Parenteral composition comprising microspheres with a diameter between 10 and 20 microns

Abstract

The present invention relates to pharmaceutical formulations suitable for targeting particular tissue and/or organ(s) with a formulated active ingredient, for example when administered upstream of the target organ or tissue, and to use of the same in treatment methods of preparing the formulations. The pharmaceutical formulations of the invention are for parenteral administration to a target tissue and comprise particles containing an active ingredient, and a biodegradable excipient, wherein 90% or more of the particles have a diameter of between 10 and 20 microns and the formulation is substantially free of particles with a diameter greater than 50 microns and less than 5 microns, such that where the formulation is administered upstream of the target tissue the ability of the active to pass through the target tissue and pass into systemic circulation is restricted.

1 . A pharmaceutical formulation for parenteral administration to a target tissue comprising particles containing an active ingredient and a biodegradable excipient, wherein 90% or more of the particles have a diameter of between 10 and 20 microns and the formulation is substantially free of particles with a diameter greater than 50 microns and less than 5 microns, such that where the formulation is administered upstream of the target tissue the ability of the active to pass through the target tissue and pass into systemic circulation is restricted. 
     
     
         2 . A pharmaceutical formulation according to  claim 1 , which is substantially free of particles with a diameter greater than 20 microns and less than 5 microns. 
     
     
         3 . A pharmaceutical formulation according to  claim 1 , wherein at least 90% of the particles have a diameter that is between 15 and 20 microns. 
     
     
         4 . A pharmaceutical composition according to  claim 1  wherein at least 95%, at least 98% or at least 99% of the particles have a diameter of between 10 and 20 microns. 
     
     
         5 . A pharmaceutical composition according to  claim 3  wherein at least 95%, at least 98% or at least 99% of the particles have a diameter of between 15 and 20 microns. 
     
     
         6 . A pharmaceutical composition according to  claim 1  wherein the size of the particles is monodispersed. 
     
     
         7 . A pharmaceutical composition according to  claim 6  wherein at least 68% of particles have a size+/−1 micron of the mean particle size. 
     
     
         8 . A pharmaceutical composition according to  claim 7  wherein at least 99% of particles have a size+/−1 micron of the mean particle size. 
     
     
         9 . A pharmaceutical composition according to  claim 1 , wherein the particles have a mean particle size of 15 microns. 
     
     
         10 . A pharmaceutical composition according to  claim 1  for parenteral administration to an ischemic tissue. 
     
     
         11 . A pharmaceutical composition according to  claim 10  for parenteral administration to a cardiac ischemic tissue. 
     
     
         12 . A pharmaceutical formulation according to  claim 11  which further comprises a growth factors selected from: HGF (hepatocyte growth factor); IGF (insulin-like growth factor) such as IGF-I; PDGF (Platelet-derived growth factor) such as PDGF-β, FGF (fibroblast growth factor) such as aFGF (FGF-I) or bFGF (FGF-2) and FGF-4; SDF-I (stromal cell-derived factor 1); EGF (epidermal growth factor); VEGF (vascular endothelial growth factor); erythropoietin (EPO); TGF β (transforming growth factor β); G-CSF (Granulocyte-colony stimulating factor); GM-CSF (Granulocyte-macrophage colony stimulating factor), Bone morphogenetic proteins (BMPs, BMP-2, BMP-4); Activin A; IL-6; Neurotrophins for example NGF (Nerve growth factor), BDNF (brain-derived neurotrophic factor), NT-3 (neurotrophin-3), NT-4 (neurotrophin-4) and (neurotrophin-1), which is structurally unrelated to NGF, BDNF, NT-3 and NT-4; TPO (Thrombopoietin); GDF-8 (Myostatin); GDF9 (Growth differentiation factor-9); Periostin, Wint 3A or Neuroregulin. 
     
     
         13 . A pharmaceutical composition according to  claim 1  containing an active ingredient selected from the group comprising HGF and/or IGF. 
     
     
         14 . A pharmaceutical composition according to  claim 13  which further comprises PDGF (Platelet-derived growth factor) such as PDGF-β, FGF (fibroblast growth factor) such as aFGF (FGF-I) or bFGF (FGF-2) and FGF-4; SDF-I (stromal cell-derived factor 1); EGF (epidermal growth factor); VEGF (vascular endothelial growth factor); erythropoietin (EPO); TGF β (transforming growth factor β); G-CSF (Granulocyte-colony stimulating factor); GM-CSF (Granulocyte-macrophage colony stimulating factor), Bone morphogenetic proteins (BMPs, BMP-2, BMP-4); Activin A; IL-6; Neurotrophins for example NGF (Nerve growth factor), BDNF (brain-derived neurotrophic factor), NT-3 (neurotrophin-3), NT-4 (neurotrophin-4) and (neurotrophin-1), which is structurally unrelated to NGF, BDNF, NT-3 and NT-4; TPO (Thrombopoietin); GDF-8 (Myostatin); GDF9 (Growth differentiation factor-9); Periostin, Wint 3A or Neuroregulin. 
     
     
         15 . A pharmaceutical composition according to  claim 14  which further comprises SCF-I. 
     
     
         16 . A pharmaceutical composition according to  claim 1 , wherein the concentration of the active ingredient is in the range of 1 ng per 1×10 6  particles up to 4 mg per 1×10 6  microspheres. 
     
     
         17 . A pharmaceutical formulation according to  claim 1 , wherein at least 30% of the active ingredient is retained in the target tissue after administration. 
     
     
         18 . A pharmaceutical formulation according to  claim 17 , wherein at least 40%, at least 50%, at least 60%, at least 70% such as at least 80% of the active ingredient is retained. 
     
     
         19 . A pharmaceutical composition according to  claim 1 , wherein the parenteral administration is intra-arterial administration. 
     
     
         20 . A pharmaceutical formulation as defined in  claim 1 , for treatment. 
     
     
         21 . A pharmaceutical formulation as defined in  claim 1 , for targeting a selected tissue or organ. 
     
     
         22 . A pharmaceutical formulation according to  claim 21 , wherein the organ is selected from the heart, lung(s), liver, kidney(s), bladder, uterus, testis, pancreas, spleen or intestines. 
     
     
         23 . A pharmaceutical formulation according to  claim 22 , for targeting cardiac tissue. 
     
     
         24 . A pharmaceutical formulation according  claim 23 , for the treatment of myocardial infarction (MI) acute or chronic, ischemic heart disease, with or without a myocardial infarction 
     
     
         25 . A method of localized delivery comprising the step of administering into the circulation upstream of cardiac tissue a pharmaceutical composition as defined in  claim 1 . 
     
     
         26 . A method according to  claim 25  wherein the localized delivery is through is intra-arterial administration. 
     
     
         27 . Use of HGF or IGF-I for regeneration in cardiac tissue by stimulating stems cells resident in mature cardiac tissue. 
     
     
         28 . Use of a growth factor as defined in  claim 12  for inducing cellular protection of cardiac tissue-specific stem cells from ischemic damage and reducing their death by apoptosis and/or necrosis 
     
     
         29 . Use of a growth factor as defined in  claim 12 , for stimulating Oct4-expressing stem cells. 
     
     
         30 . Use of a growth factor as defined in  claim 12  wherein cardiac tissue-specific stem cells are also stimulated. 
     
     
         31 . A pharmaceutical formulation according to  claim 1 , for the treatment of cerebral vascular accident (stroke). 
     
     
         32 . A pharmaceutical formulation according to  claim 1  for the treatment of any cell loss produced as a consequence of reduced blood flow (ischemia) or degenerative disease in any other tissue. 
     
     
         33 . A pharmaceutical composition according to  claim 1  wherein the pharmaceutical composition comprises a mixed population of particles, said population comprising particles having a first active ingredient in admixture with particles having one or more further distinct active ingredients.