NZ730368B2 - Stable formulations of lipids and liposomes - Google Patents
Stable formulations of lipids and liposomes Download PDFInfo
- Publication number
- NZ730368B2 NZ730368B2 NZ730368A NZ73036815A NZ730368B2 NZ 730368 B2 NZ730368 B2 NZ 730368B2 NZ 730368 A NZ730368 A NZ 730368A NZ 73036815 A NZ73036815 A NZ 73036815A NZ 730368 B2 NZ730368 B2 NZ 730368B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- kit according
- dope
- liposomes
- liposome dispersion
- nucleic acid
- Prior art date
Links
- 239000002502 liposome Substances 0.000 title claims abstract 12
- 150000002632 lipids Chemical class 0.000 title claims abstract 5
- 238000009472 formulation Methods 0.000 title abstract 3
- 239000000203 mixture Substances 0.000 title abstract 3
- 238000000034 method Methods 0.000 claims abstract 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 3
- 230000000087 stabilizing effect Effects 0.000 claims abstract 2
- 239000006185 dispersion Substances 0.000 claims 5
- 150000007523 nucleic acids Chemical class 0.000 claims 4
- 102000039446 nucleic acids Human genes 0.000 claims 4
- 108020004707 nucleic acids Proteins 0.000 claims 4
- KSXTUUUQYQYKCR-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KSXTUUUQYQYKCR-LQDDAWAPSA-M 0.000 claims 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- -1 cationic lipid Chemical class 0.000 claims 3
- 230000007062 hydrolysis Effects 0.000 claims 3
- 238000006460 hydrolysis reaction Methods 0.000 claims 3
- 239000003002 pH adjusting agent Substances 0.000 claims 3
- 239000002253 acid Substances 0.000 claims 2
- 230000002378 acidificating effect Effects 0.000 claims 2
- 239000000872 buffer Substances 0.000 claims 2
- 239000008366 buffered solution Substances 0.000 claims 2
- 239000008351 acetate buffer Substances 0.000 claims 1
- 125000002091 cationic group Chemical group 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 claims 1
- 230000006641 stabilisation Effects 0.000 claims 1
- 238000011105 stabilization Methods 0.000 claims 1
- 239000013011 aqueous formulation Substances 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
-
- 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
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
-
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
The present invention relates to aqueous lipid and/or liposome formulations with an increased chemical stability, to methods of preparing such aqueous formulations as well as to kits comprising them. The present invention further relates to methods of preparing lipid-based pharmaceutical compositions, to pharmaceutical compositions prepared by such methods and to methods of chemically stabilizing aqueous lipid and/or liposome formulations.
Claims (13)
1. A kit comprising (i) an s liposome dispersion comprising -liposomes comprising 1,2-di-(9Z-octadecenoyl)-sn-glycerophosphoethanolamine (DOPE) and at least one ic lipid selected from the group consisting of 1,2-di-O- octadecenyltrimethylammoniumpropane (DOTMA) and 1,2-dioleoyl trimethylammoniumpropane (DOTAP), said liposomes being cationic at logical pH, and - at least one pH adjusting agent, wherein the aqueous liposome dispersion has a pH of n 2 and 4.5, and (ii) in a separate container, a pharmaceutically active nucleic acid, n the pharmaceutically active nucleic acid is provided in a buffered solution having a pH of between 6 and 8.
2. The kit according to claim 1, wherein the molar ratio of the at least one cationic lipid to DOPE is from 1:4 to 4:1.
3. The kit according to claim 1 or 2, wherein the molar ratio of the at least one cationic lipid to DOPE is from 1:2 to 4:1.
4. The kit according to any one of claims 1 to 3, wherein the at least one pH adjusting agent comprises an acid and/or an acidic buffer.
5. The kit according to claim 4, wherein the acid is acetic acid.
6. The kit according to claim 4 , wherein the acidic buffer is acetate buffer.
7. The kit according to any one of claims 1 to 6, wherein the hydrolysis rates DOPE and/or DOTAP are reduced as compared to their hydrolysis rates at a pH of n 6 and 7.
8. The kit according to any one of claims 1 to 7, wherein the at least one pH adjusting agent is associated with the mes.
9. A method of preparing a pharmaceutical composition, the method comprising - providing an aqueous liposome sion as defined in any one of claims 1 to 8; and - mixing the aqueous liposome dispersion with a pharmaceutically active nucleic acid, wherein the pharmaceutically active nucleic acid is provided in a buffered solution having a pH of between 6 and 8.
10. A method of chemically stabilizing an aqueous liposome dispersion comprising liposomes comprising 1,2-di-(9Z-octadecenoyl)-sn-glycerophosphoethanolamine (DOPE) and at least one cationic lipid selected from the group consisting of 2-di-O-octadecenyl trimethylammoniumpropane (DOTMA) and 1,2-dioleoyltrimethylammoniumpropane (DOTAP), said mes being ic at physiological pH, the method comprising - adjusting the pH of the aqueous liposome dispersion to a pH of between 2 and 4.5.
11. The method according to claim 10, wherein the al stabilization occurs by inhibition of ester bond hydrolysis.
12. The kit according to any one of claims 1 to 8, ntially as herein described with reference to any example thereof and with or without reference to the accompanying drawings.
13. The method according to any one of claims 9 to 11, substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP2014/070503 WO2016045732A1 (en) | 2014-09-25 | 2014-09-25 | Stable formulations of lipids and liposomes |
| PCT/EP2015/071344 WO2016046060A1 (en) | 2014-09-25 | 2015-09-17 | Stable formulations of lipids and liposomes |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NZ730368A9 NZ730368A9 (en) | |
| NZ730368A NZ730368A (en) | 2024-02-23 |
| NZ730368B2 true NZ730368B2 (en) | 2024-05-24 |
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