Pub Date : 2024-09-27DOI: 10.1016/j.ijpharm.2024.124773
Powder blending is a critical step in pharmaceutical manufacturing that can impact product quality such as tablet tensile strength. This study utilized the Discrete Element Method (DEM) to investigate blending in a 5-liter mini-batch and a 2-liter Turbula blender. DEM parameters were calibrated using small-scale powder characterization tests, so that the particle behavior in the DEM simulations matches the measured behavior. The research explored the effects of blender designs and process conditions on blending and lubricant dispersion. A predictive model for tablet tensile strength was developed. The model takes the lubricant’s dispersion via the lubrication energy into account. The model is then used to predict the tablet tensile strength depending on the chosen process parameters, blending speed, duration, and fill level. DEM simulations enabled scaling between the two blenders, providing valuable insights for a semi-continuous manufacturing process based on mini-batch blending. The findings contribute to a deeper understanding of blending mechanics, offering potential enhancements in pharmaceutical manufacturing efficiency and product consistency.
{"title":"Demonstrating scalability between two blender types using DEM","authors":"","doi":"10.1016/j.ijpharm.2024.124773","DOIUrl":"10.1016/j.ijpharm.2024.124773","url":null,"abstract":"<div><div>Powder blending is a critical step in pharmaceutical manufacturing that can impact product quality such as tablet tensile strength. This study utilized the Discrete Element Method (DEM) to investigate blending in a 5-liter mini-batch and a 2-liter Turbula blender. DEM parameters were calibrated using small-scale powder characterization tests, so that the particle behavior in the DEM simulations matches the measured behavior. The research explored the effects of blender designs and process conditions on blending and lubricant dispersion. A predictive model for tablet tensile strength was developed. The model takes the lubricant’s dispersion via the lubrication energy into account. The model is then used to predict the tablet tensile strength depending on the chosen process parameters, blending speed, duration, and fill level. DEM simulations enabled scaling between the two blenders, providing valuable insights for a semi-continuous manufacturing process based on mini-batch blending. The findings contribute to a deeper understanding of blending mechanics, offering potential enhancements in pharmaceutical manufacturing efficiency and product consistency.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-27DOI: 10.1016/j.ijpharm.2024.124756
To prepare a PLGA microsphere loaded with the antipsychotic Blonanserin without release leg period and released in a near-zero model for long time, in this study, 15 kDa and 75 kDa PLGA were chosen to be mixed with different ratios, and Blonanserin microspheres (Bn-MS) without significant differences in the particle size, drug loading capacity, and encapsulation rate were prepared by microfluidics. The release kinetic model was fitted to the release behavior by monitoring the changes in particle size and morphology during the Bn-MS release to investigate microspheres’ in vitro release pattern. The results showed that the addition of appropriate ratios of mixed molecular weights to Bn-MS could eliminate the release hysteresis period. When the ratio of 15 kDa and 75 kDa was 1:9 (F3), the Bn-MS had a low burst release rate, moderate release rate, no release hysteresis period, a long release period of up to 35 days, and a stable release pattern close to the zero level. The results of the release mechanism study indicated that the hybrid PLGA improved the release behavior of the microspheres by adjusting the dissolution degradation rate of Bn-MS, which in turn affected the release mechanism of the microspheres.
{"title":"Preparation and release pattern study of long-term controlled release Blonanserin microspheres","authors":"","doi":"10.1016/j.ijpharm.2024.124756","DOIUrl":"10.1016/j.ijpharm.2024.124756","url":null,"abstract":"<div><div>To prepare a PLGA microsphere loaded with the antipsychotic Blonanserin without release leg period and released in a near-zero model for long time, in this study, 15 kDa and 75 kDa PLGA were chosen to be mixed with different ratios, and Blonanserin microspheres (Bn-MS) without significant differences in the particle size, drug loading capacity, and encapsulation rate were prepared by microfluidics. The release kinetic model was fitted to the release behavior by monitoring the changes in particle size and morphology during the Bn-MS release to investigate microspheres’ in vitro release pattern. The results showed that the addition of appropriate ratios of mixed molecular weights to Bn-MS could eliminate the release hysteresis period. When the ratio of 15 kDa and 75 kDa was 1:9 (F3), the Bn-MS had a low burst release rate, moderate release rate, no release hysteresis period, a long release period of up to 35 days, and a stable release pattern close to the zero level. The results of the release mechanism study indicated that the hybrid PLGA improved the release behavior of the microspheres by adjusting the dissolution degradation rate of Bn-MS, which in turn affected the release mechanism of the microspheres.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1016/j.ijpharm.2024.124759
The STING agonist stimulates an anti-tumor immune response by activating T cells, but its limited tumor-targeting specificity poses risks of cytokine storms or autoimmune reactions. Conversely, attenuated Salmonella typhimurium △ppGpp (S.t△ppGpp) exhibits superior tumor-targeting specificity and potent anti-tumor immunogenicity. However, the anti-tumor effects of Salmonella carrying STING agonists remain underexplored. In this study, we engineered a strain called SLdacA, utilizing S.t△ppGpp as a carrier, to produce c-di-AMP. This engineered strain effectively enhances dendritic cell maturation and M1-type macrophage polarization by inducing type I interferon production, thereby recruiting and activating effector T cells against tumor progression. This process is regulated by the STING/type I interferon pathway. Our findings indicate that utilizing S.t△ppGpp as a delivery vehicle for STING agonists holds promise as a strategy for synergistic bacterial-mediated immunotherapy.
STING 激动剂通过激活 T 细胞来刺激抗肿瘤免疫反应，但其有限的肿瘤靶向特异性会带来细胞因子风暴或自身免疫反应的风险。相反，减毒鼠伤寒沙门氏菌△ppGpp（S.t△ppGpp）具有更强的肿瘤靶向特异性和有效的抗肿瘤免疫原性。然而，携带 STING 激动剂的沙门氏菌的抗肿瘤作用仍未得到充分探索。在这项研究中，我们利用S.t△ppGpp作为载体，设计了一种名为SLdacA的菌株来产生c-di-AMP。这种工程菌株通过诱导I型干扰素的产生，有效地增强了树突状细胞的成熟和M1型巨噬细胞的极化，从而招募和激活效应T细胞对抗肿瘤的进展。这一过程受 STING/ I 型干扰素通路调控。我们的研究结果表明，利用S.t△ppGpp作为STING激动剂的递送载体有望成为细菌介导的协同免疫疗法的一种策略。
{"title":"Enhancing Tumor-Specific immunity with SLdacA: A attenuated Salmonella-mediated c-di-AMP delivery system targeting the STING pathway","authors":"","doi":"10.1016/j.ijpharm.2024.124759","DOIUrl":"10.1016/j.ijpharm.2024.124759","url":null,"abstract":"<div><div>The STING agonist stimulates an anti-tumor immune response by activating T cells, but its limited tumor-targeting specificity poses risks of cytokine storms or autoimmune reactions. Conversely, attenuated <em>Salmonella typhimurium</em> △ppGpp (S.t△ppGpp) exhibits superior tumor-targeting specificity and potent anti-tumor immunogenicity. However, the anti-tumor effects of <em>Salmonella</em> carrying STING agonists remain underexplored. In this study, we engineered a strain called SL<sup>dacA</sup>, utilizing S.t△ppGpp as a carrier, to produce c-di-AMP. This engineered strain effectively enhances dendritic cell maturation and M1-type macrophage polarization by inducing type I interferon production, thereby recruiting and activating effector T cells against tumor progression. This process is regulated by the STING/type I interferon pathway. Our findings indicate that utilizing S.t△ppGpp as a delivery vehicle for STING agonists holds promise as a strategy for synergistic bacterial-mediated immunotherapy.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1016/j.ijpharm.2024.124769
The choice of drug content is a critical factor as far as the solid dispersion is concerned. This investigation aims to build the relationship between the drug content, intermolecular hydrogen bonding and the crystalline of the carbamazepine-polyvinyl pyrrolidone solid dispersion. In this work, the microstructural changes of solid dispersions were investigated using experimental characterization combined with molecular simulation. Experimental investigations demonstrated that increasing the drug content enhances the intermolecular hydrogen bonding between drugs, resulting in the crystalline phase of the drug emerged in the solid dispersion. This negatively affects the solubility and stability of solid dispersions. Molecular simulations were then used to analyze the changes of intermolecular hydrogen bonding at different drug content in the system. It revealed a tenfold increase in drug-drug hydrogen bonding concentration as drug content elevated from 10% to 50%, while the drug-excipient hydrogen bonding concentration decreased by 45%. The correlation analysis proves the significant relationships among the drug content, intermolecular hydrogen bonding, and crystallinity of solid dispersion. Using polynomial fitting analysis, the quantitative relationships between the drug content and crystalline properties were investigated. This study will offer valuable insights into the impact of drug content on the performance of solid dispersion.
{"title":"Crystallization and intermolecular hydrogen bonding in carbamazepine-polyvinyl pyrrolidone solid dispersions: An experiment and molecular simulation study on drug content variation","authors":"","doi":"10.1016/j.ijpharm.2024.124769","DOIUrl":"10.1016/j.ijpharm.2024.124769","url":null,"abstract":"<div><div>The choice of drug content is a critical factor as far as the solid dispersion is concerned. This investigation aims to build the relationship between the drug content, intermolecular hydrogen bonding and the crystalline of the carbamazepine-polyvinyl pyrrolidone solid dispersion. In this work, the microstructural changes of solid dispersions were investigated using experimental characterization combined with molecular simulation. Experimental investigations demonstrated that increasing the drug content enhances the intermolecular hydrogen bonding between drugs, resulting in the crystalline phase of the drug emerged in the solid dispersion. This negatively affects the solubility and stability of solid dispersions. Molecular simulations were then used to analyze the changes of intermolecular hydrogen bonding at different drug content in the system. It revealed a tenfold increase in drug-drug hydrogen bonding concentration as drug content elevated from 10% to 50%, while the drug-excipient hydrogen bonding concentration decreased by 45%. The correlation analysis proves the significant relationships among the drug content, intermolecular hydrogen bonding, and crystallinity of solid dispersion. Using polynomial fitting analysis, the quantitative relationships between the drug content and crystalline properties were investigated. This study will offer valuable insights into the impact of drug content on the performance of solid dispersion.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1016/j.ijpharm.2024.124749
Sonophoresis is a topical drug delivery approach that utilises ultrasound as a physical stimulus to enhance permeation of active pharmaceutical ingredients through the skin. Only limited research has however been conducted to evaluate the potential of ultrasound-responsive drug carriers, such as gas microbubbles, in sonophoresis. Franz diffusion cells have been extensively used for measuring drug permeation in vitro; however, traditional systems lack compatibility with ultrasound and only limited characterisation of their acoustical behaviour has been carried out in previous research. To overcome this limitation, we designed and manufactured a novel Franz cell donor compartment coupled with a conventional glass receptor, and performed a functional characterisation of the assembly for application in sonophoresis with ultrasound-responsive agents (specifically imiquimod-loaded gas microbubbles). The donor was fabricated using a photoreactive resin via 3D printing and was designed to enable integration with a therapeutically relevant ultrasound source. The assembly was capable of effectively retaining liquids during prolonged incubation and the absorption of imiquimod onto the 3D-printed material was comparable to the one of glass. Moreover, a predictable ultrasound field could be generated at a target surface without any significant spatial distortion. Finally, we demonstrated applicability of the developed assembly in sonophoresis experiments with StratM®, wherein ultrasound stimulation in the presence of microbubbles resulted in significantly enhanced drug permeation through and partitioning within the membrane (2.96 ± 0.25 μg and 3.84 ± 0.39 μg) compared to passive diffusion alone (1.74 ± 0.29 μg and 2.29 ± 0.32 μg), over 24 h.
{"title":"Ultrasound-compatible 3D-printed Franz diffusion system for sonophoresis with microbubbles","authors":"","doi":"10.1016/j.ijpharm.2024.124749","DOIUrl":"10.1016/j.ijpharm.2024.124749","url":null,"abstract":"<div><div>Sonophoresis is a topical drug delivery approach that utilises ultrasound as a physical stimulus to enhance permeation of active pharmaceutical ingredients through the skin. Only limited research has however been conducted to evaluate the potential of ultrasound-responsive drug carriers, such as gas microbubbles, in sonophoresis. Franz diffusion cells have been extensively used for measuring drug permeation <em>in vitro</em>; however, traditional systems lack compatibility with ultrasound and only limited characterisation of their acoustical behaviour has been carried out in previous research. To overcome this limitation, we designed and manufactured a novel Franz cell donor compartment coupled with a conventional glass receptor, and performed a functional characterisation of the assembly for application in sonophoresis with ultrasound-responsive agents (specifically imiquimod-loaded gas microbubbles). The donor was fabricated using a photoreactive resin <em>via</em> 3D printing and was designed to enable integration with a therapeutically relevant ultrasound source. The assembly was capable of effectively retaining liquids during prolonged incubation and the absorption of imiquimod onto the 3D-printed material was comparable to the one of glass. Moreover, a predictable ultrasound field could be generated at a target surface without any significant spatial distortion. Finally, we demonstrated applicability of the developed assembly in sonophoresis experiments with StratM®, wherein ultrasound stimulation in the presence of microbubbles resulted in significantly enhanced drug permeation through and partitioning within the membrane (2.96 ± 0.25 μg and 3.84 ± 0.39 μg) compared to passive diffusion alone (1.74 ± 0.29 μg and 2.29 ± 0.32 μg), over 24 h.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1016/j.ijpharm.2024.124740
Resistant M. tuberculosis strains threaten pulmonary tuberculosis (P-TB) control since they limit drug options. Drug repositioning and new development strategies are urgently required to overcome resistance. Studies have already shown the beneficial role of the oral antidiabetic metformin as an anti-tuberculosis adjuvant drug. This work aimed to develop an inhalatory dry powder co-formulation of metformin and moxifloxacin to figure out a future option for P-TB treatment. Pre-formulation evaluations indicated the physicochemical compatibility of constituents, demonstrating powder crystallinity and acceptable drug content. Eight moxifloxacin-metformin dry powder formulations were produced by spray drying, and solid-state characterizations showed partial amorphization, ascribed to moxifloxacin. Four formulations containing L-leucine exhibited micromeritic and in vitro deposition profiles indicating pulmonary delivery suitability, like spherical and corrugated particle surface, geometric diameters < 5 μm, high emitted doses (>85 %), and mass median aerodynamic diameters between 1–5 μm. The use of a second spray dryer model further optimized the aerodynamic properties and yield of the best formulation, demonstrating the influence of the equipment used on the product obtained. Moreover, the final formulation showed high in vitro cell tolerability and characteristics in permeability studies indicative of good drug retention in the lungs.
{"title":"Development of inhaled moxifloxacin-metformin formulation as an alternative for pulmonary tuberculosis treatment","authors":"","doi":"10.1016/j.ijpharm.2024.124740","DOIUrl":"10.1016/j.ijpharm.2024.124740","url":null,"abstract":"<div><div>Resistant <em>M. tuberculosis</em> strains threaten pulmonary tuberculosis (P-TB) control since they limit drug options. Drug repositioning and new development strategies are urgently required to overcome resistance. Studies have already shown the beneficial role of the oral antidiabetic metformin as an anti-tuberculosis adjuvant drug. This work aimed to develop an inhalatory dry powder co-formulation of metformin and moxifloxacin to figure out a future option for P-TB treatment. Pre-formulation evaluations indicated the physicochemical compatibility of constituents, demonstrating powder crystallinity and acceptable drug content. Eight moxifloxacin-metformin dry powder formulations were produced by spray drying, and solid-state characterizations showed partial amorphization, ascribed to moxifloxacin. Four formulations containing L-leucine exhibited micromeritic and <em>in vitro</em> deposition profiles indicating pulmonary delivery suitability, like spherical and corrugated particle surface, geometric diameters < 5 μm, high emitted doses (>85 %), and mass median aerodynamic diameters between 1–5 μm. The use of a second spray dryer model further optimized the aerodynamic properties and yield of the best formulation, demonstrating the influence of the equipment used on the product obtained. Moreover, the final formulation showed high <em>in vitro</em> cell tolerability and characteristics in permeability studies indicative of good drug retention in the lungs.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.ijpharm.2024.124763
Merna A Badie, Mahmoud H Teaima, Mohamed A El-Nabarawi, Noha M Badawi
Burn wounds remain a significant global health concern, frequently exacerbated by bacterial infections that hinder healing and raise morbidity rates. Cefdinir, a third-generation cephalosporin antibiotic, is used to treat various conditions, but it has limitations such as low water solubility, limited bioavailability, and a short biological half-life. This study aimed to fabricate and optimize novel surfactant-based Cefdinir-loaded chitosan nanoparticles (CFD-CSNPs) for enhancing topical CFD delivery and efficacy in burn healing. Box-Behnken Design (BBD) was employed to develop optimized CFD-CSNPs using Design Expert® software, where the independent factors were chitosan concentration, chitosan: sodium tripolyphosphate ratio, pH, and surfactant type. Particle size PS, zeta potential ZP, Polydispersity index PDI, and entrapment efficiency EE% were evaluated as dependent factors. CFD-CSNPs were produced using the ionic gelation method. The optimized formula was determined and then examined for further in vitro and in vivo assessments. The optimized CFD-CSNPs exhibited acceptable PS, PDI, and ZP values. The EE% of CFD from CSNPs reached 57.89 % ± 1.66. TEM analysis revealed spherical morphology. In vitro release studies demonstrated a biphasic release profile up to (75.5 % ± 3.8) over 48 hrs. The optimized CFD-CSNPs showed improved antimicrobial efficacy against the tested microorganisms, exhibiting superior performance for both biofilm prevention and eradication. Enhanced wound healing activity was achieved by the optimized CFD-CSNPs in both in vitro and in vivo studies as confirmed by scratch wound assay and skin burn mice model. The current study advocates the efficacy of the innovative topical application of CFD-CSNPs for wound healing purposes and treatment of wound infections.
{"title":"Formulation and optimization of surfactant-modified chitosan nanoparticles loaded with cefdinir for novel topical drug delivery: Elevating wound healing efficacy with enhanced antibacterial properties.","authors":"Merna A Badie, Mahmoud H Teaima, Mohamed A El-Nabarawi, Noha M Badawi","doi":"10.1016/j.ijpharm.2024.124763","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2024.124763","url":null,"abstract":"<p><p>Burn wounds remain a significant global health concern, frequently exacerbated by bacterial infections that hinder healing and raise morbidity rates. Cefdinir, a third-generation cephalosporin antibiotic, is used to treat various conditions, but it has limitations such as low water solubility, limited bioavailability, and a short biological half-life. This study aimed to fabricate and optimize novel surfactant-based Cefdinir-loaded chitosan nanoparticles (CFD-CSNPs) for enhancing topical CFD delivery and efficacy in burn healing. Box-Behnken Design (BBD) was employed to develop optimized CFD-CSNPs using Design Expert® software, where the independent factors were chitosan concentration, chitosan: sodium tripolyphosphate ratio, pH, and surfactant type. Particle size PS, zeta potential ZP, Polydispersity index PDI, and entrapment efficiency EE% were evaluated as dependent factors. CFD-CSNPs were produced using the ionic gelation method. The optimized formula was determined and then examined for further in vitro and in vivo assessments. The optimized CFD-CSNPs exhibited acceptable PS, PDI, and ZP values. The EE% of CFD from CSNPs reached 57.89 % ± 1.66. TEM analysis revealed spherical morphology. In vitro release studies demonstrated a biphasic release profile up to (75.5 % ± 3.8) over 48 hrs. The optimized CFD-CSNPs showed improved antimicrobial efficacy against the tested microorganisms, exhibiting superior performance for both biofilm prevention and eradication. Enhanced wound healing activity was achieved by the optimized CFD-CSNPs in both in vitro and in vivo studies as confirmed by scratch wound assay and skin burn mice model. The current study advocates the efficacy of the innovative topical application of CFD-CSNPs for wound healing purposes and treatment of wound infections.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.ijpharm.2024.124760
Using low quantities of drug compounds is often favorable in the early stages of drug development, especially for what require a large screening investigation to define the final formulation composition, such as nano- and microsuspensions. For that reason, the dual centrifugation approach has in the recent years been used due to its reproducible and fast-milling capacity with 40 samples in 2 mL vials simultaneously without the addition of cooling breaks due to a built-in cooling system. Nonetheless, heat can be dissipated into the samples during high-intensity milling, resulting in increased sample temperatures that potentially can affect thermolabile compounds and potential influence the obtained suspensions in the screening experiments if the used stabilizer has temperature dependent variations in the performance. Hence, a systematic investigation of the influence of different process parameters on the heat dissipation in samples during milling by the dual centrifugation approach was performed in the present study. It was found that the milling speed had the highest impact on the final sample temperature, but also other parameters, such as the bead loading, bead size, and placement in the centrifuge during milling had significantly influenced the final mean temperature of the milling media. Higher temperatures were obtained with higher bead loadings, i.e., 3000 mg milling beads/mL and milling speeds (1500 rpm), and when smaller milling beads, i.e., 0.1 mm, were used during production. The study further showed that higher temperatures were measured for samples located on the bottom disk during milling, and also when located on the outer placement on the sample disk. Upscale investigations showed immensely increased sample temperatures (almost up to boiling point) when samples were prepared under similar formulation parameters and milling speed as small-volume vials. Furthermore, the study indicated that the addition of drug compounds during suspension preparation decreased the final sample temperature compared to samples that only contained purified water due to energy absorption of the drug compound.
{"title":"Temperature mapping of milling by dual centrifugation: A systematic investigation","authors":"","doi":"10.1016/j.ijpharm.2024.124760","DOIUrl":"10.1016/j.ijpharm.2024.124760","url":null,"abstract":"<div><div>Using low quantities of drug compounds is often favorable in the early stages of drug development, especially for what require a large screening investigation to define the final formulation composition, such as nano- and microsuspensions. For that reason, the dual centrifugation approach has in the recent years been used due to its reproducible and fast-milling capacity with 40 samples in 2 mL vials simultaneously without the addition of cooling breaks due to a built-in cooling system. Nonetheless, heat can be dissipated into the samples during high-intensity milling, resulting in increased sample temperatures that potentially can affect thermolabile compounds and potential influence the obtained suspensions in the screening experiments if the used stabilizer has temperature dependent variations in the performance. Hence, a systematic investigation of the influence of different process parameters on the heat dissipation in samples during milling by the dual centrifugation approach was performed in the present study. It was found that the milling speed had the highest impact on the final sample temperature, but also other parameters, such as the bead loading, bead size, and placement in the centrifuge during milling had significantly influenced the final mean temperature of the milling media. Higher temperatures were obtained with higher bead loadings, <em>i.e.,</em> 3000 mg milling beads/mL and milling speeds (1500 rpm), and when smaller milling beads, <em>i.e.,</em> 0.1 mm, were used during production. The study further showed that higher temperatures were measured for samples located on the bottom disk during milling, and also when located on the outer placement on the sample disk. Upscale investigations showed immensely increased sample temperatures (almost up to boiling point) when samples were prepared under similar formulation parameters and milling speed as small-volume vials. Furthermore, the study indicated that the addition of drug compounds during suspension preparation decreased the final sample temperature compared to samples that only contained purified water due to energy absorption of the drug compound.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.ijpharm.2024.124761
Diabetic wounds pose a significant global health challenge. Although curcumin exhibits promising wound healing and antibacterial properties, its clinical potential is limited by low aqueous solubility, and poor tissue penetration. This study aimed to address these challenges and enhance the wound healing efficacy of curcumin by loading it onto gold nanoparticles (AuNPs). The properties of the AuNPs, including particle size, polydispersity index (PDI), zeta potential, percent drug entrapment efficiency (%EE) and UV–Vis spectra were significantly influenced by the curcumin/gold chloride molar ratio used in the synthesis of AuNPs. The optimal formulation (F2) exhibited the smallest particle size (41.77 ± 6.8 nm), reasonable PDI (0.59 ± 0.17), high %EE (94.43 ± 0.25 %), a moderate zeta potential (−8.44 ± 1.69 mV), and a well-defined surface Plasmon resonance peak at 526 nm. Formulation F2 was incorporated into Pluronic® F127 gel to facilitate its application to the skin. Both curcumin AuNPs solution and gel showed sustained drug release and higher skin permeation parameters compared with the free drug solution. AuNPs significantly enhanced curcumin’s antibacterial efficacy by lowering the minimum inhibitory concentrations and enhancing antibacterial biofilm activity against various Gram-positive and Gram-negative bacterial strains. In a diabetic wound rat model, AuNPs-loaded curcumin exhibited superior wound healing attributes compared to the free drug. Specifically, it demonstrated improved wound healing percentage, reduced wound oxidative stress, increased wound collagen deposition, heightened anti-inflammatory effects, and enhanced angiogenesis. These findings underscore the potential of AuNPs as efficacious delivery systems of curcumin for improved wound healing applications.
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Pub Date : 2024-09-25DOI: 10.1016/j.ijpharm.2024.124764
Breweŕs spent grain (BSG) is the main by-product of the brewing industry, and due to its rapid decomposition, it generates serious environmental problems such as malodors and greenhouse gases emissions. On the other hand, this lignocellulosic compound contains a large number of antioxidants, being ferulic acid (FA) the most abundant. FA is a powerful antioxidant molecule that has demonstrated significant protective effects on key components of the skin, including keratinocytes, fibroblasts, collagen, and elastin. FA inhibits melanogenesis, promotes angiogenesis and accelerates the wound healing although its use is limited by its rapid oxidation. In this study, different hydrolysis treatments (chemical, enzymatic and hydrothermal) were performed on BSG to obtain FA. Herein FA-loaded ultradeformable liposomes (ULs) were designed to improve their stability and in vivo performance. These nanosystems allow FA permeability through human skin, as proven by an ex vivo skin permeability assay using Franz diffusion cells. The toxicity and anti-inflammatory activity of the formulation has been investigated. The free form and 100 nm FA_ULs were evaluated. Cell viability was dose-dependent and provided optimal results for the treatment of inflammatory skin conditions in an in vivo Oxazolone-induced Delayed Type Hypersensitivity model using Swiss CD1 mice, demonstrated by the reduction of the inflammatory cytokines expression, ear thickness, bioluminescence and histological evaluation. These results pave the way for FA-based treatments of skin and inflammatory conditions.
啤酒糟（BSG）是酿造业的主要副产品，由于其分解速度快，会产生严重的环境问题，如恶臭和温室气体排放。另一方面，这种木质纤维素化合物含有大量抗氧化剂，其中阿魏酸（FA）含量最高。阿魏酸是一种强大的抗氧化分子，对皮肤的主要成分，包括角质细胞、成纤维细胞、胶原蛋白和弹性蛋白具有显著的保护作用。FA 可抑制黑色素生成、促进血管生成并加速伤口愈合，但其快速氧化限制了它的使用。本研究对 BSG 进行了不同的水解处理（化学、酶解和水热），以获得 FA。在此基础上，设计了负载 FA 的超变形脂质体（ULs），以提高其稳定性和体内性能。利用弗朗兹扩散细胞进行的体内外皮肤渗透性试验证明，这些纳米系统可使 FA 通过人体皮肤渗透。对配方的毒性和抗炎活性进行了研究。对自由形态和 100 纳米 FA_UL 进行了评估。在使用瑞士 CD1 小鼠进行的体内 Oxazolone 诱导的延迟型超敏反应模型中，通过减少炎症细胞因子的表达、耳厚度、生物发光和组织学评估，证明细胞活力与剂量有关，并为炎症性皮肤状况的治疗提供了最佳结果。这些结果为基于 FA 的皮肤和炎症治疗铺平了道路。
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