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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.

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Presentation on theme: "TG004 - Medicine Hat 2003 Autoinjector Task group: LTC LALLEMENT, PharmD., PhD. COL CLAIR, PharmD., PhD. National POC COL ZABE, PharmD. Update on the new."— Presentation transcript:

1 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

2 TG004 - Medicine Hat 2003 Previous autoinjectors Atropine Since 1966 Multipen : atropine pralidoxime diazepam Since 1989

3 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

4 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

5 TG004 - Medicine Hat st delivery end of 2003 Casting mould : French government property deed with SEDAT for production Cartridge filled by the French military Health service

6 TG004 - Medicine Hat 2003 PHARMACOLOGICAL STUDIES ON THE MIX ATROPINE/PRALIDOXIME/AVIZAFONE Soman-intoxicated non-human primates and mice

7 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)

8 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 concentration 1/3 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)

9 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

10 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 bypass

11 TG004 - Medicine Hat 2003 GALENICAL PROCESS STERILE FILTRATION of the drugs in solution These operations are realised in one sterile area of the new pharmaceutical factory of the French military Health service FILLING of the cartridges LYOPHILIZATION

12 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

13 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 only after 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

14 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.

15 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 What could be proposed : Empty autoinjector Filled autoinjector + refill Autoinjector filled with other desired compounds POC: COL CLAIR ph (33) / fax (33) /


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