I IIIII IIIIIIII II llllll lllll lllll lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111
`US 20110276005Al
`
`c19) United States
`c12J Patent Application Publication
`Hioki et al.
`
`c10J Pub. No.: US 2011/0276005 Al
`Nov. 10, 2011
`(43) Pub. Date:
`
`(54) SYRINGE
`
`(75)
`
`Inventors:
`
`(73) Assignees:
`
`Kazutoshi Hioki, Niigata (JP);
`Kenji Nohmi, Niigata (JP);
`Yoshiaki Miyata, Tokyo (JP); Ippei
`Matsumoto, Osaka (JP); Norihiko
`Asahi, Osaka (JP)
`
`TAISEI KAKO CO., LTD.,
`Osaka-shi (JP); DENKI KAGAKU
`KOGYO KABUSHIKI KAISHA,
`Tokyo (JP)
`
`(21) Appl. No.
`
`13/132,720
`
`(22) PCT Filed:
`
`Dec. 3, 2009
`
`(86) PCT No.:
`
`PCT/JP2009/070285
`
`§ 371 (c)(l),
`(2), (4) Date:
`
`Jul. 29, 2011
`
`(30)
`
`Foreign Application Priority Uata
`
`(JP) ................................. 2008-308978
`Dec. 3, 2008
`(JP) ................................. 2008-323575
`Dec. 19, 2008
`(JP) ................................. 2009-003518
`Jan. 9, 2009
`Publication Classification
`
`(51)
`
`Int. Cl.
`A61M 5/31
`(2006.01)
`(52) U.S. Cl. ........................................................ 604/187
`ABSTR,\CT
`(57)
`
`Provided is a syringe with which it is possible to hold with
`greater stability a liquid inside the barrel while maintaining
`the slidability and air-tightness between the barrel and the
`gasket without requiring fixation of silicone oil, and which is
`excellent in terms of accuracy of visual inspection. The
`syringe has a resin barrel, a gasket slidably inserted inside the
`barrel, a plunger attached to the gasket, and a silicone film
`obtained by applying silicone oil having a kinematic viscosity
`of 500 to 10,000 cSt over the inner peripheral surface of the
`barrel in an amount of 5 to 50 µg per 1 cm2of area.
`
`'~25
`
`- -28
`
`ii/Ill/fl{/(
`
`Regeneron Exhibit 1020.001
`
`

`

`Patent Application Publication Nov. 10, 2011 Sheet 1 of 2
`
`US 2011/0276005 Al
`
`25
`
`-----28
`
`27
`
`Regeneron Exhibit 1020.002
`
`

`

`Patent Application Publication Nov. 10, 2011 Sheet 2 of 2
`
`US 2011/0276005 Al
`
`L
`i - - - - - - - - - - - - - - - -
`
`Regeneron Exhibit 1020.003
`
`

`

`US 2011/0276005 Al
`
`Nov. 10, 2011
`
`SYRINGE
`
`TECHNICAL FIELD
`
`[ 0001] The present invention relates to a syringe, and more
`particularly relates to a syringe which is excellent in terms of
`accuracy of visual inspection of the content and a prefilled
`syringe filled with a high viscosity drug that are suitable for
`injection of high viscosity drugs.
`
`BACKGROUND ART
`
`[0002]
`In recent years, prefilled syringes prefilled with
`dmgs have been used for reasons such as prevention of mis(cid:173)
`takes during medical treatment and prevention of bacterial
`contamination. A prefilled syringe has the tip opening of a
`barrel sealed with a cap member, is filled with a drug inside
`the barrcL has the rear end portion of the barrel scaled with a
`gasket, and is transported and stored in that state. When
`administering, an injection needle or an apparatus for admin(cid:173)
`istration is attached to the tip of the barrel, and by pushing a
`plunger attached to the gasket towards the tip and sliding the
`gasket inside the barrel, the drug flows out from the injection
`needle and is administered. As such, prefilled syringes have
`various advantages, such as allowing drugs to he adminis(cid:173)
`tered in accurate doses without mistakes even during emer(cid:173)
`gencies as there is no need to prepare the drugs at the point of
`treatment. being highly sanitary as there is no transferring of
`drugs, and being easy to operate.
`[0003] Since prefilled syringes are stored and circulated in
`a stale ofbeing filled with a drug, it may be several years from
`the filling of the drug in production factories to administra(cid:173)
`tion. As such, while it goes without saying that long-term
`stability is needed, it is also necessary to be able to confirm the
`safety of the drug by visually inspecting for contamination by
`impurities. For that reason, the material constituting the bar(cid:173)
`rel needs lo be highly transparent, and barrels made of glass,
`which ensures transparency, have been frequently used in
`conventional prefilled syringes.
`[0004]
`Ilowever, glass barrels crack relatively easily, need
`to be separated from the other parts and cannot be incinerated
`together therewith when discarded, and cost more, so there
`has been a demand for barrels made of resin. Resins with
`transparency comparable to that of glass barrels have
`appeared in recent years, and there has been a gradual tran(cid:173)
`sition towards resin barrels.
`[0005] Regardless of the material of the barrel, to ensure
`sufficient slidability between the barrel and gasket, a lubri(cid:173)
`cant layer composed of silicone or the like is generally pro(cid:173)
`vided on the inner peripheral surface of the barrel and/or the
`outer peripheral surface of the gasket.
`[0006]
`In the case of conventionally used glass barrels,
`typically, silicone, in the formofan emulsion, is applied to the
`inner peripheral surface of the barrels and is fixed by baking
`at a high temperature (200 to 300° C.). Silicone in itselfis not
`harmful to the human body, hut the silicone is fixed to the
`inner peripheral surface of the barrels lo avoid the silicone
`contaminating the drugs.
`[0007]
`In the case ofresin barrels, since the glass transition
`point of resins is lower than the baking temperature of sili(cid:173)
`cone, the same fixing treatment as for glass barrels cannot be
`used. In the case ofresin barrels, methods in which a radiation
`or ultraviolet-curable organopolysiloxane is used and meth(cid:173)
`ods in which a photopolymcrization catalyst such as bcn(cid:173)
`zophenone is added to silicone have been proposed as
`
`examples of methods for fixing silicone instead of baking at a
`high lemperalure (Patent Document I).
`[0008] On the other hand, as methods not involving such a
`fixing treatment, methods in which a silicone oil is simply
`applied to the inner peripheral surface of a barrel have also
`been widely used. In particular, in order to prevent the sili(cid:173)
`cone oil from dripping from the inner peripheral surface of the
`barrel and contaminating the drug and to suppress increases
`in the sliding resistance of the gasket, the addition of a fine
`silica powder to a silicone oil has been proposed (Patent
`Document 2).
`[0009] Additionally, in order to ensure sufficient slidahility
`between the barrel and gasket, a prefilled syringe involving
`the use of a sealing stopper (gasket) for a syringe, which is a
`rubber stopper with its surface laminated with a tetrafluoro(cid:173)
`ethylene resin film or an ultrahigh molecular weight polyeth(cid:173)
`ylene film, has also been proposed (Patent Document 3 ).
`[0010] Patent Document I: .TP-A 2007-244606
`[0011] Patent Document 2: JP-A 2006-94895
`[0012] Patent Document 3: JP-A HI 0-314305
`
`SUMMARY OF THE INVENTION
`
`[0013] However, since methods for the lubrication treat(cid:173)
`ment of resin barrels comprising fixation require a step of
`curing by radiation etc. as described in the above Patent
`Document 1, production efficiency is inevitably poor. Addi(cid:173)
`tionally, some curing agents etc. may affect the human body
`when contaminating a drug.
`[0014] On the other hand, when the fixing treatment is not
`performed, naturally, there is a risk of the applied silicone oil
`separating from the inner peripheral surface of the barrel
`during filling of a drug, storage or transport and contaminat(cid:173)
`ing the drug, causing turbidity. This is, as described in the
`above Patent Document 2, not a problem that can be com(cid:173)
`pletely overcome even when, for example, the silicone oil
`contains a fine silica powder. Rather, in that case, there is a
`risk of not only the silicone oil, but also the fine silica powder
`contaminating the drng.
`[0015] Such contamination by the silicone oil from the
`inner peripheral surface of the barrel is particularly notable
`when the viscosity of the drug is high. While the exact mecha(cid:173)
`nism is unclear, this is thought to be due to the high shear
`stress exerted on the silicone oil adhering to the inner periph(cid:173)
`eral surface of the barrel when filling the syringe with a drng
`of high viscosity. As mentioned a hove, silicone oil is not
`necessarily harmful to the human body, but it is not possible
`to clearly distinguish between turbidity caused by contami(cid:173)
`nation due to silicone oil and turbidity caused by substantial
`contamination due to impurities by visual inspection alone, so
`such syringes may be determined lo be defective products
`during inspection or medical practice and be forced to be
`discarded without ever being used.
`[0016] Further, even when the silicone oil adheres normally
`to the im1er peripheral surface of the barrel, the refractive
`index of the applied silicone oil differs from the refractive
`index of the drug and the refractive index of the synthetic
`resin constituting the syringe, resulting in glare on the inner
`peripheral surface of the barrel, which may interfere with
`visual inspection or make it seem as if there has been con(cid:173)
`tamination hy impurities or a defect such as a scratch on the
`barrel.
`[0017] Moreover, in the case of the sealing stopper (gasket)
`for a syringe described in Patent Document 3, since the sur(cid:173)
`face of the rubber stopper is laminated with a resin film. the
`
`Regeneron Exhibit 1020.004
`
`

`

`US 2011/0276005 Al
`
`Nov. 10, 2011
`
`2
`
`error in the i1merdiameter of the sealing stopper (gasket) for
`a syringe or the barrel could be increased due lo the disparity
`of the actual dimensions with respect to the dimensions of the
`original design, and there tended to be problems in the slid(cid:173)
`ability or scaling properties of the scaling stopper (gasket) for
`a syringe with respect to the inner surface of the barrel.
`[0018] As such, there has been a need for syringes capable
`of reducing the risk of separation and contamination by sili(cid:173)
`cone oil while not requiring fixation of the silicone oiL in
`which glare rarely occurs on the inner peripheral surface of
`the barreL and equipped with sufficient gasket slidability and
`scaling properties.
`[UU19J The present invention was achieved in view of the
`above circumstances, with an object of providing a syringe
`excellent in inspection accuracy while ensuring slidability
`and sealing properties between the barrel and gasket, and in
`particular, a syringe that is also suitable for filling with a high
`viscosity drug.
`[0020] As a result of diligent studies, the present inventors
`found that by spraying a silicone oil of a predetermined kine(cid:173)
`matic viscosity onto the i1mer peripheral surface of a resin
`barrel at a predetermined application amount per unit area, it
`is possible to suppress separation and contamination by the
`silicone oil and glare on the inner peripheral surface of the
`barrel in addition lo providing sufficient slic.labilily.
`[0021] That is, the syringe of the present invention is char(cid:173)
`acterized by having a resin barrel, a gasket slidably inserted in
`the barrel, a plunger attached to the gasket, and a silicone film
`formed by applying a silicone oil having a kinematic viscosity
`of 500 to 100,000 cSt to the inner peripheral surface of the
`above-described barrel in an amount of 5 to 50 µg per 1 cm2of
`area.
`[0022] Since a silicone oil having a kinematic viscosity of
`at least 500 cSt is used as the silicone constituting the silicone
`film in this syringe, when spraying the silicone oil, the sili(cid:173)
`cone oil is appropriately maintained on the inner peripheral
`surface of the barrel without running. Por that reason, even
`when a small amount of silicone oil is applied, it is possible to
`ensure sufficient slidabilily with the gasket. Additionally,
`since a silicone oil having a kinematic viscosity of at most
`100,000 cSt is used, it can be applied to the inner peripheral
`surface of the barrel by spraying, and the silicone oil can be
`evenly applied in the above predetem1ined application
`amorn1t per unit area.
`[0023] Further. by using a silicone oil having a kinematic
`viscosity within that range, it is possible to ensure sufficient
`slidahility between the barrel and gasket even when the
`amount oflhe silicone oil applied is al most 50 ~Lg per 1 cm2of
`area on the inner peripheral surface of the barrel, and the
`amorn1t of the silicone oil applied can be suppressed to a low
`amount. As a result thereof, when filling with a drug, even if
`the silicone oil becomes mixed into the drug, the amount of
`contamination can he kept extremely low. As such, the occur(cid:173)
`rence oflurbidily due lo contamination by the silicone oil can
`be suppressed, the causes of turbidity in a drug in a prefilled
`syringe can be limited to cases of contamination by impurities
`other than silicone oil, and accuracy in visual inspection to
`ensure safety can be substantially improved. This is particu(cid:173)
`larly applicable to cases where a high viscosity drng which is
`susceptible lo contamination by silicone oil is loaded. Fur(cid:173)
`ther, when the application amount is within this range, as long
`as observation is performed by the naked eye, there is also a
`low likelihood of glare being detected on the inner peripheral
`surface of the barrel. Moreover, when the amount of the
`
`silicone oil applied to the i1mer peripheral surface of the barrel
`is at least 5 µg per 1 cm2 area, sufficient slidability between
`the barrel and the gasket can be ensured.
`[0024] Since the viscosity of a silicone oil having a kine(cid:173)
`matic viscosity within the above range is high, it is generally
`not easy to evenly spray the oil. However, even spraying is
`possible by appropriately adjusting the liquid temperature, air
`pressure, noZ71e diameter and application time etc. In particu(cid:173)
`lar, a fine mist can be sprayed to achieve an extremely thin
`film such as one within the above range by heating the silicone
`oil within such a range as not to cause denaturation at the time
`of spraying.
`[0025] Moreover, by designing the maximum outer diam(cid:173)
`eter of the gasket to be greater than the inner diameter of the
`barrel such that the difference between the maximum outer
`diameter of the gasket and the inner diameter of the barrel is
`at least 0.02 llll1l and at most 0.50 I1illl, it is possible to
`suppress drug leakage from the gap between the gasket and
`barrel while maintaining the sealing properties of the gasket
`and ensure sufficient slidability between the barrel and gas(cid:173)
`ket.
`[0026] Purther, as a result of diligent studies, it was found
`that when, upon shining incident light with an optical axis
`orthogonally intersecting the central axis of the barrel and
`measuring the angle of refraction from the optical axis ofthe
`transmitted light scattered along the same direction as the
`central axis, glare on the inner peripheral surface of the barrel
`can be remarkably suppressed if the angle of refraction is
`within a predetermined rm1ge.
`[0027] That is, it was found that the glare could be remark(cid:173)
`ably suppressed when, upon shining an incident beam with a
`wavelength of 635 11111 to 6lJO 11111 and a beam width ofat most
`'.l.O mm on a barrel filled with a drug at an optical axis
`orlhugunally intersecting the central axis of the barrel, the
`angle of refraction from the optical axis of the transmitted
`light scattered in the same direction as the above-described
`central axis was within a range ofO.l to 0.5°.
`[0028] The "angle of refraction" in the present invention
`refers to the aperture angle from the optical axis of transmit(cid:173)
`ted light scattered along the same direction as the central axis
`of the barrel of a prefilled syringe filled with a drug when
`shining an incident beam with an optical axis orthogonally
`intersecting the central axis of the barrel.
`[0029] The barrel of a prefilled syringe will cause a trm1s(cid:173)
`mitted beam in a direction perpendicular to the central axis to
`be highly refracted with the center of curvature as the central
`axis. Accordingly, refraction occurring in the direction per(cid:173)
`pendicular to the central axis is affected by solely the shape of
`the barrel, and cmmot indicate small variations in the appli(cid:173)
`cation stale of the silicone oil on the i1mer peripheral surface
`of the barrel. On the other hand, as the barrel is not substan(cid:173)
`tially curved in the direction of the central axis, the divergence
`from the optical axis occurring in the same direction as the
`central axis, i.e. the "angle ofrefraction" in the present inven(cid:173)
`tion, is not significantly affected by the shape of the barrel,
`and can directly reflect the state of application of the silicone
`oil.
`Tl was found that when the angle of refraction ofa
`[0030]
`prefilled syringed filled with a drug is within the range ofO.l
`to 0.5°, as long as the observation is performed by the naked
`eye, there is an extremely low likelihood of glare being
`detected on the inner peripheral surface of the barrel. As such,
`
`Regeneron Exhibit 1020.005
`
`

`

`US 2011/0276005 Al
`
`Nov. 10, 2011
`
`3
`
`a prefilled syringe having such an angle of refraction can
`remarkably improve the visual inspection accuracy of the
`drng.
`[0031] According to the present invention, a drng can be
`more stably s!oreu in the barrel and the accuracy of inspection
`of the content can be substantially improved while ensuring
`the sealing properties and the slidability between the barrel
`and gasket. This makes safe and accurate operation possible.
`As such, the syringe according the present invention has great
`utility as a medical apparatus and as a cosmetic apparatus.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0032] FIG. 1 A schematic view of a prcfilled syringe
`according to an embodiment of the present invention.
`[0033] FIG. 2A schematic view showing an embodiment of
`a device for measuring an '"angle of refraction" in the present
`invention.
`
`DESCRIPTION OF REFERENCE NUMBERS
`
`l Prefilled syringe
`[0034]
`[0035] 10 Syringe
`[0036] 20 I3arrel
`[0037] 21 Tip opening
`[0038] 22 Flange
`23 Screw thread portion
`[UU39J
`[0040] 24 Gasket
`[0041] 25 Plunger
`[0042] 26 Cap member
`[0043] 27 Drng
`[0044] 28 Silicone film
`[0045] 31 Laser oscillator
`[0046] 32 Projection plate
`[0047] 33 Incident beam
`[0048] 34 Transmitted beam
`[0049] 40 Central axis
`[0050] 41 Optical axis
`[0051] 42 Projection image
`
`Y!ODES FOR CARRYING OUT THE INVENTION
`
`[0052] Herebelow, preferred embodiments of the present
`invention shall be explained in detail with reference to the
`attached drawings. FIG. 1 is a schematic view of a prefilled
`syringe which is a preferred embodiment of the present inven(cid:173)
`tion.
`[ UU53 J !'refilled syringe 1 according to the present embodi(cid:173)
`ment can basically adopt the constitution of a conventional
`prefilleu syringe as is, and as shown in FIG. 1, is constituted
`by a syringe 10 comprising a barrel 20 with a tip opening 21
`at the tip, a liquid-tight, air-tight and slidable gasket 24 in
`barrel 20, and a plunger 25 attached to the rear end of gasket
`24; a cap member 26 for sealing tip opening 21 of barrel 20;
`and a drn g 27 stored inside syringe 10. Moreover, a silicone
`film 28 formed by spraying a silirnne oil is provided on the
`inner peripheral surface of barrel 20. InFIG. l, for the sake of
`illustration, silicone 28 is shown as a film seemingly applied
`at a fixed thickness, but as long as the amount of silicone oil
`applied to the inner peripheral surface of barrel 20 is within
`
`the range of 5 to 50 ftg per 1 cni2 area, the desired effects can
`be sufficiently achieved, so it does nol necessarily need lo be
`even.
`
`<Barrel>
`
`[0054] Barrel 20, as shown in FIG. 1, is a cylindrical body
`provided with tip opening 21 at the tip for the attachment of an
`injection needle, and a pair of opposing flanges 22 at the rear
`end for the placement of fingers during drng i1tjection.
`[0055] Additionally, the below-described sealing member,
`cap member 26, is attached to tip opening 21 of barrel 20.
`Moreover, an injection needle (not shown) instead of cap
`member 26 may be directly attached. In the present embodi(cid:173)
`ment, a screw thread portion 23 is provided on the outer
`peripheral surface of tip opening 21 for attaching cap member
`26 or an injection needle.
`[0056] Barrel 20 is formed with a transparent resin material
`in order to enable visual inspection of the filled drng 27.
`While there is no particular limitation to the material forming
`barrel 20, when consiuering optical transparency, strength
`and dimensional accuracy, various resins, for example, poly(cid:173)
`styrenes, polyamides, polycarbonates, polyvinyl chloride,
`polyvinylidcnc chloride, poly-( 4-mcthylpentcnc-1 ), polyvi(cid:173)
`nyl alcohols, acrylic resins, acrylonitrile-butadiene-styrene
`copolymer, polyesters such as polyethylene terephthalate,
`cyclic polyolefins and cyclic olefin copolymers may be men(cid:173)
`tioned.
`[0057] T n the interest of visual inspection efficiency and
`accmacy of the content, cyclic olefin polymers (COP) and
`cyclic olefin copolymers (COC) which have excellent trans(cid:173)
`parency are particularly preferred. As such resins, thermo(cid:173)
`plastic saturated norborncnc resin compositions commer(cid:173)
`cially available under Zeonex (trademark) from the (Japan)
`Zeon Corporation, particularly those dispersed with a com(cid:173)
`pounuing agent such as a gum polymer that is immiscible
`with the thermoplastic saturated norbomene resin, are pre(cid:173)
`ferred. In particular, those having the following properties are
`most preferred.
`[0058] Optical transparency: 92%
`[0059] Refractive index: 1.53
`
`<Gasket>
`
`[0060] While there is no particular limitation to the material
`of gasket 24, in order to maintain air-tightness, it is preferably
`formed by an elastic body such as rnbber or a thermoplastic
`elastomer. Among them, butyl rubber, which changes little in
`dimensions upon autoclave sterilization, is particularly pre(cid:173)
`ferred as the main ingredient. As the butyl mbber, a haloge(cid:173)
`nated butyl halide that has been chlorinated or bromina!e<l in
`order to improve crosslinkability and adhesiveness etc. may
`be used. As long as the material is permitted to be used as a
`medical apparatus or has been conventionally used as a mate(cid:173)
`rial for forming the gasket of a syringe, there is no particular
`limitation. Additionally, while there is no particular limitation
`on the surface material of the gasket, from the aspect of cost
`reduction, for example, materials not surface-treated with a
`tetrafluoroethylene resin film or ultra high molecular weight
`polyethylene film arc preferred. Moreover, in order to further
`reduce the possibility of the gasket being stuck, a silicone oil
`may be applied to the surface of the gasket.
`[0061] Gasket 24 preferably has a plurality of ridge por(cid:173)
`tions (ring-shaped convex portions) as shown in FIG. 1. By
`having such a plurality of ridge portions and valley portions
`
`Regeneron Exhibit 1020.006
`
`

`

`US 2011/0276005 Al
`
`Nov. 10, 2011
`
`4
`
`(ring-shaped concave portions) provided in between, the slid(cid:173)
`ing area between gasket 24 and barrel 20 can be reduced, and
`therefore the sliding resistance between gasket 24 and barrel
`20 can be reduced. Additionally, by having such a plurality of
`ridge portions and valley portions provided in between, drug
`27 can be blocked at multiple stages, suppressing leakage of
`dmg 27 from the gap between gasket 24 and barrel 20.
`[0062] Moreover, the maximum outer diameter of gasket
`24 preferably corresponds to the outer diameter of the first
`ridge portion closest to the tip among the plurality of ridge
`portions. This is because the first ridge portion closest to the
`tip among the plurality of ridge portions of gasket 24 is in fact
`directly in contact with dmg 27, so by maximizing the outer
`diameterofthis ridge portion, leakage of drug 27 from the gap
`between gasket 24 and barrel 20 can be effectively sup(cid:173)
`pressed.
`
`<Dimensional Difference Between Barrel and Gasket>
`
`In syringe 10 of the present embodiment, the maxi(cid:173)
`[0063]
`mum outer diameter of gasket 24 needs to be greater than the
`inner diameter of barrel 20. Hy making the maximum outer
`diameter of gasket 24 greaterthan the inner diameter of barrel
`20, leakage of dmg 27 from the gap between gasket 24 and
`barrel 20 can be suppressed, and the sealing properties of
`gasket 24 can be maintained.
`[0064] Additionally, in syringe 10 of the present embodi(cid:173)
`ment, the difference between the maximum outer diameter of
`gasket 24 and the inner diameter of barrel 20 needs lo be al
`least 0.02 mm and at most 0.50 mm. This is because by
`making the difference between the maximum outer diameter
`of gasket 24 and the inner diameter of barrel 20 al least 0.02
`mm and at most 0.50 mm, leakage of drng 27 from the gap
`between gasket 24 and barrel 20 can be suppressed while
`maintaining the sealing properties of gasket 24, and sufficient
`slidability between barrel 20 and gasket 24 can be ensured.
`[0065] Moreover, the difference between the maximum
`outer diameter of gasket 24 and the inner diameter ofbarrel 20
`is preferably at least 0.10 mm, and more preferably at least
`0.15 mm. This is because the greater this difference is, the
`easier it is to suppress drng 27 from leaking from the gap
`between gasket 24 and barrel 20. On the other hand, the
`difference between the maximum outer diameter of gasket 24
`and the inner diameter of barrel 20 is preferably at most 0.40
`mm and more preferably at most 0.35 mm. This is because the
`smaller this difference is, the better is the slidability between
`the barrel and gasket.
`[UU66J The tolerance (variability in dimensional accuracy
`of the actual product with respect to the designed dimensions)
`of the maximum outer diameter of gasket 24 after autoclave
`sterilization is preferably controlled be at most ±0.10 nun,
`and is more preferably controlled to be at most ±0.05 nnn.
`This is because when the variability in dimensional accuracy
`of gasket 24 is within this range, it is stabilized by the entire
`syringe 10, and sufficient slidability and sealing properties of
`the gasket can be ensured.
`[0067] On the other hand, the tolerance (variability in
`dimensional accuracy of the actual product with respect to the
`designed dimensions) of the inner diameter of barrel 20 is
`preferably controlled to be at most ±0.10 mm, and is more
`preferably controlled lo be al most ±0.05 mm. This is because
`when the variability in dimension accuracy of barrel 20 is
`within this range, it is stabilized by almost the entire syringe
`10, and sufficient slidability and scaling properties of the
`gasket can he ensured.
`
`If gasket 24 is a structure in which a tetrafluoroeth(cid:173)
`[0068]
`ylene resin film or ultra high molecular weight polyethylene
`film is laminated on the surface of a rnbber stopper, keeping
`the difference between the maximum outer diameter of gasket
`24 and the inner diameter of barrel 20 within these ranges
`might be difficult. This is because when making a gasket 24
`with such a complex laminated strncture, the production pro(cid:173)
`cess becomes complicated, and as a consequence thereof,
`there is a tendency for the disparity in the actual dimensions
`of gasket 24 with respect to the dimensions of the original
`design to be greater. For that reason, even if the inspection
`process of the dimensional accuracy of gasket 24 were
`applied strictly, tl1e proportion of gaskets 24 outside the pre(cid:173)
`determined dimensional accuracy would be too great, stalling
`and lowering the production of gasket 24, the production
`costs would soar significantly, and too much a burden would
`be placed on the inspection process, so the actual construction
`of a production line could he difficult.
`[0069] As such, in order to control such a highly accurate
`maximum outer diameter of gasket 24, in addition to improv(cid:173)
`ing the dimensional accuracy in the production process for
`both gasket 24 and barrel 20 or strictly applying the inspec(cid:173)
`tion process for dimensional accuracy, gasket24 is preferably
`one that is nol surface-treated with a resin film. This is
`because the strncture of the gasket itself can be designed into
`a simple shape, and the production process of the gasket itself
`can be simplified by doing so. That is, in syringe 10 of the
`present embodiment, the highly accurate maximum outer
`diameter of gasket 24 is preferably controlled by improving
`the dimensional accuracy in the production process for both
`gasket 24 and barrel 20 or strictly applying the inspection
`process for dimensional accuracy in addition to using gasket
`24 that is not surface-treated with a resin film.
`
`<Plunger>
`
`[0070] Additionally, plunger 25 only needs to be equipped
`with a strength that can withstand the bending and pressing
`force required to make gasket 24 slide inside barrel 20, and
`may be made of, for example, a hard plastic material such as
`polyethylene or polypropylene, but as long as the material is
`permitted to be used as a medical apparatus or has been
`conventionally used as a material for fom1ing the gasket of a
`syringe, there is no particular limitation.
`
`<Cap Member>
`
`[0071] Cap member 26 lightly adheres lo tip opening 21 of
`barrel 20, air-tight seals tip opening 21, and may be made
`using an elastic body or hard resin such as butyl rnbber,
`high-density polyethylene, polypropylene, polystyrene, or
`polystyrene terephthalate, but as long as the material is per(cid:173)
`mitted to be used as a medical apparatus or has been conven(cid:173)
`tionally used as a material for fom1ing the gasket of a syringe,
`there is no particular limitation. In the present embodiment, a
`female thread portion for threading thread portion 23 formed
`on the outer peripheral surface of tip opening 21 of barrel 20
`is forn1ed on the inner peripheral surface of cap member 26.
`
`<Silicone Film>
`
`[0072] Silicone film 28 formed by spraying a silicone oil
`having a predetermined kinematic viscosity as described
`below is provided on the inner peripheral surface of barrel 20.
`Since the silicone oil applied to barrel 20 only needs to satisfy
`the predetern1inedapplication amount per unit area, the thick-
`
`Regeneron Exhibit 1020.007
`
`

`

`US 2011/0276005 Al
`
`Nov. 10, 2011
`
`5
`
`ness of silicone film 28 does not necessarily need to be even
`across the entirety of barrel 20.
`
`(Silicone Oil)
`
`[0073] While the silicone oil fanning silicone film 28
`applied lo the inner peripheral surface of the barrel is basi(cid:173)
`cally polydimethylsiloxane, a polydimethylsiloxane with a
`side chain or terminal substitution within a range not impair(cid:173)
`ing lubricity may be used. Specifically, for example, polym(cid:173)
`ethylphenylsiloxane and polymethylhydrogen siloxane may
`be mentioned. Various additives may be added to the silicone
`oil as necessary.
`[0074] The above-described silicone oil preferably has a
`kinematic viscosity of 500 to 100,000 cSt at 25° C.. and in
`particular, one having a kinematic viscosity of 1,000 to
`30,000 cSt is more preferably used. When the kinematic
`viscosity is at least 500 cSt, the silicone oil is appropriately
`maintained at the spraying site on the inner peripheral surface
`of barrel 20 without running from the inner peripheral surface
`ofbarrel 20, so the slidability between barrel 20 and gasket 24
`can be sufficiently ensured with a small amount of applica(cid:173)
`tion. Moreover, when the kinematic viscosity is at most 100,
`000 cSt, application to the im1er peripheral surface of barrel
`20 by spraying is possible.
`
`(111-ickness of Silicone Film)
`
`[ 0075] The application ammmt of the silicone oil constitut(cid:173)
`ing silicone film 28 is preferably 5 to 50 µg, and particularly
`preferably 10 to 30 µg, per 1 cm2of the inner peripheral
`surface of barrel 20.
`[ UU76 J If the application amount of the silicone oil is at least
`5 µg per 1 cnlof the inner peripheral surface of the barrel, a
`sufficient slidability between barrel 20 and gasket 24 can be
`ensured. Moreover, if the application amount is at most 50 µg
`per 1 cm2ofthe inner peripheral surface of the barrel, even if
`the silicone oil is niixed into the drug when loading drug 27,
`the amount of contamination can be kept extremely small.
`Further, as long as observation is perfonned by the naked eye,
`glare will no! be detected on the inner peripheral surface of
`barrel 20.
`
`(Method for Forming Silicone Film)
`
`[0077] Silicone film 28 is formed by evenly spraying a
`silicone oil having the above-