TG004 - Medicine Hat 2003 Autoinjector Task group: LTC LALLEMENT, PharmD., PhD. COL CLAIR, PharmD.,...

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


Previous autoinjectors

Atropine

Since 1966

Multipen:•atropine•pralidoxime•diazepam Since 1989


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


TWO-COMPARTMENT AUTOINJECTOR

2-compartment cartridge: - changeable when expired- content : solid / liquid or liquid / liquid

Autoinjector:- classical mecanism- 2 safety items


1st delivery end of 2003

•Casting mould : French government property•deed with SEDAT for production•Cartridge filled by the French military Health service


PHARMACOLOGICAL STUDIES ON THE MIX PHARMACOLOGICAL STUDIES ON THE MIX ATROPINE/PRALIDOXIME/AVIZAFONEATROPINE/PRALIDOXIME/AVIZAFONE

Soman-intoxicated non-human primates and mice


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


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)


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


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


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


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


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


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.


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]

TG004 - Medicine Hat 2003 Autoinjector Task group: LTC LALLEMENT, PharmD., PhD. COL CLAIR, PharmD.,...

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