Biopharmaceutics classification system

BIOPHARMACEUTICAL

CLASSIFICATION SYSTEM

Jamia HamdardPresented to: Dr. K. K.

Pillai

By: Md Shakeeb

Ahmed

CONTENTS

1.INTRODUCTION 2.SIGNIFICANCE OF BCS

3.INFLUENCE OF BCS ON BIOAVAILABILITY

INTRODUCTION

Continues to dominate the area of drug delivery technologies

Route of choice for the formulators

formulated Drug

product

KidKdd

Solubilized drug

absorbed drug

dissolutiondisintegration permeability

dispersedDrug

particles

Kp

DRUG DISSOLUTION AND ABSORPTION

BIOPHARMACEUTICAL CLASSIFICATION SYSTEM

A scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability

Established by Gordon Amidon et al.

BCS has gained importance worldwide as a drug product regulation tool For scale-up and post-approval changes

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.

BIOPHARMACEUTICS CLASSIFICATION SYSTEM (as defined by the FDA after Amidon et al.)

BCS CLASS MEMBERSHIP

Class IPropranololVerapamil

Metoprolol

Class IIKetoprofenNaproxen

Carbamazepine

Low

Hig

h

Class IVFurosemide

Hydrochlorothiazide

Class IIIRanitidineCimetidine

AtenololVancomycin

High

Low

Classification of a drug depends upon its three key parameters, that control absorption:

SolubilityDissolution

ratepermeability

Dose no.Dissolution

no.Absorption no.

that correlate with three respective dimensionless parameters

DOSE NUMBERA function of solubility of drug substance

Should be less than 1.

S

W ater

C

VD

Do

Highest Dose Unit250 mL

Solubility

It is the dose concentration/solubility ratio

DISSOLUTION NUMBERA function of drug release from formulation

Should exceed 1

• Defined as the ratio of mean residence time to mean dissolution time

Dn= [TGI/TCD]

TGI = Residence time in GI (approx. 180 min)TCD= Time required for complete dissolution

ABSORPTION NUMBER

ABS

GI

TTAn

“A function of GI Permeability to Drug Substance”

TGI = Residence time in GI (approx. 180 min)TABS = Time required for complete absorption

• Absorption number (An) is the time required to absorb the administered dose

• It is the ratio of the mean residence time to mean absorption time.

Should exceed 1

PERMEABILITY DETERMINATION

A. Determination of extent of absorption in humans:• Mass balance P/K studies • Absolute bioavailability studies

B. Intestinal permeability methods:• In vivo intestinal perfusion studies in humans• In vivo or in situ intestinal perfusion studies in animal• In vitro permeability methods using excised

human/animal intestinal tissues• In vitro permeation studies across a monolayer of

cultured epithelial cells. e.g. Caco-2 cells or TC-7 cells

DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm.

Dissolution media (900 ml): 0.1 N HCl or simulated gastric fluid, pH 4.5 buffer, and pH 6.8 buffer or simulated intestinal fluid.

Compare dissolution profiles of test and reference products using a similarity factor (f2).

N= no. of dissolution time pointsRt = dissolution value of the reference drug product at time tTt = dissolution value of the test drug product at time t

If f2= 100 ; dissolution profiles are identical

SOLUBILITY DETERMINATION

“Shake flask method”

• pH- solubility profile of test drug in aqueous media within a pH range of 1.0-7.5

• A minimum of three replicate determinations of solubility in each pH condition

• Methods other than shake flask method (with Justification). e g. acid or base titration methods

CLASS BOUNDARIES

HIGHLY SOLUBLE; the highest dose strength should be soluble in < 250 ml water over a pH range of 1 to 7.5. (The volume estimate-a glassful i.e. 8 ounce)

HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% of an administered dose

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.

BCS CLASS BOUNDARIES: OBJECTIVES

Dissolution(Product)

Solubility (Drug)

Permeability(Drug)

Rapid dissolution - ensure that in vivodissolution is not likely to be the “rate determining” step

High solubility- ensure that solubilityis not likely to limit dissolution and, therefore, absorption

High permeability - ensure that drugis completely absorbed during the limited transit time through the small intestine

Class Solubility

Permeability

Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected, if dissolution rate is slower than gastric emptying rate, otherwise limited or no correlations

II Low High Dissolution IVIVC expected, if in vitro dissolution rate is similar to in vivo dissolution rate, unless dose is very high.

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution.

IV Low Low Case by case Limited or no IVIVC is expected.

IVIVC EXPECTATIONS FOR IRP BASED ON BCS

High Solubility Low Solubility H

igh

Per

mea

bili

ty

Class 1

Abacavir

Acetaminophen

Acyclovirb

AmilorideS,I

Amitryptyline S,I

Antipyrine

Atropine

Buspironec

Caffeine

Captopril

ChloroquineS,I

Chlorpheniramine Cyclophosphamide

Desipramine

Diazepam Diltiazem S,I

Diphenhydramine Disopyramide

Doxepin Doxycycline

Enalapril

Ephedrine

Ergonovine

Ethambutol

Ethinyl Estradiol

FluoxetineI

Glucose

ImipramineI

Ketorolac Ketoprofen

Labetolol

LevodopaS

Levofloxacin S

LidocaineI Lomefloxacin

Meperidine Metoprolol

Metronidazole MidazolamS,I Minocycline Misoprostol

Nifedipine S

Phenobarbital

Phenylalanine

Prednisolone

PrimaquineS

Promazine

Propranolol I

QuinidineS,I

Rosiglitazone

Salicylic acid

Theophylline

Valproic acid

Verapamil I

Zidovudine

Class 2

Amiodarone I

AtorvastatinS, I

AzithromycinS ,I

Carbamazepine S,I

Carvedilol Chlorpromazine

I

CisaprideS

Ciprofloxacin S

Cyclosporine S, I

Danazol Dapsone Diclofenac

Diflunisal

Digoxin S

Erythromycin S,I

Flurbiprofen

Glipizide GlyburideS,I Griseofulvin

Ibuprofen

Indinavir S

Indomethacin

Itraconazole S,I

Ketoconazole I

LansoprazoleI Lovastatin S,I

Mebendazole

Naproxen

Nelfinavir S,I

Ofloxacin

Oxaprozin

Phenazopyridine

PhenytoinS

Piroxicam

Raloxifene S

Ritonavir S,I

Saquinavir S,I

Sirolimus S

Spironolactone I

Tacrolimus S,I

TalinololS

Tamoxifen I

Terfenadine I

Warfarin

High Solubility Low Solubility L

ow

Pe

rmea

bil

ity

Class 3

Acyclovir

Amiloride S,I

Amoxicillin S,I

Atenolol

Atropine

Bisphosphonates

Bidisomide

Captopril

Cefazolin

Cetirizine

Cimetidine S

Ciprofloxacin S

Cloxacillin

Dicloxacillin S

Erythromycin S,I

Famotidine

Fexofenadine S

Folinic acid

Furosemide

Ganciclovir

Hydrochlorothiazide

Lisinopril

Metformin

Methotrexate

Nadolol

Pravastatin S

Penicillins

Ranitidine S

Tetracycline

Trimethoprim S

Valsartan

Zalcitabine

Class 4

Amphotericin B

Chlorthalidone

Chlorothiazide

Colistin

Ciprofloxacin S

Furosemide

Hydrochlorothiazide

Mebendazole

Methotrexate

Neomycin

Class I - High Permeability, High Solubility• Drugs dissolved rapidly• Drugs absorbed rapidly• Rapid therapeutic action• Excellent property• Ideal for oral route• e.g. Metoprolol, Diltiazem, Verapamil, Propranolol,

CLASS – I

• Drugs dissolve slowly

• Drugs absorbed rapidly

• Controlled released drugs

• Oral / IV route for administration

• Ex. Glibenclamide, Ezetimibe, Phenytoin, Nifedipine

CLASS – II

• Dissolved rapidly

• Absorbance is limited

• Incomplete bioavailability

• Oral / IV route for administration

• Ex. Cimetidine, Acyclovir, Captopril

CLASS – III

• Low dissolution rate

• Low permeability property

• Slow or low therapeutic action

• IV or other routes are required

• Ex. Hydrochlorothiazide

CLASS – IV

Background: About biowaivers

BCS BASED BIOWAIVER

A biowaiver is an exemption from conducting human bioequivalence studies

Criteria for Biowaiver

Immediate-release solid oral dosage form

Rapid and similar dissolution.

High solubility &High permeability.

Wide therapeutic window.

Excipients used in dosage form are same as those present in approved drug product

• Companies can potentially save thousands of dollars in costs, and several months of time in development, if bioequivalence studies are avoided

REQUEST FOR BIOWAIVERS

Data Supporting :-

Rapid and Similar Dissolution

High Permeability

High Solubility

Biowaiver: Class III compounds are eligible biowaiver if they dissolve within 15 minutes in buffer media pH 1.2 –6.8 (75 rpm)

Biowaiver: Class II acids with D:S ratio < 250 ml at pH 6.8 and > 85 % dissolved within 30 minutes at pH 6.8 (75 rpm)

NO BIOWAIVER FOR:

As the BCS is only applicable to APIs which are absorbed from the small intestine; drugs absorbed from other sites (e.g. from the oral cavity) are not eligible for a biowaiver

non-oral immediate release forms with systemic action

modified release products

transdermal products

SURROGATE MARKERS

Drug product Drug Possible surrogate marker for

bioequivalence

Topical steroid Hydrocortisone Skin blanching

Anion exchange resin

Cholestyramine Binding to bile acids

Antacids Mg & Al hydroxide gel

Neutralization of acid

Topical antifungal

Ketoconazole Drug uptake into stratum corneum

SIGNIFICANCE OF BCS

Regulatory toll for replacement of certain BE studies.It can save both time and money—if the immediate -release,orally administered drug meets specific criteria, the FDA willgrant a waiver for expensive and time-consuming bio-equivalence studies.Valuable tool for formulation scientist for selection of designof formulated drug substance.When integrated with other information provide atremendous tool for efficient drug development.Reduces cost and time of approving Scale- up and postapproval challenges.Applicable in both pre-clinical and clinical drug developmentprocess.Works as a guiding tool in development of various oral drugdelivery systems.

BCS can be used as a key component to guide drug delivery system design for any route of administration

DRAWBACKS OF BCS BIOWAIVERS

• Sponsors are sometimes reluctant to apply for biowaivers due to the perceived lack of certainty of acceptance by the regulatory agencies.

• Industrial implementation of BCS may also be limited due to:

– unnecessary barriers in existing guidelines

– compartmentalization of company resources

– or a general lack of knowledge about BCS or the biowaiver process.

ELIGIBLE APIs FOR WHO BCS-BASED BIOWAIVER APPLICATIONS:

DRUG CATEGORY DRUGS ELIGIBLE FOR BIOWAIVER APPLICATIONS

antiretroviral Abacavir Emtricitabine Lamivudine Stavudine zidovudine

anti-tuberculosis Ethambutol Isoniazid Levofloxacin Ofloxacin Moxifloxacin pyrazinamide

REFERNCES

Draft guidance for industry, waiver of in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties/ active ingredients based on a biopharmaceutics classification system, February 1999, CDER/FDA.

Amidon G.L., Lennernas H., Shah V.P., Crison 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. 12: 413-420 (1995).

Guidance for industry, immediate release solid oral dosage forms: scale up and post approval changes, November 1995, CDER/FDA.

Medicamento generico from website http://www.Anvisa.Go/.

Particle size; Drug development services; Technical Brief 2011 Volume 9

REFERNCES

Devane J., Oral drug delivery technology: addressing the solubility/ permeability paradigm, pharm. Technol. 68-74, November 1998

Amidon, G. L.,Lennernäs H., Shah V. P., And Crisonj. R., A theoretical basis for a biopharmaceutics drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability, Pharmaceutical research, 12: 413-420 (1995)

Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms, FDA CDER, 1997 http://www.fda.gov/cder/guidance/1713bp1.pdf

Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, FDA CDER, August 2000 http://www.fda.gov/cder/guidance/3618fnl.htm

WHO Prequalification of Medicines Programme; General notes on Biopharmaceutics Classification System (BCS)-based biowaiver applications; Guidance Document October 2012

REFERNCES

Chi-Yuan Wu and Leslie Z. Benet, (2005); “Predicting Drug Disposition via Application of BCS: Transport/Absorption/Elimination Interplay and Development of a Biopharmaceutics Drug Disposition Classification System” ; Pharmaceutical Research, Vol. 22, No. 1, January

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