PULMONARY TUBERCULOSIS: MODERN PREVENTION AND TREATMENT
DOSING GROUPS OF GUINEA PIGS WITH TB DRUGS 6 10 COLLECTING DATA 6 11 AEROSOL DOSING CHAMBERS AND PRACTICE 6 11 1 STUDY TIMING WITH REGARD TO SCALE OF MANUFACTURING 6 11 2 ANIMAL MODEL SELECTION 6 11 3 DOSE AND DOSING REGIMEN 6 12 NEBULIZER AEROSOL DELIVERY SYSTEMS FOR LIQUIDS 6 13 DRY?POWDER AEROSOL DELIVERY SYSTEMS FOR SOLIDS 6 14 SUMMARY ACKNOWLEDGEMENTS REFERENCES 7 PRECLINICAL PHARMACOKINETICS OF ANTITUBERCULAR DRUGS INTRODUCTION FACTORS INFLUENCING THE PHARMACOKINETIC BEHAVIOR OF DRUGS 7 2 1 PHYSICOCHEMICAL PROPERTIES OF THE DRUG 7 2 2 FORMULATION AND ROUTES OF ADMINISTRATION 7 2 3 DISEASE STATE PULMONARY DELIVERY OF ANTI?TB DRUGS PHARMACOKINETIC STUDY DESIGN 7 4 1 ANIMAL MODELS 7 4 2 BIOLOGICAL SAMPLES 7 4 3 ANALYTICAL METHOD 7 4 4 CALCULATION OF PK PARAMETERS IMPLICATIONS OF PK PARAMETERS ON EFFICACY 7 5 1 TISSUE SAMPLES 7 5 2 PHARMACOKINETICS OF ANTI?TB DRUG IN GRANULOMAS 7 5 3 PK/PD CORRELATIONS CASE STUDIES (DRUGS ADMINISTERED BY CONVENTIONAL AND PULMONARY ROUTES) 7 6 1 RIFAMPICIN 7 6 2 CAPREOMYCIN 8 DRUG PARTICLE MANUFACTURE – SUPERCRITICAL FLUID, HIGH?PRESSURE HOMOGENIZATION PREPARATION OF NANO? AND MICRO?PARTICLES 8 2 1 MICROPARTICLES PREPARED BY A SUPERCRITICAL ANTISOLVENT–DRUG EXCIPIENT MIXING (SAS–DEM) TECHNIQUE 8 2 2 NANOPARTICLES PREPARED BY A SUPERCRITICAL FLUID (SCF) TECHNIQUE 8 2 3 NANOSUSPENSION 8 2 4 LIPOSOMES SPRAY DRYING STRATEGIES TO STOP TUBERCULOSIS OVERVIEW OF SPRAY DRYING 9 2 1 ADVANTAGES OF SPRAY DRYING 9 2 2 HARDWARE 9 2 3 SPRAY DRYER CLASSIFICATIONS 9 2 4 PROCESS PARAMETERS 9 2 5 PARTICLE FORMATION MECHANISM ADVANCES IN SPRAY DRYING TECHNOLOGY 9 3 1 THE ‘QUALITY BY DESIGN’ APPROACH 9 3 3 NOVEL MULTI?CHANNEL NOZZLES ANTI?TUBERCULOSIS THERAPEUTICS PRODUCED BY SPRAY DRYING 9 4 1 CONTROLLED?RELEASE MICROPARTICLES 9 4 2 MAXIMAL DRUG?LOADED MICROPARTICLES 9 4 3 VACCINES CONCLUSION FORMULATION STRATEGIES FOR ANTITUBERCULAR DRUGS BY INHALATION 10 1 INTRODUCTION 10 2 LUNG DELIVERY OF TB DRUGS 10 3 POWDERS FOR INHALATION AND LIQUIDS FOR NEBULIZATION 10 4 ANTIBACTERIAL POWDERS FOR INHALATION: MANUFACTURING OF RESPIRABLE MICROPARTICLES 10 5 ANTIBACTERIAL POWDERS FOR INHALATION: DEVICES AND DELIVERY STRATEGIES 10 6 CONCLUSIONS AND PERSPECTIVES INHALED DRUG COMBINATIONS 11 1 INTRODUCTION 11 2 STANDARD COMBINATIONS IN ORAL AND PARENTERAL REGIMENS 11 2 1 COMBINATIONS FOR THE DIRECTLY OBSERVED TREATMENT SHORT?COURSE (DOTS) REGIMEN 11 3 THE RATIONALE FOR INHALED THERAPIES OF TB 11 3 1 SINGLE DRUG, SUPPLEMENTING OTHER ORALLY ADMINISTERED DRUGS 11 3 2 SINGLE DRUG REPLACING INJECTABLE FIRST? OR SECOND?LINE AGENTS 11 3 3 MULTIPLE INHALED DRUGS, ADJUNCT OR STAND?ALONE THERAPY 11 3 4 “STIMULATE THE PHAGOCYTE” 11 4 COMBINATIONS OF ANTI?TB DRUGS WITH OTHER AGENTS 11 4 1 DRUGS THAT PRIMARILY AFFECT THE PATHOGEN 11 4 2 DRUGS THAT AFFECT HOST RESPONSES 11 4 3 DRUGS THAT AFFECT BOTH HOST AND PATHOGEN 11 5 FORMULATION OF INHALED DRUG COMBINATIONS 11 5 1 EXCIPIENT?FREE FORMULATIONS 11 5 2 APPLICATIONS OF EXCIPIENTS 11 5 3 PREPARING MULTI?COMPONENT PARTICLES AND VESICLES 11 5 4 SHELF STABILITY 11 5 5 DRUG RELEASE AND PHARMACOKINETICS 11 5 6 INHALATION DOSIMETRY 11 6 CONCLUSIONS ION PAIRING FOR CONTROLLING DRUG DELIVERY 12 1 INTRODUCTION 12 2 ION PAIRING DEFINITIONS AND CONCEPTS 12 2 1 ION PAIRING AS PHYSICOCHEMICAL TUNING TOOL 12 2 2 METAL ION COMPLEXATION 12 2 3 SOME CONSIDERATIONS ON ION PAIR AND METAL COMPLEX STABILITY 12 3 ION PAIRS, COMPLEXES AND DRUG DELIVERY 12 3 1 ORAL ROUTE 12 3 2 TRANSDERMAL/DERMAL AND MUCOSAL ROUTE 12 3 3 PARENTERAL ROUTE 12 3 4 THE PULMONARY ROUTE AND INFECTIOUS DISEASES 12 3 5 TOXICITY CONSIDERATIONS 12 4 REMARKS UNDERSTANDING THE RESPIRATORY DELIVERY OF HIGH DOSE ANTI?TUBERCULAR DRUGS 13 1 INTRODUCTION 13 2 TUBERCULOSIS 13 3 DRUGS USED TO TREAT TUBERCULOSIS, DOSES, CHALLENGES AND REQUIREMENTS FOR THERAPY IN LUNGS 13 3 1 CURRENT TB TREATMENT REGIMEN 13 3 2 CHALLENGES OF CONVENTIONAL ORAL AND PARENTERAL THERAPY 13 3 3 RATIONALE FOR RESPIRATORY DELIVERY 13 4 APPROACHES FOR RESPIRATORY DELIVERY OF DRUGS 13 5 CURRENT DPI FORMULATIONS AND THEIR MECHANISMS OF AEROSOLIZATION 13 6 DPI FORMULATIONS FOR TUBERCULOSIS AND REQUIREMENTS 13 7 ISSUES TO CONSIDER IN RESPIRATORY DELIVERY OF POWDERS FOR TUBERCULOSIS 13 8 RELATIONSHIP BETWEEN DE?AGGLOMERATION AND TENSILE STRENGTH 13 9 STRATEGIES TO IMPROVE DE?AGGLOMERATION 13 10 DPI FORMULATIONS HAVING HIGH AEROSOLIZATION 13 11 DEVICES FOR HIGH DOSE DELIVERY 13 12 FUTURE CONSIDERATIONS SECTION 4 ALTERNATIVE APPROACHES RESPIRABLE BACTERIOPHAGE AEROSOLS FOR THE PREVENTION AND TREATMENT OF TUBERCULOSIS 14 1 1 BACTERIOPHAGES 14 1 2 MYCOBACTERIOPHAGES 14 1 3 MYCOBACTERIUM TUBERCULOSIS AS A HOST FOR PHAGE INFECTION IN VIVO 14 1 4 MYCOBACTERIOPHAGES AND TB DIAGNOSIS TREATMENT OR PREVENTION OF TUBERCULOSIS USING PHAGE?BASED AGENTS 14 2 1 BACTERIOPHAGES AS THERAPEUTIC AGENTS 14 2 2 PROSPECTS FOR USING MYCOBACTERIOPHAGES FOR THERAPY OR TB PREVENTION SELECTION OF MYCOBACTERIOPHAGES RESPIRATORY DRUG DELIVERY OF PHAGES SUMMARY AND OUTLOOK RNA NANOPARTICLES AS POTENTIAL VACCINES NANOPARTICLES RNA NANOPARTICLE VACCINES PROGRESSION OF NANOMEDICINES INTO THE CLINIC THE STABILITY PROBLEM THE DELIVERY PROBLEM RNA AS TARGETING AGENT OR ADJUVANT? CHALLENGES FOR RNA NANOPARTICLE VACCINE CHARACTERIZATION ON THE HORIZON LOCAL PULMONARY HOST?DIRECTED THERAPIES FOR TUBERCULOSIS VIA AEROSOL DELIVERY 16 1 1 TUBERCULOSIS DISEASE AND CONTROL 16 1 2 CHEMOTHERAPY AND HOST IMMUNITY TO TUBERCULOSIS 16 1 3 AEROSOL DELIVERY OF HOST?DIRECTED THERAPIES FOR TUBERCULOSIS TREATMENT 16 2 LUNG IMMUNITY TO PULMONARY M TUBERCULOSIS INFECTION 16 2 1 OVERVIEW 16 2 2 INFLUENCE OF LUNG ALVEOLI ENVIRONMENT ON BACILLI SURVIVAL AND ITS IMPACT ON TUBERCULOSIS CHEMOTHERAPY 16 2 3 POTENTIAL TARGETS FOR HOST?DIRECTED THERAPY 16 3 HOST?DIRECTED THERAPIES 16 3 1 PREVIOUS STUDIES VIA SYSTEMIC ADMINISTRATION OF HOST?DIRECTED THERAPIES 16 3 2 PREVIOUS STUDIES VIA AEROSOL DELIVERY OF HOST?DIRECTED THERAPIES 16 4 LIMITATIONS OF PRECLINICAL STUDIES TO DEVELOP INHALATIONAL HOST?DIRECTED THERAPIES FOR TUBERCULOSIS 16 5 PRECLINICAL TESTING OF INHALED SMALL INTERFERENCE RNA AS HOST?DIRECTED THERAPIES FOR TUBERCULOSIS SECTION 5 FUTURE OPPORTUNITIES TREATMENTS FOR MYCOBACTERIAL PERSISTENCE AND BIOFILM GROWTH 17 1 INTRODUCTION 17 2 MYCOBACTERIAL PERSISTENCE AND DRUG TOLERANCE 17 3 MYCOBACTERIAL MULTICELLULAR GROWTH 17 4 MYCOBACTERIAL LIPIDS INVOLVED IN BIOFILM FORMATION 17 5 THERAPIES TO TREAT MYCOBACTERIAL BIOFILMS AND PERSISTENCE 17 5 1 THERAPIES TO TREAT MYCOBACTERIAL BIOFILMS 17 5 2 THERAPIES TO DISRUPT NUTRIENT ACQUISITION AND PERSISTENCE 17 5 3 TREATMENTS FOR BIOFILM DISPERSION 17 5 4 TREATMENTS DERIVED FROM HOST INNATE DEFENSES 17 5 5 TREATMENTS WITH INHALED ANTIBIOTICS 17 6 CONCLUSION DIRECTED INTERVENTION AND IMMUNOMODULATION AGAINST PULMONARY TUBERCULOSIS 18 1 INTRODUCTION 18 2 TB IMMUNOLOGY 18 2 1 EARLY EVENTS OF INFECTION 18 2 2 DELAYED ADAPTIVE IMMUNITY 18 2 3 HUMORAL IMMUNITY AND INNATE LYMPHOCYTES 18 2 4 LATENT INFECTION 18 2 5 CORRELATES OF PROTECTION AND TOLERANCE 18 2 6 NATURAL IMMUNITY AGAINST TB INFECTION 18 3 ANIMAL MODELS OF IMMUNOTHERAPIES AND VACCINES FOR TB 18 3 1 MOUSE MODEL 18 3 2 GUINEA PIG MODEL 18 3 3 NON?HUMAN PRIMATES MODEL 18 4 THE CURRENT TB VACCINE – BACILLE CALMETTE GUÉRIN 18 4 1 BCG VACCINE HISTORY 18 4 2 ALTERNATIVE ROUTES OF BCG DELIVERY 18 4 3 FAILURES OF BCG 18 5 OTHER VACCINES PLATFORMS 18 5 1 LIVE BACTERIAL VACCINES 18 5 2 INACTIVATED WHOLE?CELL VACCINES 18 5 3 VIRAL VECTOR?BASED TB VACCINES 18 5 4 HETEROLOGOUS PRIME?BOOST VACCINATION STRATEGY IN TB 18 6 PULMONARY IMMUNIZATION 18 6 1 BIOMIMICRY: HARNESSING NATURAL IMMUNITY FOR PROTECTION AGAINST TB 18 6 2 PULMONARY IMMUNIZATION FOR GLOBAL PROTECTION 18 6 3 SAFETY CONCERNS FOR PULMONARY IMMUNIZATION 18 6 4 ROLE OF ADJUVANTS 18 6 5 LIVE VS DEAD VACCINES 18 7 IMMUNOTHERAPEUTIC AGENTS AGAINST TB 18 7 1 CYTOKINES 18 7 2 VITAMIN D THERAPY 18 7 3 RE?PURPOSED DRUGS 18 7 4 STEM CELL THERAPY 18 8 CONCLUSION SECTION 6 CLINICAL PERSPECTIVE CLINICAL AND PUBLIC HEALTH PERSPECTIVES 19 1 INTRODUCTION 19 2 BACKGROUND 19 3 CLINICAL CONSIDERATIONS 19 3 1 PILL BURDEN AND FIXED?DOSE COMBINATIONS 19 3 2 NON?ADHERENCE AND MEDICATION MONITORING 19 3 3 INTERMITTENT THERAPY 19 3 4 DRUG TOXICITY 19 3 5 DRUG ABSORPTION AND THERAPEUTIC DRUG MONITORING 19 4 PUBLIC HEALTH CONSIDERATIONS 19 4 1 DOTS 19 4 2 COMMUNITY?BASED THERAPY 19 4 3 INCENTIVES AND ENABLERS TO PROMOTE ADHERENCE 19 5 INHALED DRUGS AND OTHER ALTERNATIVE DELIVERY SYSTEMS 19 5 1 POSSIBLE ADVANTAGES 19 5 2 CONCERNS AND LIMITATIONS 19 5 3 ACCEPTANCE OF NOVEL THERAPIES 19 6 CLINICAL TRIALS OF INHALED INJECTABLE DRUGS 19 6 1 CAPREOMYCIN PHASE 1 CLINICAL STUDY 19 6 2 INHALED THERAPY TO REDUCE TRANSMISSION, ESPECIALLY OF HIGHLY DRUG?RESISTANT STRAINS – A TRIAL OF INHALED COLISTIN (OR POLYMXYIN E) 19 7 OTHER NOVEL DELIVERY STRATEGIES 19 8 PEDIATRIC DELIVERY SYSTEMS 19 9 CONCLUSION CONCLUDING REMARKS: PROSPECTS AND CHALLENGES FOR ADVANCING NEW DRUG AND VACCINE DELIVERY SYSTEMS INTO CLINICAL APPLICATION 20 1 INTRODUCTION 20 2 PROGRESS IN THE FORMULATION AND MANUFACTURING OF DRUGS AND VACCINES FOR TUBERCULOSIS 20 2 1 INHALED DRUGS AND DRUG COMBINATIONS 20 3 CONSIDERATIONS IN THE DEVELOPMENT OF TB DRUG AND VACCINE DELIVERY OPTIONS 20 3 1 LUNG BIOLOGY AND PULMONARY ADMINISTRATION OF DRUGS AND VACCINES 20 3 2 CHOICE OF ANIMAL MODEL IN THE EVALUATION OF DRUG AND VACCINE DELIVERY SYSTEMS 20 3 3 DEMONSTRATING BIOEQUIVALENCE AND CLINICAL EFFICACY OF INHALED DRUGS TO ORAL/PARENTERAL DOSAGE FORMS 20 3 4 INHALED VACCINES FOR TB – ARE THERE POTENTIAL ADVANTAGES? 20 3 5 SAFETY OF PULMONARY VACCINATION 20 4 CONCLUDING REMARKS