IN VITRO- IN VIVO VITROCORRELATION ESTABLISHMENT IN ORAL FORMULATION

Presented By: Ankush Kumar (M.Pharm 1st Sem Pharmaceutics)

I.S.F COLLEGE OF PHARMACY MOGA(PUNJAB)

INTRODUCTION

IVIVC can be used in the development of new pharmaceuticals to reduce the number of human studies during the formulation development. The main objective of IVIVC is to serve as a surrogate for in-vivo bioavailability and to support biowaivers. IVIVC could also be employed to establish dissolution specification and to support and/or validate the use of dissolution methods. It can also assist in quality control for certain scale-up and post approval changes, for instance, to improve formulations or to change production processes.

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.

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 WagnerNelson Procedure or Loo-Riegelman method or by Model independent numerical deconvolution. 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. 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 doesnt reflect the entire shape of plasma drug conc. curve.

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.

BACKGROUND

In vitro-in vivo correlation (IVIVC)

the

correlation between in vitro drug dissolution and in vivo drug absorption

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.

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

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.
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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 10 solutions.

THE BENEFITS OF KNOWING THE BCS CATEGORY OF A COMPOUND

It can save both time and moneyif the immediate -release, orally administered drug meets specific criteria, the FDA will grant a waiver for expensive and timeconsuming 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.

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Combined with the dissolution, the BCS takes into account the three major factors governing bioavailability viz. dissolution, solubility and permeability. This classification is associated with drug dissolution and absorption model, which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz.

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KEY PARAMETERS CONTROLLING DRUG ABSORPTION Absorption number (An) :defined as the ratio of the mean residence time to mean absorption time.

Dissolution number (Dn) :defined as the ratio of mean residence time to mean dissolution time.

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Dose number (D0) :defined as the mass (Dose) divided by the product of (uptake volume (250 ml) and solubility of drug). D0 = Dose/(V.Cs)

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.

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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.
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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.

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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.

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IN VITRO/IN VIVO CORRELATION

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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.

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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.

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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.

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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.

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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.

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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.

TYPES OF DISSOLUTION APPRATUS Rotating basket Paddle method Reciprocating cylinder Flow through cell

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

SAMPLING TIME POINTS

Time Points IR products Test duration : 15 to 60 minutes Specifications Single point : NLT 85% in 15 minutes Dissolution profile : sampling at 5-, 10-or 15minute intervals

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

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

APPROACHES FOR DETERMINING IN-VIVO ABSORPTION Wagner-Nelson Loo-Riegelman Numerical Deconvolution One compartment Multi compartment Both model independent method

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.

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