1. ERT 420 BIOPHARMACEUTICAL ENGINEERING Semester 1 Academic Session 2012/2013 HUZAIRY HASSAN School Of Bioprocess Engineering Universiti Malaysia Perlis

2. Introduction to Biopharmaceutics Pharmaceutics : is a field of science that involves the preparation, use, or dispensing of medicines (Woolf, 1981).  Biopharmaceutics : expands this field into the science of preparing, using, and administrating drugs to living organisms or tissues. Interdependence of biological aspects of the living organism (the patient) and the physical-chemical principles that govern the preparation and behavior of the medicinal agent or drug product.

3. And, Biopharmaceutics: - is also a science that examines the interrelationship of the physicochemical properties of the drug, the dosage form, and the route of administration on the rate and extent of systemic drug absorption.

4. Pioneered in the mid-twentieth century by biopharmaceutical scientists who recognized the importance of absorption, distribution, metabolism, and elimination (ADME) on the clinical performance of medicinal agents / in vivo performance.  Biopharmaceutics has evolved into broad-based discipline including chemistry, physiology,… enzymology, and etc.  Should expert in formulation, pharmacokinetics (PK), cell-based transport, drug delivery or physical pharmacy.

5. - is a branch of biopharmaceutical science and technology that involves development and manufacturing of products, processes, and components in the pharmaceuticals industry (i.e. drugs & biologics). - brings the problem-solving principles and quantitative training of engineering to complement the other scientific fields already involved in drug development. BIOPHARMACEUTICAL ENGINEERING

6. Biopharmaceutics involves factors that influence: 1)The stability of drug within the drug product 2)The release of the drug from the drug product 3)The rate of dissolution/release of the drug at the absorption site 4)The systemic absorption of the drug

7. Physical-Chemical Properties / Principles 1)Solubility – the amount of material (a drug) that can dissolve in a given solvent at equilibrium. 2)Hydrophilicity / Lipophilicity – The partition or distribution coefficient of a drug candidate (log P or log D) is a relative measure of a compound’s tendency to partition between hydrophilic and lipophilic solvents and indicates the Hydrophilicity / Lipophilicity nature of the material. -  Lipophilicity is important since it affects partitioning into biological membranes, thus influences permeability through membranes, binding and distribution into tissues in vivo.

8. 3) Salts forms and Polymorphs - drug substances exist in multiple solid-state forms, ex: salts, solvates, hydrates, polymorphs, co-crystals or amorphous materials. - solid form can affect- solubility, dissolution rate, stability, hygroscopicity, drug product manufacturability and clinical performance. 4) Stability – is important to avoid generation of undesirable impurities, which could have pharmacologic activity and/or toxicologic implications in the drug substance. 5) Particle and powder properties

9. 6) Ionization and pKa – the presence of an ionizable group leads to pH solubility effects – that can be used to manipulate the physical properties and biological behavior of a drug. - for an ionizable compound, the aqueous solubility of ionized species is higher than unionized due to greater polarity afforded by the presence of ionized functional group.

10. Formulation Principles Goal- to manipulate the properties and environment of the Active Pharmaceutical Ingredient (API) to optimize its delivery to the target tissue by a specific route of administration and to do so in a manner compatible with large-scale product manufacture. Excipients are added to solubilize, stabilize, modify dissolution rate, improve ease of administration (e.g. swallowing or taste-masking), enable manufacturing, control release rate, or inhibit precipitation.  Intimately linked to pharmacokinetic results.

11. Physiological / Biological Principles Pharmacokinetics (PK) -Is the study of time course of ADME. -PK profile is directly related to the pharmacologic activity of a drug. 1) Absorption: - a drug must be absorbed across a biological membrane in order to reach the general circulation and/or elicit a pharmacologic response. - drug dosed intravenously may need to cross vascular endothelium to reach the target tissue or distribute into blood cells.

12. 2) Distribution: - is a measure of the relative concentrations of a drug in different body tissues as a function of time and is related to its ability to diffuse from the blood stream, tissue perfusion, relative lipophilicity, and tissue/plasma protein binding. 3) Metabolism and Elimination: - Metabolism is one of the most important mechanisms that the body has for detoxifying and eliminating drugs and other foreign substances. - Drugs delivered by the oral route must pass through the liver before reaching the general circulation. - Metabolism at this point is called “first-pass metabolism,” which can limit systemic exposure for drugs despite good absorption.

13. Continue… - Elimination of drugs from the body can occur via metabolism, excretion (renal, biliary, respiratory), or combination of both.

14. Local vs. Systemic systems Figure 13-8 Gastrointestinal (GI) tract or Digestive tract

15. Importance of drug substance and formulation to ADME… Consider the sequence of events that precede elicitation of drug’s therapeutic effect: Dosage form drug (oral, intravenous, subcutaneous, etc) taken by patient. Drug is released from the dosage form in a predictable and characterizable manner. Some fraction of drug is absorbed from site of administration into either surrounding tissue, body, or both. Drug reaches site of action. If the drug conc. Exceeds min. effective concentration (MEC), a pharmacologic response results

17. Role of Biopharmaceutics in Drug Development Discovery & Preclinical Development - Identify a potential drug candidate Preclinical Development: Preparation for Phase I Clinical studies -The selected drug candidate is tested on animal for multiple species - to establish a safety profile and guide for clinical doses. Early Clinical Development -To establish safety, PK, and pharmacodynamics, and provide guidance on a efficacious dose range (single / multiple) - BA studies: comparison of 2 or more formulations with respect to PK properties (AUC, C max, t max and half-life. - Bioequivalence study: assessing statistical equivalence among different treatment groups. - PK studies, drug-drug interaction studies, etc.

18. Advanced Clinical Development -E arlier studies data are used to define potentially efficacious clinical dose range and dosing regimen, identify patient population, and guide selection of a drug product to be used in pivotal registrational clinical studies, i.e., whose objective is to establish consistency, robustness, and predictability of the formulations. -Any changes to products must be qualified to establish its acceptability for use in clinic. Post-approval Considerations -Based on the evidence that a drug is safe and effective when administered according to the labeling. - Once product is approved by regulatory agency, any changes to formulations, manufacturing process or sites, or dosing regimen must be assessed for impact on biopharmaceutical behavious. Regulatory Considerations - ICH: International Council of Harmonization - US FDA - CMC Regulatory

19. MEDICINE OR PHARMACEUTICS OR REMEDIES ???

20. Tablet / Pill

21. Some tablet shape possibilities

22. Capsules

23. Pellets and other extrudates

24. THANK YOU