US20070031976A1 - Oxygen Indicator for Use in Medical Products - Google Patents

Oxygen Indicator for Use in Medical Products Download PDF

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Publication number
US20070031976A1
US20070031976A1 US11/461,980 US46198006A US2007031976A1 US 20070031976 A1 US20070031976 A1 US 20070031976A1 US 46198006 A US46198006 A US 46198006A US 2007031976 A1 US2007031976 A1 US 2007031976A1
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United States
Prior art keywords
oxygen
indicator
color
present
chamber
Prior art date
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Abandoned
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US11/461,980
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English (en)
Inventor
Jean Trouilly
Freddy Desbrosses
Denis Bonnot
Christian Melin
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Baxter Healthcare SA
Baxter International Inc
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Baxter Healthcare SA
Baxter International Inc
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Application filed by Baxter Healthcare SA, Baxter International Inc filed Critical Baxter Healthcare SA
Priority to US11/461,980 priority Critical patent/US20070031976A1/en
Assigned to BAXTER INTERNATIONAL INC., BAXTER HEALTHCARE S.A. reassignment BAXTER INTERNATIONAL INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BONNOT, DENIS, DESBROSSES, FREDDY, MELIN, CHRISTIAN, TROUILLY, JEAN LUC
Publication of US20070031976A1 publication Critical patent/US20070031976A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2093—Containers having several compartments for products to be mixed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B32—LAYERED PRODUCTS
    • B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B27/00—Layered products comprising a layer of synthetic resin
    • B32B27/06—Layered products comprising a layer of synthetic resin as the main or only constituent of a layer, which is next to another layer of the same or of a different material
    • B32B27/08—Layered products comprising a layer of synthetic resin as the main or only constituent of a layer, which is next to another layer of the same or of a different material of synthetic resin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N31/00—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods
    • G01N31/22—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods using chemical indicators
    • G01N31/223—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods using chemical indicators for investigating presence of specific gases or aerosols
    • G01N31/225—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods using chemical indicators for investigating presence of specific gases or aerosols for oxygen, e.g. including dissolved oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/10—Bag-type containers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/1462—Containers with provisions for hanging, e.g. integral adaptations of the container
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2003—Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
    • A61J1/202—Separating means
    • A61J1/2024—Separating means having peelable seals
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour
    • G01N21/783—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour for analysing gases

Definitions

  • the present invention is directed generally to medical solutions, containers for storing medical solutions and oxygen indicators for detecting the presence of oxygen in a medical container. More particularly, the present invention is directed to ready-to-use ternary parenteral nutritional formulations for certain patient populations, particularly fluid limited populations, the container systems for long-term storage and selective administration of such formulations and oxygen indicators for such container systems. More specifically, the present invention is directed to such formulations being stored in flexible containers having multiple chambers for isolated long-term storage of the various nutritional components of such formulations, oxygen indicators for alerting healthcare professionals of an oxygen compromised container and containers facilitating selective sterile admixing into a ready to infuse formulation and administration of such formulation.
  • the invention is directed to multi-chamber containers allowing selective admixing of two or more solutions contained in the chambers such as nutritional solutions of lipids, carbohydrates, amino acids and electrolytes and oxygen indicators able to withstand heat sterilization and having acceptable storage characteristics.
  • Medical solutions such as parenteral and enteral nutrient solutions, dialysis solutions, pharmacological solutions, and chemotherapy solutions are routinely stored in a variety of containers made of glass or plastic. While glass containers offer many benefits such as gas impermeability and virtually complete compatibility with medical solutions, glass containers are heavy, easily broken, difficult to handle and can release aluminum into the solutions. As a result, more and more medical solutions are being stored in plastic containers. Flexible containers such as bags made from plastic films have gained increased acceptance.
  • the prescription to be administered to a patient is comprised of components which will are not compatible for long storage periods.
  • One method of overcoming this limitation is to combine or compound the components just prior to administration. Such compounding may be accomplished manually or with automated compounders. However such a combination method is time consuming, may give rise to errors in formulation and increases the risks of contamination of the final mixture.
  • flexible containers can be formed with multiple chambers for separately storing medical solutions. These bags are formed with frangible connections or peal seals which provide for mixing of the all the contents of the chambers by manipulation of the connections or seals.
  • a drawback of utilizing such multi-chamber containers is that one is restricted to the formulation which are provided by the supplied components and proportional amounts which are housed in the various chambers. When seeking to address the needs of varying patient populations, particularly fluid restricted populations, such restriction may hinder the ability to utilize such a containers, cause use of only a portion of the contents of such a container or cause multiple versions of such containers to be stored.
  • multi-chamber bags have separation means that permit communication and mixing of the separately stored components or solutions.
  • Some such multiple chamber containers utilize frangible valves while others use a score line or line of weakness in the barrier separating the chambers to effect mixing of the separately stored components.
  • Still others use tear strips or tear tabs.
  • More advantageous multi-chamber containers in terms of cost and ease of use are of the type which include peel seals formed by heat or radio frequency sealing of the two sheets of thermoplastic material that comprise a flexible bag to define multiple interior chambers. The heat seal provides a barrier that is resistant to unintentional opening forces but is openable with the application of a specific force.
  • Plastic containers such as those just discussed however can also present unique issues which must be addressed.
  • heat sterilization such as autoclaving can affect certain plastic materials used to form the container and/or the heat seal separating the chambers.
  • certain plastic materials are permeable to atmospheric oxygen and may inadequately protect oxygen sensitive solutions or components.
  • certain fat soluble or lipophilic solutions or components may not be compatible with certain plastic materials.
  • lipid formulations such as Lipid emulsions used in parenteral nourishment cannot be stored in certain plastics because it can leach out some plastic material from the container. The lipid emulsion would be contaminated and the plastic containers integrity can be compromised.
  • Lipid emulsions are generally one component of a parenteral nutritional solution (PN).
  • PN parenteral nutritional solution
  • Ternary parenteral nutritional formulations are used to provide all the nutritional components required by a patient.
  • These PN formulations include also a carbohydrate component, an amino acid component, vitamin, trace element mid electrolytes components. Because of various incompatibilities, nutritional components of PN formulations are prime examples of medical solutions that cannot be stored long term as a mixture in a ready-to-use state. They can only be combined in a relatively short time period prior to administration.
  • the individual constituents of each component should be determined by the nutritional recommended requirements of the particular patient population to be treated.
  • PN formulations for adult patients may have different constituents in each component or at least different amounts of each constituent than PN formulations for infants.
  • preparation of the separate components of PN formulations for premature infants, neonatal patients or small children presents unique problems.
  • the volume of fluid that may be infused into such patients is relatively small. Seeking to provide all of the desired nutritional components in such a low volume is extremely difficult.
  • the concentration ranges for individual constituents of certain component solutions must be narrowly constricted.
  • some of the individual constituents are either interdependent or incompatible if present in certain forms and concentrations.
  • the breadth of the acceptable concentration range for magnesium for a premature infant is about 0.2 mmol.
  • the difference between the lowest acceptable concentration of magnesium and the highest acceptable concentration of magnesium is 0.2 mmol.
  • electrolytes such as calcium and phosphate may be incompatible in certain concentration levels.
  • storing the components of a PN formulation in a single or multi-chamber plastic container for sterile mixing to form the PN formulation also presents unique problems.
  • the lipid component is incompatible with certain plastic material.
  • some of the components are sensitive to oxygen which can permeate through certain plastics.
  • Overwraps or overpouches are typically used to restrict the ability of oxygen to get to the multi-chamber containers; however, the overwrap may still allow a small amount of oxygen to diffuse through.
  • the overwrap may develop a leak which would allow an excessive amount of oxygen to be exposed to the container. Such a leak may not be visible and the presence of such oxygen needs to be indicated to the health care provider.
  • oxygen indicators exist they appear to not be able to withstand heat sterilization and still function properly after prolonged storage.
  • the oxygen indicator should be able to indicate the presence of oxygen (oxidized form or positive result) such as with a change in color that is distinguishable from the condition indicating a lack of presence oxygen (reduced form or negative result). Additionally, the oxidized and reduced colors of the indicator should not fade or alter after prolonged storage so as to create uncertainty as to the result.
  • certain amino acids with thiol function such as cysteine or acetyl-cysteine can form hydrogen sulfide as a decomposition product during sterilization.
  • An excessive level of hydrogen sulfide may negatively affect some of the nutritional components.
  • the all the separately stored components are mixed to form the final PN formulation prior to administration, there are circumstances when it is undesirable to include one or more of the components found in one of the chambers in the final solution. For example, it may be desirable to not include the lipid component in the final solution for infants under septic status, coagulation abnormalities, high bilirubin level or for other reasons.
  • an oxygen indicator for detecting the presence of oxygen in medical container comprises: a) greater than 6 and less than 60 g/L, of indigo carmine; b) a buffer to adjust the pH to a range of about 9.0 to about 9.75; c) cellulose; d) a reducing agent; e) water; and f) a color of an oxidized form of the oxygen indicator being distinct from a color of a reduced form of the oxygen indicator; wherein following sterilization by autoclaving, the color of the reduced form remains distinct from the color of the oxidized form and the color of the oxidized form remains distinct from the color of the reduced form for at least six months at 40° C.
  • an oxygen indicating packet for detecting the presence of oxygen in a medical container.
  • the oxygen indicating packet comprises an oxygen indicator including: i) an oxidized color and a reduced color; the oxidized color being distinct from the reduced color; ii) greater than 6 and less than about 40 g/L of indigo carmine; iii) a buffer; iv) a reducing agent; v) cellulose; and vi) water; wherein following sterilization by autoclaving both the reduced color remains substantially visually unchanged and the oxidized color remains substantially visually unchanged after at least six months at 40° C.
  • an oxygen indicator comprises: a) water; b) greater than 6 and less than about 40 g/L of indigo carmine; c) a buffer; d) at least one reducing agent; and e) an oxidized indicator color and a reduced indicator color distinct from the oxidized indicator color; wherein the indicator is reduced by autoclaving and any subsequent oxidation of the indicator produces the oxidized color that remains distinct from the reduced color for at least six months at 40° C.
  • FIG. 1 is a plan view of one embodiment of a 300 ml container of the present invention.
  • FIG. 2 is a cross sectional view of the container of FIG. 1 ;
  • FIG. 3 shows a typical rolling method for opening all the seal of a container having multiple chambers.
  • FIG. 4 is a plan view of the container of FIG. 1 after activation of peel seals
  • FIG. 5 is a plan view of one embodiment of a 500 ml container of the present invention.
  • FIG. 6 is a plan view of one embodiment of a 1000 ml container of the present invention.
  • FIG. 7 is a plan view of another embodiment of a container of the present invention.
  • FIG. 8 is a plan view of another embodiment of a container of the present invention.
  • FIG. 9 is a plan view of another embodiment of a container of the present invention.
  • FIG. 10 is a cross sectional view of one embodiment of a flexible film material used to construct the container of the present invention.
  • FIG. 11 is a cross sectional view of one embodiment of a flexible film material used to construct the overpouch of the present invention.
  • FIG. 12 is a graph representing Absorbance Units over time of the first and second embodiments of oxygen indicator stored at three different temperature conditions.
  • FIG. 13 is a graph of the optical densities of one embodiment of an oxygen indicator of the present invention.
  • FIG. 14 is a graph of Absorbance Units over time of one embodiment of an oxygen indicator of the present invention fit in an exponential curve.
  • FIG. 15 is a graph representing Absorbance Units over time of one embodiment of an oxygen indicator of the present invention stored at three different temperature conditions.
  • FIG. 16 shows the colors of the reduced form of samples of an oxygen indicator of the present invention stored at 25° C./40% RH and categorized by Pantone® references.
  • FIG. 17 shows the colors of the reduced form of samples of an oxygen indicator of the present invention stored at 30° C./35% RH and categorized by Pantone® references.
  • FIG. 18 shows the colors of the reduced form of samples of an oxygen indicator of the present invention stored at 40° C./25% RH and categorized by Pantone® references.
  • FIG. 19 shows the colors of the reduced form of samples of an oxygen indicator of the present invention after illumination of 2000 lux with a daylight tube for 30 days at 25° C. and categorized by Pantone® references.
  • FIG. 20 shows the colors of the oxidized form of samples of an oxygen indicator of the present invention stored at 25° C./40% RH and categorized by Pantone® references.
  • FIG. 21 shows the colors of the oxidized form of samples of an oxygen indicator of the present invention stored at 30° C./35% RH and categorized by Pantone® references.
  • FIG. 22 shows the colors of the oxidized form of samples of an oxygen indicator of the present invention stored at 40° C./25% RH and categorized by Pantone® references.
  • a flexible multiple chamber container for separately storing medical solutions prior to use and facilitates selective activation of the frangible barriers separating the chambers.
  • the container is preferably constructed to permit the storage of aqueous or lipid formulations without the leaching issues discussed above and to facilitate selective opening of the frangible barriers separating the chambers.
  • FIG. 1 illustrates one embodiment of a multiple chamber container of the present invention.
  • the container 10 which is configured as a bag includes three adjacent chambers or chambers 12 , 14 , and 16 .
  • Chamber 12 is located at a lateral or side end 18 and chamber 16 is located at an opposite lateral or side end 20 .
  • the three chambers 12 , 14 , and 16 are preferably designed to hold aqueous solutions and/or lipid emulsions.
  • container 10 has a total fluid capacity of 300 ml with chamber 12 having a fluid capacity of 80 ml, chamber 14 having a capacity of 160 and chamber 16 having a capacity of 60 ml.
  • FIG. 2 shows a cross-section of container 10 and illustrates how the openable seals 22 , 24 separate the formulations contained in chambers 12 , 14 , 16 .
  • the openable seals may be in the form of peel seal or frangible seals.
  • the openable seals permit formulations to be separately stored and admixed just prior to administration thereby allowing storage in a single container of formulations which should not be stored as an admixture for an extended period of time. Opening of the seals allows communication between the chambers and mixing of the contents of the respective chambers.
  • Container 10 also preferably includes ports 26 , 28 , and 30 at the bottom end 32 of the container to provide communication with chambers 12 , 14 , and 16 respectively.
  • One or more of the ports can be constructed for use as an additive port to allow the addition of materials such as micronutrients and/or can be constructed as administration ports.
  • the port 28 is administration port and includes a membrane that can be pierced by a cannula or spike of an administration set to deliver the contents to a patient and port 26 is for additions.
  • any number of ports can be used.
  • the ports may be positioned in any number of ways; however it is preferred that the access ports are located on the same end of the container to permit more efficient manufacturing and filling of the chambers.
  • one of the seals 22 , 24 is made openable or peelable while the second seal is made permanent.
  • Administration ports are then provided on two of the chambers such that one administration port is provided so that the chamber separated by the permanent seal may be administered while a second administration port is provided to allow the admixture to be administered.
  • a hanger portion 36 which in the embodiment shown in FIG. 1 is a flap having a centrally located hole 38 for hanging the container.
  • the flap 36 defines a border 40 of the upper end of all the chambers 12 , 14 , and 16 .
  • the central portion 42 of the hanger flap 36 preferably extends a substantial distance towards the bottom end 32 of the container 10 , more preferably about one-fourth the longitudinal length L of the container 10 and even more preferably about one-third of the length L of the container 10 .
  • the flap 36 extends a greater distance towards the bottom end 32 at least at the central chamber 14 and can also extend a greater distance towards the bottom end 32 at the central chamber 14 and at one of the other chambers 12 , 16 .
  • This extra extension of the flap 36 with respect to center chamber 14 results in chamber 14 having a shorter longitudinal length than the longitudinal length of lateral or side end chambers 12 , 16 .
  • the longitudinal length of central chamber should be from about two-thirds to about three-quarters the longitudinal length of at least one of the lateral end chambers. This configuration allows for selective opening of the seals as will be discussed below.
  • the longitudinal length of the chambers is measured from their respective top borders to their respective bottom borders. For curved or irregular borders the longitudinal length is the average of the longitudinal lengths taken continuously across the border.
  • FIG. 3 illustrates the typical rolling method of opening the seals 22 , 24 to mix the contents of chambers 12 , 14 , and 16 .
  • the hanger flap 36 or top end 34 is rolled over itself in a squeezing motion.
  • rolling the bag would pressurize all the chambers too much risking unintended activation of the wrong seal.
  • multi-chamber bags having a central chamber that extends a greater distance from its bottom border to its top border than the other lateral end chambers rolling of the bag would pressurized the central chamber and randomly activate one or more seals bordering the central chamber.
  • Multi-chamber containers of the present invention however include chamber arrangements to facilitate selective activation of the seals.
  • chamber 14 does not extend as far towards the top end 34 as do chambers 12 and 16 , i.e. chamber 14 is about three-fourths the longitudinal length of the other chambers 12 , 16 ; therefore rolling the bag from the top end 34 only pressurizes chambers 12 and 16 .
  • chamber 14 In order to selectively activate only one of the seals 22 , 24 , only the end chamber adjacent to the seal desired to be activated is squeezed with a continuation of the rolling motion. Because of the extend of the hanger flap 36 , the central chamber 14 is not pressurized preventing the activation or partial activation of the second peel seal. Further rolling and squeezing of the opposite lateral end chamber would activate the other seal. In this manner sequential activation of the seal is possible with containers of the present invention. Accordingly, the formulation which on occasion may not be administered should therefore be housed in one of the chambers located at the lateral ends of the container.
  • the user may start rolling the bag 10 at the top end 34 . Without pressurizing chamber 14 , the user can squeeze the bag at the location of chamber 12 . Once seal 24 is activated, the user can stop rolling and squeezing. If the user wanted both seals 22 , 24 activated instead, bag 10 can be rolled starting at the top end 34 while squeezing down on both end chambers 12 , 16 .
  • the contents of the container 10 may be mixed by manipulation of the container and then administered to the patient by first hanging the bag from a hook using hole 38 .
  • Another rolling technique is also used to activate the seals of multi-chamber bags.
  • this technique also uses a rolling motion except instead of starting at the top end 34 , container 10 is can be rolled starting at one of the top end corners 44 , 46 .
  • rolling from a corner produces too much pressure on a central chamber risking the unintended activation of the wrong seal.
  • Using this corner rolling method with containers of the present invention would not result in the activation of an unintended seal or at least not occur as often.
  • Containers 110 and 210 shown in FIGS. 5 and 6 respectively also include three chambers 112 , 114 , and 116 and 212 , 214 , and 216 respectively.
  • Containers 110 and 210 are constructed using the same materials and similar methods as those used in container 10 . The only significant difference is the size and capacity of the containers 10 , 110 , and 210 .
  • container 110 has a fluid capacity of 500 ml with chamber 112 having a fluid capacity of 221 ml, chamber 114 having a capacity of 155 ml and chamber 116 having a capacity of 124 ml.
  • container 210 has a fluid capacity of 1000 ml with chamber 212 having a fluid capacity of 392 ml, chamber 214 having a fluid capacity of 383 ml, and chamber 216 having a fluid capacity 225 ml.
  • Containers 110 and 210 also preferably include peelable seals 122 and 124 and 222 , 224 respectively which separate the chambers aid permit opening of the chambers to allow communication between the chambers and admixing of the contents of the respective chambers. Both containers 110 and 210 also include hanger flaps 136 and 236 including hanger holes 138 and 238 , respectively.
  • containers 110 and 210 have hanger portions or flaps and chambers that are configured to facilitate selective activation of the seals.
  • containers 110 , 210 both have hanger flaps 136 , 236 that extend towards bottom ends 132 , 232 (about one fourth to about one-third the longitudinal length of the container 110 , 210 ) respectively more so with respect to central chambers 114 , 214 . Consequently, the majority of the area of chambers 114 , 214 have a longitudinal length that is about two-thirds to about three-quarter less than the longitudinal length of the majority of the area of their respective lateral end chambers 112 , 116 and 212 , 214 .
  • Rolling containers 110 , 210 starting at the top ends 134 , 234 , or one of corners 144 , 146 , 244 , 246 , respectively allows rolling of the containers 110 , 210 and squeezing of the chamber adjacent to the seal desired to be selectively activated without undue pressure being placed on the central chambers 114 , 214 which could cause unintended activation of the other seal.
  • Containers 110 and 210 also include access ports 126 , 128 , and 130 , and 226 , 228 , and 230 , respectively. These ports are constructed using the same materials and in a similar manner as access ports 26 , 28 , and 30 . To permit the same equipment to fill containers 10 , 110 , and 210 it is preferable to position so to be the same distance from each other, FIGS. 7, 8 , and 9 illustrate other embodiments of a multiple chamber container of the present invention.
  • Containers 310 , 410 , 510 all include three adjacent chambers 312 , 314 , 316 and 412 , 414 , 416 , and 512 , 514 , 516 , respectively.
  • Chambers 312 , 412 , 512 are located at lateral or side ends 318 , 418 , 518 , respectively and chambers 316 , 416 , 516 are located at opposite lateral or side ends 320 , 420 , 520 .
  • Hanger portion 336 is located at the top end 334 and includes hole 338 for hanging the container.
  • Hanger portion 336 defines the top border 340 of chambers 312 , 314 , 316 .
  • Chambers 312 is separated from chamber 314 by peelable seal 324 , and peelable seal 326 separates chamber 314 from 316 .
  • Container 410 also includes peelable seals 424 , 426 separating chamber 412 from chamber 414 and chamber 414 from chamber 416 , respectively. Peelable seal 524 separates chamber 512 from chamber 514 and peelable seal 526 separates chamber 514 from 516 .
  • the peelable seals allow isolated storage of distinct formulations in the chambers for subsequent admixing prior to administration.
  • Chamber 314 has a longitudinal length that is from about two-thirds to about three-quarters the longitudinal lengths of both lateral end chambers 312 , 316 . While the longitudinal lengths of chambers 312 , 316 are equal, differing lengths can be used. Selective activation of either peelable seal 324 , 326 can when rolling container 310 starting at top end 334 and squeezing chamber 312 or chamber 316 depending on which of the peelable seals 324 , 324 is to be activated.
  • the lateral end chamber 416 of container 410 has a longitudinal length that is from about two-thirds to about three-fourths less than the longitudinal length of chamber 412 positioned at opposite lateral end 418 and is equal to the longitudinal length of lateral end chamber 416 .
  • Chamber 412 having a longitudinal length greater than that of chamber 414 allows peelable seal 424 to be activated without the inadvertent activation of peelable seal 426 when rolling container 410 starting at top end 434 .
  • Container 510 shown in FIG. 9 includes chambers 512 , 514 , 516 all of which have longitudinal lengths that differ from each other.
  • Lateral end chamber 512 has a longitudinal length that is from about twenty five percent to about thirty three percent greater than the longitudinal length of chamber 514 which in turn has a longitudinal length that is from about twenty five percent to about thirty three percent greater than the longitudinal length of chamber 516
  • Rolling container 510 starting at the top end 534 allows selective activation of peelable seal 524 , 526 by first pressurizing chamber 512 until seal 524 activates. Further rolling would begin to pressurized chamber 514 until seal 526 activates.
  • any additional chamber included between chamber 512 and 514 and having a longitudinal length less the longitudinal length of chamber 512 but greater than the longitudinal length of chamber 514 , or between chamber 514 and 516 and having a longitudinal length less the longitudinal length of chamber 514 but greater than the longitudinal length of chamber 516 may allow sequential activation of seals starting with the seal bordering chamber 512 and end with the seal bordering chamber 516 when rolling the container starting at the top end 534 .
  • one or more of the chambers could store a non-liquid such as a solid in powder or crystalline form with at least one chamber holding a liquid for dissolving the solid once the communication is established between the chambers.
  • FIG. 10 is a cross-sectional view of one embodiment of the film or sheet 48 used to construct the container 10 .
  • the sheet 48 is made from four layers 50 , 52 , 54 and 56 .
  • the outer layer 50 is preferably formed from a high melting temperature flexible material, more preferably a polyester material such as PCCE copolyester. Such a PCCE copolyester is sold by Eastman Kodak under the designation Ecdel 9965.
  • a typical thickness of the outer layer 50 is from about 0.39 mils to about 0.71 mils with the actual thickness of the outer layer show in FIG. 3 being 0.55 mils.
  • a tie layer 52 is provided to secure the first layer 50 to a third layer 54 .
  • the tie layer is a highly reactive polymer adhesive such as EVA copolymer chemically modified with maleic acid.
  • EVA copolymer chemically modified with maleic acid is available from DuPont under the name Bynel E-361.
  • the tie layer 52 may have a varied thickness for example from 0.20 mils to 0.60 mils, e.g., 0.40 mils.
  • the third layer 54 preferably is a radio frequency (RF) responsive polymer, such as EVA copolymer. Such a material is available from DuPont under the name Elvax 3182-2.
  • RF radio frequency
  • the third layer has a thickness of about 5.56 mils to about 6.84 mils, e g., 6.20 mils.
  • This film also includes a sealant layer 56 constructed of: 1) a bulk polyolefin that is thermally stable at heat sterilization temperatures, yet melts below the outside layer melting temperature; such polymers are preferably polypropylene-ethylene copolymers, such as grades Z9450 or 8650 from Total; and 2) a thermoplastic elastomer which produces a more flexible and free radical resistant sealant layer and gives the sealant layer two melt points with the elastomer having the lower value; such polymers preferably are styrene-ethylene-butene-styrene block copolymers such as Kraton G-1652 from Kraton polymers.
  • a sealant layer 56 constructed of: 1) a bulk polyolefin that is thermally stable at heat sterilization temperatures, yet melts below the outside layer melting temperature; such polymers are preferably polypropylene-ethylene copolymers, such as grades Z9450 or 8650 from Total; and 2) a thermoplastic elastomer which produces a more flexible and free radical resistant sealant
  • the sealant layer preferably has a thickness of from about 1.28 mils to about 1.92 mils, e.g., 1.60 mils.
  • the sealant layer 56 is adjacent the interior side of the container 10 ( FIG. 1 ) such that when the seal is ruptured, communication is provided between the chambers.
  • the container 10 is constructed by overlaying two sheets on one another or by folding one sheet over onto itself or by flattening an extruded tube if tubular extrusion is used.
  • FIG. 10 shows two sheets 48 and 48 a with layer 56 contacting the corresponding layer 56 a of sheet 48 a.
  • the sheets 48 and 48 a are bonded or welded together permanently at the perimeter to form the container taking into account the placement of access ports.
  • the sheets are also bonded together at other area to form the outer contours of the chamber that will be formed later.
  • the heat seals are the formed to create the multiple chambers.
  • the peelable seals are formed preferably using a heated seal bar to heat and soften the layer 56 , but not liquefy the layer. A resulting cohesive bond develops from contact between the sheet 48 and the sheet 48 a, but fusion between the sheets, which can cause permanent bonding, does not occur.
  • the peelable seals can be formed to require a force of from about 16 to about 21 Newtons to open or activate the peelable seals, preferably about 19N.
  • the temperature of the seal bar will vary depending upon the material used to construct the container.
  • the seal bar can be heated to from about 116 to about 122° C., preferably about 118° C. It should be noted that this temperature can vary substantially between different lots of the same film material and that the cohesive bond of the peelable seal is slightly reinforced or strengthened by heat sterilization.
  • the ports 26 , 28 and 30 can be constructed by any number of methods and by a variety of materials. Ports can be made from coextruded tube with clear PVC material inside to allow solvent-bonding to regular PVC closure systems. Alternatively, non-PVC tubes can be used. However, if one of the chambers is to contain a lipid for example in chamber 16 then port 30 is preferably constructed from a non-PVC containing material. If no administration site is added on the port of the chamber containing lipid, the port will be more preferably formed of a monolayer extruded tube with the following preferred formulation:
  • some or all of the ports 22 , 24 , and 26 can be constructed from a non-PVC material such as the above formulation.
  • the same central and lateral end chambers were filled with water while the other lateral end chamber was filled with a colored solution Additional water was added in the central chamber to compensate for the added volumetric capacity. In other words even though the central chamber of container 10 had a slightly smaller volume than the central chamber of other container they were similarly inflated with water.
  • PN parenteral nutritional
  • the patient populations are pre-term infants (PT), term to two years old children (TT), and children over the age of two (OT).
  • the PN formulation can have three components which are stored separately and mixed prior to administration.
  • the three components can be a carbohydrate component, an amino acid (AA) component and a lipid component.
  • One or more electrolytes can also preferably be included in the PN formulations
  • the electrolytes can be included in one or more of the components or can be added by the healthcare professional either before or after the components are combined.
  • one or more electrolytes can be included in the carbohydrate component, but more preferably, one or more of the electrolytes are included in the amino acid component.
  • the three components of the preterm PN formulation are preferably stored in a container having three chambers separated by openable seals such as frangible or peelable seals, having a total capacity of about 300 ml and having the ability to selectively open the seals, more preferably in container 10 ( FIG. 1 ) described above.
  • the three components of the PN formulation for term to two years old children is preferably stored in a similar three chamber container except that the container has a total capacity of about 500 ml, more preferably in container 110 ( FIG. 5 ) described above.
  • the three components of the PN formulation for children over the age of two are preferably stored in a similar three chamber container, except that the container has a total capacity of about 1000 ml, more preferably in container 210 ( FIG. 6 ) described above.
  • the carbohydrate component can include an aqueous solution containing from about 10% to about 70% of one or more carbohydrates such as glucose, fructose, and or sucrose.
  • the amino acid component can include an aqueous solution containing from about 3% to about 10% of one or more amino acids.
  • the lipid component can include an emulsion containing about 10% to about 30% of lipids such as fatty acids and/or triglycerides from plant, animal or synthetic sources such as, but not limited to olive oil, Medium Chain Triglyceride oil, soybean oil and fish oil. All of the percentages are expressed in weight to volume (w/v) unless otherwise specified.
  • MNRG mean nutritional recommended guidelines
  • MMNG likely minimum to maximum nutritional guidelines
  • a PN formulation for preterm infants is provided in container 10 .
  • the PN formulation can include an amino acid component that can comprise a solution including water for injection, malic acid for pH adjustment to about 5.5 and the following amino acids: Amino Acid Concentration (g/100 ml) Lysine 0.641 Glutamic acid 0.583 Leucine 0.583 Arginine 0.489 Alanine 0.466 Valine 0.443 Isoleucine 0.390 Aspartic acid 0.350 Phenylalanine 0.245 Glycine 0.233 Serine 0.233 Histidine 0.221 Threonine 0.216 Ornithine (as 0.185 mg Ornithine 0.145 Hydrochloride) Proline 0.175 Methionine 0.140 Tryptophan 0.117 Cysteine 0.110 Taurine 0.035 Tyrosine 0.045 Totals 5.726.860
  • cysteine should be present in amino acid solutions; specifically those administered to preterm infants because cysteine is a conditionally essential amino acid and because preterm infants a limited capacity to synthesize cysteine.
  • the PN formulation can also include a lipid component that can comprise a 12 . 5 % lipid emulsion in water for injection Lipid emulsion at 12.5% Role Concentration Purified olive oil Active drug about 80% of total oil Soybean oil Active drug about 20% of total oil Egg phospholipids Emulsifier 1.2% Sodium oleate Emulsifier 0.03% Glycerol Iso-osmolarity 2.25% Water for injection Dispersant qs
  • Olive oil is a preferred lipid because of its desirable immunoneutrality.
  • the above combination is preferred because the combination evokes less peroxidation and no additional oxidative stress. While these are the preferred lipids and lipid concentration, other lipid sources may be used such as lipids from animal, vegetable or synthetic origin.
  • the PN can also include a carbohydrate component that can comprise a 50% aqueous glucose and electrolyte solution as shown in the following table: Concentration Nutrient Source (per 100 ml) Na+ Sodium Glycerophosphate 3.4-7.8 mmol P Sodium Glycerophosphate 1.7-3.9 mmol Ca++ Calcium Chloride 2.7-4.7 mmol K+ Potassium Acetate 0.0-7.8 mmol Mg++ Magnesium Acetate 0.6-1.6 mmol Cl ⁇ Calcium Chloride 5.4-9.4 mmol Acetate ⁇ Potassium Acetate 0.6-9.4 mmol and Magnesium Acetate Glucose Glucose 50.0 g
  • the electrolytes and carbohydrate may be used. It is preferred that the phosphorus comes from organic sources and the above table indicates the most preferred sources of the nutrients. It is also preferred that the pH be adjusted to about 4.0 and in the preferred embodiment the adjustment is achieved using hydrochloric acid along with other pH adjusters such as malic acid or ascetic acid to also achieve the desired level of chlorides.
  • each chamber of container 10 is filled with one of the components of the PN formulation.
  • containers of a PN formulation for pre-term infants may include about 80 ml of the carbohydrate component in chamber 12 , about 160 ml of the amino acid component in chamber 14 , and about 60 ml of the lipid component in chamber 16 .
  • it may not be advisable to administer the lipid component such as if it is the first day, the patient is suffering from septic shock, coagulation abnormalities, high bilirubin level or other reasons.
  • container 10 permits the selective opening of seal 24 .
  • the PN formulation in order to provide the MNRG (or nutrition at least at the minimum of MMNG) about 120 ml of the PN formulation should be infused per kilogram of the patient per day.
  • the 300 ml container would then provide enough PN for 2.5 kg neonate (PT) over a 24-hour period.
  • the following table illustrates the approximate values of the PN formulation in a three chambered container: Amino Component Acid Carbohydrate Lipids Total Volume concentration (%) 5.86 50 12.5 — mI/kg/day 64 32 24 120 ml/chamber 160 80 60 300
  • administering about 120 ml/kg/day of the above PN formulation for preterm patients provides about the following nutrients and electrolytes: Nutrient/Electrolytes Amount (/kg/day) Na+ 1.1-2.5 mmol K+ 0.0-2.5 mmol P 0.54-1.25 mmol P (Total) 0.77-1.48 mmol (includes phosphorus present in lipid component) Ca++ 0.9-1.5 mmol Mg++ 0.2-0.5 mmol Cl ⁇ 1.7-3.0 mmol Cl ⁇ (Total) 2.1-3.4 mmol (includes chloride from amino acid Orn HCl) Acetate ⁇ 0.2-3.0 mmol Amino Acids 3.75 grams Glucose 16 grams Lipid 3 grams
  • a PN formulation for term to two years old children is provided in a 500 ml container having three chambers preferably container 110 .
  • the PN formulation can include a carbohydrate component and can be housed in an end chamber 112 having a volumetric capacity of about 155 ml and having a longitudinal length substantially greater than the longitudinal length of the center chamber 114 . This is to permit selective opening of the seal 124 adjacent the carbohydrate containing chamber 112 without opening the seal 122 adjacent chamber 116 .
  • An amino acid component can also be included in the PN formulation and can be housed in a central chamber 114 having a volumetric capacity of about 221 ml.
  • a lipid formulation can be included in the PN formulation and can be housed in an end chamber 116 having a volumetric capacity of about 124 ml.
  • the lipid and amino acid components can be formulated as described above
  • the carbohydrate component can comprise a 50% aqueous glucose and electrolyte solution as shown in the following table: Nutrient/ Concentration Electrolytes Source (per 100 ml) Na+ Sodium 3.4-4.0 mmol Glycerophosphate Na+ Sodium Chloride 0.0-3.3 mmol K+ Potassium Acetate 3.3-7.3 mmol P Sodium Glycerophosphate 1.7-2.0 mmol Ca++ Calcium Chloride 0.8-2.0 mmol Mg++ Magnesium Acetate 0.7-1.0 mmol Cl ⁇ Calcium Chloride and Sodium Chloride 1.6-7.3 mmol Acetate ⁇ Potassium Acetate and 4.0-8.3 mmol Magnesium Acetate Glucose Glucose 50.0 g
  • Each chamber is filled with one of the components.
  • about 155 ml of the carbohydrate component can fill an end chamber 112 as described above
  • about 221 ml of the amino acid component can fill a central chamber 114 as described above
  • about 124 ml of the lipid component can fill an end chamber 116 as described above.
  • the above-described peel seal 124 allows mixing of the carbohydrate and amino acid components or all the seals 122 , 124 may be opened to create the ternary PN formulation.
  • the container permits the selective opening of only the seal adjacent an end chamber with the longitudinal length substantially greater than the longitudinal length of a central chamber without opening the seal adjacent the lipid chamber as discussed above.
  • a PN formulation for children over the age of two is provided in a 1000 ml container having three chambers, preferably container 210 .
  • the PN formulation can include a carbohydrate component and can be housed in an end chamber 212 having a volumetric capacity of about 383 ml and having a longitudinal length substantially greater than the longitudinal length of the center chamber 214 . This is to permit selective opening of the seal 224 adjacent the carbohydrate containing chamber 212 without opening the seal 222 adjacent chamber 216 .
  • An amino acid component can be included in the PN formulation and can be housed in central chamber 214 having a volumetric capacity of about 392 ml.
  • a lipid component can be included in the PN formulation and can be housed in an end chamber 216 having a volumetric capacity of about 225 ml.
  • the lipid and amino acid components can be formulated as described above.
  • the carbohydrate component can comprise a 50% aqueous glucose and electrolyte solution as shown in the following table Nutrient/ Concentration Electrolytes Source (per 100 ml) Na+ Sodium Glycerophosphate 1.0-3.7 mmol Na+ Sodium Chloride 2.2-8.0 mmol K+ Potassium Acetate 3.3-8.3 mmol P Sodium Glycerophosphate 0.65-1.83 mmol Ca++ Calcium Chloride 0.65-1.00 mmol Mg++ Magnesium Acetate 0.33-0.67 mmol Cl ⁇ Calcium Chloride, Sodium Chloride 3.5-10.0 mmol Acetate ⁇ Potassium Acetate 3.6-9.0 mmol and Magnesium Acetate Glucose Glucose 50.0 g
  • Each chamber is filled with one of the components.
  • about 383 ml of the carbohydrate component fills end chamber 212 as described above, about 392 ml of the amino acid component fills central chamber 214 as described above, and about 225 ml of the lipid component fills end chamber 216 as described above.
  • Each component can be administered to the patient separately or all the seals 222 , 224 may be opened to create the PN formulation, However, in some instances it may not be advisable to administer the lipid component such as if it is the first day, the patient is suffering from septic shock, coagulation abnormalities, high bilirubin level or other reasons.
  • the container permits the selective opening of the seal adjacent an end chamber having a longitudinal length substantially greater the longitudinal length of the central chamber without opening the seal adjacent the lipid chamber as discussed above.
  • the reduced fluid level permits the healthcare professional to administer other fluid therapy which may be desirable in certain circumstances
  • a PN formulation for children over the age of two is provided in a 1000 ml container having three chambers, preferably container 210 .
  • the PN formulation can include a carbohydrate component and can be housed in an end chamber 212 having a volumetric capacity of about 332 ml and having a longitudinal length substantially greater than the longitudinal length of central chamber 214 . This is to permit selective opening of the seal 224 adjacent the carbohydrate containing chamber 212 and without opening the seal 222 adjacent chamber 216 .
  • An amino acid component can also be included in the PN formulation and can be housed in a central chamber 214 having a volumetric capacity of about 425 ml.
  • a lipid component can also be included in the PN formulation and can be housed in an end chamber 216 having a volumetric capacity of about 243 ml.
  • the lipid and amino acid components are formulated as described above.
  • the carbohydrate component comprises a 62.5% aqueous glucose and electrolyte solution as shown in the following table Concentration Nutrient/Electrolytes Source (per 100 ml) Na+ Sodium Glycerophosphate 1.285-4.583 mmol Na+ Sodium Chloride 2.804-9.998 mmol K+ Potassium Acetate 4.09-10.415 mmol P Sodium Glycerophosphate 0.818-2.291 mmol Ca++ Calcium Chloride 0.818-1.250 mmol Mg++ Magnesium Chloride 0.409-0.833 mmol Cl ⁇ Calcium Chloride, Sodium 14.643 mmol Chloride and Magnesium Chloride Glucose Glucose 62.5 g
  • the electrolytes and carbohydrate may be used. It is preferred that the phosphorus in the carbohydrate component come from organic sources and the above table indicates the most preferred sources of the nutrients.
  • Each chamber is filled with one of the components.
  • about 332 ml of the carbohydrate component fills an end chamber 212 as described above
  • about 425 ml of the amino acid component fills a central chamber 214 as described above
  • about 243 ml of the lipid component fills an end chamber 216 as described above.
  • Each component can be administered to the patient separately or all the seals 222 , 224 may be opened to create the PN formulation. However, in some instances it may not be advisable to administer the lipid component such as if the patient is suffering from septic shock, coagulation abnormalities, high bilirubin level or other reasons.
  • the container permits the selective opening of the seal 224 adjacent an end chamber 212 having a longitudinal length substantially greater than the longitudinal length of the central chamber 214 without opening the seal 222 adjacent the lipid compartment 216 as discussed above.
  • PN formulation in order to provide the MNRG and at least at the minimum of MMNG, about 72.3 ml/kg/day of the described PN formulation should be infused per kilogram of the patient per day.
  • the 1000 ml container provides enough PN per day for about a 13.5 kg child over a 24-hour period. Thus this container provides for a larger child over a 24 hour period than the previously described embodiment of a 1000 ml chamber.
  • the following table illustrates the approximate values of the PN formulation in a three chambered container: Component Amino Acid Carbohydrate Lipids Total Volume concentration 5.86 62.5 12.5 — (%) ml/kg/day 30.7 30 17.6 72.3 ml/chamber 425 332 243 1000
  • the reduced fluid level permits the healthcare professional to administer other fluid therapy which may be desirable in certain circumstances.
  • any increase in the electrolyte concentration above the minimum level increases the buffer capacity of the carbohydrate component (aqueous glucose and electrolyte solution). This increased buffer capacity results in the lowering of the pH of the admixed PN formulation to a level potentially incompatible with the targeted pediatric populations.
  • PN parenteral nutritional
  • the more preferred PN formulation can have three components which are stored separately and mixed prior to administration.
  • the three components can be a carbohydrate component, an amino acid (AA) component and a lipid component.
  • One or more electrolytes can also preferably be included in the PN formulation, more preferably a number of electrolytes are included in the amino acid component.
  • the three components of the preterm PN formulation are preferably stored in a container having three chambers separated by openable seals such as frangible or peelable seals, having a total capacity of about 300 ml and having the ability to selectively open the seals, more preferably in container 10 ( FIG. 1 ) described above.
  • the three components of the PN formulation for term to two years old children are preferably stored in a similar three chamber container except that the container has a total capacity of 500 ml, more preferably in container 110 ( FIG. 5 ) described above.
  • the three components of the PN formulation for children over the age of two are preferably stored in a similar three chamber container except that the container has a total capacity of 1000 ml, more preferably in container 210 ( FIG. 6 ) described above.
  • the carbohydrate component can include an aqueous solution containing from about 10% to about 70% of one or more carbohydrates such as glucose, fructose and/or sucrose.
  • the amino acid component can include an aqueous solution containing from about 3% to about 10% of one or more amino acids.
  • the lipid component can include an emulsion containing about 10% to about 30% of lipids such as fatty acids and/or triglycerides from plant, animal or synthetic sources such as, but not limited to olive oil, Medium Chain Triglyceride oil, soybean oil and fish oil. All of the percentages are expressed in weight to volume (w/v) unless otherwise specified.
  • a preferred lipid component for the PN formulation for all three patient populations comprise a 12.5% lipid emulsion in water for injection as described previously.
  • Olive oil is a preferred lipid because of its desirable immunoneutrality.
  • the above combination is preferred because the combination evokes less peroxidation and no additional oxidative stress. While these are the preferred lipids and lipid concentration, other lipid sources may be used such as lipids from animal, vegetable or synthetic origins
  • a preferred carbohydrate component for the PN formulation for all three patient populations can comprise 50.0% glucose in water for injection.
  • One or more carbohydrates may be used in lieu of glucose.
  • the pH should be adjusted to about 4.0 and in a preferred embodiment the adjustment may be accomplished with hydrochloric acid.
  • a preferred amino acid component for the PN formulation for each of the three patient populations can comprise a solution of amino acids and electrolytes.
  • the approximate amounts of the constituents of the amino acid component for each patient population are shown in the following table A: Patient Patient Patient Population Population Population Compound PT TT OT Alanine 0.466 g 0.466 g 0.466 g Arginine 0.489 g 0.489 g 0.489 g Aspartic acid 0.350 g 0.350 g 0.350 g Cysteine 0.110 g 0.110 g 0.110 g Glutamic acid 0.583 g 0.583 g 0.583 g Glycine 0.233 g 0.233 g 0.233 g Histidine 0.221 g 0.221 g 0.221 g L-Isoleucine 0.390 g 0.390 g 0.390 g Leucine 0.583 g 0.583 g 0.583 g Lysine 0.644 g 0.644 g 0.644 g Methi
  • each chamber of container 10 is filled with one of the components of the PN formulation.
  • containers of a PN formulation for pre-term infants may include about 80 ml of the carbohydrate component in chamber 12 , about 160 ml of the amino acid component for the PT population in chamber 14 , and about 60 ml of the lipid component in chamber 16 .
  • it may not be advisable to administer the lipid component such as if it is the first day, the patient is suffering from septic shock, coagulation abnormalities, high bilirubin level or other reasons.
  • container 10 permits the selective opening of the seals.
  • administration of about 120 ml/kg/day of the above PN formulation for preterm patients provides about the following nutrients and electrolytes: Nutrient/Electrolytes Amount (/kg/day) Na+ 2.6 mmol K+ 2.5 mmol P 1.3 mmol P (Total) 1.5 mmol (includes phosphorus present in lipid component) Ca++ 1.5 mmol Mg++ 0.5 mmol Cl ⁇ 3.7 mmol Acetate ⁇ 3.0 mmol Amino Acids 3.75 grams Glucose 16 grams Lipid 3 grams
  • a PN formulation for term to two years old children is provided in a 500 ml container having three chambers, preferably container 110 .
  • the PN formulation can include a carbohydrate component and can be housed in an end chamber 112 having a volumetric capacity of about 155 ml and having a longitudinal length substantially greater than the longitudinal length of the center chamber 114 . This is to permit selective opening of the seal 124 adjacent the carbohydrate containing chamber 112 without opening the seal 122 adjacent chamber 116 .
  • An amino acid component can also be included in the PN formulation and can be housed in a central chamber 114 having a volumetric capacity of about 221 ml.
  • a lipid formulation can be included in the PN formulation and can be housed in an end chamber 116 having a volumetric capacity of about 124 ml.
  • the lipid component can be formulated as described above and the amino acid component can be formulated for the TT population as shown in table A above.
  • a preferred carbohydrate component for the PN formulation for all three patient populations can comprise 50.0% glucose in water for injection.
  • One or more carbohydrates may be used in lieu of glucose.
  • the pH may be adjusted to around 4.0 with hydrochloric acid.
  • Each chamber is filled with one of the components.
  • about 155 ml of the carbohydrate component can fill an end chamber 112 as described above
  • about 221 ml of the amino acid component can fill a central chamber 114 as described above
  • about 124 ml of the lipid component can fill an end chamber 116 as described above.
  • the above-described optional peel seal 124 allows to mix the carbohydrate and amino acid components or all the seals 122 , 124 may be opened to create the ternary PN formulation.
  • the container permits the selective opening of only the seal adjacent an end chamber with the longitudinal length substantially greater than the longitudinal length of a central chamber without opening the seal adjacent the lipid chamber as discussed above.
  • a PN formulation for children over the age of two is provided in a 1000 ml container having three chambers, preferably container 210 .
  • the PN formulation can include a carbohydrate component and can be housed in an end chamber 212 having a volumetric capacity of about 383 ml and having a longitudinal length substantially greater than the longitudinal length of the center chamber 214 . This is to permit selective opening of the seal 224 adjacent the carbohydrate containing chamber 212 without opening the seal 222 adjacent chamber 216 .
  • An amino acid component can be included in the PN formulation and can be housed in central chamber 214 having a volumetric capacity of about 392 ml.
  • a lipid component can be included in the PN formulation and can be housed in an end chamber 216 having a volumetric capacity of about 225 ml.
  • the lipid component can be formulated as described above and the amino acid component can be formulated for the TT population as shown in table A above.
  • a preferred carbohydrate component for the PN formulation for all three patient populations can comprise 50.0% glucose in water for injection.
  • One or more carbohydrates may be used in lieu of glucose.
  • the pH may be adjusted to around 4.0 with hydrochloric acid.
  • Each chamber is filled with one of the components.
  • about 383 ml of the carbohydrate component fills end chamber 212 as described above, about 392 ml of the amino acid component fills central chamber 214 as described above, and about 225 ml of the lipid component fills end chamber 216 as described above.
  • Each component can be administered to the patient separately or all the seals 222 , 224 may be opened to create the PN formulation. However, in some instances it may not be advisable to administer the lipid component such as if it is the first day, the patient is suffering from septic shock, coagulation abnormalities, high bilirubin level or other reasons.
  • the container permits the selective opening of only the seal adjacent an end chamber with having a longitudinal length substantially greater the longitudinal length of the central chamber without opening the seal adjacent the lipid chamber as discussed above.
  • the reduced fluid level permits the healthcare professional to administer other fluid therapy which may be desirable in certain circumstances.
  • containers of TPN formulations in accordance with the present invention may be placed in pouches selected to retain solution viability and protect the solution from degradation.
  • an overpouch is provided for housing a container 10 , 110 , 210 , 310 , 410 , 510 having multiple chambers containing a carbohydrate component, a lipid component and an amino acid component of a TPN formulation.
  • the overpouch is preferably constructed of a multi-layered plastic film or sheet and prevents oxygen from entering the interior of the overpouch. It is also preferable that the overpouch is able to withstand sterilization such autoclaving.
  • One or more of the layers of the film used to construct the overpouch can include oxygen scavenging polymers or the layer can provide a physical barrier to prevent oxygen permeation.
  • FIG. 11 shows a cross-section of one embodiment of the film 310 used to construct the overpouch.
  • the preferred film 58 comprises 4 layers 60 , 62 , 64 , and 66 .
  • Layer 60 is the exterior most layer of the film and is preferably a high melting temperature polymer having an oxygen barrier coating.
  • layer 60 is a polyester material having an aluminum oxide coating 68 .
  • the thickness of layer 60 can range from about 6 to about 18 um, preferably from about 10 to about 14 um, most preferably about 12 um.
  • the coating 68 can range in thickness from about 400 Angstrom.
  • the layer 312 is oriented so that the aluminum oxide coating faces toward the interior of the overpouch.
  • next layer 62 moving towards the interior is same as layer 60 except that the coating 70 faces the exterior.
  • a different polymer having oxygen impermeable qualities can be used instead such as an oxygen scavenging polymer.
  • the two layers 60 and 62 are bonded or welded together in a variety of ways. As shown on FIG. 111 , an adhesive 72 is placed between layers 60 and 62 .
  • the adhesive can be applied in a thickness range of from about 1.5 to about 5.5 um, preferably about 3.5 um. While many different adhesive may be used, the preferred adhesive is a polyurethane-polyester resin adhesive
  • Layer 64 is preferably a nylon material, more preferably nylon-6.
  • the thickness of layer 64 can be from about 10 to about 20 um, with the preferred thickness being about 15 um.
  • Layer 64 is bonded to layer 62 with adhesive 74 which in this embodiment is the sane adhesive and thickness as adhesive 72 .
  • Layer 66 is the interior most layer and is preferably a polypropylene material, more preferably a cast polypropylene.
  • the thickness of layer 66 can range from about 30 to about 70 um, more preferably about 50 um.
  • Layers 64 and 66 are also bonded together with an adhesive 76 which in this embodiment is the same adhesive and having the same thickness as adhesive 72 .
  • the overpouch can be made from two webs having different structures.
  • the top web can be the structure described above whereas the bottom web could be a thermoformable structure or an opaque structure or could have a sealant layer allowing peelable opening.
  • a multiple chamber container 10 ( FIG. 1 ) storing a TPN formulation is then placed in the overpouch.
  • the headspace of the overpouch is fed with an inert gas such as nitrogen to remove the atmospheric oxygen and then the overpouch can be sealed.
  • the overpouch can be closed using an adhesive or by heat sealing. Once the overpouch is seal shut the entire package can be sterilized.
  • a odor absorber (not shown) can be placed in the overpouch.
  • absorbers There are many types of absorbers that can be used and most of them contain active carbon that attracts and attaches the molecules to the surface of the pores with Van der Waals forces mechanism.
  • an oxygen absorber can also be placed in the overpouch to absorb any oxygen that may still be left inside the over pouch or that may diffuse through the overpouch material during the shelf life of the product.
  • the oxygen absorber has also the capability to absorb the H 2 S by establishing covalent bonding with iron to form iron sulfur. It is also contemplated that a combined oxygen and odor scavenger may be used.
  • the container housing the cysteine containing TPN formulation should be permeable to the hydrogen sulfide so that it can enter the interior of the overpouch were it can be absorbed or scavenged.
  • sterilization at a slightly higher temperature than the industry standard of 121 degrees centigrade may be performed to reduce the level of hydrogen sulfide.
  • sterilization at 125 degrees centigrade and for a shorter time period or sterilization cycle has been found to reduce hydrogen sulfide levels and reduce the degradation of some of the amino acids. With less degradation the formulated levels of amino acids can be closer to the levels desired after sterilization which facilitates the ability to tightly control the amino acid levels.
  • an oxygen indicator is provided.
  • Oxygen indicators are used to demonstrate that the oxygen sensitive components of TPN formulation such as lipid emulsions were not exposed to undesired oxygen levels during transport and/or storage.
  • a preferred oxygen indicator provides a distinct and marked color change to indicate oxygen is present even after undergoing heat sterilization. Moreover, once the color change has occurred the oxidized color must then remain substantially unchanged visually to the observer in circumstances in which the indicator is not observed for some time such as during prolonged storage.
  • the indicator of the present invention is placed in the overpouch and may be adhered to the medical container prior to sterilization.
  • the indicator must be able to withstand steam sterilization.
  • the reduced color of the indicator i.e. the color of the indicator prior to exposure to oxygen sufficient to oxidize the indicator, should still change color when oxidized (exposed to a sufficient amount of oxygen) and the oxidized color should remain substantially unchanged visually and distinct from the reduced color.
  • the indicator is manufactured in its oxidized form and is reduced upon steam sterilization. Additionally, both the color of the reduced forms and the color of the oxidized form should not fade or significantly change during storage of up to three months at 40° C. more preferably up to six months at 40° C. Further, both the color of the reduced form and the color of the oxidized form should not fade or significantly change during storage of up to two years at 25° C. and 30° C.
  • the oxygen indicators come in small pouches containing an indicator solution.
  • the pouches are usually constructed of a top web and bottom or base web which are sealed about their edges to each other to create a sealed pouch.
  • An adhesive such as double-side tape can be placed on the base web to fix the indicator pouch inside the secondary packaging or to the container housing the medical formulation.
  • the indicator is fixed on the surface of the oxygen absorberd.
  • the material forming the pouch can be selected to comply with the kinetic of color change requirement. Some such materials can be:
  • a pinhole exposure to an oxygen environment caused the color of the indicator to change in less than three days to indicate the presence of oxygen.
  • the indicator solution includes indigo carmine that changes from a yellow color when in reduced form which indicates a lack of oxygen to a blue when oxidized by the presence of oxygen.
  • the pouches are preferably constructed with a transparent portion to view the color of the indicating solution.
  • the indicator solution is prepared under atmospheric conditions which means that the indicator is in its oxidized form and blue in color.
  • the pouch containing the oxidized form of the indicator solution is placed in an overpouch with the container housing a TPN formulation and the overpouch is sealed and sterilized.
  • the indicator solution is reduced and the solution turns yellow.
  • the oxidation reduction reaction is shown below:
  • the reaction is reversible, i.e. the solution becomes blue again upon exposure to oxygen.
  • the indicators should be formed using components that would be nontoxic to the contents of the containers and to those users of the product who may be exposed to the indicator solution if there is a leakage through a breach in the film.
  • the components would consist of food additives that are well known for their non-toxicity.
  • An embodiment of an oxygen indicator is based on a 3 g/L indigo carmine concentration.
  • the specific formulation is a mixture of 20 ml of 1.5% indigo carmine, 80 ml of 0.13M of sodium pyrophosphate and 18 g of microcrystalline cellulose and pH adjusted to 8.75 with HCl.
  • the oxidized color of this currently available oxygen indicator produces a blue color when oxidized but this color degrades relatively quickly. After three months of storage at 40° C., the blue color fades to a skin color that it not distinct enough from the yellow color or reduced form of the indicator. This faded color would fail to provide unambiguous identification of exposure to oxygen. Similar results were observed for sample maintained at 30° C. for 8 months and 25° C. for 12 months.
  • the indigo carmine concentration was increased to 6 g/L concentration and compared to the currently available indicator (reference).
  • the table below provides details of each formulation.
  • Sodium Indigo Pyrophosphate HCl adjusted carmine 1.5% 0.13 M Cellulose pH Reference 20 mL 80 mL 18 g 8.75 Alternate1 40 mL 60 mL 30 g 8.75
  • FIG. 12 A graphical representation of the above date is shown in FIG. 12 .
  • the initial absorbance after sterilization is about 1.4 AU with the alternate 1 formulation versus 0.8 AU for the first iteration.
  • the trend of decreasing is similar for both iterations.
  • a longer stability of the oxidized color is expected but the expected 24 months' stability might be borderline with this formulation.
  • cellulose Other types were also investigated using the reference indicator formulation, specifically DS-0 TLC cellulose, colloidal micro-crystalline cellulose, powder for chromatography cellulose, powder for chromatography acid washed cellulose, low and high viscosity carboxymethyl cellulose sodium salt, acetate cellulose and methyl cellulose. No major difference was observed between the formulations including other insoluble cellulose compounds. The testing did show that insoluble cellulose cannot be replaced by soluble grafted cellulose.
  • EDTA was investigated as an additive known as a stabilizing agent. Again, the EDTA did not have a significant effect on the degradation of the oxidized color of the indicator.
  • the indicating solution includes, in addition to indigo carmine, a buffer for pH adjustment in the range of about 9.0 to about 9.75 prior to sterilization and from about 7.0 to about 9.0 after sterilization, cellulose and a reducing agent.
  • Indigo carmine is deemed as not a hazardous substance under European Community Directive 67/548/EEC.
  • the concentration of indigo carmine can be greater than 6 g/l and less than about 60 g/L, preferably from about 10 to about 40 g/L, more preferably from about 14 to about 20 g/L with the lower concentration producing a more pleasing visual indicator. Concentrations of indigo carmine above 20 g/L further exceed the solubility limit and one would observe a lack of homogeneity in the color such as spots or clumps of dark color
  • Buffers can include phosphate and acetate buffers. Specific buffers include sodium phosphate buffers and sodium acetate buffer with a preferred being sodium pyrophosphate buffer. Sodium pyrophosphate is deemed as not a hazardous substance under European Community Directive 67/548/EEC. Concentration of the sodium pyrophosphate buffer can be from about 0.11M to about 0.18M, preferably from 013M to about 017M. Other buffers may be suitable to arrive at the desired pH of 7-9 after sterilization. It has been observed that for the sterilization cycle being used for such nutritional products that a pH prior to sterilization of 9.0-10.0 will lead to the desired post sterilization pH.
  • Color and/or thickening agents can include insoluble cellulose compounds since it also has some reducing ability and is an approved food additive.
  • Preferred cellulose is microcrystalline cellulose included at from about 150 to about 210 g/L, more preferably at about 180 g/L. Microcrystalline cellulose is deemed as not a hazardous substance under European Community Directive 67/548/EEC. Levels of cellulose up to 300 g/L were used but the mixture becomes a paste like mixture which creates issues in manufacturing using preferred equipment. It is envisioned that greater concentrations are feasible using other manufacturing techniques for producing the indicator.
  • An additional reducing agent is included such as one or more reducing sugars.
  • a preferred reducing sugar can be dextrose although other reducing agents and sugars may be employed. However as previously described, in a preferred embodiment reducing sugars that are approved food additives are used.
  • dextrose is a common ingredient used in infusion fluids. The concentration of the dextrose has to be adjusted in function of the indigo carmine concentration. It can be between about 1 and about 5 g/L of anhydrous dextrose, preferably from about 2 to about 4 g/L more preferably from about 2.5 to about 4 g/L. Higher levels of dextrose lead to a decrease in pH of the resultant mixture after sterilization which negatively impacts on the performance of the indicator.
  • an indigo carmine mixture retains the yellow color and remains functional, i.e. chances from yellow to blue upon exposure to oxygen, after at least three months of storage at 40° C. and more preferably up to six months of storage at 40° C.
  • the oxidized form retains the blue color for at least three months of storage at 40° C. and more preferably up to six months of storage at 40° C.
  • an indicator mixture is made by dissolving from about 14 to about 20 grams of indigo carmine in one liter of water.
  • the water is preferably distilled.
  • the mixture also include from about 2-5 to about 4.0 grams/L dextrose and from about 60 grams/L to about 75 grams/L tetrasodium pyrophosphate.
  • a thickening agent acting as color enhancer and having reducing ability is included in the mixture such as, microcrystalline cellulose added at about 180 grams/L.
  • An indigo carmine indicator mixture was made as follows:
  • This mixture was placed in small pouches that were packed with oxygen absorber in an oxygen barrier overpouch and exposed to steam sterilization at 121° C.
  • the samples were then stored in reduced form and the reduced form, i.e. yellow color of the indicator mixture, was still yellow after storage in a substantially oxygen free environment for 112 days at 50° C.
  • An indigo carmine indicator mixture was made as follows: 14 g indigo carmine, 60 g tetrasodium pyrophosphate, 2.00 g anhydrous dextrose and 180 g microcrystalline cellulose were added to one liter of distilled water. The results were similar to those found in Example 2 above.
  • a 14 g/L indigo carmine solution was made to determine the degradation kinetics of the blue color or oxidized form during a few months storage.
  • the indicator was made by mixing 14 g of indigo carmine, 60 g of tetrasodium pyrophosphate, 2.5 g of anhydrous dextrose and 180 g of cellulose in one liter of distilled water.
  • An indigo carmine indicator mixture was made as follows:
  • this 20 g/L formulation showed no degradation of the oxidized color after 124 days, but this may be due to saturation of the detector as absorbance values approach 4 A.U. in conjunction with some water loss.
  • absorbance values approach 4 A.U. in conjunction with some water loss.
  • samples are diluted 10 times, a slight decreasing trend in absorbance is observed at 40° C. but again, the results indicate that the 6 months stability of the oxidized blue color at 40° C. will be reached with this formulation.
  • the 20 g/L formulation was made by dissolving 150 g of sodium pyrophosphate in 2000 ml of water. In this solution 40 g of indigo carmine was added followed by 8 g of anhydrous dextrose. The solution was stirred for a few minutes to maximize the dissolution of indigo carmine. 360 g of cellulose was then added. The pH was measured but not adjusted. The pH should be above 9.4.
  • a large number of small pouches were produced with half of which were filled with about 0.2 ml of the 14 g/L indicator formulation and the other half with the 20 g/L indicator formulation. These indicator pouches were then placed in separate overpouches containing multi-chambered bags of water. Half of the overpouches containing the 14 g/L indicators were heat sterilized using a short heat sterilization procedure, specifically 27 minutes exposure at 121° C. to determine if the indicators would change from the oxidized form (blue color) to the reduced form (yellow color) and the other half of the 14 g/L indicator were heat sterilized using a long heat sterilization procedure, specifically +42 minutes exposure at 122° C. to test the stability of the both the reduced color and oxidized color. The same was performed on the overpouches containing the 20 g/L indicators.
  • a subset of the stored samples was selected from the exposed lots and the unexposed lots from each room.
  • the indicator from the exposed lot was examined to determine whether the indicator still indicated the presence of oxygen by displaying a blue color.
  • the non-exposed samples were initially examined to determine if the indicator still indicated the absence of oxygen, then the overpouch was pierced with the 21 G needle to allow oxygen to flow into the overpouched product and the indicators were observed for a color shift sufficient to show the presence of oxygen.
  • a pinhole was pierced in the overpouch using a 21 G needle of all the units including the illuminated units. All units turned blue after puncturing within 1 to 67 hours.
  • the closest Pantone® reference was estimated at each temperature and period and the results for each temperature and period are shown in FIGS. 20, 21 , 22 which indicate the oxidized color of the oxygen units, did not vary significantly after 6 months storage under any of the storage conditions tested.

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