• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to a medicament container for the storage of a liquid medicament such as insulin, the container comprising a distal and proximal end and a wall, the wall comprising a wall of at least two opposite parts of the wall of polymeric material. The thickness of the polymer wall portion is between 0.3 mm and 3 mm and the light transmission through the polymer wall portion at 400 nm is at least 25%. The polymer wall portion comprises at least 70% by weight or more optionally branched polyolefin material and the olefin monomer is selected from ethylene, propylene, butylene or mixtures thereof. The material has a crystallinity of at least 35%. The container of the polymeric material is essentially inert to the drug and furthermore the container is transparent so that it can be visually inspected the contents of the container to confirm that the drug does not crystallize or polymerize. Moreover, the wall of the vessel provides a good barrier against each of the m-cresol-phenol-benzyl alcohol preservative and water. The invention also relates to the use of such medicament containers and medicament containers at least partially filled with a medicament.
    公开号:KR20000069680A
    申请号:KR1019997005727
    申请日:1997-12-16
    公开日:2000-11-25
    发明作者:부치-라스무스젠토마스；잔나스치패트릭；본네죄르겐젠에르링
    申请人:한센 핀 베네드, 안네 제헤르, 웨이콥 마리안느；노보 노르디스크 에이/에스；
    IPC主号:
    专利说明:

    Pharmaceutical containers made of linear olefin polymers for liquid pharmaceutical storage {A MEDICAMENT CONTAINER OF POLYMER OF LINEAR OLEFIN FOR STORING A LIQUID MEDICAMENT}
    Traditionally, pharmaceutical containers for storing liquid pharmaceuticals and preparations have been made of glass. Opaque polyethylene or polyester containers have also been used in certain medications, such as oral administration medications. Such polymer containers made of polyglycolic acid polyesters and terephthalic acid polyesters are described, for example, in US Pat. No. 4,565,851. This vessel is a very good barrier to oxygen and other gases, but not a sufficient barrier to preservatives and water.
    Drugs such as insulin or growth hormone are distributed in small containers or ampoules. Such ampoules generally comprise 1.5-10 ml of ready-to-use medicaments. The ampoules are stored in storage, in a hospital or pharmacy and with the user. This means that the shelf life must be long enough. Aqueous solutions or suspensions of agents such as insulin or growth hormone are generally supplied with preservatives such as phenol and / or benzyl alcohol and / or m-cresol. Addition of preservatives is necessary because final sterilization is not possible due to the sensitivity of agents containing proteins, peptides and / or DNA sequences. For example, a medicament in a container containing more than one dose for use in a storage system is at great risk of contamination. Preservatives are therefore an essential ingredient in such medicaments, in particular parenteral administration medicaments. Phenol, benzyl alcohol and m-cresol are approved in small amounts for use in parenteral agents such as, for example, intramuscular administration. An aqueous solution or suspension of a medicament containing a preservative may be stored in a glass container for two years or more.
    T. J. McCarthy, Pharm. A paper by Weekblad 107 (1972), "Interaction between Preservative Aqueous Solution and its Plastic Container, III," describes the storage of specific preservative aqueous solutions in polypropylene (PP) and poly (vinyl chloride) (PVC) containers, respectively, stained with white pearl pigments. The effect, specifically the loss of preservatives from solution, is described. There was no discussion of the storage of preservative aqueous solutions in transparent containers. Furthermore, the conclusion of this paper is that some types of preservatives are lost from solutions stored in bulk PP and PVC, but seem to provide a good barrier to preservatives. PVC cannot be used because of environmental pollution caused by its chlorine content.
    Tarr et al., "Stability and sterility of biosynthetic human insulin stored in plastic insulin syringe for 28 days", American Society of Hospital Pharmacists, vol. 48, pages 2631-34, 1991, Similar tests of storage of aqueous phenol, benzyl alcohol and m-cresol solutions, respectively, for silver polypropylene-polyethylene syringes, specifically for the loss of phenol, benzyl alcohol and m-cresol, respectively, from solution. Describe.
    This test lasted only 28 days but concluded that the polypropylene-polyethylene syringe could not be used for drug storage containing phenol and / or benzyl alcohol and / or m-cresol. Insulin or growth hormone containing ampoules are generally stored at refrigeration temperatures of about 5 ° C. when stored in storage or in hospitals or pharmacies. When stored with a user they are often stored at room temperature for more than a month. In particular insulin is stored at room temperature because the user generally must always carry with him or her. The concentrations of insulin and preservatives should be nearly constant within the storage period. If the concentration of preservative is too low, it will not be preserved enough. It may be proposed to prepare a medicament with a higher initial concentration of preservative. However, this is not suitable for parenteral administration. The loss of water must also be very low during the storage period because too much water loss results in too high a concentration of active agent and possibly too high a concentration of preservative. If too much water is lost, the user may overdose on active agents such as insulin.
    Furthermore, the user visually checks to see if the drug has not crystallized or polymerized, for example due to self-bonding or denaturation, or to see if any other visually detectable change in the drug, such as oxidation of the active agent, has occurred. It is important to be able to.
    The present invention relates to a liquid drug storage container, the use of the drug container and a drug container at least partially filled with a drug.
    It is an object of the present invention to provide a medicament container of polymeric material in which the material is essentially inert to the medicament and the container is a transparent polymeric material and to provide good barriers to m-cresol / phenol / benzyl alcohol and water respectively.
    Another object of the present invention is to provide a pharmaceutical container which is inexpensive and easy to produce.
    Yet another object of the present invention is to provide a pharmaceutical container for long term storage of an aqueous pharmaceutical agent, such as an aqueous solution of insulin or human growth hormone.
    A medicament container for the storage of a liquid medicament comprising at least one active agent, water and m-cresol and / or phenol and / or benzyl alcohol according to the invention comprises a distal and proximal end and a wall, at least two of the walls The part is of polymeric material. This polymer wall portion is between 0.3 mm and 3 mm thick, preferably between 0.5 mm and 1 mm, which is measured through both opposing vessel wall portions when the vessel is filled with water using standard spectrophotometer and air as reference. The light transmittance at 400 nm is 25% or more, and the polymer wall portion is made of a material in which the olefin monomer comprises at least 70% by weight of a linearly optionally branched polyolefin material selected from ethylene, propylene, butylene, or mixtures thereof. The material was cut into pieces of the vessel wall by differential scanning calorimetry and heated in an aluminum pan to 10 ° C.-270 ° C. to record and integrate the melt endotherm at a scanning rate of 10 ° C./min and for reference to 100 crystalline polypropylene It has a crystallinity of at least 35% by weight, preferably at least 37% by weight when the crystallinity is measured using a 209 J / g value.
    The material specifically contains inert fillers such as glass pieces having an index of refraction of about 5% by weight or less of additives selected from lubricants such as antioxidants, stearates and silicones, surface active agents, nucleating agents and clarifiers, and having a refractive index nearly equal to that of the polymeric material. Up to 30 weight percent, and up to 30 weight percent of total amount of additives and fillers.
    As described above, the scattering and absorption of visible light of the material should be low to control the quality of the drug in the container. The quality control can be a visual inspection of the foreign particles, the homogeneity of the suspension, the precipitation of the crystals, the precipitation in the solution, the degradation or polymerization of the peptide or protein in the solution and the change in the absorption spectrum of the drug solution.
    Polymerization or precipitation, the most pronounced change that affects the concentration of the active agent or drug in a solution, can be very difficult for the user to observe, especially if the vessel has low light transmission.
    For some insulin preparations, it is important that diabetics can visually observe if more than 3% of insulin has polymerized. The polymerized insulin can be observed both visually and spectrophotometer as a change in light transmittance. A typical change in the light transmittance of an insulin solution polymerized by 3% of insulin corresponds to a change in the transmittance of the 1: 400 Ph.Eur standard and a typical change in the light transmittance of an insulin solution polymerized by 30% of insulin is 1:40. Corresponds to the change in transmittance in the Ph.Eur standard. (1997 European Pharmacopeia section 2.2 Physical and Physicochemical Methods.2.2.1 Clearity and Degree of Opalescence of Liquids.)
    For glass containers the light transmittance typically varies from about 94% to about 45% at 1:40 Ph.Eur at wall thicknesses of 400 nm and 0.9 mm. For amorphous cyclic polyolefins the transmittance typically varies from about 85% to about 41% at 1:40 Ph.Eur and the change is visually discernible. For extremely transparent polypropylene, its transmission typically varies from about 40% to about 18%. For less transparent polypropylene the transmittance is typically from about 15% to about 6% or from about 4% to about 3% and all changes were measured using 1:40 Ph. Eur.
    It is clear that in drug containers with high permeability and large changes, the patient is most likely to observe such changes. In fact, in a 3 ml container with a wall thickness of 0.9 mm and filled with a commercial insulin solution such as Actrapid 100 U / ml (Novo Nordisk A / S), the permeability of more than 3% is greater than 25% at 400 nm. It is recommended to have a high transmittance.
    Several suitable materials for parenteral drug packaging that are preserved with m-cresol have surprisingly been found in the group of polyolefin materials. As described above, certain materials must perform many efficacies to prevent m-cresol and water from escaping from the drug formulation and to visually inspect the quality of the product.
    Crystalline polymers often have very low transmittances at 400 nm, mainly because some of the crystals are larger than 400 nm and scatter light. The size of the crystals is often reduced by adding nucleating agents to the polymer. The polymer sometimes gets slightly yellow after the process, which negatively affects the light transmittance in that light is absorbed at 400 nm, thereby reducing the possibility of observing the oxidation product in the desired drug.
    The pharmaceutical container of the present invention should preferably satisfy the following requirements.
    The polymer wall portion is less than 0.0072 g / m 2/24 hours of m-cresol as measured by contacting the polymer wall with an aqueous 3 mg / ml m-cresol solution after a three month storage period at 37 ° C., 12% relative humidity. Permeability and water permeability less than 0.4 g / m 2/24 hours measured after 3 months storage period at 37 ° C., 12% relative humidity, more preferably 3 months at 37 ° C., 12% relative humidity. After the storage period the polymer wall is measured by contacting with an aqueous 3 mg / ml m-cresol solution, less than 0.0070 g / m 2/24 hours, more preferably less than 0.0055 g / m 2/24 hours, even more preferably 0.0045 g Water permeability of less than 24 m 2/24 hours, and the polymer wall portion is less than 0.35 g / m 2/24 hours, more preferably 0.30 g / m 2, measured after 3 months of storage at 37 ° C., 12% relative humidity. Water permeability less than / 24 hours, even more preferably less than 0.20 g / m 2/24 hours.
    Preferably the polymer wall portion has a water permeability of less than 0.025 g / m 2/24 hours, more preferably less than 0.021 g / m 2/24 hours as measured after a 36 month storage period at 8 ° C., 13% relative humidity. .
    m-cresol, benzyl alcohol and phenol are all organic solvents with very low solubility in water. Since m-cresol is less polar than phenol and benzyl alcohol, it will diffuse faster than phenol and benzyl alcohol in hydrophobic environments such as polyolefin matrices. Moreover, the solubility of m-cresol will be higher in hydrophobic environments such as polypropylene polymers. Although phenol and benzyl alcohol are smaller molecules than m-cresol and size may be important for the diffusion rate, the loss of phenol or benzyl alcohol will be smaller than the loss of m-cresol. It turns out that it is enough.
    According to the present invention, even more preferred pharmaceutical containers specifically for application to parenteral drugs must satisfy the following requirements.
    The light transmittance should preferably be greater than 30% at 400 nm, more preferably greater than 50% at 400 nm.
    The loss of water should be less than 1.5% after 3 months of storage at 37 ° C., 12% relative humidity and less than 1% after 36 months of storage at 8 ° C., 13% relative humidity. For a 3 ml container with an inner diameter of 9.25 mm and a wall thickness of 0.9 mm, this corresponds to a permeability of about 0.35 g / m 2/24 hours at 37 ° C. and about 0.021 g / m 2/24 hours at 8 ° C.
    The loss of m-cresol should be less than 10% for the entire container, preferably less than 7.5% for the polymer wall portion of the container after 3 months storage at 37 ° C., 12% relative humidity. For a 3 ml container with an inner diameter of 9.25 mm and a wall thickness of 0.9 mm, this corresponds to a permeability of about 0.0053 g / m 2/24 hours.
    According to the present invention, a group of polymer containers is a container in which the olefin monomer comprises a crystalline polymer of a linear optionally branched polyolefin material selected from ethylene, propylene, butylene, or mixtures thereof and the crystallinity of the material is determined by differential scanning calorimetry. Cut pieces of vessel walls and heat them to 10 ° C-270 ° C in aluminum pans at a scan rate of 10 ° C / min to record and integrate melt endothermic values and use 209 J / g values for 100% crystalline polypropylene as reference It has been found that the requirements of at least 35% by weight, such as at least 37% by weight, must be satisfied when measured.
    The crystalline polymer is preferably linear or branched polypropylene or linear or branched polyethylene and more preferably is selected from polypropylene homopolymers or propylene ethylene copolymers or mixtures thereof. The content of ethylene in the propylene ethylene copolymer is preferably 1.8% by weight or less, more preferably 0.5 to 1.8% by weight and even more preferably 1% to 1.8% by weight of the total polymer wall material.
    Ethylene content using FTIR spectrophotometer and a value that is preferably from 0.5 to 1.8% by weight of the total polymer wall material measured using the propylene absorbance at 460cm -1 as an internal reference, more preferably from 1% by weight at 730cm -1 To 1.8% by weight.
    Too low ethylene content will generally result in a high crystalline polyolefin material with large crystals and will produce a material with too low light transmittance at 400 nm. However, polyolefins produced using metallocene catalyst technology can be branched in such a way that crystallinity and crystal size are adjusted to optimize the transparency of the material. The effect on crystallinity similar to that obtained by ethylene in polypropylene can be carried out using metallocene catalytic polymerization of propylene with or without other olefin monomers.
    Too much ethylene in the material generally leads to lower crystallinity and thereby poor barrier properties.
    The crystallinity of the wall material of the polymer should preferably be at most 50%, more preferably at most 45%, even more preferably at most 42% as measured as specified above.
    Moreover, the crystalline polymer wall portion preferably has a light transmittance of greater than 30% at 400 nm.
    In general, crystals are expected to be placed randomly in the polymer bulk. However, the molding conditions affect the crystallization process, resulting in an asymmetric distribution of the crystals. The surface concentration of the crystal is theoretically larger than bulk and in practice a high crystalline layer of 200 nm may be a diffusion rate limiting step in the process and such layer will not affect the transparency of the material. According to the invention the pharmaceutical container is preferably prepared using an injection molding technique.
    The density of the plastic material is determined according to the density of the crystalline phase and the density of the amorphous phase. In general, the transmittance in the crystal is negligible compared to the amorphous phase. The density of the crystalline phase is determined not only by the process conditions but also by the materials and additives. The density of the amorphous phase is determined according to the free volume and glass transition temperature of this amorphous phase. Therefore, it can be expected that the density of the amorphous phase of the crystalline polymer material is important for the barrier function.
    The glass transition temperature of the crystalline polymer material of the vessel wall portion is preferably at least -20 ° C, more preferably at least -15 ° C, more preferably at least -10 ° C.
    The remaining material is preferably at least 5% by weight of an additive selected from antioxidants, lubricants such as stearates and silicones, surface active agents, nucleating agents and clarifiers, such as glass pieces having a refractive index almost equal to the refractive index of the polymeric material. Up to 30 weight percent of inert fillers and up to 30 weight percent of total amounts of additives and fillers.
    Containers according to the invention having polymeric wall portions of crystalline material have any suitable shape. The inner surface of the wall, and preferably the outer surface of the container wall, preferably has an essentially cylindrical shape, if at least the inner surface of the container is essentially cylindrical if the flexible rubber piston is rotated to some degree in the container. This is because the tightening can maintain the effect.
    The container may preferably be a cartridge of the distal end comprising a pierceable seal and the proximal end comprising a plunger. Such cartridges are known in the art.
    The polymer wall portion preferably constitutes at least 30%, more preferably more than 50%, more preferably more than 80% of the wall area.
    The container may have a thicker and thinner wall portion. Improved transmission can be obtained by reducing the thickness of one or more portions of the vessel wall. This will obviously affect the barrier properties of this part. Improved barrier properties of the vessel can be obtained by increasing the thickness of one or more portions of the vessel wall.
    In a preferred embodiment according to the invention the container is a cartridge having an inner face of the cylinder, a distal end comprising a pierceable seal and a proximal end comprising a plunger, walls having varying thickness to provide a highly transparent window. to be.
    The wall of the container may preferably be produced by injection molding, in particular if the major part or all of the wall is made of a polymeric material.
    The invention also relates to the use of a container for the storage of a medicament comprising one or more preservatives. The medicament is preferably an aqueous solution or suspension of human growth hormone, or an aqueous insulin solution or insulin suspension, preferably between 25 and 600 U insulin, between 0.1 and 5 mg phenol or benzyl alcohol and from 0.5, per 1 ml of drug. Between 5.0 mg and m-cresol.
    In the examples the following method was used to determine the properties of the materials.
    Permeability
    The materials were molded into 3 ml containers having an outer diameter of 11.05 mm, an inner diameter of 9.25 mm, and therefore a wall thickness of 0.90 mm. The vessel was closed with a bromobutyl rubber stopper at one end with a bromobutyl / natural rubber laminate at the other end.
    Permeability of m-cresol was measured after storing the container containing insulin (Actrapid, 100 IU / ml, Novo Nordisk A / S) for 3 months at 37 ℃, 13% relative humidity.
    Permeability of water was applied to the container containing the insulin preparation (Actrapid, 100 IU / ml, Novo Nordisk A / S) for 3 months at 37 ° C and 13% relative humidity and 6, 12 and 18 at 8 ° C and 13% relative humidity. Measured after months of storage.
    Permeability of m-cresol
    m-cresol loss was determined by HPLC size-exclusion method using an equal elution with a mobile phase on a Waters Protein-Pak I-125 column having the following composition after 3 months storage at 37 ° C .: 600 g glacial acetic acid, 600 g acetone Add nitrile, 2.8 g of L-arginine and water to 4000 g. Frozen standards were used to correct for drift in HPLC systems. A glass container having the same volume as the plastic container was used to correct the loss through the rubber stopper or rubber cover. Permeability was calculated.
    Water permeability
    Water permeability was measured as weight loss after 3, 6 and 18 months of testing. The loss was proportional to time during the test period and therefore the results for 36 months at 8 ° C. can be estimated. Glass containers of the same volume were used as reference.
    Light transmittance
    Light transmittance was measured with a standard spectrophotometer using air as a reference. The vessel was positioned with the beam perpendicular to the plastic surface such that the light beam would pass through the vessel wall, the aqueous solution or the water contained therein and out to the opposite vessel wall into the detector. In this device, light passes through a double wall thickness. The diameter of the light beam was kept small compared to the diameter of the vessel to avoid reflection on the vessel surface.
    density
    The density of the plastic material was determined by measuring the volume change of the aqueous solution containing the detergent when a known weight of plastic was added to the liquid.
    Crystallinity
    The weight percent or crystallinity of the crystalline phase of the polypropylene material was measured by differential scanning calorimetry, DSC. Samples were cut out of the container and placed into an aluminum pan. The sample was then heated from 10 ° C. to 270 ° C. at a scan rate of 10 ° C./min. The peaks recorded in the melt endotherm were integrated. Crystallinity was determined by comparing the integrated peak values with reference to a value of 209 J / g for 100% crystalline polypropylene.
    Ethylene content
    The ethylene content was determined using the propylene absorbance at 460cm -1 and a, and an internal reference using a FTIR spectrophotometer at 730cm -1.
    The method was calibrated using two samples of propylene copolymer with known ethylene content and one without ethylene. If the polymer contains an additive comprising 3-4 repeating methylene groups, this additive is recognized as polymerized ethylene. In general, however, such error materials can be ignored.
    material
    In the examples the materials of Table 1 were used.
    Advanced materials from Melitek ApS sources have been developed upon request from the inventors of the present invention relating to the present invention. Other advanced materials have been received from the company: transparent materials that are not commercially available under the development of recent directives. The developed materials are therefore not commercially available for that reason but can be obtained from the distributor on request.
    Example 1
    Containers of 12 different transparent polypropylene materials as shown in Table 1 were prepared by injection molding. All 3 ml containers had an outer diameter of 11.05 mm, an inner diameter of 9.25 mm, and therefore a wall thickness of 0.90 mm. The container is closed at one end with a bromobutyl rubber stopper and at the other end with a bromobutyl / natural rubber laminate. The density, ethylene content, crystallinity, water and m-cresol permeability, and light permeability of the container sample were measured as above. The results obtained from the measurements are shown in Table 2.
    As shown in Table 2, the light transmittance varies from 11.7% to 60.0%. Fina Pro 10042GR, Rexene 41E12 and Rexene Samples of 23M10 did not meet the requirement of a minimum transmittance of 25%.
    The crystallinity of the vessel wall material varies from 32 to 43%. Permeability limit of the water and m- cresol as described above is, for example, each of 0.35g / m 2 / day and 0.0053g / m 2 / day. As can be seen from the permeability data of Table 2, a degree of crystallinity of at least 37% is required to satisfy the desired permeability limit. No. According to the invention. Five samples of 2, 3, 10, 11 and 12 were marked OK in the table.
    Ethylene content affects the degree of crystallinity and consequently also the permeability.
    Density varies within a very limited range of 0.89-0.92 g / cm 2 . There is no correlation between density and permeability data. As a result, this range cannot be used when selecting the appropriate material for the container to satisfy the permeability requirements.
    Example 2
    Polypropylene material clarified from Ferro used for vessel Sample No. 3 of Example 1 was used for further titration of the compound with respect to light transmission and barrier properties. The temperature and compound formulation of the process varied and the properties of the containers made of the resulting materials were measured as in Example 1. The results are shown in Table 3.
    The difference between Ferro NPPOONQ3246NA-22 with vessel sample number 13 and Ferro NPPOONQ3246NA-25 with sample number 14 is the molding temperature, respectively. Ferro NPPOONQ3246NA-25 was molded at 250 ° C. and made the vessel slightly yellow, increasing the absorbance at 400 nm. This results in a reduced light transmittance compared to sample number 13 processed at 220 ° C. This example shows that not only the compound itself but also the process conditions are important in permeability.
    Samples 15 to 18 were made with other compounds of Ferro, both of sample numbers 13 and 15 to 18 have light transmission and barrier properties within the requirements of the present invention and are therefore labeled "OK". This suggests that optimization of the light transmission of the compound (Ferro NPPOONQ3246NA-22) is possible within the limits of the specified barrier properties.
    Example 3
    The effect of surface-to-volume ratio on m-cresol permeability was studied with containers made of NPPOONQ3246NA-22 and closed with bromobutyl rubber stoppers at one end and bromobutyl / natural rubber laminates at the other end.
    The m-cresol loss was found to be 8.5% for the entire container and 6% for the polypropylene portion. 6% corresponds to 0.58 mg of m-cresol loss per container (area 14.62 cm 2 and volume 3.22 ml) and permeability of 0.0042 g / m 2 / day (thickness 0.9 mm).
    The surface to volume ratio is increased from 4.5cm 2 / ml to 5.7cm 2 / ml and m- cresol loss was increased from 6% to 7.6%. Using another cylindrical vessel with a volume of 3 ml and a height equal to the diameter, the surface to volume ratio is 2.5 cm 2 / ml. The expected m-cresol loss is therefore 3.5%. In a 3 ml container whose height is equal to its diameter, it corresponds to a diameter of 15.7 mm. The m-cresol loss through the rubber plug and the rubber sheath will probably increase. For practical applications the diameter of the 3 ml container is preferably 7-12 mm and the resulting loss is between 4.5 and 7.6%.
    The m-cresol loss is determined by the solubility of the m-cresol in the polymer wall material, the diffusion through the material and the absorption at the wall surface. For Ferro NPPOONQ3246NA-22 the loss will decrease if the wall thickness increases. However, increasing the wall thickness will also reduce light transmission and thereby reduce the possibility of visually inspecting the drug.
    The loss of water was found to be 1.1% for the entire vessel (surface to volume ratio 4.5 cm 2 / ml) and 1.0% for the polypropylene wall. 1.0% corresponds to a loss of 32 mg of water per container or a permeability of 0.23 g / m 2 / day (0.9 mm thick).
    权利要求:
    Claims (20)
    [1" claim-type="Currently amended] A pharmaceutical container comprising a distal and proximal end and a wall for storage of a liquid drug comprising at least one active agent, water and m-cresol and / or phenol and / or benzyl alcohol, wherein at least two opposite parts of the wall are polymeric materials At least 400%, preferably at 400 nm, when the polymer wall portion is measured through both a thickness of 0.3 mm to 3 mm, a standard spectrophotometer and the opposite vessel wall portion of the vessel filled with water using air as reference Having a light transmittance of at least 30%, the polymer wall portion linearly optionally comprising at least 70% by weight of the branched polyolefin material, the olefin monomer is selected from ethylene, propylene, butylene or mixtures thereof and the material is differential scanning heat Using the metering method, the pieces are cut out of the container wall and the aluminum is cut from 10 ° C to 270 ° C at a rate of 10 ° C / min. To record and integrate the melt endothermic amount by heating at and having a crystallinity of at least 35% by weight, preferably at least 37% by weight as measured using a value of 209 J / g for 100% crystalline polypropylene as a reference. Pharmaceutical container characterized by the above-mentioned.
    [2" claim-type="Currently amended] The container of claim 1, wherein the polymer wall material comprises at least 75% by weight, preferably more than 95% by weight, most preferably more than 98% by weight of polyolefin material.
    [3" claim-type="Currently amended] The container according to claim 1 or 2, wherein the polyolefin material is linear or branched polypropylene or linear or branched polyethylene, more preferably polypropylene homopolymer.
    [4" claim-type="Currently amended] The polyolefin material of claim 1, wherein the polyolefin material is 730 cm.-Onein 460 cm as internal reference using FTIR spectrophotometer-OneA propylene ethylene copolymer having an ethylene content of 1.8% by weight or less, preferably 0.5 to 1.8% by weight, more preferably 1 to 1.8% by weight of the total polymer wall material as measured using the propylene absorbance at A container characterized by the above-mentioned.
    [5" claim-type="Currently amended] The method according to any one of claims 1 to 4, wherein the polymer wall material is 50% by weight or less, preferably 45% by weight or less, more preferably 42% by weight or less, as measured as described in claim 1. A container characterized by having crystallinity.
    [6" claim-type="Currently amended] The container according to claim 1, wherein the polymer wall portion has a light transmittance of 30% at 400 nm when measured as described in claim 1. 7.
    [7" claim-type="Currently amended] 7. The polymer wall material according to claim 1, wherein the polymer wall material has a glass transition temperature of at least −20 ° C., preferably at least −15 ° C., more preferably greater than −10 ° C. 8. Vessel.
    [8" claim-type="Currently amended] The polymer wall material according to claim 1, wherein the polymer wall material preferably contains 5% by weight or less of an additive selected from antioxidants, lubricants, surface active agents, nucleating agents and clarifiers, and preferably polymer material. A container comprising 30% by weight or less of an inert filler, which is a glass particle having a refractive index of approximately the same as the refractive index, wherein the total amount of the additive and the filler is 30% by weight or less.
    [9" claim-type="Currently amended] 9. A container according to any one of the preceding claims, wherein the container wall has an inner surface and an outer surface, the inner surface of which has an essentially cylindrical shape.
    [10" claim-type="Currently amended] 10. A container according to any one of the preceding claims, wherein the container wall has an inner surface and an outer surface, the outer surface of which has an essentially cylindrical shape.
    [11" claim-type="Currently amended] The container of claim 1, wherein the container is a cartridge wherein the distal end comprises a pierceable seal and the proximal end comprises a plunger.
    [12" claim-type="Currently amended] 12. The polymer wall portion according to any of the preceding claims, characterized in that the polymer wall portion constitutes at least 30%, preferably more than 50%, more preferably more than 80% of the wall area. Vessel.
    [13" claim-type="Currently amended] 13. The polymer wall according to any one of claims 1 to 12, wherein the polymer wall portion is measured by contacting the polymer wall with an aqueous 3 mg / ml m-cresol solution after 3 months of storage at 37 ° C and 12% relative humidity. 0.0072g / m has a m- cresol permeability of less than 2/24 hours, 37 ℃ and 12% after 3 months storage at a relative humidity of less than 0.4g / m 2/24 h measured in, it characterized in that it has a water permeability Vessel.
    [14" claim-type="Currently amended] The method of claim 13, wherein the polymer wall portions 37 ℃ and at a relative humidity of 12% after 3 months storage as determined by contacting the polymer wall with m- cresol aqueous solution of 3mg / ml 0.0070g / m 2/ 24 sigan , preferably less than the container, characterized in that with m- cresol permeability of 0.0055g / m is less than 2/24 hours or less, more preferably 0.0045g / m 2/24 hours.
    [15" claim-type="Currently amended] Claim 13 or claim 14, wherein the polymer wall when the part is to be determined after 3 months storage at 37 ℃ and a relative humidity of 12% 0.35g / m 2/24 less than an hour, preferably from 0.30g / m 2 / A container characterized by a water permeability of less than 24 hours.
    [16" claim-type="Currently amended] According to any one of the above claims, wherein the polymer wall when the part is to be measured after storage at between 8 ℃ and a relative humidity of 13% 36 months 0.025g / m 2/24 less than an hour, preferably 0.021g / m 2 / A container characterized by a water permeability of less than 24 hours.
    [17" claim-type="Currently amended] Use of a medicament container according to any one of claims 1 to 16 for the storage of a medicament comprising one or more preservatives.
    [18" claim-type="Currently amended] 18. The method according to claim 17, wherein the medicament is preferably an aqueous insulin solution or insulin suspension comprising 25 to 600 IU of insulin, 0.1 to 5 mg of phenol and / or benzyl alcohol and 0.5 to 5 mg of m-cresol per ml of the medicament. Characteristic uses.
    [19" claim-type="Currently amended] 18. Use according to claim 17, wherein the medicament is an aqueous solution or suspension of human growth hormone.
    [20" claim-type="Currently amended] 17. A pharmaceutical container according to any one of claims 1 to 16, which is at least partially filled with a liquid pharmaceutical solution comprising at least one active agent, water and m-cresol and / or phenol and / or benzyl alcohol.
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    同族专利:
    公开号 | 公开日
    DK954272T3|
    CN1244110A|2000-02-09|
    NO314123B1|2003-02-03|
    BR9713627A|2000-04-11|
    NO993084D0|1999-06-22|
    AU741689B2|2001-12-06|
    NO993083L|1999-08-20|
    CN1244109A|2000-02-09|
    IL130432D0|2000-06-01|
    AU728503B2|2001-01-11|
    NO993083D0|1999-06-22|
    DE69711703T3|2008-04-03|
    EP0954273A1|1999-11-10|
    AU5309998A|1998-07-17|
    EP0954272B1|2002-04-03|
    CA2275894A1|1998-07-02|
    JP2001506887A|2001-05-29|
    EP0954272B2|2007-09-05|
    EP0954272A1|1999-11-10|
    RU2183110C2|2002-06-10|
    KR20000069681A|2000-11-25|
    US20030170410A1|2003-09-11|
    IL130433D0|2000-06-01|
    US5945187A|1999-08-31|
    WO1998027926A1|1998-07-02|
    WO1998027925A1|1998-07-02|
    US6680091B2|2004-01-20|
    PL334252A1|2000-02-14|
    BR9714078A|2000-05-09|
    NO993084L|1999-08-20|
    HU0000081A3|2000-07-28|
    RU2183111C2|2002-06-10|
    PT954272E|2002-09-30|
    CZ221199A3|1999-11-17|
    HU0000081A2|2000-06-28|
    DE69711703T2|2002-11-21|
    AU719221B2|2000-05-04|
    HU9904598A2|2000-10-28|
    AT215348T|2002-04-15|
    HU9904598A3|2001-03-28|
    AU5310098A|1998-07-17|
    IN186895B|2001-12-01|
    DK0954272T3|2002-07-01|
    PL334251A1|2000-02-14|
    JP4672818B2|2011-04-20|
    JP2001506888A|2001-05-29|
    CA2275903A1|1998-07-02|
    ES2174314T3|2002-11-01|
    CZ221299A3|1999-11-17|
    ZA9711380B|1998-09-02|
    ZA9711387B|1998-09-02|
    NO314122B1|2003-02-03|
    DE69711703D1|2002-05-08|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-12-23|Priority to DK149896
    1996-12-23|Priority to DK1498/96
    1997-12-16|Application filed by 한센 핀 베네드, 안네 제헤르, 웨이콥 마리안느, 노보 노르디스크 에이/에스
    2000-11-25|Publication of KR20000069680A
    2002-12-10|First worldwide family litigation filed
    优先权:
    申请号 | 申请日 | 专利标题
    DK149896|1996-12-23|
    DK1498/96|1996-12-23|
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