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.

Biotechnology is becoming a key driver of innovation in health, agriculture, industry, and sustainability worldwide. Brazil has made significant progress in this field, thanks to its strong research institutions, diverse ecosystems, and active pharmaceutical and agribusiness sectors. However, despite these strengths, the country still faces critical barriers that limit its global competitiveness in biotechnology. These include a lack of coordination between academia and industry, limited early-stage investment, underdeveloped infrastructure, regulatory delays, and low levels of internationalization. This article provides a comprehensive overview of the biotechnology landscape in Brazil. It analyzes the global context, highlights the country's current position, and identifies gaps and opportunities across the biopharmaceutical value chain. Drawing from international benchmarks and national data, the paper proposes five strategic directions to strengthen Brazil's biotechnology ecosystem: (1) fostering translational science and innovation; (2) expanding access to capital and reducing investment risk; (3) improving infrastructure through shared platforms; (4) modernizing regulatory frameworks; and (5) positioning Brazil in global markets through its unique strengths, such as biodiversity, public health expertise, and agricultural leadership. The article concludes that Brazil has the scientific foundation and market potential to become a global player in biotechnology. However, realizing this potential will require coordinated efforts from government, industry, and academia. With the right policies and investments, Brazil can turn scientific advances into innovative solutions that benefit both its population and the global bioeconomy.

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.

Purpose: Human choroid plexus papilloma (HIBCPP) cells derived from choroid plexus papilloma in the lateral ventricle are considered suitable model cells for the blood-cerebrospinal fluid barrier (BCSFB). Therefore, in this study, the transporters expressed in HIBCPP cells were identified, and the functions of representative transporters were evaluated.

Methods: Transporter protein and mRNA expression were analyzed in HIBCPP cells using quantitative proteomics and quantitative reverse transcription-PCR. Transporter functions were evaluated by cellular uptake and transcellular transport studies using typical substrates.

Results: The following solute carrier (SLC) and ATP-binding cassette (ABC) transporters involved in drug and nutrient transport were expressed in HIBCPP cells: glucose transporter 1 (GLUT1), monocarboxylate transporter 1 (MCT1), L-type amino acid transporter 1 (LAT1), cationic amino acid transporter 1 (CAT1), glutamate transporter (GLAST), SLC35F2, multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP). Furthermore, the mRNA of organic anion/cation transporters, such as organic anion transporting polypeptide 1B3 (OATP1B3) and plasma membrane monoamine transporter (PMAT), were detected. Additionally, uptake of representative substrates of the SLC transporters LAT1, CAT1, GLAST, GLUT1, MCT1, and SLC35F2 in HIBCPP cells occurred in a time- and temperature-dependent manner and decreased in the presence of specific inhibitors. Furthermore, the representative substrates of these transporters were transported in a symmetric or asymmetric manner through HIBCPP cells between the apical (cerebrospinal fluid [CSF]) and basolateral (blood) sides.

Conclusion: Various nutrient and drug transporters are functionally expressed in HIBCPP cells. Therefore, HIBCPP cells could serve as a useful human BCSFB model to evaluate nutrient and drug transport between the CSF and blood.

Objective: Bioactive peptides derived from natural or synthetic sources have shown significant potential for cancer therapy; however, their clinical application is often limited by poor tumor selectivity and systemic toxicity. In this work, we aim to develop a multifunctional antitumor peptide with enhanced tumor- targeting capability and therapeutic efficacy.

Methods: A cationic antimicrobial peptide (AMP, (KKWW)₂ K-NH₂) was chemically modified via cysteine-mediated conjugation with 4-vinylphenylboronic acid, yielding the phenylboronic acid-conjugated AMP (PBA-AMP). Molecular dynamics (MD) simulations were performed to evaluate peptide-membrane interactions. Cellular uptake, cytotoxicity, and in vivo tumor-targeting and antitumor efficacy were assessed using MCF-7 cells and 4T1 tumor-bearing mice.

Results: MD simulations demonstrated that PBA-AMP exhibited rapid and stable binding to tumor cell membranes, maintaining consistent membrane interactions over a 50 ns simulation. Cellular studies revealed enhanced cellular uptake and increased cytotoxicity of PBA-AMP against MCF-7 breast cancer cell line (IC₅₀ = 38.46 μM) compared to naive AMP (IC₅₀ = 110 μM). In vivo imaging confirmed selective and prolonged tumor accumulation of PBA-AMP. Treatment with PBA-AMP significantly suppressed tumor growth in 4T1 tumor-bearing mice without observable systemic toxicity.

Conclusions: This study presents a rational design strategy for engineering tumor-selective, microenvironment-responsive therapeutic peptides. PBA-AMP represents a promising candidate for targeted cancer therapy, offering improved efficacy and reduced off-target effects.

Background: While photostability testing conditions for biologics are often based on small molecule standards, the unique characteristics of proteins necessitate a deeper understanding of appropriate testing and controls. This study examines the effects of light stress on various presentations of somatropin, a therapeutic growth hormone.

Methods: Somatropin was exposed to light in lyophilized, reconstituted, and diluted forms. Quality attribute changes were analyzed using size exclusion chromatography, micro-fluidic imaging, imaged capillary isoelectric focusing, and liquid chromatography mass spectrometry (LC-MS).

Results: Light stress increased high molecular weight species (HMWS), particularly in liquid formulations, as shown by size exclusion chromatography (Lyophilized + 0.4%, Reconstituted + 2.7%, Diluted + 4.7%). Micro-fluidic imaging revealed no change in particle formation. All presentations exhibited shifts in charge variants, with increases in acidic species (Lyophilized + 2.8%, Reconstituted + 7.8%, Diluted + 6.2%) and basic (Lyophilized + 0.4%, Reconstituted + 0.7%, Diluted + 0.8%) . Liquid chromatography-tandem mass spectrometry (LC-MS/MS) peptide mapping detected increased methionine oxidation in light-exposed samples, correlating with higher protein concentration (M14- Lyophilized + 2.3%, Reconstituted + 7.4%, Diluted + 2.7%, M125- Lyophilized + 2.5%, Reconstituted + 2.9%). Diluted somatropin showed higher HMWS levels but reduced methionine-125 oxidation susceptibility compared to reconstituted formulations.

Conclusions: Light exposure altered product quality attributes, with more pronounced effects on liquid presentations. These findings provide insights into the distinct impacts of light exposure on different drug presentations throughout their lifecycle, highlighting the importance of tailored photostability testing for different product presentations of biologic drugs.

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.

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.