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Download An Overview of the Pharmaceutical Development Process
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Discovering New Medicinal Drugs Freddie Arocho-Perez, Ph.D. Senior Research Scientist Inhalation Products and Medical Devices Development Pharmaceutical Product Development, Inc. (PPDI) Terminology FDA – U.S. Food and Drug Administration API – Active Pharmaceutical Ingredient NCE – New Chemical Entity IND – Investigational New Drug IRB – Institutional Review Board NDA – New Drug Application GLP – Good Laboratory Practices GMP – Good Manufacturing Practices NCE/API Discovery Medicinal chemists develop compounds based on related substances. Aspirin developed as synthetic form of willow bark extract (Salicin). Willow bark is found primarily on moist soils in cold and temperate regions of the Northern Hemisphere. Ibuprofen: a based-off aspirin. Salicin Aspirin (Bayer) Ibuprofen (Advil, Motrin) NCE/API Discovery Ibuprofen: It is a non-steroidal anti-inflammatory drug (NSAID). It is used as an anti-inflammatory agent and as analgesic (painkiller). NCE/API Discovery Pharmacology Most drugs: Enter the body (by mouth, injection, etc.). Are distributed by the blood to the site of action; distribution affects concentration at site of action, sites of excretion, and bio-transformation. Are bio-transformed to several different compounds by enzymes; this event may change drug actions. Are excreted (by kidney or …???) which removes them and/or their metabolites from the body. Pharmacokinetics is the quantification of these processes. Product Development Cycle Pre Clinical Phase I Phase II Phase III NDA Review Years 2-6 0.5-1 1-2 1.5-3 1-3 Test Subjects Animal 20 100 100 1000 1000 10,000 Purpose Safety/ Efficacy Safety/ Dose in Healthy Safety/ Effect on Disease Safety/ Effect/ Side Effects Review Process and Approval Success Rate 5,000 5 into Human trials Overall process takes 6-15+ years 1 Phase I Studies Determine tolerable dose. Determine potential side effects profile. Dose ranging on healthy individuals. Side effects on healthy individuals help determine impact on patients with disease. Discover human pharmacology and drug distribution. Analysis of patient’s blood, urine and feces to determine metabolites, API half-life, and route of elimination. Phase I Studies Limited number of test subjects used (20-100). These studies use healthy, male volunteers to determine the safety of the product through dose-ranging studies. Phase I Studies: Side Effects Before After Phase II Studies Actual product development for commercial style product. Tablets, creams, liquids, injectables. These studies use test subjects with the target disease to confirm the safety, dose, and efficacy of the drug product. Number of test subjects (both sexes) increases for determination of efficacy (100-1000). These studies will determine whether the selected drug product actually works on the target disease. Phase III Studies Final product developed for commercial sale. Assessment of API on disease state. Final components, excipients, formulation. Main focus is to confirm efficacy and provide chronic use side effects profile. These studies use test subjects with the target disease to further confirm the safety, efficacy, and comparability of the drug product. Phase III Studies Number of test subjects (both sexes) increases for further determination of safety, efficacy, and comparator studies (1000-10,000). Also will track chronic, long-term use side-effects. NDA Submission NDA has 2 major sections: Chemistry, Manufacturing and Controls Discusses means of manufacturing and testing of API and drug product. Outlines performance and stability of drug product. Clinical Studies Discusses studies performed, outcomes, and statistical analysis. Outlines safety and effectiveness of product. Overall Development Process The pharmaceutical development process is a long (6-15+ years) and complicated procedure. Research and Development has 4 basic parts: API development Product development Product performance and stability Clinical studies results Introduction to Inhalation Technology Inhalation Therapy Inhaled drug products are products used for therapeutic treatment via the lungs or nasal mucosa. Inhalation therapy has been in use for a number of years to treat asthma and chronic obstructive pulmonary disease (COPD). Advantages compared to the traditional drug products: Rapid action Self-administration Directly targets the lung Minimizes dose required Avoids hepatic metabolism (drug metabolism in liver) Reduces side effects Inhalation Therapy Research has been devoted to deliver new drugs due to the large surface area and easy air-blood interface provided by the respiratory system. The lung is a very attractive target for drug delivery as it provides direct access to disease in the treatment of respiratory diseases, while providing an enormous surface area for the absorption of medications. Inhalation Therapy There are some 300 million alveoli in 2 adult lungs. These provide a surface area of approximately 160 square meters (70 square meters is the size of a tennis court). Types of Diseases Treated Asthma Chronic Obstruction Pulmonary Disease (COPD) Migraine Diabetes Cystic Fibrosis New Research: Erectile Dysfunction Osteoporosis Asthma Asthma is a chronic disease that affects your breathing. The airways become inflamed and irritated in reaction to some kind of substance, which is called a “trigger”. The airways are the tubes that carry air and oxygen into and out of the body. Airways tend to be red and swollen and are easily irritated in response to “triggers”, such as pollen and cigarette smoke. Airways’ inside walls become even more swollen and the muscles tight; the passages get narrower and less air flows to the lung tissue. Asthma Asthma in the U.S.A. In the United States alone, about 20 million citizens (9 million of them are children) have asthma. Asthma is found in 3% to 5% of adults and 7% to 10% of children. Asthma is the most prevalent chronic condition in children. Asthma can affect citizens at any age, but half of the people with asthma develop it during childhood, usually before age 10. However, you can develop asthma even as a senior citizen. Asthma in the U.S.A. Asthma also affects people of all races and ethnic backgrounds. The top 6 asthma risk factors include: Family history of asthma and/or allergies. Living in urban areas. Exposure to second-hand smoke. Low birth weight in infants. Health problems such as obesity and chronic sinusitis. Exposure to job-related irritants. Asthma in the U.S.A. According to the Asthma and Allergy Foundation of America (AAFA) on Jan. 2010, the 10 worst asthma cities are: Richmond, VA St. Louis, MO Chattanooga, TN Knoxville, TN Milwaukee, WI Memphis, TN Tulsa, OK Philadelphia, PA Augusta, GA Atlanta, GA Asthma in the U.S.A. According to the Asthma and Allergy Foundation of America (AAFA) on Jan. 2009, the 10 worst asthma cities are: St. Louis, MO Milwaukee, WI Birmingham, AL Chattanooga, TN Charlotte, NC Memphis, TN Knoxville, TN McAllen, TX Atlanta, GA Little Rock, AR Asthma in the U.S.A. Least 10 Challenging Asthma Capitals The following cities are among the 100 cities in the U.S. with the highest population. However, among those 100 cities, these are the 10 that ranked the lowest overall in the prevalence, risk, and medical factors: Cape Coral, Florida Seattle, Washington Minneapolis, Minnesota Colorado Springs, Colorado Portland, Oregon Palm Bay, Florida Daytona Beach, Florida San Francisco, California Portland, Maine Boise, Idaho Inhalation Delivery Systems Nebulizers Nasal Sprays Metered-Dose Inhalers Dry-Powder Inhalers Nebulizers Nebulizers use a powered source to create a fine mist from a solution. Dosage occurs over minutes as the patient repeatedly breathes in the mist. Drug is dissolved in purified water and inhaled over 10-30 minutes. Drug must be water soluble. Not appropriate for use as portable treatment for acute asthma attacks. Equipment is normally bulky and needs a power source. Inconvenient due to time of dosage. Nasal Sprays Nasal inhalers are designed to deposit drugs in the nasal cavities. Nasal sprays can use either a pump or propellant to power the spray. Metered-Dose Inhalers Metered-dose inhalers utilize a pressurized liquid (propellant) as the power to disperse the drug particles. Metered-Dose Inhalers The system consists of a formulation containing: API Propellant Excipients Device that uses a container, metering valve, and spray generating actuator Containers can be metal or glass. Dry-Powder Inhalers The formulation comes in the form of a dry powder. Generally, the formulation for these products consists of the drug substance and a carrier (lactose and/or glucose). The carrier prevents aggregation and helps with the flow of the drug substance. Analytical Test Methods Appearance Identification Microbial Assay Purity Water Content Dose Content Uniformity Fill Weight ACI Ethanol Content Particle Size Microscopy Spray Pattern Leak Rate Shot Weight Temperature Cycling Particle Size Distribution ACI: Andersen Cascade Impactor Apparatus with multiple levels. Each level contains different cut-off diameter ranges. The drug collected is distributed within the impactor based on the drug’s aerodynamic diameter. Impactors simulate the lung to determine particle distribution within the lung. Particle Size Distribution Next Generation Impactor (NGI) Preseparator Lid Induction Port Handle Bottom Frame Next Generation Impactor (NGI) Next Generation Impactor (NGI) Nozzle Assemblies Seal Body Cup Tray Collection Cups Next Generation Impactor (NGI) NGI Collection Cups with Typical Deposition Pattern Inhalation Therapy: General Considerations All Inhalation drug products are complex combinations of drugs and devices. Performance of the drug products vary by design. Patient use and compliance can be affected by the product design. New areas of inhalation therapy are being investigated all the time and new products will evolve from these developments.