Pub Date : 2022-12-20DOI: 10.3389/fddev.2022.1049848
Fotis Iliopoulos, B. Sil, C. Evans
Topical and transdermal delivery has historically offered an attractive and non-invasive route for administration of medicines. However, human skin is known to be a remarkably good barrier to the permeation of substances. The majority of dermatological drug products have been reported to only deliver a portion of the total dose applied, often resulting in low drug bio-availability at the site of action inside the skin. This insufficient formulation performance, coupled with the fact that percutaneous delivery is heavily influenced by the innate physicochemical properties of the active, pose limitations on effective treatment and prevention of diseases by using solely topical formulations. Generally, it is known that the rate and the extent of drug delivery to and through the skin is highly dependent on the formulation components. This work highlights the importance of the vehicle for the design of efficacious skin products, discusses current limitations in dermal delivery and explores recent advances for overcoming these challenges. Novel materials with penetration enhancing properties and innovative formulation strategies are also explored, together with future perspectives and outlooks. The emphasis here is on studies focused on passive skin transport because of clinical limitations associated with disrupting the skin barrier by physical methods. This information is believed to aid in the design and optimization of dermatological drug products for topical and transdermal delivery of actives.
{"title":"The role of excipients in promoting topical and transdermal delivery: Current limitations and future perspectives","authors":"Fotis Iliopoulos, B. Sil, C. Evans","doi":"10.3389/fddev.2022.1049848","DOIUrl":"https://doi.org/10.3389/fddev.2022.1049848","url":null,"abstract":"Topical and transdermal delivery has historically offered an attractive and non-invasive route for administration of medicines. However, human skin is known to be a remarkably good barrier to the permeation of substances. The majority of dermatological drug products have been reported to only deliver a portion of the total dose applied, often resulting in low drug bio-availability at the site of action inside the skin. This insufficient formulation performance, coupled with the fact that percutaneous delivery is heavily influenced by the innate physicochemical properties of the active, pose limitations on effective treatment and prevention of diseases by using solely topical formulations. Generally, it is known that the rate and the extent of drug delivery to and through the skin is highly dependent on the formulation components. This work highlights the importance of the vehicle for the design of efficacious skin products, discusses current limitations in dermal delivery and explores recent advances for overcoming these challenges. Novel materials with penetration enhancing properties and innovative formulation strategies are also explored, together with future perspectives and outlooks. The emphasis here is on studies focused on passive skin transport because of clinical limitations associated with disrupting the skin barrier by physical methods. This information is believed to aid in the design and optimization of dermatological drug products for topical and transdermal delivery of actives.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47627478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-14DOI: 10.3389/fddev.2022.1073815
T. Fujimoto, M. Erickson, W. Banks
The global pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists despite the progress of vaccination and increased natural immunity. SARS-CoV-2 is associated not only with pneumonia and acute respiratory distress, but also with many symptoms related to the central nervous system (CNS), including loss of the sense of taste and smell, headache, convulsions, visual disturbances, and impaired consciousness. In addition, the virus has been implicated in CNS diseases such as cerebral hemorrhage, cerebral infarction, and encephalitis. SARS-CoV-2 binds to the receptor angiotensin-converting enzyme 2 (ACE2), which is used by the virus as a cell entry receptor. Although the mechanism by which SARS-CoV-2 enters the brain is still unclear, the possibility of direct entry through the olfactory nerve tract and entry into the brain through the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) via blood circulation is indicated. The BBB likely serves as a site of entry for SARS-CoV-2 into the brain, and possibly contributes to the CNS symptoms of COVID-19 due to its dysfunction as a result of SARS-CoV-2 infection. The present review will focus on the effects of COVID-19 on the CNS, particularly on the BBB related cells involved.
{"title":"Neurotropism and blood-brain barrier involvement in COVID-19","authors":"T. Fujimoto, M. Erickson, W. Banks","doi":"10.3389/fddev.2022.1073815","DOIUrl":"https://doi.org/10.3389/fddev.2022.1073815","url":null,"abstract":"The global pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists despite the progress of vaccination and increased natural immunity. SARS-CoV-2 is associated not only with pneumonia and acute respiratory distress, but also with many symptoms related to the central nervous system (CNS), including loss of the sense of taste and smell, headache, convulsions, visual disturbances, and impaired consciousness. In addition, the virus has been implicated in CNS diseases such as cerebral hemorrhage, cerebral infarction, and encephalitis. SARS-CoV-2 binds to the receptor angiotensin-converting enzyme 2 (ACE2), which is used by the virus as a cell entry receptor. Although the mechanism by which SARS-CoV-2 enters the brain is still unclear, the possibility of direct entry through the olfactory nerve tract and entry into the brain through the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) via blood circulation is indicated. The BBB likely serves as a site of entry for SARS-CoV-2 into the brain, and possibly contributes to the CNS symptoms of COVID-19 due to its dysfunction as a result of SARS-CoV-2 infection. The present review will focus on the effects of COVID-19 on the CNS, particularly on the BBB related cells involved.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45515152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-28DOI: 10.3389/fddev.2022.1025029
Tianyang Liu, Nkiruka Ibeanu, S. Brocchini, P. Khaw, Y. Bouremel, S. Awwad
Knowledge of drug mass transfer from the anterior chamber via the iris-lens barrier has important implications for the development of front of the eye medicines that can also deliver drugs to the vitreous cavity. Here, the design and evaluation of a novel in vitro model that estimates anterior clearance (CL) kinetics is described. To mimic some aspects of the human eye to aid with pharmaceutical modelling, the model incorporated a simulation of aqueous inflow from the ciliary inlet at the physiological flow rate, two CL elimination pathways [anterior hyaloid pathway and retina choroid sclera (RCS) pathway], human cavity dimensions and use of simulated vitreous fluid (SVF). An eye movement platform that incorporated 3 different eye movements (smooth pursuit, microsaccadic and saccadic) was tested against the control (no movement) to observe any difference in anterior kinetics profile and drug convection to the posterior cavity. Both timolol and brimonidine injected in the intracameral space were evaluated in the new in vitro prototype. An initial release study with one selected eye movement (smooth pursuit) with timolol (6.8 ± 0.4 µg, 30 μL) and brimonidine (15.3 ± 1.5 µg, 30 μL) showed half-life values of 105.3 and 97.8 min respectively in the anterior cavity (AC) space. Another study evaluated the effect of all eye movements against control with both drugs with higher doses of timolol (146.0 ± 39.1 μg, 25 μL) and brimonidine (134.5 ± 39.5 μg, 25 μL). The amounts of timolol in the back of the eye (RCS membrane and outflow) were 0.07 ± 0.05%, 1.36 ± 0.88%, 1.55 ± 1.03% and 0.98 ± 0.06% by 8 h with smooth pursuit, microsaccadic, saccadic and no movement respectively; whereas brimonidine amounts were 0.70 ± 0.21%, 0.94 ± 0.40%, 1.48 ± 1.02%, and 0.76 ± 0.33% respectively. A small amount of both drugs was seen in other compartments in the model (lens part, iris part, hyaloid membrane part and silicone cornea). These results indicate that this model can be used to determine transfer of small molecules via the iris-lens barrier to help optimise front of the eye formulations to treat tissues further back in the eye.
{"title":"Development of an in vitro model to estimate mass transfer from the anterior cavity","authors":"Tianyang Liu, Nkiruka Ibeanu, S. Brocchini, P. Khaw, Y. Bouremel, S. Awwad","doi":"10.3389/fddev.2022.1025029","DOIUrl":"https://doi.org/10.3389/fddev.2022.1025029","url":null,"abstract":"Knowledge of drug mass transfer from the anterior chamber via the iris-lens barrier has important implications for the development of front of the eye medicines that can also deliver drugs to the vitreous cavity. Here, the design and evaluation of a novel in vitro model that estimates anterior clearance (CL) kinetics is described. To mimic some aspects of the human eye to aid with pharmaceutical modelling, the model incorporated a simulation of aqueous inflow from the ciliary inlet at the physiological flow rate, two CL elimination pathways [anterior hyaloid pathway and retina choroid sclera (RCS) pathway], human cavity dimensions and use of simulated vitreous fluid (SVF). An eye movement platform that incorporated 3 different eye movements (smooth pursuit, microsaccadic and saccadic) was tested against the control (no movement) to observe any difference in anterior kinetics profile and drug convection to the posterior cavity. Both timolol and brimonidine injected in the intracameral space were evaluated in the new in vitro prototype. An initial release study with one selected eye movement (smooth pursuit) with timolol (6.8 ± 0.4 µg, 30 μL) and brimonidine (15.3 ± 1.5 µg, 30 μL) showed half-life values of 105.3 and 97.8 min respectively in the anterior cavity (AC) space. Another study evaluated the effect of all eye movements against control with both drugs with higher doses of timolol (146.0 ± 39.1 μg, 25 μL) and brimonidine (134.5 ± 39.5 μg, 25 μL). The amounts of timolol in the back of the eye (RCS membrane and outflow) were 0.07 ± 0.05%, 1.36 ± 0.88%, 1.55 ± 1.03% and 0.98 ± 0.06% by 8 h with smooth pursuit, microsaccadic, saccadic and no movement respectively; whereas brimonidine amounts were 0.70 ± 0.21%, 0.94 ± 0.40%, 1.48 ± 1.02%, and 0.76 ± 0.33% respectively. A small amount of both drugs was seen in other compartments in the model (lens part, iris part, hyaloid membrane part and silicone cornea). These results indicate that this model can be used to determine transfer of small molecules via the iris-lens barrier to help optimise front of the eye formulations to treat tissues further back in the eye.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41382723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-01DOI: 10.3389/fddev.2022.1027098
Aili Sun, Kinga G. Blecharz-Lang, A. Małecki, P. Meybohm, M. Nowacka-Chmielewska, M. Burek
The blood-brain barrier (BBB) is a highly specialized structure that separates the brain from the blood and allows the exchange of molecules between these two compartments through selective channels. The breakdown of the BBB is implicated in the development of severe neurological diseases, especially stroke and traumatic brain injury. Oxygen-glucose deprivation is used to mimic stroke and traumatic brain injury in vitro. Pathways that trigger BBB dysfunction include an imbalance of oxidative stress, excitotoxicity, iron metabolism, cytokine release, cell injury, and cell death. MicroRNAs are small non-coding RNA molecules that regulate gene expression and are emerging as biomarkers for the diagnosis of central nervous system (CNS) injuries. In this review, the regulatory role of potential microRNA biomarkers and related therapeutic targets on the BBB is discussed. A thorough understanding of the potential role of various cellular and linker proteins, among others, in the BBB will open further therapeutic options for the treatment of neurological diseases.
{"title":"Role of microRNAs in the regulation of blood-brain barrier function in ischemic stroke and under hypoxic conditions in vitro","authors":"Aili Sun, Kinga G. Blecharz-Lang, A. Małecki, P. Meybohm, M. Nowacka-Chmielewska, M. Burek","doi":"10.3389/fddev.2022.1027098","DOIUrl":"https://doi.org/10.3389/fddev.2022.1027098","url":null,"abstract":"The blood-brain barrier (BBB) is a highly specialized structure that separates the brain from the blood and allows the exchange of molecules between these two compartments through selective channels. The breakdown of the BBB is implicated in the development of severe neurological diseases, especially stroke and traumatic brain injury. Oxygen-glucose deprivation is used to mimic stroke and traumatic brain injury in vitro. Pathways that trigger BBB dysfunction include an imbalance of oxidative stress, excitotoxicity, iron metabolism, cytokine release, cell injury, and cell death. MicroRNAs are small non-coding RNA molecules that regulate gene expression and are emerging as biomarkers for the diagnosis of central nervous system (CNS) injuries. In this review, the regulatory role of potential microRNA biomarkers and related therapeutic targets on the BBB is discussed. A thorough understanding of the potential role of various cellular and linker proteins, among others, in the BBB will open further therapeutic options for the treatment of neurological diseases.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41624323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-10-03DOI: 10.3389/fddev.2022.995489
Arzu Ari, B. Rubin, J. Fink
The development of mesh nebulizer technology has expanded the ability to deliver medical aerosols to infants and small children via nasal cannula and prongs. Mesh nebulizers do not require compressed gas to generate aerosols and have a smaller, lighter profile facilitating placement in delivery circuits, unlike ultrasonic nebulizers. Prior to this century, aerosol delivery with the nasal interface to 1–4 kg infants or surrogate animal models was limited to low single-digit deposition. In vitro and animal studies with the enabling mesh technology increase inhaled dose by upwards of 14% when nasal continuous positive airway pressure ventilation is in use. Recently, investigations of transnasal aerosol delivery to the lung have expanded to include nasal cannula interfaces with both high and low flow oxygen administration, nasal continuous positive airway pressure therapy, and nasal noninvasive ventilation in treating respiratory distress, respiratory insufficiency, and acute respiratory failure of infants and toddlers. We will first examine the progression of testing transpulmonary delivery of medical aerosols from in vitro models to in vivo animal and human studies. Then, we will explain current and developing applications in clinical practice to view future directions and opportunities.
{"title":"Mesh nebulizers enabling transnasal pulmonary delivery of medical aerosols to infants and toddlers: Roles, challenges, and opportunities","authors":"Arzu Ari, B. Rubin, J. Fink","doi":"10.3389/fddev.2022.995489","DOIUrl":"https://doi.org/10.3389/fddev.2022.995489","url":null,"abstract":"The development of mesh nebulizer technology has expanded the ability to deliver medical aerosols to infants and small children via nasal cannula and prongs. Mesh nebulizers do not require compressed gas to generate aerosols and have a smaller, lighter profile facilitating placement in delivery circuits, unlike ultrasonic nebulizers. Prior to this century, aerosol delivery with the nasal interface to 1–4 kg infants or surrogate animal models was limited to low single-digit deposition. In vitro and animal studies with the enabling mesh technology increase inhaled dose by upwards of 14% when nasal continuous positive airway pressure ventilation is in use. Recently, investigations of transnasal aerosol delivery to the lung have expanded to include nasal cannula interfaces with both high and low flow oxygen administration, nasal continuous positive airway pressure therapy, and nasal noninvasive ventilation in treating respiratory distress, respiratory insufficiency, and acute respiratory failure of infants and toddlers. We will first examine the progression of testing transpulmonary delivery of medical aerosols from in vitro models to in vivo animal and human studies. Then, we will explain current and developing applications in clinical practice to view future directions and opportunities.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44666112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-08DOI: 10.3389/fddev.2022.954771
E. D. del Amo
Topical ophthalmic instillation is an appealing strategy to deliver drugs to the back of the eye to treat retinal diseases such as neovascular age-related macular degeneration, diabetic retinopathy, retinal vein occlusion, and glaucomatous optic neuropathy. It has several advantages such as being non-invasive and user-friendly, e.g., allowing self-administration. However, the main obstacle has been how to achieve therapeutic drug concentrations in the retina due to the eye’s protective mechanisms, flows, and barriers. Less than 4% of the instilled drug dose enters the anterior chamber, and much less is expected to reach the posterior segment. It is crucial to understand a drug’s topical pharmacokinetics in humans and how one can extrapolate data from rabbits to humans. In this review, the available data on the retina and vitreous drug concentrations from pharmacokinetics studies conducted in human patients and rabbits have been compiled, together with the critical physiological factors to be considered for this route of administration. Improvements in the design of preclinical studies are suggested to increase their translatability to the treatment of human patients. Finally, the current status of clinical trials with topical ophthalmic formulations intended to treat the back of the eye is depicted. At present, no topical ophthalmic formulations to treat neovascular age-related macular degeneration or other retinal neurodegenerative illnesses have reached the market.
{"title":"Topical ophthalmic administration: Can a drug instilled onto the ocular surface exert an effect at the back of the eye?","authors":"E. D. del Amo","doi":"10.3389/fddev.2022.954771","DOIUrl":"https://doi.org/10.3389/fddev.2022.954771","url":null,"abstract":"Topical ophthalmic instillation is an appealing strategy to deliver drugs to the back of the eye to treat retinal diseases such as neovascular age-related macular degeneration, diabetic retinopathy, retinal vein occlusion, and glaucomatous optic neuropathy. It has several advantages such as being non-invasive and user-friendly, e.g., allowing self-administration. However, the main obstacle has been how to achieve therapeutic drug concentrations in the retina due to the eye’s protective mechanisms, flows, and barriers. Less than 4% of the instilled drug dose enters the anterior chamber, and much less is expected to reach the posterior segment. It is crucial to understand a drug’s topical pharmacokinetics in humans and how one can extrapolate data from rabbits to humans. In this review, the available data on the retina and vitreous drug concentrations from pharmacokinetics studies conducted in human patients and rabbits have been compiled, together with the critical physiological factors to be considered for this route of administration. Improvements in the design of preclinical studies are suggested to increase their translatability to the treatment of human patients. Finally, the current status of clinical trials with topical ophthalmic formulations intended to treat the back of the eye is depicted. At present, no topical ophthalmic formulations to treat neovascular age-related macular degeneration or other retinal neurodegenerative illnesses have reached the market.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43447845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-07DOI: 10.3389/fddev.2022.973599
Aneesh Thakur, You Xu, G. Cano-Garcia, Siqi Feng, Fabrice Rose, P. Gerde, P. Andersen, D. Christensen, C. Foged
Thermostability is one of the product characteristics preferred by WHO for vaccines against respiratory infections due to ease of administration, pain minimization, and low costs. Thermostable dry powder inhaler (DPI) vaccine formulations can induce protective antibodies and T cells at the site of infection in the lungs. However, the majority of licensed human vaccines is based on liquid dosage forms, and there is no licensed mucosal adjuvants. The cationic adjuvant formulation 01 (CAF®01) is a liposome-based adjuvant system that (i) induces robust T cells and antibodies, (ii) is safe and well-tolerated in clinical trials, and (iii) induces mucosal immune responses after pulmonary administration. However, the optimal DPI formulations of CAF®01 for pulmonary immunization are not known. Here, we show that DPI formulations of CAF®01 spray-dried with a combination of sugars and the amino acid leucine exhibit optimal aerosolization properties and distribute in the lung lobes upon pulmonary administration. We demonstrate that the type of amorphous sugar used as stabilizer and the amount (w/w) of leucine used during spray drying affect the physicochemical properties and aerosol performance of DPI formulations. By systematically varying the ratios (w/w) of trehalose, dextran and leucine used as excipients during spray drying, we manufactured DPI formulations of CAF®01 that displayed (i) a spherical or wrinkled surface morphology, (ii) an aerodynamic diameter and particle size distribution optimal for deep lung deposition, and (iii) solid-state and aerosolization properties suitable for lung delivery. Using a design-of-experiments-based approach, we identified the most optimal process parameters in an in vivo aerosol generator, i.e., the PreciseInhale® system, which was used to measure the flowability of the aerosols. We found that the DPI formulation of CAF®01 spray-dried with trehalose and dextran (70% w/w) and leucine (30% w/w) displayed the most optimal physicochemical, morphological, solid-state, and aerosolization properties for deep lung deposition. Upon pulmonary administration, this DPI formulation distributed in the lung lobes in a way that was almost identical to the biodistribution of the non-spray dried formulation. Hence, DPI formulations of CAF®01, prepared with trehalose and dextran sugar matrix and a leucine shell, display physicochemical and aerosol properties suitable for inhalation.
{"title":"Optimizing the design and dosing of dry powder inhaler formulations of the cationic liposome adjuvant CAF®01 for pulmonary immunization","authors":"Aneesh Thakur, You Xu, G. Cano-Garcia, Siqi Feng, Fabrice Rose, P. Gerde, P. Andersen, D. Christensen, C. Foged","doi":"10.3389/fddev.2022.973599","DOIUrl":"https://doi.org/10.3389/fddev.2022.973599","url":null,"abstract":"Thermostability is one of the product characteristics preferred by WHO for vaccines against respiratory infections due to ease of administration, pain minimization, and low costs. Thermostable dry powder inhaler (DPI) vaccine formulations can induce protective antibodies and T cells at the site of infection in the lungs. However, the majority of licensed human vaccines is based on liquid dosage forms, and there is no licensed mucosal adjuvants. The cationic adjuvant formulation 01 (CAF®01) is a liposome-based adjuvant system that (i) induces robust T cells and antibodies, (ii) is safe and well-tolerated in clinical trials, and (iii) induces mucosal immune responses after pulmonary administration. However, the optimal DPI formulations of CAF®01 for pulmonary immunization are not known. Here, we show that DPI formulations of CAF®01 spray-dried with a combination of sugars and the amino acid leucine exhibit optimal aerosolization properties and distribute in the lung lobes upon pulmonary administration. We demonstrate that the type of amorphous sugar used as stabilizer and the amount (w/w) of leucine used during spray drying affect the physicochemical properties and aerosol performance of DPI formulations. By systematically varying the ratios (w/w) of trehalose, dextran and leucine used as excipients during spray drying, we manufactured DPI formulations of CAF®01 that displayed (i) a spherical or wrinkled surface morphology, (ii) an aerodynamic diameter and particle size distribution optimal for deep lung deposition, and (iii) solid-state and aerosolization properties suitable for lung delivery. Using a design-of-experiments-based approach, we identified the most optimal process parameters in an in vivo aerosol generator, i.e., the PreciseInhale® system, which was used to measure the flowability of the aerosols. We found that the DPI formulation of CAF®01 spray-dried with trehalose and dextran (70% w/w) and leucine (30% w/w) displayed the most optimal physicochemical, morphological, solid-state, and aerosolization properties for deep lung deposition. Upon pulmonary administration, this DPI formulation distributed in the lung lobes in a way that was almost identical to the biodistribution of the non-spray dried formulation. Hence, DPI formulations of CAF®01, prepared with trehalose and dextran sugar matrix and a leucine shell, display physicochemical and aerosol properties suitable for inhalation.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49034327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-05DOI: 10.3389/fddev.2022.957732
Pronalis Tapfumaneyi, M. Imran, Yousuf H. Mohammed, M. S. Roberts
Recent advances in topical and transdermal drug delivery systems have enabled targeted delivery of therapeutics to the site of action by enhancing drug permeation across the stratum corneum and increased bioavailability. Despite various technological advancements, some dermatoses still have limited treatment options due to potential adverse effects and challenges in formulation development. To address some of the limitations posed by conventional dermatotherapy, nano-based technologies have been developed and have demonstrated a significant improvement in dermatotherapy. Their distinct physicochemical properties demonstrate their overall superior therapeutic efficacy in providing sustained and effective targeted drug release, as well as improved solubility of hydrophobic actives with optimized drug formulations. These nanocarriers are commonly classified as polymeric, lipid-based, metallic, and vesicular nanocarriers, including nanoemulsions, nanofibers, and microneedles. This mini-review aims to address recent advances in nano-based technologies, providing a brief insight on some of the current and prospective technologies and approaches aimed at improving transdermal delivery.
{"title":"Recent advances and future prospective of topical and transdermal delivery systems","authors":"Pronalis Tapfumaneyi, M. Imran, Yousuf H. Mohammed, M. S. Roberts","doi":"10.3389/fddev.2022.957732","DOIUrl":"https://doi.org/10.3389/fddev.2022.957732","url":null,"abstract":"Recent advances in topical and transdermal drug delivery systems have enabled targeted delivery of therapeutics to the site of action by enhancing drug permeation across the stratum corneum and increased bioavailability. Despite various technological advancements, some dermatoses still have limited treatment options due to potential adverse effects and challenges in formulation development. To address some of the limitations posed by conventional dermatotherapy, nano-based technologies have been developed and have demonstrated a significant improvement in dermatotherapy. Their distinct physicochemical properties demonstrate their overall superior therapeutic efficacy in providing sustained and effective targeted drug release, as well as improved solubility of hydrophobic actives with optimized drug formulations. These nanocarriers are commonly classified as polymeric, lipid-based, metallic, and vesicular nanocarriers, including nanoemulsions, nanofibers, and microneedles. This mini-review aims to address recent advances in nano-based technologies, providing a brief insight on some of the current and prospective technologies and approaches aimed at improving transdermal delivery.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45099891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-08-23DOI: 10.3389/fddev.2022.958731
Caroline Billings, David E. Anderson
In vitro drug elution experiments are commonly performed when evaluating the fitness of drug delivery devices for in vivo use. Evaluation of drug elution characteristics spans many drug delivery applications including local delivery of antimicrobials and chemotherapeutics, and is of particular interest for prevention and treatment of orthopedic infections. Despite widespread utility, there is little agreement on methodology to perform such studies, and there are recognized limitations in published works. We evaluated three of the most commonly reported in vitro drug elution methods. We utilized a commercially available collagen matrix (Fibro-Gide®, Geistlich) and an antibiotic that is widely used for local antimicrobial therapy (gentamicin). The protocols used are: 1. complete replacement of media and washing of device, 2. complete replacement of media without washing, or 3. partial replacement of media. The results show statistically significant differences in elution characteristics among the three methods utilizing this delivery vehicle and drug. These results may provide the framework for moving toward more consistent methodology for in vitro elution experiments and address certain acknowledged limitations in the literature.
{"title":"Comparison of three methods for assessment of drug elution: In vitro elution of gentamicin from a collagen-based scaffold","authors":"Caroline Billings, David E. Anderson","doi":"10.3389/fddev.2022.958731","DOIUrl":"https://doi.org/10.3389/fddev.2022.958731","url":null,"abstract":"In vitro drug elution experiments are commonly performed when evaluating the fitness of drug delivery devices for in vivo use. Evaluation of drug elution characteristics spans many drug delivery applications including local delivery of antimicrobials and chemotherapeutics, and is of particular interest for prevention and treatment of orthopedic infections. Despite widespread utility, there is little agreement on methodology to perform such studies, and there are recognized limitations in published works. We evaluated three of the most commonly reported in vitro drug elution methods. We utilized a commercially available collagen matrix (Fibro-Gide®, Geistlich) and an antibiotic that is widely used for local antimicrobial therapy (gentamicin). The protocols used are: 1. complete replacement of media and washing of device, 2. complete replacement of media without washing, or 3. partial replacement of media. The results show statistically significant differences in elution characteristics among the three methods utilizing this delivery vehicle and drug. These results may provide the framework for moving toward more consistent methodology for in vitro elution experiments and address certain acknowledged limitations in the literature.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47876133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-08-09DOI: 10.3389/fddev.2022.955569
Alyson Yamaguchi, J. van Dam, A. Dhalla, Kyle P. Horlen, M. Imran, April T. Vo, Mir Hashim
Biotherapeutics such as peptides and antibodies are highly efficacious clinically but, unlike conventional medications, cannot be administered orally as they get digested and inactivated. Thus, biotherapeutics require parenteral routes for delivery, such as intravenous, intramuscular or subcutaneous administration. However, these delivery methods have limitations such as poor patient compliance or may require clinical supervision compared to oral therapies. We explored whether a novel, orally administered transenteric delivery system (Robotic Pill) could provide equivalent bioavailability to parenterally administered drugs. Utilizing an awake canine model, we demonstrated that orally administered Robotic Pills containing either human IgG or an anti-cytokine monoclonal antibody directed against either TNFα or interleukin-17A yielded bioavailability equivalent to parenterally administered controls. The ability to achieve clinically relevant blood levels of biotherapeutics via any orally administered preparation represents an important advance in drug delivery.
{"title":"Transenteric delivery of antibodies via an orally ingestible robotic pill yields high bioavailability comparable to parenteral administration in awake canines","authors":"Alyson Yamaguchi, J. van Dam, A. Dhalla, Kyle P. Horlen, M. Imran, April T. Vo, Mir Hashim","doi":"10.3389/fddev.2022.955569","DOIUrl":"https://doi.org/10.3389/fddev.2022.955569","url":null,"abstract":"Biotherapeutics such as peptides and antibodies are highly efficacious clinically but, unlike conventional medications, cannot be administered orally as they get digested and inactivated. Thus, biotherapeutics require parenteral routes for delivery, such as intravenous, intramuscular or subcutaneous administration. However, these delivery methods have limitations such as poor patient compliance or may require clinical supervision compared to oral therapies. We explored whether a novel, orally administered transenteric delivery system (Robotic Pill) could provide equivalent bioavailability to parenterally administered drugs. Utilizing an awake canine model, we demonstrated that orally administered Robotic Pills containing either human IgG or an anti-cytokine monoclonal antibody directed against either TNFα or interleukin-17A yielded bioavailability equivalent to parenterally administered controls. The ability to achieve clinically relevant blood levels of biotherapeutics via any orally administered preparation represents an important advance in drug delivery.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48297874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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