Parental Composition Comprising Microsperes 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 - 33 . (canceled) 
     
     
         34 . A method of treating a cardiovascular disorder comprising administration of a parenteral composition, said composition 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 composition is substantially free of particles with a diameter greater than 50 microns and less than 5 microns. 
     
     
         35 . The method of  claim 34  wherein the composition is substantially free of particles with a diameter greater than 20 microns and less than 5 microns. 
     
     
         36 . The method of  claim 34  wherein at least 90% of the particles have a diameter that is between 15 and 20 microns. 
     
     
         37 . The method of  claim 34  wherein at least 95%, at least 98% or at least 99% of the particles have a diameter of between 10 and 20 microns. 
     
     
         38 . The method of  claim 36  wherein at least 95%, at least 98% or at least 99% of the particles have a diameter of between 15 and 20 microns. 
     
     
         39 . The method of  claim 34  wherein the size of the particles is monodispersed. 
     
     
         40 . The method of  claim 39  wherein at least 68% of particles have a size +/−1 micron of the mean particle size. 
     
     
         41 . The method of  claim 40  wherein at least 99% of particles have a size +/−1 micron of the mean particle size. 
     
     
         42 . The method of  claim 34  wherein the particles have a mean particle size of 15 microns. 
     
     
         43 . The method of  claim 34  wherein the composition is administered to a cardiac muscle. 
     
     
         44 . The method of  claim 34  wherein the composition comprises one or more growth factors including HGF (hepatocyte growth factor), IGF (insulin-like growth factor), IGF-I, PDGF (Platelet-derived growth factor), PDGF-β, FGF (fibroblast growth factor), aFGF (FGF-I), bFGF (FGF-2), 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, NGF (Nerve growth factor), BDNF (brain-derived neurotrophic factor), NT-3 (neurotrophin-3), NT-4 (neurotrophin-4) and (neurotrophin-1), NGF, BDNF, NT-3, NT-4, TPO (Thrombopoietin), GDF-8 (Myostatin), GDF9 (Growth differentiation factor-9), Periostin, Wint 3A, Neuroregulin and SCF-1. 
     
     
         45 . The method of  claim 34  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. 
     
     
         46 . The method of  claim 43  wherein at least 30% of the active ingredient is retained in the cardiac muscle after administration. 
     
     
         47 . The method of  claim 46  wherein at least 40%, at least 50%, at least 60%, at least 70% such as at least 80% of the active ingredient is retained. 
     
     
         48 . The method of  claim 34  wherein the composition is administered via intra-arterial administration. 
     
     
         49 . The method of  claim 34  wherein the cardiovascular disorder is acute myocardial infarction (MI), chronic MI, ischemic heart disease with a myocardial infarction or ischemic heart disease without a myocardial infarction. 
     
     
         50 . The method of  claim 43  wherein the administration is a localized delivery of the composition into the circulation upstream of the cardiac muscle which is damaged and/or at risk for damage. 
     
     
         51 . The method of  claim 44  wherein the composition comprises HGF or IGF-I. 
     
     
         52 . The method of  claim 43  wherein the cardiac muscle is regenerated by stimulating stem cells of the cardiac muscle. 
     
     
         53 . The method of  claim 43  wherein the parenteral composition protects stem cells of the cardiac muscle from ischemic damage, apoptosis and/or necrosis. 
     
     
         54 . The method of  claim 43  wherein the parenteral composition stimulates cardiac muscle-specific stem cells or Oct4-expressing stem cells of the cardiac muscle.