CA1314677C - Chemically stabilized film - Google Patents
Chemically stabilized filmInfo
- Publication number
- CA1314677C CA1314677C CA000615976A CA615976A CA1314677C CA 1314677 C CA1314677 C CA 1314677C CA 000615976 A CA000615976 A CA 000615976A CA 615976 A CA615976 A CA 615976A CA 1314677 C CA1314677 C CA 1314677C
- Authority
- CA
- Canada
- Prior art keywords
- layer
- film
- flexible
- high molecular
- molecular weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B32—LAYERED PRODUCTS
- B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
- B32B27/00—Layered products comprising a layer of synthetic resin
- B32B27/36—Layered products comprising a layer of synthetic resin comprising polyesters
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B32—LAYERED PRODUCTS
- B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
- B32B27/00—Layered products comprising a layer of synthetic resin
- B32B27/18—Layered products comprising a layer of synthetic resin characterised by the use of special additives
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B32—LAYERED PRODUCTS
- B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
- B32B7/00—Layered products characterised by the relation between layers; Layered products characterised by the relative orientation of features between layers, or by the relative values of a measurable parameter between layers, i.e. products comprising layers having different physical, chemical or physicochemical properties; Layered products characterised by the interconnection of layers
- B32B7/04—Interconnection of layers
- B32B7/12—Interconnection of layers using interposed adhesives or interposed materials with bonding properties
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B32—LAYERED PRODUCTS
- B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
- B32B9/00—Layered products comprising a layer of a particular substance not covered by groups B32B11/00 - B32B29/00
- B32B9/04—Layered products comprising a layer of a particular substance not covered by groups B32B11/00 - B32B29/00 comprising such particular substance as the main or only constituent of a layer, which is next to another layer of the same or of a different material
- B32B9/045—Layered products comprising a layer of a particular substance not covered by groups B32B11/00 - B32B29/00 comprising such particular substance as the main or only constituent of a layer, which is next to another layer of the same or of a different material of synthetic resin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
- A61J1/10—Bag-type containers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B32—LAYERED PRODUCTS
- B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
- B32B2439/00—Containers; Receptacles
- B32B2439/80—Medical packaging
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/31504—Composite [nonstructural laminate]
- Y10T428/31786—Of polyester [e.g., alkyd, etc.]
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/31504—Composite [nonstructural laminate]
- Y10T428/31786—Of polyester [e.g., alkyd, etc.]
- Y10T428/31797—Next to addition polymer from unsaturated monomers
Abstract
64536-603D ABSTRACT OF THE DISCLOSURE In a multilayer flexible film suitable for medical solution packaging, film-derived extractables are controlled by the use of a small amount of a high molecular weight stabilizer in the outer layer of the film.
Description
CHEMICALLY STABIIIZED FrLM
This invention relates to autoclavable flexible films suitable for the packaging oE medlcal solutions and is dlvided from Canadian Patent Application S.N. 536,875. In the Eilms of the present invention, film-derived extractables are controlled by the use of a small amount of high molecular weight stabilizer in the outer layer oE the film.
Currently, it is common medical practice to supply liquids such as medical solutions for parenteral administration in the form of disposable, flexible pouches. These pouches should be characterized by collapsibility, transparency, and adequate mechanical strength. They must also be able to resist the relatively high -temperatures required for heat sterilization of their contents, for example in an autoclave. Typically, medical solutions and the like are autoclaved at about 253F. for periods of 15 to 30 minutes.
Presently, such flexible pouches are typically made from a highly plasticized polyvinyl chloride. While meeting the requirements mentioned above, polyvinyl chloride may have some undesirable properties for use as a medical solution pouch because of the possibility of migration of plasticizer from the polyvinyl chloride into the medical solution or the other contents of the pouch so that the solution may become contaminated by potentially toxic material. A question has also arisen concerning whether PVC
is adequately chemically neutral to medical solutions. It has also been found that polyvinyl chloride becomes brittle at ,~
~3~
~ 3 ~
relatively low temperatures.
Embrittlement and stress-cracking, particularly of the outer surface of medical pouches, has been found to occur in other non-PVC pouches. It is desirable to provide a pouch Eor the packaging of medical solutions which substantially reduces or eliminates stress-cracking and embrittlement oE the pouch material.
One such pouch is made from a flexible film comprising a sealant layer of an ethylene propylene copolymer or modified ethylene propylene copolymer, a core layer of a very low density polyethylene, and an outer layer of a flexible copolyester. The core layer is adhered to the sealant and outer layers respectively with a suitable adhesive resin such as a modified ethylene vinyl acetate copolymer or a modified ethylene methacrylate copolymer.
An alternate structure includes a blend layer of about 50~ very low density polyethylene and about 50~ of a modified ethylene propylene copolymer between the sealant layer and core layer.
In packaging medical solutions, the amount of extractables in the medical solùtion from the packaging material must be strictly controlled. Similarly, a medical solution is often pH sensi-tive, and the pH of the solution must therefore also be kept within strict limits.
Of interest is U.S. Patent No. 4,188,443 issued to Mueller et al disclosing a multilayer film of at least three layers, at least one of the inner layers comprising a copolymer or homopolymer of ethylene and at least one of the outer layers ~ 3:~6~7 6~536-603D
comprising a polyester or copolyester.
Of interest is U.S. Patent No. 4,528,220 issued to Hwo disclosing a plastic bag for medical solutions comprising an outer and inner layer oE blended materials, the blend of the outer layer having ethylene propylene copolymer as one componen-t and the blend o-~ the inner layer having ethylene propylene copolymer as one component.
Also o:E interest is the Condensed Chemical ~ictionary, 10th Edition, at page 569 which describes Irganox* as a series of complex, high molecular weight stabilizers that inhibit oxidation and thermodegradation of many organic materials.
It is an object o:E the present invention to provide a flexible film suitable -Eor the packaging of medical solutions, in which extractables from the film are strictly controlled.
1 31'~ 6 7 1 64536-603D
Ie is also an ob~ect of the present Invention to provide a 11m suitable for tha packagin~ of medlcal solutions, in which the pH of the medical solution in a pouch formed from the flexible film is relatively unaffected by the film.
DEFINITIONS
The terms "flexibla" and the like and i'elastomeric" and the like are used herein to define specific polymeric materials as well as characteristics of a resulting pouch or bag wher2by improved flexibility and/or collapsibility of the pouch or hag is obtained by the use of these specific polymeric materials. Flexible materials may be characterlzed by a modulus of preferably less than 50,000 PSI (ASTM D-882-81) and more preferably less than 40,000 PSI (ASTM D-882-8l).
The term "film" and the like refers eo a ~her~oplaseic material suitable for packagin~ and having one or more l~yers of polymeric materials which may be bonded by any suitable means well known in the ar~.
The term "polymer"~ "polymeric", and the like9 unless speciflcally d~fined or otherwlse limited, generally includes homopolymers, copolymers and terpolymers and blends and modifications thereof.
The term "very low density polyethylene" is used herein to deflne a copolymer of polyethylene with densities balow 0.910 g~lcc, preferably between 0.900 to 0.906 g,cc. and including densities as low as 0.860 g~/cc~
as measured by ASTM D-1505.
The term "ethylene vinyl acetate copolymer" (EVA) is used herein to refer to a copolymer for~ed from ethylene and vinyl acetate monomers wherein the ethylene derived units in the copolymer are present in major amounts and the vin~l acetate darived units in the copolymar are present in minor amounts.
404l860627/4/3 3 ~ 3 ~ 7 ~4536-603D
The term "ethylene propylene copolymer" is used herein to reEer to a copolymer formed from polypropylene monomer and minor amounts, usually less than 6%, oE ethylene.
The term "copolyester" and the like is applied to polyesters synthesized from more than one diol and a dibasic acid.
Copolyesters as used herein may also be characteri~ed as copolymers of polyether and polyethylene terephthalate. More preferably copolyesters as used herein may be characteri~ed as polymeric materials derived from 1,~ cyclohexane dimethanol, 1,~
cyclohexane dicarboxylic acid, and polytetrame-thylene glycol e-ther, or equivalents of any oE the above, as reactants.
The term "modified" and the like is used herein to refer to a polymeric material in which some or all oE the substituents are replaced by other materials, providing a change in properties such as improved flexibility or elastomeric properties SUMMARY QF THE INVENTION
The present invention rela-tes to a mul-tilayer flexible film comprising: a) a layer comprising a sealable polymeric material; b) a polymeric adhesive layer; c) a layer of a flexible polymer; d) a second polymeric adhesive layer; and e) a layer of a blend of flexible polyester or copolyes-ter, and a high molecular weight stabilizer.
Another aspect of the invention relates to a method oE
producing a multilayer film comprising: a) blending a flexible polyester or copolyester, with a high molecular weight stabilizer;
` ~31~7~1 64536-~03D
and b) coextruding a multilayer Eilm comprising a layer comprising a sealable polymeric material, a polymeric adhesive layer, a layer of a flexible polymer, a second polymeric adhesive layer, and a layer containing the blend of a).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
This application will now be described in the environment of the parent application.
Thermoplastic film useEul for packaging medical solutions must be not only flexible, but also able to withstand autoclaving temperatures during an autoclaving step typically employed after the Eilm has been converted into a pouch, and a medical solution has been introduced into the pouch. One example of such a Eilm is a mul-tilayer film having a sealant layer, a core layer of a polymer which contributes flexibility to the Eilm, and an outer layer of a flexible polyester or copolyester.
Intermediate adhesive layers provide interlaminar bonding between the core layer and the sealant and outer layers respectively, holding the film together during and after autoclaving.
The sealant layer can be an ethylene propylene copolymer or modified ethylene propylene copolymer. Representative resins include M355E, a polyallomer ethylene propylene block copolymer available from Eastman, and Z4650, a modified ethylene propylene copolymer available from Cosden Oil and Chemical Company.
The core layer can be a very low density polyethylene such as DXFD 1362 available from Dow Chemical Company.
~ ~4~77 6~536-603D
The outside layer is a Elexible po]yester or copolyester such as PCCE 9967 from Eastman Chemical Products, Inc.
The intermediate adhesive layers may be identical or diEer from each other depending on the particular structure and application. CXA-E181 a modified ethylene vinyl acetate copolymer from Dupont, and Plexar* 3382, modified ethylene methacrylate copolymer available from Norchem are examples of such adhesive materials. An alternate intermediate adhesive layer for bonding the sealant layer to the core layer may comprise a blend of about 50% Z4650 with about 50~ of the same very low density polyethylene that comprises the core layer.
*Trac'e-mark 5a ~ 3~4~ 1~
64536~603~
Limiein8 the amount of ~tractable~ tbat can ~i8rat~ from the o~ter ~opolye~ter layer into a medical solution i3 of prlmary i~portance.
Blendin~ a high molecular wei~he ~tabili~er, quch as Irganox 1010 available fro~ Ciba-Gelgy Corporation into the polye~ter or oopolye~ter prior eo ex-trusion of ehe film, li~it~ th~ amou~t of extractabl2s that ene~r ~hemedlcal solution. Preferred range~ for ehe stab~lizer are betw~en about .3 Ant 1%, ant preferably about .7~ by weigh~ of the copolye~ter.
Although Irganox 1010 1~ currently added to ^ommercial copolye3~ers in the amount of aboue .2~ by weight of the re ln, lt ha~ been found thaC thi~ amount of addieiv~ i5 inqufflcien~ to conerol the extractlon of de8raded copolye~ter materlal lnto ~edlcal solutions.
Amoune~ o~ the high molecular weight ~tabilizQr above about 1% by wei~ht of the copolyester are not preferred becauqe the additive ltself can become an extractable msteri~l.
Many medical Yolueions are al~o pH sen~i~ive a~d such solutions should not vary ~r~aPly in acidity or basicity. It iY th~orized that acetic acid may be produced i~ cereal~ in~r~ediate adhe~l~e poly~aric matertals, and thereafter ~igrate ln~o the packaged ~olutlon.
In accordan~e ~lth th~ parent application, prefer~bly bet~een about ~05 a~t .15Z of a carbonate of an ~lkali m~tal, pre~erably sodium, is blendet lnto at les~t one of the int~rm~diate adheslve resin prior to extru~lon.
~ore preferably, about .1~ of a earbo~ate oP a~ alkall ~eeal, prefer~bly sotiu~ is blend~d into thQ ~odlf~ed EVA, or ~odifled ethylene meehacr~late copolymer.
Alternatively, prefesably between about .005% and .015% of a carbonate of an alkali mecal, pr~ferably sodlum, i9 blended into the very low d~nsity polyethylene or other polymeric material comprising the core layer of the flexible film. ~ore prefera~ly, about ~01% sodium carbonaee is blended into tha very lo~ den~ity polyet~ylene.
It i~ theorized tha~ eh~ sodiu~ carbonate ~eutralizes ace~ic acid or other acid compoaen~s of the inter~ediat~ adhe~ive r~sins, and possibly tha core layer re in.
*Trade-mark ~ 3 11 4 ~ 7 7 6~536~6n3D
Tha lnvention may be further und~rstood by refe~ence to ~he following examples ~howing actual embodiments cJf the inv~ntion, together with th~se of -the parent application.
~e~
About 0.6~ of Irganox 1010 ~as ble~ded wi~h PCCE 9967. About .lZ
~odium carbonate was blended into a modified ethylen~ vinyl acetate copoly~or, CXA E181. A five layer film waQ coextruded, the fil~ ha~ing a sealing layer of M355E ethylene propylene block copolymer, a core layer of DXErD 1362, assd the outer layer of PCCE 9967, with the intermediate adhesive layers of CXA E181.
10 ~
Abou~ 0.6~ of Irganox*1010 ~a~ blended into PCCE 99$7 copolyes~r resin. About .1~ sod~um carbonate wa~ blend~d ~to a CxAEl8l resIn.
A blend of 50% by we-lght DXFD 1362 and 50% by w~ight Z4650 was prepared, to which .lX odium carbo~ate wa~ added. A ~ultilayer fllm was 15coextruded having a sealaat layer of Z4650, a core layer of the DXFD 1362, an outer layer of the eopolyester 9 an adhes~ve layer b~e~een ehe core layer and sealant layer comprising the blend of 502 very lo~ density polyethylene and 50Z ethyl~ne propyleue copoly~ar, and an i~e~rmediate adhesive layer between the core layer and copolye~ter layer comprising CXA 181.
20In egamples 3 through 6, a multilayer coextrude~ film substantially like that of example 1 was prepared ~ith varyiug levels of sodium carbo~at2 in the core layer, i . e . the layer contai~ing the Yery low denRity polyethylene. This film differed from example 1 i~ that C~A 190, a motified ethylene vinyl aceta~e copolymer was used in place o~ she CXA E181 25of example 1. CXA 190 has 1000 ppm Na2C03 in the resin itself. Also, examples 1 thro~gh 6 included O.lX sodlu~ carbona~e in a~ additiollal sacri~iclal layer coex~ruded with a~d adhering to the ~ultilayer f$1~ at the *Trade-mark 1 3 ~ 4 ~ 7 7 64536-503D
sealing layPr of ~355E ethylsne propylene block copolymer. Finally, the copolyeste~ layer contained 0.52 Irganox 1010 lnstea~ of the 0.6X level of example 1.
The film of e~amples 3 through 6 had a total ehickne.qs of 9.5 mils. This includes a core layer of 4.45 mil ~ lntermediate adhe~ive layers of 0.4 mll~ each, a sealant layer of 0.75 mils, an outer layer of 1.5 mils, and a sacrificlal layer of 2.0 mils thickness.
As seen in Table 1 below, lncreasing th~ sod~um carbonate co~tene of the core layer, with the remainder of the multilayer structure remaining cons~ant, resulted in very significant improveme~t ln the reduction of pH
shift in the contained solueion. The multilayer film described above was formed into a pouch hav$ng dimensions of 3.9 inches by 5.3 inches, and fllled with lSO millillter~ of water, ehen overwrapped wlth a~ 8 mll thick overwrap of polypropyle~e, and autoclaved at a temperature of 250F for 20 minutes.
The i~it~al p~ of the water ~as 5.96.
EX~MPLE INITIAL p~ DROP IN pH
3 5.96 0 4.89 1.17 4 5.96 50 5.01 .95 5.96 100 5.45 .51 6 5.96 200 5.6R .28 pH determlnaeio~s were made on a pH meter according to USP 21 (pa~e 1124).
1 3 1 4 6 7 7 64536-60dD
A multilayer film was coextruded substantially llke that of example 1 wlth a sealing layer ehicknPss of 1.0 mils, lnter~diate adhesive layers each having a thickness of 0.5 mils, a core layer with a thickness of 4.75 mils, and an outer layer of a copolyester with a thickness of 1.75 mils. This multilayer material also included a 2.0 ~il thick sacrificlal layer of low density polyethylene as used in examples 3 through 6. This structure was irradiated with cwo megarads dosage of radiaeion and formed into a pouch with dimensions of 10 centimetezs by 15 centim~ters. The pouch was filled with 50 milliliters of dlstilled water, having an initial pH of 8Ø The pouch was overwrapped with a nylon polyethylene overwrap filled with water, and autoclaved at 250F for 20 minutes at 28psi over pressure. Example 7 listed in Table 2 below indicates the drop in pH
as an average of three samples tested. No Irganox*1010 was blended in the outer copolyester layer, and no sodium carbonate was added to any of the other layers of example 7.
Example 8 was identical to example 7, but with the presence of 0.5% Irganox*1010 by weight in che outer layer, and 0.1~ sodium carbonate in the intermediaee adhesive layers and in the sacrificlal layer.
Examples 9 and 10 in Table 2 below were substantially similar to examples 7 and 8 respectively, but wich an initial pH of 6.5 in the contained waterO The struc~ures of claims 9 and 10 were irradiated to 5 megarads instead of 2 megarads.
All pH data represents an average of 3 samples for each example.
25 EXAMPLE INITIAL pH N ~ FINAL pH DROP I~ pH
7 8.0 0 h.2 3.8 8 8.0 1000 5.7 2.3 9 6.5 0 4.6 1.9 6.5 1000 5.7 0.8 *Trade-mark l 3 1 ~ Ç~ ~ d 64536-603D
Films ln accordance wleh the present invention are preferably cross-linked . This is prPferably done by irradiatlon, i.e. bombarding che film wlch particulate and non-parti~ulate radiation~ such as hlgh energy eleccrons ~rom the accelerator to csoss-llnk the mat~rials of the film.
Cross-linkin~ may also bc ac~omplished chemlcally by the use of, for example, peroxides.
The deeailed description and specific examples whlch indicate the presently preferred embodiments of the lnventlon are given by way of illustratlon only. Various changes ~ithin the spirit and scope of the claims will be become apparent to those of ordinary skill in ~he art upon review of the above detailed descriptiQn and examples. For example9 where two different lntermediate adhesive layers are used, or wh~re identical intermediate adhesive layers are extruded through separaee extruders, the carbonate of an alkali metal can be blended ~ieh only one of ~he adhe~ive resins. The invention also contemplatPs the u~e of the carbonaea of an alkali me~al in either ons or both of the intermedlate adhesive layers, the cora layer~ or a combinaeio~ of these.
This invention relates to autoclavable flexible films suitable for the packaging oE medlcal solutions and is dlvided from Canadian Patent Application S.N. 536,875. In the Eilms of the present invention, film-derived extractables are controlled by the use of a small amount of high molecular weight stabilizer in the outer layer oE the film.
Currently, it is common medical practice to supply liquids such as medical solutions for parenteral administration in the form of disposable, flexible pouches. These pouches should be characterized by collapsibility, transparency, and adequate mechanical strength. They must also be able to resist the relatively high -temperatures required for heat sterilization of their contents, for example in an autoclave. Typically, medical solutions and the like are autoclaved at about 253F. for periods of 15 to 30 minutes.
Presently, such flexible pouches are typically made from a highly plasticized polyvinyl chloride. While meeting the requirements mentioned above, polyvinyl chloride may have some undesirable properties for use as a medical solution pouch because of the possibility of migration of plasticizer from the polyvinyl chloride into the medical solution or the other contents of the pouch so that the solution may become contaminated by potentially toxic material. A question has also arisen concerning whether PVC
is adequately chemically neutral to medical solutions. It has also been found that polyvinyl chloride becomes brittle at ,~
~3~
~ 3 ~
relatively low temperatures.
Embrittlement and stress-cracking, particularly of the outer surface of medical pouches, has been found to occur in other non-PVC pouches. It is desirable to provide a pouch Eor the packaging of medical solutions which substantially reduces or eliminates stress-cracking and embrittlement oE the pouch material.
One such pouch is made from a flexible film comprising a sealant layer of an ethylene propylene copolymer or modified ethylene propylene copolymer, a core layer of a very low density polyethylene, and an outer layer of a flexible copolyester. The core layer is adhered to the sealant and outer layers respectively with a suitable adhesive resin such as a modified ethylene vinyl acetate copolymer or a modified ethylene methacrylate copolymer.
An alternate structure includes a blend layer of about 50~ very low density polyethylene and about 50~ of a modified ethylene propylene copolymer between the sealant layer and core layer.
In packaging medical solutions, the amount of extractables in the medical solùtion from the packaging material must be strictly controlled. Similarly, a medical solution is often pH sensi-tive, and the pH of the solution must therefore also be kept within strict limits.
Of interest is U.S. Patent No. 4,188,443 issued to Mueller et al disclosing a multilayer film of at least three layers, at least one of the inner layers comprising a copolymer or homopolymer of ethylene and at least one of the outer layers ~ 3:~6~7 6~536-603D
comprising a polyester or copolyester.
Of interest is U.S. Patent No. 4,528,220 issued to Hwo disclosing a plastic bag for medical solutions comprising an outer and inner layer oE blended materials, the blend of the outer layer having ethylene propylene copolymer as one componen-t and the blend o-~ the inner layer having ethylene propylene copolymer as one component.
Also o:E interest is the Condensed Chemical ~ictionary, 10th Edition, at page 569 which describes Irganox* as a series of complex, high molecular weight stabilizers that inhibit oxidation and thermodegradation of many organic materials.
It is an object o:E the present invention to provide a flexible film suitable -Eor the packaging of medical solutions, in which extractables from the film are strictly controlled.
1 31'~ 6 7 1 64536-603D
Ie is also an ob~ect of the present Invention to provide a 11m suitable for tha packagin~ of medlcal solutions, in which the pH of the medical solution in a pouch formed from the flexible film is relatively unaffected by the film.
DEFINITIONS
The terms "flexibla" and the like and i'elastomeric" and the like are used herein to define specific polymeric materials as well as characteristics of a resulting pouch or bag wher2by improved flexibility and/or collapsibility of the pouch or hag is obtained by the use of these specific polymeric materials. Flexible materials may be characterlzed by a modulus of preferably less than 50,000 PSI (ASTM D-882-81) and more preferably less than 40,000 PSI (ASTM D-882-8l).
The term "film" and the like refers eo a ~her~oplaseic material suitable for packagin~ and having one or more l~yers of polymeric materials which may be bonded by any suitable means well known in the ar~.
The term "polymer"~ "polymeric", and the like9 unless speciflcally d~fined or otherwlse limited, generally includes homopolymers, copolymers and terpolymers and blends and modifications thereof.
The term "very low density polyethylene" is used herein to deflne a copolymer of polyethylene with densities balow 0.910 g~lcc, preferably between 0.900 to 0.906 g,cc. and including densities as low as 0.860 g~/cc~
as measured by ASTM D-1505.
The term "ethylene vinyl acetate copolymer" (EVA) is used herein to refer to a copolymer for~ed from ethylene and vinyl acetate monomers wherein the ethylene derived units in the copolymer are present in major amounts and the vin~l acetate darived units in the copolymar are present in minor amounts.
404l860627/4/3 3 ~ 3 ~ 7 ~4536-603D
The term "ethylene propylene copolymer" is used herein to reEer to a copolymer formed from polypropylene monomer and minor amounts, usually less than 6%, oE ethylene.
The term "copolyester" and the like is applied to polyesters synthesized from more than one diol and a dibasic acid.
Copolyesters as used herein may also be characteri~ed as copolymers of polyether and polyethylene terephthalate. More preferably copolyesters as used herein may be characteri~ed as polymeric materials derived from 1,~ cyclohexane dimethanol, 1,~
cyclohexane dicarboxylic acid, and polytetrame-thylene glycol e-ther, or equivalents of any oE the above, as reactants.
The term "modified" and the like is used herein to refer to a polymeric material in which some or all oE the substituents are replaced by other materials, providing a change in properties such as improved flexibility or elastomeric properties SUMMARY QF THE INVENTION
The present invention rela-tes to a mul-tilayer flexible film comprising: a) a layer comprising a sealable polymeric material; b) a polymeric adhesive layer; c) a layer of a flexible polymer; d) a second polymeric adhesive layer; and e) a layer of a blend of flexible polyester or copolyes-ter, and a high molecular weight stabilizer.
Another aspect of the invention relates to a method oE
producing a multilayer film comprising: a) blending a flexible polyester or copolyester, with a high molecular weight stabilizer;
` ~31~7~1 64536-~03D
and b) coextruding a multilayer Eilm comprising a layer comprising a sealable polymeric material, a polymeric adhesive layer, a layer of a flexible polymer, a second polymeric adhesive layer, and a layer containing the blend of a).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
This application will now be described in the environment of the parent application.
Thermoplastic film useEul for packaging medical solutions must be not only flexible, but also able to withstand autoclaving temperatures during an autoclaving step typically employed after the Eilm has been converted into a pouch, and a medical solution has been introduced into the pouch. One example of such a Eilm is a mul-tilayer film having a sealant layer, a core layer of a polymer which contributes flexibility to the Eilm, and an outer layer of a flexible polyester or copolyester.
Intermediate adhesive layers provide interlaminar bonding between the core layer and the sealant and outer layers respectively, holding the film together during and after autoclaving.
The sealant layer can be an ethylene propylene copolymer or modified ethylene propylene copolymer. Representative resins include M355E, a polyallomer ethylene propylene block copolymer available from Eastman, and Z4650, a modified ethylene propylene copolymer available from Cosden Oil and Chemical Company.
The core layer can be a very low density polyethylene such as DXFD 1362 available from Dow Chemical Company.
~ ~4~77 6~536-603D
The outside layer is a Elexible po]yester or copolyester such as PCCE 9967 from Eastman Chemical Products, Inc.
The intermediate adhesive layers may be identical or diEer from each other depending on the particular structure and application. CXA-E181 a modified ethylene vinyl acetate copolymer from Dupont, and Plexar* 3382, modified ethylene methacrylate copolymer available from Norchem are examples of such adhesive materials. An alternate intermediate adhesive layer for bonding the sealant layer to the core layer may comprise a blend of about 50% Z4650 with about 50~ of the same very low density polyethylene that comprises the core layer.
*Trac'e-mark 5a ~ 3~4~ 1~
64536~603~
Limiein8 the amount of ~tractable~ tbat can ~i8rat~ from the o~ter ~opolye~ter layer into a medical solution i3 of prlmary i~portance.
Blendin~ a high molecular wei~he ~tabili~er, quch as Irganox 1010 available fro~ Ciba-Gelgy Corporation into the polye~ter or oopolye~ter prior eo ex-trusion of ehe film, li~it~ th~ amou~t of extractabl2s that ene~r ~hemedlcal solution. Preferred range~ for ehe stab~lizer are betw~en about .3 Ant 1%, ant preferably about .7~ by weigh~ of the copolye~ter.
Although Irganox 1010 1~ currently added to ^ommercial copolye3~ers in the amount of aboue .2~ by weight of the re ln, lt ha~ been found thaC thi~ amount of addieiv~ i5 inqufflcien~ to conerol the extractlon of de8raded copolye~ter materlal lnto ~edlcal solutions.
Amoune~ o~ the high molecular weight ~tabilizQr above about 1% by wei~ht of the copolyester are not preferred becauqe the additive ltself can become an extractable msteri~l.
Many medical Yolueions are al~o pH sen~i~ive a~d such solutions should not vary ~r~aPly in acidity or basicity. It iY th~orized that acetic acid may be produced i~ cereal~ in~r~ediate adhe~l~e poly~aric matertals, and thereafter ~igrate ln~o the packaged ~olutlon.
In accordan~e ~lth th~ parent application, prefer~bly bet~een about ~05 a~t .15Z of a carbonate of an ~lkali m~tal, pre~erably sodium, is blendet lnto at les~t one of the int~rm~diate adheslve resin prior to extru~lon.
~ore preferably, about .1~ of a earbo~ate oP a~ alkall ~eeal, prefer~bly sotiu~ is blend~d into thQ ~odlf~ed EVA, or ~odifled ethylene meehacr~late copolymer.
Alternatively, prefesably between about .005% and .015% of a carbonate of an alkali mecal, pr~ferably sodlum, i9 blended into the very low d~nsity polyethylene or other polymeric material comprising the core layer of the flexible film. ~ore prefera~ly, about ~01% sodium carbonaee is blended into tha very lo~ den~ity polyet~ylene.
It i~ theorized tha~ eh~ sodiu~ carbonate ~eutralizes ace~ic acid or other acid compoaen~s of the inter~ediat~ adhe~ive r~sins, and possibly tha core layer re in.
*Trade-mark ~ 3 11 4 ~ 7 7 6~536~6n3D
Tha lnvention may be further und~rstood by refe~ence to ~he following examples ~howing actual embodiments cJf the inv~ntion, together with th~se of -the parent application.
~e~
About 0.6~ of Irganox 1010 ~as ble~ded wi~h PCCE 9967. About .lZ
~odium carbonate was blended into a modified ethylen~ vinyl acetate copoly~or, CXA E181. A five layer film waQ coextruded, the fil~ ha~ing a sealing layer of M355E ethylene propylene block copolymer, a core layer of DXErD 1362, assd the outer layer of PCCE 9967, with the intermediate adhesive layers of CXA E181.
10 ~
Abou~ 0.6~ of Irganox*1010 ~a~ blended into PCCE 99$7 copolyes~r resin. About .1~ sod~um carbonate wa~ blend~d ~to a CxAEl8l resIn.
A blend of 50% by we-lght DXFD 1362 and 50% by w~ight Z4650 was prepared, to which .lX odium carbo~ate wa~ added. A ~ultilayer fllm was 15coextruded having a sealaat layer of Z4650, a core layer of the DXFD 1362, an outer layer of the eopolyester 9 an adhes~ve layer b~e~een ehe core layer and sealant layer comprising the blend of 502 very lo~ density polyethylene and 50Z ethyl~ne propyleue copoly~ar, and an i~e~rmediate adhesive layer between the core layer and copolye~ter layer comprising CXA 181.
20In egamples 3 through 6, a multilayer coextrude~ film substantially like that of example 1 was prepared ~ith varyiug levels of sodium carbo~at2 in the core layer, i . e . the layer contai~ing the Yery low denRity polyethylene. This film differed from example 1 i~ that C~A 190, a motified ethylene vinyl aceta~e copolymer was used in place o~ she CXA E181 25of example 1. CXA 190 has 1000 ppm Na2C03 in the resin itself. Also, examples 1 thro~gh 6 included O.lX sodlu~ carbona~e in a~ additiollal sacri~iclal layer coex~ruded with a~d adhering to the ~ultilayer f$1~ at the *Trade-mark 1 3 ~ 4 ~ 7 7 64536-503D
sealing layPr of ~355E ethylsne propylene block copolymer. Finally, the copolyeste~ layer contained 0.52 Irganox 1010 lnstea~ of the 0.6X level of example 1.
The film of e~amples 3 through 6 had a total ehickne.qs of 9.5 mils. This includes a core layer of 4.45 mil ~ lntermediate adhe~ive layers of 0.4 mll~ each, a sealant layer of 0.75 mils, an outer layer of 1.5 mils, and a sacrificlal layer of 2.0 mils thickness.
As seen in Table 1 below, lncreasing th~ sod~um carbonate co~tene of the core layer, with the remainder of the multilayer structure remaining cons~ant, resulted in very significant improveme~t ln the reduction of pH
shift in the contained solueion. The multilayer film described above was formed into a pouch hav$ng dimensions of 3.9 inches by 5.3 inches, and fllled with lSO millillter~ of water, ehen overwrapped wlth a~ 8 mll thick overwrap of polypropyle~e, and autoclaved at a temperature of 250F for 20 minutes.
The i~it~al p~ of the water ~as 5.96.
EX~MPLE INITIAL p~ DROP IN pH
3 5.96 0 4.89 1.17 4 5.96 50 5.01 .95 5.96 100 5.45 .51 6 5.96 200 5.6R .28 pH determlnaeio~s were made on a pH meter according to USP 21 (pa~e 1124).
1 3 1 4 6 7 7 64536-60dD
A multilayer film was coextruded substantially llke that of example 1 wlth a sealing layer ehicknPss of 1.0 mils, lnter~diate adhesive layers each having a thickness of 0.5 mils, a core layer with a thickness of 4.75 mils, and an outer layer of a copolyester with a thickness of 1.75 mils. This multilayer material also included a 2.0 ~il thick sacrificlal layer of low density polyethylene as used in examples 3 through 6. This structure was irradiated with cwo megarads dosage of radiaeion and formed into a pouch with dimensions of 10 centimetezs by 15 centim~ters. The pouch was filled with 50 milliliters of dlstilled water, having an initial pH of 8Ø The pouch was overwrapped with a nylon polyethylene overwrap filled with water, and autoclaved at 250F for 20 minutes at 28psi over pressure. Example 7 listed in Table 2 below indicates the drop in pH
as an average of three samples tested. No Irganox*1010 was blended in the outer copolyester layer, and no sodium carbonate was added to any of the other layers of example 7.
Example 8 was identical to example 7, but with the presence of 0.5% Irganox*1010 by weight in che outer layer, and 0.1~ sodium carbonate in the intermediaee adhesive layers and in the sacrificlal layer.
Examples 9 and 10 in Table 2 below were substantially similar to examples 7 and 8 respectively, but wich an initial pH of 6.5 in the contained waterO The struc~ures of claims 9 and 10 were irradiated to 5 megarads instead of 2 megarads.
All pH data represents an average of 3 samples for each example.
25 EXAMPLE INITIAL pH N ~ FINAL pH DROP I~ pH
7 8.0 0 h.2 3.8 8 8.0 1000 5.7 2.3 9 6.5 0 4.6 1.9 6.5 1000 5.7 0.8 *Trade-mark l 3 1 ~ Ç~ ~ d 64536-603D
Films ln accordance wleh the present invention are preferably cross-linked . This is prPferably done by irradiatlon, i.e. bombarding che film wlch particulate and non-parti~ulate radiation~ such as hlgh energy eleccrons ~rom the accelerator to csoss-llnk the mat~rials of the film.
Cross-linkin~ may also bc ac~omplished chemlcally by the use of, for example, peroxides.
The deeailed description and specific examples whlch indicate the presently preferred embodiments of the lnventlon are given by way of illustratlon only. Various changes ~ithin the spirit and scope of the claims will be become apparent to those of ordinary skill in ~he art upon review of the above detailed descriptiQn and examples. For example9 where two different lntermediate adhesive layers are used, or wh~re identical intermediate adhesive layers are extruded through separaee extruders, the carbonate of an alkali metal can be blended ~ieh only one of ~he adhe~ive resins. The invention also contemplatPs the u~e of the carbonaea of an alkali me~al in either ons or both of the intermedlate adhesive layers, the cora layer~ or a combinaeio~ of these.
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A multilayer flexible film comprising:
a) a layer comprising a sealable polymeric material;
b) a polymeric adhesive layer;
c) a layer of a flexible polymer;
d) a second polymeric adhesive layer; and e) a layer of a blend of flexible polyester or copolyester, and a high molecular weight stabilizer.
a) a layer comprising a sealable polymeric material;
b) a polymeric adhesive layer;
c) a layer of a flexible polymer;
d) a second polymeric adhesive layer; and e) a layer of a blend of flexible polyester or copolyester, and a high molecular weight stabilizer.
2. The film of claim 1 wherein the high molecular weight stabilizer comprises between about .3% and 1% by weight of the polyester layer.
3. The film of claim 1 wherein the high molecular weight stabilizer comprises about .7% by weight of the polyester layer.
4. A method of producing a multilayer film comprising:
a) blending a flexible polyester or copolyester, with a high molecular weight stabilizer; and b) coextruding a multilayer film comprising a layer comprising a sealable polymeric material, a polymeric adhesive layer, a layer of a flexible polymer, a second polymeric adhesive layer, and a layer containing the blend of a).
a) blending a flexible polyester or copolyester, with a high molecular weight stabilizer; and b) coextruding a multilayer film comprising a layer comprising a sealable polymeric material, a polymeric adhesive layer, a layer of a flexible polymer, a second polymeric adhesive layer, and a layer containing the blend of a).
5. The method of claim 4 wherein between about 0.3% and 1%
of the high molecular weight stabilizer is blended with the polyester or copolyester.
of the high molecular weight stabilizer is blended with the polyester or copolyester.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/900,576 US4726997A (en) | 1986-08-26 | 1986-08-26 | Chemically stabilized film |
| US900,576 | 1986-08-26 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 536875 Division CA1292350C (en) | 1986-08-26 | 1987-05-12 | Chemically stabilized film |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1314677C true CA1314677C (en) | 1993-03-23 |
Family
ID=25412745
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 536875 Expired - Lifetime CA1292350C (en) | 1986-08-26 | 1987-05-12 | Chemically stabilized film |
| CA000615976A Expired - Lifetime CA1314677C (en) | 1986-08-26 | 1991-01-08 | Chemically stabilized film |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 536875 Expired - Lifetime CA1292350C (en) | 1986-08-26 | 1987-05-12 | Chemically stabilized film |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4726997A (en) |
| EP (1) | EP0258025B1 (en) |
| JP (3) | JP2505476B2 (en) |
| AT (1) | ATE108725T1 (en) |
| AU (2) | AU604047B2 (en) |
| BR (1) | BR8703305A (en) |
| CA (2) | CA1292350C (en) |
| DE (1) | DE3750241T2 (en) |
| DK (2) | DK442787A (en) |
| ES (1) | ES2056065T3 (en) |
| IE (1) | IE63686B1 (en) |
| NZ (1) | NZ220386A (en) |
| ZA (1) | ZA873935B (en) |
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5032463A (en) * | 1988-07-18 | 1991-07-16 | Viskase Corporation | Very low density polyethylene film from blends |
| US5055328A (en) * | 1989-06-16 | 1991-10-08 | Viskase Corporation | Differentially cross-linked multilayer film |
| US5139831A (en) * | 1990-03-02 | 1992-08-18 | W. R. Grace & Co.-Conn. | Impact modified medical film with ph control |
| US5445893A (en) * | 1992-01-30 | 1995-08-29 | W.R. Grace & Co.-Conn | pH control polymer |
| US5840422A (en) * | 1992-01-21 | 1998-11-24 | W. R. Grace & Co.-Conn. | pH control polymer |
| US5849843A (en) | 1993-11-16 | 1998-12-15 | Baxter International Inc. | Polymeric compositions for medical packaging and devices |
| US6461696B1 (en) | 1993-11-16 | 2002-10-08 | Baxter International Inc. | Multi-layered polymer based moisture barrier structure for medical grade products |
| US5998019A (en) * | 1993-11-16 | 1999-12-07 | Baxter International Inc. | Multi-layered polymer structure for medical products |
| US6297046B1 (en) | 1994-10-28 | 2001-10-02 | Baxter International Inc. | Multilayer gas-permeable container for the culture of adherent and non-adherent cells |
| US5935847A (en) * | 1994-10-28 | 1999-08-10 | Baxter International Inc. | Multilayer gas-permeable container for the culture of adherent and non-adherent cells |
| US5695840A (en) * | 1995-03-22 | 1997-12-09 | W. R. Grace & Co.-Conn. | Films for medical solution pouches |
| CA2170961C (en) * | 1995-03-22 | 2005-08-09 | Walter B. Mueller | Multilayer films for packaging and administering medical solutions |
| US6024220A (en) * | 1995-06-07 | 2000-02-15 | Baxter International Inc. | Encapsulated seam for multilayer materials |
| US6391404B1 (en) | 1995-06-07 | 2002-05-21 | Baxter International Inc. | Coextruded multilayer film materials and containers made therefrom |
| ZA978002B (en) | 1996-09-11 | 1998-03-02 | Baxter Int | Containers and methods for storing and admixing medical solutions. |
| CH692846A5 (en) | 1997-02-24 | 2002-11-29 | Baxter Biotech Tech Sarl | Multilayered co-extruded films for sterilizable containers fluids. |
| US7201966B2 (en) * | 2002-09-09 | 2007-04-10 | Curwood, Inc. | Packaging films containing coextruded polyester and nylon layers |
| US6497676B1 (en) | 2000-02-10 | 2002-12-24 | Baxter International | Method and apparatus for monitoring and controlling peritoneal dialysis therapy |
| US6969483B1 (en) | 2000-03-16 | 2005-11-29 | Baxter International Inc. | Autoclavable, non-adherent, heat sealable polymer blends for fabricating monolayer and multiple layered films |
| US6372848B1 (en) | 2000-10-10 | 2002-04-16 | Baxter International Inc. | Blend of ethylene and α-olefin copolymers obtained using a metallocene catalyst for fabricating medical films and tubings |
| US20030077466A1 (en) * | 2001-10-19 | 2003-04-24 | Smith Sidney T. | Multilayered polymer structure |
| US20030125662A1 (en) * | 2002-01-03 | 2003-07-03 | Tuan Bui | Method and apparatus for providing medical treatment therapy based on calculated demand |
| US7238164B2 (en) | 2002-07-19 | 2007-07-03 | Baxter International Inc. | Systems, methods and apparatuses for pumping cassette-based therapies |
| US20050209563A1 (en) * | 2004-03-19 | 2005-09-22 | Peter Hopping | Cassette-based dialysis medical fluid therapy systems, apparatuses and methods |
| JP2007236757A (en) * | 2006-03-10 | 2007-09-20 | Hosokawa Yoko Co Ltd | Infusion bag package and packaging bag |
| US7998115B2 (en) * | 2007-02-15 | 2011-08-16 | Baxter International Inc. | Dialysis system having optical flowrate detection |
| US8870812B2 (en) | 2007-02-15 | 2014-10-28 | Baxter International Inc. | Dialysis system having video display with ambient light adjustment |
| US8361023B2 (en) * | 2007-02-15 | 2013-01-29 | Baxter International Inc. | Dialysis system with efficient battery back-up |
| US7731689B2 (en) | 2007-02-15 | 2010-06-08 | Baxter International Inc. | Dialysis system having inductive heating |
| US8558964B2 (en) | 2007-02-15 | 2013-10-15 | Baxter International Inc. | Dialysis system having display with electromagnetic compliance (“EMC”) seal |
| JP5309048B2 (en) * | 2009-03-25 | 2013-10-09 | ローム アンド ハース カンパニー | Composition for producing porous EVA coating film |
| US8808595B2 (en) | 2009-04-07 | 2014-08-19 | Cryovac, Inc. | Multilayer film for medical solution pouches having reduced proficiency for forming bubbles |
| US11179516B2 (en) | 2017-06-22 | 2021-11-23 | Baxter International Inc. | Systems and methods for incorporating patient pressure into medical fluid delivery |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4188443A (en) * | 1978-08-30 | 1980-02-12 | W. R. Grace & Co. | Multi-layer polyester/polyolefin shrink film |
| EP0100912B2 (en) * | 1982-07-16 | 1995-08-23 | Mitsui Petrochemical Industries, Ltd. | Use of a hot-melt adhesive composition and laminated article comprising same |
| JPS5968238A (en) * | 1982-10-13 | 1984-04-18 | 富士写真フイルム株式会社 | Packing material for photosensitive substance |
| CA1243257A (en) * | 1983-10-18 | 1988-10-18 | Masakazu Ito | Multi-layer film or sheet material |
| US4528220A (en) * | 1984-02-09 | 1985-07-09 | Shell Oil Company | Plastic bags for medical solutions and blood |
| US4686125A (en) * | 1984-09-28 | 1987-08-11 | Baxter Travenol Laboratories, Inc. | Film laminate for sterile flexible containers |
| US4643926A (en) * | 1985-04-29 | 1987-02-17 | W. R. Grace & Co., Cryovac Div. | Flexible medical solution pouches |
-
1986
- 1986-08-26 US US06/900,576 patent/US4726997A/en not_active Expired - Lifetime
-
1987
- 1987-05-12 CA CA 536875 patent/CA1292350C/en not_active Expired - Lifetime
- 1987-05-20 NZ NZ22038687A patent/NZ220386A/en unknown
- 1987-06-02 ZA ZA873935A patent/ZA873935B/en unknown
- 1987-06-29 BR BR8703305A patent/BR8703305A/en unknown
- 1987-08-05 JP JP19455687A patent/JP2505476B2/en not_active Expired - Lifetime
- 1987-08-21 IE IE224487A patent/IE63686B1/en not_active IP Right Cessation
- 1987-08-24 EP EP87307462A patent/EP0258025B1/en not_active Expired - Lifetime
- 1987-08-24 ES ES87307462T patent/ES2056065T3/en not_active Expired - Lifetime
- 1987-08-24 AT AT87307462T patent/ATE108725T1/en not_active IP Right Cessation
- 1987-08-24 DE DE19873750241 patent/DE3750241T2/en not_active Expired - Lifetime
- 1987-08-25 DK DK442787A patent/DK442787A/en not_active Application Discontinuation
- 1987-08-26 AU AU77444/87A patent/AU604047B2/en not_active Ceased
-
1990
- 1990-09-03 AU AU62094/90A patent/AU623277B2/en not_active Ceased
-
1991
- 1991-01-08 CA CA000615976A patent/CA1314677C/en not_active Expired - Lifetime
-
1992
- 1992-04-14 DK DK50192A patent/DK50192A/en not_active Application Discontinuation
-
1995
- 1995-04-04 JP JP10158895A patent/JP2501308B2/en not_active Expired - Lifetime
- 1995-04-04 JP JP10167295A patent/JP2501309B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2505476B2 (en) | 1996-06-12 |
| JPS6356449A (en) | 1988-03-11 |
| EP0258025A3 (en) | 1988-12-07 |
| CA1292350C (en) | 1991-11-26 |
| JP2501308B2 (en) | 1996-05-29 |
| DK50192D0 (en) | 1992-04-14 |
| DK442787A (en) | 1988-02-27 |
| BR8703305A (en) | 1988-04-05 |
| JP2501309B2 (en) | 1996-05-29 |
| ES2056065T3 (en) | 1994-10-01 |
| IE872244L (en) | 1988-02-26 |
| AU604047B2 (en) | 1990-12-06 |
| AU7744487A (en) | 1988-03-03 |
| EP0258025A2 (en) | 1988-03-02 |
| DE3750241D1 (en) | 1994-08-25 |
| ATE108725T1 (en) | 1994-08-15 |
| DK442787D0 (en) | 1987-08-25 |
| JPH07285199A (en) | 1995-10-31 |
| AU623277B2 (en) | 1992-05-07 |
| DE3750241T2 (en) | 1994-10-27 |
| DK50192A (en) | 1992-04-14 |
| NZ220386A (en) | 1989-08-29 |
| IE63686B1 (en) | 1995-05-31 |
| EP0258025B1 (en) | 1994-07-20 |
| AU6209490A (en) | 1990-11-29 |
| ZA873935B (en) | 1987-12-02 |
| US4726997A (en) | 1988-02-23 |
| JPH07285198A (en) | 1995-10-31 |
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