A Review on Biopharmaceutical Classification System

 

Swati Saxena*, Dr. Sarang Jain

Rajeev Gandhi College of Pharmacy, Bhopal, India

*Corresponding Author E-mail: sweeto2586@gmail.com

 

ABSTRACT:

The biopharmaceutical classification system (BCS) is the result of continuous effort in the mathematical analysis. By this process we can assume kinetics and dynamics of drug in gastrointestinal tract. This process reduces time required to develop a new drug. FDA has published Biopharmaceutical Classification System in order to guide pharmaceutical companies regarding how product qualifies for biowaivers. This can be achieved by avoiding expensive in vivo bioavailability and bioequivalence studies. It helped pharmaceutical companies for easy application of NDA (New drug Application) and ANDA (Abbreviated new drug application) by combining data of drug’s aqueous solubility as well as in vitro dissolution drug release data. The main objective of this article is to make all researchers understand the concept of Biopharmaceutical classification system of drug in a simple manner. So that they can make use of this knowledge in their research work by reducing time in identifying best drug for their formulation.

 

KEYWORDS: Biopharmaceutical Classification System, solubility, permeability, dissolution, bioequivalence, immediate-release products.

 

 


INTRODUCTION:

Formulating a drug into a dosage form is a very important and difficult step to ensure adequacy of its bioavailability and therapeutic efficacy. For this purpose a wide range of pharmaceutical excipients have been approved by food and drug administration (FDA).  Dissolution and gastrointestinal permeation are mainly two major factors that affect oral bioavailability of drugs. These two parameters mainly depend on intrinsic physicochemical properties of drug like aqueous solubility and lipophilicity. Since oral administration is major target route for pharmaceutical products, so biopharmaceutical classification system is considered. [1].

 

 

To facilitate regulatory approvals for generic drugs as well as post approval changes, FDA publishes several guidelines for immediate release and extended release dosage form on the basis of in vitro in vivo correlation.[2]

 

The biopharmaceutical classification system (BCS) is the result of continuous effort in the mathematical analysis. By this process we can assume kinetics and dynamics of drug in gastrointestinal tract. This process reduces time required to develop a new drug. FDA has published Biopharmaceutical Classification System in order to guide pharmaceutical companies regarding how product qualifies for biowaivers. This can be achieved by avoiding expensive in vivo bioavailability and bioequivalence studies.

·       Abbreviated new drug application [ANDA] (221cfr 314) contain data regarding review and approval of generally not required for clinical trials.

·       Bioequivalence studies are carried out on generic product rather than clinical trials.

·       Now a day’s IVIVC correlation studies are being used for new drug development process.

·       IVIVC is mainly performed to reduce clinical trials and to obtain in vivo bioavailability data of a particular drug before its launch in market.

·       Biopharmaceutical classification system was developed in 1995 as a result of mathematical analysis.[3]

 

CONCEPT:

·       BCS or biopharmaceutical classification system is based on the principle of bioequivalence.

·       According to BCS some drug products can be considered as biowaivers

·       The term biowaivers refers to product approval based on in vitro dissolution test.

·       Previously biowaivers were applied to SUPAC ( Scale up and post approval changes).[4]

·       By this process human clinical trials were avoided.

·       It provides a scheme for manipulation of structure or physicochemical properties of some drugs to achieve better deliverability.[5]

 

OBJECTIVE:

·       To improve efficiency of drug development process by recommending a strategy for identifying expendable clinical bioequivalence test.

·       To recommend a class of immediate release solid oral dosage form for which bioequivalence test can be accessed on the basis of invitro dissolution test.

·       To recommend method for classification according to dosage form dissolution along with the solubility –permeability characteristics of drug product.[6]

 

HISTORY OF BCS SYSTEM:

·       The theoretical basis of biopharmaceutical classification system (BCS) was first described in 1995.

·       The German federal institute for drugs and medical devices (BFArm) announced a revision to the drug approval process (article 21 of German drug law)

·       In June 200 new announcement replacing 9th announcement on bioavailability and bioequivalence came in to force.

·       The German conference on BCS system was held firstly on march 2003.

·       The first biowaivers was issued by BFArm in 2002 for drug compound Sotalol hydrochloride.

 

CLASSIFICATION:

The BCS is scientific approach of classifying a drug substance on the basis of aqueous solubility and intestinal permeability.

 

 

Biopharmaceutical classification system (BCS) is also based on first fick’s law

Jw =Pw.Cw

 

JW – Drug flux

Pw – Permeability of membrane.

Cw- Drug concentration. [7]

 

BCS has been developed to predict in-vivo pharmacokinetics of oral immediate release drug. [8]

On the basis of in-vitro dissolution data BCS system depends on three major factors.

1)    Solubility

2)    Intestinal permeability

3)    Dissolution rate [9]

 

A drug is considered to be highly soluble if its highest strength gets dissolved in 250ml of aqueous media between ph 1.0-7.5 Solubility classification of BCS depends on highest strength of IR product.

 

Permeability classification of BCS depends on extent of intestinal absorption. A drug is considered to be highly permeable if its extent of absorption is 90%.

 

A drug is considered to have high dissolution rate when not less than 85% of drug dissolves within 30 minutes. [10]

 

Biopharmaceutical classification system

Class

Solubility

Permeability

I

 High

High

II

Low

High

III

High

Low

IV

Low

Low

 

Key parameters associated with BCS system:

1.       Absorption number (An):

It is defined as the ratio of mean residence time to mean absorption time.

Peff  X  Tres

An =---------------------

R

 

2.       Dissolution number (Dn):

It is defined as the ratio of mean residence time to mean dissolution time.

 

Tres

Dn =---------------------

Tdiss

 

3.       Dose number (Do):-

It is defined as ratio of mass and product uptake volume and solubility of drug. [11]

 

 

Mo

Do=-------------------

CsVo

 

Different classes of BCS system:

Class I:

·       Drug of this category have high absorption number and high dissolution number.

·       Dissolution is the rate limiting step.

·       These compounds are well absorbed and absorption rate is high.

·       These classes of drug have high absorption into the circulation.

·       These classes of drug are anticipated to have less variation in oral absorption because they are readily absorbed in small intestinal, readily released from dosage form and efficiently absorbed across intestinal epithelium.

·       These drugs are suitable for sustained and immediate release formulations.

E.g. Metoprolol, Diltiazem, Verapamil, Propanolol.

 

Class II:

·       Drugs belonging to this category have high absorption number but low dissolution number.

·       Absorption for this class of drugs is usually slower than for class I.

·       In vitro in vivo correlation (IVIVC) is usually accepted for class I and class II drugs.

·       Intestinal absorption may be limited by dissolution.

·       Oral absorption of these drugs can be improved by excipients.

E.g. Glibenclamide, Phenytoin, Danazol, Mefenamic acid, Nifidipine, Ketoprofen, Naproxen, Carbamazepine and Ketoconazole.

 

Class III:

·       Drug permeability is rate limiting step for drug absorption in this category of drugs.

·       Sustained release for this class drugs is quite difficult.

E.g. Cimetidine, Ranitidine, Acyclovir, Captopril, Atenolol.

 

Class IV:

·       Drugs for this class are difficult for effective oral absorption.

·       They have poor bioavailability and not well absorbed in intestine.

E.g. Furosemide, Hydrochlorthiazide.

 

 

Immediate release,

Sustain release,

Enteric coating

(I)

Immediate release

Sustain release,

Enteric coatings

(II)

Immediate release

Enteric coatings

(III)

Immediate release,

Enteric coatings

(IV)

 

 

Benefits of knowing BCS system of drugs:

·       If we know the BCS category of drug we can directly follow FDA guidance.

·       It will save time, money and different assets required for market launch data.

 

In vitro in vivo correlation:

 

Drug product for which bioavailability or bioequivalence may be self evident:

According to US FDA 21 CFR 320.22 specific requirements for certain drug products are as follows:

(a)  A drugs product which is in soluble form contains active ingredients combined with same solvent. It is subject to NDA approval.

(b)  Drugs products are topically applied preparation.

(c)  Drug product in oral dosage is not intended to be absorbed.

 

REFERENCES:

1.      www.accessdata.fda.gov/scripts/cder/iig/index.cfm

2.      Guidance for industry extended release oral dosage form: development, evaluation and application of invitro/ in vivo correlation

3.      Rinaki E, Valsami G; Macheras P, Quantitative biopharmaceutical classification system: the central role of dose/solubility ratio. Pharm. Res.2003, 20(12), 1917-1925.

4.      Abraham J, Lewis G, Harmonizing and competing for medicines regulation: how healthy are the European Union’s systems of drug approval. Soc sci, med.48 (1999)1655-1667.

5.      Yu L. X; Amidon GL, Polli JE; Zhao H; Mehta M U; Corner D P, shah, V.P, Lesko, L J chem., ML; Lee VHL, Biopharmaceutics classification system: The scientific basis for biowaivers extensions: Pharm. Res. 2002, 19(7) 921-925.

6.      Verma MV; Khandavilli, S; Ashokraj Y; Dhanikula A; Sood A; Thomas NS; Pillai, O; Sharma, P, Gandhi, R; Agarwal, S Nair, V; Panchaguna, R. Biopharmaceutics classification system: A scientific framework for pharmacokinetics optimization in drug research. Curr. Drug Metab 2004, 5(5), 375-388.

7.      Waiver of in vivo bioavailability and bioequivalence studies for immediate release solid –oral dosage forms based on a biopharmaceutics classification system; Guidance for industry;  US department of health and human services, Food and Drug administration, Centre for drug evaluation and research (CDER), U.S government printing office: Washington, DC, August 2000.http:// www.fda.gov/downloads/drugs/guidance /compliance regulatory information/ guidance/ucm070246 pdf (accessed on date)

8.      Shargel Leon, WuPong Sussana, Yu Andrew, Applied Biopharmaceutics and Pharmacokinetics, Mc Graw Hills Publication,2004, 5th edition, p.no367

9.      Amidon G.L; lennernas H, shah V.P., gison J.R.A. A theoretical basis for a biopharmaceutics drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 1995, 12(3), 413-419.

10.   Guidance for industry, waiver of in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage form based on biopharmaceutical classification system august 2000, CDER/FDA

11.   Lawrence X. Yu, Gordon L Amidon, James E Polli, Hong Zhao, Mehul U Mehta, Dale P Conner, Vinod P Shah; Lawrence J. Lesko, Mei-Ling chein, wincent H. L, Lee, and Ajaz S. Hussain. Biopharmaceutics classification system: The scientific basis for biowaivers extension Pharm.Res .19(7), 2002. 921-925

 

 

 

 

 

Received on 17.08.2019            Accepted on 20.09.2019           

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2019; 9 (4):267-270.

DOI: 10.5958/2231-5713.2019.00044.8