Pharmaceutical Research Center

Yong-il Kim

Formulation of Incrementally Modified Drugs by Combination

1

2

Total Sales : USD 761 mil (2014)

Total employees : 1,950 (442R&D, 2015)

Foundation : June 15, 1973

Founder : Sung-Ki, Lim

R&D Investment : USD 153 mil (2014)

Part 1. Hanmi’s FDC Development Work

Part 2. Practical FDC products by platforms

Part 3. Summary & conclusion

- Monolithic tablet : Amosartan®

- Bi-layer tablet : Rovelito®

- PolyCap : Monterizin®, Dutams®

3

4

CR up to 24hr

Dual release (IR+ER)

Pulsatile

OD/chewable (taste masking)

Liquid

New device

Monolithic / Bi-layered

Multi-layered coating

PolyCap

Inhaler Solubilizing agent

Solid dispersion

Microemulsion

Salt change

Solvate

Complex

(Metabolite) 5

1. Better efficacy : Synergistic mechanism, Improved ADME - Drugs with different treatment mechanism (Amlodipine + Valsartan : Exforge)

- Immediately acting drug + long acting drug (Salmeterol + Fluticasone : Advair)

- Drug + Adverse effect-reducing drug (Naproxen + Esomeprazole : Vimovo)

2. Less adverse event : than a higher dose of single drug - Low dose of 2 drug-combination is more effective than higher dose of single drug

(Statin + Ezetimibe : Vytorin, Atozet)

3. Improved patient compliance : Simplified medication - two or three drugs in one pill (Exforge HCT : 3 drugs in 1 pill)

- harmonized dosing regimen (Vimovo)

6

Many of treatment guidelines recommended combined administration (FDC)

(JNC8-hypertension, GOLD-COPD, ADA Diabetes Care – Diabetes)

4. Economic benefits - Lower manufacturing cost

- Lower medication cost

5. Extended ‘Drug Life Cycle’ - extended duration of exclusive rights by combination (data exclusivity, patent)

; Exforge, Vimovo, Jalyn, Vytorin…

6. Faster commercialization

- Abbreviated clinical study & Low RA huddle than NCE

7

Product Company FDA Approval

Adderall Shire 1996

Suboxone Reckitt-Benckiser 2002

Avalide Sanofi 1997

Diovan HCT Novartis 1998

Exforge Novartis 2007

Lotrel Novartis 1995

Micardis HCT Boehringer-Ingelheim 2000

Vytorin Merck 2004

Janumet Merck 2007

Yasmin Bayer 2001

Atripla Gilead 2006

Combivir GlaxoSmithKline 1997

Epzicom GloxoSmithKlin 2004

Truvada Gilead 2004

Advair GlaxoSmithKline 2000

Combivent Boehringer-Ingelheim 1996

Symbicort AstraZeneca 2006

Complera Gilead 2011 Many global companies have been

working on FDC products and received

approval from the FDA, since 1990’s

Ref> PharmaCircle (2014).

(n=230)

8

Combination rationale

Clinical evidence (synergic effect, reducing adverse effects)

Co-prescription frequency/ratio in the field

Drug-Drug interaction

Absorption mechanism of each drug

Metabolism pathway of each drug

Low possibility of interaction is ideal (Safety / RA perspective)

Dosing regimen

Same dosing regimen is preferred

If not same ; Harmonized / clinically proved dosing regimen is necessary

(need to conduct clinical study)

9

Consideration of physiochemical properties of each drug

Polymorphism

Solubility

Stability (in the stress condition)

Degradation pathway

Compatibility with excipients

Target effective dose

Target release profile

etc

Considering these properties formulation study is performed

10

Challenges of a FDC formulation

Should consider Inter-API interaction Chemical interaction (ex. acid/base reaction)

Physical interaction (effect on the drug release)

Should make an one-dosage form which is bioequivalent to each RLD Formulate to have a comparable release profile of each RLD

If not, additional clinical studies are required (dose finding, safety, efficacy, …)

Should consider a product size FDC tends to be bigger than a single product

Smaller size is preferred

Considering challenges above,

we need to study to find out a suitable FDC dosage form

11

Multi-layer Coated Tablet / Capsule & its expansion

one API is in a core + other API is in a coated layer

Plain tablet (IR or SR) / Coated layer (IR)

Bi-layered Tablet (IR or SR) / Coated layer (IR)

Multi-unit Tablet (IR & SR) / Coated layer (IR)

Hard capsule (Polycap) / Coated layer (IR)

Soft capsule / Coated layer (IR)

Dual-controlled release

IR layer SR core

Conventional monolithic tablet

Bi-layer tablet

By changing the core, various different expansions are possible. 12

PolyCap

• Easy to make a combination drug

• Retain each dosage forms

• Retain each drug release characteristic

• Improved stability (no drug-drug interaction)

Most ideal formulation concept for FDC

Innovative technology for FDC

Capsule, filled with 2~3 different dosage forms

[ pellet x granule x tablet x mini tablet x soft/hard capsule]

13

In hanmi 3 stations for conventional tablet 1 station for 10 mini tablets 1 station for 20 mini tablets 1 station for pellet 1 station for granule(powder)

14

• Monolithic tablet : Amosartan®

• Bi-layer tablet : Rovelito®

• PolyCap : Dutams®, Monterizin®

15

One of the most ideal combination drugs

for a treatment of high blood pressure

Losartan potassium Angiotensin Receptor Blocker

Amlodipine camsylate

Calcium Channel Blocker

Amlodipine camsy. + Losartan K

3 different dose strengths

5/50, 5/100, 10/50

Norvasc

(amlodipine 5,10mg, besylate)

Cozzar (losartan K 50,100mg)

16

Alternative salt of amlodipine

- patent issue

- poor solubility

Need to improve solubility of amlodipine camsylate salt

Inter-API interaction

Losartan influence on the dissolution & degradation of Amlodipine

Need to overcome inter-API Interaction

amlo. besylate

amlo. camsylate

Losartan Amlodipine

17

XRD of Amlodipine camsylate

◈ For improving solubility of Amlodipine camsylate

: Spray drying to change the crystalline form

Crystalline form Amorphous form

amorphous form

crystalline form

Spray Drying

0.0

0.5

1.0

1.5

2.0

0 10 20 30 40 50 60

Co

nc

.(m

g/m

L)

Time (hr)

Solubility test of Amlodipine camsy. (Basket, 100rpm, Water)

Camsylate(무정형)

Camsylate(결정형)

Increased solubility (2times)

by spray drying

Amorphous

Crystalline

18

Utilized two different types of disintegration agent (cros-carmellose Na / cros-povidone)

Applied separate granulation process to improve dissolution

+

* Gelling tendency of Losartan K (in gastric pH) influence on the disso. of Amlodipine

Losartan Amlodipine Physical interaction

0.0

20.0

40.0

60.0

80.0

100.0

120.0

0 15 30 45 60

Am

lod

ipin

e (

%)

Time (hr)

pH 1.2 - Amlodipine dissolution

분리과립후

일반과립

Separate granulation

Mixed granulation

Amlodipine

Wet granulation

Losartan

High-dense compacted

granulation

19

◈ Losartan accelerates the degradation of Amlodipine (oxidative reaction)

Screened stabilizer, added anti-oxidant to the formulation

to overcome this chemical interaction.

HN

O

NH2H3C

H3COOC COOCH2CH3

Cl

O

¡Ü

Amlodipine camsylate

H

N

O

NH2H3C

H3COOC COOCH2CH3

Cl

O

¡Ü

Impurity 2

Using Antioxidant

Oxidative Reaction

Losartan Amlodipine Chemical interaction

20

Spray drying

- antioxidant

Wet

granulation

Amlodipine

camsy.

Losartan K

High dense

compacted

granules

Monolithic

tablet

Mixed granules

Formulation concept & manufacturing process related patents (4)

3 granted

1 published

1 KR 1247583 Combination composition (disso)

2 KR 1160151 Combination composition (disso)

3 KR 1232296 Combination composition (stability)

4 KR 2009-0005840A Combination composition 21

Efficacy

Ph 1 DDI Ph 1BE

(FDC vs

co-admin. of RLD)

Ph 2

Dose finding

Ph 3

Efficacy

Safety

2.7 years for whole clinical study

Quite short, compared to NCE products 22

June, 2009 : Launched in Korea (Co-marketing with MSD) Amosartan & Cozzar XQ & Amzzar

Total sales was increased steadily up to 70M USD in Korea (2014)

Expect, export to more than 50 countries

Launched in Russia, Columbia, Panama, Malaysia, Turkmanistan…..

Waiting for an approval from countries in east/mid asia, mid-America, Africa….

MSD

23

24

Atorvastatin Statin

Irbesartan Angiotensin Receptor Blocker

Irbesartan + Atorvastatin

4 different strengths

150/10, 150/20, 300/10, 300/20

treatment for accompanying disease of

hypertension & hyperlipidemia

• One of the most ideal combination for a

treatment of accompanying disease of

hypertension and hyperlipidemia

Aprovel (Irbesartan 150, 300mg)

Lipitor

(atorvastatin 10, 20, 40, 80mg, Ca)

25

No chemical interaction between APIs

basic stabilizer for atorva. influence to the stability of Irbesartan

Need to prevent the interaction between Irbesartan & basic stabilizer

Irbesartan Atorvastatin API – API interaction

Basic stabilizer API – Excipient interaction

26

0

0.2

0.4

Irbesartan flake only Atorvastatin+ Irbesartan…

monolith tabletwith stabilizer

Imp. B of Irbesartan, 40℃, 75% RH

initial 3mon 6monBasic stabilizer

Acceptable criteria

• by making a bi-layer tablet, stability was improved

and meet the acceptable criteria under 6month accelerated condition

0

0.3

monolith tabletwith stabilizer

Double layer tabletwith stabilizer

Imp. B of Irbesartan (40℃, 75%RH)

initial 6mon

Acceptable

criteria

The formulation concept of Rovelito is Bi-layer,

to separate irbesartan from basic stabilizer

27

Irbesartan

Atorvastatin

+ basic stabilizer

Fluid Bed

Granulation

-rapid dissolution

Atorvastatin

0

20

40

60

80

100

120

0 15 30 45

Dis

so

luti

on

(%)

time(min)

water 900mL, paddle, 50rpm

시험약(10/150)-임상용

대조약

f2 : 88.2

Rovelito

Lipitor (Pfizer)

0

20

40

60

80

100

120

0 10 20 30

Dis

so

luti

on

(%)

0.1N HCl 1000mL, paddle, 50rpm

f2 : 62,1

Rovelito

Approvel (Sanofi)

High Shear

Granulation

- High density granule

Irbesartan

* Applied different granulation, considering physiochemical properties

& target release profile of each API

28 Obtained similar dissolution profiles to that of each RLD

* De-lamination can happen in bi-layer tablet

(During Compression, Coating, Packaging, Shipping, Storage)

Caused by

1. Insufficient interlocking in the interfacial area high interfacial surface area & roughness in the adhesion surface

2. Different thermal expansion of each layer similar excipient to each layer is better

3. Air entrapment between layers during compression

Ref. Pharmaceutical Development and Technology, 2013; 18(6): 1265–1276

International Journal of Pharmaceutics 398 (2010) 9–13

International Journal of Pharmaceutics 452 (2013) 249– 256

Formulation

consideration

Sufficient amount of binder, Minimum amount of lubricant

Utilize excipient which has large surface area (silicone dioxide)

Similar excipients was applied to each layer

During

Compression

1st Layer : minimum compression force

increase roughness of interfacial layer

2nd Layer : increased dwell time for main compression

prevent air entrapment between layers

29

Preventing delamination issue

Irbesartan 1st Layer Atorvastatin 2nd Layer

Granulation

(HSM) Binding

solution

Drying

/Sizing

Blending

Granulation

(FBG)

Binding

solution

Blending

Bi-layer

compression Coating

Drying

/Sizing

weighing weighing

Basic

stabilizer

Uncoated

weighing weighing

Film coated

150 / 10mg 150 / 20mg

Atorvastatin Ca

Irbesartan

Formulation concept & manufacturing process related patents (3)

1 granted

2 published

1 KR 1248804 Combination composition (bi-layer)

2 KR 2012-0096036A Combination composition (process)

3 KR 2012-0096477A Combination composition (stability) 30

Efficacy

Ph 1 DDI Ph 1BE

(FDC vs

co-admin of RLD)

Ph 3

Efficacy

Safety

Rovelito, a treatment of accompanying diseases

Ph2 clinical study was not required to get an approval 31

Dec. 2013, Launched in Korea (Co-promotion with Sanofi)

Total sales is gradually increased by year

& expect to reach more than 50mil USD .

Sanofi

aventis

0

5

10

2013 2014

0.1

4

Sale

s (m

illio

n d

olla

r)

Rovelito

32

33

Levocetirizine 2HCl

Histamine H1 receptor antagonist

Montelukast Na

Leucotriene D4 antagonist

Asthma

Rhinitis One of the most ideal combination of drugs for a

treatment of accompanying disease of allergic

rhinitis & asthma

Montelukast Na + Levocetirizine 2HCl

2 strengths

10/5 (adult) , 5/5 (children)

a treatment for allergic rhinitis & asthma

Singulair

(montelukast 10mg, Na)

Xyzal (levocetirizine 2HCl 5mg)

34

Inter-API interaction

Levocetirizine has a negative effect to stability of Montelukast.

Montelukast has a negative effect to stability of Levocetirizine.

have to separate APIs

Montelukast Levocetirizine

35

0.0

0.5

1.0

1.5

2.0

initial acc. 1mo acc. 3mo

Montelukast imp. A

Monte only

Monte + Levocetirizine

0.0

0.5

1.0

1.5

2.0

initial acc. 1mo acc. 3mo

Levocetirizine total imp.

Levocetirizine only

Levocetirizine + Monte

Monolithic tablet

Bi-Layered Tablet

Polycap : 2T x montelukast,

1T x levocetirizine

Montelukast imp. A Levocetirizine total imp.

0.0

0.5

1.0

1.5

2.0

monolith doublelayer

PolyCap

initial acc.1 acc.3

0.0

0.5

1.0

1.5

2.0

monolith doublelayer

PolyCap

initial acc.1 acc.3

Polycap showed better stability selected as a dosage form 36

PolyCap(w tablet) provided lower dissolution rate

result in delayed PK profile in dog tried to improve dissolution rate

0

20

40

60

80

100

120

0 15 30

%R

ele

as

ed

Time (min)

Montelukast – 0.5% SLS, 75rpm, Paddle

Singulair

Capsule

0

20

40

60

80

100

120

0 15 30

%R

ele

as

ed

Time (min)

Levocetirizine – Water, 75rpm, Paddle

Xyzal

Capsule

0

15000

30000

45000

0 6 12 18 24

Pla

sm

a levels

of

Monte

lukast(

ng/m

l)

Time (hr)

Montelukast (10mg/dog)

Singulair + xyzal combi.

Monterizine capsule

0

1500

3000

4500

0 6 12 18 24

Pla

sm

a levels

of

Levocetirizin

e(n

g/m

l)

Time (hr)

Levocetirizine (5mg/dog)

Xyzal + singulair combi.

Monterizine capsule

37

Characters • Combined characters of Polycap + MUPS

- Prevent interactions

- Make FDC more easily

- Adjust a dose by changing the number

of tablets

- Expect lower PK variability

- Expect narrow gastric empting time

- Expect rapid dissolution

• PolyCap of mini spheroidal tablets

(with diameter of less than 2mm)

MUST concept

38

• Abbreviation for Multi Unit Spheroidal Tablet • Unique and innovative technology for FDC product

Monterizin MUST capsule

20 mini tablets - 10mg Montelukast

/ 10 mini tablets – 5mg Levocetirizine

0

20

40

60

80

100

120

0 15 30

%R

ele

as

ed

Time (min)

Montelukast – 0.5% SLS, 75rpm, Paddle

Singulair

Monterizine (MUST)

Monterizine

0

20

40

60

80

100

120

0 15 30

%R

ele

as

ed

Time (min)

Levocetirizine – Water, 75rpm, paddle

Xyzal

Monterizine (MUST)

Monterizine

dissolution rate was improved, and showed similar profiles to each RLD 39

40

10T

20T

1T

Max capacity : more than 100,000 caps/h

Coating

Encapsulation

FB coating

Compression

(specified punch)

& Fluidbed

coating

Montelukast Na

mini tablet Levocetirizine 2HCl

Mini tablet

Polycap

10T 20T

encapsulation

with Polycap 1 KR 1418404 Combination composition (MUST)

2 KR 2011-0070680A Combination composition (PolyCap)

3 KR 2013-0075099A Combination composition (Stability)

Formulation concept & manufacturing process related patents (3)

1 granted

2 published

41

Clinical trial

I / III

On-going

Clinical phase III

Time (h)

0 6 12 18 24 30 36

Mon

telu

kast

con

cen

tratio

ns (

ug

/L)

0

100

200

300

400

500

Montelukast alone (N=26)

Montelukast + levocetirizine (N=27)

Time (h)

0 6 12 18 24 30 36

Levocetirizin

e c

oncentr

ations (

ug/L

)

0

50

100

150

200

250

300

Levocetirizie alone (N=26)

Montelukast + levocetirizine (N=27)

DDI, Bioequivalence (BE)

Done

Bioequivalence (BE) was proved

Clinical phase I

42

43

One of the most ideal combination of

drugs for a treatment of BPH

Benign Prostatic Hypertrophy

Tamsulosin HCl adrenergic receptor blocker relaxation in smooth muscle

therefore less resistance to urinary flow

Dutasteride

5-α reductase inhibitor covert testosterone to dehydrotestosterone

Dutasteride + Tamsulosin HCl

0.5mg / 0.4mg

for a treatment of BPH

Avodart (dutasteride 0.5mg)

Flomax (tamsulosin HCl 0.4mg)

44

Different dosage form / drug release characteristic

- Dutasteride

Immediate release, soft gelatin capsule of oil formulation

- Tamsulosin HCl

Sustained release, coated pellet

Development of a one combination dosage form,

which overcomes this difference and also is bioequivalent

to each RLD

45

PolyCap retain each dosage forms / drug release characteristics

* PolyCap, dutasteride soft capsule & tamsulosin pellet

6 oblong

(same as Avodart)

Pellet

(same as Floma)

dutasteride soft capsule

tamsulosin pellet

# 00 too big to swallow

size optimization

was necessary

size reduction of Dutasteride softgel

& amount reduction of Tamsulosin pellet was performed to make a #1 cap.

* w/o modification

By changing a formulation ‘from Oil to Oil+surfactant’

Reduced the size of dutasteride soft capsule ‘from 6 oblong to 2 oval’.

47 Bioequivalence, small one to big one was proven by human study.

Avodart 0.5mg (Reference)

Duted 0.5mg (P1501,Test)

6 oblong 350 mg

2.0 cm

2 oval 110 mg

0.9 cm

1/3 volume half length

Flomax

0.4mg / 330 mg

Hanmi

0.4mg / 155mg

• Reduced total amount of pellet in half by increasing drug load

• Changed manufacturing process

4. Enteric coating

1. Extruding 2. Spheronizing

3. Sustained release

coating

• Spherical bead (cellulose +

API)

(Like a rotor granulator)

• Coating (Enteric)

Manufacturing of spherical pellet

48

Dutasteride 0.5mg

Soft gelatin cap Tamsulosin 0.4mg

sustained release Pellet

1 2

Polycap

Encapsulation

Mixing

Capsuling

Drying

Extruding

Spheronizing

Drying

(Oven)

1st, 2nd

Coating

(FBG)

Sieving

Mixing & kneading

(HSM)

Formulation concept & manufacturing process related patents (4)

1 KR 0582350 Tamsulosin HCl Formulation (Pellet)

2 KR 2012-0007399A Dutasteride softgel composition (size reduced)

3 KR 2013-0075884A Dutasteride softgel composition (capsule shell)

4 KR 2014-0187571A Dutasteride softgel composition (size reduced)

1 granted

3 published

Dutams (# 1)

49

Clinical trial

I / III

Drug-Drug Interaction (DDI)

Bioequivalence (BE) test

On-going

Clinical phase I

will take place soon

Clinical phase III

50

51

1. For formulation of FDC,

inter-API interaction, compatibility, target dissolution profiles & dosage form size

must be considered.

2. Hanmi has various platforms for FDC,

such as Monolithic, Bi-layer, Multi-layer coating or Polycap.

3. Especially, the Polycap is an ideal platform for FDC which is possible to retain

original dosage form and drug release characteristic, and prevent an interaction

between APIs.

4. Base on these platform technologies, Amosartan and Rovelito were

successfully commercialized with global companies.

Currently, Hanmi still has 8 more developing FDC products for global markets.

Hanmi believes that FDC is highly value-added product

which has much of benefits to patients and companies. 52

Thank you 53