LEKSIR. Ltd 121614, Russia, Moscow, Krylatskie Kholmy 30, build 9 tel./fax (495) 956 76 86...

LEKSIR. Ltd121614, Russia, Moscow, Krylatskie Kholmy 30, build 9tel./fax (495) 956 76 86

INTESTINNOVATION FOR YOUR HEALTH

Do You need 3 000 000 000 friends?

Expert appraisal. Initiative - basis for progress

"Leksir" Company specializes in development, manufacturing and marketing of innovative pharmaceuticals and food supplements in three therapeutic areas: gastroenterology, pediatrics and infectious diseases (improved antibiotics). The ready made products are presented in solid drug forms (tablets, capsules, powders and suppositories)

"Leksirъ“ Trademark . We aim at quality rather than quantity

Leksir Company, Russia, is known as a reliable and dynamically developing company. It is a part of the international pharmaceutical group which includes "STI-MED-SORB“ manufacturing plant (Russia), “AVVA Pharmaceuticals AG” marketing company (Switzerland) and a pharmacy chain in Moscow. Leksir Ltd. has a wide distribution network in Russia and the CIS countries.There are 55 items of pharmaceuticals in the portfolio of the company including original formulations and brand generics.


"STI-MED-SORB“ manufacturing plant . Modern manufacturing facilities are the base of high technologies

"Leksir" Company was founded in 1996 (Russia, Moscow). Manufacture of the pharmaceutical preparations is performed at its own plant, “STI-MED-SORB“, located 1000 km from Moscow in the ecologically pure Volga region.

The manufacturing facilities are located in two buildings which were constructed from the ground up with the total area 1 188 m2 and 10 200 m2.The staff of the manufacturing plant includes 300 eminently qualified workers, experts and managers.


“STI-MED-SORB”. Following high standards

Compliance with the requirements of GOST R 52249-2005 (GMP EU) is confirmed by Certificate of conformity No 0133 issued as of 20.12.2006 by the Federal Agency on Technical Regulation and Metrology of the Russian Federation.

Manufacturing License - No 99-04-000232 dated 28.09.2006 issued by the Federal Service for Surveillance in Public Health and Social Development (former Ministry of Health of the Russian Federation)


Our manufacturing plant "STI-MED-SORB“. Modern manufacturing facilities is the base of high technologies

First production site produces uncoated and coated tablets and pellets. Production capacity is 25 mln tablets/month.

Another production site is designed for pharmaceuticals insolid gelatin capsules. Production capacity – 15 mln tablets/month.

And the third production site – production of pharmaceuticals based on hydrolyzed lignin. Production capacity – 24 mln tablets/month.

API production site – production of hydrolyzed lignin. Production capacity – 16 tons/month.The plant has high-technology equipment. Complex multilevel quality control system is introduced at the plant. "STI-MED-SORB" plant has its own R&D laboratory which develops new pharmaceuticals and their dosage forms.

The structure of the plant also includesCentral Plant Laboratory and Department of Quality Control.


“STI-MED-SORB”. Control and quality

Department of Quality Control

includes physical-chemical and microbiology laboratories which are equipped with modern devices for measuring and testing the quality of raw materials and ready-made products. Qualification of the staff (36 specialists) was confirmed by Certificate of Technical Competence No KK-0037-06 issued 28/08/2006 by Federal Service for Supervision in Public Health and Social Development

Central Plant Laboratory (CPL) was founded in 2005 to solve perspective tasks in the field of technology for ready made drug formulations and modernizing technological processes of existing manufacture. The staff (9 specialists) operate with the most advanced materials and methods from the leading pharmaceutical manufacturers.


International cooperation

Russia, Armenia, Belarus, Moldova, Kazakhstan, Ukraine, Republic of Uzbekistan, Brazil, China, India, USA, Canada

Our products are promoted in the CIS countries through Leksir subsidiaries and exclusive distributors. On far abroad markets we start our activity with marketing research and registration as well as establishing contacts with potential partners to set up outsourcing cooperation.

Leksir Ltd. develops, manufactures and markets innovative food supplements and pharmaceuticals in gastroenterology. Main R&D areas: antibiotics with enhanced safety profile, prebiotics for treatment of alimentary intoxications and intestinal infections, composite prebiotics for treatment and prevention of intestinal microflora disbalance (total: 30 new compositions in pipeline). The company offers finished formulations, with further partnership in marketing on national and international markets (Strategic Distribution Alliance).

Cooperation Tasks


INNOVATION PRODUCTS:

FILTRUM – protects from food intoxication and intestinal infections

LACTOFILTRUM – improves intestinal microflora and prevents from dysbacteriosis

New Antibiotics - antibiotics with enhanced

safety profile for intestinal microflora

FILTRUM (Lignin) tablets, capsules

LACTOFILTRUM (lignin+lactulose) tablets, capsules

Combination “ANTIBIOTIC+prebiotic” tablets, capsules

Enterosorbent fibers of plant origin neutralizing a wide range of endo- and exogenous toxins and pathogenic microorganisms in the GI tract

Double power prebiotic improving intestinal microflora

Antibiotic with enhanced safety profile for intestinal microflora


Food and alcohol intoxication. Intestinal infections. Diarrhea syndrome

Microflora disorders, atopic dermatitis, antibiotic therapy

Durable antibacterial therapy by broad spectrum antibiotics

PRODUCT OFFER SUMMARY

AVVA Pharmaceuticals AG (Switzerland)

owner of the registration dossier

“STI-MED-SORB” (Russia)Manufacturer of the ready made product

LEKSIR LTD. (Russia):STI-MED-SORB operating company

1. AVVA Pharmaceuticals AG delivers reg. dossier and Territory license to the Partner on the basis of SDA agreement.

2. STI-MED-SORB manufactures the product (registered by the Partner in the Territory) on the basis of the Manufacturing Contract.

3. The Partner on its own behalf registers and promotes/distributes the product in the Territory.

Looking forward to cooperation:Looking forward to cooperation: Strategic Distribution Alliance (SDA) Strategic Distribution Alliance (SDA)

PARTNER


AVVA Pharmaceuticals AG (owner of dossier)

Our Partner (registers the product)

Plant “STI-MED-SORB” (Contract Manufacturer)

dossier

places the order

exports the products

distributesand

promotes products

L o c a l M a r k e t

Strategic Distribution AllianceStrategic Distribution Alliance


FILTRUMFILTRUM((0,45 g LIGNIN0,45 g LIGNIN, , TABSTABS))FILTRUMFILTRUM

((0,45 g LIGNIN0,45 g LIGNIN, , TABSTABS))

NEW GENERATION ENTEROSORBENT

Life free of toxins

FILTRUMFILTRUM

Lignin fibres of plant origin to neutralize wide range of endo- and exogenous toxins and pathogenic microorganisms in GI tract

INDICATIONS: Intoxication by poor food, alcohol, drugs.

Intoxication by detrimental substances accumulating at hepatic and renal insufficiency.

Acute intestinal diseases (dysentery, salmonellosis, rota-virus infections etc.)

Diarrhea syndrom of unspecified origin

Filtrum does not affect any tissues of the gastro-intestinal tract, is does not accumulate in any organs and is entirely eliminated from the intestines.

FILTRUMFILTRUMFILTRUMFILTRUM

Lignin is formed by removal of water from sugars to create

aromatic structures. These reactions are non reversible. There are many possible monomers of lignin, and the types and proportions depend on the source in nature. Some typical monomers are shown in the sketch :The OH groups (either the alcoholic OH's on the chains or the phenolic OH's on the aromatic rings) can react with each other or with the aldehyde or ketone groups. When an OH reacts with another, an ether linkage is formed. As we see, an OH reacts with an aldehyde to form a hemiacetal. The reactions of OH groups with ketones forms ketals. An early stage in the condensation of various monomers to form lignin is shown in the next sketch :

COMPOSITION

FILTRUM / LIGNINFILTRUM / LIGNIN FILTRUM / LIGNINFILTRUM / LIGNIN

There are several groups shown in red that can react

further. Some will simply extend the polymer while others would establish cross linking. The monomer that is shaded in orange has three of its functional groups linked to other monomers, so it is starting a branch or cross link. The large lignin molecules fill three dimensions and are heavily cross linked. Sometimes lignin is isolated as a brown powder, but more often it is a gummy mixture of lignins with a wide range of molecular weights.

Lignin resists attack by most

microorganisms, and anaerobic processes tend not to attack the aromatic rings at all. Aerobic breakdown of lignin is slow and may take many days. Lignin is nature's cement along with hemicellulose to exploit the strength of cellulose while conferring flexibility.

COMPOSITION

FILTRUM / LIGNIN FILTRUM / LIGNIN

1943 / Germany – original enterosorbent product Porlisan (on the basis of lignin) appeared as anti-diarrhea product for

curing diarrhea syndrome of infection and non-infection nature 1970 / Russia – improved form of lignin was elaborated

(lignin powder with higher absorbtion properties) 1997 / Russia – tableted formulation of medical lignin

(Filtrum) was patented

There are many pores on the surface of Filtrum-sorbent: micro-, mezo- and macropores, which results in broad spectrum of absorbtion activity – from heavy metal ions to microbic cells and organic metabolits. Prevalence of mezopores enables Filtrum to neutralize middle- and long-chained molecules including endo- and exotoxins.

HISTORY AND BACKGROUND

FILTRUM vs Activated FILTRUM vs Activated Charcoal Charcoal

FILTRUM vs Activated FILTRUM vs Activated Charcoal Charcoal

FILTRUM®

Broad absorbtion spectrum

Neutralizes bacteria and its toxins

Binds gistamine and food allergens

Reparative effect of lignin on intestinal mucous surface

Activated Charcoal

Narrow absorbtion spectrum

Low absorbtion of bacteria and its toxins

Binds low spectrum of allergens

Negative influence on intestinal mucous surface

FILTRUMFILTRUM FILTRUMFILTRUM

Universal means of decreasing intoxication in case of intoxication of different etiology (poor food, acute intestinal diseases, alchogol overdosage etc.)

Neutrolizes pathogenic microflora and its toxins thus blocking the pathogenic mechanism (vs. loperamide)

No negative effect on normal microflora (vs. intestinal antiobiotics)

Does not form resistant stamps in pathogenic microflora.

High safety profile.

Can be used to prevent an assumed intoxication.

advantages in intoxication and acute intestinal diseases segment

FILTRUMFILTRUMFILTRUMFILTRUMFrequency of acute toxic infections symptoms in peoplein people

77

60

48

32

25

14

2

0 10 20 30 40 50 60 70 80 90 100

Abdominal pain

Diarrhea

Nausea, vomitting

Meteorism, swelling

Anorexia

Fever

Other

%

FILTRUM FILTRUM FILTRUM FILTRUM

According to marketing research 60% of people at

least once a year suffered from the following symptoms:

1. Gastro-intestinal disorders caused by “food poisoning”

2. Alimentary toxic infection

3. Intestinal infection

4. Gastro-intestinal disorder of unspecified toxic origin

60%

Intoxication and acute intestinal diseases


0

0,51

1,52

2,53

3,54

4,5

days

,

Fig.1 Duration of main clinical symptoms in patients with acute dysentery

Russian State Medical University (Moscow, 2001)

CLINICAL EVIDENCETreatment of acute intestinal infections Treatment of acute intestinal infections accompanied by diarrhea syndromeaccompanied by diarrhea syndrome

Control group (basic therapy): antimicrobials Furazolidon (nitrofurans) and ciprofloxacin (fluoroquinolones), and pathogenetic therapy – parenteral detoxification solutions (colloid and salt solutions), astringents, reparative drugs and adrenomimetics.

Filtrum group = standard therapy +Filtrum

Fig.2 Duration of main clinical symptoms in patients with gastrointestinal form of salmonellosis

0

0,5

1

1,5

2

2,5

3

3,5

4

days

FILTRUM FILTRUM

Russian State Medical University (Moscow 2001)

Standard therapy (control group): parenteral and oral rehydration by salt solutions and adrenomimetics

Filtrum group: standard therapy + Filtrum

Fig.3 Duration of main clinical symptoms in patients with alimentary toxic infections

0

1

2

3

4

days

FILTRUMFILTRUM

Russian State Medical University, 2001

Standard therapy (control group): parenteral and oral rehydration by salt solutions and adrenomimetics

Filtrum group: standard therapy + Filtrum


DOSAGES: Children under 6 months -

1/4 tablet 3-4 times a day 6 months - 1 year - 1/3

tablet 3-4 times a day 1-3 years - 1/2 - 1 tablet 3

times a day 4-7 years - 1 - 1,5 tablets 3

times a day over 7 years - 2 tablets 3-4

times a day1-1,5 hours before or 1-1,5

hours after meal

Conclusion 1:

Filtrum is highly effective for treatment of acute intestinal infections accompanied by diarrhea syndrome, e.g. acute dysentery, gastrointestinal form of salmonellosis and, particularly, gastroenteritic form of alimentary toxic infection. Filtrum therapy results in shortening of the major clinical signs statistical decrease (in days) over 30%.

Conclusion 2:

Filtrum can be recommended as a drug of choice for patients with mild alimentary toxic infections and salmonellosis as well as a component of combined therapy of moderate and severe dysentery, salmonellosis and alimentary toxic infections

Сlinical evidence

FILTRUM FILTRUM

Patients characteristics

Characteristic Filtrum (n=61)

Control (n=58)

Age (years) 3.420.44 4.220.79

Disease duration (days)

3.340.36 2.450.2

Etiology: Klebsiella, Salmonella, Campilobacter, Rotaviruses, Thoroviruses, Norwalk viruses, Unspecified

Filtrum STI addition to basic therapy of acute intestinal infections in children had beneficial effect on general toxicity and resulted in alleviation of fever, intoxication, nausea and vomiting and in improvement of appetite

Research Institute of Pediatric Infections (St.Petersburg, 2003)

Efficacy in combined treatment of acute intestinal infections in children

Fig.1 Duration of general infection symptoms in study and control patient groups

Days

0

0,5

1

1,5

2

2,5

3

3,5

4

4,5

Filtrum Control

Fever

Vomiting

Fatigue

Poor appetite

FILTRUMFILTRUM

Research Institute of Pediatric Infections (St. Petersburg, 2003)

(rehydration, diet)

Fig.2 Duration of local infection symptoms

0 0,5 1 1,5 2 2,5 3 3,5 4 4,5

Filtrum

Control

Abdominal pain TendernessLoose stool Mucus in feces

Undigested food remnants in feces

FILTRUMFILTRUM


Days

FILTRUMFILTRUM Clinical evidence conclusion: addition of intestinal

sorbent Filtrum to standard therapy of acute intestinal

infections significantly enhances treatment efficacy and results in a quicker clinical recovery. Good tolerability and significant therapeutic effect on the course of acute intestinal infections in children, including infants, allows giving Filtrum a positive opinion and recommendation towards a wider promotion of the drug into clinical practice


First aid natural means for protecting organism from alimentary intoxication

Multipurpose non-drug means for decreasing acute intoxication of different nature (food, intestinal infections, alcohol)

Universal anti-”Travellers diarrhea” protector Convenient first aid supplement – always at hand in

case of unexpected acute intoxication Strengthens effect of the standard therapy in case of

acute intestinal disorders Accelerates rehabilitation after food intoxication

FILTRUMFILTRUMPositioning: key messages aspects

Product improvement for children audience: confectionery, various tastes

Different formulations: caplets, capsules, sache, gel, paste Combination with additives giving detoxifying synergy

effect for specific niche demands Modifying absorption spectrum to increase neutralization

of toxic or microbe agents of definite parameters and properties

Search for new enterosorbents with unique properties beneficial for health and treatment

FILTRUMFILTRUMR & D prospects

Prehistory terminology

Probiotics/Prebiotics Lactulose

Food fibers Enterosorbents Lignin LactofiltrumLactofiltrum

Probiotics are beneficial bacteria that can be introduced into the digestive system with food. They enhance immunity, help regulate hormone balance, protect from food poisoning, allergies, and perform other important functions.

Prebiotics are non-digestible carbohydrates that pass through the small intestine undigested and are fermented in the colon by beneficial bacteria thus activating their growth.

Enterosorbents are substances that bind and deduce exogenous and endogenous toxins as well as pathogenic microorganisms and their metabolites from the gastrointestinal tract .

CompositionComposition

Medicinal lignin fibers, mg 375,0

Lactulose, mg 125,0

Moisture, % 5, 0

Total tablet weight, mg, + 5%

500,0

Shelf life: 3 years

Lactofiltrum is patented in 1999. Expiry date 2019

Specification of components:

Medicinal lignin by Russian manufacturers standard (approved by the Ministry of Health) FSP 42-02363083-02

Lignin active substance and Lactofiltrum (as finished product) are manufactured on the own plant in accordance with GMP standards. Lignin modified preparation technology and sterilization were elaborated on the basis of the own patent (1999).

Lactulose (complies with Lactulose Concentrate USP26)

New generation prebiotic for elimination of intestinal pathogenic microorganisms and their toxins as well as for activation of own bifidobacteria growth, which normalizes microflora balance Dysbacteriosis of different etiology (gastro-

intestinal chronic and acute diseases, long-term therapy by anti-inflammatory non-steroids, immunosuppresants etc.)

Irritated bowel syndrome with a tendency to constipation and unstable stool

Rehabilitation of microflora disbalance after antibiotic therapy (incl. antibiotic-associated diarrhea)

In complex therapy of atopic dermatitis (diathesis) particularly in pediatric practice

Combined treatment of acute and chronic viral hepatitis and hepatic cirrhosis.

General improvement of intestinal microbiological ecology (for aging population)

Indications:

Dysbacteriosis or microflora disbalance

Vital aspects of abnormal microflora in children

Dysbacteriosis or microflora disbalance:

Microflora disorders are diagnosed in 90% children

Slows down vitamins and minerals absorption thus negatively affecting development of bone, muscle and nervous systems as well as immunity

Often causes or aggravates atopic dermatitis

Has negative destructive influence on the intestinal mucosa causing various gastro-intestinal chronic diseases

Vital aspects of normal microflora in adults and aged peopleNormal microflora

Prevents septic processes in intestines and colon

Results in decreasing internal intoxication

Improves absorption of vitamins and minerals preventing osteoporosis

Has beneficial effect on immunity and general physiological activity

FeaturesDOUBLE MECHANISM INFLUENCE ON MICROFLORA

Lactulose - improves growth and activity of lacto - and bifidobacteria

Lignin - natural enterosorbent, adsorbs wide range of endo- and exogenous toxins and pathogenic microorganisms in the intestines

100 %

Normalization of intestinal microflora

Аdvantages vs traditional probiotic therapy

LACTOFILTRUM®

(as prebiotic)

Bacterial colonies products (probiotics)

Direct absorption of pathogenic microflora and its toxins

Unable to absorb pathogens

Free transit through gastro-intestinal tract with minimum efficacy loss

Substantial loss of activity in intestines due to interference with aggressive stomach excretion

Direct stimulation of own normal microflora growth

Binds histamines and food allergens (in allergo-dermatosis

therapy) High safety profile: can be used for a long time without side

effects

Ideal as preventive (prophylactic) means

Indirect influence on the normal microflora growth

Unable to bind toxic organic metabolites

Restrictions for durable usage

Prophylactic usage with cautions

Сlinical evidence Treatment of dysbacteriosis in children,

including those with functional and chronic gastrointestinal disturbances

0

10

20

30

40

50

60

70

80

Lactofiltrummonotherapy

Standard therapy(spasmolitics,

probiotics)

constipation

abdom. pain

meteorism

Fig. 1 Improvement of clinical condition (treatment duration 14 days)

Effi

cacy

, % p

atie

nts

Research Institute of Pediatrics (Moscow, 2003)

Lactofiltrum influence on intestinal microflora

Microflora compositionNormal

level

With Lactofiltrum (n = 45)

Control (n = 15)

Before After Before After

Bifidobacteria > 8 < 6 > 9 < 7 < 7

Lactobacteria > 6 < 5 > 8 < 5 6

E.coli, weak fermentative < 10 % 13% 5% 12% 9%

Hemolytic E.coli 0 5 0 6 2

Candida < 3 > 5 0 > 5 < 4

Lactase-negative bacteria < 5 % 7% 3% 7% 5%

Enterococcus < 7 > 9 < 3 > 8 < 3

Fig. 2

Research Institute of Pediatrics (Moscow, 2003)

DOSAGES:

Children under 6 months - 1/4 tablet 3-4 times a day

6 months - 1 year - 1/3 tablet 3-4 times a day

1-3 years - 1/2 - 1 tablet 3 times a day

4-7 years - 1 - 1,5 tablets 3 times a day

over 7 years - 2 tablets 3-4 times a day.

1-1,5 hours before or 1-1,5 hours after meal.

Lactofiltrum treatment resulted in normalization of intestinal microflora composition, namely, in elimination of opportunistic bacteria, suppression of cocci and growth of Lacto- and Bifidobacteria.

CONCLUSIONS

Сlinical evidence

CONCLUSIONS (cont.)

Lactofiltrum corrects both intestinal peristalsis and intestinal microflora composition.

Lactofiltrum is effective in pediatric patients with functional gastrointestinal disturbances like

Lactofiltrum can be used for conditioning therapy to enhance the effect of further decontamination against parasitic invasion (lambliasis)

Lacto- and Bifidobacteria-containing drugs can be reasonably used after 14-day conditioning by Lactofiltrum.

At least 14-day treatment by Lactofiltrum with further analysis of feces for dysbacteriosis appears obligatory after children are transferred from hospital to an orphanage. This measure aims at prevention of nosocomial infection in weak children by opportunistic microflora.

Lactofiltrum clinical study in patients with dysbacteriosis Dynamics of clinical symptoms during Lactofiltrum treatment

0%

20%

40%

60%

80%

100%

120%

Beforetreatment

1-st week oftreatment

2-nd week oftreatment

Appetite

Meteorism

Constipation

Unstable stool

RESULTS:

Improvement of clinical signs was associated by alleviation of intestinal dysbacteriosis.

State Medical University (Saratov, 2005)

0

2

4

6

8

10

12

14

skin hyperem ia skin pruritis skin dryness

Lactofiltrum + standardtherapy

Standard therapy (diet,antihistamins, topicals,enzymes)

Conclusions:

Lactofiltrum can be recommended for monotherapy of mild atopic dermatitis in the phase of incomplete remission of moderate disease, and for treatment of moderate atopic dermatitis in combination with local therapy.

Atopic dermatitis accompanied by intestinal disturbance with a tendency to constipation and unstable stool

Treatment duration 14 daysDays

Scientific Center of Children Health (Moscow, 2003)

Acute viral hepatitis (A, B, C)

02468

1012

Lactofiltrumtreatment

Control group

Duration of the major clinical signs

Lactofiltrum addition to standard therapy of acute viral hepatitis results in significantly lesser duration and intensity of intoxication (fatigue, headache, low appetite, anorexia, fever), dyspepsia, pain and jaundice. Such

treatment is shown to accelerate normalization of liver and thickened gallbladder wall sizes and gallbladder clearance of the solids compared to control patients.

Federal Medico-Biological Agency (Moscow, 2005)

Days

Treatment duration 21 days

0

1

2

3

4

5

6

7

8

1 2 3 4

0

1

2

3

4

5

6

7

8

1 2 3 4

Intestinal microflora components in patients with genitourinary chlamydiosis (lg CFU/g).

Control group: clarithromycin Experimental group: clarithromycin + Lactofiltrum

Before treat.

After treat.

1 - Lactobacillus spp.

2 - Bifidobacterium spp.

3 - Escherichia coli4 - Enterococcus spp.

Microflora support during oral antibacterial therapy

Institute of Epidemiology and Microbiology (St.-Petersburg)

RESULTS• Decrease of lactobacilli and bifidum bacteria content was statistically significant in the control group (р<0.001 and p< 0.05 respectively).• Analysis did not reveal significant qualitative alteration of the studied microflora components in experimental patient group.

CONCLUSIONS

1. The study confirmed the efficacy of prebiotic Lactofiltrum administration for prevention of dysbacteriosis development during chlamydiosis treatment by macrolide antimicrobial clarithromycin.

2. Lactofiltrum administration concomitantly with antimicrobial treatment of chlamydiosis facilitates preservation of normal intestinal microflora and decreases the risk of intestinal colonization by Candida spp.

3. Lactofiltrum administration decreases the risk of antimicrobials-induced dyspepsia and allergic reactions.

Lactofiltrum prevention of intestinal dysbacteriosis in surgical patients with purulent conditions receiving prolonged antimicrobial therapy (by CEPHAZOLIN, IMIPENEM, MAXIPIME)

Dysbacteriosis parameters

Study group Control group

Before treatment

After treatment

Before treatmen

t

After treatmen

t

Bifidobacteria (<107) 10% 5% - 20%

Lactobacteria (<105) 5% 5% - 30%

Lactose-negative E. coli (> 5%) 5% - 50%

E. coli with low enzyme activity (> 10%) 10% 5% - 30%

Hemolytic E. coli 5% - 40%

Proteus spp. (>103) 10% - 30%

Staphylococcus aureus 20% - 40%

Military hospital №42 (St.-Petersburg)

Microflora support during parenteral antibacterial therapy

RESULTS

Potential prolonged antimicrobial therapy results in intestinal dysbacteriosis, decrease of bifidobacteria and lacrobacteria content and appearance of opportunistic and pathogenic microflora, including Candida spp.

Lactofiltrum administration allows prevention of intestinal dysbacteriosis during antimicrobial therapy.

Lactofiltrum administration decreases the risk of Candidosis development during antimicrobial therapy.

Lactofiltrum administration allows normalization of gastrointestinal tract condition even in patients with initial dysbacteriosis – normalization of microflora profile, stool frequency and consistence, pain, discomfort and meteorism relief.

CONCLUSION Lactofiltrum inclusion into combined therapy schedule significantly

alleviates both clinical and laboratory manifestations of dysbacteriosis during prolonged parenteral antimicrobial therapy.

Sales dynamics, Russia

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

packs N60

2001 2002 2003 2004 2005 2006

Positioning: key messages aspects

Double power prebiotic for improvement of

intestinal microflora in case of gastrointestinal

disorders and atopic dermatitis High safety profile prebiotic for all groups of

population Microflora protector during antibiotic therapy Strengthens standard therapy efficacy in case of

microflora disorders (synergy)

R & D prospectsR & D prospects

Product improvement for children audience: confectionery, powders, various tastes

Miscellaneous formulations: caplets, capsules, sache, gel, paste

Combination with additives giving synergy positive effect for intestinal microflora

Modifying prebiotic component to reach better activation of definite spp.

Modifying enterosorbent component to gain more specific absorption of certain pathogens

LEKSIR. Ltd121614, Russia, Moscow, Krylatskie Kholmy 30, build 9tel./fax (495) 956 76 86

INTESTINNOVATION FOR YOUR HEALTH


Innovation product

Antibiotics with enhanced safety profile for intestinal microfloraAntibiotics with enhanced safety profile for intestinal microflora


Antibiotic + prebiotic combination: background and history of the development

1929 – A. Fleming extracted penicillin

1942 - The term “antibiotic” introduced

2000 – About 160 antibiotics used in practiceAntibiotic global sales $25 billion (13% of all drug sales)

1916 – the term “dysbacteriosis” first appeared in clinical practice.

1929 – lactulose was synthesized and described

1957 – lactulose bifidogenic effect was discovered

2006 – Innovation composition “Antibiotic+lactulose” was elaborated


Antibiotics without side effect on intestinal microflora

Unsatisfied needs for elaboration of new antibiotics

1. Worldwide growth of infection diseases being cured by antibiotics resulted in intensive growth of antibiotic consumption.

2. Antibiotics therapy is the leading factor resulting in elimination of intestinal bifidobacteria and lactobacilla along with growth of pathogenic microflora.

3. Vast prevalence of the gastrointestinal diseases in the population leading to stable disbalance of intestinal micro-ecology.

4. Rehabilitation of the normal microflora after antibiotic therapy became standard practice


You want to give your patients the most safety treatment by antibiotics. Innovation antibiotic formulations combine the well established power of widely used antibiotics with prebiotic microflora balance effect. This new formulation ensures microflora maintainance during antibiotic treatment.

Patent status:

Composition of improved antibiotics and its manufacturing technology were patented and international priority received.

The next generationThe next generation

Pharmaceutical formsPharmaceutical forms • Tablet and capsule formulation

• Powder for oral solution (sachets)

• Suspension and syrup


Inclusion of lactulose into combination with antibiotics results in the following:

Bifidobacteria and Lactobacilla maintainance during antibiotic therapy

Tendency of Candida albicans elimination

No influence on anti-infective activity of antibiotic (equal efficacy with pure antibiotic control tests)

ResultsResults

AVOID DYSBACTERIOSIS

DURING ANTIBIOTIC

THERAPY


Clinical approbations 1Clinical approbations 1

Composition “Clarithromycin + lactulose” in urogenital chlamidiosis therapyPasteur Scientific Research Institute of Epidemiology and Microbiology (St.-Petersburg, Russia, 2006)

Patients: urogenital infections caused by Clamidia trachomatis

Control group: clarithromycin 250 mg twice a day, 14 days

Test group: clarithromycin 250mg+lactulose 300mg twice a day, 14 days

0

1

2

3

4

5

6

7

8

Lactobacillus spp. Bifidobacterium spp. Enterococcus spp. Escherihia coli

Control group. Beforetreatment.

Control group. Aftertreatment

Test group. Beforetreatment

Test group. Aftertreatment


Composition “Clarithromycin + lactulose” vs Composition “Clarithromycin + lactulose” vs Claritromycin in urogenital chlamidiosis therapyClaritromycin in urogenital chlamidiosis therapy

CFU/g

Control: clarithromycin Test: clarithromycin + lactulose


ResultsResults

The control group demonstrated a considerable (p< 0.05) 100-fold decrease of lactobacilli amount and a 20-fold decrease of bifidobacteria and enterococci. The amount of escherichia per 1 g of faeces virtually did not change.

In the test group (Clarithromycin + lactulose ) there is 10-fold less decrease of lactobacilli amount (p<0.1), than in the test group. The amount of other bacteria virtually does not change in combination with antibiotic therapy.


1. The research proves that even when using such a favorable antibiotic as clarithromycin for intestinal microecology, the amount of main representatives of obligate microbial flora shows statistical decrease even in patients with unaggravated gastroenterologic anamnesis.

2. Including lactulose prebiotic into the antibiotic composition allows to minimize these changes and protect obligate microflora from antibiotic negative effect.

ConclusionConclusion


Composition “amoxicillin + clavulanic acid” with lactulose” in treating gastroduodenitis. Medical Pediatric Academy (St.-Petersburg, Russia, 2006)

Patients: Children with Helicobacter pylori-associated gastroduodenitis.

Control group: amoxicillin + clavulanic acid (675 mg) twice a day, 14 days.

Test group: amoxicillin + clavulanic acid (675 mg) + lactulose 300mg twice a day, 14 days.

Clinical approbations 2Clinical approbations 2


“ “Amoxicillin+clavulanic acid” Amoxicillin+clavulanic acid” with and without with and without lactuloselactulose” ”

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Lactobacillus spp. Bifidobacterium spp Candida albicans Escherihia coli

Control group. Beforetreatment.

Control group. Aftertreatment

Test group. Beforetreatment

Test group. Aftertreatment

CFU/g


ResultsResults

The control group (antibiotic) demonstrated a significant (p< 0,01) and substantial (from 10 to 50 times) decrease of the amount of escherichia, bifidobacteria and lactobacteria. The amount of Candida albicans increased considerably (more than 10 times)

The test group (antibiotic+lactulose) showed (p>0,01) no change of Escherichia coli, increase of bifidobacteria and lactobacilli, virtually complete sanitation of the infection candida, as well as of proteus and klebsiella (р<0.001).


1) Administration of amoxicillin (with clavulanic acid) as an antibiotic, most favourable for the intestinal microecology, without prebiotic protection results in dysbiosis that is manifested in the patients in statistically significant decrease of the main representatives of obligate microflora (Bifidobacterium., Lactobacillus, Escherichia ) and considerable increase of Candida albicans.

2) Effectiveness of combined administration of the prebiotic preparation of lactulose in the pharmaceutical composition with amoxicillin has been proved. Introduction of lactulose into the complex therapy with amoxicillin allows to avoid microflora disbalance

ConclusionConclusion

Antibiotic + lactulose combination is likely to find a role as a safe, microflora favorable option in treatment of bacterial infections by oral antibiotics


Summary of resultsSummary of results

clarithromycin

amoxicillin + clavulanic acid

azithromycin


Development status: dossier available Q3 - 2007Development status: dossier available Q3 - 2007

Development status: dossier in pipeline Q1 - 2008Development status: dossier in pipeline Q1 - 2008• Spiramycin• Cefixime• Midecamycin• Ceftibuten• Roxithromycin• Minocycline• Rifampicin• Cefuroxime• Josamycin

• Ciprofloxacin• Ofloxacin• Levofloxacin• Moxifloxacin• Natamycin• Fosfomycin• Nifuratel• Clindamycin• Thiamphenicol


Market prospects for improved antibiotics (ecobiotics):Market prospects for improved antibiotics (ecobiotics):Antibiotic market grows by 12% yearlyCautious use of antibiotics due to microflora side effectsAwareness growth of the normal microflora role in human healthGrowth of the probiotic and prebiotic market – loyalty increase towards microflora improving components

Positioning aspects

• Antibiotic therapy in pediatric practice (microflora is unstable and sensitive to antibiotics in children and infants)• Diseases requiring long term antibiotic therapy by broad spectrum antibacterial preparations

Safe antibiotics / EcobioticsPerorally Administrable Antimicrobial Composition

Antibiotics with enhanced safety profile for intestinal microflora

LEKSIR LTD

Leksir Ltd (Russia) presents the innovative project Safe antibiotics.

The use of invention «Perorally Administrable Antimicrobial Composition» (PCT/RU 2005/000434 WO 2006/025767)

safe antibiotics do not damage intestine beneficial bacteria (Bifidobacterium spp. Lactobacillus spp)

safe antibiotics prevent pathogenic microorganisms from spreading (Candida- , Proteus- and Klebsiella-associated infections)

AbstractAbstract

new patent new patent protection for the old (traditional) antibiotics for the old (traditional) antibiotics

new opportunities of marketing strategy on the drug market new opportunities of marketing strategy on the drug market

new competitive advantages on the drug market over producers of new competitive advantages on the drug market over producers of traditional forms of antibioticstraditional forms of antibiotics

Allows to produce antibiotics with limited list of side effects:

Opens new business prospects for pharmaceutical companies:

ProblemProblem

Almost any antibiotic possesses a broad spectrum of side effects

The main reason why of antibioticotherapy negative consequences is that:

antibiotics do not have selective damaging effect on the pathogenic microflora only and destroy both pathogenic organisms and protective (useful) intestinal microflora

death of protective intestinal microflora (Bifidobacterium spp. Lactobacillus spp) resulting from taking antibiotics is the basic reason for the dysbiosis

Under dysbiosis:

Development of the pathogenic organisms in the colon.

Intoxication as a result of the growing of pathogens.

Infringement of the motoric and secretion function of the colon.

Development of the anemies, hypovitaminosis, fermentopathies.

Depressed immunological status ….. etc

The use of invention «Perorally Administrable Antimicrobial Composition» can solve the problem of antibiotics-related dysbiosis

Intestinal beneficial microflora

Pathogenicorganisms

How does it work?

Аntibiotics are administered perorally

Antibiotic is absorbed from the stomach

Antibiotic eliminates pathogenic organisms

Non-absorbed part of antibioticgo to the intestine

Antibiotic damage intestinal beneficialmicroflora

As a result :

intestinal biocenose is destroyed

dysbiosis-related side effects manifest themselves (antibiotic-induced colitis, antibiotic-induced diarrhea, etc)1

Antibiotic eliminate pathogenic organisms

Antibiotic damage intestinal beneficialmicroflora

Finished product of traditional antibiotics is produced according to the formula :

Antibiotics substance + Lactose or another excipient

Finished product of Safe antibiotics is produced according to the new formula :

Antibiotics substance + Lactulose

Innovative antibiotic compositions combine the well established power of widelyused antibiotics with prebiotic microflora balance effect. This new compositionensures microflora maintainance during antibiotic treatment.

Solution

Antibiotics substance

Lactulose

Antibiotics substance

Lactose

In the colon, undigested lactulose is the ideal nutri-tional basis for health-promoting bacteria (bifidobac-teria and lactobacilli).

In the colon lactulose is degraded by saccharolyticbacteria which convert it into low-molecular organic acids, mainly lactic acid.

Lactulose stimulates selectively the growth and vitalactivity of protective intestinal microflora.

Lactulose

Lactulose is widely known and researched. In medicine, lactulose has a long track record as a successful therapy against constipation and portal hepatic encephalopathy.

The disaccharide lactulose is the ketonic analogue of lactose and consists of the two mono-saccharides galactose and fructose. Lactulose is not broken down by disaccharidases in the small intestine and is therefore not absorbed.

Dosage of lactulose, as a component of the finished form of antibiotic, is very small and do not induced constipation effect.This dosage of lactulose enter the large intestine unaltered, where it stimulates the growth of beneficial bacteria only.

Intestinal beneficial microflora

Pathogenicorganisms

How does it work?Safe antibiotics are administered perorallyAntibiotic is absorbed from the stomach Antibiotic eliminates pathogenic organismsLactulose can not be digested and absorbed through the stomachNon-absorbed part of antibiotic and lactulosegoes to the intestineAntibiotic can damage intestinal beneficialmicroflora, but …… lactulose stimulates the growth and vitalactivity of intestinal beneficial microflora

Antibiotic eliminate pathogenicorganisms

lactulose stimulates the growth and vitalactivity of intestinal beneficial microflora

Antibiotic can damage intestinal beneficialmicroflora

As a result :

intestinal biocenose remains unchanged

there’s no dysbiosis- related side-effects

Safe Antibiotics are produced by Leksir Ltd according to the new formula

in Combination with Lactulose:

Leksir LtdLeksir Ltd has carried out has carried out clinical tests, confirming the efficacy of new , confirming the efficacy of new class of antibiotics:class of antibiotics:

Clarithromicyn + Lactulose (2006)

Amoxiclav + Lactulose (2007)

Leksir Ltd plans to start the producing these antibiotics from 2009 - 2010 .

Start of project

AmoxicillinAzithromycinCefiximeCefuroximeCiprofloxacinClarithromycin

ClindamycinDoxycyclineFosfomycinLevofloxacinMidecamycin

MoxifloxacinNifuratelNifuratelNifuroxazideNifuroxazideOfloxacinOfloxacinRoxithromycin Roxithromycin SpiramycinSpiramycin

The random test sample included 30 children of both sexes aged 917 years with diagnosed Нр-associated gastrites. The initial diagnosis was substantiated by an urease test of antral

gastric bioptats obtained upon fibroesophagogastroduodenoscopy (FEGDS).

Before and after implementation of antibiotic therapy, the intestinal contents of all patients (n=30) were screened for dysbacteriosis.

Medical Pediatric Academy (St.-Petersburg, Russia, 2006)

Design of trials

Group № 1 Group № 2 Group № 3

Amoxiclav daily

dose: 1350 mg

Amoxiclav daily

dose: 1350 mg

Lactulose daily

dose: 200 mg

Amoxiclav daily

dose: 1350 mg

Lactulose daily

dose: 600 mg

Treatment course 14 days

№ patients in each of group - 10

Conclusions

The titers of bifidobacteria and lactobacilli were significantly decreased (p< 0.01), while those of Candida albicans were significantly increased.

Some characteristics of intestinal microbiocenosis in patients of the control group before and after treatment (lg CFU/g)

Results of bacteriological analysis of intestinal microflora microflora

10 patients

Bifidobacterium spp. Lactobacillus spp. Candida albicans

Before treatment

After treatment

or

Before

treatmentAfter

treatmentor

Before

treatmentAfter

treatmentor

Average 8.7±1.5 7.1±1.1 6.8±0.9 5.8±0.7 1.1 2.4±0.2

1 - Bifidobacterium spp. 2 - Lactobacillus spp.3 - Candida albicans

Results. Group №1 (Amoxiclav 1350 mg)

Conclusions

The titers of bifidobacteria and lactobacilli were similar both before and after treatment. The titers of Candida albicans sowed a tendency to decrease; however, this difference was insignificant.

Some characteristics of intestinal microbiocenosis in patients of the test group before and after treatment (lg CFU/g)


10 patients


Before treatment

After treatment

or

Before

treatmentAfter

treatmentor

Before

treatmentAfter

treatmentor

Average 8.2±1.2 8.1±1.1 5.9±0.7 6.1±0.8

2.2 ±0.2 1.8±0.1


Results. Group №2 (Amoxiclav 1350 mg + Lactulose 200 mg)

Conclusions

The titers of bifidobacteria and lactobacilli were significantly increased (p< 0.01), Candida-, Proteus- and Klebsiella-associated infections were fully eliminated.

Some characteristics of intestinal microbiocenosis in patients of the tests group before and after treatment (lg CFU/g)


10 patients


Before treatment

After treatment

or

Before

treatmentAfter

treatmentor

Before

treatmentAfter

treatmentor

Average 8.1±0.9 8.6±1.1 5.1±0.7 6.6±0.8 1.9±0.4 0.2


Results. Group №3 (Amoxiclav 1350 mg + Lactulose 600 mg)

The monotherapy with Amoxiclav causes dysbiosis manifested as a statistically significant decrease in the titers of the major representatives of the obligate microflora (Bifidobacterium, Lactobacillus, Escherichia coli) and an increase in the titers of Candida albicans.

Combined therapy with the pharmaceutical composition Lactulose + Amoxiclav has a high therapeutic potential. Lactulose added to the treatment schedule improves the state of large intestinal microflora.

Lactulose has a dose-dependent protective effect. In Group 3 patients to whom the prebiotic was administered in the daily dose of 600 mg, this effect was more apparent than in Group 2 patients (daily dose = 200 mg).

Conclusions

Summary

Safe antibiotics are ecobiotics, that is the new class of drugs which do not destroy intestinal biocenosis eco-balance.

Ecobiotic = antibiotic + prebiotic

Ecobiotics:

possess all the antibacterial properties of traditional antibiotics (penicillins, cephalosporins, tetracyclines, lincosamides, macrolides) and thus destroy pathogenic microflora (in the same way)

acquire new properties, that is, unlike traditional antibiotics, they do not damage beneficial intestinal microflora and therefore prevent the development of an infection (Candida- , Proteus- and Klebsiella-associated infections) etc.

The use of ecobiotics:

reduces both the period of in-patient and out-patient treatment

reduces infection treatment costs

reduces recovery expenses after antibioticotherapy

As evidenced by the focus group, physicians prefer ecobiotics to traditional antibiotics.

Ecobiotics will be in great demand on the drug market. Independent experts estimate the ecobiotics market at about USD 4-5 billion.

Leksir Ltd (pharmaceutical producer) cooperating with Fresenius Kabi (first-rate producer of lactulose) invites to collaboration pharmaceutical companies for producing safe antibiotics under licensing agreement.

Patent protection (PCT/RU 2005/000434 WO 2006/025767)

Claim: An antimicrobial composition for peroral administration, characterized in that it contains an antibiotic drug selected from the group including broad-spectrum penicillins, cephalosporins, tetracyclines, lincosamides, macrolides, and lactulose at the active component ratio of 1:1-1:100, with the mean particle size of lactulose ranging from 100 nm to 200 µm »

Contacts:

Leksir Ltd

121614, Russia, Moscow, Krilatskie Holmy,30, build. 9.tel/fax +7 (495) 956 7686. www.leksir.ru

[email protected]

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