United States Patent [19]
`Thijs et a1.
`
`[54] OBTURATING MEANS FOR CONTAINER
`FOR PHARMACEUTICAL AND MEDICAL
`PREPARATION
`
`[75] Inventors: Anita Thijs, Alken; Willy Van De
`P l, H k-D -St ,
`'
`_
`°e
`8’
`6 ad b°th “Belgmm
`[73] Asslgnee: gellvfertlpharma N'V" Amen’
`e g “
`490,587
`
`[21] Appl‘ No_;
`_
`[22] PCT Flledz
`[86] PCT No‘:
`
`Aug. 25, 1989
`pcr/BEsg/oomo
`
`§ 371 Date:
`
`Feb. 22, 1990
`
`_
`Feb' 22’ 1990
`§ 102(e) Date‘
`[87] PCT Pub. No.: WO90/02l50 '
`PCT Pub. Date: Mar. 8, 1990
`Foreign Application Priority Data
`_
`Belgium ........................... ..
`
`Aug, 25,
`
`[30]
`
`[51] Int. Cl.5 ............................................. .. A61M 5/32
`[52] us. or .................................. .. 604/199; 604/218;
`525/3323; 218/D1G. 4
`[58] Field of Search ............................. .. 604/199, 218;
`525/3323; 2l5/DIG. 3, DIG. 4, 247
`References Cited
`
`[56]
`
`U5’ PATENT'DOCUMENTS
`3,198,368 8/1965 Kirkland et al. ........... .. 215/DIG. 3
`3,760,969 9/ 1973 Shimamoto et al. .
`215/37 R
`
`,
`
`,
`
`£9196}? 6‘ a11- - - - - - - -
`guc 1et a.
`
`~ - - - - -
`..... ._
`
`428/421
`4,321,306 3/1982 Eguchi ........ “
`215/247
`4,366,912 1/1983 Matukura et a
`604/202
`4,381,779 5/1983 Margulies ....... ..
`4,397,903 8/1983 Allen et al. ....................... .. 428/156
`
`llllllllllllllllllllllIllllllllllllllllllllllllllllllllllllllllllllllllllll
`USOO5l63919A
`[11] Patent Number:
`5,163,919
`[45] Date of Patent:
`Nov. 17, 1992
`
`4,491,653 l/1985 McGinniss et al. ............... .. 525/356
`4,500,685 2/1985 Ogawa et a1. ............. .. 525/343
`4,600,651 7/1986 Aufdermarsh et a1.
`.... .. 428/422
`
`4,614,276 9/1986 lhara et al. . . . . . , . . . . . .
`
`. . . . .. 215/364
`
`4,997,423 3/1991 Okuda et a1. ...................... .. 604/230
`
`FOREIGN PATENT DOCUMENTS
`0205312 12/1986 European Pat. Off. .
`0264273 4/1988 European Pat. Off. .
`0338671 10/1989 European~Pat. Off. .......... .. 604/199
`3415381 11/1985 Fed. Rep. of Germany .
`3506766 12/1985 Fed. Rep. of Germany .
`0200649 11/1984 Japan .......................... .. 215/DIG. 2
`
`OTHER PUBLICATIONS
`Encyclopedia of Polymer Science and Technology,
`vol. 5, Herman F. Mark, pp. 414-421.
`Polymer Science Dictionary, Mark. S. M. Alger, pp. 71
`and 331
`Prima')’ Examiner__c~ Fred Rosenbaum
`Assistant Examiner—-Mark O. Polutta
`Attorney’ Agent, or Firm__pennie & Edmonds
`
`ABSTRACT
`[57]
`An obturating structure and a container provided with
`such an obturating structure and a syringe comprising a
`slidable obturating structure acting as a stopper; and a
`process for treating an olaturating‘ structure prepared at
`least from one elastomenc materlal and 1ntended for a
`static or dynamic seal of a container holding a pharma
`ceutical or medical preparation, in which process at
`least the elastomeric part of the obturating structure is
`at least partially subjected to a treatment with elemen
`tary llzaiogen or chemical compound(s) containing reac
`‘we a 0g”
`
`-
`
`~
`
`_
`
`-
`
`16 Claims, 2 Drawing Sheets
`
`l l
`
`Fresenius Ex. 2024
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`

`
`US. Patent
`
`Nov. 17, 1992
`
`Sheet 1 of2
`
`5,163,919
`
`Fresenius Ex. 2024
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`

`
`US. Patent
`
`Nov. 17, 1992
`
`Sheet 2 of 2
`
`5,163,919
`
`Fresenius Ex. 2024
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`

`
`1
`
`OBTURATING MEANS FOR CONTAINER FOR
`PHARMACEUTICAL AND MEDICAL
`PREPARATION
`
`5,163,919
`2
`balanced ratios in order to obtain seals possessing a
`complex of properties required for the application.
`Said seals having
`the ability to form a static, and if ‘required, dynamic
`gas- and liquidtight seal for a container containing phar
`maceutical or medical preparation (1),
`very low, and indeed pharmaceutically acceptable,
`release of extraneous material to the pharmaceutical or
`medical preparation (2), and
`durability or persistence of the required properties
`during the storage time of the container with a pharma
`ceutical or medical preparation (3),
`must additionally have, in order to be suitable to be
`used in equipment for ?lling or closing containers, the
`following properties
`ability to support currently practiced technical treat~
`ments for surface‘ cleaning and sterilization (4), and
`ability to be processed in current technical container
`?lling and closing equipment (5).
`By selecting suitable elastomeric base materials and
`further components, compounds may be obtained
`which, after curing in an appropriate shaping treatment,
`have a good balance of properties'(l), (2) and (3). Such
`compounds are proprietary to the pharmaceutical rub
`ber industry.
`It has been observed that their ?nal processing, espe
`cially on a large scale, in fast running modern machines,
`requires a certain adaptation of their surface state. By
`their nature, elastomeric objects have a relatively high
`coef?cient of friction, for instance 2.4. This hampers
`their ability to be transported in ?lling equipment and
`similar machinery and, as a consequence, such equip
`ment must be adapted in complicated and mostly costly
`ways.
`In order to overcome this problem, the elastomeric
`seals in many cases are coated with some lubricant, for
`instance silicone oil. Such treatment is additionally fa
`vorable in preventing the seals from sticking to one
`' another, which also is a frequently observed phenome
`non in uncoated seals, especially after treatment in
`40
`cleaning, cleansing, sterilization and drying equipment.
`However, the silicone oil or other lubricant spoils
`some desirable properties of the seals as an extraneous
`material, it contaminates the pharmaceutical or medical
`material stored in the container. In the case of silicone
`oil, for instance, it has been observed that a water-based
`medical preparation after contact with the silicone oil
`treated elastomeric seal, contains a relatively large
`quantity of silicone oil droplets in emulsi?ed state.
`Coatings with various materials have been proposed,
`but they generally involve the already mentioned or
`other drawbacks, for instance a decreased sealing ca
`pacity or a high application cost.
`The present invention purports to resolve the prob
`lem by applying a relatively simple and at the same time
`cost-efficient treatment, consisting of introducing in a
`carefully controlled way an amount of halogen atoms
`into the seal surface. The treated seals acquire the neces
`sary low friction coef?cient and lose their aggregation
`tendency, even upon stringent cleaning, cleansing, ster
`ilizing and drying treatment. They do not lose the desir
`able properties they already possess before the treat
`ment and release a very low amount of extraneous mate
`rial to a pharmaceutical or medical preparation.
`
`45
`
`BACKGROUND OF THE INVENTION
`The preparation of materials for pharmaceutical and
`medical use requires the utmost care. Such materials
`may be used for medication of humans or animals, as
`well as for various related purposes, such as the diagno
`sis of disorders of humans and animals.
`If the materials deviate from the required quality
`standard, they may exert obnoxious or even fatal in?u
`ence on the treated being or lead to equally dangerous
`wrong conclusions in for instance a diagnosis.
`The preparation of such materials is entrusted to
`quali?ed pharmacists. They generate the materials in
`the required quality by using appropriate equipment
`and procedures in carefully constructed premises.
`The materials, once prepared, must however be
`stored in containers in order to allow their transport to
`the application site. Between preparation and applica
`tion, a considerable time interval may elapse. It is clear
`that the container must be such that no appreciable
`deterioration of the materials takes place.
`Container systems for the purpose of storage of the
`materials have been elaborated in the past three or four
`decades for a very large number of applications. In
`many cases, the container system not only preserves the
`good‘ quality of the packed material but additionally
`facilitates or even makes possible its actual application.
`Many systems employ elastomeric (rubber) compo
`nents, functioning practically always as a sealing means
`between the container content and the environment,
`and additionally also in many cases as a means for easy
`and/or safe application. ‘
`Two typical examples from a very large body are the
`following
`1. A glass vial containing a ?uid intended for paren
`teral medication is closed with a soft elastomeric stop
`per. The stopper allows penetration with a hypodermic
`needle or a spike. The sterile ?uid may then be with
`drawn from the vial without actually opening it, thus
`avoiding the danger of contamination with microorgan
`isms or other undesirable matter.
`2. A glass tube is used as a parenteral ?uid cartridge
`by closing one end with an elastomeric stopper in the
`shape of a plunger. The other end is connected to a
`hypodermic needle. The ?uid content of the cartridge
`can be pushed out through the needle by pushing the
`elastomeric plunger with a suitable plunger rod. In this
`application, the elastomeric part must form a static seal
`during shelf life of the cartridge and a dynamic seal
`during the actual application. In the latter stage, it must
`slide very smoothly in order to allow correct medical
`action.
`From the above, it will be clear that elastomeric seals
`in this area may have a very wide variety of shapes and
`dimensions. In the following text they will be addressed
`as “elastomeric seals” for short.
`In the course of the last three decades, much work
`has been devoted to the development of suitable materi
`als for elastomeric seals in this ?eld. The work was
`complex because elastomeric materials for the produc
`65
`tion of seals are composed themselves over a number of
`starting materials. Such starting materials must be most
`carefully selected as well as combined in accurately
`
`55
`
`BRIEF DESCRIPTION OF THE INVENTION
`The invention relates to an obturating means pre
`pared at least from one elastomeric material, said means
`
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`
`

`
`5,163,919
`3
`being intended for a static and/or dynamic seal of a
`container intended to contain a pharmaceutical or medi
`cal preparation, in which at least the elastomeric part of
`the obturating means is at least partially subjected to a
`treatment with elementary halogen or chemical com
`pound(s) containing reactive halogen atoms so that said
`obturating means has at least the following properties
`ability to form at least a static gas- and liquidtight seal
`for the container;
`~
`very low release of extraneous material to the phar
`maceutical or medical preparation;
`compatibility with the pharmaceutical or medical
`preparation;
`ability to support currently practiced technical treat-'
`ments for surface cleaning and sterilization and
`ability to be processed in current technical container
`?lling and closing equipment.
`The obturating means according to the invention is
`preferably treated with ?uorine.
`In an embodiment of the obturating means according
`to the invention, the elastomeric part thereof is at least
`partially treated with a ?uorine gas after being washed.
`A preferred obturating means according to the inven
`tion is obtained by treating the elastomeric part thereof
`with fluorine gas under a pressure of at least 105 Pa,
`25
`preferably under a pressure comprised between 105 and
`5.105 Pa, during at least 60 seconds, preferably from 60
`to 900 seconds, and at a temperature comprised between
`15° and 25° C.
`The ?uorine gas is advantageously mixed with an
`inert gas and preferably with nitrogen. Such a mixture
`contains, for example, 1 to 10% ?uorine gas and 90 to
`99% nitrogen gas.
`The invention relates also to
`a container intended for pharmaceutical or medical
`preparation, said container being provided with an ob
`turating means according to the invention, and
`a syringe intended for the injection of pharmaceutical
`or medical preparation, said syringe containing a slid
`able obturating means according to the invention, said
`means acting as a stopper.
`The invention relates also to a process for treating
`obturating means prepared from at least one elastomeric
`material, said means being intended for a static or dy
`namic seal of a container for pharmaceutical or medical
`preparation. In said process, at least the elastomeric part
`of the obturating means is at least partially subjected to
`a treatment with elementary halogen or chemical com
`pound(s) containing reactive halogen so as to obtain an
`obturating means according to the invention.
`Rubber obturating means according to the invention
`as well as a process according to the invention will be
`described hereafter with reference to the attached
`drawings which show embodiments of obturating
`means according to the invention.
`
`45
`
`50
`
`55
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 is a cross-sectional view of a vulcanized obtu
`rating means according to the invention;
`FIG. 2 is a partial cross-sectional view of a vial pro
`vided with a vulcanized obturating stopper; and
`FIG. 3 is a cross-sectional side view of a slidable
`stopper of a syringe, together with the syringe itself.
`
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`Obturating means according to the invention are
`prepared from at least one elastomeric material. Obtu
`
`65
`
`4
`
`4
`rating means according to the invention are for example‘
`' elastomeric stoppers for containers with a pharmaceuti
`cal or medical preparation or elastomeric slidable stop
`pers of syringes intended for injecting pharmaceutical
`or medical preparation.
`Rubber is the generic name for a class of materials
`composed essentially of one or more elastomeric mate
`rials such as polyisoprene, copolymer of isobutene and
`isoprene, copolymer of butadiene and acrylonitrile,
`polydimethylsiloxane. Said elastomeric materials may
`contain functional atoms or molecule groups, intro
`duced before or after the polymerization. Non-elastom
`eric substances may be added to the elastomer in order
`to tailor the properties of the material to speci?c needs.
`Such substances are for instance ?nely powdered and
`puri?ed minerals (example bentonite clay), reactive
`chemicals intended to enable a crosslinking chemical
`reaction in the material after it has been converted into
`the desired shape.
`During the manufacturing process (information
`thereon is given for example in Rubber Technology and
`Manufacture edited by C. M. BLOW published for the
`Institution’of the Rubber Industry BUTTERWORTI-IS
`LONDON-1971), the various components for a given
`material are mixed to give a malleable compound. This
`7 compound is then converted into the desired shape. The
`material of the ?nal product is characterized by the fact
`that it is capable of recovering from large deformations
`quickly and forcibly. It will retract within 1 minute to
`less than 1.5‘ times its original length after being
`stretched at room temperature (18° to 29° C.) to twice
`its length and held for 1 minute before release.
`The following table gives an example of composition
`of rubber:
`
`chlorobutyl rubber
`vulcanizing agent
`?ller (silicate)
`zinc oxide
`stearine acid
`paraf?ne oil
`colorant (iron-, titane oxide)
`polyethylene wax
`
`% by weight
`50 to 55
`0.5 to 2
`40 to 45
`1 to 3
`0.5 to 2
`0.5 to 2
`0 to 2 ‘
`0.5 to 3
`
`The process according to the invention may be ap
`plied to obturating means composed of at least rubber
`or elastomeric material as described in the following
`examples, given as examples only.
`
`EXAMPLE 1
`Said process comprised the following steps:
`1. The obturating means were washed in a rotary
`drum, ?rst with warm water and a neutral detergent,
`then with ?ltered water and ?nally with pyrogen-free
`water.
`2. The “obturating means were then dried by means of
`hot ?ltered air.
`3. The obturating means were contacted in a rotary
`drum with ?uorine which was mixed with nitrogen.
`The mixture of gases contained 1% ?uorine and 99%
`volume nitrogen.
`The contact time of the obturating means with ?uo
`rine was 900 seconds.
`The obturating means were contacted with said mix
`ture of gases at a temperature of 25° C. and under a
`pressure of 5.105 Pa.
`
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`
`

`
`5
`4. The obturating means were washed with water and
`dried with hot ?ltered air.
`
`EXAMPLE 2
`Said process comprised the following steps:
`1. The obturating means were washed in a rotary
`drum, ?rst with warm water and a neutral detergent,
`then with filtered water and ?nally with pyrogen-free
`
`5
`
`Water.
`
`'
`
`2. The obturating means were then dried by means of 10
`hot ?ltered air.
`3. The obturating means were contacted in a rotary
`drum with ?uorine which was mixed with nitrogen.
`The mixture of gases contained 10% ?uorine and 90%
`volume nitrogen.
`The contact time of the obturating means with fluo
`rine was 60 seconds.
`The obturating means were contacted with said mix
`ture of gases at a temperature of 15° C. and under a
`pressure of 105 Pa.
`4. The obturating means were washed with water and
`dried with hot ?ltered air.
`Due to the ?uorination of the vulcanized rubber
`product, for example a stopper 1, it is possible with the
`process according to the invention to obtain a product
`which has at least one surface 2 which has at least par
`tially been chemically modi?ed up to a certain depth,
`said depth being at least 10 nanometers (IO-3m) and
`having a low friction coef?cient and a low aggregation
`tendency, and which at most may cause a low particles
`contamination of pharmaceutical or medical materials
`in contact therewith.
`The following table lists typical values and observa
`tions deducted from a body of experimental ?ndings
`and demonstrating the effectiveness of the treatment
`according to the invention.
`
`20
`
`25
`
`5,163,919
`6
`ability to support currently practiced technical treat
`ments for surface cleaning and sterilization, and
`ability to be processed in current technical container
`filling and closing equipment;
`'
`only by treating the obturating means according to
`the invention.
`The man skilled in the art who tried to avoid contami
`nation of pharmaceutical or medical preparation with
`particles of the obturating means had the preconceived
`idea that it was necessary to add a coating on the obtu-'
`rating means so as‘ to make a barrier between the obtu
`rating means and the pharma- ceutical or medical prepa
`ration. (For example, see European patent application 0
`264 273 or US. Pat. No. 4,808,453).
`FIG. 2 shows a vial 3 which is provided with an
`opening 4 which is sealed by a stopper 5 made of rubber
`and treated by the process according to the invention.
`Said vial is suitable for containing pharmaceuticals, for
`example cephalosporine.
`The sealing of opening 4 is perfect since the ?uori
`nated surface 2 takes the form of the opening 4 and since
`said surface 2 consists of a homogeneous and regular
`layer which is strongly bonded to the stopper.
`FIG. 3 shows a rubber stopper 6 for sealing a syringe
`7 which may be previously ?lled with a pharmaceutical
`or which may be used for extracting a pharmaceutical
`from a vial and for injecting it to a patient.
`The fluorinated surface of said stopper 6 allows that
`only a low working force has to be exerted on the stop
`per during the injection. This force is not increased after
`storing, for example, a syringe ?lled 3 years before
`using it.
`Due to the absence of silicones which previously
`were necessary in order to guarantee the sliding of the
`stopper, there is no more contamination of the pharma
`ceutical with particles.
`
`35
`
`TABLE
`Findings after additional washing
`and sterilizing treatment according
`to BS 3263: 1960
`
`aggregation
`
`processing in
`packaging equipment
`
`Treatment
`
`none
`
`friction
`coefficient“
`
`2.4
`
`l.l
`
`1.1
`
`tendency
`to aggregate
`very slight
`tendency
`to aggregate
`
`not
`possible
`easy
`
`very easy
`
`coating
`with
`silicone
`oil 350 cSt
`20 micrograms
`per cm2
`no
`according
`tendency
`to the
`to aggregate
`invention
`'l cm: of rubber surface was in contact with 2 ml of particle free water.
`"determined in comparable circumstances.
`
`Findings after contacting
`the seals with water under steam
`sterilization conditions (30¢l2l" C.)‘
`emulsion density particles ->_—
`2 p. per ml of the contact ?uid
`
`2000
`
`50 000
`
`500
`
`The table shows that the contamination due to the 5S
`vulcanized rubber treated by the process according to
`the invention is 100 times lower than the contamination
`due to rubber covered with a silicone layer.
`The man skilled in the art was not able to predict that
`it was possible to obtain obturating means having the
`following properties:
`ability to form at least a static, preferably a static and
`dynamic, gas- and liquidtight seal for the container;
`very low release of extraneous material to the phar
`maceutical or medical preparation as exempli?ed in the
`table;
`compatibility with pharmaceutical or medical prepa
`ration;
`'
`
`65
`
`Due to the fact that the surface of the rubber products
`treated by the process according to the invention is
`more hydrophobic, there is less interaction between the
`rubber and the pharmaceuticals which are in contact
`therewith. The transfer of rubber ingredients to the
`pharmaceuticals is thereby reduced so that the rubber
`products according to the invention have a better com
`patibility.
`The surface 2 of rubber products treated by the pro
`cess according to the invention has a repelling force for
`dust so that said dust is not able to be deposited on said
`surface 2. Said dust is thus not able to contaminate the
`stopper 5 even if said stopper is stored in an environ
`
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`
`

`
`10
`
`p
`
`25
`
`30
`
`35
`
`5,163,919
`8
`7
`ment slightly contaminated with particles during along
`8. The method of claim 2 which further comprises
`time.
`adding an inert gas to said ?uorine-containing gas.
`9. The method of claim 8 wherein said inert gas is
`In the obturating means according to the invention, a
`nitrogen.
`part thereof may not be subjected to a treatment with
`elementary halogen or chemical compound(s) contain
`10. The method of claim 9 wherein said obturator
`ing reactive halogen atoms, said means being provided
`surface is contacted with a ?uorine-containing gas com
`prising from about 1 to 10% ?uorine gas and from about
`with an untreated surface which is not intended to be in
`90 to 99% nitrogen gas.
`contact with a pharmaceutical or medical preparation.
`11. The method of claim 2 which further comprises
`What we claim is: -
`'
`washing at least a portion of said obturator prior to
`1. An obturator for sealing a container for medical or
`contacting said portion with the fluorine-containing
`pharmaceutical preparations, said obturator formed of
`chloro butyl rubber wherein at least a portion of a sur
`gas.
`12. A method for forming an obturator adapted for
`face of said obturator is ?uorinated upon contact
`thereof with a fluorine-containing gas such that said
`sealing a container for medical or pharmaceutical prep
`arations, which method comprises:
`?uorinated portion extends to a depth within said obtu
`forming an obturator con?gured and adapted for
`rator of at least about 10 namometers, said ?uorinated
`surface having a substantially reduced degree of reac
`sealing a container for medical or pharmaceutical
`preparations from chlorobutyl rubber;
`tivity with said medical and said pharmaceutical prepa
`rations in contrast to a corresponding surface which has
`washing at least a portion of a surface of said obtura
`not been ?uorinated.
`tor;
`drying said washed surface portion; and
`2. A method for forming an obturator adapted for
`contacting said surface portion of said obturator with
`sealing a container for medical or pharmaceutical prep
`arations, which method comprises:
`a gaseous reagent comprising from about 1 to 10%
`forming an obturator configured and adapted for
`fluorine gas and 90 to 99% nitrogen under a pres
`sure of between about 105 and 5x105 Pa. for be
`sealing a container for a medical or a pharmaceuti
`cal preparation from chloro butyl rubber; and
`tween about 60 to 900 seconds at a temperature of
`contacting a surface portion of said obturator with a
`between about 15°—25° C. so as to at least partially
`fluorinate said contacted surface portion to a depth
`?uorine-containing gas so as to ?uorinate at least a
`portion of said contacted surface.
`of at least about 10 nanometers,
`said ?uorinated surface having a substantially re
`said ?uorinated surface having a substantially re
`duced degree of reactivity with respect to said
`duced degree of reactivity with respect to said
`medical and said pharmaceutical preparations in
`medical and said pharmaceutical preparations in
`contrast to a corresponding surface which has not
`contrast to a corresponding surface which has not
`be ?uorinated.
`been ?uorinated.
`3. The method of claim 2 which further comprises
`13. Container means for storing medical or pharma~
`contacting said obturator surface with said fluorine
`ceutical preparations, said container means comprising
`an obturator produced by the process of claim 12.
`containing gas at a pressure of at least about 105 Pa.
`4. The method of claim 3 wherein said pressure
`14. Container means for storing medical or pharma
`ceutical preparations, said container means comprising
`ranges between about 105 and 5 X 105 Pa.
`5. The method of claim 3 which further comprises
`an obturator produced by the process of claim 11.
`contacting said obturator surface portion with said ?uo
`15. A syringe adapted for injecting medical or phar
`maceutical preparations, said syringe comprising a slid
`rine-containing gas for at least about 60 seconds.
`6. The method of claim 5 wherein said obturator
`able obturator formed according to the process of claim
`surface portion is contacted with said ?uorine-contain
`12 to serve as a stopper within said syringe.
`16. A syringe adapted for injecting medical or phar
`ing gas for between about 60 and 900 seconds.
`maceutical preparations, said syringe comprising a slid
`7. The method of claim 2 which further comprises
`contacting said obturator surface with said ?uorine
`able obturator formed according to the process of claim
`containing gas at a temperature of between about
`12 to serve as a stopper within said syringe.
`l5°—25° C.
`* i i * i
`
`45
`
`50
`
`55
`
`65
`
`Fresenius Ex. 2024
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254