The development of generic pharmaceuticals involves a bioequivalence study to ensure the therapeutic equivalence of the test formulation to the original innovative product. The formulation characteristics of generic products are expected to be maintained in the long term after approval. This study analyzed the factors contributing to the changes in the dissolution profiles of approved products during their life cycles. Cumulative data on the dissolution similarity of 1675 products of 127 ingredients tested by official laboratories in Japan were assessed according to Japanese bioequivalence guidelines with slight modifications. The products showing dissimilarities in dissolution profiles were analyzed for reporting year, therapeutic category, co-development, physical properties of the active pharmaceutical ingredient (API), and suspected reasons for dissolution change. The increase in the number of dissimilar products is related to the co-development of generic products. Although the solubility of the API was not associated with the dissolution change in the analysis of the total dissolution data, control of the API particle size is suggested to be important for drugs with poorly soluble APIs. Additionally, a risk factor for dissolution changes in the test solutions at a certain pH was the presence of acidic or basic residues. These results indicate the importance of proper development through a thorough evaluation of the formulation and process factors affecting the dissolution properties throughout the product lifecycle.
The authors focus on the long-term
consistency of dissolution profiles of generic pharmaceutical products. By
analyzing a vast dataset of 1675 products across 127 ingredients, the study
uncovers the intricate factors influencing changes in dissolution profiles
post-approval. It emphasizes the significance of co-development in the increase
of dissimilar dissolution products, the pivotal role of API particle size in poorly
soluble drugs, and the impact of acidic or basic residues on dissolution changes
at specific pH levels. These findings highlight the necessity for proper
development that consider formulation and process variables to ensure the
sustained bioequivalence of generic drugs.
The first enantioselective total synthesis of kopsiyunnanine B, which has a unique folded and complex pentacyclic structure containing six contiguous chiral centers, has been achieved along our originally proposed biosynthetic pathway. The key reaction of this synthesis includes a bioinspired cascade that builds three ring structures and three chiral centers in one step and features the stereoselective reduction of a β-acrylate and oxidation to an oxindole.
[Highlighted Paper selected by Editor-in-Chief]
Kopsiyunnanine B was isolated from Yunnan Kopsia arborea and
possesses a unique folded and complex pentacyclic structure containing six
contiguous chiral centers. In this article, the authors reported the asymmetric
total synthesis of Kopsiyunnanine B, along with their originally proposed
biosynthetic pathway. The key transformation is an impressive cascade reaction
that constructs three ring structures and three chiral centers in one step.
Following the stereoselective reduction of the β-acrylate and oxidation to
oxindole, the natural product is synthesized over 14 steps. Their careful
consideration of the biosynthetic hypothesis has resulted in an exceptionally
efficient synthesis with a minimal number of steps.
Five new viridogriseins B–F were isolated from Streptomyces niveoruber, along with viridogrisein and griseoviridin which belong to streptogramin family antibiotics. A combination of liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis and the advanced Marfey’s method elucidated the structures of viridogriseins B–F, each featuring distinct constituent amino acids. Consistent with other streptogramin family antibiotics, these viridogrisein analogs exhibited potent antibacterial activity against Staphylococcus aureus. Furthermore, equimolar mixtures of each viridogrisein analog and griseoviridin inhibited the growth of S. aureus more potently than each analog treatment alone. Finally, an in vitro functional analysis of SgvY, encoded in the viridogrisein biosynthetic gene cluster, revealed that SgvY detoxifies viridogrisein against S. aureus by linearization. Considering that viridogrisein is not autotoxic to S. niveoruber, SgvY likely contributes to the self-resistance system against viridogrisein in S. niveoruber.
Given
the spread of antimicrobial-resistant bacteria (AMR), there is an urgent need
for the ongoing search for novel antibacterial natural products. The authors discovered
five new viridogrisein congeners from Streptomyces niveoruber with potent
antibacterial activities against Gram-positive bacteria. Additionally,
co-treatment with griseoviridin, another natural product from the same producer,
enhanced the activity. Biosynthetic studies have revealed that SgvY, encoded in
the viridogrisein biosynthetic gene cluster, detoxifies viridogrisein against Staphylococcus
aureus by linearization, suggesting its role in the self-resistance system
in S. niveoruber. These results could facilitate the understanding of antimicrobial-resistant
mechanism for developing the countermeasures against AMR.
For powder compaction, the Kawakita equation has been used to estimate the powder behavior inside the die. The compression pressure exerted on powders is not homogeneous because of the friction on the die wall. However, the yield pressure and porosity estimated using the Kawakita equation are defined based on the assumption that homogeneous voids and compression pressure are distributed throughout the powder bed. In this study, an extended Kawakita equation was derived by considering the variation in the compression pressure as it corresponds to the distance from the loading punch surface. The yield time section estimated from the extended Kawakita equation was wider than that which was estimated via the classical equation. This result is consistent with the assumptions used to derive the extended Kawakita equation. Furthermore, a comparison of the porosity changes before and after the yield pressure was applied indicate that the direct cause of the yield is the spatial constraints of the powder particles. Equivalent stresses were defined to clarify the critical factor that constitutes the extended Kawakita equation. As a result, “taking into account the die wall friction” was considered to be the critical factor in the extended Kawakita equation. As these findings were theoretically determined by the extended Kawakita equation, a useful model was derived for a better understanding of powder compaction in die.
The
Kawakita equation has been used for estimating yield pressure and porosity of
compressed powder in the die. This equation assumes the compression pressure is
homogeneously distributed. However, in actual powders, it is not homogeneously
distributed due to the friction on the die wall. The authors extended the
Kawakita equation by accounting for the inhomogeneous distribution of
compression pressure. The extended Kawakita equation theoretically explained
the powder behavior yielding sequentially from the loading punch to fixed punch
due to the spatial limitation of particle rearrangement. Therefore, the
extended Kawakita equation advances understanding of powder compaction in die.
Medicinal Flowers. XXI. Structures of Perennisaponins A, B, C, D, E, and F, Acylated Oleanane-Type Triterpene Oligoglycosides, from the Flowers of Bellis perennis
Released on J-STAGE: April 01, 2008 | Volume 56 Issue 4 Pages 559-568
Masayuki Yoshikawa, Xuezheng Li, Eriko Nishida, Seikou Nakamura, Hisashi Matsuda, Osamu Muraoka, Toshio Morikawa
Views: 1,196
Studies on Sulfenamides. XII. : Anodic Oxidation of N-(o-Nitrophenylthio)-1, 2, 3, 4-tetrahydroquinoline and N-(o-Nitrophenylthio)-1, 2, 3, 4-tetrahydroisoquinoline
Released on J-STAGE: March 31, 2008 | Volume 34 Issue 10 Pages 4139-4143
HIROTERU SAYO, HIROMI HATSUMURA, TAKASHI MICHIDA
Views: 1,188
Effect of Plasma pH on Stability and Capacity of Aggregation of Platelets
Released on J-STAGE: March 31, 2008 | Volume 20 Issue 7 Pages 1569-1571
KIYOMI KIKUGAWA, KAZUHIRO IIZUKA, MOTONOBU ICHINO
Views: 1,181
Optical Rotatory Dispersion Curves of Some N-Salicylidene Amino-sugars.
Released on J-STAGE: March 31, 2008 | Volume 15 Issue 10 Pages 1557-1566
Shigeharu Inouye
Views: 1,087
Various Factors affecting Intestinal Absorption of Iodochlorhydroxyquin in Rat and Man
Released on J-STAGE: March 31, 2008 | Volume 24 Issue 11 Pages 2603-2609
MASAHIRO HAYASHI, TOHRU FUWA, SHOJI AWAZU, MANABU HANANO
Views: 1,040