Multilayer films for packaging and administering medical solutions

IS 2 186 756 T3

DESCRIPTION

Multilayer films for packaging and administration of medicinal solutions.

Background of the present invention

The present invention relates to multilayer films and, more specifically, to multilayer films suitable for flexible bags intended for the packaging and administration of medicinal solutions.

In routine medical practice, the supply of medicinal solutions for parenteral administration (eg intravenous) in the form of flexible disposable bags is common. There is a class of such bags that is commonly known as "IV bag." These bags must meet various functional criteria, including contractility, ooptic clarity and transparency, high temperature toxicity stability, and sufficient mechanical strength to withstand the conditions of use. Medicine solution bags must also provide a sufficient barrier to the passage of water vapor and other gases, to prevent contamination of the solution they contain.

Contractility is necessary to ensure correct and complete drainage of the bag. Unlike rigid containers for liquids, the drainage of which depends on air displacement, the dripping of medicinal solution bags is based on their ability to shrink. As it empties, atmospheric pressure contracts the bag at a rate proportional to that of the drip. In this way, the bag can be completely drained at a substantially constant rate. In order for the bag to contract, it must be made of a film. If the film is too stiff, the bag will not be completely emptied and therefore the patient may not receive the prescribed amount of the medicinal solution. Therefore, when designing the films to produce bags of medicinal solutions, it must be taken into account, above all, that they are quite flexible, so that the resulting bag has enough contraction capacity to be able to drain completely.

Before administering a medicinal solution to a patient from a bag, the medical professional in charge of the treatment will visually inspect the solution contained in it. This inspection serves to quickly check that the medicinal solution to be administered has not deteriorated or contaminated. For this, it is essential that the bag has excellent optical properties, that is, a high degree of transparency and transmission and very little veil. A bag of medicinal solution with poor optic properties can render visual inspection of the packaged solution ineffective and the medical professional will discard the bag unnecessarily. Worse still, you might not realize it was the wrong, corrupted, or tainted solution. As discussed in detail below, the general industry custom to thermally sterilize bags filled with medicinal solution greatly exacerbates the problem of maintaining their good ooptic properties.

The thermal sterilization of the medicine solution filled bags was normally carried out in an autoclave, at about 121 ° C (250 ° F) for periods of 15 to 30 minutes. Thermal sterilization is usually performed by the manufacturer and / or packager of the medicinal solution before sending it packaged to the end user, eg to a hospital, which helps to ensure that the medicinal solution packaged in the bag is basically free of contaminants. Therefore, another requirement of medicine solution bags is that they can withstand the high temperatures of thermal sterilization, without deterioration, eg without heat seal leakage or other containment failure.

In addition, the bags of medicinal solution must have sufficient mechanical resistance to withstand the wear and tear to which they are usually subjected during use. For example, in certain cases a plastic or rubber chamber is placed around the bag containing medicinal solution and pressurized, e.g. to 300-400 mm / Hg, to force the solution out of the bag and into the bag. in the patient. This type of chamber is known as a “pressure cuff” and is used, for example, when a patient is bleeding profusely, to rapidly replace lost fluids, or, for example, when a patient has a very low blood pressure. high, that it is necessary to generate a greater back pressure in the bag to introduce the medicinal solution into their veins. Medicine solution bags must have sufficient durability to remain watertight during these operations.

Currently, flexible bags for the packaging of medicinal solutions are often made of highly plasticized polyvinyl chloride (PVC). Although it generally meets the above requirements, PVC can have certain undesirable properties for use in medicine solution bags. For example, the plasticizer can migrate from the PVC bag to the solution it contains, contaminating it or roasting it with a potentially toxic material. The question has also been raised as to whether PVC is suitable as a chemically neutral material for medicinal solutions.

IS 2 186 756 T3

For these reasons, alternatives to PVC bags have been sought. These other bags are normally made up of multilayer films containing polyolefin, so that one of the outer layers of the film is resistant to wear and tear and constitutes the outside of the bag, while the other outer layer of the film is heat-sealable, that is, capable to be welded to itself by applying sufficient heat, and constitutes the inside of the bag. Likewise, the film usually has an intermediate layer to give it strength and flexibility, and also to waterproof it to gases.

A particularly difficult challenge in designing and manufacturing the polyolefin films used to produce medicinal solution bags is for the film to behave in the manner described above, after thermal sterilization of the bag. In other words, the high temperatures and steam from thermal sterilization can impair the contractility, mechanical strength, and optic properties of the bag.

Above all, the adverse effect of thermal sterilization on the optic properties of medicine solution bags is of concern. In general, the gas permeability of polyolefin films is directly proportional to the temperature of said films. Therefore, as the temperature rises, the permeability to gases increases and vice versa. During thermal sterilization, polyolephane bags of medicinal solution have a much higher gas permeability than when they are at room temperature. As a result, the steam used to heat the bags penetrates the film with which they have been formed. When the sterilization process is finished and the bag is allowed to cool, a part of the steam usually condenses and remains trapped inside the film, especially in the intermediate layer, since it is generally the thickest. Trapped condensate gives the bag a cloudy or cloudy appearance that can make it difficult to inspect the medicinal solution contained in the bag, as described above. Also, this cloudy appearance is not aesthetically attractive.

Therefore, there is a technical need for a multilayer polyolefin film, which is suitable to replace PVC as a material for making medicine solution bags and which has better optical properties after thermal sterilization of the bag.

Summary of the present invention

The present invention satisfies this need, because it provides a multilayer film capable of withstanding thermal sterilization at 121 ° C (250 ° F), which comprises:

a) an inner layer formed by a homogeneous ethylene / alpha-olefin copolymer, with a density between about 0.89 and about 0.92 grams per cubic centimeter;

b) a first outer layer formed by a material chosen from the group consisting of homopolymer or copolymer polypropylene, a mixture of homopolymer or copolymer polypropylene with elastomer, high-density polyethylene and copolyester; Y

c) a second outer layer formed by a material selected from the group consisting of polyamide, copolyamide, polyester, copolyester, high-density polyethylene and polycarbonate.

Preferably, the density of the homogeneous ethylene / alpha-olefin copolymer is between about 0.90 and about 0.91 grams per cubic centimeter.

Alternatively, the inner layer a) may comprise a mixture of two or more homogeneous ethylene / alpha-olefin copolymers, the density of which is between about 0.89 and about 0.92 grams per cubic centimeter. Preferably, the mixture has a density between about 0.90 and about 0.91 grams per cubic centimeter.

Various forms of execution of the multilayer film are possible. In one of them, the multilayer film has three layers. In such a case, the first and second outer layers are preferably formed of high-density polyethylene and are directly adhered to the inner layer (ie without an intermediate layer of adhesive).

In another form of execution, the multilayer film is four-layer. In this case, the film has an additional layer, preferably adhesive, located between the inner layer and the first outer layer, and adhered to them. The adhesive layer may be made of a material chosen from the group consisting of an ethylene / alpha-olefin copolymer with a density less than or equal to 0.89 grams per cubic centimeter, a homogeneous ethylene / alpha-olefin copolymer mixture with a density between about 0.89 and about 0.92

ES 2 186 756 T3 grams per cubic centimeter with the material constituting the first outer layer, anhydride modified ethylene / vinyl acetate copolymer, and anhydride modified ethylene / methyl acrylate copolymer. If the multilayer film of the present invention has a four-layer structure, the first outer layer is preferably formed by a blend of polypropylene homopolymer or copolymer with elastiomer. The second outer layer preferably comprises high density polyethylene and is directly adhered to the inner layer.

In another of these embodiments, the multilayer film of the present invention has a five-layer structure. In this case, the film includes two additional layers. Preferably these additional layers are adhesive. The first adhesive layer is located and adhered between the inner layer and the first outer layer. This first adhesive layer can comprise a material chosen from the group consisting of an ethylene / alpha-olefin copolymer with a density less than or equal to 0.89 grams per cubic centimeter, a homogeneous ethylene / alpha-olefin copolymer mixture with a density between about 0.89 and about 0.92 grams per cubic centimeter with the material that constitutes the first outer layer, anhydride modified ethylene / vinyl acetate copolymer, and anhydride modified ethylene / methyl acrylate copolymer.

The second adhesive layer is located and adhered between the inner layer and the second outer layer. This second adhesive layer preferably comprises a material selected from the group consisting of anhydride modified ethylene / vinyl acetate copolymer, anhydride modified ethylene / methyl acrylate copolymer, anhydride modified ethylene / ethyl acrylate copolymer, linear low poly Anhydride Modified Density, Anhydride Modified Very Low Density Polyethylene, and Anhydride Modified High Density Polyethylene.

When the multilayer film of the present invention has a five-layer structure, the first outer layer preferably comprises a blend of polypropylene homopolymer or copolymer with elastiomer. The second outer layer preferably comprises copolyether or polyamide. In such a case, the first outer layer can serve as a heat-sealing layer, while the second outer layer serves as a wear-resistant layer.

Another aspect of the present invention refers to a bag for packaging and administration of medicinal solutions, which is formed by any of the multilayer films described above.

When used to make bags of medicinal solutions, it is observed that the multilayer films of the present invention possess excellent ioptic properties (that is, transmission, transparency and veil) after having heat sterilized the bags with medicinal solution, as has been done. previously described. These post-sterilization optic properties are much better than previous polyolefin films. In particular, the inventor has found that homogeneous ethylene / alpha-olefin copolymers are superior to heterogeneous ethylene / alpha-olefin copolymers (e.g. VLDPE), in terms of their post-sterilization optical properties, when said Copolymers are used to form the inner layer of multilayer films with which medical solution bags are made. For reasons not fully understood it was found that, after thermal sterilization, there was less steam condensate (i.e. water) trapped in the homogeneous ethylene / alpha-olefin inner layers than in the heterogeneous ethylene / alpha-olefin inner layers. . As a consequence, once the thermal sterilization is completed, the transmission, transfer and veiling of the bags of medicinal solution made with multilayer films whose inner layer is of homogeneous ethylene / alpha-olefin copolymer are better than the transmission, transfer and veiling of the Medicine solution bags made with multilayer films whose inner layer is made of heterogeneous ethylene / alpha-olefin copolymer (eg VLDPE). These better ioptic properties are illustrated in the examples below.

Apart from offering excellent ioptic properties, the multilayer films of the present invention fulfill all the other functional requirements of a bag for medicinal solutions. That is, multilayer films have good flexibility / contractility and mechanical strength, and can withstand sterilization at elevated temperature. In addition, the films have good barrier properties. For these reasons, the multilayer films of the present invention are ideal for packaging and administering medicinal solutions. However, these films could also be used for any other application requiring an inner layer of homogeneous ethylene / alpha-olefin copolymer.

Definitions

As used herein, the term "film" and the like refers to a thermoplastic material, generally in sheet or lamina form, having one or more layers of polymeric materials that can

ES 2 186 756 T3 be attached in any way known from the technical state.

As used herein, the terms "polymer", "polymeric" and the like generally include homopolymers, copolymers, terpolymers, as well as mixtures and modifications thereof, unless specifically defined.

As used herein, the term "elastomeric" and the like refers to a material that, at room temperature, can repeatedly stretch to at least twice its original length. This characteristic differentiates plastics from elastiomers and rubbers, as well as the fact that the final properties of elastoimers are obtained by chewing them with fillers, process additives, antioxidants, curing agents, etc., and then vulcanizing (curing) them to high temperatures. However, a few elastoimers are thermoplastic. These thermoplastic elastiomers include the following preferred materials: styrene-ethylene-butylene-styrene copolymer (SEBS), styrene-butadiene-styrene copolymer (SBS), styrene-isoprene-styrene copolymer (SIS), ethylene-propylene rubber (EPM) and ethylene-propylene-diene terpolymer (EPDM).

As used herein, the term "ethylene / alpha-olefin copolymer" generally designates copolymers of ethylene with one or more comonoimers chosen from the group consisting of C3 to C20 alpha-olefins, such as 1-butene, 1-pentene , 1-hexene, 1-octene, methyl-pentene and analogs, in which the polymeric molecules comprise long chains with relatively few side branches. These polymers are made by low pressure polymerization processes and the resulting side branching is short compared to nonlinear polyethylenes (eg LDPE, a homopolymer polyethylene). Ethylene / alpha-olefin copolymers generally have a density between about 0.86 g / cc and about 0.94 g / cc, and can be classified into two broad categories, heterogeneous and homogeneous, both described below.

As used herein, the term "heterogeneous ethylene / alpha-olefin copolymer" refers to products obtained by reaction of ethylene / alpha-olefin copolymerization, with a fairly wide variation in molecular weight and composition distribution, which are prepared using conventional Ziegler-Natta catalysts or other heterogeneous catalysts. As is known, "heterogeneous catalysts" comprise several classes of active sites that differ with respect to Lewis acidity and the steric environment. Examples of heterogeneous Ziegler-Natta catalysts include metal halides activated by an organometallic cocatalyst, such as titanium chloride optionally containing magnesium chloride and complexed with trialkyl aluminum, as disclosed for example by US patents Nos. 4,302,565 and 4,302,566.

Generally, heterogeneous ethylene / alpha-olefin copolymers contain a fairly wide variety of chain lengths and percentages of comonomers. Examples of heterogeneous ethylene / alpha-olefin copolymers include linear low-density polyethylene (LLDPE), linear medium-density polyethylene (LMDPE), very low-density polyethylene (VLDPE), and ultra-low-density polyethylene. (ULDPE). LLDPE is generally understood to include the group of heterogeneous ethylene / alpha-olefin copolymers whose density ranges from about 0.915 to about 0.94 g / cc. Linear polyethylene with a density between about 0.926 and 0.94 is sometimes referred to as LMDPE. The lowest density heterogeneous ethylene / alpha olefin copolymers are VLDPE (commonly used to refer to the ethylene / butene copolymers supplied by Union Carbide, with a density between about 0.88 and about 0.91 g / cc) and ULDPE (commonly used to refer to ethylene / octene copolymers supplied by Dow).

As used herein, the phrase "homogeneous ethylene / alpha-olefin copolymer" refers to reaction products obtained by ethylene / alpha-olefin copolymerization, which have a relatively narrow molecular weight and compositional distribution. Homogeneous ethylene / alpha-olefin copolymers differ structurally from heterogeneous ethylene / alpha-olefin copolymers by a fairly uniform sequence of comonomers within the chain, by a specular distribution of the sequence in all chains, and by a similar length of all chains. chains, that is, by a narrower molecular weight distribution. In addition, homogeneous ethylene / alpha-olefin copolymers are often prepared using metallocenes or other single-site catalysts rather than Ziegler-Natta catalysts. These single-site catalysts typically have only one type of catalytic point, which is assumed to be the basis for the homogeneity of the polymers resulting from polymerization.

Homogeneous ethylene / alpha-olefin copolymers can be characterized more concretely by one or more of the known state-of-the-art methods, such as molecular weight distribution (Mw / Mn), compositional breadth index (CDBI), and the merger in a narrow interval

ES 2 186 756 T3 temperature or single melting point. The molecular weight distribution (M_w/ M_n), also called polydispersity, can be determined by gel chromatography. Homogeneous ethylene / alpha-olefin copolymers generally have a (Mw / Mn) less than 2.7, preferably between 1.9 and 2.5, more preferably between 1.9 and 2.3. The compositional distributive breadth onyx (CDBI) of these homogeneous ethylene / alpha-olefin copolymers will generally be greater than 70 percent. The CDBI is defined as the percentage by weight of copolymer molecules, whose comonomer content is within a range of variation of 50 percent (that is, more or less 50%) over the median of the cumulative molar fraction of comonomer. The CDBI of linear polyethylene, which does not contain a comonomer, is by definition 100%. The CDBI determination clearly distinguishes the homogeneous copolymers used in the present invention (narrow composition distribution, as evidenced by their CDBI values ​​generally higher than 70%) from commercially available VLDPEs, which tend to have a wide composition distribution, as demonstrated their CDBI values ​​normally less than 55%. The CDBI of a copolymer is easily calculated on the basis of data obtained by the application of known methods of technical state, for example fractionation by elution with a thermic gradient, as described, for example, in Wild et al., J. Poly. Sci. Poly. Phys. Ed., Vol. 20, p. 441 (1982). In general, the homogeneous ethylene / alpha-olefin copolymers in the multilayer films of the present invention also have a relatively narrow melting range, as compared to the "heterogeneous copolymers", that is, the polyomers with a CDBI of less than 55%. Preferably, homogeneous ethylene / alpha-olefin copolymers are characterized by having a basically simple melting point, with a peak (T_m) from about 60 C to about 110 C, determined by Differential Scanning Calorimetry (DSC). As used herein, the phrase "basically simple melting point" means that at least 80% by weight of the material corresponds to a single peak Tm, within a temperature range between about 60 ° C and about 60 ° C. 110 ° C, and that practically no fraction of the material has a maximum melting point higher than about 115 ° C, as determined by DSC. DSC measurements can be made on a Perkin Elmer System 7 Thermal Analysis System. The fusion report is secondary data, that is, the sample is heated at a programmed rate of 10 ° C / min., To a temperature below its chromic range. Then it is reheated (2- fusion) at a programmed speed of 10^°C / min. The presence of higher melting peaks is detrimental to film properties such as fogging.

A homogeneous ethylene / alpha-olefin copolymer can generally be prepared by copolymerizing ethylene with one or more alpha-olefins. Preferably, the alpha-olefin is a C3-C20 alpha-monoolefin, more preferably a C4-C12 alpha-monoolefin and better still C4-C8. More preferably, the alpha-olefin comprises at least one member selected from the group consisting of 1-butene, 1-pentene, 1-hexene, and 1-octene. In US patents n^° 5,206,075, 5,241,031, 5,272,236 and 5,278,272; and in PCT International Publication numbers WO 90/03414 and 93/03093, all incorporated herein in their entirety by reference, processes for the preparation and use of homogeneous polymers are disclosed.

Examples of commercially available homogeneous ethylene / alpha-olefin copolymers include EXACT^TM, metallocene catalyzed homogeneous linear ethylene / alpha olefin copolymer based resins, supplied by the Exxon Chemical Company of Baytown, Texas; the TAFMER^TM, resins based on homogeneous linear ethylene / alpha-olefin copolymers, supplied by Mitsui Petrochemical Corporation; and long-chain branched, metallocene-catalyzed, homogeneous ethylene / alpha-olefin copolymers supplied by the Dow Chemical Company, known as AFFINITY resins^TM.

As used herein, the term "olefin" refers generally to any of the class of monounsaturated aliphatic hydrocarbons of the general formula CnH2n, such as ethylene, propylene and butene. The term can also include alifaotic hydrocarbons that carry more than one double bond in the molecule, for example a diolefin or diene such as butadiene.

As used herein, the term "polyolefin" refers to olefin polymers and copolymers, especially of ethylene and propylene, and to polymeric materials that contain at least one olefinic comonomer, such as ethylene-vinyl acetate copolymers and ionomers. Polyolefins can be linear, branched, coyclic, aliphatic, aromatic, substituted or unsubstituted. The term polyolefin comprises olefin homopolymers; olefin copolymers; copolymers of an olefin and a non-olefinic comonoomer copolymerizable with the olefin, for example a vinyl monoomer; modified polymers of the foregoing, and the like. Modified polyolefins include modified polymers that are prepared by copolymerizing the olefin homopolymer or copolymer with an unsaturated carboxylic acid, eg. Maleic, fumaric or analogous acid, or one of its derivatives, such as, for example, anhydride, an ester, a metal salt or the like. They could also be obtained by incorporating to the olefin homopolymer or copolymer an unsaturated carboxylic acid, for example maleic, fumaoric or similar acids, or one

ES 2 186 756 T3 of its derivatives, such as anhydride, an ester, a metal salt or the like.

As used herein, the phrase "inner layer" refers to any layer of a multilayer film that has its two main surfaces directly adhered to another layer of the film.

As used herein, the phrase "outer layer" refers to any layer of a multilayer film that has only one of its major surfaces directly adhered to another layer of the film. In the multilayer films of the present invention there are two outer layers, each with a major surface adhered to only one other layer of the multilayer film. The other main surface of each of the two outer layers constitutes the two main and outer surfaces of the multilayer film.

As used herein, the term "adhesive layer" refers to any inner layer that has the primary mission of adhering two layers to each other.

Brief description of the drawing

Fig. 1 is a schematic cut of a five-layer film according to the present invention.

Detailed description of the preferred execution method

Fig. 1 represents a multilayer film 10 according to the present invention, with a preferred five-layer structure for making flexible bags for packaging and administering medicinal solutions. Examples of medicinal solutions packaged and administered in this way include saline solutions, dextrose solutions, and dialysis solutions. The multilayer film 10 comprises an inner layer 12, a first outer layer 14, a second outer layer 16, a first adherent layer 18 positioned between the inner layer 12 and the first outer layer 14 and glued to them, and a second adherent layer 20 positioned between the inner layer 12 and the second outer layer 16 and glued to them.

The multilayer film 10 preferably has a total thickness between about 7.62 x 10-5 and 3.56x10^-4 m (3 to 14 millisths of an inch (1 millimeter = 0.001 inches = 0.0254 mm)), preferably 1.27x10^-4 a2.54x10^-4 m (5 to 10 millimeters of an inch) and more preferably 1.65x10^-4 a2.41x10^-4 m (6.5 to 9.5 milli-inches). The outer layers 14 and 16 can be of a thickness between about 1.27x10^-5 m (0.5 milli-inch) and about 2.03x10^-4 m (8 milli-inches), but preferably they are about 1.91 x 10^-5 m (0.75 milli-inch) thick. The adherent layers 18 and 20 can be of a thickness between about 2.54x10^-6m (0.1 millimeters of an inch) and about 1.91 x 10^-5 m (0.75 milli-inch), but preferably they are about 1.02x10^-5 m (0.4 milli-inch) thick. The inner layer 12 can have a thickness between about 2.54x10^-5 m (1 millimeter of an inch) and about 2.29x10^-4 m (9 millimeters of an inch), but preferably about 1.32x10^-4 m (5.2 millimeters of an inch) thick.

As shown in fig. 1 and just described, it is preferable that the inner layer 12 is relatively thick compared to the other layers of the film 10. Said relative thickness generally facilitates the layer 12 to fulfill its primary function of imparting flexibility, strength, and barrier properties to the film. multilayer film 10. A layer that provides such functions is often referred to as a "core" layer.

Because it is the thickest layer of multilayer film 10, inner layer 12 generally has the greatest impact on the optical properties of a medicine solution bag made from film 10, once the bag has been heat sterilized. Therefore, the unexpected discovery that a homogeneous ethylene / alpha-olefin copolymer traps less vapor condensate after heat sterilization than a heterogeneous ethylene / alpha-olefin copolymer is particularly significant. However, this property alone is not enough to consider whether a material is appropriate to be used as the central layer of a multilayer film used in the manufacture of bags for medicinal solutions. The material must also 1) have a high enough melting point for the film to remain intact during the sterilization process; 2) provide adequate barrier properties, especially to oxygen and water vapor; 3) be processable (eg coextrudable) with the other layers of the film; and 4) imparting sufficient flexibility to the film so that the bag of medicinal solution made with it can drain properly. The inventor has found that if the homogeneous copolymer or ethylene / alpha-olefin copolymer blend in layer 12 has a density between about 0.89 and about 0.92 grams per cubic centimeter, it could satisfy all of the above properties ( in addition to the excellent ioptic properties resulting from a lower tendency to trap vapor condensate). Specifically, although homogeneous ethylene / alpha-olefin copolymers, or mixtures thereof, with densities below

ES 2 186 756 T3 about 0.89 g / cc can be used, it is unlikely that they will achieve a combination of sufficient thermal resistance to withstand sterilization, adequate impermeability to gases and very consistent fusion to allow their coextrusion with the other layers of the film . Similarly, if the density of the homogeneous ethylene / alpha-olefin copolymer, or copolymer blends, is greater than about 0.92 g / cc, the resulting bag of medicinal solution may be too stiff to drain properly and provide excellent results. ioptic properties after heat sterilization which, as has been found, offer homogeneous ethylene / alpha-olefin copolymers. For the homogeneous copolymer or ethylene / alpha-olefin copolymer blend, a density range of about 0.90 to 0.91 g / cc is best.

Preferably, the melt index (ASTM D-1238) of the homogeneous copolymer or mixture of ethylene / alpha-olefin copolymers is less than 20, more preferably less than 10, even less than 2.2, and most preferably between 0.1 and 1.5. Examples of homogeneous ethylene / alpha-olefin copolymers include the following types from Exxon Chemical Company: EXACT^TM 3029, with a melt index of approximately 1.2 dg / min. (ASTM D-1238 (E)), a density of about 0.91 g / cc (ASTM D-792) and a DSC peak of melting point of about 107 ° C (Exxon method); EXACT^TM 3025, with a melt index of approximately 1.2 dg / min. (ASTM D-1238 (E)), a density of about 0.91 g / cc (ASTM D-792) and a DSC peak melting point of about 103^°C (Exxon method); EXACT^TM 3028, with a melt index of approximately 1.2 dg / min. (ASTM D-1238 (E)), a density of about 0.90 g / cc (ASTM D-792) and a DSC peak melting point of about 92^°C (Exxon method); and EXACT^TM 4011, with a melt index of approximately 2.2 dg / min. (ASTM D-1238 (E)), a density of about 0.89 g / cc (ASTM D-1505) and a DSC peak melting point of about 70^°C (Exxon method). Other suitable homogeneous ethylene / alpha-olefin copolymers are AFFINITY resins.^TM from the Dow Chemical Co., such as types PL 1880, with a density of about 0.90 g / cc and a melt index of about 1.0; PL 1840, with a density of about 0.91 g / cc and a melt index of about 1.0; PL 1845, with a density of about 0.91 g / cc and a melt index of about 3.5; and FM 1570, with a density of about 0.915 g / cc and a melt index of about 1.0.

The first outer layer 14 preferably serves as a heat seal layer. In this way, when making a bag of medicinal solution with the multilayer film 10, the first outer layer 14 would form the inner surface of the bag, that is, the one that is in contact with the packaged medicinal solution. Furthermore, layer 14 forms a heat seal when film 10 is folded over on itself or joined with another film, so that two areas of layer 14 come into contact with each other, and sufficient heat is applied to predetermined segments of the layers. areas of layer 14 in contact, whereby the heated segments fuse and intermix with each other. Upon cooling, the heated segments of layer 14 become a single essentially inseparable layer. Consequently, the heated segments of layer 14 result in a liquid tight seal, commonly referred to as heat sealing. The resulting heat seals are generally tab-shaped and are bonded to form the peripheral junctions of the bag, so that it can fully contain the medicinal solution.

The first outer layer 14 comprises a material selected from the group consisting of a polypropylene homopolymer or copolymer, a blend of a polypropylene homopolymer or copolymer with an elastoimer, high-density polyethylene, and copolyether. Of the preceding materials, layer 14 is preferably formed from a blend of a polypropylene homopolymer with an elastoimer. Polypropylene provides good heat resistance to layer 14, while elastomer provides resistance to deformation and impact. If the elastoimer is combined with polypropylene so that the elastiomer weight percent ranges from 5 to 50 (on the total weight of layer 14), excellent heat seals can be produced. The best heat seals are obtained when the percentage by weight of the elastiomer is between approximately 10 and 40, more preferably between 10 and 30. These heat seals have sufficient consistency to withstand all the rigorous conditions that bags of medicinal solutions must normally endure. that is, thermal sterilization, application with a pressure cuff and rough handling in general.

The polypropylene homopolymer or copolymer is preferably a propylene / ethylene copolymer with 2 to 10 weight percent ethylene and more preferably 4 to 6 percent ethylene. A suitable propylene / ethylene copolymer is commercially supplied by Fina Oil & Chemical Company under the trademark Z9450, having an ethylene content of about 6 percent by weight. Other commercially available propylene / ethylene copolymers include, for example, PLTD 665 from Exxon. The polypropylene used in layer 14 can be of any of the types available, ie, isothiactic, syndiotactic, and, less preferably, atactic.

The elastiomer can be selected from the group consisting of styrene-ethylene block copolymer8

ES 2 186 756 T3 butylene-styrene (SEBS), styrene-butadiene-styrene block copolymer (SBS), styrene-isoprene-styrene block copolymer (SIS), ethylene-propylene rubber (EPM) and ethylene-propylene terpolymer -diene (EPDM). As commercially available SEBS, eg Kraton types G-1650, G-1652 and G-1657X are available from Shell Chemical Co. ElSBSlovende, eg Shell as Kraton D-1101, D-1102 , D-1300C, D-4122, D-4141, D-4455X and D-4460X. SIS is sold, for example, by Shell as Kraton D-1107, D-1111, D-1112 and D-1117. EPM is supplied eg by Exxon as Vistalon 719 or 503. EPDM is supplied eg by Exxon as Vistalon 3708.

Appropriate pre-prepared mixtures of polypropylene with elastoomer are also commercially available. For example, Z-4650 from Horizon Polymers is a blend of 80 weight percent Z-9450 (propylene-ethylene copolymer as described above) and 20 weight percent Kraton G-1652 (SEBS as described. above). The other materials from which layer 14 can be formed are generally commercially available.

When making a bag of medicinal solution with the multilayer film 10, the second outer layer 16 forms the outer surface of the bag. As such, the primary functions of the outer layer 16 are to provide thermal resistance to the bag during heat sealing and thermal sterilization, and mechanical resistance to handling and external abrasion. Layer 16 preferably comprises a material selected from the group consisting of polyamide, copolyamide, polyeoster, copolyether, high-density polyethylene, and polycarbonate.

Among the suitable polyamides and copolyamides, mention should be made of nylon 66, nylon 610, nylon 12 and copolymers thereof, nylon 11 and copolymers thereof, amorphous nylon and blends of the above polyamides. A preferred copolyamide is nylon 66/610. This material is commercially available from EMS-American Gricon, Inc. under the trademark XE 3303. Suitable copolyesters are supplied by Eastman Chemical Products, Inc. under the trademarks ECDEL^TM 9965, 9966 and 9967. Any of the other materials from which the second outer layer 16 can be formed is widely available commercially.

The first adherent layer 18 preferably comprises a material selected from the group consisting of an ethylene / alpha-olefin copolymer with a density less than or equal to 0.89 grams per cubic centometer, a homogeneous ethylene / alpha-olefin copolymer mixture with a density comprised between about 0.89 and about 0.92 grams per cubic centometer and the material constituting the first outer layer 14, anhydride modified ethylene / vinyl acetate copolymer, and anhydride modified ethylene / methyl acrylate copolymer.

All of the foregoing materials are compatible with the material constituting the inner layer 12 (ie, homogeneous ethylene / alpha-olefin copolymer). Thus, the specific material chosen for the adherent layer 18 depended on the composition of the first outer layer 14. For example, whether the layer 14 comprises a mixture of polypropylene homopolymer or copolymer (e.g., propylene / ethylene copolymer ) and elastoomer (eg. SEBS), the first adherent layer 18 preferably carries ethylene / alpha-olefin copolymer with a density less than or equal to 0.89 grams per cubic centimeter. More preferably, the density is less than or equal to 0.88 g / cc. Such a material has been found to adhere well to layers 12 and 14, and thus it is believed that it may improve the pressure cuff performance of medicine solution bags made from these films.

Ethylene / alpha-olefin copolymers with densities of 0.89 g / cc or less more widely available are those of the homogeneous type, eg, those catalyzed with metallocenes. These copolymers are sold by resin manufacturers such as the Dow Chemical Company and the Exxon Chemical Company. As an example of ethylene / alpha-olefin copolymers with a density equal to 0.89 g / cc or less, it is worth mentioning ENGAGE.^TM EG 8150, an ethylene / octene copolymer supplied commercially by Dow, having a density of 0.868 g / cc (ASTM D-792), a melt index of 0.5 dg / min. (ASTMD-1238) and 25% octene (ASTM D-2238, method B); the ENGAGE^TM EG 8100, an ethylene / octene copolymer having a density of 0.87g / cc (ASTM D-792), a flow onyx of 1 dg / min. (ASTMD-1238) and 24% octene (ASTM D-2238, method B); and the ENGAGE^TM EG 8200, an ethylene / octene copolymer having a density of 0.87 g / cc (ASTM D-792), a flow rate of 5 dg / min. (ASTM D-1238) and 24% octene (ASTM D-2238, method B).

The second adherent layer 20 preferably comprises a material selected from the group consisting of anhydride modified ethylene / vinyl acetate copolymer, anhydride modified ethylene / methyl acrylate copolymer, anhydride modified ethylene / ethyl acrylate copolymer, linear polyethylene of anhydride modified low density, modified very low density polyethylene

ES 2 186 756 T3 with anhydride, and anhydride modified high density polyethylene.

All of the above materials are compatible with the inner layer. Therefore, the material specifically chosen for the adherent layer 20 would depend on the material selected for the second outer layer 16. For example, if the layer 16 comprises copolyether, the adherent layer 20 preferably carries anhydride modified ethylene / methyl acrylate copolymer. . As suitable ethylene / anhydride-modified methyl acrylate copolymers, the BYNEL types are commercially available.^TMCXA E369 and BYNEL^TM CXA E374 from Du Pont and the PLEXAR^TM 3382 from Quantum Chemicals. Anhydride Modified Linear Low Density Polyethylene is sold by Mitsui under the ADMER trademarks^TM NF 500 and NF 550, and Du Pont under the BYNEL trademark^TM 4134. All other materials usable for the adherent layers 18 and 20 are also commercially available.

As those experienced in this field will appreciate, the multilayer films of the present invention are not limited to the five-layer structure described above. The present invention also encompasses films with fewer layers than the one illustrated, eg, the three and four-layer structure described at the beginning. Likewise, the present invention encompasses films with a greater number of layers than that illustrated in FIG. 1, that is, other layers could be added to the structure indicated in fig. 1, to give the film the necessary additional properties. For example, one or more layers of high-density polyethylene can be included in the film, to increase its barrier effect against moisture, if such increase is desired. If necessary, one or more oxygen barrier layers can also be included.

Various additives can be used in any one or all of the layers of the multilayer film of the present invention. This includes without limitation anti-adhesion agents, antioxidants, process additives such as calcium stearate, pigments, antistatic agents, etc. If the multilayer film is intended for the manufacture of bags of medicinal solution, it is preferable to reduce the amount of additives to a minimum, to minimize the probability that they will migrate to the medicinal solution during thermal sterilization.

The multilayer films of the present invention are preferably formed as coextruded tubular film. Containers for medical applications or other uses can be manufactured starting directly from coextruded tubular film, or from rolls of material obtained from cut and delaminated tube. A hot blowing process can also be used to manufacture the film, but the ioptic properties of the resulting bag would probably be lower than those of the bag obtained by the coextrusion process. Other processes such as extrusion coating, conventional lamination, slotted die extrusion, etc. They are also applicable for the production of the multilayer film of the present invention, but these alternative processes can be more difficult or less efficient than the preferred method.

Multilayer films according to the present invention are preferably crosslinked. Crosslinking increases the structural strength of the film at high temperatures and / or the force necessary to stretch the material before tearing it. Crosslinking is preferably achieved by irradiation, that is, by bombarding the film with particulate or non-particulate radiation, such as high-energy electrons produced by an accelerator or cobalt-60 gamma rays, to crosslink the film materials. The preferred radiation level is in the range of about 2 megarads (MR) to about 8 MR. Any conventional crosslinking technique can be used. For example, electroinic crosslinking can be accomplished by curtain beam irradiation. Chemical crosslinking techniques can also be employed, eg by the use of peroxides.

The bags made with the multilayer films of the present invention can be sealed in various ways well known from the art, including impulse welding and hot bar welding. An example of a commercially available impulse sealer is the VERTROD heat sealer.^TM. The heat seals that make up the upper and lower parts of the bags (generally shorter in length than their sides) are preferably formed in the machine direction of the multilayer film (that is, the direction in which the film is moved through the production equipment), against the transverse direction. (the perpendicular to the machine direction).

The multilayer films of the present invention have been described in relation to a bag for the packaging of medicinal solutions. However, it should be understood that films may also have other applications and that this discussion is not intended to be limited only to bags of medicinal solutions.

The present invention can be better understood by referring to the following examples, which are given by way of illustration and should not be construed as limiting the scope of the present invention.

IS 2 186 756 T3

Examples

All the films used in the examples were coextruded and crosslinked by high energy electronic radiation. They all had the five-layer structure depicted in fig. 1 and a total thickness of approximately 1.91 x10^-4 m (7.5 thousandths of an inch). The outer layers 14 and 16 were about 1.91 x10 thick.^-5 m (0.75 thousandths of an inch) each, adherent layers 18 and 20 a thickness of about 1.02x10^-5 m (0.4 thousandths of an inch) each, and the inner layer 12 a thickness of about 1.42x10^-4 m (5.6 thousandths of an inch).

The materials used in the examples are identified below. All percentages are by weight, unless otherwise indicated. All phasic properties and composition values ​​are approximate, unless otherwise stated.

"PEC-1": Z9450 (TM); propylene / ethylene copolymer, with an ethylene content of 6 percent by weight and a density of about 0.89 g / cc (ASTM D-1505); provided by Fina Oil & Chemical Company of Dallas, Texas.

"SEBS": Kraton G-1652 (TM); Styrene-ethylene-butylene-styrene block copolymer, with a tensile strength of about 4500 psi (ASTM D-412), a modulus at 300% of about 700 psi (ASTM D-412), an elongation of about 500 % (ASTM D-412), a Shore hardness of about 75, and a specific gravity of about 0.91; provided by Shell Chemical Co. of Houston, Texas.

"EAO-1": ENGAGE EG 8100 (TM); propylene / octene copolymer (presumed homogeneous), with a density of about 0.87 g / cc (ASTM D-792), a melt index of about 1 dg / min. (ASTM D-1238), and about 24% octene (ASTM D-2238, method B); provided by the Dow Chemical Company of Midland, Michigan.

"EAO-2": Exact^TM 3025; homogeneous ethylene / alpha-olefin copolymer, with an approximate melt index of 1.2 dg / min. (ASTM D-1238 (E)), a density of about 0.91 g / cc (ASTM D-792), and a DSC peak melting point of about 103^°C; provided by Exxon Chemical Co.

"EAO-3": Exact^TM 3028; homogeneous ethylene / alpha-olefin copolymer, with an approximate melt index of 1.2 dg / min. (ASTM D-1238 (E)), a density of about 0.90 g / cc (ASTM D-792), and a DSC peak melting point of about 92^°C; provided by Exxon Chemical Co.

"EAO-4": Exact^TM 4011; homogeneous ethylene / alpha-olefin copolymer, with an approximate melt index of 2.2 dg / min. (ASTM D-1238 (E)), a density of about 0.89 g / cc (ASTM D-1505), and a DSC peak melting point of about 70^°C; provided by Exxon Chemical Co.

"VLDPE": DEFD 1362 (TM); very low density polyethylene, with a density of about 0.906 g / cc and a melt index of about 0.9; provided by Union Carbide Chemicals and Plastics Company, Inc., Fort Lavaga, Texas.

"EMA": BYNEL CXA E374 (TM); anhydride modified ethylene / methyl acrylate copolymer, with a melt index of approximately 2.8 dg / min. (ASTM D-1238, 190 / 2.16) and a density of about 0.931 g / cc (ASTM D-1505); Provided by EI Du Pont de Nemours, Wilmington, Delaware.

"CPE": ECDEL 9965 (TM); copolyether-ether with a melt index of about 15 grams / 10 minutes (ASTM D-1238, 190 / 2.16) and a specific gravity of about 1.13 (ASTM D-792); provided by Eastman Chemical Products, Inc., Kingsport, Tennessee.

Example 1

A multilayer film according to the present invention having the following five-layer structure:

First outer layer 12 (heat sealant): 80% EPC-1 + 20% SEBS

First adherent layer 18: EAO-1

Inner (core) layer 12: 33% EAO-2, 33% EAO-3, 33% EAO-4

Second adherent layer 20: EMA

IS 2 186 756 T3

Second outer layer 16 (wear resistant): CPE Example 2

A multilayer film according to the present invention that had the same structure as Example 1, except for the inner (central) layer, which only carried EAO-3 (that is, not combined with EAO-2 or EAO-4). Example 3

A multilayer film according to the present invention that had the same structure as Example 1, except for the inner (central) layer, which only carried EAO-2 (that is, not combined with EAO-3 or EAO-4). Example 4 (comparative)

A comparative multilayer film with the same structure as example 1, except for the inner (central) layer, which had VLDPE, and the first adherent layer, made up of 50% of the material of the central layer (VLDPE) + 50% of heat-sealing material ( 80% EPC + 20% SEBS).

Example 5

Before making the medicine solution bags and thermally sterilizing them, the ooptic properties of the films of Examples 1-4 were tested for fogging and total transmission. The veil measurement and total transmission tests were carried out according to the ASTM D-1003 method, method A. Four samples were tested for each film. The results of the four respective samples were averaged and are listed in Table 1 below.

TABLE 1

<td>Film</td><td>Veil (%)</td><td>Total transmission (%)</td>

<td>Example 1</td><td> 4,6</td><td> 94</td>

<td>Example 2</td><td> 3,8</td><td> 94</td>

<td>Example 3</td><td> 4,0</td><td> 94</td>

<td>Example 4 (comparative)</td><td> 5,5</td><td> 93</td>

As can be seen, the ooptic properties of veiling and total transmission were similar for the four films before the thermal sterilization, with the films of examples 1-3 being somewhat better than the film of comparative example 4.

Example 6

To determine the effect of the thoracic sterilization on the optic properties of films 1-4, some bags of medicinal solution with a capacity of 2 liters were made with them. A VERTROD impulse heat sealer was used^tm to make the welds in the shape of a flange, around each bag. The bags were then filled with water through an opening in the top of the bag. The opening was then welded with the VERTROD impulse heat sealer^TM, the water being completely enclosed within each bag. Four such bags were made from each of the films in Examples 1-4.

Each bag of water was then heat sterilized in an autoclave at 121 ° C (250 ° F) for 30 minutes and then allowed to cool 24 hours at room temperature. The bags were then emptied and allowed to dry. Its ooptic properties of total transmission, haze, transparency and gloss were then measured. Total transmission and haze were determined according to ASTM D-1003 - method A, as before in Example 5. Transparency was measured according to ASTM D-1746 and gloss according to ASTM D-2457. The ooptic properties indicated in Table 2 below are the average values ​​of each of the four bags made with each of the films of Examples 1-4.

IS 2 186 756 T3

TABLE 2

<td>Film</td><td>Total transmission (%)</td><td>Veil (%)</td><td>Transparency (%)</td><td>Brightness (45 °)</td>

<td>Ex. 1</td><td> 93,1</td><td> 6,4</td><td> 11,1</td><td> 80</td>

<td>Ex. 2</td><td> 93,2</td><td> 6,4</td><td> 13,0</td><td> 77</td>

<td>Ex 3</td><td> 92,5</td><td> 7,8</td><td> 13,3</td><td> 78</td>

<td>Ex. 4 (Comp.)</td><td> 91,8</td><td> 33,8</td><td> 5,9</td><td> 62</td>

As can be seen, the bags made with the films of the films of Examples 1-3 (that is, films according to the present invention, with a homogeneous ethylene / alpha-olefin copolymer in the inner (central) layer) had better optic properties after thermal sterilization, in all four measurement categories (total transmission, veiling, transparency and gloss), than the bags made with the comparative film that carry a heterogeneous ethylene / alpha-olefin copolymer (that is, VLDPE) in the core layer. These improvements were not to be expected, given the pre-sterilization results of Example 5, which indicated much more similar optical properties between the films of Examples 1-4. The improvement in veiling and transparency of the films of Examples 1-3 with respect to the film of Comparative Example 4 is especially noteworthy. It is also notable that the veiling of the film in Comparative Example 4 worsened after the thoracic sterilization (table 2), compared to its value before the thoracic sterilization (table 1). As can be seen, the films in Examples 1-3 performed much better.

The better gloss of the films of Examples 1-3 over the film of Comparative Example 4 is beneficial because higher gloss medicine solution bags are more aesthetically attractive than lower gloss bags.

To simulate the bag containing medicinal solution, mineral oil was applied on the heat-sealed side of the previous heat-sterilized bags and the ooptic properties of these samples were measured as before. This did not have a great effect on the ooptic property values ​​indicated in Table 2 (ie, the films of the present invention still had better ooptic properties than the comparative film), except for transparency. The mineral oil decreased the transparency of each sample (with respect to the non-oiled one) and had the effect of lowering the best transparency of the films of examples 1-3 with respect to the film of comparative example 4. It is not known what it was due to. but it is believed to have occurred as a result of inconsistent or irregular application of mineral oil to the bags during the test.

Example 7

For all the films of Examples 1-4, deformation, resistance to break, elongation at break, modulus, operation with pressure sleeve and permeability to oxygen, humidity and carbon dioxide were measured. . The tests were carried out according to standard ASTM methods. Compared to the film of Example 4, the films of Examples 1-3 had somewhat higher breaking strength; similar behavior in terms of elasticity, elongation and modulus; better performance with a pressure cuff (that is, the water-filled bags made with these films lasted longer in a pressure cuff, before losing due to heat sealing); and a somewhat lower gas barrier effect (but still within acceptable limits for use as a bag of medicinal solution). This example is mentioned to illustrate that the films of the present invention not only show better optical properties after thermal sterilization, but also possess other phosphoric properties, necessary to use said films in the manufacture of bags for medicinal solutions.