ERT 420BIOPHARMACEUTICAL ENGINEERING Semester 1 Academic Session 2012/2013 HUZAIRY HASSAN School Of Bioprocess Engineering Universiti Malaysia Perlis
PHARMACOKINETICS & DISSOLUTION
PHARMACOKINETICS “After a drug is released from its dosage form, the drug is absorbed into the surrounding tissue, the body or both. The distribution through and elimination of the drug in the body varies for each patient, but can be characterized using mathematical models and statistics.” Pharmacokinetics is the science of the kinetics of drug absorption, distribution, and elimination (i.e., excretion & metabolism
PHARMACOKINETICS (PK)… - Drug disposition: the description of drug distribution and elimination. - The experimental aspects of PK involve the development of biological sampling techniques, analytical methods for drug and metabolites measurement, and procedures that facilitate data collection and manipulation. • The theoretical aspects involve the development of PK models that predict drug disposition after drug administration. • Statistical methods are used for PK parameter estimation & data interpretation for designing and prediction optimal dosing regimens for individuals or group of patients.
- Clinical PK: application of PK methods to drug therapy. • Age, gender, genetic, and ethnic differences can also result in PK differences that may affect the outcome of drug therapy. • Pharmacodynamics (PD): refers to the relationship between the drug concentration at the site of action (receptor) and pharmacologic response, including biochemical and physiological effects that influence the interaction of drug with the receptor. PK-PD models are constructed to relate plasma drug level to drug concentration in the site of action and establish the intensity and time course of the drug.
Toxicokinetics: the application of PK principles to the design, conduct, and interpretation of drug safety evaluation studies. performed in animals during preclinical drug development.
Units for expressing Blood Concentrations - Drug concentrations or levels = mass/volume • Ex: mg/mL, µg/mL, and mg/L (equivalent) • Or mg% or mg/dL[both = milligrams of drug per 100 mL (deciliter)] • Or ppm (parts of drug per million parts of blood) or ppb (part per billion) 1 ppm = 1.0 µg/mL. - for veterinary
Measurement of Drug Concentration • Drug concentrations (levels) are measured in biologic samples, ex: milk, saliva, plasma or serum, and urine. • Most frequent method: Chromatography For example: Drug concentrations in blood, plasma, or serum - Whole blood contains cellular elements including red & white blood cells, platelets, various other proteins (ex: albumin and globulins). to obtain serum, whole blood is allowed to clot and the serum is collected from the supernatant after centrifugation. Plasma is obtained from the supernatant of centrifuged whole blood to which an anticoagulant (ex: heparin) has been added.
Protein contents in both are not the same. • Plasma perfuses all the tissues of the body, including the cellular elements in the blood. - assuming the drug in the plasma is in dynamic equilibrium with the tissues, then changes in the conc. in plasma will reflect changes in tissue drug concentrations.
Plasma Level-Time Curve • Drug conc. in plasma samples taken at various time intervals after a drug product is administered. Figure 1-2 Generalized plasma level-time curve after oral administration of drug Figure 1-3 Plasma level-time curve showing peak time and concentration. The shaded portion is AUC (area under curve).
Plasma Level-Time Curve - As the drug reaches the general (systemic) circulation, plasma drug concentrations will rise up to maximum. • Usually, absorption of drug is more rapid than elimination. • When the drug is absorbed into systemic circulation, the drug is distributed to all tissues in the body, and simultaneously being eliminated.
Figures 1-2, 1-3: MEC: Min. Effective Concentration (pharmacologic effect) - reflects min. drug concentration needed at the receptors to produce desired pharmacologic effect. MTC: Min. Toxic Concentration - represents the drug concentration needed to just barely produce a toxic effect. Onsite time: time required for drug to reach MEC. Intensity: Intensity of the pharmacologic effect is proportional to the number of drug receptors occupied, which reflects- higher plasma drug conc. produce greater pharmacologic response, up to maximum. Duration: Duration of drug action is the difference between the onsite time and the time for the drug to decline back to MEC. AUC: Area under curve- related to the amount of drug absorbed systemically.
Clearance: • Is a measure of drug elimination from the body without identifying the mechanism or process. • Considers the entire body as a drug-eliminating system from which many elimination processes may occur.
DISSOLUTION • The availability of a drug in the body depends on its ability to dissolve in the gastrointestinal (GI) fluids. • If the rate of dissolution is the rate-limiting step in drug absorption, any factor affecting the dissolution rate will affect bioavailability (BA). The rate and extent to which the active ingredient or active moiety is absorbed from drug product and becomes available at the site of action
The dissolution rate of suspended, poorly soluble drugs according to the diffusion-layer model, modified Noyes-Whitney equation (Horter and Dressman, 1997; Nystrom, 1998) is as follows: D : Diffusion coefficient h : thickness of the diffusion layer at the solid-liquid interface A: surface area of drug exposed to the dissolution media v : volume of dissolution media Cs: concentration of a saturated solution of the solute in the dissolution medium at experimental temperature C : concentration of drug in solution at time t.
Based on the equation, the dissolution rate a function of: • Drug solubility • The diffusional transport of dissolved molecules away from the solid surface through a thin region of more or less stagnant solvent which surrounds the drug particles. • The solid surface area that is effectively in contact with the solvent.
Solubility • In 1980s and 1990s, most compounds that were considered poorly soluble had solubility in the range of 10-100 µg/mL. • Today, the compound with solubility range of 1 – 10 µg/mL and even < 1 µg/mL are very common.
Dissolution Testing - provides: rate & extent of drug absorption in the body assess the effects of drug substance biopharmaceutical properties and, formulation principles on the release properties of a drug product. ** Significance of Dissolution in Drug Absorption **
When a tablet or capsule is administered: 1st step: Delivery of drug into its absorption site through gastric emptying and intestinal transit flow 2nd step: Dissolution takes place in the stomach and/or in the small intestine. 3rd step: the permeation of dissolved drug across the GI membrane. 4th step: the absorbed drug passes through the liver (first pass metabolism) and reaches the systemic circulation.
If the dissolution process is slow relative to the other 3 processes (usually in the case of poor soluble drug) , then, dissolution will be rate limiting step. Therefore, the dissolution rate will determine the overall rate and extent of drug absorption into a systemic circulation, hence bioavailability.
Factors related to Drug Product Formulation • Effect of inactive ingredients (Excipients) depends on the dosage form for immediate-release dosage forms, excipients function to improve drug release from the formulation or solubilization of drug substance. Ex: Disintegrants such as starch- used to facilitate the break up of a tablet and promote deaggregation into granules or particles after administration. for poorly soluble drugs, incorporation of surfactants (e.g.polysorbate) into the formulation may increase the dissolution rate of drug products. i.e., by promoting drug wetting, forming micelles, and by decreasing surface tension of hydrophobic drug particles with the dissolution medium.
Coprecipitationwith polyvinylpyrrolidine (PVP) has significant influence the dissolution, by the formation of an energetic amorphous phase or molecular dispersion. • Disadvantage of excipients: • Lubricants such as stearates, used to reduce friction between the granulation and die wall during compression and ejection, are often hydrophobic in nature. thus, affect the wettability of drug product. For modified-release drug, specific excipients are selectet to control rate & extent of drug release from formulation matrix, ex: active ingredient is embedded in a polymer matrix, which controls drug release through mechanisms such as swelling, diffusion, erosion, or combinations.
Factors related to manufacturing process Unit operations impact: • Wet granulation- improve wettability of poorly soluble drugs by incorporating hydrophilic properties into the surface of granules results in greater dissolution rate • Tablet direct compression- propensity to de-aggregate into finer particles improve dissolution (positive effect-increase surface area) Negative effect: What?? What and why?
Negative effect of tablet compression: • Due to the enhancement in particle bonding that inhibits solvent penetration. Ex: high compression may reduce wettability of the tablet, since the formation of firmer and effective sealing layer by the lubricant is likely to occur under the high pressure that is accompanied by high pressure.
Dry granulation process IBC- Intermediate Bulk Container
Assignment 1: Find an article (in sciencedirect, scopus, etc.) related to Dissolution of Drug studies, and summarize the findings in 2 pages. Submission date: 1 October 2012