Water-activated mucoadhesive compositions and methods of delivering biologically active substances
This disclosure relates to compositions including formulated sucralfate or other aluminum-crosslinked sulfated agents and one or more biologically active substances to mucosal surfaces within the GI tract and methods for the manufacture and the use of these compositions.
1 . A method of making a stable, sulfated agent hydratable composition including a biologically active substance, the method comprising:
mixing a sulfated agent with an acid solution to form a viscous precipitate, wherein the sulfated agent comprises one or more of sucralfate, sulfated dextran, sulfated dextrin, sulfated amylopectin, sulfated amylose, sulfated cellulose, carrageenan, chondroitin sulfate, glucose sulfate, sucrose sulfate, heparin, heparin sulfate, or raffinose sulfate;
mixing the viscous precipitate with a sufficient amount of a water-miscible or water-soluble solvent for a time sufficient to obtain a particle suspension;
dehydrating the particle suspension by removing particles from the particle suspension by precipitation to obtain a stable, sulfated agent hydratable composition of dry particles;
forming the dry particles into a dry powder; and
mixing the dry powder with one or more biologically active substances, in dry powder form, and thereafter hydrating the resulting powder mixture with a pharmaceutically acceptable carrier liquid,
wherein the one or more biologically active substances comprise one or more proteins.
2 . The method of claim 1 , wherein the acid solution comprises a 0.1-1.0 N HCl solution and the sufficient amount of the water-miscible or water-soluble solvent comprises at least 30 v/v % of the water-miscible solvent.
3 . The method of claim 1 , wherein the one or more biologically active substances are protected from acid in a subject's stomach and maintain at least 10% of their biological activity when present in the intestines after passing through the subject's stomach.
4 . The method of claim 1 , wherein the sulfated agent comprises sucralfate.
5 . The method of claim 1 , wherein the water-miscible or water-soluble solvent comprises one or more of an alcohol, acetone, dimethyl sulfide (DMSO), N,N-dimethyl formamide (DMF), acetonitrile, 1,4-dioxane, tetrahydrofuran (THF), acetic acid, acetaldehyde, 1,2-butandiol, 1,3-butandiol, 1,4-butandiol, butyric acid, diethanolamine, diethylenetriamine, dimethoxyethane, ethylamine, ethylene glycol, formic acid, glycerol, methyl diethanolamine, methyl isocyanide, 1,3-propanediol, 1,5-pentanediol, propanoic acid, propylene glycol, pyridine, or triethylene glycol.
6 . The method of claim 5 , wherein the water-miscible or water-soluble solvent comprises alcohol.
7 . The method of claim 6 , wherein the alcohol comprises one or more of methanol, ethanol, isopropanol, n-propanol, reagent alcohol, 2-butoxiethanol, or furfuryl alcohol.
8 . The method of claim 5 , wherein the water-miscible or water-soluble solvent comprises DMSO.
9 . The method of claim 1 , wherein the acid solution comprises one or more of hydrochloric acid (HCl), hydroiodic acid (HI), hydrobromic acid (HBr), perchloric acid (HC1O 4 ), nitric acid (HNO 3 ), or sulfuric acid (H 2 SO 4 ).
10 . The method of claim 9 , wherein the acid solution comprises HCl at a concentration of 0.1 N to 1.0 N.
11 . A method of making a stable, sulfated agent hydratable composition including a biologically active substance, the method comprising:
mixing a sulfated agent with an acid solution to form a viscous precipitate, wherein the sulfated agent comprises one or more of sucralfate, sulfated dextran, sulfated dextrin, sulfated amylopectin, sulfated amylose, sulfated cellulose, carrageenan, chondroitin sulfate, glucose sulfate, sucrose sulfate, heparin, heparin sulfate, or raffinose sulfate;
preparing a particle suspension by mixing the viscous precipitate with a water-soluble solvent or a water-miscible solvent;
removing particles from the particle suspension by precipitation to obtain dry particles;
forming the dry particles into a dry powder; and
mixing the dry powder with a biologically active substance in dry powder form, and thereafter hydrating the resulting powder mixture with a pharmaceutically acceptable carrier liquid,
wherein the biologically active substance comprises a protein.
12 . The method of claim 11 , wherein the acid solution comprises a 0.1-1.0 N HCl solution and the water-soluble solvent or the water-miscible solvent comprises at least 30 v/v % of the water-miscible solvent.
13 . The method of claim 11 , wherein the one or more biologically active substances are protected from acid in a subject's stomach and maintain at least 10% of their biological activity when present in the intestines after passing through the subject's stomach.
14 . The method of claim 11 , wherein the sulfated agent comprises sucralfate.
15 . The method of claim 11 , wherein the water-soluble solvent or the water-miscible solvent comprises one or more of an alcohol, acetone, dimethyl sulfide (DMSO), N,N-dimethyl formamide (DMF), acetonitrile, 1,4-dioxane, tetrahydrofuran (THF), acetic acid, acetaldehyde, 1,2-butandiol, 1,3-butandiol, 1,4-butandiol, butyric acid, diethanolamine, diethylenetriamine, dimethoxyethane, ethylamine, ethylene glycol, formic acid, glycerol, methyl diethanolamine, methyl isocyanide, 1,3-propanediol, 1,5-pentanediol, propanoic acid, propylene glycol, pyridine, or triethylene glycol.
16 . The method of claim 15 , wherein the water-soluble solvent or the water-miscible solvent comprises alcohol.
17 . The method of claim 16 , wherein the alcohol comprises one or more of methanol, ethanol, isopropanol, n-propanol, reagent alcohol, 2-butoxiethanol, or furfuryl alcohol.
18 . The method of claim 15 , wherein the water-soluble solvent or the water-miscible solvent comprises DMSO.
19 . The method of claim 11 , wherein the acid solution comprises one or more of hydrochloric acid (HCl), hydroiodic acid (HI), hydrobromic acid (HBr), perchloric acid (HC1O 4 ), nitric acid (HNO 3 ), or sulfuric acid (H 2 SO 4 ).
20 . The method of claim 19 , wherein the acid solution comprises HCl at a concentration of 0.1 N to 1.0 N.