Multi-layered plastic polymeric container for the storage of pharmaceutical compositions

Abstract

Multi-layered plastic polymeric container useful for the storage and conservation of pharmaceutical compositions, sterile or non sterile, which comprises an inner layer and an outer layer, a gas barrier layer, and adhesive layers.

1 . Multi-layered plastic polymeric container for the storage of a composition comprising an inner layer and an outer layer in direct contact with the composition and the environment, respectively, a central gas barrier layer and two intermediate adhesive layers in between the central layer and the outer and inner polymeric layers, wherein the outer and inner layers comprise a mixture of polymers. 
     
     
         2 . Container of  claim 1 , wherein polymers of outer and inner layers are polyolefins or polyesters. 
     
     
         3 . Container of any one of the  claims 1  and  2 , wherein polymers of outer and inner layers are polyolefins and polyolefins are chosen among polypropylene and/or polyethylene in the form of homopolymers or copolymers. 
     
     
         4 . Container of any one of  claims 1 - 3 , wherein the outer layer comprises a mixture of polymers and at least one branched polyolefin. 
     
     
         5 . Container of any one of  claims 1 - 4 , wherein the outer layer comprises a mixture of polymers and at least one branched polyolefin, wherein the branched polyolefin in range of 5 to 25%. 
     
     
         6 . Container of any one of  claims 1 - 5 , wherein the outer layer comprises a mixture of polymers and at least one branched polyolefin, wherein the branched polyolefin is present in a proportion of 20%. 
     
     
         7 . Container of any one of  claims 1 - 6 , wherein the outer layer comprises a mixture of polymers and at least one branched polyolefin, and wherein the branched polyolefin is a polyalcene having 3 to 30 carbons, and preferably between 5 to 15 carbons. 
     
     
         8 . Container of any one of  claims 1 - 7 , wherein the outer layer comprises a mixture of polymers and at least one branched polyolefin, and wherein the branched polyolefin is a polyalcene which is present in a proportion of about 20%. 
     
     
         9 . Container of any one of  claims 1 - 8 , wherein the central gas barrier layer comprises ethylene vinyl alcohol (EVOH) or polyamide (PA). 
     
     
         10 . Container of  claim 9 , wherein the EVOH is present in a range of 20 to 60% of ethylene arms, preferably in a range of 27% to 47%, and preferably in an amount of 32%. 
     
     
         11 . Container of any one of  claims 1 - 10 , wherein the adhesive layer comprises polyolefins compounds, said polyolefins being grafted with various functional groups chosen among polyolefin, polyamide, and polycarbonate. 
     
     
         12 . Container of any one of  claims 1 - 11 , wherein the outer and inner layers further comprise up to three conventional additives. 
     
     
         13 . Container of  claim 12 , wherein the conventional additives are chosen among antioxidants, plasticizers, stabilizers, lubricants, dyes, or mechanical strengtheners. 
     
     
         14 . Container of  claim 12 , wherein the conventional additives are conventional antioxidants. 
     
     
         15 . Container of  claim 14 , wherein the conventional antioxidants are present within the range of up to 0.3% in the outer and inner layers. 
     
     
         16 . Container of  claim 15 , wherein the antioxidants are chosen among butylhydroxytoluene; ethylene bis(3,3-bis(3(1,1-diméthyléthyl)-4-hydroxy-phenyl)butanoate); pentaerythrityle tetrakis(3-(3,5-di-tert-butyl-4-hydroxy phenyl)-propionate) or IRGANOX 1010®; 4,4′,4″-(2,4,6 trimethylbenzene-1,3,5-tri-yltrismethylene)-tris(2,6-bis(1,1-dimethyl-ethyl)phenol) or IRGANOX 1330®; octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate or IRGANOX 1076®; tris(2,4-bis(1,1-dimethylethyl)-phenyle)phosphite; 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-s-triazine-2,4,6(1H,3H,5H)-trione; 2,2′-bis(octadecyloxy)-5,5′-spirobi(1,3,2-dioxaphosphinane); dioctadecyl disulfide; didodecyl 3,3′-thiodipropanoate; dioctadecyl 3,3′-thiodipropanoate; or a mixture of seven components corresponding to the reaction products of di-tert-butyl phosphite with trichloride biphosphorus, with biphenyl and 2,4-bis(1,1-dimethylethyl)phenol; copolymer of dimethyl succinate and of (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-yl)ethanol. 
     
     
         17 . Container of any one of  claims 14  and  15 , wherein the outer and inner layers comprise a combination of two additives, one being a primary additive antioxidant and a secondary antioxidant additive. 
     
     
         18 . Container of  claim 17 , wherein outer and inner layers comprise IRGAPHOS 168® as a primary antioxidant additive, and IRGANOX 1010®, IRGANOX 1330® or IRGANOX 1076® as secondary antioxidant additive. 
     
     
         19 . Container of any one of  claims 1 - 18 , wherein the outer layer comprises a mixture of polypropylene, polyoctene, and a sufficient amount of up to three antioxidant additives, wherein the inner layer comprises a mixture of polypropylene and a sufficient amount of up to three antioxidant additives. 
     
     
         20 . Container of any one of  claims 1 - 19 , wherein the outer layer comprises a mixture of polypropylene, polyoctene, and up to three antioxidant additives, wherein the inner layer comprises a mixture of polypropylene and up to three antioxidant additives, and wherein the polypropylene polymers, the polyoctene and the antioxidants are present in sufficient amounts to allow sterilization of the container at dose rates from 15 kGy to 25 kGy without inducing any modification of physical and chemical properties of the container. 
     
     
         21 . Container of any one of  claims 1 - 20 , wherein the outer layer comprises a mixture of polypropylene, polyoctene, and up to three antioxidant additives, wherein the outer layer comprises a mixture of polypropylene and up to three antioxidant additives, and wherein the polypropylene polymers, the polyoctene and the antioxidants are present in sufficient amounts to allow sterilization of the container at dose rate of 15 kGy, without any modification of the elasticity modulus of the container as measured by the Young modulus. 
     
     
         22 . Container of any one of  claims 1 - 21 , wherein the outer layer comprises a mixture of polypropylene, polyoctene, and up to three antioxidant additives, wherein the outer layer comprises a mixture of polypropylene and up to three antioxidant additives, and wherein the polypropylene polymers, the polyoctene polymers and the antioxidants are present in sufficient amounts to allow the stable storage of a sterile non aqueous composition for at least 6 months at about 40° C. 
     
     
         23 . Container of any one of  claims 1 - 22 , wherein the container comprises:
 an outer layer 1 comprising polypropylene, about 20% of polyoctene, and up to three additives chosen among IRGANOX 1010®, IRGAPHOS 168®, and IRGANOX 3114®;   a first intermediate layer 2 comprising a sufficient proportion of adhesive agent ADMER®;   a central layer 3 comprising a sufficient proportion of EVOH   a second intermediate layer 4 comprising a sufficient proportion of adhesive agent ADMER®; and   an inner layer 5 comprising polypropylene, and up to three additive chosen among IRGANOX 1010®, IRGAPHOS 168®, and IRGANOX 3114®.   
     
     
         24 . Container of any one of  claims 1 - 23  comprising the five following layers:
 an outer layer 1 in direct contact with the environment, comprising polyolefins, and having an average thickness ranging from 150 to 400 μm, preferably from 150 to 300 μm; 
 an intermediate outer layer 2 comprising adhesive agent and having an average thickness ranging from 5 to 75 μm, preferably from 5 to 50 μm; 
 a central layer 3 comprising a gas barrier copolymer agent and having an average thickness ranging from 20 to 170 μm, preferably from 20 to 100 μm; 
 an intermediate inner layer 4 comprising adhesive agent and having an average thickness ranging from 5 to 75 μm, preferably from 5 to 50 μm; and 
 an outer layer 5 in direct contact with the composition, comprising polyolefins and having an average thickness ranging from 200 to 600 μm, preferably from 450 to 600 μm. 
 
     
     
         25 . Container of any one of  claims 1 - 24  comprising the five following layers:
 an outer layer 1 in direct contact with the environment, comprising polyolefins and having an average thickness of about 250 μm; 
 an intermediate outer layer 2 comprising adhesive agent and having an average thickness of 10 μm; 
 a central layer 3 comprising a gas barrier copolymer agent and having an average thickness of about 30 μm; 
 an intermediate inner layer 4 comprising adhesive agent and having an average thickness ranging of about 10 μm; and 
 an outer layer 5 in direct contact with the composition comprising polyolefins and having an average thickness of about 500 μm. 
 
     
     
         26 . Container of any one of  claims 1 - 25 , wherein said container is sterilized by irradiation. 
     
     
         27 . Container of any one of  claims 1 - 26 , wherein said container is sterilized by gamma irradiation. 
     
     
         28 . Container of any one of  claims 26  and  27 , wherein the outer and inner layers contain no antioxidant additives after irradiation. 
     
     
         29 . Multi-layered plastic polymeric container which is sterilized by irradiation, comprising an inner layer and an outer layer respectively in direct contact with the composition and the environment, a central gas barrier layer, and two intermediate adhesive layers in between the central layer and the polymeric inner and outer layers, said outer and inner layers comprising a mixture of polymers of polyolefins and/or polyesters. 
     
     
         30 . Container of  claim 29 , wherein the outer and inner layers comprise a mixture of polyolefins. 
     
     
         31 . Container of any one of  claims 29  and  30 , wherein the outer layer comprises a mixture of polymers of polyolefins and/or polyesters and at least one branched polyolefin in a proportion ranging from 5 to 25% and the inner layer comprises a mixture of polymers of polyolefins and/or polyesters. 
     
     
         32 . Container of  claim 31 , wherein the branched polyolefin is present in a proportion of about 20% within the outer layer. 
     
     
         33 . Container of any one of  claims 31  and  32 , wherein the branched polyolefin is a polyalcene having 3 to 30 carbons, and preferably 5 to 15 carbons. 
     
     
         34 . Container of any one of  claims 31 - 33 , wherein the branched of the outer layer is a polyoctene. 
     
     
         35 . Container of any one of  claims 31 - 34 , wherein the polyoctene is present in a proportion of about 20%. 
     
     
         36 . Container of any one of  claims 29 - 35 , wherein the polyolefins of the outer and inner layers are chosen among polypropylene and/or polyethylene under the form of homopolymers or copolymers. 
     
     
         37 . Container of any one of  claims 29 - 36 , wherein the gas barrier layer comprises a gas barrier agent such as ethylene vinyl alcohol (EVOH) or polyamide (PA). 
     
     
         38 . Container of  claim 37 , wherein the EVOH is present in a range from 20% to 60% of ethylene, preferably from 27% to 47%, or preferably about 32%. 
     
     
         39 . Container of any one of  claims 29 - 38 , wherein the adhesive central layer comprises compounds of the polyolefin family, said polyolefin being grafted with variable functional groups chosen among polyolefin, polyamide, and polycarbonate. 
     
     
         40 . Container of any one of  claims 29 - 39  comprising:
 an outer layer 1 comprising polypropylene and about 20% of polyoctene; 
 a first intermediate inner layer 2 comprising a sufficient proportion of adhesive agent ADMER®; 
 a central layer 3 comprising a sufficient proportion of EVOH; 
 a second intermediate outer layer 4 comprising a sufficient proportion of adhesive agent ADMER®; and 
 an outer layer 5 comprising polypropylene. 
 
     
     
         41 . Container of any one of  claims 1 - 40 , for the storage of a sterile composition. 
     
     
         42 . Container of any one of  claims 1 - 41 , wherein the container is first sterilized by irradiation and then filled with the composition. 
     
     
         43 . Container of any one of  claims 1 - 42 , wherein the composition is first sterilized by any conventional methods of sterilization and then introduced in the container which is sterilized beforehand by gamma irradiation, the filling of the sterile container with the sterile composition is performed under sterile conditions. 
     
     
         44 . Container of any one of  claims 1 - 43 , wherein the container is first filled with the composition and the container/composition is then sterilized by irradiation. 
     
     
         45 . Container of  claim 44 , wherein the sterilization is done by gamma irradiation. 
     
     
         46 . Container of any one of  claims 1 - 45 , wherein the composition is a pharmaceutical composition. 
     
     
         47 . Container of  claim 46 , wherein the composition is a pharmaceutical non aqueous composition and comprises one or more active ingredients, a carrier comprising vegetal oils, organic solvents, heterocyclic organic solvents such as acetamides and pyrrolidone, glycol ester of oil solvents such as propylene glycol diester, or glycerides, such as triglycerides. 
     
     
         48 . Container of  claim 46  or  47 , wherein said composition comprises amoxicillin or oxytetracyclin as active ingredient. 
     
     
         49 . Container of  claim 46  or  47 , wherein said composition is a suspension of Ceftiofur HCl 5%. 
     
     
         50 . Container of  claim 46 , wherein said composition comprises a suspension of micronized powder of meloxicam, dispersed within a physiological medium, and 0.01 to 1% in weight of xanthan gum, 0.1 to 2% in weight of silicon oxide, and 50 to 70% of a mixture of polyols. 
     
     
         51 . Container of any one of  claims 1 - 50 , wherein the pharmaceutical composition is present under liquid form, aqueous or non aqueous, or under solid form, such as powders, tablets, pills, capsules, granules, pellets, pastes, or gels. 
     
     
         52 . Kit for the treatment and/or the prevention of a pathology, comprising a multi-layered plastic polymeric container as defined in any one of the  claims 1 - 45 , a pharmaceutical composition, and instructions for the treatment and/or prevention of said pathologies. 
     
     
         53 . Kit for the vaccination of a subject, comprising a multi-layered plastic polymeric container as defined in any one of the  claims 1 - 45 , a pharmaceutical composition comprising an antigenic substance capable of activating immune response of said subject against a pathogenic agent, and instructions for the vaccination of said subject. 
     
     
         54 . Kit for the diagnosis of a pathology in a patient comprising a multi-layered plastic polymeric container as defined in any one of the  claims 1 - 45 , a pharmaceutical composition comprising a diagnostic agent, and instructions for the diagnosis of said pathology in the patient. 
     
     
         55 . Method of manufacture of the multi-layered plastic polymeric container as defined in any one of the  claims 1 - 45 , wherein the various layers are obtained by extrusion-blown molding.