Patent Application
20080171790
This Application corresponds to Applicants Provisional Patent Application No. 60/880,075 filed on Jan. 12, 2007 entitled “Fatty Acids—Systemic Lipid Solubilizers Conjugates”.
This application consists of a delipidizing pharmacological compound useful in treatment of atherosclerosis and obesity.
The invention consists of compounds characterized by the conjugation of a certain fatty acid with a lipid solubilizer/detergent capable of producing a sustained bioavailability in the systemic circulation to access atherosclerotic plaques and cause dissolution of the cholesterol crystals and of the other cholesterol/lipids aggregations forming the lipidic component of an atherosclerotic plaque.
Gilat & al., working on pharmacological compounds aimed at dissolving gallstones, have noted that compounds resulting from conjugation of certain fatty acids with cholic acid via an amid bond are capable of dissolving cholesterol crystals at much higher rate that plain biliary acids in the bile environment. By considering that bile acids are not the major solubilizers of cholesterol in bile when cholesterol is in a crystallized state of aggregation, such as in the gallstones, particularly in the usually supersaturated human bile and by considering that phospholipids were rather shown to be the major physiologic cholesterol solubilizers in bile, able to normalize the rapid cholesterol crystallization, the authors first investigated whether parts of the phospholipid molecule such as fatty acids and also mono- or diglycerides could act as cholesterol solubilizers. Their studies revealed that saturated long chain fatty acids and some other parts of the phospholipid molecule had cholesterol solubilizing activity on cholesterol crystals. The FABACs (Fatty Acid Bile Acid Conjugates) were conceived and designed with the purpose of delivering a cholesterol solubilizing molecule (a long chain fatty acid) into bile using the very efficient entero-hepatic circulation of bile salts. As the Authors report in their abstract, the rationale was to combine a cholesterol solubilizing moiety (a saturated fatty acid) with a bile acid (cholic acid) as a vehicle to enable secretion into bile and entry into the entero-hepatic circulation.
The Authors report that in vitro and animal studies confirmed that FABACs are both able to prevent biliary cholesterol crystallization and dissolve preformed cholesterol crystals in rodents fed a lithogenic diet. In gallstone susceptible mice, FABACs prevented gallstone formation and dissolved gallstones. The Authors add that FABACs were found to be able to decrease blood cholesterol, and, referring to article Fatty acid bile acid conjugates inhibit atherosclerosis in the C57BL/6 mouse model, by Gonen A, Shaish A, Leikin-Frenkel A, Gilat T, Harats D, the Authors report beneficial effect on atherosclerosis, meaning beneficial effect on atherosclerosis progression and blood lipid levels in mice, as the referred article discloses.
With the present invention Applicants propose the conjugation of a fatty acid such as for instance butyric, caproic, caprylic, lauric, myristic, palmitic, stearic, arachidic, behenic, oleic, linoleic, alpha-linolenic, arachidonic, eicosapentaenoic, docosahexaenoic acid, euric acid with a biocompatible lipid solubilizer/detergent, the detergent having the property not only of functioning as a vehicle capable of maintaining a sustained bioavailability of the Fatty Acid in the systemic circulation, rather than in the entero-hepatic circulation as the FABACs disclosed by Gilat, but also functioning as a solubilizer/detergent/surfactant/emulsifier of cholesterol, the compound being capable of accessing the cholesterol deposits of the atherosclerotic plaques or via crossing of the fibrous cap or via the vasa vasorum.
A model of a biocompatible detergent having the disclosed properties of escaping in significant proportion the enterohepatic circulation and of avoiding therefore of being trapped and sequestered in the enterohepatic circulation is the Hyodeoxycholic acid. Hyodeoxycholic acid/salt has among the all known biliary acids/salts the unique property of indeed being excreted in the urine in large amount after oral administration. Analysis of urinary bile acids showed that a large proportion, up to 84%, of the administered hyodeoxycholic acid is excreted in the urine as a glucuronide as opposite to any other known biliary acid salts of which the amount excreted in the urine is negligible to zero. The bilary acids/salts excluding the hyodeoxycholic acid typically escape the systemic circulation and are sequestered in the enterohepatic circulation making themselves very poor candidates as active medications to be used in regression of atherosclerotic plaques through a mechanism of direct solubilization of the plaque lipidic core, unless a modification in their molecule allows them to leave and escape the enterohepatic circulation and be bioavailable for a reasonably sustained period of time in the systemic circulation. Besides the hyodeoxycholic acid, there are other biological biocompatible lipid solubilizers/emulsifiers that share with the hyodeoxycholic acid the properties of not entering the entero-hepatic circulation and of becoming available, therefore, in the systemic circulation where they can exert their beneficial effects. Gilat's FABACs use the biliary acid as vehicle to transport the Fatty acid to target i.e. to attack cholesterol gallstones. He does not mention nor he hints to the conjugation of fatty acids with systemic lipid solubilizers that offer the above disclosed advantages. It is expected that a systemic lipid solubilizer reinforced with conjugation with any of the above listed Fatty acids will act upon lipid/cholesterol aggregates causing regression of atherosclerotic plaques. It is expected that the crystallized cholesterol aggregations in the cholesterol plaques could be a particularly vulnerable target for such compounds. Another target could be the adipose tissue, with probable dissolution of adipose tissue, particularly for those compounds capable of reaching the subcutaneous tissue. All the above are therapeutic events impossible to achieve by Gilat's compounds, as Gilat's compounds are sequestered in the entero-hepatic circulation.
The systemic biological/biocompatible lipid solubilizers that can be conjugated with fatty acids can be classified according to several criteria.
Alkyl glycosides, which include: -D-glucopyranoside, □-D-glucopyranoside, n-octyl-□n-nonyl-D-glucopyranoside, □-D-glucopyranoside, n-hexyl-□n-heptyl-Dthioglucopyranoside, and □-D-maltoside, octyl-□-D-maltoside, decyl-□dodecyl-maltoside and others.
Glucamides, which include: MEGA-10, MEGA-9, MEGA-8, Deoxy Big CHAP, CHAP, and others.
Polyoxyethylenes, monodisperse and polydisperse which include: reduced TRITON® X-100, reduced TRITON® X-114, TRITON® X-100, NP-40, TRITON® X-114, GENAPOL® X-080, GENAPOL® X-100, C12E8, C12E9, THESIT®, LUBROL® PX, GENAPOL® C-100, BRIJ® 35, PLURONIC® F-127®, (laurate), TWEEN® 20 (oleate), TWEEN® 80, and others.
Zwittergents, which include: EMPIGEN BB® (n-dodecyl-N,Ndimethylglycine), ZWITTERGENT® 3-08, ZWITTERGENT® 3-10, ZWITTERGENT® 3-12, ZWITTERGENT® 3-14, ZWITTERGENT® 3-16, CHAPS, CHAPSO, and others.
Ionic Lipid solubilizers/detergents, which include:
Sodium n-Dodecyl Sulfate (SDS)
Sodium n-Dodecyl Sulfate (SDS), High Purity
Sodium n-Dodecyl Sulfate (SDS), Molecular Biology Grade
Sodium n-Dodecyl Sulfate (SDS), 30% Solution
n-Decanoylsucrose
n-Decyl-β-D-maltopyranoside, ULTROL® Grade 252718
n-Decyl-β-D-thiomaltoside, ULTROL® Grade
n-Dodecanoylsucrose 324374
n-Dodecyl-β-D-glucopyranoside 324355
n-Heptyl-β-D-glucopyranoside
n-Heptyl-β-D-thioglucopyranoside, ULTROL® Grade, 10% Solution
n-Hexyl-β-D-glucopyranoside
n-Nonyl-β-D-glucopyranoside
n-Octanoyl-β-D-glucosylamine (NOGA)
n-Octanoylsucrose
n-Octyl-β-D-glucopyranoside
n-Octyl-β-D-glucopyranoside, ULTROL® Grade
n-Octyl-β-D-maltopyranoside
n-Octyl-β-D-thioglycopyranoside, ULTROL® Grade
n-Undecyl-β-D-maltoside, ULTROL® Grade
Of particular interest to applicants are Triton and certain phytochemical lipid solubilizers, such as the Saponin group. The conjugation of butyric, caproic, caprylic, lauric, myristic, palmitic, stearic, arachidic, behenic, oleic, linoleic, alpha-linolenic, arachidonic, eicosapentaenoic, docosahexaenoic acid, euric acid with a Triton compound or with a Saponin will synergistically add solubilizing power to a systemic solubilizer, rendering such solubilizer capable of ubiquitously attacking atherosclerotic plaques and fatty deposits.
Applicants disclose also another way to enable the Fatty Acids conjugated with those biliary compounds which are confined/sequestered in the entero-hepatic circulation i.e. the administration of said conjugates via routes of administration which bypass the entero-hepatic circulation for bio-availability in the systemic circulation:
| Number | Date | Country | |
|---|---|---|---|
| 60880075 | Jan 2007 | US |
