A container comprising a closure means coated by an inert fluorinated material and containing a liquid pharmaceutical composition. In particular, the container comprises a closure means coated by TEFLON (polytetrafluoruethylene (PTFE)) and contains a hsa-free interferon-β formulation having the following composition: 30 to 100 μg/ml of interferon-β, an isotonicity agent, 0.1 to 2 mg/ml of Poloxamer 188, at least 0.12 mg/ml of L-Methionine and a buffer solution capable of maintaining the pH of the liquid formulation at a value between 3.0 and 4.0.
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0. 24. A pharmaceutical product comprising:
a container;
a liquid pharmaceutical composition ready for injection and comprising interferon β as active ingredient; and
a closure coated with polytetrafluoroethylene.
6. A container for a liquid pharmaceutical composition containing an interferon β as active ingredient, wherein the container is a vial, an ampoule, a small bottle or, a tube, a syringe or a cartridge, and a closure stopper which is coated with polytetrafluoruethylene (PTFE) polytetrafluoroethylene.
0. 16. A pharmaceutical product comprising:
a container selected from the group consisting of a syringe, a cartridge, a vial, a bottle and a tube;
a liquid pharmaceutical composition comprising interferon β as active ingredient; and
a closure coated with polytetrafluoroethylene.
1. A method for containing a composition comprising providing a liquid pharmaceutical composition ready for injection and comprising an interferon β as an active ingredient into a container which is a vial, an ampoule, a small bottle or, a tube, a syringe or a cartridge with a closure stopper wherein the closure stopper is coated with polytetrafluoruethylene (PTFE) polytetrafluoroethylene.
5. A method for containing a composition comprising providing a liquid pharmaceutical composition ready for injection and comprising a protein as an active ingredient into a container with a closure article coated with polytetrafluoruethylene polytetrafluoroethylene, wherein the pharmaceutical composition is a liquid hsa-free (human serum album) formulation comprising 30 to 100 μg/ml of interferon-β, an isotonicity agent, 0.1 to 2 mg/ml of a surfactant, at least 0.12 mg/ml of an antioxidant and a buffer solution capable of maintaining the pH of the liquid formulation at a value between 3.0 and 4.0.
2. The method according to
4. The method according to
8. The container according to claim 6 7, wherein the internal surface of the container is coated by an inert material.
9. The container according to claim 6 8, wherein the inert material coating the internal glass surface of the container is silicon silicone.
11. The container according to
0. 13. The container according to claim 6, wherein the container contains the liquid pharmaceutical composition with the interferon β being present in the liquid pharmaceutical composition in an amount of about 30 to about 100 μg/mL.
0. 14. The container according to claim 13, wherein the liquid pharmaceutical composition further contains a bacteriostatic agent.
0. 15. The container according to claim 14, wherein the liquid pharmaceutical composition further contains an isotonicity agent, a surfactant, an antioxidant and a buffer solution.
0. 17. The pharmaceutical product of claim 16, wherein the container is a syringe or a cartridge for autoinjector and wherein the closure is a plunger.
0. 18. The pharmaceutical product of claim 17, wherein the container is a pre-filled syringe.
0. 19. The pharmaceutical product of claim 16, wherein said liquid pharmaceutical composition further comprises a bacteriostatic agent.
0. 20. The pharmaceutical product of claim 19, wherein the liquid pharmaceutical composition further comprises an isotonicity agent, a surfactant, an antioxidant and a buffer solution.
0. 21. The pharmaceutical product of claim 16, wherein said container is made of glass.
0. 22. The pharmaceutical product of claim 21, wherein the internal surface of the container is coated by an inert material.
0. 23. The pharmaceutical product of claim 22, wherein the inert material coating the internal glass surface of the container is silicone.
0. 25. The pharmaceutical product of claim 24 wherein the liquid pharmaceutical composition is hsa-free (human serum albumin), and comprises 30 to 100 μg/mL of interferon β, an isotonicity agent, 0.1 to 2 mg/mL of a surfactant, at least 0.12 mg/mL of an antioxidant and a buffer solution capable of maintaining the pH of the liquid formulation at a value between 3.0 and 4.0.
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The present invention relates to a container containing a liquid pharmaceutical composition for injectables and containing a protein as active ingredient.
Medicines for injection are not always available from the manufacturer in a ready-to-use form. Therefore, many injections need to be prepared before they can be administered.
The process of preparation may be straightforward, for example a simple dilution, or complicated, for example involving complex calculations, or several manipulations. There are the risks of error in the calculations and during the manipulations involved, and risks of microbial and particulate contamination. The nature of the medicine and the clinical condition of the patient may affect the degree of the overall risk.
The risk of contamination is higher when injections are prepared in environments without suitable controls. Over the past thirty years, surveys on intravenous medicines prepared in near-patient areas have shown a range of contamination rates ranging from 2 to 15% (average 8%). Although most of the contamination does not lead to sepsis, the nature of the contaminating organism cannot be predicted. Therefore the risk of serious sepsis cannot be discounted, particularly if the patient is immunocompromised, or if the injection solution supports bacterial growth.
Therefore there is an increasing need for liquid pharmaceutical compositions in a ready-to-use form, i.e. ready for injection. These kinds of pharmaceutical compositions are normally sold in suitable sterile containers like vials, pre-filled syringes, ampoules, small bottle, tubues or cartridges for autoinjectors.
The preparation of liquid protein formulations for pharmaceutical compositions in a ready-to-use form is generally interfered by the low stability of the protein. In fact, it is known that proteins in the purified form are highly susceptible to degradation, even due to the normal activity of atmospheric agents. This particularity becomes even more evident for proteins produced according to recombinant DNA techniques.
The stability problem is particularly felt for interferon-β formulations, which do not comprise human serum albumin (HSA) as stabilizing agent. Nowadays formulations without HSA are preferred because HSA has two main drawbacks: the first is related to its extraction from human blood and, hence, the possibility of infection transmission, the second refers to its high cost due to its low availability.
Moreover the liquid pharmaceutical compositions may be for single-dose use or for multiple-dose use. In particular, when multi-dose are prepared, it may become necessary to add some additional excipients, which are the preservatives or bacteriotastic agents, to prevent microbial contamination after the container is opened or perforated by a needle due to repeated administrations from the same container.
Although the use of such bacteriostatic agents is necessary for the reason above, it has a negative effect on proteins stability. Because of this, the amount of bacteriostatic agents used in the multidose protein formulation has to be very low. In this case, besides the absence of contamination is not highly guaranteed, the proteins are not stable for the intended use.
To well understand the protein stability problem in the formulations for a multidose product, it has to be underlined the importance that multidose products have in the current pharmaceutical market. In fact, in the most of therapies the liquid pharmaceutical protein formulations have to be injected very often. For instance, liquid interferon-beta formulations for the treatment of multiple sclerosis have to be administered every given day to once a week depending on both the kind of interferon-beta used and if the injection is intramuscular or subcutaneous.
Because of such a frequent use of the formulations, in the last years the liquid pharmaceutical protein formulations are prepared as multidose formulations in containers that the patient can use also by using an injector device. As it is easy to understand, multidose formulations will ease the patient life.
Therefore, the need was felt to find specific conditions for obtaining liquid protein pharmaceutical composition ready for injection, having an improved stability, and being usable for both monodose and multidose use.
The Applicant has surprisingly and unexpectedly found particular containers useful to solve the above technical problem.
The main object of the present invention is the use of a closure means coated by an inert fluorinated material for a container of a liquid pharmaceutical composition ready for injection and containing a protein as active ingredient.
More preferably, the protein is an Interferon.
Preferably, the Interferon is an Interferon-β.
Another object of the present invention is a container containing a liquid pharmaceutical composition ready for injection and containing a protein as active ingredient, characterised by comprising a closure means coated by an inert fluorinated material.
More preferably, the inert fluorinated material is TEFLON® TEFLON “(polytetrafluoruethylene (PTFE))” TEFLON® (polytetrafluoroethylene (PTFE)).
Non-coated plunger (1) (FM 257/5 Helvoet Pharma)
The A formulations packaged as described in TABLE I have been stored at 25±2° C. and 40±2° C., and tested for stability
In Table II the results of the analytical test of A formulations stored at 40° C. are summarized.
TABLE II
FORMULATION
T = 0
T = 2 WEEKS
T = 3 WEEKS
% Oxidised forms
A1
1.7
2.8
3.9
A1 comp.
2.1
4.6
13.2
A2
0.9
2.4
2.2
A2 comp.
0.8
4.4
9.2
% Total aggregates
A1
3.4
3.1
3.0
A1 comp.
1.4
2.8
2.7
A2
1.7
2.0
1.5
A2 comp.
1.8
2.8
2.1
In Table III the results of the analytical test of A formulations stored at 25° C. are summarized.
TABLE III
T = 4
T = 8
T = 12
FORMULATION
T = 0
WEEKS
WEEKS
WEEKS
% Oxidised forms
A1
1.7
2.4
2.1
2.1
A1 comp.
2.1
3.5
4.8
4.9
A2
0.9
1.0
A2 comp.
0.8
1.6
% Total aggregates
A1
3.4
2.8
3.8
3.2
A1 comp.
3.4
1.6
1.8
1.4
A2
1.7
1.4
A2 comp.
1.8
1.6
Out of TABLE II and TABLE III it can be seen that formulations A have a good stability (see oxidised percentage) only when stored in a container with closure means coated by TEFLON “(polytetrafluoruethylene (PTFE))” TEFLON® (polytetrafluoroethylene (PTFE)), regardless the cartridge material. The stability difference is even more evident when the formulation A is stored at 40° C. (TABLE II).
Different packaging conditions do not seem to affect the aggregates percentage.
Three formulations (B-D) having the compositions (mg/mL) illustrated in TABLE IV have been prepared.
TABLE IV
Acetate
FORMU-
Poloxamer
Benzyl
10 mM
LATION
IFN-β-1a
Mannitol
188
L-Met
Alcohol
pH 3.5
B
0.088
54.6
1
0.12
5
Qs 1 mL
C
0.088
54.6
1
0.12
7
Qs 1 mL
D
0.088
54.6
1
0.12
9
Qs 1 mL
In this case, the presence of benzyl alcohol as bacteriostatic agent allows the use of these formulations in pharmaceutical products for a multidose administration.
The formulations B-D have been prepared in the same way described in example 1 for formulation A, except for the inclusion of benzyl alcohol in the excipients solution.
After the preparation, the formulations B-D have been packaged using different cartridges and closure means as described in Table V
TABLE V
FORMULATION
CARTIDGE
CLOSURE MEANS
B1
Non-siliconized
Coated plunger
B1 comp.
Non-siliconized
Non-coated plunger (1)
B2
Siliconized
Coated plunger
B2 comp
Siliconized
Non-coated plunger (1)
C
Siliconized
Coated plunger
C comp.
Siliconized
Non-coated plunger (2)
D
Siliconized
Coated plunger
D comp.
Siliconized
Non-coated plunger (2)
In this case, in addition to the materials described in example 1, a new closure means has been used:
Non-coated plunger (2) (4023/50, West Pharmaceutical)
Formulations B-D packaged as described in TABLE V have been stored at 25±2° C. and 40±2° C., and tested for stability
In Table VI the results of the analytical test of B-D formulations stored at 40° C. are summarized.
TABLE VI
FORMULATION
T = 0
T = 2 WEEKS
T = 3 WEEKS
% Oxidised forms
B1
1.7
3.1
4.1
B1 comp.
2.1
9.8
12.0
B2
1.7
2.9
3.3
B2 comp.
1.5
6.5
14.2
C
1.2
3.0
3.3
C comp.
0.9
4.4
10.3
D
1.1
3.5
3.5
D comp.
1.0
5.5
14.1
% Total aggregates
B1
3.4
3.5
3.4
B1 comp.
3.2
6.4
14.9
B2
1.6
2.6
2.4
B2 comp.
1.6
10.5
11.4
C
1.7
3.2
2.6
C comp.
1.6
16.9
21.1
D
1.9
4.6
4.2
D comp.
1.7
31.7
56.5
In Table VII the results of the analytical test of B-D formulations stored at 25° C. are summarized.
TABLE VII
T = 4
T = 8
T = 12
FORMULATION
T= 0
WEEKS
WEEKS
WEEKS
% Oxidised forms
B1
1.7
2.3
2.7
2.7
B1 comp.
2.1
3.6
4.7
Not
measurable
B2
1.7
1.7
B2 comp.
1.5
2.4
C
1.2
1.4
C comp.
0.9
1.5
D
1.1
2.0
D comp.
1.0
2.0
% Total aggregates
B1
3.4
2.8
3.7
3.1
B1 comp.
3.2
1.5
2.3
2.1
B2
1.6
1.4
B2 comp.
1.6
1.4
C
1.7
1.6
C comp.
1.6
1.5
D
1.9
1.7
D comp.
1.7
1.9
From the results shown in TABLE VI and TABLE VII it can be noted a higher stability of the formulations stored with closure means coated by TEFLON “(polytetrafluoruethylene (PTFE))” TEFLON® (polytetrafluoroethylene (PTFE)) regardless the cartridge material.
In particular, in this example it has been shown that also formulations comprising bacteriostatic agent can reach a very good stability when stored in containers with closure means coated by TEFLON “(polytetrafluoruethylene (PTFE))” TEFLON® (polytetrafluoroethylene (PTFE)). This is true even if they contain a large amount of bacteriostatic agent. In fact, as it is shown (in particular in TABLE VI), for the formulations stored with non-coated closure means the presence of bacteriostatic agent is responsible for the very low protein stability.
Such a good stability for this kind of formulation is very important to obtain a pharmaceutical multidose product as it has been said above.
Del Rio, Alessandra, Samaritani, Fabrizio
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