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Transcript
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/agglomerationgranulation/spray-granulation.html Coated particles Sheme Coated particle 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 drugs problem result (new formulation – new technology) therapeutic benefit financial benefit antipakinsonics levodopa ropinirole uncontrolled administration controlled administration antipsyhotics olanzapine risperidone uncontrolled administration controlled administration antiepileptics N03 cytostatics other drugs drugs for GI sistem antihypertensives uncontrolled administration controlled administration uncontrolled administration controlled administration uncontrolled administration controlled administration √ √ √ √ √ √ √ √ √ √ Inventors and patent applicants Inventors • Zdravko Dokuzović • Ljiljana Sović Brkičić Patent applicants • Ljiljana Sović Brkičić • 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&docA n=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) 100 90 80 levadopa released (%) 70 60 50 40 30 20 10 0 0 2 4 time (hours) 6 8 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 • 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 2014 2015 2016 2017 R&D (of 10 new formulations) Clinical trials (or BE studies) Location (decision) Laboratory (building) Factory (building) Registration of drugs Production of drugs Marketing • 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 2018 Drug utilisation - projection Table 1. Drug utilisation in Croatia, 2012* 1. 2. 3. 4. ATK INN Drug utilisation in Croatia, 2012 (kn), at 4.500.000 people* 5. 6. Projection of drug utilisation at 1.000.000.000 people (kn)** Projection of drug utilisation at 1.000.000.000 people (EUR)** 7. C 10AA05 atorvastatine 113.564.574 2. A02BC 02 pantoprazole 94.591.626 3. C 09BA03 80.320.444 4. C 09AA05 lisinoprile, combination ramiprile 5. N05AH03 olansapine 62.577.934 6. C 08C A01 amlodipine 61.806.772 7. M01AE01 ibuprofene 58.409.627 8. N05AX08 risperidone 51.635.139 9. C 10AA01 simvastatine 50.260.943 10. A02BA02 ranitidine 44.284.427 Total:**** Legend: * ** *** **** 62.786.622 25.236.572.000 21.020.361.333 17.848.987.556 13.952.582.667 13.906.207.556 13.734.838.222 12.979.917.111 11.474.475.333 11.169.098.444 9.840.983.778 3.364.876.267 2.802.714.844 2.379.865.007 1.860.344.356 1.854.161.007 1.831.311.763 1.730.655.615 1.529.930.044 1.489.213.126 1.312.131.170 9. Projection of market of the new formulaton, as a part of total market (EUR)*** 1% 1. 8. 5% 33.648.763 168.243.813 28.027.148 140.135.742 23.798.650 118.993.250 18.603.444 93.017.218 18.541.610 92.708.050 18.313.118 91.565.588 17.306.556 86.532.781 15.299.300 76.496.502 14.892.131 74.460.656 13.121.312 65.606.559 201.552.032 1.007.760.160 Drug utilization in Croatia, 2012, http://www.almp.hr/ Projection of drug utilization at 1.000.000.000 citizens as a part of world population (1 EUR=7,5 kn) Projection of market of new drug (our PC) as a part of total market (new technology, patent protection, better products) Corection factor (higher drug price - patent protection, factor 2 or 3) Blue colored - official dana from HALMED (http://www.almp.hr/?ln=hr&w=publikacije&d=promet_lijekova_2012) 10% 336.487.627 280.271.484 237.986.501 186.034.436 185.416.101 183.131.176 173.065.561 152.993.004 148.921.313 131.213.117 2.015.520.320 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 • R&D, protocols, bioequivalence studies, clinical trials etc. • production • licensing • other Contact • for more information • Ljiljana Sović Brkičić • [email protected] • [email protected]