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WO1997004811A2 - Utilisation de preparations liposomales en lymphographie indirecte par imagerie par resonance magnetique - Google Patents

Utilisation de preparations liposomales en lymphographie indirecte par imagerie par resonance magnetique Download PDF

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Publication number
WO1997004811A2
WO1997004811A2 PCT/DE1996/001433 DE9601433W WO9704811A2 WO 1997004811 A2 WO1997004811 A2 WO 1997004811A2 DE 9601433 W DE9601433 W DE 9601433W WO 9704811 A2 WO9704811 A2 WO 9704811A2
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WO
WIPO (PCT)
Prior art keywords
liposomes
liposome
mri
contrast
parts
Prior art date
Application number
PCT/DE1996/001433
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German (de)
English (en)
Other versions
WO1997004811A3 (fr
Inventor
Andreas Sachse
Johannes Platzek
Bernd Misselwitz
Andreas Mühler
Georg Roessling
Original Assignee
Schering Aktiengesellschaft
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 Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to AU68693/96A priority Critical patent/AU6869396A/en
Publication of WO1997004811A2 publication Critical patent/WO1997004811A2/fr
Publication of WO1997004811A3 publication Critical patent/WO1997004811A3/fr

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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
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1806—Suspensions, emulsions, colloids, dispersions
    • A61K49/1812—Suspensions, emulsions, colloids, dispersions liposomes, polymersomes, e.g. immunoliposomes

Definitions

  • the invention relates to the use of liposome formulations which contain MRI contrast agents with high stability in the biological environment and which have particularly good local tolerance in indirect lymphography.
  • lymph node metastases are found in approximately 50-69% of all patients with malignant tumors (Elke, lymphography, in: Frommhold, Stender, Thurn, eds., Radiological Diagnostics in Clinic and Practice, Volume IV, Thieme Verlag Stuttgart, 7th ed. , 434-496, 1984).
  • CT computed tomography
  • US and MRI magnetic resonance imaging
  • Lymph nodes with metastatic involvement and hyperplastic lymph nodes can be distinguished.
  • the contrast medium can be administered intravascularly or interstitially / intracutaneously (see also Siefert, HM et al., Lymphology 13: 150-157, 1980).
  • the interstitial / intracutaneous application has the advantage that the substance is transported directly from the scattering focus (eg primary tumor) through the corresponding lymphatic pathways to the potentially affected regional lymph node stations.
  • a high dose of contrast medium can also be achieved in the lymph nodes with a low dose.
  • markers to be administered interstitially are mainly used in nuclear medicine assessment (using radioactive particles such as isBAu colloid). Nuclear medicine methods have only one insufficient spatial resolution, in contrast to magnetic resonance imaging with its high spatial resolution in the fraction of a millimeter.
  • Direct x-ray lymphography injection of an oily contrast medium suspension into a prepared lymphatic vessel
  • fluorescence-labeled dextrans are also used in animal experiments in order to be able to observe the lymphatic drainage after their interstitial application. It is common for all common markers for the representation of lymphatic passages and lymph nodes after interstitial / intracutaneous application that they are substances with a particulate character ("particulates", eg emulsions and nanocrystalline suspensions) or large polymers (see also WO 90/14846).
  • particulates eg emulsions and nanocrystalline suspensions
  • large polymers see also WO 90/14846
  • liposomes are also fundamentally possible due to their great structural flexibility and their generally good tolerance. In recent years, these vesicles have become increasingly important as potential carrier systems for the various types of contrast media.
  • X-ray (also CT) or MRT (NMR) contrast-containing liposomes for diagnostic purposes, the use of corresponding liposomes in nuclear diagnostics is also described (Seltzer, St. E., Liposomes in diagnostic imaging, In: Gregoriadis, G ., Eds., Liposomes as drug carriers, John Wiley & Sons Ltd., Chichester, New York, Brisbane, Toronto, Singapore 1988, pp. 509 ff.).
  • liposomes can be effectively absorbed into local lymph nodes depending on their size and lipid composition. If there is sufficient stability, the corresponding liposomes pass from the lymphatic system into the bloodstream at a later point in time, where they have a distribution behavior analogous to that of intravenously administered liposomes (uptake in the MPS, especially the liver and spleen). Tumer et al. (Biochim. Biophys.
  • MRI in particular appears to be particularly suitable due to its high spatial resolution with comparatively low contrast agent concentrations.
  • liposomally encapsulated MRI contrast media for imaging the liver and blood pool have already attracted great interest.
  • hydrophilic contrast media, which are included in the aqueous phase, and lipophilic derivatives, which are built into the liposome membrane, were used here (Unger, E., et al., J. Liposome Res. 4, 811-834 (1994)) .
  • the object of the present invention was therefore to provide liposome formulations with contrast agent inclusions which are suitable for use in indirect lymphography.
  • the liposomal preparations according to the invention are surprisingly particularly suitable for use in indirect MRI lymphography.
  • the MRT (NMR) contrast media which are generally known from radiological practice, such as, for example, gadopentetate dimeglumine (Gd-DTPA) or gadodiamide (Gd-DTPA-BMA) are suitable.
  • Gd-DTPA gadopentetate dimeglumine
  • Gd-DTPA-BMA gadodiamide
  • substances with more stable macrocyclic ligands such as, for example, gadobutrol (Gd-DO3A-butriol), gadoterate-meglumine (Gd-DOTA) or gadoteridol (Gd-HP-DO3A)
  • Gd-DO3A-butriol gadobutrol
  • Gd-DOTA gadoterate-meglumine
  • Gd-HP-DO3A gadoteridol
  • Substances containing central atoms other than gadolinium can also be used in MRI contrast media.
  • Complexes of manganese and iron are also suitable.
  • the aqueous phase can moreover contain the auxiliaries known to the person skilled in the art, such as, for example, buffer substances and isotonic, complexing or preserving additives.
  • the lipid components used in the formulations according to the invention are commercially available (e.g. Lipoid KG, Ludwigshafen). As a rule, these are natural or synthetic phospholipids such as, for example, phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidic acid, phosphatidylinositol or sphingolipids.
  • PC phosphatidylcholine
  • PE phosphatidylethanolamine
  • PG phosphatidylglycerol
  • PS phosphatidylserine
  • phosphatidic acid phosphatidylinositol or sphingolipids.
  • SPC soy phosphatidylcholine
  • SPG soy phosphatidylglycerol
  • the corresponding synthetic phospholipids such as distearoylphosphatidylcholine (DSPC) or distearoylphosphatidylglycerol (DSPG) can be used.
  • DSPC distearoylphosphatidylcholine
  • DSPG distearoylphosphatidylglycerol
  • other synthetically or biotechnologically obtained amphiphilic substances can also be used to produce liposomes according to the invention. So-called niosomes are obtained, for example, when using non-ionogenic vesicle formers.
  • sterols such as cholesterol (CH) or other components such as fatty acids (e.g. stearic acid, palmitic acid), dicetyl phosphate or cholesterol hemisuccinate can be used as further components of the vesicle membrane.
  • CH cholesterol
  • fatty acids e.g. stearic acid, palmitic acid
  • dicetyl phosphate or cholesterol hemisuccinate can be
  • the liposome membrane can also contain preservative additives such as ⁇ -tocopherol as an antioxidant.
  • preservative additives such as ⁇ -tocopherol as an antioxidant.
  • the liposome preparations according to the invention can furthermore contain surface-modifying additives which are known to the person skilled in the art, such as, for example, DSPE-PEG or GM ⁇ (see also Allen, T.M., Advanced Drug Delivery Reviews 13, 285-309 (1994)).
  • Particularly suitable liposome formulations according to the invention contain, in addition to PC, a charge carrier in a molar fraction ⁇ 30%, preferably ⁇ 15, particularly preferably ⁇ 10%, as the membrane building block.
  • a charge carrier in a molar fraction ⁇ 30%, preferably ⁇ 15, particularly preferably ⁇ 10%, as the membrane building block.
  • natural or synthetic PG derivatives are preferably used as charge carriers.
  • CH is generally used in a molar proportion ⁇ 40%, preferably ⁇ 30, particularly preferably ⁇ 20%.
  • Natural phosphatidylcholine fractions from egg or soy lecithin are preferably used as the PC component. Excellent liposomes are obtained when the lipids are used in the following molar proportions: 6-7 parts PC, 2-3 parts CH, 0-2 parts PG, the sum of the parts giving 10.
  • the average diameter of liposome formulations according to the invention is between 60 and 400 nm. Depending on the contrast-imparting component used, however, preparations with average diameters between 100 and 300 nm or 150 and 250 nm have proven particularly suitable.
  • the processes or process steps suitable for the production of liposome preparations containing contrast agents according to the invention can generally be the standard methods known in liposome technology. (e.g. New, R.R.C, Preparation of liposomes, In: New, R.R.C, ed., Liposomes: a practical approach, Oxford University Press, New York, 1990).
  • continuous high-pressure extrusion WO 94/08626
  • other mechanical or multiphase dispersion processes can also be used, for example, to produce preparations according to the invention.
  • the liposome preparations according to the invention produced in this way can be stored directly or in lyophilized form or kept ready for use.
  • liposome preparations according to the invention are preferably used as ready-to-use suspensions.
  • the liposome suspensions according to the invention are stored and used directly in pre-filled syringes (plastic or glass).
  • the degree of encapsulation of liposome formulations according to the invention is generally between 15 and 95% of the total contrast agent concentration. Especially however, preparations are suitable in which between 35 and 90 or 45 and 80% are encapsulated.
  • the liposome formulations according to the invention are stable over a period of at least 12 months, but preferably more than 24 months. In particularly suitable cases, corresponding formulations are stable over this period even at room temperature.
  • the relaxivity of the formulations according to the invention is not significantly reduced compared to that of unencapsulated MRI contrast media.
  • a T1 relaxivity (R1) at 0.47 Tesla and 37 ° C of 6.7 to 7.4 l / mmoI * sec in blood plasma could be measured. This value was 7.6 l / mmol * sec for free gadobutrol.
  • the rapid and complete elimination of the contrast-giving component should first be emphasized in the preparations according to the invention.
  • liposome formulations according to the invention generally have residual body concentrations ⁇ 5% at this point in time, but generally ⁇ 3%.
  • the corresponding liver concentrations are generally at values ⁇ 1.5, but as a rule ⁇ 0.5 or 0.1%.
  • the liposome formulations according to the invention are quickly removed from the injection site. About 4% and 24 h after sc administration of 10 ⁇ mol / kg body weight at the guinea pig paw, about 19% and approx. 7% of the applied dose were still found at the injection site, whereas after 7 days only about 2.8% of the applied Dose could be detected. Thus, with preparations according to the invention typically 7 days pi a maximum of ⁇ 20% but usually ⁇ 12.5 or 7.5% of the applied dose at the injection site are detected.
  • the rapid removal of liposome formulations according to the invention from the interstitium requires, among other things, the extremely good local tolerance of the corresponding preparations. Thus, no toxicologically relevant histological changes at the injection site can be determined on the rabbit model 7 days after the application of liposomes according to the invention.
  • Lymph node concentrations in the range of 50-1500 ⁇ mol / l, usually 100-750 ⁇ mol / l, are usually obtained with liposome preparations according to the invention, the drop in concentration between the first and the third station not being a factor of 2 to 7, as a rule not a factor 3 - 5 exceeds.
  • liposome formulations according to the invention could be confirmed in MRI imaging studies on guinea pigs.
  • 210 minutes after subcutaneous application of 10 ⁇ mol / kg body weight gadobutrol liposomes (guinea pigs, hind paw, toe space) in fat-suppressed, ⁇ -weighted, spin-echo recordings (TR 400 ms, TE 15 ms) were both a clear signal increase observed the popliteal lymph nodes in comparison to the pre-contrast image as well as in comparison to the control side (without injection).
  • the liposome formulation according to the invention can be injected locally (either subcutaneously or percutaneously or directly (intraoperatively) into the tissue of interest).
  • Several injection sites (wheals) with a respective injection volume of 0.1-2.5 ml, preferably 0.2-1.0 ml, can be grouped around the area of interest (eg tumor).
  • the total volume injected should not exceed 5 or 10 ml.
  • Liposome formulations according to the invention therefore have gadolinium concentrations in the range from 25 to 250 mmol / l or 50 and 150 mmol / l.
  • the potential clinical dose is in the range of 1 - 30 ⁇ mol / kg body weight, preferably 5 - 10 ⁇ mol / kg body weight.
  • the application site depends on whether a specific lymphatic drainage area should be specifically "stained” from the tissue assigned to it (e.g. in the case of gynecological or rectal tumors), or whether the unknown drainage area of a specific lesion (ergo the area for a possible therapeutic intervention, for example in the case of melanoma or breast cancer) should be displayed.
  • a specific lymphatic drainage area should be specifically "stained” from the tissue assigned to it (e.g. in the case of gynecological or rectal tumors), or whether the unknown drainage area of a specific lesion (ergo the area for a possible therapeutic intervention, for example in the case of melanoma or breast cancer) should be displayed.
  • an accumulation over three successive lymph node stations with a relatively uniform distribution is sought.
  • gadolinium concentrations of at least 50 to 1500 ⁇ mol / l are required in normal lymph node tissue, where the liposomal formulation is enriched.
  • Imaging can take place (depending on the injection site and tissue) after 15-60 minutes or 1 to 24 hours, but preferably 4 to 8 hours after injection of the liposome formulation according to the invention. Since with the liposomal formulations of gadolinium complexes according to the invention in particular the T1 relaxation times of
  • lymph node tissue are affected, T1-weighted sequences are usually best able to demonstrate MRI enhancement of the lymph node stations. Since lymph nodes are very often embedded in adipose tissue and this has a very high signal intensity on such sequences, fat-suppressed measurement methods are particularly suitable. Paramagnetic
  • Gadolinium complexes in combination with fat-suppressed, T1-weighted measurement sequences have the great advantage over formulations of superparamagnetic iron oxide particles that they allow MRI images with higher spatial resolution, with lower distortion artifacts (due to susceptibility artifacts) and with a shorter exposure time. Since the lymph nodes are marked positively (i.e., the signal increases), MRI scans without contrast media are no longer absolutely necessary for comparison, which can reduce the total examination time and effort per patient.
  • Example 1 Production of MRI contrast-containing liposomes
  • Contrast-containing liposomes were produced and characterized under various conditions using the continuous high-pressure extrusion method (Schneider, T. et al., Int. J. Pharm. 117, 1-12 (1995)).
  • R1 / R2 relaxivity in IJmmol * sec at 0.47 T, 37 ° C
  • Fig. 1 shows MR images of popliteal lymph nodes both before (left side: precontrast) and 210 min after (right side) subcutaneous application (guinea pigs, hind paw, inter-toe area) of gadobutrol liposomes (10 ⁇ mol Gd / kg body weight) .
  • the fat-suppressed, T n -weighted, spin echo recordings illustrate the strong signal increase in the popliteal lymph nodes on the injected (straight arrow) compared to the non-injected (curved arrow) body side, or to the pre-contrast image.

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  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne l'utilisation de liposomes chargés en agents de contraste pour la lymphographie interstitielle.
PCT/DE1996/001433 1995-08-01 1996-07-25 Utilisation de preparations liposomales en lymphographie indirecte par imagerie par resonance magnetique WO1997004811A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU68693/96A AU6869396A (en) 1995-08-01 1996-07-25 Use of liposomal preparations in indirect mri lymphography

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19529922.1 1995-08-01
DE1995129922 DE19529922A1 (de) 1995-08-01 1995-08-01 Verwendung von liposomalen Zubereitungen in der indirekten MRT-Lymphographie

Publications (2)

Publication Number Publication Date
WO1997004811A2 true WO1997004811A2 (fr) 1997-02-13
WO1997004811A3 WO1997004811A3 (fr) 1997-08-07

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AU (1) AU6869396A (fr)
DE (1) DE19529922A1 (fr)
WO (1) WO1997004811A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115364246A (zh) * 2021-05-18 2022-11-22 上海交通大学医学院附属第九人民医院 一种靶向造影剂及其制备方法和应用

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0442962B1 (fr) * 1988-11-09 1994-01-05 UNGER, Evan C Agents liposomiques de contraste radiologique
US5277914A (en) * 1989-03-31 1994-01-11 The Regents Of The University Of California Preparation of liposome and lipid complex compositions
US5114703A (en) * 1989-05-30 1992-05-19 Alliance Pharmaceutical Corp. Percutaneous lymphography using particulate fluorocarbon emulsions
AU5174193A (en) * 1992-10-16 1994-05-09 Georg Rossling Process and device for producing liquid, dispersed systems
DE4328331A1 (de) * 1993-08-18 1995-02-23 Andreas Dr Sachse Kontinuierliches Hochdruckextrusionsverfahren zur Herstellung von Liposomen und Emulsionen
US5534241A (en) * 1993-07-23 1996-07-09 Torchilin; Vladimir P. Amphipathic polychelating compounds and methods of use
DE4341472A1 (de) * 1993-12-02 1995-06-08 Schering Ag Verfahren zur Erhöhung der Stabilität von hydrophile Wirkstoffe enthaltenden Liposomensuspensionen
CA2212162A1 (fr) * 1995-02-09 1996-08-15 Schering Aktiengesellschaft Liposomes contenant des agents de contraste pour l'imagerie relative au pool sanguin intracardiaque

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115364246A (zh) * 2021-05-18 2022-11-22 上海交通大学医学院附属第九人民医院 一种靶向造影剂及其制备方法和应用
CN115364246B (zh) * 2021-05-18 2024-07-23 上海交通大学医学院附属第九人民医院 一种靶向造影剂及其制备方法和应用

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WO1997004811A3 (fr) 1997-08-07
DE19529922A1 (de) 1997-02-06
AU6869396A (en) 1997-02-26

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