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Patent Issued for Nanoparticles Comprising a Cholesteryl Ester Transfer Protein Inhibitor and Anon-Ionizable Polymer

May 6, 2014

By a News Reporter-Staff News Editor at Life Science Weekly -- Bend Research, Inc. (Bend, OR) has been issued patent number 8703204, according to news reporting originating out of Alexandria, Virginia, by NewsRx editors (see also Bend Research, Inc.).

The patent's inventors are Bloom, Corey Jay (Bend, OR); Crew, Marshall David (Bend, OR); Smithey, Daniel Tod (Bend, OR); Miller, Warren Kenyon (Bend, OR); Morgen, Michael Mark (Bend, OR).

This patent was filed on April 23, 2008 and was published online on April 22, 2014.

From the background information supplied by the inventors, news correspondents obtained the following quote: "The present invention relates to nanoparticles comprising a poorly water-soluble cholesteryl ester transfer protein inhibitor (CETPI) and a poorly aqueous soluble non-ionizable polymer.

"Atherosclerosis and its associated coronary artery disease (CAD) is the leading cause of death in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity, lack of exercise) and treatment of dyslipidemia with dietary modification and drug therapy, coronary heart disease (CHD) remains the most common cause of death in the U.S., where cardiovascular disease accounts for 44% of all deaths, with 53% of these associated with atherosclerotic coronary heart disease.

"Risk for development of this condition has been shown to be strongly correlated with certain plasma lipid levels. While elevated LDL-cholesterol may be the most recognized form of dyslipidemia, it is by no means the only significant lipid associated contributor to CHD. Low HDL-cholesterol is also a known risk factor for CHD (Gordon, D. J., et al., 'High-density Lipoprotein Cholesterol and Cardiovascular Disease', Circulation, (1989), 79: 8-15).

"High LDL-cholesterol and triglyceride levels are positively correlated, while high levels of HDL-cholesterol are negatively correlated with the risk for developing cardiovascular diseases. Thus, dyslipidemia is not a unitary risk profile for CHD but may be comprised of one or more lipid aberrations.

"Among the many factors controlling plasma levels of these disease dependent principles, cholesteryl ester transfer protein (CETP) activity affects all three. The role of this 70,000 dalton plasma glycoprotein found in a number of animal species, including humans, is to transfer cholesteryl ester and triglyceride between lipoprotein particles, including high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL), and chylomicrons. The net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol. This effect on lipoprotein profile is believed to be pro-atherogenic, especially in subjects whose lipid profile constitutes an increased risk for CHD.

"No wholly satisfactory HDL-elevating therapies exist. Niacin can significantly increase HDL, but has serious toleration issues which reduce compliance. Fibrates and the HMG CoA reductase inhibitors raise HDL cholesterol only modestly (.+-.10-12%). As a result, there is a significant unmet medical need for a well-tolerated agent which can significantly elevate plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis.

"CETPIs have been developed which inhibit CETP activity, and thus, if present in the blood, should result in higher HDL cholesterol levels and lower LDL cholesterol levels. To be effective, such CETPIs must be absorbed into the blood. Oral dosing of CETPIs is preferred because to be effective such CETPIs must be taken on a regular basis, such as daily. Therefore, it is preferred that patients be able to take CETPIs by oral dosing rather than by injection.

"CETPIs, particularly those that have high binding activity, are generally hydrophobic, have extremely low aqueous solubility and have low oral bioavailability when dosed conventionally. Such compounds have generally proven to be difficult to formulate for oral administration such that high bioavailabilities are achieved.

"It is known that poorly water-soluble drugs may be formulated as nanoparticles. Nanoparticles are of interest for a variety of reasons, such as to improve the bioavailability of poorly water-soluble drugs, to provide targeted drug delivery to specific areas of the body, to reduce side effects, or to reduce variability in vivo.

"A variety of approaches have been taken to formulate drugs as nanoparticles. One approach is to decrease the size of crystalline drug by grinding or milling the drug in the presence of a surface modifier. See, e.g., U.S. Pat. No. 5,145,684. Another approach to forming nanoparticles is to precipitate the drug in the presence of a film forming material such as a polymer. See, e.g., U.S. Pat. No. 5,118,528.

"While these formulations may be functional for many classes of drugs, the very low water solubilities and lipophilic nature of CETPIs pose challenges when developing nanoparticle formulations. Accordingly, there is a continuing need to develop formulations of CETPIs that improve their bioavailability when dosed orally to certain mammalian species."

Supplementing the background information on this patent, NewsRx reporters also obtained the inventors' summary information for this patent: "In a first aspect, a pharmaceutical composition comprises nanoparticles, the nanoparticles comprising (a) a CETPI having an aqueous solubility of less than 1 mg/mL over the pH range of 6.5 to 7.5 at C., at least 90 wt % of the CETPI in the nanoparticle being non-crystalline, and (b) a poorly aqueous soluble non-ionizable polymer; wherein the nanoparticles have an average size of less than 500 nm, and wherein the nanoparticles comprise a core, and the CETPI and the non-ionizable polymer collectively constitute at least 80 wt % of the core.

"In one embodiment, the nanoparticles further comprise a surface stabilizer.

"In another embodiment, the CETPI is selected from the group consisting of (2R)-3-[3-(4-chloro-3-ethylphenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy- )phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol; trans-(2R,4S)-2-(4-{4-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetr- azol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-car- bonyl}-cyclohexyl)-acetamide amine; (3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluo- romethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine; 1-[1-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am- ino]-methyl}-4-trifluoromethyl-phenyl)-2-methyl-propyl]-piperidine-4-carbo- xylic acid; (3,5-bis-trifluoromethyl-benzyl)-[2-(1-methoxy-cycloheptyl)-5-trifluorome- thyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine; (3,5-bis-trifluoromethyl-benzyl)-[2-(1-cyclohexyl-1-methoxy-ethyl)-5-trif- luoromethyl-benzyl)]-(2-methyl-2H-tetrazol-5-yl)-amine; and pharmaceutically acceptable forms thereof.

"In still another embodiment, the CETPI is (2R)-3-[3-(4-chloro-3-ethylphenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy- )phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol or a pharmaceutically acceptable form thereof.

"In yet another embodiment, the non-ionizable polymer is selected from the group consisting of methylcellulose, ethylcellulose, propylcellulose, butylcellulose, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate butyrate, cellulose acetate propionate, methyl cellulose acetate, methyl cellulose propionate, methyl cellulose butyrate, ethyl cellulose acetate, ethyl cellulose propionate, ethyl cellulose butyrate, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose propionate, hydroxypropyl methylcellulose butyrate, poly(lactide), poly(glycolide), poly(.epsilon.-caprolactone), poly(lactide-co-glycolide), poly(lactide-co-.epsilon.-caprolactone), poly(ethylene oxide-co-.epsilon.-caprolactone), poly(ethylene oxide-co-lactide), and poly(ethylene oxide-co-lactide-co-glycolide), poly(isobutyl)cyanoacrylate, and poly(hexyl)cyanoacrylate.

"In another embodiment, the non-ionizable polymer is selected from the group consisting of ethylcellulose and poly(ethylene oxide-co-.epsilon.-caprolactone).

"Nanoparticles comprising a CETPI and a poorly aqueous soluble non-ionizable polymer result in a material that improves the bioavailability of the CETPI when administered to an aqueous use environment.

"Because the non-ionizable polymer is poorly aqueous soluble at physiological pH, the nanoparticles maintain the CETPI within a solid (or at least undissolved) polymer matrix when the nanoparticles are suspended in an aqueous solution.

"The foregoing and other objectives, features, and advantages of the invention will be more readily understood upon consideration of the following detailed description of the invention."

For the URL and additional information on this patent, see: Bloom, Corey Jay; Crew, Marshall David; Smithey, Daniel Tod; Miller, Warren Kenyon; Morgen, Michael Mark. Nanoparticles Comprising a Cholesteryl Ester Transfer Protein Inhibitor and Anon-Ionizable Polymer. U.S. Patent Number 8703204, filed April 23, 2008, and published online on April 22, 2014. Patent URL:

Keywords for this news article include: Lipids, Alkenes, Butyrates, Propionates, Nanoparticle, Acyclic Acids, Butyric Acids, Heart Disease, Ethylene Oxide, Nanotechnology, Epoxy Compounds, HDL Cholesterol, LDL Cholesterol, Carboxylic Acids, HDL Lipoproteins, LDL Lipoproteins, Organic Chemicals, Bend Research Inc., Risk and Prevention, Emerging Technologies.

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Source: Life Science Weekly

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