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WO1999024079A1 - Compositions de diagnostic marquees ameliorees et utilisations - Google Patents

Compositions de diagnostic marquees ameliorees et utilisations Download PDF

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Publication number
WO1999024079A1
WO1999024079A1 PCT/AU1998/000939 AU9800939W WO9924079A1 WO 1999024079 A1 WO1999024079 A1 WO 1999024079A1 AU 9800939 W AU9800939 W AU 9800939W WO 9924079 A1 WO9924079 A1 WO 9924079A1
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WO
WIPO (PCT)
Prior art keywords
composition
radioactively labelled
diagnostic composition
labelled diagnostic
patient
Prior art date
Application number
PCT/AU1998/000939
Other languages
English (en)
Inventor
Trevor G. Redgrave
Ian J. Martins
Original Assignee
Peptide Delivery Systems Pty. Ltd.
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 Peptide Delivery Systems Pty. Ltd. filed Critical Peptide Delivery Systems Pty. Ltd.
Priority to AU11358/99A priority Critical patent/AU1135899A/en
Publication of WO1999024079A1 publication Critical patent/WO1999024079A1/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
    • A61K49/1815—Suspensions, emulsions, colloids, dispersions compo-inhalant, e.g. breath tests
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors

Definitions

  • This invention relates to non-radioactive formulations useful in the diagnosis of a patient's predisposition to the development of atherosclerosis and coronary artery disease. It also relates to a method for producing such formulations and to a method of diagnosing a patient's tendency to develop the aforementioned diseases.
  • Atherosclerosis is a progressive disease of the walls of blood vessels, beginning with the accumulation of lipid substances and over a period of years leading to pathological changes such as fibrosis, ulceration and thrombosis within the vessel wall.
  • Serious diseases consequent upon atherosclerosis include myocardial infarction, aneurism, stroke and failure of adequate blood supply to organs and limbs leading to organ failure and gangrene.
  • the disease is very common in Western countries where a diet high in cholesterol, excessive fat ingestion, cigarette smoking, obesity and physical inactivity are all contributing factors. Genetic factors can also lead to the onset of atherosclerosis.
  • Chylomicrons transport fat in the form of t acylglycerols from the small intestine to fat depots.
  • the t glycerides in these particles are subject to a hydrolysis action by lipoprotein upases in the bloodstream resulting in formation of a secondary particle which still contains up to 30% thglycerides, and the whole of the particle cholesteryl ester.
  • This secondary particle is known as a chylomicron remnant or chyloremnant.
  • the chyloremnant having been divested of much of its triglyceride content, then contains a much higher relative amount of cholesterol to phospholipid.
  • the primary function of the chyloremnant is to transport cholesterol from the intestine to the liver.
  • radioactively labelled compositions and methods for diagnosing a patients predisposition to atherosclerosis and coronary heart disease Whilst effective, radioactively labelled compositions suffer from a number of drawbacks. Radioactivity adds to risk of cancer and of genetic mutations. This risk will be confined to the individual recipient if isolated from the environment. However exhaled radioactivity from an unconfined recipient will contaminate the external environment and add to risks of cancer and genetic mutations in laboratory staff and family or others in contact with the recipient.
  • the present invention provides a non-radioactively labelled diagnostic composition for testing for the presence of or propensity for atherosclerosis and coronary artery disease and the like comprising components which mimic essential features of an exogenous lipoprotein transport particle, said composition being capable of metabolisation by normal physiological pathways such that at least one non-radioactively labelled metabolite is detectable in the blood or bodily waste of a patient being tested.
  • the exogenous lipoprotein transport particle is one which mimics the chemical formulation of a chyloremnant, ie, it is preferably one which is primarily lipidic in nature.
  • non-radioactively labelled compositions Whilst non-radioactively labelled compositions have their advantages, producing such compositions is not a straight forward task.
  • non-radioactively labelled compositions must be capable of being administered in a way that utilises the physiological pathway of interest, without producing the phenomenon of saturation, yet in sufficient amount to allow accurate detection by measurement techniques that are generally available.
  • the present invention solves this problem by providing artificial lipoprotein emulsion particles enriched with cholesteryl esters and the like, labelled in the fatty acid moiety with a non- radioactive carbon label.
  • any fatty acid moiety may be labelled, preferably the non-radioactive carbon label is located within the cholesteryl ester component of the composition.
  • cholesteryl esters may be used provided that they behave as do cholesteryl esters. Suitable compounds may include vitamin A derivatives and non-endogenous xenobiotics.
  • the label is attached to the fatty acid moiety of the cholesteryl ester. Other chemistries of attaching the label to the cholesteryl ester are also possible.
  • the cholesteryl ester must be present in amounts of between about 10 to 40% of the total mass of lipid.
  • the cholesteryl ester is present in amounts of between about 10 to 30% of the total mass of lipid. More preferably, the cholesteryl ester is present in amounts of between about 15 to 25% of the total mass of lipid. In a highly preferred example of the invention the cholesteryl ester is present in amounts of between about 16.5 to 22.5% of the total mass of lipid.
  • the invention provides a non-radioactively labelled diagnostic composition for testing the presence of or propensity for atherosclerosis and coronary artery disease and the like, said composition comprising:
  • lipidic components selected in such a manner so as to mimic the essential features of a chyloremnant wherein at least one of the components is cholesteryl ester that is present in an amount of between 16 to 23% of the total mass of lipid; and wherein the composition is capable of metabolisation by normal physiological pathways such that at least one non-radioactively labelled metabolite is detectable in the blood or bodily waste of a patient being tested.
  • the non-radioactive label is one that allows for the measurement of the amount of metabolite present by mass spectrometry.
  • 13 C may be used so that the isotope enrichment ratio of 13 C relative to 12 C in the CO 2 of the expired breath of a patient can be measured.
  • Other equivalent, physiologically tolerated, stable, non-radioactive isotopes or other labels could also be incorporated into the composition.
  • Size is a determinant of metabolism, and to this extent, it is preferred that the particles be of a size that is easily metabolised.
  • the non-radioactively labelled diagnostic composition comprises particles of a diameter from 10-1000 nanometers (nm).
  • size has also been found to be an important criterion for sterilisation (for example by filtration) and stability of the particles during freezing.
  • the size of the particles in the emulsion is kept as small as possible. Emulsions are generally regarded as unstable during freezing because of crystallisation of the constituents leading to particle instability. However, mixtures of lipids in sufficiently small particles when in solutions containing glycerol were able to be supercooled or frozen and thawed without instability of the emulsified particles.
  • the size of the particles is between about 10-200nm. Desirably the range is between about 20-60nm, while particles sizes between about 30 to 40nm are highly preferred. For example the particles sizes should be approximately 35nm.
  • the invention provides a non- radioactively labelled diagnostic composition for testing the presence of or propensity for atherosclerosis and coronary artery disease and the like, said composition comprising:
  • lipidic components selected in such a manner so as to mimic the essential features of a chyloremnant wherein at least one of the components is cholesteryl ester that is present in an amount of between 16 to 23% of the total mass of lipid;
  • the particles have an average size of approximately 35 nm; wherein the composition is capable of metabolisation by normal physiological pathways such that at least one non-radioactively labelled metabolite is detectable in the blood or bodily waste of a patient being tested.
  • composition used in the invention should preferably be one that results in no untoward local or systemic reaction following introduction to the patient being tested, and should, preferably be well tolerated by the patient upon repeated administration.
  • the composition according to the invention includes triglycerides, phospholipids, cholesterol, and cholesteryl esters, at least one of these having a suitable located label.
  • Cholesteryl esters which are suitable for use in the composition of the invention include cholesteryl oleate, cholesteryl linoleate or a mixture of related esters. Cholesteryl esters are generally the carrier of the label which enables measurement of the metabolisation of the compositions according to the invention. The fatty acid moiety of the cholesteryl ester is preferably that labelled.
  • Thglycerides which may be present in the composition in an amount of 20-95% of total lipids, and which are suitable for use in the composition include triolein (TO), soybean oil, safflower oil, or other suitable substitutes such as olive oil or corn oil thglycerides.
  • TO triolein
  • soybean oil soybean oil
  • safflower oil or other suitable substitutes such as olive oil or corn oil thglycerides.
  • Suitable phospholipids include egg yolk phosphatidylcholine (PC), soybean phosphatidylcholine, dioleoyl phosphatidylcholine, or other suitable substitutes. This lipid may be present in an amount of 5-50% of total lipids.
  • Cholesterol which should be present in amounts adequate for the metabolism of the composition to mimic that of the natural exogenous lipid transport particles, is preferably present in amounts of 5-20% of total lipids. Without cholesterol it has been found that the chyloremnants remain in the plasma for much longer than occurs physiologically, and thus a composition not having cholesterol is not able to properly mimic the natural exogenous lipid transport particles and is therefore not entirely suitable for the purposes of the invention. Preferably cholesterol is present in an amount of about 5 to 15% total lipid, while 7 to 10% appears optimal. If the amount of cholesterol is too high the particles become unstable and are phagocytosed by the reticulo-endothelial system when introduced into a patient.
  • a preferred diagnostic composition according to the invention there is present 16 to 23% cholesteryl ester, 30-60% thglycerides, 8-30% phospholipids and about 7 to 10% cholesterol.
  • composition according to the invention there is present approximately 46.5% triolein, 16.5% cholesteryl oleate, 9.5% cholesterol and 27.5% egg phosphatidylcholine.
  • the components of the composition including the labelled component are preferably emulsified in a solution in water of glycerol or glycerol and salts, for example sodium chloride and buffer salts.
  • the presence of the glycerol improves the stability in storage of the composition and makes it isotonic.
  • the composition may additionally include a small quantity of an anti-oxidant to preserve the lipids against oxidation.
  • anti-oxidants as ascorbic acid or vitamin E are suitable.
  • well known techniques such as sonication or microfluidization may be used.
  • Emulsion particle size affects the kinetics of clearance, so it is desirable that the emulsion preparation procedures result in particles of the preferred size as set out hereinabove.
  • the lipid content of the composition is preferably present in amounts of 1- 50% of the total aqueous-based emulsion.
  • the labelled metabolite may be measured in the captured expired air of the patient, although a patients propensity for atherosclerosis may also be measured from samples of urine, or blood.
  • the composition is in the form of an emulsion for intravenous injection although other administration routes may be possible. If, for example, the composition is to be administered orally, it should be suitably formulated so as to be resistant to gastric degradation.
  • the present invention also provides a method of determining the presence of or propensity for atherosclerosis and coronary artery disease and the like in a patient requiring such determination comprising administering to said patient a labelled diagnostic composition which mimics essential features of an exogenous lipoprotein transport particle, and measuring the quantity of labelled metabolite in the bodily waste or blood of said patient so as to determine the quantity of labelled diagnostic composition successfully metabolised by said patient.
  • this method may be used to ascertain the level of development of atherosclerosis by a patient, because chyloremnant metabolism may vary from person to person, the method is also useful for gauging over an interval of repeated tests, a patient's decline towards an atherosclerosis state.
  • composition mimicking the essential features of the exogenous lipoprotein particle is delivered to the patient by injection.
  • said labelled diagnostic composition is one which mimics the chemical formulation of a chyloremnant, that is, it is primarily lipidic in nature.
  • the measurement of the quantity of labelled metabolite present in the blood or bodily waste of the individual is measured from the patient's expired air, and is preferably carried out at intervals over a period of several hours. Measurements of the quantity of labelled metabolite may commence as early as 15 minutes after inoculation of the patient with the compositions according to the invention, and may be concluded as long as six hours or more after the initial administration of the composition to the patient.
  • the individuals expired air may be collected in a known fashion by trapping the expelled air in a vessel containing solutions which trap CO 2 created as a result of the individuals metabolism.
  • the labelled diagnostic composition is preferably administered as an emulsion by intravenous injection, it may also be administered by a suitable alternative route such as orally.
  • a preferred composition administered in accordance with this aspect of the invention includes 20-95% by weight of total lipids of triglycerides, 5-50% by weight of total lipids of phospholipids, 2-20% by weight of total lipids of cholesterol, and 10-40% by weight of total lipids of cholesteryl esters, at least a small proportion of which may be labelled.
  • Suitable cholesteryl esters, triglycerides, phospholipids and sources of cholesterol are as previously described.
  • the labelled diagnostic composition comprises 16-23% cholesteryl ester, 30-60% triglycerides, 8-30% phospholipids and 7-10% cholesterol.
  • Figure 1 shows a graph showing the enrichment of 13 CO 2 in the expired breath of control and apo E knockout mice.
  • Figure 2 shows that abnormal remnant metabolism forms part of the metabolic syndrome accompanying visceral obesity.
  • Lipid mixtures containing TO (70 mg), PC (25 mg), cholesteryl [ 1 ⁇ C]-oleate (3 mg), and cholesterol (2 mg) were emulsified by sonication for 1 h in 8.5 ml of 2.2
  • Example 1 A volume of 100 ⁇ l of the emulsion mixture produced in Example 1 was injected via a tail vein into C57BL/6J (control) mice and apo E knockout mice. Colonies of apo E "knockout" mice were established from progenitor stocks obtained from the Jackson Laboratories, (Bar Harbor, ME). The mice were placed in a closed chamber through which a stream of room air was passed as previously described (Redgrave, T.G., et al., (1995). "Measurement of expired carbon dioxide to assess the metabolism of remnant lipoproteins.” J. Lipid Res. 36, 2670-2675). Breath samples were collected at intervals into evacuated gas sample containers (Europa Scientific Ltd, Crewe, U.K.). The enrichment of breath samples with 13 CO 2 was measured by isotope ratio-mass spectrometry (ABCA, Europa Scientific, Crewe, U. K.). The results are shown in Figure 1.
  • Lipid mixtures containing TO (135 mg), PC (75 mg), cholesteryl [ 1 3 C]-oleate (69 mg), and cholesterol (24 mg) were emulsified by sonication for 1 h in 8.5 ml of 2.2% glycerol in water.
  • Uniformly labelled [ 13 C]-oleic acid was purchased from
  • Example 3 A volume of 12-15 ml of the emulsion mixture produced in Example 3 was injected intravenously into a group of normal-weight men and overweight men for assessment of remnant catabolism. Subjects were fasted overnight before the study. A total of 27 men were included in this study. Exclusion criteria included diabetes and hypercholesterolemia. Breath samples were collected at intervals over 24 hrs and enrichment with 13 C was measured using isotope-ratio mass spectrometry (ABCA, Europa Scientific, Crewe, U. K.). The results are shown in Figure 2.
  • Results show that the enrichment of exhaled CO 2 with 13 C peaked approximately 5 hrs after injection. Enrichment varied widely between individuals, and correlated significantly with BMI, waist circumference, insulin, leptin and fasting plasma HDL, LDL and TG concentrations. Compared with the control group (waist ⁇ 95cm) the viscerally obese men (waist >95cm) showed significant differences in the breath test, as well as expected differences in BMI, and plasma insulin, leptin, cholesterol, HDL and TG concentrations. The results show that abnormal remnant metabolism forms part of the metabolic syndrome accompanying visceral obesity.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
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  • Biotechnology (AREA)
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  • Epidemiology (AREA)
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  • Radiology & Medical Imaging (AREA)
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  • General Physics & Mathematics (AREA)
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Abstract

L'invention concerne une composition de diagnostic à marquage non radioactif permettant de rechercher l'existence et d'athérosclérose et de coronaropathies etc. et la propension à ces dernières. Cette composition comprend des composés qui imitent les fonctions essentielles d'une particule de transport lipoprotéinique exogène. Elle peut être métabolisée par des processus physiologiques normaux de manière qu'au moins un des métabolites marqués de manière non radioactive est détectable dans le sang ou dans les matières éliminées par le patient examiné. L'invention concerne en outre la détermination de la présence d'athérosclérose et de coronaropathies etc. ou de la propension à ces dernières chez un patient. On procède à cette détermination en administrant au patient une composition de diagnostic marquée de manière non radioactive, qui imite les fonctions essentielles d'une particule de transport lipoprotéinique exogène, puis en mesurant la quantité de métabolites marqués dans les éliminations ou le sang du patient, de façon à déterminer la quantité de composition de diagnostic métabolisée avec succès par le patient.
PCT/AU1998/000939 1997-11-11 1998-11-11 Compositions de diagnostic marquees ameliorees et utilisations WO1999024079A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU11358/99A AU1135899A (en) 1997-11-11 1998-11-11 Improved labelled diagnostic compositions and methods of their use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPP0320 1997-11-11
AUPP0320A AUPP032097A0 (en) 1997-11-11 1997-11-11 Improved labelled diagnostic compositions and methods of their use

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WO1999024079A1 true WO1999024079A1 (fr) 1999-05-20

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0028917A2 (fr) * 1979-11-08 1981-05-20 Merck & Co. Inc. Vésicules lipidiques porteuses de surfaces carbohydratées et utilisées comme véhicules à action directe sur la lymphe pour des substances thérapeutiques et de diagnostic, leur utilisation et procédé pour leur préparation
EP0084439A2 (fr) * 1982-01-15 1983-07-27 Merck Frosst Canada Inc. Dérivés du 6-bromo chlolesterol
EP0182131A1 (fr) * 1984-11-23 1986-05-28 Vestar, Inc. Utilisation de particules micellaires pour préparer des compositions pour le bombardement des tumeurs humaines
EP0190050A2 (fr) * 1985-01-31 1986-08-06 Vestar, Inc. Procédé pour la préparation de petites vésicules par microémulsification
JPS61204137A (ja) * 1985-03-06 1986-09-10 Yutaka Mizushima 放射性造影剤
WO1986007540A1 (fr) * 1985-06-17 1986-12-31 Oncholab Ab Procede de preparation d'un support macromoleculaire charge d'une substance biologiquement active, produit ainsi obtenu et son utilisation
US4676974A (en) * 1984-05-17 1987-06-30 The Regents Of The University Of California Breath test for pancreatic exocrine function
US4933157A (en) * 1988-06-27 1990-06-12 The University Of Michigan Radioiodinated arylaliphatic ether analogues of cholesterol
US4938947A (en) * 1985-11-01 1990-07-03 Centre National De La Recherche Scientifique (Cnrs) Aerosol composition for in vivo imaging
WO1995013096A1 (fr) * 1993-11-08 1995-05-18 Peptide Delivery Systems Pty. Ltd. Compositions de diagnostic marquees et leurs procedes d'utilisation

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0028917A2 (fr) * 1979-11-08 1981-05-20 Merck & Co. Inc. Vésicules lipidiques porteuses de surfaces carbohydratées et utilisées comme véhicules à action directe sur la lymphe pour des substances thérapeutiques et de diagnostic, leur utilisation et procédé pour leur préparation
EP0084439A2 (fr) * 1982-01-15 1983-07-27 Merck Frosst Canada Inc. Dérivés du 6-bromo chlolesterol
US4676974A (en) * 1984-05-17 1987-06-30 The Regents Of The University Of California Breath test for pancreatic exocrine function
EP0182131A1 (fr) * 1984-11-23 1986-05-28 Vestar, Inc. Utilisation de particules micellaires pour préparer des compositions pour le bombardement des tumeurs humaines
EP0190050A2 (fr) * 1985-01-31 1986-08-06 Vestar, Inc. Procédé pour la préparation de petites vésicules par microémulsification
JPS61204137A (ja) * 1985-03-06 1986-09-10 Yutaka Mizushima 放射性造影剤
WO1986007540A1 (fr) * 1985-06-17 1986-12-31 Oncholab Ab Procede de preparation d'un support macromoleculaire charge d'une substance biologiquement active, produit ainsi obtenu et son utilisation
US4938947A (en) * 1985-11-01 1990-07-03 Centre National De La Recherche Scientifique (Cnrs) Aerosol composition for in vivo imaging
US4933157A (en) * 1988-06-27 1990-06-12 The University Of Michigan Radioiodinated arylaliphatic ether analogues of cholesterol
WO1995013096A1 (fr) * 1993-11-08 1995-05-18 Peptide Delivery Systems Pty. Ltd. Compositions de diagnostic marquees et leurs procedes d'utilisation

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