LIPIDS, LIPID COMPOSITIONS, AND METHODS OF USING THEM

• US 20110200582A1
• Filed: 12/21/2010
• Published: 08/18/2011
• Est. Priority Date: 12/23/2009
• Status: Abandoned Application

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: GEALL, Andrew, LABONTE, Tanzina, VARGEESE, Chandra, WEST, Laura, BOWMAN, Keith, ZHAO, Junping, LEE, Cameron, BARYZA, Jeremy
• Application Number:
  US12/974,906
• Publication Number:
  US 20110200582A1
• Time in Patent Office: Days
• US Class Current: 424/130.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/28 Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
• CPC Class Codes: A61K 47/30 Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07J 31/006 not covered by C07J31/003
• CPC Class Codes: C07J 41/0055 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
• CPC Class Codes: C07J 43/003 not condensed
• CPC Class Codes: C07J 9/00 Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Abstract

Disclosed are formulation and optimization protocols for delivery of therapeutically effective amounts of biologically active agents to liver, tumors, and/or other cells or tissues. Also provided are compositions and uses for cationic lipid compounds of formula (I).

The invention also relates to compositions and uses for stealth lipids of formula (XI).

Also provided are processes for making such compounds, compositions, and formulations, plus methods and uses of such compounds, compositions, and formulations to deliver biologically active agents to cells and/or tissues.

Claims

1. A composition comprising at least one cationic lipid, at least one helper lipid and at least one stealth lipid for delivery of a biologically active agent, wherein the biologically active agent is for delivery to a tissue or cell selected from:

a) a liver or liver cells, wherein the composition has a cationic lipid with a pKa of from about 6.2 or above;

b) a tumor or tumor cell, wherein the composition has a cationic lipid with a pKa of from about 6.2 or below;

c) a liver or liver cells, wherein the composition has a cationic lipid with a pKa of from about 5.1 to about 7.4; and

d) a tumor or tumor cell, wherein the composition has a cationic lipid with a pKa of from about 5.0 to about 6.7.

5. The composition of claim 1 comprising one or more of the compounds selected from:

a) the compound of formula (I); and

/or

b) the compound of formulat (XI).

6. The composition of claim 1, wherein the biologically active agent is for delivery to the liver or a liver cell and the cationic lipid has a pKa selected from at least:

(a) about 5.1 to about 7.4;

(b) about 5.3 to about 7.3;

(c) about 5.9 to about 7.0;

(d) about 6.2 to about 6.8; and

(e) about 6.1 or above

7. The composition of claim 1, wherein the biologically active agent is for delivery to a tumor or tumor cells and the cationic lipid has a pKa selected from at least:

(a) about 5.0 to about 6.7;

(b) about 5.2 to about 6.3;

(c) about 5.4 to about 6.2;

(d) about 5.8 to about 6.1; and

(e) about 6.1 or below.

8. The composition of claim 1 further comprising at least one neutral lipid.

9. The composition of claim 1, wherein the composition is optimized by selection of at least one of a stealth lipid, formulation method, N/P ratio, particle size, and molar ratio of the cationic lipid, an optional neutral lipid, helper lipid, stealth lipid and an optional alkyl resorcinol based lipid.

10. The composition of claim 5, wherein the cationic lipid is selected from E0001-E0171 and E0175-E0180.

11. The composition of claim 5, wherein the stealth lipid is selected from S001-S009 and S012-S026.

12. The composition of claim 1, wherein the composition is optimized for at least one parameter including but not limited to individual selection of the pKa of the cationic lipid optimized for the type of cell or organ being targeted, the cationic lipid used, the stealth lipid used, the helper lipid, the neutral lipid used, whether the neutral lipid is present or absent, the ratio of the selected helper lipid, optional neutral lipid, stealth lipid and cationic lipid, the N/P ratio, the particle size, the dosage regiment, the dose given, the formulation method, and the like.

13. The composition of claim 1, further comprising a biologically active agent.

14. The composition of claim 13, wherein the composition comprises a biologically active agent in an amount effective for therapeutic treatment of a disease or disorder.

15. The composition of claim 13, wherein said biologically active agent is selected from the group consisting of antibodies, cholesterol, hormones, antivirals, peptides, polypeptides, proteins, nucleoproteins, chemotherapeutics, low molecular weight drugs, vitamins, co-factors, nucleosides, nucleoside derivatives, nucleotides, oligonucleotides, enzymatic nucleic acids, antisense nucleic acids, triplex forming oligonucleotides, 2,5-A antisense chimeras, allozymes, aptamers, decoy RNA molecules and analogs thereof, and small nucleic acid molecules, such as an RNA interfering agent (RNAi), short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA).

16. The composition of claim 15 wherein said biologically active agent is selected from one or more of a nucleoside or nucleoside derivative, an RNAi, an siNA, an RNAi inhibitor, a miRNA, an siRNA and a shRNA.

17. The composition of claim 1 that further comprises a pharmaceutically acceptable carrier.

18. A kit comprising any one or more components of the composition of claim 1, and instructions for use.

19. A method for the treatment of a disease or condition comprising the step of administering a therapeutically effective amount of a composition of claim 1 to a patient in need thereof.

20. The method of claim 19 wherein the disease or condition is a cancer, a disease of the liver, or a disease that is responsive to treatment with an RNAi construct.

21. A method for the treatment of a disease or condition in a subject in need thereof, the method comprising the step of administering a therapeutically effective amount of a biologically active agent in a formulation comprising one or more compositions of claim 1.

22. The method of claim 21 wherein the disease or condition is a tumor, a disease of the liver, or a disease that is responsive to treatment with an RNAi construct.

2. A compound of formula (I):

3. The compound of claim 2, wherein one or more substituents are selected from one or more the following:

(a) a is selected from optionally substituted C_1-2 alkylene and optionally substituted C₁ alkylene;

(b) b is selected from optionally substituted C_0-2 alkylene and optionally substituted C₁ alkylene;

(c) c is absent or is optionally substituted C₁ alkylene; and

/or

(d) a, b and c are unsubstituted.

(e) R¹ and R² together with the nitrogen atom to which they are attached form an optionally substituted C_3-20-heterocycloalkyl, C_3-20-heterocycloalkenyl or C_3-20-heterocycloalkynyl group;

(f) wherein R¹ and R² together with the nitrogen atom to which they are attached form a compound selected from a cyclic optionally substituted C_5-16 group and a cyclic optionally substituted C_5-12 group;

(g) R¹ and R² together with the nitrogen atom to which they are attached form a cyclic optionally substituted C₅ group, C₆ group or C₇ group; and

(h) R¹ and R² together with the nitrogen atom to which they are attached are selected from at least one of the head groups H¹ to H⁵².

(i) wherein X¹ is O;

(j) wherein X² is O;

(k) wherein both X¹ and X² is O;

(l) wherein L comprises at least one heteroatom;

(m) wherein L comprises at least one O atom;

(n) wherein L^c is selected from one of formulae L^c-i to L^c-xxxxiii.

(o) wherein d is 0;

e is 0, and f is 1;

(p) wherein Y¹ is a C_12-25 group;

(q) wherein Y¹ has at least one alkene group;

(r) wherein Y¹ has at least one cis unsaturated alkene group;

(s) wherein Y¹ is selected from Y^1-i to Y^1-vii;

(t) wherein Y² is linked to L via an oxygen atom on the optionally substituted steroid;

(u) wherein Y² is a sterol in which the hydrogen atom of the hydroxy group at the 3-position of the A steroid ring has been removed;

(v) wherein Y² is the sterol of part (u), and the sterol is selected from the group consisting of;

annasterol;

avenasterol;

beta-sitosterol;

brassicasterol;

calciferol;

campesterol;

chalinosterol;

chinasterol;

cholestanol;

cholesterol;

coprostanol;

cycloartenol;

dehydrocholesterol;

desmosterol;

dihydrocalciferol;

dihydrocholesterol;

dihydroergosterol;

dinosterol;

epicholesterol;

ergosterol;

fucosterol;

hexahydrolumisterol;

hexaol;

hydroxycholesterol;

lanosterol;

lumisterol;

parkeol;

poriferasterol;

saringosterol;

sitostanol;

sitosterol;

stigmastanol;

stigmasterol;

weinbersterol;

zymosterol;

sterol bile acids (including one or more selected from cholic acid;

chenodeoxycholic acid;

glycocholic acid;

taurocholic acid;

deoxycholic acid, and lithocholic acid); and

/or a salt or a pharmaceutically acceptable derivative thereof; and

(w) wherein Y² is a cholesterol.

4. A stealth lipid of formula (XI)