(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`7 March 2013 (07.03.2013)
`
`WIPOI PCT
`
`\9
`
`(10) International Publication Number
`
`WO 2013/033453 A2
`
`CLARK, Bradley [US/US]; 100 Abbott Park Road, Ab-
`bott Park,
`Illinois 60064-6008 (US). HEMINGWAY,
`Jeremy L. [US/US]; 1263 Avon Drive, Cincinnati, Ohio
`45223 (US). ZHOU, Ji [US/US]; 270 Cambridge Drive,
`Grayslake, Illinois 60030 (US).
`
`Agents: MUELLER, Lisa V. et al.; MICHAEL BEST &
`FRIEDRICH LLP, 180 N. Stetson Avenue, Suite 2000,
`Chicago, Illinois 60601 (US).
`
`Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
`BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PII, PL, PT, QA, RO, RS, RU, RW,
`SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM,
`ZW.
`
`(51)
`
`International Patent Classification:
`A61M 5/145 (2006.01)
`A61M 5/315 (2006.01)
`
`(21)
`
`International Application Number:
`
`PCT/USZO]2/053218
`
`(22)
`
`International Filing Date:
`
`30 August 2012 (30.08.2012)
`
`(74)
`
`Filing Language:
`
`Publication Language:
`
`English
`
`English
`
`(81)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`(75)
`
`Priority Data:
`61/529,718
`61/562,275
`61/684,015
`
`31 August 2011 (31.08.2011)
`21 November 2011 (21.11.2011)
`16 August 2012 (16.08.2012)
`
`US
`US
`US
`
`Applicant for all designated States except US): ABBOTT
`LABORATORIES [US/US]; 100 Abbott Park Road, Ab-
`bott Park, Illinois 60064-6008 (US).
`
`Inventors; and
`Inventors/Applicants flor US only): GIBLER, Martin J.
`[US/US]; 5854 Old Forest Lane, West Chester, Ohio
`45069 (US). BENNETT, Mark A. [US/US]; 9788 Car-
`riage Run Court, Loveland, Ohio 45150 (US). WEABER,
`Kenneth R. [US/US]; 431 Garfield Avenue, Milford, Ohio
`45150 (US). HOGUE, Kenneth E. [US/US]; 6123 Far-
`rington Road, Apt. F2, Chapel Hill, North Carolina 27517
`(US). GILLUM, Christoph L.
`[US/US]; 5143 Spring
`Mountain Lane, Middletown, Ohio 45044 (US). HAR-
`RELL, Patrick A. [US/US]; 8120 Walcot Lane, Apt. E,
`Cincinnati, Ohio 45249 (US). PARROTT, David A.
`[US/US]; 1633 Pullan Avenue, Cincinnati, Ohio 45223
`(US). MACKEY, Sean E. [US/US]; 744 Walton Lane,
`Grayslake, Illinois 60030 (US). CONJEEVARAM, Raj
`[US/US]; 100 Abbott Park Road, Abbott Park, Illinois
`60064-6008 (US). REBNE, Thomas [US/US]; 100 Abbott
`Park Road, Abbott Park,
`Illinois 60064-6008 (US).
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG).
`Published:
`
`without international search report and to be republished
`upon receipt ofthat report (Rule 48.2(g))
`
`(54) Title: SEALING ARRANGEMENT FOR SYRINGE
`
`(57) Abstract: A syringe containing a high water content product and for use in a drug infusion system is provided. The syringe in -
`c1udes a plunger carrying front and rear o—rings made of a diene rubber compound such as chlorobutyl rubber or bromobutyl rubber
`to impart very low gas permeability characteristics to the o-rings. The plunger may be molded as a single part or in two parts. If mol -
`ded as one part with radially—engaging mold portions, the seal glands in the plunger may include parting lines from the mold. 1f mol—
`ded as two parts with axially-engaging mold portions, the front seal gland may include a sealing surface and under cut that has no
`parting line. The o—rings may be surface treated with a lubricant to improve sealing Where the molding process gives rise to parting
`lines in the seal glands, which can result in leak paths on the ID of the o-rings. The o-rings provide a gas-tight sliding seal that can
`Withstand temperature changes from —25C to 40C and the resulting thermal expansion and contraction of the high water content
`product.
`
`
`
`W02013/033453A2|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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`

`

`WO 2013/033453
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`PCT/US2012/053218
`
`SEALING ARRANGEMENT FOR SYRINGE
`
`[0001]
`
`This application claims priority to U.S. Provisional Application No. 61/529,718 filed
`
`August 31, 2011, to U.S. Provisional Application No. 61/562,275 filed November 21, 2011, and
`
`to U.S. Provisional Application No. 61/684,015 filed August 16, 2012, the contents of all of the
`
`foregoing provisional applications being incorporated herein by reference.
`
`BACKGROUND
`
`[0002]
`
`The present invention relates to a sealing arrangement for the plunger of a syringe
`
`used in a drug infusion system.
`
`SUMMARY
`
`[0003]
`
`The invention provides a syringe for use in a drug infusion system, the syringe
`
`comprising: a barrel having a front end, a rear end, and a cylindrical wall defining an outer
`
`surface and an inner surface, the rear end being open, and the front end including an orifice; a
`
`plunger within the barrel, the plunger including a contact surface at a front end of the plunger,
`
`and a front seal gland extending circumferentially around the plunger; a front o—ring made of a
`
`diene rubber compound, positioned in the front seal gland, and creating a gas—tight seal between
`
`the inner surface of the barrel and the plunger; wherein a product chamber is defined between the
`
`inner surface of the barrel, the front o—ring, and contact surface; wherein the product chamber is
`
`adapted to contain a product to be dispensed by the syringe; wherein actuation of the plunger
`
`within the barrel decreases the volume of the product chamber to dispense the product through
`
`the orifice; and wherein the front o—Iing is sized to maintain the gas tight seal through a
`
`temperature range of -25°C to 40°C.
`
`[0004]
`
`In some embodiments, the front o—rin g is surface treated with a lubricant to ensure a
`
`gas—tight seal between the front o—ring and the front seal gland. In some embodiments, the
`
`syringe further comprises: a rear seal gland axially spaced to the rear of the front seal gland and
`
`extending circumferentially around the plunger; a rear o—ring made of a diene rubber compound;
`
`wherein the rear o—ring is positioned in the rear seal gland; and wherein the rear o—ring creates a
`
`gas—tight seal between the inner surface of the barrel and the plunger. In some embodiments, a
`
`front end of the plunger defines a head that includes the contact surface; wherein an outer
`
`

`

`WO 2013/033453
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`PCT/US2012/053218
`
`diameter of the head is slightly smaller than an inner diameter of the barrel such that the head fits
`
`within the barrel with close tolerances; wherein a rear end of the plunger includes an integrally-
`
`formed molded ring having a maximum outer diameter that is slightly less than an inner diameter
`
`of the barrel such that the integrally—formed molded ring fits within the barrel with close
`
`tolerances; and wherein the head and integrally—formed molded ring resist tipping of the plunger
`
`within the barrel. In some embodiments, the front o—ring is sized to maintain the gas tight seal
`
`through a temperature range of —20°C to 40°C. In some embodiments, the plunger is molded as a
`
`single piece; wherein the front seal gland includes a parting line arising from the molding
`
`process; wherein the seal between the front o—rin g and the front seal gland includes a leak path
`
`arising from the parting line; and wherein the front o-ring is surface treated with a lubricant to
`
`gas-tightly seal the leak path. In some embodiments, the plunger is molded as a front portion and
`
`a rear portion; wherein the front portion is molded with axially-engagin g mold portions to form a
`
`portion of the front seal gland with no parting lines; and wherein the rear portion is molded with
`
`radially—engaging mold portions to form a portion of the front seal gland with parting lines; and
`
`wherein the front o—ring is received within in the front seal gland with no leak paths between the
`
`o—ring and the portion of the front seal gland having no parting lines.
`
`[0005]
`
`In some embodiments, the front seal gland includes a rear—facin g undercut surface in
`
`front of the o—ring; wherein a pocket is defined between the o—ring and the rear—facing undercut
`
`surface of the front seal gland; and wherein the plunger includes a venting slot in the rear—facing
`
`undercut surface, the venting slot communicating between the pocket and the product chamber
`
`such that air in the pocket is evacuated through the venting slot when a vacuum is applied to the
`
`product chamber. In some embodiments, the pocket is an annular pocket extending around the
`
`entire circumference of the front seal gland; wherein the venting slot includes two diametrically
`
`opposed venting slots communicating with the annular pocket. In some embodiments, the
`
`syringe further comprises a deflectable tab in the plunger and an insert that deflects the
`
`deflectable tab radially outwardly; wherein the deflectable tab, when deflected outwardly by the
`
`insert, bears against the inner surface of the barrel to prevent tipping of the plunger in the barrel.
`
`In some embodiments, the deflectable tab includes a plurality of deflectable tabs; and wherein
`
`the insert includes a ring-shaped insert the expands all deflectable tabs radially outwardly. In
`
`some embodiments, the plunger further includes a flexible wiper that engages the inner surface
`
`of the barrel to prevent tipping of the plunger in the barrel. In some embodiments, the flexible
`
`

`

`WO 2013/033453
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`wiper is integrally formed with the plunger. In some embodiments, the plunger further includes a
`
`circumferential slot; and wherein the wiper is inserted into the circumferential slot and extends
`
`radially outwardly into contact with the barrel inner surface.
`
`[0006]
`
`The invention also provides a method for storing and dispensing a product having a
`
`high content of water, the method comprising: providing a syringe barrel having a front end, a
`
`rear end, and a cylindrical wall defining an outer surface and an inner surface, the rear end being
`
`open, and the front end including an orifice; providing a plunger having a contact surface at a
`
`front end of the plunger, and a front seal gland extending circumferentially around the plunger;
`
`forming a front o—r‘ing of a diene rubber compound; positioning the front o—r‘ing in the front seal
`
`gland to define a plunger and front o—ring assembly; inserting the plunger and front o—ring
`
`assembly into the barrel such that the front o—ring is deflected between the inner surface of the
`
`barrel and the plunger to create a sliding gas-tight seal between the inner surface of the barrel
`
`and the plunger; defining a product chamber between the inner surface of the barrel, the front 0—
`
`ring, and contact surface; filling the product chamber with the product having high water
`
`content; freezing the product—filled syringe at a temperature at least as low as —20°C; in response
`
`to freezing the product—filled syringe, changing the phase of the water content of the product to
`
`ice, resulting in expansion of the product within the syringe; in response to expansion of the
`
`product within the syringe, displacing the plunger within the barrel to expand the volume of the
`
`product chamber to accommodate the product expansion, while maintaining the gas—tight seal
`
`between the front o-ring and the contact surface; storing the frozen product-filled syringe until an
`
`approximate time of use; at the approximate time of use, thawing the frozen product—filled
`
`syringe to a temperature of at least 2°C to 40°C; in response to thawing of the frozen product—
`
`filed syringe, changing the phase of the water content of the water to liquid; in response to
`
`changing the phase of the water content to liquid, contracting the product; in response to
`
`contracting the product, developing vacuum bubbles within the product, thereby giving rise to a
`
`vacuum force on the plunger that is the product of the vacuum pressure and a surface area of the
`
`contact surface; in response to the vacuum pressure, moving the plunger within the barrel to
`
`reduce the volume of the product chamber to accommodate a decreased volume occupied by the
`
`product while maintaining the gas-tight seal; and actuating the plunger to decrease the volume of
`
`the product chamber and thereby dispense the thawed product from the syringe through the
`
`orifice.
`
`

`

`WO 2013/033453
`
`PCT/US2012/053218
`
`[0007]
`
`In some embodiments, the method further comprises the step of surface treating the
`
`front o—rin g with a lubricant to ensure a gas—tight seal between the front o-ring and the front seal
`
`gland. In some embodiments, the method further comprises: providing a rear seal gland in the
`
`plunger, axially spaced to the rear of the front seal gland and extending circumferentially around
`
`the plunger; providing a rear o—ring made of a diene rubber compound; positioning the rear 0—
`
`ring in the rear seal gland; and creating a sliding gas—tight seal between the inner surface of the
`
`barrel and the plunger. In some embodiments, the method further comprises: defining a head
`
`with a front end of the plunger, the head including the contact surface, and an outer diameter of
`
`the head being slightly smaller than an inner diameter of the barrel such that the head fits within
`
`the barrel with close tolerances; forming in a rear end of the plunger an integrally—formed
`
`molded ring having a maximum outer diameter that is slightly less than an inner diameter of the
`
`barrel such that the integrally—formed molded ring fits within the barrel with close tolerances;
`
`and resisting tipping of the plunger within the barrel with the head and integrally—formed molded
`
`ring during movement of the plunger within the barrel. In some embodiments, the step of
`
`freezing the product—filled syringe includes freezing the product—filled syringe at a temperature of
`
`about —25°C while maintaining the gas—tight seal; and wherein the step of thawing the frozen
`
`product—filled syringe includes thawing the product—filled syringe to temperatures of about 40°C
`
`while maintaining the gas—tight seal. In some embodiments, providing a plunger includes
`
`molding the plunger as a single piece with a parting line in the front seal gland arising from the
`
`molding process; the method further comprising the step of surface treating the front o-ring with
`
`a lubricant to gas—tightly seal the front o—ring with respect to the parting line in the front seal
`
`gland. In some embodiments, providing a plunger includes separately molding a front portion of
`
`the plunger and a rear portion of the plunger; wherein molding the front portion includes using
`
`axially—engagin g mold portions to form a portion of the front seal gland with no parting lines;
`
`wherein molding the rear portion includes using radially—engaging mold portions to form a
`
`portion of the front seal gland with parting lines; the step of providing a plunger further
`
`comprising snap—fitting the front portion of the plunger and rear portion of the plunger together
`
`to define the front seal gland; wherein the front seal gland includes no leak paths between the o-
`
`ring and the portion of the front seal gland provided by the front portion of the plunger.
`
`[0008]
`
`The invention also provides a syringe for use in a drug infusion system, the syringe
`
`comprising: a barrel having a front end, a rear end, and a cylindrical wall defining an outer
`
`

`

`WO 2013/033453
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`PCT/US2012/053218
`
`surface and an inner surface, the rear end being open, and the front end including an orifice; a
`
`plunger within the barrel, the plunger including a front end and defining an external seal surface;
`
`an overmolded seal constructed of one of a thermoplastic rubber and a thermoplastic elastomer
`
`covering the front end of the plunger and the external seal surface, the overmolded seal covering
`
`the front end of the plunger to define a contact surface over the front end of the plunger, and a
`
`radially—extending wiper that creates a gas—tight seal between the inner surface of the barrel and
`
`the plunger; wherein a product chamber is defined between the inner surface of the barrel, the
`
`radial wiper of the overmolded seal, and the contact surface; wherein the product chamber is
`
`adapted to contain a product to be dispensed by the syringe; wherein actuation of the plunger
`
`within the barrel decreases the volume of the product chamber to dispense the product through
`
`the orifice; and wherein the radial wiper is sized to maintain the gas tight seal through a
`
`temperature range of -25°C to 40°C.
`
`[0009]
`
`In some embodiments, the overmolded seal is molded over the front end of the
`
`plunger to ensure a gas—tight seal between the overmolded seal and the external seal surface of
`
`the plunger. In some embodiments, the plunger includes a rear circumferential seal gland axially
`
`spaced to the rear of the overmolded seal, the syringe further comprising: a rear o—ring made of a
`
`diene rubber compound; wherein the rear o—rin g is positioned in the rear seal gland; and wherein
`
`the rear o—ring creates a gas—tight seal between the inner surface of the barrel and the plunger. In
`
`some embodiments, a rear end of the plunger includes an integrally—formed molded ring having a
`
`maximum outer diameter that is slightly less than an inner diameter of the barrel such that the
`
`integrally—formed molded ring fits within the barrel with close tolerances; and wherein the
`
`radially—extending wiper and the integrally—formed molded ring resist tipping of the plunger
`
`within the barrel. In some embodiments, the radial wiper is sized to maintain the gas tight seal
`
`through a temperature range of —20°C to 40°C. In some embodiments, the radial wiper is a front
`
`radial wiper, the overmolded seal further including a rear radial wiper spaced axially from the
`
`front radial wiper; wherein the rear radially—extending wiper creates a gas—tight seal between the
`
`inner surface of the barrel and the plunger.
`
`[0010]
`
`In some embodiments, the syringe further comprises a deflectable tab in the plunger
`
`and an insert that deflects the deflectable tab radially outwardly; wherein the deflectable tab,
`
`when deflected outwardly by the insert, bears against the inner surface of the barrel to prevent
`
`

`

`WO 2013/033453
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`PCT/US2012/053218
`
`tipping of the plunger in the barrel. In some embodiments, the deflectable tab includes a plurality
`
`of deflectable tabs; and wherein the insert includes a ring—shaped insert the expands all
`
`deflectable tabs radially outwardly. In some embodiments, the plunger further includes a second
`
`flexible wiper that is not part of the overmolded seal, the second flexible wiper engaging the
`
`inner surface of the barrel to prevent tipping of the plunger in the barrel. In some embodiments,
`
`the flexible wiper is integrally formed with the plunger. In some embodiments, the plunger
`
`further includes a circumferential slot; and wherein the wiper is inserted into the circumferential
`
`slot and extends radially outwardly into contact with the barrel inner surface.
`
`[0011]
`
`Other aspects of the invention will become apparent by consideration of the detailed
`
`description and accompanying drawings.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0012]
`
`Fig. 1 illustrates an exemplary drug infusion system in which the present invention
`
`may be used.
`
`[0013]
`
`Fig. 2 is an exploded view of a syringe for use in the system illustrated in Fig. l, the
`
`syringe including a barrel, a pair of o—rings, and a single—piece plunger according to a first
`
`embodiment of the invention.
`
`[0014]
`
`Fig. 3 is an enlarged perspective view of the single—piece plunger according to the
`
`first embodiment.
`
`[0015]
`
`Fig. 4 is a cross—section view of the syringe including the single—piece plunger
`
`according to the first embodiment.
`
`[0016]
`
`Fig. 5 is a schematic illustration of the molding process for the single-piece plunger
`
`according to the first embodiment.
`
`[0017]
`
`Fig. 6 is an exploded view of a syringe for use in the system illustrated in Fig. l, the
`
`syringe including a barrel, a pair of o—rings, and a two—piece plunger according to a second
`
`embodiment of the invention.
`
`[0018]
`
`Fig. 7 is an enlarged exploded view of the two—piece plunger according to the second
`
`

`

`WO 2013/033453
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`PCT/US2012/053218
`
`embodiment.
`
`[0019]
`
`Fig. 8 is an enlarged exploded View of the two-piece plunger according to the second
`
`embodiment, taken from a perspective different from that of Fig. 7.
`
`[0020]
`
`Fig. 9 is a cross-section view of the syringe including the two—piece plunger
`
`according to the second embodiment.
`
`[0021]
`
`Fig. l0 is a schematic illustration of the molding process for the front portion of the
`
`two—piece plunger according to the second embodiment.
`
`[0022]
`
`Fig. 11 is a schematic illustration of the molding process for the rear portion of the
`
`two—piece plunger according to the second embodiment.
`
`[0023]
`
`Fig. 12 is an exploded View of a syringe for use in the system illustrated in Fig. l, the
`
`syringe including a barrel, an o—ring, an overmolded seal, and a plunger according to a third
`
`embodiment of the invention.
`
`[0024]
`
`Fig. 13 is an enlarged perspective View of the plunger and seal assembly of Fig. 12.
`
`[0025]
`
`Fig. 14 is an enlarged perspective View of the plunger and seal assembly of Fig. 12
`
`from a perspective different from Fig. 13.
`
`[0026]
`
`Fig. 15 is a cross—section View of the syringe including the plunger and seal assembly
`
`of Fig. 12.
`
`[0027]
`
`Fig. 16 is an exploded View of a syringe for use in the system illustrated in Fig. l, the
`
`syringe including a barrel, an overmolded seal, and a plunger according to a fourth embodiment
`
`of the invention.
`
`[0028]
`
`Fig. 17 is an enlarged perspective View of the plunger of Fig. 16.
`
`[0029]
`
`Fig. 18 is an enlarged perspective view of the plunger of Fig. 16 from a perspective
`
`different from Fig. 17.
`
`[0030]
`
`Fig. 19 is a cross-section View of the syringe including the plunger and seal assembly
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`PCT/US2012/053218
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`of Fig. 16.
`
`[0031]
`
`Fig. 20 is a perspective view of another embodiment of the plunger, including venting
`
`slots for the front o-ring.
`
`[0032]
`
`Fig. 21 is an enlarged side section view of the front gland of the plunger illustrated in
`
`Fig. 20, with a vacuum being pulled in the syringe barrel.
`
`[0033]
`
`Fig. 22 illustrates another alternative plunger configuration.
`
`[0034]
`
`Fig. 23 is a cross sectional view of the plunger of Fig. 22 in the barrel of the syringe.
`
`[0035]
`
`Fig. 24 illustrates another alternative plunger configuration.
`
`[0036]
`
`Fig. 25 is a cross sectional view of the plunger of Fig. 24 in the barrel of the syringe.
`
`[0037]
`
`Fig. 26 illustrates another alternative plunger configuration.
`
`[0038]
`
`Fig. 27 is a cross sectional view of the plunger of Fig. 26 in the barrel of the syringe.
`
`DETAILED DESCRIPTION
`
`[0039]
`
`Before any embodiments of the invention are eXplained in detail, it is to be
`
`understood that the invention is not limited in its application to the details of construction and the
`
`arrangement of components set forth in the following description or illustrated in the following
`
`drawings. The invention is capable of other embodiments and of being practiced or of being
`
`carried out in various ways.
`
`[0040]
`
`Fig. 1 illustrates a drug infusion system 10 that includes a pump 15, a syringe 20, and
`
`a delivery tube 25 that can be inserted into a patient’ s small intestine. The pump 15 actuates the
`
`syringe 20, which displaces product from the syringe 20 into the patient through the tube 25. In
`
`many drug infusion systems, the pump actuates the syringe in a slow, steady manner, such that
`
`the patient receives the product at an optimal rate over an extended period. The pump can be
`
`programmed to deliver the product at a desired rate or according to a desired profile, and the
`
`program can be modified in response to the patient’s reaction to the product.
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`WO 2013/033453
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`PCT/US2012/053218
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`[0041]
`
`An example of a pump that is currently used for drug infusion systems is the Cane
`
`Crono pump. Information regarding the Cane Crono pump is available at the company’s website
`
`www.microjetit. The Cane Crono pump is cited as merely one example of a pump which can be
`
`used in a drug infusion system as contemplated by the present invention. The findings and
`
`leamings of the present invention can be applied to drug infusion systems utilizing other pumps;
`
`the present invention should not be limited to the specific system illustrated or described. Indeed,
`
`the invention involves advances in syringe design (and, more specifically, the design of the
`
`plunger and sealing arrangements in the syringe) and should not be viewed as limited to the
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`application of a drug infusion system. A drug infusion system is one environment in which such
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`syringe design may be used and is provided here as an example only.
`
`[0042]
`
`One example of a product administered through a drug infusion system is the
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`Levodopa Carbidopa Intestinal Gel (LCIG) sold under the trademark DUODOPA by Abbott
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`Laboratories. LCIG is used for treating patients with Advanced Parkinson’s Disease. As the
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`name implies, LCIG is a gel. The gel is about ninety—six per cent (96%) water and therefore
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`behaves much as water behaves during phase changes. Other formulations of LCIG may include
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`a water content of about 94—95%, about 94.58%, or a water content of at least 84%.
`
`[0043]
`
`LCIG is typically filled into a syringe post—manufacture, and the syringe and its
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`contents are frozen and stored. Depending on its specific composition, the LCIG may have a
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`freezing temperature of about —2°C (28.4OF). To ensure the LCIG is solidly frozen, it may be
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`exposed to and stored at temperatures well below the freezing point. The syringes for LCIG
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`product must be gas tight during a two-year storage period and during any shipping of the
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`product. The storage and shipping environment may be maintained, for example, at about
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`negative twenty degrees Celsius (—20°C) (—4°F) to ensure the product is solidly frozen.
`
`[0044]
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`Materials of construction should be compatible with LCIG during shelf life. The
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`syringe should withstand stress during shipping.
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`[0045]
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`The LCIG must be free from leak paths (i.e., it must be gas tight) during storage,
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`shipping, thawing, and administering. Thawing may be done in a refrigerator at about two
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`degrees Celsius to eight degrees Celsius (2 to 8°C) (35.6OF to 46.4OF), for example, prior to
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`being administered to a patient through the drug infusion system. To meet the expected freezing,
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`shipping, thawing, and administering environments, the syringes should accommodate any
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`temperatures and ranges of temperatures between negative twenty—five and forty degrees Celsius
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`(-25°C to 40°C) (-l3°F to 104°F) while maintaining seal integrity (i.e., a gas—tight seal that is
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`free from leak paths). Within this range, the syringes should remain gas tight during a phase
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`change of the gel from liquid to solid and from solid to liquid, which may occur, for example,
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`around —2°C (28.4°F). Expected temperature ranges for the syringes include —20°C to 2°C (—4°F
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`to 35.6°F), —20°C to 8°C (—4°F to 46.4°F), —20°C to 40°C (—4°F to 104°F), and —25°C to 40°C (—
`
`13°F to 104°F). The syringes should remain gas tight without regard to the rate of thawing.
`
`[0046]
`
`Because of the high water content, the product expands as it freezes, and contracts as
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`it thaws. When a filled syringe is placed at —20°C, the gel expands about nine per cent (~9%)
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`primarily in the axial direction & pushes the plunger outwards. The stability of the product can
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`be compromised upon mixing with air, the addition of air to the gel may result in a decrease in
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`delivery accuracy of the product to the patient, and there is no provision for the patient or care
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`giver to remove air from the product prior to administration. Consequently, the syringe must
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`accommodate expansion and contraction of the product without permitting air to permeate
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`through the various seals within the syringe.
`
`[0047]
`
`During the freeze—thaw cycle of a syringe with a conventional, known plunger sealing
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`arrangement, it was observed that: there is a difference in thermal contraction between
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`thermoplastic material, such as polypropylene, and rubber components; there are inadequate
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`dimensions to provide sufficient sealing between the plunger and the syringe barrel over a wide
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`temperature range (-25 to 40°C); and the plunger can tilt/cock/rack during freezing or thawing
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`reducing seal integrity. The result of these conditions leads to ingression of air into the gel during
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`the thaw cycle.
`
`[0048]
`
`With reference to Fig. 2, the syringe 20 includes a front end 30 and a rear end 35 and
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`defines a longitudinal axis 40 extending between the front and rear ends 30, 35. Throughout this
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`specification, the terms “front” and “forward” refer to portions, elements, and directions close to
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`or in the direction of the front end 30 of the syringe 20, and the terms “rear” and “rearward” refer
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`to portions, elements, and directions close to or in the direction of the rear end 35 of the syringe
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`20. The terms “axial” and “axially” mean in a direction parallel to the longitudinal axis 40 of the
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`syringe 20, and the terms “radial” and “radially” mean in a direction perpendicular to the
`
`longitudinal axis 40.
`
`[0049]
`
`The syringe 20 includes a barrel 45, a front o-ring 50, a rear o—ring 55, and a plunger
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`110 (which may also be referred to as a piston). The barrel 45 is made of thermoplastic material,
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`such as polypropylene, and includes a front end 60 and a rear end 65. The barrel 45 is generally
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`cylindrical, having an outer surface 70 and an inner surface 75 (Fig. 4). The inner surface 75 of
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`the barrel 45 defines a barrel diameter 80 (Fig. 4). An orifice 85 is formed in the front end 60.
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`The orifice 85 communicates with the tube 25. The barrel 45 may include a flange for mounting
`
`the barrel 45 in the pump 15.
`
`[0050]
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`With reference again to Fig. 2, the front and rear o—rings 50, 55 are substantially
`
`identical. Each has an inner diameter (or “ID”) 90, an outer diameter (or “‘OD”) 95, and a
`
`thickness 97. The cross-sectional shape of the o-rings 50, 55 is circular, and the term “thickness”
`
`refers to the diameter of the cross—sectional shape of the o—ring when it is undeflected and at rest.
`
`[0051]
`
`The o—rings 50, 55 are constructed of an appropriate formulation of diene rubber. As
`
`used herein, the phrase “diene rubber” includes butyl rubber, halogenated butyl rubber (such as
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`chlorobutyl rubber and bromobutyl rubber), polybutadiene rubber, styrene—butadiene copolymer,
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`synthetic polyisoprene, natural polyisoprene, styrene—isoprene copolymer, styrene—isoprene—
`
`butadiene terpolymer, solution—polymerized styrene—butadiene rubber, and emulsion—polymerized
`
`styrene—butadiene rubber, ethylene—propylene—diene rubber or combinations thereof. Although
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`any diene rubber compound may be employed, two particularly suitable diene rubber compounds
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`for use in pharmaceutical applications are chlorobutyl rubber and bromobutyl rubber, either of
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`which may be used in the present invention. Bromobutyl or chlorobutyl rubber o—rin gs have
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`significantly lower gas permeability (about 400X lower) than silicone.
`
`[0052]
`
`Silicone rubber is an appropriate material o—rings in gas—tight seal applications in
`
`which there are no large pressure gradients across the seal. A potential example of an appropriate
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`application for a silicone o—ring seal would be an environment in which the syringe and its
`
`contents are not frozen and then thawed. The present application involves a potentially large
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`pressure gradient arising from vacuum developing within the LCIG during thawing, as will be
`
`discussed in detail below. As a result, silicone rubber would provide inadequate gas
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`imperrneability for the present application.
`
`[0053]
`
`The phrases “gas tight,” “gas-tightly,” and variations of these phrases, when used in
`
`reference to a seal in the present disclosure, refer to the seal precluding the movement of air or
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`other gases from one side of the seal to the other side of the seal in the presence of pressure
`
`gradients across the seal of a magnitude experienced during thawing of the product within the
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`syringe as discussed herein, w