Pharmaceutical Research

Kinch, Michael S.

doi: 10.1007/s11095-024-03666-6pmid: 38291163

Despite unprecedented advancements in our understanding of disease process and targeting opportunities, our continued ability to discover and develop new medicines is fundamentally in doubt. These challenges reflect a growing recognition of the escalating risks of drug development (in terms of dollars and time) by established pharmaceutical companies and investors. Such hurdles are surmountable and require new thinking. This opinion piece conveys an overview of the challenge and an example of how we might overcome these challenges with constructive and forward-looking incentives for drug discovery.

Yang, Qiannan; Zhang, Tingting; Wu, Yujie; Liang, Qianyue; Zhao, Wanqi; Liu, Rui; Jin, Xin

doi: 10.1007/s11095-024-03658-6pmid: 38337104

PurposeIn the local administration methods for treating eye diseases, the application of microneedles has great potential due to the shortcomings of low efficacy and significant side effects of local administration preparations. This article provides ideas for the research on the application of ophthalmic microneedle in the treatment of eye diseases.ResultsThis article analyzes the physiological structures of the eyes, ocular diseases and its existing ocular preparations in sequence. Finally, this article reviews the development and trends of ocular microneedles in recent years, and summarizes and discusses the drugs of ocular microneedles as well as the future directions of development. At the same time, according to the inspiration of previous work, the concept of “microneedle with spinule” is proposed for the first time, and its advantages and limitations are discussed in the article.ConclusionsAt present, the application of ocular microneedles still faces multiple challenges. The aspects of auxiliary devices, appearance, the properties of the matrix materials, and preparation technology of ophthalmic microneedle are crucial for their application in the treatment of eye diseases.Graphical abstract[graphic not available: see fulltext]

Bodenlenz, Manfred; Yeoh, Thean; Berstein, Gabriel; Mathew, Shibin; Shah, Jaymin; Banfield, Christopher; Hollingshead, Brett; Steyn, Stefanus J.; Osgood, Sarah M.; Beaumont, Kevin; Kainz, Sonja; Holeček, Christian; Trausinger, Gert; Raml, Reingard; Birngruber, Thomas

doi: 10.1007/s11095-023-03645-3

Alimpertis, Nikolaos; Simitopoulos, Antony; Tsekouras, Athanasios A.; Macheras, Panos

doi: 10.1007/s11095-024-03653-xpmid: 38191705

PurposeTo revise the IVIVC considering the physiologically sound Finite Absorption Time (F.A.T.) and Finite Dissolution Time (F.D.T.) concepts.MethodsThe estimates τ and τd for F.A.T. and F.D.T., respectively are constrained by the inequality τd ≤ τ; their relative magnitude is dependent on drug’s BCS classification. A modified Levy plot, which includes the time estimates for τ and τd was developed. IVIVC were also considered in the light of τ and τd estimates. The modified Levy plot of theophylline, a class I drug, coupled with the rapid (30 min) and very rapid (15 min) dissolution time limits showed that drug dissolution/absorption of Class I drugs takes place in less than an hour. We reanalyzed a carbamazepine (Tegretol) bioequivalence study using PBFTPK models to reveal its complex absorption kinetics with two or three stages.ResultsThe modified Levy plot unveiled the short time span (~ 2 h) of the in vitro dissolution data in comparison with the duration of in vivo dissolution/absorption processes (~ 17 h). Similar results were observed with the modified IVIVC plots. Analysis of another set of carbamazepine data, using PBFTPK models, confirmed a three stages absorption process. Analysis of steady-state (Tegretol) data from a paediatric study using PBFTPK models, revealed a single input stage of duration 3.3 h. The corresponding modified Levy and IVIVC plots were found to be nonlinear.ConclusionsThe consideration of Levy plots and IVIVC in the light of the F.A.T. and F.D.T. concepts allows a better physiological insight of the in vitro and in vivo drug dissolution/absorption processes.

Sang, Lan; Zhou, Zhengying; Luo, Shizheng; Zhang, Yicui; Qian, Hongjie; Zhou, Ying; He, Hua; Hao, Kun

doi: 10.1007/s11095-023-03644-4pmid: 38148384

ObjectiveAntineoplastic agent-induced systolic dysfunction is a major reason for interruption of anticancer treatment. Although targeted anticancer agents infrequently cause systolic dysfunction, their combinations with chemotherapies remarkably increase the incidence. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a potent in vitro model to assess cardiovascular safety. However, quantitatively predicting the reduction of ejection fraction based on hiPSC-CMs is challenging due to the absence of the body's regulatory response to cardiomyocyte injury.MethodsHere, we developed and validated an in vitro-in vivo translational platform to assess the reduction of ejection fraction induced by antineoplastic drugs based on hiPSC-CMs. The translational platform integrates drug exposure, drug-cardiomyocyte interaction, and systemic response. The drug-cardiomyocyte interaction was implemented as a mechanism-based toxicodynamic (TD) model, which was then integrated into a quantitative system pharmacology-physiological-based pharmacokinetics (QSP-PBPK) model to form a complete translational platform. The platform was validated by comparing the model-predicted and clinically observed incidence of doxorubicin and trastuzumab-induced systolic dysfunction.ResultsA total of 33,418 virtual patients were incorporated to receive doxorubicin and trastuzumab alone or in combination. For doxorubicin, the QSP-PBPK-TD model successfully captured the overall trend of systolic dysfunction incidences against the cumulative doses. For trastuzumab, the predicted incidence interval was 0.31–2.7% for single-agent treatment and 0.15–10% for trastuzumab-doxorubicin sequential treatment, covering the observations in clinical reports (0.50–1.0% and 1.5–8.3%, respectively).ConclusionsIn conclusion, the in vitro-in vivo translational platform is capable of predicting systolic dysfunction incidence almost merely depend on hiPSC-CMs, which could facilitate optimizing the treatment protocol of antineoplastic agents.

Dehghani, Pouya; Varshosaz, Jaleh; Mirian, Mina; Minaiyan, Mohsen; Kazemi, Mohammad; Bodaghi, Mahdi

doi: 10.1007/s11095-023-03648-0pmid: 38263341

IntroductionExosomes are extracellular vesicles in the range of 40-150 nm released from the cell membrane. Exosomes secreted by keratinocytes can communicate with other keratinocytes and immune cells with specific biomarkers at their surface, which may be effective on inflammation of psoriasis and its pathogenesis.ObjectiveThe present study aimed to formulate and study effectiveness of an exosomal delivery system of tofacitinib (TFC).MethodsTFC was loaded by different methods in exosomes and then characterized for particle size, zeta potential, drug loading efficiency, and release efficiency. By comparing these parameters, the probe sonication method was chosen to load TFC into exosomes. The MTT assay was used to compare the cytotoxicity of the free drug with the TFC-loaded exosomes (TFC-Exo), and Real-time PCR was used to determine the expression levels of several genes involved in psoriasis expressed in the A-431 keratinocyte and their suppression after treatment. Animal model of psoriasis was induced in BALB/c mice by imiquimod and the efficacy of free TFC, and TFC-Exo were studies on macroscopic appearance and histopathological symptoms.ResultsExosomes encapsulating TFC showed lower cytotoxicity in MTT assay, higher suppression the expression of TNF-a, IL-23, IL-6, and IL-15 genes in real-time PCR and better therapeutic effect on animal models compered to free TFC.ConclusionsThis method of drug delivery for TFC may be effective on enhancing its therapeutic effects and reduction its side effects favorably in chronic administration.Graphical abstract[graphic not available: see fulltext]

Pang, Meng-Juan; Wang, Meng-Wen; Mao, Li-Fei; Guo, Ze; Qian, Ci; Zheng, Xiao-He; Fang, Wei-Jie

doi: 10.1007/s11095-023-03650-6pmid: 38172366

PurposesHighly concentrated monoclonal antibody (mAb) formulations for subcutaneous administration are becoming increasingly preferred within the biopharmaceutical industry for ease of use and improved patient compliance. A common phenomenon observed in the industry is that osmolality detected via freezing-point depression (FPD) in high-concentration mAb formulations is much higher than the theoretical concentrations, yet the occurrence of this phenomenon and its possible safety issues have been rarely reported.MethodsThe current study summarized theoretical osmolality of U.S. Food and Drug Administration approved high-concentration mAb formulations and evaluated effects of high osmolality on safety using hemolysis experiments for the first time. Two mAbs formulated at 150 mg/mL were used as models and configured into two isotonic solutions: a, a theoretically calculated molarity in the isotonic range (H) and b, an osmolality value measured via the FPD in the isotonic range (I). The H and I formulations of each mAb were individually subjected to hemolysis experiments, and the hemolysis rates of the two formulations of the same mAb were compared. Besides, the effect of mAb concentration on osmolality detected by FPD was explored as well.ResultsThe results indicated that the hemolysis rates were similar between the H and I formulations of mAbs at the same sample addition volume, and the osmolality values increased approximately linearly with the increase in mAb concentration.ConclusionsHigh osmolality for high-concentration mAb formulations would not affect product safety and the excipients could be added at relatively high levels to maintain product stability, especially for labile products.

Xia, Ziyun; Yu, Minzhi; Liu, Yayuan; Yuan, Wenmin; Wang, Yan; Xu, Xiaoming; Bae, Jungeun; Schwendeman, Anna

doi: 10.1007/s11095-023-03651-5pmid: 38212593

PurposeA multivesicular liposome (MVL) is a liposomal vehicle designed to achieve sustained release characteristics for drugs with short half-lives. For example, a commercial MVL formulation of bupivacaine has been approved by the U.S. Food and Drug Administration for local and regional analgesia. For complex formulations like those containing MVLs, challenges in developing an in vitro release testing (IVRT) method may hinder generic development and regulatory approval. In this study, we developed an accelerated rotator-based IVRT method with the ability to discriminate bupivacaine MVLs with different quality attributes.MethodsThree IVRT experimental setups including mesh tube, horizontal shaker, and vertical rotator were screened to ensure that at least 50% of bupivacaine can release from MVLs in 24 h. Sample dilution factors, incubation temperature, and the release media pH were optimized for the IVRT. The reproducibility of the developed IVRT method was validated with commercial bupivacaine MVLs. The discriminative capacity was assessed via comparing commercial and compromised bupivacaine MVL formulations.ResultsThe rotator-based release setup was chosen due to the capability to obtain 70% of drug release within 24 h. The optimized testing conditions were chosen with a 50-fold dilution factor, a temperature of 37ºC, and a media pH of 7.4.ConclusionsAn accelerated rotator-based IVRT method for bupivacaine MVLs was developed in this study, with the discriminatory ability to distinguish between formulations of different qualities. The developed IVRT method was a robust tool for generic development of MVL based formulations.

Lee, Jihui; Neustrup, Malene A.; Slütter, Bram; O’Mahony, Conor; Bouwstra, Joke A.; van der Maaden, Koen

doi: 10.1007/s11095-024-03665-7pmid: 38332390

PurposeA dissolving microneedle array (dMNA) is a vaccine delivery device with several advantages over conventional needles. By incorporating particulate adjuvants in the form of poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) into the dMNA, the immune response against the antigen might be enhanced. This study aimed to prepare PLGA-NP-loaded dMNA and to compare T-cell responses induced by either intradermally injected aqueous-PLGA-NP formulation or PLGA-NP-loaded dMNA in mice.MethodsPLGA NPs were prepared with microfluidics, and their physicochemical characteristics with regard to encapsulation efficiencies of ovalbumin (OVA) and CpG oligonucleotide (CpG), zeta potentials, polydispersity indexes, and sizes were analysed. PLGA NPs incorporated dMNA was produced with three different dMNA formulations by using the centrifugation method, and the integrity of PLGA NPs in dMNAs was evaluated. The immunogenicity was evaluated in mice by comparing the T-cell responses induced by dMNA and aqueous formulations containing ovalbumin and CpG (OVA/CpG) with and without PLGA NP.ResultsPrepared PLGA NPs had a size of around 100 nm. The dMNA formulations affected the particle integrity, and the dMNA with poly(vinyl alcohol) (PVA) showed almost no aggregation of PLGA NPs. The PLGA:PVA weight ratio of 1:9 resulted in 100% of penetration efficiency and the fastest dissolution in ex-vivo human skin (< 30 min). The aqueous formulation with soluble OVA/CpG and the aqueous-PLGA-NP formulation with OVA/CpG induced the highest CD4 + T-cell responses in blood and spleen cells.ConclusionsPLGA NPs incorporated dMNA was successfully fabricated and the aqueous formulation containing PLGA NPs induce superior CD4+ and CD8+ T-cell responses.

Jin, Meng-Jia; Ge, Xin-Zhe; Huang, Qiong; Liu, Jia-Wei; Ingle, Rahul G.; Gao, Dong; Fang, Wei-Jie

doi: 10.1007/s11095-024-03657-7pmid: 38291165

PurposesWe previously reported an unexpected phenomenon that shaking stress could cause more protein degradation in freeze-dried monoclonal antibody (mAb) formulations than liquid ones (J Pharm Sci, 2022, 2134). The main purposes of the present study were to investigate the effects of shaking stress on protein degradation and sub-visible particle (SbVP) formation in freeze-dried mAb formulations, and to analyze the factors influencing protein degradation during production and transportation.MethodsThe aggregation behavior of mAb-X formulations during production and transportation was simulated by shaking at a rate of 300 rpm at 25°C for 24 h. The contents of particles and monomers were analyzed by micro-flow imaging, dynamic light scattering, size exclusion chromatography, and ultraviolet − visible (UV–Vis) spectroscopy to compare the protective effects of excipients on the aggregation of mAb-X.ResultsShaking stress could cause protein degradation in freeze-dried mAb-X formulations, while surfactant, appropriate pH, polyol mannitol, and high protein concentration could impact SbVP generation. Water content had little effect on freeze-dried protein degradation during shaking, as far as the water content was controlled in the acceptable range as recommended by mainstream pharmacopoeias (i.e., less than 3%).ConclusionsShaking stress can reduce the physical stability of freeze-dried mAb formulations, and the addition of surfactants, polyol mannitol, and a high protein concentration have protective effects against the degradation of model mAb formulations induced by shaking stress. The experimental results provide new insight for the development of freeze-dried mAb formulations.