Chronic endobronchial bacterial infections represent the primary cause of morbidity (declining lung function) and mortality in cystic fibrosis (CF). Inhaled antibiotics have become an increasingly attractive therapeutic modality compared to IV antibiotics, as inhaled drug is delivered directly to the site of infection while minimizing systemic exposure/toxicity. Nevertheless, short half-lives (typical t1/2 ~0.8 hr) in infected sputum limit antibiotic efficacy and necessitate multiple daily dosing. This shortcoming is especially critical for -lactam antibiotics, whose maximum efficacy relies on maintaining drug concentration above the minimum inhibitory concentration (MIC);the only approved inhaled -lactam (Cayston(r)) fails to sustain drug levels in CF sputum above MIC90 for even half the duration between dosing (3x daily). Previous attempts to achieve sustained local delivery of antibiotics were mostly based on polymeric or liposomal particles that do not possess Kala's proprietary mucus-resistant coatings (conventional particles, or ""CP""). However, CP are extensively trapped at the very surface of the viscoelastic sputum lining the airways of CF patients, and are thus readily eliminated by mucociliary and cough-driven sputum clearance (thus precluding extended drug release). To overcome the sputum barrier, Hanes (co-founder of Kala) and coworkers pioneered the mucus-penetrating particle (MPP) technology, exclusively licensed to Kala. MPP rapidly penetrate into deep mucus layers and, thus, can persist longer and provide unprecedented drug-release durations at mucosal surfaces. A variety of MPP systems, including MPP composed entirely of excipients regarded by FDA as GRAS (Generally Recognized As Safe), have been engineered to penetrate purulent sputum expectorated from CF patients. In Phase I, we will build upon this work to formulate MPP for inhalation that slowly releases -lactam antibiotics. We expect that MPP will enhance bactericidal effectiveness against endobronchial bacterial infections by maintaining -lactam antibiotics above MIC90 in sputum for extended durations compared to free drug. In Specific Aim 1, we will formulate MPP that contain two common IV -lactams for CF lung infections. We will measure particle size, mobility in sputum, drug loading, drug release kinetics and storage stability. We will advance the MPP with the most suitable drug delivery characteristics to animal studies. In Specific Aim 2, we will administer -lactam- loaded MPP to the lungs of healthy rats, and confirm if drug levels in lung mucus are maintained above MIC90 for at least 24 hrs. Successful completion of these studies will lead to a Phase II proposal to develop -lactam MPP into a suitable pharmaceutical dosage form for extensive preclinical efficacy and safety testing in preparation for clinical trials. The overall goal is to develop a shelf-stable, sustained-release -lactam formulation that is efficacious with convenient 1W-daily dosing (by maintaining sputum drug levels above MIC90 for at least 24 hrs). By offering improved pharmacokinetics in the lung, we expect -lactam MPP will also improve therapies against bacterial infections in other pulmonary diseases, such as severe asthma and COPD.
Public Health Relevance: Chronic endobronchial bacterial infections represent the primary cause of morbidity and mortality in cystic fibrosis. The only marketed -lactam antibiotic for inhalation (Cayston(r)) provides drug levels in the lung needed for maximally-effective bactericidal activity for only ~10-12 hours per day despite frequent administration (3 times daily). Kala Pharmaceuticals seeks to prove that our proprietary delivery systems can provide local delivery of -lactam antibiotics to the lungs that will markedly enhance current antibacterial therapy by providing a once-daily product that maintains drug concentration for 24h/day.
Thesaurus Terms: Acute;Address;Adhesions;Adverse Effects;Animals;Anti-Bacterial Agents;Antibacterial Agents;Antibiotic Agents;Antibiotic Drugs;Antibiotic Therapy;Antibiotic Treatment;Antibiotics;Asthma;Bacterial Infections;Blood Plasma;Body Tissues;Breathing;Bronchial Asthma;Bronchioalveolar Lavage;Bronchoalveolar Lavage;Bronchopulmonary Lavage;Cf Patients;Coad;Copd;Canine Species;Canis Familiaris;Ceftazidime;Characteristics;Chemicals;Chronic;Chronic Obstructive Airway Disease;Chronic Obstructive Lung Disease;Chronic Obstructive Pulmonary Disease;Clinical;Clinical Trials;Common Rat Strains;Coughing;Cystic Fibrosis;Development;Diffuse;Diffusion;Dogs;Dogs Mammals;Dosage Forms;Dose;Drug Carriers;Drug Delivery;Drug Delivery Systems;Drug Formulations;Drug Kinetics;Drug Targeting;Drugs;Effectiveness;Engineering;Ensure;Excipients;Fiber;Formulation;Frequencies (Time Pattern);Frequency;Glycolates;Goals;Hplc;Head;High Performance Liquid Chromatography;High Pressure Liquid Chromatography;High Speed Liquid Chromatography;Hour;Human;Infection;Inhalation;Inhaling;Intercellular Fluid;Interstitial Fluids;Investigational New Drug Application;Kinetics;Loinc Axis 4 System;Lactam Antibiotics;Lactams;Lead;Legal Patent;Licensing;Liposomal;Liposomes;Lung;Lung Lavage;Lung Parenchyma;Lung Respiratory System;Lung Tissue;Lung Diseases;Macrogols;Man (Taxonomy);Marketing;Measures;Medication;Methods;Minimum Inhibitory Concentration Measurement;Minimum Inhibitory Concentrations;Miscellaneous Antibiotic;Modality;Modern Man;Monitor;Monobactam Antibiotics;Monobactams;Monocyclic Beta-Lactams;Morbidity;Morbidity - Disease Rate;Mortality;Mortality Vital Statistics;Mucociliary Clearance;Mucociliary Transport;Mucous Body Substance;Mucoviscidosis;Mucus;Particle Size;Patents;Pb Element;Pharmaceutic Preparations;Pharmaceutical Agent;Pharmaceutical Preparations;Pharmaceuticals;Pharmacokinetics;Pharmacologic Substance;Pharmacological Substance;Phase;Piperacillin;Pipercillin;Pipracil;Plasma;Plasma Serum;Polyethylene Glycols;Polyethylene Oxide;Polyethyleneoxide;Polymers;Polyoxyethylenes;Powder Dose Form;Powders;Preparation;Process;Production;Pulmonary Diseases;Pulmonary Disorder;Pyridinium, 1-((7-(((2-Amino-4-Thiazolyl)((1-Carboxy-1-Methylethoxy)Imino)Acetyl)Amino)-2-Carboxy-8-Oxo-5-Thia-1-Azabicyclo(4.2.0)Oct-2-En-3-Yl)Methyl)-, Inner Salt, Pentahydrate, (6r-(6alpha,7beta(Z)))-;Quality Control;Rat;Rats Mammals;Rattus;Research Institute;Resistance;Respiratory Aspiration;Respiratory Disease;Respiratory Infections;Respiratory Inspiration;Respiratory System Disease;Respiratory System Disorder;Respiratory Tract Infections;Respiratory Physiology;Reticuloendothelial System, Serum, Plasma;Sbir;Sbirs (R43/44);Saline;Saline Solution;Site;Small Business Innovation Research;Small Business Innovation Research Grant;Sprague-Dawley Rats;Sputum;Structure Of Parenchyma Of Lung;Surface;System;Technology;Testing;Therapeutic;Thick;Thickness;Time;Tissues;Toxic Effect;Toxicities;Treatment Side Effects;Work;Absorption;Anti-Bacterial;Antibacterial;Bacterial Disease;Bacterial Disease Treatment;Bacterial Infectious Disease Treatment;Bactericidal;Bactericide;Base;Beta Lactam Antibiotic;Bronchopulmonary Lavage Therapy;Canine;Clinical Efficacy;Clinical Investigation;Cystic Fibrosis Patients;Developmental;Domestic Dog;Drug/Agent;Glycolic Acid;Good Laboratory Practice;Heavy Metal Pb;Heavy Metal Lead;Improved;Inspiration;Lung Disorder;Lung Function;Male;Meetings;Mucous;Nano Particle;Nanoparticle;Particle;Patients With Cf;Patients With Cystic Fibrosis;Pre-Clinical;Preclinical;Preclinical Efficacy;Preclinical Safety;Pulmonary;Reconstitute;Reconstitution;Resistant;Respiratory;Respiratory Function;Safety Study;Safety Testing;Side Effect;Tandem Mass Spectrometry;Therapy Adverse Effect;Treatment Adverse Effect
