Inhalable powder formulations of alginate oligomers

Abstract

Spray dried particles are for inhalation. The particles consist of (i) at least about 70% w/w of an alginate oligomer, (ii) at least about 10% w/w in total of a phospholipid and an anti-adherent compound. and (iii) no greater than about 10% w/w of further excipients. The phospholipid is solid at room temperature, and is present at no less than 0.5% w/w. The anti-adherent compound is present at no less than 0.5% w/w. The particles, capsules and dry powder inhalers including the particles can be for therapeutic use, such as in the treatment or reduction of likelihood of a respiratory infection or a respiratory disorder.

1 . Spray dried particles for inhalation, said particles consisting of:
 (i) at least about 70% w/w of an alginate oligomer,   (ii) at least about 10% w/w in total of a phospholipid and an anti-adherent compound, wherein said phospholipid is solid at room temperature, and wherein said phospholipid is present at no less than 0.5% w/w and said anti-adherent compound is present at no less than 0.5% w/w, and   (iii) no greater than about 10% w/w of further excipients.   
     
     
         2 . The spray dried particles of  claim 1 , wherein said particles contain at least about 75% w/w of the alginate oligomer. 
     
     
         3 . The spray dried particles of  claim 1 , wherein said particles contain about 80% w/w of the alginate oligomer. 
     
     
         4 . The spray dried particles of  claim 1 , wherein said particles contain at least about 15% w/w in total of the phospholipid and the anti-adherent compound. 
     
     
         5 . The spray dried particles of  claim 1 , wherein said particles contain about 20% w/w in total of the phospholipid and the anti-adherent compound. 
     
     
         6 . The spray dried particles of  claim 1 , wherein said particles contain no less than 3% w/w of the phospholipid. 
     
     
         7 . The spray dried particles of  claim 1 , wherein said particles contain about 5% w/w of the phospholipid. 
     
     
         8 . The spray dried particles of  claim 1 , wherein said particles contain no less than 10% w/w of the anti-adherent compound. 
     
     
         9 . The spray dried particles of  claim 1 , wherein said particles contain about 15% w/w of the anti-adherent compound. 
     
     
         10 . The spray dried particles of  claim 1 , wherein the relative amounts of phospholipid and anti-adherent compound present in the particles are in a ratio of 1:3. 
     
     
         11 . The spray dried particles of  claim 1 , wherein the relative amounts of the alginate oligomer, the phospholipid and anti-adherent compound present in the particles are in a ratio of 8:0.5:1.5. 
     
     
         12 . The spray dried particles of  claim 1 , wherein said particles contain essentially no further excipients. 
     
     
         13 . The spray dried particles of  claim 1 , wherein said particles consist of about 80% w/w of the alginate oligomer, about 15% of the w/w anti-adherent compound and about 5% w/w of the phospholipid. 
     
     
         14 . The spray dried particles of  claim 1 , wherein said particles have a geometric particle size distribution in which d50 is <5 μm and d90 is <10 μm. 
     
     
         15 . The spray dried particles of  claim 14  wherein the particles have a geometric particle size distribution in which d10 is <1.5 μm 
     
     
         16 . The spray dried particles of  claim 1 , wherein said particles have a FPM<4.46 μm of greater than about 10 mg per 40 mg of particles. 
     
     
         17 . The spray dried particles of  claim 1 , wherein said particles have an emitted dose of greater than about 65%. 
     
     
         18 . The spray dried particles of  claim 1 , wherein the alginate oligomer has an average molecular weight of less than 35,000 Daltons. 
     
     
         19 . The spray dried particles of  claim 1 , wherein the alginate oligomer has a degree of polymerization (DP), or a number average degree of polymerization (DPn) of 4 to 100, 4 to 75, 4 to 50, 4 to 35, 4 to 30, 4 to 25, 4 to 22, 4 to 20, 4 to 18, 4 to 16 or 4 to 14. 
     
     
         20 . The spray dried particles of  claim 1 , wherein the alginate oligomer has a degree of polymerization (DP), or a number average degree of polymerization (DPn) of
 (i) 5 to 50, 5 to 35, 5 to 30, 5 to 25, 5 to 22, 5 to 20, 5 to 18, 5 to 16 or 5 to 14,   (ii) 6 to 50, 6 to 35, 6 to 30, 6 to 25, 6 to 22, 6 to 20, 6 to 18, 6 to 16 or 6 to 14, or   (iii) 8 to 50, 8 to 35, 8 to 30, 8 to 25, 10 to 25, 10 to 22, 10 to 20, 10 to 18, or 10 to 15.   
     
     
         21 . The spray dried particles of  claim 1 , wherein the alginate oligomer has at least 70% G residues, or at least 80%, or at least 85%, or at least 90%, or at least 95% G residues. 
     
     
         22 . The spray dried particles of  claim 21 , wherein at least 80% of the G residues of the alginate oligomer are arranged in G-blocks. 
     
     
         23 . The spray dried particles of  claim 1 , wherein the alginate oligomer has a number average degree of polymerization in the range 5 to 20, a guluronate fraction (FG) of at least 0.85 and a mannuronate fraction (FM) of no more than 0.15. 
     
     
         24 . The spray dried particles of  claim 1 , wherein the alginate oligomer has at least 70% M residues, or at least 80%, or at least 85%, or at least 90%, or at least 95% M residues. 
     
     
         25 . The spray dried particles of  claim 24 , wherein at least 80% of the M residues of the alginate oligomer are arranged in M-blocks. 
     
     
         26 . The spray dried particles of  claim 1 , wherein the phospholipid is selected from the group consisting of phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols and a combination thereof. 
     
     
         27 . The spray dried particles of  claim 26 , wherein the phospholipid is selected from the group consisting of saturated phosphatidyl choline, unsaturated choline, phosphatidyl ethanol amine, phosphatidyl glycerol, phosphatidyl serine, phosphatidyl inositol, dioleoylphosphatidylcholine, dimyristoyl phosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC; 1,2-Dipalmitoyl-snglycero-3-phosphocholine), distearoyl phosphatidylcholine, 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), diarachidoyl phosphatidylcholine, dibenoyl phosphatidylcholine, ditricosanoyl phosphatidylcholine, dilignoceroylphatidylcholine, dimiristoylphosphatidylethanolamine, dipalmitoyl-phosphatidylethanoalamine, pipalmitoleoylphosphatidylethanolamine, distearoyl-phosphatidylethanolamine, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidyl glycerol, dipalmitolcoylphosphatidylglycerol and hydrogenated derivatives, and a combination thereof. 
     
     
         28 . The spray dried particles of  claim 27 , wherein the phospholipid is selected from the group consisting of DPPC and DSPC and a mixture thereof. 
     
     
         29 . The spray dried particles of  claim 1 , wherein the anti-adherent compound is selected from the group consisting of an amino acid, a monosaccharide, a disaccharide and a combination thereof. 
     
     
         30 . The spray dried particles of  claim 29  wherein the amino acid is selected from the group consisting of leucine, isoleucine, alanine, valine, phenylalanine, lysine, glycine, and a combination thereof. 
     
     
         31 . The spray dried particles of  claim 1 , said particles consisting of:
 (i) about 80% w/w of an alginate oligomer, wherein said alginate oligomer has a number average degree of polymerization in the range 5 to 20, a guluronate fraction (FG) of at least 0.85 and a mannuronate fraction (FM) of no more than 0.15.   (ii) about 5% w/w of DPPC, and   (iii) about 15% w/w glycine.   
     
     
         32 . A method for the preparation of an organic-in-aqueous liquid emulsion for spray drying so as to form the spray dried particles as defined in  claim 1 , said method comprising
 (a) providing
 (i) an aqueous liquid composition comprising an alginate oligomer as defined in  claim 1  and an aqueous liquid composition comprising an anti-adherent compound as defined in  claim 1  or 
 (ii) an aqueous liquid composition comprising an alginate oligomer as defined in  claim 1  and an anti-adherent compound as defined in  claim 1 , 
   (b) providing an organic liquid composition comprising a phospholipid as defined in  claim 1 ,   (c) combining a volume of the organic liquid composition with a volume of the aqueous liquid compositions of (i) or the aqueous liquid composition of (ii), wherein the volume of the organic liquid composition is smaller than the total volume of the aqueous liquid composition with which it is combined, and   (d) homogenizing the combination so formed at any time during step (c) or on upon completion of step (c) to form the organic-in-aqueous liquid emulsion for spray drying so as to form the spray dried particles as defined in  claim 1 .   
     
     
         33 . The method of  claim 32 , wherein the organic liquid composition is a solution of the phospholipid in an organic solvent selected from the group consisting of alcohols, ketones, acetates, halogenated solvents and aliphatic solvents. 
     
     
         34 . The method of  claim 33  wherein the organic solvent is selected from the group consisting of methanol, ethanol, C3 alcohols and C4 alcohols, acetone, ethyl acetate, dichloromethane, chloroform, heptane, hexane and pentane. 
     
     
         35 . A method for the preparation of the spray dried particles, said method comprising performing the method for the preparation of an organic-in-aqueous liquid emulsion for spray drying of  claim 32  and spray drying the organic-in-aqueous liquid emulsion formed in step (d). 
     
     
         36 . Spray dried particles obtainable from the method of  claim 35 . 
     
     
         37 . An organic-in-aqueous liquid emulsion for spray drying obtainable from the method of  claim 34 . 
     
     
         38 . A capsule adapted for use in a dry powder inhaler, said capsule containing the spray dried particles of  claim 1 . 
     
     
         39 . A dry powder inhaler, said dry powder inhaler comprising the spray dried particles of  claim 1 . 
     
     
         40 . A therapeutic method comprising obtaining the spray dried particles as defined in  claim 1 . 
     
     
         41 . A method of treatment or reduction of likelihood of a respiratory infection or a respiratory disorder, said treatment or reduction comprising administering the spray dried particles according to  claim 1  to the airways of a subject in need thereof by inhalation. 
     
     
         42 . The method of  claim 41 , wherein said respiratory disorder is a disorder or condition which involves microbial infection and/or abnormal mucus. 
     
     
         43 . The method of  claim 41 , wherein the respiratory disorder is any condition associated with or characterized by defective CFTR ion channel function, COPD, COAD, COAP, bronchitis, emphysema, lung cancer, asthma and pneumonia or a complication thereof. 
     
     
         44 . The method of  claim 43  wherein the condition associated with or characterized by defective CFTR ion channel function is an obstructive respiratory disorder, or a respiratory disorder characterized by a chronic inflammatory state, airway remodelling and exacerbations due to respiratory tract infections. 
     
     
         45 . The method of  claim 44 , wherein said condition associated with or characterized by defective CFTR ion channel function is cystic fibrosis (CF) or a medical disorder or condition associated with CF, non-compound CFTR gene mutation heterozygosity, abnormal mucus clearance in the respiratory tract and/or breathing difficulties resulting from chronic particulate inhalation, COPD, chronic bronchitis, emphysema, bronchiectasis, asthma or chronic sinusitis, or a complication thereof.