Patent
أعرض في EDS

Method of making hepatocyte-selective oil-in-water emulsion

التفاصيل البيبلوغرافية
العنوان: Method of making hepatocyte-selective oil-in-water emulsion
Patent Number: 5,985,941
تاريخ النشر: November 16, 1999
Appl. No: 08/497,283
Application Filed: June 30, 1995
مستخلص: A heat and shelf-stable oil-in-water emulsion useful as a tissue or cell-selective delivery vehicle. Radioactive or stable, synthetic or semi-synthetic polyhalogenated triglycerides, such as 2-oleoylglycerol-1,3-bis[7-(3-amino-2,4,6-triiodophenyl)heptanoate] or 2-oleoylglycerol-1,3-bis[.omega.-(3,5-bis-trifluoromethyl)hepatanoate] or phenyl acetate, can be incorporated into the lipophilic core of a lipoprotein-like emulsion particle. The lipophilic core is surrounded by a phospholipid membrane comprising cholesterol and apolipoproteins. For hepatocyte-selective delivery, the emulsion is chylomicron remnant-like by being in a size range of 50 to 200 nm as measured by number weighting analysis with a narrow size distribution (
Inventors: Counsell, Raymond E. (Ann Arbor, MI); Longino, Marc A. (Ann Arbor, MI); Weichert, Jamey P. (Ann Arbor, MI); Bakan, Douglas A. (Ann Arbor, MI)
Assignees: University of Michigan (Ann Arbor, MI)
Claim: What is claimed is
Claim: 1. A method of making a heat stable hepatocyte-selective oil-in-water emulsion comprising the steps of
Claim: (a) preblending the lipophilic components of an oil-in-water emulsion including nonpolar core lipids, polar lipid emulsifiers, and other lipophilic components to form a preblended lipid phase;
Claim: (b) homogenizing the preblended lipid phase and sodium ion-free aqueous components to form a crude oil-in-water emulsion; and
Claim: (c) subjecting the crude oil-in-water emulsion to ultra high energy mixing emulsification to produce a fine oil-in-water emulsion having a mean particle diameter of the oil phase between 50 to 200 nm with greater than 98% of the particles being less that 300 nm.
Claim: 2. The method of claim 1 comprising the further step of
Claim: subjecting the fine oil-in-water emulsion to sequential filtering.
Claim: 3. The method of claim 1 wherein the step of preblending comprises the steps of
Claim: mixing the lipophilic components with one or more organic solvents in an amount sufficient to facilitate blending of the lipophilic components; and
Claim: removing the organic solvents.
Claim: 4. The method of claim 1 wherein the step of homogenizing comprises
Claim: adding an aqueous osmolality adjusting agent and mixing the lipophilic components and osmolality adjusting agent in a high speed mixer at a first speed; and adding the remainder of the aqueous components and mixing in the high speed mixer at a second speed in excess of the first speed.
Claim: 5. The method of claim 4 wherein the high speed mixer is operated at a first speed of about 12.500 rpm for at least about 5 minutes at a temperature which is greater than or equal to the transition temperature or melting point of the lipophilic components and less than the temperature at which any one of the lipophilic components will degrade.
Claim: 6. The method of claim 5 wherein the second speed is about 25,000 rpm for at least about 5 minutes.
Claim: 7. The method of claim 4 wherein the high speed mixer is a Polytron homogenizer.
Claim: 8. The method of claim 1 wherein the step of subjecting comprises
Claim: processing the crude oil-in-water emulsion in an ultra high pressure homogenizer.
Claim: 9. The method of claim 8 wherein the ultra high pressure homogenizer is operated in a recycling mode at a pressure of between about 10,000 and 30,000 psi and temperature between about 30.degree. C. and 60.degree. C. for up to 20 minutes.
Claim: 10. The method of claim 9 wherein the pressure is between about 12,500 and 18,200 psi.
Claim: 11. The method of claim 8 wherein the ultra high pressure homogenizer is a Microfluidizer.
Claim: 12. The method of claim 1 further including the step of
Claim: sterilizing the fine oil-in-water emulsion.
Claim: 13. The method of claim 12 wherein said step of sterilizing comprises heat sterilization.
Claim: 14. A heat stable hepatocyte-selective oil-in-water emulsion made by a method a comprising the steps of
Claim: a) preblending the lipophilic components of the oil-in-water emulsion, the lipophilic components comprising triolein and a polyhalogenated triglyceride in a molar ratio of 1:1, the triolein and polyhalogenated triglyceride comprising an amount of up to 50% (w/v) of the total emulsion with a phospholipid emulsifier, the phospholipid being in an amount of up to 10% (w/v) and cholesterol, so that cholesterol comprises less than about 5% (w/v) and is present in a molar ratio of cholesterol to phospholipid of 0.4;
Claim: b) adding the aqueous components to the preblended lipophilic components, the aqueous components being up to 5% (w/v) glycerol and the remainder water;
Claim: c) homogenizing the preblended lipid phase and aqueous components to form a crude oil-in-water emulsion;
Claim: (d) subjecting the crude oil-in-water emulsion to ultra high energy mixing to produce a fine oil-in-water emulsion having a mean particle diameter of the oil phase between 50 to 200 nm with greater than 98% of the particles being less that 300 nm; and
Claim: (e) filtering the fine oil-in-water emulsion through sequentially through filters having smaller pores.
Current U.S. Class: 516/56; 424/401; 514/938; 516/930
Current International Class: B01J 1300; A61K 9107
Patent References Cited: Re32393 April 1987 Wretlind et al.
3992513 November 1976 Petkau et al.
4073943 February 1978 Wretlind et al.
4309289 January 1982 Head
4816247 March 1989 Desai et al.
4873075 October 1989 Counsell et al.
4917880 April 1990 Wretlind et al.
4957729 September 1990 Counsell et al.
4970209 November 1990 Wretlind et al.
5004756 April 1991 Ogawa et al.
5005303 April 1991 Riley, Jr.
5039527 August 1991 Tabibi
5080885 January 1992 Long, Jr.
5093042 March 1992 Counsell et al.
5093044 March 1992 Wretlind et al.
5098606 March 1992 Nakajima et al.
5116599 May 1992 Rogers, Jr. et al.
5152923 October 1992 Weder et al.
5171737 December 1992 Weiner et al.
5234680 August 1993 Rogers et al.
5445811 August 1995 Norrlind et al.
5851510 December 1998 Counsell et al.
Other References: Longino et al.:"Importance of Emulsification Method on the Particle Size of Fluorotriglyceride Microemulsions for Hepatic .sup.19 F-MR Imaging", Book of Abstracts, vol. 2. Society of Magnetic Resonance, 1989, p. 820.
Clark, et al., "Phosphatidylcholine Composition of Emulsions Influences Triacylglycerol Lipolysis and Clearance from Plasma," Biochimica et Biophysica Acta, vol. 920, pp. 37-46 (1987).
Cooper, et al., "Rates of Removal and Degradation of Chylomicron Remnants by Isolated Perfused Rat Liver," J. Lipid Research, vol. 19, pp. 635-643 (1978).
Cooper, "Hepatic Clearance of Plasma Chylomicron Remnants,"vol. 12, No. 4, pp. 386-396 (1992).
Counsell, et al., "Lipoproteins as Potential Site-Specific Delivery Systems for Diagnostic and Therapeutic Agents," J. Med. Chem., vol. 25, No. 10, pp. (1982).
Damle, et al., "Potential Tumor- or organ-imaging Agents XXIV: Chylomicron Remnants as Carrier for Hepatographic Agents," J. Pharm. Science., vol. 72, No. 8, pp. 898-901 (1983).
Gardner, et al., "Comparison of the Metabolism of Chylomicrons and Chylomicron Remnants by the Perfused Liver," Biochem. J., vol. 170, pp. 47-55 (1978).
Grimes, "Formulation and Evaluation of Ethiodized Oil Emulsion for Intravenous Hepatography," J. Pharm. Sci., vol. 68, No. 1, pp. 52-56 (1979).
"Handbook of Chemistry and Physics," 38th edition, CRC Press, B-303-B-305 (1977-1978).
Hamilton, et al., "Apolipoprotein E Localization in Rat Hepatocytes by immunogold Labeling of Cryothin Sections," J. Lipid Research, vol. 31, pp. 1589-1603 (1990).
Ivancev, et al., "Effect of Intravenously Injected Iodinate Lipid Emulsions on the Liver," Acta Radiologica, vol. 30, Fasc. 3, pp. 291-297 (1989).
Ivancev, et al., "Experimental Investigation of a New Iodinated Lipid Emulsion for Computed Tomography of the Liver," Acta Radiologica, vol. 30, Fasc. 4, pp. 407-412 (1989).
Ivancev, et al., "Clinical Trials With a New Iodinated Lipid Emulsion for Computed Tomography of the Liver," Acta Radiologica, vol. 30, Fasc. 5, pp. 449-457, Sep.-Oct. 1989.
Jones, et al., "Uptake and Processing of Remnants of Chylomicrons and Very Low Density lipoproteins by Rat Liver," J. Lipid Res., vol. 25, pp. 1151-1158 (1984).
Kowal, et al., "Low Density Lipoprotein Receptor-related Protein Mediates Uptake of Cholesteryl Esters Derived from Apoprotein E-enriched Lipoproteins," Biochemistry, vol. 86, pp. 5810-5814 (1989).
Lange, et al., "Esophageal Anastomotic Leaks: Preliminary results of Treatment with Balloon Dilation," Radiology, vol. 165, pp. 45-47 (1987).
Longino, et al., "Importance of Emulsification Method on the Particle Size of Fluorotriglyceride Microemulsions for Hepatic .sup.19 F-MR Imaging," Book of Abstracts, vol. 2, Soc. of Magnetic Resonance , p. 820 (1989).
Longino, et al., Abstract, Association of University Radiologists, vol. 9(1):53 (1990).
Longino, et al., Abstract 8-7, Investigative Radiology, vol. 25, No. 12, p. 1357 (1990).
Nagata, et al., "Role of Low Density Lipoprotein Receptor-dependent and - Independent Sites in Binding and Uptake of Chylomicron Remnants in Rat Liver," J. Biol. Chem., vol. 263, No. 29, pp. 15151-15158 (1988).
Nilsson-Ehle and Schotz, "A Stable, Radioactive Substrate Emulsion for Assay of Lipoprotein Lipase," J. of Lipid Research, vol. 17, p. 536 (1976).
Pattniak, et al., "Effect of Size and Competition by Lipoproteins and Apolipoproteins on the Uptake of Chylomicrons and Chylomicron Remnants by Hepatoma Cells in Culture," Biochimica et Biophysica Acta, vol. 617, pp. 335-346 (1980).
Redgrave, et al., "Cholesterol is Necessary for Triacylglycerol-phospholipid Emulsions to Mimic the Metabolism of Lipoproteins," Biochimica et Biophysica Acta, vol. 921, pp. 154-157 (1987).
Redgrave, et al., "The Effect of Triacyl-sn-glycerol Structure on the Metabolism of Chylomicrons and Triacylglycerol-rich Emulsion in the Rat," J. Biol. Chem., vol. 263, pp. 5115-5123 (1988).
Schumacher, et al., "Experimental Data on the Problem of Specific Hepatosplenography with Radiodense Lipomicrons," Europ. J. Radiol., vol. 5, pp. 167-174 (1985).
Schwendner, et al., "Potential Organ or Tumor Imaging Agents. 32. A Triglyceride Ester of p-Iodophenyl Pentadecanoic Acid as a Potential Hepatic Imaging Agent," Nucl. Med. Biol., vol. 19, No. 6, pp. 639-650 (1992).
Sherrill, et al., "Characterization of the Sinusoidal Transport Process Responsible for Uptake of Chylomicron by the Liver," J. Biol. Chem., vol. 253, No. 6, pp. 1859-1867 (1978).
Stryer, Biochemistry, 2d Ed., pp. 213-214 and 470-471 (1981).
Sultan, et al., "Inhibition of Hepatic Lipase Activity Impairs Chylomicron Remnant-removal in Rats," Biochimica et Biophysica Acta, vol. 1042, pp. 150-152 (1990).
Vermess, et al., Development and Experimental Evaluation of a Contrast Medium for Computed Tomographic Examination of the Liver and Spleen, J. Computer Assisted Tomography, vol. 31, No. 1, pp. 25-31 (1979).
Washington and Davis, The Production of Parenteral Feeding Emulsions by Microfluidizer, Int'l. J. Pharm., vol. 44, pp. 169-176 (1988).
Weichert, et al., J. Med. Chem., vol. 29, pp. 1674 and 2457 (1986).
Weichert, et al., Abstract of 7th Annual SMRM, vol. I, p. 484 (Aug. 22-26 1988).
Primary Examiner: Lovering, Richard D.
Attorney, Agent or Firm: Rohm & Monsanto, PLC
رقم الانضمام: edspgr.05985941
قاعدة البيانات: USPTO Patent Grants
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USPTO Patent Grants
edspgr.05985941
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Patent
patent
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PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&scope=site&db=edspgr&AN=edspgr.05985941&custid=s6537998&authtype=sso
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Items Array ( [Name] => Title [Label] => Title [Group] => Ti [Data] => Method of making hepatocyte-selective oil-in-water emulsion )
Array ( [Name] => DocumentID [Label] => Patent Number [Group] => Patent [Data] => 5,985,941 )
Array ( [Name] => DateEntry [Label] => Publication Date [Group] => Patent [Data] => November 16, 1999 )
Array ( [Name] => DocumentID [Label] => Appl. No [Group] => Patent [Data] => 08/497,283 )
Array ( [Name] => DateFiled [Label] => Application Filed [Group] => Patent [Data] => June 30, 1995 )
Array ( [Name] => Abstract [Label] => Abstract [Group] => Ab [Data] => A heat and shelf-stable oil-in-water emulsion useful as a tissue or cell-selective delivery vehicle. Radioactive or stable, synthetic or semi-synthetic polyhalogenated triglycerides, such as 2-oleoylglycerol-1,3-bis[7-(3-amino-2,4,6-triiodophenyl)heptanoate] or 2-oleoylglycerol-1,3-bis[.omega.-(3,5-bis-trifluoromethyl)hepatanoate] or phenyl acetate, can be incorporated into the lipophilic core of a lipoprotein-like emulsion particle. The lipophilic core is surrounded by a phospholipid membrane comprising cholesterol and apolipoproteins. For hepatocyte-selective delivery, the emulsion is chylomicron remnant-like by being in a size range of 50 to 200 nm as measured by number weighting analysis with a narrow size distribution ( )
Array ( [Name] => Author [Label] => Inventors [Group] => Patent [Data] => <searchLink fieldCode="ZA" term="%22Counsell%2C+Raymond+E%2E%22">Counsell, Raymond E.</searchLink> (Ann Arbor, MI); <searchLink fieldCode="ZA" term="%22Longino%2C+Marc+A%2E%22">Longino, Marc A.</searchLink> (Ann Arbor, MI); <searchLink fieldCode="ZA" term="%22Weichert%2C+Jamey+P%2E%22">Weichert, Jamey P.</searchLink> (Ann Arbor, MI); <searchLink fieldCode="ZA" term="%22Bakan%2C+Douglas+A%2E%22">Bakan, Douglas A.</searchLink> (Ann Arbor, MI) )
Array ( [Name] => OtherAuthors [Label] => Assignees [Group] => Patent [Data] => <searchLink fieldCode="ZS" term="%22University+of+Michigan%22">University of Michigan</searchLink> (Ann Arbor, MI) )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => What is claimed is )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => 1. A method of making a heat stable hepatocyte-selective oil-in-water emulsion comprising the steps of )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => (a) preblending the lipophilic components of an oil-in-water emulsion including nonpolar core lipids, polar lipid emulsifiers, and other lipophilic components to form a preblended lipid phase; )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => (b) homogenizing the preblended lipid phase and sodium ion-free aqueous components to form a crude oil-in-water emulsion; and )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => (c) subjecting the crude oil-in-water emulsion to ultra high energy mixing emulsification to produce a fine oil-in-water emulsion having a mean particle diameter of the oil phase between 50 to 200 nm with greater than 98% of the particles being less that 300 nm. )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => 2. The method of claim 1 comprising the further step of )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => subjecting the fine oil-in-water emulsion to sequential filtering. )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => 3. The method of claim 1 wherein the step of preblending comprises the steps of )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => mixing the lipophilic components with one or more organic solvents in an amount sufficient to facilitate blending of the lipophilic components; and )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => removing the organic solvents. )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => 4. The method of claim 1 wherein the step of homogenizing comprises )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => adding an aqueous osmolality adjusting agent and mixing the lipophilic components and osmolality adjusting agent in a high speed mixer at a first speed; and adding the remainder of the aqueous components and mixing in the high speed mixer at a second speed in excess of the first speed. )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => 5. The method of claim 4 wherein the high speed mixer is operated at a first speed of about 12.500 rpm for at least about 5 minutes at a temperature which is greater than or equal to the transition temperature or melting point of the lipophilic components and less than the temperature at which any one of the lipophilic components will degrade. )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => 6. The method of claim 5 wherein the second speed is about 25,000 rpm for at least about 5 minutes. )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => 7. The method of claim 4 wherein the high speed mixer is a Polytron homogenizer. )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => 8. The method of claim 1 wherein the step of subjecting comprises )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => processing the crude oil-in-water emulsion in an ultra high pressure homogenizer. )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => 9. The method of claim 8 wherein the ultra high pressure homogenizer is operated in a recycling mode at a pressure of between about 10,000 and 30,000 psi and temperature between about 30.degree. C. and 60.degree. C. for up to 20 minutes. )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => 10. The method of claim 9 wherein the pressure is between about 12,500 and 18,200 psi. )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => 11. The method of claim 8 wherein the ultra high pressure homogenizer is a Microfluidizer. )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => 12. The method of claim 1 further including the step of )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => sterilizing the fine oil-in-water emulsion. )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => 13. The method of claim 12 wherein said step of sterilizing comprises heat sterilization. )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => 14. A heat stable hepatocyte-selective oil-in-water emulsion made by a method a comprising the steps of )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => a) preblending the lipophilic components of the oil-in-water emulsion, the lipophilic components comprising triolein and a polyhalogenated triglyceride in a molar ratio of 1:1, the triolein and polyhalogenated triglyceride comprising an amount of up to 50% (w/v) of the total emulsion with a phospholipid emulsifier, the phospholipid being in an amount of up to 10% (w/v) and cholesterol, so that cholesterol comprises less than about 5% (w/v) and is present in a molar ratio of cholesterol to phospholipid of 0.4; )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => b) adding the aqueous components to the preblended lipophilic components, the aqueous components being up to 5% (w/v) glycerol and the remainder water; )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => c) homogenizing the preblended lipid phase and aqueous components to form a crude oil-in-water emulsion; )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => (d) subjecting the crude oil-in-water emulsion to ultra high energy mixing to produce a fine oil-in-water emulsion having a mean particle diameter of the oil phase between 50 to 200 nm with greater than 98% of the particles being less that 300 nm; and )
Array ( [Name] => Comment [Label] => Claim [Group] => Patent [Data] => (e) filtering the fine oil-in-water emulsion through sequentially through filters having smaller pores. )
Array ( [Name] => CodeClass [Label] => Current U.S. Class [Group] => Patent [Data] => 516/56; 424/401; 514/938; 516/930 )
Array ( [Name] => CodeClass [Label] => Current International Class [Group] => Patent [Data] => B01J 1300; A61K 9107 )
Array ( [Name] => Ref [Label] => Patent References Cited [Group] => Patent [Data] => <searchLink fieldCode="RF" term="%22Re32393%22">Re32393</searchLink> April 1987 Wretlind et al.<br /><searchLink fieldCode="RF" term="%223992513%22">3992513</searchLink> November 1976 Petkau et al.<br /><searchLink fieldCode="RF" term="%224073943%22">4073943</searchLink> February 1978 Wretlind et al.<br /><searchLink fieldCode="RF" term="%224309289%22">4309289</searchLink> January 1982 Head<br /><searchLink fieldCode="RF" term="%224816247%22">4816247</searchLink> March 1989 Desai et al.<br /><searchLink fieldCode="RF" term="%224873075%22">4873075</searchLink> October 1989 Counsell et al.<br /><searchLink fieldCode="RF" term="%224917880%22">4917880</searchLink> April 1990 Wretlind et al.<br /><searchLink fieldCode="RF" term="%224957729%22">4957729</searchLink> September 1990 Counsell et al.<br /><searchLink fieldCode="RF" term="%224970209%22">4970209</searchLink> November 1990 Wretlind et al.<br /><searchLink fieldCode="RF" term="%225004756%22">5004756</searchLink> April 1991 Ogawa et al.<br /><searchLink fieldCode="RF" term="%225005303%22">5005303</searchLink> April 1991 Riley, Jr.<br /><searchLink fieldCode="RF" term="%225039527%22">5039527</searchLink> August 1991 Tabibi<br /><searchLink fieldCode="RF" term="%225080885%22">5080885</searchLink> January 1992 Long, Jr.<br /><searchLink fieldCode="RF" term="%225093042%22">5093042</searchLink> March 1992 Counsell et al.<br /><searchLink fieldCode="RF" term="%225093044%22">5093044</searchLink> March 1992 Wretlind et al.<br /><searchLink fieldCode="RF" term="%225098606%22">5098606</searchLink> March 1992 Nakajima et al.<br /><searchLink fieldCode="RF" term="%225116599%22">5116599</searchLink> May 1992 Rogers, Jr. et al.<br /><searchLink fieldCode="RF" term="%225152923%22">5152923</searchLink> October 1992 Weder et al.<br /><searchLink fieldCode="RF" term="%225171737%22">5171737</searchLink> December 1992 Weiner et al.<br /><searchLink fieldCode="RF" term="%225234680%22">5234680</searchLink> August 1993 Rogers et al.<br /><searchLink fieldCode="RF" term="%225445811%22">5445811</searchLink> August 1995 Norrlind et al.<br /><searchLink fieldCode="RF" term="%225851510%22">5851510</searchLink> December 1998 Counsell et al. )
Array ( [Name] => Ref [Label] => Other References [Group] => Patent [Data] => Longino et al.:"Importance of Emulsification Method on the Particle Size of Fluorotriglyceride Microemulsions for Hepatic .sup.19 F-MR Imaging", Book of Abstracts, vol. 2. Society of Magnetic Resonance, 1989, p. 820.<br />Clark, et al., "Phosphatidylcholine Composition of Emulsions Influences Triacylglycerol Lipolysis and Clearance from Plasma," Biochimica et Biophysica Acta, vol. 920, pp. 37-46 (1987).<br />Cooper, et al., "Rates of Removal and Degradation of Chylomicron Remnants by Isolated Perfused Rat Liver," J. Lipid Research, vol. 19, pp. 635-643 (1978).<br />Cooper, "Hepatic Clearance of Plasma Chylomicron Remnants,"vol. 12, No. 4, pp. 386-396 (1992).<br />Counsell, et al., "Lipoproteins as Potential Site-Specific Delivery Systems for Diagnostic and Therapeutic Agents," J. Med. Chem., vol. 25, No. 10, pp. (1982).<br />Damle, et al., "Potential Tumor- or organ-imaging Agents XXIV: Chylomicron Remnants as Carrier for Hepatographic Agents," J. Pharm. Science., vol. 72, No. 8, pp. 898-901 (1983).<br />Gardner, et al., "Comparison of the Metabolism of Chylomicrons and Chylomicron Remnants by the Perfused Liver," Biochem. J., vol. 170, pp. 47-55 (1978).<br />Grimes, "Formulation and Evaluation of Ethiodized Oil Emulsion for Intravenous Hepatography," J. Pharm. Sci., vol. 68, No. 1, pp. 52-56 (1979).<br />"Handbook of Chemistry and Physics," 38th edition, CRC Press, B-303-B-305 (1977-1978).<br />Hamilton, et al., "Apolipoprotein E Localization in Rat Hepatocytes by immunogold Labeling of Cryothin Sections," J. Lipid Research, vol. 31, pp. 1589-1603 (1990).<br />Ivancev, et al., "Effect of Intravenously Injected Iodinate Lipid Emulsions on the Liver," Acta Radiologica, vol. 30, Fasc. 3, pp. 291-297 (1989).<br />Ivancev, et al., "Experimental Investigation of a New Iodinated Lipid Emulsion for Computed Tomography of the Liver," Acta Radiologica, vol. 30, Fasc. 4, pp. 407-412 (1989).<br />Ivancev, et al., "Clinical Trials With a New Iodinated Lipid Emulsion for Computed Tomography of the Liver," Acta Radiologica, vol. 30, Fasc. 5, pp. 449-457, Sep.-Oct. 1989.<br />Jones, et al., "Uptake and Processing of Remnants of Chylomicrons and Very Low Density lipoproteins by Rat Liver," J. Lipid Res., vol. 25, pp. 1151-1158 (1984).<br />Kowal, et al., "Low Density Lipoprotein Receptor-related Protein Mediates Uptake of Cholesteryl Esters Derived from Apoprotein E-enriched Lipoproteins," Biochemistry, vol. 86, pp. 5810-5814 (1989).<br />Lange, et al., "Esophageal Anastomotic Leaks: Preliminary results of Treatment with Balloon Dilation," Radiology, vol. 165, pp. 45-47 (1987).<br />Longino, et al., "Importance of Emulsification Method on the Particle Size of Fluorotriglyceride Microemulsions for Hepatic .sup.19 F-MR Imaging," Book of Abstracts, vol. 2, Soc. of Magnetic Resonance , p. 820 (1989).<br />Longino, et al., Abstract, Association of University Radiologists, vol. 9(1):53 (1990).<br />Longino, et al., Abstract 8-7, Investigative Radiology, vol. 25, No. 12, p. 1357 (1990).<br />Nagata, et al., "Role of Low Density Lipoprotein Receptor-dependent and - Independent Sites in Binding and Uptake of Chylomicron Remnants in Rat Liver," J. Biol. 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