Protein based excipient for active pharmaceutical ingredients

Abstract

Provided herein is a pharmaceutical formulation comprising a protein based excipient in combination with an active pharmaceutical ingredient (API) wherein said formulation is substantially amorphous and form a substantially homogenous mixture; and further a method for producing said pharmaceutical formulation; and said pharmaceutical formulation for use as a medicament.

1 - 47 . (canceled) 
     
     
         48 . A formulation comprising:
 a protein based excipient obtained from a protein composition or a hydrolysate thereof which comprises proteins—as per monomer—of at least 10 amino acids in length; and   an active pharmaceutical ingredient (API);   
       characterized therein that said protein based excipient and said API form a homogenous and amorphous solid dispersion, which dispersion contains less than 10% traces of heterogeneity and less than 10% traces of crystallinity; and, 
       wherein the mass ratio (w/w) of API to excipient is between at least 5% API and at most 95% excipient (5/95) to at most 50% API and at least 50% excipient (50/50); wherein 100% is defined as the total mass of the API and excipient. 
     
     
         49 . The formulation according to  claim 48 , wherein said protein based excipient and said API are both completely amorphous and/or form a completely homogenous mixture. 
     
     
         50 . The formulation according to  claim 48 , wherein the protein based excipient is substantially not denaturized, preferably completely not denaturized; and/or retains at least part of its biological activity, preferably substantially retains its biological activity; more preferably retains almost completely its biological activity, most preferably retains completely its biological activity. 
     
     
         51 . The formulation according to  claim 48 , wherein the protein based excipient is obtained from a protein composition or a hydrolysate thereof which comprises proteins—as per monomer—of at least 10 amino acids in length; preferably at least 20 amino acids in length; preferably at least 50 amino acids in length; more preferably at least 100 amino acids in length; most preferably at least 250 amino acids in length, for example 500 amino acids or 700 amino acids. 
     
     
         52 . The formulation according to  claim 48 , wherein at least one protein of the protein composition or a hydrolysate thereof is chosen from soy protein, pea protein, blood proteins, Immunoglobulins, milk proteins, gelatine, keratin, corn, wheat, hemp, rye, oats, peanut, barley, casein, albumin, whey protein (lactalbumin), Hydrolysed Whey Protein Isolate (HWPI), hydrolyzed collagen, plasma proteins, serum albumin, bovine serum albumin (BSA), human serum albumin (HSA), egg albumin, fish albumin, elastin, collagen, recombinant proteins, artificial proteins, recombinant versions of naturally occurring binding scaffolds, artificial binding scaffolds, and/or a combination thereof; preferably HSA, BSA, gelatine and/or a combination thereof. 
     
     
         53 . The formulation according to  claim 48 , wherein the API exhibits a low solubility, dissolution level, supersaturation state and/or bioavailability. 
     
     
         54 . The formulation according to  claim 48 , wherein the API is classified as poorly or not soluble, poorly or not permeable, and/or slowly dissolving according to the biopharmaceutics classification system. 
     
     
         55 . The formulation according to  claim 48 , wherein the API is a class II, class III or a class IV API; preferably a class II or a class IV API; most preferably a class II API according to the biopharmaceutics classification system. 
     
     
         56 . The formulation according to  claim 48 , wherein the API is selected from the following list: Flubendazole, Carbamazepine, Griseofulvin, Phenytoin, Nifedipine, Verapamil, Azithromycin, Nitrofurantoin, Iopanoic acid, Itraconazole, Ibuprofen, Indomethacin, Glibenclamide, Bicalutamide, Ezetimibe, Aceclofenac, Ketoconazole, Oxfendazole, Ritonavir, Fenofibrate, Cinnarizin, Darunavir, Diazepam, Testosterone undecanoate, or Naproxen. 
     
     
         57 . The formulation according to  claim 48 , wherein said API is Flubendazole and wherein said protein based excipient obtained from a protein composition or a hydrolysate thereof which comprises serum albumin (HSA, BSA) and/or gelatin. 
     
     
         58 . The formulation according to  claim 48 , wherein said formulation is characterized by having a particle size between 1 μm and 1 mm; preferably between 5 μm and 50 μm; most preferably between 10 μm and 20 μm. 
     
     
         59 . The formulation according to  claim 48 , wherein the mass ratio (w/w) of API to excipient is between at least 5% API and at most 95% excipient (5/95) to at most 40% API and at least 60% excipient (40/60); preferably is between at least 5% API and at most 95% excipient (5/95) to at most 30% API and at least 70% excipient (30/70); more preferably is between at least 5% API and at most 95% excipient (5/95) to at most 20% API and at least 80% excipient (20/80); most preferably is between at least 10% API and at most 90% excipient (10/90) to at most 20% API and at least 80% excipient (20/80). 
     
     
         60 . The formulation according to  claim 48 , wherein said formulation is provided in a solid-dosage form, preferably in a form adapted for oral administration such as a tablet, lozenge, pill or capsule, or as components for reconstituting an injectable. 
     
     
         61 . The formulation according to  claim 60 , wherein the solid-dosage form is a unit-dose that contains a predetermined amount of API sufficient for one regular application or use of said API, and wherein the unit-dose is suitable for unit-dose packaging, such as blisters packs. 
     
     
         62 . A method for producing a pharmaceutical formulation comprising:
 a protein based excipient obtained from a protein composition or a hydrolysate thereof which comprises proteins—as per monomer—of at least 10 amino acids in length; and   an active pharmaceutical ingredient (API);   wherein said protein based excipient and said API form a homogenous and amorphous solid dispersion, which dispersion contains less than 10% traces of heterogeneity and less than 10% traces of crystallinity; and,   wherein the mass ratio (w/w) of API to excipient is between at least 5% API and at most 95% excipient (5/95) to at most 50% API and at least 50% excipient (50/50); wherein 100% is defined as the total mass of the API and excipient;   
       the method comprising at least the steps of:
 preparing the API through the steps of 
 (a) dissolving the API using a solvent to obtain a solution; and, 
 (b) drying the solution of step (a) to obtain said API; 
 
       characterized in that the solvent for preparing the API is an organic acid or an organosulfur compound, or is a solvent mixture comprising an organic acid and/or an organosulfur compound; and,
 preparing the protein based excipient through the steps of 
 (i) dissolving the protein composition or hydrolysate thereof using a solvent to obtain a solution; and 
 (ii) drying the solution of step (i) to obtain said protein based excipient; 
 
       characterized in that the solvent for preparing the excipient is an organic acid or an organosulfur compound, or is a solvent mixture comprising an organic acid and/or an organosulfur compound. 
     
     
         63 . The method according to  claim 62 , wherein said protein based excipient and said API are both completely amorphous and the drying of step (b) drying is performed to obtain a powder that is completely amorphous. 
     
     
         64 . The method according to  claim 62 , wherein said protein based excipient and said API form a completely homogenous mixture. 
     
     
         65 . The method according to  claim 62 , wherein the solutions of steps (a) and (i) are dissolved using a common or different solvent. 
     
     
         66 . The method according to  claim 62 , wherein the solvent is an organic acid chosen from formic acid, trifluoroacetic acid, or acetic acid; is a mixture of said organic acids; or is a mixture comprising one or more organic acids chosen from formic acid, and/or trifluoroacetic acid, and/or acetic acid, and traditional solvents, such as alcohols (e.g. methanol, ethanol), acetone, DCM, THF, methylene chloride, methyl ethyl ketone, acetonitrile, organosulfur compound, DMSO, polyethylene glycols. 
     
     
         67 . The method according to  claim 62 , wherein the solvent is a solvent mixture comprising at least 5% of acetic acid and/or formic acid to at most 90% acetic acid and/or formic acid (v/v); preferably 10% to 90% acetic acid and/or formic acid; more preferably 15% to 90% acetic acid and/or formic acid; most preferably 20% to 90% acetic acid and/or formic acid. 
     
     
         68 . The method according to  claim 62 , wherein the solvent is a binary solvent mixture comprising one organic acid chosen from acetic acid or formic acid, and one other (traditional) solvent, preferably chosen from alcohol, acetone, DCM, THF, methylene chloride, methyl ethyl ketone, acetonitrile, or polyethylene glycols. 
     
     
         69 . The method according to  claim 62 , wherein the solvent is a ternary solvent mixture, comprising at least one organic acid chosen from acetic acid and/or formic acid, more preferably are acetic acid or formic acid, and at least one other (traditional) solvents, preferably chosen from alcohol, acetone, DCM, THF, methylene chloride, methyl ethyl ketone, acetonitrile, and/or polyethylene glycols. 
     
     
         70 . The method according to  claim 62 , wherein the solvent is a solvent mixture comprising dimethyl sulfoxide (DMSO) in an amount of at least 5% to at most 90% (v/v); preferably 10% to 90% DMSO; preferably 10% to 90% DMSO; more preferably 15% to 90% DMSO; most preferably 20% to 90% DMSO. 
     
     
         71 . The method according to  claim 62 , wherein the solvent is a binary solvent mixture comprising one organosulfur compound, preferably DMSO, and one other (traditional) solvent, preferably chosen from alcohol, acetone, DCM, THF, methylene chloride, methyl ethyl ketone, acetonitrile, DMSO, or polyethylene glycols. 
     
     
         72 . The method according to  claim 62 , wherein the solvent is a ternary solvent mixture comprising at least one organosulfur compound, preferably DMSO, and at least one other (traditional) solvent, preferably chosen from alcohol, acetone, DCM, THF, methylene chloride, methyl ethyl ketone, acetonitrile, DMSO, or polyethylene glycols. 
     
     
         73 . The method according  claim 62 , wherein the solvent is a quaternary solvent mixture, comprising at least one organic acid chosen from acetic acid and/or formic acid, preferably are acetic acid and formic acid, and at least one other (traditional) solvents, preferably chosen from alcohol, acetone, DCM, THF, methylene chloride, methyl ethyl ketone, acetonitrile, DMSO, and/or polyethylene glycols. 
     
     
         74 . The method according to  claim 62 , wherein the solvent is a quaternary solvent mixture, comprising at least one organosulfur compound, preferably DMSO, and at least one other (traditional) solvent, preferably chosen from alcohol, acetone, DCM, THF, methylene chloride, methyl ethyl ketone, acetonitrile, DMSO, and/or polyethylene glycols. 
     
     
         75 . The method according to  claim 62 , wherein the drying is performed by spray drying, freeze drying, vacuum drying, flash drying, paddle drying, air drying, condensation drying, and/or a combination thereof; preferably by spray drying and/or freeze drying. 
     
     
         76 . The method according to  claim 62 , wherein the solvent comprises an organic acid, preferably acetic acid and/or formic acid, and the drying is spray drying. 
     
     
         77 . The method according to  claim 62 , wherein solvent comprises an organosulfur compound, preferably DMSO, and the drying is freeze drying. 
     
     
         78 . The method according to  claim 62 , wherein the drying process is followed by a solid dosage forming process, such as compression or molding. 
     
     
         79 . The method according to  claim 62 , wherein the method is freeze drying and the formulation is freeze dried directly into a solid dosage form; for example freeze dried directly into blisters to produce a tablet or pill. 
     
     
         80 . The method according to  claim 62 , wherein the protein based excipient is obtained from a protein composition or a hydrolysate thereof which comprises proteins—as per monomer—of at least 10 amino acids in length; preferably at least 20 amino acids in length; preferably at least 50 amino acids in length; more preferably at least 100 amino acids in length; most preferably at least 250 amino acids in length, for example 500 amino acids or 700 amino acids. 
     
     
         81 . The method according to  claim 62 , wherein the API is classified as poorly or not soluble, poorly or not permeable, and/or slowly dissolving according to the biopharmaceutics classification system. 
     
     
         82 . The method according to  claim 62 , wherein the API is a class II, class III or a class IV API; preferably a class II or a class IV API; most preferably a class II API according to the biopharmaceutics classification system. 
     
     
         83 . The method according to  claim 62 , wherein the API is selected from the following list: Flubendazole, Carbamazepine, Griseofulvin, Phenytoin, Nifedipine, Verapamil, Azithromycin, Nitrofurantoin, Iopanoic acid, Itraconazole, Ibuprofen, Indomethacin, Glibenclamide, Bicalutamide, Ezetimibe, Aceclofenac, Ketoconazole, Oxfendazole, Ritonavir, Saquinavir, Fenofibrate, Cinnarizin, Darunavir, Diazepam, Bifonazole, Testosterone undecanoate, or Naproxen; preferably Flubendazole, Ibuprofen, Indomethacin, Ritonavir, Naproxen, Phenytoin, Nifedipine, Vemurafenib, Griseofulvin, Itraconazole, or Verapamil; most preferably Flubendazole. 
     
     
         84 . The method according to  claim 62 , wherein at least one protein of the protein composition or a hydrolysate thereof is chosen from soy protein, pea protein, blood proteins, Immunoglobulins, milk proteins, gelatine, keratin, corn, wheat, hemp, rye, oats, peanut, barley, casein, albumin, whey protein (lactalbumin), Hydrolysed Whey Protein Isolate (HWPI), hydrolyzed collagen, plasma proteins, serum albumin, bovine serum albumin (BSA), human serum albumin (HSA), egg albumin, fish albumin, elastin, collagen, recombinant or artificial proteins, recombinant versions of natural or artificial binding scaffolds, and/or a combination thereof; preferably HSA, BSA, gelatine and/or a combination thereof. 
     
     
         85 . A method of treatment of a subject in need of an active pharmaceutical ingredient (API) comprising the steps of:
 administering to a subject a formulation comprising a protein based excipient obtained from a protein composition or a hydrolysate thereof which comprises proteins—as per monomer—of at least 10 amino acids in length and the API;   
       characterized in that said protein based excipient and said API form a homogenous and amorphous solid dispersion, which dispersion contains less than 10% traces of heterogeneity and less than 10% traces of crystallinity; and, 
       wherein the mass ratio (w/w) of API to excipient is between at least 5% API and at most 95% excipient (5/95) to at most 50% API and at least 50% excipient (50/50); wherein 100% is defined as the total mass of the API and excipient. 
     
     
         86 . The method according to  claim 85 , wherein the formulation is administered orally or parenterally.