It is mandatory to detect the powder cohesiveness of biopharmaceutical dry powder inhaler (Bio-DPI) formulations and their effect on their performance. Normally, Bio-DPI formulations consist of highly cohesive components with higher drug amounts than small molecules. Herein, a formulation study of a high-drug-ratio Bio-DPI was performed, detecting the risk of powder caking in DPI formulations. The Bio-DPI formulation was manufactured via the spray-dry method followed by mixing with excipients. Powder caking was detected through the void forming index (VFI), which was calculated using pressure drop measured by inverse gas chromatography (iGC). Since VFI can be used to evaluate the structural changes induced by powder caking over time with less than 1 g of sample, VFI is considered suitalbe to apply for DPI formulation screening. The risk of powder caking was detected in spray dryed particles at more than 45% relative humidity (RH) humidity condition, mannitol (as a carrier particle) and magnesium stearate (as a lubricant) were added to the formulations. With formulation screening, addition of more than 40% of mannitol was suggested to reduce the risk of powder caking. Selected DPI formulation remained higher emitted ratio (95.6%), than spray dried particle (52.5%) at 25 °C 65% RH condition for 1-month storage. In conclusion, VFI measurement is useful for selecting the DPI formulation by mitigating powder caking risk with limited samples.
Biopharmaceutical dry powder inhaler
(Bio-DPI) is an attractive formulation for non-invasive administration method
for biopharmaceutical compounds. In Bio-DPI to ensure spray stability, it is
important to control the powder caking risk of the formulation. To detect
powder caking risk, Void Forming Index (VFI) is a useful method for DPI
The authors conducted formulation screening
using VFI, to develop a high-dose Bio-DPI formulation containing 50 mg of
lysozyme per capsule. As a result, VFI clarified the powder caking risk of each
formulations and contributed to selection of high spray stability formulation.
In this study, 21 tea types (six black, four green, three Oolong, two herb, and five medicinal) were used to remove ionic dye from wastewater, as they could be potential adsorbents for several ionic dyes without purification or activated treatment. The majority of the 21 teas could adsorb cationic (MB) and anionic (ORII) dyes, with greater suitability for cationic dyes, as well as BB54 and BR46. Black dye (KBla), a mixture of several dyes, was adsorbed to a high degree. The tea waste treatment resulted in chromaticity reduction of the dye solution and turbidity changes. Dye adsorption was greater at higher temperatures than lower ones, although the effect of temperature was not strong. The adsorptions fit the pseudo-second-order-model; therefore, they involved chemical adsorption. The tea waste had great potential for the adsorption of several types of dyes without purification or activated treatment, although the mechanisms are yet to be determined. Therefore, the physical properties and structural components of each tea type should be analyzed by comparing common or different features of tea types. Taken together, many types of tea that are consumed worldwide can be used for efficient adsorption of ionic dyes by application of the tea waste.
Habiterpenol is a G2 checkpoint inhibitor isolated from the culture broth of Phytohabitans sp. 3787_5. Here, we report the synthesis of new habiterpenol analogs through the total synthesis process of habiterpenol and evaluating the analogs for G2 checkpoint inhibitory activity. We investigated two different synthetic approaches for total synthesis, with intramolecular conjugate addition and Ti(III)-mediated radical cyclization as key reactions. Although the former was unsuccessful, the latter reaction facilitated stereoselective total synthesis and determination of the absolute configuration of habiterpenol. The extension of these chemistries to a structure–activity relationship (SAR) study gave new habiterpenol analogs, which could not be derived from natural habiterpenol and only be synthesized by applying the total synthesis. Therefore, this study provides important insights into SAR studies of habiterpenol.
paper describes the synthesis of new derivatives of habiterpenol and their structure-activity
relationships. Habiterpenol is a G2 checkpoint inhibitor that has recently
attracted attention as a new vital molecular-targeting therapeutic agent. Combination
therapy using low-doses of anticancer agents and G2 checkpoint inhibitors has
great potential as an effective treatment for cancer because it minimizes the
dosage of the DNA-damaging anticancer agents and results in fewer side effects.
The authors have independently developed a total synthesis to obtain new habiterpenol
derivatives that cannot be derived from natural products, and have further
studied their structure-activity relationships.
The antitumor drug paclitaxel has low water solubility, and its bioavailability is limited by the dissolution rate. To overcome this low water solubility, the currently marketed drug, Taxol, is formulated in a vehicle including Cremophor EL and ethanol mixture (1/1, v/v). However, Cremophor EL has been shown to have serious adverse side effects, such as hypersensitivity reactions and neurotoxicity. Improving the solubility of paclitaxel makes it possible to reduce side effects and enhance drug efficacy during antitumor therapy. One way to improve the solubility of poorly soluble drugs is to decrease their particle size to the nano-range to increase the surface area and dissolution rate. In the present study, we aimed to develop a new method for paclitaxel nanoparticle production. Polymeric nanoparticles of paclitaxel were prepared by laser irradiation at 1064 nm, which is the wavelength in the near-IR region. The prepared nanoparticles had a mean size of 57.9 nm and were spherical in shape. X-ray powder diffraction analysis showed that paclitaxel in the nanoparticles was in an amorphous state. These results demonstrate that the preparation of nanoparticles by laser irradiation is effective in improving the solubility of paclitaxel. Furthermore, the nanoparticles had an equivalent efficacy to Taxol in cell growth inhibition against breast cancer MCF-7 cells and drug efficacy in MCF-7 tumor-bearing mice as determined using positron emission tomography. Our method for preparing paclitaxel nanoparticles may be more effective in treating tumors with fewer adverse side effects than conventional Taxol.
Propranolol is used as the first-line treatment for infantile hemangiomas (IHs). As oral formulations can cause systemic adverse drug reactions (ADRs), we prepared topical propranolol formulations and evaluated their pharmaceutical profiles. We also present three cases of pediatric patients with IHs who were treated with the propranolol formulations. Propranolol cream (hydrophilic cream, 1, 3, and 5%) and gels (carboxyvinyl polymer, hydroxypropyl methylcellulose, gellan gum, 1%) were prepared. The in vitro skin permeability of these formulations was assessed using Franz-type diffusion cells. The pharmaceutical profiles, including propranolol content, pH, and ductility, of the propranolol creams were evaluated. For the stability test, similar pharmaceutical evaluations were performed after the creams were stored at 25 °C and 56% relative humidity for 3 months. We examined three patients treated with propranolol cream to investigate the clinical course of IH and adverse events after the propranolol cream was applied for 5–12 months. In the in vitro skin permeability assay, topical propranolol formulations made of hydrophilic cream and gellan gum permeated the most. The amount of propranolol that permeated increased with propranolol concentration. After storage for 3 months, no substantial changes were observed in any pharmaceutical profile. The IHs were discolored in all patients. Tumor size also decreased in some patients. Furthermore, no adverse events caused by propranolol cream were observed during application. In conclusion, propranolol cream can be prepared as a hospital formulation with adequate quality. Topical propranolol therapy is effective in reducing the incidence of systemic ADRs.
A novel alkaloid caulophyine A (1) was isolated from the roots of Caulophyllum robustum Maxim., along with six known alkaloids 2–7. The structure of 1 was elucidated by extensive NMR and high resolution-time-of-flight (HR-TOF)-MS analyses, it is a rare nitrogen containing polycyclic aromatic hydrocarbon. The in vitro bioassays revealed that 2 presented remarkable cytotoxicity against A549 with an IC50 value of 3.83 µM in comparison with the positive control etoposide (IC50 = 11.63 µM). Compounds 1 and 2 also displayed weak Acetylcholinesterase (AChE) inhibitory activity with IC50 values of 123.03 and 80.74 µM respectively.
This paper reports one rare azapyrene alkaloid named caulophyine A along with six known compounds identified
from the roots of Caulophyllum robustum
which was collected on Taibai mountain, the highest peak of the Qinling
mountains, Shaanxi province, China. Caulophyine A is a nitrogen containing polycyclic aromatic
hydrocarbon, possess a naphtho[2,1,8-def]isoquinoline
fragment. This is the first
report of the nitrogen containing azapyrene alkaloid identified from plant. The
in vitro bioassays revealed that caulophyine A displayed weak acetylcholinesterase (AChE) inhibitory
Five new crotofolanes, named crotocascarins R–V (1–5), one rearranged trinorcrotofolane, crotocascarin δ, and one phorbol derivative were isolated from the EtOAc-soluble fraction of the MeOH extract of the leaves of Croton cascarilloides. Crotocascarins R (1), T (3), and U (4) possessed isobutyric acid as an acyl moiety and crotocascarin B (2) an acetyl group, whereas crotocascarin V (5) was elucidated to be a hydroxylated compound of crotocascarin K at the 9-position. Crotocascarin δ (6) was a trinor rearranged crotofolane with a tertiary hemiketal functional group at the 8-position. The absolute configuration of the 8-position was determined by the comparison of the experimental electronic circular dichroism (ECD) spectrum and calculated ECD spectra. Compound 7 was a phorbol ester derivative with a peroxide functional group. The fatty acid attached at the 12-position was found to be a single species—i.e., lauric acid (C-12)—from the evidence of the mass spectral data.
We designed and synthesized non-peptide organic molecular ligands for integrin αvβ3. Candidate ligands featured amidino analog and carboxy groups as binding sites on either side of a spacer, which consisted of benzophenone or an analog, such as diphenyl sulfide, diphenyl sulfoxide, diphenyl sulfone, or diphenyl ether. Competitive binding assays to integrin αvβ3 with respect to [125I]echistatin were used to determine inhibitory activity of the synthetic ligands. Ligands bearing 2-aminobenzimidazoyl and glycyl groups separated by a benzophenone spacer demonstrated more potent binding than did a linear Arg-Gly-Asp (RGD) tripeptide that represents the native integrin αvβ3 binding motif. Ligands possessing 2-aminobenzimidazoyl and carboxy groups and diphenyl sulfoxide or diphenyl ether spacers inhibited binding of [125I]echistatin with IC50 values similar to that of the linear RGD tripeptide.
A p-quinone analog having the komaroviquinone pharmacophore fused with a more conformationally flexible cycloheptane ring, was semisynthesized from natural demethlsalvicanol isolated from Perovskia abrotanoides via four steps in 26% overall yield. The IC50 for the antitrypanosomal activity of the analog was 0.55 µM.
Prodrugs have seen increased clinical applications as therapeutic agents, as they reduce undesirable side effects and improve the therapeutic potential of drugs. While microorganisms produce numerous secondary metabolites with useful medicinal properties, there are only a handful of naturally occurring prodrugs discovered to date. The techniques of isolating secondary metabolites with therapeutic potential from natural product producers have been developed extensively over the years. However, the methods of identifying prodrugs from microbes have not been examined in depth, partly because prodrug-type compounds inherently lack the biological activities that are often used to screen for therapeutically useful secondary metabolites. Therefore, we hypothesized that the difficulty in searching for natural prodrug-type compounds may be addressed by simulating human prodrug activation within natural product-producing microbes. We chose to introduce human CYP (hCYP) into natural product-producing filamentous fungi, because hCYPs are the key enzymes that activate prodrugs in human body, and filamentous fungi are known to be prolific producers of a wide variety of natural products. Here, we successfully identified a cytotoxic, antibiotic and potential anti-diabetic natural product leporin B from Aspergillus flavus that was previously not known to produce this compound. Through bioinformatic and metabolite analyses, we identified the prodrug-equivalent compound leporin C that is converted into leporin B by the action of the hCYP isoenzyme 3A4. By employing various prodrug-activating enzymes and microbes that biosynthesize diverse arrays of natural products, we should be able to probe wider biosynthetic space for identification of interesting prodrug-type natural products.
The authors successfully demonstrated that expression of a hCYP
gene in a filamentous fungus led to the identification of a bioactive natural
product from a strain previously not reported to produce the compound, and a
prodrug-like secondary metabolite that can be activated by an hCYP. Our
approach can be further developed by employing other types of CYPs and
prodrug-activating enzymes in combination with microbes, with differing
secondary metabolite biosynthetic potentials, to explore a wider biosynthetic
space for identification of interesting prodrug-type natural products.