WO2024003503A1 - Plastic container containing an injectable solution of fentanyl - Google Patents
Plastic container containing an injectable solution of fentanyl Download PDFInfo
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- WO2024003503A1 WO2024003503A1 PCT/FR2023/050978 FR2023050978W WO2024003503A1 WO 2024003503 A1 WO2024003503 A1 WO 2024003503A1 FR 2023050978 W FR2023050978 W FR 2023050978W WO 2024003503 A1 WO2024003503 A1 WO 2024003503A1
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- WIPO (PCT)
- Prior art keywords
- fentanyl
- solution
- container according
- container
- terminal sterilization
- Prior art date
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- 229960002428 fentanyl Drugs 0.000 title claims abstract description 68
- 239000004033 plastic Substances 0.000 title claims abstract description 23
- 229920003023 plastic Polymers 0.000 title claims abstract description 23
- 229940102223 injectable solution Drugs 0.000 title claims abstract description 9
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 title abstract description 61
- 239000006172 buffering agent Substances 0.000 claims abstract description 15
- 230000001954 sterilising effect Effects 0.000 claims description 25
- 238000004659 sterilization and disinfection Methods 0.000 claims description 25
- 239000004743 Polypropylene Substances 0.000 claims description 21
- 229920001155 polypropylene Polymers 0.000 claims description 21
- -1 polyethylene Polymers 0.000 claims description 17
- 229920000089 Cyclic olefin copolymer Polymers 0.000 claims description 15
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 claims description 13
- 239000004713 Cyclic olefin copolymer Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000004698 Polyethylene Substances 0.000 claims description 4
- 229960004207 fentanyl citrate Drugs 0.000 claims description 4
- 229920000573 polyethylene Polymers 0.000 claims description 4
- 239000003708 ampul Substances 0.000 claims description 2
- 238000001802 infusion Methods 0.000 claims description 2
- 150000001336 alkenes Chemical class 0.000 claims 1
- 229920005565 cyclic polymer Polymers 0.000 claims 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 68
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000011521 glass Substances 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940060128 fentanyl injectable solution Drugs 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229920005556 chlorobutyl Polymers 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 230000001256 tonic effect Effects 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000002788 crimping Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000000806 elastomer Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002357 osmotic agent Substances 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013097 stability assessment Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000011125 type II (treated soda lime glass) Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Definitions
- the present invention relates to a plastic container containing an injectable solution of fentanyl.
- Fentanyl or N N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenyl-propanamide, is a fat-soluble opioid analgesic first synthesized in the late 1950s. It is approximately 100 times more powerful than morphine.
- Fentanyl is notably marketed in the form of an injectable solution for intravenous (IV) or epidural administration. It is used in neuroleptanalgesia protocols, balanced general anesthesia, and high-dose analgesic anesthesia. Fentanyl can also be used: for post-operative analgesia exclusively in patients subject to intensive medical monitoring (intensive care unit, recovery room), by epidural route, either in isolation, or in combination with local anesthetics.
- Injectable fentanyl solutions are currently marketed at a concentration of 50pg/mL. These solutions contain, in addition to fentanyl, an osmotic agent (sodium chloride) and a pH adjuster (sodium hydroxide). Furthermore, according to the pharmacopoeia (see for example USP Monograph Fentanyl citrate injection), the pH of these solutions can vary from 4 to 7.5.
- injectable fentanyl solutions are exclusively stored and marketed in glass containers.
- the Fresenius company recently put on the market a glass syringe containing a fentanyl solution ready to be injected (Simplist® Fentanyl Citrate Injection).
- the fentanyl solution in this syringe contains 50 pg/ml fentanyl, sodium chloride and sodium hydroxide. Its pH varies from 4 to 7.5. This solution is free of any adjuvant.
- plastic containers especially when it comes to syringes pre-filled with a solution ready to be injected, have a certain number of advantages compared to glass containers.
- plastic containers make it possible to avoid the release of metal ions which is observed with glass containers, they are less fragile and easier to produce/mold, in particular, when it comes to syringes (connectors Luer-Lock type being easier to mold when they are made of polypropylene).
- an injectable solution of fentanyl free of buffering agent was stable in the short, medium and long term when stored in a plastic container, regardless of whether the latter did the subject or not of a terminal sterilization, such a solution notably having a loss of active ingredient of less than 6%, preferably less than 3% after terminal sterilization.
- the subject of the present invention is a plastic container comprising an injectable fentanyl solution whose pH is between 3 and 4.5, said fentanyl solution being free of buffering agent.
- injectable solution means any solution that can be injected parenterally, in particular intravenously (IV), epidural, intramuscular (IM), subcutaneous, or intrathecal, whether it is ready to be injected or requires prior dilution;
- “fentanyl” designates or N N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenyl-propanamide, with CAS number 437-38-7 and chemical structure: as well as its pharmaceutically acceptable salts, in particular its citrate salt (whose CAS number is 990-73-8);
- the term “pharmaceutically acceptable salt” of an active principle is understood to mean any addition salt of said active principle with a mineral or organic acid by the action of such an acid in an organic or aqueous solvent such as an alcohol, a ketone, an ether or a chlorinated solvent, and which is acceptable from a pharmaceutical point of view;
- buffer agent means any compound or combination of compounds making it possible to maintain the pH of a solution at a stable value (+/- 1, preferably +/- 0.5).
- a buffer agent citrate, phosphate, acetate, glutamate, tartrate, benzoate, lactate, malate, gluconate, succinate, aspartate, glycine, TRIS, histidine and HEPES as well as associated salts.
- the present invention therefore relates to a plastic container comprising an injectable solution of fentanyl free of buffering agent whose pH varies from 3 to 4.5.
- the present invention relates to a plastic container comprising an injectable solution of fentanyl having the following characteristics, taken alone or in combination:
- the container is chosen to be a sealed container. More preferably, the container is chosen to be a bottle, an ampoule, an infusion bag or a syringe. Most preferably, the container is chosen to be a syringe;
- the container is made of polyethylene (PE), polypropylene (PP), PVC, cyclic olefin copolymer (COC), or cyclic olefin polymer (COP). More preferably, the container is made of polypropylene, cyclic olefin copolymer (COC) or cyclic olefin polymer (COP). Very preferably, the container is made of polypropylene;
- the fentanyl solution contains from 1 pg/ml to 100 pg/ml of fentanyl. More preferably, the fentanyl solution contains from 5 pg/ml to 100 pg/ml of fentanyl. Most preferably, the fentanyl solution contains 50 ⁇ g/ml of fentanyl;
- the pH of the fentanyl solution is less than 4.5. More preferably, the pH of the fentanyl solution is between 3 and 4. Most preferably, the pH of the fentanyl solution is between 3.5 and 4;
- the fentanyl solution contains a tonic agent. More preferably, the fentanyl solution contains a toning agent chosen from dextrose, glycerin, mannitol, potassium chloride, sodium chloride. Very preferably, the fentanyl solution contains a toning agent chosen to be sodium chloride;
- the fentanyl solution contains a tonic agent in proportions suitable to obtain an isotonic solution whose osmolarity is between 200-400mOsm/kg, preferably between 250-350mOsm/kg.
- the fentanyl solution can thus contain from 1 g/l to 50 g/l of toning agent.
- the solution of fentanyl contains 5 g/l to 10 g/l of sodium chloride or 40 g/l to 50 g/l of glucose; and or
- the volume of the container varies from 1 ml to 500 ml. More preferably, the volume of the container varies from 1 ml to 100 ml. Most preferably, the volume of the container varies from 1 ml to 50 ml.
- the container according to the present invention is obtained by filling with a fentanyl solution as defined above followed by crimping. Preferably, the container thus obtained is then subjected to terminal sterilization.
- This terminal sterilization step is carried out according to any process conventionally used by those skilled in the art. In particular, the terminal sterilization step is carried out in an autoclave, the product being exposed to a temperature of 121°C for at least 15 minutes.
- the fentanyl solution included in the plastic container according to the present invention can be prepared according to any method conventionally used by those skilled in the art.
- a process for preparing a solution as defined above we can in particular cite the process comprising the following steps: introduction and mixing of each of the ingredients of the solution in a given volume of water; pH adjustment; and filtration.
- Example 1 Stability of a fentanyl solution contained in a polypropylene (PP) syringe following terminal sterilization
- the pH is finally adjusted with hydrochloric acid and/or sodium hydroxide.
- the volume is finally made up to 100% with water then the solution is filtered on a 0.22 pm Millipore PVDF disk.
- Polypropylene (PP) syringes or glass vials (GLASS) pre-filled with a fentanyl solution whose characteristics are reported in Table 2 below were prepared according to the process described below.
- a Borealis HD-850MO silicone-coated PP syringe is filled with 5 ml of a fentanyl solution as described above, then capped with an elastomer cap (Aptar chlorobutyl C1797 6422NR 6DDP1). A piston is then added manually.
- a 10 ml type II glass vial is filled with 5 ml of a fentanyl solution as described above, then stoppered with a chlorobutyl stopper (Aptar Stelmi C5394 6422GS 6 DH1).
- the container When the container is subjected to terminal sterilization, it is then placed in an autoclave at 121°C (inside the product using a sample in which a temperature probe is inserted) for at least 15 minutes.
- the containers are then stored at room temperature and protected from light until the analyzes reported in point 1.3 below are carried out.
- the syringes and vials are placed away from light.
- the solutions contained in the syringes and vials prepared above are evaluated visually (color, turbidity and presence of particles) at to (i.e. after preparation and possible terminal sterilization).
- the pH of the solution is measured and the fentanyl concentration of the solution is also evaluated by HPLC.
- the syringes are placed in climatic chambers.
- the solutions contained in the syringes prepared above are evaluated visually (color, turbidity and presence of particles) at to (i.e. after preparation and terminal sterilization), to+1 month and to+3 months after storage away from the light at 25°C and 40°C.
- the pH of the solution is measured and the fentanyl concentration of the solution is also evaluated by HPLC.
Abstract
A plastic container containing an injectable solution of fentanyl having a pH of 3 to 4.5, said solution being devoid of a buffering agent.
Description
CONTENANT EN PLASTIQUE COMPRENANT UNE SOLUTION INJECTABLE DE FENTANYL PLASTIC CONTAINER INCLUDING FENTANYL INJECTABLE SOLUTION
La présente invention a pour objet un contenant en plastique contenant une solution injectable de fentanyl. The present invention relates to a plastic container containing an injectable solution of fentanyl.
Le fentanyl, ou N N-(1-(2-phényléthyl)-4-pipéridinyl)-N-phényl-propanamide, est un analgésique opioïde liposoluble synthétisé pour la première fois à la fin des années 50. Il est environ 100 fois plus puissant que la morphine. Fentanyl, or N N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenyl-propanamide, is a fat-soluble opioid analgesic first synthesized in the late 1950s. It is approximately 100 times more powerful than morphine.
Le fentanyl est notamment commercialisé sous la forme d’une solution injectable pour administration par voie intraveineuse (IV) ou péridurale. Il est utilisé dans les protocoles de neuroleptanalgésie, d'anesthésie générale balancée, d'anesthésie analgésique à doses élevées. Le fentanyl peut également être utilisé: en analgésie post-opératoire exclusivement chez les patients soumis à une surveillance médicale intensive (unité de soins intensifs, salle de réveil), par voie péridurale, soit de façon isolée, soit en association aux anesthésiques locaux. Fentanyl is notably marketed in the form of an injectable solution for intravenous (IV) or epidural administration. It is used in neuroleptanalgesia protocols, balanced general anesthesia, and high-dose analgesic anesthesia. Fentanyl can also be used: for post-operative analgesia exclusively in patients subject to intensive medical monitoring (intensive care unit, recovery room), by epidural route, either in isolation, or in combination with local anesthetics.
Les solutions injectables de fentanyl sont actuellement commercialisées à une concentration de 50pg/mL Ces solutions contiennent, outre le fentanyl, un agent osmotique (chlorure de sodium) et un ajusteur de pH (hydroxyde de sodium). Par ailleurs, selon la pharmacopée (voir par exemple USP Monograph Fentanyl citrate injection), le pH de ces solutions peut varier de 4 à 7,5. Injectable fentanyl solutions are currently marketed at a concentration of 50pg/mL. These solutions contain, in addition to fentanyl, an osmotic agent (sodium chloride) and a pH adjuster (sodium hydroxide). Furthermore, according to the pharmacopoeia (see for example USP Monograph Fentanyl citrate injection), the pH of these solutions can vary from 4 to 7.5.
A la date de la présente invention, les solutions injectables de fentanyl sont exclusivement stockées et commercialisées dans des contenants en verre. Ainsi, la société Fresenius a récemment mis sur le marché une seringue en verre contenant une solution de fentanyl prête à être injectée (Simplist® Fentanyl Citrate Injection). La solution de fentanyl contenue dans cette seringue contient 50 pg/ml de fentanyl, du chlorure de sodium et de l’hydroxyde de sodium. Son pH varie de 4 à 7,5. Cette solution est exempte de tout adjuvant. At the date of the present invention, injectable fentanyl solutions are exclusively stored and marketed in glass containers. Thus, the Fresenius company recently put on the market a glass syringe containing a fentanyl solution ready to be injected (Simplist® Fentanyl Citrate Injection). The fentanyl solution in this syringe contains 50 pg/ml fentanyl, sodium chloride and sodium hydroxide. Its pH varies from 4 to 7.5. This solution is free of any adjuvant.
Le choix du contenant en verre s’explique notamment par les problématiques de stabilité des solutions de fentanyl lorsque celles-ci sont conservées dans des contenants en plastique. En effet, le fentanyl a tendance à s'absorber sur les composants en plastique,
en particulier en cas de stérilisation terminale, ce qui entraîne une perte de concentration du principe actif. Cette instabilité des solutions injectables de fentanyl contenues dans des contenants en plastique pose d’autant plus de difficultés que les autorités sanitaires telles que l’EMA (European Medicines Agency) recommandent, pour une meilleure conservation, de procéder à une stérilisation terminale du contenant une fois celui-ci rempli avec la solution qu’il contient. The choice of the glass container is explained in particular by the stability issues of fentanyl solutions when they are stored in plastic containers. Indeed, fentanyl tends to be absorbed onto plastic components, particularly in case of terminal sterilization, which results in a loss of concentration of the active ingredient. This instability of injectable fentanyl solutions contained in plastic containers poses all the more difficulties as health authorities such as the EMA (European Medicines Agency) recommend, for better conservation, carrying out terminal sterilization of the container once once it is filled with the solution it contains.
Or, les contenants en plastique, notamment lorsqu’il s’agit de seringues préremplies avec une solution prête à être injectée, présentent un certain nombre d’avantages en comparaison des contenants en verre. Ainsi, les contenants en plastique permettent d’éviter le relargage d’ions métalliques qui est observé avec les contenants en verre, ils sont moins fragiles et plus faciles à produire/mouler, notamment, lorsqu’il s’agit de seringues (les connectiques de type Luer-Lock étant plus faciles à mouler lorsqu’elles sont en polypropylène). However, plastic containers, especially when it comes to syringes pre-filled with a solution ready to be injected, have a certain number of advantages compared to glass containers. Thus, plastic containers make it possible to avoid the release of metal ions which is observed with glass containers, they are less fragile and easier to produce/mold, in particular, when it comes to syringes (connectors Luer-Lock type being easier to mold when they are made of polypropylene).
Il existe donc un besoin pour identifier des solutions de fentanyl qui seraient stables à court, moyen et long terme lorsqu’elles sont stockées dans un contenant en plastique, que celui-ci fasse l’objet ou non d’une stérilisation terminale. There is therefore a need to identify fentanyl solutions that would be stable in the short, medium and long term when stored in a plastic container, whether or not it is subject to terminal sterilization.
En réponse à ces difficultés et ce besoin, la demande de brevet internationale WO-A-2021/014184 décrit une solution de fentanyl prête à être injectée, stable dans le temps, y compris lorsqu’elle est soumise à une stérilisation terminale dans un contenant en plastique, ladite solution présentant un pH variant de 3 à 4,5 et contenant systématiquement un agent tampon. Il est expliqué dans la demande qu’en l’absence d’agent tampon, la solution ne présente pas la stabilité attendue lorsqu’elle est soumise à une stérilisation terminale dans un contenant en plastique. Or, la présence d’agent tampon dans des solutions injectables, surtout à faible pH, augmentent les risques de ressenti d’une douleur au moment de l’injection. En outre, la présence d’additif supplémentaire tel qu’un agent tampon présente toujours un risque en termes d’effet secondaire à l’état natif ou s’il se dégrade lors de la stérilisation terminale ou du stockage. In response to these difficulties and this need, international patent application WO-A-2021/014184 describes a fentanyl solution ready to be injected, stable over time, including when subjected to terminal sterilization in a container made of plastic, said solution having a pH varying from 3 to 4.5 and systematically containing a buffering agent. It is explained in the application that in the absence of a buffering agent, the solution does not exhibit the expected stability when subjected to terminal sterilization in a plastic container. However, the presence of buffering agent in injectable solutions, especially at low pH, increases the risk of feeling pain at the time of injection. Furthermore, the presence of additional additive such as a buffering agent always poses a risk in terms of side effect in its native state or if it degrades during terminal sterilization or storage.
Or, il été découvert, de façon totalement inattendue, qu’une solution injectable de fentanyl exempte d’agent tampon était stable à court, moyen et long terme lorsqu’elle est stockée dans un contenant en plastique, que celui-ci fasse l’objet ou non d’une
stérilisation terminale, une telle solution présentant notamment une perte d’actif inférieure à 6%, de préférence inférieure à 3% après stérilisation terminale. However, it was discovered, completely unexpectedly, that an injectable solution of fentanyl free of buffering agent was stable in the short, medium and long term when stored in a plastic container, regardless of whether the latter did the subject or not of a terminal sterilization, such a solution notably having a loss of active ingredient of less than 6%, preferably less than 3% after terminal sterilization.
Ainsi, la présente invention a pour objet un contenant en plastique comprenant une solution injectable de fentanyl dont le pH est compris entre 3 et 4,5, ladite solution de fentanyl étant exempte d’agent tampon. Thus, the subject of the present invention is a plastic container comprising an injectable fentanyl solution whose pH is between 3 and 4.5, said fentanyl solution being free of buffering agent.
Il a été observé qu’une solution injectable de fentanyl exempte d’agent tampon stockée dans un contenant en plastique et dont le pH peut varier de 3 à 4,5 était stable à court, moyen et long terme, que le contenant subisse ou non une stérilisation terminale. En revanche, il a été observé qu’une solution injectable de fentanyl exempte d’agent tampon et dont le pH était supérieur à 4,5 était instable lorsqu’elle était stockée dans un contenant en plastique, que le contenant subisse ou non une stérilisation terminale It was observed that a fentanyl injectable solution free of buffering agent stored in a plastic container and whose pH can vary from 3 to 4.5 was stable in the short, medium and long term, whether or not the container was subjected to terminal sterilization. In contrast, a fentanyl injectable solution free of buffering agent and with a pH greater than 4.5 was observed to be unstable when stored in a plastic container, whether or not the container underwent sterilization. terminal
Dans le cadre de la présente invention : In the context of the present invention:
- on entend par « solution injectable » toute solution pouvant être injectée par voie parentérale, notamment par voie intraveineuse (IV), péridurale, intramusculaire (IM), sous-cutanée, ou intrathécale, que celle-ci soit prête à être injectée ou nécessite une dilution préalable ; - the term “injectable solution” means any solution that can be injected parenterally, in particular intravenously (IV), epidural, intramuscular (IM), subcutaneous, or intrathecal, whether it is ready to be injected or requires prior dilution;
- « fentanyl » désigne le ou N N-(1-(2-phényléthyl)-4-pipéridinyl)-N-phényl- propanamide, de numéro CAS 437-38-7 et de structure chimique :
ainsi que ses sels pharmaceutiquement acceptables, en particulier son sel de citrate (dont le numéro CAS est 990-73-8) ; - “fentanyl” designates or N N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenyl-propanamide, with CAS number 437-38-7 and chemical structure: as well as its pharmaceutically acceptable salts, in particular its citrate salt (whose CAS number is 990-73-8);
- on entend par « sel pharmaceutiquement acceptable » d’un principe actif tout sel d’addition dudit principe actif avec un acide minéral ou organique par action d’un tel acide au sein d’un solvant organique ou aqueux tel qu’un alcool, une cétone, un éther ou un solvant chloré, et qui soit acceptable d’un point de vue pharmaceutique ; et- the term “pharmaceutically acceptable salt” of an active principle is understood to mean any addition salt of said active principle with a mineral or organic acid by the action of such an acid in an organic or aqueous solvent such as an alcohol, a ketone, an ether or a chlorinated solvent, and which is acceptable from a pharmaceutical point of view; And
- on entend par « agent tampon » tout composé ou combinaison de composés permettant de maintenir le pH d’une solution à une valeur stable (+/- 1 , de préférence +/- 0,5). Comme exemple d’agent tampon on peut notamment citer le citrate, le phosphate, l’acétate, le glutamate, le tartrate, le benzoate, le lactate, le malate, le
gluconate, le succinate, I’aspartate, la glycine, le TRIS, l’histidine et l’HEPES ainsi que les sels associés. - the term “buffer agent” means any compound or combination of compounds making it possible to maintain the pH of a solution at a stable value (+/- 1, preferably +/- 0.5). As an example of a buffer agent, citrate, phosphate, acetate, glutamate, tartrate, benzoate, lactate, malate, gluconate, succinate, aspartate, glycine, TRIS, histidine and HEPES as well as associated salts.
La présente invention a donc pour objet un contenant en plastique comprenant une solution injectable de fentanyl exempte d’agent tampon dont le pH varie de 3 à 4,5. Préférentiellement, la présente invention a pour objet un contenant en plastique comprenant une solution injectable de fentanyl présentant les caractéristiques suivantes, prises seules ou en combinaison : The present invention therefore relates to a plastic container comprising an injectable solution of fentanyl free of buffering agent whose pH varies from 3 to 4.5. Preferably, the present invention relates to a plastic container comprising an injectable solution of fentanyl having the following characteristics, taken alone or in combination:
- le contenant est choisi comme étant un contenant scellé. De préférence encore, le contenant est choisi comme étant un flacon, une ampoule, une poche de perfusion ou une seringue. De façon tout à fait préférée, le contenant est choisi comme étant une seringue ; - the container is chosen to be a sealed container. More preferably, the container is chosen to be a bottle, an ampoule, an infusion bag or a syringe. Most preferably, the container is chosen to be a syringe;
- le contenant est en polyéthylène (PE), en polypropylène (PP), en PVC, en copolymère d'oléfine cyclique (COC), ou en polymère cyclique d’oléfine (COP). De préférence encore, le contenant est en polypropylène, en copolymère d'oléfine cyclique (COC) ou en polymère cyclique d’oléfine (COP). De façon tout à fait préférée, le contenant est en polypropylène ; - the container is made of polyethylene (PE), polypropylene (PP), PVC, cyclic olefin copolymer (COC), or cyclic olefin polymer (COP). More preferably, the container is made of polypropylene, cyclic olefin copolymer (COC) or cyclic olefin polymer (COP). Very preferably, the container is made of polypropylene;
- le contenant a été soumis à une stérilisation terminale ; - the container has been subjected to terminal sterilization;
- le fentanyl est présent dans la solution sous forme de fentanyl citrate ; - fentanyl is present in the solution in the form of fentanyl citrate;
- la solution de fentanyl contient de 1 pg/ml à 100 pg/ml de fentanyl. De préférence encore, la solution de fentanyl contient de 5 pg/ml à 100 pg/ml de fentanyl. De façon tout à fait préférée, la solution de fentanyl contient 50 pg/ml de fentanyl ; - the fentanyl solution contains from 1 pg/ml to 100 pg/ml of fentanyl. More preferably, the fentanyl solution contains from 5 pg/ml to 100 pg/ml of fentanyl. Most preferably, the fentanyl solution contains 50 μg/ml of fentanyl;
- la solution de fentanyl est prête à être injectée ; - the fentanyl solution is ready to be injected;
- le pH de la solution de fentanyl est inférieur à 4,5. De préférence encore, le pH de la solution de fentanyl est compris entre 3 et 4. De façon tout à fait préférée, le pH de la solution de fentanyl est compris entre 3,5 et 4 ; - the pH of the fentanyl solution is less than 4.5. More preferably, the pH of the fentanyl solution is between 3 and 4. Most preferably, the pH of the fentanyl solution is between 3.5 and 4;
- la solution de fentanyl contient un agent de tonicité. De préférence encore, la solution de fentanyl contient un agent de tonicité choisi parmi le dextrose, la glycérine, le mannitol, le chlorure de potassium, le chlorure de sodium. De façon tout à fait préférée, la solution de fentanyl contient un agent de tonicité choisi comme étant le chlorure de sodium ; - the fentanyl solution contains a tonic agent. More preferably, the fentanyl solution contains a toning agent chosen from dextrose, glycerin, mannitol, potassium chloride, sodium chloride. Very preferably, the fentanyl solution contains a toning agent chosen to be sodium chloride;
- la solution de fentanyl contient un agent de tonicité dans des proportions est adaptée pour obtenir une solution isotonique dont l’osmolarité est comprise entre 200- 400mOsm/kg, de préférence entre 250-350mOsm/kg. La solution de fentanyl peut ainsi contenir de 1 g/l à 50 g/l d’agent de tonicité. De préférence encore, la solution de
fentanyl contient de 5 g/l à 10 g/l de chlorure de sodium ou de 40 g/l à 50 g/l de glucose ; et/ou - the fentanyl solution contains a tonic agent in proportions suitable to obtain an isotonic solution whose osmolarity is between 200-400mOsm/kg, preferably between 250-350mOsm/kg. The fentanyl solution can thus contain from 1 g/l to 50 g/l of toning agent. Preferably still, the solution of fentanyl contains 5 g/l to 10 g/l of sodium chloride or 40 g/l to 50 g/l of glucose; and or
- le volume du contenant varie de 1 ml à 500 ml. De préférence encore, le volume du contenant varie de 1 ml à 100 ml. De façon tout à fait préférée, le volume du contenant varie de 1 ml à 50 ml. - the volume of the container varies from 1 ml to 500 ml. More preferably, the volume of the container varies from 1 ml to 100 ml. Most preferably, the volume of the container varies from 1 ml to 50 ml.
Le contenant selon la présente invention est obtenu par remplissage avec une solution de fentanyl telle que définie précédemment suivi d’un sertissage. De préférence, le contenant ainsi obtenu est ensuite soumis à une stérilisation terminale. Cette étape de stérilisation terminale est conduite selon tout procédé classiquement utilisé par l’homme du métier. En particulier, l’étape de stérilisation terminale est conduite au sein d’un autoclave, le produit étant exposé à une température de 121 °C durant au moins 15 minutes. The container according to the present invention is obtained by filling with a fentanyl solution as defined above followed by crimping. Preferably, the container thus obtained is then subjected to terminal sterilization. This terminal sterilization step is carried out according to any process conventionally used by those skilled in the art. In particular, the terminal sterilization step is carried out in an autoclave, the product being exposed to a temperature of 121°C for at least 15 minutes.
La solution de fentanyl comprise dans le contenant en plastique selon la présente invention peut être préparée selon tout procédé classiquement utilisé par l’homme du métier. Comme exemple de procédé de préparation d’une solution telle que définie précédemment, on peut notamment citer le procédé comprenant les étapes suivantes : introduction et mélange de chacun des ingrédients de la solution dans un volume d’eau donné ; ajustement du pH ; et filtration. The fentanyl solution included in the plastic container according to the present invention can be prepared according to any method conventionally used by those skilled in the art. As an example of a process for preparing a solution as defined above, we can in particular cite the process comprising the following steps: introduction and mixing of each of the ingredients of the solution in a given volume of water; pH adjustment; and filtration.
La présente invention est illustrée de manière non limitative par les exemples suivants. The present invention is illustrated in a non-limiting manner by the following examples.
Exemple 1 - Stabilité d’une solution de fentanyl contenue dans une seringue en polypropylène (PP) suite à une stérilisation terminale Example 1 - Stability of a fentanyl solution contained in a polypropylene (PP) syringe following terminal sterilization
1.1 - Préparation d’une solution de fentanyl 1.1 - Preparation of a fentanyl solution
Des solutions de fentanyl dont les compositions sont rapportées dans le Tableau 1 suivant ont été préparées selon le procédé décrit ci-après.
Fentanyl solutions whose compositions are reported in Table 1 below were prepared according to the process described below.
Tableau 1 - Solutions de fentanyl Table 1 - Fentanyl Solutions
Pour les solutions contenant un agent tampon, du citrate de sodium dihydraté et de l'acide citrique sont dissous sous agitation magnétique dans 70 % du volume total d'eau pour préparations injectables, puis le fentanyl est ajouté sous agitation magnétique. For solutions containing a buffering agent, sodium citrate dihydrate and citric acid are dissolved with magnetic stirring in 70% of the total volume of water for injections, then fentanyl is added with magnetic stirring.
Du chlorure de sodium est ensuite ajouté à la solution pour ajuster la tonicité. Sodium chloride is then added to the solution to adjust the tonicity.
Le pH est finalement ajusté avec de l'acide chlorhydrique et/ou de la soude. The pH is finally adjusted with hydrochloric acid and/or sodium hydroxide.
Le volume est enfin complété à 100% avec de l'eau puis la solution est filtrée sur disque PVDF Millipore 0,22 pm. The volume is finally made up to 100% with water then the solution is filtered on a 0.22 pm Millipore PVDF disk.
1.2 - Préparation d’une seringue en polypropylène ou d’un flacon en verre prérempli avec une solution de fentanyl 1.2 - Preparation of a polypropylene syringe or glass vial pre-filled with fentanyl solution
Des seringues en polypropylène (PP) ou des flacons en verre (GLASS) préremplis d’une solution de fentanyl dont les caractéristiques sont rapportées dans le Tableau 2 suivant ont été préparées selon le procédé décrit ci-après.
Polypropylene (PP) syringes or glass vials (GLASS) pre-filled with a fentanyl solution whose characteristics are reported in Table 2 below were prepared according to the process described below.
Tableau 2 - Seringues en polypropylène ou flacons en verre préremplies Table 2 - Pre-filled polypropylene syringes or glass vials
Une seringue PP Borealis HD-850MO enduite de silicone est remplie avec 5 ml d’une solution de fentanyl telle que décrite ci-dessus, puis bouchée avec un bouchon en élastomère (Aptar chlorobutyle C1797 6422NR 6DDP1 ). Un piston est ensuite ajouté manuellement. A Borealis HD-850MO silicone-coated PP syringe is filled with 5 ml of a fentanyl solution as described above, then capped with an elastomer cap (Aptar chlorobutyl C1797 6422NR 6DDP1). A piston is then added manually.
Un flacon verre de type II 10 ml est rempli avec 5 ml d’une solution de fentanyl telle que décrite ci-dessus, puis bouché avec un bouchon en chlorobutyl (Aptar Stelmi C5394 6422GS 6 DH1). A 10 ml type II glass vial is filled with 5 ml of a fentanyl solution as described above, then stoppered with a chlorobutyl stopper (Aptar Stelmi C5394 6422GS 6 DH1).
Lorsque le contenant est soumis à une stérilisation terminale, celui-ci est alors placé dans un autoclave à 121 °C (à l'intérieur du produit à l'aide d'un échantillon dans lequel une sonde température est insérée) pendant au moins 15 minutes.
Les contenants sont ensuite conservés à température ambiante et à l'abri de la lumière jusqu’à ce que les analyses rapportées au point 1 .3 suivant soient pratiquées. When the container is subjected to terminal sterilization, it is then placed in an autoclave at 121°C (inside the product using a sample in which a temperature probe is inserted) for at least 15 minutes. The containers are then stored at room temperature and protected from light until the analyzes reported in point 1.3 below are carried out.
1.3 - Evaluation de la stabilité 1.3 - Stability assessment
1.3.1 - Protocole 1.3.1 - Protocol
Une fois remplis de la solution de fentanyl (et après avoir éventuellement subie une stérilisation terminale), les seringues et les flacons sont placés à l’abri de la lumière. Once filled with the fentanyl solution (and after possibly having undergone terminal sterilization), the syringes and vials are placed away from light.
Les solutions contenues dans les seringues et flacons préparés ci-dessus sont évaluées visuellement (couleur, turbidité et présence de particules) à to (i.e. après préparation et éventuelle stérilisation terminale). The solutions contained in the syringes and vials prepared above are evaluated visually (color, turbidity and presence of particles) at to (i.e. after preparation and possible terminal sterilization).
Le pH de la solution est mesuré et la concentration de la solution en fentanyl est également évaluée par HPLC. The pH of the solution is measured and the fentanyl concentration of the solution is also evaluated by HPLC.
1.3.2 - Résultats 1.3.2 - Results
Les résultats de ces analyses sont rapportés dans le Tableau 3 suivant.
The results of these analyzes are reported in the following Table 3.
Tableau 3 - Stabilité des solutions de fentanyl contenues dans des seringues en polypropylene ou des flacons en verre suite à une stérilisation terminale Table 3 - Stability of fentanyl solutions contained in polypropylene syringes or glass vials following terminal sterilization
1.3.3 - Con elusions 1.3.3 - Con elusions
On note que, contrairement aux contenants en verre (GLASS-A1 et GLASS-A2) pour lesquels la stérilisation terminale n’a pas (ou très peu) d’impact sur la stabilité de la solution, on observe une forte perte en actif pour les solutions contenues dans un contenant en plastique lorsque le pH est supérieur à 4,5 (PP-A1, PP-B2 et PP-C1). La diminution du pH de la solution à un niveau inférieur ou égal à 4,5 permet de limiter de manière importante la perte d’actif (PP-D2, PP-E1 , PP-F2, PP-G2, PP-H2 et PP-I2).
En outre, on observe que, lorsque le pH est inférieur ou égal à 4,5, la présence d’un agent tampon ne permet pas d’améliorer la stabilité de la solution contenue dans un contenant en plastique suite à une stérilisation terminale (PP-H2 vs PP-G2 et PP-D2 vs PP-E1 ). En revanche, la présence d’un agent tampon dans une solution dont le pH est supérieur à 4,5 augmente de façon significative la perte d’actif (PP-C1 vs PP-B2). d’une solution de fentanyl contenue dans une
We note that, unlike glass containers (GLASS-A1 and GLASS-A2) for which terminal sterilization has no (or very little) impact on the stability of the solution, we observe a strong loss of active ingredient for solutions contained in a plastic container when the pH is greater than 4.5 (PP-A1, PP-B2 and PP-C1). Reducing the pH of the solution to a level less than or equal to 4.5 makes it possible to significantly limit the loss of active ingredient (PP-D2, PP-E1, PP-F2, PP-G2, PP-H2 and PP -I2). Furthermore, it is observed that, when the pH is less than or equal to 4.5, the presence of a buffering agent does not improve the stability of the solution contained in a plastic container following terminal sterilization (PP -H2 vs PP-G2 and PP-D2 vs PP-E1). On the other hand, the presence of a buffering agent in a solution whose pH is greater than 4.5 significantly increases the loss of active ingredient (PP-C1 vs PP-B2). of a fentanyl solution contained in a
2.1 - Protocole 2.1 - Protocol
Une fois remplies de la solution de fentanyl (et après avoir éventuellement subi une stérilisation terminale), les seringues sont placées en enceintes climatiques. Once filled with the fentanyl solution (and after possibly undergoing terminal sterilization), the syringes are placed in climatic chambers.
Les solutions contenues dans les seringues préparées ci-dessus sont évaluées visuellement (couleur, turbidité et présence de particules) à to (i.e. après préparation et stérilisation terminale), to+1 mois et to+3 mois après conservation à l’abri de la lumière à 25°C et 40°C. The solutions contained in the syringes prepared above are evaluated visually (color, turbidity and presence of particles) at to (i.e. after preparation and terminal sterilization), to+1 month and to+3 months after storage away from the light at 25°C and 40°C.
Le pH de la solution est mesuré et la concentration de la solution en fentanyl est également évaluée par HPLC. The pH of the solution is measured and the fentanyl concentration of the solution is also evaluated by HPLC.
2.2 - Résultats 2.2 - Results
Les résultats de ces analyses sont rapportés dans les Tableaux 4 et 5 suivants.
The results of these analyzes are reported in Tables 4 and 5 below.
Tableau 4 - Stabilité des solutions de fentanyl contenues dans des seringues en polypropylène à 25° C
Table 4 - Stability of fentanyl solutions contained in polypropylene syringes at 25°C
Tableau 5 - Stabilité des solutions de fentanyl contenues dans des seringues en polypropylène à 40° C
2.3 - Conclusions Table 5 - Stability of fentanyl solutions contained in polypropylene syringes at 40° C 2.3 - Conclusions
Ces résultats mettent en avant que la présence d’un agent tampon ne permet pas d’améliorer la stabilité à court et moyen terme d’une solution de fentanyl dont le pH est inférieur à 4,5 contenue dans un contenant en plastique, que celui-ci ait subi ou non une stérilisation terminale.
These results highlight that the presence of a buffering agent does not make it possible to improve the short and medium term stability of a fentanyl solution whose pH is less than 4.5 contained in a plastic container, that that whether or not it has undergone terminal sterilization.
Claims
1. Contenant en plastique comprenant une solution injectable de fentanyl dont le pH est compris entre 3 et 4,5, ladite solution étant exempte d’agent tampon. 1. Plastic container comprising an injectable solution of fentanyl whose pH is between 3 and 4.5, said solution being free of buffering agent.
2. Contenant selon la revendication 1 caractérisé en ce qu’il s’agit d’un flacon, d’une ampoule, d’une poche de perfusion ou d’une seringue. 2. Container according to claim 1 characterized in that it is a bottle, an ampoule, an infusion bag or a syringe.
3. Contenant selon la revendication 1 ou 2, caractérisé en ce que celui-ci est en en polyéthylène (PE), en polypropylène (PP), en PVC, en copolymère d'oléfine cyclique (COC), ou en polymère cyclique d’oléfine (COP). 3. Container according to claim 1 or 2, characterized in that it is made of polyethylene (PE), polypropylene (PP), PVC, cyclic olefin copolymer (COC), or cyclic polymer of olefin (COP).
4. Contenant selon la revendication 3, caractérisé en ce que celui-ci est en polypropylène (PP), en copolymère d'oléfine cyclique (COC) ou en polymère cyclique d’oléfine (COP). 4. Container according to claim 3, characterized in that it is made of polypropylene (PP), cyclic olefin copolymer (COC) or cyclic olefin polymer (COP).
5. Contenant selon l’une quelconque des revendications 1 à 4, caractérisé en ce que le fentanyl est présent dans la solution sous forme de fentanyl citrate. 5. Container according to any one of claims 1 to 4, characterized in that the fentanyl is present in the solution in the form of fentanyl citrate.
6. Contenant selon l’une quelconque des revendications 1 à 5, caractérisé en ce que la solution de fentanyl contient de 1 pg/ml à 100 pg/ml de fentanyl. 6. Container according to any one of claims 1 to 5, characterized in that the fentanyl solution contains from 1 pg/ml to 100 pg/ml of fentanyl.
7. Contenant selon l’une quelconque des revendications 1 à 6, caractérisé en ce que le pH de la solution de fentanyl est inférieur à 4,5. 7. Container according to any one of claims 1 to 6, characterized in that the pH of the fentanyl solution is less than 4.5.
8. Contenant selon la revendication 7, caractérisé en ce que le pH de la solution de fentanyl est compris entre 3 et 4 8. Container according to claim 7, characterized in that the pH of the fentanyl solution is between 3 and 4
9. Contenant selon la revendication 8, caractérisé en ce que le pH de la solution de fentanyl est compris entre 3,5 et 4. 9. Container according to claim 8, characterized in that the pH of the fentanyl solution is between 3.5 and 4.
10. Contenant selon l’une quelconque des revendications 1 à 9, caractérisé en ce que la solution de fentanyl contient un agent de tonicité. 10. Container according to any one of claims 1 to 9, characterized in that the fentanyl solution contains a toning agent.
11. Contenant selon l’une quelconque des revendications 1 à 10, caractérisé en ce que celui-ci a été soumis à une stérilisation terminale.
11. Container according to any one of claims 1 to 10, characterized in that it has been subjected to terminal sterilization.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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FR2206551A FR3137275A1 (en) | 2022-06-29 | 2022-06-29 | PLASTIC CONTAINER INCLUDING FENTANYL INJECTABLE SOLUTION |
FRFR22/06551 | 2022-06-29 |
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WO2024003503A1 true WO2024003503A1 (en) | 2024-01-04 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2023/050978 WO2024003503A1 (en) | 2022-06-29 | 2023-06-28 | Plastic container containing an injectable solution of fentanyl |
Country Status (2)
Country | Link |
---|---|
FR (1) | FR3137275A1 (en) |
WO (1) | WO2024003503A1 (en) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4486423A (en) * | 1983-04-21 | 1984-12-04 | Janssen Pharmaceutica Inc. | Stable fentanyl composition |
US20160367476A1 (en) * | 2015-06-19 | 2016-12-22 | Sun Pharmaceutical Industries Ltd. | Ready-to-administer solution of fentanyl citrate |
WO2020021567A1 (en) * | 2018-07-23 | 2020-01-30 | Sun Pharmaceutical Industries Limited | Injection device of fentanyl |
WO2021014184A1 (en) | 2019-07-19 | 2021-01-28 | Hikma Pharmaceuticals International Limited | Ready-to-administer fentanyl formulations |
-
2022
- 2022-06-29 FR FR2206551A patent/FR3137275A1/en active Pending
-
2023
- 2023-06-28 WO PCT/FR2023/050978 patent/WO2024003503A1/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4486423A (en) * | 1983-04-21 | 1984-12-04 | Janssen Pharmaceutica Inc. | Stable fentanyl composition |
US20160367476A1 (en) * | 2015-06-19 | 2016-12-22 | Sun Pharmaceutical Industries Ltd. | Ready-to-administer solution of fentanyl citrate |
WO2020021567A1 (en) * | 2018-07-23 | 2020-01-30 | Sun Pharmaceutical Industries Limited | Injection device of fentanyl |
WO2021014184A1 (en) | 2019-07-19 | 2021-01-28 | Hikma Pharmaceuticals International Limited | Ready-to-administer fentanyl formulations |
Non-Patent Citations (1)
Title |
---|
CAS, no. 990-73-8 |
Also Published As
Publication number | Publication date |
---|---|
FR3137275A1 (en) | 2024-01-05 |
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