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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 drug. Described technology is usable to marketed or novel pharmaceutical products. Croatia, Zagreb, June 10, 2015 Ljiljana Sović Brkičić Presentation • new formulation of drug - Pharmaceutical composition (PC) • The Technology • The Platform • Therapeutic benefits • Financial benefits 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) 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 Coated particle 3. enteric layer (pH dependent) 2. bioadhesive layer 1. controlled release layer 0. drug resin complex diameter 100-500 µm 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 2016 I 1 2 3 4 5 6 II 2017 III IV I II 2018 III IV I II III R&D (characterisation of complex) R&D (optimatization of PC of levodopa) Production in GMP process Bioaviliability studies Project management Publication of project 6 month method 12 month R&D duration of project 6 month BE studies 12 month registration IV 2019 I 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 antipakinsonics antipsyhotics risperidone drugs levodopa olanzapine ropinirole risperidone olanzapine problem uncontrolled uncontrolled administration administration result controlled controlled alendronate antiepileptics N03 cytostatics other drugs drugs for GI sistem antihypertensives (new formulation – new technology) administration administration uncontrolled administration controlled administration uncontrolled administration controlled administration uncontrolled administration controlled administration therapeutic benefit financial benefit √ √ √ √ √ √ √ √ √ √ Patent application Patent application • 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/publicationD etails/biblio?CC=WO&NR=2012136816A2&KC= A2&FT=D&ND=3&date=20121011&DB=EPODO C&locale=en_EP Inventors and applicants Inventors • Zdravko Dokuzović • Ljiljana Sović Brkičić Patent applicants • Ljiljana Sović Brkičić • Cvjetko Brkičić 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) 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) Competing solutions (levodopa) grade description 5 too good 4 excelent 3 2 A Technological complexity B Innovativeness C Therapeutical benefit 1 acceptable 0 bad D E F G Side effects Availabilility for patients Simplicity for use Price Highlights Therapeutic benefits • improved safety, efficacy and tolerability • improved compliance Economical benefits • patent extension • line extension • for payers Trials (plan) • Bioavailability study • Bioequivalence study • Small clinical trials Trials (note) • known main substance • known additional substances • NO - big clinical trials Concept – tested earlier • WO/1998/027961 • TRL – technology readiness level Benefits Therapeutic benefits • 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 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) 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. 1% 1. 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 8. 9. Projection of market of the new formulaton, as a part of total market (EUR)*** 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 data 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 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): Year 1. 2. 3. 4. 5. Share of market (%) 2 4 6 8 10 Number of DDDs Number of capsules 8,760,000 26,280,000 17,520,000 52,560,000 26,280,000 78,840,000 35,040,000 105,120,000 43,800,000 131,400,000 Legend: 1 EURO = 7,6 HRK; DDD for levodopa + carbidopa 0,6 g Revenue (EURO) 18,603,474 37,206,947 55,810,421 74,413,894 93,017,368 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 Project Development Proceeding 1 Proceeding 2 Registration Production in GMP proces Trials Proceeding 3 Proceeding 4 Proceeding 5 and Proceeding 6 Future Commercialization The Opportunity… 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 Contact • http://www.pharmaceutica.blc.hr/ • Ljiljana Sović Brkičić • [email protected]