Improved Solubility

Improved Bioavailability

Improved Efficacy

Bottom-up particle assembly during

spray-drying process

Flowable, stable, instant powder.

Upon dispersion in aqueous media

forms nano-colloids

Depressed melting temperature and enthalpy of API

Improved dissolution and solubility in bio-relevant media

Less ordered-crystalline lattice

Submicron particles of API are

homogeneously dispersed in

polymer matrix

SolumerTM is composed of porous micro-

aggregates

Scientific Evidence Based Solumer Technology

SolumerTM is a Solubest proprietary, patent protected technology to produce stable and instant formulations of liphophilic compounds.

SolumerTM Introduction

Particle engineering during spray-drying process

Solubest’s proprietary technology implements spray-drying of API and polymer blend to produce submicron particles of API dispersed in a polymeric matrix. To achieve the optimum dispersion and smallest particle size, expertise based consideration is given to the composition of the feed solution and polymeric matrix.

Depressed melting point and enthalpy

Formulated API demonstrates significant reduction in melting temperature and enthalpy in comparison with raw crystalline material. Such high energy state requires less energy for dissolution!

SolumerTM: porous micro-aggregates

During the spray-drying process of API and polymer proprietary blend porous micro-aggregates of polymers embed the API nano-particles. The optimum result is achieved due to expertise based choice of the polymeric matrix composition.

Nano and Submicron particles of active compound are embedded in polymer matrix

Upon contact with water or biological fluids Solumer™ powder is self-dispersed to form uniform nano-colloids with mean particle size in a range of 0.5-5 µm. The colloidal particle is not entire monolith; it is built from subunits of 50-100 nm.

Less ordered-crystalline lattice:

Formulated API possesses a high energy crystalline structure, stabilized by interaction with polymers. Such disordered structure reduces the dissolution energy barrier, inherent in the typical rigid crystal of poorly soluble actives!

Improved dissolution and solubility

Formulated API exhibits significantly higher solubility in standard and biorelevant media in comparison with raw API and commercial drugs. Similarity in the saturation solubility of Solubest products in Fed and Fasted State Simulating Intestinal Fluids (FaSSIF& FeSSIF) can be translated to the decrease or complete eliminating of the drug food effect.

Powder characteristics

Flowability – easy handling and processing Compressability – allows multiple dosage forms Stability – long shelf life Bulk instant powder is easy to disperse in liquid

Solubility of native resveratrol and Solu-Resveratrol at 0.1% and 1% concentrations

SEM images demonstrate that SoluResveratrol is constructed from the porous polymer aggregates (100-200 µm) covered by submicron-micron particles of resveratrol (0.5-5 µm)

www.solubest.com/ +972-8-940-3023/ info@solubest.com

SolumerTM Essential Characteristics

200 nm

Freeze Fracture TEM image of SoluFenofibrate colloidal particle

Thermal X-Ray diffractograms demonstrate that SoluFenofibrate melts between 55oC and 65oC, while raw API stable at 70oC

Particle Size Distribution

0.01 0.1 1 10 100 1000 3000

Particle Size (µm)

0

2

4

6

8

Volu

me (

%)

SoluGris-105-47+us2, 15:53:54 2010 ץרמ 08 ינש םוי

SoluGris-105-47+us2, 15:54:10 2010 ץרמ 08 ינש םוי

SoluGris-105-47+us2, 15:54:26 2010 ץרמ 08 ינש םוי

D10=421 nm D50=1027 nm

D90=5880 nm

SoluGriseofulvin particle size distribution measured by Laser Diffraction technique (Malvern instrument)

4.9300 mg

Integral -256.73 mJ normalized -52.08 Jg^-1Onset 44.35 °CPeak Height 7.02 mWPeak 49.20 °CExtrapol. Peak 49.92 °CEndset 53.42 °CPeak Width 5.60 °C

Integral -15.52 mJ normalized -3.15 Jg^-1Onset 56.88 °CPeak Height 0.44 mWPeak 63.57 °CExtrapol. Peak 63.91 °CEndset 66.90 °CPeak Width 5.84 °C

Integral -409.31 mJ normalized -81.86 Jg^-1Onset 80.09 °CPeak Height 23.71 mWPeak 81.74 °CExtrapol. Peak 81.73 °CEndset 84.80 °CPeak Width 2.77 °C

Method: DSC-30-100-10-N2-pan hermetically sealeddt 1.00 s 30.0-100.0°C 10.00°C/min, N2 80.0 ml/minSynchronization enabled

SF-PR-PD-19

5.000 mgFenofibrate

mW

10

°C30 35 40 45 50 55 60 65 70 75 80 85 90 95

^exo

--

16.05.2007 10:46:52

STARe SW 9.01

Lab: Ana

Melting of API in formulation

Melting of Raw Fenofibrate

Polymer Melting

Physical Mixture

80oC

55oC

DSC thermograms show that formulated fenofibrate possess depressed melting point in comparison with raw material or API in the physical mixture with polymers

5 10 15 20 25 30 35 40

0

2000

4000

6000

8000

SoluTU-LG-114-126

Testosterone IndecanoateRM, Lot 110605

Inte

nsi

ty [

counts

]

2 Theta [deg]

Powder X-ray diffraction patterns of raw Testosterone ester and SoluBest Testosterone ester formulation. A broadening of the major formulated drug diffraction peak can be attributed to reduction of its effective crystallite size.

0

20

40

60

80

100

120

0 20 40 60 80 100 120 140

% d

rug

dis

olv

er

Time (min)

Dissolution of SoluStatin NCE vs Raw API in FaSSIF and FeSSIF

Statin NCE in FaSSIF

SoluStatin NCE in FaSSIF

Statin NCE in FeSSIF

SoluStatin NCE in FeSSIF

API API CHARACTERISTICS FORMULATION CHARACTERISTICS

T melt (ºC) ΔH melt (J/g) T melt (ºC) ΔH melt (J/g) Particle size (nm)

Fenofibrate 81.5 74.3 64.4 9.3 669

Resveratrol 267.4 253.6 199.7 104.8 1190

Nifedipine 172.4 113.4 140.9 8.4 749

Itraconazole 169.7 84.4 155.6 21.9 910

Tacrolimus 135.0 60.5 118.0 52.0 836

Clarithromycin 227.6 70.2 207.9 40.1 836

Albendazole 215.2 209.7 161.4 31.2 555

Griseofulvin 220.1 120.4 198.2 52.0 703

Prednisolone 235.4 145.2 205.9 56.4 2752

Indomethacin 160.5 111.1 No peak of melting 2959

Diclofenac 179.1 143.1 No peak of melting 2936

Ritonavir 127.9 92.5 No peak of melting 1203

Statin NCE 73.5 60.0 No peak of melting 108

Docetaxel 173.2 28.7 No peak of melting 3711

SolumerTM technology meets the challenges related to formulation of drugs, belonging to Class II (low solubility) and Class IV (low solubility and permeability) of Biopharmaceutical classification system (BCS). More than 30 lipophilic crystalline active compounds were formulated producing a novel type of solid dispersion. SolumerTM technology is clinically and industrially validated.

The formulation is composed of submicron-particles of API dispersed in multi-polymeric water soluble matrix. SolumerTM confer features for improving drug stability, solubility and bioavailability.

G. Temsin-Krayz, Ph.D, M Averbuch, Ph.D, L. Gitis, Ph.D, Prof. G. Ratner, MD, A Berman, MSc.