Methods and compositions for stable liquid drug formulations

Abstract

The invention features a powdered composition including a pharmaceutically active compound and a protein or a hydrolyzed protein. In particular, the powdered composition forms a stable solution or dispersion suitable for oral administration in which the protein or the hydrolyzed protein is bound to the pharmaceutically active compound. The invention also provides a method of administering the composition, such as to a patient with dysphasia; liquid or semi-solid formulations of the composition; methods for preparing the composition; and kits including the composition.

What is claimed is: 
     
         1 . A method of administering a pharmaceutically active compound to a patient, the method comprising the steps of:
 (a) providing a powdered composition comprising a pharmaceutically active compound and a protein or a hydrolyzed protein, wherein the protein or the hydrolyzed protein is from 500 Da to 10,000,000 Da;   (b) mixing the powdered composition with a liquid or semi-solid to form a stable solution or dispersion in which the protein or the hydrolyzed protein is bound to the pharmaceutically active compound; and   (c) orally administering the solution or dispersion to the patient.   
     
     
         2 . The method of  claim 1 , wherein the pharmaceutically active compound and the protein or the hydrolyzed protein are present in a ratio of from 1:1 to 1:1,000. 
     
     
         3 . The method of  claim 1 , wherein the composition comprises 1% to 30% (w/w) the pharmaceutically active compound and 90% to 99% (w/w) of the protein or the hydrolyzed protein. 
     
     
         4 . The method of  claim 3 , where the protein or the hydrolyzed protein is from 500 Da to 1,000,000 Da. 
     
     
         5 . The method of  claim 1 , wherein the composition is denatured or partially denatured. 
     
     
         6 . The method of  claim 1 , wherein the size of the powder is from 1 to 100 mesh. 
     
     
         7 . The method of  claim 1 , wherein the liquid is water or an aqueous solution. 
     
     
         8 . The method of  claim 1 , wherein the viscosity of the dispersion is from 1 cP to 450 cP. 
     
     
         9 . The method of  claim 1 , wherein the viscosity of the dispersion is from 50,000 cP to 200,000 cP. 
     
     
         10 . The method of  claim 1 , wherein the pharmaceutically active compound is less than 500 Da. 
     
     
         11 . The method of  claim 1 , wherein the pharmaceutically active compound is one or more of a 5-HT 1A  receptor agonist, a 5-HT 2  receptor antagonist, an α-adrenergic receptor agonist, an α-adrenergic receptor antagonist, a β-adrenergic receptor agonist, a β-adrenergic receptor antagonist, an acetylcholinesterase inhibitor, an anesthetic, an angiotensin receptor antagonist, an angiotensin converting enzyme inhibitor, an antibiotic, an anticholinergic agent, an anticoagulant, an anticonvulsant, an antidepressant, an antidiabetic agent, an antifungal agent, an antiinflammatory agent, an antihistamine, an antipsychotic agent, an antiplatelet agent, an antiviral agent, an anxiolytic agent, a cholesterol-lowering drug, a dopamine agonist, a dopamine antagonist, an eicosanoid inhibitor, a glucocorticoid, an ion channel blocking agent, a monoamine oxidase B inhibitor, an N-methyl d-aspartate receptor antagonist, a norepinephrine reuptake inhibitor, a prostaglandin, a proton pump inhibitor, a renin antagonist, a serotonergic, a steroidal anti-inflammatory agent, a tricyclic, a thromboxane A2 agonist, a triptan, a vasodilator, or a nutraceutical. 
     
     
         12 . The method of  claim 1 , wherein the protein or the hydrolyzed protein is one or more of gelatin, casein, whey protein, albumin, or soy protein. 
     
     
         13 . The method of  claim 12 , wherein the protein or the hydrolyzed protein is gelatin selected from the group consisting of type A gelatin and type B gelatin. 
     
     
         14 . The method of  claim 12 , wherein the protein or the hydrolyzed protein is whey protein selected from the group consisting of alpha-lactalbumin, beta lactoglobulin, bovine serum albumin, a glycomacropeptide, immunoglobulin, lactoferrin, and lactoperoxidase. 
     
     
         15 . The method of  claim 12 , wherein the protein or the hydrolyzed protein is albumin selected from the group consisting of bovine serum albumin and human serum albumin. 
     
     
         16 . The method of  claim 12 , wherein the protein or the hydrolyzed protein is soy protein selected from the group consisting of β-conglycinin and glycinin. 
     
     
         17 . The method of  claim 12 , wherein the protein or the hydrolyzed protein comprises from 70% to 95% (w/w) of whey protein or from 80% to 95% (w/w) of casein. 
     
     
         18 . The method of  claim 1 , wherein the composition further comprises one or more agents selected from the group consisting of an absorption enhancing agent, an antimicrobial, an antioxidant, a buffering agent, a colorant, a dispersing agent, a flavoring agent, a preservative, a solubilizing agent, a stabilizing agent, a surfactant, a sweetener, a taste masking agent, a viscosity controlling agent, and a vitamin. 
     
     
         19 . The method of  claim 18 , wherein the agent is the absorption enhancing agent selected from the group consisting of achitosan, type A gelatin, and type B gelatin. 
     
     
         20 . The method of  claim 18 , wherein the agent is the antimicrobial selected from the group consisting of methylparaben, propylparaben, sodium benzoate, propyl benzoate, sodium sorbate, potassium sorbate, and calcium sorbate. 
     
     
         21 . The method of  claim 18 , wherein the agent is the buffering agent selected from the group consisting of citric acid, malic acid, tartaric acid, phosphoric acid, and pharmaceutically acceptable salts thereof. 
     
     
         22 . The method of  claim 21 , wherein the amount of the buttering agent results in the dispersion having a pH from 6 to 8. 
     
     
         23 . The method of  claim 22 , wherein the pH is from 6.8 to 7.2. 
     
     
         24 . The method of  claim 18 , wherein the agent is the dispersing agent selected from the group consisting of a polyvinylpyrrolidine, an alkyhydroxy cellulose, a dextrin, a cyclodextrin, and a polyhydroxyalcohol. 
     
     
         25 . The method of  claim 18 , wherein the agent is the preservative selected from the group consisting of ethylenediaminetetraacetic acid and a 4-hydroxy benzoic ester. 
     
     
         26 . The method of  claim 18 , wherein the agent is the solubilizing agent selected from the group consisting of 200 Da to 1000 Da polyethylene glycol, sorbitol, a glycol polyol, and dipropylene glycol polyethylene. 
     
     
         27 . The method of  claim 18 , wherein the agent is the stabilizing agent selected from the group consisting of glycerin, pentaerythritol, and sodium alginate. 
     
     
         28 . The method of  claim 18 , wherein the agent is the surfactant selected from the group consisting of a polyoxylglyceride, a caprylate, a laurate, an oleate, a monoethyl ether, a sorbitan-based nonionic surfactant, a polyoxyethylene sorbitan-based surfactant, an emulsifier blend, and tocopherol polyethyleneglycol 1000 succinate. 
     
     
         29 . The method of  claim 18 , wherein the agent is the sweetener selected from the group consisting of an L-aspartylyphenylalanine methyl ester, a stevia saccharin salt, a cyclamate salt, acefulfam-K, aspartame, sucralose, a glycyrrhizanate, glucose, xylose, ribose, mannose, fructose, dextrose, sorbitol, mannitol, thymidine, and monellin. 
     
     
         30 . The method of  claim 18 , wherein the agent is the taste masking agent selected from the group consisting of sodium alginate, xanthum gum, carageenan, hydroxypropylmethyl cellulose, methyl cellulose, microcrystalline cellulose, or sodium carboxy methyl cellulose. 
     
     
         31 . The method of  claim 18 , wherein the agent is the viscosity controlling agent selected from the group consisting of gelatin, alginic acid, agarose, agar, carrageenan, xanthan gum, locust bean gum, guar gum, tragacanth, gum karaya, natural gum, methyl cellulose, glucomannan, galactomannan, and gulaman. 
     
     
         32 . A powdered composition comprising:
 a pharmaceutically active compound, and   a protein or a hydrolyzed protein of greater than 500 kDa,   wherein the composition when admixed with a liquid or semi-solid forms a stable solution or dispersion suitable for oral administration in which the protein or the hydrolyzed protein is bound to the pharmaceutically active compound.   
     
     
         33 . The composition of  claim 32 , wherein the pharmaceutically active compound and the protein or the hydrolyzed protein are present in a ratio of from 1:1 to 1:1000. 
     
     
         34 . The composition of  claim 32 , wherein the composition comprises 1% to 30% (w/w) the pharmaceutically active compound and 90% to 99% (w/w) of the protein or the hydrolyzed protein. 
     
     
         35 . The composition of  claim 32 , wherein the composition is denatured or partially denatured. 
     
     
         36 . The composition of  claim 32 , wherein the size of the powder is from 1 to 100 mesh. 
     
     
         37 . The composition of  claim 32 , wherein the liquid is water or an aqueous solution. 
     
     
         38 . The composition of  claim 32 , wherein the viscosity of the dispersion is from 1 to 450 cP. 
     
     
         39 . The composition of  claim 32 , wherein the viscosity of the dispersion is from 50,000 cP to 200,000 cP. 
     
     
         40 . The composition of  claim 32 , wherein the pharmaceutically active compound is greater than 500 Da. 
     
     
         41 . The composition of  claim 32 , wherein the pharmaceutically active compound is one or more a 5-HT 1A  receptor agonist, a 5-HT 2  receptor antagonist, an α-adrenergic receptor agonist, an α-adrenergic receptor antagonist, a β-adrenergic receptor agonist, a β-adrenergic receptor antagonist, an acetylcholinesterase inhibitor, an anesthetic, an angiotensin receptor antagonist, an angiotensin converting enzyme inhibitor, an antibiotic, an anticholinergic agent, an anticoagulant, an anticonvulsant, an antidepressant, an antidiabetic agent, an antifungal agent, an antiinflammatory agent, an antihistamine, an antipsychotic agent, an antiplatelet agent, an antiviral agent, an anxiolytic agent, a cholesterol-lowering drug, a dopamine agonist, a dopamine antagonist, an eicosanoid inhibitor, a glucocorticoid, an ion channel blocking agent, a monoamine oxidase B inhibitor, an N-methyl d-aspartate receptor antagonist, a norepinephrine reuptake inhibitor, a prostaglandin, a proton pump inhibitor, a renin antagonist, a serotonergic, a steroidal anti-inflammatory agent, a tricyclic, a thromboxane A2 agonist, a triptan, a vasodilator, or a nutraceutical. 
     
     
         42 . The composition of  claim 32 , wherein the protein or the hydrolyzed protein is one or more of gelatin, casein, whey protein, albumin, or soy protein. 
     
     
         43 . The composition of  claim 42 , wherein the protein or the hydrolyzed protein is gelatin selected from the group consisting of type A gelatin and type B gelatin. 
     
     
         44 . The composition of  claim 42 , wherein the protein or the hydrolyzed protein is whey protein selected from the group consisting of alpha-lactalbumin, beta lactoglobulin, bovine serum albumin, a glycomacropeptide, immunoglobulin, lactoferrin, and lactoperoxidase. 
     
     
         45 . The composition of  claim 42 , wherein the protein or the hydrolyzed protein is albumin selected from the group consisting of bovine serum albumin and human serum albumin. 
     
     
         46 . The composition of  claim 42 , wherein the protein or the hydrolyzed protein is soy protein selected from the group consisting of l-conglycinin and glycinin. 
     
     
         47 . The composition of  claim 42 , wherein the protein or the hydrolyzed protein comprises from 70% to 95% (w/w) of whey protein or from 80% to 95% (w/w) of casein. 
     
     
         48 . The composition of  claim 32 , further comprising one or more agents selected from the group consisting of an absorption enhancing agent, an antimicrobial, an antioxidant, a buffering agent, a colorant, a dispersing agent, a flavoring agent, a preservative, a solubilizing agent, a stabilizing agent, a surfactant, a sweetener, a taste masking agent, a viscosity controlling agent, and a vitamin. 
     
     
         49 . The composition of  claim 48 , wherein the agent is the absorption enhancing agent selected from the group consisting of achitosan, type A gelatin, and type B gelatin. 
     
     
         50 . The composition of  claim 48 , wherein the agent is the antimicrobial selected from the group consisting of methylparaben, propylparaben, sodium benzoate, propyl benzoate, sodium sorbate, potassium sorbate, and calcium sorbate. 
     
     
         51 . The composition of  claim 48 , wherein the agent is the buffering agent selected from the group consisting of citric acid, malic acid, tartaric acid, phosphoric acid, and pharmaceutically acceptable salts thereof. 
     
     
         52 . The composition of  claim 52 , wherein the amount of the buffering agent results in the dispersion having a pH from 6 to 8. 
     
     
         53 . The composition of  claim 53 , wherein the pH is from 6.8 to 7.2. 
     
     
         54 . The composition of  claim 48 , wherein the agent is the dispersing agent selected from the group consisting of a polyvinylpyrrolidine, an alkyhydroxy cellulose, a dextrin, a cyclodextrin, and a polyhydroxyalcohol. 
     
     
         55 . The composition of  claim 48 , wherein the agent is the preservative selected from the group consisting of ethylenediaminetetraacetic acid and a 4-hydroxy benzoic ester. 
     
     
         56 . The composition of  claim 48 , wherein the agent is the solubilizing agent selected from the group consisting of 200 Da to 1000 Da polyethylene glycol, sorbitol, a glycol polyol, and dipropylene glycol polyethylene. 
     
     
         57 . The composition of  claim 48 , wherein the agent is the stabilizing agent selected from the group consisting of glycerin, pentaerythritol, and sodium alginate. 
     
     
         58 . The composition of  claim 48 , wherein the agent is the surfactant selected from the group consisting of a polyoxylglyceride, a caprylate, a laurate, an oleate, a monoethyl ether, a sorbitan-based nonionic surfactant, a polyoxyethylene sorbitan-based surfactant, an emulsifier blend, and tocopherol polyethyleneglycol 1000 succinate. 
     
     
         59 . The composition of  claim 48 , wherein the agent is the sweetener selected from the group consisting of an L-aspartylyphenylalanine methyl ester, a stevia saccharin salt, a cyclamate salt, acefulfam-K, aspartame, sucralose, a glycyrrhizanate, glucose, xylose, ribose, mannose, fructose, dextrose, sorbitol, mannitol, thymidine, and monellin. 
     
     
         60 . The composition of  claim 48 , wherein the agent is the taste masking agent selected from the group consisting of sodium alginate, xanthum gum, carageenan, hydroxypropylmethyl cellulose, methyl cellulose, microcrystalline cellulose, and sodium carboxy methyl cellulose. 
     
     
         61 . The composition of  claim 48 , wherein the agent is the viscosity controlling agent selected from the group consisting of gelatin, alginic acid, agarose, agar, carrageenan, xanthan gum, locust bean gum, guar gum, tragacanth, gum karaya, natural gum, methyl cellulose, glucomannan, galactomannan, and gulaman. 
     
     
         62 . A liquid or semi-solid formulation prepared by mixing the powdered composition of any of  claims 32  to  61  with a liquid or semi-solid. 
     
     
         63 . The liquid formulation of  claim 62 , wherein the liquid is an aqueous solution. 
     
     
         64 . The liquid formulation of  claim 63 , wherein the pH is between 6 and 8. 
     
     
         65 . The liquid formulation of  claim 64 , wherein the pH is between 6.8 and 7.2. 
     
     
         66 . The liquid formulation of  claim 62 , wherein the viscosity is from 1 cP to 450 cP. 
     
     
         67 . The liquid formulation of  claim 62 , wherein the viscosity is from 50,000 cP to 200,000 cP. 
     
     
         68 . A method for preparing a powdered composition comprising:
 dispersing a protein or a hydrolyzed protein in an aqueous solution at a first temperature ranging from 10° C. to 50° C. to form a protein mixture;   adding an effective amount of a pharmaceutically active compound to the protein mixture;   before or after the compound has been added to the protein mixture, heating the protein mixture to a second temperature ranging from 23° C. to 60° C., wherein the amount of the protein or the hydrolyzed protein is in excess of the effective amount of the compound;   cooling the mixture to a third temperature ranging from 5° C. to 23° C.; and   separating the mixture from the aqueous solution to obtain the powdered composition.   
     
     
         69 . The method of  claim 68 , wherein the protein or the hydrolyzed protein is one or more of gelatin, casein, whey protein, albumin, or soy protein. 
     
     
         70 . The method of  claim 68 , wherein the aqueous solution is water or a buffer. 
     
     
         71 . The method of  claim 70 , wherein the buffer has a pH between 6 and 8. 
     
     
         72 . The method of  claim 68 , wherein the aqueous solution further comprises one or more agents selected from the group consisting of an absorption enhancing agent, an antimicrobial, an antioxidant, a buffering agent, a colorant, a dispersing agent, a flavoring agent, a preservative, a solubilizing agent, a stabilizing agent, a surfactant, a sweetener, a taste masking agent, a viscosity controlling agent, and a vitamin. 
     
     
         73 . The method of  claim 68 , wherein the first temperature range is from 20° C. to 25° C. 
     
     
         74 . The method of  claim 68 , wherein the second temperature range is from 25° C. to 37° C. 
     
     
         75 . The method of  claim 68 , wherein the third temperature range is from 23° C. to 37° C. 
     
     
         76 . A kit comprising:
 (a) a powdered composition that can be admixed with a liquid to form a stable solution or dispersion suitable for oral administration to a patient, said composition comprising:
 i. 1% to 30% (w/w) of a pharmaceutically active compound and 
 ii. 70% to 99% (w/w) of a protein or a hydrolyzed protein of greater than 500 kDa, wherein said compound is bound to said protein; 
   (b) a liquid; and   (c) instructions on admixing the powdered composition with the liquid.   
     
     
         77 . The kit of  claim 76 , wherein the powdered composition comprises the pharmaceutically active compound selected from the group consisting of a 5-HT 1A  receptor agonist, a 5-HT 2  receptor antagonist, an α-adrenergic receptor agonist, an α-adrenergic receptor antagonist, a β-adrenergic receptor agonist, a β-adrenergic receptor antagonist, an acetylcholinesterase inhibitor, an anesthetic, an angiotensin receptor antagonist, an angiotensin converting enzyme inhibitor, an antibiotic, an anticholinergic agent, an anticoagulant, an anticonvulsant, an antidepressant, an antidiabetic agent, an antifungal agent, an antiinflammatory agent, an antihistamine, an antipsychotic agent, an antiplatelet agent, an antiviral agent, an anxiolytic agent, a cholesterol-lowering drug, a dopamine agonist, a dopamine antagonist, an eicosanoid inhibitor, a glucocorticoid, an ion channel blocking agent, a monoamine oxidase B inhibitor, an N-methyl d-aspartate receptor antagonist, a norepinephrine reuptake inhibitor, a prostaglandin, a proton pump inhibitor, a renin antagonist, a serotonergic, a steroidal anti-inflammatory agent, a tricyclic, a thromboxane A2 agonist, a triptan, a vasodilator, or a nutraceutical. 
     
     
         78 . The kit of  claim 76 , wherein the powdered composition comprises the protein or the hydrolyzed protein selected from the group consisting of gelatin, cascin, whey protein, albumin, and soy protein. 
     
     
         79 . The kit of  claim 76 , wherein the liquid comprises one or more agents selected from the group consisting of an absorption enhancing agent, an antimicrobial, an antioxidant, a buffering agent, a colorant, a dispersing agent, a flavoring agent, a preservative, a solubilizing agent, a stabilizing agent, a surfactant, a sweetener, a taste masking agent, a viscosity controlling agent, and a vitamin.