SBIR-STTR Award

We propose to develop a long-acting in-situ gel nasal spray containing povidone iodine in combination with budesonide for the treatment of chronic rhinosinusitis. Chronic rhinosinusitis (CRS) is often the result of mixed inflammatory and infectious processes that concurrently affect the nose and para-nasal sinuses. The condition is defined by a constellation of symptoms and prolonged clinical course, affecting as many as 30 million US adults per year. Persistence of infection can lead to chronic mucosal inflammation, altered sinonasal ciliary function, and nasal polyp formation. The treatment of multiple drug-resistant rhinosinusitis remains largely ineffective. The established role of bacterial biofilms in chronic diseases, such as CRS, and their formidable resistance to conventional medical and surgical therapies poses a significant problem to the treating physician. We had previously developed a novel, proprietary irrigation suspension, IVIEW-1501: Povidone Iodine combination with budesonide, for the treatment of chronic rhinosinusitis (CRS). By employing a non-toxic, highly biocidal antiseptic with a powerful nasal steroid, we have demonstrated that we can control both infectious and inflammatory aspects of CRS. However, a significant challenge of nasal drug development is to overcome the protective barriers of the nasal cavity without causing permanent tissue damage. The major problems that persist with nasal solutions are cleared off rapidly from nasal cavity. Because human nasal mucosa is covered with approximately 0.1 ml mucus, which consists of sodium, potassium and calcium ions, a solution-gel phase transition can be expected with ion-sensitive gel formulations to decrease the mucocilliary clearance and prolong the residence time at the nasal absorption site and thereby facilitate the uptake of the drug. We propose in this SBIR Phase I to optimize an in-situ gel forming nasal spray formulation containing both povidone iodine and budesonide by using polysaccharide gel matrix, where the effective concentrations of drug substances are maintained by the equilibrium between solution drug substances and the gel bound components resulting in a long lasting, less toxic pharmacological effect, in the mean time to reduce sedimentation of budesonide suspension. During the Phase I project, we will carry out formulation optimizations, studies of in-vitro drug release, drug retention on nasal mucosa, and in-vitro antibiofilm studies of IVIEW-1502 on established biofilms of Staphylococcus aureus, Psuedomonas aeruginosa and Candida Albicans and in-vivo animal tolerability and toxicity studies. The project's goal is to confirm feasibility of the proposed Phase I project. Upon successful Phase I project, further in-vivo topical toxicity and efficacy studies of the optimized in-situ gel PVP-I/budesonide formulations will be pursued by a phase II SBIR proposal.

Public Health Relevance Statement:
Narrative Development of a long-acting in-situ gel nasal spray containing povidone iodine in combination with budesonide for the treatment of chronic rhinosinusitis, represents a major advance in rhinology. If approved, this will be the first broad-spectrum anti-infectious drug/steroid combination against all causes of pathogens with no drug resistance, long duration in the nasal cavity with better patient compliance and minimized irritation profile.

Project Terms:
absorption; Adult; Adverse effects; Affect; animal efficacy; Animals; Anti-Bacterial Agents; Antifungal Agents; Applications Grants; Area; Bacteria; Bacterial Model; Budesonide; Calcium ion; Candida albicans; Canis familiaris; Characteristics; Child; Chronic; Chronic Disease; chronic rhinosinusitis; Clinical; commercialization; Compliance behavior; Cystic Fibrosis; Delayed-Action Preparations; Dermatology; Development; Disease; Drug Delivery Systems; drug development; Drug resistance; efficacy study; Equilibrium; Formulation; functional disability; fungus; Gel; Goals; Histopathologic Grade; Hour; Human; In Situ; In Vitro; in vivo; Infection; Inflammatory; Ions; Irrigation; irritation; Lead; Licensing; Local Anti-Infective Agents; Medical; Microbial Biofilms; Modeling; Mucositis; Mucous body substance; Multi-Drug Resistance; Nasal cavity; Nasal Polyps; New Zealand; Nose; novel; Operative Surgical Procedures; ophthalmic drug; Ophthalmology; Oryctolagus cuniculus; Otolaryngology; pathogen; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase II Clinical Trials; Phase Transition; physical symptom; Physicians; Polysaccharides; potassium ion; Povidone-Iodine; Process; Property; Pseudomonas aeruginosa; Rattus; Recurrence; residence; Resistance; rhinosinusitis; Rodent; Role; Safety; Saline; Secondary to; Sedimentation process; Sheep; Sinus; Sinusitis; Site; Small Business Innovation Research Grant; sodium ion; Staphylococcus aureus; Steroids; Structure of mucous membrane of nose; Study models; Surface; Suspensions; Symptoms; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicology; treatment duration; uptake; Viscosity

/Summary We propose to develop a long-acting in-situ gel nasal spray containing povidone iodine in combination with budesonide for the treatment of chronic rhinosinusitis. Chronic rhinosinusitis (CRS) is often the result of mixed inflammatory and infectious processes that concurrently affect the nose and para-nasal sinuses. The condition is defined by a constellation of symptoms and prolonged clinical course, affecting as many as 30 million US adults per year. Persistence of infection can lead to chronic mucosal inflammation, altered sinonasal ciliary function, and nasal polyp formation. The treatment of multiple drug-resistant rhinosinusitis remains largely ineffective. The established role of bacterial biofilms in chronic diseases, such as CRS, and their formidable resistance to conventional medical and surgical therapies poses a significant problem to the treating physician. We had previously developed a novel, proprietary irrigation suspension, IVIEW-1501: Povidone Iodine combination with budesonide, for the treatment of chronic rhinosinusitis (CRS). By employing a non-toxic, highly biocidal antiseptic with a powerful nasal steroid, we have demonstrated that we can control both infectious and inflammatory aspects of CRS. However, a significant challenge of nasal drug development is to overcome the protective barriers of the nasal cavity without causing permanent tissue damage. The major problems that persist with nasal solutions are cleared off rapidly from nasal cavity. Because human nasal mucosa is covered with approximately 0.1 ml mucus, which consists of sodium, potassium and calcium ions, a solution-gel phase transition can be expected with ion-sensitive gel formulations to decrease the mucocilliary clearance and prolong the residence time at the nasal absorption site and thereby facilitate the uptake of the drug. We propose in this SBIR Phase I to optimize an in-situ gel forming nasal spray formulation containing both povidone iodine and budesonide by using polysaccharide gel matrix, where the effective concentrations of drug substances are maintained by the equilibrium between solution drug substances and the gel bound components resulting in a long lasting, less toxic pharmacological effect, in the mean time to reduce sedimentation of budesonide suspension. During the Phase I project, we will carry out formulation optimizations, studies of in-vitro drug release, drug retention on nasal mucosa, and in-vitro antibiofilm studies of IVIEW-1502 on established biofilms of Staphylococcus aureus, Psuedomonas aeruginosa and Candida Albicans and in-vivo animal tolerability and toxicity studies. The project's goal is to confirm feasibility of the proposed Phase I project. Upon successful Phase I project, further in-vivo topical toxicity and efficacy studies of the optimized in-situ gel PVP-I/budesonide formulations will be pursued by a phase II SBIR proposal.

Public Health Relevance Statement:
Narrative Development of a long-acting in-situ gel nasal spray containing povidone iodine in combination with budesonide for the treatment of chronic rhinosinusitis, represents a major advance in rhinology. If approved, this will be the first broad-spectrum anti-infectious drug/steroid combination against all causes of pathogens with no drug resistance, long duration in the nasal cavity with better patient compliance and minimized irritation profile.

NIH Spending Category:
Biodefense; Biotechnology; Emerging Infectious Diseases; Infectious Diseases

Project Terms:
absorption; Adult; Adverse effects; Affect; animal efficacy; Animals; Anti-Bacterial Agents; Antifungal Agents; Applications Grants; Area; Bacteria; Bacterial Model; Budesonide; Calcium ion; Candida albicans; Canis familiaris; Characteristics; Child; Chronic; Chronic Disease; chronic rhinosinusitis; Clinical; commercialization; compliance behavior; Cystic Fibrosis; Delayed-Action Preparations; Dermatology; Development; Disease; Drug Delivery Systems; drug development; Drug resistance; efficacy study; Equilibrium; Formulation; functional disability; fungus; Gel; Goals; Histopathologic Grade; Hour; Human; In Situ; In Vitro; in vivo; Infection; Inflammatory; Ions; Irrigation; irritation; Lead; Licensing; Local Anti-Infective Agents; Medical; Microbial Biofilms; Modeling; Mucositis; Mucous body substance; Multi-Drug Resistance; Nasal cavity; Nasal Polyps; New Zealand; Nose; novel; Operative Surgical Procedures; ophthalmic drug; Ophthalmology; Oryctolagus cuniculus; Otolaryngology; pathogen; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase II Clinical Trials; Phase Transition; physical symptom; Physicians; Polysaccharides; potassium ion; Povidone-Iodine; Process; Property; Pseudomonas aeruginosa; Rattus; Recurrence; residence; Resistance; rhinosinusitis; Rodent; Role; Safety; Saline; Secondary to; Sedimentation process; Sheep; Sinus; Sinusitis; Site; Small Business Innovation Research Grant; sodium ion; Staphylococcus aureus; Steroids; Structure of mucous membrane of nose; Study models; Surface; Suspensions; Symptoms; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicology; treatment duration; uptake; Viscosity