WO2006076826A1 - Composition de contraste pour ultrasons utilisant un phospholipide filmogene et procede de preparation de celle-ci - Google Patents

Composition de contraste pour ultrasons utilisant un phospholipide filmogene et procede de preparation de celle-ci Download PDF

Info

Publication number
WO2006076826A1
WO2006076826A1 PCT/CN2005/000075 CN2005000075W WO2006076826A1 WO 2006076826 A1 WO2006076826 A1 WO 2006076826A1 CN 2005000075 W CN2005000075 W CN 2005000075W WO 2006076826 A1 WO2006076826 A1 WO 2006076826A1
Authority
WO
WIPO (PCT)
Prior art keywords
freeze
composition
phospholipid
ultrasonic
film
Prior art date
Application number
PCT/CN2005/000075
Other languages
English (en)
Chinese (zh)
Inventor
Xingguo Mei
Sicheng Li
Yingzheng Zhao
Jie Tang
Yan Zhang
Xinhui Luan
Original Assignee
Institute Of Pharmacology Toxicology, Academy Of Military Medical Sciences
Cheng Du Yiping Medical Technology Co. Tld.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Institute Of Pharmacology Toxicology, Academy Of Military Medical Sciences, Cheng Du Yiping Medical Technology Co. Tld. filed Critical Institute Of Pharmacology Toxicology, Academy Of Military Medical Sciences
Priority to PCT/CN2005/000075 priority Critical patent/WO2006076826A1/fr
Publication of WO2006076826A1 publication Critical patent/WO2006076826A1/fr

Links

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
    • A61K49/227—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
    • 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
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres

Definitions

  • the present invention relates to an ultrasonic contrast agent composition, and more particularly to an ultrasonic contrast agent composition coated with a fluorocarbon-based inert gas using a phospholipid component as a film-forming material and a preparation method thereof.
  • the new ultrasound contrast agent combined with new ultrasound technology can effectively enhance the two-dimensional ultrasound image and blood flow Doppler signal of the normal organs such as myocardium, liver, kidney and brain, reflecting the different blood of normal tissues and diseased tissues (tumor, ischemic myocardium). Flow perfusion significantly improves the sensitivity and specificity of ultrasound diagnosis.
  • ultrasound contrast agents carrying genes and drugs have broad application prospects in therapy.
  • the ideal new ultrasound contrast agent has the following characteristics: high scattering, low dispersion, low solubility, no biological activity (no harm to human body, self-extraction through capillaries, uniform size of microbubbles, good tissue development, effective enhancement Tissue development is sufficient for inspection time).
  • a new generation of ultrasound contrast agents mostly use fluorine-containing gas as the core of microbubbles. Because of the inert gas of fluorine-containing carbon gas, the molecular weight is large, the solubility and dispersion in the blood are poor, and the stability is good. There are albumin, surfactants, bricks, and polymers depending on the material of the fluorocarbon gas.
  • the use of phospholipids as a film-forming material contrast agent has more advantages due to: (1) targeting. After the phospholipid contrast agent is introduced into the body, it is preferentially taken up by tissues rich in reticuloendothelial cells such as liver, spleen and bone marrow. (2) Good stability.
  • Phospholipids Contrast agents are chemically stable, can be stored for several months at room temperature, and are easy to commercialize; (3) Safe.
  • the phospholipid membrane constituting the phospholipid contrast agent is biodegradable and harmless to the human body; and the albumin-based contrast agent has a risk of transmitting blood diseases due to human albumin as a carrier. Summary of the invention
  • the present invention adopts the following technical solutions:
  • the contrast agent composition provided with the lipid component as a film-forming material is a composition which uses a phospholipid substance as a main component to form a film-forming material, and the film-forming material and fluorocarbon type.
  • the inert gas is mixed together for the purpose of imaging.
  • the composition of the film-forming material includes components such as a phospholipid component, a foaming agent, a polymer component, a stabilizer, etc.; the weight percentage of these components in the contrast agent composition is, the ratio of the phospholipid substances is 1 to 10 The weight %, the proportion of the foaming agent is 5 to 15 parts by weight. /.
  • the stabilizer ratio is 0.5 to 10 parts by weight. /.
  • the polymer composition ratio is 70 to 90% by weight, and the rest is a fluorocarbon inert gas.
  • the above contrast agent composition may be present in unit dosage form, for example, as a vial, and when administered, different doses may be applied according to the needs of the patient, and each dosage unit may contain a fluorocarbon inert gas of 0.15 to 0.5 ml.
  • the phospholipid component is selected from at least one of the following: lecithin (PC), hydrogenated soy phosphatidylcoline (HSPC), hydrogenated egg phosphatidylcoline (HSPC), two palms Acylphosphatidylethanol (DPPE), dipalmitoylphosphatidylcholine (DPPC), dioleylphosphatidylethanolamine (DOPE), polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE), 1, 2-dipalmitoyl-sn-glycero-3-phosphatidic acid glyceryl-sodium salt (DPPG), 1,2-distearoyl-sn-glyceryl-3-phosphatidylcholine (DSPC), 1, 2-dipalmitoyl-sn-glycero-3-phosphatidic acid-sodium salt (DPPA), 1,2-dipalsyl-sn-glyceryl-3-phosphatidylcholine (DPPC).
  • PC lec
  • Said foaming agent is selected from at least one nonionic surfactant, nonionic surfactants such as Tween, Span; the purpose of using a foaming agent is to increase the preparation of contrast microbubbles The yield of microbubbles at the same time has a stabilizing effect on the lipid membrane.
  • the polymer is selected from at least one high molecular polymer, such as a poloxamer, and the high molecular weight polymer is used as a lipid component and a foaming agent to form a contrast film.
  • a high molecular polymer such as a poloxamer
  • the high molecular weight polymer is used as a lipid component and a foaming agent to form a contrast film.
  • the stabilizer used is selected from the group consisting of polyethylene glycol, glyceryl monostearate, palmitic acid, preferably polyethylene glycol 1500 (PEG1500), and the purpose of applying stabilizers is to reduce the mutual interaction of contrast microbubbles.
  • the tendency of fusion improves the hydrophilic lipophilic effect of the lipid bilayer and enhances the stability of the contrast microbubbles.
  • the role of the fluorocarbon-based inert oxidizing gas in the contrast agent is to provide a high-intensity reflection interface for the ultrasonic waves together with the film-forming material, the fluorocarbon-based inert gas being selected from the group consisting of fluoride gas, fluoride gas, specifically It includes perfluorocarbon gas, sulfur fluoride gas, etc. In the application, it is mainly perfluoropropane and sulfur hexafluoride.
  • the contrast agent composition of the present invention can be prepared by the following method:
  • the film-forming material phospholipid component, foaming agent, polymer component, stabilizer and other components (such as HEPC; Poloxamer 188, Tween 80 and PEG 1500) and a small amount of anhydrous or water-containing nonaqueous solvent Contact, using ultrasonic and heating to make it a uniform solution system, using a temperature of 45 ⁇ 65 ° C, the time is 20 ⁇ 40 minutes.
  • the nonaqueous solvent described in the above step is a linear or branched alcohol such as butanol which is anhydrous or contains a trace amount of water.
  • the nonaqueous solvent described in the more preferred embodiment is tert-butanol.
  • the temperature required for the film material to be dispersed and dissolved in a linear or branched alcohol such as t-butanol is 45 to 65 ° C for 20-40 minutes.
  • the ultrasonic mode may be a water bath or probe type ultrasound, and the ultrasonic mode described in the more preferred embodiment is probe type ultrasound.
  • Freeze-drying with a freeze dryer freeze-drying time is 20 ⁇ 25 hours, and the vacuum suction pressure is 50 ⁇ in freeze-drying; 120 X l (T 3 mBar, freeze-drying temperature control is -40 ⁇ - 50 °C.
  • the freeze-dried lyophilized product is pulverized in a strictly controlled sterile chamber, and dispensed into a vial to prepare a powder injection, and a fluorocarbon-based inert gas is injected into the bottle to cover the cake.
  • the superiority of the invention is as follows: 1.
  • the microbubble yield is high, and the microbubble concentration reaches lx l0 9 /ml, and And the uniformity of microbubbles is good, the microbubbles with diameter of 2 ⁇ 6 ⁇ ⁇ account for 50 ⁇ 70% (see Figure 1); 2.
  • the effective enhancement time of contrast agent in tissue development is long; 3.
  • the cost is low, the product cost is much lower than Similar products.
  • Figure 1 shows the morphology of the microbubbles at different times after the configuration (the contrast agent is diluted 4 times and observed under a 400-fold light microscope).
  • Figure 2 is a contrast-enhanced image of contrast agent after renal artery injection into the rabbit ear vein; the figure shows the dose of O.lmL/kg before the bolus (a), contrast agent bolus Kidney development after 30 seconds (b), 1 minute (c).
  • Figure 3 is a contrast-enhanced image of the contrast agent after contrast-enhanced administration of the rabbit ear vein vein.
  • the figure shows the dose of 0.1 mL/kg at 10 seconds (a), 30 seconds after the bolus injection. (b), 1 minute (c) liver parenchymal development. detailed description
  • Example 1 Preparation of a contrast agent using a phospholipid component as a film-forming material
  • PC polyegrose lecithin
  • Tween 80 Tween 80
  • the particle size distribution is 2 ⁇ 8 ⁇
  • the cell wall thickness is 200-800 nm.
  • Example 3 had stronger development strength and longer development time than Examples 1 and 2, indicating that the product exhibited better development effects than those of Examples 1 and 2.
  • mode (3) (repeated freeze-thaw mode: 0-4 °C coagulation - water bath 15_ 2 2 °C ultrasound to emulsion-like -4 ⁇ coagulation) and mode (4) (15-22 'C room temperature placed
  • the concentration of microbubbles, the average particle size and the percentage of microbubbles of 2 ⁇ 8 ⁇ obtained from 0-4 C refrigerated lOmin after liquid solidification were the best.
  • the development effects of the modes (3) and (4) are better than those of the embodiment 3.
  • poloxamer 188 (POLoxamer 188) 150 mg, hydrogenated egg fat 5 mg and Tween 80 25 mg ⁇ t in 2 ml of tert-butanol, and sonicating in a water bath at 60 °C. 18-22 Place at room temperature until the liquid solidifies (40 min), 0-4. C refrigerated for 10 min. Freeze for 20 hours. The lOOmg lyophilized sample was weighed into a 5 ml vial and filled with perfluoropropane gas and condensed to prepare a solid ultrasonic contrast agent.
  • the liver and kidney of rabbits were subjected to contrast-enhanced ultrasound using the contrast agent prepared in Example 5, and administered to the rabbit ear vein at a dose of 0.03 ml/k g .
  • the liver and kidneys showed significant enhanced imaging in about 10 seconds. , 30 seconds to reach the peak, effective enhancement time of more than 1 minute.
  • Poloxamer 188 (POLoxamer 188) 150 mg, hydrogenated lecithin 8 mg and Tween 80 20 mg ⁇ t were weighed into 2 ml of anhydrous tert-butanol, and sonicated in a water bath at 60 °C. Refrigerate at 0-4 ° C until the liquid is solidified, ultrasonically to an emulsion at 37-39 ° C, and set to solidify at room temperature. Freeze for 20 hours. A lOOmg lyophilized sample was weighed into a 5 ml vial, filled with perfluoropropane gas, and sealed to obtain a solid ultrasonic contrast agent.
  • the contrast agent prepared in Example 6 was better than that in Example 5.
  • the effective enhancement of renal imaging was more than 2 minutes, and the gray scale of liver parenchyma was still higher than that before non-contrast at 10 minutes.

Abstract

L’invention concerne une composition liposomique de contraste pour ultrasons et sa préparation. La composition est constituée de matériaux filmogènes et d’un gaz fluorocarboné. Lesdits matériaux filmogènes sont constitués de 1 à 10 % en poids d’un phospholipide, de 5 à 15 % en poids d’un agent moussant, de 0,5 à 10 % en poids d’un stabilisateur et de 70 à 90 % en poids d’un polymère. La composition vésiculaire de contraste pour ultrasons est sous une forme galénique mono-dose contenant de 0,15 à 0,5 ml de gaz fluorocarboné.
PCT/CN2005/000075 2005-01-18 2005-01-18 Composition de contraste pour ultrasons utilisant un phospholipide filmogene et procede de preparation de celle-ci WO2006076826A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2005/000075 WO2006076826A1 (fr) 2005-01-18 2005-01-18 Composition de contraste pour ultrasons utilisant un phospholipide filmogene et procede de preparation de celle-ci

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2005/000075 WO2006076826A1 (fr) 2005-01-18 2005-01-18 Composition de contraste pour ultrasons utilisant un phospholipide filmogene et procede de preparation de celle-ci

Publications (1)

Publication Number Publication Date
WO2006076826A1 true WO2006076826A1 (fr) 2006-07-27

Family

ID=36691961

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2005/000075 WO2006076826A1 (fr) 2005-01-18 2005-01-18 Composition de contraste pour ultrasons utilisant un phospholipide filmogene et procede de preparation de celle-ci

Country Status (1)

Country Link
WO (1) WO2006076826A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112190720A (zh) * 2020-11-03 2021-01-08 贵州医科大学 一种可负载治疗药物的超声造影治疗剂及其制备方法
CN113440627A (zh) * 2021-07-30 2021-09-28 北京诺康达医药科技股份有限公司 一种冻干粉末及其制备方法与应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1213971A (zh) * 1996-02-19 1999-04-14 奈科姆成像有限公司 热稳定的造影剂
CN1227502A (zh) * 1996-08-02 1999-09-01 奈科姆成像有限公司 造影剂及其相关造影剂的改进
CN1404878A (zh) * 2002-09-06 2003-03-26 中国人民解放军第三军医大学 新型脂质体超声造影剂及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1213971A (zh) * 1996-02-19 1999-04-14 奈科姆成像有限公司 热稳定的造影剂
CN1227502A (zh) * 1996-08-02 1999-09-01 奈科姆成像有限公司 造影剂及其相关造影剂的改进
CN1404878A (zh) * 2002-09-06 2003-03-26 中国人民解放军第三军医大学 新型脂质体超声造影剂及其制备方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112190720A (zh) * 2020-11-03 2021-01-08 贵州医科大学 一种可负载治疗药物的超声造影治疗剂及其制备方法
CN113440627A (zh) * 2021-07-30 2021-09-28 北京诺康达医药科技股份有限公司 一种冻干粉末及其制备方法与应用
CN113440627B (zh) * 2021-07-30 2022-11-25 北京诺康达医药科技股份有限公司 一种冻干粉末及其制备方法与应用

Similar Documents

Publication Publication Date Title
JP4229918B2 (ja) 超音波のコントラスト増強のためのリン脂質を含む安定な気体エマルジョン
KR100500334B1 (ko) 조영제또는그와관련된개선
KR101076053B1 (ko) 초음파 조영제 및 그것의 제조방법
JP4067116B2 (ja) オストワルド係数の低いフッ素化エーテルで安定化させたガスエマルジョン
KR100295173B1 (ko) 초음파콘트라스트매질로서유용한가스혼합물
JP3135919B2 (ja) 超音波検査法のための強化剤としての安定性微小泡懸濁液
JP5420410B2 (ja) ポリマー修飾脂質を含むガス封入微小胞
JPH11508871A (ja) 脂質および安定化用物質の新規な組成物
JPH09506098A (ja) 局所的および皮下的適用のための気体マイクロスフェア
JP2008260775A (ja) 新規な分散性脂質配合物及びそれらの使用
US10456483B2 (en) Gas-encapsulated acoustically responsive stabilized microbubbles and methods for treating cardiovascular disease
WO2010083778A1 (fr) Composition pharmaceutique injectable de liposome ciblant les poumons
JPH0737394B2 (ja) 微小気泡及び微粒子から成る超音波造影剤及びその製法
Zhou et al. Folate-targeted perfluorohexane nanoparticles carrying bismuth sulfide for use in US/CT dual-mode imaging and synergistic high-intensity focused ultrasound ablation of cervical cancer
Reusser et al. Phospholipid oxygen microbubbles for image-guided therapy
CN101721718B (zh) 脂质微泡及其制备方法
Chattaraj et al. Ultrasound responsive Noble gas microbubbles for applications in image‐guided gas delivery
CN1321697C (zh) 一种以磷脂类成分为成膜材料的超声造影剂组合物及其制备方法
CN109562068A (zh) 含有弱酸性剂的微脂体组合物
WO2006076826A1 (fr) Composition de contraste pour ultrasons utilisant un phospholipide filmogene et procede de preparation de celle-ci
JP2001515055A (ja) 造影剤に関する改良
CN107233582B (zh) 一种基于叔丁醇/水混合溶剂制备超声造影剂的方法
KR20020062916A (ko) 연속 주입에 의한 중력 분리 용액 투여
JP6903318B2 (ja) 一酸化窒素内包バブルリポソーム及びその利用
CN101721719A (zh) 超声造影剂及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 05700449

Country of ref document: EP

Kind code of ref document: A1

WWW Wipo information: withdrawn in national office

Ref document number: 5700449

Country of ref document: EP