Pharmaceutical Research最新文献

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.

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.

Objective: The purpose of this study is to analyze the impact of the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) transport characteristics of drugs on their intracerebral distribution in male cynomolgus monkeys.

Methods: Steady-state concentrations of 15 drugs (13 drugs and 2 compounds) transported by passive diffusion or via solute carrier (SLC) and/or ATP-binding cassette (ABC) transporters were measured in the frontal cortex interstitial fluid (ISF), lateral ventricular cerebrospinal fluid (CSF) and lumbar CSF of monkey brain by means of microdialysis and lumbar puncture methods. The values of brain ISF (or CSF)/plasma unbound concentration ratio (K_p,uu) were calculated to quantify the intracerebral distribution characteristics.

Results: The K_{p,uu,ISF,cortex} values of substrates of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)were much lower than unity. The ISF concentration of these drugs were increased by the co-administration of elacridar, suggesting active efflux of these drugs at the BBB. Contrary to expectations, some of P-gp substrates were efficiently distributed into the brain with K_{p,uu,ISF,cortex} > 2. The lateral ventricular CSF concentrations of drugs tended to be higher than the ISF concentrations, while the lumbar CSF concentrations were comparable to the ISF concentrations.

Conclusion: The results of this study suggest that the intracerebral distribution of the test drugs from the blood in the monkey brain should consider the contribution of influx transporters as well as efflux transporters. In addition, the lumbar CSF concentrations of the test drugs appear to be a useful surrogate marker of the ISF concentrations.

Objective: Polymeric microspheres (MS) have been developed with moderate success using aqueous emulsification (AqE) for small molecules and peptides with a few approved products. AqE faces a challenge to achieve optimal encapsulation of large hydrophilic molecules such as proteins/mAbs. To overcome this, a novel non-aqueous emulsification platform, "FluoriPack" (FP), was developed. FP is a solid/hydrocarbon/fluorocarbon (S/H/F) platform that enables high biologic loading within MS, with minimal impact on biologic integrity.

Methods: To develop MS using FP, a model protein was encapsulated in polyorthoester (POE) MS via non-aqueous emulsification. The continuous phase was Fluorinert™ FC-40 containing a fluorosurfactant (PicoSurf™ 1). Protein loaded MS were evaluated for morphology, PSD, % loading & in-vitro release (IVR), accelerated stability testing, and toxicity of blank microspheres. Encapsulated protein released from MS were evaluated for integrity and potency.

Results: Preliminary evaluation indicates that MS prepared via FP (FP-MS) were superior to AqE-MS, indicated by the surface morphology (non-porous versus porous), encapsulation (> 60% versus < 10%), and burst release (< 40% versus > 75%). FP-MS had a mean diameter of ~ 40 µm and were stable over 1-month at accelerated conditions. No toxicity was observed in mammalian cells with > 80% viability post FP-MS treatment. The biologic retained integrity post-encapsulation with minimal aggregation (Δ 1.1%) and high potency (> 80%). In vitro release evaluation revealed a sustained release of biologic over 9 days (~ 8% every 24 h).

Conclusion: MS prepared using FluoriPack achieved the desired quality attributes, enabling it to be a promising tool for sustained delivery of biologics.

Objective: The effectiveness of pressurized metered-dose inhalers (pMDIs) relies on correct inhalation technique. While prior studies investigated idealized breathing, the impact of real-life irregularities remains less understood. This study explores how real-life irregularities-pausing, coughing, and premature exhalation-alter aerosol transport and deposition in the airways.

Methods: Large-eddy simulations combined with a discrete phase model were performed on a realistic male airway geometry extending from the oral cavity to the fourth bronchial generation. Computational predictions were validated against in vitro experiments conducted under constant inhalation.

Results: Breathing irregularities substantially modified airflow dynamics and shifted deposition toward the upper airways. Coughing generated the strongest vortical structures and turbulence, followed by premature exhalation. Deposition in the left lung decreased from 19.9% during standard COPD inhalation to 2.1% during exhalation and 0.9% during coughing, while mouth-throat deposition increased to 35.2% during coughing compared to 14.5% under the COPD baseline condition. Exhalation caused higher overall particle loss (27.9%) than coughing (24.1%), but coughing produced more pronounced inertial impaction in the upper airways. Fine particles (< 2 µm) were largely exhaled (approximately 80%), whereas particles in the 2-5 µm range-considered optimal for deep lung delivery-were redirected and lost under disturbed flow conditions.

Conclusions: Irregular breathing patterns markedly decrease deep lung deposition and increase upper airway losses. Repeated puffs without adequate intervals may exacerbate this problem, leading to excessive upper-airway deposition and increasing the likelihood of side effects. These findings provide guidance for physicians to tailor puff number and timing, improving therapeutic efficacy while minimizing risks to patient safety.

Cancer continues to remain a global health challenge, and conventional chemotherapy has its own limitations such as poor solubility, systemic toxicity, nonspecific biodistribution, and multidrug resistance (MDR). Nanostructured Lipid Carriers (NLCs) have proved as one of the effective drug delivery systems which can overcome all challenges of conventional technologies by enhancing therapeutic efficacy with reduced side effects. Therefore, this comprehensive review describes, in detail the structure, composition, formulation characteristics of NLCs, and manufacturing techniques. NLCs have shown significant advantages including enhanced drug solubility, controlled release characteristics, and encapsulation of hydrophilic as well as lipophilic drugs. Passive and active targeting enables NLCs to maximize the accumulation of drugs at targeted tumor sites through the enhanced permeation retention (EPR) effect. In addition, MDR targeting and long-circulating NLCs can enhance effectiveness against the resistance mechanisms of cancer cells. Cancer theranostics integrated with NLCs provide real-time diagnosis and treatment opportunities. Despite all these potential advantages, NLCs are still facing a few challenges of large-scale manufacturing, toxicity issues, and regulatory approvals. Yet, recent progress in personalized medicine and lipid-based nanotechnology reflects the potential of NLCs as a versatile and efficient delivery system for anticancer drugs. This review tries to clarify the evolving aspect of NLCs as well as the challenges faced in cancer treatment and strategies to overcome them by focusing on their ability to reshape chemotherapy and improve patient compliance.

Purpose: Earlier studies have reported the ability of GPNMB protein (GPNMB) to promote osteoblast differentiation and function. However, the realization of clinical potential of GPNMB in bone regeneration will require suitable delivery systems to overcome challenges pertaining to poor dosing and poor retention at target sites. Distribution of osteogenic therapeutics away from the desired bone regeneration sites has been linked to serious adverse effects.

Method: We developed thermoresponsive GPNMB-hydrogels using PLA-b-PEG-b-PLA copolymer (10-30% w/v) and demonstrated the ability to undergo solution-to-gel transition at physiologically relevant temperatures. The hydrogel formulations were characterized by vial inversion techniques, dynamic light scattering, rheological assessments and bioretention studies. GPNMB loading (1-10 µg/mL) did not interfere with hydrogel's thermo-reversibility and viscoelastic behaviors as obtained from rheological strain and frequency sweep tests.

Results: The in-vitro release of GPNMB reflected a diffusion-controlled kinetic and is supported by hydrogel degradation pattern involving a rapid loss of the PEG units throughout the 8-week period and a delayed degradation of the PLA units. In-vivo long- and short-term safety studies, following GPNMB treatments, showed acceptable serum levels of tissue function and inflammatory markers. There were no detectable signals of ectopic bone formation. Efficacy assessment of GPNMB-hydrogel was based on in-vitro osteoblast differentiation and in-vivo bone regeneration studies in a murine calvaria defect model.

Conclusion: The biofunctional properties of GPNMB-hydrogels were supported by enhancement of bone regeneration. Additional studies are warranted to fully examine the potential of GPNMB-hydrogel in bone regeneration using a disease model of fracture healing.

Objective: Globally, a significant overlap exists between females affected by HIV and HSV-2 infections, and who have an unmet need for contraception. Intravaginal rings (IVRs) have become widely accepted by women worldwide for contraception and hormone replacement therapy and provide a promising platform as a multipurpose prevention technology (MPT).

Methods: Using state-of-the-art 3D printing process known as continuous liquid interface production (CLIP™), IVRs with an internal honeycomb (HC 2.53 mm) geometry were fabricated with a silicone-urethane resin. IVRs were loaded with a triple-drug combination of an anti-HIV drug (Dapivirine, DPV, 30 mg), an anti-herpes drug (Pritelivir, PTV, 20 mg) and a contraceptive hormone (Levonorgestrel, LNG, 2.0 mg) using a solvent swelling method in acetone.

Results: IVRs elicited zero-order release kinetics following an initial burst for all three APIs when formulated individually or in combination. Release rates were above benchmark therapeutic targets for DPV and LNG (200 µg/day DPV, 20 µg/day LNG). A series of accelerated stability studies demonstrated the physical integrity of IVRs after 6 months of storage at 40ºC/75%RH. DPV remained stable over 6 months, whereas PTV and LNG exhibited significant decrease in concentration after 3 months of storage with presence of degradation products detected by HPLC. Mouse size placebo rings (3 mm OD) elicited 100% cell viability in relevant cell lines and were well tolerated in vivo in mice.

Conclusions: Collectively, these results demonstrate that this first-in-line 3D printed MPT IVR has potential to expand preventative choices for young women and girls against HIV, HSV, and unplanned pregnancy.

The convergence of peptides and nanoparticles through bionanoconjugation has emerged as a transformative strategy to address the persistent challenges in treating neurodegenerative disorders. Peptides, particularly short sequences (< 45 amino acids), offer unique advantages as protein mimetics, including structural flexibility, target specificity and blood-brain barrier permeability. Their clinical translation is hindered by rapid enzymatic degradation, short half-life, and poor bioavailability. Conjugation with nanoparticles, overcomes these limitations by enhancing stability, prolonging circulation, and enabling precise targeting. Peptide-nanoparticle conjugates, including TAT-functionalized gold nanoparticles and RGD-decorated polymeric systems, have shown significant improvements in blood brain barrier penetration. These advancements are associated with a reduction in amyloid-beta aggregation and the inhibition of tau hyperphosphorylation in preclinical models. These hybrids leverage peptides dual roles as therapeutic agents and drug carriers, often exploiting receptor-mediated transport for brain delivery. This review critically evaluates covalent and noncovalent conjugation strategies, such as carbodiimide chemistry, ligand exchange, and click reactions, highlighting their impact on structural stability and bioactivity. We further discuss advances in peptide classes, including cell-penetrating peptides, nuclear localization signals, targeting peptides and bioactive peptides, emphasizing their applications in mitigating oxidative stress, neuroinflammation, and protein misfolding in neurodegenerative disorders. Despite promising preclinical outcomes, challenges such as scalability, immunogenicity, and heterogeneous blood brain barrier models remain barriers to clinical translation. This review outlines a strategy for enhancing peptide-NP conjugates as future neurotherapeutics by integrating existing methodologies, therapeutic results, and challenges. This underscores the importance of collaborative efforts across various disciplines to bridge the gap between advancements in nanotechnology and their clinical applications.