Pub Date : 2025-01-30DOI: 10.1016/j.ijpharm.2025.125254
Aszad Alam , Peddapapannagari Kalyani , Arif Khan , Mudrika Khandelwal
This review explores the transformative potential of Bacterial cellulose (BC) in an increasingly vital avenue of transdermal drug delivery systems (TDDS) for multi-scale therapeutic applications with patient-centric approach. In this review, we have not only highlighted the role of BC as the main matrix material for TDDS but emphasized the other possible role that BC can play in TDDS. For this purpose, we have delved into the avenues of the physico-chemical interactions that BC can offer in governing the incorporation of different length-scales of therapeutics as well as tuning their extent of loading. Furthermore, this review underscores BC’s potential in developing need-specific drug release profiles and stimuli-responsive release platforms, enabling their application in TDDS for wound healing, pain management, and targeted delivery for chronic diseases. Apart from the existing literature, this review focuses on patient comfort, which is an often-overlooked aspect, and highlights how BC’s unique physicochemical properties enhance user experience. Additionally, this review justifies the potential of BC in compliance with the other parameters of the TDDS, including shelf-life, design requirements, and evaluation strategies in ensuring their clinical translation and user acceptance. To harness BC’s potential in the new era of personalized TDDS, this review also sheds light on the challenges of standardizing BC production processes with appropriate data disclosure, ensuring adhesion and anti-microbial actions, along with the integration of passive and active technologies.
{"title":"Bacterial cellulose in transdermal drug delivery systems: Expanding horizons in multi-scale therapeutics and patient-centric approach","authors":"Aszad Alam , Peddapapannagari Kalyani , Arif Khan , Mudrika Khandelwal","doi":"10.1016/j.ijpharm.2025.125254","DOIUrl":"10.1016/j.ijpharm.2025.125254","url":null,"abstract":"<div><div>This review explores the transformative potential of Bacterial cellulose (BC) in an increasingly vital avenue of transdermal drug delivery systems (TDDS) for multi-scale therapeutic applications with patient-centric approach. In this review, we have not only highlighted the role of BC as the main matrix material for TDDS but emphasized the other possible role that BC can play in TDDS. For this purpose, we have delved into the avenues of the physico-chemical interactions that BC can offer in governing the incorporation of different length-scales of therapeutics as well as tuning their extent of loading. Furthermore, this review underscores BC’s potential in developing need-specific drug release profiles and stimuli-responsive release platforms, enabling their application in TDDS for wound healing, pain management, and targeted delivery for chronic diseases. Apart from the existing literature, this review focuses on patient comfort, which is an often-overlooked aspect, and highlights how BC’s unique physicochemical properties enhance user experience. Additionally, this review justifies the potential of BC in compliance with the other parameters of the TDDS, including shelf-life, design requirements, and evaluation strategies in ensuring their clinical translation and user acceptance. To harness BC’s potential in the new era of personalized TDDS, this review also sheds light on the challenges of standardizing BC production processes with appropriate data disclosure, ensuring adhesion and anti-microbial actions, along with the integration of passive and active technologies.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"671 ","pages":"Article 125254"},"PeriodicalIF":5.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074499","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 : 2025-01-30DOI: 10.1016/j.ijpharm.2025.125299
Honglin Li , Ya Chen , Yue Qiu
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and repetitive, stereotyped behaviors. There is no universally effective pharmacological treatment targeting its core symptoms. Oxytocin, an endogenous polypeptide known as the “social hormone”, has shown potential in improving emotional recognition and social interactions in individuals with ASD. However, its clinical application has been limited due to its short half-life and poor blood–brain barrier penetration. To address these challenges, we utilized peptide lipidation technology to enhance the pharmacokinetic properties and brain bioavailability of oxytocin. A series of lipidated oxytocin analogs was designed and synthesized, exhibiting superior brain distribution and pharmacokinetic profiles in valproic acid-induced autistic rat models compared to unmodified oxytocin. Among these analogs, C16-modified oxytocin (C16-OT), administered intrathecally, achieved the most extensive brain distribution with limited presence in the blood, resulting in long-lasting improvements in autistic behaviors. These improvements, including enhanced social behaviors and reduced stereotypical actions, were sustained for up to 42 days, contrasting with the brief effects typically reported in previous studies. Furthermore, a comparison of administration routes revealed that intrathecal injection achieved higher brain concentrations and more prolonged social behavioral improvements than intranasal delivery. These findings provide robust preclinical evidence that C16-OT, through optimized lipidation and intrathecal delivery, offers sustained central nervous system activity and significant, long-term reversal of social behavioral deficits in rats with autism.
{"title":"Oxytocin lipidation expanding therapeutics for long-term reversal of autistic behaviors in rats","authors":"Honglin Li , Ya Chen , Yue Qiu","doi":"10.1016/j.ijpharm.2025.125299","DOIUrl":"10.1016/j.ijpharm.2025.125299","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and repetitive, stereotyped behaviors. There is no universally effective pharmacological treatment targeting its core symptoms.<!--> <!-->Oxytocin, an endogenous polypeptide known as the “social hormone”, has shown potential in improving emotional recognition and social interactions in individuals with ASD. However, its clinical application has been limited due to its short half-life and poor blood–brain barrier penetration. To address these challenges, we utilized peptide lipidation technology to enhance the pharmacokinetic properties and brain bioavailability of oxytocin. A series of lipidated oxytocin analogs was designed and synthesized, exhibiting superior brain distribution and pharmacokinetic profiles in valproic acid-induced autistic rat models compared to unmodified oxytocin. Among these<!--> <!-->analogs, C16-modified oxytocin (C16-OT), administered intrathecally, achieved the most extensive brain distribution with limited presence in the blood, resulting in long-lasting improvements in autistic behaviors. These improvements, including enhanced social behaviors and reduced stereotypical actions, were sustained for up to 42 days, contrasting with the brief effects typically reported in previous studies. Furthermore, a comparison of administration routes revealed that intrathecal injection achieved higher brain concentrations and more prolonged social behavioral improvements than intranasal delivery. These findings provide robust preclinical evidence that C16-OT, through optimized lipidation and intrathecal delivery, offers sustained central nervous system activity and significant, long-term reversal of social behavioral deficits in rats with autism.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125299"},"PeriodicalIF":5.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074530","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 : 2025-01-30DOI: 10.1016/j.ijpharm.2025.125284
Xiaoyuan Qiu, Danni Yan, Linghui Xu, Ying Wang, Yi Mao, Cheng Yang, Yunxing Li, Yajuan Sun
Pickering emulsions, stabilized by particulate particles, have emerged as a promising vehicle for topical delivery. Herein, Pickering emulsions stabilized by differently charged spirulina protein isolate – chitosan (SC) composite particles were studied for effective topical delivery of α-Bisabolol (ABS). The composite particles were synthesized via electrostatic assembly of spirulina protein isolate (SPI) and chitosan (CS), and their surface charge was assessed using zeta potential measurements. The Pickering emulsions stabilized by SC composite particles with different charges were all stable over 30 days and had a high encapsulation efficiency for ABS. In vitro skin permeation study revealed that positively charged emulsions significantly increased ABS retention within the skin, predominantly in the stratum corneum layer. The underlying delivery mechanism was further explored using attenuated total reflection Fourier transform infrared spectroscopy. Lastly, the influence of particle concentration and oil phase volume fraction on the topical delivery efficiency was conducted to optimize the Pickering formulations. This study provides insight into the role of particle charge in enhancing topical delivery of Pickering emulsions.
{"title":"Topical delivery performance of Pickering emulsions stabilized by differently charged spirulina protein isolate/Chitosan composite particles","authors":"Xiaoyuan Qiu, Danni Yan, Linghui Xu, Ying Wang, Yi Mao, Cheng Yang, Yunxing Li, Yajuan Sun","doi":"10.1016/j.ijpharm.2025.125284","DOIUrl":"10.1016/j.ijpharm.2025.125284","url":null,"abstract":"<div><div>Pickering emulsions, stabilized by particulate particles, have emerged as a promising vehicle for topical delivery. Herein, Pickering emulsions stabilized by differently charged <em>spirulina</em> protein isolate – chitosan (SC) composite particles were studied for effective topical delivery of <em>α</em>-Bisabolol (ABS). The composite particles were synthesized via electrostatic assembly of <em>spirulina</em> protein isolate (SPI) and chitosan (CS), and their surface charge was assessed using zeta potential measurements. The Pickering emulsions stabilized by SC composite particles with different charges were all stable over 30 days and had a high encapsulation efficiency for ABS. <em>In vitro</em> skin permeation study revealed that positively charged emulsions significantly increased ABS retention within the skin, predominantly in the stratum corneum layer. The underlying delivery mechanism was further explored using attenuated total reflection Fourier transform infrared spectroscopy. Lastly, the influence of particle concentration and oil phase volume fraction on the topical delivery efficiency was conducted to optimize the Pickering formulations. This study provides insight into the role of particle charge in enhancing topical delivery of Pickering emulsions.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"671 ","pages":"Article 125284"},"PeriodicalIF":5.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074574","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 : 2025-01-30DOI: 10.1016/j.ijpharm.2025.125302
Catherine Su , Tushar Saha , Shubhra Sinha , Cody P. Hird , Sophie X.Y. Smith , Miguel E. Quiñones-Mateu , Shyamal C. Das
SARS-CoV-2, the virus responsible for the COVID-19 pandemic, predominantly affects the respiratory tract, underscoring the need to develop antiviral agents in an inhalable formulation that can be delivered as prophylactic and/or therapeutic drugs directly to the infection site. Since the beginning of the pandemic, our group has been exploring the possibility of developing combinations of antiviral drugs that can be delivered as inhalable therapy, including combinations of remdesivir and ebselen or remdesivir and disulfiram prepared using a spray-drying technique. In this study, we used a similar spray-drying technique to develop inhalable dry powders combining the controversial drugs ivermectin and niclosamide, which have been reported to exhibit synergistic activity against SARS-CoV-2 in vitro. The combined dry powders were within the size range of 1–5 μm, amorphous in nature and displayed characteristic morphology after spray drying. The emitted dose (ED) of the spray-dried powders ranged from 68 to 83 %, whereas the fine particle fraction (FPF) ranged between 50 and 74 %. All the prepared dry powders remained stable under different humidity conditions (<15 % RH and 53 % RH). Interestingly, the optimized combinational dry powder of ivermectin and niclosamide showed an improved cytotoxic profile (CC50 value of 45.99 µM) and enhanced anti-SARS-CoV-2 activity in vitro (EC50 of 2.67 µM) compared to the single dry powders of ivermectin (CC50 = 20.25 µM and EC50 = 8.61 µM) and niclosamide (CC50 = 21.36 µM and EC50 = 5.28 µM). In summary, we developed a stable and inhalable combinational dry powder containing ivermectin and niclosamide, capable of inhibiting SARS-CoV-2 replication in vitro, demonstrating the potential to prepare dry powders that could be developed and delivered as inhalable antiviral drugs to prevent and/or treat SARS-CoV-2 or similar respiratory viruses.
{"title":"Inhalable spray-dried dry powders combining ivermectin and niclosamide to inhibit SARS-CoV-2 infection in vitro","authors":"Catherine Su , Tushar Saha , Shubhra Sinha , Cody P. Hird , Sophie X.Y. Smith , Miguel E. Quiñones-Mateu , Shyamal C. Das","doi":"10.1016/j.ijpharm.2025.125302","DOIUrl":"10.1016/j.ijpharm.2025.125302","url":null,"abstract":"<div><div>SARS-CoV-2, the virus responsible for the COVID-19 pandemic, predominantly affects the respiratory tract, underscoring the need to develop antiviral agents in an inhalable formulation that can be delivered as prophylactic and/or therapeutic drugs directly to the infection site. Since the beginning of the pandemic, our group has been exploring the possibility of developing combinations of antiviral drugs that can be delivered as inhalable therapy, including combinations of remdesivir and ebselen or remdesivir and disulfiram prepared using a spray-drying technique. In this study, we used a similar spray-drying technique to develop inhalable dry powders combining the controversial drugs ivermectin and niclosamide, which have been reported to exhibit synergistic activity against SARS-CoV-2 <em>in vitro</em>. The combined dry powders were within the size range of 1–5 μm, amorphous in nature and displayed characteristic morphology after spray drying. The emitted dose (ED) of the spray-dried powders ranged from 68 to 83 %, whereas the fine particle fraction (FPF) ranged between 50 and 74 %. All the prepared dry powders remained stable under different humidity conditions (<15 % RH and 53 % RH). Interestingly, the optimized combinational dry powder of ivermectin and niclosamide showed an improved cytotoxic profile (CC<sub>50</sub> value of 45.99 µM) and enhanced anti-SARS-CoV-2 activity <em>in vitro</em> (EC<sub>50</sub> of 2.67 µM) compared to the single dry powders of ivermectin (CC<sub>50</sub> = 20.25 µM and EC<sub>50</sub> = 8.61 µM) and niclosamide (CC<sub>50</sub> = 21.36 µM and EC<sub>50</sub> = 5.28 µM). In summary, we developed a stable and inhalable combinational dry powder containing ivermectin and niclosamide, capable of inhibiting SARS-CoV-2 replication <em>in vitro</em>, demonstrating the potential to prepare dry powders that could be developed and delivered as inhalable antiviral drugs to prevent and/or treat SARS-CoV-2 or similar respiratory viruses.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"671 ","pages":"Article 125302"},"PeriodicalIF":5.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074524","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 : 2025-01-30DOI: 10.1016/j.ijpharm.2025.125283
Nina Burduja , Nicola F. Virzì , Giuseppe Nocito , Giovanna Ginestra , Maria G. Saita , Fabiola Spitaleri , Salvatore Patanè , Antonia Nostro , Valeria Pittalà , Antonino Mazzaglia
The Periprosthetic Joint Infection (PJI) is one of the most important complications of the joint arthroplasty. This surgical procedure is rising worldwide and is further affecting the public health because of the widespread resistance to antibiotics. New therapeutic strategies and innovative antimicrobial biomaterials development are needed to eradicate pathogens without inducing resistance and accelerating recovery. In this direction, herein Curcumin I- (Cur-) loaded DAC® (Defensive Antibacterial Coating, a hydrogel based on hyaluronic acid conjugated to polylactic acid, hereafter named DAC) has been built on. To incorporate Cur in the DAC, thus obtaining Cur-DAC (Cur ≅ 0.93 mg/g), the generally recognized as safe (GRAS) propylene glycol (PG) was used as cosolvent. The drugs combinations of Cur (≅ 0.93 mg/g) and Vancomycin (Van) (at low dose that is ≅ 0.033 mg/g) within the hydrogel (Cur/Van-DAC) was alsoexperienced . Hydrogels were prepared and characterized by rheological investigations and their erosion together with the drug release profile over the time evaluated in physiological conditions. The nanohydrogels produced upon water dilution were characterized by AFM, DLS, and UV/Vis absorption and emission spectroscopies. Superior Cur stability over pH-, solvent- and photoinduced degradations resulted in the DAC matrix. The photoinduced antimicrobial activity of Cur-DAC against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium was evaluated by spreading loaded DAC-based hydrogel onto titanium disk mimicking prosthesis, thus detecting a good reduction of bacterial load after 30 min of exposure to light and a subsequent decrease of cells number at 24 h in the absence of nutrients. The drug association in Cur/Van-DAC demonstrated the best activity against MRSA, even in the presence of nutrients, with respect to established DAC loaded with high amounts of Van (ranging from 18.7 mg/g to 45.8 mg/g) used during the surgery, due to the photoantibacterial activity of Cur, becoming promising to prevent and control joint infections.
{"title":"Curcumin-laden hydrogel coating medical device for periprosthetic joint infection prevention and control","authors":"Nina Burduja , Nicola F. Virzì , Giuseppe Nocito , Giovanna Ginestra , Maria G. Saita , Fabiola Spitaleri , Salvatore Patanè , Antonia Nostro , Valeria Pittalà , Antonino Mazzaglia","doi":"10.1016/j.ijpharm.2025.125283","DOIUrl":"10.1016/j.ijpharm.2025.125283","url":null,"abstract":"<div><div>The Periprosthetic Joint Infection (PJI) is one of the most important complications of the joint arthroplasty. This surgical procedure is rising worldwide and is further affecting the public health because of the widespread resistance to antibiotics. New therapeutic strategies and innovative antimicrobial biomaterials development are needed to eradicate pathogens without inducing resistance and accelerating recovery. In this direction, herein Curcumin I- (Cur-) loaded DAC® (Defensive Antibacterial Coating, a hydrogel based on hyaluronic acid conjugated to polylactic acid, hereafter named DAC) has been built on. To incorporate Cur in the DAC, thus obtaining Cur-DAC (Cur ≅ 0.93 mg/g), the generally recognized as safe (GRAS) propylene glycol (PG) was used as cosolvent. The drugs combinations of Cur (≅ 0.93 mg/g) and Vancomycin (Van) (at low dose that is ≅ 0.033 mg/g) within the hydrogel (Cur/Van-DAC) was alsoexperienced . Hydrogels were prepared and characterized by rheological investigations and their erosion together with the drug release profile over the time evaluated in physiological conditions. The nanohydrogels produced upon water dilution were characterized by AFM, DLS, and UV/Vis absorption and emission spectroscopies. Superior Cur stability over pH-, solvent- and photoinduced degradations resulted in the DAC matrix. The photoinduced antimicrobial activity of Cur-DAC against methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) and vancomycin-resistant <em>Enterococcus faecium</em> was evaluated by spreading loaded DAC-based hydrogel onto titanium disk mimicking prosthesis, thus detecting a good reduction of bacterial load after 30 min of exposure to light and a subsequent decrease of cells number at 24 h in the absence of nutrients. The drug association in Cur/Van-DAC demonstrated the best activity against MRSA, even in the presence of nutrients, with respect to established DAC loaded with high amounts of Van (ranging from 18.7 mg/g to 45.8 mg/g) used during the surgery, due to the photoantibacterial activity of Cur, becoming promising to prevent and control joint infections.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125283"},"PeriodicalIF":5.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074511","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 : 2025-01-30DOI: 10.1016/j.ijpharm.2025.125286
Jiawei Han , Zhimin Yue , Wen Sun , Weitao Fang , Yunran Zhang , Xiaoqian Liu , Jue Wang , Jiaxin Chen
With the expansion of gel research, organic small molecule gels are beginning to gain attention. Whether the small-molecule gel approach can be a new formulation strategy of solubilization and permeation promotion for poorly soluble drugs needs to be explored in this study. The model ingredient indomethacin (IND) as a nonsteroidal anti-flammatory drug shows limited therapeutic application mainly due to its low water solubility. Herein, the IND small molecule hydrogel was design to co-formed with a small molecule ligand by integrating theory-model-experiment techniques. Then, the formed IND small molecule hydrogels (i.e., IND-MEG hydrogel and IND-ARG hydrogel) with meglumine (MEG) or arginine (ARG) appeared typical 3-D network with good rheology. In comparison to crystalline IND, the solubilities of IND-MEG hydrogel and IND-ARG hydrogel exhibited 506.71-fold and 479.63-fold improvements, respectively. Meanwhile, both IND hydrogels performed significantly enhanced release rate and degree, and maintained supersaturation for a long time arising from the complexation reaction of IND and ligand, which was revealed by phase solubility and fluorescence quenching studies. Furthermore, the designed IND hydrogels significantly promoted IND membrane permeability compared to the commercial IND hydrogel, and enhanced the development potential of novel IND hydrogels for oral and transdermal applications. Therefore, this study provides a new formulation technique to increase the solubility/release and permeability of poorly water-soluble drugs by designing their small molecule hydrogel systems.
{"title":"Design of indomethacin novel small molecule hydrogels for concomitant release and permeability increases","authors":"Jiawei Han , Zhimin Yue , Wen Sun , Weitao Fang , Yunran Zhang , Xiaoqian Liu , Jue Wang , Jiaxin Chen","doi":"10.1016/j.ijpharm.2025.125286","DOIUrl":"10.1016/j.ijpharm.2025.125286","url":null,"abstract":"<div><div>With the expansion of gel research, organic small molecule gels are beginning to gain attention. Whether the small-molecule gel approach can be a new formulation strategy of solubilization and permeation promotion for poorly soluble drugs needs to be explored in this study. The model ingredient indomethacin (IND) as a nonsteroidal anti-flammatory drug shows limited therapeutic application mainly due to its low water solubility. Herein, the IND small molecule hydrogel was design to co-formed with a small molecule ligand by integrating theory-model-experiment techniques. Then, the formed IND small molecule hydrogels (i.e., IND-MEG hydrogel and IND-ARG hydrogel) with meglumine (MEG) or arginine (ARG) appeared typical 3-D network with good rheology. In comparison to crystalline IND, the solubilities of IND-MEG hydrogel and IND-ARG hydrogel exhibited 506.71-fold and 479.63-fold improvements, respectively. Meanwhile, both IND hydrogels performed significantly enhanced release rate and degree, and maintained supersaturation for a long time arising from the complexation reaction of IND and ligand, which was revealed by phase solubility and fluorescence quenching studies. Furthermore, the designed IND hydrogels significantly promoted IND membrane permeability compared to the commercial IND hydrogel, and enhanced the development potential of novel IND hydrogels for oral and transdermal applications. Therefore, this study provides a new formulation technique to increase the solubility/release and permeability of poorly water-soluble drugs by designing their small molecule hydrogel systems.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125286"},"PeriodicalIF":5.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074515","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 : 2025-01-30DOI: 10.1016/j.ijpharm.2025.125259
Elisa Vettorato, Paola Volonté, Umberto M. Musazzi, Francesco Cilurzo, Antonella Casiraghi
The synergistic effect of corticosteroids and 5-fluorouracil (5-FU) for the treatment of pathological scarring is widely documented. While topical administration can be a painless, convenient way to convey the two active ingredients, physical enhancement techniques such as microneedling are required to deepen their skin penetration and achieve the therapeutic effect. A novel approach to keloid and scar treatment is given by microincision, i.e., micrometric-sized columnar perforations which allow the drugs to diffuse into the skin and promote tissue proliferation in a more physiological structure. Combining the delivery of triamcinolone acetonide (TAC) and 5-FU with microincision is an innovative approach that could improve the speed and efficacy of regenerative treatments.
This study evaluated the effectiveness of the skin treatment with a device combining microincisions and photobiomodulation, in the skin permeation of a combination of TAC and 5-FU. Increasing treatment times (4, 6, and 8 min) led to higher drug penetration compared to intact skin, with a more noticeable effect for 5-FU compared to TAC. Specifically, all treatment durations were significantly more effective (p < 0.05) than the control for 5-FU, while TAC showed less variation between treatments. Moreover, it was shown that in-vitro, the permeation improvement given by the red-light treatment was mainly due to the mechanical massage, which pushed the actives into the microchannels created by the treatment. The application of prolonged skin microincision times ensured much higher skin permeation of both TAC and 5-FU compared to microneedling on healthy excised skin.
{"title":"Skin microincision technique to enhance drug penetration for the treatment of keloid and hypertrophic scars","authors":"Elisa Vettorato, Paola Volonté, Umberto M. Musazzi, Francesco Cilurzo, Antonella Casiraghi","doi":"10.1016/j.ijpharm.2025.125259","DOIUrl":"10.1016/j.ijpharm.2025.125259","url":null,"abstract":"<div><div>The synergistic effect of corticosteroids and 5-fluorouracil (5-FU) for the treatment of pathological scarring is widely documented. While topical administration can be a painless, convenient way to convey the two active ingredients, physical enhancement techniques such as microneedling are required to deepen their skin penetration and achieve the therapeutic effect. A novel approach to keloid and scar treatment is given by microincision, <em>i.e.</em>, micrometric-sized columnar perforations which allow the drugs to diffuse into the skin and promote tissue proliferation in a more physiological structure. Combining the delivery of triamcinolone acetonide (TAC) and 5-FU with microincision is an innovative approach that could improve the speed and efficacy of regenerative treatments.</div><div>This study evaluated the effectiveness of the skin treatment with a device combining microincisions and photobiomodulation, in the skin permeation of a combination of TAC and 5-FU. Increasing treatment times (4, 6, and 8 min) led to higher drug penetration compared to intact skin, with a more noticeable effect for 5-FU compared to TAC. Specifically, all treatment durations were significantly more effective (p < 0.05) than the control for 5-FU, while TAC showed less variation between treatments. Moreover, it was shown that <em>in-vitro</em>, the permeation improvement given by the red-light treatment was mainly due to the mechanical massage, which pushed the actives into the microchannels created by the treatment. The application of prolonged skin microincision times ensured much higher skin permeation of both TAC and 5-FU compared to microneedling on healthy excised skin.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"671 ","pages":"Article 125259"},"PeriodicalIF":5.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074565","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 : 2025-01-30DOI: 10.1016/j.ijpharm.2025.125298
Lucy M. Newman, Oisín N. Kavanagh, Tatiane C. Machado
Synchronising both cocrystal dissolution and drug precipitation processes is the key for the development of cocrystal systems with desired dissolution-supersaturation-precipitation (DSP) behaviours. Our findings with ketoconazole (KTZ) − p-aminobenzoic acid (PABA) 1:1 cocrystal show that this can be achieved by generating non-stoichiometric coformer concentrations that allow us to modulate the maximum theoretical cocrystal supersaturation SA (thermodynamic limit) below the drug critical supersaturation σcrit (kinetic limit). The application of our conceptual graphical approach combined with the two metrics SA and the DSPindex answer the question of how much additional coformer is needed to target optimal sustained drug supersaturation levels. Modulating SA < σcrit and DSPindex > 1 allowed for a stable and sustained KTZ release system with supersaturation levels of 6 by 24 h. Findings provide a direct approach for better early decisions regarding cocrystal dose design and/or coformer concentration to be added to formulations to ultimately fine-tune drug supersaturation by coupling dissolution and precipitation processes.
{"title":"DSPindex guides dose selection to extend drug supersaturation lifetime during cocrystal dissolution","authors":"Lucy M. Newman, Oisín N. Kavanagh, Tatiane C. Machado","doi":"10.1016/j.ijpharm.2025.125298","DOIUrl":"10.1016/j.ijpharm.2025.125298","url":null,"abstract":"<div><div>Synchronising both cocrystal dissolution and drug precipitation processes is the key for the development of cocrystal systems with desired dissolution-supersaturation-precipitation (DSP) behaviours. Our findings with ketoconazole (KTZ) − <em>p</em>-aminobenzoic acid (PABA) 1:1 cocrystal show that this can be achieved by generating non-stoichiometric coformer concentrations that allow us to modulate the maximum theoretical cocrystal supersaturation SA (thermodynamic limit) below the drug critical supersaturation σ<sub>crit</sub> (kinetic limit). The application of our conceptual graphical approach combined with the two metrics SA and the DSP<sub>index</sub> answer the question of how much additional coformer is needed to target optimal sustained drug supersaturation levels. Modulating SA < σ<sub>crit</sub> and DSP<sub>index</sub> > 1 allowed for a stable and sustained KTZ release system with supersaturation levels of 6 by 24 h. Findings provide a direct approach for better early decisions regarding cocrystal dose design and/or coformer concentration to be added to formulations to ultimately fine-tune drug supersaturation by coupling dissolution and precipitation processes.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"671 ","pages":"Article 125298"},"PeriodicalIF":5.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074523","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 : 2025-01-30DOI: 10.1016/j.ijpharm.2025.125252
Binghua Wang , Yiwen Gao , Zhihui Song , Yuru Zhang , Peibo Fan , Xiang Lu , Hongling Zhang , Zhenzhong Zhang
Simultaneous co-delivery of both antigens and adjuvants is crucial for the efficient activation of dendritic cells (DCs), but it has often been overlooked in the context of tumor cell-based vaccines. Building on the significant advancements in cationic nano-adjuvants, we proposed a straightforward and effective strategy for crafting personalized cancer vaccines, in which tumor cell vesicle antigens were paired with cationic nano-adjuvants to form nano-network through electrostatic adherence. Our pioneering research indicates that densely arranged nanoparticles can be simultaneously taken up by DCs, thus facilitating the co-delivery of adjuvants and antigens. To further enhance the interaction between DCs and antigens, the antigens-adjuvants nano-network was reconstructed using high aspect ratio silicon dioxide (SiO2) rods to generate 3D structures with ample interparticle spaces. This fosters a conducive environment for DCs infiltration, thereby optimizing the spatial and temporal orchestration of antigen cross-presentation. When combined with programmed death ligand 1 (PD-L1) immune checkpoint inhibitors, the dual-scale cancer vaccine effectively inhibits tumor proliferation through T cell-mediated mechanisms, resulting in a survival rate of 60 % in mice for over 40 days. In summary, our study introduces an innovative approach to the spatiotemporal orchestration of antigen cross-presentation, providing fresh insights into the construction of cancer vaccines based on tumor cells.
{"title":"Pairing tumor cell vesicle antigens with cationic nano-adjuvants by electrostatic adherence for personalized cancer vaccine","authors":"Binghua Wang , Yiwen Gao , Zhihui Song , Yuru Zhang , Peibo Fan , Xiang Lu , Hongling Zhang , Zhenzhong Zhang","doi":"10.1016/j.ijpharm.2025.125252","DOIUrl":"10.1016/j.ijpharm.2025.125252","url":null,"abstract":"<div><div>Simultaneous co-delivery of both antigens and adjuvants is crucial for the efficient activation of dendritic cells (DCs), but it has often been overlooked in the context of tumor cell-based vaccines. Building on the significant advancements in cationic nano-adjuvants, we proposed a straightforward and effective strategy for crafting personalized cancer vaccines, in which tumor cell vesicle antigens were paired with cationic nano-adjuvants to form nano-network through electrostatic adherence. Our pioneering research indicates that densely arranged nanoparticles can be simultaneously taken up by DCs, thus facilitating the co-delivery of adjuvants and antigens. To further enhance the interaction between DCs and antigens, the antigens-adjuvants nano-network was reconstructed using high aspect ratio silicon dioxide (SiO<sub>2</sub>) rods to generate 3D structures with ample interparticle spaces. This fosters a conducive environment for DCs infiltration, thereby optimizing the spatial and temporal orchestration of antigen cross-presentation. When combined with programmed death ligand 1 (PD-L1) immune checkpoint inhibitors, the dual-scale cancer vaccine effectively inhibits tumor proliferation through T cell-mediated mechanisms, resulting in a survival rate of 60 % in mice for over 40 days. In summary, our study introduces an innovative approach to the spatiotemporal orchestration of antigen cross-presentation, providing fresh insights into the construction of cancer vaccines based on tumor cells.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125252"},"PeriodicalIF":5.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074539","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 : 2025-01-28DOI: 10.1016/j.ijpharm.2025.125294
Yubo Wang , Yong Zhou , Jinling Wang , Lu Zhang , Chen Liu , Ding Guo , Yanlin Yu , Roumei Ye , Yun Wang , Bing Xu , Yiming Luo , Dengyue Chen
The limited selectivity and high systemic toxicity of traditional chemotherapy hinder its efficacy in treating diffuse large B-cell lymphoma (DLBCL). The combination of sonodynamic therapy (SDT) with chemotherapy has emerged as a novel strategy for cancer treatment, aiming to improve therapeutic outcomes and reduce systemic toxicity. However, challenges such as elevated drug clearance rates and non-selecitivity remain to be resolved. This study has developed a biocompatible nanomedicine delivery system, PA-HM@DOX/ICG, employing hollow mesoporous silica nanoparticles (HMSNs) as the nanocarrier. The nanomedicine incorporates the chemotherapeutic agent doxorubicin (DOX) along with the sonosensitizer indocyanine green (ICG) within its encapsulation, and undergoes additional surface modification using lipid-nucleic acid conjugates (DSPE-PEG-AS1411) to facilitate active targeted delivery. In vitro cellular experiments have validated that PA-HM@DOX/ICG can specifically recognize and be internalized by SU-DHL-4 lymphoma cells due to the overexpression of nucleolin on their surface. The synergistic effects of DOX-induced DNA damage and reactive oxygen species (ROS) generated by ultrasound-activated ICG induce apoptosis in these cells. Furthermore, PA-HM@DOX/ICG displays minimal toxicity towards LO2 normal hepatocytes, indicating a favorable biosafety profile. In vivo animal studies have shown that PA-HM@DOX/ICG effectively accumulates in tumor sites in mice through both the enhanced permeability and retention (EPR) effect and nucleolin-mediated targeting. Under ultrasound irradiation, PA-HM@DOX/ICG significantly inhibits tumor growth. This study introduces a nanoplatform that integrates chemotherapy with sonodynamic therapy, offering a novel approach for the efficient treatment of DLBCL.
{"title":"Nucleolin-targeted silicon-based nanoparticles for enhanced chemo-sonodynamic therapy of diffuse large B-cell lymphoma","authors":"Yubo Wang , Yong Zhou , Jinling Wang , Lu Zhang , Chen Liu , Ding Guo , Yanlin Yu , Roumei Ye , Yun Wang , Bing Xu , Yiming Luo , Dengyue Chen","doi":"10.1016/j.ijpharm.2025.125294","DOIUrl":"10.1016/j.ijpharm.2025.125294","url":null,"abstract":"<div><div>The limited selectivity and high systemic toxicity of traditional chemotherapy hinder its efficacy in treating diffuse large B-cell lymphoma (DLBCL). The combination of sonodynamic therapy (SDT) with chemotherapy has emerged as a novel strategy for cancer treatment, aiming to improve therapeutic outcomes and reduce systemic toxicity. However, challenges such as elevated drug clearance rates and non-selecitivity remain to be resolved. This study has developed a biocompatible nanomedicine delivery system, PA-HM@DOX/ICG, employing hollow mesoporous silica nanoparticles (HMSNs) as the nanocarrier. The nanomedicine incorporates the chemotherapeutic agent doxorubicin (DOX) along with the sonosensitizer indocyanine green (ICG) within its encapsulation, and undergoes additional surface modification using lipid-nucleic acid conjugates (DSPE-PEG-AS1411) to facilitate active targeted delivery. In vitro cellular experiments have validated that PA-HM@DOX/ICG can specifically recognize and be internalized by SU-DHL-4 lymphoma cells due to the overexpression of nucleolin on their surface. The synergistic effects of DOX-induced DNA damage and reactive oxygen species (ROS) generated by ultrasound-activated ICG induce apoptosis in these cells. Furthermore, PA-HM@DOX/ICG displays minimal toxicity towards LO2 normal hepatocytes, indicating a favorable biosafety profile. In vivo animal studies have shown that PA-HM@DOX/ICG effectively accumulates in tumor sites in mice through both the enhanced permeability and retention (EPR) effect and nucleolin-mediated targeting. Under ultrasound irradiation, PA-HM@DOX/ICG significantly inhibits tumor growth. This study introduces a nanoplatform that integrates chemotherapy with sonodynamic therapy, offering a novel approach for the efficient treatment of DLBCL.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"671 ","pages":"Article 125294"},"PeriodicalIF":5.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064645","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}
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