MXPA99005887A - A medicament container of polymer of linear olefin for storing a liquid medicament - Google Patents

Abstract

The present invention relates to a medicament container for storing a liquid medicament, such as insulin, the container comprising a distal and a proximal end portion and a wall, at least two opposite portions of the wall being of a polymer material. The thickness of the polymer wall portions is between 0.3 mm and 3 mm, and the light transmission through the polymer wall portions at 400 nm are at least 25%. The polymer wall portions are of a material comprising at least 70%by weight of a linear optionally branched polyolefin material, the olefin monomer being selected from ethylene, propylene, butylene or a mixture thereof. The material has a crystallinity above 35%. The container of the polymer material is substantially inert to the medicament, and furthermore, the container is transparent, whereby it is possible visually to inspect the content of the container to make sure that the medicament is not crystallised or polymerised. Furthermore, the walls of the container provide a good barrier against m-cresol-phenol-benzyl alcohol preservatives and water, respectively. The invention also relates to the use of such medicament container, and a medicament container at least partly filled with medicament.

Description

MEDICINAL CONTAINER, LINEAR OLEFINE POLYMER FOR STORING A LIQUID MEDICINE DESCRIPTION OF THE INVENTION The present invention relates to a container of medicament, for storing a liquid medicament, to the use of such a container of medicament, and a medicament container at least partially filled with medicament. Traditionally, medicine containers for storing liquid medicines and liquid preparations have been made of glass. For certain medicaments, such as drugs for peroral administration, containers of opaque polyethylenes or polyesters have also been used. Such a polymeric container made of a polyester of polyglycolic acid and a terephthalic polyester is disclosed, for example, in US Patent No. 4,565,851. This container provides a very good barrier against oxygen and other gases, but does not provide a sufficient barrier against preservatives and water. REF .: 30573 Medications, such as insulin or growth hormone, are distributed in small containers or ampoules. Such ampules usually comprise between 1.5 and 10 ml of the ready-to-use medicine. This ampules are stored in reserve, in hospitals or pharmacies, and with the user. This means that the shelf life must be long enough. Aqueous solutions or suspensions of medicaments, such as insulin or growth hormones, are usually provided with a preservative, such as phenol and / or benzyl alcohol and / or m-cresol. The addition of preservatives is necessary because a terminal sterilization is not possible due to the sensitivity of drugs containing proteins, peptides and / or DNA sequences. Medications in containers that comprise more than one dose, for example, for use in storage systems, are at a high risk of contamination. Therefore, preservatives are essential ingredients in such medications, particularly in medicines for parenteral administration. Phenol, benzyl alcohol and m-cresol are approved in small amounts for use in parenteral medicaments, for example for intramuscular administration. Aqueous solutions or suspensions of medicines that comprise a preservative can be stored in glass containers for up to 2 years. Article ? Interaction between aqueous preservative solutions and their plastic containers, III "by TJ cCarthy, Pharm. Eekbland 107 (1972), describes the effects of storing certain aqueous solutions of preservatives in polypropylene (PP) containers colored with white pearlescent pigment and poly (chloride) of vinyl (PVC), respectively, in particular with respect to the loss of preservatives from the solutions.There are no discussions regarding the storage of aqueous solutions of preservatives in transparent containers.In addition, the conclusion in this article is that They lose large quantities of some types of preservatives from the solutions stored in PP.The PVC, however, seems to provide a good barrier against the preservatives.As a consequence of its chlorine content, PVC is not acceptable for use due to the environmental contamination European Patent EP-A 0622410 describes a medicinal article produced from a mixture that of syndiotactic polypropylene and isotactic polypropylene, with the mixture having "exceptional clarity". The improved transmission of polypropylene is achieved by decreasing the crystallization of the polymer and thereby achieving a lower turbidity. European Patent EP-A-0622410 does not mention the specific values of crystallization and is not related to the improvement of barrier properties. EP 564 206 relates to medicament containers having a multilayer structure comprising a linear polyolefin material and a crystalline polyolefin, selected from propylene or 1-butene. The material comprises atactic polypropylene, non-crystalline, amorphous for the reduction of the crystallinity and with this for the increase of the softness of the material. This invention is not related to the barrier properties of the material. Tarr et al., "Stability and sterility of biosynthetic human insulin stored in plastic syringe for 28 days," American Society of Hospital Pharmacists, vol. 48, pages 2631-34, 1991, discloses a similar test for storage of aqueous solutions of phenol, benzyl alcohol and m-cresol, respectively, in polypropylene-polyethylene syringes, in particular with respect to the loss of phenol, of benzyl alcohol and the m-cresol, respectively, of the solutions. The test covers only 28 days, but from this test it is concluded that the polypropylene-polyethylene syringes can not be used to store drugs comprising phenol and / or benzyl alcohol and / or m-cresol. The bulbs containing insulin or growth hormone are normally stored at refrigerator temperature of about 5 ° C when stored in reserve or in hospitals or pharmacies. When stored with the user, they are often stored at room temperature for up to one month. In particular, insulin is stored at room temperature, because the user usually has to carry insulin with him at all times. The concentration of insulin and preservative should be almost constant within the storage period. If the concentration of the preservative is too low, the medication will not be sufficiently preserved. It could be suggested to prepare the medication with a higher initial concentration of the preservative. However, this may be acceptable for parenteral use. The water loss should also be very low during the storage time, due to the loss of a very large amount of water which could result in a very high concentration of active drug, and possibly a too high concentration of preservatives. If too much water is lost, the user can overdose on the active medication, such as insulin. In addition, it is important that the user can visually inspect the medication to be certain that the medication has not crystallized or polymerized due to eg self-association or denaturation, or that any other visually detectable change in the medication has occurred, such as oxidation of the active medication. The object of the present invention is to provide a medicament container of a polymeric material, which material is substantially inert to the medicament, and whose container is transparent and -provides a good barrier against m-cresol / phencl / benzyl alcohol and water, respectively.

Yet another object of the invention is to provide a container of medicament, which is inexpensive and easy to produce. Still another object of the present invention is to provide a container of medicament for the long-term storage of aqueous medicaments, such as aqueous solutions of insulin or human growth hormone. The containers of medicaments according to the present invention, for the storage of a liquid medicament comprising one or more active medicaments, water and m-cresol and / or phenol and / or benzyl alcohol, comprise a distal end portion and a proximal end portion. a wall, at least two portions of the wall that are made of a polymeric material. These polymer wall portions have a thickness between 0.3 mm and 3 mm, preferably between 0.5 mm and 1 mm, a light transmission at 400 nm of 25% or more, measured through both opposite wall portions of the container, when the vessel is filled with water, using a standard spectrophotometer and air as a reference, and the polymer wall portions are made of a material comprising at least 70% by weight of a linear, optionally branched polyolefin material, the olefin monomer being selected of ethylene, propylene, butylene or a mixture thereof, the material having a crystallinity greater than 35%, preferably greater than 37% by weight, measured by differential scanning calorimetry, by cutting pieces from the walls of the container and heating them in an aluminum pan from 10 ° C to 270 ° C at a scanning speed of 10 ° C / minute by recording and integrating the fusion endotherms, and using the value of 209 J / g for crystalline polypropylene 100 as a reference. The material can comprise up to 5% by weight of additives, in particular selected from antioxidants, lubricants such as stearates and silicones, surface active agents, nucleating and clarifying agents, and up to 30% by weight of inert fillers, such as particles of glass having a refractive index approximately equal to the refractive index of the polymeric material, the total amount of additives and fillers being up to 30% by weight. As explained above, the dispersion and absorbency of the visible light of the material must be low in order to control the quality of the drug in the container. Quality control can be a visual inspection for foreign particles, the homogeneity of a suspension, the sedimentation of crystals, precipitation in solutions, fibrillation or polymerization of peptides or proteins in solutions, and changes in the absorbance spectrum of the solution of the medicine. More critical are the changes that affect the concentration of the drug or active drug in the solution, and of these, a polymerization or precipitation can be very difficult to observe by a user, especially if the container has a low light transmission. For some insulin formulations, it is important that a diabetic patient can visually observe if more than 3% of the insulin is polymerized. Polymerized insulin can be observed visually and with a spectrophotometer, as a change in the transmission of light. The typical transmission change from an insulin solution where 3% of the insulin is polymerized corresponds to the transmission change in a European Pharmacopoeia standard of 1: 400 and a typical change in the transmission of an insulin solution where 30% of insulin has been polymerized, corresponds to the change in transmission in the European Pharmacopoeia standard of 1:40. (European Pharmacopoeia 1997, section 2.2 Physical and Physicochemical Methods 2.2.1 Clarity and Degree of Opalescence of Liquids). In a glass container, the transmission typically changes from about 94% to about 45% with a European Pharmacopoeia standard of 1:40 to 400 nm and a wall thickness of 0.9 mm. In an amorphous cyclic polyolefin, the transmission typically changes from approximately 85% to approximately 41% with a European Pharmacopoeia standard of 1:40, changes visually perceived by the eye. In highly transparent polypropylene, the transmission typically changes from about 40% to about 18%. In a less transparent polypropylene, the transmission typically changes from about 15% to about 6%, or even from about 4% to about 3%, all changes being determined using a European Pharmacopoeia standard of 1:40. It is obvious that the patient has the best chance of observing such a problem in a medication container, where the transmission is high, and where the changes are large. In practice, transmission in a 3 ml container with a wall thickness of 0.9 mm and filling with a commercial insulin solution, such as Actrapid 100 U / ml (Novo Nordisk A / S), is recommended to be greater than 25% at 400 nm, in order to make it possible to visually observe a polymerization greater than 3%. A few suitable materials for packaging parenteral drugs preserved with m-cresol have surprisingly been found among the group of polyolefin materials. As explained above, any material must meet a number of specifications to be able to prevent m-cresol and water from disappearing from the drug formulation, which is capable of allowing visual inspection of product quality. Crystalline polymers often have very low transmission at 400 nm, mainly because some crystals are larger than 400 nm and thus scatter light. The size of the crystals is frequently diminished by the addition of a nucleating agent to the polymer. The polymers have sometimes attained a slight yellowing after processing, which influences the transmission of light negatively in that light at 400 nm is absorbed, and therefore provides a diminished possibility of observing the oxidation products in the drug. interest, The medicine containers of the present invention should preferably meet the following requirements: The polymer wall portions have an m-cresol permeability of less than 0.0072 g / m2 / 24 hours, measured after a storage period of three months at 37 ° C and 12% relative humidity (RH) upon contacting the polymer wall with an aqueous solution of 3 mg / ml m-cresol, and a water permeability of less than 0.4 g / m2 / 24 hours , measured after a storage period of three months at 37 ° C and 12% relative humidity, more preferably, the polymer wall portions have an m-cresol permeability of less than 0.0 070 g / m2 / 24 hours, more preferably less than 0.0055 g / m2 / 24 hours, and even more preferably less than 0.0045 g / m2 / 24 hours, measured after a storage period of three months at 37 ° C and 12 % relative humidity, by contacting the polymer wall with an aqueous solution of 3 mg / ml m-cresol, and preferably the polymer wall portions have a water permeability of less than 0.35 g / m2 / 24 hours, more preferably less than 0.30 g / m2 / 24 hours, and even more preferably less than 0.20 g / m2 / 24 hours, measured after a storage period of three months at 37 ° C and 12% relative humidity. Preferably, the polymer wall portions have a water permeability of less than 0.025 g / m2 / 24 hours, measured after a storage period of three months at 8 ° C and 13% relative humidity for 36 months, more preferably less of 0.021 g / m2 / 24 hours. The m-cresol, the benzyl alcohol and the phenol are all organic solvents with very low water solubility. M-cresol is less polar than phenol and benzyl alcohol and will therefore diffuse faster than phenol and benzyl alcohol in a hydrophobic environment, such as a polyolefin matrix. further, the solubility of m-cresol will be higher in a hydrophobic environment such as a polypropylene polymer. Even though phenol and benzyl alcohol are molecules smaller than m-cresol and that size may be important for diffusion velocity, it was found that the loss of phenol or benzyl alcohol will be less than the loss of m-cresol. cresol, and is therefore sufficient to determine the loss of m-cresol. According to the present invention, it is even more preferred that the drug container, in particular for parenteral drug applications, meet the following requirements: The transmission should preferably be greater than 30% at 400 nm, and even more preferably greater than 50. % at 400 nm. The water loss must be less than 1.5% after storage at 37 ° C and 12% relative humidity for 3 months and less than 1% after storage at 8 ° C and 13% relative humidity for 36 months. For a 3 ml container with an internal diameter of 9.25 mm and a wall thickness of 0.9 mm, this corresponds to a permeability at approximately 37 ° C of 0.35 g / m2 / 24 hours and at 8 ° C of approximately 0.021 g / m2 /24 hours. The loss of m-cresol should be less than 10% for the entire container, and preferably 7.5% for the polymeric wall portions of the container after storage at 37 ° C and 12% relative humidity for 3 months. For a 3 ml container with an internal diameter of 9.25 mm and a wall thickness of 0.9 mm, this corresponds to a permeability of approximately 0.0053 g / m2 / 24 hours. The present invention relates to a medicament container at least partially filled with a solution of liquid medicament, comprising one or more active medicaments, water and m-cresol and / or phenol and / or benzyl alcohol. According to the invention, it has been found that a group of polymeric containers meet the specification, namely the containers comprising the crystalline polymers of a linear, optionally branched polyolefin material, the olefin monomer being selected from ethylene, propylene, butylene or a mixture thereof, the material having a crystallinity greater than 35% by weight, such as above 37% by weight, measured by differential scanning calorimetry, by cutting the pieces of the walls of the container and heating them in a pan aluminum from 10 ° C to 270 ° C at a scanning speed of 10 ° C / minute, registering and integrating the fusion endotherms, and using the value of 209 J / g for 100% crystalline polypropylene as a reference. In the present invention the polymeric wall material comprises at least 75%, preferably more than 95%, and more preferably more than 98% by weight of a polyolefin material. The crystalline polymer is preferably a linear or branched polypropylene or a linear or branched polyethylene, more preferably selected from a polypropylene homopolymer or a propylene-ethylene copolymer or a mixture thereof. The ethylene content in the propylene-ethylene copolymer is preferably up to 1.8% by weight, more preferably between 0.5 and 1.8% by weight, and even more preferably between 1% and 1.8% by weight of the total polymer wall material. The ethylene content was measured using a FTIR spectrophotometer at 730 cm -1, and using the absorbance of propylene at 460 cm -1 as an internal reference, preferably between 0.5 and 1.8% by weight, more preferably between 1% and 1.8% by weight of the total polymer wall material. Too low ethylene content will generally result in a high crystallinity polyolefin material with large crystals, producing a material with too low light transmission at 400 nm. However, the polyolefins produced by the use of metallocene catalyst technology can be branched such that the crystallinity and the size of the crystals are controlled to provide the transparency of the material. An effect on crystallinity similar to the effect obtained by ethylene in a polypropylene, this can be achieved with the use of the polymerization of the metallocene catalyst, of propylene with or without other olefin monomers. Too much ethylene in the material will generally result in lower crystallinity and thus poor barrier properties. The crystallinity of the polymeric wall material should preferably be up to 10% more preferably up to 45%, and even more preferably up to 42% by weight, measured as specified above. In addition, it is preferred that the crystalline polymer wall portions have a light transmission greater than 30% at 400 nm. In general, crystals are expected to be randomly distributed in the bulk polymer. However, the condition of the molding can affect the crystallization process and result in an asymmetric distribution of the crystals. The surface concentration of the crystals may theoretically be greater than the total volume, and indeed a crystalline layer of 200 nm high may be the limiting step of the diffusion rate in the process, and such a layer will not affect the transparency of the material. According to the present invention, the medicament containers are preferably produced using injection molding technique. The density of a plastic material depends on the density of the crystalline phase and the density of the amorphous phase. In general, the permeability rate is negligible in the crystals compared to the amorphous phase. The density of the crystalline phase depends for example on the material, on the additives, but also on the processing conditions. The density of the amorphous phase, for example, depends on the free volume in this amorphous phase and the glass transition temperature. In this way, one would expect that the density of the amorphous phase of the crystalline polymeric materials would be important for the barrier effect. However, the density is not important for the barrier effect of the crystalline polymeric materials. It is preferred that the crystalline polymer material of the wall portions of the container preferably have a glass transition temperature of at least -20 ° C, more preferably at least -15 ° C, and even more preferably at least -10 ° C. The rest of the material may preferably be up to 5% by weight of the additives, in particular selected from antioxidants, lubricants, such as stearates and silicones, surface active agents, nucleating and clarifying agents, and inert fillers, such as particles of glass having a refractive index approximately equal to the refractive index of the polymeric material, the total amount of additives and fillers constituting up to 30% by weight. The container according to the invention having polymeric wall portions of crystalline material can have any suitable shape. It is preferred that the inner surface of the wall, and preferably also the outer surface of the wall of the container, have a substantially cylindrical shape, because if a flexible rubber piston is rotated a few degrees in the container, it it can only maintain its tightening-or sealing effect if at least the internal surface of the container has a substantially cylindrical shape. The container may preferably be a cartridge, the distal end portion thereof comprises a pierceable seal, and the proximal end portion comprises a plunger. Such cartridges are known in the art. The polymer wall portions preferably constitute at least 30%, preferably more than 50%, and more preferably more than 80% of the area of the wall. The container may have thicker and thinner wall parts. Improved transmission can be obtained by decreasing the thickness of one or more parts of the vessel wall. This will obviously affect the barrier properties in these parts. The improved barrier properties of the container can be obtained by increasing the thickness of one or more parts of the container wall. In a preferred embodiment according to the invention, the container is a cartridge having a polymer wall with an internal cylindrical side, and a distal end portion comprising a pierceable seal, and a proximal end portion comprising a plunger, the wall having a varying thickness to provide a very transparent window . The wall of the container can be processed preferably by injection molding, in particular if the main part of the entire wall is made of polymeric material. The invention also relates to the use of containers for storing a medicament comprising one or more preservatives. The medicament is preferably an aqueous solution or suspension of human growth hormones, or an aqueous solution of insulin or insulin suspension, preferably comprising between 25 and 600 U of insulin, between 0.1 and 5 mg of phenol or benzyl alcohol, and between 0.5 and 5 mg of m-cresol per my medication. In the examples, the following methods have been used to determine the properties of the materials: Permeability The materials were molded in 3 ml containers with an outer diameter of 11.05 mm, an internal diameter of 9.25 mm, and thus a wall thickness of 0.90 mm. The containers were closed with a bromobutyl rubber stopper at one end and a bromobutyl / natural rubber laminate at the other end. The permeability of m-cresol was measured after storage of the container with insulin (Actrapid, 100 IU / ml, Novo Nordisk A / S) at 37 ° C, 13% relative humidity for 3 months. The water permeability was measured after storage of the insulin formulation container (Actrapid, 100 IU / ml, Novo Nordisk A / S) at 37 ° C, 13% relative humidity. or 3 months and at 8 ° C, 13% relative humidity for 6, 12 and 18 months.

Permeability of m-cresol The loss of m-cresol was measured after a storage period of three months at 37 ° C, with a size exclusion method by high performance liquid chromatography (HPLC) using isocratic elution with a mobile phase, on a Waters column. Protein-Pak 1-125, with the following composition: 600 g of glacial acetic acid, 600 g of acetonitrile, 2.8 g of L-arqinine and water added up to 4000 g. Frozen standards were used to correct the displacement in the HPLC system. The glass containers with the same dimensions as the plastic containers were used to correct the losses through the rubber stopper and the rubber closure. The permeability was calculated. Water permeability The water permeability was measured as a weight loss after the 3, 6 and 18 month trial period. The loss was linear with time in the trial period and the results can therefore be extrapolated to 36 months at 8 ° C. Glass containers with the same dimensions were used as a reference.

Transmission The transmission was measured with a standard spectrophotometer, using air as a reference. The container was placed with the beam of light perpendicular to the plastic surface, so that the beam of light passed through the wall of the container, through the solution of water or water contained therein, and out through the opposite wall of the container towards the detector. In this setting, the light passes through the double-thick wall. The diameter of the light beam was kept small, in comparison with the diameter of the container, to avoid reflection on the surface of the container. Density The densities of the plastic materials were determined by measuring the volumetric change of an aqueous solution, which contained detergent, when a known weight of the plastic is added to the liquid.

Crystallinity The weight percentage of the crystalline phase, for example, the crystallinity, of the polypropylene materials was evaluated by differential scanning calorimetry, DSC. The samples were cut from the containers and placed in aluminum pans. The samples were subsequently heated from 10 ° C to 270 ° G at a scanning speed of 10 ° C / minute. The peaks recorded in the fusion endotherms were integrated. The crystallinities were evaluated by comparing the values of the integrated peaks with a reference value of 209 J / g for 100% crystalline polypropylene.

Ethylene content The ethylene content was measured using an FTIR spectrophotometer at 730 cm "1, and using the absorbance of propylene at 460 cm-1, as an internal reference The method was calibrated by using two samples of the propylene copolymer with known content of ethylene, and one that did not contain ethylene If the polymer contains additives that comprise 3 to 4 repeating methylene groups, these additives can be recognized as polymerized ethylene, however, normally this source of error can be neglected. materials In the examples, the materials in Table 1 were used.

Table 1 Materials used in 15 samples Polypropylenes: Distributor Development Sample Used in the example (Yes / No) No. Fine Pro Fina, Denmark Yes 1 PPH 10042GR Fine Thin, Denmark SI PPH 9010 Ferro NPP00 Melitek ApS, SI HQ3246NA-22 DENMARK Rexene © Melitek ApS, NO 41E 12 DENMARK Rexene © Melitek ApS, NO 23H10 DENMARK Rexene © Melitek ApS, NO 13T10 DENMARK Borealis® Borealis, Denmark SI RF 3650 Borealis® Borealis, Denmark SI XC20.76CN Borealis® Borealis, Denmark SI XB 80 Escorene® Exxon, Denmark NO PP1444 Escorene® Exxon, Denmark NO 9074H1 Hoechst Hoechst, Denmark SI Hostacan® Ferro NPPOO Melitek ApS, SI 2 + 3 Q3296NA-22 DENMARK Ferro NPPOO- Melitek ApS, SI NQ3296NA-25 DENMARK Ferro RS Melitek ApS, SI 2971-1 DENMARK Ferro RS Melitek ApS, SI 2071 -2 DENMARK Ferro NPPOO Melitek ApS, SI NQ3246NA-P DENMARK Ferro NPPOO Melitek ApS, SI HQ3296NA-P2 DENMARK The Melitek ApS materials were developed at the request of the inventors of the present invention in connection with the present invention. The other development materials were received from the companies as: transparent materials not commercially available, under development for the subsequent introduction to the market. The development materials are therefore not commercially available as such, but can be obtained from the distributor upon request.

Example 1 Containers of 12 different polypropylene materials, transparent, see table 1, were produced by injection molding. The containers of 3 mi had outer diameters of 11.05 mm, internal diameters of 9.25 mm, and thus a wall thickness of 0.90 mm. The containers were closed with a bromobutyl rubber stopper at one end, and a bromobutyl / natural rubber laminate at the other end. The density, ethylene content, crystallinity, water permeability and m-cresol, and light transmission of the container samples were evaluated as described above. The results of the evaluation are shown in table 2. As shown in table 2, light transmission varies from 11.7 to 60.0%. The samples of Fina Pro 10042GR, Rexene® 41E12 and Rexene® 23M10 fail to meet the requirement in a minimum transmission of 25%. The crystallinity of the container wall materials varies between 32 and 430. As described above, the permeability limits of water and m-cresol may for example be 0.35 g / m2 / day, and 0.0053 g / m2 / day, respectively. As can be seen from the permeability data in Table 1, a degree of cystallinity greater than 37% is required if these preferred permeability limits have to be met. The 5 samples us. 2, 3, 10, 11 and 12 according to the invention are marked with OK_ in the table.

Table 2 The m-cresol permeability and water permeability data are obtained at 37 ° C as described above.

Wall material Transmission Permeability Permeability Density g / ml Content of Crystallinity OK (sample No.) to m-cresol to ethylene water V.% G / m2 / day g / m2 / day Fine Pro PPH 10042GR 16.6 0.0045 0.25 0.90 0.1 43 (1) Fine PPH 9010 30.9 0.0035 0.25 0.91 0.2 42 (2) Ferro NPPOO HQ3246NA-22 30.5 0.0042 0.23 0.90 1.6 39 (3) Rexene® 41E12 17.9 0.0045 0.17 0.90 0.0 42 (4) Rexene® 23H 10 11.7 0.0049 0.30 0.89 2.1 33 (5) Rexene 13T10 46.2 0.0079 0.33 0.91 3.5 32 (6) Borealis® RF 3650 29.9 0.0082 0.30 0.90 4.2 33 (7) Borealis® XC20.76CN 47.3 0.0073 0.32 0.90 3.2 34 (8) Borealis® XB 80 55.7 0.0077 0.29 0.91 2.6 35 (9) Escorene® PP1444 26.0 0.0033 0.28 0.92 1.7 38 (10) Escorene® 9074H1 37.6 0.0069 0.22 0.90 1.8 37 (1 1) Hoechst Hostacan® 60.0 not measured not measured 0.90 0.2 39 (12) The ethylene content has an influence on the degree of crystallinity and, as a consequence, also on the permeability. The density varies within a very limited range, 0.89-0.92 g / m2. There is no correlation between density and permeability data. Consequently, this parameter can not be used when a suitable material is selected for a container, in order to meet the permeability requirements.

Example 2 Ferro clarified polypropylene material, used for container sample no. 3 in Example 1, it was used for the subsequent optimization of the compounds with respect to transmission and barrier properties. The temperature of the process and the formulation of the compound were varied, and the properties of the containers prepared from the resulting materials were evaluated as in example 1. The results are shown in table 3.

Table 3 The m-cresol permeability and water permeability data are obtained at 37 ° C as described above.

Wall material Transmission Permeability permeability Density Crystallinity Content O (shows No.) to m-cresol to ajua Sisal ethylene * /. g / m2 / day g / m2 / day Ferro NPPOO Q3296NA-22 30-5 0.0042 0.23 0.90 1.6 39 (13) Ferro NPPOO- NQ3296NA-25 19.2 0.0042 0.25 0.90 1.6 36 (14) Ferro RS 2971-1 26.3 0.0034 0.20 0.93 1.1 38 (15) Ferro RS 2071-2 34.0 0.0038 0.21 0.91 1.3 41 (16) Ferro NPPOO NQ3246NA-P 33.0 0.0036 0.24 0.90 1.3 39 + (17) Ferro NPPOO HQ3296NA-P2 34.2 0.0038 0.25 0.92 1.0 30 + (18) The difference between the container sample no. 13 of Ferro NPPOONQ3246NA-22 and the sample no. 14 of Ferro NPPOONQ3246NA-25, respectively, is the molding temperature. Ferro NPPOONQ3246NA-25 was molded at 250 ° C, which gave the vessel a slightly yellow color, and therefore the absorption at 400 nm is increased. This results in a decrease in transmission compared to sample No. 13, processed at 220 ° G. This example shows the importance of the conditions of the process, and not only of the compound itself, on the transmission. Samples 15 to 17 are made from different Ferro compositions, samples Nos. 13 and 15 through 17 have transmission and barrier properties within the specification of the invention and are therefore marked "OK". This indicates that an additional optimization of the composition transmission (Ferro NPPOONQ3246NA-22) is possible within the specified limits of the barrier properties.

Example 3 The influence of the surface to volume ratio on m-cresol permeability was studied in vessels made of Ferro NPPOONQ3246NA-22 and closed with a bromobutyl rubber stopper at one end and a bromobutyl / natural rubber laminate at the other end . The loss of m-cresol was found to be 8.5% for the entire container, and 6% for the polypropylene part. 6% corresponds to a loss of 0.58 mg m-cresol per container (area 14.62 cm2 and 3.22 ml volume), or a permeability of 0.0042 g / m2 / day (0.9 mm thickness). When the surface to volume ratio increases from 4.5 cm2 / ml to 5.7 cm2 / ml, the loss of m-cresol increases from 6% to 7.6%. Using another cylindrical container with a volume of 3 ml, where the height is equal to the diameter, the ratio of surface to volume is 2.5 cm2 / ml. Thus, the expected loss of m-cresol should be 3.5%. In a 3 ml container, where the height is equal to the diameter, this could correspond to a diameter of 15.7 mm. The loss of m-cresol through a rubber stopper, and rubber closure, could probably increase. For practical applications, the diameter of a 3 ml container should preferably be 7 to 12 mm, resulting in a loss between 4.5 and 7.6%. The loss of m-cresol is dependent on the solubility of m-cresol in the polymeric wall material, the diffusion through this material, and the adsorption on the surface of the wall. For Ferro NPPOONQ3246NA-22, the loss will decrease if the thickness of the wall increases. However, an increase in the thickness of the wall will also decrease the transmission of light, and with this will reduce the possibility of visual inspection of the drug. It was found that the water loss was 1.1% for the complete container (surface to volume ratio of 4.5 cm2 / ml), and 1.0% for the polypropylene wall. The 1.0% corresponds to a loss of 32 mg of water per container, or a permeability of 0.23 g / cm2 / day (thickness of 0.9 mm).

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the p > present description of the invention.

Claims (20)

RE IVINDICATIONS Having described the invention as above, the content of the following claims is claimed as property:

1. A container for medication for storing a liquid medicament comprising one or more active medicaments, water and m-cresol and / or phenol and / or benzyl alcohol, the container is characterized in that it comprises a distal end portion and a proximal end portion and a wall, at least two opposite portions of the wall, which are made of a polymeric material, the polymeric wall portions have a thickness between 0.3 mm and 3 mm, a light transmission at 400 nm of 25% or more, preferably of 30% or more, measured through both opposite wall portions of the container, when the container is filled with water, using a spectrophotometer and air as reference, the polymer wall portions are made of a material comprising at least 70% by weight of a linear or branched polyolefin material, the ethylene, propylene, olefin monomer being selected. butylene or a mixture thereof, the material has a crystallinity of greater than 35%, preferably greater than 37% by weight, as measured by differential scanning calorimetry, by cutting pieces of the vessel walls by heating them in a 10 ° aluminum pan C at 270 ° C at a scanning speed of 10 ° C / minute, recording and integrating the fusion endotherms, and using the value of 209 J / g for 100% crystalline polypropylene as a reference.

2. A container according to claim 1, characterized in that the polymeric wall material comprises at least 75%, preferably more than 95%, and still more preferably more than 98% by weight of a polyolefin material.

3. A container according to claim 1 or 2, characterized in that the polyolefin material is a linear or branched polypropylene or a linear or branched polyethylene, more preferably a polypropylene homopolymer.

4. A container according to claim 1 or 2, characterized in that the polyolefin material is a propylene-ethylene copolymer having an ethylene content of up to 1.8% by weight, measured using an FTIR spectrophotometer at 730 cm "1, and using the absorbance of propylene at 460 cm "1 as internal reference, preferably between 0.5 and 1.8% by weight, more preferably between 1% and 1.8% by weight of the total wall polymer material.

5. A container according to any of claims 1 to 4, characterized in that the polymeric wall material has a crystallinity of up to 50%, preferably up to 45%, and more preferably up to 42% in weight, measured as specified in accordance with Claim 1

6. A container according to any of claims 1 to 5, characterized in that the polymer wall portions have a light transmission at 400 nm greater than 30%, measured as defined in accordance with claim 1.

7. A container according to any one of claims 1 to 6, characterized in that the wall polymeric material has a glass transition temperature of at least -20 ° C, preferably at least -15 ° C, and more preferably greater than -10. ° C.

8. A container according to any of claims 1 to 7, characterized in that the polymeric wall material comprises up to 5% by weight of additives, preferably selected from antioxidants, lubricants, surface active agents, nucleating and clarifying agents, and up to 30% by weight of inert fillers, preferably glass particles having a refractive index approximately equal to the refractive index of the polymeric material, the total amount of additives and fillers is up to 30% by weight.

9. A container according to any of claims 1 to 8, characterized in that the wall of the container has an internal surface and an external surface, the internal surface has a substantially cylindrical shape.

10. A container according to any of claims 1 to 9, characterized in that the wall of the container has an internal surface and an external surface, the external surface of the wall has a substantially cylindrical shape.

11. A container according to any of claims 1 to 10, characterized in that the container is a card, the distal end portion thereof comprises a pierceable seal and the proximal end portion comprises a plunger.

12. A container according to any of claims 1 to 11, characterized in that the polymer wall portions constitute at least 30%, preferably more than 50%, and more preferably more than 80% of the wall area.

13. A container according to any of claims 1 to 12, characterized in that the polymer wall portions have an m-cresol permeability of less than 0.0072 g / m2 / 24 hours, measured after a storage period of three months to 37 ° C and 12% relative humidity by contacting the polymer wall with an aqueous solution of m-cresol at 3 mg / ml, and a water permeability of less than 0.4 g / m2 / 24 hours, measured after a period storage three months at 37 ° C and 13% relative humidity.

14. A container according to claim 13, characterized in that the polymer wall portions have an m-cresol permeability of less than 0.0070 g / m2 / 24 hours, preferably less than 0.0055 g / m2 / 24 hours, and more preferably less than 0.0045 g / m2 / 24 hours, measured after a storage period of three months at 37 ° C and 13% relative humidity, by contacting the polymer wall with an aqueous solution of m-cresol at 3 mg / ml.

15. A container according to claim 13 or 14, characterized in that the polymer wall portions have a water permeability of less than 0.35 g / m2 / 24 hours, preferably less than 0.30 g / m2 / 24 hours, measured after a period of storage three months at 37 ° C and 13% relative humidity.

16. A container according to claim 13, 14 or 15, characterized in that the polymer wall portions have a water permeability of less than 0.025 g / m2 / 24 hours, preferably less than 0.021 g / m2 / 24 hours, measured after a storage period of three months at 8 ° C and 13% relative humidity.

17. The use of a container for medication according to any of claims 1 to 16, for storing a medicament comprising one or more preservatives.

18. The use according to claim 17, wherein the medicament is an aqueous solution of insulin or aqueous suspension of insulin, preferably comprising between 25 and 600 U of insulin, between 0.1 and 5 mg of phenol or benzyl alcohol, and between 0.5 and 5 mg of m-cresol per my medication.

19. The use according to claim 17, wherein the medicament is an aqueous solution or aqueous suspension of the human growth hormone.

20. A container for medicament according to any one of claims 1 to 16, at least partially filled with a liquid drug solution, characterized in that it comprises one or more active medicaments, water and m-cresol and / or phenol and / or benzyl alcohol . SUMMARY OF THE INVENTION The present invention relates to a container for medicament, for storing a liquid medicament, such as insulin, the container comprises a distal end portion and a proximal end portion and a wall, at least two opposite portions of the wall that are a polymeric material. The thickness of the polymer wall portions is between 0.3 mm and 3 mm, and the transmission of light through the polymer wall portions at 400 nm is at least 25%. The polymer wall portions are made of a material comprising at least 70% of the weight of a linear polyolefin materialoptionally branched, the olefin monomer being selected from ethylene, propylene, butylene or a mixture thereof. The material has a crystallinity greater than 35%. The container of the polymeric material is substantially inert to the medicament, and in addition, the container is transparent, whereby it is possible to visually inspect the contents of the container to ensure that the medicament has not crystallized or polymerized. In addition, the walls of the container provide a good barrier against the preservatives of m-cresol-phenol-benzyl alcohol and water, respectively. The invention also relates to the use of such a container for medicament, and a container for medicament at least partially filled with medicament.