Enhancing Drug Delivery through Site-Specific Release: A Pharmaceutical Innovation Presentation

1. The Pharmaceutical CompositionMethodology described in this presentation has been developed to improve controlled drug delivery through site specific release of drug.Described technology is usable to marketed or novel pharmaceutical products. Croatia, Zagreb, June 10, 2015 Ljiljana SovićBrkičić

2. Presentation • newformulationof drug - Pharmaceutical composition (PC) • The Technology • The Platform • Therapeutic benefits • Financial benefits

3. The Pharmaceutical Composition Oral pharmaceutical composition • capsules (particles placed in capsules) • other formulations (tablets, suspension etc.) Controlled drug release • a lot of small particles which will be placed in capsules • drug is released during the time (from PC) • size of the coated particle is preferably about 20 to 5000 µm • this results with highly reproducible controlled release • it is better controlled release of drug compared to existing oral formulations Site specific drug release • a lot of small particles which are retained and released at targeted place • this site specific drug release is pH dependent • release of drug is possible at diferent segment of GI system (for levodopa targeted place is duodenum)

4. The Technology • it was developed the technology (our own technology) • it was described process of preparation of new PC • the technology is fluid bad spray granulation (modified) • modification: • number od coatings • the order of coatings • www.glatt.com

5. Coated particle

6. The Platform • the technology is usable to different (numerous) drugs depending on the molecular structure • it is 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... _____ • EU project • timetable • R&D - levodopa

7. 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

8. Patent application Patent application Inventors and applicants Inventors ZdravkoDokuzović Ljiljana SovićBrkičić Patent applicants Ljiljana SovićBrkičić CvjetkoBrkičić • the application prepared by patent attorney from Germany • filed European patent application (EP) • priority date: 6 April 2011 • filed PCT application • international filing date: 5 April 2012 • Original document: WO2012136816  (A2) ― published 2012-10-11 • filed applications at national phases (at 90 countries) • „search report” of October 17, 2013 • http://worldwide.espacenet.com/publicationDetails/biblio?CC=WO&NR=2012136816A2&KC=A2&FT=D&ND=3&date=20121011&DB=EPODOC&locale=en_EP

9. Why and What? • to solve problems at treatment of Parkinson disease (PD) • PD is long-lasting disease (end life) • dopamine deficiency causes PD • dopamine is a neurotransmitter (brain) • levodopa (LD) is a dopamine precursor • 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 is 30 to 50 years • duration of good LD treatment is 3 to 5 years (with existing formulations) • uncontrolled administration of LD causes more side effects • drug treatment – low and slow • the idea was to prepared oral formulation of levodopa with good CR • we were solved problems of uncontrolled administration of levodopa (with new PC) • it was developed new PC • it is PC with controlled administration of drug • it is controlled release of drug • it is site specific release of drug • it enables controlled blood levels of drug • it causes less side effects of drug (levodopa) • it was developed the new technology • it is The Platform • it is usable to all molecules containing nitrogen (N) • the technology will be presented at the example of levodopa • levodopa is used as a model drug • technology will enable great therapeutic benefit to persons with PD • potential financial benefits will be bigger on the other examples • it is technology for blockbusters (past and future)

10. Dissolution profiles (in vitro) Figure 2. In vitro dissolution profile (of existing formulation of levodopa) Figure 3. In vitro dissolution profiles (of our profiles of levodopa)

11. Competing solutions (levodopa)

12. Highlights Therapeutic benefits • improved safety, efficacy and tolerability • improved compliance Trials (plan) • Bioavailability study • Bioequivalence study • Small clinical trials Concept – tested earlier • WO/1998/027961 Economical benefits • patent extension • line extension • for payers Trials (note) • known main substance • known additional substances • NO - big clinical trials • TRL – technology readiness level

13. Benefits Therapeutic benefits Economical benefits production of better products with competitive advantages compared to existing formulations lower costs of drug treatment (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) • it is highly reproducible controlled release • it enables better absorption and better bioavailability • it enables controlled blood levels of drug • it enables lower fluctuations of blood levels of drug • it causes lower side effects • it will be applied lower single dose • it will be applied lower number of single doses a day

14. Drug utilisation - projection

15. 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 price of drug is higher than what is projected – it is the new technology, patent protection, better products • usable to different drugs (blockbusters – past and future) • Market potential of new formulation of levodopa (project):

16. Possible cooperation? Pharmaceutical company or Investor • R&D of new formulations (fast development of new products) • Trials – Bioavailability studies or small clinical trials • Production • Licensing ________________ • Project • Steps

17. TheOpportunity… Patient • better drug treatment (better therapy) Pharmaceutical company • business opportunity Investor • investment to project with global potential Innovator • to find way for finalization of project

18. Contact • http://www.pharmaceutica.blc.hr/ • Ljiljana SovićBrkičić • ljiljana.sovic@gmail.com