1. The Pharmaceutical Composition Methodology described in this presentation has been developed to improve controlled drug delivery through site specific release of marketed or novel pharmaceutical products.

2. Presentation Pharmaceutical composition (PC) The Technology
The Platform
Therapeutic benefits
Financial benefits

3. The Pharmaceutical Composition
Oral pharmaceutical composition
capsulas
other formulations (tablete, suspension etc.)
Controlled drug release
a lot of small particles which are retained and released at targeted place
size of the coated particles is preferably about 20 to about 5000 µm
this results highly reproducible controlled release
better controlled release of drug than existing oral formulations
Site specific drug release
drug is released in targeted segment of GI system (duodenum for levodopa)
this site specific drug release is pH dependent
applicable at diferent segment of GI system (cytostatics etc….)

4. Technology developed technology for the preparation of new PC
described process for preparing of new oral PC
technology - fluid bed spray granulation
it is known technology (modified)
modification – number and the order of layers over the base
(explanation at next slides)

5. Figure 1. Spray Granulation

6. Coated particles Sheme Coated particle 0. drug resin complex
0. drug resin complex
1. controlled release layer
2. bioadhesive layer
3. enteric layer (pH dependent)
diameter µm

7. The Platform
the technology is usable to different (numerous) drugs depending on the molecular structure
usable to all molecules containing N (nitrogen)
the technology is suitable for active agents belonging to Class I of the Biopharmaceutics Classification System (BCS) which are characterized with high permeability and high solubility
preferred group of drugs: antiparkinsonics, antiepileptics, antipsychotics, antihypertensives, cytostatics etc...

8. The potential The potential of the technology – it is applicable to:
all innovative drugs
innovative drugs at the end of patent protection (to prolong the patent protection)
generic drugs (for preparation of the generic drugs with an additional value)
Finalized formulations:
levodopa + carbidopa or benzerazide and entacapone
ropinirole
risperidone
olanzapine
alendronate

9. Some Other Examples

10. Inventors and patent applicants
Zdravko Dokuzović
Ljiljana Sović Brkičić
Patent applicants
Cvjetko Brkičić

11. Patent Application
the application prepared by patent attorney in Germany
filed European patent application (EP)
priority date: 6 April 2011
filed PCT application
international filing date: 5 April 2012
Original document: WO   (A2) ―
filed applications at national phases (at 90 countries)

12. Why did we develop a new PC?
to solve problems at treatment of Parkinson disease (PD)
PD is long-lasting disease (life long disease)
PD is characterized by a dopamine deficiency
dopamine is a neurotransmitter in the brain
levodopa (LD) is a dopamine precursor (levodopa  dopamine)
it is the drug of choice in the treatment of PD (“gold standard”)
it is the most effective drug in the treatment of PD
duration of PD (30 to 50 years)
duration of LD treatment is 3 to 5 years (existing formulations)
uncontrolled administration of LD causes more side effects
solved problems (with new PC)
________________
Duodopa (model drug) – good CR, uncomfortable application

13. What Did We Expect of a New Drug Formulation?
new (better) forumlation of levodopa
controlled administration of drug (levodopa)
controlled blood level of drug
(it will result with controlled level of levodopa in the brain)
less side effects of drug (levodopa)
developed technology (The Platform)
which is usable to all molecules containing N (nitrogen)
___________________
problem – uncontrolled administration of drug 
(blood level of drug is out of therapeutic window – piks)

14. Dissolution profiles (in vitro)
Figure 2. In vitro dissolution profile of levodopa
Figure 3. In vitro dissolution profiles of levodopa
(our pharmaceutical compositions)

15. Clinical Developement Plan
Produce model drug at GMP process
Bioequivalence studies (BE studies)
to compare our PC with existing CR formulations
Clinical trials
small clinical trials
for drugs without comparable CR formulations
the presentation of additional benefits
__________________
similar concept is tested earlier (marketed products)
PCT Patent WO/1998/027961
(DRC + coated particles –dextormetorphane...)

16. Highlights Therapeutic benefits Economical benefits
improved safety, efficacy and tolerability
improved compliance
Economical benefits
patent extension
line extension
for payers

17. Potential Therapeutic Benefits
Competitive advantages of new formulation compared with existing products:
highly reproducible controlled release
better absorption
controlled drug blood level
lower drug level fluctuations
lower side effects than in existing formulations
lower single dose
lower number of single doses per day
better bioavailability

18. Economical Benefits
production of better products with competitive advantages compared to existing drugs
lower costs of drug tretment (duration of PD – 50 years)
higher price of drug - compared to the price of existing drugs – (new position – use, features, price)
broadly acceptable technology (The Platform)
higher costs of production – new technology (compensation at higher price, better products, market ratio)

19. Timetable time – the most important factor of this project
(international filing date: 5 April 2012)
duration of patent protection – 20 years
every waste day – lost benefit

20. Drug utilisation - projection

21. Market potential market potential is bigger than presented at Table 1.
targeted population is bigger than projected at Table 1.
market of EU (Croatia is member of EU)
market of Asia and Africa region
other markets – USA, Canada, Japan
(not included in projection)
potential drug price ih higher than projected – new technology, patent protection, better products

22. Possible cooperation? Cooperation: Business cooperation R&D production
R&D, protocols, bioequivalence studies, clinical trials etc.
production
licensing
other

23. Contact for more information Ljiljana Sović Brkičić lj.s@vip.hr