Nasal Powder Research Articles

Long-Term Safety and Tolerability of STS101, A Novel Investigational Dihydroergotamine Nasal Powder: Initial Data from the ASCEND Study (P13-2.002)

Long-Term Safety and Tolerability of STS101, A Novel Investigational Dihydroergotamine Nasal Powder: Initial Data from the ASCEND Study (P13-2.002)

Cardiovascular Safety of STS101, A Novel Investigational DHE Nasal Powder Product: Initial Data from the ASCEND Study (P14-2.006)

Cardiovascular Safety of STS101, A Novel Investigational DHE Nasal Powder Product: Initial Data from the ASCEND Study (P14-2.006)

Dual targeting powder formulation of antiviral agent for customizable nasal and lung deposition profile through single intranasal administration

Unpredictable outbreaks due to respiratory viral infections emphasize the need for new drug delivery strategies to the entire respiratory tract. As viral attack is not limited to a specific anatomic region, antiviral therapy that targets both the upper and lower respiratory tract would be most effective. This study aimed to formulate tamibarotene, a retinoid derivative previously reported to display broad-spectrum antiviral activity against influenza and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), as a novel dual particle size powder formulation that targets both the nasal cavity and the lung by a single route of intranasal administration. Spray freeze drying (SFD) and spray drying (SD) techniques were employed to prepare tamibarotene powder formulations, and cyclodextrin was used as the sole excipient to enhance drug solubility. With the employment of appropriate atomizing nozzles, particles of size above 10 μm and below 5 μm could be produced for nasal and lung deposition, respectively. The aerosol performance of the powder was evaluated using Next Generation Impactor (NGI) coupled with a glass expansion chamber and the powder was dispersed with a nasal powder device. By blending powder of two different particle sizes, a single powder formulation with dual aerosol deposition characteristic in both the nasal and pulmonary regions was produced. The aerosol deposition fractions in the nasal cavity and pulmonary region could be modulated by varying the powder mixing ratio. All dry powder formulations exhibited spherical structures, amorphous characteristics and improved dissolution profile as compared to the unformulated tamibarotene. Overall, a novel dual targeting powder formulation of tamibarotene exhibiting customizable aerosol deposition profile was developed. This exceptional formulation strategy can be adopted to deliver other antimicrobial agents to the upper and lower airways for the prevention and treatment of human respiratory infections.

Evaluation of the usefulness of hydroxypropyl cellulose and sucrose in the nasal influenza vaccine

The preventative efficacy of the influenza vaccine could be induced by the administration on the surface of the nasal mucosa, thereby enabling secretory IgA antibody production on the mucosal surface. For effective induction of the mucosal immune response, the vaccines have to reach the nasopharyngeal lymphoid tissue located in the deep part of the nasal cavity. To achieve this, vaccines should be formulated in powder form, in order to preserve the antigen physicochemical characteristics. Although proteins are generally stable in the powder form in the presence of amorphous sucrose, this amorphous sugar is particularly hygroscopic, undergoing facile deliquescence, and becoming unsuitable for intranasal administration. In this study, it was demonstrated that a stable powder could be manufactured by co-spray-drying hydroxypropyl cellulose and sucrose. The influenza antigen was then formulated with these excipients as a powdered pharmaceutical product, and the activity of the antigen was confirmed following long-term storage. In addition, following long-term storage, the powder was nasally administered to mice to evaluate its immunogenicity, and it was confirmed that secretory IgA production was induced on the mucosal surface. Thus, using sucrose and hydroxypropyl cellulose as excipients for a nasal influenza powder vaccine, a technology was established to stabilize the powdered influenza antigen.

Development and Testing of a Spray-Dried Tuberculosis Vaccine Candidate in a Mouse Model.

Converting a vaccine into a thermostable dry powder is advantageous as it reduces the resource burden linked with the cold chain and provides flexibility in dosage and administration through different routes. Such a dry powder presentation may be especially useful in the development of a vaccine towards the respiratory infectious disease tuberculosis (TB). This study assesses the immunogenicity and protective efficacy of spray-dried ID93+GLA-SE, a promising TB vaccine candidate, against Mycobacterium tuberculosis (Mtb) in a murine model when administered via different routes. Four administration routes for the spray-dried ID93+GLA-SE were evaluated along with relevant controls—1) reconstitution and intramuscular injection, 2) reconstitution and intranasal delivery, 3) nasal dry powder delivery via inhalation, and 4) pulmonary dry powder delivery via inhalation. Dry powder intranasal and pulmonary delivery was achieved using a custom nose-only inhalation device, and optimization using representative vaccine-free powder demonstrated that approximately 10 and 44% of the maximum possible delivered dose would be delivered for intranasal delivery and pulmonary delivery, respectively. Spray-dried powder was engineered according to the different administration routes including maintaining approximately equivalent delivered doses of ID93 and GLA. Vaccine properties of the different spray-dried lots were assessed for quality control in terms of nanoemulsion droplet diameter, polydispersity index, adjuvant content, and antigen content. Our results using the Mtb mouse challenge model show that both intranasal reconstituted vaccine delivery as well as pulmonary dry powder vaccine delivery resulted in Mtb control in infected mice comparable to traditional intramuscular delivery. Improved protection in these two vaccinated groups over their respective control groups coincided with the presence of cytokine-producing T cell responses. In summary, our results provide novel vaccine formulations and delivery routes that can be harnessed to provide protection against Mtb infection.

Harnessing Intranasal Delivery Systems of Sumatriptan for the Treatment of Migraine.

Sumatriptan (ST) is a commonly prescribed drug for treating migraine. The efficiency of several routes of ST administration has been investigated. Recently, the intranasal route with different delivery systems has gained interest owing to its fast-acting and effectiveness. The present study is aimed at reviewing the available studies on novel delivery systems for intranasal ST administration. The oral route of ST administration is common but complicated with some problems. Gastroparesis in patients with migraine may reduce the absorption and effectiveness of ST upon oral use. Furthermore, the gastrointestinal (GI) system and hepatic metabolism can alter the pharmacokinetics and clinical effects of ST. The bioavailability of conventional nasal liquids is low due to the deposition of a large fraction of the delivered dose of a drug in the nasal cavity. Several delivery systems have been utilized in a wide range of preclinical and clinical studies to enhance the bioavailability of ST. The beneficial effects of the dry nasal powder of ST (AVP-825) have been proven in clinical studies. Moreover, other delivery systems based on microemulsions, microspheres, and nanoparticles have been introduced, and their higher bioavailability and efficacy were demonstrated in preclinical studies. Based on the extant findings, harnessing novel delivery systems can improve the bioavailability of ST and enhance its effectiveness against migraine attacks. However, further clinical studies are needed to approve the safety and efficacy of employing such systems in humans.

New Fast Acting Glucagon for Recovery from Hypoglycemia, a Life-Threatening Situation: Nasal Powder and Injected Stable Solutions.

The goal of diabetes care is to achieve and maintain good glycemic control over time, so as to prevent or delay the development of micro- and macrovascular complications in type 1 (T1D) and type 2 diabetes (T2D). However, numerous barriers hinder the achievement of this goal, first of all the frequent episodes of hypoglycemia typical in patients treated with insulin as T1D patients, or sulphonylureas as T2D patients. The prevention strategy and treatment of hypoglycemia are important for the well-being of patients with diabetes. Hypoglycemia is strongly associated with an increased risk of cardiovascular disease in diabetic patients, due probably to the release of inflammatory markers and prothrombotic effects triggered by hypoglycemia. Treatment of hypoglycemia is traditionally based on administration of carbohydrates or of glucagon via intramuscular (IM) or subcutaneous injection (SC). The injection of traditional glucagon is cumbersome, such that glucagon is an under-utilized drug. In 1983, it was shown for the first time that intranasal (IN) glucagon increases blood glucose levels in healthy volunteers, and in 1989–1992 that IN glucagon is similar to IM glucagon in resolving hypoglycemia in normal volunteers and in patients with diabetes, both adults and children. IN glucagon was developed in 2010 and continued in 2015; in 2019 IN glucagon obtained approval in the US, Canada, and Europe for severe hypoglycemia in children and adults. In the 2010s, two ready-to-use injectable formulations, a stable non-aqueous glucagon solution and the glucagon analog dasiglucagon, were developed, showing an efficacy similar to traditional glucagon, and approved in the US in 2020 and in 2021, respectively, for severe hypoglycemia in adults and in children. Fast-acting glucagon (nasal administration and injected solutions) appears to represent a major breakthrough in the treatment of severe hypoglycemia in insulin-treated patients with diabetes, both adults and children. It is anticipated that the availability of fast-acting glucagon will expand the use of glucagon, improve overall metabolic control, and prevent hypoglycemia-related complications, in particular cardiovascular complications and cognitive impairment.

Glucagon: Its evolving role in the management of hypoglycemia.

More than 10% of the United States population has diabetes, characterized by hyperglycemia. Insulin and other agents used to treat diabetes predispose people to hypoglycemia, which can be life threatening. Glucagon is an emergency medication that can save lives by quickly raising glucose in people who are unconscious or unable to consume glucose due to severe hypoglycemia. Although glucagon has been commercially available since 1960, earlier formulations required reconstitution of a dry powder with diluent immediately prior to injection, due to lack of long-term stability once reconstituted. Glucagon has been underutilized due to the lack of confidence or ability to administer in emergency situations. More recently, new formulations including a nasal powder glucagon and liquid-stable glucagon have become available. This article discusses the evidence surrounding new glucagon formulations compared with the original glucagon emergency kit including ease of use, efficacy, and safety with a focus on important patient counseling points and relevant clinical information on hypoglycemia.

Flurbiprofen sodium microparticles and soft pellets for nose-to-brain delivery: Serum and brain levels in rats after nasal insufflation

Neuroinflammation in Alzheimer’s disease (AD) revamped the role of a preventive therapeutic action of non steroidal anti-inflammatory drugs; flurbiprofen could delay AD onset, provided its access to brain is enhanced and systemic exposure limited. Nasal administration could enable direct drug access to central nervous system (CNS) via nose-to-brain transport. Here, we investigated the insufflation, deposition, dissolution, transmucosal permeation, and in vivo transport to rat brain of flurbiprofen from nasal powders combined in an active device.Flurbiprofen sodium spray-dried microparticles as such, or soft pellets obtained by agglomeration of drug microparticles with excipients, were intranasally administered to rats by the pre-metered insufflator device. Blood and brain were collected to measure flurbiprofen levels.Excipient presence in soft pellets lowered the metered drug dose to insufflate. Nevertheless, efficiency of powder delivery by the device, measured as emitted fraction, was superior with soft pellets than microparticles, due to their coarse size. Both nasal powders resulted into rapid flurbiprofen absorption. Absolute bioavailability was 33% and 58% for microparticles and pellets, respectively. Compared to intravenous flurbiprofen, the microparticles were more efficient than soft pellets at enhancing direct drug transport to CNS. Direct Transport Percentage index evidenced that more than 60% of the intranasal dose reached the brain via direct nose-to-brain transport for both powders. Moreover, remarkable drug concentrations were measured in the olfactory bulb after microparticle delivery. Bulb connection with the entorhinal cortex, from where AD initiates, makes flurbiprofen sodium administration as nasal powder worth of further investigation in an animal model of neuroinflammation.

Nasal biocompatible powder of Geraniol oil complexed with cyclodextrins for neurodegenerative diseases: physicochemical characterization and in vivo evidences of nose to brain delivery

Recently, many studies have shown that plant metabolites, such as geraniol (GER), may exert anti-inflammatory effects in neurodegenerative diseases and, in particular, Parkinson's disease (PD) models. Unfortunately, delivering GER to the CNS via nose-to-brain is not feasible due to its irritant effects on the mucosae. Therefore, in the present study β-cyclodextrin (βCD) and its hydrophilic derivative hydroxypropyl-beta-cyclodextrin (HPβCD) were selected as potential carriers for GER nose-to-brain delivery. Inclusion complexes were formulated and the biocompatibility with nasal mucosae and drug bioavailability into cerebrospinal fluid (CSF) were studied in rats. It has been demonstrated by DTA, FT-IR and NMR analyses that both the CDs were able to form 1:1 GER-CD complexes, arising long-term stable powders after the freeze-drying process. GER-HPβCD-5 and GER-βCD-2 complexes exhibited comparable results, except for morphology and solubility, as demonstrated by SEM analysis and phase solubility study, respectively. Even though both complexes were able to directly and safely deliver GER to CNS, GER-βCD-2 displayed higher ability in releasing GER in the CSF. In conclusion, βCD complexes can be considered a very promising tool in delivering GER into the CNS via nose-to-brain route, preventing GER release into the bloodstream and ensuring the integrity of the nasal mucosa.

Low pH Hypromellose (Taffix) nasal powder spray could reduce SARS-CoV-2 infection rate post mass-gathering event at a highly endemic community: an observational prospective open label user survey

ABSTRACT Objectives: Bney Brak city tops Israel’s COVID-19 infection rate and mortality. Before the Jewish New Year (two-day gathering) SARS-CoV-2 PCR positivity rates were 17.6% and reached 28.1% two weeks later Taffix – an innovative nasal powder creates a protective gel over the nasal mucosa blocking viruses from infecting nasal cells, was tested for efficacy in preventing SARS CoV2 infection. Methods: In a prospective users survey, 243 members of an ultra-orthodox community that participated in two days prayers were followed for 14 days following this ‘superspread’ event. Eighty-three used Taffix throughout holiday’s prayers and the following two weeks (ITT). Eighty-one used it regularly (PP). Two used it rarely if at all. The remaining 160 did not use Taffix. Results: After 14 days, 0/81 (0%) of (PP) Tafffix users, 2/83 (2.4%) of (ITT) Taffix users and 16/160 (10%) nonusers were infected. Odds ratio for infection among Taffix users was 0.22, a reduction of 78% (95%CI 1%–95%). No side effects reported. Conclusion: Taffix could be an additional tool against COVID19 spread, in addition to recommended safety measures. This is the first time that a prevention measure of SARS-CoV-2, beyond the use of masks, has proved effective.

Nasal Powder Formulations: In-Vitro Characterisation of the Impact of Powders on Nasal Residence Time and Sensory Effects.

Nasal drug delivery is still primarily associated with locally-effective drugs, but next-generation products utilising the benefits of nasal administration—such as easy access to a relatively permeable mucosa, the presence of immunocompetent cells, and a direct route to the brain—are under investigation. Nasal powders offer the potential to improve the drugs’ effects by providing higher resistance against the mucociliary clearance, and thus prolonging the contact time of the drug with its target site. However, suitable and easy-to-use in-vitro setups tailored to the characterisation of this effect are missing. In this study, a selection of excipients for powder formulations were used to evaluate the applicability of different methods which investigate the influence on the contact time. The combination of the assessment of rheological properties, dynamic vapour sorption, and adhesiveness on agar–mucin plates was found to be a valuable predictive tool. For the additional assessment of the sensations associated with the close contact of powders and the mucosa, a slug mucosal irritation assay was conducted and adapted to powders. These methods are regarded as being especially useful for comparative screenings in early formulation development.

TaffiX® Nasal Powder forms an Effective Barrier against SARS-CoV-2

Barbara J Mann1*, G Brett Moreau1, Tair Lapidot2 and Dalia Megiddo2 Author Affiliations 1University of Virginia School of Medicine, Department of Medicine, Division of Infectious Diseases and International Health, Charlottesville, VA, USA 2Nasus Pharma, 29 Harakevet St, Tel Aviv, Israel Received: January 13, 2021| Published: January 27, 2021 Corresponding author:Barbara J Mann, P.O. Box 801340, University of Virginia Health System, Charlottesville, VA 22908, USA DOI: 10.26717/BJSTR.2021.33.005405

Taffix® Nasal Powder Spray Forms an Effective Barrier Against Infectious New Variants of SARS-Cov-2 (Alpha, Beta and Delta)

While vaccination efforts against SARS-CoV-2 around the world are ongoing, new highly infectious virus variants continue to evolve. The protection provided by the available vaccines against some of the new variants is weaker. Additional preventive measures will therefore be needed to protect the population until effective vaccinations are widely available. TaffiX® is an anti-viral nasal powder spray comprised of low-pH hypromellose, which forms a protective mechanical barrier that prevents viruses from engaging with nasal cells. The current study aimed to test the protective effect of TaffiX® against SARS-CoV-2 Alpha (B.1.1.7; hCoV-19/Israel/CVL-46879-ngs/ 2020), Beta, (B.1.351; hCoV-19/Israel/CVL-2557-ngs/2020) and Delta (B.1.617.2; hCoV-19/Israel/ VVL-12806/2021), three highly infectious and pathogenic SARS-CoV-2 strains.

Evaluation of Systemic and Mucosal Immune Responses Induced by a Nasal Powder Delivery System in Conjunction with an OVA Antigen in Cynomolgus Monkeys.

An immune response for a nasal ovalbumin (OVA) powder formulation with an applied nasal delivery platform technology, consisting of a powdery nasal carrier and a device, was evaluated in monkeys with similar upper respiratory tracts and immune systems to those of humans, in order to assess the applicability to a vaccine antigen. Nasal distribution and retention studies using a 3D nasal cavity model and manganese-enhanced MRI were conducted by administering nasal dye and manganese powder formulations with the applied technology. Systemic and mucosal immune responses for the nasal OVA powder formulation were evaluated by determining serum IgG and nasal wash IgA antibody titers. The nasal dye and manganese powder formulations showed wider distribution and longer retention time than did a nasal liquid formulation. The nasal OVA powder formulation also showed comparable and higher antigen-specific IgG antibody titer to an injection and nasal liquid formulation, respectively. Furthermore, antigen-specific IgA antibody response was detected only for the nasal OVA powder formulation. The present study suggests that the technology, originally designed for drug absorption, is promising for nasal vaccines, enabling both a mucosal immunity response as the first line of defense and systemic immunity response as a second line of defense against infection.

Microfluidic spray dried and spray freeze dried uniform microparticles potentially for intranasal drug delivery and controlled release

Microparticulate formulations of intranasal drug administration, i.e. nasal powder, have aroused widespread interest in academia and industry. However, low drug bioavailability due to poor hydrophilicity and rapid clearance of nasal mucosa remains an important challenge. Herein, with resveratrol as poorly water-soluble model drug, hydroxypropyl-β-cyclodextrin as complexation agent and excipient, chitosan as mucoadhesive enhancer, a series of uniform microparticles were fabricated using a self-designed microfluidic spray granulation platform. The effects of feed solution composition and process technique on particle size, morphology, density and flowability were investigated. The obtained powder presented the significantly enhanced resveratrol dissolubility over 1800 times pure resveratrol and the excellent antioxidant activity with Net AUC value exceeding 60. Chitosan played an important role in adjusting resveratrol release behavior and improving particle mucoadhesive property. This study shows promise for facile and scalable production of high-quality nasal powder using combined complexation method with spray drying and spray freeze drying technique.

Nasal Powder Formulation of Tranexamic Acid and Hyaluronic Acid for the Treatment of Epistaxis.

The aim of this study was to develop a nasal powder formulation of the antifibrinolytic drug, tranexamic acid (TXA), in combination with the wound-healing agent hyaluronic acid (HA) for the local treatment of epistaxis (nose bleeding). Formulations of TXA alone and with different concentrations of HA were freeze-dried and characterised according to their physicochemical properties. Aerosol performance was assessed to ensure nasal deposition with minimal lung deposition. Nasal epithelial cells were used to assess cytotoxicity, transport across the nasal epithelium, antioxidant, wound-healing and anti-inflammatory properties of all formulations. Formulations containing TXA and HA were produced and found to be mostly deposited in the nasal cavity (more than 90%). Formulation of TXA + 0.3%HA showed wound reduction of 29.3% when assessed in ALI culture. At this concentration, formulations also reduced ROS production in RPMI 2650, and IL-8 production in primary nasal epithelial cells. Furthermore, for formulations containing HA, the higher viscosity may lead to larger residence time in the nasal cavity. Combination of TXA with HA shows promising results for the treatment of nasal epistaxis.

Stability study of nasal powder formulation containing nanosized lamotrigine

Drug administration through the nose offers great possibilities which have been discovered in the past few decades. Besides the most known local effect, systemic and central nervous system effect is also available, the administration is non-painful and the degradation effect of the gastrointestinal tract can be avoided. Amongst the nasal formulations, powders have become more popular as their stability is favorable compared to the liquid formulations and a higher dose can be administered in powder form. The quality insurance and stability of the products in the pharmaceutical field have gained considerable attention in the last decades. Due to this fact, the aim was to execute a long-term stability study of a previously developed, nanosized lamotrigine (LAM) containing nasal powder (NP) formulation. The results of the stability test showed that the NP formulation preserved its key properties (particle size, morphology, structure and in vitro drug release) after 6 months of storage.

Investigation of the Absorption of Nanosized lamotrigine Containing Nasal Powder via the Nasal Cavity.

Nasal drug delivery has become a popular research field in the last years. This is not surprising since the nose possesses unique anatomical and physical properties. Via the nasal mucosa local, systemic, and directly central nerve systemic (CNS) effect is achievable. Powders have favorable physicochemical properties over liquid formulations. Lamotrigine (LAM) is an antiepileptic agent with a relatively mild side effect spectrum, but only available in tablet form on market. Reducing the particle size to the nano range can affect the bioavailability of pharmaceutical products. The aim of this article was to continue the work started, compare the in vitro properties of a nanonized lamotrigine containing nasal powder (nanoLAMpowder) and its physical mixture (PM) that were prepared by dry milling. Moreover, to study their trans-epithelial absorption to reach the blood and target the brain by axonal transport. Due to the dry milling technique, the particle size of LAM, their surface and also their structure changed that led to higher in vitro dissolution and permeability rate. The results of the in vivo tests showed that the axonal transport of the drug was assumable by both intranasal formulations because the drug was present in the brain within a really short time, but the LAM from the nanoLAMpowder liberated even faster.

Systemic Delivery of Peptide Hormones Using Nasal Powders: Strategies and Future Perspectives

Background: Peptide Hormones (PH) are mainly administered as parenteral injections due to their peculiar physicochemical properties, and susceptibility to enzymatic degradation after oral administration. With invasive routes, however, patient safety, acceptability, and compliance become a concern, especially when a patient has a chronic condition that requires repeated injections. The delivery of peptide hormones via the nasal route has gained momentum over the last few decades as a noninvasive alternative to parenteral injections and commercially available nasal liquid products. Objective: The aim of this paper was to review: (1) The benefits and limitations of nasal powder products, (2) Formulation strategies to enhance nasal delivery of peptide hormone drugs, (3) Nasal powder devices, and (4) Future perspectives of therapeutic nasal powders. The drugs examined specifically include calcitonin, desmopressin, ghrelin, glucagon, human growth hormone, insulin, octreotide, and oxytocin. Methods:: Nasal delivery of peptide hormones using powders was reviewed with the following databases: EBSCO, PUBMED, Web of Science, ClinicalTrials.gov, and EU Clinical Trials Register. Results: Nasal powders are a promising drug delivery system that may be safer and more effective than traditional injections and presently marketed nasal liquids for peptide hormone drugs. Conclusion: With sustained interest and growing body of supporting evidence, a range of nasal powders for systemic delivery of these drugs and delivery devices can be expected to enter the market in the future and offer more options to patients