Pub Date : 2025-12-30DOI: 10.1016/j.xphs.2025.104149
Richieline S. Cual, Tajmarah Ayyah M. Sandato, Mae Quenie T. Pontanar
Insulin, a pancreatic hormone regulating blood glucose, is available in forms of syringe, pen, or implants; however, these methods presented challenges related to skin adverse reactions and patient compliance. Oral insulin delivery has long been explored due to higher compliance and reduced costs. Similar to natural insulin secretion, but prone to GIT breakdown and low bioavailability. SNEDDS has been investigated to address these in protein formulations. This study formulated Insulin into SNEDDS with trimethyl chitosan and spray-dried for stability, then analyzed for properties and drug release. The study successfully prepared Insulin-TMC SNEDDS with a 36.17±4.02 s emulsification time, forming a Grade B nanoemulsion. Droplet sizes remained nanoscale (134.20–287.20 nm for liquid, 188.77–214.93 nm for solid), preserving characteristics post–spray drying. Stability was confirmed in TMC-free formulations, while TMC variants showed sedimentation over time. TMC-containing Solid-SNEDDS showed moisture content below 5 %, indicating good stability. Insulin release varied with pH—highest at pH 2.5 with 3 mg/mL TMC (105.48 % cumulative percent drug release), while lower releases were seen at pH 6.6 (61.73±1.38 %) and 7.0 (61.73±1.38 %) without TMC. The study supports TMC-based SNEDDS and spray drying as a potential method for oral insulin delivery.
{"title":"Preparation and characterization of oral insulin-trimethyl chitosan complex-loaded solid self-nanoemulsifying drug delivery systems (SNEDDS)","authors":"Richieline S. Cual, Tajmarah Ayyah M. Sandato, Mae Quenie T. Pontanar","doi":"10.1016/j.xphs.2025.104149","DOIUrl":"10.1016/j.xphs.2025.104149","url":null,"abstract":"<div><div>Insulin, a pancreatic hormone regulating blood glucose, is available in forms of syringe, pen, or implants; however, these methods presented challenges related to skin adverse reactions and patient compliance. Oral insulin delivery has long been explored due to higher compliance and reduced costs. Similar to natural insulin secretion, but prone to GIT breakdown and low bioavailability. SNEDDS has been investigated to address these in protein formulations. This study formulated Insulin into SNEDDS with trimethyl chitosan and spray-dried for stability, then analyzed for properties and drug release. The study successfully prepared Insulin-TMC SNEDDS with a 36.17±4.02 s emulsification time, forming a Grade B nanoemulsion. Droplet sizes remained nanoscale (134.20–287.20 nm for liquid, 188.77–214.93 nm for solid), preserving characteristics post–spray drying. Stability was confirmed in TMC-free formulations, while TMC variants showed sedimentation over time. TMC-containing Solid-SNEDDS showed moisture content below 5 %, indicating good stability. Insulin release varied with pH—highest at pH 2.5 with 3 mg/mL TMC (105.48 % cumulative percent drug release), while lower releases were seen at pH 6.6 (61.73±1.38 %) and 7.0 (61.73±1.38 %) without TMC. The study supports TMC-based SNEDDS and spray drying as a potential method for oral insulin delivery.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104149"},"PeriodicalIF":3.8,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-30DOI: 10.1016/j.xphs.2025.104151
Weronika Śliżewska , Filomena Martins , Rodrigo F.M. de Almeida , Joaquim T. Marquês
Tuberculosis is one of the most important causes of death in the world. The emergence and increased prominence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb), non-susceptible to currently available therapies, has toughened the fight to eradicate this disease. This study focuses on further investigating the therapeutic potential of promising antitubercular compounds, namely, isoniazid (INH), and three INH derivatives, N'-decanoylisonicotinohydrazide (INH-C10), N'-(E)-(4-phenoxybenzylidene)isonicotinohydrazide (N34) and N’-(4-phenoxybenzyl)isonicotinohydrazide (N34red). INH-C10 and N34 have been selected due to their high selectivity index against the Mtb mutant bearing the primary mutation responsible for INH drug resistance. In opposition, N34red, which differs from N34 only in the saturation of the N′ = C bond, exhibits a poor selectivity index. Moreover, INH-C10 and N34 interact with human serum albumin and model lipid membranes mimicking the plasma membrane of human cells, showing their promising potential. In the current study, the interaction of these compounds with models of the lung surfactant (LS) and of the mycolic acid (MA)-enriched Mtb cell wall was assessed, in order to further explore their ability to interact with and cross the various biological barriers to be encountered on their way to the molecular target inside Mtb. We show that all the INH derivatives were able to interact with both the LS and the mycolic acid-enriched cell wall models. INH-C10 and N34 had a smaller impact than N34red on the pulmonary surfactant model. On the other hand, INH-C10 promoted the most extensive perturbation of the MA-enriched cell wall model, which correlates well with the previously shown ability of this compound to incorporate into and disturb gel-phase lipid bilayers. This indicates that INH-C10 may penetrate a MA rich barrier more easily, reaching higher intracellular levels, and increase its permeability. These traits contribute to explain the high antimicrobial activity of this derivative against the most common drug-resistant Mtb mutant.
{"title":"Interaction of isoniazid derivatives active against drug-resistant tuberculosis with models of the lung surfactant and of the Mycobacterium tuberculosis cell wall","authors":"Weronika Śliżewska , Filomena Martins , Rodrigo F.M. de Almeida , Joaquim T. Marquês","doi":"10.1016/j.xphs.2025.104151","DOIUrl":"10.1016/j.xphs.2025.104151","url":null,"abstract":"<div><div>Tuberculosis is one of the most important causes of death in the world. The emergence and increased prominence of multidrug-resistant strains of <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>), non-susceptible to currently available therapies, has toughened the fight to eradicate this disease. This study focuses on further investigating the therapeutic potential of promising antitubercular compounds, namely, isoniazid (INH), and three INH derivatives, <em>N</em>'-decanoylisonicotinohydrazide (INH-C10), <em>N</em>'-(<em>E</em>)-(4-phenoxybenzylidene)isonicotinohydrazide (N34) and <em>N</em>’-(4-phenoxybenzyl)isonicotinohydrazide (N34red). INH-C10 and N34 have been selected due to their high selectivity index against the <em>Mtb</em> mutant bearing the primary mutation responsible for INH drug resistance. In opposition, N34red, which differs from N34 only in the saturation of the <em>N</em>′ = C bond, exhibits a poor selectivity index. Moreover, INH-C10 and N34 interact with human serum albumin and model lipid membranes mimicking the plasma membrane of human cells, showing their promising potential. In the current study, the interaction of these compounds with models of the lung surfactant (LS) and of the mycolic acid (MA)-enriched <em>Mtb</em> cell wall was assessed, in order to further explore their ability to interact with and cross the various biological barriers to be encountered on their way to the molecular target inside <em>Mtb</em>. We show that all the INH derivatives were able to interact with both the LS and the mycolic acid-enriched cell wall models. INH-C10 and N34 had a smaller impact than N34red on the pulmonary surfactant model. On the other hand, INH-C10 promoted the most extensive perturbation of the MA-enriched cell wall model, which correlates well with the previously shown ability of this compound to incorporate into and disturb gel-phase lipid bilayers. This indicates that INH-C10 may penetrate a MA rich barrier more easily, reaching higher intracellular levels, and increase its permeability. These traits contribute to explain the high antimicrobial activity of this derivative against the most common drug-resistant <em>Mtb</em> mutant.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104151"},"PeriodicalIF":3.8,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recombinant adeno-associated virus (rAAV) is widely used as a gene delivery vector. Sedimentation velocity analytical ultracentrifugation (SV–AUC) is the gold standard for quantifying the ratio of full particles (FPs) to the sum of empty particles (EPs) and FPs (F/E ratio) of rAAVs. Here, we experimentally determined the molar extinction coefficients (ε) and mass extinction coefficients of highly purified FPs and EPs of AAV serotypes 2, 5, 6, 8, and 9 using SV–AUC with interference and multi-wavelength absorbance detection. At 230 nm, the difference in ε between EPs and FPs was the smallest, although the ε of FPs remained 1.2-fold higher than that of EPs. Expectedly, the differences in ε between FPs and EPs were almost identical across serotypes with the same genome length and increased linearly in a genome length-dependent manner, although both sets of ε differed across serotypes. Consequently, accurate quantification of F/E ratio requires the use of distinct ε values for EPs and FPs. The ε per base of single-stranded DNA was independent of serotype and genome length, allowing estimation of the ε of FPs from that of EPs. Coupling these ε values with SV–AUC enables the determination of absolute rAAV concentrations. This study provides practical guidance for accurate absorbance-based rAAV quantification.
{"title":"Experimental determination of extinction coefficients by sedimentation velocity analytical ultracentrifugation for accurate quantification of recombinant adeno-associated virus","authors":"Yuki Yamaguchi , Takahiro Maruno , Takaaki Kurinomaru , Risa Shibuya , Mitsuko Fukuhara , Yasuo Tsunaka , Susumu Uchiyama","doi":"10.1016/j.xphs.2025.104150","DOIUrl":"10.1016/j.xphs.2025.104150","url":null,"abstract":"<div><div>Recombinant adeno-associated virus (rAAV) is widely used as a gene delivery vector. Sedimentation velocity analytical ultracentrifugation (SV–AUC) is the gold standard for quantifying the ratio of full particles (FPs) to the sum of empty particles (EPs) and FPs (F/E ratio) of rAAVs. Here, we experimentally determined the molar extinction coefficients (<em>ε</em>) and mass extinction coefficients of highly purified FPs and EPs of AAV serotypes 2, 5, 6, 8, and 9 using SV–AUC with interference and multi-wavelength absorbance detection. At 230 nm, the difference in <em>ε</em> between EPs and FPs was the smallest, although the <em>ε</em> of FPs remained 1.2-fold higher than that of EPs. Expectedly, the differences in <em>ε</em> between FPs and EPs were almost identical across serotypes with the same genome length and increased linearly in a genome length-dependent manner, although both sets of <em>ε</em> differed across serotypes. Consequently, accurate quantification of F/E ratio requires the use of distinct <em>ε</em> values for EPs and FPs. The <em>ε</em> per base of single-stranded DNA was independent of serotype and genome length, allowing estimation of the <em>ε</em> of FPs from that of EPs. Coupling these <em>ε</em> values with SV–AUC enables the determination of absolute rAAV concentrations. This study provides practical guidance for accurate absorbance-based rAAV quantification.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104150"},"PeriodicalIF":3.8,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-26DOI: 10.1016/j.xphs.2025.104148
Shun Takayama , Yukiko Nagai , Tomomi Sugiyama , Fumiyuki Ito , Jun Miyazaki
Light-sensitive pharmaceuticals are susceptible to alteration or degradation under ambient light conditions, such as sunlight or artificial lighting, requiring pharmacists and patients to prevent exposure of these drugs to light. However, the transition from fluorescent to light-emitting diode (LED) light has altered the ambient light characteristics within buildings. Dacarbazine, chemically known as 5-(3,3-dimethyl-1-triazen-1-yl)-1H-imidazole-4-carboxamide (DTIC), is a light-sensitive anticancer drug. Its photodegradation product, Diazo-IC (5-diazoimidazole-4-carboxamide) is known to cause vascular pain in patients during infusion. Utilizing UV/Vis spectroscopy, this study examines the photodegradation of DTIC in aqueous solution under fluorescent and light-emitting diode (LED) lighting conditions, which are both prevalent in contemporary buildings. Results indicate that DTIC remained stable when exposed to LED light, with no decomposition observed, whereas photodegradation occurred under fluorescent light. The residual ratio revealed that DTIC remained stable for 240 min under LED illumination, indicating that LED light exposure does not induce DTIC photodegradation. These findings suggest that the ongoing replacement of fluorescent lighting with LED in healthcare settings and patient residences may eliminate vascular pain associated with DTIC photodegradation in the near future.
{"title":"Photodegradation of dacarbazine irradiated by common lighting sources: An examination of the differences between light-emitting diode (LED) and fluorescent light","authors":"Shun Takayama , Yukiko Nagai , Tomomi Sugiyama , Fumiyuki Ito , Jun Miyazaki","doi":"10.1016/j.xphs.2025.104148","DOIUrl":"10.1016/j.xphs.2025.104148","url":null,"abstract":"<div><div>Light-sensitive pharmaceuticals are susceptible to alteration or degradation under ambient light conditions, such as sunlight or artificial lighting, requiring pharmacists and patients to prevent exposure of these drugs to light. However, the transition from fluorescent to light-emitting diode (LED) light has altered the ambient light characteristics within buildings. Dacarbazine, chemically known as 5-(3,3-dimethyl-1-triazen-1-yl)-1<em>H</em>-imidazole-4-carboxamide (DTIC), is a light-sensitive anticancer drug. Its photodegradation product, Diazo-IC (5-diazoimidazole-4-carboxamide) is known to cause vascular pain in patients during infusion. Utilizing UV/Vis spectroscopy, this study examines the photodegradation of DTIC in aqueous solution under fluorescent and light-emitting diode (LED) lighting conditions, which are both prevalent in contemporary buildings. Results indicate that DTIC remained stable when exposed to LED light, with no decomposition observed, whereas photodegradation occurred under fluorescent light. The residual ratio revealed that DTIC remained stable for 240 min under LED illumination, indicating that LED light exposure does not induce DTIC photodegradation. These findings suggest that the ongoing replacement of fluorescent lighting with LED in healthcare settings and patient residences may eliminate vascular pain associated with DTIC photodegradation in the near future.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104148"},"PeriodicalIF":3.8,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-25DOI: 10.1016/j.xphs.2025.104146
Masato Takahashi, Shintaro Sakamoto, Nao Sakamoto, Sora Nishimura, Seonho Hwang, Jihyun Kim, Masakiyo Hosokawa
Ester-based prodrugs are often prematurely hydrolyzed by intestinal carboxylesterases, leading to reduced bioavailability and potential gastrointestinal (GI) toxicity. To overcome this limitation, a series of diester, carbonate-linked ester, and carbamate-linked ester prodrugs were synthesized and evaluated using human liver microsomes (HLM), human intestinal microsomes (HIM), and recombinant carboxylesterases (CES1A1 and CES2A1). Under strongly acidic conditions (pH 1.2), all prodrugs remained highly stable (>98% remaining after 6 h). In human plasma, however, diester prodrugs showed relatively rapid degradation (approximately 50% remaining after 6 h), whereas carbonate- and carbamate-linked esters displayed enhanced stability. Diester and carbonate-linked ester prodrugs were hydrolyzed by both HLM and HIM, indicating non-selective activation. By contrast, several carbamate-linked ester prodrugs showed high HLM/HIM selectivity, with CES1A1/CES2A1 hydrolysis rate ratios exceeding 50. Docking simulations showed favorable active-site binding of carbamate-linked ester prodrugs to CES1A1 but not to CES2A1, supporting the selectivity of CES1A1. These findings suggest that carbamate-based prodrug strategies can be employed to improve intestinal stability and enable controlled systemic activation, potentially reducing off-target effects and enhancing oral drug delivery. This strategy may also be applicable to liver- or lung-targeted prodrug design.
{"title":"Design and synthesis of carbamate-linked ester prodrugs selectively activated by carboxylesterase 1 with enhanced stability against intestinal hydrolysis","authors":"Masato Takahashi, Shintaro Sakamoto, Nao Sakamoto, Sora Nishimura, Seonho Hwang, Jihyun Kim, Masakiyo Hosokawa","doi":"10.1016/j.xphs.2025.104146","DOIUrl":"10.1016/j.xphs.2025.104146","url":null,"abstract":"<div><div>Ester-based prodrugs are often prematurely hydrolyzed by intestinal carboxylesterases, leading to reduced bioavailability and potential gastrointestinal (GI) toxicity. To overcome this limitation, a series of diester, carbonate-linked ester, and carbamate-linked ester prodrugs were synthesized and evaluated using human liver microsomes (HLM), human intestinal microsomes (HIM), and recombinant carboxylesterases (CES1A1 and CES2A1). Under strongly acidic conditions (pH 1.2), all prodrugs remained highly stable (>98% remaining after 6 h). In human plasma, however, diester prodrugs showed relatively rapid degradation (approximately 50% remaining after 6 h), whereas carbonate- and carbamate-linked esters displayed enhanced stability. Diester and carbonate-linked ester prodrugs were hydrolyzed by both HLM and HIM, indicating non-selective activation. By contrast, several carbamate-linked ester prodrugs showed high HLM/HIM selectivity, with CES1A1/CES2A1 hydrolysis rate ratios exceeding 50. Docking simulations showed favorable active-site binding of carbamate-linked ester prodrugs to CES1A1 but not to CES2A1, supporting the selectivity of CES1A1. These findings suggest that carbamate-based prodrug strategies can be employed to improve intestinal stability and enable controlled systemic activation, potentially reducing off-target effects and enhancing oral drug delivery. This strategy may also be applicable to liver- or lung-targeted prodrug design.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104146"},"PeriodicalIF":3.8,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-25DOI: 10.1016/j.xphs.2025.104141
Kristian Le Vay, Benjamin Steinborn, Constanze Helbig, Andrea Arsiccio, Maksymilian M. Zegota, Christa von der Schulenburg, Angelika Reichel, Tim Menzen, Andrea Hawe
Surfactants such as polysorbate 20 (PS20), polysorbate 80 (PS80), and poloxamer 188 (P188) are integral to the stabilization of protein therapeutics, yet their removal is often required during formulation development and analytical characterization. This work investigates the efficiency of surfactant removal by commercial spin columns and tangential flow filtration (TFF), using liquid chromatography with charged aerosol detection (LC-CAD) to evaluate subspecies specific behavior. Spin column experiments demonstrated effective PS20 clearance from monoclonal antibody formulations, while PS80 removal was limited, particularly for PS80 polyester species. TFF enabled selective removal of unesterified and monoester species for both polysorbates, with PS20 showing the highest overall clearance, especially when processed below its critical micelle concentration (CMC). PS80 removal was ineffective again due to retention of polyester species, while P188 exhibited slower and incomplete removal kinetics. These findings underscore the need for improved surfactant removal strategies and the importance of subspecies profile analysis in surfactant quantification.
{"title":"Challenges in surfactant removal from biopharmaceutical formulations using tangential flow filtration (TFF) and spin columns","authors":"Kristian Le Vay, Benjamin Steinborn, Constanze Helbig, Andrea Arsiccio, Maksymilian M. Zegota, Christa von der Schulenburg, Angelika Reichel, Tim Menzen, Andrea Hawe","doi":"10.1016/j.xphs.2025.104141","DOIUrl":"10.1016/j.xphs.2025.104141","url":null,"abstract":"<div><div>Surfactants such as polysorbate 20 (PS20), polysorbate 80 (PS80), and poloxamer 188 (P188) are integral to the stabilization of protein therapeutics, yet their removal is often required during formulation development and analytical characterization. This work investigates the efficiency of surfactant removal by commercial spin columns and tangential flow filtration (TFF), using liquid chromatography with charged aerosol detection (LC-CAD) to evaluate subspecies specific behavior. Spin column experiments demonstrated effective PS20 clearance from monoclonal antibody formulations, while PS80 removal was limited, particularly for PS80 polyester species. TFF enabled selective removal of unesterified and monoester species for both polysorbates, with PS20 showing the highest overall clearance, especially when processed below its critical micelle concentration (CMC). PS80 removal was ineffective again due to retention of polyester species, while P188 exhibited slower and incomplete removal kinetics. These findings underscore the need for improved surfactant removal strategies and the importance of subspecies profile analysis in surfactant quantification.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104141"},"PeriodicalIF":3.8,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1016/j.xphs.2025.104147
Molham Sakkal , Abdallah Abou Hajal
The development of effective drug delivery systems (DDS) faces persistent challenges, including biological barriers, formulation stability, low bioavailability, and complex regulatory demands. While artificial intelligence (AI) and machine learning (ML) have gained traction in pharmaceutical research, the role of large language models (LLMs) in DDS design and development remains an emerging and underexplored area. This review provides a structured overview of the intersection between LLMs and pharmaceutical formulation. It introduces the foundational principles of LLMs, frames key formulation challenges within drug delivery, and critically examines how existing LLM-powered tools are being applied to literature mining, protocol generation, molecular property prediction, and preformulation guidance. Practical examples from recent studies are discussed to illustrate potential use cases.
We further identify key limitations in current LLM integration, including the lack of domain-specific models, limited data accessibility, risks of hallucinated outputs, and usability challenges for non-specialists. Finally, we propose essential future research directions to bridge these gaps and enhance real-world applicability. This review equips pharmaceutical scientists, formulation researchers, and interdisciplinary R&D teams with critical insights to support the responsible adoption of LLMs, ultimately accelerating the development of personalized and efficient drug delivery solutions.
{"title":"Large language models in drug delivery: A review of the current landscape and future perspectives","authors":"Molham Sakkal , Abdallah Abou Hajal","doi":"10.1016/j.xphs.2025.104147","DOIUrl":"10.1016/j.xphs.2025.104147","url":null,"abstract":"<div><div>The development of effective drug delivery systems (DDS) faces persistent challenges, including biological barriers, formulation stability, low bioavailability, and complex regulatory demands. While artificial intelligence (AI) and machine learning (ML) have gained traction in pharmaceutical research, the role of large language models (LLMs) in DDS design and development remains an emerging and underexplored area. This review provides a structured overview of the intersection between LLMs and pharmaceutical formulation. It introduces the foundational principles of LLMs, frames key formulation challenges within drug delivery, and critically examines how existing LLM-powered tools are being applied to literature mining, protocol generation, molecular property prediction, and preformulation guidance. Practical examples from recent studies are discussed to illustrate potential use cases.</div><div>We further identify key limitations in current LLM integration, including the lack of domain-specific models, limited data accessibility, risks of hallucinated outputs, and usability challenges for non-specialists. Finally, we propose essential future research directions to bridge these gaps and enhance real-world applicability. This review equips pharmaceutical scientists, formulation researchers, and interdisciplinary R&D teams with critical insights to support the responsible adoption of LLMs, ultimately accelerating the development of personalized and efficient drug delivery solutions.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104147"},"PeriodicalIF":3.8,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1016/j.xphs.2025.104145
Rafeek F. Shokry
The specification for a combination product represents a critical covenant of its quality. Too often, the current intellectual framework for forging this covenant remains a fragmented patchwork of legacy pharmaceutical and medical device paradigms. This paper argues that significant product failures are not random accidents but predictable consequences of these historical limitations. We therefore propose a novel, deductive framework—Quality by Design in Specification (QbD-S)—that complements existing empirical methods to address this systemic challenge. This paper presents a formal intellectual engine, the Universal Attribute Generator (UAG), which deconstructs therapeutic failure into five foundational Tenets and uses a rigorous "Interrogatory Filter" (Stress > Capacity) to systematically derive a comprehensive set of quality attributes. This framework introduces the Criticality Vector to contextualize consequence by adding the dimension of "Context" to the standard scalar of "Severity," and mandates a Structured Falsification Protocol to build scientific confidence in its conclusions. The ultimate output is a "Master Control Strategy"—a binding regulatory mandate that legislates the "Fate" of each attribute, enabling either "Input-Controlled" Real-Time Release or mandating traditional "Symptom-Controlled" testing. QbD-S provides a systematic engine for translating patient needs into a scientifically rigorous and defensible covenant of quality.
{"title":"Forging certainty: A novel framework for the specification of combination products","authors":"Rafeek F. Shokry","doi":"10.1016/j.xphs.2025.104145","DOIUrl":"10.1016/j.xphs.2025.104145","url":null,"abstract":"<div><div>The specification for a combination product represents a critical covenant of its quality. Too often, the current intellectual framework for forging this covenant remains a fragmented patchwork of legacy pharmaceutical and medical device paradigms. This paper argues that significant product failures are not random accidents but predictable consequences of these historical limitations. We therefore propose a novel, deductive framework—Quality by Design in Specification (QbD-S)—that complements existing empirical methods to address this systemic challenge. This paper presents a formal intellectual engine, the Universal Attribute Generator (UAG), which deconstructs therapeutic failure into five foundational Tenets and uses a rigorous \"Interrogatory Filter\" (Stress > Capacity) to systematically derive a comprehensive set of quality attributes. This framework introduces the Criticality Vector to contextualize consequence by adding the dimension of \"Context\" to the standard scalar of \"Severity,\" and mandates a Structured Falsification Protocol to build scientific confidence in its conclusions. The ultimate output is a \"Master Control Strategy\"—a binding regulatory mandate that legislates the \"Fate\" of each attribute, enabling either \"Input-Controlled\" Real-Time Release or mandating traditional \"Symptom-Controlled\" testing. QbD-S provides a systematic engine for translating patient needs into a scientifically rigorous and defensible covenant of quality.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104145"},"PeriodicalIF":3.8,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Many active pharmaceutical ingredients (APIs) currently being developed are poorly soluble in water, which enhances their solubility and bioavailability critical challenges. The evaporation/condensation (EV) method, wherein crystalline APIs are dissolved in organic solvents and adsorbed onto porous materials, is used to improve the solubility of APIs. However, the use of residual organic solvents during evaporation is challenging. Recently, the sealed heating (SH) method, in which a mixture of porous materials and a sublimated API is heated in a sealed container, has been reported as an alternative to the EV method. This study focuses on mesoporous silica (MPS-4R or -2R) as a porous material. The SH method was used to investigate the adsorption of ibuprofen (IBU) on MPSs. In the PXRD study, the IBU crystals were amorphized using the SH method. The elution rate of SH mixture containing 10 wt% IBU was approximately 2.7 times higher than that of the IBU crystals at 10 min after the start of the test. Based on these results, the SH method is a novel approach for amorphizing and enhancing the solubility of poorly water-soluble drugs without the use of organic solvents.
{"title":"New method for adsorbing the pharmaceuticals on mesoporous silica: Adsorption behavior of ibuprofen on mesoporous silica via the sealed and heating method","authors":"Yayoi Kawano , Kazuya Nomura , Nobuyuki Natori , Takuma Oba , Chihiro Ozawa , Kaoru Hirose , Takehisa Hanawa","doi":"10.1016/j.xphs.2025.104140","DOIUrl":"10.1016/j.xphs.2025.104140","url":null,"abstract":"<div><div>Many active pharmaceutical ingredients (APIs) currently being developed are poorly soluble in water, which enhances their solubility and bioavailability critical challenges. The evaporation/condensation (EV) method, wherein crystalline APIs are dissolved in organic solvents and adsorbed onto porous materials, is used to improve the solubility of APIs. However, the use of residual organic solvents during evaporation is challenging. Recently, the sealed heating (SH) method, in which a mixture of porous materials and a sublimated API is heated in a sealed container, has been reported as an alternative to the EV method. This study focuses on mesoporous silica (MPS-4R or -2R) as a porous material. The SH method was used to investigate the adsorption of ibuprofen (IBU) on MPSs. In the PXRD study, the IBU crystals were amorphized using the SH method. The elution rate of SH mixture containing 10 wt% IBU was approximately 2.7 times higher than that of the IBU crystals at 10 min after the start of the test. Based on these results, the SH method is a novel approach for amorphizing and enhancing the solubility of poorly water-soluble drugs without the use of organic solvents.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104140"},"PeriodicalIF":3.8,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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