# US 8,568,772 B2 · Modified drugs for use in liposomal nanoparticles

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- Number: US 8,568,772 B2
- Document ID: US8568772B2
- Status: Granted
- Kind: B2
- Application number: 13/866,913
- Filed: 2013-04-19
- Published: 2013-09-05
- Granted: 2013-10-29
- Earliest claimed: 2008-05-23
- Assignees: The University of British Columbia
- Applicants: The University of British Columbia
- Inventors: Pieter Cullis; Marcel Bally; Marco Ciufolini; Norbert Mauer; Igor Jigaltsev
- Web page: https://patentgrep.com/patent/US8568772B2

## CPC

- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 9/1278: Post-loading, e.g. by ion or pH gradient
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/4525: containing a five-membered ring with oxygen as a ring hetero atom
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 31/706: containing six-membered rings with nitrogen as a ring hetero atom
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 305/14: condensed with carbocyclic rings or ring systems
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 498/14: Ortho-condensed systems
- C07H 17/04: Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07J 41/005: {the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives}
- C07J 43/003: {not condensed}
- C07K 7/645: {Cyclosporins; Related peptides}
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- C07J: STEROIDS (seco-steroids C07C)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Drug derivatives are provided herein which are suitable for loading into liposomal nanoparticle carriers. In some preferred aspects, the derivatives comprise a poorly water-soluble drug derivatized with a weak-base moiety that facilitates active loading of the drug through a LN transmembrane pH or ion gradient into the aqueous interior of the LN. The weak-base moiety can optionally comprise a lipophilic domain that facilitates active loading of the drug to the inner monolayer of the liposomal membrane. Advantageously, LN formulations of the drug derivatives exhibit improved solubility, reduced toxicity, enhanced efficacy, and/or other benefits relative to the corresponding free drugs.

## Claims

### Claim 1

A method for treating cancer, the method comprising administering a pharmaceutical formulation to a subject in need thereof,
wherein:
the cancer is selected from the group consisting of ovarian cancer, breast cancer, and prostate cancer;
the pharmaceutical formulation comprises a liposomal nanoparticle having an interior compartment; and
the interior compartment contains a docetaxel derivative having the structure:
or a pharmaceutically acceptable salt thereof,
wherein —C(═O)-(Spacer)-[N] is selected from the group consisting of:

### Claim 2 (depends on 1)

The method of claim 1, wherein the liposomal nanoparticle comprises a phosphatidylcholine containing saturated C14-C22 carbon chains.

### Claim 3 (depends on 2)

The method of claim 2, wherein the liposomal nanoparticle further comprises a sterol.

### Claim 4 (depends on 3)

The method of claim 3, wherein the liposomal nanoparticle comprises the sterol and the phosphatidylcholine in a molar ratio of from 0.1:1 to 1:1.

### Claim 5 (depends on 1)

The method of claim 1, wherein the interior compartment comprises an aqueous, low pH buffer.

### Claim 6 (depends on 5)

The method of claim 5, wherein the low pH buffer comprises citrate.

### Claim 7 (depends on 1)

The method of claim 1, wherein the interior compartment comprises an aqueous solution containing ammonium sulfate.

### Claim 8 (depends on 1)

The method of claim 1, wherein the ratio of the docetaxel derivative to the lipids in the liposomal nanoparticle is from about 0.01:1 to about 10:1 by weight.

### Claim 9 (depends on 1)

The method of claim 1, wherein the lipid concentration of the formulation is from about 0.5 mg/mL to about 100 mg/mL.

### Claim 10 (depends on 9)

The method of claim 9, wherein the lipid concentration is from about 10 mg/mL to about 50 mg/mL.

### Claim 11 (depends on 1)

The method of claim 1, wherein the liposomal nanoparticle is between about 0.1 and 0.5 microns in size.

### Claim 12 (depends on 1)

The method of claim 1, wherein the liposomal nanoparticle is suspended in a medium selected from the group consisting of water, buffered water, and 0.9% isotonic saline.

### Claim 13 (depends on 1)

The method of claim 1, wherein the formulation further comprises one or more substances selected from the group consisting of a pH adjusting agent, a buffering agent, a tonicity adjusting agent, a free radical quencher, and an antioxidant.

### Claim 14 (depends on 1)

The method of claim 1, wherein the liposomal nanoparticle has an in vivo release half-life of between about 1 to about 96 hours.

### Claim 15 (depends on 1)

The method of claim 1, wherein the formulation is administered via parenteral injection.

### Claim 16 (depends on 15)

The method of claim 15, wherein the formulation is administered as an intravenous bolus injection or an intravenous infusion.

### Claim 17 (depends on 1)

The method of claim 1, wherein the dose of the docetaxel derivative is selected from the group consisting of 31 mg/kg, 50 mg/kg, and 110 mg/kg.

### Claim 18 (depends on 1)

The method of claim 1, wherein:
the liposomal nanoparticle is between about 0.1 and 0.5 microns in size;
the liposomal nanoparticle comprises a sterol and a phosphatidylcholine in a molar ratio of from 0.1:1 to 1:1, the phosphatidylcholine containing saturated C14-C22 carbon chains;
the interior compartment comprises an aqueous, low-pH citrate buffer;
the liposomal nanoparticle is suspended in an aqueous external medium;
the lipid concentration of the formulation is from about 10 mg/mL to about 50 mg/mL; and
the ratio of the docetaxel derivative to the lipids in the liposomal nanoparticle is from about 0.01:1 to about 10:1 by weight.

### Claim 19 (depends on 1)

The method of claim 1, wherein the docetaxel derivative has the structure:

### Claim 20 (depends on 18)

The method of claim 18, wherein the docetaxel derivative has the structure:

### Claim 21 (depends on 1)

The method of claim 1, wherein the cancer is ovarian cancer.

### Claim 22 (depends on 1)

The method of claim 1, wherein the cancer is breast cancer.

### Claim 23 (depends on 1)

The method of claim 1, wherein the cancer is prostate cancer.