Lipid-based nanoparticles and use of same in optimized insulin dosing regimens

Abstract

The invention provides methods of treating a subject having diabetes mellitus and/or a metabolic derangement.

1 . A method of eliminating or minimizing events of iatrogenic hyperinsulinemia or hypoglycemia in a subject having diabetes mellitus or a metabolic derangement,
 wherein the subject is originally administered an amount of bolus non-HDV insulin and an amount of basal insulin such that the subject originally has greater than about 8.5% HbA1c,   the method comprising:
 administering to the subject a bolus insulin HDV composition in place of the original bolus non-HDV insulin, wherein the amount of insulin in the bolus insulin HDV composition is lower than in the original bolus non-HDV insulin; 
 administering to the subject a basal insulin; 
 varying the administered amount of the bolus insulin HDV composition and the administered amount of the basal insulin so as to identify the optimized amount of the bolus insulin HDV composition and the optimized amount of the basal insulin to be administered to the subject to afford therapeutically effective blood glucose control without, or with minimized, events of iatrogenic hyperinsulinemia or hypoglycemia; 
   
       wherein the bolus insulin HDV composition comprises a lipid-based nanoparticle, wherein the bolus insulin is dispersed within the nanoparticle,
 wherein the nanoparticle is enclosed by a bipolar lipid membrane comprising cholesterol, dicetyl phosphate, an amphipathic lipid, and a hepatocyte receptor binding molecule; 
 wherein the amphipathic lipid comprises at least one selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycerol-[3-phospho-rac-(1-glycerol)], 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-di stearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine; 
 wherein the at least one hepatocyte receptor binding molecule extends outward from the nanoparticle; and 
 wherein the size of the nanoparticle ranges from about 10 nm to about 150 nm. 
 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the insulin ratio between the optimized administered bolus insulin HDV composition and the optimized administered basal insulin is equal to or lower than 1:1. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . A method of eliminating or minimizing events of iatrogenic hyperinsulinemia or hypoglycemia in a subject having diabetes mellitus or a metabolic derangement,
 wherein the subject is originally administered an amount of bolus non-HDV insulin and an amount of basal insulin such that the subject originally has about 6.5-8.5% HbA1c,   the method comprising:
 administering to the subject a bolus insulin HDV composition in place of the original bolus non-HDV insulin; 
 administering to the subject a reducing amount of basal insulin as compared to the amount of basal insulin originally administered to the subject; and 
   varying the administered amount of the bolus insulin HDV composition so as to identify the optimized amount of the bolus insulin HDV composition and the optimized amount of the basal insulin to be administered to the subject such that the diabetes is well controlled in the subject without, or with minimized, events of iatrogenic hyperinsulinemia or hypoglycemia;   
       wherein the bolus insulin HDV composition comprises a lipid-based nanoparticle, wherein the bolus insulin is dispersed within the nanoparticle,
 wherein the nanoparticle is enclosed by a bipolar lipid membrane comprising cholesterol, dicetyl phosphate, an amphipathic lipid, and a hepatocyte receptor binding molecule; 
 wherein the amphipathic lipid comprises at least one selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycerol-[3-phospho-rac-(1-glycerol)], 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine; 
 wherein the at least one hepatocyte receptor binding molecule extends outward from the nanoparticle; and 
 wherein the size of the nanoparticle ranges from about 10 nm to about 150 nm. 
 
     
     
         7 . The method of  claim 6 , wherein the subject before optimization has about 80-100 mg/dL fasting blood sugar. 
     
     
         8 . The method of  claim 6 , wherein at least one of the following results is observed upon optimization:
 (a) the subject experiences fewer hypoglycemia as compared to the treatment without HDV;   (b) the subject experiences weight loss as compared to the treatment without HDV   
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 6 , wherein the bolus insulin HDV composition further comprises a GLP-1 agonist or serotonin. 
     
     
         11 . The method of  claim 10 , wherein the GLP-1 agonist comprises liraglutide, semaglutide, or repaglinide. 
     
     
         12 . The method of  claim 6 , wherein the basal insulin is formulated in a composition comprising a lipid-based nanoparticle, wherein the basal insulin is dispersed within the nanoparticle;
 wherein the nanoparticle is enclosed by a bipolar lipid membrane comprising cholesterol, dicetyl phosphate, an amphipathic lipid, and a hepatocyte receptor binding molecule;   wherein the amphipathic lipid comprises at least one selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycerol-[3-phospho-rac-(1-glycerol)], 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine;   wherein the at least one hepatocyte receptor binding molecule extends outward from the nanoparticle; and   wherein the size of the nanoparticle ranges from about 10 nm to about 150 nm.   
     
     
         13 . The method of  claim 6 , wherein the basal insulin is administered continuously to the subject over a period of at least 24 hours. 
     
     
         14 . The method of  claim 6 , wherein the composition is administered continuously to the subject using a pump. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 6 , wherein the membrane further comprises at least one agent selected from the group consisting of a stabilizer and stearoyl lysophosphatidylcholine. 
     
     
         17 . The method of  claim 16 , wherein the stabilizer is selected from the group consisting of m-cresol, benzyl alcohol, methyl 4-hydroxybenzoate, thiomersal, and butylated hydroxytoluene (2,6-di-tert-butyl-4-methylphenol). 
     
     
         18 . The method of  claim 16 , wherein the stabilizer ranges from about 10% to about 25% (w/w) in the membrane, or the stearoyl lysophosphatidylcholine ranges from about 5% to about 30% (w/w) in the membrane. 
     
     
         19 . The method of  claim 6 , wherein the insulin is covalently bound to the nanoparticle or the insulin is not covalently bound to the nanoparticle. 
     
     
         20 . The method of  claim 6 , wherein the nanoparticle is suspended in an aqueous solution comprising a free dissolved insulin that is not dispersed within the nanoparticle. 
     
     
         21 . The method of  claim 20 , wherein the nanoparticle-dispersed insulin and the free dissolved insulin are independently selected from the group consisting of insulin lispro, insulin aspart, regular insulin, insulin glargine, insulin zinc, extended human insulin zinc suspension, isophane insulin, human buffered regular insulin, insulin glulisine, recombinant human regular insulin, recombinant human insulin isophane, insulin detemir, biphasic human insulin, and insulin deglude, and any combinations thereof. 
     
     
         22 . The method of  claim 6 , wherein the amphipathic lipid comprises at least one selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)], 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl). 
     
     
         23 . The method of  claim 6 , wherein the hepatocyte receptor binding molecule comprises biotin. 
     
     
         24 . The method of  claim 23 , wherein the biotin-containing hepatocyte receptor binding molecule comprises at least one selected from the group consisting of N-hydroxysuccinimide (NHS) biotin; sulfo-NHS-biotin; N-hydroxysuccinimide long chain biotin; sulfo-N-hydroxysuccinimide long chain biotin; D-biotin; biocytin; sulfo-N-hydroxysuccinimide-S—S-biotin; biotin-BMCC; biotin-HPDP; iodoacetyl-LC-biotin; biotin-hydrazide; biotin-LC-hydrazide; biocytin hydrazide; biotin cadaverine; carboxybiotin; photobiotin; p-aminobenzoyl biocytin trifluoroacetate; p-diazobenzoyl biocytin; biotin DHPE (2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate); biotin-X-DHPE (2,3-diacetoxypropyl 2-(6-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)hexanamido) ethyl phosphate); 12-((biotinyl)amino)dodecanoic acid; 12-((biotinyl)amino)dodecanoic acid succinimidyl ester; S-biotinyl homocysteine; biocytin-X; biocytin x-hydrazide; biotinethylenediamine; biotin-XL; biotin-X-ethylenediamine; biotin-XX hydrazide; biotin-XX-SE; biotin-XX, SSE; biotin-X-cadaverine; α-(t-BOC)biocytin; N-(biotinyl)-N′-(iodoacetyl) ethylenediamine; DNP-X-biocytin-X-SE; biotin-X-hydrazide; norbiotinamine hydrochloride; 3-(N-maleimidylpropionyl)biocytin; ARP; biotin-1-sulfoxide; biotin methyl ester; biotin-maleimide; biotin-poly(ethyleneglycol) amine; (+) biotin 4-amidobenzoic acid sodium salt; Biotin 2-N-acetylamino-2-deoxy-β-D-glucopyranoside; Biotin-α-D-N-acetylneuraminide; Biotin-α-L-fucoside; Biotin lacto-N-bioside; Biotin-Lewis-A trisaccharide; Biotin-Lewis-Y tetrasaccharide; Biotin-α-D-mannopyranoside; and biotin 6-O-phospho-α-D-mannopyranoside. 
     
     
         25 . The method of  claim 23 , wherein the biotin-containing hepatocyte receptor binding molecule comprises at least one selected from the group consisting of biotin DHPE and biotin-X-DHPE. 
     
     
         26 . The method of  claim 6 , wherein at least one applies:
 (a) the cholesterol ranges from about 5% to about 25% (w/w) in the membrane;   (b) the dicetyl phosphate ranges from about 10% to about 25% (w/w) in the membrane;   (c) the DSPC ranges from about 40% to about 75% (w/w) in the membrane;   (d) the hepatocyte receptor binding molecule ranges from about 0.5% to about 10% (w/w) in the membrane.   
     
     
         27 . The method of  claim 16 , wherein the amount of the stearoyl lysophosphatidylcholine in the membrane is about 5%-30% (w/w) of the amount of DSPC in the membrane. 
     
     
         28 . The method of  claim 16 , wherein the membrane comprises one of the following:
 (a) cholesterol, dicetyl phosphate, DSPC, stearoyl lysophosphatidylcholine, m-cresol, and at least one selected from the group consisting of biotin DHPE and biotin-X-DHPE;   (b) cholesterol, dicetyl phosphate, DSPC, m-cresol, and at least one selected from the group consisting of biotin DHPE and biotin-X-DHPE; and   (c) cholesterol, dicetyl phosphate, DSPC, stearoyl lysophosphatidylcholine, and at least one selected from the group consisting of biotin DHPE and biotin-X-DHPE.   
     
     
         29 . The method of  claim 16 , wherein the membrane comprises cholesterol, dicetyl phosphate, DSPC, stearoyl lysophosphatidylcholine, m-cresol, and biotin DHPE in a % (w/w) ratio selected from the group consisting of:
 (a) about 9.4:18.1:56.8:14.1:0.0:1.5;   (b) about 7.7:15.0:58.6:0.0:17.4:1.3; and   (c) about 8.4:16.2:47.5:7.6:19.0:1.3.   
     
     
         30 . (canceled) 
     
     
         31 . The method of  claim 1 , wherein the bolus insulin HDV composition further comprises a GLP-1 agonist or serotonin. 
     
     
         32 . The method of  claim 31 , wherein the GLP-1 agonist comprises liraglutide, semaglutide, or repaglinide. 
     
     
         33 . The method of  claim 1 , wherein the basal insulin is administered continuously to the subject over a period of at least 24 hours. 
     
     
         34 . The method of  claim 1 , wherein the composition is administered continuously to the subject using a pump. 
     
     
         35 . The method of  claim 1 , wherein the membrane further comprises at least one agent selected from the group consisting of a stabilizer and stearoyl lysophosphatidylcholine. 
     
     
         36 . The method of  claim 35 , wherein the stabilizer is selected from the group consisting of m-cresol, benzyl alcohol, methyl 4-hydroxybenzoate, thiomersal, and butylated hydroxytoluene (2,6-di-tert-butyl-4-methylphenol). 
     
     
         37 . The method of  claim 35 , wherein the stabilizer ranges from about 10% to about 25% (w/w) in the membrane, or the stearoyl lysophosphatidylcholine ranges from about 5% to about 30% (w/w) in the membrane. 
     
     
         38 . The method of  claim 1 , wherein the insulin is covalently bound to the nanoparticle or the insulin is not covalently bound to the nanoparticle. 
     
     
         39 . The method of  claim 1 , wherein the nanoparticle is suspended in an aqueous solution comprising a free dissolved insulin that is not dispersed within the nanoparticle. 
     
     
         40 . The method of  claim 39 , wherein the nanoparticle-dispersed insulin and the free dissolved insulin are independently selected from the group consisting of insulin lispro, insulin aspart, regular insulin, insulin glargine, insulin zinc, extended human insulin zinc suspension, isophane insulin, human buffered regular insulin, insulin glulisine, recombinant human regular insulin, recombinant human insulin isophane, insulin detemir, biphasic human insulin, and insulin deglude, and any combinations thereof. 
     
     
         41 . The method of  claim 1 , wherein the amphipathic lipid comprises at least one selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)], 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl). 
     
     
         42 . The method of  claim 1 , wherein the hepatocyte receptor binding molecule comprises biotin. 
     
     
         43 . The method of  claim 42 , wherein the biotin-containing hepatocyte receptor binding molecule comprises at least one selected from the group consisting of N-hydroxysuccinimide (NHS) biotin; sulfo-NHS-biotin; N-hydroxysuccinimide long chain biotin; sulfo-N-hydroxysuccinimide long chain biotin; D-biotin; biocytin; sulfo-N-hydroxysuccinimide-S—S-biotin; biotin-BMCC; biotin-HPDP; iodoacetyl-LC-biotin; biotin-hydrazide; biotin-LC-hydrazide; biocytin hydrazide; biotin cadaverine; carboxybiotin; photobiotin; p-aminobenzoyl biocytin trifluoroacetate; p-diazobenzoyl biocytin; biotin DHPE (2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate); biotin-X-DHPE (2,3-diacetoxypropyl 2-(6-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)hexanamido) ethyl phosphate); 12-((biotinyl)amino)dodecanoic acid; 12-((biotinyl)amino)dodecanoic acid succinimidyl ester; S-biotinyl homocysteine; biocytin-X; biocytin x-hydrazide; biotinethylenediamine; biotin-XL; biotin-X-ethylenediamine; biotin-XX hydrazide; biotin-XX-SE; biotin-XX, SSE; biotin-X-cadaverine; α-(t-BOC)biocytin; N-(biotinyl)-N′-(iodoacetyl) ethylenediamine; DNP-X-biocytin-X-SE; biotin-X-hydrazide; norbiotinamine hydrochloride; 3-(N-maleimidylpropionyl)biocytin; ARP; biotin-1-sulfoxide; biotin methyl ester; biotin-maleimide; biotin-poly(ethyleneglycol) amine; (+) biotin 4-amidobenzoic acid sodium salt; Biotin 2-N-acetylamino-2-deoxy-β-D-glucopyranoside; Biotin-α-D-N-acetylneuraminide; Biotin-α-L-fucoside; Biotin lacto-N-bioside; Biotin-Lewis-A trisaccharide; Biotin-Lewis-Y tetrasaccharide; Biotin-α-D-mannopyranoside; and biotin 6-O-phospho-α-D-mannopyranoside. 
     
     
         44 . The method of  claim 42 , wherein the biotin-containing hepatocyte receptor binding molecule comprises at least one selected from the group consisting of biotin DHPE and biotin-X-DHPE. 
     
     
         45 . The method of  claim 1 , wherein at least one applies:
 (a) the cholesterol ranges from about 5% to about 25% (w/w) in the membrane;   (b) the dicetyl phosphate ranges from about 10% to about 25% (w/w) in the membrane;   (c) the DSPC ranges from about 40% to about 75% (w/w) in the membrane;   (d) the hepatocyte receptor binding molecule ranges from about 0.5% to about 10% (w/w) in the membrane.   
     
     
         46 . The method of  claim 35 , wherein the amount of the stearoyl lysophosphatidylcholine in the membrane is about 5%-30% (w/w) of the amount of DSPC in the membrane. 
     
     
         47 . The method of  claim 35 , wherein the membrane comprises one of the following:
 (a) cholesterol, dicetyl phosphate, DSPC, stearoyl lysophosphatidylcholine, m-cresol, and at least one selected from the group consisting of biotin DHPE and biotin-X-DHPE;   (b) cholesterol, dicetyl phosphate, DSPC, m-cresol, and at least one selected from the group consisting of biotin DHPE and biotin-X-DHPE; and   (c) cholesterol, dicetyl phosphate, DSPC, stearoyl lysophosphatidylcholine, and at least one selected from the group consisting of biotin DHPE and biotin-X-DHPE.   
     
     
         48 . The method of  claim 35 , wherein the membrane comprises cholesterol, dicetyl phosphate, DSPC, stearoyl lysophosphatidylcholine, m-cresol, and biotin DHPE in a % (w/w) ratio selected from the group consisting of:
 (a) about 9.4:18.1:56.8:14.1:0.0:1.5;   (b) about 7.7:15.0:58.6:0.0:17.4:1.3; and   (c) about 8.4:16.2:47.5:7.6:19.0:1.3.