Modified drugs for use in liposomal nanoparticles

Patent metadata

Field	Value
Publication number	US-9968554-B2
Application number	US-201414302537-A
Country	US
Kind code	B2
Filing date	Jun 12, 2014
Priority date	May 23, 2008
Publication date	May 15, 2018
Grant date	May 15, 2018

Abstract

Drag derivatives are provided herein which are suitable for loading into liposomal nanoparticle carriers. In some preferred aspects, the derivatives comprise a poorly water-soluble drag derivatized with a weak-base moiety that facilitates active loading of the drag 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 drag to the inner monolayer of the liposomal membrane. Advantageously, LN formulations of the drag derivatives exhibit improved solubility, reduced toxicity, enhanced efficacy, and/or other benefits relative to the corresponding free drags.

First claim

What is claimed:

1. A compound having the formula I:

or a pharmaceutically acceptable salt thereof,
wherein Z is a Liposome Solubilization Unit selected from one of the following:
(i) Z comprises formula II:

wherein
[L] is selected from the group consisting of: carboxy, carboxyamido, and alkyl silyl;
[S] is selected from the group consisting of:

 and
[N] is a Solubilization Domain of the general formula III:

wherein R and R′ are independently selected from the group consisting of: H; C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, each optionally substituted with halo; cycloalkyl, heterocyclyl, aryl, and heteroaryl, each optionally substituted with halo; and a protonable nitrogen-containing heterocyclic system; or R and R′ together with the nitrogen atom to which they are attached form a heterocyclic ring having four to five carbon atoms, which may comprise one of multiple rings within a ring system; or
(ii) Z is selected from the group consisting of:

wherein
A is selected from the group consisting of: carbonyl, methylene, and NR—C═O, where R is H or C 1 -C 5 alkyl;
R 1 and R 2 are independently selected from the group consisting of: linear or branched C 1 -C 30 alkyl, C 2 -C 30 alkenyl, and C 2 -C 30 alkynyl; and
R 3 and R 4 are independently selected from the group consisting of: H; C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, each optionally substituted with halo; and cycloalkyl, heterocyclyl, aryl, and heteroaryl, each optionally substituted with halo; or
R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocyclic ring having four to five carbon atoms, which may comprise one of multiple rings within a ring system.

2. The compound of claim 1 , wherein the [N] is selected from the group consisting of:

3. A composition comprising a compound of claim 1 in admixture with a pharmaceutically acceptable carrier, and optionally, wherein said pharmaceutically acceptable carrier comprises a liposome having a particle size of from 80 nm to 120 nm.

4. A liposome composition comprising the compound of claim 1 or an acceptable salt thereof, a phosphatidyl choline lipid and cholesterol.

5. The liposome composition of claim 4 , wherein said phosphatidyl choline lipid is a C 14 to C 22 saturated fatty acid phosphatidyl choline lipid, and optionally, wherein said phosphatidyl choline lipid is selected from the group consisting of: distearoylphosphatidyl choline, dipalmitoylphosphatidyl choline and dimyristoylphosphatidyl choline.

6. The liposome composition of claim 4 , wherein the molar ratio of cholesterol:phosphatidyl choline lipid is from 0.1 to 1.0.

7. The liposome composition of claim 4 , further comprising a negatively or positively charged lipid, and optionally,
wherein said negatively charged lipid is selected from the group consisting of dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dimyristoylphosphatidic acid, dipalmitoylphosphatidic acid, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine and cardiolipin; and
wherein said positively charged lipid is selected from the group consisting of N,N′-dimethyl-N,N′-dioctacyl ammonium bromide (DDAB) and N,N′-dimethyl-N,N′-dioctacyl ammonium chloride (DDAC), N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), 3β-[N-(N′,N′-dimethylaminoethyl)carbamoyl) cholesterol (DC-chol), 1,2-dioleoyloxy-3-[trimethylammonio]-propane (DOTAP), 1,2-dioctadecyloxy-3-[trimethylammonio]-propane (DSTAP), and 1,2-dioleoyloxypropyl-3-dimethyl-hydroxyethyl ammonium chloride (DORI).

8. The liposome composition of claim 4 , further comprising a polymer layer coating for said liposomes, and optionally,
wherein the polymer layer coating comprises poly(ethylene glycol)-conjugated lipids, and further optionally,
wherein said poly(ethylene glycol)-conjugated lipids are selected from the group consisting of 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N4methoxy(polyethylene glycol)-350] (mPEG 350 PE); 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-550] (mPEG 550 PE); 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-750] (mPEG 750 PE); 1,2-diacyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-1000] (mPEG 1000 PE); 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N[methoxy(polyethylene glycol)-2000] (mPEG 2000 PE); 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-3000] (mPEG 3000 PE); 1,2-diacylsn-glycero-3-phosphoethanolamine-N4methoxy(polyethylene glycol)-5000] (mPEG 5000PE); N-acyl-sphingosine-1-[succinyl(methoxy polyethylene glycol) 750] (mPEG 750 Ceramide); N-acyl-sphingosine-1-[succinyl(methoxy polyethylene glycol) 2000] (mPEG 2000 Ceramide); and N-acyl-sphingosine-1-[succinyl(methoxy polyethylene glycol) 5000] (mPEG 5000 Ceramide).

9. The liposome composition of claim 4 , wherein the liposome has a particle size of from about 80 nm to about 120 nm.

10. A pharmaceutical formulation for treating inflammation comprising a liposomal nanoparticle having an interior compartment; and wherein the interior compartment contains a prednisone compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the liposomal nanoparticle comprises a phosphatidylcholine lipid containing saturated C 14 -C 22 carbon chains and a sterol lipid.

11. The pharmaceutical formulation of claim 10 , wherein the liposomal nanoparticle comprises the sterol and the phosphatidylcholine in a molar ratio of from 0.1 to 1.0.

12. The pharmaceutical formulation of claim 10 ,
wherein the interior compartment comprises an aqueous, low pH buffer, and optionally, wherein the low pH buffer comprises citrate, or
wherein the interior compartment comprises an aqueous solution containing ammonium sulfate.

13. The pharmaceutical formulation of claim 10 , wherein the ratio of the prednisone compound to the lipids in the liposomal nanoparticle is from 0.01:1 to 10:1 by weight.

14. The pharmaceutical formulation of claim 10 ,
wherein the lipid concentration of the formulation is from 0.5 mg/mL to 100 mg/mL, or
wherein the lipid concentration is from 10 mg/mL to 50 mg/mL.

15. The pharmaceutical formulation of claim 10 , wherein the liposomal nanoparticle is between 0.1 and 0.5 microns in size.

16. The pharmaceutical formulation of claim 10 , wherein the liposomal nanoparticle is suspended in a medium selected from the group consisting of water, buffered water, and 0.9% isotonic saline, and optionally, wherein the formulation further comprises one or more substances selected from the g

Assignees

• Univ British Columbia

Inventors

• Cullis Pieter
• Bally Marcel
• Ciufolini Marco
• Maurer Norbert
• Jigaltsev Igor

Classifications

• C07J41/005

  the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives · CPC title

• A61K31/337 Primary

  having four-membered rings, e.g. taxol · CPC title

• A61K47/542

  Carboxylic acids, e.g. a fatty acid or an amino acid · CPC title

• C07D305/14

  condensed with carbocyclic rings or ring systems · CPC title

• A61K31/573

  substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone · CPC title