Research

11 pages, 2998 KiB

Open AccessArticle

Arginine-Rich Cell-Penetrating Peptide-Mediated Transduction of Mouse Nasal Cells with FOXP3 Protein Alleviates Allergic Rhinitis

by Toru Miwa, Yumi Takemiya, Kazuki Amesara, Hiroko Kawai and Yuichi Teranishi

Pharmaceutics 2023, 15(6), 1770; https://doi.org/10.3390/pharmaceutics15061770 - 19 Jun 2023

Viewed by 1141

Abstract

Intranasal corticosteroids are effective medications against allergic rhinitis (AR). However, mucociliary clearance promptly eliminates these drugs from the nasal cavity and delays their onset of action. Therefore, a faster, longer-lasting therapeutic effect on the nasal mucosa is required to enhance the efficacy of [...] Read more.

Intranasal corticosteroids are effective medications against allergic rhinitis (AR). However, mucociliary clearance promptly eliminates these drugs from the nasal cavity and delays their onset of action. Therefore, a faster, longer-lasting therapeutic effect on the nasal mucosa is required to enhance the efficacy of AR management. Our previous study showed that polyarginine, a cell-penetrating peptide, can deliver cargo to nasal cells; moreover, polyarginine-mediated cell-nonspecific protein transduction into the nasal epithelium exhibited high transfection efficiency with minimal cytotoxicity. In this study, poly-arginine-fused forkhead box P3 (FOXP3) protein, the “master transcriptional regulator” of regulatory T cells (Tregs), was administered into the bilateral nasal cavities of the ovalbumin (OVA)-immunoglobulin E mouse model of AR. The effects of these proteins on AR following OVA administration were investigated using histopathological, nasal symptom, flow cytometry, and cytokine dot blot analyses. Polyarginine-mediated FOXP3 protein transduction induced Treg-like cell generation in the nasal epithelium and allergen tolerance. Overall, this study proposes FOXP3 activation-mediated Treg induction as a novel and potential therapeutic strategy for AR, providing a potential alternative to conventional intranasal drug application for nasal drug delivery. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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15 pages, 5372 KiB

Open AccessArticle

Permeation of Phytochemicals of Selected Psychoactive Medicinal Plants across Excised Sheep Respiratory and Olfactory Epithelial Tissues

by Anja Haasbroek-Pheiffer, Alvaro Viljoen, Jan Steenekamp, Weiyang Chen and Josias Hamman

Pharmaceutics 2023, 15(5), 1423; https://doi.org/10.3390/pharmaceutics15051423 - 06 May 2023

Viewed by 1104

Abstract

The intranasal route of drug administration offers an opportunity to bypass the blood–brain barrier and deliver compounds directly into the brain. Scientific evidence exists for medicinal plants (e.g., Centella asiatica and Mesembryanthemum tortuosum) to treat central nervous system conditions such as anxiety [...] Read more.

The intranasal route of drug administration offers an opportunity to bypass the blood–brain barrier and deliver compounds directly into the brain. Scientific evidence exists for medicinal plants (e.g., Centella asiatica and Mesembryanthemum tortuosum) to treat central nervous system conditions such as anxiety and depression. The ex vivo permeation of selected phytochemicals (i.e., asiaticoside and mesembrine) has been measured across excised sheep nasal respiratory and olfactory tissue. Permeation studies were conducted on individual phytochemicals and C. asiatica and M. tortuosum crude extracts. Asiaticoside exhibited statistically significantly higher permeation across both tissues when applied alone as compared to the C. asiatica crude extract, while mesembrine permeation was similar when applied alone or as M. tortuosum crude extract. Permeation of all the phytocompounds was similar or slightly higher than that of the drug atenolol across the respiratory tissue. Permeation of all the phytocompounds was similar to or slightly lower than that of atenolol across the olfactory tissue. In general, the permeation was higher across the olfactory epithelial tissue than across the respiratory epithelial tissue and therefore showed potential for direct nose-to-brain delivery of the selected psychoactive phytochemicals. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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17 pages, 2740 KiB

Open AccessArticle

Sinonasal Stent Coated with Sustained-Release Varnish of Mometasone Furoate Inhibits Pro-Inflammatory Cytokine Release from Macrophages: An In Vitro Study

by Alessandra Cataldo Russomando, Doron Steinberg, Irith Gati, Ronit Vogt Sionov, Ron Eliashar, Michael Friedman and Menachem Gross

Pharmaceutics 2023, 15(3), 1015; https://doi.org/10.3390/pharmaceutics15031015 - 22 Mar 2023

Cited by 1 | Viewed by 1162

Abstract

The aim of the study was to develop a sustained-release varnish (SRV) containing mometasone furoate (MMF) for sinonasal stents (SNS) to reduce mucosa inflammation in the sinonasal cavity. The SNS’ segments coated with SRV-MMF or an SRV-placebo were incubated daily in a fresh [...] Read more.

The aim of the study was to develop a sustained-release varnish (SRV) containing mometasone furoate (MMF) for sinonasal stents (SNS) to reduce mucosa inflammation in the sinonasal cavity. The SNS’ segments coated with SRV-MMF or an SRV-placebo were incubated daily in a fresh DMEM at 37 °C for 20 days. The immunosuppressive activity of the collected DMEM supernatants was tested on the ability of mouse RAW 264.7 macrophages to secrete the cytokines’ tumor necrosis factor α (TNFα) and interleukin (IL)-10 and IL-6 in response to lipopolysaccharide (LPS). The cytokine levels were determined by respective Enzyme-Linked Immunosorbent Assays (ELISAs). We found that the daily amount of MMF released from the coated SNS was sufficient to significantly inhibit LPS-induced IL-6 and IL-10 secretion from the macrophages up to days 14 and 17, respectively. SRV-MMF had, however, only a mild inhibitory effect on LPS-induced TNFα secretion as compared to the SRV-placebo-coated SNS. In conclusion, the coating of SNS with SRV-MMF provides a sustained delivery of MMF for at least 2 weeks, maintaining a level sufficient for inhibiting pro-inflammatory cytokine release. This technological platform is, therefore, expected to provide anti-inflammatory benefits during the postoperative healing period and may play a significant role in the future treatment of chronic rhinosinusitis. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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13 pages, 1729 KiB

Open AccessArticle

Chitosan-Based Nanoparticles for Targeted Nasal Galantamine Delivery as a Promising Tool in Alzheimer’s Disease Therapy

by Dilyana Georgieva, Denitsa Nikolova, Elena Vassileva and Bistra Kostova

Pharmaceutics 2023, 15(3), 829; https://doi.org/10.3390/pharmaceutics15030829 - 03 Mar 2023

Cited by 6 | Viewed by 1706

Abstract

Natural alkaloid galantamine is widely used for the treatment of mild to moderate Alzheimer’s dementia. Galantamine hydrobromide (GH) is available as fast-release tablets, extended-release capsules, and oral solutions. However, its oral delivery can cause some unwanted side effects, such as gastrointestinal disturbances, nausea, [...] Read more.

Natural alkaloid galantamine is widely used for the treatment of mild to moderate Alzheimer’s dementia. Galantamine hydrobromide (GH) is available as fast-release tablets, extended-release capsules, and oral solutions. However, its oral delivery can cause some unwanted side effects, such as gastrointestinal disturbances, nausea, and vomiting. Intranasal administration is one possible way to avoid such unwanted effects. In this work, chitosan-based nanoparticles (NPs) were studied as potential GH delivery vehicles for nasal application. The NPs were synthesized via ionic gelation and studied using dynamic light scattering (DLS) as well as by spectroscopic and thermal methods. The GH-loaded chitosan–alginate complex particles were also prepared as a way to modify the release of GH. The high loading efficiency of the GH was confirmed for both types of particles, at 67% for the GH-loaded chitosan NPs and 70% for the complex chitosan/alginate GH-loaded particles. The mean particle size of the GH-loaded chitosan NPs was about 240 nm, while the sodium alginate coated chitosan particles loaded with GH were expectedly bigger, with a mean particle size of ~286 nm. GH release profiles in PBS at 37 °C were obtained for both types of NPs, and it was found that the GH-loaded chitosan NPs allowed the prolonged release of the incorporated drug for a period of 8 h, while the complex GH-loaded chitosan/alginate NPs released the incorporated GH faster. The stability of the prepared GH-loaded NPs was also demonstrated after 1 year of storage at 5 °C ± 3 °C. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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16 pages, 3307 KiB

Open AccessArticle

Nasal Tumor Vaccination Protects against Lung Tumor Development by Induction of Resident Effector and Memory Anti-Tumor Immune Responses

by Michael Donkor, Jamie Choe, Danielle Marie Reid, Byron Quinn, Mark Pulse, Amalendu Ranjan, Pankaj Chaudhary and Harlan P. Jones

Pharmaceutics 2023, 15(2), 445; https://doi.org/10.3390/pharmaceutics15020445 - 29 Jan 2023

Cited by 4 | Viewed by 2036

Abstract

Lung metastasis is a leading cause of cancer-related deaths. Here, we show that intranasal delivery of our engineered CpG-coated tumor antigen (Tag)-encapsulated nanoparticles (NPs)—nasal nano-vaccine—significantly reduced lung colonization by intravenous challenge of an extra-pulmonary tumor. Protection against tumor-cell lung colonization was linked to [...] Read more.

Lung metastasis is a leading cause of cancer-related deaths. Here, we show that intranasal delivery of our engineered CpG-coated tumor antigen (Tag)-encapsulated nanoparticles (NPs)—nasal nano-vaccine—significantly reduced lung colonization by intravenous challenge of an extra-pulmonary tumor. Protection against tumor-cell lung colonization was linked to the induction of localized mucosal-associated effector and resident memory T cells as well as increased bronchiolar alveolar lavage-fluid IgA and serum IgG antibody responses. The nasal nano-vaccine-induced T-cell-mediated antitumor mucosal immune response was shown to increase tumor-specific production of IFN-γ and granzyme B by lung-derived CD8⁺ T cells. These findings demonstrate that our engineered nasal nano-vaccine has the potential to be used as a prophylactic approach prior to the seeding of tumors in the lungs, and thereby prevent overt lung metastases from existing extra pulmonary tumors. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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13 pages, 682 KiB

Open AccessArticle

Pharmacokinetic Study of Intranasal Dexamethasone and Methylprednisolone Compared with Intravenous Administration: Two Open-Label, Single-Dose, Two-Period, Two-Sequence, Cross-Over Study in Healthy Volunteers

by Graciela Cárdenas, Raúl J. Bobes, Gladis Fragoso, Nicolas I. Pérez-Osorio, Marisela Hernández, Alejandro Espinosa, Agnes Fleury, José Flores, The Revival Project Consortium, Juan Pedro Laclette, Edda Sciutto and Helgi Jung-Cook

Pharmaceutics 2023, 15(1), 105; https://doi.org/10.3390/pharmaceutics15010105 - 28 Dec 2022

Cited by 5 | Viewed by 2545

Abstract

Dexamethasone (DXM) and methylprednisolone (MEP) are potent glucocorticoids used to control several inflammatory conditions. Evidence of delayed DXM reaching the central nervous system (CNS) as well as tachyphylaxis and systemic, undesirable side effects are the main limitations of peripheral delivery. Intranasal administration offers [...] Read more.

Dexamethasone (DXM) and methylprednisolone (MEP) are potent glucocorticoids used to control several inflammatory conditions. Evidence of delayed DXM reaching the central nervous system (CNS) as well as tachyphylaxis and systemic, undesirable side effects are the main limitations of peripheral delivery. Intranasal administration offers direct access to the brain as it bypasses the blood–brain barrier. The Mucosal Atomization Device is an optimal tool that can achieve rapid absorption into the CNS and the bloodstream across mucosal membranes. This study was designed to evaluate and compare the bioavailability of DXM and MEP after intranasal versus intravenous administration. Two open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover studies were conducted, which involved healthy male and female adult volunteers. After intranasal administration, DXM and MEP were detected in plasma after the first sampling time. Mean peak concentrations of DXM and MEP were 86.61 ng/mL at 60 min and 843.2 ng/mL at 1.5 h post-administration, respectively. DXM and MEP showed high absolute bioavailability, with values of 80% and 95%, respectively. No adverse effects were observed. DXM and MEP systemic bioavailability by intranasal administration was comparable with the intravenous one, suggesting that the intranasal route can be used as a non-invasive and appropriate alternative for systemic drug delivery. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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12 pages, 2502 KiB

Open AccessArticle

Formulation of SARS-CoV-2 Spike Protein with CpG Oligodeoxynucleotides and Squalene Nanoparticles Modulates Immunological Aspects Following Intranasal Delivery

by Hui-Min Ho, Chiung-Yi Huang, Chung-Hsiang Yang, Shih-Jen Liu, Hsin-Wei Chen, Guann-Yi Yu, Jen-Kun Chen, Tsung-Hsien Chuang and Ming-Hsi Huang

Pharmaceutics 2022, 14(11), 2539; https://doi.org/10.3390/pharmaceutics14112539 - 21 Nov 2022

Cited by 3 | Viewed by 2039

Abstract

Nasal spray vaccination is viewed as a promising strategy for inducing both mucosal and systemic protection against respiratory SARS-CoV-2 coronavirus. Toward this goal, a safe and efficacious mucosal adjuvant is necessary for the transportation of the antigen across the mucosal membrane and antigen [...] Read more.

Nasal spray vaccination is viewed as a promising strategy for inducing both mucosal and systemic protection against respiratory SARS-CoV-2 coronavirus. Toward this goal, a safe and efficacious mucosal adjuvant is necessary for the transportation of the antigen across the mucosal membrane and antigen recognition by the mucosal immune system to generate broad-spectrum immune responses. This study describes the immunological aspects of SARS-CoV-2 spike (S)-protein after being formulated with CpG oligodeoxynucleotides (ODNs) and squalene nanoparticles (termed PELC). Following intranasal delivery in mice, higher expression levels of major histocompatibility complex (MHC) class II and costimulatory molecules CD40 and CD86 on CD11c⁺ cells were observed at the draining superficial cervical lymph nodes in the CpG-formulated S protein group compared with those vaccinated with S protein alone. Subsequently, the activated antigen-presenting cells downstream modulated the cytokine secretion profiles and expanded the cytotoxic T lymphocyte activity of S protein-restimulated splenocytes. Interestingly, the presence of PELC synergistically enhanced cell-mediated immunity and diminished individual differences in S protein-specific immunogenicity. Regarding humoral responses, the mice vaccinated with the PELC:CpG-formulated S protein promoted the production of S protein-specific IgG in serum samples and IgA in nasal and bronchoalveolar lavage fluids. These results indicate that PELC:CpG is a potential mucosal adjuvant that promotes mucosal/systemic immune responses and cell-mediated immunity, a feature that has implications for the development of a nasal spray vaccine against COVID-19. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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17 pages, 1533 KiB

Open AccessArticle

Early Negativization of SARS-CoV-2 Infection by Nasal Spray of Seawater plus Additives: The RENAISSANCE Open-Label Controlled Clinical Trial

by Luca Cegolon, Giuseppe Mastrangelo, Enzo Emanuelli, Riccardo Camerotto, Giacomo Spinato and Daniele Frezza

Pharmaceutics 2022, 14(11), 2502; https://doi.org/10.3390/pharmaceutics14112502 - 18 Nov 2022

Cited by 15 | Viewed by 4696

Abstract

Background: COVID-19 is an asymptomatic condition in 40% of cases, and most symptomatic patients present with mild/moderate disease not requiring hospitalization or intensive care, especially during the Omicron wave, when the hospitalization rate was estimated to be 0.3%. The main port of [...] Read more.

Background: COVID-19 is an asymptomatic condition in 40% of cases, and most symptomatic patients present with mild/moderate disease not requiring hospitalization or intensive care, especially during the Omicron wave, when the hospitalization rate was estimated to be 0.3%. The main port of entry for SARS-CoV-2 in the human body is the nasal cavity and the upper respiratory tract is affected since the early stages of the infection. Nasal irrigation or aerosol by isotonic or hypertonic saline solution is a traditional therapeutic approach for respiratory or nasal inflammation, also featured by prophylactic properties against upper respiratory infections. Methods: We conducted a prospective open-label controlled study to assess the superiority of an already existing medication (Tonimer Lab Panthexyl 800)—a sterile hypertonic solution containing seawater, xylitol, panthenol and lactic acid—to reduce the viral shedding time in patients affected by asymptomatic or mild COVID-19. COVID-19 patients (N = 108) were split into two groups: a treatment arm (50 participants receiving standard of care plus nasal spray 3 times/day with Tonimer Lab Panthexyl 800) and a control arm (58 participants receiving standard of care but nasal spray with Tonimer Lab Panthexyl 800). The two groups, both testing initially positive for SARS-CoV-2 at real-time PCR (RT-PCR) on nasal swab, were followed up over time to assess the daily number of positive swab tests turning negative (study endpoint). Treatment effectiveness at various time lags since the first positive RT-PCR swab test was measured by rate of events in the experimental arm (EER) and in the control arm (CER), absolute risk increase (ARI) = (EER − CER), and number needed to treat (NNT) = (1/ARI). To investigate the endpoint, we used logistic and Cox regression models, expressing the result as odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (95%CI), respectively. The symptoms recorded with a modified COVID-Q questionnaire at both diagnosis and first negative antigenic swab test were compared in each group (treated versus controls) by exact symmetry test. Results: During the first five days of treatment, COVID-19 patients treated with Tonimer Lab Panthexyl 800 were more likely to become negative two days before controls. According to NNT, four subjects had to be treated for five days to achieve the study endpoint in one individual. The negativization rate in patients treated with Tonimer Lab Panthexyl 800 was significantly higher than patients’ treated with standard of care alone (OR = 7.39, 95%CI: 1.83–29.8; HR = 6.12, 95%CI: 1.76–21.32). There was no evidence of side effects. Conclusions: Nasal spray with Tonimer Lab Panthexyl 800 was effective against SARS-CoV-2, stopping viral shedding in the treatment arm two days before the control group. This treatment should be continued for at least five days after the first positive swab test for SARS-CoV-2. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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16 pages, 1898 KiB

Open AccessArticle

Development of In Vitro Evaluation System for Assessing Drug Dissolution Considering Physiological Environment in Nasal Cavity

by Daisuke Inoue, Ayari Yamashita and Hideto To

Pharmaceutics 2022, 14(11), 2350; https://doi.org/10.3390/pharmaceutics14112350 - 31 Oct 2022

Cited by 1 | Viewed by 1691

Abstract

Estimating the dissolution behavior of a solid in the nasal mucus is challenging for solid dosage forms designed for the nasal application as the solid dissolves into nasal mucus and permeates through the mucosa. In the current study, the dissolution behavior of powders [...] Read more.

Estimating the dissolution behavior of a solid in the nasal mucus is challenging for solid dosage forms designed for the nasal application as the solid dissolves into nasal mucus and permeates through the mucosa. In the current study, the dissolution behavior of powders in the artificial nasal fluid was investigated using a 3D-printed chamber system to establish in vitro evaluation system for the dissolution of solid formulations that can simulate the intranasal environment in vivo. The dissolution rates of the five model drugs correlated with their solubility (r² = 0.956, p < 0.01). The permeation rate of drugs across the Calu-3 cell layers after powder application depends on the membrane permeability of the drug. An analysis of membrane permeability considering the dissolution of powders showed the possibility of characterizing whether the drug in the powder was dissolution-limited or permeation-limited. This suggests that critical information can be obtained to understand which mechanism is more effective for the improvement of drug absorption from powders. This study indicates that the elucidation of drug dissolution behavior into nasal mucus is an important factor for the formulation of nasal powders and that the in vitro system developed could be a useful tool. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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21 pages, 3806 KiB

Open AccessArticle

Development and In Vitro-Ex Vivo Evaluation of Novel Polymeric Nasal Donepezil Films for Potential Use in Alzheimer’s Disease Using Experimental Design

by Paraskevi Papakyriakopoulou, Dimitrios M. Rekkas, Gaia Colombo and Georgia Valsami

Pharmaceutics 2022, 14(8), 1742; https://doi.org/10.3390/pharmaceutics14081742 - 21 Aug 2022

Cited by 6 | Viewed by 2156

Abstract

The objective and novelty of the present study is the development and optimization of innovative nasal film of Donepezil hydrochloride (DH) for potential use in Alzheimer’s disease. Hydroxypropyl-methyl-cellulose E50 (factor A) nasal films, with Polyethylene glycol 400 as plasticizer (factor B), and Methyl-β-Cyclodextrin, [...] Read more.

The objective and novelty of the present study is the development and optimization of innovative nasal film of Donepezil hydrochloride (DH) for potential use in Alzheimer’s disease. Hydroxypropyl-methyl-cellulose E50 (factor A) nasal films, with Polyethylene glycol 400 as plasticizer (factor B), and Methyl-β-Cyclodextrin, as permeation enhancer (factor C), were prepared and characterized in vitro and ex vivo. An experimental design was used to determine the effects of the selected factors on permeation profile of DH through rabbit nasal mucosa (response 1), and on film flexibility/foldability (response 2). A face centered central composite design with three levels was applied and 17 experiments were performed in triplicate. The prepared films exhibited good uniformity of DH content (90.0 ± 1.6%–99.8 ± 4.9%) and thickness (19.6 ± 1.9–170.8 ± 11.5 μm), storage stability characteristics, and % residual humidity (<3%), as well as favourable swelling and mucoadhesive properties. Response surface methodology determined the optimum composition for flexible nasal film with maximized DH permeation. All selected factors interacted with each other and the effect of these interactions on responses is strongly related to the factor’s concentration ratios. Based on these encouraging results, in vivo serum and brain pharmacokinetic study of the optimized nasal film, in comparison to DH oral administration, is ongoing in an animal model. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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Review

Jump to: Research, Other

19 pages, 2764 KiB

Open AccessReview

Challenges in the Development and Application of Organ-on-Chips for Intranasal Drug Delivery Studies

by Muhammad Usman Khan, Xinyu Cai, Zhiwei Shen, Taye Mekonnen, Agisilaos Kourmatzis, Shaokoon Cheng and Hanieh Gholizadeh

Pharmaceutics 2023, 15(5), 1557; https://doi.org/10.3390/pharmaceutics15051557 - 22 May 2023

Cited by 1 | Viewed by 1947

Abstract

With the growing demand for the development of intranasal (IN) products, such as nasal vaccines, which has been especially highlighted during the COVID-19 pandemic, the lack of novel technologies to accurately test the safety and effectiveness of IN products in vitro so that [...] Read more.

With the growing demand for the development of intranasal (IN) products, such as nasal vaccines, which has been especially highlighted during the COVID-19 pandemic, the lack of novel technologies to accurately test the safety and effectiveness of IN products in vitro so that they can be delivered promptly to the market is critically acknowledged. There have been attempts to manufacture anatomically relevant 3D replicas of the human nasal cavity for in vitro IN drug tests, and a couple of organ-on-chip (OoC) models, which mimic some key features of the nasal mucosa, have been proposed. However, these models are still in their infancy, and have not completely recapitulated the critical characteristics of the human nasal mucosa, including its biological interactions with other organs, to provide a reliable platform for preclinical IN drug tests. While the promising potential of OoCs for drug testing and development is being extensively investigated in recent research, the applicability of this technology for IN drug tests has barely been explored. This review aims to highlight the importance of using OoC models for in vitro IN drug tests and their potential applications in IN drug development by covering the background information on the wide usage of IN drugs and their common side effects where some classical examples of each area are pointed out. Specifically, this review focuses on the major challenges of developing advanced OoC technology and discusses the need to mimic the physiological and anatomical features of the nasal cavity and nasal mucosa, the performance of relevant drug safety assays, as well as the fabrication and operational aspects, with the ultimate goal to highlight the much-needed consensus, to converge the effort of the research community in this area of work. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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26 pages, 2813 KiB

Open AccessReview

Nanosystems for Brain Targeting of Antipsychotic Drugs: An Update on the Most Promising Nanocarriers for Increased Bioavailability and Therapeutic Efficacy

by Maria Daniela Ferreira, Joana Duarte, Francisco Veiga, Ana Cláudia Paiva-Santos and Patrícia C. Pires

Pharmaceutics 2023, 15(2), 678; https://doi.org/10.3390/pharmaceutics15020678 - 17 Feb 2023

Cited by 7 | Viewed by 3529

Abstract

Orally administered antipsychotic drugs are the first-line treatment for psychotic disorders, such as schizophrenia and bipolar disorder. Nevertheless, adverse drug reactions jeopardize clinical outcomes, resulting in patient non-compliance. The design formulation strategies for enhancing brain drug delivery has been a major challenge, mainly [...] Read more.

Orally administered antipsychotic drugs are the first-line treatment for psychotic disorders, such as schizophrenia and bipolar disorder. Nevertheless, adverse drug reactions jeopardize clinical outcomes, resulting in patient non-compliance. The design formulation strategies for enhancing brain drug delivery has been a major challenge, mainly due to the restrictive properties of the blood–brain barrier. However, recent pharmacokinetic and pharmacodynamic in vivo assays confirmed the advantage of the intranasal route when compared to oral and intravenous administration, as it allows direct nose-to-brain drug transport via neuronal pathways, reducing systemic side effects and maximizing therapeutic outcomes. In addition, the incorporation of antipsychotic drugs into nanosystems such as polymeric nanoparticles, polymeric mixed micelles, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, nanoemulgels, nanosuspensions, niosomes and spanlastics, has proven to be quite promising. The developed nanosystems, having a small and homogeneous particle size (ideal for nose-to-brain delivery), high encapsulation efficiency and good stability, resulted in improved brain bioavailability and therapeutic-like effects in animal models. Hence, although it is essential to continue research in this field, the intranasal delivery of nanosystems for the treatment of schizophrenia, bipolar disorder and other related disorders has proven to be quite promising, opening a path for future therapies with higher efficacy. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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27 pages, 2214 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Intranasal Liposomes for Drug, Gene, and Vaccine Delivery

by Van-An Duong, Thi-Thao-Linh Nguyen and Han-Joo Maeng

Pharmaceutics 2023, 15(1), 207; https://doi.org/10.3390/pharmaceutics15010207 - 06 Jan 2023

Cited by 24 | Viewed by 4871

Abstract

Liposomes are safe, biocompatible, and biodegradable spherical nanosized vesicles produced from cholesterol and phospholipids. Recently, liposomes have been widely administered intranasally for systemic and brain delivery. From the nasal cavity, liposome-encapsulated drugs and genes enter the systemic circulation primarily via absorption in the [...] Read more.

Liposomes are safe, biocompatible, and biodegradable spherical nanosized vesicles produced from cholesterol and phospholipids. Recently, liposomes have been widely administered intranasally for systemic and brain delivery. From the nasal cavity, liposome-encapsulated drugs and genes enter the systemic circulation primarily via absorption in the respiratory region, whereas they can be directly transported to the brain via the olfactory pathway. Liposomes can protect drugs and genes from enzymatic degradation, increase drug absorption across the nasal epithelium, and prolong the residence time in the nasal cavity. Intranasal liposomes are also a potential approach for vaccine delivery. Liposomes can be used as a platform to load antigens and as vaccine adjuvants to induce a robust immune response. With the recent interest in intranasal liposome formulations, this review discusses various aspects of liposomes that make them suitable for intranasal administration. We have summarized the latest advancements and applications of liposomes and evaluated their performance in the systemic and brain delivery of drugs and genes administered intranasally. We have also reviewed recent advances in intranasal liposome vaccine development and proposed perspectives on the future of intranasal liposomes. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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26 pages, 1241 KiB

Open AccessReview

Development of Nasal Vaccines and the Associated Challenges

by Xuanxuan Nian, Jiayou Zhang, Shihe Huang, Kai Duan, Xinguo Li and Xiaoming Yang

Pharmaceutics 2022, 14(10), 1983; https://doi.org/10.3390/pharmaceutics14101983 - 20 Sep 2022

Cited by 14 | Viewed by 3397

Abstract

Viruses, bacteria, fungi, and several other pathogenic microorganisms usually infect the host via the surface cells of respiratory mucosa. Nasal vaccination could provide a strong mucosal and systemic immunity to combat these infections. The intranasal route of vaccination offers the advantage of easy [...] Read more.

Viruses, bacteria, fungi, and several other pathogenic microorganisms usually infect the host via the surface cells of respiratory mucosa. Nasal vaccination could provide a strong mucosal and systemic immunity to combat these infections. The intranasal route of vaccination offers the advantage of easy accessibility over the injection administration. Therefore, nasal immunization is considered a promising strategy for disease prevention, particularly in the case of infectious diseases of the respiratory system. The development of a nasal vaccine, particularly the strategies of adjuvant and antigens design and optimization, enabling rapid induction of protective mucosal and systemic responses against the disease. In recent times, the development of efficacious nasal vaccines with an adequate safety profile has progressed rapidly, with effective handling and overcoming of the challenges encountered during the process. In this context, the present report summarizes the most recent findings regarding the strategies used for developing nasal vaccines as an efficient alternative to conventional vaccines. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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32 pages, 9780 KiB

Open AccessReview

Nose-to-Brain Delivery of Therapeutic Peptides as Nasal Aerosols

by Wafaa Alabsi, Basanth Babu Eedara, David Encinas-Basurto, Robin Polt and Heidi M. Mansour

Pharmaceutics 2022, 14(9), 1870; https://doi.org/10.3390/pharmaceutics14091870 - 05 Sep 2022

Cited by 23 | Viewed by 6850

Abstract

Central nervous system (CNS) disorders, such as psychiatric disorders, neurodegeneration, chronic pain, stroke, brain tumor, spinal cord injury, and many other CNS diseases, would hugely benefit from specific and potent peptide pharmaceuticals and their low inherent toxicity. The delivery of peptides to the [...] Read more.

Central nervous system (CNS) disorders, such as psychiatric disorders, neurodegeneration, chronic pain, stroke, brain tumor, spinal cord injury, and many other CNS diseases, would hugely benefit from specific and potent peptide pharmaceuticals and their low inherent toxicity. The delivery of peptides to the brain is challenging due to their low metabolic stability, which decreases their duration of action, poor penetration of the blood-brain barrier (BBB), and their incompatibility with oral administration, typically resulting in the need for parenteral administration. These challenges limit peptides’ clinical application and explain the interest in alternative routes of peptide administration, particularly nose-to-brain (N-to-B) delivery, which allows protein and peptide drugs to reach the brain noninvasively. N-to-B delivery can be a convenient method for rapidly targeting the CNS, bypassing the BBB, and minimizing systemic exposure; the olfactory and trigeminal nerves provide a unique pathway to the brain and the external environment. This review highlights the intranasal delivery of drugs, focusing on peptide delivery, illustrating various clinical applications, nasal delivery devices, and the scope and limitations of this approach. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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28 pages, 1682 KiB

Open AccessEditor’s ChoiceReview

Self-Emulsifying Drug Delivery Systems: An Alternative Approach to Improve Brain Bioavailability of Poorly Water-Soluble Drugs through Intranasal Administration

by Sara Meirinho, Márcio Rodrigues, Adriana O. Santos, Amílcar Falcão and Gilberto Alves

Pharmaceutics 2022, 14(7), 1487; https://doi.org/10.3390/pharmaceutics14071487 - 18 Jul 2022

Cited by 8 | Viewed by 2949

Abstract

Efforts in discovering new and effective neurotherapeutics are made daily, although most fail to reach clinical trials. The main reason is their poor bioavailability, related to poor aqueous solubility, limited permeability through biological membranes, and the hepatic first-pass metabolism. Nevertheless, crossing the blood–brain [...] Read more.

Efforts in discovering new and effective neurotherapeutics are made daily, although most fail to reach clinical trials. The main reason is their poor bioavailability, related to poor aqueous solubility, limited permeability through biological membranes, and the hepatic first-pass metabolism. Nevertheless, crossing the blood–brain barrier is the major drawback associated with brain drug delivery. To overcome it, intranasal administration has become more attractive, in some cases even surpassing the oral route. The unique anatomical features of the nasal cavity allow partial direct drug delivery to the brain, circumventing the blood–brain barrier. Systemic absorption through the nasal cavity also avoids the hepatic first-pass metabolism, increasing the systemic bioavailability of highly metabolized entities. Nevertheless, most neurotherapeutics present physicochemical characteristics that require them to be formulated in lipidic nanosystems as self-emulsifying drug delivery systems (SEDDS). These are isotropic mixtures of oils, surfactants, and co-surfactants that, after aqueous dilution, generate micro or nanoemulsions loading high concentrations of lipophilic drugs. SEDDS should overcome drug precipitation in absorption sites, increase their permeation through absorptive membranes, and enhance the stability of labile drugs against enzymatic activity. Thus, combining the advantages of SEDDS and those of the intranasal route for brain delivery, an increase in drugs’ brain targeting and bioavailability could be expected. This review deeply characterizes SEDDS as a lipidic nanosystem, gathering important information regarding the mechanisms associated with the intranasal delivery of drugs loaded in SEDDS. In the end, in vivo results after SEDDS intranasal or oral administration are discussed, globally revealing their efficacy in comparison with common solutions or suspensions. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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36 pages, 2644 KiB

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Maximizing Postoperative Recovery: The Role of Functional Biomaterials as Nasal Packs—A Comprehensive Systematic Review without Meta-Analysis (SWiM)

by Rabiatul Adawiyah Razali, Ubashini Vijakumaran, Mh Busra Fauzi and Yogeswaran Lokanathan

Pharmaceutics 2023, 15(5), 1534; https://doi.org/10.3390/pharmaceutics15051534 - 18 May 2023

Cited by 2 | Viewed by 2291

Abstract

Numerous biomaterials have been developed over the years to enhance the outcomes of endoscopic sinus surgery (ESS) for patients with chronic rhinosinusitis. These products are specifically designed to prevent postoperative bleeding, optimize wound healing, and reduce inflammation. However, there is no singular material [...] Read more.

Numerous biomaterials have been developed over the years to enhance the outcomes of endoscopic sinus surgery (ESS) for patients with chronic rhinosinusitis. These products are specifically designed to prevent postoperative bleeding, optimize wound healing, and reduce inflammation. However, there is no singular material on the market that can be deemed the optimal material for the nasal pack. We systematically reviewed the available evidence to assess the functional biomaterial efficacy after ESS in prospective studies. The search was performed using predetermined inclusion and exclusion criteria, and 31 articles were identified in PubMed, Scopus, and Web of Science. The Cochrane risk-of-bias tool for randomized trials (RoB 2) was used to assess each study’s risk of bias. The studies were critically analyzed and categorized into types of biomaterial and functional properties, according to synthesis without meta-analysis (SWiM) guidelines. Despite the heterogeneity between studies, it was observed that chitosan, gelatin, hyaluronic acid, and starch-derived materials exhibit better endoscopic scores and significant potential for use in nasal packing. The published data support the idea that applying a nasal pack after ESS improves wound healing and patient-reported outcomes. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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