US 2010.0143419A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0143419 A1 McAffer et al. (43) Pub. Date: Jun. 10, 2010

(54) STORAGE OF CONTAINING (86). PCT No.: PCT/GBO8/OOOT6 PHARMACEUTICAL FORMULATIONS USING ASEALED S371 (c)(1), COMPRISING AN OXYGEN SCAVENGER (2), (4) Date: Nov. 24, 2009 (30) Foreign Application Priority Data (75) Inventors: Ian Gardener, Cameron McAffer, Tatsfield (GB); Peter Ernest Tasko, Jan. 9, 2007 (GB) ...... O7OO380.9 Tatsfield (GB) Publication Classification Correspondence Address: (51) Int. Cl. STERNE, KESSLER, GOLDSTEIN & FOX P.L. A6IR 9/00 (2006.01) L.C. A63L/439 (2006.01) 1100 NEW YORKAVENUE, N.W. A6IP II/08 (2006.01) WASHINGTON, DC 20005 (US) A6IP II/06 (2006.01) (52) U.S. Cl...... 424/400: 514/299 (73) Assignee: Breath Ltd, Tatsfield (GB) (57) ABSTRACT (21) Appl. No.: 12/522,680 Ampoules made of plastics material and containing 0.5 to 5 ml of a pharmaceutical formulation are sealed, together with (22) PCT Filed: Jan. 9, 2008 an oxygen scavenger, within a pouch. US 2010/0.143419 A1 Jun. 10, 2010

STORAGE OF AMPOULES CONTAINING production costs and times and the efficiency of nitrogen PHARMACEUTICAL FORMULATIONS entrapment within the pouch varies and is not totally efficient USING ASEALED CONTAINER 0007 An object of the present invention is to solve or at COMPRISING AN OXYGEN SCAVENGER least ameliorate the above-identified issues. An object of pre ferred embodiments of the invention is to provide alternative, FIELD OF THE INVENTION more preferably improved methods of storing ampoules within sealed and to provide alternative, prefer 0001. The present invention relates to the sealing of con ably improved sealed containers containing ampoules. tainers which can be used for storage of ampoules containing pharmaceutical formulations, and in particular to sealing SUMMARY OF THE INVENTION ampoules within a pouch to reduce or prevent oxidation of the formulations over time. The invention relates also to the 0008. The invention is based on the use of an oxygen sealed containers, in particular containing such ampoules. Scavenger to reduce or prevent oxidation of formulations within ampoules sealed within containers. 0009. In a first aspect, the invention provides a sealed BACKGROUND TO THE INVENTION container comprising (i) one or more ampoules containing up 0002 Pharmaceutical formulations are presented in a vari to 10 ml of a pharmaceutical formulation and (ii) an oxygen ety of different packaging, including packaging made of Scavenger. 0010 Preferably, the one or more ampoules are made of , metal, plastic and natural materials. For liquid formu plastics material. Also preferably, the ampoules contain an lations, e.g. solutions or Suspensions, the packaging must be inhalation pharmaceutical. The one or more ampoules and the and remain sealed to prevent leakage. However, a number of oxygen Scavenger are sealed within the container. In some technical and practical difficulties exist with all such contain embodiments the container material comprises a metal or CS. metal compound, for example as a on or incorporated 0003. It is known to administer drugs to the lungs of a patient using a nebuliser, allowing a patient to administer the into an outside Surface. drug whilst breathing normally. The drugs are provided in a 0011. In a preferred embodiment of the invention the con unit dose (UDA), containing a relatively small Vol tainer is a pouch. ume, typically 1 mL-5 mL, of Solution and typically made of 0012. In a second aspect, the invention provides a method plastics material. A method of making ampoules is by Blow of reducing oxidative degradation of the content of an Fill-Seal (BFS), under aseptic conditions, in which the ampoule, the method comprising sealing the ampoule in a ampoule is formed by extrusion and filled with solution in a container containing an oxygen Scavenger. multi-part but essentially one-step process. If necessary, and 0013. In a third aspect, the invention provides a method of provided the contents are not heat labile, heat sterilization can reducing moisture egress from a container, the method com be used, e.g. ampoules can be sterilised by terminal sterilisa prising sealing the container in a pouch containing an oxygen tion methods, i.e. after the ampoule has been filled and sealed. Scavenger. These methods are well established and accepted by regula 0014. In a fourth aspect, the invention provides a method tory authorities worldwide. of sealing an ampoule wherein one or more ampoules are 0004. A known problem with existing ampoules is that sealed within a pouch containing an oxygen scavenger. they allow oxygen, other gases and other Volatile compounds 0015. In a fifth aspect, the invention provides an ampoule into the ampoule and allow water (moisture) to exit. Testing of made of plastics material, wherein the ampoule is sealed the contents has revealed that, during storage, contaminants within a pouch containing an oxygen scavenger. can pass through the plastic of ampoule walls and be absorbed 0016. In a sixth aspect, the invention provides the use of an into the formulation. As one specific example, unacceptable oxygen scavenger to reduce or prevent oxidation of formula amounts of vanillin have been found inside ampoules, leading tions within one or more ampoules sealed within a container. to failure of the product and refusal of regulatory authorities to licence the ampoules without safeguards against this exter DETAILED DESCRIPTION OF THE INVENTION nal contamination. 0017. The invention provides a package made up of an 0005. The US FDA has recently required that ampoules be ampoule wrapped within a container (e.g. a pouch) compris over-wrapped by a sealing pouch to avoid environmental ing an oxygen Scavenger. The invention also provides 5, 10. contamination of the ampoule contents. The pouch material is 2030 or more ampoules sealed with the oxygen Scavenger typically a tri-laminate of and/or polymer, aluminium within the container, the ampoules conveniently being in a and low density (LDP). This pouch is regarded strip. Alternatively, individual ampoules or a combination of as an acceptable solution but the contents are still Susceptible one or more strips and one or more individual ampoules may to oxidation over time. This is particularly an issue with drug be sealed within the container. In use the presence of the formulations containing oxygen sensitive materials. oxygen scavenger is found to significantly reduce the oxygen 0006. It is known to carry out the blow-fill-seal method of content within the container, reducing oxidation of the making and fillingampoules using nitrogen rather than sterile ampoule contents over time and also improving the stability air during as many steps as possible in the process. Nitrogen of the ampoule contents. can be used to cap the Solution in the ampoule. Nitrogen can 0018 When a strip of ampoules is sealed within a con be introduced into the pouch at the time the ampoules are tainer and the container is opened to detach one ampoule from sealed inside the pouch. It is, however, a problem that using the strip the remaining ampoules will be exposed to the air. nitrogen in this process requires specialised equipment or However, this may not be a significant problem as oxidation modification of existing equipment. Health and safety pre of the contents of the ampoules only occurs after exposure to cautions associated with the use of nitrogen tend to increase air over a relatively extended period of time compared to time US 2010/0.143419 A1 Jun. 10, 2010 in storage and the ampoules within the open container would typically all be used before significant oxidation could occur. 0019. In one particular embodiment of the invention the container is re-sealable, allowing a single ampoule to be Time O. content within foil removed by the user. The container is then closed to again O hours 19.9% form a sealed container with the oxygen scavenger still in 16 hours 566 ppm 23 hours 435 ppm place. This will act to remove oxygen that entered the pouch 8 days Oppm while it was open and to “mop up' any further oxygen that 14 days Oppm may diffuse into the pouch. Accordingly, the lower oxygen 28 days Oppm content of the container results in reduced oxidation of the 84 days Oppm contents of the remaining ampoules over time. 0020. In particularly preferred embodiments the container 0031. A control package with no oxygen scavenger mea may comprise a pouch wherein the pouch material typically comprises a metal or metal compound and in Some embodi sured 20.5% O at 8 days. ments may comprise a tri-laminate. A typical tri-laminate composition may comprise paper and/or polymer, aluminium Example 2 and low density polyethylene. 0032. This study was designed to demonstrate the effec 0021. In a preferred embodiment of the invention the tiveness of oxygen Scavengers in preventing degradation of pouch is gas impermeable. the product, thereby reducing the impurity levels present in 0022. The ampoules typically comprise or are made of the solution after storage. plastics material, especially or polyethylene, 0033. The solutions for nebulisation were manufactured in low or high density or other polymer used in manufacture of 3 ml LDPE ampoules using blow-fill-seal technology. The ampoules or in the drinks industry, e.g. polyethylene tereph strips of 5 were then sealed in a foil over wrap to prevent water thalate. Further, the ampoules typically contain a pharmaceu loss from and external contamination of the product. tical agent, such an inhalation or injection drug, in combina 0034. One batch of Levalbuterol/Ipratropium Bromide tion with a pharmaceutically acceptable carrier. Solution for Nebulisation (1.25 mg/0.5 mg/2 ml) combina 0023. In preferred embodiments of the invention tion product was manufactured in 2006. Two sublots of this ampoules are made of plastics material. batch were produced and labelled Sublot 1 (ampoules were 0024. Theampoules described herein may typically have a sealed in a foil pouch containing an oxygen Scavenger) and volume of up to 10 ml, preferably 0.5 ml or more, or 1 to 5 ml. Sublot 2 (ampoules were sealed in a standard foil pouch) For example, the ampoules may contain 2 to 4 ml of an stored for 12 months and then tested as set out below. inhalation pharmaceutical. 0035. The related substance data summarised below is for 0025. In preferred embodiments the ampoules contain 1 product that has been stored for 12 months at 25°C./60% RH. ml or more or 2-3 ml of an inhalation pharmaceutical in a pharmaceutically acceptable carrier. 0026. The oxygen scavenger as used in the invention is generally a commercially available or as used Batch 04906A and approved by the food industry. These oxygen Scavengers Subot 1 Sublot 2 (No do not contain leachables thereby avoiding contamination of (Oxygen Scavenger) Oxygen Scavenger) the product with which they are stored. 0027. The size of oxygen scavenger is typically in the Known impurities: range of 20 to 2000 cc, indicating the Volume of oxygen it can H-Tropic acid O.04% O.09% absorb, preferably 20 to 1000 cc, more preferably 20 to 500 Apo-Ipratropium Below detectable O.O.3% cc. In one embodiment of the invention a 50 cc packet is used. levels Notwithstanding this, it will be apparent to the skilled person Bis Ether Salbutamol O.15% 0.13% that the size and capacity of the oxygen scavenger used can be Total known impurities O.19% O.25% varied depending upon the size of the container, the number Largest unknown impurity O.11% O.19% of ampoules within the container, and the collective volume Total unknown impurties O.15% O.25% of the ampoules. Total Impurities O.34% O.S.0% 0028. The following examples are provided in support of the invention. The content of the examples are for illustration 0036. It can be seen that the impurity levels detected in the only and are not intended to limit the scope of the invention in product packaged with the oxygen scavenger were in general any way. 25-40% lower than those observed in product packaged with out the oxygen scavenger. Total impurity levels showed a Example 1 30% reduction when the oxygen Scavenger was present in the pouch. 0029 Packages were prepared each containing one 4-am 0037. This study supports the hypothesis that oxygen poule card and one Fresh Pax D-50 oxygen Scavenger packet scavengers placed within the foil pouch improve the stability (MultiSorb) and sealed infoil. The packages were prepared in profile of Solutions for nebulisation in ampoules. normal atmospheric conditions and contained air when sealed. Example 3 0030 The oxygen scavenging data was analysed at timed intervals using a Mocon Head Space Analyzer, the results of 0038. This study was designed to demonstrate the effec which can be seen below: tiveness of oxygen Scavengers in generating and maintaining US 2010/0.143419 A1 Jun. 10, 2010 an oxygen-free environment when ampoules are stored inside 1. A sealed container comprising a plurality of ampoules a foil pouch containing an oxygen Scavenger. containing up to 10 ml of a pharmaceutical formulation and 0039 Ampoules were manufactured using blow-fill-seal an OXygen Scavenger. technology in normal atmospheric conditions and contained 2. The container of claim 1, wherein the ampoules contain only air when sealed. Packages were prepared each contain a solution of an inhalation pharmaceutical in a pharmaceuti ing four empty ampoules sealed within an aluminium pouch cally acceptable carrier. containing one Fresh Pax D-50 oxygen Scavenger packet 3. The container of claim 1, wherein the ampoules are made (MultiSorb). of plastics material and are manufactured by the blow-fill-seal 0040. The packages were prepared in normal atmospheric method. conditions and the oxygen content of air inside the pouches 4. (canceled) and ampoules on sealing was 20.5%. The packages were 5. The container of claim 1, containing 10 or more stored for 18 months and then tested as set out below. Oxygen ampoules. content inside each pouch and inside two ampoules from each 6. The container of claim 1, wherein the oxygen Scavenger pouch was measured following internal protocols SAP 392. can absorb 20 to 2000 cc of oxygen. 01 and SEP 156.01. 7. The container of claim 1, wherein the container is made 0041 A Systech Gaspace Advance Oxygen Micro Head of material comprising a metal or metal compound. space Analyser was used to measure oxygen content. The 8. The container of claim 1, wherein the container is made Gaspace instrument was calibrated with a certified gas con of material comprising aluminum. taining 2.00% of oxygen and was also calibrated with ambi 9. The container of claim 1, wherein the container is re ent air. The oxygen concentration in the headspace of the sealable. pouches and the ampoules was measured using a Timed 10. The container of claim 1, wherein the container is a method. A test time of 45 seconds was used. A self- pouch. septum was affixed to the pouch and plastic ampoule to ensure 11. A method of reducing oxidative degradation of the a good seal was obtained when sampling. contents of a plurality of ampoules containing up to 10 ml of 0042. The oxygen headspace results are presented in the a pharmaceutical formulation, comprising sealing the following table: ampoules in a container containing an oxygen scavenger. 12. The method of claim 11, wherein the ampoules contain a solution of an inhalation pharmaceutical in a pharmaceuti Oxygen Concentration in Aluminium Oxygen Concentration in Plastic cally acceptable carrier. Pouches (molar% + SD) n = 3 Ampoules (molar % it SD) n = 6 13. The method of claim 11, wherein the ampoules are OOOOOO 4.99 - 3.85 made of plastics material manufactured by the blow-fill-seal method. 14. (canceled) 0043. It can be seen that oxygen was completely removed 15. The method of claim 11, wherein the container com from the pouches while the ampoules showed a 76% reduc prises 10 or more ampoules. tion in oxygen content. 16. The method of claim 11, wherein the oxygen scavenger 0044. In conclusion, the presence of the oxygen scavenger can absorb 20 to 2000 cc of oxygen. within the pouches appeared to draw oxygen out of the pouch 17. The method of claim 11, wherein the container is made and out of the headspace of the ampoule. Surprisingly, these of material comprising a metal or metal compound. results contrasted with the findings of previous internal stud ies which have shown that in pouches purged with nitrogen 18. The method of claim 11, wherein the container is made and not containing an oxygen scavenger there was no equili of material comprising aluminum. bration of oxygen concentration between the headspace of the 19. The method of claim 11, wherein the container is re ampoule and the interior of the pouch (data not shown). One sealable. possible explanation for the equilibration observed in the 20. The method of claim 11, wherein the container is a present study is that the oxygen Scavenger acts as a driving pouch. force towards equilibrium between the two environments. 21. (canceled) 0045 Total equilibrium may have been achieved between 22. (canceled) the ampoules and the pouches in this study following a longer 23. A sealed pouch comprising: storage period or, alternatively, by using a larger oxygen (i) 5 or more plastic ampoules containing up to 5 ml of an Scavenger. Of course, the ampoules used in this study were inhalation pharmaceutical in a pharmaceutically accept completely filled with air and thus contained significantly able carrier and more oxygen than ampoules filled with actives would con (ii) an oxygen Scavenger, tain. It is possible that due to their lower oxygen volume wherein the pouch is made of material comprising a metal or ampoules filled with actives would reach total equilibrium a metal compound and the oxygen Scavenger can absorb 20 to under the conditions of the present study. 2,000 cc of oxygen. 0046. The invention hence provides sealed containers con taining ampoules and methods of obtaining the same.