GLUCOTEK® proprietary topical remedy for osteoarthritis clinically tested approved as OTC

GLUCOTEK® Highly effective delivery of glucosamine sulphate & excipients through skin into microcapillaries & synovial fluid of affected joint

GLUCOTEK® Unique No marketed equivalent Know-how Trancutaneous delivery system deposits actives into synovial fluid of damaged joint

GLUCOTEK® Compared to standard courses of treatment Amount of glucosamine sulfate delivered is comparable to injection forms and up to two times higher than for oral forms of Glucosamine sulfate

GLUCOTEK® Efficacy of action 1 Promotes direct restoration of cartilage surfaces in the peripheral and vertebral joints including intervertebral discs Possesses bright anti- inflammatory and analgesic (anti-pain) properties. Non invasive treatment

GLUCOTEK® Efficacy of action 2 Helps decrease dosage of NSAIDs or/and anti-pain drugs up to completely discontinue them (on doctor’s advice)

GLUCOTEK® Safety The side-effects are unknown Can be used with nonsteroidal anti-inflammatory drugs (NSAIDs) as remedy to reduce side effects of their usage Non invasive treatment

Droplet sizes GLUCOTEK® micelles 20-80 nm Using dynamic light scattering (photon correlation spectroscopy) using Zetasizer Nano ZS device (Malvern, Great Britain) with 532 nm wave length laser light source a sample of GLUCOTEK® was tested and found that 17.9% of droplets have a diameter ranging from 15 to 80 nm and the rest of the sample contains droplets having a diameter ranging from 0.5 to 5 µm.

GLUCOTEK® Transportation mechanism Micelles effectively & atraumatically penetrates intracellular space of skin cells & microcapillaries into bloodstream Droplet membrane destroyed on contact with blood releasing glucosamine sulfate & excipients that diffuse into synovial fluid of damaged joint

GLUCOTEK® Mechanism of action Mechanism of action based on the general Glucosamine sulfate property to act as substrate & stimulator of synthesis of glycosaminoglycans & proteoglycans

GLUCOTEK® Mechanism of cartilage tissue restoration Glucosamine sulfate Glycosaminoglycans + Protein Proteoglycans + Hyaluronic acid Hyaluronic acid Chondroitin sulfate Dermatan sulfate Keratan sulfate Heparin and Heparan sulfate Glucosamine is a specific substrate and a stimulator of synthesis of endogenic glycosaminoglycans Belongs to a class of amino saccharides It is a universal precursor and a building block of glycosaminoglycans and subsequently of proteoglycans Proteoglycan is a constituent part of the extracellular matrix of body connective tissue (fasciae, ligaments, tendons, cartilages, joint, articular capsule, intervertebral discs) Cartilage

GLUCOTEK® Indication of use Osteoarthrosis, osteochondrosis of peripheral and vertebral joints Inflammatory joint diseases Prevention of osteoarthrosis & inflammatory joint and ligament diseases after traumas

GLUCOTEK® Indication of use Protection of joints from side effects of nonsteroidal anti- inflammatory drugs & hormones (indometacinum, orthophen, diclofenac, prednisolone) Muscle pain myalgias myositis

GLUCOTEK® Comparative pharmacokinetics for injections oral & topical administration in rats Oral (ug/ml) TGC (ug/ml) The diagram depicts concentration values of glucosamine in the blood of an experimental animal after the oral* intake, after Glucotek® application on the shaved skin of the animal in adequate doses (350-400 mg/kg of weight) and after it was injected at a dose of 25 mg/kg of weight. * Ali Aghazadeh and others, High Performance Liquid Chromatographic Determination of Glucosamine in Rat Plasma, J Pharm Pharmaceutical Sci 5(2): 17180, 2002 Перорально (мкг/мл) – orally (µg/mL) ТГК Глюкотек® (мкг/мл) – TGC Glucotek® (µg/mL) Инъекционно (мкг/мл) – in injections (µg/mL) Injections (ug/ml) 14

GLUCOTEK® Pharmacokinetics in rats for topical administration Approx 4.1% glucosamine from GLUCOTEK® delivered through skin & into blood in 4 hours after application The mean value of specific diffusion of glucosamine when applying TGC on the animal’s skin at the dose of 0.033 g/cm² constitutes 26.9 µg/cm²/hour.

GLUCOTEK® Comparative pharmacokinetics for injections & topical administration in rats When applying at the amount of 400 mg/kg of the experimental animal’s weight 3 times a day daily during a week, the amount of glucosamine introduced into the plasma may be assessed as 89% of the amount obtained after a single injection of glucosamine sulfate (GS) to the animal at the dose of 400 mg/kg of animal’s body weight. When applying GLUCOTEK® in the amount of 400 mg/kg of the experimental animal’s weight 3 times daily during one week, the amount of glucosamine introduced into the plasma via GLUCOTEK® is equivalent to 89% of amount obtained after a single injection of glucosamine sulfate (GS) to the animal at the same dose of 400 mg/kg of animal’s body weight. 0.033 g/cm² delivers 26.9 µg/cm²/hour.

GLUCOTEK® Clinical studies assessing efficacy in the volunteer patients In order to obtain additional data on the efficacy of GLUCOTEK®, the following studies on 80 volunteers have been conducted: OPEN COMPARATIVE RANDOMIZED CLINICAL STUDIES TO ASSESS EFFICACY, SAFETY AND TOLERABILITY OF CHONDROXID® MAXIMUM (Trade name of GLUCOTEK® in Russian Federation), 8% CREAM FOR EXTERNAL USE MANUFACTURED BY LICHT FAR EAST (S) PTE LTD, SINGAPORE AND VOLTAREN® EMULGEL®, GEL FOR EXTERNAL USE MANUFACTURED BY NOVARTIS CONSUMER HEALTH SA, SWITZERLAND, IN PATIENTS WITH STAGE I-III OSTEOARTHROSIS OF A KNEE JOINT. When applying GLUCOTEK® in the amount of 400 mg/kg of the experimental animal’s weight 3 times daily during one week, the amount of glucosamine introduced into the plasma via GLUCOTEK® is equivalent to 89% of amount obtained after a single injection of glucosamine sulfate (GS) to the animal at the same dose of 400 mg/kg of animal’s body weight. 0.033 g/cm² delivers 26.9 µg/cm²/hour.

GLUCOTEK® Clinical studies assessing efficacy in the volunteer patients SUMMARY • The efficacy of treatment with GLUCOTEK® was same or slightly higher than the efficacy of treatment with VOLTAREN® EMULGEL® according to the specified parameter. • The number of positive results in 4 weeks after discontinuation of the drugs (long-lasting effect) was significantly higher in the main group according to both the patient’s and the study doctor’s opinion. I.e., while having a similar efficacy, GLUCOTEK® is superior to VOLTAREN® EMULGEL® in the duration of the aftereffect. During the 4 weeks that followed the discontinuation, the positive effect was maintained in the group that used GLUCOTEK®. • No side-effects and adverse events were observed during the study conduction for GLUCOTEK®. When applying GLUCOTEK® in the amount of 400 mg/kg of the experimental animal’s weight 3 times daily during one week, the amount of glucosamine introduced into the plasma via GLUCOTEK® is equivalent to 89% of amount obtained after a single injection of glucosamine sulfate (GS) to the animal at the same dose of 400 mg/kg of animal’s body weight. 0.033 g/cm² delivers 26.9 µg/cm²/hour.

GLUCOTEK® Clinical trial of structure-modifying effects SUMMARY The main purpose of this study was to assess effects of direct restoration of the articular cartilage based on the analysis of serial MRI scans of knee joints. Clinical data as measured by WOMAC index were evaluated simultaneously. Before the treatment all patients underwent MRI No.1 of the target knee joint with calculation of algofunctional index by WOMAC scales of "pain", "stiffness", and "dysfunction". Follow-up MRIs No.2 and No.3 with assessment of changes in the WOMAC index over time was performed with 3-month interval at the 3rd and 6th months. When applying GLUCOTEK® in the amount of 400 mg/kg of the experimental animal’s weight 3 times daily during one week, the amount of glucosamine introduced into the plasma via GLUCOTEK® is equivalent to 89% of amount obtained after a single injection of glucosamine sulfate (GS) to the animal at the same dose of 400 mg/kg of animal’s body weight. 0.033 g/cm² delivers 26.9 µg/cm²/hour.

GLUCOTEK® Clinical trial of structure-modifying effects CONCLUSION The marked anti-inflammatory effect and structure-modifying effect of TGC were observed in 19 patients with gonarthrosis. Growth of the patellar cartilage volume was observed in more than 50% of patients. Clinical benefits were noted, in particular reduced: pain, stiffness and dysfunction. Clinical effects were seen in all patients, regardless of documented anti-inflammatory or structure-modifying effects. Those patients with no MRI changes over time showed decreased pain and increased motor activity. The greatest structure-modifying effect was observed in patients under 45 years of age (cases B, C, D, E) who had a history of knee joint trauma. The maximum effect of TGC appears by Week 12 of treatment, followed by a phase of clinical stabilization. This suggests that a course treatment should last no more than 12 weeks. When applying GLUCOTEK® in the amount of 400 mg/kg of the experimental animal’s weight 3 times daily during one week, the amount of glucosamine introduced into the plasma via GLUCOTEK® is equivalent to 89% of amount obtained after a single injection of glucosamine sulfate (GS) to the animal at the same dose of 400 mg/kg of animal’s body weight. 0.033 g/cm² delivers 26.9 µg/cm²/hour.

GLUCOTEK® Final Conclusions Uniquely combines two principles of osteoarthrosis treatment Rapid anti-inflammatory & analgesic effect Direct restoration of cartilage Safe for the long-term use No side effects* *Some cases of mild dermatitis have been recorded None required intervention of drugs to recover

GLUCOTEK® Administration & dosage Apply 2-3 times daily to skin over lesion as 2-3 cm strip Rub in until completely absorbed Apply daily for min 4 weeks up to 12 weeks for maximum effect Course can be repeated