Solubilization
through
Nanotechnology
1

SoluBest’s Technological Focus: Improving
Bioavailability by Improving Solubility
The number of insoluble compounds is growing
GI Tract Absorbtion “window”
2

SoluBest’s Unique Two‐Pronged Approach to
Solubilization Using Solumer™ Platform
Reduction to Nanosize
Reduction of Crystal Lattice Energy
A facile, reproducible self‐assembly process
leading to consistently stable products
3

Overview: Solumer ™ Technology
Proprietary "bottom up" process: All components in
liquid feed
Select Multi‐Polymer Components creating “Solubility
Bridge”
Self Assembly Conditions for Drug‐Polymer Construct
upon drying
Creation of Free Flowing Powders with “Fingerprint”
Characteristics
4

Solumer Distinct Features
The Solumer nano‐technology platform possesses distinct features which
collectively differentiate it from other competitive technologies
One step process: liquid feed spray dried to yield product
Resultant powder is well‐defined and exhibits the unique analytical
“fingerprints” of Solumer complexes
Solubilized drug homogeneously interwoven into a polymer construct
Modified thermal behavior of the drug with depressed melting temperature
and enthalpy of melting
Spontaneous formation of nano‐colloidal dispersions upon contact with
aqueous biological media
Enhanced dissolution rate / solubility of the drug
Unique design allows pH control of drug release which is advantageous for
pH‐sensitive drugs
stomach‐related side effects
consistent onset of release
5

Solumer™ Platform Advantages:
Industrial Considerations
Use only equipment readily available in industry
Facile scale‐up: Laboratory to Commercial
Two‐ step, continuous robust process
No post processing necessary (i.e. post drying)
Enviornmentally Friendly
6

Solumer™ Platform Advantages
Product Considerations
High Batch to Batch Reproducibility
Good Shelf‐Stability (up to 2 years)
Free flowing powder amenable to varied dosage
forms
Simple Powder Compression to tabletation possible
7

Solumer™ Platform Advantages
Drug Candidate Considerations
No limitations on melting temp. of drug (Tg)
No limitations on glass transition temp. of drug (Tg)
No necessity for friability (brittleness) of drug
No limitations on low pH stability of drug
Possible low shelf stability/decomposition of drug
No chemical changes to drug in formulation
All excipients used are off the shelf & FDA‐
approved
Rapid feasibility screening of drugs (2‐4 weeks)
8

Solumer™ Platform Advantages
Intellectual Property Considerations
Patent Protected
Collective “Fingerprint” characteristics of products
are proprietary
Non‐infringing prior art
FTO for PoC cardiovascular product
9

Profiles of Drugs Amenable to Solumer
Technology
1) Low solubility in aqueous media (< 10 mg/ml);
2) Log P up to 8
3) Small organic molecules (up to ~MW 1200)
4) Belonging to biopharmaceutics classification system (BCS)
group II (low solubility‐high permeability)/group IV (low
solubility‐low permeability)
5) Organic compounds comprising aromatic, herterocyclic,
esteric, etheric, amidic and other functionalities possessing
donor‐acceptor groups
6) Preferable loading up to ~ 200mg
7) Preferable solubility in polar solvents
10

Validation of the Solumer Platform
No Insoluble Drug Molecular Solubility Log P Use
weight μg/ml
1 Resveratrol 228 0.03 3.14 Antioxidant
2 Hesperetin 302 Slightly sol* 2.44 Antioxidant
3 Nifedipine 346 0.016 3.05 Lowering of blood pressure
4 Fenofibrate 361 Insoluble** 4.80 Cardiovascular
5 Tacrolimus 804 Insoluble** 3.96 Immunosuppressive
6 Clarithromycin 748 0.17 ‐ 0.33 3.24 Macrolide antibiotic
7 Albendazole 265 Insoluble** 3.01 Treats worm infestation
8 Fenbendazole 299 Insoluble** 4.26 Treats worm infestation
9 Itraconazole 706 Insoluble** 3.29 Antifungal agent
* 1‐10 mg/ml
* *less than 0.1 mg/ml (USP 30‐NF 25 S1; General Notices)
9 3
OH
HO
4 5
1 7
OH
11

Solumer Fingerprints
Raw starting DH melt ΔH melt Partical size
T melt (°C) Formulation T melt (°C)
drug (J/g) (J/g drug) nm
Fenofibrate 81.5 74.3 FF‐IZ‐74‐12 64.4 9.3 669
Albendazole 215.2 209.7 ABZ‐LG‐97‐14 161.4 31.2 555
Fenbendazole 239.2 166.3 FNZ‐IZ‐87‐117 203.7 8.9 892
Hesperetin 231 166.2 HES‐LG‐97‐70 No peak of melting 1310
Clarithromycin 227.6 70.2 CLM‐IZ‐87‐100 207.9 40.1 836
Tacrolimus 135.0 60.5 TS‐OS‐90‐4 118.0 52.0 910
Resveratrol 267.4 253.6 RES‐IZ‐98‐45 199.1 14.0 1224
Itraconazole 169.7 84.4 It‐OS‐90‐11 155.6 21.9 749
Nifedipine 172.4 113.4 NF‐IZ‐87‐102 140.9 8.4 1190
Application of SoluBest’s current technology to a wide range of lipophilic crystalline drugs
with different structures and properties results in a self‐assembled drug‐polymer complex
possessing two inherent features required for the improvement of bioavailability:
Depression of melting temperature and energy
Formation of colloidal nano‐dispersions upon contact with aqueous media
12

SoluDrug Formulation and Characterization
10 μm
Reactor with agitator Spray SEM image of spray
and heating system Dryer dried material
(BUCHI ) Dispersing in
Dissolution
aqueous media
Raw crystalline drug
melting 100
700
D is s o lv e d d ru g ( % )
Solumer formulation – 80
SoluDrug 3
60
Depression of drug Raw API
40
melting 20
0
0 10 20 30 40 50
Time (min) nm
Dissolution profile of SoluDrug 3 Typical particle
vs Raw crystalline API size of SoluDrugs
SoluDrug thermal behavior dispersion
fingerprint
13

SoluDrug Dissolution Profile
Increased surface area speeds dissolution Interactions with polymers and
modification of lattice energy increase
saturated solubility
Dissolution test in 0.05 M SLS for SoluFeno vs Saturation solubility test for Resveratrol in Model Fasted Solution
Raw Fenofibrate and Commercial Preparates
1400
120
c o n c e n t r a t io n , u g /m l
1200
100 SoluFeno powder
1000
[Fenofibrate], % of
R e s v e ra t ro l
80 800
dissoved
TriCor 145 (powder from Resveratrol raw powder
60 tablet) 600
SoluRes-IZ-98-2
400
40 Fenofibrate, powder
from capsule (200 mg) 200
20
Fenofibrate, powder 0
0 0 10 20 30 40 50 60 70 80
(Chemagis)
0 10 20 30 40 50 60 70
Time (min) Time, min
Dissolution profile of SoluAlbendazole
vs Raw crystalline API in 0.05 M SLS
100
90
80 SoluDrugs demonstrate
Dissolved drug (%)
70
60
50
SoluABZ
Raw API
significantly increased dissolution
40
30
rate/solubility vs. raw materials
20
10
and commercial products
0
0 10 20 30 40 50
Tim e (m in)
14

Preclinical PoC and Therapeutic Efficacy
of SoluDrugs
Pharmacokinetic Profiles In Pigs Efficacy of Solu‐Albendazole vs
Albendazole vs Commercial Suspension Commercial Suspension
4.5
Albendazole 5mg/kg Albendazole - 5 mg/kg
4
SoluABZ 5mg/kg Albendazole -10 mg/kg
A lb e n d a z o le in p la s m a
3.5
Albendazole 10mg/kg 100
SoluABZ - 5 mg/kg
3 90
D e h e lm in t iz a t io n
SoluABZ 10mg/kg 80 SoluABZ 10 mg/kg
2.5
o f p ig s ( % )
(u g /m l)
70
60
2
50
1.5 40 `
30
1 20
10
0.5
0
0 0 1 3 5 10 15
0 5 10 15 20 25 30 Days after administration
Time (hrs)
• Solu‐Albendazole demonstrates • Solu‐Albendazole has a higher efficacy at a
significantly higher bioavailability as lower dose
compared to marketed micronized • A good correlation between efficacy and
products pharmacokinetic studies is demonstrated
15

Scale‐up from Lab to Pilot and
Manufacturing
~ 10X
~ 15X
Buchi Mini Spray Dryer
Niro Mobile Minor
Pilot Spray Dryer Cone of Pharmaceutical
Spray Dryer (PSD‐4)
in Niro GMP facility
Resultant powder met SoluBest specifications showing good
stability
16

Technological Aspects:
Reproducibility and Stability: SoluFeno
Temperature of Enthalpy of melting Particle size of
Batch no.
melting (ºC) (J/g FF) dispersion (nm)
FF‐IZ‐87‐64 64.4 10.4 812
FF‐IZ‐87‐72 64.4 9.3 936
FF‐IZ‐87‐76 64.4 11.0 945
SF‐PR‐PD‐33 63.9 13.2 683
SF‐PR‐PD‐34 63.4 13.4 852
SF‐PR‐PD‐35 63.7 16.5 744
SF‐PR‐PD‐36 63.6 13.2 799
Average 63.9 12.4 823.6
STDEV 0.43 2.40 96.1
Batch to batch reproducibility of SoluDrug properties highlights
SoluBest’s stable and robust manufacturing process
17

Reproducibility and Stability (cont)
Solu‐Resveratrol
Time in Melting Melting Saturation
Condition of Assay
Batch storage point enthalpy solubility in
storage (mg/g)
(months) (°C) (J/gResv) MFDS (μg/ml)
Raw Resveratrol Initial 0 966.3 267.0 255.3 95.9
Initial 0 229.1 199.2 14.0 530
SoluRes‐98‐45 25°C, 60% RH 6 226.8 206.2 20.4 640
4‐10°C 6 237.0 203.5 22.0 590
Initial 0 234.6 196.9 9.1 530
SoluRes‐98‐44 25°C, 60% RH 6 229.6 218.2 24..4 720
4‐10°C 6 238.5 198.8 12.3 630
Initial 0 233.4 193.2 10.4 na
SoluRes—97‐74 25°C, 60% RH 5 234.0 207.8 20.8 550
4‐10°C 5 230.4 206.8 22.4 600
SoluResveratrol powders demonstrate stability of the active
compound and maintain ” fingerprint” values
18

Characterization of Scaled‐up Products:
SoluFenofibrate
Fenofibrate
Fenofibrate Organic Melting Melting
assay in Water
Batch assay in powder Solvent temperature enthalpy
liquid feed %
mg/g % ºC J/g
mg/ml
SF‐PR‐PD‐29
16.1 245.7 2.97 NA 64.1 2.85
Lab scale
SF‐Niro‐test 10
15.4 242.5 4.13 0.6 63.8 0.95
Pilot scale
SF‐Niro‐test 8
16.1 246.2 3.90 0.3 63.8 0.96
Production scale
SoluResveratrol
Resveratrol Saturation Melting Melting
Water
Batch assay in powder solubility in temperature enthalpy
%
mg/g MFDS (μg/ml) ºC J/g
SR‐98‐45
237 .0 na 589 199.2 14.0
Lab scale
SR‐02‐08
235.6 4.2 590 198.2 13.7
Production scale
The Solumer process is scalable: ensuing batches met required specifications
19

Value Proposition: Heightened Clinical
Bio‐performance
Significantly higher bioavailability of SoluRes as compared to
marketed products
20

Bioequivalence of SoluFeno to leading
Nanodrug, Tricor 145
PK clinical study of SoluFenofibrate
vs nano-drug Tricor 145 (volunteers)
9
8 Commercial nano-drug Tricor 145
Fe nofibric a c id in
7
pla s m a ( μ g/m l)
6 SoluFeno 1
5
SoluFeno 2
4
3
2
1
0
0 5 10 15 20 25
Time (hrs)
21

Solumer™ Technology Benefits
Feature Benefit
No chemical change in drug , Streamlined regulatory track‐
use of FDA‐approved polymers ANDA, 505b2
No induction of high energy shear Continuous, Reproducible and
homogenization processes Simpler Manufacturing
No need for multi‐step manufacturing, Robust, Continuous and Cost‐Effective
preparation feed as homogeneous liquid Production
Good shelf stability Attractive and versatile products
Batch‐to‐batch reproducibility Ease of manufacturing
Modified thermal behavior of drug : Non‐patent infringement /LCM,
depressed melting temperature and enthalpy superior dissolution
of melting
Creation of proprietary nano‐particles in Increased bioavailability/ decreased
aqueous media variability/ elimination of food effect
22

Solumer™ Features Competitive Technology Characteristics
I. Simple two step process: Commercialized Processes for Marketed Products:
1.Clear homogeneous Drug‐ Self‐emulsifying drug delivery systems (SEDDS) ‐ Novartis, Abbott , HLR
Polymer Solution Preparation Use of mixture of oils, surfactants, solvents and co‐solvents
Capsule dosage form only with semi‐liquids
Primarily water‐based
process NanoCrystals –Elan
Stable for greater than 1 High Shear Dyno Mill used in wet milling of a crystalline drug suspension
week Use of polymers and surfactants as surface stabilizers
Spray‐granulation in the presence of sugars as anti‐aggregation agents
2.Spray drying of the clear
homogeneous feed solution Insoluble Drug Delivery (IDD®) technology ‐ SkyePharma
Preparation of an emulsion with lipids or surfactants
Free flowing powder Process at elevated temperatures using high shear forces
No need for post drying step
High stability under required Beads built from a core coated with a thin film of a polymer‐drug dispersion
conditions – Valeant, Janssen, Astellas
Possibility of various dosage Dissolving/dispersing of drug‐polymer mixture in organic solvent.
forms Spraying of a drug‐polymer mixture onto an inert carrier
Need for Post Drying
MeltDose‐ LifeCycle Pharma
Melting of drug with polymer carriers
Spraying of the melt onto inert carrier
23 Confidential

Solumer™ Differentiating Competitive Technology Characteristics
Features
II. Product design and performance: Commercialized Technologies with Marketed Products
1.Self –assembled drug –polymer entities
with built in hydrophobic‐hydrophilic
gradient
NanoCrystals–Elan
No restrictions for glass transition
Raw crystalline material must be friable
(Tg) of drugs
Cannot change the thermal properties
No restrictions for melting
Formulation can be redispersed to crystalline particles of 200‐500
temperatures (Tm) of drugs
nm
No requirements for drug friability
Combined use of amphiphilic and
MeltDose‐LifeCycle Pharma
hydrophilic polymers
Solid solution of drug in polymers
2. Unique design of the Solumer Polymers are restricted in their Tm values in order not to result in
products provide for the following thermal
features: degradation
Depressed melting temperature and Drug needs to be soluble in the melted polymers
energy
Formation of reproducible Self‐emulsifying drug delivery systems (SEDDS) ‐ Novartis, Abbott ,
nanodispersions (600 ‐1000 nm) upon HLR
contact with water Customized approach to formulation ‐ only very specific
Nano colloidal particles are pharmaceutical
aggregates of ultra‐fine particles (40‐ combinations will lead to efficient self‐emulsifying systems
50 nm) Drug can crystallize out in GI tract as result of phase separation
High dissolution rate and release of
the drug Beads built from core coated with thin film of polymer‐drug
dispersion – Valeant, Janssen, Astellas
Thin drug‐polymer film covers inert carrier 24
24 Confidential Polymers need to be amphiphilic

Summary
Product‐driven, customer‐centric strategy
Strong IP positioning around enabling platform
Innovative process allows circumvention of current
nanotechnology produced drugs
Use of FDA‐approved polymers may lower
regulatory risk; lower regulatory risk = faster time‐
to‐market
Elegant, cost‐efficient, easy‐to‐scale manufacturing
process minimizes/eliminates equipment
modification, footprint expansion
25