Pharmaceutical Research[JOURNAL]
Sun
200 papers
Correction: Photosensitizer-Antibody Conjugates (PhotoBodies): Emerging Frontiers in the Field of Theranostics.
Kulkarni SS, Khandave PY, Tiwatane AK … +3 more , Rawat K, Bhaumik J, Pande AH
Pharm Res · 2026 Jan · PMID 41507557 · Publisher ↗
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Characterization of EpiIntestinal Duodenum Microtissue as an In Vitro Model for Studying Intestinal Drug Permeability, Transport, and Metabolism.
Cheong J, Jorski J, Chhin C … +4 more , Ayehunie S, Stevens Z, Oldach J, Salphati L
Pharm Res · 2026 Feb · PMID 41507556 · Publisher ↗
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 develop...
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 cm/s) following the addition of elacridar and ketoconazole compared to the control Papp of 2.8 × 10 cm/s and the Papp with elacridar at 3.7 × 10 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.
Integrative In-silico, Network Pharmacology, Pharmacogenomics and In-vitro Evaluation of Fulvestrant-Loaded Zinc Oxide Nanoparticles Targeting HER2 Positive Breast Cancer.
D M, K KNP, N J … +5 more , Rajeshkumar R, M E, Kayal P, Swaroop AK, S J
Pharm Res · 2026 Mar · PMID 41507555 · Publisher ↗
BACKGROUND: HER2-positive breast cancer is characterized by the absence of estrogen and progesterone receptors and the overexpression of the HER2 receptor. Existing targeted therapies, leads to side effects like cardioto...
BACKGROUND: HER2-positive breast cancer is characterized by the absence of estrogen and progesterone receptors and the overexpression of the HER2 receptor. Existing targeted therapies, leads to side effects like cardiotoxicity, diarrhoea and suffer from poor penetration of the blood brain barrier. Zinc oxide nanoparticles have emerged as a promising drug delivery platform by improving biocompatibility, selective cytotoxicity via reactive oxygen species generation and facilitating effective penetration across biological barriers. OBJECTIVE: Our aim was to synthesize and characterize the Fulvestrant-zinc oxide nanoparticles, evaluate its efficacy in-vitro and ascertain its potential as a therapeutic agent for HER2-positive breast cancer. METHODS: Pharmacogenomics and gene enrichment process were applied to select target by following computational drug design strategy. Based on molecular docking, MMGBSA and molecular dynamics were undertaken to assess the stability. Subsequently, Fulvestrant-zinc oxide nanoparticles were synthesized and characterized using FT-IR, SEM and DSC techniques. In-vitro assessments involved MTT assays and AO/EtBr staining method. RESULTS: Computational results showed Fulvestrant superior HER2 binding, confirmed by molecular dynamics studies. In vitro studies revealed cytotoxicity and apoptosis. CONCLUSION: This study highlights the Fulvestrant-zinc oxide nanoparticles as a promising therapeutic intervention for HER2-positive breast cancer. By undergoing computational approaches, Network analysis and pharmacogenomics.
Design, Development, and Characterization of a Tannic Acid-loaded Transfersomal Gel for Psoriatic Skin.
Shaif M, Kushwaha P, Usmani S … +1 more , Pandey S
Pharm Res · 2026 Jan · PMID 41507554 · Publisher ↗
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...
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/cm/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.
In Vitro Inhalation and Deposition of Salbutamol in Upper Airway Geometries.
Almirall BV, Wong CYJ, Pille P … +4 more , Ang HQ, Traini D, Singh N, Inthavong K
Pharm Res · 2026 Feb · PMID 41507553 · Publisher ↗
PURPOSE: Accurate prediction of aerosol deposition in the extrathoracic airway is critical for designing inhaled therapies, yet many experimental and computational studies rely on geometries that are either simplified or...
PURPOSE: Accurate prediction of aerosol deposition in the extrathoracic airway is critical for designing inhaled therapies, yet many experimental and computational studies rely on geometries that are either simplified or subject-specific but not necessarily physiologically consistent with oral inhalation. This inconsistency can lead to varying estimates of drug delivery efficiency, particularly in the mouth-throat region where flow behavior and particle deposition are highly sensitive to physiological detail. METHODS: This study investigated the influence of airway geometry on aerosol drug delivery by quantifying the deposition of salbutamol sulfate across simplified and subject-specific extrathoracic models. An artificially opened mouth, derived from a closed mouth CT scan and a realistic oral inhalation geometry, were compared to a simplified airway model and the pharmaceutical standard model. All experiments were performed at an inhalation flow rate of 30 l min using a metered dose inhaler (Ventolin ). RESULTS: Each airway was segmented into 10 regions, from the device mouthpiece through the mouth-throat, larynx, and trachea, to the eight stages representing the lower airway. The artificial open mouth geometry produced the lowest ling deposition only 9% , while the realistic oral inhalation had lung deposition of 45%, more consistent with the simplified models. CONCLUSIONS: Subject-specific airway models are not inherently more realistic than simplified models. When physiological features of oral inhalation-specifically soft palate elevation and a smaller mouth opening than a fully opened mouth-are not captured in the model geometry, simplified geometries based on oral inhalation conditions may more accurately represent true deposition patterns than subject-specific models derived from restful breathing CT scans.
Investigation of Renal Tissue Deposition of the Calcineurin Inhibitors Voclosporin, Cyclosporine and Tacrolimus Using MALDI-MSI Imaging.
Zhou S, Rajanayake KK, He M … +7 more , Wen B, Lkhagva A, Yap E, Sun D, Cross J, Engelke K, Huizinga RB
Pharm Res · 2026 Jan · PMID 41507552 · Full text
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 o...
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.
Pharmaceutical Roots to Mitochondrial Routes: Targeting Neurodegeneration.
Sood A, Mehrotra A
Pharm Res · 2026 Jan · PMID 41507551 · Publisher ↗
BACKGROUND: Mitochondria besides being the powerhouse of the cell are also involved in performing a multitude of critical cellular functions. Any failure in maintenance of these organelles is implicated in multiple human...
BACKGROUND: Mitochondria besides being the powerhouse of the cell are also involved in performing a multitude of critical cellular functions. Any failure in maintenance of these organelles is implicated in multiple human pathologies, including neurodegenerative disorders. Over the past two decades, significant efforts have been made to investigate the pharmacodynamic propensity of various potential compounds, which could be engaged as efficient therapeutic approach in modulating mitochondrial dynamics during neuronal dysfunctions. METHOD: This review comprehensively overviews the contribution of potential compounds that could be employed as mitochondrial medicine in reversing neurological pathologies, with special focus on their significant roles as: metabolic antioxidants, conjugated molecules for mitochondrial function modulation, mitochondrial targeted peptides, optogenetic based induction of the mitochondria, potential mitochondrial biomarkers and other advanced transportation systems for mitochondrial delivery to brain. RESULTS AND DISCUSSION: The manuscript discusses the mechanism of action of potential compounds (natural and pharmacologically synthesized), and other advance approaches that could efficiently modulate mitochondrial machinery in terms of regulating mitochondrial biogenesis, mitophagy, bioenergetics pathways, oxidative stress, calcium homeostasis and mitochondrial DNA stability. CONCLUSION: The optimal maintenance of mitochondrial dynamics offered by variety of mitochondria targeting compounds highlights their prospective value for considering them as futuristic neurotherapeutic agents, which could be considered in managing neurodegenerative conditions.
Transcutaneous Delivery of Dual-Approach Oxaprozin and Apricot Kernel Oil Through a QbD Driven Nanoemulgel: Therapeutic Potential Against Osteoarthritis-Induced Animal Model.
Ali A, Farooq U, Siddiqui A … +4 more , Kumar V, Hamidullah CAR, Iqbal Z, Mirza MA
Pharm Res · 2026 Jan · PMID 41491875 · Publisher ↗
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....
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.
Polymorphism Control of Carbamazepine Based on Deep Eutectic Solvents.
Sun X, Yu S, Lv C … +1 more , Xue F
Pharm Res · 2026 Feb · PMID 41429995 · Publisher ↗
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...
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.
Polymers as Stabilizing Excipients for Spray-Dried Protein Formulations.
Patil CD, Huang Y, Arte KS … +6 more , Kafle N, Renawala HK, Liu J, Nie H, Zhou QT, Qu LL
Pharm Res · 2026 Feb · PMID 41429994 · Full text
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,...
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.
Advanced in Co-Delivery, Controllable Therapy using Microneedle: From Design to Therapeutic Effects.
Nguyen-Thi PT, Nguyen NTT, Le HT … +2 more , Nguyen TT, Van Vo G
Pharm Res · 2026 Jan · PMID 41429993 · Publisher ↗
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...
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.
A General Strategy to Compare Stability Slopes of Biologics Using Short-Term data from Post-Change Batches Versus Long-Term Data from Pre-Change Batches.
Weusten J, Kim JY
Pharm Res · 2026 Jan · PMID 41408020 · Publisher ↗
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 b...
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.
Tabletability Flip in Dry Granulated Systems.
Wang Z, Wang C, Gao T … +1 more , Sun CC
Pharm Res · 2025 Dec · PMID 41408019 · Publisher ↗
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 dire...
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.
Multi-Target Anticoagulant Regulation by Peptides from Medicinal Leeches: A Unique Natural Strategy against Thrombosis.
Shi F, Hu Q, Lin Y … +7 more , Fan S, Cao X, Yang D, Chen Y, Kong D, Liu K, Liu Z
Pharm Res · 2026 Jan · PMID 41402686 · Publisher ↗
BACKGROUND: Thrombotic diseases remain a major global health burden. Current anticoagulants are often limited by bleeding risks and narrow therapeutic windows, largely due to their single-target mechanisms. In contrast,...
BACKGROUND: Thrombotic diseases remain a major global health burden. Current anticoagulants are often limited by bleeding risks and narrow therapeutic windows, largely due to their single-target mechanisms. In contrast, medicinal leeches secrete diverse peptides that naturally and synergistically modulate multiple steps of the hemostatic system. METHODS: This paper systematically reviews published biochemical, structural, functional, and omics studies on leech-derived anticoagulant peptides, classifying them according to their molecular targets and antithrombotic mechanisms. RESULTS: Leech-derived peptides act synergistically at multiple key points of the coagulation cascade: (1) they inhibit platelet adhesion and aggregation by blocking the vWF-collagen interaction or suppressing GPIIb/IIIa; (2) they directly inhibit core coagulation proteases, such as thrombin and factor Xa; and (3) they interfere with fibrin stabilization and promote its dissolution by inhibiting factor XIIIa or modulating the fibrinolytic and intrinsic protease systems. From a molecular perspective, multispecies omics analyses have revealed a significant expansion of antithrombotic gene families and identified numerous novel peptide candidate genes. CONCLUSIONS: Leech-derived peptides provide a unique natural platform for multi-target anticoagulation and represent promising leads for next-generation antithrombotic agents. Combining traditional purification with genomics-guided discovery will accelerate mechanism elucidation, structural optimization, and translational development.
A Novel Non-Aqueous Emulsification Platform to Fabricate Polymeric Microspheres for Sustained Delivery of Biologics.
Kulkarni NS, James R, Saraswat A … +6 more , Lakshmi D, Fazily R, Rayaprolu B, Chen HH, Bhalla AS, Shameem M
Pharm Res · 2026 Feb · PMID 41402685 · Publisher ↗
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...
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.
Intracerebral Distribution of Drugs with Diverse Blood-brain Barrier Transport Characteristics: In vivo Analysis using Brain Microdialysis in Cynomolgus Monkeys.
Fujita T, Kamikozawa Y, Ozawa M … +14 more , Tajima Y, Kurosawa T, Katagiri Y, Kawaguchi H, Kakuuchi A, Miyamoto R, Wakayama K, Nagai M, Taguchi T, Bessho K, Watanabe D, Ogihara T, Kusuhara H, Deguchi Y
Pharm Res · 2026 Feb · PMID 41402684 · Publisher ↗
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...
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) were calculated to quantify the intracerebral distribution characteristics. RESULTS: The K 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 > 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.
Deep Dive into Generic Drug Applications to Seek Harmonization of Bioequivalence Criteria for Narrow Therapeutic Index Drugs.
Mina M, Zhang Z, Sun W … +3 more , Anim Anno K, Zhang L, Jiang W
Pharm Res · 2025 Dec · PMID 41402683 · Full text
PURPOSE: U.S. Food and Drug Administration (FDA) recommends reference scaled limits and variability comparison for bioequivalence (BE) demonstration of narrow therapeutic (NTI) drugs while most other regulatory agencies...
PURPOSE: U.S. Food and Drug Administration (FDA) recommends reference scaled limits and variability comparison for bioequivalence (BE) demonstration of narrow therapeutic (NTI) drugs while most other regulatory agencies apply direct tightening of BE limits. This study evaluates strengths and limitations of different BE criteria using abbreviated new drug application (ANDA) data received by FDA to support harmonization of NTI drug BE criteria. METHODS: We analyzed four-way fully-replicated crossover BE study data in NTI ANDAs, applying BE criteria from different agencies and alternative criteria (e.g., Paixão's criteria, modified Paixão's and FDA criteria) to compare passing rates. RESULTS: Current EMA and FDA criteria seem stringent with NTI drugs having moderate and low within-subject variability (e.g., S), respectively. Capping BE limits at 90.00-111.11% when σ ≤ 0.10 in alternative FDA criteria improved passing rates and better aligns with NTI quality standards. An additional point estimate constraint of 90.00-111.11% enforced geometric mean ratio closer to 1 but reduced passing rates when S was moderate to high. FDA's regulatory constant resulted in slightly less stringent scaled BE limits than Paixão's, but may better align with observed S ranges for NTI drugs. Alpha adjustment reduced Type I error but slightly decreased study passing rates. CONCLUSION: Alternative FDA criteria with capping at 90.00-111.11% when σ ≤ 0.10 and applying alpha adjustment provides reasonably stringent standards for BE demonstration of NTI drugs. This in-depth analysis of ANDA BE data will help ICH M13C Expert Working Group make informed decisions about harmonization options for BE demonstration of NTI drugs.
Physicochemical Differences Observed in Photostability Studies of Lyophilized, Reconstituted, and Diluted Somatropin.
Pritts JD, Ortega-Rodriguez U, Rao VA
Pharm Res · 2026 Jan · PMID 41402682 · Full text
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...
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.
Development, Optimization, and Evaluation of Nano Self-Emulsifying Drug Delivery System Formulation Platform for Oral Bioavailability Enhancement of Sulfasalazine and Disulfiram in Lung Cancer Chemoprevention.
Desai P, Bang K, Chowdhury MRH … +5 more , Wang ZK, Wang J, Prabhu S, Liang X, Kassie F
Pharm Res · 2026 Jan · PMID 41402681 · Full text
OBJECTIVE: Lung cancer chemoprevention modalities are gaining wide attention as it is the second most diagnosed cancer type and the leading cause of cancer-related deaths. Our previous studies reported unique lung cancer...
OBJECTIVE: Lung cancer chemoprevention modalities are gaining wide attention as it is the second most diagnosed cancer type and the leading cause of cancer-related deaths. Our previous studies reported unique lung cancer chemoprevention capability with a repurposed drug combination of sulfasalazine (SAS) and disulfiram (DSF). However, their efficacy is limited by poor bioavailability. To overcome this challenge, we developed bioenhanced oil-in-water (o/w) nano self-emulsifying drug delivery system (Nano-SEDDS) formulations of SAS and DSF. METHODS: Unique isotropic Nano-SEDDS of SAS and DSF were developed and optimized using a single-step mix method followed by in vitro physicochemical characterization and stability studies. An in vivo pharmacokinetic and tissue-biodistribution study was undertaken to test the proposed hypothesis of bioavailability enhancement with Nano-SEDDS of SAS and DSF. RESULTS: The optimal Nano-SEDDS formulation exhibited low nanodroplet sizes (< 200 nm), high drug content, and 4.5-fold (p < 0.01) and 3.75-fold (p < 0.01) enhancement in in vitro dissolution of SAS and DSF compared to the respective free drugs. The Nano-SEDDS formulations were also confirmed to be stable at room temperature in compliance with ICH guidelines. Further, SAS Nano-SEDDS showed a dose-dependent increment in oral bioavailability as shown by a significant 7.9-fold (p < 0.0001) enhancement in dose-normalized AUC at a dose of 10 mg/kg compared to free drug treatment at a control dose of 250 mg/kg. CONCLUSION: Overall, the studies corroborated the successful formulation of bioavailability-enhanced SAS and DSF Nano-SEDDS with future co-delivery applications for lung cancer prevention.
Next Generation of Drug Discovery and Delivery Strategies.
Kumar MNVR
Pharm Res · 2025 Dec · PMID 41402680 · Publisher ↗
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