Transcript Oral pharmaceutical composition

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:
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•
•
•
•
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
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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:
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•
•
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•
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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]