Powder Compositions for Inhalation

Abstract

A pharmacological powder for inhalation comprising fine particles of a drug and particles of a force-controlling agent, wherein the particles of said force-controlling agent are disposed on the surface of the active particles as either a particulate coating, or as a continuous or discontinuous film. The powder may further comprise particles of a carrier material for supporting the drug particles. The force-controlling agent may be selected from: amino acids, peptides and polypeptides having a molecular weight of from 0.25 to 1000 KDa; phospholipids; titanium dioxide; aluminium dioxide; silicon dioxide; starch; and salts of fatty acids. Also disclosed is a method of making such a powder for inhalation comprising mixing a force-controlling agent with particles of one or more pharmacologically active materials to obtain a mixture in which the particles of said force-controlling agent are disposed on the surface of the active particles as either a particulate coating, or as a continuous or discontinuous film. The mixing step may be achieved by sieving, mixing or blending, micronising and/or co-micronising the particles of one or more pharmacologically active material and particles of force-controlling agents.

1 . A pharmacological powder for inhalation comprising fine particles of a drug and particles of a force-controlling agent, wherein the particles of said force-controlling agent are disposed on the surface of the active particles as either a particulate coating, or as a continuous or discontinuous film. 
   
   
       2 . A pharmacological powder for inhalation comprising fine particles of a drug, particles of a carrier material for supporting drug particles, and force-controlling agent particles, wherein the force-controlling agent particles are disposed on the surface of the active particles as either a particulate coating, or as a continuous or discontinuous film. 
   
   
       3 . A powder according to  claim 1  or  claim 2  wherein the force-controlling agent is selected from the group consisting of amino acids, peptides and polypeptides having a molecular weight of from 0.25 to 1000 KDa; phospholipids; titanium dioxide; aluminium dioxide; silicon dioxide; starch; and salts of fatty acids. 
   
   
       4 . A powder according to  claim 1  or  claim 2  wherein the force-controlling agent is a salt of a fatty acid selected from the group consisting of lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid. 
   
   
       5 . A powder according to  claim 1  or  claim 2  wherein the force-controlling agent is magnesium stearate. 
   
   
       6 . A powder according to  claim 1  or  claim 2  wherein the force-controlling agent is present in amounts of up to 5.0% by weight. 
   
   
       7 . A powder according to  claim 1  or  claim 2  wherein the force-controlling agent is present in amounts of 0.01 to 5.0% by weight. 
   
   
       8 . A powder according to  claim 1  or  claim 2  wherein the carrier material is selected from a mono- or di-saccharides such as glucose, lactose, lactose mono-hydrate, sucrose or trehalose; sugar alcohols such as mannitol or xylitol; polylactic acid; or mixtures thereof. 
   
   
       9 . A powder according to  claim 1  or  claim 2  wherein the carrier material is lactose mono-hydrate. 
   
   
       10 . A powder according to  claim 1  or  claim 2  wherein the drug is selected from those drugs having a contact angle against water that is less than 90°. 
   
   
       11 . A powder according to  claim 1  or  claim 2  wherein the drug is selected from those drugs having an octanol-water partition coefficient (log P) smaller than 2. 
   
   
       12 . A powder according to  claim 1  or  claim 2  wherein the drug is selected from the group consisting of a beta-mimetic selected from the group consisting of Levalbuterol, Terbutalin, Reproterol, Salbutamol, Salmeterol, Formoterol, Fenoterol, Clenbuterol, Bambuterol, Tulobuterol, Broxaterol, Epinephrin, Isoprenaline or Hexoprenaline; an anticholinergic selected from the group consisting of Tiotropium, Ipratropium, Oxitropium or Glycopyrronium; a Corticosteroid selected from the group consisting of Butixocart, Rofleponide, Budesonide, Ciclosenide, Mometasone, Fluticasone, Beclomethasone, Loteprednol or Triamcinolone; a Leukotriene antagonist selected from the group consisting of Andolast, Iralukast, Pranlukast, Imitrodast, Seratrodast, Zileuton, Zafirlukast or Montelukast; a Phosphodiesterase-Inhibitor selected from the group consisting of Filaminast or Piclamilast; aPAF-Inhibitor selected from the group consisting of Apafant, Forapafant or Israpafant; a potassium channel opener selected from the group consisting of Amiloride or Furosemide; a pain killer selected from the group consisting of Morphine, Fentanyl, Pentazocine, Buprenorphine, Pethidine, Tilidine, Methadone or Heroin; a potency agent selected from the group consisting of Sildenafil, Alprostadil or Phentolamine; proteins, peptides, oligopeptides, polypeptides, polyamino acids nucleic acid, polynucleotides, oligo-nucleotides and high molecular weight polysaccharides; macromolecules, selected from the group consisting of: Albumins (preferably, human serum Insulin; albumin); BSA; IgG; IgM; insulin; GCSF; GMCSF; LHRH; VEGF; hGH; lysozyme; alpha-lactoglobulin; basic fibroblast growth factor basic fibroblast growth factor; (bFGF); asparaginase; tPA; urokinase-VEGF; chymotrypsin; trypsin; streptokinase; interferon; carbonic anhydrase; ovalbumin; glucagon; ACTH; oxytocin; phosphorylase b; alkaline phosphatase-secretin; vasopressin; levothyroxin; phatase; beta-galactosidase; parathyroid hormone, calcitonin; fibrinogen; polyaminoacids selected from DNAse, alpha1 antitrypsin; polylysine, polyarginine; angiogenesis inhibitors or pro-immunoglobulins; moters; somatostatin and analogs; casein; collagen; gelatin; soy protein; and cytokines; immunoglobulins; peptide hormones, cytokines, growth factors, factors acting on the cardiovascular system, factors acting on the central and peripheral nervous systems, factors acting on humoral electrolytes and hemal substances, factors acting on bone and skeleton, factors acting on the gastrointestinal system, factors acting on the immune system, factors acting on the respiratory system, factors acting on the genital organs, and enzymes; hormones and hormone modulators including insulin, proinsulin, C-peptide of insulin, a mixture of insulin and C-peptide of insulin, hybrid insulin cocrystals; growth hormone, parathyroid hormone, luteinizing hormone-releasing hormone (LH-RH), adrenocorticotropic hormone (ACTH), amylin, oxytocin, luteinizing hormone, (D-Tryp6)-LHRH, nafarelin acetate, leuprolide acetate, follicle stimulating hormone, glucagon, prostaglandins, estradiols, testosterone, and other factors acting on the genital organs and their derivatives, analogues and congeners; hematopoietic or thrombopoietic factors selected from the group consisting of erythropoitin, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage stimulating factor (GM-CSF) and macrophage colony stimulating factor (M-CSF), leukocyte proliferation factor preparation (Leucoprol, Morinaga Milk), thrombopoietin, platelet proliferation stimulating factor, megakaryocyte proliferation (stimulating) factor, and factor VIII; therapeutic factors acting on bone and skeleton and agents for treating osteoporosis including bone GLa peptide, parathyroid hormone and its active fragments, histone H4-related bone formation and proliferation peptide and their muteins, derivatives and analogs thereof; enzymes and enzyme cofactors selected from the group consisting of pancrease, L-asparaginase, hyaluronidase, chymotrypsin, trypsin, tPA, streptokinase, urokinase, pancreatin, collagenase, trypsinogen, chymotrypsinogen, plasminogen, streptokinase, adenyl cyclase, and superoxide dismutase (SOD); vaccines include Hepatitis B, MMR (measles, mumps, and rubella), and Polio vaccines; growth factors include nerve growth factors (NGF, NGF-2/NT-3), epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), transforming growth factor (TGF), platelet-derived cell growth factor (PDGF), and hepatocyte growth factor (HGF); factors acting on the cardiovascular system including factors which control blood pressure and arteriosclerosis, selected from endothelins, endothelin inhibitors and endothelin antagonists; endothelin producing enzyme inhibitors vasopressin, renin, angiotensin I, angiotensin II, angiotensin III, angiotensin I inhibitor, angiotensin II receptor antagonist, atrial naturiuretic peptide (ANP), and antiarrythmic peptide; Factors acting on the central and peripheral nervous systems including opioid peptides (e.g. enkephalins, endorphins), neurotropic factor (NTF), calcitonin gene-related peptide (CGRP), thyroid hormone releasing hormone (TRH), salts and derivatives of TRH, and neurotensin; factors acting on the gastrointestinal system including secretin and gastrin; factors acting on humoral electrolytes and hemal substances including factors which control hemagglutination, plasma cholesterol level or metal ion concentrations, such as calcitonin, apoprotein E and hirudin. Laminin and intercellular adhesion molecule 1 (ICAM 1) represent exemplary cell adhesion factors; factors acting on the kidney and urinary tract including substances which regulate the function of the kidney, such as brain-derived natriuretic peptide (BNP), and urotensin; factors which act on the sense organs including factors which control the sensitivity of the various organs; chemotherapeutic agents, selected from the group consisting of paclitaxel, mytomycin C, BCNU, and doxorubicin; factors acting on the immune system including factors which control inflammation and malignant neoplasms and factors which attack infective microorganisms, selected from the group consisting of chemotactic peptides and bradykinins; and Naturally occurring, chemically synthesized or recombinant peptides or proteins which may act as antigens, such as cedar pollen and ragweed pollen, and these materials alone or together coupled to haptens, or together with an adjuvant; and a pharmaceutically acceptable derivative or salt of any of the foregoing compounds or classes of compounds. 
   
   
       13 . A powder according to  claim 1  or  claim 2  wherein the drug is selected from the group consisting of an anti-cholinergic in salt form such as oxitropium bromide, glycopyrronium bromide (glycopyrrolate), ipratropium bromide or tiotropium bromide. 
   
   
       14 . A method of making a powder for inhalation comprising the step of mixing a force-controlling agent with particles of one or more pharmacologically active materials in order to obtain a mixture wherein the particles of said force-controlling agent are disposed on the surface of the active particles as either a particulate coating, or as a continuous or discontinuous film. 
   
   
       15 . A method according to  claim 14  wherein the mixing step is achieved by one or more of the processes of sieving, mixing or blending, micronising or co-micronising the particles of one or more pharmacologically active material and particles of force-controlling agents. 
   
   
       16 . A method according to  claim 14  or  claim 15  comprising the step of mixing or blending said mixture with a carrier material. 
   
   
       17 . A method according to  claim 16  wherein in a first step the mixture is mixed or blended with a first portion of the carrier material to form a second mixture, and in a subsequent step the remainder of the carrier material is mixed with said second mixture. 
   
   
       18 . A method according to  claim 14  wherein the mixing or blending is carried out in a diffusion blender, tumble blender, bin blender or conical blender, or a high shear mixer, and wherein the micronisation or co-micronisation is carried out in an air-jet mill. 
   
   
       19 . A DPI device comprising a powder according to  claim 1  or  claim 2 . 
   
   
       20 .- 21 . (canceled) 
   
   
       22 . A method of treating a medical condition comprising administering to a patient in need thereof a pharmacological powder as claimed in  claim 1 ,  claim 2  or claim  21 . 
   
   
       23 . A method of treating a medical condition comprising administering to a patient in need thereof a pharmacological powder made in accordance with the method of  claim 14 .