Bioavailability & Bioequivalence ppt
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The document discusses bioavailability and bioequivalence, focusing on the extent and rate at which a drug enters systemic circulation and the importance of ensuring that the delivered dose is effective. It outlines objectives for bioavailability studies, methods for improvement, and different assessment techniques, including pharmacokinetic and pharmacodynamic methods. Additionally, it covers in vitro dissolution testing and the conditions under which bioequivalence can be established, particularly regarding generic drugs.
Bioavailability & Bioequivalence ppt
- 1. BIOAVAILABILITY AND BIOEQUIVALENCE Presented by: Aditya Sharma M.S. (Pharm) Pharmaceutical Analysis NIPERGuwahati
- 2. BIOAVAILABILITY • It is relative amount of drug from an administered dosage form which enters the systemic circulation and rate at which the drug appears in the systemic circulation. • The extent and rate at which its active moiety is delivered from pharmaceutical form and becomes available in the systemic circulation
- 3. Why do we care about BIOAVAILABILITY? The “true dose” is not the drug swallowed; BUT is the drug available to exert its effect. Bioavailable fraction (F), refers to the fraction of administered dose that enters the systemic circulation. F = Bioavailable dose Administered dose
- 4. Objectives of bioavailability studies • Development of new formulation. • Determination of influence of excipients, patient related factors and possible interaction with other drugs on the efficiency of absorption. • Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage, stability on drug absorption. • Primary stages of the development of a suitable dosage form for a new drug entity. • To formulate a new dosage form of the existing drug molecule which can be used during emergency
- 5. REASONS OF POOR BIOAVAILABILITY Poor aqueous solubility Inappropriate partition coefficient First-pass metabolism Degradation due to low pH in stomach Degradation due to chemical reactions taking place in gastrointestinal tract Interaction with food Route of administration
- 6. HOW TO IMPROVE BIOAVAILABILITY • By increasing the aqueous drug solubility ie. by making salts of the drug. • By maintaining the drugs partition coefficient. • By synthesizing pro drugs. • Enteric coating of drugs prevents its degradation in stomach pH. • If food is present in stomach than it may decreases the drugs absorption and for this the medication can be preferred before meal or after 2-3 hours. • I/V given drug has highest bioavailability.
- 8. RELATIVE BIOAVAILABILITY • Compares the bioavailability of a formulation (A) of a certain drug when compared with another formulation (B) of the same drug, usually an established standard • Fr=AUCA AUCB • Eg. Comparison of amoxicillin cap and suspension
- 9. ASSESSMENT OF BIOAVAILABILITY ➢Pharmacokinetics method – This method is more practical and discriminative. Pharmacokinetic methods are of two types. a) Determination of whole blood, plasma or serum concentration b) Urinary excretion method ➢ Pharmacodynamic methods: • Acute Pharmacologic Response Method : When bioavailability measurement by pharmacokinetic method is difficult, an acute pharmacologic effect such as effect on pupil diameter, heart rate or BP can be useful as an index of drug bioavailability. • Bioavailability can then be determined by construction of pharmacological effect- time curve as well as dose response graphs • Disadvantage: It tends to be complex, expensive, time-consuming and require a sensitive and quantitative measure of the desired response. • Therapeutic Response Method: Clinical response of the drug for which it is intended to be used is measured. • E.g.: heart rate, body temperature, blood sugar levels, and for anti-inflammatory drugs, reduction in inflammation is determined. • Drawbacks: quantification of observed response is too improper to allow for reasonable assessment of relative bioavailability between two dosage forms of the same drug.
- 10. A) The blood (or serum or plasma) concentration-time curve - • Widely used and based on assumption that Pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Plasma Level- Time Studies: • Most common type of human bioavailability studies. • Based on the assumption that there is a direct relationship between the concentration of drug in blood or plasma and the concentration of drug at the site of action. • Following the administration of a single dose of a medication, blood samples are drawn at specific time intervals and analyzed for drug content. • If the drugs are given to the volunteers through iv dose, the blood samples should be withdraw after 5min. And the frequency of sampling should be 15min.
- 11. • A profile is constructed showing the concentration of drug in blood at the specific times the samples were taken. • Bioavailability (the rate and extent of drug absorption) is generally assessed by the determination of following three parameters. They are.. • Cmax (Peak plasma concentration) • tmax(time of peak) • Area under curve
- 13. AUC: The AUC is proportional to the total amount of drug reaching the systemic circulation, and thus characterizes the extent of absorption. Cmax: Gives indication whether drug is sufficiently absorbed systemically to provide a therapeutic response. Tmax: The Tmax reflects the rate of drug absorption, and decreases as the absorption rate increases. MEC: The minimum plasma concentration of the drug required to achieve a given pharmacological or therapeutic response MSC: plasma concentration of the drug beyond which adverse effects are likely to happen
- 15. Urinary Excretion Studies • Urinary excretion of unchanged drug is directly proportional to plasma concentration of drug. • Thus, even if a drug is excreted to some extent (at least 10 to 20%) in the bioavailability can be determined. eg: Thiazide diuretics, Sulphonamides. • Method is useful when there is lack of sufficiently sensitive analytical technique to measure drug concentration. • Noninvasive method, so better patient compliance. • This technique of studying bioavailability is most useful for those drugs that are not extensively metabolized prior to urinary elimination.
- 17. The three major parameters examined in urinary excretion data are as follow: 1.(dXu/dt)max : maximum urinary excretion rate, gives the rate of appearance of drug in the urine is proportional to its concentration in systemic circulation. Its value increases as the rate of and/or extent of absorption increases. 2. (tu)max : time for maximum excretion rate, is analogous to the of plasma level data, its value decreases as the absorption rate increases. 3. Xu : cumulative amount of drug excreted in the urine is related to the AUC of plasma level data and increases as the extent of absorption increases
- 20. INVITRO DRUG DISSOLUTION TESTING
- 21. DISSOLUTION • It is a process by which drug released from solid dosage form and immediately goes into molecular solution. • It is a Rate Determining Step. • If the drug is hydrophilic with high aqueous solubility then dissolution is rapid and rate determining step in the absorption of such drugs is rate of permeation through the bio membrane. • Absorption of such drugs is said to be permeation rate limited or Tran’s membrane rate limited.
- 23. NEED FOR DISSOLUTION TESTING: Evaluation of bioavailability. Batch to batch drug release uniformity. Development of more efficacious and therapeutically ACTIVE dosage forms. Ensures quality and stability of the product.
- 24. IN-VITRO DISSOLUTION TESTING MODELS Non-Sink methods 1) NATURAL CONVECTION NON SINK METHODS: a) Klein solvmeter method b) Nelson hanging pellet method c) Levy static disk method 2) FORCED CONVECTION NON SINK METHODS: a) Tumbling method b) Levy or Beaker method c) Rotating disk method d) Particle size method e) USP Rotating basket apparatus f) USP Paddle apparatus
- 25. Sink Methods 3) FORCED CONVECTION SINK DEVICES: a) Wurster pollis adsorption method b) Partition method c) Dialysis method s d) Rotating disk apparatus 4) CONTINOUS FLOW/FLOW THROUGH METHODS: a) Pernarowski method b) Langenbucher method c) Baun and Walker d) Tingstad and Reigelman e) Modified column apparatus f) Takenaka method
- 26. NATURAL CONVECTION NONSINK METHOD Klein Solvmeter method: •Carrier device surrounded by flat and is immersed in dissolution medium •When dosage form is placed in the boat the bar moves and as dosage form dissolves it moves upwards •Amount of dosage form dissolved is revealed from the difference in height of bar movement
- 27. Levy static Disk method: • Acrylic holder containing dosage form is inserted into a known volume of medium through rubber stopper. • The vial is inverted and placed in incubator at 37 C .At specific time intervals the vial is removed from incubator and samples are analyzed. • Disadvantages :- effect of conc. On dissolution medium is ignored and the surface area of dosage form while dissolving is assumed constant which is not impractical.
- 28. FORCED CONVECTION NON SINK METHODS a. Tumbling Method: • The Drug/ Dosage form with the dissolution medium is placed in test tube that is in turn clamped to the revolving drum which is rotated at the speed of 6- 12rpm in water bath at 37 C • The test tubes are removed and the medium is assayed at regular time points for the dissolved drug amount b. Beaker method • Reported by Levy and Hayes(1960). • Dissolution medium, 250ml of 0.1N HCl at 37°C placed in a 400ml beaker. • Agitation by three blade polyethylene stirrer,5cm diameter and rotates at 60 rpm. • Stirrer immersed to a depth of 2.7 cm in medium and in the center. • Tablets are placed in a beaker and test was carried out. • Samples are removed and assayed for the content
- 29. c. Rotating disk method: • Developed by late Eino nelson and described by Levy and Sahli. • In this method ,the drug is compressed in a non-disintegrating disc without excipients. • The disc is mounted in a holder so that only one face of the disc is exposed to the dissolution medium. • The holder and disc are immersed in medium and held in a fixed position as in static disc method and rotated at a given speed in rotating disc method. • Samples are collected at predetermined times. • Surface area of the drug through which dissolution occurs is kept constant –intrinsic dissolution rate.
- 30. d. USP ROTATING BASKET: • DESIGN: Vessel: -Made of borosilicate glass. -Semi hemispherical bottom -Capacity 1000ml Shaft : -Stainless steel 316 -Rotates smoothly without significance wobble(100 rpm) -Speed regulator Water bath:-Maintained at 37±0.5ºC USE: Tablets, capsules, delayed release suppositories, floating dosage forms.
- 31. Forced Convection Sink Devices: A. Wurster-Polli Adsorption Method: In this method the dissolved drug is adsorbed by charcoal or bentonite. Care should be taken regarding the adsorbent, adsorbent should not alter the viscosity of the medium B. Partition Method: In this device organic phase is employed to remove the dissolved drug such that the drug would partition between the lipophilic and hydrophilic phases. selection of organic phase plays a critical role.
- 32. Flow Through Devices a) CONTINUOUS FLOW APPARATUS BY PERNAROWSKI • It consists of 10 mesh stainless steel basket stirrer assembly with an adjustable stirrer. • the chamber is 3 necked flask of 33 mm and the rest two of 20 mm diameter. • 1L of medium is employed within the flask. the dissolution characteristics are dependent upon the amount of medium pumped through the dissolution chamber
- 33. B. LANGENBUCHER COLUMN • This device is according to the dissolution basic design . • The screen is constructed such that the medium flows equally through the entire cross section in a laminar pattern. • This is again closed by a secondary screen, filter which prevents the undissolved drug from being eluted.
- 35. C. CONTINUOUS FLOW APPARATUS BY TAKENAKA • The release of drug is measured with the aid of in vitro simulator device consisting of flow type dissolution container. • The dosage form is placed in the basket rotating at 94 rpm with 300 ml of medium. • Then the medium is removed by collecting reservoir using peristaltic pump. • Aliquots are withdrawn using syringe and then filtered using Whatman filter paper and the same volume is • Replaced immediately with fresh medium.
- 37. Bioequivalence • Bioequivalence :- It is a relative term which denotes that the drug substance in two or more identical dosage forms, reaches the systemic circulation at the same relative rate and to the same relative extent i.e. their plasma concentration-time profiles will be identical without significant statistical differences • When a generic drug is claimed bioequivalent to a Reference drug, it is assumed that they are therapeutically equivalent
- 38. Therapeutic equivalence Two products are therapeutically equivalent if • pharmaceutically equivalent • their effects, with respect to both efficacy and safety, will be essentially the same as derived from appropriate studies including bioequivalence studies, pharmacodynamic studies, clinical studies, in vitro studies
- 40. TYPES OF BIOEQUIVALENCE STUDIES •Bioequivalence can be demonstrated either – In vivo, or In vitro.
- 41. In vivo bioequivalence studies are conducted in the usual manner as discussed for bioavailability studies, i.e. the pharmacokinetic and the pharmacodynamic methods. 1. Pharmacokinetic Methods a)Plasma level-time studies b) Urinary Excretion studies 2. Pharmacodynamic Methods a)Acute pharmacological response b)Therapeutic response
- 42. In vitro studies, i.e. dissolution studies can be used in lieu of in vivo bioequivalence under certain circumstances, called as biowaivers(exemptions) 1. The drug product differs only in strength of the active substance It contains, provided all the following conditions hold – • Pharmacokinetics are linear. • The qualitative composition is the same. • The ratio between active substance and the excipients is the same, or (in the case of small strengths) the ratio between the excipients is the same. • Both products are produced by the same manufacturer at the same production site. • A bioavailability or bioequivalence study has been performed with a original product. • Under the same test conditions, the in vitro dissolution rate is the same
- 51. METHODS TO ENHANCE THE DISSOLUTION RATE 1. Increase in the effective surface area of the drug. 2. Particle size reduction 3. Incorporation of surface active agents in formulation. EG non-ionic surfactants like polysorbates are widely used. 4. Solute-Solvent complexation reactions. 5. Polymorphism. E.g. Riboflavin exist in 1,2,3 forms but form 3 is 20 times more soluble than 1 6. Molecular encapsulation with cyclodextrins or complexation with cyclodextrins. 7. Prodrug approach. 8. Salt formation of drug.
- 52. References • Chow SC, Liu JP. Design and Analysis of Bioavailability and Bioequivalence Studies. 3. Chapman Hall/CRC Press, Taylor& Francis; New York, New York, USA: 2008. • Balant LP. Is there a need for more precise definitions of bioavailability? European Journal of Clinical Pharmacology. 1991;40:123–126. • Chen ML, Lesko L, Williams RL. Measures of exposure versus measures of rate and extent of absorption. Clinical Pharmacokinetics. 2001;40:565–572. • Chow SC, Shao J. An alternative approach for the assessment of bioequivalence between two formulations of a drug. Biometrical Journal. 1990;32:969–976 • http://www.slideworld.com/slideshow.aspx/Bioavailability-and- Bioequivalenceppt- 2810356