プランルカスト水和物の経口持続性製剤化を目指した胃内滞留性製剤の設計に関する研究

難吸収性薬物であるプランルカスト水和物について、1 日1 回服用型の経口持続性製剤としての設計を目指して検討を行った。プランルカスト水和物は難溶解性、難膜透過性薬物であることから、製剤設計の方向性を見極めるためにヒト消化管の吸収部位差を評価したところ、遠位小腸および結腸からの吸収性は非常に乏しく、吸収部位が小腸上部に限定されることが明らかとなり、プランルカスト水和物を経口持続性製剤化するためには、製剤を胃内に滞留させて徐放する必要があることが分かった。胃の生理的なストレス存在下でも十分な大きさに膨潤して、かつ薬物を徐放できる胃内膨潤性製剤（GSS）の設計検討を実施した。ヒトにおいて製剤設計コンセプトを確認するため、GSS を経口投与後の体内挙動をガンマシンチグラフィーによって評価したところ、胃内に10 時間以上滞留することが確認でき、十分な胃内滞留機能を有していることを明らかとした。また、市販品であるオノン®カプセルに比べて血中濃度は明らかに持続する結果が得られた。GSS を夕食後投与したところ吸収性が更に増大し、夕食後投与において効果が最も発揮されることが分かった。これらの結果から、GSS はプランルカスト水和物のように、消化管の吸収部位が限定される薬物の経口持続性製剤化に有用な技術であることを提示することができた。In a human site-of-absorption study pranlukast hydrate was demonstrated to have extremely poor absorption properties inthe lower gastrointestinal tract. The ratios of AUC0-24 in the distal small bowel and colon compared to stomach delivery wereapproximately 1/7 and 1/70, respectively. As a consequence, a gastroretentive double-layered tablet formulation (gastric swellingsystem; GSS), consisting of a swelling layer and a drug release layer, was developed for once-daily dosing. To study the gastricretention of the optimized GSS, an in vivo gamma scintigraphic study was carried out in nine healthy volunteers. The transit profilesdemonstrated that the GSS was retained in the stomach for more than 10 hr. The plasma profile was prolonged, especially followingadministration after an evening meal. The human data validated the design concept and suggest that GSS could be a promisingapproach for the development of a sustained-release formulation for drugs with a limited absorption window in the upper smallbowel

Prostaglandin E2 receptor type 2-selective agonist prevents the degeneration of articular cartilage in rabbit knees with traumatic instability

[Introduction]Osteoarthritis (OA) is a common cause of disability in older adults. We have previously reported that an agonist for subtypes EP2 of the prostaglandin E2 receptor (an EP2 agonist) promotes the regeneration of chondral and osteochondral defects. The purpose of the current study is to analyze the effect of this agonist on articular cartilage in a model of traumatic degeneration. [Methods]The model of traumatic degeneration was established through transection of the anterior cruciate ligament and partial resection of the medial meniscus of the rabbits. Rabbits were divided into 5 groups; G-S (sham operation), G-C (no further treatment), G-0, G-80, and G-400 (single intra-articular administration of gelatin hydrogel containing 0, 80, and 400 μg of the specific EP2 agonist, ONO-8815Ly, respectively). Degeneration of the articular cartilage was evaluated at 2 or 12 weeks after the operation. [Results]ONO-8815Ly prevented cartilage degeneration at 2 weeks, which was associated with the inhibition of matrix metalloproteinase-13 (MMP-13) expression. The effect of ONO-8815Ly failed to last, and no effects were observed at 12 weeks after the operation. [Conclusions]Stimulation of prostaglandin E2 (PGE2) via EP2 prevents degeneration of the articular cartilage during the early stages. With a system to deliver it long term, the EP2 agonist could be a new therapeutic tool for OA

利き耳・非利き耳側への聴覚刺激が重心動揺に与える効果 足圧中心(COP)総軌跡長・矩形面積・外周面積に着目して

本研究は，利き耳・非利き耳側からの聴覚刺激が重心動揺に与える効果について検討した．被験者は健常若年者30名である．本研究は横断研究である．重心動揺の測定には重心動揺計を使用し，足圧中心（COP）総軌跡長・矩形面積・外周面積を抽出して比較検討した．研究条件は条件①：聴覚刺激無，条件②：利き耳側からの聴覚刺激，条件③：非利き耳側からの聴覚刺激である．結果，聴覚刺激無（条件①）と，利き耳側から聴覚刺激（条件②）では両群で有意な差を示さなかった．非利き耳側からの聴覚刺激（条件③）は，聴覚刺激無（条件①）と利き耳側から聴覚刺激（条件②）を比較したところ重心動揺が有意に減少していた．これにより，非利き耳側から入力された聴覚刺激は脳の側性化により対側半球の空間認知機能局在に情報が伝搬され，姿勢の調整に影響を与えていることが推察された．The purpose of this study was to examine the effect of auditory stimulation from dominant ear/nondominant ear on body sway. The subject were 30 healthy young people. This study was a Cross-Sectional study. The assessment of body sway was taken as the total length of Center of pressure（COP） displacements, Rectangular area, and Environmental area of COP using the stabilometer. Research Condition ①：Conditions that do not give auditory stimulation. Research Condition ②：Conditions of giving an auditory stimulus from the dominant ear side. Research Condition ③：Conditions for giving an auditory stimulus from the non-dominant ear side. As a result, Condition ① and Condition ② showed no significant difference in both groups. Condition ③ decreased significantly than Condition ① . Condition ③ also decreased significantly than condition ② . These results, auditory stimulation input from the non-dominant ear is sent to the cerebral hemisphere on the opposite side by laterality. From this, it is considered that the effect was given the body sway

Appropriate selection of an aggregation inhibitor of fine particles used for inhalation prepared by emulsion solvent diffusion

<p><b>Context:</b> Dry powder inhaler (DPI) formulations have been developed to deliver large amounts of drugs to the lungs.</p> <p><b>Objective:</b> Fine particles of a poorly water-soluble drug, the model drug ONO-2921, were prepared by the emulsion solvent diffusion (ESD) method for use in a DPI.</p> <p><b>Methods:</b> The effects of additives on the fine particle formation of ONO-2921 were estimated when droplets of an ethanolic drug solution were dispersed into aqueous media containing various additives. Subsequently, the suspensions were freeze-dried to create powdered samples to estimate the inhalation properties using a twin impinger and an Andersen cascade impactor.</p> <p><b>Results:</b> This simple ESD method produced submicron-sized ONO-2921 particles (approximately 600 nm) in combination with suitable additives. In addition, the freeze-dried powder produced using additives exhibited superior <i>in vitro</i> inhalation properties. Among these methods, the freeze-dried powder produced with 0.50% weight/volume one type of polyvinyl alcohol (PVA-205) displayed the most efficient features in the fine particle fraction (FPF). These results could be explained by the stabilization of the ONO-2921 suspension by PVA-205, indicating that PVA-205 acts as an aggregation inhibitor of fine particles.</p> <p><b>Conclusions:</b> The ESD method, in combination with appropriate types and amounts of additives, may be useful for preparing a DPI suitable for delivering drugs directly to the lungs without the assistance of carrier particles.</p