WO1998027925A1 - A medicament container of polymer of cyclic hydrocarbon for storing a liquid medicament - Google Patents

A medicament container of polymer of cyclic hydrocarbon for storing a liquid medicament Download PDF

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Publication number
WO1998027925A1
WO1998027925A1 PCT/DK1997/000569 DK9700569W WO9827925A1 WO 1998027925 A1 WO1998027925 A1 WO 1998027925A1 DK 9700569 W DK9700569 W DK 9700569W WO 9827925 A1 WO9827925 A1 WO 9827925A1
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WO
WIPO (PCT)
Prior art keywords
container
medicament
container according
polymer
hours
Prior art date
Application number
PCT/DK1997/000569
Other languages
French (fr)
Inventor
Thomas Buch-Rasmussen
Patric Jannasch
Erling BONNE JØRGENSEN
Original Assignee
Novo Nordisk A/S
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Priority to AT97949988T priority Critical patent/ATE215348T1/en
Priority to AU5309998D priority patent/AU719221B2/en
Priority to PL97334252A priority patent/PL334252A1/en
Priority to CA002275894A priority patent/CA2275894A1/en
Priority to JP52825398A priority patent/JP2001506887A/en
Priority to IL13043297A priority patent/IL130432A0/en
Priority to BR9713627-1A priority patent/BR9713627A/en
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU53099/98A priority patent/AU728503B2/en
Priority to EP97949988A priority patent/EP0954272B2/en
Priority to HU0000081A priority patent/HUP0000081A3/en
Priority to DE69711703T priority patent/DE69711703T3/en
Priority to DK97949988T priority patent/DK0954272T3/en
Publication of WO1998027925A1 publication Critical patent/WO1998027925A1/en
Priority to NO19993083A priority patent/NO314122B1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/06—Ampoules or carpules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/06—Ampoules or carpules
    • A61J1/062—Carpules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/10—Bag-type containers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L23/00—Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers
    • C08L23/02—Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers not modified by chemical after-treatment
    • C08L23/04—Homopolymers or copolymers of ethene
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L23/00—Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers
    • C08L23/02—Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers not modified by chemical after-treatment
    • C08L23/10—Homopolymers or copolymers of propene
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L23/00—Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers
    • C08L23/02—Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers not modified by chemical after-treatment
    • C08L23/10—Homopolymers or copolymers of propene
    • C08L23/12—Polypropene
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/13—Hollow or container type article [e.g., tube, vase, etc.]
    • Y10T428/1352—Polymer or resin containing [i.e., natural or synthetic]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/13—Hollow or container type article [e.g., tube, vase, etc.]
    • Y10T428/1352—Polymer or resin containing [i.e., natural or synthetic]
    • Y10T428/1397—Single layer [continuous layer]

Definitions

  • the present invention relates to a medicament container for storing a liquid medicament, use of such medicament container, and a medicament container at least partly filled with medicament.
  • medicament containers for storing liquid medicaments and preparations have been made of glass.
  • containers of opaque polyethylenes or polyesters have also been used.
  • Such a polymer container made of a polyglycolic acid polyester and a terephthalic polyester is e.g. described in US 4,565,851. This container provides a very good barrier against oxygen and other gasses, but it does not provide a sufficient barrier against preservatives and water.
  • Medicaments such as insulin or growth hormone
  • ampoules are distributed in small containers or ampoules.
  • Such ampoules normally comprise between 1.5 and 10 ml of ready-to- use medicament. These ampoules are stored in stock, at the hospitals or pharmacies, and with the user. This means that the shelf-life must be sufficiently long.
  • Aqueous solutions or suspensions of medicaments, such as insulin or growth hormones are normally provided with a preservative, such as phenol and/or benzyl alcohol and/or m- cresol. Addition of preservatives is necessary because a terminal sterilisation is not possible due to the sensitivity of medicaments containing proteins, peptides and/or DNA sequences.
  • Medicaments in containers comprising more than one dose e.g.
  • preservatives are essential ingredients in such medicaments, in particular in medicaments for parenteral administration.
  • Phenol, benzyl alcohol and m-cresol are approved in small amounts for use in parenteral medicaments, e.g. for intramuscular administration.
  • Aqueous solutions or suspensions of medicaments comprising a preservative may be stored in glass containers for up to 2 years.
  • Insulin or growth hormone containing ampoules are normally stored at refrigerator temperature about 5 °C when stored in stock or at hospitals or pharmacies. When stored with the user, they are often stored at roomtemperature for up to one month. In particular insulin is stored at room temperature, because the user normally has to carry insulin with him or her all the time. The concentration of insulin and preservative must be close to constant within the storage period. If the concentration of preservative is too low, the medicament will not be sufficiently preserved. It could be suggested to prepare the medicament with a higher initial concentration of preservative.
  • the loss of water should also be very low during the time of storage, because loosing a too large amount of water would result in a too high concentration of active medicament, and possibly a too high concentration of preservatives. If too much water is lost, th user may get an overdose of the active medicament, such as insulin.
  • the object of the present invention is to provide a medicament container of a polymer material, which material is substantially inert to the medicament, and which container is transparent and provides a good barrier against m-cresol/phenol/benzyl alcohol and water, respectively.
  • Another object of the invention is to provide a medicament container, which is cheap and easy to produce.
  • Yet another object of the invention is to provide a medicament container for long-time storage of aqueous medicaments, such as aqueous solutions of insulin or human growth hormone.
  • the medicament containers according to the present invention for storing a liquid medicament comprising one or more active medicaments, water and m-cresol and/or phenol and/or benzyl alcohol, comprises a distal and a proximal end portion and a wall, at least two portions of the wall being of a polymer material.
  • These polymer wall portions have a thickness of 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 of the opposite container wall portions when the container is filled with water, using a standard spectrophotometer and air as reference, and the polymer wall portions being of a material comprising at least 70 % by weight of a copolymer material composed of aliphatic cyclic or bicylic hydrocarbons with 5 to 7 membered ring or rings and ethylene or propylene, the material having a glass transition temperature above 50 °C, measured by differential scanning calorimetry, by cutting pieces from the container walls and heating them in an aluminium pan from 10 °C to 270 °C at a scanning rate of 10 °C/min, the glass transition temperature being determined as the temperature at the inflection point, and a density of 0.95 g/cm 3 or more.
  • the material may 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 glass particles having a refractive index about equal to the refractive index of the polymer material, the total amount of additives and fillers being up to 30 % by weight.
  • 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 glass particles having a refractive index about equal to the refractive index of the polymer material, the total amount of additives and fillers being up to 30 % by weight.
  • inert fillers such as glass particles having a refractive index about equal to the refractive index of the polymer material, the total amount of additives and fillers being up to 30 % by weight.
  • a diabetic patient can visually observe if more than 3 % of the insulin are polymerised.
  • the polymerised insulin can visually and with a spectrophotometer be observed as a change in light transmission.
  • the typical change in transmission from an insulin solution where 3 % of the insulin are polymerised corresponds to the transmission change in a 1 :400 Ph.Eur standard and a typical change in transmission from an insulin solution where 30 % of the insulin are polymerised, corresponds to the transmission change in 1 :40 Ph.Eur standard. (1997 European Pharmacopeia section 2.2 Physical and Physicochemical Methods. 2.2.1 Clearity and Degree of Opalescence of Liquids.)
  • the transmission In a glass container, the transmission typically changes from about 94 % to about 45 % with a 1 :40 Ph Eur at 400 nm and 0.9 mm wall thickness. In an amorphous cyclic polyolefin, the transmission typically changes from about 85 % to about 41 % with a 1 :40 Ph.Eur, changes visually perceivable by 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 1 :40 Ph.Eur.
  • the patient has the best possibility of observing such a problem in a medicament container where the transmission is high, and where the changes are large.
  • the transmission in a 3 ml container with a wall thickness of 0,9 mm and filled with a commercial insulin solution, such as Actrapid 100 IU/ml (Novo Nordisk A/S) is recommended to be higher than 25 % at 400 nm in order to be able to visually observe a polymerisation larger than 3 %.
  • any material for packaging parenteral drugs preserved with m-cresol has surprisingly been found among the group of polyolefin materials. As explained above, any material must fulfil a number of specifications to be able to prevent m-cresol and water from disappearing from the drug formulation, and to be able to allow visual inspection of the product quality.
  • the medicament containers of the present invention should preferably meet the following requirements:
  • the polymer wall portions have a permeability of m-cresol of less than 0.0072 g/m 2 /24hours, measured after a storing period of three months at 37 °C and 12 % relative humidity (RH) by contacting the polymer wall with an aqueous 3 mg/ml m- cresol solution, and a permeability of water of less than 0.4 g/m 2 /24 hours, measured after a storing period of three months at 37 °C and 12 % RH, more preferably the polymer wall portions have a permeability of m-cresol of less than 0.0055 g/m 2 /24 hours, and even more preferably less than 0.0020 g/m 2 /24 hours, measured after a storing period of three months at 37 °C and 12 % RH by contacting the polymer wall with an aqueous 3 mg/ml m-cresol solution, and preferably the polymer wall portions have a permeability of water of less than 0.35 g
  • the polymer wall portions have a permeability of water of less than 0.025 g/m 2 /24 hours, measured after a storing period of three months at 8 °C and 13 % RH for 36 months, more preferably less than 0.021 g/m 2 /24 hours.
  • M-cresol, benzyl alcohol and phenol are all organic solvents with very low solubility in water. M-cresol is less polar than phenol and benzyl alcohol and will therefore diffuse faster than phenol and benzyl alcohol in a very hydrophobic environment. Further, the solubility of m-cresol will be higher in a hydrophobic environment such as a cyclic polymer. Even though phenol and benzyl alcohol are smaller molecules than m-cresol and that the size can be important for the diffusion rate, it has been found that the loss of phenol or benzyl alcohol will be smaller than the loss of m-cresol, and it is therefore sufficient to determine the loss of m-cresol.
  • the medicament container in particular for parenteral drug applications, meet the following requirements:
  • the loss of water should be less than 1 ,5 % after storage at 37 °C and 12 % RH for 3 months and be less than 1 % after storage at 8 °C and 13 % RH for 36 months.
  • this corresponds to a permeability at 37 °C of about 0.35 g/m 2 /24 hours and at 8 °C of about 0.021 g/m 2 /24 hours.
  • the loss of m-cresol should be less than 10 % for the whole container, and preferably
  • a group of polymer containers have been found to meet the specification, namely the containers comprising amorphous polymers composed of aliphatic cyclic or bicylic hydrocarbons with 5 to 7 membered ring or rings and ethylene or propylene, the material having a glass transition temperature above 50 °C, measured by differential scanning calorimetry, by cutting pieces from the container walls and heating them in an aluminium pan from 10 °C to 270 °C at a scanning rate of 10 °C/min, the glass transition temperature being determined as the temperature at the inflection point; and a density of 0.95 g/cm 3 or more.
  • the amorphous copolymer material is preferably composed of aliphatic cyclic hydrocarbons with 5 to 7 membered ring or rings and ethylene, and preferably the copolymer material is completely amorphous, say it has a crystallinity of less than 1% by weight. Most preferably, the amorphous copolymer material is of the type sold under the trademark "Topas", marketed by Schott and Hoechst(see table 1 ).
  • the amorphous polymer wall portions of the container according to the invention have a light transmission at 400 nm of 60 % or more, and more preferably a light transmission at 400 nm of 75 % or more, measured as specified above.
  • the density of the amorphous polymer wall portions of the container according to the invention is preferably between 0.95 g/cm 3 and 1.05 g/cm 3 , more preferably about
  • the glass transition temperature (Tg) is preferably at least 75°C, and more preferably at least 100 °C, measured as specified above. Water steam sterilisation is available for sterilisation of the containers having Tg's above these temperatures. For containers of polymers having lower Tg's gamma sterilisation is useful.
  • the water barrier properties are correlated to the content of the cyclic component in the polymer, in that the water barrier is increased by lowering the amount of cyclic component relative to linear component until a certain degree.
  • the polymer material comprises at least 20 % linear olefin, preferably at least 50 % linear olefin, such as ethylene.
  • the glass transition temperature is preferably at most 200 °C, such as at most 170 °C, more preferably at most 150 °C.
  • the amorphous polymer preferably comprises at least 75 %, more preferably more than 95 %, and most preferably 98 % by weight or more of a polyolefin material.
  • the remainder of the material may preferably be 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 inert fillers, such as glass particles having a refractive index about equal to the refractive index of the polymer material, the total amount of additives and fillers being up to 30 % by weight.
  • additives in particular selected from antioxidants, lubricants, such as stearates and silicones, surface active agents, nucleating and clarifying agents, and inert fillers, such as glass particles having a refractive index about equal to the refractive index of the polymer material, the total amount of additives and fillers being up to 30 % by weight.
  • the container according to the invention having polymer wall portions of amorphous polymer material may 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, has a substantially cylindrical shape, because if a flexible rubber piston is rotated a few degrees in the container, it can only keep its tightening effect if at least the inner surface of the container has a substantially cylindrical shape.
  • the container may preferably be a cartridge, the distal end portion comprising a pierceable seal, and the proximal end portion comprising a plunger.
  • 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.
  • An improved transmission may be obtained by decreasing the thickness of one or more parts of the container wall. This will obviously affect the barrier properties in these parts.
  • Improved barrier properties of the container may be obtained by increasing the thickness of one or more parts of the container wall.
  • the container is a cartridge having a polymer wall with a cylindrical inner side, and a distal end portion comprising a pierceable seal, and a proximal end portion comprising a plunger, the wall having a varying thickness so as to provide a very transparent window.
  • the wall of the container may preferably be made by injection moulding, in particular if the main part or all of the wall is made from polymer material.
  • the invention also relates to the use of the 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 insulin solution or insulin suspension, preferably comprising between 25 and 600 IU of insulin, between 0.1 and 5 mg of phenol or benzyl alcohol, and between 0.5 and 5 mg of m-cresol per ml medicament.
  • the materials were moulded into 3 ml containers with an outer diameter of 11.05 mm, an inner diameter of 9.25 mm, and thus a wall thickness of 0.90 mm.
  • the containers were closed with a bromobutyl rubber stopper in one end and a bromobutyl/natural rubber laminate in the other end.
  • the permeability of m-cresol was measured after storage of the container with insulin (Actrapid, 100U/ml, Novo Nordisk A/S) at 37 °C, 13 % relative humidity (RH) for 3 months.
  • the permeability of water was measured after storage of the container with insulin formulation (Actrapid, 100 lU/ml, Novo Nordisk A/S) at 37 °C, 13 % RH for 3 months and at 8 °C, 13 % RH for 6, 12 and 18 months.
  • insulin formulation Actrapid, 100 lU/ml, Novo Nordisk A/S
  • the m-cresol loss was measured after a storing period of three month at 37 °C, with a HPLC size-exclusion method using isocratic elution with a mobile phase, on a Waters Protein-Pak 1-125 column, with the following composition: 600 g of glacial acetic acid,
  • the water permeability was measured as a weight loss after the test period of 3, 6 and 18 months. The loss was linear with time in the test period and the results can therefore be extrapolated to 36 months at 8 °C Glass containers with the same dimensions were used as reference. Transmission
  • the transmission was measured with a standard spectrophotometer, using air as reference.
  • the container was placed with the light beam perpendicularly to the plastic surface, so that the light beam passed through the container wall, through the water solution or water contained therein, and out through the opposite container wall into the detector. In this setup, the light passes through the double wall thickness.
  • the diameter of the light beam was kept small, as compared with the diameter of the container, to avoid reflection on the container surface.
  • the densities of the plastic materials were determined by measuring the volumetric change of an aqueous solution, containing a detergent, when adding a known weight of the plastic to the liquid.
  • Ethylene content may be measured using proton NMR.
  • the glass transition temperature of the cyclic polyolefin materials was evaluated by differential scanning calorimetry, DSC. Samples were cut from the containers and put into aluminium pans. The samples were subsequently heated from 10 °C to 270 °C at a scanning rate of 10 °C/min. The glass transition temperature was evaluated as the temperature at the inflection point on the step in heat flow which was associated with the glass transition of the material. Materials
  • the developmental materials were received from the companies as: not commercially available transparent materials, under development for later marked introduction.
  • the deveiopmentals material are therefore not commercially avaible as such, but may be obtained from the distributor on request.
  • Containers of 4 different cyclic polyolefins were produced by injection moulding.
  • the 3 ml containers all had outer diameters of 11 ,05 mm, inner diameters of 9,25 mm, and thus a wall thickness of 0,90 mm.
  • the containers were closed with a bromobutyl rubber stopper in one end, and a bromobutyl/natural rubber laminate in the other end.
  • the Topas materials produced by Hoechst are build up by bicyclic monomer-elements in combination with ethylene-elements and the CZ-resin from Daikyo is build up by monocyclic monomer elements.
  • the water permeability in the materials were measured at 3 different conditions.
  • the m-cresol permeability was measured at 37°C.
  • Approximate ethylene content were supplied from the manufacture.
  • Glass transition temperature (Tg) were measured with DSC.
  • Permeability data at 25°C for Topas 6015 and 6017 are estimated from manufacture data and marked with "*".
  • the sample of Topas® 8007, having a glass transition temperature of 76°C has a slightly lower permeability than the samples of Topas® 5013 and Topas® 6013, having a higher glass transition temperature of 137 and 143 °C, respectively.
  • the CZ-resin is studied as comparison, the ethylene content of CZ-resin being 0, whereby the cyclic component constitutes 100 % of the polymer.
  • the high content of cyclic component impairs the water permeability at all tested temperatures, especially at 8 °C. Also the m-cresol barrier properties are reduced compared to the polymers according to the invention.

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 copolymer material composed of aliphatic cyclic or bicyclic hydrocarbons with 5 to 7 membered ring or rings and ethylene or propylene, the material having a glass transition temperature above 50 °C, and a density of 0.95 g/cm3 or more. 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

A medicament container of polymer of cyclic hydrocarbon for storing a liquid medicament
The present invention relates to a medicament container for storing a liquid medicament, use of such medicament container, and a medicament container at least partly filled with medicament.
Traditionally, medicament containers for storing liquid medicaments and preparations have been made of glass. For certain medicaments, such as medicaments for peroral administration, containers of opaque polyethylenes or polyesters have also been used. Such a polymer container made of a polyglycolic acid polyester and a terephthalic polyester is e.g. described in US 4,565,851. This container provides a very good barrier against oxygen and other gasses, but it does not provide a sufficient barrier against preservatives and water.
Medicaments, such as insulin or growth hormone, are distributed in small containers or ampoules. Such ampoules normally comprise between 1.5 and 10 ml of ready-to- use medicament. These ampoules are stored in stock, at the hospitals or pharmacies, and with the user. This means that the shelf-life must be sufficiently long. Aqueous solutions or suspensions of medicaments, such as insulin or growth hormones, are normally provided with a preservative, such as phenol and/or benzyl alcohol and/or m- cresol. Addition of preservatives is necessary because a terminal sterilisation is not possible due to the sensitivity of medicaments containing proteins, peptides and/or DNA sequences. Medicaments in containers comprising more than one dose, e.g. for use in pen systems, are at a high risk of contamination. Therefore, preservatives are essential ingredients in such medicaments, in particular in medicaments for parenteral administration. Phenol, benzyl alcohol and m-cresol are approved in small amounts for use in parenteral medicaments, e.g. for intramuscular administration. Aqueous solutions or suspensions of medicaments comprising a preservative may be stored in glass containers for up to 2 years.
The article "Interaction between aqueous preservative solutions and their plastic containers, III" by T. J. McCarthy, Pharm. Weekblad 107 (1972), describes the effects storing certain aqueous solutions of preservatives in containers of polypropylene (PP) coloured with white pearl pigment and poly(vinylchloride) (PVC), respectively, in particular with respect to the loss of preservatives from the solutions. There were no discussions about storing aqueous solutions of preservatives in transparent containers. Further, the conclusion in this article is that large amounts of some types of preservatives are lost from the solutions stored in PP. PVC, however, seems to provide a good barrier against preservatives. As a consequence of its chlorine content, PVC is not acceptable for use due to environmental pollution.
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 , describes a similar test of storing aqueous solutions of phenol, benzyl alcohol and m-cresol, respectively, in polypropylene-polyethylene syringes, in particular with respect to the loss of phenol, benzyl alcohol and m-cresol, respectively, from the solutions.
The test covers only 28 days, but from this test it is concluded that the polypropylene- polyethylene syringes cannot be used for storing medicaments comprising phenol and/or benzyl alcohol and/or m-cresol. Insulin or growth hormone containing ampoules are normally stored at refrigerator temperature about 5 °C when stored in stock or at hospitals or pharmacies. When stored with the user, they are often stored at roomtemperature for up to one month. In particular insulin is stored at room temperature, because the user normally has to carry insulin with him or her all the time. The concentration of insulin and preservative must be close to constant within the storage period. If the concentration of preservative is too low, the medicament will not be sufficiently preserved. It could be suggested to prepare the medicament with a higher initial concentration of preservative. This would, however, not be acceptable for parenteral use. The loss of water should also be very low during the time of storage, because loosing a too large amount of water would result in a too high concentration of active medicament, and possibly a too high concentration of preservatives. If too much water is lost, th user may get an overdose of the active medicament, such as insulin.
Further, it is important that the user can visually inspect the medicament to make sure that the medicament is not crystallised or polymerised due to e.g. self association or denaturation, or that any other visually detectable change of the medicament has occurred, such as oxidation of the active medicament. The object of the present invention is to provide a medicament container of a polymer material, which material is substantially inert to the medicament, and which container is transparent and provides a good barrier against m-cresol/phenol/benzyl alcohol and water, respectively.
Another object of the invention is to provide a medicament container, which is cheap and easy to produce.
Yet another object of the invention is to provide a medicament container for long-time storage of aqueous medicaments, such as aqueous solutions of insulin or human growth hormone.
The medicament containers according to the present invention for storing a liquid medicament comprising one or more active medicaments, water and m-cresol and/or phenol and/or benzyl alcohol, comprises a distal and a proximal end portion and a wall, at least two portions of the wall being of a polymer material. These polymer wall portions have a thickness of 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 of the opposite container wall portions when the container is filled with water, using a standard spectrophotometer and air as reference, and the polymer wall portions being of a material comprising at least 70 % by weight of a copolymer material composed of aliphatic cyclic or bicylic hydrocarbons with 5 to 7 membered ring or rings and ethylene or propylene, the material having a glass transition temperature above 50 °C, measured by differential scanning calorimetry, by cutting pieces from the container walls and heating them in an aluminium pan from 10 °C to 270 °C at a scanning rate of 10 °C/min, the glass transition temperature being determined as the temperature at the inflection point, and a density of 0.95 g/cm3 or more.
The material may 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 glass particles having a refractive index about equal to the refractive index of the polymer material, the total amount of additives and fillers being up to 30 % by weight. As explained above, the scattering and absorbence of visible light of the material must be low in order to control the quality of the medicament in the container. Quality control can be a visual inspection for foreign particles, homogeneity of a suspension, sedimentation of crystals, precipitation in solutions, fibrillation or polymerisation of peptides or proteins in solutions, and changes in the absorbance spectrum of the medicament solution.
Most critical are changes which affect the concentration of the active medicament or drug in the solution, and of these, a polymerisation or a precipitation can be very difficult for a user to observe, 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 are polymerised. The polymerised insulin can visually and with a spectrophotometer be observed as a change in light transmission. The typical change in transmission from an insulin solution where 3 % of the insulin are polymerised, corresponds to the transmission change in a 1 :400 Ph.Eur standard and a typical change in transmission from an insulin solution where 30 % of the insulin are polymerised, corresponds to the transmission change in 1 :40 Ph.Eur standard. (1997 European Pharmacopeia section 2.2 Physical and Physicochemical Methods. 2.2.1 Clearity and Degree of Opalescence of Liquids.)
In a glass container, the transmission typically changes from about 94 % to about 45 % with a 1 :40 Ph Eur at 400 nm and 0.9 mm wall thickness. In an amorphous cyclic polyolefin, the transmission typically changes from about 85 % to about 41 % with a 1 :40 Ph.Eur, changes visually perceivable by 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 1 :40 Ph.Eur.
It is obvious that the patient has the best possibility of observing such a problem in a medicament container where the transmission is high, and where the changes are large. In practice, the transmission in a 3 ml container with a wall thickness of 0,9 mm and filled with a commercial insulin solution, such as Actrapid 100 IU/ml (Novo Nordisk A/S), is recommended to be higher than 25 % at 400 nm in order to be able to visually observe a polymerisation larger 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 fulfil a number of specifications to be able to prevent m-cresol and water from disappearing from the drug formulation, and to be able to allow visual inspection of the product quality.
The medicament containers of the present invention should preferably meet the following requirements:
The polymer wall portions have a permeability of m-cresol of less than 0.0072 g/m2/24hours, measured after a storing period of three months at 37 °C and 12 % relative humidity (RH) by contacting the polymer wall with an aqueous 3 mg/ml m- cresol solution, and a permeability of water of less than 0.4 g/m2/24 hours, measured after a storing period of three months at 37 °C and 12 % RH, more preferably the polymer wall portions have a permeability of m-cresol of less than 0.0055 g/m2/24 hours, and even more preferably less than 0.0020 g/m2/24 hours, measured after a storing period of three months at 37 °C and 12 % RH by contacting the polymer wall with an aqueous 3 mg/ml m-cresol solution, and preferably the polymer wall portions have a permeability of water of less than 0.35 g/m2/24 hours, more preferably less than 0.30 g/m/24 hours, and even more preferably less than 0.20 g/m2/24 hours, measured after a storing period of three months at 37 °C and 12 % RH.
Preferably, the polymer wall portions have a permeability of water of less than 0.025 g/m2/24 hours, measured after a storing period of three months at 8 °C and 13 % RH for 36 months, more preferably less than 0.021 g/m2/24 hours.
M-cresol, benzyl alcohol and phenol are all organic solvents with very low solubility in water. M-cresol is less polar than phenol and benzyl alcohol and will therefore diffuse faster than phenol and benzyl alcohol in a very hydrophobic environment. Further, the solubility of m-cresol will be higher in a hydrophobic environment such as a cyclic polymer. Even though phenol and benzyl alcohol are smaller molecules than m-cresol and that the size can be important for the diffusion rate, it has been found that the loss of phenol or benzyl alcohol will be smaller than the loss of m-cresol, and it is therefore sufficient to determine the loss of m-cresol.
According the present invention it is even more preferred that the medicament container, in particular for parenteral drug applications, meet the following requirements:
The loss of water should be less than 1 ,5 % after storage at 37 °C and 12 % RH for 3 months and be less than 1 % after storage at 8 °C and 13 % RH for 36 months. For a 3 ml container with an inner diameter of 9.25 mm, this corresponds to a permeability at 37 °C of about 0.35 g/m2/24 hours and at 8 °C of about 0.021 g/m2/24 hours.
The loss of m-cresol should be less than 10 % for the whole container, and preferably
7,5 % for the polymer wall portions of the container after storage at 37 °C and 12 % RH for 3 months. 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 0,0053g/m2/24 hours.
According to the invention, a group of polymer containers have been found to meet the specification, namely the containers comprising amorphous polymers composed of aliphatic cyclic or bicylic hydrocarbons with 5 to 7 membered ring or rings and ethylene or propylene, the material having a glass transition temperature above 50 °C, measured by differential scanning calorimetry, by cutting pieces from the container walls and heating them in an aluminium pan from 10 °C to 270 °C at a scanning rate of 10 °C/min, the glass transition temperature being determined as the temperature at the inflection point; and a density of 0.95 g/cm3 or more.
The amorphous copolymer material is preferably composed of aliphatic cyclic hydrocarbons with 5 to 7 membered ring or rings and ethylene, and preferably the copolymer material is completely amorphous, say it has a crystallinity of less than 1% by weight. Most preferably, the amorphous copolymer material is of the type sold under the trademark "Topas", marketed by Schott and Hoechst(see table 1 ).
Also, it is preferred that the amorphous polymer wall portions of the container according to the invention have a light transmission at 400 nm of 60 % or more, and more preferably a light transmission at 400 nm of 75 % or more, measured as specified above.
The density of the amorphous polymer wall portions of the container according to the invention is preferably between 0.95 g/cm3 and 1.05 g/cm3, more preferably about
1.02 g/cm3.
The glass transition temperature (Tg) is preferably at least 75°C, and more preferably at least 100 °C, measured as specified above. Water steam sterilisation is available for sterilisation of the containers having Tg's above these temperatures. For containers of polymers having lower Tg's gamma sterilisation is useful.
Generally, the higher the ratio of cyclic components to linear components in the copolymer the higher the Tg of the polymer. The water barrier properties are correlated to the content of the cyclic component in the polymer, in that the water barrier is increased by lowering the amount of cyclic component relative to linear component until a certain degree. Preferably the polymer material comprises at least 20 % linear olefin, preferably at least 50 % linear olefin, such as ethylene.
Accordingly, the glass transition temperature is preferably at most 200 °C, such as at most 170 °C, more preferably at most 150 °C.
The amorphous polymer preferably comprises at least 75 %, more preferably more than 95 %, and most preferably 98 % by weight or more of a polyolefin material.
The remainder of the material may preferably be 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 inert fillers, such as glass particles having a refractive index about equal to the refractive index of the polymer material, the total amount of additives and fillers being up to 30 % by weight.
The container according to the invention having polymer wall portions of amorphous polymer material, may 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, has a substantially cylindrical shape, because if a flexible rubber piston is rotated a few degrees in the container, it can only keep its tightening effect if at least the inner surface of the container has a substantially cylindrical shape.
The container may preferably be a cartridge, the distal end portion comprising a pierceable seal, and the proximal end portion comprising 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. An improved transmission may be obtained by decreasing the thickness of one or more parts of the container wall. This will obviously affect the barrier properties in these parts. Improved barrier properties of the container may 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 a cylindrical inner side, and a distal end portion comprising a pierceable seal, and a proximal end portion comprising a plunger, the wall having a varying thickness so as to provide a very transparent window.
The wall of the container may preferably be made by injection moulding, in particular if the main part or all of the wall is made from polymer material.
The invention also relates to the use of the 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 insulin solution or insulin suspension, preferably comprising between 25 and 600 IU of insulin, between 0.1 and 5 mg of phenol or benzyl alcohol, and between 0.5 and 5 mg of m-cresol per ml medicament.
In the examples, the following methods of determining the properties of the materials have been used: Permeability
The materials were moulded into 3 ml containers with an outer diameter of 11.05 mm, an inner diameter of 9.25 mm, and thus a wall thickness of 0.90 mm. The containers were closed with a bromobutyl rubber stopper in one end and a bromobutyl/natural rubber laminate in the other end.
The permeability of m-cresol was measured after storage of the container with insulin (Actrapid, 100U/ml, Novo Nordisk A/S) at 37 °C, 13 % relative humidity (RH) for 3 months.
The permeability of water was measured after storage of the container with insulin formulation (Actrapid, 100 lU/ml, Novo Nordisk A/S) at 37 °C, 13 % RH for 3 months and at 8 °C, 13 % RH for 6, 12 and 18 months.
M-cresol permeability
The m-cresol loss was measured after a storing period of three month at 37 °C, with a HPLC size-exclusion method using isocratic elution with a mobile phase, on a Waters Protein-Pak 1-125 column, with the following composition: 600 g of glacial acetic acid,
600 g of acetonitrile, 2,8 g of L-arginine and water added to 4000 g. Frozen standards were used to correct for drift in the HPLC system. Glass containers with the same dimensions as the plastic containers were used to correct for 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 test period of 3, 6 and 18 months. The loss was linear with time in the test period and the results can therefore be extrapolated to 36 months at 8 °C Glass containers with the same dimensions were used as reference. Transmission
The transmission was measured with a standard spectrophotometer, using air as reference. The container was placed with the light beam perpendicularly to the plastic surface, so that the light beam passed through the container wall, through the water solution or water contained therein, and out through the opposite container wall into the detector. In this setup, the light passes through the double wall thickness. The diameter of the light beam was kept small, as compared with the diameter of the container, to avoid reflection on the container surface.
Density
The densities of the plastic materials were determined by measuring the volumetric change of an aqueous solution, containing a detergent, when adding a known weight of the plastic to the liquid.
Ethylene content
Ethylene content may be measured using proton NMR.
Glass transition temperature
The glass transition temperature of the cyclic polyolefin materials was evaluated by differential scanning calorimetry, DSC. Samples were cut from the containers and put into aluminium pans. The samples were subsequently heated from 10 °C to 270 °C at a scanning rate of 10 °C/min. The glass transition temperature was evaluated as the temperature at the inflection point on the step in heat flow which was associated with the glass transition of the material. Materials
In the examples, the materials of table 1 were used.
Table 1
Materials used
Cyclic olefins: Distributor Development Used in example
Sample (Yes/No) No
Schott Hoechst, Denmark No
Topas® 8007 Schott Schott, Denmark No
Topas® 5013 Schott Schott, Denmark Yes
Topas® 6013 Schott Hoechst, Denmark No
Topas® 6015 Schott Hoechst, Denmark No
Topas® 6017 Daikyo Daikyo Yes CZ-resin
The developmental materials were received from the companies as: not commercially available transparent materials, under development for later marked introduction. The deveiopmentals material are therefore not commercially avaible as such, but may be obtained from the distributor on request.
Example 1
Containers of 4 different cyclic polyolefins (see table 1 ) were produced by injection moulding. The 3 ml containers all had outer diameters of 11 ,05 mm, inner diameters of 9,25 mm, and thus a wall thickness of 0,90 mm. The containers were closed with a bromobutyl rubber stopper in one end, and a bromobutyl/natural rubber laminate in the other end. The Topas materials produced by Hoechst are build up by bicyclic monomer-elements in combination with ethylene-elements and the CZ-resin from Daikyo is build up by monocyclic monomer elements.
The water permeability in the materials were measured at 3 different conditions. The m-cresol permeability was measured at 37°C. Approximate ethylene content were supplied from the manufacture. Glass transition temperature (Tg) were measured with DSC. Permeability data at 25°C for Topas 6015 and 6017 are estimated from manufacture data and marked with "*".
Table 2
Figure imgf000014_0001
As can be seen in table 2, the containers of Topas® 8007, of Topas® 5013 and of Topas® 6013 are all excellent with respect to both transmission and barrier properties.
The sample of Topas® 8007, having a glass transition temperature of 76°C has a slightly lower permeability than the samples of Topas® 5013 and Topas® 6013, having a higher glass transition temperature of 137 and 143 °C, respectively.
The CZ-resin is studied as comparison, the ethylene content of CZ-resin being 0, whereby the cyclic component constitutes 100 % of the polymer. The high content of cyclic component impairs the water permeability at all tested temperatures, especially at 8 °C. Also the m-cresol barrier properties are reduced compared to the polymers according to the invention.

Claims

PATENT CLAIMS:
1. A medicament container for storing a liquid medicament comprising one or more medicaments, water and m-cresol and/or phenol and/or benzyl alcohol, 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, said polymer wall portions having a thickness of between 0.3 mm and 3 mm, a light transmission at 400 nm of 25 % or more, measured through both of said opposite container wall portions when the container is filled with water, using a standard spectrophotometer and air as reference, the polymer wall portions being of a material comprising at least 70 % by weight of a copolymer material composed of aliphatic cyclic or bicylic hydrocarbons with 5 to 7 membered ring or rings and ethylene or propylene, the material having a glass transition temperature above 50 ┬░C, measured by differential scanning calorimetry, by cutting pieces from the container walls and heating them in an aluminium pan from 10 ┬░C to 270 ┬░C at a scanning rate 10 ┬░C/min, the glass transition temperature being determined as the temperature at the inflection point; and a density of 0.95 g/cm3 or more.
2. A container according to claim 1 , wherein the polymer wall material comprises at least 75 %, preferably more than 95 %, and most preferably more than 98 % by weight of the copolymer material
3. A container according to claim 1 or 2, wherein the polymer wall material comprises up to 5 % by weight of additives, preferably from between 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 about equal to the refractive index of the polymer material, the total amount of additives and fillers being up to 30 % by weight.
4. A container according to claims 1 , 2 or 3, wherein the copolymer material is composed of cyclic 5 to 7 membered, preferably bicyclic ring and ethylene.
5. A container according to any of the claims 1 to 4, wherein the polymer material comprises at least 20 % ethylene, preferably at least 50 % ethylene.
6. A container according to any of the claims 1 to 5, wherein the copolymer material is completely amorphous.
7. A container according to any of the claims 1 to 6, wherein the polymer wall portions have a light transmission at 400 nm of 60 % or more, preferably a light transmission at 400 nm of 75 % or more, measured as defined in claim 1.
8. A container according to any of the claims 1 to 7, wherein the polymer wall material has a density between 0.95 g/cm and 1.05 g/cm3, preferably about 1.02 g/cm3.
9. A container according to any of the claims 1 to 8, wherein the polymer wall material has a glass transition temperature of at least 75 ┬░C, preferably at least 100 ┬░C.
10. A container according to any of the claims 1 to 9, wherein the polymer wall material has a glass transition temperature of at most 200 ┬░C, preferably at most 170 ┬░C, more preferably at most 150 ┬░C.
11. A container according to any of the claims 1 to 10, wherein the container wall has an inner surface and an outer surface, the inner surface having a substantially cylindrical shape.
12. A container according to any of the claims 1 to 11 , wherein the container wall has an inner surface and an outer surface, the outer surface of the wall having a substantially cylindrical shape.
13. A container according to any of the claims 1 to 12, wherein the container is a cartridge, the distal end portion comprising a pierceable seal and the proximal end portion comprising a plunger.
14. A container according to any of the claims 1 to 13, wherein the polymer wall portions constitute at least 30 %, preferably more than 50 %, and more preferably more than 80 % of the area of the wall.
15. A container according to any of the claims 1 to 14, wherein the polymer wall portions have a permeability of m-cresol of less than 0.0072 g/m2/24 hours, measured after a storing period of three months at 37 ┬░C and 12 % RH by contacting the polymer wall with an aqueous 3 mg/ml m-cresol solution, and a permeability of water of less than 0.4 g/m2/24 hours, measured after a storing period of three months at 37 ┬░C and 12 % RH.
16. A container according to claim 15, wherein the polymer wall portions have a permeability of m-cresol of less than 0.0070 g/m2/24 hours, preferably less than
0.0055 g/m2/24 hours, and more preferably less than 0.0020 g/m2/24 hours, measured after a storing period of three months at 37 ┬░C and 12 % RH by contacting the polymer wall with an aqueous 3 mg/ml m-cresol solution.
17. A container according to claim 15 or 16, wherein the polymer wall portions have a permeability of water of less than 0.35 g/m2/24 hours, preferably less than 0.30 g/m2/24 hours, and more preferably less than 0.20 g/m 724 hours, measured after a storing period of three months at 37 ┬░C and 12 % RH .
18. A container according to claim 15, 16 or 17, wherein the polymer wall portions have a permeability of water of less than 0.025 g/m2/24 hours, preferably less than 0.021 g/m2/24 hours, measured after a storing period of 36 months at 8 ┬░C and 13 % RH .
19. Use of a medicament container according to any of the claims 1 to 18 for storing a medicament comprising one or more preservative.
20. Use according to claim 19, wherein the medicament is an aqueous insulin solution or insulin suspension, preferably comprising between 25 and 600 U of insulin, between 0.1 and 5 mg of phenol and/or benzyl alcohol, and between 0.5 and 5 mg of m-cresol per ml medicament.
21. Use according to claim 19, wherein the medicament is an aqueous solution or suspension of human growth hormone.
22. A medicament container according to any of the claims 1 to 18 at least partly filled with a liquid medicament solution, comprising one or more active medicaments, water and m-cresol and/or phenol and/or benzyl alcohol.
PCT/DK1997/000569 1996-12-23 1997-12-16 A medicament container of polymer of cyclic hydrocarbon for storing a liquid medicament WO1998027925A1 (en)

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DK97949988T DK0954272T3 (en) 1996-12-23 1997-12-16 Polymer drug container
BR9713627-1A BR9713627A (en) 1996-12-23 1997-12-16 Medicine container for storage of a liquid medicine, and use of it
PL97334252A PL334252A1 (en) 1996-12-23 1997-12-16 Cyclic hydrocarbon polymer therapeutic agent holding container for storing a liquid therapeutic agent
CA002275894A CA2275894A1 (en) 1996-12-23 1997-12-16 A medicament container of polymer of cyclic hydrocarbon for storing a liquid medicament
JP52825398A JP2001506887A (en) 1996-12-23 1997-12-16 Drug container comprising a polymer of a cyclic hydrocarbon for storing a liquid drug
IL13043297A IL130432A0 (en) 1996-12-23 1997-12-16 A medicament container of polymer of cyclic hydrocarbon for storing a liquid medicament
AU53099/98A AU728503B2 (en) 1996-12-23 1997-12-16 A medicament container of polymer of cyclic hydrocarbon for storing a liquid medicament
AT97949988T ATE215348T1 (en) 1996-12-23 1997-12-16 A POLYMERIC CYCLIC HYDROCARBONS CONTAINER FOR STORING LIQUID MEDICATIONS
AU5309998D AU719221B2 (en) 1996-12-23 1997-12-16 A medicament container of polymer of cyclic hydrocarbon for storing a liquid medicament
EP97949988A EP0954272B2 (en) 1996-12-23 1997-12-16 A medicament container of polymer of bicyclic hydrocarbon for storing a liquid medicament
HU0000081A HUP0000081A3 (en) 1996-12-23 1997-12-16 A medicament container of polymer of cyclic hydrocarbon for storing a liquid medicament
DE69711703T DE69711703T3 (en) 1996-12-23 1997-12-16 A CONTAINER OF POLYMERIC CYCLIC HYDROCARBONS FOR STORING LIQUID MEDICAMENTS
NO19993083A NO314122B1 (en) 1996-12-23 1999-06-22 Cyclic hydrocarbon polymer drug container for liquid drug storage and use of the drug container

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