Solumer™ Technology

Clinically -Proven

Solumer™- The Highlights

• SolumerTM is a homogenous solid

dispersion of a poor water soluble Active

Ingredient in a polymer matrix.

• The SolumerTM-Active ingredient shows

altered properties that result in improved

dissolution and solubility.

• SolumerTM demonstrates improved

bioperformance, long term stability and

scalability.

Solubility of native RSV and Solu-RSV at 1% concentrations (normalized to RSV concentration)

Solumer™ Characteristics

Vehicle Load of active compound

Powder particles size Stability Mechanism of Release

Hydrophilic polymers based matrix

High ~ 25% Unisize and uniform in a range of 1±0.5 – uo to 5 ±2 µm

Stable under pH=4-8

In water media form nano-colloid particles of 1±0.5 µm (subunits <200 nm)

Synergy of Essential Solumer™ Parameters

Improved Solubility

Improved Bioavailability

Improved Efficacy

Bottom-up particle assembly during

spray-drying process

SolumerTM is composed of porous

micro-aggregates

Flowable, stable, instant powder. Upon dispersion in aqueous

media forms nano-colloids

Improved dissolution and solubility in bio-

relevant media

Less ordered-crystalline lattice

Depressed melting temperature and enthalpy of API

Submicron particles of API are

homogeneously dispersed in polymer

matrix

Solumerized API have both higher dissolution rate and higher absolute solubility

• Faster dissolution rate for

compared to original API

• Better saturation solubility

• ~25% of API load.

• Versatility>30 lipophilic crystalline

active compounds were formulated

SolumerTM Technology Validation on <30 compounds

Case 4: Solumer™ holds promise for quick for pain killers:

dissolution vs. branded NSAIDs. Fast onset of action=> less contact

with gastric mucosa, better side effects profile.

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% d

isso

lved

Time (min)

Indocin capsules 25 mg

Capsules with SoluInd-105-87 granules

Ultra fast dissolution of NSAIDs may translate to on demand onset of pain,* inflammation and fever relief. Applicable for pediatric and geriatric use, sachets can be dissolved in favorite beverages without effect on beverage taste.

Solu Ibuprofen vs. Advil

SoluIbuprofen vs. Naproxen

Solu-Indomethacin vs. Indocin

Case 4: Dissolution of Solumer™ “instant” anti-inflammatory

drug candidates vs. raw API in FaSSIF.

SOLUMER TM – A Solid Dispersion to Improve the

Bioavailability of Biopharmaceutical Classification System Class II and IV Molecules

Case Studies- Class II:

• Fenofibrate (clinical stage)

• Albendazole (pre-clinical stage)

9

Saturation Solubility of SoluFeno vs

Tricor 145 in FaSSIF and FeSSIF

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Time (min)

Co

nc

en

tra

tio

n o

f F

en

ofi

bra

te

(ug

/ml)

Tricor 145 in FaSSIF

Tricor 145 in FeSSIF

SoluFeno in FaSSIF

SoluFeno in FeSSIF

Fenofibrate: SoluFeno is a clinical stage product.

Similarity in the saturation solubility of Solubest products in Fed and Fasted State Simulating Intestinal Fluids (FaSSIF& FeSSIF) can be translated to the decrease of food dependency or complete eliminating of the drug food effect. This feature is very important for the patient compliance and drug potency.

Summary of Pharmacokinetic Data: an exploratory clinical study with SoluFeno

PK clinical study of SoluFenofibrate

vs nano-drug Tricor 145 (volunteers)

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Fe

no

fib

ric

ac

id in

pla

sm

a (m

g/m

l)

Commercial nano-drug Tricor 145

SoluFeno 1

SoluFeno 2

Saturation Solubility of SoluAlbendazole

in FaSSIF and FeSSIF vs Raw Albendazole

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Time (min)

Co

nc

en

tra

tio

n (

ug

/ml)

SoluABZ in FaSSIF

SoluABZ in FeSSIF

Raw API in FaSSIIF

Albendazole: Solu-ABZ is a pre-clinical stage product (big animals).

Better solubility is translated into better efficacy and reproducibility

• Higher efficacy

at a lower dose

• Less toxicity

• Good PK/PD

correlation

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De

he

lmin

tiz

atio

n o

f p

igs,

%

TIme, days

Albazen, 5 mg/kg

Albazen, 10 mg/kg

Solu-ABZ, 5 mg/kg

Solu-ABZ, 10 mg/kg

Outcomes of the two-tailed Fisher’s exact test: ** p<0.01, *** p<0.001

**

***

** **

SOLUMER TM – A Solid Dispersion to Improve the

Bioavailability of Biopharmaceutical Classification System Class II and IV Molecules

Biopharmaceutical Classification System Class IV.

14

Case Studies: Resveratrol (clinical stage) and Testesterone Undeconate (pre-clinical stage)

SoluRSV is a clinical stage product. Saturation Solubility of SoluResveratrol

vs Raw Resveratrol in FaSSIF and FeSSIF

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Time (min)

Co

ncen

trati

on

of

Resvera

tro

l (u

g/m

l)

Raw Resveratrol in FaSSIF

Raw Resveratrol in FeSSIF

SoluRes 02-09 in FeSSIF

SoluRes 02-09 in FaSSIF

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% d

iss

olv

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Time (min)

Dissolution of SoluResveratrol in FaSSIF vs Resveratrol raw material & Longevinex

Resveratrol Raw material, 100 mg Res/500 ml FaSSIF

SoluResveratrol: Clinical Pharmacokinetic Data

Pharmacokinetic Profile of Resveratrol Metabolites

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Time (hrs)

Meta

bo

lite

s in

pla

sm

a,

mg

/m SoluResveratrol

Raw Resveratrol

Pharmacokinetic Profile of Resveratrol in Human Plasma

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Time, hrs

Resvera

tro

l in

p

lasm

a,

mg

/ml

SoluResveratrol

Raw Resveratrol

12 healthy volunteers study with SoluResveratrol

Significantly higher bioavailability was demonstrated for resveratrol metabolites and trans-resveratrol itself after oral administration of Solu-Resveratrol

Preclinical Study: SoluTU, Solumer- formulated Testosterone Undeconate vs. Commercial product.

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Test

ost

ero

ne

(n

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T (hr)

PK of SoluBest and Commercial Formulations (6 fasted dogs)

AUC= 23.96 hr*nm/ml

AUC= 11.42 hr*nm/ml

SoluBest

Commercial

Solubest oral formulation showed clear advantage in the oral absorption: twice higher AUC, 1.6 fold increase in Cmax and prolongation of Tmax. In addition our formulation has a manufacturing benefit: hard gelatin capsule with powder vs liquid (oil) gel capsule

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Change in Plasma Glucose Profile after Single Oral

Dose of Insulin

-2.5

-2

-1.5

-1

-0.5

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0.5

-10 10 30 50 70 90 110

Time (min)

D G

luco

se (

mM

)

Ability of Insulin

absorption from GI tract

(though relatively high

variability).

Tablets were administered

to the jejunum canulas of

four healthy pigs.

The average dose is 7.2

U/kg.

Oral insulin delivery- in vivo PoC study

New Phys-Chem features -Patentability

SoluFenofibrate 87-72

Raw Fenofibrate

Solubest maintains the formulated drug in the modified crystalline form. The major peaks of the drug in the formulations are more broaden than in the raw material due to their smaller crystallite size.

Advantages & Benefits Provided by Solumer™ Solutions

• Improved PK for BCS class II and IV drugs is translated into the improved performance: – Reduce of dose and better efficacy – Decrease of the food dependency – Reduction of variability

• Unique Solumer™ physico-chemical structure results in:

– Better stability in solid dispersion – New patent creation and Freedom to Operate by the creation

of polymorphs and other unique fingerprints – Instant colloid formation may be translated into the rapid

onset of action – Solumer™ technology may offer new applications, such as

transmucosal delivery or oral delivery of peptides

Publications

1. Temtsin Krayz G., et al. Oral delivery with novel solid dispersions: stable self-assembled formulations of lipophilic drugs with improved bioperformance. Drug Development & Delivery 2012: 9 (7): 36

2. Lee R., et al. Solumer technology: a viable oral dosage form option for BCS class II molecules. ONdrugDelivery. 2011: 26

3. Shi D., et al. A novel spray-drying technology to improve the bioavailability of biopharmaceutical classification system class II molecules. Drug Development & Delivery. 2012: 12(1): 26.

4. Gwozdz R. Polymers for solid oral dosage forms. Drug Development &Delivery 2012: 12 (2): 34

Intellectual Property

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• United States Patent 7,081,450 (issued 25 July 2006) • United States Patent 6,878,693 (issued 12 April 2005) • EP 2 200 588 (published 30 June 2010) • United States Patent Application 2009/0098200 (published 16

April 2009)

Examples for drug candidates suitable for Solumer™

platform

Challenges to overcome: improved bioavailability (BA), less variability, faster onset of action

Solumer™ drug candidates with very low BA (<20%).

confidential

Brand API Indication

Boniva Ibandronate Osteoporosis

Viread Tenofovir HIV infection

Kaletra* Lopinavir/ ritonavir HIV infection

Pulmicort Budesonide Asthma

TriCor*, Lipanthyl Fenofibrate Cholesterol

Zocor Simvastatin Cholesterol

Seroquel Quetiapine Schizophrenia, Bipolar

Lipitor* Atorvastatin Cholesterol

Lorelco Probucol Anti-atherosclerosis

Legalon Silymarin Hepato-protector

(*: green-marked

proven

to be applicable

to Solumer

platform)

(*: green-marked proven to be applicable to Solumer platform)

Brand Indication API

Emend* Anti-emetic Aprepitant

Sporanox* Anti-fungal Itracanazole

Sirulimus Immuno-suppresant Rapamycin

Albenza* Anti-worm, known as anti-cancer Albendazole

Neoral Immuno-suppresant Cyclosporin A

Noxafil Anti-fungal Posaconazole

Prograf Immuno-suppresant Tacrolimus

Kaletra* Anti-HIV Retinovir+Lopinavir

Sustiva Anti-HIV Efavirenz

Celastrol Autoimmune and neurodegenerative Tripterine

Roaccutane Severe acne (oral) Isotretinoin

Vepesid Cancer Etoposide

Challenge: to reduce food dependency to improve performance in patients that suffer from nausea, oral mucositis, loss of appetite, etc.).

Brand name API Indication

Neoral, Sandimmune Ciclosporin Transplant rejection

Cialis Tadalafil Erectile dysfunction

Wellbutrin Bupropion Depression

Accutane, Roaccutane Isotretinoin Severe Acne

Persantine Dipyrimidole thrombus formation

Daflon Flavonoids diosmin &hesperdin Venous circulation disorders

Entocort Budesonide asthma and non-infectious rhinitis

Andriol Testosterone undecanoate* Androgen replacement therapy

Challenge: to reduce food dependency and high variability of PK.

(*: green-

marked

proven

to be

applicable to

Solumer

platform)

Next R&D Challenges: Apply Solumer™ platform for transmucosal delivery

• To accelerate Cmax for on-demand onset, examples:

• Bupernorphine (Pain)

• Grainsteron (Antiemetic)

• Fentanyl (Pain)

• Triptan (Migraine)

• Steroids/ corticoids (Asthma)

• To eliminate need of injection of therapeutic peptides, examples:

– Human growth factor

– Insulin/ Glucagon

Two Pronged Business Model

• A: To establish multiple customized services through leverage on Solubest expertise in development of challengeable formulations.

• B: Spinning off of matured, in vivo or/and clinically proven products into new ventures focused on product approvals and commercialization.