JP2013512877A5

JP2013512877A5 -

Info

Publication number: JP2013512877A5
Application number: JP2012541498A
Authority: JP
Filing date: 2010-12-02
Publication date: 2014-02-13

Claims

At least 5 stem cell stimulants and at least one pharmaceutically acceptable excipient , wherein the at least 5 stem cell stimulants are TGFβ-1, BMP-4, FGF-2, IGF-1, A human or veterinary pharmaceutical composition (B) for stimulation of stem cells selected from the group consisting of activin-A, cardiotrophin 1, cardiogenol C and mixtures thereof .

The pharmaceutical composition according to claim 1 , wherein the stem cell stimulating agent is TGFβ-1, BMP-4, FGF-2, IGF-1, activin-A, cardiotrophin 1 and cardiogenol C.

The pharmaceutical composition of claim 1, wherein the composition further comprises a thrombin inhibitor.

The pharmaceutical composition according to any one of claims 1 to 3, further comprising at least one substance selected from the group consisting of growth factors, cytokines, hormones and combinations thereof.

The at least one substance is
A bone morphogenetic protein (BMP), for example BMP-1, BMP-2, BMP-5, BMP-6;
-Epidermal growth factor (EGF);
-Erythropoietin (EPO);
-Fibroblast growth factor (FGF), e.g. FGF-1, FGF-4, FGF-5, FGF-12, FGF-13, FGF-15, FGF-20;
-Granulocyte colony stimulating factor (G-CSF);
Granulocyte-macrophage colony stimulating factor (GM-CSF);
-Growth differentiation factor-9 (GDF-9);
-Hepatocyte growth factor (HGF);
An insulin-like growth factor (IGF), for example IGF-2;
-Myostatin (GDF-8);
-Neurotrophins such as NT-3, NT-4, NT-1 and nerve growth factor (NGF);
Platelet derived growth factor (PDGF), eg PDGF-β, PDGF-AA, PDGF-BB;
-Thrombopoietin (TPO);
-Transforming growth factor alpha (TGF-alpha)
Transforming growth factor β (TGF-β), for example TGF-β1, TGF-β2, TGF-β3;
-VEGF (vascular endothelial growth factor), e.g. VEGF-A, VEGF-C;
-TNF-alpha, leukemia inhibitory factor (LIF), interleukin 6 (IL-6), retinoic acid, S DF-1 (stromal cell-derived factor -1), BDNF (brain-derived neurotrophic factor), periostin, angiotensin II , Flt3 ligand, glial-derived neurotrophic factor, insulin-like growth factor binding protein-3, insulin-like growth factor binding protein-5, interleukin-3, interleukin-8, midkine, progesterone, putrescine, stem cell factor, TGF- α, WntI, Wnt3a, Wnt5a, caspase-4, chemokine ligand 1, chemokine ligand 2, chemokine ligand 5, chemokine ligand 7, chemokine ligand 11, chemokine ligand 20, haptoglobin, lectin, cholesterol 25-hydroxy Ase, syntaxin-8, syntaxin-11, ceruloplasmin, complement component 1, complement component 3, integrin α6, lysosomal acid lipase 1, β2 microglobulin, ubiquitin, macrophage migration inhibitory factor, cofilin, cyclophilin A, FKBP12, NDPK , Profilin 1, cystatin C, calcyclin, stanniocalcin-1, PGE-2, mpCCL2, IDO, iNOS, HLA-G5, M-CSF, angiopoietin, PIGF, MCP-1, extracellular matrix molecule, CCL2 (MCP- 1), CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES), CCL7 (MCP-3), CCL20 (MIP-3α), CCL26 (eotaxin-3), CX3CL1 (fractalkine) Selected from the group consisting of CXCL5 (ENA-78), CXCL11 (i-TAC), CXCL1 (GROα), CXCL2 (GROβ), CXCL8 (IL-8), CCL10 (IP-10) and combinations thereof The pharmaceutical composition according to claim 4 .

The pharmaceutical composition according to any one of claims 1 to 5, wherein the stem cells to be stimulated are resident cardiac stem cells, circulating stem cells or injected stem cells.

The pharmaceutical composition according to any one of claims 1 to 6, further comprising primary particles.

8. The pharmaceutical composition of claim 7 , wherein the primary particles are selected from the group consisting of alginate, chitosan, dextran, cellulose, liposomes, polyester microspheres , and polyester nanospheres.

9. The pharmaceutical composition according to claim 8, wherein the polyester is selected from the group consisting of PLGA, polycaprolactone and copolyester.

The pharmaceutical composition according to claim 8 or 9, wherein the primary particles encapsulate the stem cell stimulant of the pharmaceutical composition.

It is selected from the group consisting of the pharmaceutical composition (B) according to any one of claims 1 to 10, insulin-like growth factor 1 (IGF-1), hepatocyte growth factor (HGF), and an HGF variant. A pharmaceutical preparation comprising a composition (A) comprising at least one pharmaceutically active substance.

12. The pharmaceutical formulation of claim 11, wherein the HGF variant is NK1, 1K1, 1K2, HP11, HP21 or a combination thereof.

The pharmaceutical formulation according to claim 11 or 12, wherein the composition A further comprises SCF-1.

The composition (A) further comprises secondary particles selected from the group consisting of alginate, chitosan, dextran, cellulose, liposomes, polyester microspheres , and polyester nanospheres. The pharmaceutical preparation according to any one of claims 11 to 13.

14. The pharmaceutical composition according to claim 13, wherein the polyester is selected from the group consisting of PLGA, polycaprolactone and copolyester.

15. A pharmaceutical formulation according to claim 14, wherein the secondary particles encapsulate the at least one pharmaceutically active substance.

17. A medicament according to claims 14-16, wherein the secondary particles are configured to allow delivery of substances encapsulated therein prior to delivery of stem cell stimulants encapsulated in primary particles. Formulation .

At least 5 stem cell stimulants and at least one pharmaceutically acceptable excipient, wherein the at least 5 stem cell stimulants are TGFβ-1, BMP-4, FGF-2, IGF-1, Method for producing a medicament for the treatment of heart disease in humans or animals using a pharmaceutical composition (B) selected from the group consisting of activin-A, cardiotrophin 1, cardiogenol C and mixtures thereof

The manufacturing method of Claim 18 which administers the said pharmaceutical composition (B) to the said human or animal.

The agent further comprises a composition (A) comprising at least one pharmaceutically active substance selected from the group consisting of insulin-like growth factor 1 (IGF-1); hepatocyte growth factor (HGF) and an HGF variant. The manufacturing method according to claim 18.

The production method according to claim 20, wherein the administration of the pharmaceutical composition (B) follows the pre-administration of the composition (A).

24. The method of claim 21, wherein the duration between administration of the pharmaceutical composition (B) and administration of the composition (A) is up to about 2 weeks.

The manufacturing method of Claim 19 which repeats administration of the said pharmaceutical composition (B).

The production method according to claim 21, wherein at least one of the administrations is repeated.

The manufacturing method according to claim 23 or 24, wherein a duration between two consecutive administrations of the pharmaceutical composition (B) is 1 hour to 180 days.

22. A method according to claim 19 or claim 21, wherein the or each administration is in vivo.

The production method according to claim 19 or 21, wherein the or each administration is performed by injection.

The production method according to claim 19 or 21, wherein the or each administration is a continuous injection.

The production method according to claim 19 or 21, wherein the or each administration is administered parenterally.

22. A method according to claim 19 or claim 21, wherein the or each administration is administered to heart tissue.

The method according to claim 19 or 21, wherein the or each administration is administered to a human or animal circulatory system.

The method according to claim 19 or 21, wherein the or each administration is administered intravenously and / or intraarterially.

The production method according to claim 21, wherein administration of the pharmaceutical composition (B) is intracoronary, and preliminary administration of the composition (A) is intravenous.