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.

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

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….)

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)

Figure 1. Spray Granulation http://www.glatt.com/cm/en/process-technologies/agglomeration-granulation/spray-granulation.html

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 100-5000 µm

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...

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

Some Other Examples

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

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: WO2012136816  (A2) ― 2012-10-11 http://worldwide.espacenet.com/publicationDetails/biblio?CC=WO&NR=2012136816A2&KC=A2&FT=D&ND=3&date=20121011&DB=EPODOC&locale=en_EP filed applications at national phases (at 90 countries) http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012136816&recNum=6&docAn=EP2012056366&queryString=amlodipine&maxRec=4229

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

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)

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

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...)

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

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

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)

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

Drug utilisation - projection

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

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

Contact for more information Ljiljana Sović Brkičić lj.s@vip.hr ljiljana.sovic@gmail.com