GOHSENOL EGas an excipient

Confidential As of 1, Dec. 2012

NIPPON GOHSEI

Contents

1. Product Information Grade Line up

Production

Regulatory

2. Application Information FDA approved Drug list which contains PVA

Detailed information of each Applications Film Coating

Binder

Cataplasm/Gel Patch

Ophthalmic

Film Drugs

Confidential

What’s Gohsenol EG?

Polyvinyl alcohol is a polyvinyl resin having hydroxyl groups

and is obtained through saponification of polyvinyl acetate.

GOHSENOL EG is a series of high-quality polyvinyl alcohols

with the Extra High purity property.

Make use of this character, GOHSENOL EG series are widely

used for the application of pharmaceuticals, cosmetics,

electronics materials and ceramics.

Structural formula-(CH2-CH)m-(CH2-CH)n-

| |OH【Hydroxyl group】 OCOCH3【Acetic group】

Polymerization degree : m+nSaponification degree : 〔m / (ｍ+n) 〕×100

Structural formula-(CH2-CH)m-(CH2-CH)n-

| |OH【Hydroxyl group】 OCOCH3【Acetic group】

Polymerization degree : m+nSaponification degree : 〔m / (ｍ+n) 〕×100

Production

Information of the manufacturing site Located in Kuamoto Prefecture Japan

Plant Completion: April 2012

Dedicated to EG-grades

Approx. 500kg / Batch

Confidential

More information of Nippon Gohsei group

Product Information

Grade Line up

Fine Powder

Granule

Fine Powder

Granule

Fine Powder

Granule

Productform

86.5-89.0BinderEG-30PW

Binder SREG-40PW

Ophthalmic

40.0-46.0EG-40P

Ophthalmic

27.0-33.0EG-30P

Film CoatingEG-05PW

Binder IR

4.8-5.8EG-05P

MainApplication

4% Viscosity

[mPa･s]

Degree of

Hydrolysis

[mol%]

Grade

ConfidentialIR / SR : immediate / sustained release

Regulatory

Gohsenol EG DMF No. 26119

CAS No. 25213-24-5

HS No. 39053000

EP, USP, JPE compliant

E1203 Food Additives by EG-05PW

The following Certificates/Statements available

Kosher and Halal Certificate under consideration

GMO Free

Gluten Free

OVI Free

BSE/TSE Free

Residual Solvent

Allergens statement

BfR status

Radiation Free

Confidential

Application Information

FDA Approved Drugs which contain PVA More than 800 drugs

Tablets >700, Solution, Liquid >60, Patch >30

More than 40 API’s

Major API’s and number of drugs

acetaminophen 179(13)

ibuprofen 80(16)

naproxen sodium 65(11)

levetiracetam 31

tramadol hydrochloride 21(14)

metformin hydrochloride 16(5)

topiramate 15

phenylephrine hydrochloride 12

sertraline hydrochloride 10

zolpidem tartrate 10

ibuprofen

naproxen

acetaminophen

Confidential

Application

Recommended Grade and Expected advantages

Tablets

Granulating Agent

EG-05P, EG-05PW

Moisture Barrier, Oxygen Barrier

Binder, immediate release

EG-05PW

Less impurity compared to other polymers

Binder, sustained release

EG-40PW

Less impurity compared to other polymers

Film Coating, immediate release

EG-05PW

Moisture barrier, Gas Barrier, Taste Masking

Confidential

Binder Application

HPMC, high viscosity

PVP, high viscosity

Sustained release

(SR)

Immediate release

(IR)Functions

Sustained releaseproperty

Fast Disintegrationtime

Advantages of PVA

HPMC, low viscosity

PVP, low viscosityCompete with

EG-40PWEG-05PWRecommended

Grades

Confidential

21

Formulation for Tablet

Confidential

100650Total Weight

16.5Magnesium StearateLubricant

213Croscarmellose SodiumDisintegrant

1.332.5Several Different

PolymersBinder

15.198Microcrystalline Cellulose

(PH-101)Diluent

76.9500Metformin hydrochlorideAPI

%mg

Quantity for 1 tabletIngredientFunction / Purpose

EG-05PW as immediate release binder

- Lab test by ICT / Mumbai -

28

Evaluation of powder performancewith different binders

Confidential

Polyvinyl pyrrolidone

( PVP )

Polyvinyl alcohol

( PVA )Polymer

2.523.163.70Moisture Content [%]

1.2731.3381.265Hausner Ratio

21.425.320.9Carr’s Index

0.4790.5570.531Tap Density [g/ml]

0.420

25.7

EG-05PW

0.416

29.8

K-30

0.376Bulk Density [g/ml]

30.0Angle of repose

[Degree]

K-90Grade

EG-05PW as immediate release binder

- Lab test by ICT / Mumbai -

22

Process flow sheet for the tablet

Sifting Metformin hydrochloride and Microcrystalline Cellulose

Dry Mixing in Double Cone Blender

Granulation

Drying

Sizing

Lubrication

Tablet Compression

Confidential

←Addition of Binder

EG-05PW as immediate release binder

- Lab test by ICT / Mumbai -

28

Evaluation Result ofmetformin hydrochloride Tablet

Confidential

Polyvinyl pyrrolidone

( PVP )

Polyvinyl alcohol

( PVA )Polymer

101.5±0.64103.0±1.7102.2±5.7Drug Content

12.96±0.402.26±0.121.71±0.30Disintegration time

[min]

0.310.320.36Friability [%]

5.58±0.3705.91±0.5806.16±0.408Hardness [kg/cm2]

4.61±0.024

649.5±3.8

EG-05PW

4.63±0.01

651.4±3.3

K-30

4.70±0.012Thickness [mm]

652.0±3.7Weights [mg]

K-90Grade

EG-05PW as immediate release binder

EG-40PW performs same as other binders such as PVP and HPMC

EG-40PW as binder forsustained Release

Confidential

API: metfolmin hcl

EG-40PW as sustained release binder

- Lab test by ICT / Mumbai -

Film Coating Application

Immediate release, Gastric coatingApplications

Plasticizer required

Formulation required

Sticking

No Enteric coating

Disadvantage of PVA

Film properties

Moisture, Gas Barrier

Less dosage

Better productivity

Advantages of PVA

KOLLICOAT IRHPMC, low viscosityCompete with

EG-05PWRecommended

Grades

Confidential

18

Comparison ofEG-05PW and HPMC polymer film

106115Linear Expansion (%)

0.00800.0649Adhesion force of film (N)

2251672Younge modulus (MPa)

17657Glass transition Temp. (oC)

Hydroxypropyl MethylCellulose(HPMC)

Polyvinyl Alcohol

(PVA)Product

METHOCEL-E5-LV*EG-05PWGrade

47119Tensile Strength (MPa)

103188Elongation (%)

HighLowWater vapor permeability

Confidential

EG-05PW as immediate film coating

* Dow

- Lab test by ICT / Mumbai -

Water Vapor Permeability ofPolymer film

0.00

0.01

0.02

0.03

0.04

2 4 6 8 10 12 24 48 72 96 120

Time(hr)

Avera

ve

WV

P(g･ m

m/m

2･ h

･ kP

a)

EG-05PW

HPMC

Confidential

EG-05PW as immediate film coating

- Lab test by ICT / Mumbai -

Moisture barrier coating

Many Pharmaceutical actives are degraded

by atomospheric agents such as

oxygen or light, particularly where there

are opportunities for the ingress of

atomospheric moisture during storage.

Coating system can be formulated to

provide, effective barrier to water vapor,

oxygen and light and can thus provide

an effective means of improving stability

and increasing product shelf life.

>>> What’s EG’s performance?

The most important performance for the film coating

Confidential15

Good for moisture sensitive APIs Aspirin

Talc 0.2%w/wAnti-tacking

agent

Titanium Dioxide 0.2%w/wOpacifier

---

---

+++

---

+++

---

+

---

++

PEG-6000

---

---

++

---

++

---

+

---

++

PEG-4000

---

---

+

---

+

---

---

---

---

PEG-1500

+++

---

+++

+++

++

---

+++

---

---

PEG-400

+++

---

+++

++

++

---

++

---

---

Glycerol

++

---

+++

+++

+++

---

+++

---

++

Triethylcitrate

-Plasticizer

1%w/w

EG-05PW 10%w/wPVOH

++Roughness

+Picking

---Splitting

---Cracking

+++Orange Peel

---Twinning

+++Chipping

---Blooming

+Blistering

Visual observations for defects- Effect of Plasticizers -

EG-05PW as immediate film coating

- Lab test by ICT / Mumbai -

Best!

26

Formulation for film coating

HPMCPVAProduct

Solvent

Opacifier

Anti-tacking agent

Plasticizer

Polymer

Grade

←

←

←

←

10

-

METHOCEL-E5-LV

0.2Titanium Dioxide

1PEG-1500

0.2Talc

q.s.Purified Water

-HPMC

10EG-05PW

EG-05PW

(wt%)

Confidential

EG-05PW as immediate film coating

- Lab test by ICT / Mumbai -

Coating Machine & Conditions

30±5oCBed temperature

60±5oCDry air temperature

Circular, occasionally ellipticalSpray pattern type

Process variables Adjusted specifications

25-30cmBed to Gun Distance

30rpmRotational Speed of Pan

40-50p.s.i.Spray Pressure (Operational)

45gmPan load

12cm diameter with 3 bafflesPan design / Baffling

Coating Machine Lab-scale pan coater (Alfred Herbert Ltd., India)

EG-05PW as immediate film coating

- Lab test by ICT / Mumbai -

28

The results of Coated Tablets

-

43

0.26

5.4

-

UncoatedTablet

7.14.4Weight

Gain(%)

171

-

-

0.18±0.01

HPMC

-Friability(%)

58Disintegration

time (sec)

-Diametral crushing

strength(kg/cm2)

0.11±0.01Cast film

thickness (mm)

EG-05PW

Confidential

EG-05PW as immediate film coating

- Lab test by ICT / Mumbai -

29

HPMCPVAProduct

++Roughness

+---Picking

---

---

---

---

---

---

---

METHOCEL-E5-LV

---Splitting

---Cracking

+Orange Peel

---Twinning

---Chipping

---Blooming

---Blistering

EG-05PWGrade

Visual observations fordefects in the coated formulations

Yes-(+++), Slight-(++), Very Slight-(+), No-(---)

Confidential

EG-05PW as immediate film coating

- Lab test by ICT / Mumbai -

Other Application

Recommended Grade and Expected advantages

Ophthalmic

EG-05P, 30P, 40P Thickener, preventing dry-eyes

Injection EG-05P

Cataplasms/Gel Patches EG-05P,PW, EG-18P, EG-30P,PW

For base material

Confidential

Ophthalmic Application

To prevent dry eyes

ThickenerFunctions

TBCDisadvantage ofPVA

Making aqueous film on eye surface.

Variety of ViscosityAdvantages of PVA

HPMC, PVP

Hyaluronic acidCompete with

EG-05P, EG-30P, EG-40PRecommended

Grades

Confidential

Cataplasms/Gel Patches

Keep moisture and API’sFunctions

Solvent InsolubleTBCDisadvantage ofPVA

Less odor

Less skin irritationAdvantages of PVA

PVPPoly Acrylic AcidCompete with

EG-05P,30P,40P

EG-05PW, 30PW, 40PW

RecommendedGrades

Confidential

?QUESTION?

Thank you for your attention

Please visit our web site ;Company : http://www.nichigo.co.jp/english/index.htmlGohsenol EG : http://www.gohsenol.com/doc_e/spcl/spcl_01/spcl_08.shtml