{"title":"Development of a New Jelly Coating Technology (Oral Jelly Coating) to Improve Prescribed Medication Adherence.","authors":"Junya Yamashita, Shota Asai, Hiroki Shingaki, Masakane Hayakawa","doi":"10.1248/bpb.b23-00625","DOIUrl":"10.1248/bpb.b23-00625","url":null,"abstract":"<p><p>Tablets are the most commonly prescribed dosage form for oral drug administration. Historically, improvement of medication adherence of tablets has been facilitated through, for example, the use of smaller tablets, distinctive shaped tablets and sugar-coated tablets. In addition, new formulation technologies such as orally disintegrating tablets (OD tablets), micro tablet-type granules, jellies, and film formulations are making it possible to create more easily ingested dosage forms. We have developed a new oral jelly coating formulation that can be applied to any sized tablet without reducing the size of the formulation. It was found that this new jelly layer formed on the tablet surface improved the tablet's slipperiness with an appropriate amount of water, while ensuring no change in the dissolution profile. In addition, the jelly layer was ensured storage stability over time without affecting the dissolution profile. Although further studies are needed, this coating technology can quickly change the tablet surface to a jelly-like state after the tablet is taken, giving the tablet the same slipperiness as if it were taken in jelly, making it easier to pass through the pharynx, and thus improving medication adherence.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":" ","pages":"259-271"},"PeriodicalIF":2.0,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138797445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Rheological Properties and Composition Affecting the Skin Permeation of a Model of a Hydrophilic Drug in Lecithin Reverse Wormlike Micelles.","authors":"Yoshiyuki Miyasaka, Kaname Hashizaki, Kohsuke Shibasaki, Makiko Fujii, Hiroyuki Taguchi","doi":"10.1248/bpb.b23-00704","DOIUrl":"10.1248/bpb.b23-00704","url":null,"abstract":"<p><p>We investigated the effect of the rheological properties and composition of lecithin reverse wormlike micelles (LRWs) on the skin permeation of a model of a hydrophilic drug to determine whether LRWs support uniform hydrophilic drug/oil-based formulations and good drug penetrate into skin. Here, we prepared LRWs with D (-)-ribose (RI) or glycerol (GL) as polar compounds, liquid paraffin (LP) or isopropyl myristate (IPM) as oils, and 6-carboxyfluorescein (CF) as a model for a hydrophilic drug, and evaluated the rheological properties and skin penetration characteristics of the preparations. The LRWs showed moderate viscosity at 25 °C, a typical storage temperature, but decreasing viscosity at 32 °C, the surface temperature of human skin, suggesting that the LRWs would penetrate the microstructure of skin (e.g., wrinkles and hair follicles). The highest skin permeability of CF was observed when IPM was used as the oil, suggesting that both the stratum corneum and hair follicle routes are involved in drug permeation. The penetration of CF into hair follicles is influenced not only by the rheology of the formulation but also by the interaction between IPM and sebum in the hair follicles.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":" ","pages":"245-252"},"PeriodicalIF":2.0,"publicationDate":"2024-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138797448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Influence of Endogenous Substances on Site-II to Site-I Displacement of Diclofenac Bound to Albumin in the Aqueous Humor of Patients with Cataract.","authors":"Saya Ishii, Mineo Ozaki, Norito Takamura, Kenji Ogata, Jin Tokunaga, Ryuji Ikeda","doi":"10.1248/bpb.b23-00301","DOIUrl":"10.1248/bpb.b23-00301","url":null,"abstract":"<p><p>Diclofenac instillation is useful in preventing intraoperative miosis and macular edema caused by postoperative inflammation in cataract surgery; however, optimum efficacy is not attained when the instilled diclofenac strongly binds to albumin in patients' aqueous humor. Therefore, a method that inhibits diclofenac binding and increases the concentration of its free fraction is needed. We conducted a basic study regarding the effects of inhibitors on the binding of instilled diclofenac to albumin and endogenous substances in aqueous humor. Aqueous humor samples from 16 patients were pooled together for analysis. The free fraction of diclofenac was measured using ultrafiltration methods in various experiments with pooled and mimic aqueous humor. Free fraction of diclofenac, a site II drug, in pooled aqueous humor was 0.363 ± 0.013. The binding of diclofenac in the presence of phenylbutazone (PB), a site I inhibitor, was significantly inhibited (free fraction = 0.496 ± 0.013); however, no significant inhibition by ibuprofen, a site II inhibitor, (free fraction = 0.379 ± 0.004), was observed. The unexpected result was due to free fatty acids (FFAs; palmitic acid (PA)) and L-tryptophan (Trp). The inhibition of diclofenac binding by PB in the mimic aqueous humor containing these endogenous substances revealed significant binding inhibition in the presence of PA and Trp. Diclofenac is strongly rebound from site II to site I in the presence of FFAs and Trp in the aqueous humor because FFAs and Trp induce a conformational change in albumin. Therefore, PB significantly inhibits the binding of diclofenac to albumin.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":" ","pages":"213-220"},"PeriodicalIF":2.0,"publicationDate":"2024-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138497751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Dictamnine Ameliorates DNFB-Induced Atopic Dermatitis Like Skin Lesions in Mice by Inhibiting M1 Macrophage Polarization and Promoting Autophagy.","authors":"Yihan Huang, Chenrui Zhao, Guodong Zheng, Yujuan Yuan, Ling Gong, Rui Liu, Jingang An","doi":"10.1248/bpb.b23-00436","DOIUrl":"10.1248/bpb.b23-00436","url":null,"abstract":"<p><p>Autophagy and M1 macrophage polarization play important roles in the regulation of inflammation in atopic dermatitis (AD). Dictamnine is one of the main ingredients in Cortex Dictamni, a widely used traditional Chinese medicine for the treatment of dermatitis. In the present study, we investigated the anti-inflammatory effects of dictamnine on AD like skin lesions and M1 macrophage polarization. A 2,4-dinitrofluorobenzene (DNFB) triggered AD like skin lesions models in mice was established to identify the ameliorative effects of dictamnine on AD in vivo. In addition, an M1 macrophage polarization model was co-stimulated by lipopolysaccharide (LPS) and interferon-γ (IFN-γ) using phorbol myristate acetate (PMA) differentiated THP-1 cells, to investigate the effect of dictamnine on promoting autophagy and inhibiting inflammatory factor release. Dictamnine suppressed DNFB-induced skin inflammation by inhibiting M1 macrophage polarization, up-regulating the expression of microtubule-associated protein 1A/1B-light chain 3 (LC3) expression, and promoting macrophage autophagy at inflammatory sites. Dictamnine also could reduce the release of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and interleukin-8 (IL-8), and down-regulate the mRNA expression of these genes in LPS-IFN-γ triggered M1 polarized macrophages. Dictamnine ameliorates AD like skin lesions by inhibiting M1 macrophage polarization and promoting autophagy. Hence, dictamnine is expected to be a potential therapeutic candidate for AD.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":" ","pages":"175-186"},"PeriodicalIF":2.0,"publicationDate":"2024-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138797447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Efficient Loading into and Controlled Release of Lipophilic Compound from Liposomes by Using Cyclodextrin as Novel Trapping Agent.","authors":"Sae Akaki, Mika Hosokawa, Saki Maeda, Yusuke Kono, Hideko Maeda, Ken-Ichi Ogawara","doi":"10.1248/bpb.b24-00558","DOIUrl":"https://doi.org/10.1248/bpb.b24-00558","url":null,"abstract":"<p><p>Lipid bilayer vesicles, liposomes are representative drug delivery carriers. High encapsulation efficiency and release control of drugs are essential for clinical application of liposomes. For efficient drug loading into liposomes, remote loading method using driving force like transmembrane gradients of pH and ions are utilized. Ions are called as \"trapping agents,\" which are also critical for the controlled release of drugs loaded into liposomes inside. It is difficult to apply ions as trapping agents to various drugs because of limited physicochemical compatibility between drugs and ions. Cyclodextrins (CDs) with hydrophobic cavity can make inclusion complexes with various hydrophobic compounds. Therefore, we aimed to evaluate the potential of CDs as a novel trapping agent using sulfobutylether-β-cyclodextrin (SBE-β-CD) and ibuprofen (IB), a weak acid hydrophobic drug. Encapsulation efficiency of IB in liposomes with pH gradient was approximately 27%, and it was enhanced by intraliposomal SBE-β-CD inclusion in addition to pH gradient, which was SBE-β-CD concentration-dependent. In liposomes with pH gradient, a large fraction of IB was released in a short time. This early-stage rapid IB release was significantly suppressed by the inclusion of SBE-β-CD inside liposomes. Thus, novel remote loading technology by intraliposomal SBE-β-CD enabled the efficient encapsulation of the hydrophobic drug into the aqueous phase of liposomes as well as their controlled release. This technology should be applied to various drugs that can be included into CDs in order to enhance their therapeutic benefits.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 11","pages":"1832-1835"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Downregulation of Genes for Skeletal Muscle Extracellular Matrix Components by Cisplatin.","authors":"Yu Miyauchi, Miho Kiyama, Shinki Soga, Hayato Nanri, Takayuki Ogiwara, Shiori Yonamine, Risako Kon, Nobutomo Ikarashi, Yoshihiko Chiba, Tomoo Hosoe, Hiroyasu Sakai","doi":"10.1248/bpb.b24-00428","DOIUrl":"https://doi.org/10.1248/bpb.b24-00428","url":null,"abstract":"<p><p>The extracellular matrix (ECM) in skeletal muscle is involved in a variety of physiological functions beyond the mechanical support of muscle tissue, nerves, and blood vessels; however, the role of the ECM in skeletal muscle remains unclear. There is little information regarding changes in the expression of factors comprising the ECM during cisplatin-induced muscle atrophy. In the present study, we examined the changes in gene expressions for skeletal muscle extracellular matrix components in skeletal muscle during cisplatin-induced muscle atrophy. Intraperitoneal administration of cisplatin caused muscle atrophy in mice and during this cisplatin-induced muscle atrophy, the expression of many procollagen genes (Col1a1, Col1a2, Col3a1, Col4a1, Col5a1, and Col5a2), elastin (Eln), fibronectin (Fn1), Laminin (Lama1, Lama2, and Lamb1) decorin (Dcn), heparan sulphate proteoglycans (Hspg2) and integrin (Itgb1) constituting the ECM was suppressed. Additional studies are needed to elucidate the pathological significance and mechanisms of reduced gene expression of ECM components associated with cisplatin-induced muscle atrophy.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 11","pages":"1846-1850"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Expression of Epithelial-Mesenchymal Transition Markers in Epidermal Layer of Atopic Dermatitis.","authors":"Kazuyuki Kitazawa, Kazunori Tanaka, Yoshiki Kubota, Mina Musashi, Kiyoshi Higashi, Teruaki Nagasawa, Miyuki Kobayashi, Tatsuro Kamakura, Rie Igarashi, Yoko Yamaguchi","doi":"10.1248/bpb.b23-00291","DOIUrl":"10.1248/bpb.b23-00291","url":null,"abstract":"<p><p>The epithelial-mesenchymal transition (EMT) is a phenomenon, in which epithelial cells acquire a mesenchymal cell phenotype. It is important during wound healing; however, chronic inflammation leads to excessive EMT and causes tissue barrier dysfunction with hyperplasia. EMT is induced by several cytokines, such as interleukin (IL)-4 and IL-13. Additionally, IL-4 and IL-13 are known to increase in atopic dermatitis (AD) characterized by intense itching and eczema. Therefore, we assumed that there was commonality between the respective EMT and AD phenotypes. Herein, we evaluated EMT marker expression in AD skin and demonstrated that EMT-maker Snai1 and Twist expression were increased in AD mice model and patients with AD. Moreover, the epithelial-marker keratin 5 and mesenchymal marker Vimentin were co-expressed in the skin epidermis of mice with AD, suggesting the existence of hybrid epithelial-mesenchymal (E/M) cells possessing both epithelial and mesenchymal characteristics. In fact, we found that ΔNp63a, a stabilizing factor for hybrid E/M cells, was upregulated in the skin epidermis of the AD model mouse. Interestingly, increased expression of EMT markers was observed even at a nonlesion site in a patient with AD without initial inflammation or scratching. Therefore, EMT-like phenomena may occur independently of wound healing in skin of patients with AD.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 1","pages":"49-59"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139085744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jun Takouda, Moeka Nakamura, Akane Murasaki, Waka Shimosako, Aoi Hidaka, Shino Honda, Susumu Tanimura, Fumito Ishibashi, Norihiko Kawasaki, Jun Ishihara, Tsutomu Fukuda, Kohsuke Takeda
{"title":"Identification of Azalamellarin N as a Pyroptosis Inhibitor.","authors":"Jun Takouda, Moeka Nakamura, Akane Murasaki, Waka Shimosako, Aoi Hidaka, Shino Honda, Susumu Tanimura, Fumito Ishibashi, Norihiko Kawasaki, Jun Ishihara, Tsutomu Fukuda, Kohsuke Takeda","doi":"10.1248/bpb.b23-00569","DOIUrl":"10.1248/bpb.b23-00569","url":null,"abstract":"<p><p>Pyroptosis is a form of regulated cell death that promotes inflammation; it attracts much attention because its dysregulation leads to various inflammatory diseases. To help explore the precise mechanisms by which pyroptosis is regulated, in this study, we searched for chemical compounds that inhibit pyroptosis. From our original compound library, we identified azalamellarin N (AZL-N), a hexacyclic pyrrole alkaloid, as an inhibitor of pyroptosis induced by R837 (also called imiquimod), which is an agonist of the intracellular multiprotein complex nucleotide-binding and oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. However, whereas the effect of AZL-N on R837-induced pyroptosis was relatively weak, AZL-N strongly inhibited pyroptosis induced by extracellular ATP or nigericin, which are different types of NLRP3 inflammasome agonists. This was in contrast with the results that MCC950, a well-established NLRP3 inhibitor, consistently inhibited pyroptosis irrespective of the type of stimulus. We also found that AZL-N inhibited activation of caspase-1 and apoptosis-associated speck-like proteins containing a caspase activation and recruitment domain (ASC), which are components of the NLRP3 inflammasome. Analysis of the structure-activity relationship revealed that a lactam ring of AZL-N, which has been shown to contribute to the strong binding of AZL-N to its known target protein kinases, is required for its inhibitory effects on pyroptosis. These results suggest that AZL-N inhibits pyroptosis by targeting molecule(s), which may be protein kinase(s), that act upstream of NLRP3 inflammasome activation, rather than by directly targeting the components of the NLRP3 inflammasome. Further identification and analysis of target molecule(s) of AZL-N will shed light on the regulatory mechanisms of pyroptosis, particularly those depending on proinflammatory stimuli.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 1","pages":"28-36"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139085746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"New Maintenance Culture Method for Intestinal Stem Cells Derived from Human Induced Pluripotent Stem Cells.","authors":"Shota Mizuno, Yumi Jinnoh, Ayaka Arita, Shimeng Qiu, Tadahiro Hashita, Eisei Hori, Takahiro Iwao, Tamihide Matsunaga","doi":"10.1248/bpb.b23-00573","DOIUrl":"10.1248/bpb.b23-00573","url":null,"abstract":"<p><p>Most orally administered drugs exert their effects after being absorbed in the small intestine. Therefore, new drugs must undergo nonclinical pharmacokinetic evaluations in the small intestine. Enterocytes derived from human induced pluripotent stem cells (hiPSCs) are expected to be used in the evaluation system, as they reflect human intestinal characteristics more accurately; moreover, several differentiation protocols are available for these cells. However, enterocytes derived from hiPSCs have drawbacks such as time, cost, and lot-to-lot differences. Hence, to address these issues, we attempted to maintain hiPSC-derived intestinal stem cells (ISCs) that can differentiate into various intestinal cells by regulating various pathways. Although our previous attempt was partly successful, the drawbacks of elevated cost and complicated handling remained, because more than 10 factors (A 83-01, CHIR99021, epidermal growth factor, basic fibroblast growth factor, SB202190, nicotinamide, N-acetylcysteine, valproic acid, Wnt3a, R-spondin 1, and noggin) are needed to maintain ISCs. Therefore, in this study, we successfully maintained ISCs using only five factors, including growth factors. Moreover, we generated not only enterocytes but also intestinal organoids from the maintained ISCs. Thus, our novel findings provided a time-saving and cost-effective culture method for enterocytes derived from hiPSCs.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 1","pages":"120-129"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139085748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}