CONTAINER FOR A SOLUTION OF HUMAN PLASMA PROTEINS AND METHOD FOR OBTAINING THEREOF

Abstract

A container for a solution of human plasma proteins has a primary inner bag made up of a first multilayer polymer film with two outer layers of polyethylene (PE) and an intermediate layer of ethylene vinyl alcohol (EVOH) copolymer, and a secondary outer bag made up of a second multilayer film with layers of polyethylene terephthalate (PET)-silicon oxides (SiOx), oriented polyamide (OPA), polypropylene (PP)-silicon oxides (SiOx) and polypropylene (PP), referred to as multilayer PP-SiOx.

Claims

1. -13. (canceled).

14. A container for a solution of human plasma proteins, comprising: a) a primary inner bag comprising a first multilayer polymer film, wherein the first multilayer polymer film comprises two outer layers of polyethylene (PE) and an intermediate layer of ethylene vinyl alcohol (EVOH) copolymer, and b) a secondary outer bag comprising a second multilayer film, wherein the second multilayer polymer film comprises layers of polyethylene terephthalate (PET)-silicon oxides (SiOx), oriented polyamide (OPA), polypropylene (PP)-silicon oxides (SiOx) and polypropylene (PP).

15. The container according to claim 1, wherein the primary bag comprises an inlet cap comprising two closure positions, wherein a first closure position comprises a reversible hermetic closure and a second closure position comprises an irreversible hermetic closure by welding.

16. The container according to claim 2, wherein the welding is produced by ultrasound.

17. The container according claim 2, wherein a welding between a connector and the sheets of the bag is produced by heat contact.

18. The container according to claim 1, wherein the primary bag comprises an inlet comprising two small wings to facilitate the heating and welding of said inlet to the sheets of the primary bag.

19. The container according to claim 1, wherein an inside of an inlet cap of the primary bag comprises a toric protrusion which provides a hermetic seal around a perforation introduced through a valve membrane of the primary bag.

20. The container according to claim 1, wherein the human plasma proteins obtained from human plasma and contained in the primary bag comprise albumin, -1-antitrypsin, von Willebrand factor, coagulation factors such as factor VII, factor VIII and factor IX, immunoglobulins, plasminogen, plasmin, antithrombin III, fibrinogen, fibrin, thrombin or combinations thereof.

21. The container according to claim 7, wherein the human plasma proteins comprise immunoglobulins.

22. The container according to claim 1, wherein the outer bag is designed in peelable form.

23. A method for preparing a container according to claim 1 for human plasma proteins, the method comprising the following steps: a) sterile filtering of a solution of human plasma proteins through a 0.2 m membrane to obtain a sterile solution; b) filling the primary bag by lifting the cap of said inner bag in a sterile environment and introducing the sterile solution obtained at step a); c) inserting an inlet cap into the inlet of the primary bag in a sterile environment, and providing a hermetic closure therebetween by welding; d) inserting the primary bag obtained at step c) into the secondary bag and welding said secondary bag.

24. The method according to claim 10, wherein the human plasma proteins obtained from human plasma and contained in the primary bag comprise albumin, -1-antitrypsin, von Willebrand factor, coagulation factors such as factor VII, factor VIII and factor IX, immunoglobulins, plasminogen, plasmin, antithrombin III, fibrinogen, fibrin, thrombin or combinations thereof,.

25. The method according to claim 11, wherein the human plasma proteins comprise immunoglobulins.

26. The method according to claim 10, wherein the method comprises an additional incubation step for 21 days at 252 C.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0032] For a better understanding, the present invention is described below with reference to the accompanying drawings, which are presented as an example and which in no case are intended to limit the present invention. Equivalent or similar structures between the different figures have been designated with the same numeral.

[0033] FIG. 1 is a front view of an embodiment of the primary bag of the container of the present invention filled with a solution of human plasma protein.

[0034] FIG. 2 is an embodiment of the container of the present invention.

[0035] FIG. 3 is a cross section of the inlet of the primary bag of the container of the present invention.

[0036] FIG. 4 is a cross section of the cap of the primary bag of the container of the present invention.

[0037] FIG. 5 shows the results for weight loss in an accelerated stability study (12 months at 40 C.) of a primary bag which contains a solution of human plasma albumin without a secondary bag and with different secondary containers: 150 m thick polypropylene (PP), 300 m thick polypropylene (PP) and polypropylene coated with silicon oxides (multilayer PP-SiOx).

[0038] FIG. 6 shows the results for weight loss in a stability study (12 months at 5 C.) of a primary bag which contains a solution of human plasma albumin without a secondary bag and with different secondary containers: 150 m thick polypropylene (PP), 300 m thick polypropylene (PP) and polypropylene coated with silicon oxides (multilayer PP-SiOx).

[0039] FIG. 7 shows the results for weight loss in an accelerated stability study (2 months at 40 C.) of a primary bag which contains a solution of human plasma albumin with secondary bags of polypropylene coated with silicon oxides (multilayer PP-SiOx) and polypropylene covered with aluminium oxides (PP-AlOx).

DETAILED DESCRIPTION

[0040] As mentioned previously, FIG. 1 is a front view of an embodiment of the primary bag of the present invention. Said figure shows a container -1- which contains a solution of human plasma proteins -2-, said container comprising an inlet/cap structure -3- made up of a cap -4- and an inlet -5-. Said cap -4- is inserted into said inlet -5-, providing a hermetic closure of the container -1-.

[0041] FIG. 2 is a front view of an embodiment of the container of the present invention. Said system is made up of a primary bag -1-, similar to that described in FIG. 1, and a secondary bag -6-, which contains said first bag -1-. Said primary bag -1- contains a solution of human plasma proteins -2-, and comprises an inlet/cap structure -3- made up of a cap -4- and an inlet -5-.

[0042] FIG. 3 is a cross section of the inlet of the primary bag of the container of the present invention. As can be seen, said inlet comprises some small wings -7-, -7-, which facilitate the heating and welding thereof to the sheets of the primary bag.

[0043] Furthermore, FIG. 4 is a cross section of the cap of the primary bag of the container of the present invention. Said cap has a toric protrusion -8- at a distance from the valve membrane that ensures that when the end of the punch begins to perforate the membrane, for example during administration of the medicinal product to a patient, there is a hermetic fit between the punch and the toric protrusion, ensuring the seal of said primary bag.

EXAMPLES

Example 1

Accelerated Stability Study of a Primary Bag Which Contains Albumin, With and Without a Secondary Outer Bag

[0044] Four primary bags of different volumes (50, 100, 250 and 500 ml) were prepared, made up of a material composed of three layers of polymer: two layers of polyethylene (PE) on the outer sides and an intermediate layer of ethylene vinyl alcohol (EVOH) copolymer (Solmed Infuflex 9101, Renolit), with a 20% solution of human plasma albumin. Said primary bags were inserted into secondary bags made of different materials: 150 m thick polypropylene (PP), 300 m thick polypropylene (PP) and 140 m thick polypropylene coated with silicon oxides (multilayer PP-SiOx) (Mediflex, Amcor, Belgium). One primary bag was not placed inside a secondary bag. All the containers and the primary bag without a secondary bag were kept for 12 months at 40 C. and at the end of this time the weight loss of the container and the bag was determined expressed as a percentage (%).

[0045] The results can be seen in FIG. 3. A reduction was observed in the weight loss of the primary bags which were placed in secondary bags, the greatest reduction being in the case of the secondary bag of multilayer PP-SiOx (Mediflex, Amcor, Belgium).

Example 2

Stability Study of a Primary Bag Which Contains Albumin, With and Without a Secondary Bag

[0046] Containers prepared in the same way as in example 1 were kept for 12 months at 5 C. and at the end of that time the weight loss of each container was determined expressed as a percentage (%).

[0047] The results can be seen in FIG. 4. As with example 1, a reduction is observed in the weight loss of the primary bags which were placed inside secondary bags, the greatest reduction being in the case of the secondary bag made of multilayer PP-SiOx (Mediflex, Amcor, Belgium).

Example 3

Stability Study of a Primary Bag Which Contains Albumin, With Secondary Bags Made of Different Types of Coated Polypropylene

[0048] Two primary bags of different volumes (50 and 100 ml) were prepared, made up of a material composed of three layers of polymer: two layers of polyethylene (PE) on the outer sides and an intermediate layer of ethylene vinyl alcohol (EVOH) copolymer (Solmed Infuflex 9101, Renolit), with a 20% solution of human plasma albumin. Said primary bags were inserted into secondary bags made of two different materials: polypropylene coated with silicon oxides (multilayer PP-SiOx) (Mediflex, Amcor, Belgium) and 140 m thick polypropylene coated with aluminium oxides (PP-AlOx). All the prepared containers were kept for two months at 40 C. and at the end of that time the weight loss of the container was determined expressed as a percentage (%).

[0049] The results can be seen in FIG. 5. A reduction is observed in the weight loss of the primary bags which were placed in secondary bags made of multilayer PP-SiOx (Mediflex, Amcor, Belgium) compared with secondary bags made of PP-AlOx.

Example 4

Stability Study of a Container According to the Present Invention Which Contains Immunoglobulins

[0050] Three containers according to the present invention were prepared (Solmed Infuflex 9190/Mediflex PP-SiOx) which contained a 10% solution of human immunoglobulins for intravenous use, similar to that marketed under the name Gamunex (Grifols S.A, Spain). Said containers were kept at 5 C. for three months and different parameters were compared with the same immunoglobulin solution but packed in glass vials (n=6) at the beginning (T=0) and at the end of three months. The results are shown in Table 1.

TABLE-US-00001 TABLE 1 Results of the stability study of the container of the present invention compared with glass vials with immunoglobulins at 5 C. for three months IGIV in containers IGIV in glass vials n = 3 n = 6 Parameter t = 0 3 months 3 months Appearance Correct Correct Correct PH 4.1-4.2 4.2 4.1-4.2 Turbidity (NTU) 2.6-3.3 2.5-2.7 n.a. Osmolality 256-261 258-263 n.a. (mOsm/kg) Molecular distribution Polymers and aggregates 0.1-0.2 0.1-0.3 <1 Dimers + monomers 99.1-99.3 98.9-99.2 100 Weight loss 0.00 0.01-0.04 n.a. (%) n.a.: not analysed

[0051] As can be seen in Table 1, all the parameters measured meet the specifications of the European

[0052] Pharmacopoeia and the United States Pharmacopoeia for three months at 5 C.

Example 5

Accelerated Stability Study of a Container According to the Present Invention Which Contains Immunoglobulins

[0053] Three containers according to the present invention were prepared (Solmed Infuflex 9190/Mediflex PP-SiOx) which contained a 10% solution of human immunoglobulins for intravenous use, similar to the one marketed under the name Gamunex (Grifols S.A, Spain). Said containers were kept at 30 C. for three months and different parameters were compared with the same immunoglobulin solution but packed in glass vials (n=6) at the beginning (T=0) and at the end of three months. The results are shown in Table 2.

TABLE-US-00002 TABLE 2 Results of the accelerated stability study of the container of the present invention compared with glass vials with immunoglobulins at 30 C. for three months IGIV in containers IGIV in glass vials n = 3 n = 6 Parameter t = 0 3 months 3 months Appearance Correct Correct Correct PH 4.1-4.2 4.2 4.1-4.3 Turbidity (NTU) 2.6-3.3 2.6 n.a. Osmolality 256-261 257-267 n.a. (mOsm/kg) Molecular distribution Polymers and aggregates 0.1-0.2 0.3-1.1 0-1 Dimers + monomers 99.1-99.3 96.1-97.0 96-97 Weight loss 0.00 0.19-0.21 n.a. (%) n.a.: not analysed

[0054] As can be seen in Table 2, all the parameters measured meet the specifications of the European Pharmacopoeia and the United States Pharmacopoeia for three months at 30 C.

Example 6

Colour Stability Study of an Immunoglobulin Solution Packed in the Container According to the Present Invention

[0055] In addition to the parameters measured in Examples 4 and 5 above, the colour (optical density at 350-500 nm) of the immunoglobulin solution was determined in both stability studies and in the glass vials. As explained above, the colour of the intravenous immunoglobulin solution must meet the requirement imposed by the European Pharmacopoeia, that is, the solution must be clear and of a pale yellow to light brown colour. The results obtained are shown in Table 3.

TABLE-US-00003 TABLE 3 Results for optical density (OD.sub.350-500 nm) in the 10% immunoglobulin stability studies 3 months at 3 months at Receptacle t = 0 (n = 3) 5 C. (n = 3) 30 C. (n = 3) Containers 0.0504-0.0542 0.0540-0.0572 0.1013-0.1210 Glass vials n.a. 0.0526-0.0587 0.1229-0.1557

[0056] As can be seen, the colour in the container of the present invention is comparable to the colour obtained in the glass vials.

[0057] Although the invention has been described with respect to examples of preferred embodiments, said examples should not be considered to limit the invention, which will be defined by the widest interpretation of the following claims.