In vitro - In vivo Correlation

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In vitro - In vivo Correlation:

In vitro - In vivo Correlation Presented by: Madhur Singhal Faculty of Pharmacy, Jamia Hamdard New Delhi, India Presented to: RESPECTED ZEENAT IQBAL MADAM. LEC. DEPT. OF PHARMCEUTICS. FACULTY OF PHARMACY,JAMIA HAMDARD NEW DELHI,INDIA

In vitro - In vivo Correlation:

In vitro - In vivo Correlation 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. The main objective of an IVIVC is to serve as a surrogate for in vivo bioavailability . IVIVCs could also be employed to establish dissolution specifications and to support and/or validate the use of dissolution methods

DEFINITIONS:

DEFINITIONS United State Pharmacopoeia (USP) definition The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form. Food and Drug Administration (FDA) definition IVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.

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OFFICIAL METHOD OF IN-VITRO DISSOLUTION

Rotating Basket Apparatus (Apparatus 1):

Rotating Basket Apparatus (Apparatus 1) It is basically a closed-compartment, beaker type apparatus. It comprising of a cylindrical glass vessel with hemispherical bottom of one liter capacity partially immersed in a water bath. A cylindrical basket made of # 22 mesh is located centrally in the vessel at a distance of 2 cm from the bottom and rotated by a variable speed motor through a shaft. 5

Rotating Paddle Apparatus (Apparatus 2):

Rotating Paddle Apparatus (Apparatus 2) Here, basket is replaced with a stirrer. A small, loose, wire helix may be attached to the dosage form that would otherwise float. The position and alignment of the paddle are specified in the official books.

The Reciprocating Cylinder Method (Apparatus 3):

The Reciprocating Cylinder Method (Apparatus 3) This method adopts the USP disintegration “basket and rack” assembly for the dissolution test. This method is less suitable for precise dissolution testing due to the amount of agitation and vibration involved. E.g. Chlorpheniramine ER tablets, Carbamazepine chewable tablet

Paddle over Disk method (Apparatus 5):

Paddle over Disk method (Apparatus 5) Modification of Apparatus 2. Here, stainless steel disk designed for holding transdermal system at the bottom of the vessel. The disk/device should not sorb, react with, or interfere with the specimen being tested. The disk holds the system flat and is positioned such that the release surface is parallel with the bottom of the paddle blade.

CORRELATION LEVELS:

CORRELATION LEVELS The concept of correlation level is based upon the ability of the correlation to reflect the complete plasma drug level-time profile which will result from administration of the given dosage form .

HOW WE PREDICT % AMOUNT OF DRUG ABSORBED FROM IN VITRO DISSOLUTION DATA????(Deconvolution):

HOW WE PREDICT % AMOUNT OF DRUG ABSORBED FROM IN VITRO DISSOLUTION DATA????( Deconvolution ) The predicted fraction of the drug absorbed is calculated from the observed fraction of the drug dissolved. α and β are the intercept and slope of the regression line, respectively.

Level A correlation:

Level A correlation Highest category correlation Represents point to point relationship Developed by two stage procedure 1-convolution 2- Then evaluating the predictabilty

CONVOLUTION:

CONVOLUTION The predicted fraction of the drug absorbed is then convolved to the predicted drug plasma conentration Predicted fraction of drug absorbed  Predicted plasma drug concentration

Evaluating the Predictability of a Level A Correlation :

Evaluating the Predictability of a Level A Correlation In This predicted bioavailability is then compared to the observed bioavailability for each formulation and a determination of prediction error is made. %PE= <(observed value-predicted value) /observed value>*100 Criteria: 1) Average absolute percent prediction error (% PE) of 10% or less for C max and AUC establishes the predictability of the IVIVC. In addition, the %PE for each formulation should not exceed 15%.

ADVANTAGE::

ADVANTAGE: It reflects complete plasma level curve. since a point to point correlation is developed using every plasma level & dissolution point. A change in manufacture site, method of manufacturing raw material supplies, minor formulation modification & even product strength using the same formulation can be justified.

LEVEL B CORRELATION:  :

LEVEL B CORRELATION : It utilizes the principle of STATISTICAL MOMENT ANALYSIS in which the mean residence time (MRT) of the drug in the body is related to the mean dissolution time (MDT) in vitro . MRT : It is the first moment of the distribution. It is defined as the mean time for drug molecules to transit through the body .& involve any kinetic process. MDT: It represents the mean time for drug molecules to completely dissolve.

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Limitation: level B uses all the in vitro and in vivo data, but it is not considered a point to point correlation, because it does not reflect the actual plasma level curve , The in vitro data of such correlation can not be used to obtain the extreme limits of the quality control standard.

LEVEL C CORRELATION :

LEVEL C CORRELATION IT is a single point correlation. This category relates a dissolution time point (t50%, t90%, etc) to a pharmacokinetic parameter such as AUC, C max or T max LIMITATION: it is a weakest level of correlation as partial relationship between absorption & dissolution established. since level C correlation does not utilize all the data, it can not reflect the complete plasma conc. time curve.

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APPLICABILITY : Since this type of correlation does not allow prediction of the actual performance of the in vivo product, it is useful only as a guide to the development of formulations or as a production quality control routine It can useful in the early stages of formulation development when pilot formulations are being selected . PREDICTIBILITY: T he methods & criteria for assessing the predictability of level C correlation are same as those of level A correlation.

GENERAL CONSIDERATION IN DEVLOPMENT OF IVIVC.   :

GENERAL CONSIDERATION IN DEVLOPMENT OF IVIVC. Human data should be supplied for regulatory consideration of an IVIVC. Bioavailability studies for IVIVC development should be performed with enough subjects to characterize adequately the performance of the drug product under study. parallel studies or cross-study analyses is preferred . IVIVC are usually developed in the fasted state. When a drug is not tolerated in the fasted state, studies may be conducted in the fed state . Any in vitro dissolution method may be used to obtain the dissolution characteristics of the ER dosage form.

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The preferred dissolution apparatus is USP apparatus I (basket) or II (paddle), used at recognized rotation speeds (e.g., 100 rpm for the basket and 50-75 rpm for the paddle). An aqueous medium, either water or a buffered solution preferably not exceeding pH 6.8, is recommended as the initial medium for development of an IVIVC The dissolution profiles of at least 12 individual dosage units from each lot should be determined

PRODUCT DEVLOPMENT STAGES.:

PRODUCT DEVLOPMENT STAGES. 1-Product  2-target 3-prototype formulation4- pilot pk ( retroseptive ivir )  5-defined formulation5- ivir pk study( proseptive ivivr )  6-clinical studies 7-registration 8-approval.

Biopharmaceutical Classification System (BCS):

Biopharmaceutical Classification System (BCS) - Biopharmaceutical classification is use for classifying the drug on the basis of their aqueous solubilty and intestinal permiabilty .

BCS Classes :

BCS Classes Class I Highly permeable Highly soluble Class II Highly permeable Poorly soluble Class III Poorly permeable Highly soluble Class IV Poorly permeable Poorly soluble

Biopharmaceutical Classification System (BCS):

Biopharmaceutical Classification System (BCS) According to the FDA guidelines, a high solubility drug is defined as one that, in the largest dose strength, fully dissolves in 250 mL of aqueous medium with the pH ranging from 1 to 7.5 at 37 ° C. Otherwise, drugs are considered poorly soluble. In other words, the highest therapeutic dose must dissolve in 250 mL of water at any physiological pH In the same guidance as mentioned above, a drug is considered highly permeable if the extent of oral absorption is greater than 90%

Biopharmaceutical Classification System (BCS) objectives:

Biopharmaceutical Classification System (BCS) objectives To guide decisions with respect to in vivo and in vitro correlations and the need for bioequivalence studies To provide a useful framework to identify appropriate dosage form designs that are aimed at overcoming absorption barriers posed by solubility and permeability related challenges

BCS Class I: High Solubility and High Permeability:

BCS Class I: High Solubility and High Permeability Compounds belonging to this class are normally expected to dissolve quickly in gastric and intestinal fluids, and readily cross the intestinal wall through passive diffusion BCS Class I are unlikely to show bioavailability or bioequivalence issues Therefore, for BCS class I drugs, in vitro dissolution studies are thought to provide sufficient information to assure in vivo product performance making full in vivo bioavailability / bioequivalence studies unnecessary

BCS Class II: Poor Solubility and High Permeability:

BCS Class II: Poor Solubility and High Permeability By definition, poor solubility and/or slow dissolution are the rate-limiting steps for oral absorption of BCS class II compounds For compounds with a very large dose-to-solubility ratio, poor solubility is likely to be the rate-limiting step for absorption. In other words, the compounds may dissolve quickly enough to reach their equilibrium solubility, but the solubility is too low to establish a wide enough concentration gradient to drive passive diffusion

BCS Class III: High Solubility and Low Permeability:

BCS Class III: High Solubility and Low Permeability Since passive diffusion is the rate-limiting step for oral absorption of BCS class III compounds, the most effective way to improve absorption and bioavailability of this class of compounds is to increase the membrane permeability Approaches to improve permeability: Prodrugs Permeation enhancers

BCS Class IV: Low Solubility and Low Permeability :

BCS Class IV: Low Solubility and Low Permeability Class IV compounds exhibit both poor solubility and poor permeability, and they pose tremendous challenges to formulation development As a result, a substantial investment in dosage form development with no guarantee of success should be expected A combination of class II and class III technologies could be used to formulate class IV compounds, although the success rate is not expected to be high

REFERENCES:

REFERENCES http://www.ualberta.ca/~csps/JPPS9_2/Jaber_Emami/MS_190.htm WWW.LOCUMUSA.COM pharmaceutical science. Banakar u.v ., pharmaceutical dissolution testing . SHARGEL L, AND Y U . www.fda.gov/cder/guidance

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