Chemistry: analytical and immunological testing – Process or composition for sterility or package integrity test
Reexamination Certificate
2000-04-27
2003-09-30
Warden, Jill (Department: 1743)
Chemistry: analytical and immunological testing
Process or composition for sterility or package integrity test
C422S051000, C422S051000, C436S002000, C436S003000, C436S005000, C436S127000, C436S136000, C436S138000, C436S166000
Reexamination Certificate
active
06627443
ABSTRACT:
FIELD OF INVENTION
The present invention relates to color compositions comprising iron(II), an agent containing gallic acid entities and an organic acid which are especially suitable to be included in an oxygen indicator. The inventive indicators enable improvements related to the production of containers for storing oxygen sensitive pharmaceuticals and other sensitive products.
BACKGROUND OF THE INVENTION
In the pharmaceutical industry it is strongly desired to develop containers of polymeric materials to replace traditional glass containers in order to provide less resource consuming, cheaper and more convenient packaging systems. It is, however, a considerable technical problem to develop safe and cheap containers made of polymeric material which can replace glass as a barrier forming material against the environment and be compatible with a variety of fluids including lipophilic fat emulsions for parenteral nutrition. There have been many attempts to introduce polymeric materials for such lipophilic agents, but problems with degradation from penetrating oxygen and migration of components from the polymeric material into the stored fluids, especially after sterilization with steam at autoclaving conditions have prevented a wide-spread commercial use.
A highly sophisticated container for long-time storage of fluids aimed for parenteral administration is disclosed in the Swedish patent application SE 9601348-7 which hereby is incorporated as a reference. By a careful selection of polymeric materials, this type of container is capable of withstanding steam sterilization when finally filled and assembled and yet form a suitable barrier against environmental oxygen to protect oxygen degradation sensitive components during storage without involving any material that is incompatible with lipids. This container consists of an inner container, having one or several compartments for storage of drugs which readily can be mixed, just prior to the administration, enclosed in a substantially airtight outer envelope. In the space between the inner container and the envelope, an oxygen scavenging composition is placed to consume residual oxygen and the small amounts of oxygen penetrating through the envelope. To improve on the safety of the product, an oxygen indicator can be placed between the envelope and the inner container through which the transparent envelope visually indicates an oxygen leakage by a change in color. Especially for such oxygen sensitive products like parenteral nutrients comprising polyunsaturated fatty acids and certain amino acids, there is a demand to have simple and reliable indication of the integrity of the products, since many of the patients dependent on such a therapy are confined to self-administration in their homes with a supply of containers.
The demands of an oxygen indicator for a medical container for parenteral nutrients are equally high as the other features of the container. It must be capable to withstand autoclavation procedures (steam sterilization at about 121° C. for a prescribed time period, usually about 19 to 20 minutes) without losing its characteristics. It must consist of safe and non-toxic components which have a negligible tendency to migrate and waste the stored products and it must be fully compatible with the remaining parts of the container. The indicator function must be suitably sensitive and reliable so a distinct change in color visualizes a predetermined exposure to oxygen and thus the potential waste of the product which then must be discarded. In addition, a functional oxygen indicator should be cheap and easy to produce and assemble with the package.
Conventional visual oxygen indicators known to the art used in the form of tablets inside packages for pharmaceuticals or certain food products, such as Ageless-Eye KS from Mitsubishi based on methylene blue as a coloring agent, will not be able to withstand autoclavation. After autoclavation, the color change will be less distinct and instead of a homogenous blue color, a patchy or stained blue to pink colors will appear that severely impairs the sensitivity of their oxygen indicating capacity. This type of indicator is also normally recommended with a limited shelf-life of six months.
Oxygen indicators agents may also be possible to disperse in the polymeric packaging material, as suggested in the International patent application WO 95/29394 to W. R. Grace & Co. This material have a drawback in that its riboflavin indicator component is sensitive to heat and will not withstand autoclavation with maintained capacity. It would also be wasted by high temperature welding processes of the packaging material. Obviously, there still is a desire for improvements related to oxygen indicators. Especially to find reliable, cheap, non-migrating visual oxygen indicators to be included in container systems storing oxygen sensitive parenteral drugs intended to be steam sterilized after their final assembly.
The present invention aims to provide new color compositions suitable to be comprised in an oxygen indicator as well as being incorporated in water based surface treatment compositions.
It is an object of the present invention to provide improved oxygen indicators based on said colored compositions which are especially suitable to be a part of a container for long-time storage of oxygen sensitive pharmaceuticals for parenteral administration.
Another object of the present invention is to provide an oxygen indicator which can withstand autoclavation without losing any important characteristics and which has suitable characteristics for being assembled with a container for storing oxygen sensitive pharmaceuticals.
A further object of the present invention is to provide an oxygen indicator which is composed of constituents with less potential toxicity and thereby being especially suitable for the pharmaceutical and the food industry.
A still further object of the invention is to provide an oxygen indicator with high reliability which may serve as guarantee that patients dependent on parenteral nutrition not will infuse accidentally oxidized solutions.
DESCRIPTION OF INVENTION
The present invention relates to a color composition comprising an agent containing pyrogallol entities, and an iron (II) salt and an acid.
The salts of iron (II) useful in the present invention must be readily soluble to avoid the formation of precipitations of poorly soluble complexes with other components of the color composition. Preferably, the iron(II) salts are selected from a group consisting of iron(II)sulfates, iron(II)acetate, iron(II)nitrate, iron(II)chloride and iron(II)trifluoroacetate.
The agent containing pyrogallol entities are capable of complex binding iron(III), thus forming a colored product. It may consist of pyrogallol derivatives preferably gallic acid and its derivatives, particularly various esters of gallic acid. However, pure pyrogallol or gallic acid (which is carboxylated pyrogallol) can also be used, in particular when the toxicity of pyrogallol can be controlled or is of limited importance. A suitable agent is tannin of natural, synthetic or semi-synthetic origin comprising ester bridges in a network between a plurality of gallic acid entities.
The acid component is preferably selected to avoid the formation of poorly soluble complexes with iron ions and it should not be so strong that it hydrolyses the agent having gallic acid entities to free gallic acid which should be avoided since it may modify the predicted color characteristics of the composition. Preferably, an organic acid having at least two carboxylic groups is selected for the color composition and most preferably an organic acid having general formula HOOC—(CR
1
R
2
)
n
—COOH, wherein n=1-4, R
1
is hydrogen or a hydroxyl radical, and R
2
is hydrogen or a carboxyl radical. In order to obtain a reversible color reaction, an alpha-hydroxy acid having at least two carboxylic groups, such as citric acid is suitable as the acid component in the color compositions.
From this information, it is possible to select alternati
Karlsson Lars
Löfgren Anders
Nystrom Bo
Skolling Otto
Stenholm Åke
Cross LaToya
Fresenius Kabi AB
Katten Michin Zavis Rosenman
Sira Serge
Villacorta Gilberto M.
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