U.S. patent application number 12/522680 was filed with the patent office on 2010-06-10 for storage of ampoules containing pharmaceutical formulations using a sealed container comprising an oxygen scavenger.
This patent application is currently assigned to Breath Ltd. Invention is credited to Ian Gardener, Cameron McAffer, Peter Ernest Tasko.
Application Number | 20100143419 12/522680 |
Document ID | / |
Family ID | 37801921 |
Filed Date | 2010-06-10 |
United States Patent
Application |
20100143419 |
Kind Code |
A1 |
McAffer; Ian Gardener, Cameron ;
et al. |
June 10, 2010 |
Storage of Ampoules Containing Pharmaceutical Formulations Using a
Sealed Container Comprising an Oxygen Scavenger
Abstract
Ampoules made of plastics material and containing 0.5 to 5 ml of
a pharmaceutical formulation are sealed, together with an oxygen
scavenger, within a pouch.
Inventors: |
McAffer; Ian Gardener, Cameron;
(Tatsfield, GB) ; Tasko; Peter Ernest; (Tatsfield,
GB) |
Correspondence
Address: |
STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C.
1100 NEW YORK AVENUE, N.W.
WASHINGTON
DC
20005
US
|
Assignee: |
Breath Ltd
Tatsfield
GB
|
Family ID: |
37801921 |
Appl. No.: |
12/522680 |
Filed: |
January 9, 2008 |
PCT Filed: |
January 9, 2008 |
PCT NO: |
PCT/GB08/00076 |
371 Date: |
November 24, 2009 |
Current U.S.
Class: |
424/400 ;
514/299 |
Current CPC
Class: |
A61J 1/067 20130101;
B65D 81/266 20130101; A61P 11/08 20180101; A61J 1/10 20130101; A61P
11/06 20180101; B65D 81/268 20130101 |
Class at
Publication: |
424/400 ;
514/299 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/439 20060101 A61K031/439; A61P 11/08 20060101
A61P011/08; A61P 11/06 20060101 A61P011/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 9, 2007 |
GB |
0700380.9 |
Claims
1. A sealed container comprising a plurality of ampoules containing
up to 10 ml of a pharmaceutical formulation and an oxygen
scavenger.
2. The container of claim 1, wherein the ampoules contain a
solution of an inhalation pharmaceutical in a pharmaceutically
acceptable carrier.
3. The container of claim 1, wherein the ampoules are made of
plastics material and are manufactured by the blow-fill-seal
method.
4. (canceled)
5. The container of claim 1, containing 10 or more ampoules.
6. The container of claim 1, wherein the oxygen scavenger can
absorb 20 to 2000 cc of oxygen.
7. The container of claim 1, wherein the container is made of
material comprising a metal or metal compound.
8. The container of claim 1, wherein the container is made of
material comprising aluminum.
9. The container of claim 1, wherein the container is
re-sealable.
10. The container of claim 1, wherein the container is a pouch.
11. A method of reducing oxidative degradation of the contents of a
plurality of ampoules containing up to 10 ml of a pharmaceutical
formulation, comprising sealing the ampoules in a container
containing an oxygen scavenger.
12. The method of claim 11, wherein the ampoules contain a solution
of an inhalation pharmaceutical in a pharmaceutically acceptable
carrier.
13. The method of claim 11, wherein the ampoules are made of
plastics material manufactured by the blow-fill-seal method.
14. (canceled)
15. The method of claim 11, wherein the container comprises 10 or
more ampoules.
16. The method of claim 11, wherein the oxygen scavenger can absorb
20 to 2000 cc of oxygen.
17. The method of claim 11, wherein the container is made of
material comprising a metal or metal compound.
18. The method of claim 11, wherein the container is made of
material comprising aluminum.
19. The method of claim 11, wherein the container is
re-sealable.
20. The method of claim 11, wherein the container is a pouch.
21. (canceled)
22. (canceled)
23. A sealed pouch comprising: (i) 5 or more plastic ampoules
containing up to 5 ml of an inhalation pharmaceutical in a
pharmaceutically acceptable carrier and (ii) an oxygen scavenger,
wherein the pouch is made of material comprising a metal or a metal
compound and the oxygen scavenger can absorb 20 to 2,000 cc of
oxygen.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the sealing of containers
which can be used for storage of ampoules containing pharmaceutical
formulations, and in particular to sealing ampoules within a pouch
to reduce or prevent oxidation of the formulations over time. The
invention relates also to the sealed containers, in particular
containing such ampoules.
BACKGROUND TO THE INVENTION
[0002] Pharmaceutical formulations are presented in a variety of
different packaging, including packaging made of glass, metal,
plastic and natural materials. For liquid formulations, e.g.
solutions or suspensions, the packaging must be and remain sealed
to prevent leakage. However, a number of technical and practical
difficulties exist with all such containers.
[0003] It is known to administer drugs to the lungs of a patient
using a nebuliser, allowing a patient to administer the drug whilst
breathing normally. The drugs are provided in a unit dose ampoule
(UDA), containing a relatively small volume, typically 1 mL-5 mL,
of solution and typically made of plastics material. A method of
making ampoules is by Blow-Fill-Seal (BFS), under aseptic
conditions, in which the ampoule is formed by extrusion and filled
with solution in a multi-part but essentially one-step process. If
necessary, and provided the contents are not heat labile, heat
sterilization can be used, e.g. ampoules can be sterilised by
terminal sterilisation methods, i.e. after the ampoule has been
filled and sealed. These methods are well established and accepted
by regulatory authorities worldwide.
[0004] A known problem with existing ampoules is that they allow
oxygen, other gases and other volatile compounds into the ampoule
and allow water (moisture) to exit. Testing of the contents has
revealed that, during storage, contaminants can pass through the
plastic of ampoule walls and be absorbed into the formulation. As
one specific example, unacceptable amounts of vanillin have been
found inside ampoules, leading to failure of the product and
refusal of regulatory authorities to licence the ampoules without
safeguards against this external contamination.
[0005] The US FDA has recently required that ampoules be
over-wrapped by a sealing pouch to avoid environmental
contamination of the ampoule contents. The pouch material is
typically a tri-laminate of paper and/or polymer, aluminium and low
density polyethylene (LDP). This pouch is regarded as an acceptable
solution but the contents are still susceptible to oxidation over
time. This is particularly an issue with drug formulations
containing oxygen sensitive materials.
[0006] It is known to carry out the blow-fill-seal method of making
and filling ampoules using nitrogen rather than sterile air during
as many steps as possible in the process. Nitrogen can be used to
cap the solution in the ampoule. Nitrogen can be introduced into
the pouch at the time the ampoules are sealed inside the pouch. It
is, however, a problem that using nitrogen in this process requires
specialised equipment or modification of existing equipment. Health
and safety precautions associated with the use of nitrogen tend to
increase production costs and times and the efficiency of nitrogen
entrapment within the pouch varies and is not totally efficient
[0007] An object of the present invention is to solve or at least
ameliorate the above-identified issues. An object of preferred
embodiments of the invention is to provide alternative, more
preferably improved methods of storing ampoules within sealed
containers and to provide alternative, preferably improved sealed
containers containing ampoules.
SUMMARY OF THE INVENTION
[0008] The invention is based on the use of an oxygen scavenger to
reduce or prevent oxidation of formulations within ampoules sealed
within containers.
[0009] In a first aspect, the invention provides a sealed container
comprising (i) one or more ampoules containing up to 10 ml of a
pharmaceutical formulation and (ii) an oxygen scavenger.
[0010] Preferably, the one or more ampoules are made of plastics
material. Also preferably, the ampoules contain an inhalation
pharmaceutical. The one or more ampoules and the oxygen scavenger
are sealed within the container. In some embodiments the container
material comprises a metal or metal compound, for example as a
coating on or incorporated into an outside surface.
[0011] In a preferred embodiment of the invention the container is
a pouch.
[0012] In a second aspect, the invention provides a method of
reducing oxidative degradation of the content of an ampoule, the
method comprising sealing the ampoule in a container containing an
oxygen scavenger.
[0013] In a third aspect, the invention provides a method of
reducing moisture egress from a container, the method comprising
sealing the container in a pouch containing an oxygen
scavenger.
[0014] In a fourth aspect, the invention provides a method of
sealing an ampoule wherein one or more ampoules are sealed within a
pouch containing an oxygen scavenger.
[0015] In a fifth aspect, the invention provides an ampoule made of
plastics material, wherein the ampoule is sealed within a pouch
containing an oxygen scavenger.
[0016] In a sixth aspect, the invention provides the use of an
oxygen scavenger to reduce or prevent oxidation of formulations
within one or more ampoules sealed within a container.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The invention provides a package made up of an ampoule
wrapped within a container (e.g. a pouch) comprising an oxygen
scavenger. The invention also provides 5, 10, 20 30 or more
ampoules sealed with the oxygen scavenger within the container, the
ampoules conveniently being in a strip. Alternatively, individual
ampoules or a combination of one or more strips and one or more
individual ampoules may be sealed within the container. In use the
presence of the oxygen scavenger is found to significantly reduce
the oxygen content within the container, reducing oxidation of the
ampoule contents over time and also improving the stability of the
ampoule contents.
[0018] When a strip of ampoules is sealed within a container and
the container is opened to detach one ampoule from the strip the
remaining ampoules will be exposed to the air. However, this may
not be a significant problem as oxidation of the contents of the
ampoules only occurs after exposure to air over a relatively
extended period of time compared to time in storage and the
ampoules within the open container would typically all be used
before significant oxidation could occur.
[0019] In one particular embodiment of the invention the container
is re-sealable, allowing a single ampoule to be removed by the
user. The container is then closed to again form a sealed container
with the oxygen scavenger still in place. This will act to remove
oxygen that entered the pouch while it was open and to "mop up" any
further oxygen that may diffuse into the pouch. Accordingly, the
lower oxygen content of the container results in reduced oxidation
of the contents of the remaining ampoules over time.
[0020] In particularly preferred embodiments the container may
comprise a pouch wherein the pouch material typically comprises a
metal or metal compound and in some embodiments may comprise a
tri-laminate. A typical tri-laminate composition may comprise paper
and/or polymer, aluminium and low density polyethylene.
[0021] In a preferred embodiment of the invention the pouch is gas
impermeable.
[0022] The ampoules typically comprise or are made of plastics
material, especially polypropylene or polyethylene, low or high
density or other polymer used in manufacture of ampoules or in the
drinks industry, e.g. polyethylene terephthalate. Further, the
ampoules typically contain a pharmaceutical agent, such an
inhalation or injection drug, in combination with a
pharmaceutically acceptable carrier.
[0023] In preferred embodiments of the invention ampoules are made
of plastics material.
[0024] The ampoules described herein may typically have a volume of
up to 10 ml, preferably 0.5 ml or more, or 1 to 5 ml. For example,
the ampoules may contain 2 to 4 ml of an inhalation
pharmaceutical.
[0025] In preferred embodiments the ampoules contain 1 ml or more
or 2-3 ml of an inhalation pharmaceutical in a pharmaceutically
acceptable carrier.
[0026] The oxygen scavenger as used in the invention is generally a
commercially available packet or sachet as used and approved by the
food industry. These oxygen scavengers do not contain leachables
thereby avoiding contamination of the product with which they are
stored.
[0027] The size of oxygen scavenger is typically in the range of 20
to 2000 cc, indicating the volume of oxygen it can absorb,
preferably 20 to 1000 cc, more preferably 20 to 500 cc. In one
embodiment of the invention a 50 cc packet is used. Notwithstanding
this, it will be apparent to the skilled person that the size and
capacity of the oxygen scavenger used can be varied depending upon
the size of the container, the number of ampoules within the
container, and the collective volume of the ampoules.
[0028] The following examples are provided in support of the
invention. The content of the examples are for illustration only
and are not intended to limit the scope of the invention in any
way.
Example 1
[0029] Packages were prepared each containing one 4-ampoule card
and one FreshPax D-50 oxygen scavenger packet (MultiSorb) and
sealed in foil. The packages were prepared in normal atmospheric
conditions and contained air when sealed.
[0030] The oxygen scavenging data was analysed at timed intervals
using a Mocon Head Space Analyzer, the results of which can be seen
below:
TABLE-US-00001 Time O.sub.2 content within foil 0 hours 19.9% 16
hours 566 ppm 23 hours 435 ppm 8 days 0 ppm 14 days 0 ppm 28 days 0
ppm 84 days 0 ppm
[0031] A control package with no oxygen scavenger measured 20.5%
O.sub.2 at 8 days.
Example 2
[0032] This study was designed to demonstrate the effectiveness of
oxygen scavengers in preventing degradation of the product, thereby
reducing the impurity levels present in the solution after
storage.
[0033] The solutions for nebulisation were manufactured in 3 ml
LDPE ampoules using blow-fill-seal technology. The strips of 5 were
then sealed in a foil over wrap to prevent water loss from and
external contamination of the product.
[0034] One batch of Levalbuterol/Ipratropium Bromide Solution for
Nebulisation (1.25 mg/0.5 mg/2 ml) combination product was
manufactured in 2006. Two sublots of this batch were produced and
labelled Sublot 1 (ampoules were sealed in a foil pouch containing
an oxygen scavenger) and Sublot 2 (ampoules were sealed in a
standard foil pouch) stored for 12 months and then tested as set
out below.
[0035] The related substance data summarised below is for product
that has been stored for 12 months at 25.degree. C./60% RH.
TABLE-US-00002 Batch 04906A Sublot 1 Sublot 2 (No (Oxygen
Scavenger) Oxygen Scavenger) Known impurities: H-Tropic acid 0.04%
0.09% Apo-Ipratropium Below detectable 0.03% levels Bis Ether
Salbutamol 0.15% 0.13% Total known impurities 0.19% 0.25% Largest
unknown impurity 0.11% 0.19% Total unknown impurties 0.15% 0.25%
Total Impurities 0.34% 0.50%
[0036] It can be seen that the impurity levels detected in the
product packaged with the oxygen scavenger were in general 25-40%
lower than those observed in product packaged without the oxygen
scavenger. Total impurity levels showed a 30% reduction when the
oxygen scavenger was present in the pouch.
[0037] This study supports the hypothesis that oxygen scavengers
placed within the foil pouch improve the stability profile of
solutions for nebulisation in ampoules.
Example 3
[0038] This study was designed to demonstrate the effectiveness of
oxygen scavengers in generating and maintaining an oxygen-free
environment when ampoules are stored inside a foil pouch containing
an oxygen scavenger.
[0039] Ampoules were manufactured using blow-fill-seal technology
in normal atmospheric conditions and contained only air when
sealed. Packages were prepared each containing four empty ampoules
sealed within an aluminium pouch containing one FreshPax D-50
oxygen scavenger packet (MultiSorb).
[0040] The packages were prepared in normal atmospheric conditions
and the oxygen content of air inside the pouches and ampoules on
sealing was 20.5%. The packages were stored for 18 months and then
tested as set out below. Oxygen content inside each pouch and
inside two ampoules from each pouch was measured following internal
protocols SAP 392.01 and SEP 156.01.
[0041] A Systech Gaspace Advance Oxygen Micro Headspace Analyser
was used to measure oxygen content. The Gaspace instrument was
calibrated with a certified gas containing 2.00% of oxygen and was
also calibrated with ambient air. The oxygen concentration in the
headspace of the pouches and the ampoules was measured using a
`Timed` method. A test time of 45 seconds was used. A self-adhesive
septum was affixed to the pouch and plastic ampoule to ensure a
good seal was obtained when sampling.
[0042] The oxygen headspace results are presented in the following
table:
TABLE-US-00003 Oxygen Concentration in Aluminium Oxygen
Concentration in Plastic Pouches (molar % .+-. SD) n = 3 Ampoules
(molar % .+-. SD) n = 6 0.00 .+-. 0.00 4.99 .+-. 3.85
[0043] It can be seen that oxygen was completely removed from the
pouches while the ampoules showed a 76% reduction in oxygen
content.
[0044] In conclusion, the presence of the oxygen scavenger within
the pouches appeared to draw oxygen out of the pouch and out of the
headspace of the ampoule. Surprisingly, these results contrasted
with the findings of previous internal studies which have shown
that in pouches purged with nitrogen and not containing an oxygen
scavenger there was no equilibration of oxygen concentration
between the headspace of the ampoule and the interior of the pouch
(data not shown). One possible explanation for the equilibration
observed in the present study is that the oxygen scavenger acts as
a driving force towards equilibrium between the two
environments.
[0045] Total equilibrium may have been achieved between the
ampoules and the pouches in this study following a longer storage
period or, alternatively, by using a larger oxygen scavenger. Of
course, the ampoules used in this study were completely filled with
air and thus contained significantly more oxygen than ampoules
filled with actives would contain. It is possible that due to their
lower oxygen volume ampoules filled with actives would reach total
equilibrium under the conditions of the present study.
[0046] The invention hence provides sealed containers containing
ampoules and methods of obtaining the same.
* * * * *