# US 10,369,105 B2 · Nanoparticulate compositions for targeted delivery of acid labile, lipophilic prodrugs of cancer chemotherapeutics and their preparation

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,369,105 B2
- Document ID: US10369105B2
- Status: Granted
- Kind: B2
- Application number: 15/910,913
- Filed: 2018-03-02
- Published: 2018-08-23
- Granted: 2019-08-06
- Earliest claimed: 2014-09-13
- Assignees: Veiled Therapeutics LLC
- Applicants: Veiled Therapeutics LLC
- Inventors: James D. McChesney; Igor Nikoulin; Steve J. Bannister; Douglas L. Rodenburg
- Web page: https://patentgrep.com/patent/US10369105B2

## CPC

- A61K 9/1275: Lipoproteins or protein-free species thereof, e.g. chylomicrons; Artificial high-density lipoproteins [HDL], low-density lipoproteins [LDL] or very-low-density lipoproteins [VLDL]; Precursors thereof
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/5123: {Organic compounds, e.g. fats, sugars}
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/357: having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K 31/365: Lactones
- A61K 31/366: having six-membered rings, e.g. delta-lactones
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375)
- A61K 31/5685: having an oxo group in position 17, e.g. androsterone
- A61K 31/575: substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7056: containing five-membered rings with nitrogen as a ring hetero atom
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 31/7076: containing purines, e.g. adenosine, adenylic acid
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

In one embodiment, the present application discloses synthetic LDL nanoparticles comprising mixtures of components selected from the group consisting of phospholipids, triglycerides, cholesterol ester and free cholesterol; optionally further comprising an agent selected from the group consisting of natural antioxidants, ubiquinol and vitamin E, and methods for preparing the synthetic nanoparticles. The disclosed synthetic LDL nanoparticles are capable of selectively delivering lipophilic drugs and prodrugs to cellular targets expressing LDL receptors after intra venous injection.

## Claims

### Claim 1

A method for the treatment of cancer in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of the stable, synthetic low density lipoprotein (LDL) nanoparticle comprising:
a) a lipophilic anti-cancer agent of the formula 1a, 1b or formula 2a:
wherein:
for formula 1a or 1b R1 is hydrogen, C1-C4 alkyl or C5-C22 alkyl; and R2 is C5-C22 alkyl;
for formula 2a: R2 is C1-C22 alkyl; and X is hydrogen or is selected from the group consisting of Cl, Br and I; and
R is a hydroxyl bearing cancer chemotherapeutic agent (HBCCA) selected from the group consisting of paclitaxel and docetaxel;
b) phospholipids (PL) wherein the phospholipid is selected from the group consisting of phosphotidylcholine, phosphotidylethanolamine, symmetric or asymmetric 1,2-diacyl-sn-glycero-3-phosphorylcholines, 1,2-dimyristoyl-sn-glycero-3-phosphorylcholine, 1,2-dimyristoyl-sn-glycero-3-phosphorylethanolamine, egg phospholipids, egg phosphatidyl glycerol, dipalmitoylphosphatidyl glycerol, egg lecithin, soy lecithin, lecithin (NOS) and mixtures thereof; and
c) triglycerides (TG);
wherein the LDL nanoparticle has a mean particle size of 40-80 nm;
wherein the cancer is breast cancer.

### Claim 2 (depends on 1)

The method of claim 1, wherein the lipophilic anti-cancer agent of the formula 1a, 1b or formula 2a is ALLMC of paclitaxel or ALLMC of docetaxel:
wherein -ALL1 is hydrogen;
wherein for the formula ALLMC of paclitaxel, -ALL2 is hydrogen; and
wherein for the formula ALLMC of docetaxel, -ALL2 is hydrogen and -ALL3 is hydrogen.

### Claim 3 (depends on 1, 2)

The method of claim 1 or 2, wherein the lipophilic anti-cancer agent of the formula 1a is:

### Claim 4 (depends on 1)

The method of claim 1, wherein the LDL nanoparticle has a mean size distribution of 60 nm.

### Claim 5 (depends on 1)

The method of claim 1, further comprising cholesterol ester (CE) or cholesterol (C), or mixtures of cholesterol ester and cholesterol.

### Claim 6 (depends on 5)

The method of claim 5, wherein the cholesterol ester (CE) is selected from the group consisting of C16-22 esters of cholesterol and mixtures thereof; and the triglyceride is selected from the group consisting of soybean oil, triolein, glyceryl tripalmitate and mixtures thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the stable, synthetic low density lipoprotein (LDL) nanoparticle further comprises an agent selected from the group consisting of triolein, BHT, ubiquinol, ubiquinol 10, vitamin E, alpha-tocopherol, gamma-tocopherol, lycopene, and betacarotene, or mixtures thereof.

### Claim 8 (depends on 5)

The method of claim 5, wherein the weight ratio of PL:TG:CE:C ranges from 73:12:2:1 to 78:12:2:1; optionally further comprising an additive selected from the group consisting of triolein, BHT, ubiquinol, ubiquinol 10, vitamin E, alpha-tocopherol, gamma-tocopherol, lycopene, and betacarotene, or mixtures thereof.

### Claim 9 (depends on 8)

The method of claim 8, wherein the weight ratio of PL:TG:CE:C is 77:10:2:1.

### Claim 10 (depends on 1)

The method of claim 1, wherein the stable, synthetic low density lipoprotein (LDL) nanoparticle further comprises poloxamers that are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), or mixtures thereof.