DE10201110B4 - Container for Parenteralia / Injectabila - Google Patents

Abstract

Container for Parenteralia / Injectabila out a plastic material having homopolymers or copolymers, which under Use of cycloolefins, the homo- and copolymers by polymerization of cycloolefinic monomers in the presence of one or more metallocene compounds Catalyst available are characterized in that the container is a syringe, the unsolvable connected to a hypodermic needle.

Description

The The invention relates to a container in the form of a syringe for Parenteralia / Injectabila made of a plastic material containing homo- and / or copolymers obtained by using cycloolefins getting produced. In particular, the invention relates to Syringes which are gamma and / or ethylene oxide sterilizable and have a particularly low permeability to water vapor.

Container for Inclusion of medical or pharmaceutical solutions must do so be suitable, highly effective preparations over several Store safely for years. The material from which these containers are made have to be different Have properties. A great transparency of the material allows visual inspection of the preparation on precipitates or impurities. The sterility of the container is ensured by sterilization reached. This can be done with steam at 121 ° C, with gamma rays, or with Ethylene fumigation can be achieved. The material should be opposite as possible many solvents be inert and do not release any chemicals into the solution. Necessary is moreover low water vapor and gas permeability, as otherwise the drug change could.

EP 0 556 034 A1 and EP 0 524 802 B1 disclose the use of cycloolefin polymers for the manufacture of containers for medical purposes. Because of their transparency in conjunction with their high glass transition temperature, which is important for steam sterilization, cycloolefin polymers are suitable for this purpose. This plastic is inert and releases only small amounts of low molecular weight substances into the solution.

One Another document describing the state of the art is the Publication "Metallocenes Catalyzed Polymer - A New Area in Pharmaceutical Packaging "by Andres Löfgren, in" Pharmaceutical Technology Europe ", Vol. 9, no. 4, page 39-43 has appeared. It describes that plastic materials, the metallocene catalyzed polymerized for the preparation of Packaging material for Pharmaceuticals are suitable. These polymers have a more favorable Molar mass distribution, a smaller proportion of residual monomers and a lower level of catalyst compared to conventionally polymerized materials on. The good processability and environmental compatibility of these plastics as well as cost advantages usual Materials are highlighted.

The polymerization of cyclic olefins with metallocene catalysts has been reported by DE 3922546 A1 disclosed. In this patent document, as well as in the other above-mentioned documents, special attention is drawn both to the excellent thermoplastic processability of these substances and to their optical properties.

The cycloolefinic material of EP 0 524 802 B1 has the same water vapor permeability as polypropylene. Lower water vapor permeability of cycloolefinic plastic materials is not disclosed by any of the above documents. In order to safely store highly effective preparations over several years, it is necessary to improve this property. This has been achieved by lamination. Thus, in claim 9 of EP 0 524 802 B1 a container of glass protected laminated with the cycloolefinic plastic material. With this approach, however, the known disadvantages of glass containers must be accepted. In particular, their low resistance to breakage can be mentioned here. In addition, lamminated glass containers are more expensive to manufacture and worse to use than containers made of cycloolefinic plastic material.

DE-A- 19633641 relates to elastomeric cycloolefin copolymers used in the preparation of catheters and other elastic materials in the field the medical and medical technology are suitable.

A Dropper bottle for medical and cosmetic purposes from cycloolefin copolymers in DE-A-19957788.

Of the Invention is based on the object, a container in the form of a syringe for parenterals / injectables from a transparent plastic material to create a has particularly low water vapor permeability, and many solvents Thus, the preparations are inert over one can be stored for a particularly long period of time.

The solution of this object is achieved with a container according to claim 1 for Parenteralia / Injectabila from a plastic material having homopolymers or copolymers prepared using cycloolefins, wherein the homo- or copolymers by the polymerization of cycloolefinic monomers in the presence of a or more metallocene-containing catalyst available are gekkzeichnet, characterized in that the container is a syringe, which is permanently connected to a hypodermic needle.

The inventive measures make it possible to produce a container made of a plastic material having a water vapor permeability of <0.08 g / (m ² × d) based on a wall thickness of 500 microns. The high transparency of the material allows the visual control of the contents for precipitation or contamination. The container according to the invention can be gamma sterilized without impairing its chemical and physical properties, in particular brittleness and color. Gamma sterilization is a very simple and inexpensive process, so that containers according to the invention can be provided much more cheaply than the conventional ones. The plastic material according to the invention is inert to most solvents and releases no chemicals into the solution.

Further Advantages of the invention will become apparent in connection with the drawing 1 shown.

1 shows in longitudinal section a prefillable sterile disposable syringe for medical purposes. The syringe body consists of a syringe barrel 1 , which at one end a handle bar 2 having. In the syringe barrel 1 there is an injection piston 4 that by means of a piston rod 3 is displaceable in the syringe barrel. In the prefilled, fully assembled state of the syringe is the syringe plunger 4 near the handle 2 , After application is as in 1 also shown, the syringe plunger at the other end of the syringe barrel.

At this end, the syringe barrel goes into a syringe head 5 on, at which, as will be explained, an injection needle 6 insoluble, that is not non-destructively releasable, is attached. The injection needle 6 is through a protective cap 7 coverable. The syringe head has a ring collar 8th on. On the cylindrical surface of the ring collar 8th lies the cap shirt of the protective cap 7 sealingly. For the training of this cap 7 the expert has a number of options available. Thus, for example, the protective cap made of an elastomer, preferably made of rubber, and the wall thickness be chosen so large that the tip of the cannula 6 is sealed by the material of the protective cap, wherein the cannula pierces when placing the cap in this. It is also conceivable to provide a plastic cap made of relatively hard-elastic material, which is lined inside, at least in the area of the cannula syringe, with a soft elastic sealing material. As a result, this soft elastic material can be selected for optimum sealing properties (sealing function), while the hard elastic material is suitable for counteracting mechanical external impairments (protective function).

The syringe barrel 1 with integrated handle 2 and syringe head 5 as well as the piston rod 3 are made of the plastic according to the invention, whereas the injection needle 6 As usual, consist of a metallic material and the syringe plunger of a soft elastic material.

The injection needle 6 is in the embodiment according to 1 held without the use of an additional adhesive alone by the encapsulation. The design of the contact surface of the syringe head, on which the protective cap 7 sealingly abuts, as a ring collar leads to only small accumulations of material in the area of Nadelumspritzung. The encapsulation of the needle with plastic is made as partially thin, whereby the plastic can shrink after encapsulation and thereby achieved on cooling after injecting the plastic into the mold sufficient sealing and holding effect.

worin R¹, R², R³, R⁴, R⁵, R⁶, R⁷ und R⁸ gleich oder verschieden sind und ein Wasserstoffatom oder einen C₁-C₈- Alkylrest bedeuten, wobei gleiche Reste in den verschiedenen Formeln eine unterschiedliche Bedeutung haben können, polymerisiert. Ggf. wird auch ein monocyclisches Olefin der Formel V,

worin n eine Zahl von 2 bis 10 ist, verwendet. Ein anderes Comonomer ist ein acyclische 1-Olefin der Formel VI,

worin R⁹, R¹⁰, R¹¹ und R¹² gleich oder verschieden sind und ein Wasserstoffatom oder einen C₁-C₈-Alkylrest bedeuten. Bevorzugt sind Ethylen oder Propylen.To produce the plastic material according to the invention, at least one polycyclic olefin of the formula I-II-III or IV, preferably a cycloolefin of the formulas I or III,

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are the} same or different and represent a hydrogen atom or a C ₁ -C ₈ - alkyl radical, wherein the same radicals in the various formulas one may have different meaning, polymerized. Possibly. is also a monocyclic olefin of the formula V,

where n is a number from 2 to 10. Another comonomer is an acyclic 1-olefin of formula VI,

wherein R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and represent a hydrogen atom or a C ₁ -C ₈ alkyl radical. Preferred are ethylene or propylene.

Especially are copolymers of polycyclic olefins of formula I and III produced. The polycyclic olefin (I-IV) is added in an amount from 0.1-100 Wt .-%, the monocyclic olefin (V) in an amount of 0-99 wt .-% and the acyclic 1-olefin (VI) in an amount of 0-99.9 wt% each based on the total amount of monomers used.

und/oder der Formel VIII für den linearen Typ

und mindestens einem Metallocen der Formel IX.

The catalyst to be used according to the invention consists of an aluminoxane of the formula VII for the cyclic type

and / or the formula VIII for the linear type

and at least one metallocene of the formula IX.

In formula XI, M ^{1 is} a metal from the group titanium, zirconium, hafnium, vanadium, niobium and tantalum, preferably zirconium and hafnium. R ¹⁴ and R ¹⁵ are identical or different and denote a hydrogen atom, a C ₁ -C ₁₀ , preferably C ₁ -C ₃ -alkyl group, a C ₁ -C ₁₀ , preferably C ₁ -C ₃ -alkoxy, a C ₆ - C ₁₀ , preferably C ₆ -C ₈ -aryl, C ₆ -C ₁₀ , preferably C ₆ -C ₈ -aryloxy, C ₂ -C ₁₀ , preferably C ₂ -C ₄ -alkenyl, C ₇ -C ₄₀ , preferably C ₇ -C ₁₀ arylalkyl group, a C ₇ -C ₄₀ , preferably C ₇ -C ₁₂ alkylaryl group, a C ₈ -C ₄₀ , preferably C ₈ -C ₁₂ arylalclenyl group or a halogen atom, preferably chlorine. C ₁₆ are C ₁₇ are identical or different and denote a mononuclear or polynuclear hydrocarbon radical which can form a sandwich structure with the central atom M ¹ . Preferably, R ¹⁶ and R ^{17 are} either both indenyl or tetrahydroindenyl or R ^{16 is} fluorenyl and R ^{17 is} cyclopentadienyl.

=BR¹⁹, =ALR¹⁹, -Ge-, -Sn-, -O-, -S-, =SO, =SO₂ =NR¹⁹, =CO, =PR¹⁹ oder =P(O)R¹⁹ ist, wobei R¹⁹, R²⁰ und R²¹ gleich oder verschieden sind und ein Wasserstoffatom, ein Halogenatom, vorzugsweise Chlor, eine C¹-C¹⁰, vorzugsweise C₁-C₃-Alkylgruppe, insbesondere Methylgruppe, eine C₁-C₁₀-Fluoralkylgruppe, vorzugsweise CF₃-Gruppe, eine C₆-C₁₀-Fluorarylgruppe, vorzugsweise Pentafluorphenylgruppe, eine C₆-C₁₀, vorzugsweise C₆-C₈-Arylgruppe, eine C₁-C₁₀, vorzugsweise C₁-C₄-Alkoxygruppe, insbesondere Methoxygruppe, eine C₂-C₁₀, vorzugsweise C₂–C₄–Alkenylgruppe, eine C₇-C₄₀, vorzugsweise C₇-C₁₀-Arylalkylgruppe, eine C₈-C₄₀, vorzugsweise C₈-C₁₂-Arylalkenylgruppe oder eine C₇-C₄₀, vorzugsweise C₇-C₁₂-Alkylarylgruppe bedeuten, oder R¹⁹ und R²⁰ oder R¹⁹ und R²¹ bilden jeweils zusammen mit den sie verbindenden Atomen einen Ring.R ¹⁸ is a mono- or multi-membered bridge which links and means the radicals R ¹⁶ and R ¹⁷

= BR ¹⁹ , = ALR ¹⁹ , -Ge, -Sn, -O-, -S-, = SO, = SO ₂ = NR ¹⁹ , = CO, = PR ¹⁹ or = P (O) R ¹⁹ , wherein R ¹⁹ , R ²⁰ and R ^{21 are the} same or different and a hydrogen atom, a halogen atom, preferably chlorine, a C ¹ -C ¹⁰ , preferably C ₁ -C ₃ alkyl group, in particular methyl group, a C ₁ -C ₁₀ fluoroalkyl group , preferably CF ₃ group, a C ₆ -C ₁₀ fluoroaryl group, preferably pentafluorophenyl group, a C ₆ -C ₁₀ , preferably C ₆ -C ₈ aryl group, a C ₁ -C ₁₀ , preferably C ₁ -C ₄ alkoxy group , in particular methoxy group, a C ₂ -C ₁₀ , preferably C ₂ -C ₄ -alkenyl group, a C ₇ -C ₄₀ , preferably C ₇ -C ₁₀ -arylalkyl, a C ₈ -C ₄₀ , preferably C ₈ -C ₁₂ - Arylalkenyl group or a C ₇ -C ₄₀ , preferably C ₇ -C ₁₂ alkylaryl group, or R ¹⁹ and R ²⁰ or R ¹⁹ and R ²¹ each form a ring together with the atoms connecting them.

M ² silicon, germanium or tin, preferably silicon or germanium. R ¹⁸ is preferably = R ¹⁹ C ²⁰ , = SiR ¹⁹ R ²⁰ , = GeR ¹⁹ R ²⁰ , -O-, -S-, = SO, = PR ¹⁹ or P (O) R ¹⁹ .

method for the representation of the metallocenes are known from the literature.

Prefers metallocenes used are rac-dimethylsilyl-bis- (1-indenyl) -zirconium dichloride, rac-dimethylgermyl-bis (1-indenyl) -zirconium dichloride, rac-phenylmethylsilyl-bis- (1-indenyl) -zirconium dichloride, rac-Phenylvinylsilyl-bis- (1-indenyl) zirconium dichloride, 1-Silycylobutyl-bis (1'-indenyl) zirconium dichloride, rac-ethylene-bis- (1-indenyl) zirconium dichloride, rac-diphenyl-bis- (1-indenyl) -hafmiumdichlorid, rac-phenylmethylsilylbis (1-indenyl) -hafnium dichloride, rac-dimethylsilylbis (1-indenyl) -hafnium dichloride, rac-diphenylsilylbis (1-indenyl) -zirconium dichloride, Diphenylmethylene (9-fluorenyl) cyclopentadienyl zirconium dichloride, isopropylene (9-fluorenyl) cyclopentadienyl zirconium dichloride or their mixtures.

The cocatalyst is an aluminoxane of the formula VII for the linear type and / or the formula VIII for the cyclic type. In these formulas, R ^{13 is} a C ₁ -C ₆ alkyl group, preferably methyl, ethyl or isobutyl, butyl or neopentyl, or phenyl or benzyl. Preferred is methyl. n is an integer from 2 to 50, preferably 50 to 40. However, the exact structure of the aluminoxane is not known. The preparation of the aluminoxane is known from the literature. The concentration of the aluminoxane in the solution is in the range of about 1 wt .-% to the saturation limit, preferably from 5-30 wt .-% in each case based on the total solution. The metallocene can be used in the same concentration, but it is preferably used in an amount of about 10 ^{-4 to} 1 mol per mol of aluminoxane.

The Polymerization is in a for the Ziegler low-pressure process used interten solvent carried out, for example in an aliphatic or cycloaliphatic hydrocarbon; when such as butane, pentane, hexane, heptane, isooctane, Cyclohexane, called methylcyclohexane. Furthermore, a gasoline or hydrogenated diesel oil fraction, the carefully has been freed of oxygen, sulfur compounds and moisture is to be used. Also useful is toluene.

Finally, can also the monomers to be polymerized as a solvent or as a suspending agent be used. In the case of Norbonen become such bulk polymerizations at a temperature above 45 ° C carried out. The molar mass of the polymer can be controlled in a known manner; preferably Hydrogen is used for this purpose.

The Polymerization is carried out in known manner in solution, in suspension or in Gaspase continuously or discontinuously in one or more stages at a temperature of -78 ° C to 150 ° C, preferably -20 ° C to 80 ° C performed. Of the Pressure is 0.5 to 64 bar and is either by the gaseous olefins or with the help of inert gas.

In this case, the metallocene compound is used in a concentration, based on the transition metal, of 10 ^-3 to 10 ^-7 , preferably 10 ^-5 to 10 ^-6 mol of transition metal per dm ³ reactor volume. The aluminoxane is used in a concentration of 10 ^-4 to 10 ^-1 , preferably 10 ^-4 to 2 × 10 ^-2 mol per dm ³ reactor volume, based on the content of aluminum. In order to combine the polymerization properties of various metallocenes, it is possible to use mixtures of several metallocenes.

The plastic material according to the invention may also have other polymers. The alloys can be in Melt or in solution getting produced. The alloys each have one for certain applications favorable Property combination of the components.

example 1

Preparation of rac-dimethylsilylbis (1-indenyl) zirconium dichloride (Metallocene A)

All subsequent operations are under inert gas atmosphere Use of absolute solvents carried out been (Schlenk technique).

A solution of 30 g (0.23 mol) filtered over Aluminoxid indene (technical 91%) in 200 cm ^{3 of} diethyl ether (0.20 mol) under ice-cooling with 80 cm ³ of a 2.5 molar solution of n-butyl lithium in Hexane spiked. The mixture was stirred for 15 minutes at room temperature and the orange solution was added via cannula within 2 hours to a solution of 13.0 g (0.10 mol) of dimethyldichlorosilane (99%) in 30 cm ³ diethyl ether. The orange suspension was stirred overnight and shaken three times with 100-150 cm ^{3 of} water. The yellow organic phase was dried twice over sodium sulphate and evaporated in a rotary evaporator. The remaining orange oil was held at 40 ° C for four to five hours in an oil pump vacuum and freed from any excess indene, precipitating a white precipitate. Addition of 40 cm ^{3 of} methanol and crystallization at -35 ° C. allowed a total of 20.4 g (71%) of the compound (CH ₃ ) ₂ Si (Ind) ₂ to be isolated as a white to beige powder. FP 79-81 ° C (diastereomers).

A solution of 5.6 g (19.4 mmol) of (CH ₃ ) ₂ Si (Inds) ₂ in 40 cm ³ THF became slowly at room temperature with 15.5 cm ³ (38.7 mmol) of a 2.5 molar Hexane solution of butyllithium added. One hour after completion of the addition, the deep red solution was added dropwise within 4-6 hours to a suspension of 7.3 g (19.4 mol) of ZrCl ₄ .2THF in 60 cm ^{3 of} THF. After stirring for 2 hours, the orange precipitate was filtered off with suction through a glass frit and recrystallized from CH ₂ Cl ² . This gave 1.0 g (11%) of rac- (CH ₃ ) ₂ Si (Inds) ₂ ZrCl ₂ in the form of orange crystals, which decompose gradually from 200 ° C. Correct elementary analyzes. The E1 mass spectrum showed M ⁺ = 448, ¹ H-NMR spectrum (CDCl ₃ ): 7.04-7.60 (m, 8, arom.H), 6.90 (dd, s, β-Ind H ), 6.08 (d, 2, a-Ind H), 1.12 (s, 6, SiCH ₂ ).

Example 2

A clean and dry 1.5 dm ³ polymerization reactor with a stirrer was purged with nitrogen and with ethylene and filled ³ of toluene with a solution of 25 g of norbornene in 750 cm. Thereafter, 20 cm ^{3 of} toluene solution of methylaluminoxane (10.1 wt .-% methylaluminoxane with molecular weight 1300 g / mol by cryoscopic determination) were metered into the reactor and the mixture stirred for 15 minutes at 20 ° C, maintained by metering the ethylene pressure at 1 bar was (saturation of the toluene with ethylene). In parallel, 30.5 mg of metallocene A in 10 cm ^{3 of} toluene solution of methylaluminoxane (concentration and quality is as above) were dissolved and preactivated by standing for 50 minutes. Then the solution of the complex was metered into the reactor. With stirring (750 rpm) was then polymerized for 1 hour at 20 ° C, the ethylene pressure was kept after dosing at 1 bar. Then, the contents of the reactor were quickly discharged into a stirred vessel in which 100 cm ^{3 of} isopropanol were initially charged. This mixture was added with 2 cm ^{3 of} acetone, stirred for 10 minutes, and then the suspended polymeric solid was filtered off. The polymer was then abfiltriere ³ in 300 cm of a mixture of 2 parts of 3-normal hydrochloric acid and 1 part of ethanol, and this suspension was stirred for 2 hours. The polymer was then filtered off again, washed neutral with water and dried at 80 ° C and 0.2 bar for 15 hours. A product amount of 55 g was obtained. On the product, a viscosity number VZ of 244 cm ³ / g and a glass transition temperature Tg of 32 ° C was measured.

Example 3

A polymerization experiment was carried out according to Example 2, wherein instead of norbornene under 110 g of 1,4,5,8-dimethano-1,2,3,4,4 ', 5,8,8a-octahydronaphthalene (DMON) and instead of 30, 5 mg 61.5 mg of metallocene A were used. 17 g of polymer was obtained. On the polymer, a viscosity number VZ = 120 cm ³ / g and a glass transition temperature Tg = 124 ° C was measured.

Claims (6)

Parenteral / Injectable container of a plastic material comprising homopolymers or copolymers prepared using cycloolefins, which homopolymers and copolymers are obtainable by polymerization of cycloolefinic monomers in the presence of a catalyst comprising one or more metallocene compounds, characterized that the container is a syringe which is permanently connected to a hypodermic needle. container according to claim 1, characterized in that the cycloolefin Norbonen is. container according to claim 1, characterized in that the cycloolefin 1,4,5,8-dimethano-1,2,3,4,4,5,8,8a-octahydronaphthalene (DMON) is. container according to one of the claims 1 to 3, characterized in that the metallocene compound ethylene bis (1-indenyl) zirconium dichloride is. Container according to one of claims 1 to 4, characterized in that the plastic material has a water vapor permeability <0.08 g / cm ² × d based on a wall thickness of 500 microns. container according to one of the claims 1 to 5, characterized in that the container gammasterilisierbar and / or ethylene oxide is sterilizable, without affecting chemical and physical Properties of the plastic material, in particular brittleness and color, dysfunctional change.