bio availability

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bio availability

  1. 1. BIO-AVAILABILITY PRESENTED BY PREMSAI.K I M PHARM PHARMACEUTICS KRUPANDHI COLLEGE OF PHARMACY BANGALORE
  2. 2. CONTENT  Definition  Purpose of bio availability  Factors affecting bio availability  Measurements of bio availability  Reasons for poor availability  Approches to enhance the bio availability  Methods of enhancement of bio availability  Reference
  3. 3. BIO AVAILABILITYBIO AVAILABILITY  BIO AVAILABILITY means the rate and extent of drug reaches the systemic circulation in its unchanged form following the administration of a dosage form
  4. 4. PURPOSE OF BIOAVAILABILITYPURPOSE OF BIOAVAILABILITY  For marketing approval of new drug, FDA meets bioavailability studies  Establish the pharmacokinetic characters and it is useful in establish dosage regimens  Bio availability studies are useful in determining the safety, efficacy, identity, strength, quality and purity of the drug product
  5. 5. Factors affecting Bioavailability
  6. 6. A)Pharmaceutic factors : 1) Physicochemical properties of drug  Drug solubility & dissolution rate.  Particle size & effective surface area.  Polymorphism & Amorphism.  Amorphous > metastable > stable  Pseudopolymorphism (Hydrates / Solvates )  Anhydrates > hydrates e.g. Theophylline, Ampicillin  Organic solvates > non solvates e.g. fludrocortisone
  7. 7.  Salt form of the drug.  Weakly acidic drugs – strong basic salt e.g.barbiturates , sulfonamides.  Weakly basic drugs – strong acid salt  Lipophilicity of the drug .  pKa of the drug & pH .  Drug stability.
  8. 8. 2) Dosage form characteristics & Pharmaceutic Ingredients  Disintegration time (tab/cap)  Dissolution time.  Manufacturing variables.  Pharmaceutic ingredients( excipients / adjuvants )  Nature & type of dosage form.  Solutions> Emulsions> Suspensions> Cap> Tab> Enteric Coated Tab > Sustained Release  Product age & storage conditions.
  9. 9. B)Patient related factors  Age  Gastric emptying time .  Intestinal transit time .  Gastrointestinal pH .(HCL > Acetic > citric )  Disease States .  Blood flow through the gastrointestinal tract .  Gastrointestinal contents :  Other drugs . 
  10. 10.  Food .  Fluids  Other normal g.i. contents  Presystemic metabolism (First – Pass effect ) by :  Luminal enzymes .  Gut wall enzymes .  Bacterial enzymes .  Hepatic enzymes .
  11. 11. C)Routes of administration :  Parentral > Rectal > Oral > Topical
  12. 12.  Route Bioavailability (%) characterstics   Intravenous 100 (by definition) Most rapid onset  (IV)   Intramuscular 75 to ≤ 100 Large volumes often feasible;  (IM) may be painful  Subcutaneous 75 to ≤ 100 Smaller volumes than IM; may be painful  (SC)   Oral (PO) 5 to < 100 Most convenient; first pass effects may be significant   Rectal (PR) 30 to < 100 Less first-pass effects than oral   Inhalation 5 to < 100 Often very rapid onset  Transdermal 80 to ≤ 100 Usually very slow absorption;  used lack of first-pass effects; prolonged duration of action
  13. 13. MEASUREMENT OF BIO AVAILABILITYMEASUREMENT OF BIO AVAILABILITY  Divided in to three categories. Pharmacokinetic method Pharmacodynamic method scientgraphy study  Selection of method depends on the:  Purpose of the study  Analytical method of drug measurement  Nature of the drug product
  14. 14. PHARMACOKINETIC METHODPHARMACOKINETIC METHOD It is also called as Indirect method  Plasma level-time studies  Urinary excretion studies
  15. 15. PLASMA LEVEL-TIME STUDIESPLASMA LEVEL-TIME STUDIES PRINCIPLE: It is based on the assumption that two dosage forms that exhibit super imposable plasma level time profile in a group of subjects should result in identical therapeutic activity
  16. 16. FOR SINGLE DOSE STUDYFOR SINGLE DOSE STUDY  It requires collection of serial blood samples for a period of 2 to 3 biological half lives, after drug administration  And then analysis for drug concentration  By making a plot of concentration vs corresponding time of sample collection to obtain plasma level time profile
  17. 17. FOR MULTIPLE DOSEFOR MULTIPLE DOSE  Method involves drug administration for at least 5 biological half lives  A blood sample should be taken at the end of previous dosing interval and 8 to 10 samples after the administration of next dose
  18. 18. PARAMETERSPARAMETERS 3 parameters of these method used to estimate the bio availability are: Cmax : Peak plasma concentration. Tmax : Peak time AUC : Area under the plasma level- time curve
  19. 19. Time tmax CMAX P L A S M A C O N C PLASMA DRUG LEVEL-TIME CURVE
  20. 20. MEASUREMENT OF AUCMEASUREMENT OF AUC  1)PHYSICAL METHODS A)CUT AND WEIGHT METHOD B)PLANIMETER  2)TRAPEZOIDAL METHOD  3)INTEGRATION METHOD
  21. 21. RELATIONSHIP BETWEEN AUC AND DOSE AU C Dose AU C Dose
  22. 22. CUT & WEIGH AND PLANIMETERCUT & WEIGH AND PLANIMETER METHODSMETHODS  CUT & WEIGH: Plasma concentration profile are plotted on smooth paper, these can be cut out and weighed and the weight of the papers is directly proportional to AUC  PLANIMETER : A planimeter is a percision instrument which allows the calculation of areas by tracing there outlines
  23. 23. TRPEZOIDAL METHODTRPEZOIDAL METHOD  It involves the breaking up of the plasma con vs time profile in to several trapezoids calculating the area of each trapezoid and add them to obtain the AUC  AUC = [(co+c1)(t1- to)/2]+……… + (cn-1+cn)(tn-tn-1)/2
  24. 24. INTEGRATION METHODINTEGRATION METHOD  AUC=A(1/Ke-1/Ka) where Ke=overall elimination constant Ka=absorption constant
  25. 25. EXTENT OF BIOAVAILABILITYEXTENT OF BIOAVAILABILITY FOR SINGLE DOSE STUDYFOR SINGLE DOSE STUDY F=[AUC]oralDiv/ [AUC]ivDoral Fr=[AUC]testDstd/[AUC]stdDtest D = DOSE ADMINISTERED
  26. 26. EXTENT OF BIOAVAILABILITYEXTENT OF BIOAVAILABILITY FOR MULTIPLE DOSE STUDYFOR MULTIPLE DOSE STUDY Fr=[AUC]testDstdTtest/[AUC]stdDtestTstd T=Dosing interval Bioavailability can also be measured by peak plasma concentration at steady state, Fr=[Cssmax]testDstdTtest/[Cssmax]stdDtestTstd T=dosing interval
  27. 27. URINARY EXTRECTION STUDIESURINARY EXTRECTION STUDIES  PRINCIPLE: It involves urinary excretion of unchanged drug is directly proportional toplasma concentration of drug  Eg : thiazide diuretics, sulphonamides For drugs that have urine as site of action eg: urinary antiseptics : nitrofurantoin.
  28. 28. METHOD FOR URINARY EXCRETIONMETHOD FOR URINARY EXCRETION STUDIESSTUDIES  It involves collection of urine at regular intervals for a time span equal to 7 biological half lives  Then analysis for unchanged drug in the collected sample  Then determined the amount of drug excreted in each interval and cumulative amount excreted
  29. 29. PARAMETERS (dxu/dt)max: Max urinary excretion rate.  (Tu)max: Time for Max excretion rate. (Xu):Cumulative amount of drug excreted in the urine
  30. 30. E X C R E T I O N URINE COLLECTION ((dxu/dt)maxdxu/dt)max (Tu)max(Tu)max URINARY EXCRETIONURINARY EXCRETION STUDIESSTUDIES
  31. 31. EXTENT OF BIOAVAILABILITY FOR SINGLE DOSE F=(Xu)oralDiv/(Xu)ivDoral Fr=(Xu)testDstd/(Xu)Dstd
  32. 32. EXTENT OF BIOAVAILABILITY FOR MULTIPLE DOSE STUDY AT STEADY STATE Fr=(Xu,ss)testDstdTtest/(Xu,ss)stdDtestTstd (Xu,ss) It is the amount of drug excreted in unchanged form during a single dosing interval at Steadystate
  33. 33. ADVATAGES OF URINARY EXCRETION STUDIES  These method is useful when there is a lack of sufficiently sensitive analytic tech to measure concentration of drugs in plasma with accuracy  Convenince of collecting urine samples.  Direct measurement of absolute and relative bioavailablity is possible without the neccesity of fitting the data to a mathematic model  When coupled with plasma level-time data,it can be used to estimate renal clearance of un changed drug,by CLR=total amount of drug excreted unchanged / AUC
  34. 34. PHARMACODYNAMIC METHOD It is also called as direct method Acute pharmacological response Therapeutic response
  35. 35. ACUTE PHARMACOLOGICAL RESPONSE Acute pharmacological effect such as change in ECG OR EEG readings,pupil diameter etc is related to the time course of a given drug  Bioavailability can be determined:  By construction of pharmacologic effect - time curve  By dose-response graphs
  36. 36. THERAPEUTIC RESPONSE  This method is based on observing the clinical response to a drug formulation given to a patient suffering from disease for which it is intended to be used  Draw back is difficult assessment of relative bio availability between two dosage forms of the same drug
  37. 37. SCIENTGRAPHY STUDY  Radioactive substances is used to investigate the extent of absorption of drugs, which are directly introduced to the colon or targeted to colon
  38. 38. REASONS FOR POOR BIO-AVAILABILITY Poor aqueous solubility or slow dissolution rate. Poor stability of the dissolved drug at the physiologic PH Inadequate partition coefficient and thus poor permeation through the bio membrane.  Extensive pre-systemic metabolism.
  39. 39. APPROACHES TO ENHANCE THE BIOAVAILABILITY  THE PHARMACEUTIC APPROACH  THE PHARMACOKINETIC APPROACH  THE BIOLOGIC APPROACH
  40. 40. METHODS FOR ENHANCEMENT OF BIOAVAILABILITY  MICRONIZATION: Steroidal drugs, sulfa drugs, griseofulvin  USE OF SURFACTANTS: Polysorbates increases the bio avaialability of spiranolactone  USE OF SALT FORMS : Alkali metal salts of acidic drugs like pencillin, strong acid salts of basic drugs like atropine have more water soluble than parent drug
  41. 41. ALTERATION OF PH OFALTERATION OF PH OF MICROENVIRONM ENT OF DRUG:MICROENVIRONM ENT OF DRUG: by twoby two waysways A) In situ salt formation B) additionA) In situ salt formation B) addition of buffers eg: buffered aspirin tabletsof buffers eg: buffered aspirin tablets USE OF META STABLE POLYMORPHSUSE OF META STABLE POLYMORPHS :: Eg: B- chloramphenicol palmitate is moreEg: B- chloramphenicol palmitate is more water soluble than A and Cwater soluble than A and C SELECTIVE ADSORPTION ON INSOLUBLESELECTIVE ADSORPTION ON INSOLUBLE CARRIERSCARRIERS : Bentonite can enhance the: Bentonite can enhance the dissolution of poorly water soluble drugsdissolution of poorly water soluble drugs such as indometacin,prednisone by twosuch as indometacin,prednisone by two reasons weak physical bonding betweenreasons weak physical bonding between adsorbate and adsorbent and hydration,adsorbate and adsorbent and hydration, sweeling of clay in aqueous mediasweeling of clay in aqueous media
  42. 42. SOLID SOLUTIONS: a) use of solid solutions b)use of eutectic mixtures c)use of solid dispersions reduces the particle size by different mechanisms and thus enhances the bioavailability. MOLECULAR ENCAPSULATION WITH CYCLODEXTRIN : the beta dextrins and there derivatives have ability to molecular inclusion complexes with hydro phobic drugs having poor water solubility.the out side of the host molecule have water soluble and thus improves the aqueous solubility and dissolution rate and thus bio availability. Eg: thiazides diuretics
  43. 43. REFERENCES  1. D.M. Brahmankar, Biopharmaceutics and Pharmacokinetics, Vallabh prakashan, second editon, 2009  2. Shagel Wu-pong yu, bio pharmaceutics &pharmacokinetics, fifth edition ,2005  3. www. Goggle.com  4. en.wikipedia.org  5. Amidd.inon,g.l,Lennernas, A therotical basis for a biopharmaceutical drug classification  WWW.pubmed

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