Development of Amorphous Solid Dispersion Sustained-Release Formulations with Polymer Composite Matrix-Regulated Stable Release Plateaus.

PURPOSE: This study was designed to develop ibuprofen (IBU) sustained-release amorphous solid dispersion (ASD) using polymer composites matrix with drug release plateaus for stable release and to further reveal intrinsic links between polymer' matrix ratios and drug release behaviors. METHODS: Hydrophilic polymers and hydrophobic polymers were combined to form different composite matrices in developing IBU ASD formulations by hot melt extrusion technique. The intrinsic links between the mixed polymer matrix ratio and drug dissolution behaviors was deeply clarified from the dissolution curves of hydrophilic polymers and swelling curves of composite matrices, and intermolecular forces among the components in ASDs. RESULTS: IBU + ammonio methacrylate copolymer type B (RSPO) + poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP VA64) physical mixtures presented unstable release behaviors with large error bars due to inhomogeneities at the micrometer level. However, IBU-RSPO-PVP VA64 ASDs showed a "dissolution plateau phenomenon", i.e., release behaviors of IBU in ASDs were unaffected by polymer ratios when PVP VA64 content was 35% ~ 50%, which could reduce risks of variations in release behaviors due to fluctuations in prescriptions/processes. The release of IBU in ASDs was simultaneously regulated by the PVP VA64-mediated "dissolution" and RSPO-PVP VA64 assembly-mediated "swelling". Radial distribution function suggested that similar intermolecular forces between RSPO and PVP VA64 were key mechanisms for the "dissolution plateau phenomenon" in ASDs at 35% ~ 50% of PVP VA64. CONCLUSIONS: This study provided ideas for developing ASD sustained-release formulations with stable release plateau modulated by polymer combinations, taking full advantages of simple process/prescription, ease of scale-up and favorable release behavior of ASD formulations.

Specific surface area of mannitol rather than particle size dominant the dissolution rate of poorly water-soluble drug tablets: A study of binary mixture.

The dissolution behavior of tablets, particularly those containing poorly water-soluble drugs, is a critical factor in determining their absorption and therapeutic efficacy. Traditionally, the particle size of excipients has been considered a key property affecting tablet dissolution. However, lurasidone hydrochloride (LH) tablets prepared by similar particle size mannitol, namely M200 (D90 = 209.68 ± 1.42 µm) and 160C (D90 = 195.38 ± 6.87 µm), exhibiting significant differences in their dissolution behavior. In order to find the fundamental influential factors of mannitol influencing the dissolution of LH tablets, the properties (particle size, water content, true density, bulk density, tapped density, specific surface area, circularity, surface free energy, mechanical properties and flowability) of five grades mannitol including M200 and 160C were investigated. Principal component analysis (PCA) was used to establish a relationship between mannitol properties and the dissolution behavior of LH. The results demonstrated that specific surface area (SSA) emerged as the key property influencing the dissolution of LH tablets. Moreover, our investigation based on the percolation theory provided further insights that the SSA of mannitol influences the probability of LH-LH bonding and LH infinite cluster formation, resulting in the different percolation threshold states, then led to different dissolution behaviors. Importantly, it is worth noting that these findings do not invalidate previous conclusions, as reducing particle size generally increases SSA, thereby affecting the percolation threshold and dissolution behavior of LH. Instead, this study provides a deeper understanding of the underlying role played by excipient SSA in the dissolution of drug tablets. This study provides valuable guidance for the development of novel excipients aimed at improving drug dissolution functionality.

[Clinical Characteristics of CD4-CD56+ Blastic Plasmacytoid Dendritic Cell Neoplasm].

OBJECTIVE: To explore the clinical manifestations, pathological features, immunophenotype, as well as diagnosis, treatment and prognosis of patients with CD4-CD56+ blastic plasmacytoid dendritic cell neoplasm (BPDCN), in order to further understand the rare disease. METHODS: The clinical data, laboratory examinations and treatment regimens of two patients with CD4-CD56+ BPDCN in the First Affiliated Hospital of Wannan Medical College were retrospectively analyzed. RESULTS: The two patients were both elderly males with tumor involved in skin, bone marrow, lymph nodes, etc. Immunohistochemical results of skin lesions showed that both CD56 and CD123 were positive, while CD4, CD34, TdT, CD3, CD20, MPO and EBER were negative. Flow cytometry of bone marrow demonstrated that CD56, CD123, and CD304 were all positive, while specific immune markers of myeloid and lymphoid were negative. Two patients were initially very sensitive to acute lymphoblastic leukemia or lymphomatoid chemotherapy regimens, but prone to rapid relapse. The overall survival of both patients was 36 months and 4 months, respectively. CONCLUSION: CD4-CD56+ BPDCN is very rare and easily misdiagnosed as other hematological tumors with poor prognosis. Acute lymphoblastic leukemia or lymphomatoid therapy should be used first to improve the poor prognosis.

Thermosensitive methyl-cellulose-based injectable hydrogel carrying oxaliplatin for the treatment of peritoneal metastasis in colorectal cancer.

Advanced colorectal cancer (CRC) with peritoneal metastasis (PM) is a highly aggressive malignancy with poor prognosis. Systematic chemotherapy and local treatments are the primary therapeutic approaches. However, systemic chemotherapy is limited by low accumulation of drugs at the tumor site and systemic toxicity. Local treatments include cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). However, CRS faces challenges related to incomplete tumor resection, while HIPEC is restricted by the uneven distribution of drugs and potential complications. Herein, a thermosensitive methyl-cellulose-based injectable hydrogel carrying oxaliplatin (OXA) was synthesized to improve this situation. Specifically, methyl cellulose (MC) coagulated into a hydrogel, and OXA was loaded into the MC hydrogel to construct the OXA-MC hydrogel. We explored the OXA-MC hydrogel for the treatment of PM in CRC. The results demonstrated that the OXA-MC hydrogel had favorable biocompatibility and thermo-sensitivity and could act as a local slow-release drug carrier. Moreover, in a CT-26 tumor-bearing model, it showed a remarkable anti-tumor effect by inhibiting proliferation and promoting apoptosis. Additionally, transcriptome analysis indicated that the OXA-MC hydrogel might be involved in the regulation of the PI3K-AKT signaling pathway. In summary, we successfully prepared the OXA-MC hydrogel and provided a valid approach in the treatment of PM in CRC, which lays a foundation for other PM treatments.

Trace polymer coated clarithromycin spherulites: Formation mechanism, improvement in pharmaceutical properties and development of high-drug-loading direct compression tablets.

Clarithromycin (CLA) is a high dose antibiotic drug exhibiting poor flowability and tabletability, making the tablet development challenging. This study aims to develop spherulitic CLA by introducing trace amount of polymer in crystallization solution. Its formation mechanism, physicochemical properties and potential for the direct compression (DC) tablets development were also investigated. Morphological analyses and the in situ observation on crystallization process revealed that the CLA spherulites are formed by fractal branching growth from both sides of the threadlike precursor fibers. 1H NMR analysis and nucleation time monitoring indicated that the existence of hydroxypropyl cellulose in solution slowed down the crystal nucleation and growth rate by forming hydrogen bonding interactions with CLA molecules, making the system maintain high supersaturation, providing high driving forces for CLA spherulitic growth. In comparison to commercial CLA, the CLA spherulites exhibit profoundly improved flowability, tabletability and dissolution behaviors. XPS, contact angle and Raman mapping analysis confirmed the presence of a thin HPC layer on the surfaces and interior of CLA spherulitic particles, resulting in increasing powder plasticity, interparticulate bonding strength and powder wettability, thus better tabletability and dissolution performances. The improved flowability and tabletability of CLA spherulites also enabled the successful development of DC tablet formulation with a high CLA loading (82.8 wt%) and similar dissolution profiles to reference listed drug. This study provides a novel solid form of CLA with superior manufacturability for further development.

Effects of Benzo (a) Pyrene and 2,2',4,4'-Tetrabromodiphenyl Ether Exposure on the Thyroid Gland in Rats by Attenuated Total Reflection Fourier-Transform Infrared Spectroscopy.

Benzo[a]pyrene (B[a]P) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) are widespread environmental pollutants and can destroy thyroid function. We assessed the biochemical changes in the thyroid tissue of rats exposed to B[a]P and BDE-47 using attenuated total reflection Fourier-transform infrared spectroscopy combined with support vector machine(SVM). After B[a]P and BDE-47 treatment in rats, the structure of thyroid follicles was destroyed and epithelial cells were necrotic, indicating that B[a]P and BDE-47 may lead to changes of the thyroid morphology of the rats. These damages are mainly related to C=O stretch vibrations of lipids (1743 cm-1), as well as the secondary structure of proteins [amide I (1645 cm-1) and amide II (1550 cm-1)], and carbohydrates [C-OH (1138 cm-1), C-O (1106 cm-1, 1049 cm-1, 991 cm-1), C-C (1106 cm-1) stretching] and collagen (phosphodiester stretching at 922 cm-1) vibration modes. When SVM was used for classification, there was a substantial separation between the control and the exposure groups (accuracy = 96%; sensitivity = 98%; specificity = 87%), and there was also a major separation between the exposed groups (accuracy = 93%; sensitivity = 94%; and specificity = 92%).

Crystal defects creation in Mannitol@CaCl2 metal-organic framework by induced dehydration strategy for enhanced excipient mechanical properties.

The mechanical properties of solid pharmaceutical excipients are important for assisting drug tables production, and they determine the quality of the drug tablets. The purpose of this study was to explore the potential and mechanism of crystal defect engineering to improve the mechanical properties of Mannitol@CaCl2 MOF, a pharmaceutical excipient with metal-organic framework (MOF) structure designed and prepared in our previous study. In this study, a simple and efficient "induced dehydration strategy" was proposed to prepare Mannitol@CaCl2 MOF with crystal defects (DEMOF). SEM, TEM, HRTEM, PXRD, FTIR, DSC-TGA, and N2 adsorption-desorption isotherm revealed the successful introduction of lattice vacancy and macrostructural defects while preserving MOF's skeleton structure. Tabletability profiles indicated that DEMOF presented much better mechanical properties than the original MOF at the powder level. On single crystal and atomic scales, nanoindentation and DFT calculations revealed that the defect structure increased plasticity, decreased brittleness, and improved compressibility, resulting in DEMOF tablets with much higher tensile strength that met the criteria for direct compression excipients. The achieved performance modification illustrated the capability of defect engineering to tune mechanical properties of MOFs, and the Mannitol@CaCl2 DEMOF exhibited great potential to serve as a new direct compression pharmaceutical excipient.