Oral delivery systems based on in situ forming protein/polysaccharide coacervates

Abstract

An oral delivery system based on in situ forming protein/polysaccharide coacervates is described herein. The system comprises an active ingredient dispersed in a dry, homogenous powder mixture of a protein powder and a polysaccharide powder, which is able to form a protein/polysaccharides complex coacervate in situ upon immersion in gastric fluid, thereby conferring gastric protection and/or modified-release to the active ingredient. Varying the ratio of protein powder to polysaccharide powder in the oral delivery system varies the level of gastric protection and/or rate of release to the active ingredient. The ability of the system described herein to be based on natural and/or naturally-derived biopolymers provides commercial advantages in terms of regulatory approval and/or growing consumer demand for such products.

1 - 21 . (canceled) 
     
     
         22 . A process for preparing a solid oral dosage form, the process comprising dispersing an active ingredient in a dry homogenous mixture comprising blended protein and polysaccharide powders, and formulating the resulting mixture into a solid oral dosage form, the polysaccharide powder having powder flow characteristics enabling interaction with the protein powder such that immersion of the solid oral dosage form in a gastric fluid results in formation of a protein/polysaccharide complex coacervate in situ, thereby conferring gastric protection and/or modified-release to the active ingredient, and wherein the polysaccharide powder has, or is conditioned to have, one or more of the following powder flow characteristics, prior to blending:
 (a) an angle of repose (α) greater than 28 degrees;   (b) a dynamic cohesive index greater than 10;   (c) a compressibility index (Carr index) greater than 15%;   (d) a Hausner ratio greater than 1.18; or   (e) any combination of (a) to (d).   
     
     
         23 . The process of  claim 22 , wherein the polysaccharide powder, prior to blending, has one or more of the following powder flow characteristics: 
 (a) an angle of repose (α) greater than 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65 degrees;   (b) a dynamic cohesive index greater than 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50;   (c) a compressibility index (Carr index) greater than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, or 38%;   (d) a Hausner ratio greater than 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, or 1.6; or   (e) any combination of (a) to (d).   
     
     
         24 . The process of  claim 22 , wherein the polysaccharide powder, prior to blending, has or is conditioned to have all the powder flow characteristics as defined in (a), (b), (c) and (d). 
     
     
         25 . The process of  claim 22 , wherein the blended protein and polysaccharide powder mixture forms a protein/polysaccharide complex coacervate in situ upon immersion of the solid oral dosage form in a solution of pH below the pKa of the polysaccharide. 
     
     
         26 . The process of  claim 22 , wherein:
 (a) increasing the ratio of polysaccharide powder to protein powder in the solid oral dosage form increases the level of gastric protection and/or decreases the rate of release to the active ingredient;   (b) the weight ratio of polysaccharide powder to protein powder in the solid oral dosage form is 1:20 to 1:2;   (c) the solid oral dosage form comprises about 5% to 50% w/w of the protein and polysaccharide mixture; or   (d) any combination thereof.   
     
     
         27 . The process of  claim 22 , wherein:
 (a) the blended protein and polysaccharide powder mixture forms a protein/polysaccharide complex coacervate in situ upon immersion of the solid oral dosage form in a simulated gastric fluid (SGF) consisting of a 37% v/v solution of diluted HCl at pH 1.0, containing 2 g/L of NaCl and 0.1 g/L of pepsin;   (b) the active ingredient’s rate of release is inversely proportional to the strength of the protein/polysaccharide complex coacervate formed in situ upon immersion of the solid oral dosage form in the gastric fluid;   (c) the protein/polysaccharide complex coacervate formed in situ upon immersion of the solid oral dosage form in the SGF is characterized by the presence of intramolecular beta-sheets, alpha-helices, and/or unordered structures; or   (d) any combination thereof.   
     
     
         28 . The process of  claim 22 , wherein the solid oral dosage form is:
 (i) a delayed-release oral delivery system;   (ii) an extended-release oral delivery system;   (iii) an oral delivery system providing increased gastric protection to the active ingredient upon oral administration, as compared to administration of an unformulated active ingredient; or   (iv) any combination thereof.   
     
     
         29 . The process of  claim 28 , wherein:
 (i) the delayed release oral delivery system delays the time required for 50% of the active ingredient to be released by at least 30 minutes, as compared to a corresponding oral delivery system lacking the polysaccharide powder;   (ii) the extended-release oral delivery system results in release of the active ingredient over a period of at least 3 hours; and/or   (ii) the oral delivery system provides increased gastric protection to the active ingredient as compared to administration of an unformulated active ingredient; 
upon dissolution testing comprising immersion of the oral delivery system at 37° C. in SGF for two hours followed by immersion in simulated intestinal fluid (SIF), wherein the SGF consists of a 37% v/v diluted HCl solution, pH 1.0, containing 2 g/L of NaCl and 0.1 g/L of pepsin, and the SIF consists of a 50 mM NaH 2 PO 4  or KH 2 PO 4  buffer solution at pH 6.9, containing 0.5 g/L of pancreatin. 
     
     
         30 . The process of  claim 22 , wherein the protein powder comprises or consists of: natural proteins, food-grade and/or pharmaceutical-grade proteins, native proteins, denatured proteins, chemically unmodified proteins, chemically modified proteins, plant proteins, animal proteins, dairy proteins, legume proteins, fruit protein, cereal proteins, or any mixture thereof. 
     
     
         31 . The process of  claim 22 , wherein the polysaccharide powder comprises or consists of: natural polysaccharides, food-grade and/or pharmaceutical-grade polysaccharides, chemically unmodified polysaccharides, chemically modified polysaccharides, plant polysaccharides, animal polysaccharides; polysaccharides containing negatively charged/acidic groups, or any mixture thereof. 
     
     
         32 . The process of  claim 22 , wherein the polysaccharide powder comprises or consists of: carrageenan, xanthan gum, alginate, pectin, agar, gellan, guar gum, carboxymethylcellulose, locust bean gum, mannan, glucomannan, hyaluronan, tamarind gum, psyllium seed gum, tara gum, acacia gum, arabic gum, ghatti gum, tragacanth gum, karaya gum, cassia gum, rhamsan gum, welan gum, macrophomopsis gum, curdlan, pullulan, fucoidan, or any mixture thereof. 
     
     
         33 . The process of  claim 22 , wherein the active ingredient is a dietary supplement, a drug, a probiotic, a vitamin, an amino acid, a food extract, or an herbal supplement. 
     
     
         34 . The process of  claim 22 , further comprising one or more nutraceutically or pharmaceutically acceptable excipients and/or additives. 
     
     
         35 . The process of  claim 34 , wherein the additive is or comprises microcrystalline cellulose, magnesium stearate, and/or silicon dioxide. 
     
     
         36 . The process of  claim 22 , wherein the solid oral dosage form is a tablet or a capsule. 
     
     
         37 . The process of  claim 22 , wherein the solid oral dosage form does not comprise an enteric coating. 
     
     
         38 . The process of  claim 22 , wherein the amount by weight of protein powder in the solid oral dosage form is greater than the amount by weight of the polysaccharide powder. 
     
     
         39 . The process of  claim 22 , wherein the polysaccharide powder, prior to blending, has a Carr compressibility index of greater than 25%. 
     
     
         40 . The process of  claim 22 , wherein the active ingredient is a probiotic. 
     
     
         41 . A method for treating a disease or condition ameliorated by administration to a subject of an active ingredient which would benefit from gastric protection and/or modified-release, the method comprising providing the active ingredient formulated in the solid oral dosage form produced by the process of  claim 22 , and orally administering the solid oral dosage form to a subject, wherein the protein and polysaccharide powder mixture forms a protein/polysaccharide complex coacervate in situ upon immersion of the oral delivery system in the subject’s gastric fluid.