liufn CORPORATE
`l!W TRANSLATIONS
`
`Cmporate Translations, Inc.
`77 llartland St. 1 East Hartford, CT 06108
`Tel: 860-727-6000 I Fax: 860-727-6001
`www.c01pb:ansinc.com
`
`CERTIFICATION
`
`Tllis is to certify that Cotporate Translations, Inc. has performed a hue translation of the patent described
`below:
`
`Requesting Company:
`
`Sandoz Inc.
`
`Source Filename:
`
`Invention Title:
`
`Publication Date:
`
`Patent Number:
`
`Application Date:
`
`Application Number:
`
`Source Language:
`
`Target LaUJ?:uage /Country:
`
`JP2002177364A.pdf
`
`DRUG CONTAINER
`
`25 Jruie 2002
`
`No. 2002-177364
`,(P2002-177364A)
`
`19 December 2000
`
`2000-386029
`
`Japanese
`
`English/US
`
`Corporate Translations Job Number:
`
`SN100825
`
`This document was translated by a transhtor who is bilingual in Japanese and English.
`
`"Subscribed and sworn to before me
`
`Maty Gawlicki
`Pmidmt
`C01porate Translations, Inc.
`
`Date: _ ___ -d-T,anccu.,a~t:yl--22-"'1,'-'2"'0'-"124 _ __ _
`
`Driuen by Definition'
`
`Notary Publit
`
`~ '""'~"'""~'
`ILDA BRUI<O
`y Pu·b.lic-Connecticut
`Commission Expires
`
`Date Conunission Expires: ~~~;;;;-~-~-~)"~l?""~c-.3§'l§-§b§'-;:;;-;;,;-;.;;;:;;==""
`
`Sandoz Exhibit 1004 Page 1
`
`

`

`(19) Japan Patent Office (JP)
`
`(12) UNEXAMINED PATENT
`GAZETTE (A)
`
`ID Symbol
`
`
`
`(51) Int. Cl.7
`A61J
`A61M
`
`
`
`
`1/05
`5/178
`5/31
`
`
`
`FI
`A61M
`A61J
`
`
`A61M
`
`(11) Unexamined Patent Application
`No. 2002-177364
`(P2002–177364A)
`(43) Published June 25, 2002
`Topic Codes (for reference)
`4C066
`
`5/31
`1/00
`
`
`5/18
`Request for Examination: Not yet submitted
`Number of Claims: 12 OL (8 pages total)
`
`311
`313
`315
`
`
`
`
`(21) Application No.:
`
`
`(22) Application Date:
`
`No. 2002-177364 (P2002–
`177364A)
`
`December 19, 2000
`
`
`
`(54) TITLE OF THE INVENTION: DRUG
`CONTAINER
`
`(57) ABSTRACT
`PROBLEM TO BE SOLVED: To provide a prefilled
`syringe having little adsorption of a drug.
`SOLUTION: The problem is solved by a drug container
`having a Parylene layer, and a ratio (b/a) (maintenance
`ratio) of 90% or greater between (a) the substantial
`amount of the drug in the drug liquid at the time when
`the drug liquid is charged and (b) the substantial amount
`of the drug in the drug liquid at the time when the drug
`liquid is preserved packed and sealed with a lid material
`for six months at 40°C × 100.
`
`
`
`(71) Applicant: 000109543
`
`TERUMO CORPORATION
`
`2-44-1 Hatagaya, Shibuya-ku, Tokyo
`(72) Inventor: Ken’ichi SHIMURA
`
`c/o Terumo Corporation
`
`1727-1 Tsuiji-arai, Showa-cho,
`Nakakoma-gun, Yamanashi
`(72) Inventor: Shin’ichi MIZUNO
`
`c/o Terumo Corporation
`
`1727-1 Tsuiji-arai, Showa-cho,
`Nakakoma-gun, Yamanashi
`(72) Inventor: Akira MOCHIZUKI
`
`c/o Terumo Corporation
`
`1500 Inokuchi, Nakai-machi,
`Ashigarikami-gun, Kanagawa
`F topics (for reference)
`4C066 AA09 BB01 CC01
`DD08 DD12 EE14 FF05
`GG01 GG11
`
`
`
`
`
`
`Fig. 1
`
`
`
`Sandoz Exhibit 1004 Page 2
`
`

`

`
`
` CLAIMS
`Claim 1. A drug container having a container made of
`synthetic resin for receiving a liquid containing a
`pharmacologically effective substance and a
`lid
`material for sealing an opening of the container,
`characterized in that at least a portion of a surface
`contacting the liquid is covered with a Parylene layer
`and configured so as to bring the container into contact
`with the lid material through the Parylene layer, and a
`ratio (b/a) (maintenance ratio) of 90% or greater
`between (a) the substantial amount of the substance in
`the liquid at the time when the container is charged with
`the liquid and (b) the substantial amount of the
`substance in the liquid at the time when the liquid is
`preserved packed in the container and sealed with the
`lid material for six months at 40°C × 100.
`Claim 2. The drug container according to claim 1,
`wherein the Parylene layer covers all of the surface
`whereon the lid material is to be formed, and the
`preservation in (b) occurs with the liquid in contact
`with the lid material.
`Claim 3. The drug container according to claim 1,
`wherein the thickness of the Parylene layer is 1-30 μm.
`Claim 4. The drug container according to any of claims
`1 to 3, wherein the Parylene layer comprises Parylene N
`represented by the following chemical formula 1.
`CHEMICAL EXPRESSION 1
`
`
`
`
`
`Chemical Formula 1
`Claim 5. The drug container according to any of claims
`1 to 4, wherein the lid material is a rubber or elastomer
`elastic body.
`Claim 6. The drug container according to any of claims
`1 to 5, wherein the container comprises an optically
`transparent plastic.
`Claim 7. The drug container according to any of claims
`1 to 6, wherein the container has a melting point or a
`glass transition point of 120°C or higher.
`Claim 8. The drug container according to any of claims
`1 to 7, wherein the container comprises polypropylene,
`poly(4-methylpentene-1),
`cyclic
`polyolefin,
`or
`polyethylene naphthalate.
`Claim 9. The drug container according to any of claims
`1 to 7, wherein the container, while receiving a liquid
`containing a pharmacologically effective substance, has
`a Parylene layer on a portion of a side of the container
`in contact with the liquid.
`Claim 10. The drug container according to any of
`claims 1 to 9, wherein the pharmacologically effective
`substance is any of a group consisting of nitroglycerin,
`isosorbide dinitrate, and nicardipine hydrochloride.
`Claim 11. A drug container having a container made of
`synthetic resin for receiving a liquid containing a
`pharmacologically effective substance and a
`lid
`material for sealing an opening of the container,
`characterized in that at least a portion of a surface
`contacting the liquid is covered with a Parylene layer
`and configured so as to bring the container into contact
`with the lid material through the Parylene layer, and a
`ratio (b/a) (maintenance ratio) of 90% or greater
`
`[cut off] (2) 002–177364 (P2002–177364A)
`
`between (a) the substantial amount of nitroglycerin in
`the aqueous solution at the time when the container is
`charged with a 0.5 mg/mL nitroglycerin aqueous
`solution and (b) the substantial amount of nitroglycerin
`in the aqueous solution at the time when the aqueous
`solution is preserved packed in the container and sealed
`with the lid material for six months at 40°C × 100.
`Claim 12. The drug container according to any of
`claims 1 to 11, wherein the container is a tube having a
`front end sealed but capable of opening, and an opening
`in a back end, the lid material is a gasket for slidably
`forming a blockade inside the tube, and the drug
`container has a syringe shape.
`DETAILED EXPLANATION OF THE INVENTION
`[0001]
`INDUSTRIAL FIELD OF APPLICATION: The
`present invention relates to a drug container. More
`particularly,
`the present
`invention
`relates
`to a
`transparent plastic drug container having a Parylene
`layer formed on at least a portion of a surface
`contacting the drug.
`[0002]
`PRIOR ART: Glass vials are used as drug containers.
`Glass vials, however, may be dropped and break during
`transport or when handling, and are physically
`cumbersome for transporters and clinic technicians due to
`their weight. Containers have been made of plastic as a
`solution for these problems, and plastic containers have
`replaced glass containers as containers
`for most
`transfusion-related drugs today. A so-called prefilled
`syringe has begun to be used recently, in which a syringe
`having the front end of the syringe sealed is filled with a
`drug liquid or an injection liquid before transporting and
`preserving with the other end sealed with a gasket, and
`when administering, an injection needle or a dosing
`appliance is attached to the front end of the syringe and the
`drug liquid or injection liquid is ejected to allow the drug
`to be administered by pressing and sliding the gasket
`within
`the syringe. A prefilled syringe has many
`advantages, such as being very simple to operate, allowing
`correct dosing without dose error because the drug liquid
`and dose have already been set, and avoiding bacterial
`infection because the drug does not need to be prepared,
`even in an emergency. Prefilling various drugs has come
`to be demanded in clinical settings from standpoints such
`as therapeutic effectiveness, medical malpractice, and
`preventing bacterial
`infections. A prefilled syringe,
`however, demands high airtightness during transport and
`preservation, but must break the seal and slide when the
`drug is administered, and so demands the mutually
`contradictory functions of airtightness and low sliding
`property.
`[0003] The biggest problem in making a drug container
`of plastic is reduced potency due to the drug adsorbing
`to the container. Reduced content of nitroglycerin and
`many highly fat-soluble drugs such as cyclosporin and
`benzodiazepine
`in various drug containers and
`transfusion sets has already been reported, and
`interaction between
`injection
`liquids and dosing
`(Journal of
`appliances has become a problem
`
`
`
`Sandoz Exhibit 1004 Page 3
`
`

`

`
`
`Pharmaceutical Science 71, 55-59, 1982, American
`Journal of Hospital Pharmacy 41, 142-144, 1984,
`American Journal of Hospital Pharmacy 43, 94-97,
`1984, American Journal of Hospital Pharmacy 40, 417-
`423, 1983, and Journal of the Nippon Hospital
`Pharmacists Association, 2, 1996, 167-1996). In
`particular, isosorbide dinitrate (ISDN) and nitroglycerin
`(GTN) injection liquids are used, for example, to treat
`severe angina, myocardial infarction, and acute cardiac
`insufficiency, during cardiac
`surgery, and
`for
`postoperative management, and demand accurate dose
`control. Most recently, precise automatic fluid delivery
`systems have been used for the reason that patients with
`strong symptoms of blood congestion should not
`increase their intake of water, and in an increasing
`number of cases, injection fluids for these systems are
`used as undiluted solutions. As a result, a drug
`container is demanded which does not cause reduced
`content (so-called reduced potency) of the drug in the
`container, and a prefilled syringe is demanded which
`has high airtightness during transport and preservation
`and low sliding property of the gasket portion during
`actual use. Due to this drug adsorption problem, either a
`glass container, as before, or a prefilled syringe made of
`glass is used for drugs that are prone to drug adsorption,
`and these containers pose a great physical and mental
`burden today on physicians, nurses, and transporters.
`[0004]
`IS TO
`INVENTION
`PROBLEMS THAT THE
`SOLVE: The present invention is designed to overcome
`the poor operability (proneness to damage due to
`weight) of drug containers used previously, beginning
`with glass vials and prefilled syringes used for drugs
`having high drug adsorption, by making the drug
`container of plastic. Specifically, the present invention
`provides a drug container made of plastic having
`minimal reduction in the potency of a drug or the
`substantial effective amount of
`the drug during
`transport or preservation by covering at least a portion
`of the drug-contacting site of a drug container, which
`comprises an elastic lid material and a container body
`comprising a specified plastic material, with a Parylene
`layer. The present invention also provides a syringe
`container having previously unobtainable low drug
`adsorption. Although
`Japanese Examined Patent
`Publication H3-58742 has disclosed the technique of
`using Parylene in a drug container, this publication has
`disclosed only preventing elution of metal ions such as
`calcium or aluminum ions from a lid material by
`coating an elastic lid material with Parylene, and has
`not in any way disclosed a technique for preventing
`drug adsorption.
`[0005]
`MEANS OF SOLVING THE PROBLEMS
`These and other objects are achieved by the following
`aspects (1)-(12) of the present invention.
`(1) A drug container having a container made of
`synthetic resin for receiving a liquid containing a
`pharmacologically effective substance and a
`lid
`material for sealing an opening of the container,
`
`
`
`[cut off] (3) 002–177364 (P2002–177364A)
`
`characterized in that at least a portion of a surface
`contacting the liquid is covered with a Parylene layer
`and configured so as to bring the container into contact
`with the lid material through the Parylene layer, and a
`ratio (b/a) (maintenance ratio) of 90% or greater
`between (a) the substantial amount of the substance in
`the liquid at the time when the container is charged with
`the liquid and (b) the substantial amount of the
`substance in the liquid at the time when the liquid is
`preserved packed in the container and sealed with the
`lid material for six months at 40°C × 100.
`(2) The drug container according to (1), wherein the
`Parylene layer covers all of the surface whereon the lid
`material is to be formed, and the preservation in (b)
`occurs with the liquid in contact with the lid material.
`(3) The drug container according to (1), wherein the
`thickness of the Parylene layer is 1-30 μm. (4) The drug
`container according to any of (1) to (3), wherein the
`Parylene layer comprises Parylene N represented by the
`following chemical formula 1.
`[0006]
`CHEMICAL EXPRESSION 2
`
`
`
`
`
`Chemical Formula 1
`[0007] (5) The drug container according to any of (1) to
`(4), wherein the lid material is a rubber or elastomer
`elastic body.
`(6) The drug container according to any of (1) to (5),
`wherein
`the
`container
`comprises
`an optically
`transparent plastic.
`(7) The drug container according to any of (1) to (6),
`wherein the container has a melting point or a glass
`transition point of 120°C or higher.
`(8) The drug container according to any of (1) to (7),
`wherein the container comprises polypropylene, poly(4-
`methylpentene-1), cyclic polyolefin, or polyethylene
`naphthalate.
`(9) The drug container according to any of (1) to (8),
`wherein
`the container, while receiving a
`liquid
`containing a pharmacologically effective substance, has
`a Parylene layer on a portion of a side of the container
`in contact with the liquid.
`(10) The drug container according to any of (1) to (9),
`wherein the pharmacologically effective substance is
`any of a group consisting of nitroglycerin, isosorbide
`dinitrate, and nicardipine hydrochloride.
`[0008](11) A drug container having a container made of
`synthetic resin for receiving a liquid containing a
`pharmacologically effective substance and a
`lid
`material for sealing an opening of the container,
`characterized in that at least a portion of a surface
`contacting the liquid is covered with a Parylene layer
`and configured so as to bring the container into contact
`with the lid material through the Parylene layer, and a
`ratio (b/a) (maintenance ratio) of 90% or greater
`between (a) the substantial amount of nitroglycerin in
`the aqueous solution at the time when the container is
`charged with a 0.5 mg/mL nitroglycerin aqueous
`solution and (b) the substantial amount of nitroglycerin
`in the aqueous solution at the time when the aqueous
`solution is preserved packed in the container and sealed
`with the lid material for six months at 40°C × 100.
`
`Sandoz Exhibit 1004 Page 4
`
`

`

`
`
`(12) The drug container according to any of (1) to (11),
`wherein the container is a tube having a front end
`sealed but capable of opening, and an opening in a back
`end, the lid material is a gasket for slidably forming a
`blockade inside the tube, and the drug container has a
`syringe shape.
`[0009] In the present invention, the substantial amount of a
`substance in a liquid containing a pharmacologically
`effective substance or the fixed amount of nitroglycerin in
`a nitroglycerin aqueous solution was determined by liquid
`chromatography, and the area ratio between the chart area
`of the substance in the liquid or the aqueous solution at the
`time when the container is charged with the liquid or the
`aqueous solution, and the chart area of the substance in the
`liquid or the aqueous solution at the time when preserved
`packed in the container and sealed with the lid material for
`six months at 40°C, was found and expressed as the
`amount (%) of the substance or nitroglycerin. The
`concentration of nitroglycerin in the nitroglycerin aqueous
`solution was set at 0.5 mg/mL, and the nitroglycerin used
`was Millisrol injection made by Nippon Kayaku Co., Ltd.
`[0010]
`EMBODIMENT OF THE INVENTION: The drug
`container of the present invention will be limited hereafter
`to the most complicated container shape of a prefilled
`syringe, and described in detail on the basis of the
`following schematic drawings. The present invention,
`however, is not limited to this shape, and includes drug
`containers using various types of elastic bodies as lid
`materials found, for example, in rubber-stoppered glass
`vials and transfusion bags. Although Fig. 1 and 2 show
`sectional views of syringes, these are no more than
`examples of syringe shapes, and the syringe container of
`the present invention is not limited to these examples. The
`cylinder 2 in these drawings corresponds to the container
`for receiving a liquid containing a pharmacologically
`effective substance in the present invention, and the gasket
`4 corresponds to the lid material to be used with this
`container. A syringe 1 comprises a cylinder 2, a plunger 3,
`and a gasket 4 located on the front end of the plunger. A
`space 22 for holding a drug liquid is formed inside the
`cylinder 2, and an opening 21 for aspiring and expelling a
`drug liquid is made in the front end of the space. The
`gasket 4 in Fig. 1 and 2 has a gasket body 41 and a
`Parylene layer 42 formed on the surface thereof. In the
`case of a prefilled syringe, a sealing material 5 separating
`the space 22 from the external environment is affixed in a
`readily peelable manner to the opening 21. The sealing
`material 5 may be the same type of material as the cylinder
`2 described below
`[0011] The cylinder 2 comprises a cylindrical body
`having a projection on the front end in which is formed
`the opening 21 for aspiring and expelling a liquid, such
`as a drug liquid or blood, and a flange 23 formed
`around an opening on the base end. The cylinder 2 is
`formed of a synthetic resin, such as a polyolefin
`synthetic resin or a polyester synthetic resin. Among
`such resins, the cylinder is preferably formed of an
`optically transparent material having a glass transition
`point or melting point of 110°C or higher; for example,
`a
`polyolefin
`such
`as
`polypropylene,
`poly(4-
`methylpentene-1), or cyclic polyolefin, or a polyester
`such as polyethylene
`terephthalate, polyethylene
`
`
`
`[cut off] (4) 002–177364 (P2002–177364A)
`
`naphthalate, or amorphous polyallylate. Polypropylene,
`poly(4-methylpentene-1),
`cyclic
`polyolefin,
`and
`polyethylene terephthalate are especially preferred in
`terms of transparency, steam sterilization, and non-
`adsorption of drugs. Besides
`the cylinder,
`these
`materials may be used for all of the container for
`receiving a liquid containing a pharmacologically
`effective substance. In the case that the drug container
`is a bag shape, a PP-based or PE-based elastomer or the
`like may be used besides the materials just described. In
`the case that all surfaces of the container contacting the
`drug are coated with Parylene, the material is not
`limited to these resins, and other types of synthetic
`resins may be used.
`[0012] The plunger 3 is formed of a material such as
`polypropylene, and has means on the front end for
`detachably affixing the gasket 4. The plunger 3 plays
`the role of both aspiring a drug liquid or blood into the
`space 22 by moving toward the base end together with
`the gasket 4, and expelling a drug liquid or blood stored
`in the space 22 by moving toward the front end. The
`gasket 4 is detachably affixed by means such as
`engaging with the front end of the plunger 3, and
`comprises the gasket body 41 and the Parylene layer 42
`formed on the surface thereof. Examples of the gasket
`are polyolefins such as styrene-based elastomer,
`hydrogenated styrene elastomer, or copolymers thereof
`with polypropylene, polybutene, or an α-olefin; and
`mixtures of an oil such as liquid paraffin or process oil,
`and an inorganic powder such as talc, cast, or mica.
`Other examples are materials constructed of rubber
`materials (especially vulcanized rubber materials) such
`as polyvinyl chloride-based elastomers, olefin-based
`elastomers, polyester-based elastomers, polyamide-
`based elastomers, polyurethane-based elastomers,
`natural
`rubber,
`isoprene
`rubber, butyl
`rubber,
`chloroprene rubber, nitrile-butadiene rubber, styrene-
`butadiene rubber, silicon rubber, and mixtures thereof.
`Among these materials, styrene-based elastomers, butyl
`rubber, and silicone
`rubber are preferred
`from
`standpoints such as elastic characteristics and steam
`sterilization. Besides the gasket, these materials may
`also be used for the lid material of the present
`invention.
`[0013] Although not shown in the drawings, a syringe
`formed integrally of a plunger and a gasket is called a
`two-part syringe. Needless to say, however, the gasket
`in this case is formed on the front end of the plunger;
`that is, on both the portion that contacts a liquid such as
`a drug solution or blood, and the portion that contacts
`the cylinder. In the case of such a two-part syringe, the
`Parylene layer 42 may be formed over all of the
`plunger, or may be formed so as to include the portion
`that contacts a liquid such as a drug solution or blood,
`and the portion that contacts the cylinder.
`[0014] Next, the Parylene used in the present invention
`will be described. “Parylene” in the present invention
`includes basic Parylene having no substituent on the
`benzene ring shown
`in
`the
`following chemical
`formula 1 (hereafter called Parylene N), and Parylene in
`which, for example, various functional groups have
`been introduced on the benzene ring or the hydrogen of
`
`Sandoz Exhibit 1004 Page 5
`
`

`

`[cut off] (5) 002–177364 (P2002–177364A)
`
`
`
`
`
`the methylene next to the benzene ring has been
`substituted; for example, Parylene C having chlorine
`introduced onto the benzene ring (chemical formula 2),
`Parylene M having methyl
`introduced (chemical
`formula 3), and Parylene F having fluorine introduced
`in the methylene (chemical formula 4). In light of
`recent environmental problems, Parylene N or Parylene
`M, which do not contain halogens, is preferably used.
`In the case that these Parylene are used in a prefilled
`syringe, coating the surface of the gasket reduces the
`sliding resistance of the gasket, and Parylene N had the
`lowest resistance in the test examples. Therefore, when
`all of these factors are considered together, using
`Parylene N is most advantageous in the case that the
`container in the present invention is a syringe.
`[0015]
`CHEMICAL EXPRESSION 3
`
`
`
`Chemical Formula 1
`
`
`
`
`[0016]
`CHEMICAL EXPRESSION 4
`
`Chemical Formula 2
`
`
`
`
`[0017]
`CHEMICAL EXPRESSION 5
`
`Chemical Formula 3
`
`
`
`
`[0018]
`CHEMICAL EXPRESSION 6
`
`
`
`Chemical Formula 4
`
`
`
`
`
`
`
`
`
`
`[0019] The container for receiving a liquid containing a
`pharmacologically effective substance in the present
`invention, and the surface of at least the portion that
`contacts the pharmacologically effective substance in a
`structure to be used with the container, may be covered
`with Parylene, and may be any material provided that
`the container and the lid material are contacted through
`the Parylene. Therefore, a layer of Parylene represented
`by chemical formulas 1-4 may be coated in multiple
`layers in the present invention. The effects of the
`present invention may also be achieved using a
`copolymer prepared from a di-p-xylylene copolymer
`corresponding to the Parylene represented by chemical
`formulas 1-4. The method of coating Parylene in the
`present invention comprises three steps, as shown in
`Fig. 3: (A) a step for causing di-p-xylylene in a solid
`dimer of the raw material to sublimate, (B) a step for
`thermally cracking the dimer to generate diradical
`
`
`
`p-xylylene, and (C) a stem for polymerizing radical
`monomers on the surface of the container and the lid
`material to form a poly-p-xyxlylene (Parylene) layer.
`The following Table 1 shows the processing conditions
`in these steps A to C.
`[0020]
`TABLE 1
`Table 1
`Step
`
`
`
`
`Pressure
`
`
`
`
`Temperature
`
`
`Room temperature
`
`
`
`[0021] The resulting Parylene layer has excellent heat
`resistance, chemical
`resistance, and gas barrier
`property, and may be coated on members having a
`complicated shape due to being formed by gas phase
`polymerization. Therefore, the Parylene layer may be
`coated on a lid material and a container having a
`complicated shape, as in the present invention. The
`thickness of the coating layer of Parylene used in the
`present invention may be controlled by the temperature
`and pressure in Table 1 and the coating time. The
`thickness of a coating layer for achieving significant
`effects in the present invention is usually 1-30 μm, and
`more preferably 2-20 μm. Less than 1 μm does not
`sufficiently control drug adsorption, and greater than
`30 μm causes the problem of the Parylene layer peeling.
`[0022] Next, drug adsorption will be described. As
`described earlier, many drugs, such as nitroglycerin,
`cyclosporin, and benzodiazepine, are
`reportedly
`reduced in content in drug containers or transfusion
`sets, and interaction between injection liquids and
`dosing appliances has become a problem (Journal of
`Pharmaceutical Science 71, 55-59, 1982, American
`Journal of Hospital Pharmacy 41, 142-144, 1984,
`American Journal of Hospital Pharmacy 43, 94-97,
`1984, American Journal of Hospital Pharmacy 40, 417-
`423, 1983, and Journal of the Nippon Hospital
`Pharmacists Association, 2, 1996, 167-1996). Reduced
`content is also a problem in prefilled syringes, and a
`prefilled syringe is demanded which does not cause
`reduced content (so-called reduced potency) in the drug
`container besides having high airtightness during
`transport and preservation and low sliding property
`during actual use. Parylene has high resistance to
`solvents, as shown in Table 2, and high crystallinity,
`suggesting that Parylene has little adsorption of drugs to
`the surface of a drug container.
`[0023]
`TABLE 2
`
`Sandoz Exhibit 1004 Page 6
`
`

`

`Table 2: Change in area when immersed in different solvents
`Solvent
`Parylene C
`Parylene N
`Dichlorobenzene
`
`
`Trichloroethylene
`
`
`Acetone
`
`
`Isopropyl alcohol
`
`
`From Encyclopedia of Polymer Science and Engineering 17, 1989
` [0024] The syringe in the present invention is an
`elastomer was selected as a gasket base material,
`example of a syringe associated with the operation of
`polypropylene and cyclic polyolefin were selected as
`pressing a plunger to slide into an airtight holding
`cylinder base materials, and sheet-form samples were
`portion, such as an all-purpose syringe for uses such as
`used for assessment. A 10 mm × 10 mm × 1 mm sheet
`administering a drug to a patient or collecting blood from
`a patient and mixing with a drug liquid, a microsyringe
`comprising the styrene elastomer (JSR TR made by JSR
`for uses such as administering insulin, or a dental syringe
`Corporation) was coated with Parylene under the
`for use during dental treatments. The syringe in the
`conditions in Table 1. The thickness of the Parylene in
`present invention, however, is especially advantageously
`the resulting sample was measured using an electron
`an example of a prefilled syringe for making a long-term
`indirect liquid while the syringe is prefilled with a drug.
`microscope (Scanning Electron Microscope JSM-5300
`In the case of a prefilled syringe, a drug liquid is placed
`made by JEOL DATUM). The lubricity of the resulting
`in the cylinder as required. The type of drug in the drug
`sample was assessed by measuring the coefficient of
`liquid is not specifically limited, and may be any drug,
`friction. The coefficient of friction was calculated from
`such as an antibiotic, vitamins (multivitamins), various
`the frictional resistance generated between the sample
`amino acids, an anticoagulant such as heparin, insulin, an
`antitumor agent, an analgesic, a heart stimulant, an
`and the surface of another material, using a surface
`intravenous anesthetic, an antiparkinsonism drug, an
`property tester (TRIBOGEAR TYPE 14S/14DR made
`antitumor agent, a corticosteroid, an antiarrhythmic
`by SHINTO Scientific Co., Ltd.). Specifically, a sample
`agent, supplementary electrolytes, an antiviral agent, or
`on which a Parylene film had been formed was affixed
`an immunostimulant. The effectiveness of a prefilled
`syringe is especially demonstrated, however, when used
`to the movable mount of the tester and contacted from
`for lipophilic drugs for which drug adsorption is a
`above by a sheet comprising polypropylene (Chisso
`problem.
`Polypro made by Chisso Corporation) or polyolefin
`[0025]
`(APEL made by Mitsui Chemicals) while under a
`EXAMPLES
`The present invention will be described in greater detail
`vertical load of 10 g, and the frictional resistance was
`hereinafter by citing examples and [comparative]
`measured when the sample was moved at a speed of
`examples.
`100 mm/min at room temperature. Table 3 shows the
`• Sliding Property:
`(Examples 1-6, Comparative
`results.
`Examples 1 and 2)
`[0026]
`To study the feasibility of a syringe gasket, styrene
`TABLE 3
`
`
`
`
`
`
`
`
`
`Table 3
`
`Example 1
`
`[cut off] (6) 002–177364 (P2002–177364A)
`
`
`
`Parylene M
`
`
`
`
`
`Material A
`Parylene C formed
`styrene elastomer
`Parylene C formed
`styrene elastomer
`Parylene N formed
`styrene elastomer
`
`Parylene N formed
`styrene elastomer
`Parylene N formed
`styrene elastomer
`Parylene C formed
`styrene elastomer
`Parylene F formed
`styrene elastomer
`Parylene N formed
`styrene elastomer
`
`
`
`Material B
`Polypropylene
`
`Polypropylene
`
`Polypropylene
`
`Cyclic polyolefin
`
`Cyclic polyolefin
`
`Cyclic polyolefin
`
`Polypropylene
`
`Polypropylene
`
`Styrene elastomer
`
`Polypropylene
`
`Coating thickness
`(fm)
`
`
`
`Coefficient
`of friction
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Example 2
`
`Example 3
`
`Example 4
`
`Example 5
`
`Example 6
`
`Example 7
`
`Comparative
`Example 1
`
`Comparative
`Example 2
`
`
`
`[0027] Table 3 reveals that a styrene elastomer coated
`with at least 1 μm of Parylene showed good sliding
`property against all of polypropylene, polyethylene, and
`cyclic polyolefin.
`
`[0028] Drug Adsorption: (Examples 1-8)
`As a typical example of a drug adsorption test, drug
`adsorption was compared and studied for nitroglycerin
`(Millisrol made by Nippon Kayaku), for which
`
`
`
`Sandoz Exhibit 1004 Page 7
`
`

`

`
`
`adsorption and diffusion onto containers is a problem. Five
`milliliters of a 0.5 mg/mL nitroglycerin aqueous solution
`were dispensed
`into a 20-mL cylinder made of
`polypropylene
`(Chisso Polypro made by Chisso
`Corporation) or polyolefin and sealed with a gasket (made
`by Asahi Rubber) coated with Parylene, then sterilized in
`an autoclave and preserved in a 40°C oven for six months
`to carry out an accelerated drug adsorption test. The fixed
`amount of nitroglycerin was determined using a high-
`speed liquid chromatograph system Shimadzu LC-9A
`(made
`by
`Shimadzu Corporation)
`for
`liquid
`chromatography, Interstil ODS (0.46 mm diameter ×
`250 mm, made by GL Sciences) for the column, an
`
`[cut off] (7) 002–177364 (P2002–177364A)
`
`ultraviolet absorptiometer (at 220 nm) for the detector,
`and water/methanol (2:3) for the mobile phase. The
`amount of nitroglycerin (%) was determined by the area
`ratio between the various samples and the chart area of
`nitroglycerin in an unsealed glass ampoule.
`[0029] (Comparative Examples 1-5) A nitroglycerin
`adsorption test in the form of syringes was carried out
`on uncoated gaskets in the same manner as Example 1.
`Table 4 shows the results.
`[0030]
`TABLE 4
`
`
`
`Table 4
`
`
`Example 1
`
`Example 2
`
`Example 4
`
`Example 5
`
`Example 6
`
`Example 7
`
`Example 8
`
`Example 9
`
`Example 10
`
`Parylene C formed
`butyl rubber
`
`Parylene N formed
`butyl rubber
`
`Parylene N formed
`butyl rubber
`Parylene N formed
`butyl rubber
`
`Parylene N formed
`SB rubber
`
`Parylene N formed
`SB rubber
`
`Parylene N formed
`SB rubber
`
`Parylene C formed
`butyl rubber
`
`Parylene C formed
`SB rubber
`
`Comparative
`Example 1
`
`Parylene N formed
`butyl rubber
`
`Comparative
`Example 2
`Comparative
`Example 3
`
`Uncoated butyl
`rubber
`Parylene N formed
`butyl rubber
`
`Comparative
`Example 4
`
`Parylene N formed
`butyl rubber
`
`Comparative
`Example 5
`
`Parylene N formed
`butyl rubber
`
`Gasket
`
`
`
`Cylinder material
`
`