F;
`' Filing Dale
`First Named Inventor
`
`'
`
`Group Art Unit
`
`U.5. PATENT DOCUMENTS
`
`E of
`
`US. Patent Document
`
`
`
`
`
`
`
`
`
`--
`_-—
` —
`—-—
`— —_
` ——
`_- —
`— ——
`_-—_
`--—-
`—: —
`_— —
`-— —
`—- —
`
`Examiner
`Initiels
`
`FOREIGN PATENT DOCUMENTS
`
`Foreign Patent Document
`Application or
`Patent Number
`0 390 244
`
`Kind
`Code
`1
`
`D1.-'641B7
`02.015709
`04.-‘O52-401
`
`1
`A2
`
`IIHEEI P7
`
`Name of Patentee or Applicant
`
`‘Data of Publication
`
`Duphar International Research
`
`Maelor Pharmaceuticals Limited
`Bharal Serums 8. Vaccines Ltd.
`
`American Biosciences, Inc.
`
`Oct. 3. 1990
`
`Sea.7,2001
`Jun.?3,2002
`Jun.24,2004
`
`Examiner
`Initials
`
`OTHER - NON PATENT LITERATURE DOCUMENTS
`Include name of the author (in CAPITAL LETTERS). title of the article (when appropriate), title of the item
`(book, magazine, journal. serial. symposium. catalog. etc.), date. psgets). volume-issue number (s). publisher.
`c’
`andior count where - ublished.
`
`BAUER et aI., Phannazeutische Technoioie,: 256-257 1986
`FARINOTTI, Annaies Frencaises d'Anesthesie et de Reanimation., 13:-453-456 1994
`JON ES. Anaesthesia and intensive Care, 28(5): 587 October 2000
`NAGUIB el al.. Anesthesiology Abstracts of Scientific Papers Annual Meeting; 1
`October 13, 2003
`-
`SAUTOU-MIRAN DA et a!.. intemationai Joumai "of Pharmaceutics, 130(2): 251-255
`1996
`
`TRAPANI et aI.. international Journal of Pharmaceutics, 278 t : 91-98 June 18. 2004
`West Furotec Barrier Fiim,: ‘I-2 (December 3. 2003}
`.
`[http:iiweb.archive.orgiwebi20031203023530ihttp:iiwww.westpharmacorniproductsiflur
`
`— ‘’‘“° ‘’°“’‘'‘‘‘*'‘’‘‘—
`" A concise statement of relevance is being submitted in lieu of a translation. 37 CFR 1.98(a){3)_
`+ An English-language equivalentipatent. or an Engiisiblanguage abstract, or an Eng|ieh—|anguage version of the search report or action by a foreign
`patent office In a counterpart foreign application indicating the degree of relevance found by the foreign office is being submitted in lieu of a concise
`explanation of relevance under 37 CFR 1.98[a)(3}.
`-
`-
`
`FRE-DPN-0000716
`
`

`
`Europalsches Patentan-it
`
` European Patent Office
`
`Office eurepéen des brevets
`
`(9 Publication number:
`
`0
`
`®
`
`EUROPEAN PATENT APPLICATION
`
`® Application number: 902Dtl587.5
`
`Int. GL5; A61J ‘U06, A61M S!315
`
`® Date of filing: 13.03430
`
`(9 Priority: 20.03.09 NL 0900747
`
`Date of publication of application:
`03.10.90 Bulletin 90140
`
`Designated Contracting States:
`AT BE CH DE DK ES FR GB GR IT LI LU NL SE
`
`@ Applicant: DUPHAR INTERNATIONAL
`RESEARCH e.v
`C.J. van Houtenlaan 35
`
`NL-1381 GP Weesp(NL)
`
`(79 Inventor: Van den Heuvel, Johan
`cfo Doctrobureau Zoan B.V., C.-I. van
`I-ioutenlaan 35
`NL-1380 weesp(NL)
`
`Representative: Swaters, Pieter D. et al
`OCTFIODIBUHEAU ZOAN B.V. P.O. BOX 140
`NL-1330 AC weesptl-IL)
`
`
`
`® Pre-filled Injection device comprising a barrel wherein a liquid dlazepam formulation is
`accomodated.
`
`® The invention relates to a pre-filled injection device. comprising 0) a barrel which is open at each end in
`which. before using the device. a liquid diazepam formulation is accommodated in a sealed manner and which
`comprises at least one rubber sealing member to seal the said formulation. and (ii) an injection needle or a
`needle connection at the front end of the barrel. said sealing member being manufactured at least substantially
`from bromobutyl rubber.
`
`EP0390244A1
`
`BNSDOCED: -(E P_________{):]9(fi4¢A|_[_5
`
`Xerox Copy Centre
`
`FRE-DPN-0000717
`
`

`
`EP 0 390 244 A1
`
`Pre-liiled injection device comprising a barrel wherein a liquid diazepam formulation is accom-
`rnodated.
`
`The invention relates to a pre-filled injection device. comprising fil a barrel which is open at each end
`and in which. betore using the device. a liquid diazepam formulation is accommodated in a sealed manner
`and which comprises at least one rubber seating member to seal the said formulation. and (ii) an injection
`needle or a needle connection means at the tram end of the barrel.
`
`5
`
`As is welt-known. diazepam has good pharrnacotherapeutlc properties and is hence generally used as a
`sedative. as a hypnotic and as a muscle relaxant. Useful lormulations for the parenteral administration of
`diazepam have meanwhile also become available. These fiquld formulations comprise.
`in addition to
`diazepam and water. auxiliary substances in the ‘lorm of organic solvents andlor formulation agents. As a
`result of this a solution or emulsion of diazepam which is suitable for parenteral administration can be
`obtained by a correct choice and dosing of the auxiliary substances.
`Such liquid diazeparn iorrnulations are often stored for considerable periods of time. As a result of this.
`suitable reservoirs are required in which the liquid can be accommodated in a sealed manner. Such
`reservoirs which usually are rnanuiactured lrorn glass or irorn a suitable synthetic material which is
`compatible with the diazepam formulation. are preferably sealingly closed by means of rubber sealing
`15 members.
`
`to
`
`4
`
`an
`
`25
`
`so
`
`as
`
`«to
`
`45
`
`so
`
`Reservoirs which should permit the long-term storage of injection liquids are found in particular in pre-
`lilled injection devices- There is an increasing demand for such injection devices which are supplied to the
`user while already filled with injection liquid. These so-called pre—fi||ed injection devices should often be
`stored for
`long periods of time before being used and must hence be able to stand up against the
`conditions in which the devices are stored. This means that the injection devices should be able to still
`tunclion properly after a storage term guaranteed by the supplier and that the contents of the injection
`devices. i.e.. the injection liquid, may not have suffered any detrimental efiects from the storage.
`it will hence be obvious that high requirements have to be imposed on such injection devices for the
`prolonged storage of injection liquids. both as regards to the maintenance of mechanical properties of the
`injection device. and as regards the preservation of the injection liquid during the storage period. Much
`attention has been paid to the choice and optional pre—treatmertt oi the rubber sealing members for the
`barrels of such injection devices in which the injection liquids are sealingly stored before use of the devices.
`Ol course. the type oi’ rubber must be completely inert with respect to the medicament to be injected. also
`during the often long storage period. but must moreover satisfy high requirements as regards the
`impermeability to gases. in particular oxygen. and be sufficiently resistant to the external
`influences to
`which the injection device is exposed during storage. for example. heat. air oxygen and light.
`in particular
`UV-light.
`In addition to the said physico-chemical requirements which the selected type oi rubber must
`satisfy.
`the rubber sealing members should have certain mechano- dynamical properties. This applies in
`particular to the piston and to the stopper or stoppers optionally movable in the barrel, which on the one
`hand must well seal the injection liquid In the barrel before use of the injection device, but on the other
`hand must easily be movable in the barrel during use of the device. or course, the shape of the piston and
`of the stopperlsj plays an important part in said easy movability in the barrel, as well as the desired pre-
`treatment. for example. with silicon oil. High demands should equally be made upon the mechanical
`properties oi sealing members having a central diaphragm which bursts under pressure and than permits
`the injection liquid to reach the needle.
`It will be obvious that said diaphragm should remain its sealing
`iunction prior to use of the syringe. but should burst open at the proper instant to allow passage of the
`injection liquid.
`Butyl rubbers including bromobutyl rubber and chlorobutyl rubber. can be used lor the manufacture of
`pistons tor Injection devices: this is disclosed. e.g..
`in US. Patent Specification 4.381.779. Chlorobutyl
`rubber has been found to be an excellent material for the manufacture of sealing members tor reservoirs. in
`particular for barrels for injection devices. Sealing members manufactured from chlorobutyl rubber satisfy
`the above—menlioned requirements excellently. while in general the medicaments present in the injection
`liquid do not experience any detrimental influence from prolonged contact with this type of rubber. I..iquld
`diazepam formulations.
`i.e.. diazepam formulations for parenteral administration. however. constitute an
`exception. As a matter of fact it has been found that the shelf-life of the said fonnulations. after prolonged
`contact with chlorobutyl rubber sealing members,
`leaves to be desired. This is a serious disadvantage
`because as a result of this not only the concentration of diazepam decreases during the storage period. as
`a result of which a smaller quantity of the therapeutic than is desired is injected. but also undesired by-
`products may be iorrned which may arrive in the patient's body.
`
`2
`
`BNSDOCID: «art
`
`, __co9ua-I4m_i_s
`
`FRE-DPN-0000718
`
`

`
`EP 0 390 244 A‘!
`
`It is the object of the present invention to provide a pre-tilted injection device as defined in the opening
`paragraph. comprising a barrel. wherein a liquid diazepam formulation can be stored in prolonged contact
`with at least one rubber seating member without unacceptable deterioration in quality of the said formulation
`taking place.
`.
`‘
`This object can be achieved by means 0? an injection device. comprising a barrel in which a liquid
`diazepam formulation. sealingly closed by at least one sealing member. is accomodated. which device is
`characterised according to the present
`invention in that said seating member is manufactured at least
`substantially trorn bromobutyl rubber.
`Bromobutyl rubber consists ot a brornine-—containing copolymer of isobutene and isopropene as a basic
`elastomer to which fitters. auxiliary substances. pigments and the like are added in certain concentrations to
`obtain the desired properties. After vulcanization a rubber quality is obtained which - like the chlorobutyl
`rubber described hereinbetore - has the properties required for sealing members.
`in particular sealing
`members tor the barrels of
`injection devices. As will become apparent from the examples. however.
`brornobutyl rubber - in contrast with chlerobutyi rubber - causes no unacceptable deterioration in quality of
`a iiquid diazepam formulation in prolonged contact herewith.
`Many examples are to be found in iiterature of pretilled injectors In which the injection iiquid is sealingly
`enclosed between a piston and a stopper with pierceable central portion said stopper being rigidly
`connected to the front end of the barrel. when using such an injector. said central portion is pierced so that
`the injection liquid can reach the injection needle and can be injected. In a favourable modttled embodiment
`the stopper rigidly connected to the barrel comprises centrally a diaphragm which bursts under pressure
`and thus permits the injection liquid to reach the needle; an example hereot is to he tound in Netherlands
`Patent Application No. 7603511 in the name of the Applicants. More recently. one has proceeded to
`enclosing the injection liquid between a piston and a stopper which is movable in the barrel: see. for
`example. Netherlands Patent Application No. ‘i'714308. also in the name of Applicants. When such an
`injector is used. both the piston and the stopper and the intermediately situated injection liquid are removed
`forward in the barrel. in which the stopper is moved out of its seating position and the injection liquid can
`reach the injection needle past the stopper. By using several stoppers. such injection device can be made
`suitable for accommodating therein several injection liquids which may not be in contact with each other
`during the storage period.
`In such pre-filled injection devices. the liquid diazepam formulation can be stored in the barrel while
`enclosed between two rubber sealing members. According to the invention.
`these injection devices
`comprise two seating members of brornobutyt rubber with which the diazepam torrnulatlon can be in
`prolonged contact without deterioration of the quality of said formulation.
`Automatic injection devices - or autoinjectors -actually constitute a special category within the pre-filled
`injection devices.
`In tact. automatic injection devices are also pre-tilled with injection liquid; they are.
`however, intended tor being used by unqualified persons. For that purpose they are constructed so that the
`injection liquid can be administered automatically by a person not trained in giving injections. Consequently.
`automatic injection devices are designed tirst of all for use by persons who at a given instant. which is not
`known betorehand, have to administer an injection into their own body. These persons include. for example.
`soldiers after they_have been exposed to an enemy warfare gas, tor exampte, a nerve gas. However, many
`of the medicamants used in automatic injection devices show undesired side etiects or are insutticlently or
`incompletely active in therapeutic dosages. For example, atropine or obldoxlm is generally used in an attack
`with nerve gas In order to neutralise the toxic effects of organophosphate poisons, the active constituents of
`most nerve gases. However. these organophosphate poisons also cause paralyses or spasm conditions 0!
`the muscles which are insufficiently controlled by the above-mentioned medicaments. Therefore, the activity
`of the said medicaments is often made up with benzodiazeplnes. for example diazepam. which is known to
`have a muscle-relaxing activity. Diazeparn in a liquid formulation. suitable for parenteral administration. is
`preferably accommodated in the injection device while separated from the other rnedicarnents in view of the
`mutual compatibility. Suitable rnuiti—compartment automatic injectors in which several injection liquids can
`be accommodated while separated from each other are disclosed.
`for example,
`In European Patent
`Applications 7205? and 219899, both in the name of the Applicants.
`in addition to the therapeutic activity
`mentioned here-before. diazepam also has a sedative effect, as a result of which the fighting value of the
`soldiers at the tront is restored. For this latter purpose the soldier in the tield is preferably provided with a
`separate automatic injection device which is tilled with a liquid diazepam torrnulation. Such an injector is
`especially intended for appeasing a buddy In the battle tield who has panicked as a result or war acts or
`injuries: "buddy aid".
`it will be obvious from the above that still considerably higher requirements regarding the reliability
`have to be imposed upon automatic Injectors than upon pre-tilted non-automatic injection devices. Such
`
`5
`
`to
`
`re
`
`20
`
`as
`
`so
`
`as
`
`«to
`
`46
`
`so
`
`55
`
`BNSDOCID: <EP
`
`0a9n244.iu_|_;.
`
`FRE-DPN-0000719
`
`

`
`EP 0 390 244 A1
`
`injectors are usually stored for many years at a time and. moreover. will be kept by the potential users for
`long periods of time under varying conditions; not only the proper operation oi the injection devices must
`be sufficiently ensured. but the contents of the eutoinjectors.
`i.e.. the injection liquid or injection liquids.
`must. of course. remain sutticienuy intact to ensure the intended therapeutic activity.
`The present invention thereiore also relates more in particular to such an automatic injection device for
`the prolonged storage of a liquid diazepam formulation. comprising. in addition to a power source. a banal
`which is open at each end.
`to the front end of which an injection needle is attached and in which a
`diazepam formulation is accommodated between rubber sealing members, the sealing members being
`manufactured at ieast substantially from bromobutyl rubber.
`It has been found that the stringent stability
`requirements mentioned hereinbefore can be satisfied when bromobutyl rubber sealing members are used
`in an automatic injection device.
`As stated hereinbetore. bromobutyl rubber is a match for chlorobutyl rubber. known for this purpose. as
`regards the mechano-dynamic properties. This means that bromobutyl rubber is excellently suitable for the
`manufacture oi piston and stoppers which. when using automatic injectors, must move in the barrel thareot
`so as to permit the injection liquids to be expelled. Automatic injectors. for example. as disclosed in the
`European Patent Applications 77057 and 219899 mentioned hereinbefore, in which the diazepam formula-
`tion is accommodated between two stoppers which are movable in the barrel or between a piston which is
`movable in the barrel and a stopper which is also movable herein. may hence advantageously comprise
`stoppers or a piston and a stopper which are manufactured from bromobutyl rubber.
`The invention will now be described in greater detail with reference to the ensuing specific exarnpie.
`
`5
`
`1'0
`
`rs
`
`20
`
`EXAMPLE
`
`Storage stability t£s__t of liquid diazeparn ‘lormuiations between rubber stoppers
`
`A liquid diazepam formulation is prepared by making up 5 mg of diazepam. 0.4 ml of propylene glycol.
`0.1 ml (100%) of ethanol. 0.015 ml of benzyl alcohol. 48 mg 0! sodium benzoate and 2 mg of benzoic acid
`so with water to a volume of 1 ml. The pH of the resulting solution is 6.1’. Flubber stoppers and a glass barrel
`which is open at each end and has a diameter of 11.4 mm are pre-treated in the conventional manner by
`washing. siliconising and sterilising. The barrel is then dispensed with the above diazepam tormulation and
`sealed at each end by means of the rubber stoppers. For the experiments three types of rubber are
`compared with each other. namely chlorcbutyl rubber [Cl-bu}. and two qualities of bromobutyl rubber: Br-bu
`1 and Br-bu 2. The barrels are stored at a given temperature tor a given period of time. after which the
`diazepam concentration is determined by means of HPLC. The decrease oi the diazepam content (in
`percent) is recorded in the Table A below. The analyses have been carried out in triplicate: the recorded
`data are average results.
`
`35
`
`40
`
`45
`
`50
`
`55
`
`TABLE A
`
`Decrease ciiazepam content after ...{t) at
`
`% decrease dlazepam using
`-. rubber
`
`. 13
`
`Elm
`5.9
`6.7
`1 1.4
`19.1
`25.3
`422
`
`6
`13
`3
`6
`13
`
`The experiments have been repeated with a liquid diazepam tormulation comprising 6 mg oi diazepam
`instead of 5 mg diazepam. The results are recorded in Table 8.
`
`4
`
`ensoocro: -:EP
`
`u.=.9o244nI_I_:.
`
`FRE-DPN-0000720
`
`

`
`EP 0 390 244 A1
`
`TABLE B
`
`Decrease diazepam content after ...(tj at ...{Tl
`
`% decrease diazepam using
`.. rubber
`
`we» 31
`
`41
`41
`61
`61
`B1
`
`13
`B
`13
`3
`6
`31
`
`It will be obvious irom the above results that the chlorobutyl stoppers cause a considerably larger
`decrease of the diazepam content than the stoppers manufactured from the two qualities of brcmobutyl
`rubber. The diazepam concentration, namely 6 with respect to 5 rngirni. has no essential influence on the
`said decrease.
`
`Claims
`
`1. A pre-fiiied injection device. comprising 11) a barre! which is open at each end in which, before using
`the device. a liquid diazeparn formulation is accommodated in a sealed manner and which comprises at
`least one rubber sealing member to seal the said torn-tulation. and (ii) an injection needle or a needle
`connection means at the front end of the barrel, said device being characterised in that said sealing
`member is manufactured at ieast substantially from bromobutyl rubber.
`2. An injection device as claimed in Claim 1, in which the liquid diazepam formulation. before using the
`device. is seaiingiy accommodated between two rubber sealing members in the barrel. said device being
`characterised in that the sealing rnern bets are manufactured at {east substantially from bromclbutyl rubber.
`3. An injection device as claimed in Claim 2 tor the automatic injection of injection liquid under the
`
`influence of a power source. comprising. in addition to the power source, a barrel, which is open at each
`end, to the front end at which an injection neeclie is attached and in which a liquid diazeparn tormulation is
`accommodated between two mbber sealing members. said device being characterised in that the sealing
`members are manufactured at least substantially ircm bromobutyi rubber.
`4. An automatic injection device. claimed in Claim 3.
`in which the diazepern formulation is accom-
`
`rncdated between two stoppers which are movabie in the barrel or between a piston which is movable in
`the barrel and a stopper which is also movable therein, said device being characterised in that both
`stoppers or the plunger and the stopper. respectively. are manufactured at
`least substantially trorn
`bromobutyl rubber.
`
`5
`
`10
`
`1'5
`
`25
`
`3°
`
`as
`
`da
`
`45
`
`so
`
`55
`
`BNSDOGID: «E9
`
`o3uo2.¢,4A1_|_,
`
`5
`
`FRE-D PN-0 D0 0172 1