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TG004 - Medicine Hat 2003
Autoinjector Task group:
LTC LALLEMENT, PharmD., PhD.
COL CLAIR, PharmD., PhD. National POC
COL ZABE, PharmD.
Update on the new French two-compartment autoinjector
TG004 - Medicine Hat 2003
Previous autoinjectors
Atropine
Since 1966
Multipen:•atropine•pralidoxime•diazepam Since 1989
TG004 - Medicine Hat 2003
Development of a New Autoinjector
Rationale– Production of Multipen stopped– drugs
expired period of use non changeable
The project– Started end of 1997– French company SEDAT chosen in 1998
TG004 - Medicine Hat 2003
TWO-COMPARTMENT AUTOINJECTOR
2-compartment cartridge: - changeable when expired- content : solid / liquid or liquid / liquid
Autoinjector:- classical mecanism- 2 safety items
TG004 - Medicine Hat 2003
1st delivery end of 2003
•Casting mould : French government property•deed with SEDAT for production•Cartridge filled by the French military Health service
TG004 - Medicine Hat 2003
PHARMACOLOGICAL STUDIES ON THE MIX PHARMACOLOGICAL STUDIES ON THE MIX ATROPINE/PRALIDOXIME/AVIZAFONEATROPINE/PRALIDOXIME/AVIZAFONE
Soman-intoxicated non-human primates and mice
TG004 - Medicine Hat 2003
Avizafone injection
Quick built-up of a high plasmatic diazepam concentration
Tmax ca 30 min vs ca 1 h (monkey)
Advantage : quicker neuroprotective and antilethal effficacy
BUT :
Elimination of diazepam from plasma quicker following avizafone injection compared to diazepam administration T1/2 elim ca 40 min vs ca 1 h
Reference : Lallement et al. Arch Toxicol (2000) 74 480-486
TG004 - Medicine Hat 2003
Lyophilization does not modify the antilethal efficacy of the 3-drug association atropine/pralidoxime/avizafone
Avizafone injection
Reduced biodisponibility and only 2/3 of the theoretical diazepam concentration1/3 unaccounted for : non-transformed or bound ?
To get a similar diazepam plasma concentration, injection of 1.5 more avizafone (mol)
In the new autoinjector
20mg of avizafone
(équivalent neuroprotective dose to 7.5mg of diazepam).
Antilethal efficacy increased by 30 % (mice)
TG004 - Medicine Hat 2003
GALENICAL ISSUES
Evolutive composition based on antidotal progress - HI6- any new relevant drug
Evolutive Cartridge: may allow different mixes liquid/liquid - liquid/lyophilized
Plastic two-compartment cartridge
TG004 - Medicine Hat 2003
The Cartridge
Polypropylene, two-compartment cartridge One compartment for solid mix: 3 drugs in lyophilized form Second compartment for liquid solvent: water Special bypass: small holes let water go with increased pressure
that allows 95% dissolution w/o shaking With shaking (ca 5 s) 100% dissolution
Special bypassSpecial bypass
TG004 - Medicine Hat 2003
GALENICAL PROCESSSTERILE FILTRATION of the drugs in solution
These operations are realised in onesterile area of the new pharmaceutical factory of the French military Health service
FILLING of the cartridges
LYOPHILIZATION
TG004 - Medicine Hat 2003
STABILITY ISSUES
Stability studies at different temperature (standard conditions ICH) :
- for the lyophilized mix in cartridge
+5°C / +25°C, 60% RH / +40°C, 75 % RH- for the mix in solution after dissolution of the lyophilized pellet: same conditions and +30°C, 35 et 70% RH
For these studies, analytical methods have been developed and standard degradation products have been synthetized
TG004 - Medicine Hat 2003
RESULTS
- for the lyophilized mix in cartridge, stability is excellent at +5°C or +25°C. At +40°C, organoleptic features decline onlyafter 6 months
- Stability of the mix in solution after dissolution of the lyophilized pellet is excellent for at least 3 months whatever the condition of test
TG004 - Medicine Hat 2003
STUDIES IN PROGRESS
Stability in field conditions and shelf life : studies done with filled cartridges placed into packaged autoinjectors
Preclinical studies (toxicological and pharmacokinetical data)with the mix in solution are just finished.
This will be followed during 4-6 months by a safety study in humans
Clinical agreement for human use by the French drug agency.
TG004 - Medicine Hat 2003
Conclusions
Licensing end and production for the French MOD:
end of 2nd semester 2003 / beginning of 2004
Later production: French civil defense
Availability for foreign countries ca. 2005What could be proposed :
Empty autoinjectorFilled autoinjector + refill
Autoinjector filled with other desired compounds
POC: COL CLAIR ph (33) 2 38 60 73 11 / fax (33) 2 38 60 74 70 / e-mail : [email protected]