Article
Medicine, Research & Experimental
Reynaldo Salas-Zuniga, Karina Mondragon-Vasquez, Sergio Alcala-Alcala, Enrique Lima, Herbert Hopfl, Dea Herrera-Ruiz, Hugo Morales-Rojas
Summary: Nanoconfinement is a recent strategy to improve solubility and dissolution rate of active pharmaceutical ingredients (APIs) with poor biopharmaceutical properties. Combining cocrystals of racemic praziquantel (PZQ) with glutaric acid (PZQ-GLU) and confining them in mesoporous silica material leads to increased solubility and dissolution rate. The confined PZQ-GLU phase shows transient supersaturation behavior in simulated gastric fluid, providing a dissolution advantage over pristine PZQ.
MOLECULAR PHARMACEUTICS
(2022)
Article
Medicine, Research & Experimental
Makoto Kataoka, Ayaka Yonehara, Keiko Minami, Toshihide Takagi, Shinji Yamashita
Summary: This study demonstrates the control of cocrystal dissolution in vitro and in vivo by utilizing drug supersaturation/precipitation based on the solubility product. A cocrystal model, KTZ-4ABA, was used and the presence of 4ABA in the dissolution media significantly reduced the dissolution rate of KTZ-4ABA and regulated the supersaturation/precipitation of KTZ. In vitro dissolution study showed that the combined solid form of KTZ-4ABA and a ten-fold amount of 4ABA lowered the degree of KTZ supersaturation without precipitation. An in vivo study with rats confirmed the control of cocrystal dissolution in the gastrointestinal tract. Overall, this study demonstrates the promising strategy of using cocrystal formulations for oral use.
MOLECULAR PHARMACEUTICS
(2023)
Article
Medicine, Research & Experimental
Xuezhi Zhuo, Zeyneb Sener, Aleksei Kabedev, Min Zhao, Anis Arnous, Donglei Leng, Vito Fodera, Korbinian Lobmann
Summary: Protein-based amorphous solid dispersions (ASDs) are a promising approach for enhancing drug solubility. This study investigates the dissolution behavior of different model drugs in protein-based ASDs in various pH media and explores the mechanisms underlying the solubility improvement.
MOLECULAR PHARMACEUTICS
(2023)
Article
Pharmacology & Pharmacy
Nikita A. Vasilev, Artem O. Surov, Alexander P. Voronin, Ksenia Drozd, German L. Perlovich
Summary: In this study, the cocrystallization of itraconazole with 4-aminobenzoic acid and 4-hydroxybenzamide led to the formation of two new solid forms, with detailed analysis on their stoichiometry, polymorphic forms, and dissolution behavior. The cocrystallization with 4OHBZA was found to significantly increase the drug solubility and exhibited higher AUC values compared to the drug.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2021)
Article
Medicine, Research & Experimental
Nethrue Pramuditha Mendis, Richard Lakerveld
Summary: Cocrystals can be used to improve the aqueous solubility of drugs, but their dissolution process can lead to precipitation of the drug, affecting its bioavailability. This study presents a model that accurately describes the dissolution-supersaturation-precipitation process of cocrystals and considers the effect of surface precipitation. The model successfully captures experimental trends and predicts dose-dependent behavior with reasonable accuracy.
MOLECULAR PHARMACEUTICS
(2023)
Article
Chemistry, Multidisciplinary
Kejing Shi, Mingzhong Li
Summary: The study focuses on using polymers to inhibit surface precipitation and maximize the dissolution performance of pharmaceutical cocrystals. A single polymer can prevent surface precipitation but cannot maintain supersaturation in the solution. A combination of two polymers shows a synergistic inhibition effect and enhances the dissolution advantage of the cocrystals.
PHARMACEUTICAL RESEARCH
(2023)
Article
Medicine, Research & Experimental
Makoto Kataoka, Keiko Minami, Toshihide Takagi, Gregory E. Amidon, Shinji Yamashita
Summary: This study evaluated the in vitro-in vivo correlation of cocrystal dissolution based on the behavior of coformer. Three different cocrystals of poorly water-soluble drugs with 4ABA showed varying dissolution rates in vitro, which corresponded well with their in vivo dissolution rates and oral drug absorption enhancement in rats.
MOLECULAR PHARMACEUTICS
(2021)
Article
Pharmacology & Pharmacy
Marii Shigemura, Maaya Omori, Kiyohiko Sugano
Summary: In this study, the effects of various polymers on the solution-mediated phase transformation (SMPT) of cocrystal particles in both the particle surface (PS-SMPT) and bulk phase solution (BP-SMPT) were compared. The polymers demonstrated different inhibitory effects on PS-SMPT and BP-SMPT processes, highlighting the importance of selecting a potent inhibitor of PS-SMPT for successful cocrystal formulation development.
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
(2022)
Article
Chemistry, Medicinal
Dana E. Moseson, Tze Ning Hiew, Yongchao Su, Lynne S. Taylor
Summary: Through matrix crystallization, an amorphous solid can transform into a more stable crystalline state, reducing the driving force for dissolution. This study investigated the mechanism of matrix crystallization in amorphous solid dispersions (ASDs) and examined its implications for formulation and process design. The results showed that systems with high drug loading, mechanical activation, and surfactants were at greater risk of matrix crystallization, while systems with rapid and congruent drug and polymer release had greater resistance to matrix crystallization.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Aoi Sakamoto, Kiyohiko Sugano
Summary: The study investigated the impact of bicarbonate and phosphate buffers on the dissolution profiles of ASDs composed of ionizable polymers. Results showed that HPMCAS and AMC ASDs had slower dissolution rates in bicarbonate buffer compared to phosphate buffer at the same buffer capacity, while the dissolution profile of HPMC ASD was not affected by the buffer species.
PHARMACEUTICAL RESEARCH
(2021)
Article
Pharmacology & Pharmacy
Yang Kong, Wenhan Wang, Changzhao Wang, Lintao Li, Donglei Peng, Bin Tian
Summary: Amorphous solid dispersion (ASD) is a potential approach for improving the solubility and bioavailability of poorly water-soluble drugs by generating supersaturated drug solutions. The dissolution behavior of ASD has attracted increasing attention. This review highlights recent advancements in ASD dissolution, including the generation and maintenance of supersaturated drug solutions and the mechanisms of drug release. It also discusses the formation of drug-rich nanodroplets during dissolution and their underlying mechanisms, as well as the impact of phase separation morphology on the dissolution behavior of hydrated ASD. The review also explores the effects of polymers and surfactants on the physical stability of supersaturated drug solutions.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2023)
Article
Pharmacology & Pharmacy
Masafumi Fukiage, Kyosuke Suzuki, Maki Matsuda, Yohei Nishida, Michinori Oikawa, Takuya Fujita, Kohsaku Kawakami
Summary: This study explored the preparation of naftopidil ASDs using different materials, revealing the potential occurrence of LLPS during dissolution, and finding that Eudragit ASD, despite poor dissolution behavior, offered the best oral absorption.
Article
Pharmacology & Pharmacy
Tatyana V. Volkova, Olga R. Simonova, German L. Perlovich
Summary: This study investigated the complex formation of antiandrogen bicalutamide (BCL) with methylated and acetylated beta-cyclodextrins, and its effect on dissolution/permeation processes. The results revealed a higher binding affinity of BCL to acetylated beta-cyclodextrin compared to methylated beta-cyclodextrin. The solid dispersion of BCL with acetylated beta-cyclodextrin showed improved dissolution and supersaturation compared to the raw drug and physical mixture. The presence of polymers (PVP and HPMC) prolonged the supersaturation state and enhanced dissolution and permeation processes.
Article
Chemistry, Multidisciplinary
Victor Ribay, Arnab Dey, Benoit Charrier, Clement Praud, Joris Mandral, Jean-Nicolas Dumez, Marine P. M. Letertre, Patrick Giraudeau
Summary: Hyperpolarized nuclear magnetic resonance (NMR) methods, particularly Dissolution Dynamic Nuclear Polarization (d-DNP), greatly enhance the sensitivity of detecting C-13 NMR signals. This study demonstrates the first application of d-DNP-enhanced C-13 NMR analysis of biofluid (urine) at natural abundance, providing unprecedented resolution and sensitivity. Accurate quantitative information on multiple targeted metabolites can be obtained through a standard addition procedure.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Pharmacology & Pharmacy
Thamer Alzoubi, Gary P. Martin, David J. Barlow, Paul G. Royall
Summary: The study demonstrates that heating of lactose powders results in reversible epimerization associated with dehydration. This process follows zero-order kinetics and no additional chemical degradation was detected.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2021)
Article
Chemistry, Multidisciplinary
Takeshi Morita, Sayaka Mukaide, Ziqiao Chen, Kenjirou Higashi, Hiroshi Imamura, Kunikazu Moribe, Tomonari Sumi
Summary: The study revealed the potential interaction surface between drug-entrapped polymeric micelles through experiments and theoretical analysis. The results directly clarified the importance of interactions between micelles for drug carrier efficiency, and provided a deeper insight into the monomer contribution to the extremely stable dispersion of the nanocarrier.
Article
Pharmacology & Pharmacy
Chisa Aoki, Xiaohan Ma, Kenjirou Higashi, Yuya Ishizuka, Keisuke Ueda, Kazunori Kadota, Kaori Fukuzawa, Yuichi Tozuka, Kohsaku Kawakami, Etsuo Yonemochi, Kunikazu Moribe
Summary: This study demonstrates that alpha-Glycosyl rutin (Rutin-G) stabilizes amorphous carbamazepine (CBZ) by forming hydrogen bonds with CBZ, resulting in improved dissolution rate and supersaturation level. Rutin-G, with high glass transition temperature (T-g), good miscibility with drugs, and rapid and pH-independent dissolution properties, shows potential as a non-polymeric additive for stabilizing amorphous drug formulations.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2021)
Article
Medicine, Research & Experimental
Ziqiao Chen, Kenjirou Higashi, Keisuke Ueda, Kunikazu Moribe
Summary: Amorphous drug nanoparticles often have low storage stability, and a comprehensive understanding of the molecular states and physicochemical properties is crucial for stable formulation design. In this study, a nanosuspension of amorphous cyclosporin A (CyA) was prepared using wet bead milling and showed a transformation into uniform CyA nanocrystals during storage with improved stability. Characterization analysis revealed the aggregation of primary particles and the role of P407 in the stability of amorphous CyA nanoparticles.
MOLECULAR PHARMACEUTICS
(2022)
Article
Medicine, Research & Experimental
Keisuke Ueda, Kenjirou Higashi, Kunikazu Moribe, Lynne S. Taylor
Summary: This study investigates the thermodynamic mechanism of polymer partitioning in amorphous solid dispersion (ASD) formulations. The results show that the temperature dependency of polymers affects their ability to distribute into drug-rich phases. Polymers have a significant impact on drug solubility, and different polymers have varying degrees of influence. Furthermore, polymer partitioning is an endothermic but entropically favorable process, with higher temperatures favoring partitioning. The findings of this study are important for understanding polymer selection and achievable supersaturation levels in ASD formulations.
MOLECULAR PHARMACEUTICS
(2022)
Article
Chemistry, Multidisciplinary
Keisuke Ueda, Neo Yamamoto, Kenjirou Higashi, Kunikazu Moribe
Summary: This study characterized the molecular states of supersaturated drugs and crystallization inhibitors using NMR, revealing the inhibition mechanism of drug crystal nucleation in drug-supersaturated solutions. It was found that PVP effectively inhibited CLT crystallization and maintained CLT in a supersaturated state by interacting with CLT through hydrophobic interactions. The study demonstrated the importance of the molecular weight of crystallization inhibitors on their ability to suppress the molecular mobility of self-associated drugs and inhibit nucleation.
CRYSTAL GROWTH & DESIGN
(2022)
Article
Pharmacology & Pharmacy
Kun Sodalee, Waree Limwikrant, Thaned Pongjanyakul, Keisuke Ueda, Kenjirou Higashi, Kunikazu Moribe, Satit Puttipipatkhachorn
Summary: In this study, chitosan-OSA starch PEC was used as a stabilizer for redispersible dry nanoemulsion containing fenofibrate. The dry nanoemulsions were prepared by spray drying and showed improved dissolution of fenofibrate. The formulation variables such as type of stabilizer, starch to oil ratio, PEC formation method, and lactose amount were investigated for their effects on droplet size and drug dissolution.
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
(2022)
Article
Medicine, Research & Experimental
Keisuke Ueda, Kenjirou Higashi, Kunikazu Moribe
Summary: In this study, the effects of solubilizers CTAB and EUD-E on the solubility of ketoprofen (KTP) were investigated. It was found that adding EUD-E increased the solubility of KTP, while adding CTAB decreased the solubility of KTP. NMR analysis revealed that CTAB distributed into the KTP-rich phase, resulting in a reduction of KTP's chemical potential in the phase. Therefore, solubilizer selection is important for the development of supersaturating formulations for improved oral absorption.
MOLECULAR PHARMACEUTICS
(2022)
Article
Chemistry, Multidisciplinary
Ziqiao Chen, Kenjirou Higashi, Keisuke Ueda, Kunikazu Moribe
Summary: The crystallization mechanisms of organic molecules are still poorly understood, and this study provides direct evidence of mesocrystal formation and oriented attachment in organic pharmaceuticals, which sheds new light on the crystallization of organic molecules and nonclassical crystallization theories.
Article
Chemistry, Multidisciplinary
Arisa Ishimoto, Hiroshi Sasako, Masaki Omori, Kenjirou Higashi, Keisuke Ueda, Kazuo Koyama, Kunikazu Moribe
Summary: This study prepared drug-loaded nanocarriers with a core-shell structure of ChO/gamma-CD, obtaining two nanosuspensions with different particle sizes and structures. The drug carbamazepine (CBZ) was unexpectedly loaded into the shell as a CBZ/gamma-CD inclusion complex crystalline nanosheet.
Article
Chemistry, Multidisciplinary
Ziqiao Chen, Kenjirou Higashi, Yuki Shigehisa, Keisuke Ueda, Keiji Yamamoto, Kunikazu Moribe
Summary: A nanoparticle-based drug delivery system was established for high-dose ascorbic acid therapy. The morphology of self-assembled nanoparticles was modulated using PEGylated lipids, resulting in different structures. The surface of the particles was stabilized by PEGylated lipids. The inner tunnel size of the nanoparticles was affected by the PEG molecular weight. The rod-to-tube transformation was proposed to be influenced by surface-layer free-energy changes and PEG chain repulsion.
Article
Pharmacology & Pharmacy
Mengyao Liu, Kenjirou Higashi, Keisuke Ueda, Kunikazu Moribe
Summary: This study investigated the effect of CD derivatives on stabilizing drug supersaturation. Results showed that beta-CD and gamma-CD derivatives enhanced the solubility of carvedilol and chlorthalidone. Methylated CD derivatives outperformed unmethylated CD derivatives in stabilizing drug supersaturation. The structure and hydrophobicity of CD derivatives strongly influenced crystallization inhibition.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2023)
Article
Medicine, Research & Experimental
Keisuke Ueda, Kenjirou Higashi, Kunikazu Moribe
Summary: This study used temperature-variable nuclear magnetic resonance (NMR) spectroscopy to explore the impact of a solubilizing agent on the ketoprofen (KTP) supersaturation region. The results showed that the solubilizing agent CTAB increased both the crystalline and amorphous solubilities of KTP, shifting the supersaturation region to a higher concentration range. The effect of CTAB on the supersaturation region differed depending on the enantiomeric composition, and CTAB also affected the distribution of KTP during liquid-liquid phase separation. The findings emphasize the importance of considering the molecular-level impact of solubilizing agents on drug supersaturation for optimized formulations.
MOLECULAR PHARMACEUTICS
(2023)
Article
Medicine, Research & Experimental
Keisuke Ueda, Kenjirou Higashi, Kunikazu Moribe
Summary: This study investigated the effects of polymer-additive and drug chiralities on the supersaturation region of ketoprofen (KTP) using temperature-variable nuclear magnetic resonance (NMR) analysis. The results showed that the amorphous solubilities of racemic KTP and S-enantiomer (rac- and s-KTP) were similar, but the crystalline solubility of s-KTP was higher. PVP reduced the amorphous solubility of both rac- and s-KTP, while the crystalline solubility remained unchanged. The distribution of PVP into the KTP-rich phase decreased the chemical potential and amorphous solubility of KTP, narrowing the supersaturation region and reducing the maximum supersaturation temperature.
MOLECULAR PHARMACEUTICS
(2023)
Article
Medicine, Research & Experimental
Yuta Hatanaka, Hiromasa Uchiyama, Shun Kaneko, Keisuke Ueda, Kenjirou Higashi, Kunikazu Moribe, Shingo Furukawa, Mai Takase, Shinya Yamanaka, Kazunori Kadota, Yuichi Tozuka
Summary: In this study, a novel coamorphous salt was developed to improve drug permeability and absorption through ionic interactions. The coamorphous salt significantly increased TMS solubility while decreasing AML solubility. It was found that the coamorphous salt enhanced drug permeation and oral absorption, particularly for TMS.
MOLECULAR PHARMACEUTICS
(2023)
Article
Chemistry, Physical
Takeshi Morita, Hitomi Okada, Taisei Yamada, Ryo Hidaka, Takeshi Ueki, Kazuyuki Niitsuma, Yuzo Kitazawa, Masayoshi Watanabe, Keiko Nishikawa, Kenjirou Higashi
Summary: This study investigates the interaction between poly(benzyl methacrylate) (PBnMA) and an ionic liquid, 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)amide ([C(2)mim][NTf2]), using magic-angle spinning NMR spectroscopy and small-angle scattering techniques. The results reveal that PBnMA adopts a random coil conformation and exhibits low mobility in [C(2)mim][NTf2]. Furthermore, the binding between PBnMA and the ionic liquid is strengthened at higher temperatures.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2022)