Pharmaceutical Research最新文献

Background: Calcineurin inhibitors (CNIs) are immunosuppressive agents that inhibit calcineurin (CN) and are recommended for the treatment of lupus nephritis (LN). In clinical trials, differences in the safety profiles of CNIs have been observed. Emerging data suggests that small molecule therapeutics may be differentially distributed and retained within organ tissues, potentially explaining these safety profile disparities.

Methods: This study investigated the renal distribution and retention of the CNIs voclosporin (VCS), tacrolimus (TAC), and cyclosporine A (CSA) in CD-1 mice using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-MSI).

Results: Distinct patterns of the distribution and retention of these compounds were observed. VCS showed a moderate cortical distribution, peaking between 15- and 30 min post administration, and was then rapidly excreted with minimal renal retention observed by 2 h post-dosing. In contrast, CSA exhibited a diffuse, persistent distribution in renal structures for up to 4 h post-dosing. TAC showed a diffuse distribution pattern, with retention observed in the renal medulla for up to 7 h post-dosing.

Conclusions: These data indicate that CNIs display different renal handling profiles. The shorter duration of renal retention of VCS demonstrated in the healthy mice indicates a differentiated profile compared to the other CNIs. Further research on the body-wide tissue distribution and renal handling of TAC, VCS and CSA in humans will aid in delineating the distinct clinical profiles of CNIs and optimize their use in treating immune disorders.

Purpose: The intestinal absorption of compounds administered orally can be impacted by permeability, metabolism and uptake/efflux transport. This study aimed to characterize the EpiIntestinal duodenum microtissue developed from duodenum enterocytes and assess whether permeability, metabolism and transport could be simultaneously investigated in this model.

Methods: Healthy human primary duodenum enterocytes were cultured on a permeable support. Their ability to predict drug absorption was evaluated using a set of drugs with known human absorption. Intestinal drug-metabolizing enzymes and transporters were assessed by analyzing their protein expression and functional activities using specific probe substrates and inhibitors.

Results: The permeability (Papp) of the drug set showed a positive correlation with human % Fa. The expression and functional activities of P-gp, BCRP, MRPs (efflux ratio > 2), and PEPT1 were demonstrated in the microtissues. The functional activities of CYP3A4/5, CYP2C19, CYP2C8, UGT1A1 and SULT1B1 were also confirmed by the formations of probe substrate metabolites. In addition, the dominant effect of CYP3A4/5 over P-gp on the Papp of nicardipine was observed with a significant increase in permeability (Papp = 6.6 × 10^-6 cm/s) following the addition of elacridar and ketoconazole compared to the control Papp of 2.8 × 10^-6 cm/s and the Papp with elacridar at 3.7 × 10^-6 cm/s.

Conclusions: These findings suggest that the EpiIntestinal duodenum microtissue can effectively replicate the complex interplay of permeability, metabolism, and transport in the gut, thereby improving the prediction of oral drug absorption.

Background: Psoriasis is a chronic immune-mediated skin disorder marked by excessive keratinocyte proliferation, inflammation, and impaired barrier function, all of which limit effective topical drug delivery.

Objectives: To develop and optimize a tannic acid-loaded transfersomal gel to improve transdermal delivery, skin deposition, and therapeutic efficacy in psoriatic skin.

Methods: Transfersomes were prepared using the thin-film hydration method and optimized through a Box-Behnken design evaluating surfactant type, total lipid content, and phospholipid-to-surfactant ratio. The optimized vesicles were analyzed for particle size, PDI, zeta potential, and entrapment efficiency. Transfersomes were incorporated into a carbopol gel, and evaluated through rheological testing, in vitro release, ex vivo permeation studies, and in vivo antipsoriatic activity using an imiquimod-induced psoriasis mouse model.

Results: The optimized Span-80-based formulation showed a particle size of 205 nm, PDI 0.209, zeta potential -26.0 mV, and 84% entrapment efficiency. Gel incorporation provided suitable rheology and sustained release (63.7% over 24 h). Ex vivo studies revealed a flux of 4.99 μg/cm²/hr, a 2.74-fold improvement over conventional gel. In vivo, the transfersomal gel significantly reduced PASI scores from 10.8 ± 0.33 (disease control) to 4.5 ± 0.24. Histopathology confirmed decreased epidermal hyperplasia and inflammation.

Conclusions: The combination of ultradeformable transfersomes with tannic acid produced enhanced permeation, sustained release, and significant antipsoriatic effects. This optimized transfersomal gel demonstrates strong potential as an effective topical therapy for psoriasis.

Purpose: Osteoarthritis is a degenerative joint disease that causes painful inflammation with cartilaginous damage that highly impacts geriatric health, demanding advanced therapy with limited complications on treatment. Conventional therapies focused on associated pain only, thus failing to treat the root cause of inflammatory degenerative cartilaginous tissue of the joints. To overcome the related issues, a holistic approach is the combinatorial therapy of Oxaprozin (OXA) and Apricot kernel oil (AKO) which encompasses the excellent analgesic and restoration of lipid-balance activities.

Method: The scalable targeted transcutaneous delivery of OXA-loaded Apricot oil-based nanoemulgel (OXA-NEG) was optimized and evaluated. Further, preclinical studies aligned with better therapeutic outcomes.

Result: The GC-MS study of the AKO identified potential components, including vitamins, fatty acids, and antioxidants. The optimized nanoemulsion with an average globule size of 208.5 ± 5.97 nm, PDI 0.2502 ± 0.045, and zeta potential of -16.33 ± 0.241 mV, revealed promising delivery. The OXA-NEG exhibited good spreadability and extrudability in texture analysis. The in-vitro and ex-vivo studies demonstrated sustained release with high permeation flux compared to conventional gel. The therapeutic potential was assessed on an osteoarthritis-induced animal model, where radiographic examination revealed that the OXA-NEG group of rats showed prominent recovery of the swollen joint cartilage in contrast to the control group. The plasma TNF-α and IL-6 levels also showed substantial variation (p < 0.001) compared to the control group.

Conclusion: It is concluded that the proposed formulation has promising dual therapeutic potential for transcutaneous delivery, meeting safety aspects and could be aligned with better clinical acceptance.

Microneedles (MNs) provide a minimally invasive and efficient platform for transdermal drug delivery, offering precise control over dosage and release kinetics. Recent advances in dual-drug delivery using dissolvable MNs have focused on optimizing structural design, material composition, and programmable release mechanisms. Dual-layer or core-shell MN configurations allow spatial and temporal separation of drugs, while stimuli-responsive polymers enable release in response to physiological cues such as glucose concentration, pH, or reactive oxygen species (ROS). This review summarizes emerging strategies for co-delivery through dissolving MNs, emphasizing how design parameters including morphology, materials, and nanoformulations influence mechanical performance and drug-release profiles. Applications in cancer, diabetes, wound healing, and inflammatory diseases are highlighted. For example, a dual-drug MN co-loaded with an anti-PD-L1 antibody and 1-methyl-D,L-tryptophan (1-MT) achieved prolonged intratumoral retention and enhanced antitumor efficacy. Similarly, MNs incorporating MnSH nanozymes and polymyxin B demonstrated synergistic antibacterial and pro-angiogenic effects in wound models. The integration of nanocarriers and responsive polymers has expanded the therapeutic potential of MN-based systems, enabling precise, localized, and sustained co-delivery of active agents. Finally, current challenges including large-scale manufacturing, reproducibility, clinical validation, and regulatory approval are discussed to outline future directions for translating MN-based dual-drug delivery into clinical practice.

Objectives: Carbamazepine (CBZ) is a drug that exists in multiple crystal forms and hydrates. In this study, CBZ was used as the model drug, and an attempt was made to regulate the crystal form and morphology of the drug using the DES system. The effects of deep eutectic solvents (DESs) on the crystal form of CBZ were systematically investigated.

Methods: The solubility of CBZ in different DES mass ratios was determined. Single crystals of the CBZ crystal form VI were prepared and the structure were analyzed. The differences between the new crystal form of CBZ and other crystal forms have been discussed. Molecular electrostatic potential surface (MEPS), Hirshfeld surface (HS), and molecular dynamics calculation (MD) were conducted to elucidate these phenomena at the molecular level.

Results: Form VI was successfully obtained under specific experimental conditions. The constitute and mass ratio of DES in methanol solution and the degree of supersaturation were found to influence the morphology of form VI.

Conclusions: The new crystal form VI of CBZ was obtained through the DES solvent system. The existence of DES can alter the interactions between molecules, thereby providing the possibility for the formation of new crystal forms and morphologies.

Purpose: Drying is widely used to enhance the storage stability of biologic drug products which are susceptible to degradation in aqueous solutions. Compared to conventional freeze-drying, spray drying offers continuous, high-throughput manufacturing. Stabilizing excipients are critical for protecting proteins from stresses during drying and storage. This study evaluated the potential of polysaccharide- and protein-lysate-based polymeric excipients as alternatives to commonly used stabilizers such as trehalose and mannitol, using bovine serum albumin (BSA) as a model protein.

Methods: Spray-dried BSA formulations were prepared with (2-hydroxypropyl)-β-cyclodextrin (HPβCD), hydrolyzed gelatin, dextran 20 kDa, or sodium carboxymethyl cellulose (NaCMC) polymers, either alone or in combination with trehalose or mannitol. Protein stability was assessed by monitoring monomer loss under stressed storage (40°C, 3 months). Crystallinity and changes in the secondary structure were analyzed using powder X-ray diffraction (PXRD) and solid-state Fourier transform infrared spectroscopy (ssFTIR), respectively. Particle size and size distribution, surface morphology and reconstitution time were also evaluated.

Results: Spray-dried BSA formulations containing HPβCD or hydrolyzed gelatin, either alone or with sugars, exhibited lower monomer loss than the trehalose- or mannitol-only formulations. In contrast, formulations with Dextran 20 kDa and NaCMC showed poor stability. PXRD revealed progressive sodium chloride crystallization during storage. ssFTIR detected secondary structure changes in the BSA over 3 months. The spray-dried powders with polysaccharides generally showed longer reconstitution times than those with polymers.

Conclusion: HPβCD and hydrolyzed gelatin improved the physical stability of spray-dried BSA compared to sugar excipients, which highlights their potential use as stabilizing additives.

Objective: Pharmaceutical products are under constant development and improvements are continuously made. Implementing a change can have impact on the stability of the product. Comparing stability slopes of post-change batches monitored over short duration with those of pre-change batches monitored during long-term studies is not entirely straightforward as the longer the time frame the lower the uncertainty on the estimated slope, and therefore the pre-change and post-change slopes cannot be compared directly. The purpose is to develop a procedure making maximal use of all the information in the pre-change batches.

Methods: The knowledge in the complete pre-change data set in terms of slopes and variability is captured in a posterior distribution using a Bayesian analysis. Using this pre-change knowledge together with the time points used for a post-change batch, it is then studied if the observed slope of the post-change batch is in line with the predictive distribution for the post-change slope as based on the pre-change data.

Results: The proposed methodology is presented and applied to real data obtained in a stability comparability study at Merck & Co., Inc., Rahway, NJ, USA.

Conclusion: The method is suitable for assessing comparability of stability slopes.

Purposes: The tabletability flip phenomenon (TFP), where an active pharmaceutical ingredient (API) with poorer tabletability exhibits better tabletability when formulated with excipients, has been well documented in direct compression systems. However, the impact of granulation on TFP remains unexplored. Hence, the purpose of this work was to investigate the occurrence and underlying mechanisms of TFP in dry-granulated formulations.

Methods: Acetaminophen (APAP) and ibuprofen (IBU) were used as model APIs since they exhibit TFP in non-granulated blends. Granules of each API were prepared at two porosity levels (9% and 19%) by controlling compaction pressure. Granules with and without varying levels of extragranular magnesium stearate (MgSt) were evaluated for tabletability, bonding area (BA), and bonding strength (BS).

Results: For the more porous granules (19% porosity), extensive fragmentation during compaction preserved TFP through the same mechanism observed in the pre-blends. In contrast, the less porous granules (9% porosity) remained largely unfragmented during compaction, allowing their intrinsic mechanical properties to govern the BA-BS interplay. Although APAP granules showed smaller BA due to lower deformability, the higher BS led to superior tabletability, thus maintaining TFP. The incorporation of ≥ 1% MgSt minimized BS difference between formulations, effectively eliminating TFP, since the softer IBU granules exhibited higher tabletability due to larger BA.

Conclusion: These results demonstrated the applicability of the BA-BS framework in explaining TFP in granulated systems and highlight the importance of controlling granule porosity and MgSt levels to optimize tabletability in dry granulation processes.