Evolution of EUDRAGIT Applications with the New TechnologiesEvolution of EUDRAGIT ® Applications...

1

Evolution of EUDRAGIT®

Applications with the New

Technologies

-Options to Meet

Modern Therapeutic Needs

Dr. Brigitte Skalsky

Evonik Industries, Pharma Polymers

Barcelona, December 2, 2010

Pharma Polymers | Brigitte Skalsky 2010-12-02 Barcelona Page | 2

EUDRAGIT® polymers

and their applications

Enteric coatings

Insoluble in acidic media

Taste masking &

moisture protection

Soluble in gastric fluid /

fast disintegrating

Sustained release

Insoluble but permeable,

pH independent

EUDRAGIT® L- & S-Polymers EUDRAGIT® E-Polymer

EUDRAGIT® NE- & NM-Polymer EUDRAGIT® RL- & RS-Polymer

EUDRAGIT®

2


Agenda

Matrix Formulations:

• pH-controlled

• Time-controlled

• Case study: Bupropion HCl SR tablets

Multi-layer coatings

• Drug delivery system EUDRACOL®

• Modulated drug release

Solubility enhancement:

• Melt extrusion

• Spray drying


Agenda


• pH-controlled

• Time-controlled






• Melt extrusion

• Spray drying

3


EUDRAGIT® polymers applications

in matrix formulations

RL PO, RS PO �� time-control

L100, L 100-55 �� pH-control

S100, �� time-control

Roller compaction

RL PO, RS PO �� time-control

L 100-55 L100 �� pH-control

S100 �� time-control

Direct compression

RL 100, RS 100, RL PO, RS PO �� time-control

L 100-55 �� pH-control

Hot melt

granulation / pelletization / extrusion

RL 100, RS 100, RLPO, RSPO �� time-control

L 100-55, L100, L 12,5 �� pH-control

S 12,5, S100 �� time-control

Organic granulation / pelletization

RL 30 D, RS 30 D �� time-control

NE 30 D, NE 40 D, NM 30 D �� time-control

L 100-55, L 30 D-55, L100 �� pH-control

S100 �� time-control

Aqueous granulation / pelletization

EUDRAGIT® gradeProcess technology

Pharma Polymers | Brigitte Skalsky 2010-12-02 Barcelona

Anionic EUDRAGIT® types

in matrix applications

≥≥≥≥ pH 7.0FS 30 D

≥≥≥≥ pH 7.0BS 100

S 12,5

≥≥≥≥ pH 6.0AL 100

L 12,5

≥≥≥≥ pH 5.5CL 30 D-55

L 100-55

SolubilityMethacrylic Acid

Copolymer

USP/NF Type

EUDRAGIT®

Type

time controlled matrices

with S / FS under

physiological conditions

pH controlled matrices

4


Drug release from inert matrices –pH controlled with EUDRAGIT® L polymers


EUDRAGIT® L 30 D-55 matrix pH profile

35% Diltiazem, 20% polymer, fluid bed, 500mg tablet, 15 kN

0

10

2030

40

50

60

7080

90

100

0 60 120 180 240 300 360 420 480 540

Time (min)

% D

isso

lved

pH 1

pH 6

pH 6.8

pH 7.4

�EUDRAGIT® L 30 D-55 provides pH dependent release

5


Drug release from inert matrices –time controlled with EUDRAGIT® NE, NM, RL/RS, S, FS


0

10

20

30

40

50

60

70

80

90

100

0 60 120 180 240 300 360 420 480 540

Time (min)

% D

isso

lved

pH 1

pH 6

pH 6.8

�� EUDRAGIT® FS 30 D provides pH independent release

EUDRAGIT® FS 30 D matrix pH profile

35% Diltiazem, 20% polymer, fluid bed, 500mg tablet, 15 kN

6


Release Profile at pH=1.0

0102030405060708090100

0 100 200 300 400 500

Time [min]

%Dis

solv

ed

Aquacoat® ECD (20%)

Methocel® E5 (20%)

Methocel® K4M (20%)

Methocel® K15M(20%)

EUDRAGIT® NE 30D (20%)

EUDRAGIT® NE 30D (7.5%)

Release Profile at pH=6.8

0102030405060708090100

0 100 200 300 400 500

Time [min]

% D

issolv

ed

Aquacoat® ECD (20%)

Methocel® E5 (20%)



EUDRAGIT® NE 30D (20%)

EUDRAGIT® NE 30D (7.5%)

SR Potential of different matrix formers

• Retardation of Methocel

types depends on molecular

weight

• Methocel matrices show

some pH dependency

• 7.5% EUDRAGIT® NE

similar to 20% Aquacoat


�� Superior compressibility with EUDRAGIT® NE 30 D

0

50

100

150

200

Crushing

st rengt h ( N )

Aquacoat® ECD (20%) Methocel® E5 (20%) Methocel® K4M (20%) Methocel® K15M

(20%)

EUDRAGIT® NE 30D

(20%)

EUDRAGIT® NE 30D

(7.5%)

Compression f o rce ( 15kN )

Compressibility of different matrix formers

35% Diltiazem, 500mg tablet weight, fluid bed granulation

7


SR matrix pellets by melt extrusion

0

20

40

60

80

100

120

0 100 200 300 400 500 600 700 800

time t [min]

Dis

solu

tion T

heophyllin

[%

] RS(80)+RL(00)+Theophyllin(20)

RS(40)+RL(40)+Theophyllin(20)



RS(32,5)+RL(32,5)+Theophyllin(35)





pH 1.2 pH 6.8

RL PO only + Theophyllin

RL PO + RS PO + Theophyllin

RS PO only + Theophyllin

• round shaped Micro Spheres can be obtained by

an air-cooled hot-face cutting process

• the combination of EUDRAGIT® RL/RS gives a

high variability in dissolution kinetics

• optional coatings to add functionalities


Melt extrusion pellets from

LEISTRITZ Micro Pelletizer (1)

Extruder

Knife

Nozzle

Ring Nozzle Plate

Heat Sealing Cap

Extruder Screws

Polymer Melt

8


Melt extrusion pellets from

LEISTRITZ Micro Pelletizer (2)


Agenda


• pH-controlled

• Time-controlled






• Melt extrusion

• Spray drying

9


Buproprion hydrochloride

BCS Classification : Class I

Solubility : High solubility i.e. 312 mg /ml in water,

193 mg/ml in alcohol,

333 mg/ml 0.1 N HCl (Merck Index).

Appearance : White crystalline powder, bitter in taste

Therapeutic class : Antidepressant

USP SPECIFICATIONS

Not less than 80%8

60 to 85 4

25 to 45 1

Drug released [%]Time [hours]


EUDRAGIT® FS 30 D matrix granulation –

top spray fluid bed

Dry Mixing

150Bupropion hydrochloride

15L-Cysteine hydrochloride

133Microcrystalline cellulose

Granulation

60EUDRAGIT® FS 30 D

(Solid Content)

Lubrication

24PVP K-90

16Glyceryl behenate

2Calcium stearate

400Total

Weight per tablet (mg)

10


0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Time in hours

% Release of Bupropion HCl ± SD

Water

Buffer pH 1.2

Buffer pH 3.0

Buffer pH 4.5

Release of Bupropion independent from EUDRAGIT® FS matrix tablets

Robust drug release in different media


Storage stability

Final formula contains 15% w/w EUDRAGIT® FS 30 D per tablet

0

20

40

60

80

100

0 2 4 6 8Time in hours

%Release of Bupropion HCl + SD

Initial

3M 40ºC-75% RH

USP LOWER LIMITS

USP UPPER LIMITS

Tablet Hardness: 200-250 N, Friability: 0,1%

11


Agenda


• pH-controlled

• Time-controlled






• Melt extrusion

• Spray drying


The EUDRACOL® design

EUDRAGIT® RL / RS layer

● Sustained release behaviour

varies with polymer ratio & film thickness

EUDRAGIT® FS layer

● Colon Targeting

a

Drug containing pellet

a) Sugar bead & layered drug (low drug loading)

b

b) Drug pellet (high drug loading)

12


How does EUDRACOL® work?


In-vivo proof of concept

A. EUDRACOLTM delivers drug along the colonic transit

B. IR Pellets delivers drug to the colon

C. IR Reference releases drug in stomach

Caffein

edis

solv

ed

[%]

In-vitro dissolution profiles

0

20

40

60

80

100

0

time [h]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

0.1 N HCl

buffer pH 7.5

0 4 8 12 16 20 24

0

3

6

9

12

15

18

21

Human plasma profiles

time [h]

Seru

m level[µ

mol/L]

Arrival in colon t lag

13


Agenda


• pH-controlled

• Time-controlled






• Melt extrusion

• Spray drying


CH2

C

C=O

CH3

CH2

C

C=O

H

OC2H5

CH2

C

C=O

CH3

OCH3 O

C2H4N

+(CH3)3Cl-

CH3COO-Na+

+CH3COO

-

C2H4N+(CH3)3

+

Na+Cl-

Ionic

Interaction

Modulated drug release based on

EUDRAGIT® RL/RS 30 D features

Increased permeability

by enhanced swelling

14


How does it work?Tailor made profiles based on EUDRAGIT® RL/RS + NE

Water

Controlled release of salt

Salts interacts with

outer polymer layer

Modulated Drug

Release

Initial diffusion

of drug

Slow-Quick Release

0

20

40

60

80

100

0 2 4 6 8 10 12 14

Zero-order Release

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14

Accelerated Release

0

20

40

60

80

100

0 2 4 6 8 10 12 14

Quick-Slow Release

0

20

40

60

80

100

0 2 4 6 8 10 12 14

CR layer

EUDRAGIT® RL/RS

Modulating layer

EUDRAGIT® NE

Salt

Drug layer

1

2

3

4

5


0

20

40

60

80

100

0 2 4 6 8 10 12

Pellets containing different salts as cores and coated

with EUDRAGIT® RS as the controlled release layer

(20%w/w)

Time in hours

% T

heophyllin

e rele

ased

Acetate

Citrate

Succinate

Chloride

0

20

40

60

80

100

0 2 4 6 8 10 12

Tool box (1 of 4)

Influence of modulator ions

● Different modulator ions in the core result in different release patterns.

● Release enhancing or retarding effects

Pellets containing different salts as a core and coated

with EUDRAGIT®RS as the controlled release layer

(25% w/w)

Acetate

Citrate

Succinate

Chloride

% M

eto

pro

lolSuccin

ate

rele

ased

±SD

Time in hours

15


0

20

40

60

80

100

0 2 4 6 8 10

0

20

40

60

80

100

0 2 4 6 8 10

● Release control of the modulator ion

● Fine tuning of release pattern

Tool box (2 of 4)

Influence of modulator layer

Time in hours

% T

heophyllin

e rele

ased

±SD

Time in hours

% M

eto

pro

lolSuccin

ate

rele

ased

±SD

0% EUDRAGIT® NE

20% EUDRAGIT® NE

40% EUDRAGIT® NE

0% EUDRAGIT NE

10% EUDRAGIT NE

20% EUDRAGIT NE

Pellets containing Sodium Succinate as core and

coated with different levels of modulating layer and

25% w/w EUDRAGIT® RS as the controlled release layer

Pellets containing Sodium Succinate as core and

coated with different levels of modulating layer and

25% w/w EUDRAGIT® RS as the controlled release layer


0

20

40

60

80

100

0 2 4 6 8 10 12

0

20

40

60

80

100

0 2 4 6 8 10

20% EUDRAGIT RS

25% EUDRAGIT RS

30% EUDRAGIT RS

● Increased thickness of controlled release layer decreases drug release.

● Slope of the curve can be controlled by altering the thickness of the layer.

Tool box (3 of 4)

Influence of sustained release layer

Pellets containing Sodium Succinate core and coated

with different thickness of EUDRAGIT®RS as the

controlled release layer

Time in hours

% T

heophyllin

e rele

ased +

SD

Pellets containing Sodium Citrate core and coated with

different thickness of EUDRAGIT®RS as the controlled

release layer

Time in hours

% M

eto

pro

lolSuccin

ate

rele

ased

±SD

10% EUDRAGIT® RS

15% EUDRAGIT® RS

20% EUDRAGIT® RS

25% EUDRAGIT® RS

16


Tool box (4 of 4)

Tailored release profiles can be formulated

Modulator ions

Acetate

Citrate

Succinate

Cloride

Modulator layer

EUDRAGIT® NE 30 D

Sustained release layer

EUDRAGIT® RL / RS

API

if of ionic nature


0

20

40

60

80

100

120

0 1 2 3 4 5 6 7 8 9 10 11 12

0,0

1,0

2,0

3,0

4,0

5,0

0 5 10 15 20 25 30 35 40 45

Case Study Terbutaline sulphate

32.52

77.16

5.19

60.33

4.32

Bricanyl®

(7.5mg)

18.46

60.70

30.70

70.13

AUC inf (ng.h/ml)

%CV

5.32

43.00

4.09

EUDRAMODETM

(7.5mg)

4.52

69.30

C max (ng/ml)

% CV

2.61T max

Terbul

( 2*2.5mg)

% Terb

uta

line

Sulp

hate

rele

ased

±SD

Time in hours

EUDRAMODE™

Bricanyl

Terbul

Mean

Pla

sm

a T

erb

utlin

e

Concentration

±S. D. (n

g/m

l)

Time in hours

EUDRAMODETM

Bricanyl

Terbul

17


5080Rel BA

%

518.6

89.7

812.9

80.7

AUC inf (ng.h/ml)

%CV

79.6

64.1

10.8

EUDRAMODETM

32.2

69.8

C max (ng/ml)

% CV

9.1T max

Beloc-zok®

Case Study Metoprolole

0

20

40

60

80

0 5 10 15 20 25 30 35 40 45 50Mean

Pla

sm

a M

eto

pro

lolConcentration

(ng/m

L)

EUDRAMODETM

Beloc-zok®

% M

eto

pro

lolSuccin

tere

leased

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14 16 18 20

EUDRAMODETM

Beloc-zok®

Time in hoursTime in hours


0

20

40

60

80

100

0 2 4 6 8 10 12

0

20

40

60

80

100

0 2 4 6 8 10 12

Storage stability

Terbutaline and Metoprolole formulations

● Assay within the limits of 95 -105% of dose with 2% RSD.

● Dissolution within the range of about ±10 % from the initial reading

in all storage conditions.

Stability of EUDRAMODETM:

Terbutaline Sulphate formulation

Time in hours

% T

erb

uta

line

Sulp

hate

rele

ased

±S.D

.

Stability of Pellets of Terbutaline Sulphate formulation

studied as per ICH conditions

Stability of EUDRAMODETM:

Metoprolol Succinate formulation

Time in hours

% M

eto

pro

lolre

leased

±S.D

.

Stability of Pellets of Metoprolol Succinate formulation

studied as per ICH conditions

Initial release

1 year stability-25 deg /60 % RH


6 month stability-40 deg /75 % RH

Initial release



6 month stability-40 deg /75 % RH

18


Agenda


• pH-controlled

• Time-controlled






• Melt extrusion

• Spray drying


The number of poorly soluble drugs

is increasing

Marketed drugs

25%

10%

30%

35%

BCS I BCS II BCS III BCS IV

Solubility

Perm

eability

Biopharmaceutical Classification System

IV III

II I

New Chemical Entities

5%

20%5%

70%

BCS I BCS II BCS III BCS IV

Class I: High solubility and high GI absorption

Class II: Low solubility and high GI absorption

Class III: High solubility and low GI absorption

Class IV: Low solubility and low GI absorptionFrom: Benet L. Wu C.-Y. et al 2006,

Bulletin Technique Gattefosse 99:9-16

19


Improving drug solubility

Physical methods:

• Micronization/nanosizing

• Polymorph

• Changing the crystal habit

• Complexation

• Solubilization

• Solid dispersions

Chemical methods:

• More soluble prodrugs

• Salt formation

Leuner C, Dressman J: Improving drug solubility for oral delivery using solid dispersions

Eur J Pharm Biopharm 50 (2000), 47-60

Processes:

• Melt extrusion

• Spray drying

• Coprecipitation

• Freeze drying

• Mechanical activation (co-grinding)


Case study Felodipine

Model drug: Felodipine

�1,4-Dihydropyridin calcium channel blocker

� Hypertension, angina pectoris

� neutral

� Fp: 145°C,

� Dosage: 5 to 10mg

� BCS Class II

� Aqueous solubility: 1µg/ml at 37°C

NH

Cl

Cl

O

O

O

O

NH

Cl

Cl

O

O

O

O

20


110 120120115 130 150 140 70 0

P(melt)

Ca. 12 bar

0,7 kg/h

n: 150 rpm

I: 39 %,

49%,53%

T(M2)127 °C

T(M1)146 °C

T(M3)

92 °C

1 x D 1,0

Doser 2

Powderblend

100 %

Doser 1

0 %

Balance

Conveyingdry Ice

Formulation:10%, 30%, 50%

Felodipine in

EUDRAGIT® E

Extrusion parameters

Granules were milled and sieved (<250 µm)


0

20

40

60

80

100

0 20 40 60 80 100 120

time (min)

% felo

dip

ine d

issolv

ed

Drug load optimization

USP method II (Paddle); 100 rpm, 500 ml SGFsp pH 1.2, 37°C± 0,5°C; Sample: equivalent to 10 mg felodipine

10% felodipine

30% felodipine

50% felodipine

Cryst. felodipine

Extrudates

Physical mixture

(10% felodipine)

Formation of a glassy solution leads to an inital high increase in dissolution!

21


0

20

40

60

80

100

0 30 60 90 120

crystalline Felodipine Extrudate with EUDRAGIT EPO

Extrudate with EUDRAGIT E and 5% EUDRAGIT NE

0

20

40

60

80

100

0 30 60 90 120


Extrudate with EUDRAGIT E and 5% EUDRAGIT NE

Stabilization of oversaturated solution

with EUDRAGIT® NE 30 D (5%)

� water insoluble polymers can stabilize felodipine in the

oversaturated solution by adsorption effects


Melt extrusion and spray drying

show comparable results

0

20

40

60

80

100

0 15 30 45 60time (min)

% F

elo

dip

ine d

issolv

ed

Spray dried sample Extrudate felodipine

Dissolution test in pH 1.2

5 10 15 20 25 30 35

2θ (deg.)

impuls

e (re

lative)

Felodipine PM Extrudate

5 10 15 20 25 30 35

2θ (deg.)

impuls

e (re

lative)

Felodipine PM SD

22


Storage stability

� extrudates with EUDRAGIT® E, EUDRAGIT® NE and felodipine were stable over

1 year and did not show recrystallization of felodipine

� the stabilizing effect of EUDRAGIT® NE was maintained over storage time

extrudate with EUDRAGIT E, EUDRAGIT NE and felodipine

5 10 15 20 25 30 35 40

Position (2 Theta)

impuls

e (re

lativ)

1 year, 25°C/60%

1 year, 40°C/75%

6 months, 25°C/60%

40°C/75%, 6 months

freshly prepared

felodipine

Dissolution in SGFsp pH 1.2

0

20

40

60

80

100

0 30 60 90 120

time (min)

dis

solu

tion (%

)

6 months, 40°C/75% freshly prepared 1 month, 40°C/75%6 months, 25°C/60% 1 year, 25°C/60% 1 year, 40°C/75%1 month, 25°C/60%


In-vivo study in dogs

Dissolution of extrudates in SGFsp pH 1.2

0

20

40

60

80

100

0 30 60 90 120

time (min)

% d

issolv

ed


Extrudate with EUDRAGIT E and EUDRAGIT NE Extrudate with acid

Dissolution of extrudates in SGFsp pH 1.2

0

20

40

60

80

100

0 30 60 90 120

time (min)

% d

issolv

ed


Extrudate with EUDRAGIT E and EUDRAGIT NE Extrudate with acid

27079 (± 1704) 8210 (± 2333) 1,9 (± 1,5)D

22612 (± 8230) 10090 (± 6130) 1,5 (± 0,86)C

n.d.

9967 (±5830)

Cmax (ng/l)

25529 (±1575) 1,5 (± 1,06)B

n.d.

tmax (h)

n.d.A

AUC (ng/l/h)Form.

Mean plasma concentrations of felodipine

0

2000

4000

6000

8000

10000

0 1 2 3 4 5 6 7 8 9 10 11 12

Time (h)

Concentration (ng/l)

Formulation C: extrudate w ith EUDRAGIT E and EUDRAGIT NEFormulation B: extrudate w ith EUDRAGIT EFomrulation D: extrudate w ith acidFormulation A: physical mixture w ith EUDRAGIT E

23

Pharma Polymers | Brigitte Skalsky 2010-12-02 Barcelona

Summary

Leveraging their functionalities and characteristics EUDRAGIT® polymers

can be used for advanced formulations increasing therapeutic benefits.

EUDRAGIT® polymers behave as effective SR matrix formers with excellent

binding properties. Polymer quantities of 6-20% are sufficient to generate

strong retardation which in particular enables matrix formulations for highly

soluble and highly dosed actives.

By flexible double coating drug delivery systems individually designed

release characteristics can be achieved. EUDRACOL® provides colon

targeting with sustained drug release along the colonic transit.

Solid solutions based on EUDRAGIT® E enhance drug solubility with

advantageous storage stability showing increased bioavailability.


EVONIK Röhm GmbH

Pharma Polymers

www.pharma-polymers.com

phone: +49 (0)6151 18 4389

e-mail: [email protected]

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