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Gas micro-liposome compound

A technology of liposomes and complexes, applied in the directions of liposome delivery, drug combination, peptide/protein composition, etc., can solve the problems of poor ultrasound imaging quality, disappointing diagnostic results, and inability to quantify, and achieve improved contrast, excellent Acoustic response characteristics, the effect of small segregation

Inactive Publication Date: 2005-05-25
BRISTOL MYERS SQUIBB PHARMA CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] Although these contrast agents disclosed above have been used, the resulting ultrasound images of, for example, myocardial tissue may be of relatively poor quality, highly variable and not quantifiable
All diagnoses to date have been somewhat disappointing

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] A saline glycerol solution (100 ml) was prepared comprising glycerol (10 ml) and NaCl (680±2 mg) dissolved in water (final volume 100 ml). In a 100ml volumetric flask, DPPC (dipalmitoylphosphatidylcholine) (40.0mg), MPEG500 DPPE (dipalmitoylphosphatidylethanolamine) (30.0mg) and DPPA (4.5mg) were mixed with propylene glycol (10ml), and The volumetric flask was placed in a hot water bath (70°C) and sonicated for 15 minutes until the solution was clear. A saline / glycerol solution was then added to bring the mixture to a final volume of 100 ml, and the suspension was mixed well. The suspension (1.6ml) was transferred to a 2ml borosilicate glass vial. The headspace was purged with perfluoropropane gas and the vials were stoppered and sealed. The stoppers were West Gray V 50 lyo 13mm, 4416 / 50 elastic formula. The sealing ring is an aluminum sealing strip that can be torn off gently. Using IONOS Ionomix  The vial containing the lipid suspension was shaken for 45 seconds...

Embodiment 2

[0120] Part A. 1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine-cyclo(arginine-glycine-aspartic acid-D-phenylalanine-lysine)-dodecanoate Synthesis of conjugates

[0121]

[0122] Under stirring (5 minutes), disuccinimidyl dodecanoate (0.424 g, 1 mmol), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) (1.489 g, 1 mmol ) and cyclic (arginine-glycine-aspartic acid-D-phenylalanine-lysine) TFA salt (0.831g, 1mmol) (for the synthesis of the cyclic peptide targeting part, refer to US Patent Series No. 09 / 281,474, the method of which is incorporated herein by reference) was dissolved in chloroform (25 ml). Sodium carbonate (1 mmol) and sodium sulfate (1 mmol) were added and the solution was stirred at room temperature under nitrogen (18 hours). Chloroform was removed in vacuo and the title compound was purified from the crude product mixture by preparative HPLC or recrystallization.

[0123] Part B. Preparation of Control Agent Compositions

[0124] Coupling of 1,2-dipa...

Embodiment 3

[0126] Part A. Omega-Amino-PEG 3400 - Preparation of the ring (arginine-glycine-aspartic acid-D-phenylalanine-lysine):

[0127]

[0128] Add triethylamine (3mmol) to N-Boc-PEG 3400 -Succinimidyl ester (1 mmol) and cyclo(arginine-glycine-aspartate-D-phenylalanine-lysine) (1 mmol) in dimethylformamide (DMF) (25 mL) middle. The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere and the solvent was removed in vacuo. The crude product was dissolved in trifluoroacetic acid / dichloromethane (1:1 v / v) and stirred for 4 hours. The volatiles were removed and the TFA salt of the title compound was isolated by trituration in diethyl ether.

[0129] Part B: DPPE-PEG 3400 - Preparation of cyclic (arginine-glycine-aspartic acid-D-phenylalanine-lysine)-dodecanoate conjugates:

[0130]

[0131]Disuccinimidyl dodecanoate (1 mmol), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) (1 mmol) and ω-amino-PEG were mixed with stirring for 5 minutes...

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Abstract

Formulations comprising a gas microsphere liposome composite suspended in a medium, wherein the gas mcirosphere liposome composite comprises: a gas-filled microsphere; at least one of a lipid and a surfactant adsorbed onto the surface of the gas-filled microsphere; and liquid-filled liposomes attached to the lipid or surfactant are described. Methods of preparing the same and using them in ultrasound imaging are also described. The present invention also comprises used of the same in treating heart disease, inflammation, infection, cancer or thromboembolic disease in a patient.

Description

technical field [0001] The present invention provides formulations comprising gas microsphere-liposome complexes (MSLC) suspended in a medium. The gas microsphere-liposome complex includes gas-filled microspheres; at least one lipid and surfactant adsorbed on the surface of the gas-filled microspheres; and liquid-filled liposomes attached to the lipid or the surfactant. The outer surface of the liquid-filled liposome can be combined with a targeting ligand (ie, a diagnostic drug targeting moiety) for the orientation of various MSLCs for selective imaging of receptors, enzymes, mRNA and other related biological targets freed. Additionally, one or more drugs (eg, therapeutic and / or diagnostic drugs) may be included within the interior volume of the liquid-filled liposomes. In this way, the therapeutic drugs or diagnostic drugs can be selectively released to diseased organs or sites for targeted release. Accelerated drug release can be stimulated by the use of acoustic energy ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/475A61K31/519A61K9/127A61K31/675A61K31/704A61K31/7068A61K33/24A61K38/00A61K41/00A61K47/06A61K47/14A61K47/18A61K47/20A61K47/32A61K47/36A61K47/38A61K47/42A61K47/44A61K49/00A61K49/04A61K49/22A61P7/02A61P9/02A61P29/00A61P31/04A61P35/00
CPCA61K41/0028A61K49/223A61P29/00A61P31/04A61P35/00A61P7/02A61P9/02A61K9/127
Inventor A·P·小卡尔彭特G·C·斯拉克
Owner BRISTOL MYERS SQUIBB PHARMA CO
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