Compositions for delivery of therapeutics and other materials

• US 8,257,682 B2
• Filed: 08/31/2009
• Issued: 09/04/2012
• Est. Priority Date: 02/27/2002
• Status: Active Grant

• Current Assignee: Pharmain Corporation
• Original Assignee: Pharmain Corporation
• Inventors: Bolotin, Elijah M., Castillo, Gerardo M.
• Primary Examiner(s): Jones, D L
• Application Number:
  US12/551,203
• Publication Number:
  US 20100098636A1
• Time in Patent Office: 1,100 Days
• Field of Search: 424/1.11, 424/1.49, 424/1.65, 424/1.73, 424/9.1, 424/9.3, 424/9.4, 424/9.5, 424/9.6, 424/9.7, 424/9.8, 534/7, 534 10- 16, 530/300
• US Class Current: 424/1.65
• 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 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 47/6911 the form being a liposome
• CPC Class Codes: 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
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

This disclosure relates to compositions for delivering agents to a subject, and in particular, to compositions for delivery of therapeutic agents or diagnostic agents in the presence or absence of targeting moieties. In part, this disclosure relates to compositions comprising a hydrophobic group with a first end and a second end, a first metal binding domain linked to the hydrophobic group, a metal ion capable of being chelated to the first metal binding domain, and an agent linked to a second metal binding domain capable of chelating to the metal ion.

Claims

1. A composition with a metal bridge comprising:

a first molecule comprising;

a first hydrophobic group comprising a first and second end;

a first metal binding domain (FMBD) covalently linked to the first end of the first hydrophobic group;

a metal ion chelated to the FMBD;

an active agent comprising a second metal binding domain (SMBD) coordinately bonded to the metal ion; and

a hydrophilic group,

wherein the hydrophilic group is covalently linked to the second end of the first hydrophobic group.

2. The composition of claim 1, further comprising a second molecule comprising:

a second hydrophobic group; and

a second hydrophilic group, wherein the hydrophilic group is covalently linked to the second hydrophobic group.

3. The composition of claim 2, further comprising a third molecule comprising:

a third hydrophobic group; and

a third hydrophilic group comprising a first and second end, wherein the first end of the third hydrophilic group is covalently linked to the third hydrophobic group and

a targeting group covalently linked to the second end of the third hydrophilic group.

4. The composition of claim 1, further comprising a second molecule comprising:

A second hydrophobic group; and

a second hydrophilic group comprising a first and second end, wherein the first end of the second hydrophilic group is covalently linked to the second hydrophobic group; and

a targeting group covalently linked to the second end of the second hydrophilic group.

5. The composition of claim 1, further comprising:

a targeting group covalently linked to the hydrophilic group.

6. The composition of claim 5, further comprising a second molecule comprising:

a second hydrophobic group; and

a second hydrophilic group comprising, wherein the second hydrophilic group is covalently linked to the second hydrophobic group.

7. The composition of claim 6, further comprising:

a third metal binding domain (TMBD) covalently linked to the second hydrophobic group.

8. The composition of any one of claims 1-7, wherein the FMBD, the SMBD, or the TMBD is selected from a nitrogen containing poly carboxylic acid or a polypeptide.

9. The composition of any one of claims 1-7, wherein the metal ion is a transition metal ion (d-block of the periodic table).

10. The composition of any one of claims 1-7, wherein the active agent is an imaging agent or a therapeutic agent.

11. The composition of any one of claims 3-7, wherein the targeting group is selected from the group consisting of an antibody, a cell surface receptor ligand, a cell surface receptor binding drug, a cell surface binding saccharide ligand, an extracellular matrix ligand, a cytosolic receptor ligand, a growth factor, a cytokine, an incretin, a hormone, and a lectin.

12. The composition of any one of claims 1-7, wherein the FMBD, the SMBD, or the TMBD are individually selected from N-(hydroxy-ethyl)ethylenediaminetriacetic acid;

nitrilotriacetic acid (NTA);

ethylene-bis(oxyethylene-nitrilo)tetraacetic acid;

1,4,7,10-tetraazacyclodo-decane-N,N′

,N″

,N′

″

-tetraacetic acid;

1,4,7,10-tetraaza-cyclododecane-N,N′

,N″

-triacetic acid;

1,4,7-tris(carboxymethyl)-10-(2′

-hydroxypropyl)-1,4,7,10-tetraazocyclodecane;

1,4,7-triazacyclonane-N,N′

,N″

-triacetic acid;

1,4,8,11-tetraazacyclotetra-decane-N,N′

,N″

,N′

″

-tetraacetic acid;

diethylenetriamine-pentaacetic acid (DTPA);

ethylenedicysteine;

bis(aminoethanethiol)carboxylic acid;

triethylenetetraamine-hexaacetic acid;

ethylenediamine-tetraacetic acid (EDTA);

or 1,2-diaminocyclohexane-N,N,N′

,N′

-tetraacetic acid.

13. The composition of claim 8, wherein the FMBD, the SMBD, or the TMBD is a metal binding polypeptide of formula:

(AxHy)p where A is any amino acid, H is histidine, x is an integer from 0-6;

y is an integer from 1-6; and

p is an integer from 1-6.

14. The composition of any one of claims 1-7, wherein the hydrophobic group has a molecular weight ranging from about 50 to about 1000 Daltons.

15. The composition of any one of claims 1-7, wherein the hydrophobic group comprises one or more linear fatty acyl groups with a formula of [CH₃(CH₂)_xCO—

] wherein x is an integer from 6-50.

16. The composition of any one of claims 1-7, wherein the hydrophobic group is a branched or straight chain C₅-C₅₀ alkyl, a substituted branched or straight chain C₅-C₅₀ alkyl, poly-glycine, a substituted poly-glycine, poly-alanine, poly-valine, poly-leucine, poly-isoleucine, poly-phenylalanine, poly-proline, poly-methionine, phenyl, napthyl, cholesterol, vitamin D, or vitamin E.

17. The composition of any one of claims 1-7, wherein a hydrophobic group has a general formula of [P_vN_wC_xH_yO_z—

] wherein v is an integer from 0-3;

w is an integer from 0-3;

x is an integer from 8-48;

y is an integer from 15-95; and

z is an integer from 1-13.

18. The composition of any one of claims 1-7, wherein a hydrophilic group comprises a polymer selected from poly(ethylene glycol);

alkoxy poly(ethyleneglycol);

methoxy poly(ethylene glycol);

dicarboxylic acid esterified poly(ethylene glycol) monoester;

poly(ethylene glycol)-diacid;

copolymer of poly(ethylene glycol);

poly(ethylene glycol) monoamine;

methoxy poly(ethyl ene glycol) monoamine;

methoxy poly(ethyl ene glycol) hydrazide;

methoxy poly(ethyl ene glycol) imidazolide;

blockcopolymer of poly(ethylene glycol);

poly-lactide-glycolide co-polymer;

polysaccharide;

oligosaccharides;

polyamidoamine; and

polyethyleneimine.

19. A method of delivering an active agent to a target site comprising administration of a composition to a subject, the composition comprising:

a first molecule comprising;

a first hydrophobic group comprising a first and second end;

a first metal binding domain (FMBD) covalently linked to the first end of the first hydrophobic group;

a metal ion chelated to the FMBD;

an active agent comprising a second metal binding domain (SMBD) coordinately bonded to the metal ion;

a hydrophilic group, wherein the hydrophilic group is covalently linked to the second end of the first hydrophobic group

wherein after administration of the composition to the subject, the active agent is released in a sustained manner, and the active agent is a therapeutic or a diagnostic agent.