no drugs can regenerate lung tissue in COPD patients, and differentiation-inducing drugs that can effectively treat damaged alveoli are needed. In addition, the presence of systemic comorbidities is also considered problematic.

A novel diagnostic system to evaluate epidermal growth factor receptor impact as a prognostic and therapeutic indicator for lung adenocarcinoma.

Many driver pathways for cancer cell proliferation have been reported. Driver pathway activation is often evaluated based on a single hotspot mutation such as EGFR L858R. However, because of complex intratumoral networks, the impact of a driver pathway cannot be predicted based on only a single gene mutation.

Efficient optimization of high-dose formulation of novel lyophilizates for dry powder inhalation by the combination of response surface methodology and time-of-flight measurement.

Inhalation of proteins/peptides has recently received attention as various biopharmaceuticals have emerged on the market. Novel lyophilisates for dry powder inhalation (LDPIs), which are aerosolized by air impact, have been reported and LDPIs are considered an attractive option for the pulmonary administration of biopharmaceuticals. However, desirable disintegration and aerosolization properties have been unavailable in high-dose formulations, which has been a critical issue.

Method for Pulmonary Administration Using Negative Pressure Generated by Inspiration in Mice.

When developing inhaled medicines for respiratory diseases, such as chronic obstructive pulmonary disease, drugs need to be administered by pulmonary delivery to animals in non-clinical tests. Common methods require application of pressure during administration, and it may cause lung injury, so we focused on the inhalation of liquid medicines by mice themselves. This study aimed to evaluate a negative pressure method of pulmonary administration in mice by self-inhalation.

Induction of by a histone deacetylase inhibitor is involved in amelioration of insulin sensitivity via adipocyte differentiation in ob/ob mice.

We previously reported that a histone deacetylase inhibitor (HDACi) increases D-site binding protein () mRNA expression in adipose tissue and subsequently improved insulin sensitivity of obese (ob/ob) mice. However, the potential mechanism of this phenomenon was unclear. Thus, the aim of this study was to clarify the molecular mechanism involved in enhanced mRNA expression and improvement of insulin sensitivity in mice.

Mechanism of collapse of amorphous-based lyophilized cake induced by slow ramp during the shelf ramp process.

We previously found that a slow ramp rate during the shelf ramp process induced product collapse. However, the cause of the collapse could not be explained by the hypothesized mechanism of collapse. To identify the cause, drying parameters such as sublimation rate and dry layer resistance (R) were calculated from cycle data by mathematical model.

Effect of temperature ramp rate during the primary drying process on the properties of amorphous-based lyophilized cake, Part 2: Successful lyophilization by adopting a fast ramp rate during primary drying in protein formulations.

In the lyophilization process for injections, the shelf temperature (T) and chamber pressure (P) have mainly been investigated to optimize the primary drying process. The objective of this study was to show that lyophilization of protein formulations can be achieved by adopting a fast ramp rate of T in the beginning of the primary drying process. Bovine serum albumin was used as the model protein, and seven different lyophilized formulations obtained were stored at elevated temperature.

Pulmonary administration of curcumin inhibits B16F10 melanoma lung metastasis and invasion in mice.

Purpose: Curcumin is expected to have beneficial effects including an anti-cancer effect. However, its lower bioavailability is a critical concern and limits the utility of curcumin in clinical practice. In this study, we investigated whether transpulmonary delivery of curcumin is pharmacologically effective along with improving its bioavailability in mice with lung metastasis.

Identification and characterization of a novel mutation in adult pancreatoblastoma.

During next generation sequencing (NGS) analysis, many missense mutations were found in a well-known oncogene, many of which were variant of uncertain significance mutations. We recently treated an adult patient with pancreatoblastoma by chemotherapy. Using an NGS cancer panel, we found a previously unreported missense mutation in the 1835 codon of the () gene.