Dry blend formulation of tetrahydrobiopterin

Abstract

Dry blend powder formulations comprising a pharmaceutical formulation containing tetrahydrobiopterin, and methods of making and using the same, are disclosed herein.

What is claimed is: 
     
         1 . A pharmaceutical composition, comprising a dry blend powder of a BH4 or BH4-related compound and an excipient. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the amount of the BH4 or BH4-related compound in the composition is between about 5% and about 55% by weight. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the excipient is a sweetening agent selected from the group consisting of acesulfam potassium, isomalt, Magna Sweet, maltitol, mannitol, sorbitol, sucralose, xylitol, alitmae, neohesperidin dihydrochalcone, trehalose, tagatose, neotame, saccharin and salts thereof, stevioside, erythritol, isomaltulose, polydextrose, luo han guo, monatin, cyclamate, osladine, sucrose, fructose, and glucose, and combinations thereof. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the excipient is a flavoring agent selected from the group consisting of cherry, grape, orange, pink lemonade, raspberry, grape, lemon, orange, strawberry, tutti-frutti, tangerine, apple, watermelon, pineapple, banana, peach, kiwi, mango, mixed berry, raspberry lemonade, wild blackberry, blue raspberry, citrus, blueberry, lime, lemon lime, grapefruit, pomegranate, pear, and plum flavors, and combinations thereof. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the excipient is a flavor enhancer selected from the group consisting of anhydrous citric acid, citric acid monohydrate, malic acid, tartic acid, sodium citrate, potassium citrate dihydrate, sodium potassium tartate, ascorbic acid, and sodium ascorbate, and combinations thereof. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the excipient is a filler selected from the group consisting of isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol, sucrose, and fructose, and combinations thereof. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the dry blend powder comprises about 15% to about 30% of the BH4 or BH4-related compound by weight. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the dry blend powder comprises about 30% to about 50% of the BH4 or BH4-related compound by weight. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the BH4 or BH4-related compound is (6R)-L-erythro-tetrahydrobiopterin dihydrochloride. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the BH4 or BH4-related compound is the polymorph B form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the BH4 or BH4-related compound is packaged in a hermetically sealed container. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the BH4 or BH4-related compound is packaged in a non-hermetically sealed container. 
     
     
         13 . A single chamber sachet dosage form, comprising the composition of  claim 1 . 
     
     
         14 . A dual chamber sachet dosage form, comprising the composition of  claim 1  in one chamber and a dry flavor blend in the other chamber. 
     
     
         15 . The sachet dosage form of  claim 13 , further comprising a desiccant. 
     
     
         16 . The sachet dosage form of  claim 13 , wherein the dosage is mixed with a liquid prior to ingestion. 
     
     
         17 . The sachet dosage form of  claim 13 , wherein the dosage comprises about 5%, about 7.5%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%, about 27.5%, about 30%, about 32.5%, about 35%, about 37.5%, about 40%, about 42.5%, about 45%, about 47.5%, about 50%, about 52.5%, or about 55% BH4 dihydrochloride by weight. 
     
     
         18 . The sachet dosage form of  claim 13 , wherein the dosage comprises between about 50 mg and about 1300 mg of the BH4 or BH4-related compound. 
     
     
         19 . The sachet dosage form of  claim 13 , wherein the dosage comprises an additional pharmaceutical formulation. 
     
     
         20 . The sachet dosage form of  claim 13 , wherein the pharmaceutical formulation produces a clear solution when dissolved in an aqueous solution. 
     
     
         21 . The sachet dosage form of  claim 13 , wherein the sachet is a hermetically sealed sachet. 
     
     
         22 . The sachet dosage form of  claim 13 , wherein the dosage comprises about 32% BH4 dihydrochloride, about 55.1% mannitol, about 1.9% sucralose micronized, about 10.4% potassium citrate monohydrate, and about 1.6% ascorbic acid fine powder by weight. 
     
     
         23 . The sachet dosage form of  claim 13 , wherein the dosage comprises about 32% BH4 dihydrochloride, about 55.4% mannitol, about 1.6% sucralose, about 10.4% potassium citrate, and about 1.6% ascorbic acid by weight. 
     
     
         24 . The sachet dosage form of  claim 13 , wherein the dosage comprises about 200 mg BH4 dihydrochloride, about 338 mg mannitol, about 12 mg sucralose micronized, about 65 mg potassium citrate monohydrate, and about 10 mg ascorbic acid fine powder. 
     
     
         25 . The sachet dosage form of  claim 13 , wherein the dosage comprises about 100 mg BH4 dihydrochloride. 
     
     
         26 . The sachet dosage form of  claim 13 , wherein no less than about 90% of the initial amount of the BH4 or BH4-related compound is present after 3 months at 40° C. and 75% Relative Humidity. 
     
     
         27 . The sachet dosage form of  claim 13 , wherein no less than about 90% of the initial amount of the BH4 or BH4-related compound is present after 2 years at room temperature. 
     
     
         28 . The sachet dosage form of  claim 13 , wherein at least about 90% of the initial amount of the BH4 or BH4-related compound remains, and wherein at least about 85% of the initial amount of the BH4 or BH4-related compound dissolves within about 15 minutes, after the sachet dosage form is stored at about 40° C. and about 75% RH for a period of about three months. 
     
     
         29 . A stable capsule dosage form comprising a pharmaceutical formulation comprising an initial amount of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a crystalline form designated polymorph B, and one or more pharmaceutically acceptable excipients, wherein:
 a. the capsule has a shell that is essentially free of pullulan, and   b. at least about 98% of the initial amount of the tetrahydrobiopterin dihydrochloride remains after the capsule dosage form is stored in a container at about 40° C. and about 75% relative humidity for a period from about three months to about six months.   
     
     
         30 . The stable capsule dosage form of  claim 29 , wherein the container is a heat induction-sealed, screw cap high-density polyethylene bottle. 
     
     
         31 . The stable capsule dosage form of  claim 29 , wherein the container contains no desiccant. 
     
     
         32 . The stable capsule dosage form of  claim 29 , wherein the initial amount of the tetrahydrobiopterin dihydrochloride in the capsule dosage form is in a range from about 100 mg to about 500 mg. 
     
     
         33 . The stable capsule dosage form of  claim 29 , wherein the initial amount of the tetrahydrobiopterin dihydrochloride in the capsule dosage form is about 150 mg, or about 160 mg, or about 200 mg, or about 250 mg, or about 300 mg per capsule. 
     
     
         34 . The stable capsule dosage form of  claim 29 , wherein the shell of the capsule comprises one or more substances selected from the group consisting of cellulose derivatives; hydroxypropyl methylcellulose; starch derivatives; carrageenans; acacia; gelatin; polyethylene glycol; homopolymers and copolymers formed from polyvinyl alcohol, acrylic acid, and methyl methacrylate; and combinations thereof. 
     
     
         35 . The stable capsule dosage form of  claim 29 , wherein the shell of the capsule comprises gelatin or hydroxypropyl methylcellulose. 
     
     
         36 . The stable capsule dosage form of  claim 29 , wherein the one or more excipients are selected from the group consisting of ascorbic acid, silicon dioxide, mannitol, microcrystalline cellulose, crospovidone, povidone, stearyl fumaric acid, salt forms of stearyl fumarate, dicalcium phosphate, and 5-methyltetrahydrofolate (5-MTHF), and salt forms thereof. 
     
     
         37 . The stable capsule dosage form of  claim 29 , wherein the one or more excipients comprise crospovidone, and stearyl fumaric acid or a salt form of stearyl fumarate. 
     
     
         38 . The stable capsule dosage form of  claim 29 , wherein the one or more excipients further comprise ascorbic acid, silicon dioxide, and mannitol. 
     
     
         39 . The stable capsule dosage form of  claim 29 , wherein the pharmaceutical formulation comprises an initial amount of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a range from about 30% to about 60%, crospovidone from about 3% to about 6%, sodium stearyl fumarate from about 1% to about 3%, ascorbic acid from about 1% to about 10%, silicon dioxide from about 0.2% to about 2%, and mannitol from about 20% to about 50% by weight of the formulation. 
     
     
         40 . The stable capsule dosage form of  claim 29 , wherein the pharmaceutical formulation further comprises 5-hydroxytryptophan. 
     
     
         41 . The stable capsule dosage form of  claim 29 , wherein the pharmaceutical formulation comprises an initial amount of 5-hydroxytryptophan in a range from about 20% to about 40% by weight of the formulation. 
     
     
         42 . The stable capsule dosage form of  claim 29 , wherein the pharmaceutical formulation comprises an initial amount of (6R)-L-erythro-BH4 dihydrochloride from about 40% to about 50%, ascorbic acid from about 40% to about 50%, crospovidone from about 3% to about 6%, sodium stearyl fumarate from about 1% to about 3%, silicon dioxide from about 0.2% to about 2%, and calcium salt of 5-methyltetrahydrofolate from about 0.01% to about 0.5% by weight of the formulation. 
     
     
         43 . The stable capsule dosage form of  claim 29 , wherein the pharmaceutical formulation is made by mixing the tetrahydrobiopterin dihydrochloride and the one or more pharmaceutically acceptable excipients, without addition of liquid water. 
     
     
         44 . The stable capsule dosage form of  claim 29 , wherein the dosage is useful for reducing blood phenylalanine levels in patients with hyperphenylalaninemia due to tetrahydrobiopterin-response phenylketonuria. 
     
     
         45 . The stable capsule dosage form of  claim 29 , wherein the dosage is useful for reducing blood phenylalanine levels in patients with hyperphenylalaninemia due to tetrahydrobiopterin-response phenylketonuria in conjunction with a phenylalanine restricted diet. 
     
     
         46 . The stable capsule dosage form of  claim 29 , wherein the dosage is useful for treating or ameliorating conditions associated with elevated phenylalanine levels or decreased tyrosine or tryptophan levels. 
     
     
         47 . The stable capsule dosage form of  claim 29 , wherein the dosage is useful for treating or ameliorating autism. 
     
     
         48 . The stable capsule dosage form of  claim 29 , wherein the dosage is useful for treating or ameliorating conditions or disorders that would benefit from enhancement of nitric oxide synthase (NOS) activity and subjects suffering from vascular diseases, ischemic or inflammatory diseases, or insulin resistance. 
     
     
         49 . The stable capsule dosage form of  claim 29 , wherein the dosage is useful for treating or ameliorating the symptoms of sickle cell disease, peripheral arterial disease, chronic kidney disease, or hypertension. 
     
     
         50 . The stable capsule dosage form of  claim 29 , comprising administering the dosage to a mammal with food to increase absorption of the tetrahydrobiopterin dihydrochloride. 
     
     
         51 . The stable capsule dosage form of  claim 50 , wherein the food is a high-fat, or a high-calorie, or a high-fat and high-calorie meal. 
     
     
         52 . The stable capsule dosage form of  claim 29 , wherein at least about 90% of the initial amount of the tetrahydrobiopterin dihydrochloride remains after the capsule dosage form is stored in the container at about 40° C. and about 75% relative humidity for a period of three months. 
     
     
         53 . The stable capsule dosage form of  claim 29 , wherein at least about 99% of the initial amount of the tetrahydrobiopterin dihydrochloride remains after the capsule dosage form is stored in the container at about 40° C. and about 75% relative humidity for a period of three months. 
     
     
         54 . The stable capsule dosage form of  claim 29 , wherein the initial amount of tetrahydrobiopterin dihydrochloride remains after the capsule dosage form is stored in the container at about 40° C. and about 75% relative humidity for a period of six months. 
     
     
         55 . The stable capsule dosage form of  claim 29 , wherein at least about 85% of the initial amount of the tetrahydrobiopterin dihydrochloride dissolves within about 15 minutes after the capsule dosage form is stored in the container at about 40° C. and about 75% RH for a period from about three months to about six months, and wherein the dissolution is determined according to U.S.P. Method II at 50 r.p.m. in 0.1N hydrochloric acid maintained at 37° C. 
     
     
         56 . The stable capsule dosage form of  claim 29 , wherein at least about 90% of the initial amount of the tetrahydrobiopterin dihydrochloride remains, and wherein at least about 85% of the initial amount of the tetrahydrobiopterin dihydrochloride dissolves within about 15 minutes, after the capsule dosage form is stored in the container at about 40° C. and about 75% RH for a period of about three months. 
     
     
         57 . The stable capsule dosage form of  claim 29 , wherein the stable capsule dosage form is for oral administration. 
     
     
         58 . A method of treating hyperphenylananinemia due to BH4 deficiency, wherein the hyperphenylalaninemia due to BH4 deficiency is associated with deficiency in or reduced activity of any one or any combination of the enzymes GTP cyclohydrolase 1,6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, dihydropteridine reductase, and pterin-4-carbinolamine dehydratase, comprising administering the composition of  claim 1 . 
     
     
         59 . A method of reducing blood phenylalanine levels in patients with hyperphenylalaninemia due to tetrahydrobiopterin-responsive phenylketonuria, comprising administering the composition of  claim 1 . 
     
     
         60 . A method of reducing blood phenylalanine levels in patients with hyperphenylalaninemia due to tetrahydrobiopterin-responsive phenylketonuria, comprising administering the composition of  claim 1 . 
     
     
         61 . A method of treating or ameliorating conditions associated with elevated phenylalanine levels or decreased tyrosine or tryptophan levels, comprising administering the composition of  claim 1 . 
     
     
         62 . A method of treating or ameliorating autism, comprising administering the composition of  claim 1 . 
     
     
         63 . A method of treating or ameliorating conditions or disorders that would benefit from enhancement of nitric oxide synthase (NOS) activity or subjects suffering from vascular diseases, ischemic or inflammatory diseases, or insulin resistance, comprising administering the composition of  claim 1 . 
     
     
         64 . A method of treating or ameliorating the symptoms of sickle cell disease, peripheral arterial disease, chronic kidney disease, or hypertension, comprising administering the composition of  claim 1 . 
     
     
         65 . A method of administering the pharmaceutical composition of  claim 1  to a mammal with food to increase absorption of the BH4 or BH4-related compound. 
     
     
         66 . The method of  claim 65 , wherein the food is a high-fat, or a high-calorie, or a high-fat and high-calorie meal. 
     
     
         67 . A process for preparing a stable, dry blend powder of  claim 1 , comprising:
 blending half of a filler with the BH4 or BH4-related compound and a flavor enhancer in a blender to achieve an adequate mixture;   further blending a portion of the first blended mixture with acesulfame potassium or sucralose, and ascorbic acid;   passing the second mixture through a suitable sieve; and   blending the remainder of the first mixture with the second mixture to achieve a homogenous mixture.   
     
     
         68 . A pharmaceutical composition of  claim 1 , prepared by a process comprising:
 blending half of a filler with the BH4 or BH4-related compound and a flavor enhancer in a blender to achieve an adequate mixture;   blending a portion of the first blended mixture with acesulfame potassium or sucralose, the filler, and ascorbic acid;   passing the second mixture through a suitable sieve; and   blending the remainder of the first mixture with the second mixture to achieve a homogenous mixture.   
     
     
         69 . The process of  claim 67 , wherein the sieve is a #20 mesh sieve. 
     
     
         70 . The pharmaceutical composition of  claim 68 , wherein the sieve is a #20 mesh sieve. 
     
     
         71 . The process of  claim 67 , wherein the blender is a V-blender. 
     
     
         72 . The pharmaceutical composition of  claim 68 , wherein the blender is a V-blender.