1. Leopold-Franzens-Universität Innsbruck
Preactivated thiomer for nasal delivery of apomorphine synthesis and in vitro evaluation
Kesinee Netsomboon
Institute of Pharmacy,
University of Innsbruck, Austria

2. INTRODUCTION
Parkinson’s disease
Movement disorder

3. Apomorphine Dopamine agonist Treat “off” episodes
INTRODUCTION
Apomorphine
Dopamine agonist
mimicking the action of dopamine
Treat “off” episodes
Help to improve symptoms when an “off” episode has already begun

4. Apomorphine (cont.) rapidly degraded in the GI tract
INTRODUCTION
Apomorphine (cont.)
rapidly degraded in the GI tract
high “first-pass” effect
oral bioavailability of 1.7%
high oral dose
gastrointestinal complications
nephrotoxicity
Available only in parenteral forms

5. Nasal drug delivery Advantages rapid absorption highly vascularized
avoidance of hepatic metabolism
offers nasal-to-brain delivery
Nasal cavity
Olfactory Region
Brain Tissue
Blood
Tissue/organs
Elimination
CSF
Disadvantages
local irriation
mucociliary clearance
J.Controlled Release, 2003, (87):187-98

6. Thiomers for mucosal drug delivery
INTRODUCTION
Thiomers for mucosal drug delivery SH
Thiolated-
Polymer backbone
(PAA, chitosan, etc.)
Disadvantage of thiomers
-subject to thiol oxidation at pH above 5
Mucoadhesive property improvement
prolonging drug residence time
J.Controlled Release, 2003, (1):29-38
Biomaterials, 2011, 12(11):

7. Preactivated thiomer Preactivated- Polymer backbone
INTRODUCTION
Preactivated thiomer
2MNA
Preactivated- SH
Polymer backbone
(PAA, chitosan, etc.)
Thiolated-

8. PURPOSE
Purpose of the study
to investigate an improvement of apomorphine absorption in vitro through nasal mucosa by co-administration with a newly synthesized preactivated thiomer

9. Synthesis of thiomers Dialysis and lyophilize PAA250 + H2O pH 4.5
SYNTHESIS AND CHARACTERIZATION OF THIOMERS AND PREACTIVATED THIOMERS
Synthesis of thiomers
PAA250 + H2O
pH 4.5
+ EDAC
20 min incubation, RT
180 min incubation, RT, pH 4.5
+ L-cyteine HCl
Dialysis and lyophilize

10. Preactivation of thiomers
SYNTHESIS AND CHARACTERIZATION OF THIOMERS AND PREACTIVATED THIOMERS
Preactivation of thiomers
PAA250-cys-2MNA
High degree: +DMSO +
PAA250-cys + H2O
2,2‘-dithiodinicotinic acid
High degree: pH = 6
Medium degree: pH = 7-8
Dialysis and lyophilize

11. Characterization of thiomers and preactivated thiomers
SYNTHESIS AND CHARACTERIZATION OF THIOMERS AND PREACTIVATED THIOMERS
Characterization of thiomers and preactivated thiomers
Polymer
Total amount of thiol groups
(mol/g of polymer)
Amount of free thiol groups
% of conjugated 2MNA
(%)
PAA250
0.4 0.1 -
PAA250-cys
 185.0
 344.1
PAA250-cys-2MNA (M)
 214.6
521.2  70.2
67.3
PAA250-cys-2MNA (H)
 100.2
282.5  17.4
82.6

12. In vitro model Freshly excised porcine nasal mucosa
IN VITRO EVALUATION OF NASAL DELIVERY
In vitro model
Freshly excised porcine nasal mucosa
Apomorphine concentration of 0.5 mg/ml
Ussing chamber
KRB pH 5.5
30C
5% CO2 aerated
Sampling time: 0, 60, 120 and 180 min
Determination of apomorphine: HPLC-UV (274 nm)

13. Permeation of apomorphine across porcine nasal mucosa
IN VITRO EVALUATION OF NASAL DELIVERY
Permeation of apomorphine across porcine nasal mucosa

14. Conclusion
High degree preactivated thiolated PAA250 could be considered as promising excipient for nasal apomorphine delivery

15. Acknowledgement
Technology Grants Asia financed by Austrian Federal Ministry for Science and Research