Current Implementation of BCS Guidance for Regulatory

Applications and Its Extension Opportunities

 Key Topics of This Presentation

 Development Background of BCS Guidance

 Current Implementation Status of BCS Rules

 Issues and Controversies Related to BCS

 Dissolution of Solid Oral Dosage Forms

Dissolution

Dissolution
Absorption
Rapidly Dissolving Products Containing Highly
Soluble and Highly Permeable Drugs

• Absorption will be “rapid and complete”

• When dissolution is rapid in gastric fluid, the rate of

absorption is primarily a function of gastric emptying

• High solubility plus high permeability classification

ensures extent of absorption

• Dissolution tests may serve as a sensitive tool to ensure

the rate of absorption
 Biopharmaceutics Classification System

0.001
Jejunal Permeability (cm/sec)

Class I: HS, HP Class II: LS, HP

Dissolution rate > Gastric Dissolution is rate-limiting
emptying time

0.0001
Class III: HS, LP Class IV: LS, LP
Absorption is rate-limiting Problem drugs; in vitro
0.00001 dissolution is not reliable

0.000001
1 10 100 1000 10000 100000 mL

Aqueous volume required (1 to 7.5 pH range)

Biopharmaceutics Classification System (BCS) Guidance

 Classification of drugs based on solubility and

intestinal permeability

 Waiver of in vivo BE studies for IR (Immediate

Release) solid oral dosage forms

 Reduction in the costs of approving SUPAC

 Solubility Criterion: D/S Ratio

Dose Dose (mg)

  250 mL
So lub ility Aqueous Solubility (mg/mL)

(a) When D/S is < 250 mL over a pH range of 1 to 7.5;

(b) When D/S is > 250 mL;

D/S = 33 liters
Log P = 2.18

Class 2 Drug Candidate?

Griseofulvin: S = 15 g/mL; Dose = 500 mg

Comparison of Gastric Emptying Time After
Administration of 50- and 200-mL volumes

100 50 mL
Gastric emptying half-time (min) 200 mL
80

60

40

20

0
I II late II/III

Gastric Mobility (IMMC) phase

Gastroenterology 99 (1990) 1275

 Excipient Effect upon Bioavailability

• Sodium pyrophosphate (cathartic laxative): Bioavailability of raniti

dine decreased ?

• Mannitol, sorbitol (cimetidine, theophylline; case studies with chewa

ble tablets and syrups)

• Myristic acid: gastric emptying time increased (nitrofurantoin)

• Polysorbate 80, cremophor, and other surfactants: inhibitors of Pgp

(Pgp substrates’ BE may increase)

• Oleic acid-bile acids (propranolol BE increased); lymphatic uptake

 Common Excipients in IR Tablets
(inactive ingredient guide)

Mg. stearate
Starch
Microcrystalline cellulose
Lactose
Silicone dioxide
Sodium starch glycolate
Stearic acid
Excipients

Povidone
Hydroxypropylmethyl cellulose
Titanium dioxide
Croscarmellose sodium
Polyethylene glycol
Sodium lauryl sulfate
Calcium phosphate
Talc
Sucrose
Hydroxypropyl cellulose
Carnuba wax
Crospovidone
Polysorbate 80
Ethyl cellulose
Acacia
Propylene glycol
Gelatin
Methyl cellulose

0 500 1000 1500 2000 2500

Number of Submissions
 Key Topics of This Presentation

 Development Background of BCS Guidance

 Current Implementation Status of BCS Rules

 Issues and Controversies Related to BCS

 Examples of Class I Drugs
O
O H
H3C N
CH3 C NH OH N
N
O N

Acetaminophen, Paracetamol CH3

OCH3 Theophylline (NTI)

CN CH3
CH3O CCH2CH2CH2NCH2CH2 OCH3 HCl
CH3
CH(CH3)2 OCH2CHCH2NHCH
CH3O CH3
OH HCl
Verapamil
Propranolol
H
N

CH3

Metoprolol OCH2CHCH2NH C H Pindolol

OH CH3
Examples of Class I Drugs (continued)

   December 26

Fluoxetine
Effect of Rotational Speed on Dissolution of
Acetaminophen from IR Dosage Forms

100

80
% Release

60 Panadol tablets (50 rpm)

Panadol tablets (100 rpm)
40

20

0
0 10 20 30 40
Time (rpm)
Dissolution Data of Metoprolol Reference Drug Prod
uct (ANDA & UMAB)

105
90
% Drug Released

75
60
45
30
15
0
0 5 10 15 20 25 30 35
Time (Min)
 Examples of Class II Drugs

Ketoconazole (pKa = 6.5, 2.9) Dipyridamole (pKa = 6.4)

Atovaquone
Carbamazepine
Glibenclamide
Griseofulvin
Danazol
Troglitazone
Ibuprofen
 Examples of Class III Drugs

Acyclovir Atenolol (F = 0.5)

Neomycin Cimetidine (F = 0.84)

Lisinopril Ranitidine (F = 0.52)

 Examples of Class III Drugs (continued)
O O O
S
H2N S NH
O
Cl N
H

Hydrochlorothiazide (0.71) Doxazosin

H CH3
HS O

N H
O

OH

Amiloride
Captopril (0.37)

H2N NH2 O
N
C N CH2SCH2CH2 C N S NH2
H2N S O

Famotidine (0.45) Enalapril

 Formulation Approaches

(1) (2) Nanoparticles

Salt/polymorph derivatives
Liquid-filled capsules
Human Permeability

Self-emulsifying vehicles
Addition of surfactants
Solid dispersions
(3) (4)

Mucoadhesion Liquid-filled capsules with

Absorption-enhancer absorption-enhancer
Efflux inhibitors

D/S 1 100 250 500 1,000 10,000 100,000

 BCS Waiver Candidates: NCE (NDA)

Unknown
60

HS, HP (24%)
50  NDA approvals over the
% Frequency

40 period of 1998 to 2001

30
LS, HP
HS, LP
LS, LP

20
 PO IR formulation (N = 54)
10

0 0 1 2 3 4 5 6

Drug Class
 Direct Cost Savings: Industry

Sample packaging/maintenance: $15,000

Clinical cost: $125,000
Bioanalytical cost: $70,000
Data analysis, report generation: $20,000
Internalization: $20,000

Total BE study cost = $250,000

Savings = # BE studies/yr x $250,000 x

24%
(390 ㅡ 630)
 BCS Waiver Candidates: ANDA

Current Rules (1.5%)

With Extensions
 In-vivo studies to be waived
Infeasible
by BCS guidance are small.

 Drugs qualified for BCS re-

quirement are very few.

 So far, very few submissions

were made to FDA.
 Key Topics of This Presentation

 Development Background of BCS Guidance

 Current Implementation Status of BCS Rules

 Issues and Controversies Related to BCS

 Are BCS Criteria Too Conservative?

Statement of Advisory Committee for Pharm. Sci. (11/16/2000):

“The public concerns are that FDA appraoch relevant to BCS is overly
conservative, and people have argued that FDA should extend the application
of biowaivers for Class II and III drugs. We felt that it was more prudent
at this time to take a more conservative step because this is such a significant
paradigm shift, in terms of risk. It was felt more prudent to be more conservative
at this time.”

Are there any biowaiver extension opportunities for

Class II and III drugs?
 Extension Opportunities for Class II Drugs:
Solubility Issue (pH)

CH3
CH3
CHCH2 CHCO2H
 Some class 2 drugs with pKa <4.5 a CH3
nd instrinsic solubility of > 0.01 mg/
mL are consistently and completely
absorbed after oral administration
8
Intrinsic solubility: 0.064 mg/mL

Ibuprofen solubility (mg/mL)

pKa = 4.39
 These drugs will have solubility o
6
f >1 mg/mL in the jejunum (pH 6.
5), resulting in fast and reliable diss
olution of the drug. However, they 4
can’t fulfill the BCS solubility crite
ria (poorly soluble at gastirc pH)! 2

0
0 2 4 6
pH
 Other Class II Drugs: Solubility (pH)

Compound pKa Human Sol, pH 1.2 Sol, pH 7.4 Dose

BA (%) (mg/mL) (mg/mL) (mg)
Fenoprofen 4.5 85 0.1 > 3.1 200

Flurbiprofen 4.3 92 0.007 2.6 100

Ibuprofen 4.4 > 80 0.06 2.3 200

Ketoprofen 4.6 100 0.13 > 1.4 75

Naproxen 4.2 99 0.005 > 2.5 200

Oxaprozin 4.3 95 ㅡ 100 0.004 1.7 600

 Extension Opportunities for Class II Drugs:
Solubility Issue (Dissolution Medium)

SDS effect upon drug dissolution FaSSIF effect upon drug dissolution
(0.5 ㅡ 2.0%) (Micellar solubilization)
 Medroxyprogesterone acetate ta

blet
 Danazol capsule KH2PO4 3.9 g
 Carbamazepine tablet Na taurochlolate 3 mM
 Flutamide tablet
Lecithin 0.75 mM
KCl 7.7 g
NaOH q.s. pH 6.5
Distilled water q.s. 1 Liter
(Ibuprofen, naproxen)

The necessity of developing dissolution media

simulating physiologically relevant in vivo situation!
 Extension Opportunities for Class III Drugs:
(HS, LP)

 Permeability-limited absorption
 Absorption is less dependent upon IR formulation
 If drug dissolution is rapid ( > 85% in 15-min), IR form
will act as an oral solution in vivo.

If two IR dosage forms with a class III drug dissolve rapidly and
drug absorption is not affected by excipients, their bioequivalence
is assured. Biowaiver can be granted!
 Extension Opportunities for Class III Drugs:
(HS, LP)

Solution vs Tablet Solution vs Tablet

AUCinf Ratio Cmax Ratio
Acebutolol 0.91 ㅡ 1.01 0.96 ㅡ 1.04

Captopril 0.88 ㅡ 1.03 0.88 ㅡ 1.17

Doxazosin 0.94 ㅡ 1.08 0.91 ㅡ 1.05

(IR tablets with various formulations)

 Expert Opinion Based on Atenolol Database

Solubility Permeability Dissolution

Biowaiver is justified,
if IR products meet rapidly dissolving FDA requirements
(NLT 85% in 15 min,900 mL of 0.1 N-HCl, 50 rpm, paddle)
 Permeability Determination for BCS

Pharmacokinetic Studies Intestinal Permeabililty Studies

• Absolute bioavailability stu • Jejunal perfusion method

dies
• In vitro Caco-2 permeability stud
• Mass balance studies with y
use of radiolabeled drug
 Comparison of Drug Permeability (Caco-2 cell)

 High Permeability (F > 0.9)

Acetaminophen Acetylsalicylic acid Antipyrine
Caffeine Labetalol Metoprolol
Naproxen Pindolol Propranolol
Theophylline Ibuprofen Ketoprofen

 Moderate Permeability (F = 0.5 ㅡ 0.89)

Amiloride Atenolol Furosemide]
Ranitidine Hydrochlorothiazide

 Low Permeability (F < 0.50)

Chlorothiazide Dextran Famotidine
Nadolol Sulfasalazine
Permeability Assay: Method Suitability

Extent of Absorption (% fa)

100

80

60 Class I Class II

40 Class III

20
Class IV
0
0 20 40 60 80
Papp (x 10-6 cm/sec)
Permeability of GSK Drugs with That of Metoprolol

Drug BA % Permeability (cm/sec x 106)

Ileum Colon Caco-2

GSK A 99 22 71 120

GSK B 94 1.8 6.5 48

Metoprolol > 90 33 50 78
 Acceptability of Literature Data

Current BCS Rules Modification of BCS Rules

 Solubility  Solubility

 Dissolution  Dissolution

 Caco-2 cell assay  Literature data on BA

(Permeability  BA)
 Conclusions: What Will Be Next Moves?

 Implementation of industrial and academic inputs into the BCS gui

dance

 Further research to extend BCS-based biowaivers

 Taking initiatives in educating health-care professionals and the pu

blic

 International harmonization efforts