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

Abstract

An oxygen indicator is provided for revealing the presence of oxygen in a container housing a medical formulation. The indicator can be formulated with components deemed safe for use with medical products. A preferred oxygen indicator can withstand heat sterilization and prolonged storage and can provide a distinct and marked color change to indicate oxygen is present. Preferably, the indicator can be manufactured in its oxidized form and reduced upon steam sterilization. Additionally, both the color of the reduced from and the color of the oxidized form should not fade or significantly change during storage. Moreover, once a color change has occurred indicating the presence of oxygen, the oxidized color preferably remains substantially unchanged visually to the observer even after prolonged storage. The oxygen indicator can be housed in a polymeric pouch of packet having a transparent portion for viewing the color of the indicator.

Description

• This application claims the benefit of U.S. Provisional Application Ser. No. 60/704,555 filed on Aug. 2, 2005.
BACKGROUND OF THE INVENTION
• 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. Even more specifically, 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.
• Frequently 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.
• To overcome the drawbacks of long tern incompatibility and reduce the risks of compounding, 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.
• As described previously, flexible containers having multiple chambers such as 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. These types of multiple chamber containers are disclosed in U.S. Pat. No. 6,319,243 which is incorporated herein by reference.
• Plastic containers such as those just discussed however can also present unique issues which must be addressed. One possible issue is that heat sterilization such as autoclaving can affect certain plastic materials used to form the container and/or the heat seal separating the chambers. Another possible issue is that certain plastic materials are permeable to atmospheric oxygen and may inadequately protect oxygen sensitive solutions or components. Yet another is that certain fat soluble or lipophilic solutions or components may not be compatible with certain plastic materials. For example, 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). 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. For example, 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. Moreover, preparation of the separate components of PN formulations for premature infants, neonatal patients or small children presents unique problems. For one, 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. For example, the concentration ranges for individual constituents of certain component solutions must be narrowly constricted. In addition, some of the individual constituents are either interdependent or incompatible if present in certain forms and concentrations. For example, the breadth of the acceptable concentration range for magnesium for a premature infant is about 0.2 mmol. In other words, the difference between the lowest acceptable concentration of magnesium and the highest acceptable concentration of magnesium is 0.2 mmol. In addition, there is a limit to the amount of chloride a premature infant can tolerate; so in an attempt to provide the required amount of certain electrolytes such as magnesium and calcium as a chloride, the chloride maximum may be exceeded. Furthermore, electrolytes such as calcium and phosphate may be incompatible in certain concentration levels.
• Also, 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. As already discussed above, the lipid component is incompatible with certain plastic material. In addition, 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. In addition, 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. While oxygen indicators exist they appear to not be able to withstand heat sterilization and still function properly after prolonged storage. In other words, 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.
• Furthermore, 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. Moreover, while 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.
• Therefore, there is a need for a flexible multiple chamber container that facilitates selective opening of one but not another frangible barrier, less than all the frangible barriers or the frangible barriers in a sequential manner.
• There is also a need for individual components of a PN formulation that meets the recommended volume and nutritional requirements for certain patient populations and in particular infants or small children at different stages of development.
• In addition, there is a need for means of providing a reliable indicator that atmospheric oxygen may have contaminated the contents of the container, a low level of hydrogen sulfide in case the formulation contains cysteine or derivatives amino acids and an oxygen absorber to eliminate residual oxygen in the overpouch. It would be desirable to provide absorbers and/or indicators that can withstand heat sterilization and prolonged storage and still possess the ability to indicate that an unacceptable amount of oxygen has been exposed to the container.
SUMMARY OF THE INVENTION
• In a first aspect of the present invention an oxygen indicator for detecting the presence of oxygen in medical container is provided. The oxygen indicator 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.
• In a second aspect of the present invention an oxygen indicating packet for detecting the presence of oxygen in a medical container is provided. 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.
• In a third aspect of the present invention an oxygen indicator is provided The 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.
BRIEF DESCRIPTION OF THE DRAWINGS
• 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 ofFIG. 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 ofFIG. 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.
DETAILED DESCRIPTION OF THE INVENTION
• In one embodiment of the present invention, there is provided 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. Preferably, thecontainer10 which is configured as a bag includes three adjacent chambers orchambers12,14, and16.Chamber12 is located at a lateral orside end18 andchamber16 is located at an opposite lateral orside end20. The threechambers12,14, and16 are preferably designed to hold aqueous solutions and/or lipid emulsions. As illustrated inFIG. 1,container10 has a total fluid capacity of 300 ml withchamber12 having a fluid capacity of 80 ml,chamber14 having a capacity of 160 andchamber16 having a capacity of 60 ml.
• Preferably, frangible barriers oropenable seals22 and24 are used to separate the chambers,FIG. 2 shows a cross-section ofcontainer10 and illustrates how theopenable seals22,24 separate the formulations contained inchambers12,14,16. 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. While containers having frangible seals are known, it is very difficult if not impossible to selectively open only one or less than all the seals using the typical method of rolling the multi-chamber bag. Selective activation of the seals is desirable because there are occasions when one of the formulations of a three formulation container is not to be administered. The selective opening of the seals will be discussed in more detail below.
• Container10 also preferably includesports26,28, and30 at thebottom end32 of the container to provide communication withchambers12,14, and16 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. Preferably, theport28 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 andport26 is for additions. In an alternate embodiment, there are twoadministration ports28,30 such that the admixture of formulations housed inchambers12,14 such an admixture of amino acid and glucose solution can be administered separately or at a different rate from the formulation housed inchamber16 such as a lipid emulsion if desired. Of course, any number of ports can be used. In addition, 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. In a further embodiment, one of theseals22,24 is made openable or peelable while the second seal is made permanent. This allows two of the chambers to be mixed while one of the chambers stays separated permanently The admixture and separated solution may then be administered separately without requiring selective activation of the openable seals. 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.
• At thetop end34 of thecontainer10, preferably oppositeend32 where the administration port(s) are located, there is provided ahanger portion36 which in the embodiment shown inFIG. 1 is a flap having a centrally locatedhole38 for hanging the container. Theflap36 defines aborder40 of the upper end of all thechambers12,14, and16. Thecentral portion42 of thehanger flap36 preferably extends a substantial distance towards thebottom end32 of thecontainer10, more preferably about one-fourth the longitudinal length L of thecontainer10 and even more preferably about one-third of the length L of thecontainer10. Preferably, theflap36 extends a greater distance towards thebottom end32 at least at thecentral chamber14 and can also extend a greater distance towards thebottom end32 at thecentral chamber14 and at one of theother chambers12,16. This extra extension of theflap36 with respect tocenter chamber14 results inchamber14 having a shorter longitudinal length than the longitudinal length of lateral orside end chambers12,16. 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.
• Before addressing how the configuration of thechambers12,14,16 and/orhanger flap36 facilitates selective opening of theseals22,24 chambers it would be instructive to describe the typical method of opening theseals22,24.
• FIG. 3 illustrates the typical rolling method of opening theseals22,24 to mix the contents ofchambers12,14, and16. Thehanger flap36 ortop end34 is rolled over itself in a squeezing motion. In multi-chamber bags where all the chambers extend substantially the same distance from their respective bottom borders to their respective top borders, rolling the bag would pressurize all the chambers too much risking unintended activation of the wrong seal. Also, 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.
• Incontainer10,chamber14 does not extend as far towards thetop end34 as dochambers12 and16, i.e.chamber14 is about three-fourths the longitudinal length of theother chambers12,16; therefore rolling the bag from thetop end34 only pressurizeschambers12 and16. In order to selectively activate only one of theseals22,24, 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 thehanger flap36, thecentral chamber14 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.
• Specifically, if the user wanted to activate only seal24, the user may start rolling thebag10 at thetop end34. Without pressurizingchamber14, the user can squeeze the bag at the location ofchamber12. Onceseal24 is activated, the user can stop rolling and squeezing. If the user wanted bothseals22,24 activated instead,bag10 can be rolled starting at thetop end34 while squeezing down on bothend chambers12,16.
• Referring briefly toFIG. 4 after theseals18 and20 have been opened the contents of thecontainer10 may be mixed by manipulation of the container and then administered to the patient by first hanging the bag from ahook using hole38.
• Another rolling technique is also used to activate the seals of multi-chamber bags. Referring toFIG. 1, this technique also uses a rolling motion except instead of starting at thetop end34,container10 is can be rolled starting at one of thetop end corners44,46. Again in multi-chamber bags where all the chambers extend substantially the same distance from the bottom, i.e. have substantially equal longitudinal lengths or bags having a central chamber that extends a greater distance from the bottom to the top end than the other end chambers, i.e. a central chamber having a longitudinal length greater than either of the other chambers, 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.
• In the chamber arrangement ofcontainer10, selective activation ofseal24 using the corner rolling technique is as follows.Container10 is rolled starting atcorner44. The rolling would continue untilchamber12 is sufficiently pressurized enough to causeseal24 to activate.Chamber12 can also be squeezed in order to prevent rolling the container too far. Sincechamber14 does not extend towards thetop end34 as far aschamber12, the rolling is not enough to pressurizechamber14 to the degree necessary to activateseal22 by thetime seal24 is activated. Therefore, ifchamber14 were to extend the length of the container to the same degree aschambers12, much more attention and care would have to be exercised to prevent inadvertent pressurizing of chamber,14 if it could be accomplished at all.
• Two other embodiments of the container of the present invention are shown inFIGS. 5 and 6.Containers110 and210 shown inFIGS. 5 and 6, respectively also include threechambers112,114, and116 and212,214, and216 respectively.Containers110 and210 are constructed using the same materials and similar methods as those used incontainer10. The only significant difference is the size and capacity of thecontainers10,110, and210. As illustrated inFIG. 5, in a preferred embodiment,container110 has a fluid capacity of 500 ml withchamber112 having a fluid capacity of 221 ml,chamber114 having a capacity of 155 ml andchamber116 having a capacity of 124 ml.
• As illustrated inFIG. 6, in apreferred embodiment container210 has a fluid capacity of 1000 ml withchamber212 having a fluid capacity of 392 ml,chamber214 having a fluid capacity of 383 ml, andchamber216 having a fluid capacity 225 ml.
• Containers110 and210 also preferably includepeelable seals122 and124 and222,224 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. Bothcontainers110 and210 also include hanger flaps136 and236 including hanger holes138 and238, respectively.
• Just ascontainer10,containers110 and210 have hanger portions or flaps and chambers that are configured to facilitate selective activation of the seals. For example,containers110,210 both havehanger flaps136,236 that extend towards bottom ends132,232 (about one fourth to about one-third the longitudinal length of thecontainer110,210) respectively more so with respect tocentral chambers114,214. Consequently, the majority of the area ofchambers114,214 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 respectivelateral end chambers112,116 and212,214.Rolling containers110,210 starting at the top ends134,234, or one ofcorners144,146,244,246, respectively allows rolling of thecontainers110,210 and squeezing of the chamber adjacent to the seal desired to be selectively activated without undue pressure being placed on thecentral chambers114,214 which could cause unintended activation of the other seal.
• Containers110 and210 also includeaccess ports126,128, and130, and226,228, and230, respectively. These ports are constructed using the same materials and in a similar manner asaccess ports26,28, and30. To permit the same equipment to fillcontainers10,110, and210 it is preferable to position so to be the same distance from each other,FIGS. 7, 8, and9 illustrate other embodiments of a multiple chamber container of the present invention.Containers310,410,510 all include threeadjacent chambers312,314,316 and412,414,416, and512,514,516, respectively.Chambers312,412,512 are located at lateral or side ends318,418,518, respectively andchambers316,416,516 are located at opposite lateral or side ends320,420,520.Hanger portion336 is located at thetop end334 and includeshole338 for hanging the container.Hanger portion336 defines thetop border340 ofchambers312,314,316.Chambers312 is separated fromchamber314 bypeelable seal324, andpeelable seal326 separateschamber314 from316.Container410 also includespeelable seals424,426separating chamber412 fromchamber414 andchamber414 fromchamber416, respectively.Peelable seal524 separateschamber512 fromchamber514 andpeelable seal526 separateschamber514 from516. The peelable seals allow isolated storage of distinct formulations in the chambers for subsequent admixing prior to administration.
• Chamber314 has a longitudinal length that is from about two-thirds to about three-quarters the longitudinal lengths of bothlateral end chambers312,316. While the longitudinal lengths ofchambers312,316 are equal, differing lengths can be used. Selective activation of eitherpeelable seal324,326 can when rollingcontainer310 starting attop end334 and squeezingchamber312 orchamber316 depending on which of thepeelable seals324,324 is to be activated.
• As is shown inFIG. 8, thelateral end chamber416 ofcontainer410 has a longitudinal length that is from about two-thirds to about three-fourths less than the longitudinal length ofchamber412 positioned at oppositelateral end418 and is equal to the longitudinal length oflateral end chamber416.Chamber412 having a longitudinal length greater than that ofchamber414 allowspeelable seal424 to be activated without the inadvertent activation ofpeelable seal426 when rollingcontainer410 starting attop end434.
• Container510 shown inFIG. 9 includeschambers512,514,516 all of which have longitudinal lengths that differ from each other.Lateral end chamber512 has a longitudinal length that is from about twenty five percent to about thirty three percent greater than the longitudinal length ofchamber514 which in turn has a longitudinal length that is from about twenty five percent to about thirty three percent greater than the longitudinal length ofchamber516Rolling container510 starting at thetop end534 allows selective activation ofpeelable seal524,526 by first pressurizingchamber512 untilseal524 activates. Further rolling would begin topressurized chamber514 untilseal526 activates. Any additional chamber included betweenchamber512 and514 and having a longitudinal length less the longitudinal length ofchamber512 but greater than the longitudinal length ofchamber514, or betweenchamber514 and516 and having a longitudinal length less the longitudinal length ofchamber514 but greater than the longitudinal length ofchamber516 may allow sequential activation of seals starting with theseal bordering chamber512 and end with theseal bordering chamber516 when rolling the container starting at thetop end534.
• It is contemplated that 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 orsheet48 used to construct thecontainer10. Preferably, thesheet48 is made from fourlayers50,52,54 and56. Theouter layer50 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 theouter layer50 is from about 0.39 mils to about 0.71 mils with the actual thickness of the outer layer show inFIG. 3 being 0.55 mils.
• Atie layer52 is provided to secure thefirst layer50 to athird layer54. Preferably the tie layer is a highly reactive polymer adhesive such as EVA copolymer chemically modified with maleic acid. Such a material is available from DuPont under the name Bynel E-361. Thetie layer52 may have a varied thickness for example from 0.20 mils to 0.60 mils, e.g., 0.40 mils.
• Thethird layer54 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. Preferably 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 asealant layer56 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. The sealant layer preferably has a thickness of from about 1.28 mils to about 1.92 mils, e.g., 1.60 mils. Thesealant layer56 is adjacent the interior side of the container10 (FIG. 1) such that when the seal is ruptured, communication is provided between the chambers.
• Thecontainer10 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 twosheets48 and48awithlayer56 contacting thecorresponding layer56aofsheet48a.Thesheets48 and48aare 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 thelayer56, but not liquefy the layer. A resulting cohesive bond develops from contact between thesheet48 and thesheet48a,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. In order to obtain such an activation force, the temperature of the seal bar will vary depending upon the material used to construct the container. Forfilm48, 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.
• A more detailed explanation of forming the peelable seal is provided in U.S. Pat. No. 6,319,243 which incorporated herein by references.
• Referring toFIG. 1, theports26,28 and30 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 inchamber16 thenport30 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:
• 60% Polypropylene Total 8473
• 40% Styrene ethylene butylenes styrene copolymer Kraton G1652
• This port is then sealed off after filling.
  If an administration site is added on the port of the chamber containing lipid, the port will be more preferably formed of a three layer coextruded tube with the following preferred formulations:
• External layer (+/−330 um):
• 100% Polypropylene Solvay Eltex PKS490
• or
• 60% Polypropylene Total 8473
• 40% Styrene ethylene butylenes styrene copolymer Kraton G1652
• Medium layer (+/−170 um)
• 35% Polypropylene Fortilene 4265
• 25% Polyethylene Tafmer A4085
• 10% Styrene ethylene butylenes styrene copolymer Kraton FG1924
• 10% Polyamide Macromelt TPX16-159
• 20% EVA Escorene UL00328)
• or
• 50% Styrene ethylene butylenes styrene copolymer Kraton G1660
• 38% Polyester Dupont Hytrel 4056
• 10% EVA AT Plastic Ateva 2803G
• 2% Polypropylene Total 6232
• Internal layer (+/−330 um)
• 50% EVA Escorene UL00119
• 50% EVA Escorene UL00328
• or
• 50% EVA Ateva 2803G
• 50% EVA Ateva 1807G
• In a preferred embodiment some or all of theports22,24, and26 can be constructed from a non-PVC material such as the above formulation.
EXAMPLE 1
• A comparison was of a 300 ml multi-chamber container of the present invention best exemplified bycontainer10 was compared to a currently available multi-chamber container which was the same in all respects tocontainer10 expect that the hanger flap extended only about half as far into the central chamber ashanger flap36 extends intochamber14 making the central chamber of this bag slightly larger in capacity. 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 ofcontainer10 had a slightly smaller volume than the central chamber of other container they were similarly inflated with water.
• Twenty operators were selected (10 male & 10 female). Each operator received 5 units of each design and the following instructions:
• Instructions: For the ten containers, we are asking you to use the rolling procedure starting from the hanger end of the container to open only the peel seal separating the two compartments filled with colorless water. The peel seal separating the compartment filled with blue colored water should not be opened.
• The operators were asked “Which design allows an easier and more efficient activation of only one peel seal of the bag?” All twenty selectedcontainer10 of the present invention
• In different embodiment of the present invention, six parenteral nutritional (PN) formulations are provided for three patient populations. 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. Preferably, 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 container10 (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 container110 (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 container210 (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.
• Several members of the scientific community have determined mean nutritional recommended guidelines (MNRG) for the amino acids, carbohydrate, and lipid components and the likely minimum to maximum nutritional guidelines (MMNG) for the electrolytes see below per kilogram per day for the three patient populations as shown in the following table:

  NUTRIENT	PT (/kg/day)	TT (/kg/day)	OT (/kg/day)

  Amino acid	3.75	g	2.5	g	1.8	g
  Carbohydrate	16	g	15	g	15	g
  Lipid	3	g	3	g	2.2	g
  Sodium	0.0-2.5	mmol	2.0-2.2	mmol	1.0-3.5	mmol
  Potassium	0.0-2.5	mmol	1.0-2.2	mmol	1.0-2.5	mmol
  Phosphorus	1.0-2.25	mmol	0.5-0.6	mmol	0.2-0.6	mmol
  Calcium*	1.3-2.25	mmol	0.5-0.6	mmol	0.2-0.3	mmol
  Magnesium	0.2-0.5	mmol	0.2-0.3	mmol	0.1-0.2	mmol
  Chloride	<6	mmol	2-3	mmol	3-5	mmol
  Fluids (water)	120	ml	100	ml	80	ml
  *The ratio of calcium to phosphorus should be between 1:1 and 1:1.1.

• Referring toFIG. 1 in one embodiment of the present invention a PN formulation for preterm infants is provided incontainer10. 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

• While the above amino acids at their respective amounts are preferred, other amino acids in different amounts and combinations may be used. Nevertheless, 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 a12.5% 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

• Other sources and amounts for 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.
• Referring toFIG. 1, each chamber ofcontainer10 is filled with one of the components of the PN formulation. In particular, containers of a PN formulation for pre-term infants may include about 80 ml of the carbohydrate component inchamber12, about 160 ml of the amino acid component inchamber14, and about 60 ml of the lipid component inchamber16. 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. In this case,container10 permits the selective opening ofseal24.
• 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

• In one embodiment, 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+	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

• It is desirable to provide calcium and phosphate levels above the lower end of the mean recommended requirements. However increasing the sodium glycerophosphate would cause the sodium level to exceed the upper range of the mean recommended requirement range. Although calcium can easily be increased by adding more calcium chloride, this would alter the recommended calcium to phosphorus ratio of 1:1 or 1:1.1. In one embodiment, an inorganic form of phosphorus is added to the amino acid component to meet the mean recommended requirement. In conjunction with this addition, more calcium is preferably added to maintain the proper ratio.
• It may be desirable to provide less fluid than the mean recommended requirement so that other fluid therapy could be provided by the healthcare practitioner. Such fluid therapy is often necessary in patients that require PN. To allow the administration of other fluids, 120 ml/kg/day was chosen as being supplied in nutritional volume, while the overall required fluid level intake in preterm neonates is 150-170 ml/kg/day.
• Referring toFIG. 5 in another embodiment of the present invention a PN formulation for term to two years old children is provided in a 500 ml container having three chambers preferablycontainer110. The PN formulation can include a carbohydrate component and can be housed in anend chamber112 having a volumetric capacity of about 155 ml and having a longitudinal length substantially greater than the longitudinal length of thecenter chamber114. This is to permit selective opening of theseal124 adjacent thecarbohydrate containing chamber112 without opening theseal122adjacent chamber116. An amino acid component can also be included in the PN formulation and can be housed in acentral chamber114 having a volumetric capacity of about 221 ml. Also, a lipid formulation can be included in the PN formulation and can be housed in anend chamber116 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

• Other sources, amounts and combinations for the electrolytes and carbohydrate may be used. It is preferred that the phosphorus in the carbohydrate component comes from organic sources and the above table indicates the most preferred sources of the nutrients.
• Each chamber is filled with one of the components. In particular, about 155 ml of the carbohydrate component can fill anend chamber112 as described above, about 221 ml of the amino acid component can fill acentral chamber114 as described above, and about 124 ml of the lipid component can fill anend chamber116 as described above. The above-describedpeel seal124 allows mixing of the carbohydrate and amino acid components or all theseals122,124 may be opened to create the ternary PN formulation. So, in some instances where it may not be advisable to administer the lipid component such as if it is the first day of life, if 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 the longitudinal length substantially greater than the longitudinal length of a central chamber without opening the seal adjacent the lipid chamber as discussed above.
• In order to provide the MNRG and at least at the minimum of MMNG about 96.7 ml/kg/day of the PN formulation should be infused per kilogram of the patient per day. The 500 ml container would then provide enough PN for about a 5 kg child 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	—
  ml/kg/day	42.7	30	24	96.7
  ml/chamber	221	155	124	500

• Administration of 96.7 ml/kg/day of the above PN formulation for term to two years old children provides approximately the following nutrients and electrolytes:

  Nutrient/Electrolytes	Amount (per kg/day)

  Na+	1.0-2.2	mmol
  K+	1.0-2.2	mmol
  P	0.5-0.6	mmol
  P(Total)	0.73-0.83	mmol
  (includes phosphorus present in lipid component)
  Ca++	0.24-0.60	mmol
  Mg++	0.2-0.3	mmol
  Cl−	0.5-2.2	mmol
  Cl−(Total)	0.7-2.4	mmol
  (includes chloride from amino acid Orn HCl)
  Acetate−	1.2-2.5	mmol
  Amino Acids	2.5	grams
  Glucose	15	grams
  Lipid	3	grams

• With all lipids added, phosphorus intake is higher and the P/Ca ratio increases, however, this patient population can accommodate such a small excess of phosphorus. The reduced fluid amount permits the healthcare professional to administer other fluid therapy if necessary which may be advantageous in certain circumstances.
• Referring toFIG. 6, in another embodiment of the present invention, a PN formulation for children over the age of two is provided in a 1000 ml container having three chambers, preferablycontainer210. The PN formulation can include a carbohydrate component and can be housed in anend chamber212 having a volumetric capacity of about 383 ml and having a longitudinal length substantially greater than the longitudinal length of thecenter chamber214. This is to permit selective opening of theseal224 adjacent thecarbohydrate containing chamber212 without opening theseal222adjacent chamber216. An amino acid component can be included in the PN formulation and can be housed incentral chamber214 having a volumetric capacity of about 392 ml. In addition, a lipid component can be included in the PN formulation and can be housed in anend chamber216 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

• Other sources, amounts and combinations for 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. In particular, about 383 ml of the carbohydrate component fillsend chamber212 as described above, about 392 ml of the amino acid component fillscentral chamber214 as described above, and about 225 ml of the lipid component fillsend chamber216 as described above. Each component can be administered to the patient separately or all theseals222,224 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. In this case, 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.
• In order to provide the MNRG and at least at the minimum of MMNG), about 78.3 ml/kg/day of the PN formulation should be infused per kilogram of the patient per day, The 1000 ml container would then provide enough PN for about a 12.5 kg child over a 24-hour period. 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	50	12.5	—
  (%)
  ml/kg/day	30.7	30	17.6	78.3
  ml/chamber	392	383	225	1000

• Administration of about 78.3 ml/kg/day of the above PN formulation for children over the age of two provides about the following nutrients and electrolytes:

  	Nutrient/Electrolytes	Amount (per kg/day)

  	Na+	1.0-3.5	mmol
  	K+	1.0-2.5	mmol
  	P	0.20-0.55	mmol
  	P(Total)	0.37-0.72	mmol
  	(includes phosphorus present in lipid
  	component)
  	Ca++	0.2-0.3	mmol
  	Mg++	0.1-0.2	mmol
  	Cl−	1.0-3.0	mmol
  	Cl−(Total)	1.1-3.1	mmol
  	(includes chloride from amino acid
  	Orn HCl)
  	Acetate−	1.1-2.7	mmol
  	Amino Acids	1.8	grams
  	Glucose	15	grams
  	Lipid	2.2	grams

• The reduced fluid level permits the healthcare professional to administer other fluid therapy which may be desirable in certain circumstances
• In another embodiment of the present invention a PN formulation for children over the age of two is provided in a 1000 ml container having three chambers, preferablycontainer210. The PN formulation can include a carbohydrate component and can be housed in anend chamber212 having a volumetric capacity of about 332 ml and having a longitudinal length substantially greater than the longitudinal length ofcentral chamber214. This is to permit selective opening of theseal224 adjacent thecarbohydrate containing chamber212 and without opening theseal222adjacent chamber216. An amino acid component can also be included in the PN formulation and can be housed in acentral chamber214 having a volumetric capacity of about 425 ml. A lipid component can also be included in the PN formulation and can be housed in anend chamber216 having a volumetric capacity of about 243 ml. The lipid and amino acid components are formulated as described above. In the preferred embodiment 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

• Other sources, amounts and combinations for 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. In particular, about 332 ml of the carbohydrate component fills anend chamber212 as described above, about 425 ml of the amino acid component fills acentral chamber214 as described above, and about 243 ml of the lipid component fills anend chamber216 as described above. Each component can be administered to the patient separately or all theseals222,224 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. In this case, the container permits the selective opening of theseal224 adjacent anend chamber212 having a longitudinal length substantially greater than the longitudinal length of thecentral chamber214 without opening theseal222 adjacent thelipid compartment216 as discussed above.
• 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

• Administration of about 72.3 ml/kg/day of the above PN formulation for children over the age of two provides the following nutrients and electrolytes:

  Nutrient/Electrolytes	Amount (/kg/day)

  Na+	1.0-3.5	mmol
  (includes sodium glycerophosphate and
  sodium chloride)
  K+	1.0-2.5	mmol
  P	0.2-0.55	mmol
  P(Total)	0.2-0.715	mmol
  (includes phosphorus present in lipid
  component)
  Ca++	0.2-0.3	mmol
  Mg++	0.1-0.2	mmol
  Cl−	3.4	mmol
  (Magnesium chloride, calcium chloride and
  sodium chloride)
  Cl−(Total)	3.51	mmol
  (includes chloride from amino acid Orn HCl)
  Amino Acids	1.8	grams
  Glucose	15	grams
  Lipid	2.2	grams

• The reduced fluid level permits the healthcare professional to administer other fluid therapy which may be desirable in certain circumstances.
• In some instances it has been determined that 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.
• As a result, it may be preferable to either not include electrolytes beyond the minimum concentration shown above, to not include electrolytes beyond the minimum concentration shown above in the PN formulation as manufactured but allowing the addition of electrolytes by the healthcare practitioner prior to administration) or to include the electrolytes even at concentrations above the minimum base level in another component.
• Therefore in these instances, in more preferred embodiments of the present invention, three parenteral nutritional (PN) formulations are provided for the above described patient populations, i.e. pre-term infants (PT), term to two years old children (TT), and children over the age of two (OT). 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 container10 (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 container110 (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 container210 (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 (PT, TT and OT) 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 (PT, TT and OT) 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 (PT, TT and OT) 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
  Methionine	0.140 g	0.140 g	0.140 g
  Ornithine	0.145 g	0.145 g	0.145 g
  (as L-Ornithine	(0.185 g)	(0.185 g)	(0.185 g)
  hydrochloride)
  Phenylalanine	0.245 g	0.245 g	0.245 g
  Proline	0.175 g	0.175 g	0.175 g
  Serine	0.233 g	0.233 g	0.233 g
  Taurine	0.035 g	0.035 g	0.035 g
  Threonine	0.216 g	0.216 g	0.216 g
  Tryptophane	0.117 g	0.117 g	0.117 g
  Tyrosine	0.045 g	0.045 g	0.045 g
  Valine	0.443 g	0.443 g	0.443 g
  Sodium	3.9 mmol	5.1 mmol	11.4 mmol
  (source(s) can include sodium
  glycerophosphate and/or
  sodium chloride)
  Potassium	3.9 mmol	5.1 mmol	8.2 mmol
  (source(s) can include
  potassium acetate)
  Magnesium	0.78 mmol	0.70 mmol	0.65 mmol
  (source(s) can include
  magnesium acetate)
  Calcium	2.35 mmol	1.40 mmol	0.98 mmol
  (source(s) can include calcium
  chloride)
  Phosphate	2.0 mmol	1.45 mmol	1.85 mmol
  Acetate (the amount of acetate	4.7 mmol	5.9 mmol	8.8 mmol
  my vary depending on the	appr.	appr.	appr.
  source of the other
  electrolytes)
  Malate	1.9 mmol	1.9 mmol	2.0 mmol
  Chloride (the amount of	5.8 mmol	6.2 mmol	11.0 mmol
  chloride my vary depending	appr.	appr.	appr.
  on the source of the other
  electrolytes)
  Malic acid	qs to pH 5.5	qs to pH 5.5	qs to pH 5.5
  Water for injection	qs to 100 ml	qs to 100 ml	qs to 100 ml

• Other sources, combinations and amounts for the electrolytes and amino acids 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.
• Referring toFIG. 1, each chamber ofcontainer10 is filled with one of the components of the PN formulation. In particular, containers of a PN formulation for pre-term infants may include about 80 ml of the carbohydrate component inchamber12, about 160 ml of the amino acid component for the PT population inchamber14, and about 60 ml of the lipid component inchamber16. 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. In this case,container10 permits the selective opening of the seals.
• In order to provide the MNRG for the amino acids, carbohydrate, lipid and electrolytes 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:

  Component	Amino Acid	Carbohydrate	Lipids	Total Volume

  concentration	5.86	50	12.5	—
  (%)
  ml/kg/day	64	32	24	120
  ml/chamber	160	80	60	300

• In one embodiment, 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

• It is desirable to provide calcium and potassium levels above the lower end of the mean recommended requirements. However increasing the sodium glycerophosphate would cause the sodium level to exceed the upper range of the mean recommended requirement range. Although calcium can easily be increased by adding more calcium chloride, this would alter the recommended calcium to phosphorus ratio of 1:1 or 1:1.1. In one embodiment, an inorganic form of phosphorus is added to the amino acid component to meet the mean recommended requirement. In conjunction with this addition, more calcium is preferably added to maintain the proper ratio.
• It may be desirable to provide less fluid than the mean recommended requirement so that other fluid therapy could be provided by the healthcare practitioner. Such fluid therapy is often necessary in patients that require PN. To allow the administration of other fluids, 120 ml/kg/day was chosen as being supplied in nutritional volume, while the overall required fluid level intake in preterm neonates is 150-170 ml/kg/day.
• Referring toFIG. 5 in another embodiment of the present invention a PN formulation for term to two years old children is provided in a 500 ml container having three chambers, preferablycontainer110. The PN formulation can include a carbohydrate component and can be housed in anend chamber112 having a volumetric capacity of about 155 ml and having a longitudinal length substantially greater than the longitudinal length of thecenter chamber114. This is to permit selective opening of theseal124 adjacent thecarbohydrate containing chamber112 without opening theseal122adjacent chamber116. An amino acid component can also be included in the PN formulation and can be housed in acentral chamber114 having a volumetric capacity of about 221 ml. Also, a lipid formulation can be included in the PN formulation and can be housed in anend chamber116 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 (PT, TT and OT) can comprise 50.0% glucose in water for injection. One or more carbohydrates may be used in lieu of glucose. In the preferred embodiment the pH may be adjusted to around 4.0 with hydrochloric acid.
• Each chamber is filled with one of the components. In particular, about 155 ml of the carbohydrate component can fill anend chamber112 as described above, about 221 ml of the amino acid component can fill acentral chamber114 as described above, and about 124 ml of the lipid component can fill anend chamber116 as described above. The above-describedoptional peel seal124 allows to mix the carbohydrate and amino acid components or all theseals122,124 may be opened to create the ternary PN formulation. So, in some instances where it may not be advisable to administer the lipid component such as if it is the first day of life, if 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 the longitudinal length substantially greater than the longitudinal length of a central chamber without opening the seal adjacent the lipid chamber as discussed above.
• In order to provide the MNRG for the amino acids, carbohydrate, lipid and electrolytes about 96.7 ml/kg/day of the PN formulation should be infused per kilogram of the patient per day. The 500 ml container would then provide enough PN for about a 5 kg child over a 24-hour period. 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	50	12.5	—
  (%)
  ml/kg/day	42.7	30.0	24	96.7
  ml/chamber	221	155	124	500

• Administration of 96.7 of the above PN formulation for term to two years old children provides approximately the following nutrients and electrolytes:

  	Nutrient/Electrolytes	Amount (per kg/day)

  	Na+	2.3	mmol
  	K+	2.2	mmol
  	P	0.62	mmol
  	P(Total)	0.84	mmol
  	(includes phosphorus present in lipid
  	component)
  	Ca++	0.60	mmol
  	Mg++	0.30	mmol
  	Cl−	2.7	mmol
  	Acetate−	2.5	mmol
  	Amino Acids	2.5	grams
  	Glucose	15	grams
  	Lipid	3	grams

  
  With all lipids added, phosphorus intake is higher and the P/Ca ratio increases, however, this patient population can accommodate such a small excess of phosphorus. The reduced fluid amount permits the healthcare professional to administer other fluid therapy if necessary which may be advantageous in certain circumstances. Referring toFIG. 6, in another embodiment of the present invention, a PN formulation for children over the age of two is provided in a 1000 ml container having three chambers, preferablycontainer210. The PN formulation can include a carbohydrate component and can be housed in anend chamber212 having a volumetric capacity of about 383 ml and having a longitudinal length substantially greater than the longitudinal length of thecenter chamber214. This is to permit selective opening of theseal224 adjacent thecarbohydrate containing chamber212 without opening theseal222adjacent chamber216. An amino acid component can be included in the PN formulation and can be housed incentral chamber214 having a volumetric capacity of about 392 ml. In addition, a lipid component can be included in the PN formulation and can be housed in anend chamber216 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 (PT, TT and OT) can comprise 50.0% glucose in water for injection. One or more carbohydrates may be used in lieu of glucose. In the preferred embodiment the pH may be adjusted to around 4.0 with hydrochloric acid.
• Each chamber is filled with one of the components. In particular, about 383 ml of the carbohydrate component fillsend chamber212 as described above, about 392 ml of the amino acid component fillscentral chamber214 as described above, and about 225 ml of the lipid component fillsend chamber216 as described above. Each component can be administered to the patient separately or all theseals222,224 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. In this case, 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.
• In order to provide the MNRG for the amino acids, carbohydrate, lipid and electrolytes, about 78.3 ml/kg/day of the PN formulation should be infused per kilogram of the patient per day. The 1000 ml container would then provide enough PN for about a 12.5 kg child over a 24-hour period. The following table illustrates the approximate values of the PN formulation in a three chambered:

  Component	Amino Acid	Carbohydrate	Lipids	Total Volume

  concentration	5.86	50	12.5	—
  (%)
  ml/kg/day	30.7	30	17.6	78.3
  ml/chamber	392	383	225	1000

• Administration of about 78.3 ml/kg/day of the above PN formulation for children over the age of two provides about the following nutrients and electrolytes:

  	Nutrient/Electrolytes	Amount (per kg/day)

  	Na+	3.6	mmol
  	K+	2.5	mmol
  	P	0.57	mmol
  	P(Total)	0.73	mmol
  	(includes phosphorus present in lipid
  	component)
  	Ca++	0.30	mmol
  	Mg++	0.20	mmol
  	Cl−	3.4	mmol
  	Amino Acids	1.8	grams
  	Glucose	15	grams
  	Lipid	2.2	grams

• The reduced fluid level permits the healthcare professional to administer other fluid therapy which may be desirable in certain circumstances.
• Referring toFIG. 11, 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. In one embodiment of the present invention, an overpouch is provided for housing acontainer10,110,210,310,410,510 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 thefilm310 used to construct the overpouch. Thepreferred film58 comprises 4layers60,62,64, and66.Layer60 is the exterior most layer of the film and is preferably a high melting temperature polymer having an oxygen barrier coating. As illustrated,layer60 is a polyester material having analuminum oxide coating68. The thickness oflayer60 can range from about 6 to about 18 um, preferably from about 10 to about 14 um, most preferably about 12 um. Thecoating68 can range in thickness from about 400 Angstrom. Thelayer312 is oriented so that the aluminum oxide coating faces toward the interior of the overpouch.
• Preferably, thenext layer62 moving towards the interior is same aslayer60 except that thecoating70 faces the exterior. A different polymer having oxygen impermeable qualities can be used instead such as an oxygen scavenging polymer.
• The twolayers60 and62 are bonded or welded together in a variety of ways. As shown onFIG. 111, an adhesive72 is placed betweenlayers60 and62. 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
• Layer64 is preferably a nylon material, more preferably nylon-6. The thickness oflayer64 can be from about 10 to about 20 um, with the preferred thickness being about 15 um.Layer64 is bonded to layer62 with adhesive74 which in this embodiment is the sane adhesive and thickness asadhesive72.
• Layer66 is the interior most layer and is preferably a polypropylene material, more preferably a cast polypropylene. The thickness oflayer66 can range from about 30 to about 70 um, more preferably about 50 um.
• Layers64 and66 are also bonded together with an adhesive76 which in this embodiment is the same adhesive and having the same thickness asadhesive72.
• In another embodiment, 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 container10 (FIG. 1) storing a TPN formulation is then placed in the overpouch. Preferably the headspace of the overpouch is fled 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.
• It is known that heat sterilization of amino acid solutions having amino acids with a thiol function such as cysteine or N-acetyl-cysteine can produce hydrogen sulfide gas as a decomposition product and most likely also ppb levels of other unidentified volatile organic sulphured compounds noticeable by their odor. Hydrogen sulfide equilibrates between the liquid phase and the gaseous phase or headspace if present. A limit of 1 ppm of hydrogen sulfide in the aqueous phase has been assessed as non-toxic for the patient by intravenous route. But even if this limit in the aqueous phase is applied, some hydrogen sulfide and related sulphured compounds in the gaseous phase can still be present at a very low level but at a level sufficient to produce an unpleasant odor, (hydrogen sulfide can be smelled from levels of 0.1 ppm in the gaseous phase). This unpleasant odor can be disconcerting to the patient and others in the area and create an impression that the TPN formulation is stale or contaminated.
• In this regard, to remove any unpleasant odor linked to very low levels of hydrogen sulfide and/or related sulphured compounds in the gaseous phase, before the overpouch is sealed shut a odor absorber (not shown) can be placed in the overpouch. 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. In addition, 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 H₂S by establishing covalent bonding with iron to form iron sulfur. It is also contemplated that a combined oxygen and odor scavenger may be used.
• It should be noted that 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.
• In a further embodiment of the present invention, sterilization at a slightly higher temperature than the industry standard of 121 degrees centigrade may be performed to reduce the level of hydrogen sulfide. For example, 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.
• In another embodiment of the present invention 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.
• In an embodiment of an indicator the indicator of the present invention is placed in the overpouch and may be adhered to the medical container prior to sterilization. Thus the indicator must be able to withstand steam sterilization. In other words 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. In a preferred embodiment, 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.
• Typically 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. In a preferred embodiment, 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:
• top web: Oriented polypropylene (OPP) 25μ/Cast polypropylene (CCP) 40μ. A multi color printing can be applied between the OPP and CPP layers
• base web: Polyethylene terephthalate (PET) 12μ/Oriented polypropylene (OPP) 20μ/Cast polypropylene 30μ. Any printing such as a white opaque printing can be placed between the PET layer and the OPP layer.
• In one embodiment utilizing the above described film, 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. During manufacturing 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. During the sterilization cycle, 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. In a preferred embodiment 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. In a more preferred embodiment, 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.
• In one attempt to overcome this shortcoming, 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

  	20mL	80 mL	18 g	8.75
  Alternate1	40mL	60 mL	30 g	8.75

• Since cellulose is provided to act as a reducing agent, the cellulose content was increased in this second embodiment (alternate 1) of indicator to compensate for the increase indigo carmine. In other words, more cellulose is needed to ensure the indicator reduces during sterilization.
• Samples of each of the indicators were analyzed for their optical densities in absorption units (AU) at 610 nm, which is the absorbance range for the blue oxidized color, after formulation, sterilization and storage at a few temperatures over time. The results are show in the following table.

  	REF-	REF-	REF-	ALT1-	ALT1-	ALT1-
  Days	25° C.	30° C.	40° C.	25° C.	30° C.	40° C.

  0	1.185	1.281	1.281	2.116	2.116	2.116
  1	0.814	0.827	0.82	1.4614	1.3934	1.4246
  15				1.3382	1.2337	1.1308
  21	0.7162	0.603	0.2973
  40				1.2816	1.1279	0.711
  46	0.6312	0.4465	0.1168
  63				1.1903	1.1008	0.4358
  69	0.5975	0.3726	0.0964
  82				1.0662	0.9486	0.2445
  87	0.5645	0.332	0.0574
  Day 0 means solution prior to sterilization whileday 1 means solution after sterilization

• A graphical representation of the above date is shown inFIG. 12.
• The initial absorbance after sterilization is about 1.4 AU with the alternate 1 formulation versus 0.8 AU for the first iteration. As shown onFIG. 9, 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.
• Other types of cellulose 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. In addition, 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.
• Further increasing the concentration of the indigo carmine manufacturing complications caused by increasing the cellulose content and it was seen that increasing the level above the 300 g/L cellulose used in the alternate 1 indicator hampered manufacturability of the indicating pouch and created an undesirably paste like mixture. Any further increase would further exacerbate these issues and yet failure to increase the level of cellulose led to an inability to adequately reduce the higher levels of indigo carmine during sterilization.
• It has been determined that adding an appropriate amount of a reducing agent and in a preferred example a stronger reducing sugar such as dextrose allows the indigo carmine concentration to be increased beyond the 6 g/L concentration while maintaining the cellulose content at the more preferred level of 180 g/L.
• In one embodiment, 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. For example 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.
• In one embodiment of an indicator of the present invention, 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. In addition, once exposed to oxygen 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.
• In one embodiment, 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.
EXAMPLE 2
• An indigo carmine indicator mixture was made as follows:
• 14 g indigo carmine, 60 g tetrasodium pyrophosphate, 2.75 g anhydrous dextrose, and 180 g microcrystalline cellulose were added to one liter of distilled water.
• 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.
• When similar packages were exposed to oxygen after being first placed in a reduced state as described above, the mixture changed to the oxidized form, i.e. dark blue color. The mixture remained dark blue after storage for 112 days at 50° C.
EXAMPLE 3
• 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.
EXAMPLE 4
• 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.
• Empty bags ofnominal volume 50 ml were filled with this 14 g/L indicator formulation, then overpouched with oxygen absorber and sterilized. During sterilization, the color of the indicating mixture turns from blue (oxidized form) to yellow (reduced form).
• The overpouch was then pierced and the indicating mixture was allowed to react with atmospheric oxygen under ambient conditions. Then the color of the indicating mixture turns back to blue (oxidized form). Using a syringe with a needle, a 1.0 ml of indicating mixture was withdrawn through the medication port of the container. This aliquot was diluted to 50 ml with water and the cellulose was removed by filtration or centrifugation. Finally, 200 μl of the solution were dispensed in a well of a polystyrene microtitration plate and the absorbance was recorded at 610 nm, i.e. the maximum wavelength at peak optical densities of the indigo carmine in its oxidized form. A graph of optical densities (O.D.), measured from 350 to 750 nm is shown inFIG. 13.
• The test units were then stored at 25° C., 30° C. and 40° C. Samples were taken at several time intervals and spectrometric measurements were made. The following table shows the results:

  	Formulation with 14 g/l
  	Optical density @ 610 nm
  	(A.U.)

  	Days	T = 25° C.	T = 30° C.	T = 40° C.

  	0	3.1118	2.9853	2.7592
  	0	3.0046	2.7807	2.7297
  	15	3.1118	2.9853	2.7592
  	15	3.0046	2.7807	2.7297
  	57	3.0515	2.9714	2.5663
  	57	2.9727	2.8054	2.3863
  	130	2.7753	2.6868	2.3288
  	130	2.7006	2.6237	2.0991
  	note:
  	P0 measurements are not available and P15 measurements were therefore reported at P0

• These data fit an exponential curve which is shown inFIG. 14.
• The values recorded up to 130 days indicate that the oxidized color is acceptable after 3 months at the three temperatures and that the six months stability of the oxidized blue color will most likely be reached at the three storage temperatures,
EXAMPLE 5
• An indigo carmine indicator mixture was made as follows:
• 20 g indigo carmine, 75 g tetrasodium pyrophosphate, 4.0 g anhydrous dextrose and 180 g microcrystalline cellulose were added to one liter of distilled water. 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.
• When similar packages were exposed to oxygen after being first placed in a reduced state as described above, the mixture changed to the oxidized form, i.e. dark blue color. The mixture remained dark blue after storage for 112 days at 50° C.
• Spectrographic analysis was conducted on the oxidized form of this indicating mixture (20 g/L) in the same manner described with regards to the formulation with 14 g/L indigo carmine and the results are shown in the following table:

  	Formulation with 20 g/l
  	Optical density @ 610 nm
  	(A.U.)

  	Days	T = 25° C.	T = 30° C.	T = 40° C.

  	0	3.434	3.473	3.465
  	7	3.4463	3.5024	3.6194
  	51	3.5678	3.5471	4.0000
  	124	3.5293	3.5593	4.0000

  After 1/10dilution

  	0	0.606	0.683	0.634
  	7	0.613	0.562	0.620
  	51	0.731	0.711	0.646
  	124	0.631	0.626	0.572

• The results are also represented graphically inFIG. 15.
• According to the absorbance data 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. When 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.
EXAMPLE 6
• Long term stability studies were then conducted to show that the indicators would function over the desired shelf life of the products which would be employing the indicator. Two liters of a 14 g/L indigo carmine indicator and a 20 g/L indigo carmine indicator formulation were made to determine indicator activity and color degradation. The 14 g/L formulation was made by dissolving 120 g of sodium pyrophosphate in 2000 ml of water. In this solution 28 g of indigo carmine was added followed by 5 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. 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.
• Half of the samples or each lot were exposed to oxygen by piercing the overpouch using a 21 G needle to create a pinhole. The all these indicators in these exposed samples then turned blue.
• All of the samples were divided and stored in controlled climatic rooms. One of the rooms was maintained at 25° C., and 40% relative humidity, a second room was maintained at 30° C., 35% relative humidity, and a third room was maintained at 40° C., 25% relative humidity. These rooms were maintained at these conditions with a tolerance of ±2° C. for temperature and ±5% for relative humidity. Samples maintained at 40° C. were tested at 0, 2, 4, 6 months and samples in the 25° C. and 30° C. rooms were tested at 0, 2, 4, 6, 9, 12, 15, months for each storage condition. The samples were visually inspected and categorized at the closest Pantone® reference via the Pantone® formula guide—solid coated (second edition 2004) for each period and at each temperature. At each testing period 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.
• In summary, at 40 C and 6 months all of the samples of oxygen indicators performed as desired. All of the exposed samples continued to display a bluish color sufficient to indicate the presence of oxygen. All of the non-exposed samples displayed the yellowish color to indicate the absence of oxygen. When the overpouch was pierced, all of the now exposed, non-exposed samples changed to the bluish color sufficient to indicate the presence of oxygen. After 6 months the testing at 40 C was concluded.
• Similar results were found in the samples kept at 25 C and 30 C at the 2, 4, 6, 9, 12, 15 month intervals. Exposed samples continued to display a color indicating the presence of oxygen and non-exposed sample continued to display a color indicating the absence of oxygen. When the non-exposed samples were then exposed to oxygen by penetration of the overpouch with a needle, the samples changed colors to indicate the presence of oxygen within 67 hours.
• The results are shown inFIGS. 16, 17 and18. which indicate the reduced color of the oxygen units, did not vary significantly after 6 months storage under any of the storage conditions tested.
• After sterilization two units per formulation per sterilization cycle (8 units total) were exposed to constant illumination of 2000 lux with TL tube (tube daylight) for 30 days at 25° C., using a light box. The Pantone® references are shown inFIG. 20 which indicate the formulations were not deteriorated by light exposure.
• 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 inFIGS. 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.
• From the foregoing, it will be observed that numerous variations and modifications may be effected without departing from the spirit and scope of the invention. It is to be understood that no limitation with respect to the specific apparatus illustrated herein is intended or should be inferred. It is, of course, intended to cover by the appended claims all such modifications as fall within the scope of the claims.

Claims (21)

1. An oxygen indicator for detecting the presence of oxygen in medical container, the oxygen indicator comprising:

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.

2. The oxygen indicator ofclaim 1 wherein the indigo carmine is present at from about 10 to about 40 g/L, the buffer is a phosphate buffer, and the reducing agent is a reducing sugar.

3. The oxygen indicator ofclaim 2 wherein the indigo carmine is present at from about 14 to about 20 g/L, the buffer is tetrasodium pyrophosphate, and the reducing agent is dextrose.

4. The oxygen indicator ofclaim 3 further including cellulose wherein the tetrasodium pyrophosphate is present at from about 50 to about 80 g/L and dextrose is present at from about 1 to about 5 g/LA.

5. The oxygen indicator ofclaim 4 wherein the tetrasodium pyrophosphate is present at from about 60 to about 75 g/L, the dextrose is present at from about 2.5 to about 4 g/L and the cellulose is a water insoluble cellulose present at about 180 g/L.

6. The oxygen indicator ofclaim 5 further includes an oxygen permeable packet housing an amount of the oxygen indicator, the oxygen indicator including about 14 g/L of indigo carmine, about 60 g/L of tetrasodium pyrophosphate, about 2.5 g/L of dextrose, about 180 g/L of water insoluble cellulose and water.

7. The oxygen indicator ofclaim 5 further including an oxygen permeable packet housing an amount of the oxygen indicator, the oxygen indicator including about 20 g/L of indigo carmine, about 75 g/L of tetrasodium pyrophosphate, about 4 g/L of dextrose, about 180 g/L of water insoluble cellulose and water.

8. The oxygen indicator ofclaim 7 wherein the oxygen permeable packet is adhered to a multiple chamber container having frangible barriers separating the multiple chambers, each chamber housing a component of a nutritional formulation for fluid restricted patients, one of the components including cysteine.

9. An oxygen indicating packet for detecting the presence of oxygen in a medical container, the oxygen indicating packet comprising:

a) 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.

10. The oxygen indicating packet ofclaim 9 wherein the indigo carmine is present at from about 9 to about 30 g/L, the buffer is a phosphate buffer, the reducing agent is a reducing sugar, and the binder is cellulose.

11. The oxygen indicating packet ofclaim 10 wherein the indigo carmine is present at from about 14 to about 20 g/L, the buffer is tetrasodium pyrophosphate, the reducing agent is dextrose and the binder is water insoluble cellulose.

12. The oxygen indicating packet ofclaim 11 wherein the tetrasodium pyrophosphate is present at from about 50 to about 80 g/L, the dextrose is present at from about 1 to about 5 g/L and the water insoluble cellulose is present at from about 150 to about 210 g/L.

13. The oxygen indicating packet ofclaim 12 wherein the tetrasodium pyrophosphate is present at from about 60 to about 75 g/L, the dextrose is present at from about 2.5 to about 4 g/L and the water insoluble cellulose present at about 180 g/L.

14. The indicating packet ofclaim 13 wherein an amount of the oxygen indicator is housed in an oxygen permeable polymeric pouch having a transparent portion, the oxygen indicator including about 14 g/L of indigo carmine, about 60 g/L of tetrasodium pyrophosphate, about 2.5 g/L of dextrose, about 180 g/L of water insoluble cellulose and water.

15. The oxygen indicator ofclaim 14 wherein an amount of the oxygen indicator is housed in an oxygen permeable polymeric pouch having a transparent portion, the oxygen indicator including about 20 g/L of indigo carmine, about 75 g/L of tetrasodium pyrophosphate, about 4 g/L of dextrose and about 180 g/L of water insoluble cellulose.

16. An oxygen indicator comprising:

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.

17. The oxygen indicator ofclaim 16 wherein the indigo carmine is present at from about 9 to about 30 g/L, the buffer is a phosphate buffer, and the reducing agent is dextrose and cellulose.

18. The oxygen indicator ofclaim 17 wherein the indigo carmine is present at from about 14 to about 20 g/L, the buffer is tetrasodium pyrophosphate present at from about 50 to about 80 g/L, the dextrose is present at from about I to about 5 g/L and the cellulose is present at from about 150 to about 210 g/L.

19. The oxygen indicator ofclaim 18 wherein the tetrasodium pyrophosphate is present at from about 60 to about 75 g/L, the dextrose is present at from about 2.5 to about 4 g/L and the cellulose is a water insoluble cellulose present at about 180 g/L.

20. The oxygen indicator ofclaim 19 further including an oxygen permeable polymeric packet having a transparent portion and housing an amount of the oxygen indicator, the oxygen indicator including about 14 g/L of indigo carmine, about 60 g/L of tetrasodium pyrophosphate, about 25 g/L of dextrose, about 180 g/L of water insoluble cellulose and water.

21. The oxygen indicator ofclaim 19 further including an oxygen permeable polymeric packet having a transparent portion and housing an amount of the oxygen indicator, the oxygen indicator including about 20 g/L of indigo carmine, about 75 g/L of tetrasodium pyrophosphate, about 4 g/L of dextrose, about 180 g/L of water insoluble cellulose and water.

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