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Jatin ivivc

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Jatin ivivc

  1. 1. Presentation Title
  2. 2. INTRODUCTION • IVIVC can be used in the development of new pharmaceuticals to reduce the number of human studies during the formulation development. • In recent years, the concept and application of the in vitro-in vivo correlation (IVIVC) for pharmaceutical dosage forms have been a main focus of attention of pharmaceutical industry, academia, and regulatory sectors. • IVIVC could also be employed to establish dissolution specification and to support and/or validate the use of dissolution methods.
  3. 3. DEFINITIONS • Acc. to FDA: It is defined as a predictive mathematical model describing the relationship between an in-vitro property(rate or extent of drug dissolution or release) of a dosage form and an in vivo response(plasma drug concentration or amount of drug absorbed.) • Acc. To USP: The establishment of the relationship b/w a biological property, or a parameter derived form a biological property produced from a dosage form, and a physicochemical property of same dosage form.
  4. 4. CORRELATION LEVELS • Level A correlation: Highest category of correlation and represent a point to point relationship b/w in-vitro dissolution rate and in-vivo input rate of the drug from the dosage form. Percent of drug absorbed may be calculated by means of model dependent technique such as Wagner- Nelson Procedure or Loo-Riegelman method or by Model independent numerical deconvolution.
  5. 5. CORRELATION LEVELS(contd.) • Level B correlation: In this level of correlation, the mean in- vitro dissolution time(MDT vitro) of the product is compare to either mean in vivo residence time MRT or in vivo dissolution time (MDT vivo). It uses all of the in vivo or in vitro data and not to be considered a point to point correlation.
  6. 6. CORRELATION LEVELS(contd.) • Level C Correlation: In this level one dissolution time point ( t50% , t90%, etc) is compare to one mean pharmacokinetic parameter such as AUC, tmax or cmax. It is weakest level of correlation as partial relationship b/w absorption and dissolution is established and represents a single point correlation and doesn’t reflect the entire shape of plasma drug conc. curve.
  7. 7. CORRELATION LEVELS(contd.) • Multiple Level Correlation: It relates one or several pharmacokinetic parameters of interest (cmax, AUC or any other suitable parameters) to the amount of drug dissolved at several time points of the dissolution profile. It should be based on at least three dissolution time points covering the early, middle, and late stage of the dissolution profile. • Level D Correlation: It is rank order and qualitative analysis and is not considered useful for regulatory purposes. It is not formal correlation but serve as an aid in the development of a formulation or processing procedure.
  8. 8. THE CORRELATION BETWEEN IN VITRO DRUG DISSOLUTION AND IN VIVO DRUG ABSORPTION
  9. 9. Biopharmaceutics Classification System (BCS) • The (BCS) has been developed to provide a scientific approach to allow for the prediction of in vivo pharmacokinetics of oral immediate release (IR) drug products by classifying drug compounds based on their solubility related to dose and intestinal permeability in combination with the dissolution properties of the dosage form.
  10. 10. BCS Classification According to the BCS, drug substances are classified as follows: • Class I - High Permeability, High Solubility • Class II - High Permeability, Low Solubility • Class III - Low Permeability, High Solubility • Class IV - Low Permeability, Low Solubility
  11. 11. BCS (Contd.) • The BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption from IR solid oral dosage forms: dissolution, solubility, and intestinal permeability.
  12. 12. CLASS BOUNDARIES • A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5. • A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose. • A drug product is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of < 900 ml buffer solutions.
  13. 13. The benefits of knowing the BCS category of a compound • It can save both time and money—if the immediate -release, orally administered drug meets specific criteria, the FDA will grant a waiver for expensive and time-consuming bio-equivalence studies. • The aim of the BCS is to provide a regulatory tool for the replacement of certain BE studies by conducting accurate in vitro dissolution tests. • Combined with the dissolution, the BCS takes into account the three major factors governing bioavailability viz. dissolution, solubility and permeability.
  14. 14. Key Parameters Controlling Drug Absorption • Absorption number (An) :- defined as the ratio of the mean residence time to mean absorption time. Radius of GI Residence time in GI ( ) ABS GI GI eff T T T R P An =      = Effective permeability Time required for complete absorption
  15. 15. Key Parameters Controlling Drug Absorption (contd.) • Dissolution number (Dn) :- defined as the ratio of mean residence time to mean dissolution time. ( )       =            = DISS GI GI S T T T C r D Dn ρ2 3 Diffusivity 5x10-6 cm2 /s Particle Radius 25 µm Solubility mg/mL Density 1.2 mg/cm3 Residence time in GI 180 min Time required forcomplete dissolution
  16. 16. Key Parameters Controlling Drug Absorption (contd.) • Dose number (D0) :- defined as the mass (Dose) divided by the product of (uptake volume (250 ml) and solubility of drug).           = S Water C V D Do Highest Dose Unit 250 mL Solubility
  17. 17. Class I • Class I drugs exhibit a high absorption number and a high dissolution number. The rate limiting step is drug dissolution. • If dissolution is very rapid, then gastric emptying rate becomes the rate determining step. • e.g. Metoprolol, Diltiazem, Verapamil, Propranolol.
  18. 18. Class II • Class II drugs have a high absorption number but a low dissolution number. In vivo drug dissolution is then a rate limiting step for absorption except at a very high dose number. The absorption for class II drugs is usually slower than class I and occurs over a longer period of time. • In vitro- In vivo correlation (IVIVC) is usually excepted for class I and class II drugs. • e.g. Phenytoin, Danazol, Ketoconazole, Mefenamic acid, Nifedinpine.
  19. 19. Class III • For Class III drugs, permeability is rate limiting step for drug absorption. These drugs exhibit a high variation in the rate and extent of drug absorption. • Since the dissolution is rapid, the variation is attributable to alteration of physiology and membrane permeability rather than the dosage form factors. • e.g. Cimetidine, Acyclovir, Neomycin B, Captopril.
  20. 20. Class IV • Class IV drugs exhibit a lot of problems for effective oral administration. Fortunately, extreme examples of class IV compounds are the exception rather than the rule and are rarely developed and reach the market. Nevertheless a number of class IV drugs do exist. e.g. Taxol.
  21. 21. Applications of BCS in oral drug delivery technology • Once the solubility and permeability characteristics of the drug are known it becomes an easy task for the research scientist to decide upon which drug delivery technology to follow or develop.
  22. 22. CLASS I DRUGS • The major challenge in development of drug delivery system for class I drugs is to achieve a target release profile associated with a particular pharmcokinetic and/or pharmacodynamic profile. • Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug.
  23. 23. CLASS II DRUGS • The systems that are developed for class II drugs are based on micronisation, lyophilization, addition of surfactants, formulation as emulsions and microemulsions systems, use of complexing agents like cyclodextrins.
  24. 24. CLASS III DRUGS • Class III drugs require the technologies that address to fundamental limitations of absolute or regional permeability. Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days.
  25. 25. CLASS IV DRUGS • Class IV drugs present a major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral with the formulation containing solubility enhancers.
  26. 26. IN VITRO-DISSOLUTION • Purpose of the in vitro dissolution studies in the early stage of the drug development is to select the optimum formulation, evaluate the active ingredient and excipient, and assess any minor changes for drug products. • For the ivivc perspective, dissolution is proposed to be a surrogate of drug bioavailability.
  27. 27. Why do we study dissolution? Disintegration Dissolution Absorption Drug in the blood and the body
  28. 28. TYPES OF DISSOLUTION APPARATUS Apparatus   Name Apparatus 1 Rotating basket Apparatus 2 Paddle Apparatus 3 Reciprocating cylinder Apparatus 4 Flow cell Apparatus 5 Paddle over disk Apparatus6 Cylinder Apparatus7 Reciprocating disc
  29. 29. Apparatus 1 (ROTATING BASKET) • In case of none-disintegrating dosage forms this apparatus is superior to apparatus 2 since it constraints the dosage form in a steady state fluid flow • It is inferior for testing dosage forms which contains gums due to clogging of screen matrix
  30. 30. Apparatus 2 (ROTATING PADDLE) • This apparatus is identical to apparatus 1 except that the paddle is substituted for the rotating basket • Frequently used for both disintegrating and non-disintegrating dosage forms
  31. 31. Apparatus 3 (RECIPROCATING CYLINDER) • One advantage of the reciprocating cylinder is that the gastrointestinal tract conditions can be easily simulated, as it is easy to make time dependent pH changes • This apparatus is most suitable for nondisintegrating (extended release) or delayed release (enteric coated) dosage forms
  32. 32. Apparatus 4 (FLOW CELL) • The advantage of flow through cell apparatus is the ability to test drugs of very low aqueous solubility and the ability to change the pH conveniently during the test
  33. 33. Apparatus 5 (PADDLE OVER DISK) • In paddle over the disc apparatus the disc is placed and above that the paddle is rotated . • Mainly use in case of trandermal preperations.
  34. 34. Apparatus 6 (CYLINDER) • The cylinder method (Apparatus 6) for testing transdermal preparation is modified from the basket method (Apparatus 1). In place of the basket, a stainless steel cylinder is used to hold the sample.
  35. 35. Apparatus 7 (RECIPROCATING DISK METHOD ) • In the reciprocating disk method for testing transdermal products, a motor drive assembly (Apparatus 7) is used to reciprocate the system vertically, and the samples are placed on disk-shaped holders using cuprophan supports
  36. 36. DISSOLUTION MEDIUM • Water or simulated gastric fluid(pH1.2) or intestinal fluid( pH6.8 or 7.4) without enzyme, Buffer with a pH range(4.5-7.5) • For sparingly water soluble drugs surfactant may be added in dissolved medium
  37. 37. SAMPLING TIME POINTS Time Points IR products • Test duration : 15 to 60 minutes Specifications • Dissolution profile : sampling at 5-, 10-or 15-minute intervals
  38. 38. SAMPLING TIME POINTS(contd.) • Extended-Release Products Test time : at least 3 test times • Early time point : 1-2 hours : potential dose dumping • Intermediate time point : define the release profile • Final time point : show complete release of the drug
  39. 39. IN VIVO ABSORPTION • FDA requires in-vivo bioavailability test for NDA • Bioavailability studies performed in young healthy male volunteers. under some restriction conditions like :- • fasting • Non smoking • No intake of other medications
  40. 40. APPROACHES FOR DETERMINING IN-VIVO ABSORPTION Wagner-Nelson - One compartment Loo-Riegelman - Multi compartment Numerical Deconvolution - Both model independent method
  41. 41. BIOAVAILABILITY STUDIES FOR DEVELOPMENT OF IVIVC • A bioavailability study should be performed to characterize the plasma concentration versus time profile for each of the formulation. • Bioavailability studies for IVIVC development should be performed with sufficient number of subjects to characterize adequately the performance of the drug product under study
  42. 42. EVALUATION OF PREDICTABILITY OF IVIVC • An IVIVC should be evaluated to demonstrate that predictability of in vivo performance of a drug product from its in vitro dissolution characteristics is maintained over a range of in vitro dissolution release rates and manufacturing changes • Depending on the intended application of an IVIVC and the therapeutic index of the drug, evaluation of prediction error internally and/or externally may be appropriate.
  43. 43. EVALUATION OF PREDICTABILITY OF IVIVC (contd.) External predictability evaluation is not necessary unless the drug is a narrow therapeutic index, or only two release rates were used to develop the IVIVC, or, if the internal predictability criteria are not met i.e. prediction error internally is inconclusive
  44. 44. INTERNAL PREDICTABILITY All IVIVCs should be studied regarding internal predictability. One recommended approach involves the use of the IVIVC model to predict each formulation’s plasma concentration profile (or Cmax and/or AUC for a multiple Level C IVIVC) from each respective formulation’s dissolution data.
  45. 45. EXTERNAL PREDICTABILITY • Therefore, it may be important to establish the external predictability of the IVIVC. This involves using the IVIVC to predict the in vivo performance for a formulation with known bioavailability that was not used in developing the IVIVC model.
  46. 46. EXTERNAL PREDICTABILITY(contd.) • Most important when using an IVIVC as a surrogate for bioequivalence is confidence that the IVIVC can predict in vivo performance of subsequent lots of the drug product.
  47. 47. CONCLUSION • IVIVC includes in vivo relevance to in vitro dissolution specifications and can serve as surrogate for in vivo bioavailability and to support biowaivers. • Furthermore, IVIVC can also allow setting and validating of more meaningful dissolution methods and specifications.
  48. 48. CONCLUSION(contd.) • It can also assist in quality control for certain scale-up and post-approval changes
  49. 49. REFERENCES • Venkateswarlu V. , “Biopharmaceutics and Pharmacokinetics”, edition 2004, PharmaMed press, Hyderabad. • Brahmankar D.M., Jaiswal B. Sunil, “bipharmaceutics and pharmacokinetics- a treatise”, first edition 1995, Vallabh prakashan, New Delhi. • Sharge leon , yu pc andrew, applied biopharmaceutics and pharmacokinetics, third edition.
  50. 50. THANK YOU

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