Biomaterials Review Slides PDF

Topic 1 review Important topics Types of biomaterials Advantages of polymer Natural polymer Extracellular matrix 1 Biomaterials What can be considered as a biomaterial A material intended to interface with biological systems to evaluate, treat, augment, or replace any tissue, organ or function of the body. - The Williams Dictionary of Biomaterials 2 Types of Biomaterials Metals Strong Adaptable to form different shapes Conduct electricity Ceramics Provide strong resistance against degradation in many biological environments Polymers Versatile with a wide range of physical and chemical properties, eg elastic properties, water holding capacity Hybrid materials 3 Advantages of using polymers for biomedical applications Large number of polymers available Ease of fabrication into many different forms – Films, tubes, fibers, solids, gels, solutions, textiles, particles Flexibility for soft tissues Very low or non-toxicity Light weight / density Low cost 4 Polymer classification Thermoplastic polymer: "Plastic", softens (melts) upon heating without chemical degradation. Upper limit of extensibility of 20-100%. polyethylene (low and high density), polypropylene, polystyrene (styrofoam), polyvinylchloride (PVC), polytetrafluorethylene (Teflon) Thermoset polymer: Degrades or decomposes upon heating; (cross-linked), cannot be dissolved. epoxy (resin), polycyanoacrylates (super glue) Elastomer: Highly deformable: Upper limit of extensibility of 100-1000%. 5 Biodegradable polymers Biodegradable: Materials that can be broken down by the physiological environment. Biological Chemical Synthetic Polymers: polyesters polyanhydride polyurethanes Natural polymers: Proteins: collagen, serum albumin, elastin, silk Carbohydrates: cellulose, alginate, chitosan, dextran Nucleic acid: deoxyribose nucleic acid 6 Biodegradable polymer: hydrolysis Hydrolysis of biocompatible polymer Poly (lactic acid) Lactic acid PLA Oligmers 7 Natural-polymers Extracellular matrix (ECM) protein-based materials – Collagen – Fibronectin – Laminin Fibrin / Fibrinogen Polysaccharides Glycosaminoglycans Hyaluronic acid-based materials 8 What is Extracellular Matrix (ECM)? ECM is a collection of extracellular molecules secreted by cells that provides structural and biochemical support to the surrounding cells Mainly consists of: Cell Fibrous proteins collagen, elastin, fibronectin, laminin Glycoaminoglycans (GAGs) Heparan sulfate, chondroitin ECM sulfate 9 10 Hydrogel High water contents Hydrogels are polymeric structures held together as water-swollen gels 1. primary covalent cross-links 2. ionic forces 3. hydrogen bonds 4. affinity or “bio-recognition interactions 5. hydrophobic interactions 6. polymer crystallites 7. physical entanglements of individual polymer chains 8. a combination of two or more of the above interactions. 11 Biointerfaces Describe the importance of biointerfaces in the context of nanomedicine and nanobiotechnology Understand how cells react to materials Use the binding affinity model to analyze binding on surfaces Explain the theory behind low fouling surfaces 12 Biointerfaces Any time a material is in contact with a living system – Bandage: skin/wound – Dental fillings: tooth – Stent: blood, arteries – Contact lens: eye – Water filter: bacteria etc in water – Many more… How do cells adhere to biomaterials? Cell adhesion molecules (A) Initial contact between cell and (receptors) surface Proteins (ligands) on substrate surface (B) Formation of bonds between cell surface receptors and adhesion ligands (C) Cytoskeletal reorganisation with progressive spreading of the cell on the substrate for increased attachment strength https://www.youtube.com/watch?v=ErMAdQ5MZpQ https://www.youtube.com/watch?v=Mq26QPet0cs 14 Integrins Cell-cell and cell-ECM interactions Dimeric proteins Many subunits: Cell membrane – 17 α-units and 8 β-units 51 – > 22 heterodimers integrin Not catalytically active but trigger series of cellular Protein responses via their linkage structure of fibronectin to cytoskeleton and specific signal transduction cascades Cell-matrix adhesion is modulated in activity and number of integrins expressed. de-adhesion factors promote cell migration 15 Driving forces for protein adsorption Secondary bond formation  Electrostatic ionic bonds, H-bond Hydrophobic interactions 16 MIT OCW Adsorption onto biomaterials changes protein activity Increase local concentration Change in reactivity – Access to cell binding site is increased/decreased – Decrease binding to cell adhesion receptors Denaturation – Protein tertiary conformation may change – Decreases binding to cell adhesion receptors 17 MIT OCW Summary Introduction and overview of course Introduction and review of biomaterials Review of polymer Introduction to extracellular matrix Introduction to biointerface Protein adsorption / proteins presented on material surface facilitate cell-materials adhesion / interaction – Cell-material or cell-ECM binding via integrin Low fouling surfaces: binding affinity Self-assembled monolayers (SAMs) References Biomaterials Science: An Introduction to Materials in Medicine, 3rd edition. By Buddy D. Ratner, Allan S Hoffman, Frederick J Schoen and Jack E Lemons. Academic Press. 2012. 19 Topic 2 Part 1 review Key topics Introduction to micro- and nanoparticles Emulsion – Emulsifiers – HLB: determination of HLB. Suspension – Formulation criteria for making suspension products 2 Micro- and nanoparticles Wide-range of biomedical applications including drug delivery, imaging, and basic research: – micron (1–1000 μm), – sub-micron (100–1000 nm), and – nanometer (1–100 nm) Design of any miniaturized system is dependent on the endpoint application. 3 Materials used for microparticle synthesis Natural materials Synthetic polymers 6 Materials used for microparticle synthesis 7 Materials used for microparticle synthesis 8 Microparticle preparation (emulsion based) Single and double emulsion Precipitation and coacervation – Coacervation is a three-step process in which a W/O emulsion is formed with polymer dissolved in the organic phase and drug dispersed in the aqueous phase. 9 Submicron-sized particles: Liposomes and micelles Liposomes: submicron-sized spheres with an aqueous core and a bilayer membrane (e.g., lamella) Micelles: an aqueous core surrounded by a single layer of lipids. Encapsulate hydrophobic drug between the lipophilic bilayers and hydrophilic drug Liposomal delivery example: rifampicin, budesonide, diclofenac, methotrexate, vaccine antigens, nucleic acids, peptides, and immunomodulatory agents 12 (Brief) introduction to nanoparticles Materials – Noble metals (e.g. gold NPs) – Magnetic materials (e.g. superamagnetic iron oxide NPs) – Quantum dots Fluorescent nanocrystal from semiconductor materials – Polymer and lipids – Silica (e.g. mesoporous silica) 13 Disperse systems Dispersed systems consist of particulate matter known as dispersed phase, dispersed throughout a continuous or dispersion medium. Dispersed systems are classified according to particle size Molecular dispersion < 1 nm True solutions Colloidal dispersion 1 nm– 0.5 µm colloid Coarse dispersion > 0.5 µm Suspension & emulsion 17 Emulsions Heterogeneous systems consisting of at least one immiscible liquid phase intimately dispersed throughout a second phase in the form of droplets or globules. Types Water-in-oil (W/O) Water: disperse phase Dispersed phase Oil: continuous phase. Internal phase Oil-in-water (O/W) Dispersion medium Oil: dispersed phase External/continuous Water: continuous phase phase 18 Characteristics Thermodynamically unstable mixtures because of immiscible phases These system are stabilized by using emulsifying agents. Emulsifying agents reduce interfacial surface tension Disperse particles typically range in 100 nm to 100 µm Ranges from lotion with relatively low viscosity to semi-solid ointments and creams. 19 How do Emulsifying agents Work? Emulsifier – The Stabilizer Lipophilic Tail & Hydrophilic Head Lipophilic tails Hydrophilic heads align with oil align with water Emulsifying agents stabilize emulsions by 3 mechanisms: 1. Reduction of interfacial tension. 2. Formation of a rigid interfacial film- mechanical barrier to coalescence 3. Formation of an electric double layer-electric barrier to approach of particles. 22 How do Emulsifying agents Work? Reduction of interfacial tension. ∆E = SL * ∆ A Formation of a rigid interfacial film-mechanical barrier to coalescence. If the concentration of the emulsifier is high enough, it forms a rigid film between the immiscible phases, which hinders mechanically the coalescence of the emulsion droplets. Formation of an electric double layer- electric barrier to coalescence. In case of an ionic surfactant, the hydrocarbon tail is dissolved in the oil ++ + + droplet, while the ionic heads are facing + + the continuous aqueous phase. + + ++ + As a result, the surface of the droplet is + + charged. This creates a repulsive effect ++ between the oil droplets and thus hinders coalescence. 23 Theory of Emulsification: How Emulsions are Stabilized? Emulsifiers: mostly surfactants Hydration forces: O/W Steric forces: W/O Electrostatic forces: ionic surfactant Polymers: steric forces (entropy stabilization) Solid powders: hydrophobic forces (wetting) 24 Emulsifying agent's ideal properties Surface active Be absorbed quickly around the droplets Impart an adequate electrical charge to droplet Increase the viscosity of the emulsion Effective at low concentration Resistant to chemical degradation Compatible with other components Nontoxic and nonirritating Odorless, Colorless, and tasteless 25 Types of Emulsifying agents Anionic (phosphatee, sulfonates sulfates...) e.g. Sodium stearate; Sodium lauryl sulfate; Triethanolamine stearate Cationic (quatemary ammonium) E.g. Cetrimide, Cetylpyridinium chloride Benzalkonium chloride Amphoteric (betaines) E.g. Betains, Aminoacids, Lecithin Nonionic (Ethoxylates) Cetyl and stearyl alcohols; Glyceryl monostearate; Sorbitan esters of fatty acids (Spans) Polyethylene glycol derivatives of the 26 sorbitan esters (Tweens) Synthetic emulsifiers Nonionic neutral and stable over wide pH range Less sensitive to changes in electrolyte concentration heat stable greater degree of compatibility than anionic and cationic emulgents. low toxicity and irritancy for parenteral and oral administration can form O/W or W/O may require additional viscosity enhancing agent Commercially available surfactant: The hydrophilic group is usually an alcohol group or ethylene oxide. The lipophilic group is usually a fatty acid or a fatty alcohol. http://en.wikipedia.org/wiki/File:Surfactant.jpg&d ocid=iVEH7P0QXDQumM&w=604&h=345&ei=K8 B8TumsLIHz0 gHf8Lwf&zoom=1 30 Non-ionic surfactants Example Polysorbates (Tweens) Polyethylene glycol derivatives of the sorbitan esters (Polyoxtethylene sorbitan ester of fatty acids). Variations in the type of fatty acid produce different tweens chain with different oil and water solubility, (Tween 20, 40, 60 and 80). Advantages of tweens: Compatible with other types of surfactants. Stable to heat, pH change and electrolytes. Low toxicity, for oral and parenteral preparations. Disadvantages: Unpleasant taste. Inactivate some preservatives as parabenze by complexation 34 Hydrophile Lipophile Balance (HLB) Invented in 1940s by William C. Griffin from Atlas Powder Company. HLB describes the interaction between oil and surfactants. HLB was invented for use with nonionic surfactant. HLB can be used to predict how the surfactant behaves in the organic phase. A emulsion formulation can be stabilized by matching the HLB value of the surfactant with the required HLB (RHLB). 38 Matching HLB to application needed The HLB number increases with increasing hydrophilicity. According to the HLB number, surfactants may be utilized for different purposes: Function HLB Range Antifoaming agent (oil mix) 1-3 Emulsifier, (w/o emulsion) 3-6 Wetting agent (powder into oil) 7-9 Emulsifier, (o/w emulsion) 8-18 Detergent 13-15 Solubilizer 15-18 40 Choosing an emulsifying agent HLB HLB < 10: lipophilic HLB > 10: hydrophilic for O/W emulsion: HLB 8-18 is desirable for W/O emulsion: HLB 3-6 is desirable Choose an emulsifying agent which has an HLB of the same value as the oil phase. Can combine emulsifying agents to obtain desired HLB (HLB values are additive). Be careful on the polarity of material being emulsified. Choosing surfactant with a higher HLB gives more “hydrophilic” appearance. 41 Required HLB for O/W The required HLB gives the lowest interfacial tension between the oil phase and water phase. Required HLB can be used to determine the minimum amount of surfactant to achieve emulsification. Required emulsifying agent (or combination) with HLB the same value as the oil phase. Class Required HLB Vegetable oil 6 Silicone oils 8-12 Petroleum oils 10 Ester emollient 12 Fatty acid and alcohol 14-15 43 Steps to calculate HLB of oil phase Determine the weight composition of the formulation mixture. Determine which ingredients belong to the lipophilic phase. Determine the wt% of the lipophilic phase. Multiply the wt% by the required HLB of the individual oil. Add these numbers together to get the required HLB. 44 Example (required HLB) Composition of matter in an O/W formulation for a topical application. Heavy mineral oil. 8% Material Req. HLB Req. HLB Capric triglyceride. 2% W/O O/W isopropyl isostearate. 2% Stearic acid -- 17 cetyl alcohol. 4% Cetyl Alcohol -- 15.5 emulsifiers. 4% Lanolin 8 15 polyols. 5% Light mineral oil 4 11 water solute compound. 1% Heavy mineral oil 4 10.5 water. 74%. Capric triglyceride -- 5 fragrance 1000 nm Macroemulsions 10 – 200 nm Microemulsions Microemulsions thermodynamically stable, transparent droplet diameter 10 -100 nm dispersion of oil in water applications in rapid and efficient absorption of lipophilic drugs. (e.g. NEORAL® SANDIMMUNE®) 59 Stability of Emulsions What are the characteristics of a stable emulsion? A stable emulsion is one in which: dispersed globules retain their initial character and remain uniformly distributed throughout the continuous phase. Breaking emulsions 62 Chemical Instability of Emulsion Chemically incompatibility of the emulgent system with the active agent and with the other emulsion ingredients Ionic emulsifying agents are usually incompatible with materials of opposite charge. i.e. anionic and cationic emulgents. Addition of electrolyte may cause salting out of the emulsifying agent or phase inversion Emulgents may be precipitated by the addition of materials in which they are insoluble Changes in pH 63 Chemical Instability of Emulsion Oxidation Many of the oils and fats used in emulsion formulation are of animal or vegetable origin and can be susceptible to oxidation by: Atmospheric oxygen. The action of microorganisms. This can be controlled by the use of: Antioxidants. Antimicrobial preservatives. 64 Physical Instability of emulsions 67 Creaming and Sedimentation Creaming and Sedimentation: – This process results from external forces, usually gravitational or centrifugal. – When such forces exceed the thermal motion of the droplets (Brownian motion), a concentration gradient builds up in the system such that the larger droplets move more rapidly, either: to the top resulting in CREAMING (if their density is less than that of the medium) or to the bottom resulting in SEDIMENTATION (if their density is greater than that of the medium) of the container. results temporary changes of emulsion into two regions, one of which is richer in the disperse phase than the other 70 Flocculation & Ostwald ripening Flocculation: Aggregation of the droplets (without any change in primary droplet size) into larger units. Ostwald Ripening (Disproportionation) : Aggregation of the droplets with change in primary droplet size. In polydisperse emulsion, the smaller droplets will have a greater solubility when compared to larger droplets (due to curvature effects). With time, the smaller droplets disappear and their molecules diffuse to the bulk and become deposited on the larger droplets. 71 Coalescence (Breaking, Cracking) Process of thinning and disruption of the liquid film between the droplets, with the result that fusion of two or more droplets occurs to form larger droplets. Cracking or coalescence of an emulsion leads to the separation of dispersed phase as a layer. Cracking is an irreversible process (permanent loss) Weak interfaces between droplets break, allowing droplets to merge 73 Inversion of Emulsions (Phase inversion) O/W→ W/O Nature of emulsifier: Making the emulsifier more oil soluble tends to produce a W/O emulsion (and vice versa). [Bancroft's rule] Phase volume ratio Oil/Water ratio  →W/O emulsion (and vice versa). Temperature of the system:  Temperature of O/W makes the emulsifier more hydrophobic and the emulsion may invert to W/O. 74 Suspensions Coarse dispersion in which insoluble solid particles (10- 50 µm) are dispersed in a liquid medium Routes of administration : oral, topical (lotions), parenteral (intramuscular), some ophthalmics Used for drugs that are unstable in solution (ex. antibiotics). Allow for the development of a liquid dosage form containing sufficient drug in a reasonably small volume 76 Oral suspensions For elderly, children etc., liquid drug form is easier to swallow Liquid form gives flexibility in dose range Majority are aqueous with the vehicle flavored and sweetened. Supplies insoluble, distasteful substance in form that is pleasant to taste Examples Antacids, tetracycline HCl, indomethacin 77 Topical suspensions Most often are aqueous Intended to dry on skin after application (thin coat of medicinal component on skin surface) Label stating “to be shaken before use” and “for external use only” Examples : calamine lotion (8% ZnO, 8% ZnO Fe2O3) hydrocortisone 1 - 2.5 % betamethasone 0.1% 78 Ophthalmics Used to increase corneal contact time (provide a more sustained action) 79 Intramuscular Formation of drug depots (sustained action) Examples : Procaine penicillin G Insulin Zinc Suspension addition of ZnCl2 suspended particles consist of a mixture of crystalline and amorphous zinc insulin (intermediate action) Extended Insulin Zinc Suspension solely zinc insulin crystals - longer action Contraceptive steroids 80 Formulation criteria Slow settling and readily dispersed when shaken Constant particle size throughout long periods of standing Pours readily and easily OR flows easily through a needle Topical: spreads over surface but doesn’t run off dry quickly, remain on skin, provide an elastic protective film containing the drug acceptable odor and color Common : therapeutic efficacy, chemical stability, aesthetic appeal 81 Disadvantages of suspension Uniformity and accuracy of dose - not as good as tablet or capsule adequate particle dispersion Sedimentation, cake formation Product is liquid and bulky Formulation of an effective suspension is more difficult than for a tablet or capsule 82 Parameters affecting suspension stability Particle size Rate of sedimentation Zeta potential (electrical properties) Particle surface hydration Flocculation Structured vehicles 83 Preparation of suspensions Reduce drug powder to desired size Add drug and wetting agent to solution Prepare solution of suspending agent Add other ingredients: electrolytes, color, flavor Homogenize medium Package 91 References Biomaterials Science: An Introduction to Materials in Medicine, 3rd edition. By Buddy D. Ratner, Allan S Hoffman, Frederick J Schoen and Jack E Lemons. Academic Press. 2012. The HLB system, a time saving guide to surfactant selection. Presentation to the Midwest chapter of the Society of Cosmetic Chemists. March 9th 2004. 92 Topic 2 Part 2 review Key topics Typical composition of a tablet Tablet types Manufacturing of tablets Granulation Compression and Compaction (not the details on equipment) 2 Tablets background Definition: Tablets are solid preparations each containing a single dose of one or more active ingredients and obtained by compressing uniform volumes of particles. The most common way of administration. A century old technology Commonly made by powder compaction. “Pill” a dosage form for oral administration as spherical remained the most popular solid dosage form. 4 Tablets: advantages and limitations Advantages: A convenient and safe way of drug administration. Chemical and physical stability of the dosage form. Tamper resistant. Enables accurate dosing. Low cost on manufacturing, packing and shipping. Uniform dosage. 5 Tablets: advantages and limitations Limitations: Amorphous and low-density drugs are difficult to compress into tablet; Hygroscopic drugs are not suitable for compressed tablets. Difficult to formulate liquid in tablet and swallowing is difficult especially for children and ill patients. The manufacture of tablets requires a series of unit operations (weighing, milling, drying, mixing) with product loss at each stage in the formulation process Oxygen-sensitive drugs may require special coating. Additional coating and encapsulation increase cost. Absorption of medicament from tablets is dependent on physiological factors 6 Quality attributes of tablets Include the claimed dose of the drug. Able to withstand stresses of manufacture, transport and handling Can be released from the tablet in a controlled and reproducible way. Biocompatible, does not include excipients, contaminants and micro-organisms that could cause harm to patients. The tablet should be chemically, physically stable during the lifetime of the product. Patient compliance. 7 Tablet composition Total weight: approximately 250 mg Active ingredient drug (5-10%) Excipients: inactive substance used as a carrier of active ingredient to ensure tablet with consistent quality, quantity, Fillers (80%) Binders (2-10%) Disintegrates (1-5%) Antifriction agents glidants (1-2%), lubricants (1%) miscellaneous 9 Filler Provide bulk volume/size of the tablet Properties Chemically inert, non-hydroscopic Posses good water soluble or hydrophilic properties Has an acceptable taste Must be cheap Most common fillers: lactose, glucose, sugar alcohol, cellulose 10 Disintegrant Function is to break up the tablet into small fragments, leads to rapid drug dissolution Two steps: Liquid wets the solid and penetrate the pores of the tablet. Tablet disintegrates into aggregates and separate from the primary drug particles. Examples: starch, bicarbonate 11 Binder and glidant Binder Adhesives to ensure tablets can be formed with required mechanical strength Examples: starch, sucrose, hydroxypropyl methylcellulose. Glidant Improves the flowability of the powder Examples: silica, magnesium stearate. 12 Lubricants Ensure the tablet formation and ejection can occur with low friction between the solid and the die wall. Prevent fragmentation, capping, or scratches Exhibit low resistance toward shearing 13 Other components Flavor Improve patient compliance, with a more pleasant taste Colorant For product identification Improve quality control 14 Classification of tablets Immediate release Disintegrating Chewable Eﬀervescent Sublingual and buccal tablets Extended release Delayed release 15 Disintegrate tablets The most common type of tablet. Disintegration and dissolution time depends on the choice of excipients. Dissolution rate is the rate limiting step for hydrophobic drugs 17 Effervescent tablets Dissolution in water prior to administration. Used to obtain rapid drug action, fast bioavailability Achieved by using bicarbonate Used for analgesic drugs 18 Sublingual and buccal tablets Sublingual tablets Under the tongue e.g. Nitroglycerine Both regions have high density of blood vessels A rapid plasma drug concentration can be achieved without ﬁrst‐pass liver metabolism. Other tablet in oral cavity: troches or lozenges, dental cone 19 Tablet manufacturing Stages in tablet formation: Die ﬁlling Tablet formation Granulation Compression Compaction Tablet ejection 20 Terminologies Compression: reduction in volume Compaction: packing all the necessary components or features into a designed space Powders: describe a dosage form in which a drug powder has been mixed with other powdered excipients to produce the final product. Granules: describe a dosage form in which powder particles are aggregated to form a larger particle (>2mm in diameter). 22 Tablet production via granulation Granulation: a process in which powder particles are made to adhere to form large, multi-particle entities known as granules. Granulation commences after drying mixing of powdered formulations so that a uniform distribution of each ingredients through the mix is achieved. Granules can either be packed as an independent dosage form, or further mixed with other excipients for tablet compaction or capsule filling. Pharmaceutical granules size 0.2 and 4 mm. https://www.youtube.com/watch?v=wbuC6bpWQM8 Pharmasquire, Mumbai, India 23 Reasons for granulation (1) To prevent segregation of the constituents of the powder mix Segregation is caused by the difference in the size or density of the powder mix. Uneven distribution observed in the tablet since tablet press hopper fills by volume rather than weight. 24 Reasons for granulation (2) To improve the flow properties of the mix Smaller and irregular shaped particles can be cohesive and not able to flow Protect materials that are hydroscopic and prone to adhesion and caking Granules can increase the size and isodiametric properties and improve flowability To improve the compaction characteristics of the mix To reduce hazards associated with the toxic dust during handling of powders. To reduce cost of storage or shipment since granules are more dense than their parent powder mix, thereby having higher volume/mass ratio. 25 Mechanisms of granulation Dry granulation: Adhesion between particles is resulted of applied pressure. Typically forms a compact sheet, followed by milling and sieving. Wet granulation: Dry powders are mixed with liquid under mechanical agitation Particles adhere to each other within a liquid film Steps: Nucleation Transition Ball growth 26 33 Compaction vs Compression Fundamentals of compaction of powders Fundamentals of compression Relationship between material properties and tablet strength 34 Direct compaction (without granulation) Process: Powder mixing Compaction in a tablet press Example of Unit Advantages: apparatus operation Excipient Minimize production time and cost Mixing Improve drug stability given lack Dry binder of heat or wetting treatment High shear Disintegrant Mixing mixer Lubricant Usages: Antiadherent Soluble drugs Rotary press Tabletting Glidant Can be processed as coarse particles Potent drugs Needs a few milligrams per tablet particles 35 Challenges and limitations via direct compaction Needs extra care on mixing Difficult to obtain homogeneity (color) Particles are prone to segregation Requires a large quantity of excipients for drugs with poor compactibility Require specially designed fillers and dry binders (expensive) Require a large number of quality tests before production 36 Compactability of powders Compactability of granules refers to the ability of granules to cohere during the compression process and form a porous specimen of defined shape. Granules and powders with poor compactability would have lower resistance towards capping and lamination. 37 Fundamentals of granule compression Compressibility of granules and powders: when held within a confined space, to reduce in volume while loaded. Processes Rearrangement of particles in the die resulting in a closer packing structure and less porosity. As compression force continue to apply, the reduced space and interparticulate friction will prevent further interparticulate movements. 38 Technical problems associated with manufacturing of tablets Variation in weight and dose Low mechanical strength of the tablets Capping and lamination of the tablets Adhesion or sticking of powder materials to punch tips High friction during tablet ejection 43 Evaluation of compression Characterization of Characterization of the ejected tablets compression and Determination of the decompression events pore structure and pore Punch force vs time size/size distribution Tablet volume vs punch force 44 Evaluation of tablet strength Tablet without capping/lamination Tablet tensile strength, or tablet fracture stress: most common way to assess powder compactability. Tablet with calculated based on capping/ lamination diametral compression testing Capping and lamination weaken the tablet strength. https://gamlentableting.com/compaction-science/usp- 45 1062-tablet-compression-characterization/ Topic 3 Part 1 review Neurophysiology key points Organization and components – Neurons and glial cells Central nervous system and peripheral nervous system Signal transmission in nervous system Action potential, myelin, synapse Overview of autonomic nervous system 4 Cell types in nervous system Neurons – Functional cell type (main component) in carrying the chemical-electrical signals throughout the nervous system Glial cells (neuroglia) – Supportive cells – Do not participate in signal transmission, but play important roles in assisting and facilitating the signal transmission in neurons – Different types in central vs. peripheral nervous system. 7 Neurons have four functional regions Input component (dendrite) Trigger area (soma) Conductive component (axon) Output component (synapse) 8 Glial: support cells for neurons Produce myelin to insulate the nerve cell axon Take up chemical transmitters released by neurons at the synapse Form a lining around blood vessels: blood- brain barrier 10 How is the nervous system organized? Central Nervous system Brain Spinal Cord Afferent Division Efferent Division Peripheral Nervous system Somatic nervous Autonomic Nervous Sensory Stimuli Visceral Stimuli system system Sensory and special Motor senses system 12 The central nervous system is divided into seven parts The spinal cord. – Receives and processes sensory information from skin and muscles Medulla – Autonomic function. Pons – Control of posture and balance Cerebellum – Learning, memory, and control of movement. Midbrain – Eye movements Diencephalon – Thalamus. sensory – Hypothalamus: regulates autonomic and endocrine function Cerebral hemispheres – Hippocampus: memory – Basal ganglia: control of movement – Amygdala: autonomic and endocrine response in emotional states. – Cerebral cortex 14 Blood supply of the brain 19 http://www.nursingceu.com/courses/422/index_nceu.html http://www.rjmatthewsmd.com/Definitions/peripheral_vascular_disease.htm Blood brain barrier and cerebral spinal fluid Produced in the ventricles Cushion and buffer Autoregulation of blood circulation 20 Peripheral nerve Peripheral nerve consist of motor and sensory axons bundled into defined trunk. 21 Action Potential Rapid, transient self-propagating electric excitation in the plasma membrane of a cell such as a neuron or muscle cell resulting from a series of potential changes – Voltage-dependent ion channel in the plasma membrane Action potentials allow long distance signaling in the nervous system It is the basis of the signal carrying ability of nerve cells Patterns encode information Membrane potential (Vm): − Difference in electrical potential between intracellular and extracellular compartment Vm = Vin – Vout – Usual range in neurons: -60mV to -70mV – Current flow: movement of positive charges 23 Ionic concentration gradients equilibrium and membrane potential Ion Extracellular Intracellular Equilibrium concentration (mM) concentration (mM) potential (mV) Na+ 145 10 70 K+ 4 135 -94 Ca2+ 2 10-4 132 RT [X] o Ex = equilibrium or Nernst potential for Ex = ln species x intracellular z x F [X] i z = charge number [K + ]o F = Faraday’s number = 61.5ln10 + E K =61.5log EK = Potassium equilibrium potential [K ]i extracellular Action potential is an “all-or-none” response Supra-threshold Response: Action Sub-threshold response Potential Propagate down the axon without Not self-regenerating and will not decrement propagate down in the axon https://www.youtube.com/watch?v=plFOiU7sTO4 https://www.youtube.com/watch?v=ZAmUjvgoO0A 25 Electrical Tracing of Action Potential Depolarization Polarization 26 Phases of Action Potential: Na + channel Phase 0: Resting Potential Phase 1: Depolarization—rising Membrane depolarizes to > threshold, opening the voltage- gated Na+ channel. 27 Phases of Action Potential: Na + channel Phase 2: Overshoot / peak Phase 3: Repolarization (falling) Phase 4: Hyperpolarization Continued closure of Na+ and opening of K+ 28 Myelination Functions of myelin – Insulation – Decrease capacitance cross cell membrane – Increase conduction velocity Examples of disease (demyelination) – Inflammatory: multiple sclerosis – Genetic (inherited) 29 Comparison of conduction 30 Difference in CNS and PNS: Glial cells Glial cells in PNS: Schwann cells, satellite cells Glial cells in CNS: astrocytes, oligodendrocytes, microglial, ependymal cell 31 The sequence of signals 32 Synaptic transmission Mechanism of synaptic transmission electrical transmission - direct flow of ions from one neuron to another, hence direct influence of electric current from one to another chemical transmission- neurotransmitter substance released from presynaptic cell, diffuses across synaptic cleft, produced effect on postsynaptic neuron 33 Neurotransmitters Substance mediate chemical signaling between neurons – Present in the presynaptic terminal – Synthesized by cells – Release upon depolarization of the terminal – Specific mechanism exists for removing it from its site of action (e.g. receptors at postsynaptic membrane) 34 Small-molecular transmitter substance and key biosynthetic enzymes Transmitter Enzymes Activity / Notes Acetylcholine Choline acetyltransferase Specific -motor neurons @neuromuscular junctions -ANS Biogenic amines Dopamine Tyrosine hydroxylase Specific -mid-brain; Parkinson’s Disease Norepinephrine Tyrosine hydroxylase and dopamine β- Specific hydroxylase Epinephrine Tyrosine hydroxylase and dopamine β- Specific hydroxylase Serotonin Tryptophan hydroxylase Specific -depression Histamine Histidine decarboxylase Specificity uncertain Amino acids γ-Aminobutyric Glutamic acid decarboxylase Probably specific acid (GABA) - Major inhibitory transmitter Glycine Enzymes operating in general metabolism Specific pathway undetermined Glutamate Enzymes operating in general metabolism Specific pathway undetermined 35 Overview of sensory system How are sensory pathways arranged? How do sensory receptors encode sensation? 38 Example of sensory pathway: reaction to a pin Signal travels Signal travels from thalamus to via efferents to spinal cord reach muscles Signal travels to spinal cord Signal via afferents Reaches Cortex Reflex withdrawal of the affected limb Activation of Pain Receptors 39 How do sensory receptors encode sensation? Modality Adequate stimulus: type of stimulus to which a receptor is sensitive to Touch vs. tissue damage Temperature: cold vs. warm Intensity Duration Location and acuity 41 Overview of motor system What are the type of movement? What are the component of motor system? How to facilitate voluntary movement? 48 Autonomic nervous system (ANS) The autonomic nervous system regulates visceral organs (smooth and cardiac muscles), and is mostly involuntary-maintain homeostasis (constant internal environment) Controlled through hypothalamus – Hypothalamus acts on ANS and endocrine system 54 Organization Sympathetic system – “fight or flight response” – Intermediolateral cell column (lateral horn) in the thoracic and upper lumbar segments of spinal cord. – Ipsilateral ganglia control autonomic function on the same side; except bilateral innervation of intestine and pelvic viscera Parasympathetic system – Cranial nerve nuclei, intermediate region of sacral spinal cord 55 Organization Visceral fiber – Supply information that originates from sensory receptors in viscera – Operate at a subconscious level for homeostatic regulation and adjustment to external stimuli – For example: baroreceptor (CV unit) Enteric Nervous system – GI system – Subdivide into myenteric plexus (between longitudinal and circular muscle layers) and submucosal plexus (submucosa layer) 56 The sympathetic nervous system is distributed to more tissues than is the parasympathetic nervous system The sympathetic and parasympathetic divisions of the autonomic nervous system tend to have opposite effects on dually-innervated effector tissues + 58 Baroreceptors Baroreceptor reflexes regulate blood pressure adequately, but not “perfectly” Baroreceptor reflexes are short- term regulators Stretch receptors in blood vessels Like all stretch receptors, they adapt. They are not useful for controlling arterial pressure over periods of more than days 60 Anticipatory autonomic regulation requires inputs from the forebrain The forebrain is necessary for anticipatory autonomic regulation. 63 Summary ANS assist the body in maintaining a constant internal environment (homeostasis) Sympathetic and parasympathetic systems The sympathetic and parasympathetic divisions of the autonomic nervous system tend to have opposite effects on dually-innervated effector tissues. The sympathetic nervous system is distributed to more tissues than is the parasympathetic nervous system Baroreceptor reflexes are short-term regulators 64 Cardiovascular physiology key points Anatomic organization – Heart and vessel Cardiac system – Excitation-contraction coupling – Cardiac cycle (PV loop) Vascular system – Hemodynamics: resistance and compliance – Vascular smooth muscle cells – Arterial pressure Regulation 2 Anatomic perspective of circuitry Vessel types: Arterial: distributing tubes Capillaries: rapid exchange Venous: collecting tubes Vessels of a type are arranged in parallel, and the different vessel types are arranged in series 3 Structure of the heart Mechanical Electrical (pace marker, e-c coupling) Vasculature (high metabolic needs) 5 Muscle Three types of muscle cells: – Skeletal muscle – Smooth muscle – Cardiac muscle Skeletal and cardiac muscle cells have – well-defined contractile protein structures of sarcomeres – Sarcoplasmic reticulum (SR): intracellular calcium storage – T-tubules: deep invaginations of surface membrane Cardiac muscle cell are electrically coupled to each other by gap junctions to form a large syncytium. 7 Cross-bridge cycle—sarcomere shortening 8 https://www.youtube.com/watch?v=sIH8uOg8ddw Excitation-contraction coupling Elementary steps in the E-C coupling cascade: Surface membrane depolarization Calcium entry Calcium release from sarcoplasmic reticulum Increase in intracellular free Ca 2+ Calcium binding to troponin C Crossbridge cycling Force generation More calcium entry should produce more contractile force As extracellular calcium concentration is raised, intracellular free Ca2+ and force both increase 9 The cardiac cycle: electrical signals 1. Self-initiating action potentials in sinoatrial node (SAN)—no need for neural initiation 2. Spreads through atria by direct cell-cell gap junctions 3. Hits beginning of conduction system at atrioventricular node (AVN), which delays spread of excitation to ventricles. Needed to allow atrial volume to fill ventricles Rapid spread of excitation via Purkinje fibers comprising specialized conduction system. Then spread from cell- to-cell to ventricular cells, via gap junctions Conduction system produces synchronized electrical excitation, which leads to synchronized ventricular contraction – E-C coupling starts off at about same time in different parts of ventricle 14 Cardiac cycles Temporal relationship of ventricular volume, ventricular pressure, aortic pressure, venous pressure, electrical events and heart sounds Heart sounds (two sounds in normal heart) are caused by the closing of heart valves Ventricular contraction → increase in pressure → open aortic valve and to drive blood flow from ventricle to aorta (to the systemic circulation) The different phases of cardiac cycles https://www.youtube.com/watch?v=IS9TD9fHFv0 16 Cardiac cycle: electro-mechanical events—link to ECG and E-C coupling ECG: – P is atrial depolarization – QRS is caused by ventricular depolarization – T is caused by ventricular repolarization – Magnitude of current – Direction of current E-C coupling help in pharmacologic treatment of arrhythmias Intracellular Ca2+ 22 Cardiac output Cardiac output: the total volume of blood pumped by heart per min Cardiac output = stroke volume x heart rate Amount of blood pumped by each ventricle per minute Stroke volume (SV) = EDV – ESV – Stroke volume determined by Preload Afterload Heart contractility Ejection Fraction EF = SV/EDV 24 Blood vessel structure and function Function: Transport Oxygen, carbon dioxide Nutrients and metabolic breakdown products Cells of the immune system Chemical messengers (hormones, clotting factors) Microcirculation is the part concerned with the exchange of gases, fluids, nutrients and metabolic waste products. 28 Quick review in hemodynamics Poiseuille Equation Consider viscosity Valid only if the flow is – Steady – Laminar – Newtonian – In cylindrical tube Flow is proportional to the pressure difference inversely proportional to viscosity and length of tube proportional to the fourth power of the diameter 31 Resistance to flow (hydraulic resistance) Flow resistance is proportional to viscosity and length of tube Flow resistance is inversely proportional to the fourth power of the diameter of tube 32 The arterial system Aorta – Large artery – Small Artery – Arterioles Hydraulic filters – Main features of the arterial system Compliance Resistance – Advantages of hydraulic filters damping the impact of pulsatile pressure maintain steady flow in capillary networks – If the aorta loses its compliance, the impact of pulsatile pressure will gradually destroy the arterial system !! 35 Vascular smooth muscle Smooth muscle cells – Irregularly shaped, joined into bundles or sheets – Electrically coupled at gap junction—function as a syncytium – Smooth muscle cells (SMCs) are important part of blood vessels (both arterial and venous) Alteration in contraction do not depend on action potentials in VSM Smooth muscle contraction is slower in comparison with skeletal or cardiac muscle VSM utilize a contractile mechanism common to skeletal and cardiac muscle – Contractions are elicited by increases in intracellular Ca2+, which can arise from either electromechanical coupling or pharmacomechanical coupling Initiating stimuli: electrical or pharmacological Diversity of signals contribute to an ongoing modulation of vascular tone Vascular tone: summation of cellular response to a variety of stimuli 38 Arterial pressure Arterial blood volume and arterial compliance directly affect arterial pressure Pa CO = cardiac output (the total volume of blood pumped by heart per min, usually in mL/ min; therefore, it’s flow rate in the system) TPR = total peripheral resistance Cardiac output and peripheral resistance affect arterial blood volume and arterial compliance 39 Arterial blood pressure Systolic pressure (Ps): peak pressure during systole Diastolic pressure (Pd): lowest pressure during diastole Pulse pressure = (Ps - Pd) Mean arterial pressure (MAP): pressure that propels blood to tissue during entire cardiac cycle MAP = Pd + (Ps-Pd)/3 MAP = TPR x CO Blood pressure is influenced by CO, TPR, blood volume The area under the arterial pressure curve = the area under the mean arterial pressure 40 Regulation of arterial blood pressure Short term—Alternation of peripheral resistance – Neural mechanisms – Chemicals in blood Long term—Alternation of blood volume – Renal mechanism 41 Baroreceptor reflexes Location: primarily in aorta and carotid arteries Mechanoreceptor: stimulated by stretch in arterial wall (increase BP) Rapid response to short-term changes in BP Relatively ineffective in sustained changes in BP 44 Summary of cardiovascular physiology Anatomical organization Cardiac system: – Electrical excitation Fast (ventricular) and slow (SAN) action potential – Cardiac cycle Electro-mechanical events ECG – Pressure-volume relationship Heart as a time varying elastance Vascular system: – Hemodynamics: resistance and compliance – Arterial pressure 49 Renal Physiology Functions of the human kidney: – Regulation of volume, osmolarity, mineral composition and acidity in extracellular fluid – Removal of metabolic waste products from the blood and their excretion in the urine – Removal of foreign chemicals from the blood and their excretion in the urine – Gluconeogenesis (during prolong fasting) – Secretion of hormones Renin, (angiotensin, aldosterone) Erythropoietin (EPO) 1,25-dihydroxyvitamin D3 3 Body fluid compartments Water accounts for ~60% of body weight Vary with age and gender Total body water (TBW) = intracellular fluid (ICF) + extracellular fluid (ECF) ICF ~ 2/3 TBW, ECF ~ 1/3 TBW ECF = plasma + Interstitial fluid Fluid = solutes + water When osmolality of ECF and ICF differs, water will transport by osmosis until the new osmotic equilibrium is reached. 4 Review of osmotic pressure Osmolarity = osmotically active solutes / volume Osmolarity is a measure of the osmoles of solute per volume (L), while the osmolality is a measure of the osmoles of solute per mass of solvent (kg). van’t Hoff’s law: π = RT(Φic) (review in physiology reference book) – π=osmotic pressure – R=ideal gas constant – T=absolute temperature – Φ=osmotic coefficient – i=# ions formed by dissociation of a solute molecule – c=molar concentration of solute Osmolarity = Φic Oncotic pressure = osmotic pressure of plasma protein 5 Nephron Functional unit of kidney 1.25 million nephrons per kidney Function for blood plasma Cortex processing and urine formation. A tiny funnel 3 cm long. Cortical nephron: short Loop of Henle 85% of all nephrons, in cortex. Medulla Juxtamedullary nephron: long Loop of Henle lies in the interface of cortex and medulla, and extends into medulla. 9 Transepithelial solute and water transport Transcellular: through cells Paracellular: between cells Apical or luminal side face tubule lumen Baso-lateral face capillary and interstitial space 14 Excretion = Filtered – Reabsorbed + Secreted Glomerular filtration Tubular reabsorption Artery Afferent arteriole Glomerular capillary – Transfer from tubular lumen to Efferent capillary plasma arteriole Tubular secretion – Transfer from capillary plasma to tubular lumen Bowman’s Excretion capsule 1.Glomerular filtration – Substance excreted = substance in 2.Tubular secretion the final urine 3.Tubular tubule Reabsorption Substance Amount filtered Amount % Peritubular / day excreted reaborbed capillary Water, L 180 1.8 99 vein Na+, g 630 3.2 99.5 Urinary Glucose, g 180 0 100 excretion Urea, g 56 28 50 Glomerular flow rate (GFR) Kidney function depends on adequate filtration Filtration barrier—size and charge selective (overall negative charge) Filtrate = plasma – high MW components Starling force – Net ultrafiltration pressure: Glomerular ultrafiltration coefficient, Kf – Permeability – Area available for filtration Rate of blood flow through glomerular capillary: ↑flow, ↑GFR Mesangial cell contraction: ↓ area GFR = Kf × PUF = Kf × [(PGC+πBS) – (PBS +πGC)] 17 Glomerular filtration rate (GFR) of drug compound The unbound drug in the plasma are ﬁltered in Bowman’s capsule. drugs bound to plasma proteins are not ﬁltered. Drugs that are not bound to plasma protein, neither secreted nor reabsorbed, will head to renal clearance. eg. creatinine, inulin can be used to determine GFR 18 Renal clearance measurement of glomerular filtration rate and renal blood flow Clearance of a substance is the volume of plasma from which that substance is completely cleared by the kidneys per unit time. Conservation of Mass: – Mass of substance cleared from plasma through kidney = mass of substance in urine in the same time period For a substance (x) that is freely filterable across the glomerulus into Bowman’s space, but not secreted, reabosrbed, or metabolized by the tubules, and has no effect on GFR: – Polysaccharide inulin can be used to measured GFR, but it requires IV administration – Creatinine is usually used to estimate GFR in clinical practice 19 Renal clearance measurement of glomerular filtration rate and renal blood flow For a substance (x) that is freely filterable across the glomerulus into Bowman’s space, but not secreted, reabosrbed, or metabolized by the tubules Amount filtered = amount excreted Mass of x filtered / time = Mass of x excreted / time Mass of x excreted / time = Ux × V Ux = urine concentration of x V = urine volume per unit time Mass of x filtered / time = GFR × Px Px = arterial plasma concentration of x GFR x Px = Ux × V For example, if x is inulin.. Ux  V U in  V GFR = GFR = Px Pin 20 Renal: Summary 99% of (water) glomerular filtrates are reabsorbed Excretion = Filtered – Reabsorbed + Secreted No cell will be filtered (small amount) GFR Autoregulation (volume sensing): GFR Renal clearance Tubule function – Water (passive) – Na – HCO3- 28 Gastrointestinal (GI) tract components and functions The GI tract (alimentary canal) – Salivary glands, esophagus, stomach, pancreas, liver, biliary tract, small intestine, colon and rectum Functions: – Break food down into forms that can be absorbed (digestion) – Absorb nutrients and water electrolytes GI tract is the major organ system of digestion and nutrient absorption, second most important organ system in water / electrolyte homeostasis. 3 Functions and actions in different part of GI tract Functions: 1. Digestion 2. Secretion (chemical digestion) 3. Absorption 4. Motility (mechanical digestion, propulsion, defecation) 7 Digestion: Mechanical and Chemical Mechanical: chewing and GI movement Chemical: secretion and enzymes Hydrolysis: addition of water molecules as H+ and OH- to break up molecular bonds 1. Carbohydrates: polysaccharides → monosaccharides 2. Lipids: triglycerides → fatty acids 3. Proteins: peptides → amino acids 11 Functions of a liver Production of proteins e.g. albumin Detoxification and metabolic Endogenous toxins: NH3 from protein metabolism Exogenous toxins: drugs, alcohol bilirubin from breakdown of old RBCs Homeostasis of carbohydrates (blood glucose) Homeostasis of lipids and production of cholesterol – stores substances such as glycogen and fats Storage of vitamins, minerals Produces bile – excretes cholesterol and bilirubin. Blood enters the liver from the digestive tract by the hepatic portal system, providing liver with first choice of absorbed nutrients. 16 Major mechanisms of absorption of nutrients Diffusion – Simple diffusion – monoglycerides and fatty acids – Facilitated diffusion – fructose, amino acids Active transport – Primary active - sodium – Secondary active – glucose, amino acids and peptides 23 GI: Summary Motility Digestion and absorption of carbohydrates, proteins and lipids Secretion for digestion and protection of GI tract Liver functions 32 References Berne & Levy Physiology, 6th / 7th / 8th edition, by Bruce M. Koeppen and Bruce A. Stanton. Mosby, St. Louis. Open source textbook: – Anatomy and Physiology. By Betts JG, Desaix P, Johnson E, Johnson JE, Korol O, Kruse D, Poe B, Wise JA, Womble M, Young KA. OpenStax. Rice University. 2017. (free online textbook) – https://d3bxy9euw4e147.cloudfront.net/oscms- prodcms/media/documents/AnatomyandPhysiology- OP_xxKIcSo.pdf 33 Topic 4 Key topics Pharmacokinetics 1. Introduction ADME Routes of delivery Plasma level vs time curve 2. Bioequivalence and bioavailability 3. Absorption 4. Distribution: Compartment models Apparent volume of distribution 5. Metabolism 6. Excretion: Clearance 2 Pharmacokinetics Pharmacokinetics: the science of the kinetics of drug absorption, distribution, metabolism (biotransformation) and elimination (excretion). Pharmacodynamics: study of the relationship between the drug concentration at the site of action, and pharmacologic response and the physiological eﬀect that inﬂuence the interaction of drug with the receptor. 4 Pharmacokinetics The study of the disposition of a drug The disposition of a drug includes the processes of ADME Absorption Distribution Metabolism Elimination Excretion 8 Routes of Drug Administration Oral (per os, p.o.) (Enteral) Inhalation vapors, gases, smoke Mucous membranes intranasal (sniffing) sublingual rectal suppositories Injection (parenteral) intravenous (IV) intramuscular (IM) subcutaneous (SC) intraperitoneal (IP; nonhumans) Transdermal 10 Oral Drug Administration Advantages: relatively safe, economical, convenient, practical Disadvantages: Blood levels are difficult to predict due to multiple factors that limit absorption. Some drugs are destroyed by stomach acids. Some drugs irritate the GI system. 11 Administration by injection or IV Advantages of Injection Disadvantages/Risks of Routes Injection Absorption is more rapid than A rapid onset of action can be with oral administration. dangerous in overdosing Rate of absorption depends on occurs. blood flow to particular tissue Too rapid administration will site (I.P. > I.M. > S.C.). affect heart and respiratory Advantages specific to functions. Drugs insoluble in water or IV injection dissolved in oily liquids can No absorption involved (inject not be given IV directly into blood). Sterile techniques are Rate of infusion can be necessary to avoid the risk of controlled. infection A more accurate prediction of dose is obtained. 12 Routes of administration Route dosage form tablets, capsules, solutions, suspensions, oral powders, emulsions, gels, lozenges ointments, creams, pastes, lotions, gels, topical solutions parenteral injections (i.v., s.c., i.m., i.p., i.t., i.a, …) ointments, creams, lotions, transdermal patches, infusion pumps Systemic delivery intraocular solutions, suspensions vs. /nasal/aural Localized delivery pulmonary aerosols rectal solutions, ointments, suppositories solutions, ointments, vaginal suppositories, gels, foams urethral solutions, suppositories 13 Dose Dose is typically normalized with respect to body weight (BW) or body surface area (BSA) 𝐵𝑊 0.73 𝐵𝑆𝐴 = ( ) × 1.73𝑚2 70𝑘𝑔 Oral unit Parenteral Unit General mg mg/hr BW mg/kg mg/kg/hr BSA mg/1.73m2 mg/1.73m2 14 Measurement of concentration Sampling: invasive methods: sampling blood, spinal ﬂuid, synovial ﬂuid, tissue biopsy, or anything requires parenteral or surgical intervention. noninvasive: urine, saliva, feces, expired air, or anything without parenteral or surgical intervention. Drug concentration: drug retention, transportation, results of drug dosing, and drug metabolite transport. 15 Drug concentration in blood, plasma, or serum Most direct approach to assessing pharmacokinetics of drug in the body. Blood components: red blood cells, and white blood cells, platelets, and proteins, electrolytes. Serum: obtained by centrifugation, supernatant of clotted whole blood (blood- cells-clotting factors) Plasma: supernatant of whole blood in the presence of anticoagulant, eg. heparin. (blood-cells) In many cases, the changes in drug concentration in plasma will reﬂect changes in tissue drug concentrations. 16 Plasma drug concentration Measuring whole blood is more diﬃcult due to the presence of interfering compounds. Almost all drug concentration in blood is expressed as plasma drug concentration. Note that tissues and organs are perfused with blood, NOT just plasma. Hence correction factor can be made by Blood/plasma concentration ratio: λ ≈ 1: Drug concentration in cellular and plasma components of drug are very similar. 𝐶𝑤ℎ𝑜𝑙𝑒𝑏𝑙𝑜𝑜𝑑 𝜆= 𝐶𝑝𝑙𝑎𝑠𝑚𝑎 17 Plasma Level vs. Time Curve Drug concentration in plasma samples taken at various time internals after a drug product is administered. absorption absorption phase elimination phase phase elimination phase plasma concentration time after administration time after administration Oral administration Injection administration 18 Therapeutic Window minimum toxic concentration (MTC) plasma Cp max concentration Intensity Cp Therapeutic minimum effective Window (TW) concentration (MEC) duration onset Tmax time after administration MEC: concentration of drugs needed to produce desired pharmacological effect. MTC: concentration of drugs needed to produce an undesirable toxic effect. Onset: time required to reach MEC. Duration: different between onset time and time when Cp reaches MEC. 19 Plasma level - time curve Peak plasma level: time of maximum drug concentration in the plasma. AUC (area under curve): amount of drug absorbed systemically. To be revisited: Cmax, Tmax, AUC 20 Summary Pharmacokinetics Introduction of ADME Routes of drug administration Drug plasma concentration vs time 22 Bio-equivalent products Pharmaceutical equivalent or pharmaceutical alternative products that display comparable bioavailability when studied under similar experimental conditions. Bio-equivalent drug products For systemically absorbed drugs, two drugs shall be considered equivalent if the rate and extent of absorption of the tested drug do not show a signiﬁcant diﬀerence from the rate and extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple dose. Or, the extent of absorption of the test drug does not show a signiﬁcant diﬀerence from the extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single or multiple doses. 4 Bioequivalence Cp C max AUC time 80-125% Bioequivalence rule 5 Bioequivalent and Bioavailability Bioequivalence studies are used to compare the bioavailability of the same drug from various products. If the drug products are bioequivalent and therapeutically equivalent, the the clinical eﬃcacy and the safety proﬁle of these drug products are assumed to be similar and may be substituted for each other. Bioavailability is related to essential pharmaceutical parameters: rate and extent of absorption, elimination half-life, rate of excretion and metabolism. Bioavailability tests are used to deﬁne the eﬀect of changes in the physiochemical properties of the drug substance and the eﬀect of drug dosage form on the pharmacokinetics of the same drug. 6 Bio-equivalence Studies Studies: 2 drugs or 2 sets of formulation of the same drug are compared to show that they have nearly equal bioavailability and PK parameters. Example: generic drugs or when a formulation of a drug is changed during development The test and reference drug formulations must contain the pharmaceutical equivalent drug in the same dose strength, in similar dosage form, and be given by the same route of administration. Bioequivalence is established if the bioavailability of a test drug does not diﬀer in the product's rate and extent of drug absorption, as determined by comparison of measured parameters, from that of the reference drug when administered at the same molar dose of the active moiety under similar experimental conditions, either single dose or multiple dose. 7 Relative Bioavailability Bioavailability: Drug plasma concentration – time curve (AUC) measures the total amount of unaltered drug that reaches the systemic circulation. Relative bioavailability: The availability of the drug compared to a recognized standard dosage formulation. 𝐴𝑈𝐶𝐴 Same dose 𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐵𝑖𝑜𝑎𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = 𝐴𝑈𝐶𝐵 Different dose 𝐴𝑈𝐶𝐴 × 𝐷𝐵 𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐵𝑖𝑜𝑎𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = 𝐴𝑈𝐶𝐵 × 𝐷𝐴 8 Absolute bioavailability The absolute bioavailability of a drug is the systemic availability of a drug after extravascular administration compared to i.v. administration. This measurement is valid as long as VD and Ke are independent of the route of administration. The absolute availability after oral drug administration can be determined by 𝐴𝑈𝐶𝑜𝑟𝑎𝑙 /𝐷𝑜𝑠𝑒𝑜𝑟𝑎𝑙 𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝐵𝑖𝑜𝑎𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = 𝐹 = 𝐴𝑈𝐶𝑖𝑣 /𝐷𝑜𝑠𝑒𝑖𝑣 VD: Volume of distribution and Ke elimination rate constant 9 Bioavailability Bioavailability (F) is the fraction of the dose which reaches the systemic circulation as intact drug. The level of bioavailability depends on both absorption: how well the drug is absorbed ﬁrst-pass clearance: proportion of drug being removed by the liver before reaching the systemic circulation Absorption (oral administration) the extend to which intact drug is absorbed from the gut lumen into the portal circulation. absorption fg: is expressed as fraction of the dose absorbed from the gut. 11 First-pass clearance The extent to which a drug is removed by the liver during its ﬁrst passage in the portal blood through the liver to the systemic circulation. fH: the fraction of of drug which escape ﬁrst-pass clearance from the portal blood. Bioavailability can be determined by knowing the fraction of drug absorbed and the fraction of drug escaped from the ﬁrst-pass clearance. 𝐹 = 𝑓𝑔 × 𝑓𝐻 12 Measuring bioavailability for oral administration Absolute bioavailability measured against an intravenous reference dose the bioavailability of an intravenous dose is 100% by deﬁnition dose iv F * dose oral AUCiv = AUCoral = clearance clearance AUCoral F  doseoral = AUCiv doseiv if the oral and iv dose are the same, then 𝐴𝑈𝐶𝑜𝑟𝑎𝑙 𝐹= 𝐴𝑈𝐶𝑖𝑣 16 Absorption Must be able to get medications into the patient’s body Drug characteristics that affect absorption: Molecular weight, ionization, solubility, & formulation Factors affecting drug absorption related to patients: Route of administration, gastric pH, contents of GI tract 2 Gastrointestinal tract The major physiological processes that occur in the GI system are secretion, digestion, and absorption. The total transit time including gastric emptying, small intestinal transit, and colonic transit, ranges from 0.4 to 5 days. The most critical site for drug absorption is the small intestine. 3 Route of absorption Colon: Lined with mucin for lubrication and protection. Ideal for sustained drug release in combination with small intestine. pH: 5.5‐7. Rectum: Highly perfused by hemorrhoidal vein (rectal vein). Partially by-pass hepatic portal system pH: 7. 6 Factors influencing drug absorption Gastric emptying time Eﬀect of food Gastrointestinal mobility Perfusion of the gastrointestinal tract 7 Gastric Emptying Time A delay in the gastric emptying time for the drug to reach duodenum can slow the rate and the extent of drug absorption, and prolong the drug onset time. Prolonged GET is undesirable for drug that is unstable in acid and decompose, and for drug that irritates the gastric mucosa. Liquids are emptied faster than solids. Liquids and small particles less than 800 µm, which are generally not retained in the stomach. Meal high in fat and cold beverage can delay gastric emptying time. 8 Factors influencing gastric emptying time Factor Influence on Gastric emptying 1 Volume The larger the starting volume, the greater the initial rate of emptying, after this initial period, the larger the original volume, the slower the rate of emptying 2 Type of meal Fatty acids Reduction in the rate of emptying is in direct proportion to their concentration and carbon chain length; little difference is detected from acetic to octanoic acids; major inhibitory influence is seen in chain lengths greater than 10 carbons (decanoic to stearic acids). Triglycerides Reduction in rate of emptying; unsaturated triglycerides are more effective than saturated ones; the most effective in reducing emptying rate were linseed and olive oils. Carbohydrates Reduction in rate emptying, primarily as a result of osmotic pressure; inhibition of emptying increases as concentration increases. Amino acids Reduction in rate or emptying to an extent directly dependent upon concentration, probably as a result of osmotic pressure. 3 Osmotic Reduction in rate of emptying to an extent dependent upon concentration for pressure salts and nonelectrolytes; rate of emptying may increase at lower concentrations and then decrease at higher concentrations. 4 Physical state of Solutions or suspensions of small particles empty more rapidly than do chunks of gastric content material that must be reduced in size prior to emptying. 9 Factors influencing gastric emptying time Factor Influence on Gastric emptying 6 Drugs Anticholinergics Reduction in rate of emptying Narcotic Reduction in rate of emptying analgesics Metoclopramide Increase in rate of emptying Ethanol Reduction in rate of emptying 7 Miscellaneous Body Position Rate of emptying is reduced in a patient lying on left side Viscosity Rate of emptying is greater for less viscous solutions. Emotional states Aggressive or stressful emotional states increase stomach concentrations and emptying rate; depression reduces stomach concentration and emptying. Bile salts Rate of emptying is reduced Disease states Rate of emptying is reduced in some diabetics and in patients with local pyloric tensions (duodenal or pyloric ulcers; pyloric stenosis) and hypothyroidism; gastric emptying rate is increased in hyperthyroidism Exercise Vigorous exercise reduces emptying rate. Gastric surgery Gastric emptying difficulties can be a serious problem after surgery 10 Effect of food Eﬀects of food on bioavailability: Delaying in gastric emptying Stimulation of bile ﬂow A change in the pH of the GI tract Change in luminal metabolism Physico-chemical interactions with the drug Meals with high total calories and fat are more likely to aﬀect GI physiology and bioavailability. Food‘s eﬀect on absorption varies Antibiotics, e.g. penicillin, decreases bioavailability Lipid-soluble drugs, e.g. Metaxalone, increases bioavailability. 11 Effect of disease states on drug absorption Drug absorption can be inﬂuenced by the changes in: intestinal blood ﬂow GI mobility stomach emptying time gastric pH that aﬀects drug solubility permeability of the gut wall bile secretion digestive enzyme secretion 15 Summary (Part3) Absorption (oral administration) Recap of the GI system Factors influencing drug absorption Gastric emptying time Eﬀect of food Effect of disease Others: Effect of water Gastrointestinal mobility Perfusion of the gastrointestinal tract 16 Distribution Site of action of most compounds can be related back to the concentration of the compound in the plasma, although the relationship is not always clear. Compounds distribute differentially within body. Membrane permeability cross membranes to site of action Plasma protein binding may limit distribution bound drugs do not cross membranes malnutrition = albumin =  free drug Lipophilicity of drug Lipophilic compounds may accumulate in fatty tissues Liver, kidneys and other excretory organs often show high concentrations of compounds. Distribution can be studied using 14C-labeled compounds Volume of distribution 3 Drug Distribution Blood flow to tissue Initial distribution Cell Membranes Capillaries Drug affinities for plasma proteins Bound molecules cannot cross capillary walls Blood Brain Barrier Concentrations in brain are often very different from plasma concentrations Tight junctions in capillaries Less developed in infants Weaker in certain areas, e.g. area postrema in brain stem Cerebral trauma can decrease integrity Placenta Not a barrier to lipid soluble substances. 4 Pharmacokinetics models Compartment model: mammillary model one compartment model two compartment model Catenary model Physiologic pharmacokinetic model 6 Two fundamental concepts Clearance Volume of distribution 12 Clearance: CL Clearance describes the efficiency of irreversible elimination of a drug from the systemic circulation. excretion of the unchanged drug into urine, gut, expired air, sweat, etc. metabolized drug: the parent drug can be considered cleared or eliminated. Clearance deﬁnition: the volume of blood cleared of drug per unit time. CL = volume / time = mL/hr Clearance is also deﬁned as the constant relating the concentration of drug in the plasma to the rate at which the drug is eliminated from the body. Elimination rate = CL * Cdrug plasma concentration mg/hr L/hr mg/L 13 Clearance If clearance of drug A in liver is 30 L/hr, and that the liver blood ﬂow is 90 L/hr. Means 30/90 of the drugs entering the liver is irreversibly cleared by the liver in one pass. Extraction Ratio: Drug concentration cleared / concentration entered Clearance determines the maintenance dose rate at steady state. steady state: rate of drug admin

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