EF10 May 6, Hall A #1, John Giannone (Cognis).ppt · Suppository Masses Moisturizers Surfactants Drug Delivery Agents in solid, semi-solid and liquid pharmaceutical dosage forms PharmaLineTM

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Cognis

Pharmaceuticals & Healthcare

John GiannoneMay 2010

Solutions for Insolubility!

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Agenda

Overview on Cognis PharmaLine

Lipid Based Solvents

Solubilizer for Poorly Soluble Drugs

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Cognis in Brief

• Leading global specialty chemicals company headquartered in Monheim, Germany

• Sales 2009: € 2,584 billionAdjusted EBITDA 2008: € 364 million

• Approx. 5,600 employees operating in 29 production sites and/or service centers in about 30 countries

• Over 160 years‘ experience in nature-based chemistry and oleochemicals

• Owners since November 30, 2001, are private equity funds advised by: Permira / GS Capital Partners / SV Life Sciences

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§Hair / Body / Oral Care§Skin Care§Home Care§ Industrial & Insti-

tutional Cleaning§Silicates

§Coatings & Inks§Synlubes Technology§AgroSolutions§Mining & Ion-Transfer

Technology

§Food Technology§Functional Food§Dietary Supplements§Pharmaceuticals

& Healthcare

A global player with a clear positioning




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The Production Flow of Oleochemistry

Raw materials

veg.Oils&Fats

Fatty acidmethylesters

Fattyalcohols

Sulpho fatty acid esters

Guerbet alcoholsAlkyl chlorides

Technical estersAlkyl polyglycosides

Conjugated fatty acidsAlkyl epoxyestersDimer acidsFatty acid ethoxylatesAzelaic/Pelargonic acidsFatty acid esters

TriacetinsPartial glyceridesGlycerine

Fatty acids

Basic oleochemicals Derivatives

Surfactants

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PharmaLine™ - Product Purity and Process IntegrityExtensive Purity Data• Residual Solvents• Microbiology• Aflatoxins• Heavy Metals• Polycyclic Aromatic

Hydrocarbons (PAH)

Distribution• Direct Deliveries from Cognis or• Deliveries through an Approved

Pharma Distributor

Auditing SystemInternal Audits and Assessments according to:• ISO 9001• ISO 14001• IPEC – PQG GMP• Kosher Certificate

External:• Customer Audits• Questionnaires

Individual Customer ServiceWe are able to specify additional parameters according to individual customer requirements and toproduce customized excipients

IPEC* – PQG** GMP• GMP Guide for Bulk

Pharmaceutical Excipients• Change Control Agreements• Long-Term Contracts• Defined Production Lines• IPEC-PQG GMP Conformity

Declaration

EP and USP/NF(optionally JP/JPE)• Specifications• Analytical Methods• US-DMF’s (type IV)

*IPEC = International Pharmaceutical Excipients Council**PQG = Pharmaceutical Quality Group




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Cognis PharmaLine™ excipients used by pharmaceutical companies in their topical, oral, parenteral and other pharmaceutical formulations such as:

Tableting Aids Solubilizers & SolventsConsistency Factors Emulsifiers

Emollients Cream Bases, self-emulsifying

Suppository Masses Moisturizers

Surfactants Drug Delivery Agents

in solid, semi-solid and liquid pharmaceutical dosage forms

PharmaLineTM – Product Range

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Poorly Soluble APIsIntroduction




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Solubility of New Chemical Entities

Taken from Homepage of

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Methods for Enhancing Drug Solubility

●Chemical modification using pro-drug concept

●Physical modification of the drug via size reduction and surface modification

●PH control using a buffer system

●Using co-solvents as absorption enhancers

●Complexation

[S. Yalkowsky (1999), Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington D.C and Oxford University Press, NY.]




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Lipid SolventsProduct Overview Cognis

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Lipid Based Solvents Main job: „solvent for APIs"

MCT Oils – Medium Chain Triglycerides

Fatty Acid Esters

Oleyl Oleate (Ph. Eur.)

Cocoyl Caprylocaprate (Ph. Eur.)

Cetostearyl Isononanoate (Ph. Eur.)

Decyl Oleate (Ph. Eur.)

Cetyl Palmitate (Ph. Eur.)

Isopropyl Palmitate

Isopropyl Myristate

Vegetable oilsCorn oil – Mon0, Di, Tri Glyceride mixtures




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Lipid Based Drug Delivery Solutions


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Challenge:

_Matching of solubilisant and solubilizer

_Matching of solubilizer to end product

water or water / ethanol

Lipophilic Susbtance

solubilizer

‘Solubilization is an essential process in the incorporation of sparingly soluble auxiliaries and active ingredients....‘

SÖFW, 1998, 124, 744-750.

Why Solubilizers?




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Increasing Challenges for Formulators

● Increasing importance of poorly soluble APIs and biologics

● 90 % of New Chemical Entities (NCEs) are poorly soluble

● Limited number of solubilizers and active drug delivery agents described for pharma applications.

● Applicability of solubilizers for NCEs can hardly be predicted.

● High demand for effective solubilizers and bioavailability enhancers due to growing poorly soluble NCE demand.

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Excipients Currently Used for Solubilization

Hydrophilic Solvents

HydrophobicSolvents

SolubilizersPolymeric

EmulsifiersMonomeric

● Propylene

glycol, NF

● Polyethylene

glycol, NF

● Alcohol, USP

● Propylene

carbonate, NF

● Povidone, NF

● Vegetable oils,

Soybean oil, NF

Corn oil, NF

Oleic acid, NF

● Hydrogenated

vegetable oil, NF

● Tocopherols,

USP/NF

● Triacetin, NF

● Diethyl phthalate

● Vitamin E TPGS, NF

● Polyoxyl 35 castor

oil, NF

● Polyoxyl 40

hydrogenated

castor oil, NF.

● Polysorbate 20,

40, 60, and 80 NF

● Poloxamers, NF

● Lauroyl, or stearoyl

Macrogolglycerides

● Sodium caprate

● Medium-chain

glycerides

● Mono- and di-

glycerides

● Bile salts

● Sorbitan

alkanoates

● Phosphatidyl

choline

Items in Red Available from Cognis Pharmaline




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ExampleCognis Brand name: Eumulgin RO 35 PH

Structure: PEG-35 Castor Oil is a polyethylene glycol derivative of Ricinus Communis (Castor) Oil (q.v.) with an average of 35 moles of ethylene oxide

Conforms to: Ph. Eur.: "Macrogolglycerol Ricinoleate 35"NF: "Polyoxyl 35 Castor Oil"

Field of application: Used as a non-ionic O/W emulsifier and/ or solubiliser, in particular for fat soluble vitamins and essential oils

Dosage Forms: Creams, capsules, tabletts, liquids

Production: Following IPEC-PQG GMP

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Case Specific Performance

0

0.5

1

1.5

2

2.5

3

0% 5% 10% 20%

Solubiliser Concentration

Solu

bilit

y in

mg/

mL

Popular Brand

Cognis Eumulgin® RO 35 PH

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0% 5% 10% 20%

Solubilise r Conce ntration

Solu

bilit

y in

mg/

mL

Popular Brand

Cognis Eumulgin® RO 35 PH

Estradiol




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Solubalizers in co-solvent systems

20

0,0

1,0

2,0

3,0

4,0

5,0

6,0

Orange Oil

Almond Oil

Vitamin E Acetate

Shea Butter

Eumulgin® SML 20Eumulgin® HRE 40Eumulgin® LEumulgin® HPSAethoxal® B

In Water In Water / Ethanol(75 : 25)

Influence of Solvent Systems on Solubilisation

Solubilisation in Water vs. Water / Ethanol

Eumulgin®

Eumulgin® L

Eumulgin® HPS

Aethoxal® B0,0

1,0

2,0

3,0

4,0

5,0

6,0

Eumulgin® SML 20

Eumulgin® HRE 40 PH

Eumulgin® L

Eumulgin® HPS

Eumulgin® ES




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Trends for Solubilisation in Water / Ethanol

• Improved solubilisation with increasing concentration of ethanol for Eumulgin®

HPS and Eumulgin®

HRE 40 PH

• Eumulgin® L also suitable for water / ethanolic systems

Orange oil with 10% solubilizer

0,0

1,0

2,0

3,0

4,0

5,0

6,0

Eumulgin® SML 20

Eumulgin® L

Eumulgin® HRE 40

Eumulgin® HPS

Eumulgin® ES

WaterWater / EtOH (75 : 25)

[% orange oil]

• Ethanol as cosolvent increases solubility of actives

• But: interest to avoid ethanol in pharmaceutical fomulations, especially for pediatric applications

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Effect of % Ethanol on Solubilisation

Eumulgin® LEumulgin® HPS

Eumulgin® HRE 40

Ethanol

65%

25%incr

easi

ng s

olub

iliza

tion

increasing solubilization




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„New“ Solubilizers

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*… PPG-1 PEG-9 Lauryl Glycol Ether + Coceth-7

New Market Product Launches with Solubilizers (1/2003 – 12/2005 worldwide)

Polysorbate 20

PEG-40 Hydrogenated Castor Oil

Polysorbate 80


PPG-1 PEG-9 Lauryl Glycol Ether

PEG-40 Hydrogenated Castor Oil +… *

PPG-5 Laureth-5

Source: GNPD




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Cognis Solubilizer Portfolio

D-alpha Tocopheryl PEG1000 succinate

Macrogolglycerol Ricinoleate 35



Polysorbate 20

Polysorbate 80

Oleth-10 Eumulgin® O 10

PPG-1-PEG-9 Lauryl Glycol Ether Eumulgin® L

PEG-40 Hydrogenated Castor Oil, Eumulgin® HPSPPG-1-PEG-9 Lauryl Glycol Ether, Coceth-7

PPG-5 Laureth-5 Eumulgin® ES

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Why new solubilizers??

Better Performance

10 % Solubilizer in water at RT

0

0.5

1

1.5

2

2.5

Diazepam Erythromycin Itraconazol Estradiol

Solu

bilit

y in

mg/

mL

No solubilizer

Polysorbate 80

PEG 15 Hydroxystearate

Eumulgin L

Eumulgin HPS

Oleth - 10

PEG 35 Castor Oil

TPGS

Eumulgin ES

*

* Solubility for Itraconazol given in 0,01 mg/mL

New Solubilizers consistently give higher Solubility!!!




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Why new solubilizers??

Solubilisation of Sunscreen Actives

0

10

20

30

40

50

60

70

80

Methylc

innamat

Ethylcinn

amat

Isopro

pylcin

namat

Isobu

tylcin

namat

Butylcin

namat

Phene

thylcin

namat

Solu

bilit

y in

Wat

er m

g/m

L

Eumulgin® HPS

Eumulgin® ES

Eumulgin® L

Oleth - 10

PEG 35 Castor Oil

Speziol® TPGS

(10 % solubilizer in water)

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(10% solubilizer)

Why new solubilizers??Solubilisation of Vitamin E Acetate in Different Media

[% Vit. E Acetate]

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

4,0

4,5

5,0

Water Water / Ethanol(75:25)

SLES/CAPB (9 : 3)* SLES/APG (9 : 3)*

no solubilizerPolysorbate 20 PHPEG -40 Hydrog. CastorEumulgin® LEumulgin® HPSEumulgin® ES

* SLES: Sodium Laureth SulfateCAPB: Cocamidopropyl Betaine APG: Caprylyl / Capryl Glucoside




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Speziol ® TPGS – Product InfoNames:● Synonym – D-alpha tocopheryl polyethylene glycol 1000 succinate● Acronym – TPGS, Vitamin E TPGS

Product Data:● Physical Form: Waxy solid● M.P.: 37-41 deg. C● Stability: Stable in air, under heating and at pH 4.0 – 8.0

Application Information:● Water-miscibility: miscible● Solubility in PEG 400: miscible● HLB Value: ~13.2● Surface Active, CMC: 0,11 wt. % at 22 °C

Production:● IPEC-PQG GMP compliant, DSHEA compliant

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Structures of Lipophilic APIs

Diazepam:“Classical" Benzodiazepine, Anticonvulsant

N N NNN

O

O

O

O

Cl

Cl

NN

NItraconazol:Triazole Antifungal, broad spectrumof activity

OH

OH

Estradiol:Steroid, Hormone, Hypoestrogenism Therapies

Erythromycin:Antibiotic

N

N

O




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TPGS as Solubilizer for Lipophilic APIs

0

0,5

1

1,5

2

2,5

0,0% 0,5% 2,5% 5,0% 7,5% 10,0% 15,0%

TPGS Concentration in Water

Sol

ubili

ty in

[mg/

ml]*

DiazepamErythromycinEstradiolItraconazol

* Solubility of Itraconazol is given in 0,01 mg/mL

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Gaining Approval for First Time Use




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What to Look For

● NCE versus First Time Use

●Full Formulation Testing

●Existing FDA Approved uses

●Full Toxicity Profile

●Regulatory Support from Manufacturer

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TPGS – Solution for Insolubility• USP/NF Monograph• FDA Inactive Ingredients List• Applicable in oral, topical & parenteral dosage forms

TPGS –1st Choice Solubilizer

Regulatory

• Solubilizer for lipophilic APIs• Enhances drug permeation• Vehicle in semi-solid formulations• Self emulsifying

Drug Delivery

Stability

Toxicity

• Antioxidant• Stable under heating and air• Stable under sterilization conditions

• Excellent toxicity profile• NOAEL: 1000 mg/kg bw/day• Not genotoxic & carcinogenic• Vitamin E source in supplements




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Agenerase from GlaxoSmithKline

Agenerase – Soft CapsulesHuman Immunodeficiency Virus (HIV) Infection

● Actives:1 Soft Capsule contains 50 mg / 150 mg Amprenavir

● Additional Components: (for 50 mg Capsule)

Tocofersolan (TPGS) (36,3 IU Vitamin E), Macrogol 400 (PEG 400) (246,7 mg), Propylene Glycol (19 mg)Capsule shell: Sorbitol, Sorbitol sol., Gelatine, Glycerol, Titanium Dioxide, Edible Red Ink

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First Time Solubilizers for PharmaExample: Eumulgin L

Structure: Polyoxypropylen-1-polyoxyethylen-9-laurylether

Monograph: Not monographedSimilar structure: Polyoxyl Laurylether (USP/NF)

Toxicology: Not toxic or harmful in acute toxicity test in ratsLD50 (rats) = 2560 mg/kg bwNot considered as skin sensitizerNo Observed Adverse Effect Level: 80 mg/kg bwNo potential for gene mutations detected in Ames test

Regulatory Approval: Submission of an US-DMF Type IVIntroduce Eumulgin L in healthcare products Develop monograph for USP/NF and Ph. Eur.Clinical studies of pharma formulations by customersSupport customers with toxicology data and regulatoryListing in the FDA Inactive Ingredients List




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Market Examples for Eumulgin® L

Altopou Anti Lice ShampooArkopharma, NetherlandsArkopharma Altopou Anti Luis (Anti Lice Shampoo) for children, contains what are described as 100 % natural essential oils of lavender, geranium, rosemary, and tea tree. It is claimed to calm the itching and expedite the recovery of the skin with antiseptic properties.

Ingredients:

Water, sodium laureth sulphate, cocamidopropyl hydroxysultaine, acetic acid, sodium lauroyl sarcosinate, decyl glucoside, PED-120 methyl glucose dioleate, lavandula angustifolia, pelargonium asperum, rosmarinus officinalis, melaleuca alternifolia, PPG-1-PEG-9 lauryl glycol ether, disodium EDTA, linalool, geraniol, citronellol, limonene

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Insect Repellent Spray From Beiersdorf, Israel

A spray which is said to provide up to four hours protection against mosquitoes. It is formulated with soothing aloe vera and is suitable for face and body.

Ingredients

Alcohol denat., aqua, ethyl butylacetylaminopropionate, glycerin, aloe barbadensis, hamelis virginia, PPG-1-PEG-9 lauryl glycol-ether, benzophenone-2, alcohol, parfum

Market Examples for Eumulgin® L




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Summary

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Solubilizers Summary • Consider lipid solvents

• Remember there are differences between currently used solubalizers

• Consider using multiple solubalizers- Off-the shelf solution with- regulatory approval and- good solubilization properties

• Consider the use of cosmetic grade solubilizers where- Physical properties feasible for use in pharma production- Documented history-of-use in humans incl. safety data- Solubilization is superior to existing established solutions- Need an aqueous system.

• Choose an experienced partner




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Questions?

Contact:John Giannone

Phone: +1-610-613-4390Email: [email protected]

See us at Booth 42

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mailto:[email protected]



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Back-ups

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Summary New Solubilizers

Water / Ethanol Systems

Eumulgin® HPSEumulgin® HRE 40

Eumulgin® LEumulgin® SML 20

Eumulgin® HPSEumulgin® HRE 40

Eumulgin® LEumulgin® SML 20

Surfactant Media

Eumulgin® ES

Eumulgin® HPSEumulgin® L

Eumulgin® ES

Eumulgin® HPSEumulgin® L

Water Systems

Eumulgin® HPSEumulgin® RO35 PHEumulgin® O10

Eumulgin® LEumulgin® HRE 40Eumulgin® SML 20

Eumulgin® HPSEumulgin® RO35 PHEumulgin® O10

Eumulgin® LEumulgin® HRE 40Eumulgin® SML 20

Goo

d S

olub

ilize

rsS

uita

ble

Sol

ubili

zers




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Comparison New SolubilizersSolubilizer Characteristics Best Solvent

SystemComment

Eumulgin® HPS Easy to handle, clear, fluid at low temp‘s, quickly water soluble

Water

Water/Ethanol

Excellent for water systems, good sensitory

Eumulgin® O10 Easy to handle, clear, fluid at low temp‘s,

Water

Water/Ethanol

Very good results for a range of APIs

Eumulgin® ES Easy to handle, clear, fluid at low temp‘s, quickly water soluble

Surfactant Media Best solubilizer in surfactant media

Eumulgin® L Easy to handle, clear, fluid at low temp‘s, quickly water soluble

All Very flexible for universal use in different media

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üü«Eumulgin® SML 20

«««Eumulgin® HRE 40 PH

«

-

«

Water

««Eumulgin® L

«-Eumulgin® ES*

««Eumulgin® HPS

SurfactantWater / EthanolProduct Name

« = exceptional / «= recommended / ü = possible

Solubilization results depend on the solubilisant, temperature, batch, other ingredients, etc. and should be tested case by case

Overall Solubilisation in Different Media




Documents

EF10 May 6, Hall A #1, John Giannone (Cognis).ppt · Suppository Masses Moisturizers Surfactants Drug Delivery Agents in solid, semi-solid and liquid pharmaceutical dosage forms PharmaLineTM