GB2620382A - Container - Google Patents
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- Publication number
- GB2620382A GB2620382A GB2209645.7A GB202209645A GB2620382A GB 2620382 A GB2620382 A GB 2620382A GB 202209645 A GB202209645 A GB 202209645A GB 2620382 A GB2620382 A GB 2620382A
- Authority
- GB
- United Kingdom
- Prior art keywords
- container
- inhalation formulation
- liquid inhalation
- cop
- liquid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 238000009472 formulation Methods 0.000 claims abstract description 121
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- 238000012384 transportation and delivery Methods 0.000 claims abstract description 10
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- 239000008186 active pharmaceutical agent Substances 0.000 claims description 24
- 229930003827 cannabinoid Natural products 0.000 claims description 13
- 239000003557 cannabinoid Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 12
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- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 125000003367 polycyclic group Chemical group 0.000 claims description 6
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- CDOOAUSHHFGWSA-OWOJBTEDSA-N (e)-1,3,3,3-tetrafluoroprop-1-ene Chemical compound F\C=C\C(F)(F)F CDOOAUSHHFGWSA-OWOJBTEDSA-N 0.000 claims description 5
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 claims description 5
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- NPNPZTNLOVBDOC-UHFFFAOYSA-N 1,1-difluoroethane Chemical compound CC(F)F NPNPZTNLOVBDOC-UHFFFAOYSA-N 0.000 claims description 4
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- FXRLMCRCYDHQFW-UHFFFAOYSA-N 2,3,3,3-tetrafluoropropene Chemical compound FC(=C)C(F)(F)F FXRLMCRCYDHQFW-UHFFFAOYSA-N 0.000 claims description 3
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- 230000000007 visual effect Effects 0.000 description 4
- DITBWPUMEUDVLU-UHFFFAOYSA-N 1h-indazole-3-carboxamide Chemical class C1=CC=C2C(C(=O)N)=NNC2=C1 DITBWPUMEUDVLU-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
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- ZPNWJGPRXXTUNI-UHFFFAOYSA-N 1-(1h-indol-2-yl)-2-phenylethanone Chemical class C=1C2=CC=CC=C2NC=1C(=O)CC1=CC=CC=C1 ZPNWJGPRXXTUNI-UHFFFAOYSA-N 0.000 description 2
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- CRSBERNSMYQZNG-UHFFFAOYSA-N 1-dodecene Chemical compound CCCCCCCCCCC=C CRSBERNSMYQZNG-UHFFFAOYSA-N 0.000 description 2
- UAJRSHJHFRVGMG-UHFFFAOYSA-N 1-ethenyl-4-methoxybenzene Chemical compound COC1=CC=C(C=C)C=C1 UAJRSHJHFRVGMG-UHFFFAOYSA-N 0.000 description 2
- GQEZCXVZFLOKMC-UHFFFAOYSA-N 1-hexadecene Chemical compound CCCCCCCCCCCCCCC=C GQEZCXVZFLOKMC-UHFFFAOYSA-N 0.000 description 2
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- KWKAKUADMBZCLK-UHFFFAOYSA-N 1-octene Chemical compound CCCCCCC=C KWKAKUADMBZCLK-UHFFFAOYSA-N 0.000 description 2
- HFDVRLIODXPAHB-UHFFFAOYSA-N 1-tetradecene Chemical compound CCCCCCCCCCCCC=C HFDVRLIODXPAHB-UHFFFAOYSA-N 0.000 description 2
- FAMPSKZZVDUYOS-UHFFFAOYSA-N 2,6,6,9-tetramethylcycloundeca-1,4,8-triene Chemical compound CC1=CCC(C)(C)C=CCC(C)=CCC1 FAMPSKZZVDUYOS-UHFFFAOYSA-N 0.000 description 2
- ZWWRREXSUJTKNN-FUHWJXTLSA-N 2-[(1s,3r)-3-hydroxycyclohexyl]-5-(2-methyloctan-2-yl)phenol Chemical compound OC1=CC(C(C)(C)CCCCCC)=CC=C1[C@@H]1C[C@H](O)CCC1 ZWWRREXSUJTKNN-FUHWJXTLSA-N 0.000 description 2
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
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- PXLDPUUMIHVLEC-UHFFFAOYSA-N [1-(5-fluoropentyl)indol-3-yl]-(2,2,3,3-tetramethylcyclopropyl)methanone Chemical compound CC1(C)C(C)(C)C1C(=O)C1=CN(CCCCCF)C2=CC=CC=C12 PXLDPUUMIHVLEC-UHFFFAOYSA-N 0.000 description 2
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- 239000001257 hydrogen Substances 0.000 description 1
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- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
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- UBMPKJKGUQDHRM-UHFFFAOYSA-N jwh-081 Chemical compound C12=CC=CC=C2N(CCCCC)C=C1C(=O)C1=CC=C(OC)C2=CC=CC=C12 UBMPKJKGUQDHRM-UHFFFAOYSA-N 0.000 description 1
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- NUMHUJZXKZKUBN-UHFFFAOYSA-N methyl 4-ethenylbenzoate Chemical compound COC(=O)C1=CC=C(C=C)C=C1 NUMHUJZXKZKUBN-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001442 methylidyne group Chemical group [H]C#[*] 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
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- 150000002773 monoterpene derivatives Chemical class 0.000 description 1
- 235000002577 monoterpenes Nutrition 0.000 description 1
- 230000003843 mucus production Effects 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- DMHWDSGURMXMGE-FQEVSTJZSA-N n-[(2s)-1-amino-1-oxo-3-phenylpropan-2-yl]-1-(cyclohexylmethyl)indazole-3-carboxamide Chemical compound C([C@@H](C(=O)N)NC(=O)C=1C2=CC=CC=C2N(CC2CCCCC2)N=1)C1=CC=CC=C1 DMHWDSGURMXMGE-FQEVSTJZSA-N 0.000 description 1
- KJNZIEGLNLCWTQ-KRWDZBQOSA-N n-[(2s)-1-amino-3-methyl-1-oxobutan-2-yl]-1-(cyclohexylmethyl)indazole-3-carboxamide Chemical compound C12=CC=CC=C2C(C(=O)N[C@@H](C(C)C)C(N)=O)=NN1CC1CCCCC1 KJNZIEGLNLCWTQ-KRWDZBQOSA-N 0.000 description 1
- ZAGGGZCIFUQHOH-UHFFFAOYSA-N n-[2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]benzimidazol-5-yl]ethanesulfonamide Chemical compound CC(C)(C)C1=NC2=CC(NS(=O)(=O)CC)=CC=C2N1CC1CCC(F)(F)CC1 ZAGGGZCIFUQHOH-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- VAKGBPSFDNTMDJ-UHFFFAOYSA-N naphthalen-1-yl-(1-pentylindazol-3-yl)methanone Chemical compound C1(=CC=CC2=CC=CC=C12)C(=O)C1=NN(C2=CC=CC=C12)CCCCC VAKGBPSFDNTMDJ-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229960004286 olodaterol Drugs 0.000 description 1
- COUYJEVMBVSIHV-SFHVURJKSA-N olodaterol Chemical compound C1=CC(OC)=CC=C1CC(C)(C)NC[C@H](O)C1=CC(O)=CC2=C1OCC(=O)N2 COUYJEVMBVSIHV-SFHVURJKSA-N 0.000 description 1
- DMYGECJTVMCGEP-UHFFFAOYSA-N org 28312 Chemical compound C1=2C(OC)=CC=CC=2C(C(=O)N2CC(C)N(C)C(C)C2)=CN1CC1CCCCC1 DMYGECJTVMCGEP-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- QYZLKGVUSQXAMU-UHFFFAOYSA-N penta-1,4-diene Chemical compound C=CCC=C QYZLKGVUSQXAMU-UHFFFAOYSA-N 0.000 description 1
- 239000003209 petroleum derivative Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
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- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229940113115 polyethylene glycol 200 Drugs 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229940057847 polyethylene glycol 600 Drugs 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 150000003097 polyterpenes Chemical class 0.000 description 1
- ASUAYTHWZCLXAN-UHFFFAOYSA-N prenol Chemical compound CC(C)=CCO ASUAYTHWZCLXAN-UHFFFAOYSA-N 0.000 description 1
- 239000011164 primary particle Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- HJWLCRVIBGQPNF-UHFFFAOYSA-N prop-2-enylbenzene Chemical group C=CCC1=CC=CC=C1 HJWLCRVIBGQPNF-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- GDPRIIMJONZXBY-UHFFFAOYSA-N pyrrolo[2,3-h][1,2]benzoxazine Chemical class C1=NOC2=C3C=CN=C3C=CC2=C1 GDPRIIMJONZXBY-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- OZCYJKDWRUIFFE-UHFFFAOYSA-N rcs-4 Chemical compound C12=CC=CC=C2N(CCCCC)C=C1C(=O)C1=CC=C(OC)C=C1 OZCYJKDWRUIFFE-UHFFFAOYSA-N 0.000 description 1
- 239000002990 reinforced plastic Substances 0.000 description 1
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
- 229960002586 roflumilast Drugs 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- MDJYHWLDDJBTMX-UHFFFAOYSA-N sdb-001 Chemical compound C12=CC=CC=C2N(CCCCC)C=C1C(=O)NC1(C2)CC(C3)CC2CC3C1 MDJYHWLDDJBTMX-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
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- 229930004725 sesquiterpene Natural products 0.000 description 1
- 150000004354 sesquiterpene derivatives Chemical class 0.000 description 1
- 229930002368 sesterterpene Natural products 0.000 description 1
- 150000002653 sesterterpene derivatives Chemical class 0.000 description 1
- 239000003421 short acting drug Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
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- 239000010935 stainless steel Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003535 tetraterpenes Chemical class 0.000 description 1
- 235000009657 tetraterpenes Nutrition 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical compound O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- 229940110309 tiotropium Drugs 0.000 description 1
- 125000005369 trialkoxysilyl group Chemical group 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 229940005782 umeclidinium / vilanterol Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D83/00—Containers or packages with special means for dispensing contents
- B65D83/14—Containers or packages with special means for dispensing contents for delivery of liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant for a product delivered by a propellant
- B65D83/75—Aerosol containers not provided for in groups B65D83/16 - B65D83/74
- B65D83/752—Aerosol containers not provided for in groups B65D83/16 - B65D83/74 characterised by the use of specific products or propellants
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D85/00—Containers, packaging elements or packages, specially adapted for particular articles or materials
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D83/00—Containers or packages with special means for dispensing contents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L23/00—Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers
- C08L23/02—Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers not modified by chemical after-treatment
- C08L23/04—Homopolymers or copolymers of ethene
- C08L23/08—Copolymers of ethene
- C08L23/0807—Copolymers of ethene with unsaturated hydrocarbons only containing more than three carbon atoms
- C08L23/0815—Copolymers of ethene with aliphatic 1-olefins
- C08L23/0823—Copolymers of ethene with aliphatic cyclic olefins
Landscapes
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
Abstract
A container suitable for a liquid inhalation formulation is made of a cyclo-olefin polymer (COP). The COP has a 5-membered ring in the main chain. The invention also relates to a liquid delivery device comprising the container.
Description
CONTAINER
TECHNICAL FIELD
This invention relates to a container for a liquid formulation. In particular, though not exclusively, this invention relates to a container for a liquid inhalation formulation, particularly a pressurised liquid inhalation formulation, wherein the container is made of a cyclo-olefin polymer (COP).
BACKGROUND
Pressurised inhalation formulations, such as soft mist inhaler (SMI) and in particular pressurised metered-dose inhaler (pMDI) products, are generally formulated with pressurised propellants. These are usually fluorinated propellants, like HFA 227 (1,1,1,2,3,3,3-Heptafluoropropane), 134a (1,1,1,2-Tetrafluoroethane) or 152a (1,1-difluoroethane), or the hydrofluoroolefin HF0-1234ze (1,3,3,3-Tetrafluoropropene). Other propellants may be used, such as CO2 or butadiene, for example.
Containers that can withstand the pressures generated by the use of such propellants must be used to contain the pressurised formulations. In addition to being pressure resistant, the containers must be chemically resistant to these propellants, and also to solvents such as ethanol. The containers must also be impermeable to moisture or oxygen from the atmosphere, must not degrade from contact with the active ingredients (e.g. active pharmaceutical ingredients) and excipients used in the formulation, must be heat resistant, and must be chemically inert with low leachables and extractables profiles in order to not introduce foreign compounds in the formulation.
Ideally, the container should be optically transparent (i.e. see-through) to enable visual monitoring of the formulation inside the container, either during the R&D process, or during manufacturing and stability studies of the product (i.e. the container when containing the formulation). It is particularly desirable for the container to be optically transparent when in use by end users, such that end users can check the quantity of formulation remaining, and to therefore act as a usage indicator acting as a dose indicator and/or as a substitute to a dose indicator or counter.
The main hurdle to make an optically transparent pressurised container is to find a material from which to make the container that has all of these properties, i.e. one which can withstand the pressure of the propellants, be compatible with the inhaler formulations, withstand heat, and offer an acceptable leachable and extractables profile, and can be sterilised. European directives on aerosols require that pressurised inhalers be stress-tested at 55 °C ± 5 °C over 2.5 to 3.5 min (Directive No. 2008/47/EC of 08/04/08 amending Council Directive 75/324/EEC). Providing a container with sufficient heat resistance properties, in addition to optical transparency, remains a problem to be solved.
Current pressurised inhaler containers are made of aluminium. Although these containers may have some of the physical properties, such as adequate heat resistance and being sufficiently chemically inert for use with liquid inhalation formulations, they are opaque containers and therefore mask the formulation contained in the container. Transparent containers are generally made of polyethylene terephthalate (PET or PETE), but these containers have limited heat resistance and are not chemically inert to solvents such as ethanol. Some containers are made of plastic coasted glass, but these are fragile, opaque and can only be used with pressurised inhalation formulations with difficulties.
There therefore remains a need for containers for liquid inhalation formulations, particularly for pressurised liquid inhalation formulations, that have suitably high transparency, heat resistance, pressure resistance, and resistance to degradation by contact with chemicals such as solvents, active ingredients, and excipients, and can be sterilised.
SUMMARY OF THE INVENTION
A first aspect of the invention is a container for a liquid inhalation formulation, wherein the container is made of a cyclo-olefin polymer (COP), wherein said COP is a polymer or copolymer comprising repeating units having formula A, formula B, or a mixture thereof: R1 R2 Formula A R1 R2 Formula B wherein R1 and R2 each individually represent a hydrogen atom, a heterocycle, a halogen atom, or a hydrocarbon group, or wherein R1 and R2 may together form a saturated or unsaturated monocyclic or polycyclic ring.
A second aspect of the invention is a liquid delivery device comprising a container for a liquid inhalation formulation according to any preceding claim.
A third aspect of the invention is the use of a container according to the first aspect of the invention for containing a liquid inhalation formulation.
A fourth aspect of the invention is a method of forming a container according to the first aspect of the invention, comprising i) providing a cyclo-olefin polymer (COP), wherein said COP is a polymer or copolymer comprising repeating units having formula A, formula B, or a mixture thereof: R1 R2 Formula A R1 R2 Formula B wherein R1 and R2 each individually represent a hydrogen atom, a heterocycle, a halogen atom, or a hydrocarbon group, or wherein R1 and R2 may together form a saturated or unsaturated monocyclic or polycyclic ring; fi) optionally, softening said COP; and ii) forming the container for a liquid inhalation formulation from said COP by extrusion blow molding, injection blow molding, or injection stretch blow molding.
Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", mean "including but not limited to", and do not exclude other components, integers or steps. Moreover, the singular encompasses the plural unless the context otherwise requires: in particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
Preferred features of each aspect of the invention may be as described in connection with any of the other aspects. Within the scope of this application it is expressly intended that the various aspects, embodiments, examples and alternatives set out in the preceding paragraphs, in the claims and/or in the following description, and in particular the individual features thereof, may be taken independently or in any combination. That is, all embodiments and/or features of any embodiment can be combined in any way and/or combination, unless such features are incompatible.
DETAILED DESCRIPTION OF THE INVENTION
A first aspect of the invention is a container for a liquid inhalation formulation, wherein the container is made of a cyclo-olefin polymer (COP), wherein said COP is a polymer or copolymer comprising repeating units having formula A, formula B, or a mixture thereof: R1 R2 Formula A R1 R2 Formula B wherein R1 and R2 each individually represent a hydrogen atom, a heterocycle, a halogen atom, or a hydrocarbon group, or wherein R1 and R2 may together form a saturated or unsaturated monocyclic or polycyclic ring.
Examples of the heterocycle include pyrrolidine, pyrroline, furan, tetrahydrofuran, thiophene, imidazole, oxazole, thiazole, indole, and the like, including any isomers of these. Additional heterocycles are described, for example, in Alan R. Katritzky, Handbook of Heterocyclic Chemistry, Pergammon Press, 1985, and in Comprehensive Heterocyclic Chemistry, A. R. Katritzky et al., eds, Elsevier, 2d. ed., 1996.
The halogen atom may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
Examples of the hydrocarbon group that may be represented by R1 or R2 include an alkyl group, an alkenyl group, a cycloalkyl group, a cycloalkenyl group, an aromatic hydrocarbon group, and the like. The number of carbon atoms of the hydrocarbon group is preferably 1 to 20, although the number of carbon atoms is not particularly limited.
Examples of the hydrocarbon group that may be represented by R1 or R2 include an alkyl group having from 1 to 20 carbon atoms, such as a methyl group, an ethyl group, an npropyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, and an n-decyl group; a cycloalkyl group such as a cyclopentyl group and a cyclohexyl group; an alkylidene group such as a methylidyne group and an ethylidene group; an alkenyl group such as a vinyl group and a propenyl group; a cycloalkenyl group such as a cyclohexenyl group and a cyclopentenyl group; an alkynyl group such as an ethynyl group and a propargyl group; an aromatic hydrocarbon group such as a phenyl group, 1-naphthyl group, 2-naphthyl group group; and the like.
Each of the hydrocarbon groups that may be represented by R1 or R2 may be substituted or unsubstituted. Where R1 or R2 are a substituted hydrocarbon, it is meant that the hydrocarbon group comprises at least one further substituent that does not consist solely of carbon and/or hydrogen. Examples of such a substituent include a halogen atom, a silicon atom, an oxygen atom, or a nitrogen atom; an alkoxy group such as a methoxy group and an ethoxy group; a hydroxy group; a hydroxyalkyl group such as a hydroxymethyl group and a 2-hydroxyethyl group; a carboxy group; an alkoxycarbonyl group such as a methoxycarbonyl group and an ethoxycarbonyl group; a cyano group; a trialkylsilyl group such as a trimethylsilyl group; a trialkoxysilyl group such as a trimethoxysilyl group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; and the like.
The COP may be a copolymer comprising repeating units having Formula A, Formula B, or a mixture thereof, and further comprising repeating units derived from one or more monomers selected from aromatic vinyl compounds and alpha-olefin compounds.
Examples of the aromatic vinyl compound include styrene; monoalkylstyrene or polyalkylstyrene which may be replaced with a halogen atom such as o-methylstyrene, mmethylstyrene, p-methylstyrene, o,p-dimethylstyrene, o-ethylstyrene, m-ethylstyrene, pethylstyrene, and p-chloromethylstyrene; functional group-containing styrene derivatives such as p-methoxystyrene, p-ethoxystyrene, p-vinylbenzoic acid, methyl p-vinylbenzoate, 4-vinylbenzyl acetate, p-hydroxystyrene, o-chlorostyrene, p-chlorostyrene, and divinylbenzene; vinylnaphthalene; a-substituted styrenes such as a-methylstyrene and 1,1-diphenylethane; and the like.
Examples of the alpha-olefin compound include alpha-olefin compounds having 2 to 20 carbon atoms, such as linear alpha-olefins having 2 to 20 carbon atoms such as ehylene, propylene, 1-butene, 1-pentene, 1-hexene, 1-octene, 1-decene, 1-dodecene, 1-tetradecene, 1-hexadecene, 1-octadecene, and 1-eicosene; diolefins such as 1,4-pentadiene and 1,5-hexadiene; branched alpha-olefins having 4 to 20 carbon atoms such as 4-methyl1-pentene, 3-methyl-1-pentene, 3-methyl-1-butene, and vinylcyclohexane; branched diolefins such as vinylcyclohexene; alpha-olefins having an aromatic ring such as 3-phenylpropylene and 4-phenylbutene; and the like.
These alpha-olefins may be used either individually or in combination of two or more. Of these, linear alpha-olefins having 2 to 12 carbon atoms are preferred, and linear alpha-olefins having 2 to 8 carbon atoms are more preferred, with ethylene being particularly preferred.
Cyclo-olefin polymers (COP) that are suitable for use in containers of the present invention include those available from TOPAS(RTM), JSR Corporation, Mitsui Chemicals, SigmaAldrich(RTM) and Zeon Corporation, such as those made available under the trade names Apel(RTM), Zeonex(RTM) and Zeonor(RTM), in particular TOPAS(RTM) 5013L-10, TOPAS(RTM) 50135-04, TOPAS(RTM) 6013M-07, TOPAS(RTM) 60155-04, TOPAS(RTM) 60175-04, TOPAS(RTM) 80075-04, TOPAS(RTM) 8007X10, TOPAS(RTM) Elastomer E-140, Apel(RTM) APL5014CL, Apel(RTM) APL5014CL(04), Apel(RTM) APL5014KL, Apel(RTM) APL5015AL, Apel(RTM) APL5016SL, Apel(RTM) APL5013VH, Apel(RTM) APL5014XH, Apel(RTM) APL5014BH, Apel(RTM) APL5014DP, Zeonex(RTM) 690R, Zeonex(RTM) 790R, and Zeonor(RTM) 1020R.
The COPs that are for use in the present invention may be synthesised by any method known in the art, e.g. ring-opening metathesis polymerisation (ROMP), radical polymerisation, cationic polymerisation, or vinyl-type polymerisation. Examples of suitable COPs for use in the present invention, and the synthesis thereof, are provided in EP2248839A1, EP1862484A1, and U52017306080A1, each of which are herein incorporated by reference in their entirety.
In the context of the present invention and for the avoidance of doubt, the term "inhalation" as used herein includes nasal delivery to the lungs.
When suitable COPs as hereinbefore described are used in the present invention, the container may be made of a COP having a glass transition temperature (Tg) of 60-170 °C, preferably 75-120 °C, and more preferably 80-105 °C. To be suitable for use as a container for a liquid inhalation formulation (and preferably for use as a container for a pressurised liquid inhalation formulation) as hereinbefore described, a container must be capable of maintaining its structural integrity after heating to a minimum of 50 °C for 6 minutes.
When suitable COPs as hereinbefore described are used in the present invention, the container may be made of a COP having a light transmittance at 3 mm, as measured according to method ASTM D1003, of between 85 and 99%.
ASTM D1003 is an internationally recognised Standard Test Method for Haze and Luminous Transmittance of Transparent Plastics (https:/lwww.c1ocurnenLcenter.corn/standards/shcw/ASTM-D10C)3).
A container as hereinbefore described may preferably be made of a COP having a light transmittance at 3 mm, as measured according to method ASTM D1003, of between 90 and 95%. An advantage of the use of such COPs in the containers as hereinbefore defined is that optical transparency permits the end user to assess the remaining level of liquid inhalation formulation in the container. As such, the container as described herein may itself function as a dose indicator or counter, in the sense that the amount of liquid inhalation formulation present in the container is a visual indicator of the remaining number of doses. Such a container may be used instead of, or in addition to, a standard dose counter.
When suitable COPs as hereinbefore described are used in the present invention, the container may be made of a COP having a melt flow rate of between 5 and 30 g/10 minutes, as measured according to method HS K719 at a temperature of 280 °C under a load of 21.18 N, and preferably between 15 and 25 g/10 minutes. The melt flow rate may be associated with the processability of the COP used, and may affect the degree of variation between containers manufactured using a particular COP. For example, the use of a COP that has a melt flow rate that is outside of this range may result in processing difficulties in the manufacture of containers, and therefore produce unacceptable variation between manufacturing batches of containers. In addition, poor processability may also produce containers that contain imperfections or flaws and hence are less structurally sound, e.g. to heat and/or pressure than containers that are mode from a COP having a melt flow rate that is within this range.
When suitable COPs as hereinbefore described are used in the present invention, the container may be made of a COP having a flexural modulus of between 1800 and 3000 mPa, as measured by a flexural test according to method ASTM D790, and preferably between 2000 and 2200 mPa.
ASTM D790 is an internationally recognised Standard Test Method for Flexural Properties of Unreinforced and Reinforced Plastics and Electrical Insulating Materials (httos://www.document-center.com/standards/show/ASTM-D790).
The container as described herein may, in use, be a primary container. In the context of the present application, a primary container is one which is suitable for containing a formulation, e.g. a liquid formulation, preferably a liquid inhalation formulation and more preferably a pressurised liquid inhalation formulation, and in which the formulation is in contact with the inner walls of the primary container. For the avoidance of doubt, this does not preclude the presence of a coating on the interior walls of the primary container, such that the formulation is in contact with the coated inner walls of the primary container.
The container as described herein may, in use, be a secondary container. In the context of the present application, a secondary container is one which further contains a primary container, wherein the primary container is suitable for containing a formulation, e.g. a liquid formulation, preferably a liquid inhalation formulation and more preferably a pressurised liquid inhalation formulation, and in which the formulation is in contact with the inner walls of the primary container. Thus in this arrangement the formulation is, at least initially, not in contact with the inner walls of the secondary container. In use the secondary container may be pierced, broken, or otherwise deformed such that the formulation is moved from the interior of the primary container to the interior of the secondary container. An example of such an arrangement of a primary container and a secondary container is a "bag in bottle" arrangement, such as that described in U5698849681, U5905042882, and W02020094761A1, each of which are herein incorporated by reference in their entirety.
The container as described herein may have a wall thickness of between 0.8 and 2.0 mm. By "wall thickness" it will be understood that the container comprises walls that define the shape of the container (i.e. which define the edges of the container, and which have an interior surface and an exterior surface), with a hollow interior that is suitable for containing a liquid inhalation. The hollow interior of the container is defined by the interior surface of the walls. The dimension of a first, inner edge to a second, outer edge of the wall is its thickness, i.e. the wall thickness. In containers as described herein, the wall thickness may be between 0.8 and 2.0 mm, e.g. 0.8 mm, 0.9 mm, 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, or 2.0 mm.
In some containers as described herein, the wall thickness at different points of the container may vary. For example, the container may have side walls having a first wall thickness, and a bottom wall having a second wall thickness. The first wall thickness (i.e. the wall thickness of the side walls) may be between 0.8 and 2.0 mm, e.g. 0.8 mm, 0.9 mm, 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, or 2.0 mm. Preferably the first wall thickness (i.e. the wall thickness of the side walls) is between 1.0 and 1.4 mm, more preferably about 1.2 mm. The second wall thickness (i.e. the wall thickness of the bottom wall) may be between 0.8 and 2.0 mm, e.g. 0.8 mm, 0.9 mm, 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, or 2.0 mm. Preferably the second wall thickness (i.e. the wall thickness of the bottom wall) is between 0.8 and 1.0 mm, more preferably about 1.0 mm.
The container as described herein may have an internal volume of between 1 and 150 cm3. The internal volume of the container is defined by the interior face of the walls, i.e. the interior face of the side walls and the bottom walls (generally there will be no top wall, as this end of the container will be open). In the context of internal volume, the uppermost extent of the side walls (i.e. not the end of the side walls that is in contact with the bottom wall) will be used to determine the top face of the container. In other words, the internal volume of the container is the maximum volume of a fluid (e.g. a liquid inhalation formulation) that may be contained in the container.
The container as described herein may have an internal volume of between 5 and 140 cm3, i.e. about 5 cm3, about 10 cm3, about 20 cm3, about 30 cm3, about 40 cm3, about 50 cm3, about 60 cm3, about 70 cm3, about 80 cm3, about 90 cm3, about 100 cm3, about 110 cm3, about 120 cm3, about 130 cm3 or about 140 cm3. Preferably the container as described herein has an internal volume of between 50 and 100 cm3, more preferably between 75 and 95 cm3.
The container as described herein may have a cross section that is circular. That is, the base of the container is substantially circular. An advantage of this circular cross section is that the container is better able to withstand internal pressure, e.g. from a pressurised liquid inhaler formulation, than other shapes.
The container as described herein may further comprise an opening, wherein said opening is configured to cooperate with an inhaler valve, such as (but not limited to) a pressurised metered dose inhaler (pMDI) valve. The opening may be configured to cooperate with a continuous valve or a metered valve.
The container as hereinbefore described may further comprise one or more graduations marked on or embedded in the container. The purpose of such graduations in a container as described herein is that, in combination with the optical transparency of the container that results from the use of appropriate COPs as described herein, they act as a form of dose counter or indicator. By visually comparing a level of a formulation contained in the container, e.g. a liquid inhalation formulation, against the one or more graduations, the user may make a quantitative or semi-quantitative assessment of the amount of formulation, and hence the number of doses, that remain in the container.
The container as described herein may be for, i.e. may be suitable for, a pressurised liquid inhalation formulation. This use case of the container of the present invention may be particularly advantageous, as the use of pressurised liquid inhalation formulations present numerous technical challenges for a container, which have not previously been solved in combination.
Containers for pressurised liquid inhalation formulations must be capable of withstanding the vapour pressure of the propellant used in such a formulation, for example a hydrofluoroalkane (HFA) propellant as previously discussed herein. Previous containers known in the art are made of plastic or plastic-coated glass bottles, or more typically a metal can, for example a stainless steel can or aluminium can which may be anodised, organic coated, such as lacquer-coated and/or plastic coated (see, for example, W000/30608). Such metal cans are not optically transparent, i.e. they are opaque. Glass containers are fragile, and if coated with a layer of plastic to make them fail safe, have reduced optical transparency. Glass containers also require thick walls to withstand the pressure of the propellants, further reducing their optical clarity. In addition, these thick walls mean their geometry makes them unsuitable for most metered valves and manufacturing equipment. They are also very heavy and not suitable for patient use.
Polyethylene terephthalate (PET) containers are in some respects an improvement over metal and glass containers, but because PET has a softening point of about 60 °C, PET containers are not heat resistant. This is a problem as it limits the sterilisation conditions that may be used with such containers to temperatures that are safely below this 60 °C upper limit. PET is also not ethanol resistant, which limits the types of liquid inhalation formulations that may be used with PET containers.
The container as described herein may further comprise an ultraviolet (UV) dye, i.e. the walls of the container may further comprise a UV dye. In the context of the present application, this means a dye that absorbs and/or reflects radiation that degrades the contents of the container. For example, some formulations may be sensitive to (i.e. at least partially degraded by) UV light, visible light, or a combination thereof, e.g. daylight. The purpose of the UV dye is to reduce, preferably minimise, and even more preferably substantially eliminate the degradation of the contents of the container by exposure to such radiation, e.g. daylight.
In an embodiment of the invention, the container as hereinbefore described contains a liquid inhalation formulation. By "liquid inhalation formulation" it will be understood that any liquid formulation that is suitable for inhalation is meant. It will also be understood that "inhalation" in this context includes nasal administration.
The liquid inhalation formulation may comprise one or more of a solution, suspension, lipidic formulation, or a nanosuspension formulation. A "nanosuspension" as used herein refers to a suspension of nanoparticles or nanodroplets in a solvent, such as, for example, a HFA, water, ethanol, or a mixture thereof. The nanosuspension may additionally comprise stabilizing agents, or other compounds. A nanosuspension comprises a poorly water-soluble compound in the form of nanoparticles suspended in a solvent. Such a nanosuspension may be used to enhance the "solubility" (or dispersibility) of a compound that is poorly soluble in a solvent, a lipid media, or both. As a result of this increased solubility, the delivery of a compound in the liquid inhalation formulation may be improved. The terms "suspension" and "dispersion" may be used interchangeably, as they refer to solid particles in a solvent or solvent mixture. An example of a nanosuspension as described herein as a nanoemulsion, such as an oil in water suspension wherein the oil particles are nanoparticles as defined above.
Nanoparticles as used herein are particles having a particle size of below 1000 nm. Nanoparticles in the solvent may be primary particles, or alternatively or additionally may be agglomerated particles composed of smaller particles. The particle size in a nanosuspension may be measured with a laser diffraction analyzer (e.g. Beckman Coulter LS 13320 or Horiba LA-950).
For the avoidance of doubt, the term "nanoparticles" in the context of the present application includes nanodroplets.
The liquid inhalation formulation may comprise water, a hydrofluoroalkane (HFA), a hydrofluoroolefin (HFO), a C2-05 alkene, a natural oil, a mineral oil, a synthetic oil, an alcohol, or mixtures thereof.
In containers as described herein wherein the liquid inhalation formulation comprises a hydrofluoroalkane (HFA), the hydrofluoroalkane (HFA) may be selected from FIFA 227 (1,1,1,2,3,3,3-Heptafluoropropane), FIFA 134a (1,1,1,2-Tetrafluoroethane) or HFA 152a (1,1-difluoroethane). Preferably the hydrofluoroalkane may be HFA 152a (1,1-difluoroethane).
In containers as described herein wherein the liquid inhalation formulation comprises a hydrofluoroolefin (HFO), the hydrofluoroolefin (HFO) may be selected from HFO-1234yf (2,3,3,3-tetrafluoropropene), HFO-1234ze (E) (trans-1,3,3,3-Tetrafluoroprop-1-ene) or HF01234a.
Liquid inhalation formulations, and in particular pressurised liquid inhalation formulations, that comprise an HFA or an HFO present particular technical challenges for containers, as they have relatively high vapour pressures. It is an advantage of the containers described herein that they may be suitable for use with liquid inhalation formulations (e.g. pressurised liquid inhalation formulations) comprising an HFA or an HFO, and have additional desirable properties, such as high heat resistance (which makes them more resistant to high temperature, i.e. >50 °C, sterilisation conditions) and good optical properties such as optical transparency.
The liquid inhalation formulation may, additionally or alternatively, comprise an alcohol, particularly preferably wherein the alcohol is ethanol or methanol. Ethanol may be a useful solvent or cosolvent in liquid inhalation formulations for improving the solubility of compounds that are otherwise insoluble or relatively poorly soluble in e.g. HFAs and/or HFOs. However, ethanol may be incompatible with the materials used in the container or other components of an apparatus containing the container. For example, polyethylene terephthalate (PET) containers are incompatible with ethanol-containing formulations, as ethanol degrades the PET container. It is an advantage of the containers are described herein that they may be used with, or may contain, liquid inhalation formulations (e.g. pressurised liquid inhalation formulations) comprising ethanol, while also having additional desirable properties, such as high heat resistance (which makes them more resistant to high temperature, i.e. >50, preferably >55, most preferably > 60 °C, sterilisation conditions), good optical properties such as optical transparency, and relatively low weight (e.g. in comparison to glass containers).
For the avoidance of doubt, the liquid inhalation formulation described herein may comprise an alcohol, e.g. ethanol, in addition to other solvents, such as one or more HFAs and/or one or more HF0s, water, or any other suitable solvent.
When the liquid inhalation formulation described herein comprises an alcohol, e.g. ethanol, the alcohol may be present in an amount of less than 50% w/w, such as less than 40% w/w, less than 30% w/w, less than 20% w/w, less than 15°A, w/w, less than 10% w/w, less than 5°/a w/w, or less than 1% w/w. For example, the alcohol may be present in an amount of between 0.1 and 50% w/w, such as between 0.5 and 40% w/w, between 1 and 30% w/w, between 2 and 20% w/w, or between 5 and 15°/o w/w. A particularly preferred range is between 0.1 and 15% w/w, e.g. about 0.5% w/w, about 1% w/w, about 5% w/w, about 10% w/w, or about 15°Th w/w.
The container described herein, further comprising a liquid inhalation formulation (e.g. a pressured liquid inhalation formulation), may comprise one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients for use in a liquid inhalation formulation (e.g. a pressured liquid inhalation formulation) are known to the person skilled in the art, and may include (but are not limited to) albumin from human serum, benzoic acid, benzyl alcohol, citric acid monohydrate, citric acid anhydrous, docusate sodium, glycerol, L(+)-ascorbic acid, L-alanine, L-arginine, L-cysteine, L-methionine, Lproline, lecithin, leucin, palmitic acid, Poloxamer 188 (Kolliphor(RTM) 188), polyethylene glycol 200 (PEG 200), polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), polyethylene glycol 600 (PEG 600), polysorbate 80 (Tween-80), Polysorbate 20 (Tween 20), sodium chloride. Excipients may also include processing aids and stabilisers.
Other pharmaceutically acceptable excipients that may be present in the liquid inhalation formulation described herein, in the alternative to or in addition to, preferably in addition to, the pharmaceutically acceptable excipients listed above are natural and synthetic oils, such as vegetable oils and mineral oils. Examples of suitable natural oils include, but are not limited to, sesame oil, olive oil, and vegetable oils. Examples of suitable mineral oils include, but are not limited to, petroleum distillates, liquid paraffin, and any other commercially available substance that is made available under the description "mineral oil".
The container described herein, further comprising a liquid inhalation formulation (e.g. a pressured liquid inhalation formulation), may comprise at least one active pharmaceutical ingredient (API). The at least one active pharmaceutical ingredient (API) may preferably be an anti-inflammatory drug (such as a corticosteroid, or any other steroid), or a bronchodilator (such as a Long-acting beta agonist (LABA) or a long-acting muscarinic receptor agonist (LAMA)) for a patient suffering from asthma or chronic obstructive pulmonary disease (COPD), or combinations thereof.
For example, the liquid inhalation formulation (e.g. a pressurised liquid inhalation formulation) may comprise a combination of active pharmaceutical ingredients such as a first medicament active, or a mixture of medicament actives, that is an anti-inflammatory drug (such as a corticosteroid, or any other steroid), and a second medicament active, or a mixture of medicament actives, that is a bronchodilator (such as a long-acting beta agonist (LABA) or a long-acting muscarinic receptor agonist (LAMA)). The bronchodilator as the active medicament component may be employed for dilating bronchi and bronchioles, and for increasing airflow to the lungs. Furthermore, the anti-inflammatory as the active medicament component may be employed for reducing swelling, decreasing airway sensitivity caused by inflammation and reducing mucus production. A combination of these pharmaceutically active ingredients comprising a bronchodilator and an anti-inflammatory is generally administered to a patient suffering from asthma. It will be appreciated that in combination therapy the different medicament actives typically function synergistically to improve a severity of a given medical condition, such as asthma in the above example, over a period of time of using the said medicament actives.
The container described herein comprising a liquid inhalation formulation (e.g. a pressurised liquid inhalation formulation) may comprise at least one active pharmaceutical ingredient (API) suitable for the treatment of chronic pulmonary obstructive disease (COPD), asthma, cystic fibrosis, pulmonary hypertension, and lung infections. The at least one API may be selected from several classes known to be suitable for the treatment of COPD, including 32-agonists, anticholinergics, methylxanthines, various combination therapies (including bronchodilators with inhaled corticosteroids (ICSs)), and the phosphodiesterase (PDE)-4 inhibitor roflumilast. Examples of combination therapies include 32-agonist/anticholinergic combinations include the combination of the short-acting agents, albuterol and ipratropium; the combination long-acting 132-agonists (LABAs)/long-acting anticholinergics (also called long-acting muscarinic antagonists (LAMAs)) umeclidinium/vilanterol, tiotropium/olodaterol, glycopyrrolate/indacaterol, and glycopyrrolate/formoterol fumarate.
Alternatively or additionally, the container described herein comprising a liquid inhalation formulation (e.g. a pressurised liquid inhalation formulation) may comprise at least one active pharmaceutical ingredient (API) suitable for the treatment of diseases other than lung diseases. For example, the liquid inhalation formulation may be suitable for the systemic delivery, via inhalation, of at least one active pharmaceutical ingredient (API) or a combination of active pharmaceutical ingredients. An example of an active pharmaceutical ingredient (API) that may be included in a liquid inhalation formulation (e.g. a pressurised liquid inhalation formulation) as described herein that is suitable for systemic delivery, via inhalation, for treatment of diseases other than lung diseases, is aspirin (acetylsalicylic acid). The person skilled in the art will be aware of other such molecules that may be delivered via inhalation for systemic delivery for the purpose of treating diseases other than lung disease.
For the avoidance of doubt, the above lists of active pharmaceutical ingredients is merely exemplary and is not limiting. Other APIs may be suitable for use in the liquid inhalation formulations described herein.
The container described herein, further comprising a liquid inhalation formulation (e.g. a pressured liquid inhalation formulation), may further comprise at least one natural or synthetic cannabinoid. The at least one natural or synthetic cannabinoid may comprise 49-THC (tetrahydrocannabinol) and/or CBD (cannabidiol), and/or dronabinol The at least one natural or synthetic cannabinoid may be selected from classical cannabinoids, non-classical cannabinoids, hybrid cannabinoids, aminoalkylindoles, and eicosanoids.
The at least one natural or synthetic cannabinoid may be selected from adamantoylindoles or indazole carboxamides such as 5F-AKB-48, APICA, STS-135; benzimidazoles such as AZ-11713908, AZD-1940; phenylacetylindoles such as JWH-250, RCS-8; cyclohexylphenols such as CP-47,947, CP-55,940; dibenzopyrans such as JWH-051, JWH-056; eicosanoids such as AM-883, AM-1346, 0-585, 0-689; naphtylindenes such as JWH-171, JWH-176; indazole carboxamides such as AB-PINACA, AB-FUBINACA; indazole-3-carboxamides such as AB-CHMINACA, AB-FUBINACA, PX-2, PX-3; indole-3-carboxamides such as CUMYL-BICA, CUMYL-CBMICA, Org 28312, Org 28611; indole-3-carboxylates or aryloxycarbonylindoles such as FDU-PB-22, FUB-PB-22; naphthoylindazoles such as THJ-018, THJ-2201; naphthoylindoles such as AM-1221, AM-2201, JWH-007, JWH-018, JWH-073, JWH-200, JWH-398, WIN-55,212-2; phenylacetylindoles such as1WH-167, JWH-203; pyrazolecarboxamides such as 5F-AB-FUPPYCA, AB-CHFUPYCA; pyrrolobenzoxazines or naphtoylindoles such as WIN 55,212-2; quinolinyl esters or aryloxycarbonylindoles such as PB-22, 5F-PB-22; tetramethylcyclo-propylcarbonylindazoles such as FAB-144; tetramethylcyclo-propylcarbonylindoles such as A-796,260, A-834,735, UR-144, XLR-11, XLR-12, XLR-11.
In addition, the at least one natural or synthetic cannabinoid may be selected from the list including HU-210; AM-694; RCS-4; WIN 48,098; CP-47,497; JWH-018; JWH-019; IN/H-073; JWH-081; JWH-122; JWH-210; AM-2201; JWH-203; JWH-250; RCS-8.
In addition to or in the alternative to the at least one natural or synthetic cannabinoids described herein, preferably in addition to, the liquid inhalation formulation described herein that comprises at least one natural or synthetic cannabinoid may also comprise at least one terpene or terpenoid, preferably at least one terpene. The person skilled in the art is aware of which compounds are classified as terpenes, including isoprene and isoprene derivatives (e.g. prenol and isovaleric acid), monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, triterpenes, sesquarterpenes, tetraterpenes, polyterpenes, and norisoprenoids. Particularly preferred terpenes for use in combination with the at least one natural or synthetic cannabinoid include Beta-caryophyllene, Beta-pinene, Humulene, Limonene, Unaloci, and Myrcene. For the avoidance of doubt, this list of exemplary terpenes is non-limiting.
The container described herein comprising a liquid inhalation formulation (e.g. a pressurised liquid inhalation formulation) may comprise nicotine. The nicotine may be the sole active compound in the liquid inhalation formulation, or may be present in addition to at least one natural or synthetic cannabinoid, and/or at least one active pharmaceutical ingredient (API), and/or one or more pharmaceutically acceptable excipients.
A further aspect of the invention is a liquid delivery device comprising a container for a liquid inhalation formulation (e.g. a pressurised liquid inhalation formulation) as described herein. Suitable liquid delivery devices are known in the art and are described in, for example, EP3993857. The liquid delivery device may be an inhaler for nebulising pharmaceutical liquids, including (but not limited to) being a soft mist inhaler (SMI) or a pressurised metered dose inhaler (pMDI).
A further aspect of the invention is the use of a container as hereinbefore described for containing a liquid inhalation formulation. Preferably the liquid inhalation formulation (e.g. a pressurised liquid inhalation formulation) is a liquid inhalation formulation as hereinbefore described.
A further aspect of the invention is a method of forming a container according to any one of claims 1 to 12, comprising i) providing a cyclo-olefin polymer (COP), wherein said COP is a polymer or copolymer comprising repeating units having formula A, formula B, or a mixture thereof: R1 R2 Formula A R1 R2 Formula B wherein R1 and R2 each individually represent a hydrogen atom, a heterocycle, a halogen atom, or a hydrocarbon group, or wherein R1 and R2 may together form a saturated or unsaturated monocyclic or polycyclic ring; fi) optionally, softening said COP; and ii) forming the container for a liquid inhalation formulation from said COP by extrusion blow molding, injection blow molding, or injection stretch blow molding.
The method may optionally comprise a step of filling the container with a liquid inhalation formulation, e.g. a pressurised liquid inhalation formulation.
EXAMPLES
All sample containers were manufactured by blow moulding of the specified material under controlled environmental conditions.
Each of Materials 1, 2 and 3 are commercially available cyclo-olefin polymers (COPs).
Select properties Material 1 Material 2 Material 3 Glass transition temperature, 136 162 102 Tg (°C) light transmittance at 3 mm, 92 92 92 ASTM D1003 (%) melt flow rate, HS K719 280 17 6 20 °C / 21.18 N (g/10 min) flexural modulus, ASTM D790 2200 2600 2100 (mPa)
Example 1
Small pieces of each of materials 1, 2 and 3 were placed into one glass vial per piece of material. Three glass vials each containing a sample of material 1 were then filled with HFA 134a (1,1,1,2-Tetrafluoroethane). Three glass vials each containing a sample of material 1 were then filled with a solvent mixture comprise 90% w/w HFA 134a (14,1,2-Tetrafluoroethane) and 10% w/w ethanol.
This was repeated separately for each of materials 2 and 3. All eighteen glass vials, each containing a sample of a material and a solvent, were then sealed and left for five days at ambient temperature and pressure.
All glass vials were then visually inspected for any dissolved material. No dissolved material was observed in any of the vials. None of the samples of materials 1, 2 or 3 were observed to have altered in shape or appearance.
All glass vials were then opened, and each of the samples of materials 1, 2 and 3 were examined visually. No sample had become more brittle or lost its visual quality.
This demonstrates that each of materials 1, 2 and 3 are suitable for use with common propellants, e.g. HFA 134a, without the material being damaged at ambient temperature for several days. This is an indication that each material is suitable for use in a container according to the invention.
Example 2
Containers made of material 2 were placed in a temperature control unit at 80 °C / 50% relative humidity. These conditions replicate accelerated storage conditions, and use in extreme environmental conditions. After seven days, the containers were removed from the temperature control unit and examined at ambient temperature.
No changes to the appearance of the containers were observed. The containers were manually squeezed and did not deform.
This demonstrates that containers according to the invention are stable at higher temperatures than conventional containers, which typically are not suitable for heating above about 60 °C.
Example 3
One container made of material 2 was filled with 100°/0 ethanol. Another such container was filled with 100% sesame oil. Both were stored at ambient temperature (i.e. between about 20 to 25 °C) and pressure for 3 weeks. No changes to the appearance of the containers were observed.
This demonstrates that containers according to the invention are compatible with a wider range of solvents (and hence formulations) than conventional containers. Polyethylene terephthalate (PET) containers, for example, are not suitable for use with ethanol, unlike containers according to the invention.
Example 4
Three containers made of material 2 were placed in a temperature control unit at 100 °C / 50% relative humidity. After seven days, the containers were removed from the temperature control unit and examined at ambient temperature.
One container was manually squeezed and did not deform. The optical qualities of the container were also not impaired.
The dimensions (i.e. diameter and overall length) of the containers were taken prior to and after heating for seven days at 100 °C / 50% relative humidity. The containers were left to cool to ambient temperature before the measurements were taken. Measurements were taken using Vernier callipers. The results are shown in Table 1 below. All measurements are in millimetres (mm).
container Length Length Diameter Diameter (before) (after) (before) (after) 1 74.35 74.35 21.84 21.84 2 74.44 74.44 21.78 21.78 3 74.21 74.21 21.81 21.81
Table 1
It can be seen from Table 1 that the length and diameter of each of the containers did not change after heating for seven days at 100 °C / 50% relative humidity. This demonstrates that containers according to the invention are stable at higher temperatures than conventional containers, which typically are not suitable for heating above about 60 °C, to such an extent that their physical dimensions are not altered after prolonged heating at 100 °C.
Example 5
Containers made of material 3 were placed in a temperature control unit at 50 °C / 50% relative humidity. After ten days, the containers were removed from the temperature control unit and examined at ambient temperature.
No changes to the appearance of the containers were observed. The containers were manually squeezed and did not deform.
Example 6
One container made of material 3 was filled with 100% ethanol. Another such container was filled with 100% sesame oil. Both were stored at ambient temperature and pressure for 1 week. No changes to the appearance of the containers were observed.
This demonstrates that containers according to the invention are compatible with a wider range of solvents (and hence formulations) than conventional containers. Polyethylene terephthalate (PET) containers, for example, are not suitable for use with ethanol, unlike containers according to the invention.
Example 7
Four containers made of material 3 were placed in a temperature control unit at 65 °C / 50°/o relative humidity. After three days, the containers were removed from the temperature control unit and examined at ambient temperature.
One container was randomly selected from the four tested and manually squeezed, and did not deform.
The dimensions (i.e. diameter and overall length) of the containers were taken prior to and after heating for three days at 65 °C / 50% relative humidity. The containers were left to cool to ambient temperature before the measurements were taken. Measurements were taken using Vernier callipers. The results are shown in Table 2 below. All measurements are in millimetres (mm).
container Length Length Diameter Diameter (before) (after) (before) (after) 1 74.95 74.95 21.94 21.94 2 74.88 74.88 21.92 21.92 3 74.93 74.93 21.93 21.93 4 74.80 74.80 21.93 21.93
Table 2
It can be seen from Table 2 that the length and diameter of each of the containers did not change after heating for three days at 65 °C / 50% relative humidity. This demonstrates that containers according to the invention are stable at higher temperatures than conventional containers, which typically are not suitable for heating above about 60 °C, to such an extent that their physical dimensions are not altered after prolonged heating at 65 °C.
As an additional test the original four containers plus 4 "fresh" containers were heated at 50 °C / 50% relative humidity for 24 hours. No adverse visual effects were seen in any of the containers.
Example 8
A container made of material 3 was placed in a temperature control unit at 100 °C / 50% relative humidity. After 25 minutes, the container was removed from the temperature control unit and examined at ambient temperature.
The container was manually squeezed and did not deform.
A container made of material 3 was placed in a temperature control unit at 100 °C / 50°/o relative humidity. After 30 minutes, the base of the container was seen to visually distort. After one week at 100 °C / 50% relative humidity, the container was removed from the temperature control unit and examined at ambient temperature.
The container was manually squeezed and did not deform. Example 9 Containers made of material 2 were pressurised until they burst, and the temperature at which each container burst was recorded. The results of this pressure burst testing are shown in Table 3 below.
Burst pressure Number of vials range (bar) burst 0 0 0-5 3 5-10 3 10-15 4 15-20 7 20-25 8 25-30 7 30-35 2 35-40 2 40-45 0 45-50 0 50-55 1 55-60 13
Table 3
In addition, six containers of material 2 were tested to a maximum equipment pressure of 60 bar and held for 60 seconds without bursting.
It can therefore be seen from Table 3 and this additional experiment that containers made of material 2 according to the invention generally have a high tolerance to pressures of above 50 bar.
Example 10
Containers made of material 3 were pressurised until they burst, and the temperature at which each container burst was recorded. The results of this pressure burst testing are shown in Table 4 below.
Burst pressure Number of vials range (bar) burst 0-56 0 56-56.5 1 56.5-57 0 57-57.5 3 57.5-58 1 58-58.5 9 58.5-59 7 59-59.5 7 59.5-60 3 60-60.5 1
Table 4
It can be seen from Table 4 above that all of the containers of material 3 had a burst pressure tolerance of greater than 56 bar. It can also be seen by comparison to Table 3 above, which records the burst pressures of containers of material 2, that there is a much narrower distribution of burst pressures for containers of material 3 compared to those of material 2. That is, containers of material 3 have a more consistent burst pressure resistance profile than those of material 2. It is thought that this more consistent pressure tolerance profile is related to the improved ease of manufacturing of containers of material 3, as there is a reduced number of flaws and faults in containers made of this material that would make the containers less resistant to high pressures.
Example 11
Containers made of material 2 were filled with the following solvents: 1) HFA 134a; 2) HFA 134a + 10% ethanol; 3) HFA 152a; 4) HFA 152a + 10% ethanol.
No adverse effects were seen to the containers. This demonstrates that containers made of material 2 according to the invention are suitable for use with liquid inhalation formulations comprising HFA propellants and HFA propellants in combination with ethanol.
Example 12
Containers made of material 3 were filled with the following solvents: 1) HFA 134a; 2) HFA 134a + 10% ethanol; 3) FIFA 152a; 4) HFA 152a + 10% ethanol; 5) HFA 227b; 6) HFA 227b + 10% ethanol.
No adverse effects were seen to the containers. This demonstrates that containers made of material 3 according to the invention are suitable for use with liquid inhalation formulations comprising a range of HFA propellants and HFA propellants in combination with ethanol.
Claims (29)
- CLAIMS1. A container for a liquid inhalation formulation, wherein the container is made of a cyclo-olefin polymer (COP), wherein said COP is a polymer or copolymer comprising repeating units having formula A, formula B, or a mixture thereof: R1 R2 Formula A R1 R2 Formula B wherein R1 and R2 each individually represent a hydrogen atom, a heterocycle, a halogen atom, or a hydrocarbon group, or wherein R1 and R2 may together form a saturated or unsaturated monocyclic or polycyclic ring.
- 2. The container of claim 1, wherein the COP is a copolymer comprising repeating units having Formula A, Formula B, or a mixture thereof, and further comprising repeating units derived from one or more monomers selected from aromatic vinyl compounds and alpha-olefin compounds.
- 3. The container of claim 1 or claim 2, wherein said COP has a glass transition temperature (Tg) in the range of from 60-170 °C.
- 4. The container of any preceding claim, wherein said COP has a light transmittance at 3 mm, as measured according to method ASTM D1003, in the range of from between 85 and 99%.
- 5. The container of any preceding claim, wherein said COP has a melt flow rate in the range of from between 5 and 30 g/10 minutes, as measured according to method JIS K719 at a temperature of 280 °C under a load of 21.18 N.
- 6. The container of any preceding claim, wherein said COP has a flexural modulus in the range of from between 1800 and 3000 mPa, as measured by a flexural test according to method ASTM D790.
- 7. The container of any preceding claim, wherein said container is a primary container.
- 8. The container of any preceding claim, wherein the container has a wall thickness in the range of from between 0.8 and 2.0 mm.
- 9. The container of any preceding claim, wherein the container has an internal volume in the range of from between 1 and 150 cm3.
- 10. The container of any preceding claim, further comprising an opening, wherein said opening is configured to cooperate with an inhaler valve, preferably a pressurised metered dose inhaler (pMDI) valve.
- 11. The container of any preceding claim, further comprising one or more graduations marked on or embedded in the container.
- 12. The container of any preceding claim, wherein the container is for a pressurised liquid inhalation formulation.
- 13. The container of any preceding claim, wherein said container contains a liquid inhalation formulation.
- 14. The container of claim 13, wherein the liquid inhalation formulation comprises one or more of a solution, suspension, lipidic formulation, or a nanosuspension formulation.
- 15. The container of claim 13 or claim 14, wherein the liquid inhalation formulation comprises water, a hydrofluoroalkane (HFA), a hydrofluoroolefin (HFO), a C2-05 alkene, a natural oil, a mineral oil, a synthetic oil, an alcohol, or mixtures thereof.
- 16. The container of claim 15, wherein the liquid inhalation formulation comprises a hydrofluoroalkane (HFA), wherein the hydrofluoroalkane (HFA) is selected from HFA 227 (1,1,1,2,3,3,3-Heptafluoropropane), HFA 134a (1,1,1,2-Tetrafluoroethane) or HFA 152a (1,1-difluoroethane).
- 17.The container of claim 15, wherein the liquid inhalation formulation comprises a hydrofluoroolefin (HFO), wherein the hydrofluoroolefin (HFO) is selected from HFO1234yf (2,3,3,3-tetrafluoropropene), HFO-1234ze (E) (trans-1,3,3,3-Tetrafluoroprop-1-ene) or HF01234a.
- 18.The container of claim 15, wherein the liquid inhalation formulation comprises an alcohol, wherein the alcohol is ethanol.
- 19.The container of any one of claims 13 to 18, wherein the liquid inhalation formulation comprises one or more pharmaceutically acceptable excipients.
- 20.The container of any one of claims 13 to 19, wherein the liquid inhalation formulation comprises at least one active pharmaceutical ingredient (API).
- 21. The container of claim 20, wherein the at least one active pharmaceutical ingredient (API) is an anti-inflammatory drug (such as a corticosteroid, or any other steroid), or a bronchodilator (such as a Long-acting beta agonist (LABA) or a long-acting muscarinic receptor agonist (LAMA)) for a patient suffering from asthma or chronic obstructive pulmonary disease (COPD), or combinations thereof.
- 22. The container of any one of claims 13 to 21, wherein the liquid inhalation formulation comprises at least one natural or synthetic cannabinoid.
- 23.The container of any one of claims 13 to 22, wherein the liquid inhalation formulation comprises at least one terpene or terpenoid.
- 24. The container of any one of claims 13 to 23, wherein the liquid inhalation formulation comprises nicotine.
- 25. A liquid delivery device comprising a container for a liquid inhalation formulation according to any preceding claim.
- 26. The liquid delivery device of claim 25, being an inhaler for nebulising pharmaceutical liquids.
- 27. The liquid delivery device of claim 25 or claim 26, being a soft mist inhaler (SMI) or a pressurised metered dose inhaler (pMDI).
- 28. Use of a container according to any one of claims 1 to 24 for containing a liquid inhalation formulation.
- 29. A method of forming a container according to any one of claims 1 to 12, comprising i) providing a cyclo-olefin polymer (COP), wherein said COP is a polymer or copolymer comprising repeating units having formula A, formula B, or a mixture thereof: R1 R2 Formula A R1 R2 Formula B wherein R1 and R2 each individually represent a hydrogen atom, a heterocycle, a halogen atom, or a hydrocarbon group, or wherein R1 and R2 may together form a saturated or unsaturated monocyclic or polycyclic ring; fi) optionally, softening said COP; and fi) forming the container for a liquid inhalation formulation from said COP by extrusion blow molding, injection blow molding, or injection stretch blow molding.
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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JPH08299438A (en) * | 1995-04-28 | 1996-11-19 | Tokuyama Corp | Syringe cylinder and medicine filling container |
EP3202389A1 (en) * | 2014-10-02 | 2017-08-09 | Terumo Kabushiki Kaisha | Medical container for accommodating protein solution preparation therein |
JP2022015026A (en) * | 2020-07-08 | 2022-01-21 | 共同印刷株式会社 | Delamination container |
US20220259418A1 (en) * | 2019-06-26 | 2022-08-18 | Kuraray Co., Ltd. | Resin Composition, and Multilayer Structure and Packaging Material Using Same |
CN115073664A (en) * | 2022-07-04 | 2022-09-20 | 广东新华粤石化集团股份公司 | Cycloolefin polymer film with optical anisotropy and preparation method thereof |
EP4067406A1 (en) * | 2019-11-29 | 2022-10-05 | Zeon Corporation | Cyclic olefin polymer, method for producing same, and optical element |
-
2022
- 2022-06-30 GB GB2209645.7A patent/GB2620382A/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08299438A (en) * | 1995-04-28 | 1996-11-19 | Tokuyama Corp | Syringe cylinder and medicine filling container |
EP3202389A1 (en) * | 2014-10-02 | 2017-08-09 | Terumo Kabushiki Kaisha | Medical container for accommodating protein solution preparation therein |
US20220259418A1 (en) * | 2019-06-26 | 2022-08-18 | Kuraray Co., Ltd. | Resin Composition, and Multilayer Structure and Packaging Material Using Same |
EP4067406A1 (en) * | 2019-11-29 | 2022-10-05 | Zeon Corporation | Cyclic olefin polymer, method for producing same, and optical element |
JP2022015026A (en) * | 2020-07-08 | 2022-01-21 | 共同印刷株式会社 | Delamination container |
CN115073664A (en) * | 2022-07-04 | 2022-09-20 | 广东新华粤石化集团股份公司 | Cycloolefin polymer film with optical anisotropy and preparation method thereof |
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