US20010003580A1 - Preparation of a lipid blend and a phospholipid suspension containing the lipid blend - Google Patents
Preparation of a lipid blend and a phospholipid suspension containing the lipid blend Download PDFInfo
- Publication number
- US20010003580A1 US20010003580A1 US09/229,258 US22925899A US2001003580A1 US 20010003580 A1 US20010003580 A1 US 20010003580A1 US 22925899 A US22925899 A US 22925899A US 2001003580 A1 US2001003580 A1 US 2001003580A1
- Authority
- US
- United States
- Prior art keywords
- process according
- suspension
- lipid
- lipid blend
- aqueous solvent
- 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.)
- Abandoned
Links
- 150000002632 lipids Chemical class 0.000 title claims abstract description 174
- 239000000203 mixture Substances 0.000 title claims abstract description 143
- 239000000725 suspension Substances 0.000 title claims abstract description 84
- 150000003904 phospholipids Chemical class 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 80
- 230000008569 process Effects 0.000 claims abstract description 66
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 87
- 239000003125 aqueous solvent Substances 0.000 claims description 58
- 239000000243 solution Substances 0.000 claims description 58
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 50
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 30
- 239000011780 sodium chloride Substances 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 239000007864 aqueous solution Substances 0.000 claims description 28
- 238000001914 filtration Methods 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 27
- 235000011187 glycerol Nutrition 0.000 claims description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 230000001954 sterilising effect Effects 0.000 claims description 22
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 19
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 18
- 230000007704 transition Effects 0.000 claims description 17
- 238000004090 dissolution Methods 0.000 claims description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 claims description 8
- 229960004065 perflutren Drugs 0.000 claims description 8
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical compound FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 claims description 6
- 229940068886 polyethylene glycol 300 Drugs 0.000 claims description 4
- 239000002961 echo contrast media Substances 0.000 abstract description 3
- 239000002245 particle Substances 0.000 description 15
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 14
- 239000012071 phase Substances 0.000 description 14
- 238000009472 formulation Methods 0.000 description 13
- 238000013329 compounding Methods 0.000 description 10
- 238000002156 mixing Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 7
- 239000008364 bulk solution Substances 0.000 description 6
- 238000009826 distribution Methods 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 239000008215 water for injection Substances 0.000 description 5
- TXLHNFOLHRXMAU-UHFFFAOYSA-N 2-(4-benzylphenoxy)-n,n-diethylethanamine;hydron;chloride Chemical compound Cl.C1=CC(OCCN(CC)CC)=CC=C1CC1=CC=CC=C1 TXLHNFOLHRXMAU-UHFFFAOYSA-N 0.000 description 4
- 239000012736 aqueous medium Substances 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- -1 fatty acid esters Chemical class 0.000 description 4
- 230000036571 hydration Effects 0.000 description 4
- 238000006703 hydration reaction Methods 0.000 description 4
- 238000012792 lyophilization process Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000011146 sterile filtration Methods 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 238000003828 vacuum filtration Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000004973 liquid crystal related substance Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000013020 final formulation Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- YOVIBSARTYNQTL-UHFFFAOYSA-K CC.CC.CCCCCCCCCCCCCCCC(=O)OCC(COP(=O)([O-])O)OC(=O)CCCCCCCCCCCCCCC.CCCCCCCCCCCCCCCC(=O)OCC(COP(=O)([O-])OCCN(C)(C)C)OC(=O)CCCCCCCCCCCCCCC.CCCCCCCCCCCCCCCC(=O)OCC(COP(=O)([O-])OCCNC(=O)OCCOC)OC(=O)CCCCCCCCCCCCCCC.[Na+].[Na+] Chemical compound CC.CC.CCCCCCCCCCCCCCCC(=O)OCC(COP(=O)([O-])O)OC(=O)CCCCCCCCCCCCCCC.CCCCCCCCCCCCCCCC(=O)OCC(COP(=O)([O-])OCCN(C)(C)C)OC(=O)CCCCCCCCCCCCCCC.CCCCCCCCCCCCCCCC(=O)OCC(COP(=O)([O-])OCCNC(=O)OCCOC)OC(=O)CCCCCCCCCCCCCCC.[Na+].[Na+] YOVIBSARTYNQTL-UHFFFAOYSA-K 0.000 description 1
- STCYHJNZGDQVNI-UEMMRENRSA-N CC.CC.CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(=O)(O)O)O[C@@H](O)CCCCCCCCCCCCCCC.CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(=O)(O)OCCN(C)(C)C)OC(=O)CCCCCCCCCCCCCCC.CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(=O)(O)OCCN[C@H](O)OCCOC)OC(=O)CCCCCCCCCCCCCCC Chemical compound CC.CC.CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(=O)(O)O)O[C@@H](O)CCCCCCCCCCCCCCC.CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(=O)(O)OCCN(C)(C)C)OC(=O)CCCCCCCCCCCCCCC.CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(=O)(O)OCCN[C@H](O)OCCOC)OC(=O)CCCCCCCCCCCCCCC STCYHJNZGDQVNI-UEMMRENRSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000907661 Pieris rapae Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000013190 lipid storage Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000012569 microbial contaminant Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 238000011045 prefiltration Methods 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
-
- 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
- A61K9/1277—Processes for preparing; Proliposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
-
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/227—Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
-
- 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
-
- 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
Definitions
- the present invention relates generally to processes for the preparation of a lipid blend and a uniform filterable phospholipid suspension containing the lipid blend, such suspension being useful as an ultrasound contrast agent.
- Manufacturing of a phospholipid contrast agent can be divided into the following steps: (1) preparation of lipid blend; (2) compounding the bulk solution, which involves the hydration and dispersion of the lipid blend in an essentially aqueous medium to produce a lipid suspension; (3) filtration of the bulk solution through a sterilizing filter(s) to render the suspension free of microbial contaminants; (4) dispensing the sterile suspension into individual vials in a controlled aseptic area; (5) loading the dispensed vials into a lyophilizer chamber to replace the vial headspace gas with perfluoropropane gas (PFP); (6) transferring the sealed vials after gas exchange to an autoclave for terminal sterilization.
- PFP perfluoropropane gas
- Phospholipid blends are typically produced by dissolving or suspending the required lipids in an appropriate aqueous or non-aqueous solvent system, and then reducing the volume either by lyophilization or distillation. Ideally, this process produces blended solids with high content uniformity and purity. However, while working well on a small, laboratory scale, this simple approach is frequently problematic upon scale-up to production-size quantities.
- Difficulties include: (1) maintaining content uniformity during the solvent removal step (due to differential solubilities); (2) maintaining purity (frequently a problem when water is used due to hydrolytic side-reactions); (3) enhancing purity; (4) minimizing solvent volume; and (5) recovery of the final solids (e.g., it is not practical to scrape solids out of a large reactor).
- the lipids would accumulate in the filters causing a restriction in the flow rate, and in most cases, the filters would be completely blocked shortly after. Further reduction in the suspension particle size cannot be achieved through a conventional batching process, even after extended mixing (e.g., 6 hours) at elevated temperatures (e.g., 40° C. to 80° C.) with a commonly used marine propeller.
- one object of the present invention is to provide a novel process for preparing a lipid blend.
- Another object of the present invention is to provide a novel process for preparing a phospholipid suspension from the lipid blend.
- the present invention provides a novel process for preparing a phospholipid suspension, comprising:
- the non-aqueous solvent is selected from propylene glycol, ethylene glycol, and polyethylene glycol 300.
- the non-aqueous solvent is propylene glycol.
- the lipid blend comprises:
- step (1) the non-aqueous solvent is heated to a temperature of about 30 to 70° C. prior to contacting with the lipid blend.
- the non-aqueous solvent is heated to a temperature of about 50 to 55° C. prior to contacting with the lipid blend.
- the ratio of lipid blend to non-aqueous solvent is from about 5 mg of lipid blend per mL of non-aqueous solvent to about 15 mg/mL.
- the ratio of lipid blend to non-aqueous solvent is about 10 mg/mL.
- the aqueous solution is selected from water, saline, a saline/glycerin mixture, and a saline/glycerin/non-aqueous solvent mixture.
- the aqueous solution is a saline and glycerin mixture.
- the aqueous solution is a saline, glycerin, and propylene glycol mixture.
- 1.0 mg/mL of lipid blend are present.
- step (2) the aqueous solution is heated to a temperature of about 45 to 60° C. prior to contacting with the solution from step (1).
- the aqueous solution is heated to a temperature of about 50 to 55° C. prior to contacting with the solution from step (1).
- the process further comprises:
- step (3) heating the lipid suspension from step (2) to a temperature about equal to or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the suspension.
- step (3) the lipid suspension is heated to a temperature of at least about 67° C.
- the process further comprises:
- step (4) the filtration is performed using two sterilizing filter cartridges.
- the sterilizing filter cartridges are at a temperature of from about 70 to 80° C.
- step (4) 0.2 ⁇ m hydrophilic filters are used.
- the process further comprises:
- the process further comprises:
- the perfluorocarbon gas is perfluoropropane.
- exchange of headspace gas is performed using a lyophilizing chamber.
- the process further comprises:
- step (7) the vial is sterilized at about 126-130° C. for 1 to 10 minutes.
- the present invention provides a novel process for preparing a lipid blend, comprising:
- step (a) the lipids are:
- the first non-aqueous solvent is a mixture of methanol and toluene.
- the second non-aqueous solvent is a methyl t-butyl ether.
- step (a) the solution is warmed to a temperature sufficient to complete dissolution of the lipids into the solvent.
- step (a) the solution is warmed to about 25 to 75° C.
- step (d) the solids collected are washed with methyl t-butyl ether and dried in vacuo.
- the present invention provides a novel phospholipid suspension, comprising:
- the suspension is prepared by the process, comprising:
- step (3) heating the lipid suspension from step (2) to a temperature about equal to or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the suspension;
- the lipid blend comprises:
- the non-aqueous solvent is heated to a temperature of about 50 to 55° C. prior to contacting with the lipid blend.
- the ratio of lipid blend to non-aqueous solvent is about 10 mg/mL.
- the aqueous solution is a saline, glycerin, and propylene glycol mixture.
- the aqueous solution is heated to a temperature of about 50 to 55° C. prior to contacting with the solution from step (1).
- step (3) the lipid suspension is heated to a temperature of at least about 67° C.
- step (4) in step (4), two 0.2 ⁇ m hydrophilic filters are used.
- Multigram scale is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more.
- Multikilogram scale is intended to mean the scale wherein more than one kilogram of at least one starting material is used.
- Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
- Lipid blend or phospholipid blend is intended to represent two or more lipids which have been blended.
- the lipid blend is generally in a powder form.
- at least one of the lipids is a phospholipid.
- the lipid blend contains 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phosphotidic, mono sodium salt (DPPA), and N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn- glycero-3-phosphatidylethanolamine, monosodium salt (MPEG5000-DPPE).
- the amount of each lipid present in the blend will depend on the desired end product. Preferred ratios of each lipid are described in the Examples section. A wide variety of other lipids, like those described in Unger et al, U.S. Pat. No. 5,469,854, the contents of which are hereby incorporated by reference, may be used in the present process.
- Phospholipid is a fatty substance containing an oily (hydrophobic) hydrocarbon chain(s) with a polar (hydrophilic) phosphoric head group. Phospholipids are amphiphilic. They spontaneously form boundaries and closed vesicles in aqueous media. Phospholipids constitute about 50% of the mass of animal cell plasma membrane.
- the lipid blend may be prepared via an aqueous suspension-lyophilization process or an organic solvent dissolution-precipitation process using organic solvents.
- the desired lipids are suspended in water at an elevated temperature and then concentrated by lyophilization. Preferably a dissolution procedure is used.
- the organic solvent dissolution-precipitation procedure involves contacting the desired lipids (e.g., DPPA, DPPC, and MPEG5000 DPPE) with a first non-aqueous solvent system.
- This system is typically a combination of solvents, for example CHCl 3 /MeOH, CH 2 Cl 2 /MeOH, and toluene/MeOH.
- the first non-aqueous solvent is a mixture of toluene and methanol. It may be desirable to warm the lipid solution to a temperature sufficient to achieve complete dissolution. Such a temperature is preferably about 25 to 75° C., more preferably about 35 to 65° C.
- the solution is then concentrated to a thick gel/semisolid. Concentration is preferably done by vacuum distillation. Other methods of concentrating the solution, such as rotary evaporation, may also be used.
- the temperature of this step is preferably about 20 to 60° C., more preferably 30 to 50° C.
- the thick gel/semisolid is then dispersed in a second non-aqueous solvent.
- the mixture is slurried, preferably near ambient temperature (e.g., 15-30° C.).
- Useful second non-aqueous solvents are those that cause the lipids to precipitate from the filtered solution.
- the second non-aqueous solvent is preferably methyl t-butyl ether (MTBE). Other ethers and alcohols may be used.
- the solids produced upon addition of the second non-aqueous solvent are then collected.
- the collected solids are washed with another portion of the second non-aqueous solvent (e.g., MTBE).
- Collection may be performed via vacuum filtration or centrifugation, preferably at ambient temperature. After collection, it is preferred that the solids are dried in vacuo at a temperature of about 20-60° C.
- a lipid blend is contacted with a non-aqueous solvent, whereby the lipid blend substantially dissolves in the non-aqueous solvent.
- the individual lipids may be contacted with the non-aqueous solvent sequentially in the order: DPPC, DPPA, and MPEG5000-DPPE; DPPC, MPEG5000-DPPE, and DPPA; MPEG5000-DPPE, DPPA, and DPPC; or MPEG5000-DPPE, DPPC, and DPPA.
- the DPPA being the least soluble and least abundant of the lipids is not added first. Adding one of the other lipids prior to or concurrently with adding the DPPA facilitates dissolution of the DPPA.
- the individual lipids can be combined in their solid forms and the combination of the solids contacted with the non-aqueous solvent.
- Substantial dissolution is generally indicated when the mixture of lipid blend and non-aqueous solven becomes clear.
- phospholipids are generally not water soluble.
- direct introduction of a blend of phospholipid blend into an aqueous environment causes the lipid blend to aggregate forming clumps that are very difficult to disperse.
- the present invention overcomes this limitation by dissolving the lipid blend in a non-aqueous solvent prior to introduction of the aqueous solution. This allows one to evenly disperse the lipid blend into a liquid. The liquid dispersion can then be introduced into a desired aqueous environment.
- Non-aqueous is intended to mean a solvent or mixture of solvents wherein the amount of water present is sufficiently low as to not impede dissolution of the lipid blend.
- the amount of non-aqueous solvent required will depend on the solubility of the lipid blend and also the final desired concentration of each component. As one of ordinary skill would appreciate, the level of water present in the non-aqueous solvent, which may be tolerated will vary based on the water solubilities of the individual lipids in the lipid blend. The more water soluble the individual phospholipids, the more water which may be present in step (1).
- propylene glycol is used as the non-aqueous solvent.
- other members of the polyol family such as ethylene glycol, and polyethylene glycol 300 may be used.
- the temperature at which step (1) may be performed can range from ambient to the boiling point of the chosen solvent. Preferably the temperature is from about 30 to about 70° C., more preferably about 45 to about 60° C., and even more preferably about 50, 51, 52, 53, 54, or 55° C. When ethylene glycol or polyethylene glycol 300 is used, it is preferred that the temperature be from about 50 to about 60° C. and more preferably about 55° C. Maintaining the solution at an elevated temperature should reduce solution viscosity and ease formulation preparation.
- a preferred procedure for dissolving the lipid blend is as follows: (a) Add propylene glycol to an appropriate weighing container. (b) Warm the propylene glycol to about 40-80° C. in a heating bath. (c) Weigh the lipid blend into a separate container. (d) When the propylene glycol has reached the desired temperature range, transfer the solution into the container containing the lipid blend. (e) Place the container back into the heating bath until the solution is clear. (f) Mechanically mix the Lipid Blend/Propylene Glycol solution to further assure complete dissolution and uniform dispersion of the lipid blend.
- the ratio of lipid blend to non-aqueous solvent will, of course, be limited by the solubility of the lipid blend. This ratio will also be influenced by the desired amount of lipid blend in the final formulation. Preferably, the ratio is from about 1 mg of lipid blend per mL of solvent (mg/mL) to about 100 mg/mL. More preferably, the lipid blend is present in about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mg/mL. Even more preferably, the lipid blend is present in about 10 mg/mL.
- the second step involves contacting the solution from step (1) with an aqueous solution to form a lipid suspension.
- the aqueous solution can be water, saline, a saline/glycerin mixture or a saline/glycerin/non-aqueous solvent mixture.
- Non-aqueous solvent is as defined previously, preferably propylene glycol.
- Suspension as used herein, is intended to indicate a dispersion in which insoluble particles are dispersed in a liquid medium.
- the resulting solution can then be introduced to an aqueous solution.
- the aqueous solution may contain one or more components selected from sodium chloride, glycerin, and a non-aqueous solvent.
- the aqueous solution contains glycerin and sodium chloride.
- a sufficient amount of propylene glycol is present in the aqueous solution, prior to addition of the solution from step 1, in order to achieve the final desired concentration of propylene glycol.
- the lipid-blend solution is added to water, which may already contain the above-noted additional components. Additional desired components can then be added. It is more preferred that the lipid-blend solution is added a solution of water and sodium chloride (i.e., saline). It is further preferred that the lipid-blend solution is added a solution of water, sodium chloride, and glycerin. It is still further preferred that the lipid-blend solution is added a solution of water, sodium chloride, glycerin, and propylene glycol.
- sodium chloride i.e., saline
- the lipid-blend solution is added a solution of water, sodium chloride, and glycerin. It is still further preferred that the lipid-blend solution is added a solution of water, sodium chloride, glycerin, and propylene glycol.
- 0.1 mL of Glycerin per mL of formulation is present.
- a final concentration of 0.1 mL of Propylene Glycol per mL of formulation is preferred.
- the final pH of the formulation is preferably about 5.5-7.0.
- the lipid blend is preferably present in an amount of 0.75-1.0 mg/mL of formulation.
- the temperature of the aqueous solution can range from ambient to 70° C. Preferably, the temperature is about 45 to 60° C., with 50, 51, 52, 53, 54, or 55 being even more preferred.
- the mixture will need to be agitated, preferably stirred.
- the pH of the solution may need to be adjusted, depending on the desired final formulation. Either acid (e.g., HCl) or base (e.g., NaOH) can be added to make such an adjustment.
- the lipid suspension will contain liquid particles of varying sizes.
- One of the benefits of the present invention is the ability to consistently obtain small particles of a nearly uniform size. Thus, it is preferred that the majority of particles obtained are less than 100 nm in diameter, more preferable less than 50 nm.
- a preferred procedure for dissolving the lipid blend is as follows: (a) Add Water for Injection (WFI) into a compounding vessel. (b) Start mixing and ensure temperature is from 50-55° C. (c) Add sodium chloride to the compounding vessel. Wait until the solid has completely dissolved before proceeding to the next step. (d) Add glycerin to the compounding vessel. Allow sufficient time for complete mixing. (e) Add the remaining Propylene Glycol that is not in the Lipid Blend/Propylene Glycol solution. Allow time for thorough mixing. (f) Reduce mixing rate to reduce turbulence in the compounding vessel. (g) Add the Lipid Blend/Propylene Glycol solution to the compounding vessel. (h) Readjust mixing to original rate. (i) Add additional WFI if necessary. (j) Continue to mix for approximately 25 minutes and assure complete mixing. (k) Verify and adjust the solution to target pH.
- WFI Water for Injection
- Step three involves heating the lipid suspension obtained from step (2) to a temperature about equal to or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the solution.
- One of the objects of this step is to provide a filterable suspension.
- a solution/suspension is considered filterable if there is no significant reduction in flow rate within a normal process, and there is no significant increase in the pressure drop in the filtration system.
- DPPC and DPPA show phase transitions of 41° C. and 67° C. respectively.
- MPEG5000-DPPE is soluble in water, therefore it does not exhibit a gel-liquid crystal phase transition which is characteristic of most hydrated lipid suspensions.
- the highest phase transition temperature, 67° C. is preferably used to filter the solution. By maintaining temperature at or beyond 67° C., all the lipids are beyond their respective phase transition, assuring the loose configuration while passing through the filters.
- Heating may be achieved by jacketing the compounding vessel with a heat exchanging coil.
- Hot water/steam from a controlled source e.g., a hot water bath, or a water heater, would deliver sufficient heat to maintain the compounding solution at a set temperature.
- a controlled source e.g., a hot water bath, or a water heater
- Other heat sources known to thsoe of skill in the art could also be used.
- Step four is performed by filtering the lipid suspension through a sterilizing filter.
- the purpose behind this step being to provide a substantially bacteria-free suspension.
- a filtrate is considered substantially bacteria-free when the probability of the filtrate to contain at least one colony forming microorganism is less than 10 ⁇ 6 .
- Filtration is preferably done using sterilizing filter cartridges. Also, a means of forcing the solution through the filters may be required (e.g., pumping or pressurizing). Since the solution being filtered needs to be maintained at a temperature at or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the solution, the filtration should be performed at about this same temperature. In order to accomplish this, the filter (e.g., sterilizing filter cartridges) are preferably enclosed in jacketed filter housings which are continuously heated, e.g., by a hot water stream from a temperature controlled water bath, to ensure that the suspension is above the lipid phase transition temperatures.
- the filter e.g., sterilizing filter cartridges
- jacketed filter housings which are continuously heated, e.g., by a hot water stream from a temperature controlled water bath, to ensure that the suspension is above the lipid phase transition temperatures.
- the temperature of the sterilizing filter is preferably from 50 to 100° C., more preferably from 60 to 90° C., and even more preferably 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80° C.
- One or more sterilizing filters may be used to filter the suspension. The required number will be based on their effectiveness at removing bacteria. It is preferred that two filters are used. The size of the filter pores will be limited by the need to provide a bacteria-free suspension. Preferably, 0.2 ⁇ m hydrophilic filters are used.
- a bulk solution of the preferred formulation was continuously filtered through two 0.2 ⁇ m hydrophilic filters for up to 3 hours at a rate of approximately 1 liter per minute (1 L/min.), i.e., passing a total of 180 liters of the suspension solution through the filters.
- the experimental results shows that there is no apparent blockage of filters. Lipid assays indicates that there is no measurable loss during the filtration process (due to accumulation in the filter medium).
- a bulk solution of the preferred formulation was compounded at 40° C.-80° C., and the suspension was cooled to ambient temperature prior to sterile filtration. No apparent clogging of the filters were observed indicating the suspension particle size distribution is well below 0.2 ⁇ m of the filter pore size. It is desirable to use heat during filtration in order to ensure maximum recover of the lipid blend in the sterile filtrate (i.e., to minimize potential retention of lipid particles in the filter medium).
- a preferred procedure for filtering the lipid suspension is as follows: (a) Assure all jacketed filters are at 70° C.-80° C. (b) Assure all valves in the filtration unit are closed. (c) Connect filtration inlet hose to the outlet of the compounding vessel. (d) Open valves to allow solution to pass through the filters. (e) Flush three liters of solution through the filters before collecting filtrate. (f) Continue filtration until complete.
- Dispensing the filtered solution into a vial completes step five. Preferably, this step is performed in a controlled aseptic area.
- this step is performed in a controlled aseptic area.
- the vial selected and amount of suspension delivered to the vial would depend on the end use considered for the lipid suspension.
- Dispensing can be achieved via a variety of methods, including pipette, hand-held syringe dispenser (e.g., Filamatic® syringe dispensing machine), or industrial auto dispensing machine (e.g., Cozzoli or TL auto filling machine).
- Step six is performed by exchanging the headspace gas of the vials from step five with a perfluorocarbon gas.
- a preferred method of exchange is to load the dispensed vials into a lyophilizer chamber and replace the vial headspace gas with a perfluorocarbon gas.
- a preferred gas is perfluoropropane (PFP).
- PFP perfluoropropane
- the vials are sealed at the completion of the vial headspace gas exchange cycle.
- the lyophilizer chamber pressure is brought back to atmospheric pressure by charging into the chamber with PFP.
- Vial stoppers are seated to seal the vials.
- Step seven involves terminally sterilizing a vial after step six.
- One method of terminal sterilization is through the use of an autoclave.
- the sealed vials can be terminally sterilized in a steam sterilizer to further enhance the sterility assurance of the product. Care must be taken in the sterilization process as some degradation of lipids may be observed as a result of autoclaving.
- the vial is sterilized at about 126-130° C. for 1 to 10 minutes.
- a flask is charged with toluene (3.3 L), methanol (1.2 L), DPPA (59.6 g), DPPC (535 g), and MPEG5000 DPPE (405 g). After rinsing solid contact surfaces with 0.9 L methanol, the slurry is warmed to 45-55° C. until dissolution is complete.
- a rotary evaporation flask is charged sequentially with toluene (3,300 mL), methanol (1,200 mL), DPPA (122.9 g; corrected for “use as” purity of 97.0%), DPPC (1,098.5 g total; 500.8 g from a lot with 98.4% “use as” purity and 597.7 g from a lot with 96.7% “use as” purity), and MPEG5000 DPPE ( 815.7 g; corrected for “use as” purity of 99.3%).
- the flask After rinsing residual solids into the flask with methanol (900 mL), the flask is placed on a rotary evaporator (no vacuum) and the slurry is warmed to between 45 and 55° C. (external). After dissolution is complete, the external temperature is reduced to between 35 and 45° C., a vacuum is applied, and the solution is concentrated to a white semi-solid. The flask is removed from the evaporator and solids are broken up with a spatula. The flask is reapplied to the evaporator and concentration is continued.
- methanol 900 mL
- MTBE (5,400 mL) is added through the rotary evaporator's addition tube, the vacuum is discontinued, and the mixture is slurried for 15 to 45 min at 15 to 30° C. Solids are isolated by either centrifugal or vacuum filtration, rinsed with MTBE (3,800 mL), and dried to constant weight in a vacuum oven (40 to 50° C.). Prior to transferring to polyethylene bottles with polypropylene caps, solids are delumped through a screen (0.079 inch mesh), affording 1,966.7 g (98%) of lipid blend (SG896) as a white solid.
- the preferred lipid suspension contains:
- DPPA 1,2-dipalmitoyl-sn-glycero-3-phosphotidic, mono sodium salt
- DPPC 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine
- N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine, monosodium salt MPEG5000-DPPE
- the finished product fill volume can be from 1.0-2.0 mL/vial.
- the presently claimed process is useful for preparing ultrasound contrast agents. Such agents should be useful for a variety of imaging applications, including enhancing contrast in echocardiographic and radiologic ultrasound images.
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Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
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US09/229,258 US20010003580A1 (en) | 1998-01-14 | 1999-01-13 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
US10/667,931 US8084056B2 (en) | 1998-01-14 | 2003-09-22 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
US13/195,734 US8658205B2 (en) | 1998-01-14 | 2011-08-01 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
US13/361,771 US20120128595A1 (en) | 1998-01-14 | 2012-01-30 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
US13/949,105 US8685441B2 (en) | 1998-01-14 | 2013-07-23 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
US13/950,348 US8747892B2 (en) | 1998-01-14 | 2013-07-25 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
US14/188,598 US9545457B2 (en) | 1998-01-14 | 2014-02-24 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
US15/374,147 US20170312375A1 (en) | 1998-01-14 | 2016-12-09 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
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US7133298P | 1998-01-14 | 1998-01-14 | |
US09/229,258 US20010003580A1 (en) | 1998-01-14 | 1999-01-13 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
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US13/195,734 Expired - Fee Related US8658205B2 (en) | 1998-01-14 | 2011-08-01 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
US13/361,771 Abandoned US20120128595A1 (en) | 1998-01-14 | 2012-01-30 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
US13/949,105 Expired - Fee Related US8685441B2 (en) | 1998-01-14 | 2013-07-23 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
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US15/374,147 Abandoned US20170312375A1 (en) | 1998-01-14 | 2016-12-09 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
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US10/667,931 Expired - Fee Related US8084056B2 (en) | 1998-01-14 | 2003-09-22 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
US13/195,734 Expired - Fee Related US8658205B2 (en) | 1998-01-14 | 2011-08-01 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
US13/361,771 Abandoned US20120128595A1 (en) | 1998-01-14 | 2012-01-30 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
US13/949,105 Expired - Fee Related US8685441B2 (en) | 1998-01-14 | 2013-07-23 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
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US14/188,598 Expired - Fee Related US9545457B2 (en) | 1998-01-14 | 2014-02-24 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
US15/374,147 Abandoned US20170312375A1 (en) | 1998-01-14 | 2016-12-09 | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
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- 1999-01-14 EA EA200000765A patent/EA002978B1/ru not_active IP Right Cessation
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- 1999-01-14 HU HU0100206A patent/HUP0100206A3/hu active Protection Beyond IP Right Term
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- 1999-01-14 EP EP99901466A patent/EP1027035A2/en not_active Withdrawn
- 1999-01-14 EE EEP200000422A patent/EE04900B1/xx not_active IP Right Cessation
- 1999-01-14 PL PL99342473A patent/PL193672B1/pl unknown
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- 1999-01-14 WO PCT/US1999/000747 patent/WO1999036104A2/en not_active Application Discontinuation
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- 1999-01-14 AT AT04075388T patent/ATE447976T1/de active
- 1999-01-14 CN CNB998021024A patent/CN1191822C/zh not_active Expired - Lifetime
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- 1999-01-14 KR KR1020007007716A patent/KR100711663B1/ko not_active IP Right Cessation
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2003
- 2003-09-22 US US10/667,931 patent/US8084056B2/en not_active Expired - Fee Related
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2004
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2013
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2014
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US20100057264A1 (en) * | 1999-12-03 | 2010-03-04 | Baxter International Inc. | Method and apparatus for controlling the compounding of a pharmaceutical admixture |
US20070110775A1 (en) * | 2005-11-16 | 2007-05-17 | Murthy Yerramilli V | Phospholipid gel compositions for delivery of aptamers and methods of treating conditions using same |
US8017159B2 (en) | 2005-11-16 | 2011-09-13 | Idexx Laboratories, Inc. | Phospholipid gel compositions for delivery of aptamers and methods of treating conditions using same |
US8951450B2 (en) | 2009-09-02 | 2015-02-10 | Biomedcore, Inc. | Apparatus and method for production of liposomes |
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