Research

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22 pages, 1868 KiB

Open AccessArticle

Ion-Triggered In Situ Gelling Intranasal Spray of Dronedarone Hydrochloride Nanocarriers: In Vitro Optimization and In Vivo Pharmacokinetic Appraisal

by Mahmoud H. Teaima, Doaa A. Helal, Jihad M. Alsofany, Mohamed A. El-Nabarawi and Mohamed Yasser

Pharmaceutics 2022, 14(11), 2405; https://doi.org/10.3390/pharmaceutics14112405 - 08 Nov 2022

Cited by 3 | Viewed by 1382

Abstract

The current study aims to develop niosomal nanocarriers for intranasal delivery of dronedarone hydrochloride to ameliorate its limited bioavailability. Niosomes were prepared by ethanol injection method and optimized using 3² full factorial experimental design. Both Span^® type (X1) and Span^®: [...] Read more.

The current study aims to develop niosomal nanocarriers for intranasal delivery of dronedarone hydrochloride to ameliorate its limited bioavailability. Niosomes were prepared by ethanol injection method and optimized using 3² full factorial experimental design. Both Span^® type (X1) and Span^®: cholesterol ratio (X2) were set as independent variables. Vesicle size (Y1), polydispersity index (Y2), zeta potential (Y3), and entrapment efficiency (Y4) were set as responses. The optimal formula was further incorporated into an ion-sensitive in situ gelling polymer for intranasal delivery. Optimal formula (N7), which is composed of Span^® 80: cholesterol (1:1), was of the least vesicle size (121.27 ± 13.31 nm), least polydispersity index (0.43 ± 0.073), highest zeta potential (−22.23 ± 2.84 mV) and highest entrapment efficiency (73.44 ± 2.8%). About 75.86% and 60.29% of dronedarone hydrochloride were released from N7 dispersion and in situ gel, respectively, within 12 h, compared to only 13.3% released from a drug-free suspension. In vivo pharmacokinetic study on male New Zealand rabbits resulted in significantly higher C_max, AUC_0–72, and AUC_0–∞ of intranasal niosomal in situ gel compared to oral suspension. Almost twofold amplification of relative bioavailability was obtained after intranasal administration of niosomal in situ gel (195.7%) compared to oral suspension. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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15 pages, 3516 KiB

Open AccessArticle

Intranasal Methylprednisolone Ameliorates Neuroinflammation Induced by Chronic Toluene Exposure

by Manuel F. Giraldo-Velásquez, Iván N. Pérez-Osorio, Alejandro Espinosa-Cerón, Brandon M. Bárcena, Arturo Calderón-Gallegos, Gladis Fragoso, Mónica Torres-Ramos, Nayeli Páez-Martínez and Edda Sciutto

Pharmaceutics 2022, 14(6), 1195; https://doi.org/10.3390/pharmaceutics14061195 - 02 Jun 2022

Cited by 3 | Viewed by 2082

Abstract

Inhalants are chemical substances that induce intoxication, and toluene is the main component of them. Increasing evidence indicates that a dependence on inhalants involves a state of chronic stress associated to the activation of immune cells in the central nervous system and release [...] Read more.

Inhalants are chemical substances that induce intoxication, and toluene is the main component of them. Increasing evidence indicates that a dependence on inhalants involves a state of chronic stress associated to the activation of immune cells in the central nervous system and release of proinflammatory mediators, especially in some brain areas such as the nucleus accumbens and frontal cortex, where the circuits of pleasure and reward are. In this study, anti-neuroinflammatory treatment based on a single dose of intranasal methylprednisolone was assessed in a murine model of chronic toluene exposure. The levels of proinflammatory mediators, expression levels of Iba-1 and GFAP, and histological changes in the frontal cortex and nucleus accumbens were evaluated after the treatment. The chronic exposure to toluene significantly increased the levels of TNF-α, IL-6, and NO, the expression of GFAP, and induced histological alterations in mouse brains. The treatment with intranasally administered MP significantly reduced the expression of TNF-α and NO and the expression of GFAP (p < 0.05); additionally, it reversed the central histological damage. These results indicate that intranasally administered methylprednisolone could be considered as a treatment to reverse neuroinflammation and histological damages associated with the use of inhalants. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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16 pages, 3211 KiB

Open AccessArticle

Utility of Downstream Biomarkers to Assess and Optimize Intranasal Delivery of Oxytocin

by Megan DuBois, Angela Tseng, Sunday M. Francis, Ann F. Haynos, Carol B. Peterson and Suma Jacob

Pharmaceutics 2022, 14(6), 1178; https://doi.org/10.3390/pharmaceutics14061178 - 31 May 2022

Cited by 1 | Viewed by 2044

Abstract

Oxytocin (OT), a mammalian neurohormone associated with social cognition and behavior, can be administered in its synthetic form intranasally (IN) and impact brain chemistry and behavior. IN-OT shows potential as a noninvasive intervention for disorders characterized by social challenges, e.g., autism spectrum disorder [...] Read more.

Oxytocin (OT), a mammalian neurohormone associated with social cognition and behavior, can be administered in its synthetic form intranasally (IN) and impact brain chemistry and behavior. IN-OT shows potential as a noninvasive intervention for disorders characterized by social challenges, e.g., autism spectrum disorder (ASD) and anorexia nervosa (AN). To evaluate IN-OT’s efficacy, we must quantify OT uptake, availability, and clearance; thus, we assessed OT levels in urine (uOT) before and after participants (26 ASD, 7 AN, and 7 healthy controls) received 40 IU IN-OT or placebo across two sessions using double-blind, placebo-controlled crossover designs. We also measured uOT and plasma (pOT) levels in a subset of participants to compare the two sampling methods. We found significantly higher uOT and pOT following intranasal delivery of active compound versus placebo, but analyses yielded larger effect sizes and more clearly differentiated pre–post-OT levels for uOT than pOT. Further, we applied a two-step cluster (TSC), blinded backward-chaining approach to determine whether active/placebo groups could be identified by uOT and pOT change alone; uOT levels may serve as an accessible and accurate systemic biomarker for OT dose–response. Future studies will explore whether uOT levels correlate directly with behavioral targets to improve dosing for therapeutic goals. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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10 pages, 674 KiB

Open AccessArticle

Impact of Magnesium on Oxytocin Receptor Function

by Vimala N. Bharadwaj, Justin Meyerowitz, Bende Zou, Michael Klukinov, Ni Yan, Kaustubh Sharma, David J. Clark, Xinmin Xie and David C. Yeomans

Pharmaceutics 2022, 14(5), 1105; https://doi.org/10.3390/pharmaceutics14051105 - 21 May 2022

Cited by 7 | Viewed by 2947

Abstract

Background and Purpose: The intranasal administration of oxytocin (OT) reduces migraine headaches through activation of the oxytocin receptor (OTR). Magnesium ion (Mg²⁺⁾ concentration is critical to the activation of the OTR, and a low serum Mg²⁺ concentration is predictive of a [...] Read more.

Background and Purpose: The intranasal administration of oxytocin (OT) reduces migraine headaches through activation of the oxytocin receptor (OTR). Magnesium ion (Mg²⁺⁾ concentration is critical to the activation of the OTR, and a low serum Mg²⁺ concentration is predictive of a migraine headache. We, therefore, examined the functional impact of Mg²⁺ concentration on OT-OTR binding efficacy using two complimentary bioassays. Experimental Approach: Current clamp recordings of rat trigeminal ganglia (TG) neurons measured the impact of Mg²⁺ on an OT-induced reduction in excitability. In addition, we assessed the impact of Mg²⁺ on intranasal OT-induced craniofacial analgesia in rats. Key Results: While OT alone dose-dependently hyperpolarized TG neurons, decreasing their excitability, the addition of 1.75 mM Mg²⁺ significantly enhanced this effect. Similarly, while the intranasal application of OT produced dose-dependent craniofacial analgesia, Mg²⁺ significantly enhanced these effects. Conclusions and Implications: OT efficacy may be limited by low ambient Mg²⁺ levels. The addition of Mg²⁺ to OT formulations may improve its efficacy in reducing headache pain as well as for other OT-dependent processes. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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19 pages, 4297 KiB

Open AccessArticle

Brain-Targeted Intranasal Delivery of Zotepine Microemulsion: Pharmacokinetics and Pharmacodynamics

by Sravanthi Reddy Pailla, Sunitha Sampathi, Vijayabhaskarreddy Junnuthula, Sravya Maddukuri, Sujatha Dodoala and Sathish Dyawanapelly

Pharmaceutics 2022, 14(5), 978; https://doi.org/10.3390/pharmaceutics14050978 - 30 Apr 2022

Cited by 12 | Viewed by 2586

Abstract

The purpose of our study was to improve the solubility, bioavailability, and efficacy of zotepine (ZTP) by brain-targeted intranasal delivery of microemulsion (ME) and its physicochemical properties, the pharmacokinetic and pharmacodynamic parameters were evaluated. The optimized ME formulations contain 10% w/w of oil [...] Read more.

The purpose of our study was to improve the solubility, bioavailability, and efficacy of zotepine (ZTP) by brain-targeted intranasal delivery of microemulsion (ME) and its physicochemical properties, the pharmacokinetic and pharmacodynamic parameters were evaluated. The optimized ME formulations contain 10% w/w of oil (Capmul MCM C8, monoglycerides, and diglycerides of caprylic acid), 50% w/w of S_mix (Labrasol and Transcutol HP, and 40% w/w of water resulting in a globule size of 124.6 ± 3.52 nm with low polydispersity index (PDI) (0.212 ± 0.013) and 2.8-fold higher permeation coefficient through porcine nasal mucosa compared to pure drug). In vitro cell line studies on RPMI 2650, Beas-2B, and Neuro-2A revealed ZTP-ME as safe. ZTP-ME administered intranasally showed higher AUC_0–t24 (18.63 ± 1.33 h × µg/g) in the brain by approximately 4.3-fold than oral ME (4.30 ± 0.92 h × µg/g) and 7.7-fold than intravenous drug solutions (2.40 ± 0.36 h × µg/g). In vivo anti-schizophrenic activity was conducted using catalepsy test scores, the formulation showed better efficacy via the intranasal route; furthermore, there was no inflammation or hemorrhage in the nasal cavity. The results concluded that the ZTP microemulsion as a safe and effective strategy could greatly enhance brain distribution by intranasal administration. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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22 pages, 4598 KiB

Open AccessEditor’s ChoiceArticle

Novel Nanoparticles Based on N,O-Carboxymethyl Chitosan-Dopamine Amide Conjugate for Nose-to-Brain Delivery

by Adriana Trapani, Stefania Cometa, Elvira De Giglio, Filomena Corbo, Roberta Cassano, Maria Luisa Di Gioia, Sonia Trombino, Md Niamat Hossain, Sante Di Gioia, Giuseppe Trapani and Massimo Conese

Pharmaceutics 2022, 14(1), 147; https://doi.org/10.3390/pharmaceutics14010147 - 08 Jan 2022

Cited by 12 | Viewed by 2445

Abstract

A widely investigated approach to bypass the blood brain barrier is represented by the intranasal delivery of therapeutic agents exploiting the olfactory or trigeminal connections nose-brain. As for Parkinson’s disease (PD), characterized by dopaminergic midbrain neurons degeneration, currently there is no disease modifying [...] Read more.

A widely investigated approach to bypass the blood brain barrier is represented by the intranasal delivery of therapeutic agents exploiting the olfactory or trigeminal connections nose-brain. As for Parkinson’s disease (PD), characterized by dopaminergic midbrain neurons degeneration, currently there is no disease modifying therapy. Although several bio-nanomaterials have been evaluated for encapsulation of neurotransmitter dopamine (DA) or dopaminergic drugs in order to restore the DA content in parkinsonian patients, the premature leakage of the therapeutic agent limits this approach. To tackle this drawback, we undertook a study where the active was linked to the polymeric backbone by a covalent bond. Thus, novel nanoparticles (NPs) based on N,O-Carboxymethylchitosan-DA amide conjugate (N,O-CMCS-DA) were prepared by the nanoprecipitation method and characterized from a technological view point, cytotoxicity and uptake by Olfactory Ensheating Cells (OECs). Thermogravimetric analysis showed high chemical stability of N,O-CMCS-DA NPs and X-ray photoelectron spectroscopy evidenced the presence of amide linkages on the NPs surface. MTT test indicated their cytocompatibility with OECs, while cytofluorimetry and fluorescent microscopy revealed the internalization of labelled N,O-CMCS-DA NPs by OECs, that was increased by the presence of mucin. Altogether, these findings seem promising for further development of N,O-CMCS-DA NPs for nose-to-brain delivery application in PD. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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15 pages, 2385 KiB

Open AccessArticle

Development of an MRI-Compatible Nasal Drug Delivery Method for Probing Nicotine Addiction Dynamics

by Rajat Kumar, Lilianne R. Mujica-Parodi, Michael Wenke, Anar Amgalan, Andrew Lithen, Sindhuja T. Govindarajan, Rany Makaryus, Helene Benveniste and Helmut H. Strey

Pharmaceutics 2021, 13(12), 2069; https://doi.org/10.3390/pharmaceutics13122069 - 03 Dec 2021

Viewed by 1855

Abstract

Substance abuse is a fundamentally dynamic disease, characterized by repeated oscillation between craving, drug self-administration, reward, and satiety. To model nicotine addiction as a control system, a magnetic resonance imaging (MRI)-compatible nicotine delivery system is needed to elicit cyclical cravings. Using a concentric [...] Read more.

Substance abuse is a fundamentally dynamic disease, characterized by repeated oscillation between craving, drug self-administration, reward, and satiety. To model nicotine addiction as a control system, a magnetic resonance imaging (MRI)-compatible nicotine delivery system is needed to elicit cyclical cravings. Using a concentric nebulizer, inserted into one nostril, we delivered each dose equivalent to a single cigarette puff by a syringe pump. A control mechanism permits dual modes: one delivers puffs on a fixed interval programmed by researchers; with the other, subjects press a button to self-administer each nicotine dose. We tested the viability of this delivery method for studying the brain’s response to nicotine addiction in three steps. First, we established the pharmacokinetics of nicotine delivery, using a dosing scheme designed to gradually achieve saturation. Second, we lengthened the time between microdoses to elicit craving cycles, using both fixed-interval and subject-driven behavior. Finally, we demonstrate a potential application of our device by showing that a fixed-interval protocol can reliably identify neuromodulatory targets for pharmacotherapy or brain stimulation. Our MRI-compatible nasal delivery method enables the measurement of neural circuit responses to drug doses on a single-subject level, allowing the development of data-driven predictive models to quantify individual dysregulations of the reward control circuit causing addiction. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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22 pages, 13568 KiB

Open AccessArticle

Selective CNS Targeting and Distribution with a Refined Region-Specific Intranasal Delivery Technique via the Olfactory Mucosa

by Frank Maigler, Simone Ladel, Johannes Flamm, Stella Gänger, Barbara Kurpiers, Stefanie Kiderlen, Ronja Völk, Carmen Hamp, Sunniva Hartung, Sebastian Spiegel, Arghavan Soleimanizadeh, Katharina Eberle, Rebecca Hermann, Lukas Krainer, Claudia Pitzer and Katharina Schindowski

Pharmaceutics 2021, 13(11), 1904; https://doi.org/10.3390/pharmaceutics13111904 - 10 Nov 2021

Cited by 14 | Viewed by 2893

Abstract

Intranasal drug delivery is a promising approach for the delivery of drugs to the CNS, but too heterogenous, unprecise delivery methods without standardization decrease the quality of many studies in rodents. Thus, the lack of a precise and region-specific application technique for mice [...] Read more.

Intranasal drug delivery is a promising approach for the delivery of drugs to the CNS, but too heterogenous, unprecise delivery methods without standardization decrease the quality of many studies in rodents. Thus, the lack of a precise and region-specific application technique for mice is a major drawback. In this study, a previously developed catheter-based refined technique was validated against the conventional pipette-based method and used to specifically reach the olfactory or the respiratory nasal regions. This study successfully demonstrated region-specific administration at the olfactory mucosa resulting in over 20% of the administered fluorescein dose in the olfactory bulbs, and no peripheral bioactivity of insulin detemir and Fc-dependent uptake of two murine IgG1 (11C7 and P3X) along the olfactory pathway to cortex and hippocampus. An scFv of 11C7 showed hardly any uptake to the CNS. Elimination was dependent on the presence of the IgG’s antigen. In summary, it was successfully demonstrated that region-specific intranasal administration via the olfactory region resulted in improved brain targeting and reduced peripheral targeting in mice. The data are discussed with regard to their clinical potential. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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18 pages, 6153 KiB

Open AccessArticle

In Vitro Ciliotoxicity and Cytotoxicity Testing of Repeated Chronic Exposure to Topical Nasal Formulations for Safety Studies

by Larisa Tratnjek, Nadica Sibinovska, Katja Kristan and Mateja Erdani Kreft

Pharmaceutics 2021, 13(11), 1750; https://doi.org/10.3390/pharmaceutics13111750 - 20 Oct 2021

Cited by 3 | Viewed by 2216

Abstract

Certain active drugs and excipients of nasal formulations may impair ciliary function and mucociliary clearance. The ciliary beat frequency (CBF) is a key parameter for determining mucociliary clearance rate, and in vitro assessments of CBF have proven to be accurate and reproducible. Since [...] Read more.

Certain active drugs and excipients of nasal formulations may impair ciliary function and mucociliary clearance. The ciliary beat frequency (CBF) is a key parameter for determining mucociliary clearance rate, and in vitro assessments of CBF have proven to be accurate and reproducible. Since topical nasal formulations are applied with repeated doses, it is essential to elucidate their chronic, as opposed to acute, effect on mucociliary clearance and nasal mucosa. The aim of this study was to assess for the first time the ciliotoxicity and cytotoxicity of nasal sprays intended for chronic treatment (with repeated doses) using a previously designed set-up for CBF measurements. For 2 weeks, the 3D nasal MucilAir™ in vitro models were treated daily with undiluted or clinically relevant doses of mometasone nasal spray, placebo nasal spray, culture medium, or they were untreated. We demonstrated a dose-dependent and time-dependent (cumulative) effect of the nasal sprays on ciliary activity and cytotoxicity using CBF measurements and ultrastructural analysis, respectively. Our results indicate that repeated administration of clinically relevant doses of mometasone nasal spray is safe for in vivo use, which is in good agreement with a previous clinical study. Overall, our study suggests that such in vitro assays have great potential for topical nasal drug screening. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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9 pages, 1121 KiB

Open AccessCommunication

Evaluation of the Pharmacokinetics of Intranasal Drug Delivery for Targeting Cervical Lymph Nodes in Rats

by Tomoyuki Furubayashi, Daisuke Inoue, Shunsuke Kimura, Akiko Tanaka and Toshiyasu Sakane

Pharmaceutics 2021, 13(9), 1363; https://doi.org/10.3390/pharmaceutics13091363 - 30 Aug 2021

Cited by 4 | Viewed by 2331

Abstract

A well-developed lymphatic network is located under the nasal mucosa, and a few drugs that permeate the nasal mucosa are absorbed into the lymphatic capillaries. Lymph from the nasal cavity flows to the cervical lymph nodes (CLNs). In this study, we evaluated the [...] Read more.

A well-developed lymphatic network is located under the nasal mucosa, and a few drugs that permeate the nasal mucosa are absorbed into the lymphatic capillaries. Lymph from the nasal cavity flows to the cervical lymph nodes (CLNs). In this study, we evaluated the pharmacokinetics of the direct transport of intranasally administered drugs to CLNs through the nasal mucosa of Wistar rats using methotrexate as a model drug. The drug targeting index, which was calculated based on the areas under the concentration–time curves after intravenous and intranasal administration, was 3.78, indicating the benefits of nasal delivery of methotrexate to target CLNs. The direct transport percentage, which was indicative of the contribution of the direct nose–CLN pathway of methotrexate after intranasal administration, was 74.3%. The rate constant of methotrexate from the nasal cavity to CLNs was 0.0047 ± 0.0013 min⁻¹, while that from systemic circulation to CLNs was 0.0021 ± 0.0009 min⁻¹. Through pharmacokinetic analysis, this study demonstrated that the direct nasal–CLN pathway contributed more to the transport of methotrexate to the CLNs than the direct blood–CLN pathway. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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23 pages, 2799 KiB

Open AccessArticle

Quality by Design Approach for the Development of Liposome Carrying Ghrelin for Intranasal Administration

by Cecília de Barros, Norberto Aranha, Patrícia Severino, Eliana B. Souto, Aleksandra Zielińska, André Lopes, Alessandra Rios, Fernando Batain, Kessi Crescencio, Marco Chaud and Thais Alves

Pharmaceutics 2021, 13(5), 686; https://doi.org/10.3390/pharmaceutics13050686 - 10 May 2021

Cited by 13 | Viewed by 3945

Abstract

The therapeutic use of peptides has increasingly recognized in the development of new therapies. However, the susceptible enzymatic cleavage is a barrier that needs to overcome. Nose-to-brain delivery associated with liposomes can protect peptides against biodegradation and improve the accessibility to brain targets. [...] Read more.

The therapeutic use of peptides has increasingly recognized in the development of new therapies. However, the susceptible enzymatic cleavage is a barrier that needs to overcome. Nose-to-brain delivery associated with liposomes can protect peptides against biodegradation and improve the accessibility to brain targets. The aim was to develop a liposomal formulation as ghrelin carrier. The quality by design (QbD) approach was used as a strategy for method development. The initial risk assessments were carried out using a fishbone diagram. A screening design study was performed for the critical material attributes/critical process parameters (CMAs/CPPs) on critical quality attributes (CQAs). Liposomes were obtained by hydrating phospholipid films, followed by extrusion or homogenization, and coated with chitosan. The optimized liposome formulation was produced by high-pressure homogenization coated with chitosan, and the resulted were liposomes size 72.25 ± 1.46 nm, PDI of 0.300 ± 0.027, the zeta potential of 50.3 ± 1.46 mV, and encapsulation efficiency of 53.2%. Moreover, chitosan coating improved performance in ex vivo permeation and mucoadhesion analyzes when compared to the uncoated liposome. In this context, chitosan coating is essential for the performance of the formulations in the ex vivo permeation and mucoadhesion analyzes. The intranasal administration of ghrelin liposomes coated with chitosan offers an innovative opportunity to treat cachexia. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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Review

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24 pages, 2512 KiB

Open AccessReview

Non-Cellular Layers of the Respiratory Tract: Protection against Pathogens and Target for Drug Delivery

by Eleonore Fröhlich

Pharmaceutics 2022, 14(5), 992; https://doi.org/10.3390/pharmaceutics14050992 - 05 May 2022

Cited by 4 | Viewed by 3966

Abstract

Epithelial barriers separate the human body from the environment to maintain homeostasis. Compared to the skin and gastrointestinal tract, the respiratory barrier is the thinnest and least protective. The properties of the epithelial cells (height, number of layers, intercellular junctions) and non-cellular layers, [...] Read more.

Epithelial barriers separate the human body from the environment to maintain homeostasis. Compared to the skin and gastrointestinal tract, the respiratory barrier is the thinnest and least protective. The properties of the epithelial cells (height, number of layers, intercellular junctions) and non-cellular layers, mucus in the conducting airways and surfactant in the respiratory parts determine the permeability of the barrier. The review focuses on the non-cellular layers and describes the architecture of the mucus and surfactant followed by interaction with gases and pathogens. While the penetration of gases into the respiratory tract is mainly determined by their hydrophobicity, pathogens use different mechanisms to invade the respiratory tract. Often, the combination of mucus adhesion and subsequent permeation of the mucus mesh is used. Similar mechanisms are also employed to improve drug delivery across the respiratory barrier. Depending on the payload and target region, various mucus-targeting delivery systems have been developed. It appears that the mucus-targeting strategy has to be selected according to the planned application. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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13 pages, 1020 KiB

Open AccessReview

Effects of Intranasal Administration of Oxytocin and Vasopressin on Social Cognition and Potential Routes and Mechanisms of Action

by Shuxia Yao and Keith Maurice Kendrick

Pharmaceutics 2022, 14(2), 323; https://doi.org/10.3390/pharmaceutics14020323 - 29 Jan 2022

Cited by 14 | Viewed by 4589

Abstract

Acute and chronic administration of intranasal oxytocin and vasopressin have been extensively utilized in both animal models and human preclinical and clinical studies over the last few decades to modulate various aspects of social cognition and their underlying neural mechanisms, although effects are [...] Read more.

Acute and chronic administration of intranasal oxytocin and vasopressin have been extensively utilized in both animal models and human preclinical and clinical studies over the last few decades to modulate various aspects of social cognition and their underlying neural mechanisms, although effects are not always consistent. The use of an intranasal route of administration is largely driven by evidence that it permits neuropeptides to penetrate directly into the brain by circumventing the blood–brain barrier, which has been considered relatively impermeable to them. However, this interpretation has been the subject of considerable debate. In this review, we will focus on research in both animal models and humans, which investigates the different potential routes via which these intranasally administered neuropeptides may be producing their various effects on social cognition. We will also consider the contribution of different methods of intranasal application and additionally the importance of dose magnitude and frequency for influencing G protein-coupled receptor signaling and subsequent functional outcomes. Overall, we conclude that while some functional effects of intranasal oxytocin and vasopressin in the domain of social cognition may result from direct penetration into the brain following intranasal administration, others may be contributed by the neuropeptides either entering the peripheral circulation and crossing the blood–brain barrier and/or producing vagal stimulation via peripheral receptors. Furthermore, to complicate matters, functional effects via these routes may differ, and both dose magnitude and frequency can produce very different functional outcomes and therefore need to be optimized to produce desired effects. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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13 pages, 827 KiB

Open AccessReview

Intranasal Administration for Pain: Oxytocin and Other Polypeptides

by Vimala N. Bharadwaj, Alexander Z. Tzabazis, Michael Klukinov, Neil A. Manering and David C. Yeomans

Pharmaceutics 2021, 13(7), 1088; https://doi.org/10.3390/pharmaceutics13071088 - 16 Jul 2021

Cited by 20 | Viewed by 4742

Abstract

Pain, particularly chronic pain, remains one of the most debilitating and difficult-to-treat conditions in medicine. Chronic pain is difficult to treat, in part because it is associated with plastic changes in the peripheral and central nervous systems. Polypeptides are linear organic polymers that [...] Read more.

Pain, particularly chronic pain, remains one of the most debilitating and difficult-to-treat conditions in medicine. Chronic pain is difficult to treat, in part because it is associated with plastic changes in the peripheral and central nervous systems. Polypeptides are linear organic polymers that are highly selective molecules for neurotransmitter and other nervous system receptors sites, including those associated with pain and analgesia, and so have tremendous potential in pain therapeutics. However, delivery of polypeptides to the nervous system is largely limited due to rapid degradation within the peripheral circulation as well as the blood–brain barrier. One strategy that has been shown to be successful in nervous system deposition of polypeptides is intranasal (IN) delivery. In this narrative review, we discuss the delivery of polypeptides to the peripheral and central nervous systems following IN administration. We briefly discuss the mechanism of delivery via the nasal–cerebral pathway. We review recent studies that demonstrate that polypeptides such as oxytocin, delivered IN, not only reach key pain-modulating regions in the nervous system but, in doing so, evoke significant analgesic effects. IN administration of polypeptides has tremendous potential to provide a non-invasive, rapid and effective method of delivery to the nervous system for chronic pain treatment and management. Full article

(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)

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