US 2013 0336945A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0336945 A1 Rustomjee et al. (43) Pub. Date: Dec. 19, 2013

(54) STABLE COMPOSITIONS OF (30) Foreign Application Priority Data TETRAHYDROBOPTERN Mar. 1, 2011 (IN) ...... 573/MUM/2011 (71) Applicants: Maharukh Tehmasp Rustomjee, Mumbai (IN); Anilkumar Surendrakumar Gandhi, Mumbai (IN) Publication Classification (72) Inventors: Maharukh Tehmasp Rustomjee, (51) Int. Cl. Mumbai (IN); Anilkumar A 6LX3/59 (2006.01) Surendrakumar Gandhi, Mumbai (IN) (52) U.S. Cl. (73) Assignee: RUBICON RESEARCH PRIVATE CPC ...... A6 IK3I/519 (2013.01) LIMITED, MUNBAI (IN) USPC ...... 424/94.1: 514/249 (21) Appl. No.: 14/002,313 (57) ABSTRACT (22) PCT Filed: Mar. 1, 2013 The present invention relates to stable pharmaceutical com (86). PCT No.: PCT/IB12/SO959 positions of tetrahydrobiopterin and processes for producing Such compositions. Particularly the present invention relates S371 (c)(1), to stable pharmaceutical compositions comprising tetrahy (2), (4) Date: Aug. 29, 2013 drobiopterin and at least one stabilizing agent. US 2013/0336945 A1 Dec. 19, 2013

STABLE COMPOSITIONS OF unpalatable. Further the strict regimen of dietary protein is TETRAHYDROBOPTERN practically impossible for patients of all ages to adhere to in daily life. FIELD OF THE INVENTION 0006 Thus there remains a need to obviate the dietary restrictions and replace or Supplement the same with oral 0001. The present invention relates to stable compositions treatment by providing an oral composition of tetrahydro of tetrahydrobiopterin and processes for producing Such com . positions. Particularly the present invention relates to stable 0007 Further BH4-responsive PAH deficiency has also compositions comprising sapropterin or pharmaceutically been diagnosed as a variant of or acceptable salts thereof and at least one stabilizing agent. caused by mutations in the human PAH gene that responds to oral BH4 loading by stimulating BACKGROUND OF THE INVENTION activity and therefore lowering serum . BH4 is said to have a chaperon-like effect on PAH synthesis and/or is 0002 Amino acids represent the source of life and make a protecting against enzyme auto-inactivation and up twenty percent of the human body. They are divided into degradation. two categories—essential amino acids, which are not synthe sized in the body and must be taken from food; and non 0008. Therefore, since administration of BH4, alone has essential amino acids. Phenylalanine is one of the eight essen been proven effective in the treatment of BH4-responsive tial amino acids that is an important precursor for the hyperphenylalaninemia, for which the only available treat synthesis of that serves as a precursor for synthesis of ment has been a diet therapy, development of effective treat many and thyroid hormones. Physiologic ments for the disease, in particular, development of effective requirements for phenylalanine are met exclusively by tetrahydrobiopterin preparations is an urgent need. dietary protein intake. Usual dietary intake of protein pro 0009 Sapropterin dihydrochloride is a synthetic version vides excess amounts of phenylalanine and blood phenylala of naturally occurring tetrahydrobiopterin. Sapropterin dihy nine levels are maintained within non-toxic levels via utiliza drochloride is chemically represented as (6R)-2-amino-6- tion, and excretion. However when the body is (1R,2S)-1,2-dihydroxypropyl-5,6,7,8-tetrahydro-4(1H)- unable to metabolize phenylalanine to tyrosine, the level of pteridinone dihydrochloride. The 6R-form is phenylalanine in the body is elevated leading to a rare condi pharmacologically effective while the 6S form may cause tion called hyperphenylalaninemia that severely impairs inactivation of phenylalanine hydroxylase, thus inhibiting the effects of the 6R form. Sapropterin dihydrochloride is a crys functions of the central nervous system. talline powder, hygroscopic and very soluble in water with 0003 Hyperphenylalaninemia (HPA) is a congenital solubility being greater than 1 g/ml. It exhibits polymorphism metabolic disorder inherited as an autosomal recessive trait and many crystalline forms have been identified; among all and characterized by the presence of blood phenylalanine the polymorphic forms. Form B was identified to be thermo levels that exceed the limits of the upper reference range of 2 dynamically stable crystalline anhydrate form. Sapropterin mg/dL or 120 mmol/L. HPA is divided into (i) HPA caused dihydrochloride is currently available as oral soluble tablets due to deficiency in enzyme phenylalanine hydroxylase of 100 mg under the brand name KuvanTM. It is marketed by (PAH) that is required for the conversion of ingested pheny BioMarin in the US and Merck Serono in Europe. KuvanTM lalanine to tyrosine, due to absent or mutated PAH enzyme: has been designated as an orphan medication since hyperphe the condition being known as Phenylketonuria (PKU) or (ii) nylalaninemia is a rare disease. KuvanTM is indicated to HPA resulting from a deficiency intetrahydrobiopterin (BH4) reduce blood phenylalanine levels in patients with hyperphe cofactor of the enzyme PAH, due to defects in its nylalaninemia due to tetrahydrobiopterin responsive phe or recycling. nylketonuria. It is to be used in conjunction with phenylala 0004 Tetrahydrobiopterin is a biogenic amine of the natu nine restricted diet. In patients with phenylketonuria the role rally occurring family that is a cofactor for a number of of sapropterin dihydrochloride is to enable endogenous phe different , including phenylalanine hydroxylase, nylalanine hydroxylase activity and to partially restore oxi , hydroxylase and nitric dative metabolism of phenylalanine, resulting in decreased oxide synthase regulating their activity and catalysis. These blood phenylalanine levels. In patients with BH4 deficiency, enzymes further are rate limiting in the biosynthesis of the sapropterin dihydrochloride is proposed to restore endog neurotransmitters (5-hydroxytryptamine), melato enous phenylalanine hydroxylase activity by providing an nin, , (noradrenaline), epinephrine exogenous source of the missing cofactor. (), and (NO). 0010 Tetrahydrobiopterin is an unstable compound; at 0005. In order to control hyperphenylalaninemia caused ambient temperature it is prone to autoxidation in the pres due to both the conditions mentioned herewith above, dietary ence of molecular oxygen (Davis et al., Eur: J. Biochem., Vol intervention is followed. Such dietary intervention typically 173, 345-351, 1988). It also undergoes auto-oxidation in demand administering to the patient, food that is natural and aqueous solutions at pH 7.4 to form 7,8- free from or low in phenylalanine. However such a dietary (BH2) (Thény et al., 2000). Tetrahydrobiopterin is also very regimen, apart from providing low phenylalanine, eliminates hygroscopic. Therefore the development of stable oral com many other sources of other essential amino acids, position comprising tetrahydrobiopterin that is prone to deg and minerals. Consequently such a diet provides inadequate radation at room temperature is a challenging task. protein, vitamins and minerals thereby hindering normal 0011. The formulation of KuvanTM as disclosed in the U.S. growth and development. Apart from adults, for babies too Pat. No. 7,566,462 describes use of polymorph B, of (6R)-L- infantformulae which have low phenylalanine content are the erythro-tetrahydrobiopterin dihydrochloride, an , primary food source. The phenylalanine-free protein formu and a pharmaceutically acceptable excipient, diluent, or car lae that are available are mostly bitter tasting making the food rier for preparation of stable tablet formulation; wherein a US 2013/0336945 A1 Dec. 19, 2013 specific weight ratio of the antioxidant to the (6R)-L-erythro least one stabilizing agent. Particularly the present invention tetrahydrobiopterin dihydrochloride of about 1:5 to about relates to stable compositions of sapropterin dihydrochloride. 1:30 has been used. Such a composition after six months in a container at room temperature and about 60% humidity is DETAILED DESCRIPTION OF THE INVENTION said to retain at least about 95% of the initial amount of 0016. The present invention relates to stable compositions (6R)-L-erythro-tetrahydrobiopterin dihydrochloride. of tetrahydrobiopterin, processes for producing Such compo KuvanTM has a shelflife of 3 years when stored below 25°C. Further European Publication 1757293A1 discloses a phar sitions and methods of using Such compositions. Particularly maceutical preparation for the treatment of BH4-responsive the present invention relates to stable compositions compris hyperphenylalaninemia provided in the form of granule, fine ing tetrahydrobiopterin and at least one stabilizing agent. granule, or dry syrup, comprising sapropterin hydrochloride 0017 Tetrahydrobiopterin as employed in the composi as an active ingredient; a flavoring agent; a coloring agent tions of the present invention may be in the form of free base, which is stable to acid and oxidation; and ascorbic acid or free acid or pharmaceutically acceptable salts, , pre L-cysteine hydrochloride as a stabilizer, wherein the prepa cursors, active metabolites, derivatives, analogs, polymorphs, ration has a moisture content (weight loss on drying) of 0.9% Solvates, hydrates, amorphous forms, enantiomers, optical or less. This European Publication 1757293A1 discloses that isomers, tautomers, racemic mixtures and the like or any the decomposition of sapropterin hydrochloride caused by mixtures thereof. Suitable precursors of tetrahydrobiopterin moisture can be prevented by keeping the moisture content of that may be employed include, but are not limited to, dihy the preparation at 0.9% or lower during the production. U.S. droneopterin triphosphate, biopterin, , 7.8-dihy Pat. No. 4,778,794 discloses pharmaceutical compositions drobiopterin and the like or mixtures thereof. Suitable deriva comprising in addition to carriers, that stabilize tives of tetrahydrobiopterin that may be employed include, tetrahydrobiopterin; with the weight ratio of the antioxidant but are not limited to, N2-methyl H4biopterin, N5-methyl to active ranging from 0.2-1.5. Further tetrahydrobiopterin H4biopterin, N5-formyl H4biopterin, N5-acetyl tablets from Schircks Laboratories contain antioxidantascor H4biopterin, 1,2'-diacetyl-5,6,7,8-tetrahydrobiopterin, bic acid in a ratio of 1:1 with active and at room temperature 6-methyl-5,6,7,8-tetrahydropterin, 6-hydroxymethyl-5.6.7. these tablets have a shelflife of 2 months and at 5°C. or colder 8-tetrahydropterin, 6-phenyl-5,6,7,8-tetrahydropterin, are stable for 4 months. hydrazine derivatives of tetrahydrobiopterin, 2-N-stearoyl-1'. 0012. Thus though researchers have developed composi 2'-di-O-acetyl-L-biopterin, L-tetrahydrobiopterin, tetrahy tions of sapropterin comprising stabilizers in variety of ratios, drofuranylpyrimidine derivative, 7,8-dihydrobiopterin, the stability of these compositions is low at room temperature derivative of tetrahydrobiopterin such as dihydro or 40°C./75% relative humidity and need to be stored under lipoic acid and the like or mixtures thereof. Suitable analogs refrigeration. Low stability of such tetrahydrobiopterin com of tetrahydrobiopterin that may be employed include, but are positions is commercially undesirable and significant degra not limited to, 6-methoxymethyl-tetrahydropterin, , dation due to improper storage could hinder therapy. Need neopterin, biopterin, 7,8-dihydrobiopterin, 6-methyltetrahy therefore, exists for preparations of tetrahydrobiopterin that dropterin, 6-substituted tetrahydropterin, 6R-L-erythro-tet are more stable and retain desired amount of active over a rahydrobiopterin, sepiapterin, 6,7-dimethyltetrahydropterin, longer time even when not refrigerated. 6-methyl biopterin, 7-tetrahydrobiopterin and the like or mix 0013 Further the amount and type of stabilizer and other tures thereof. excipients present in the compositions of sapropterin deter 0018 Suitable pharmaceutically acceptable salts, such as, mine the stability of the active and compositions thereof. Too but not limited to, acid or base addition salts may be little or too much stabilizer can affect the stability of the employed. Suitable pharmaceutically acceptable base addi compositions of sapropterin and an appropriate amount of tion salts of tetrahydrobiopterin may be formed with metals stabilizer must therefore be present in these compositions. oramines, such as, but not limited to, alkali and alkaline earth Further tetrahydrobiopterin also decomposes in the presence metals or organic amines. Pharmaceutically acceptable salts of moisture and it may also react with reducing Sugars or may may also be prepared with a pharmaceutically acceptable cause discoloration of some excipients due to its strong reduc cation Such as, but not limited to, alkaline, alkaline earth, ing power. The stability of sapropterin also needs to be ammonium and quaternary ammonium cations. Suitable met ensured during the process of preparation of compositions als include, but are not limited to sodium, potassium, magne sium, ammonium, calcium, or ferric, and the like. Suitable thereof. amines include, but are not limited to isopropylamine, trim 0014 Need therefore exists to develop stable composi ethylamine, histidine, N,N'-dibenzylethylenediamine, chlo tions of tetrahydrobiopterin that have adequate amount of roprocaine, choline, diethanolamine, dicyclohexylamine, stabilizing agents and/or other excipients therein. The present ethylenediamine, N-methylglucamine, and procaine. Suit inventors after thorough research have overcome the chal lenges associated with stabilization of tetrahydrobiopterin able pharmaceutically acceptable acid addition salts include, and developed oral composition comprising tetrahydrobiop but are not limited to, inorganic or organic acid salts. Examples of suitable acid salts include, but are not limited to, terin and at least one stabilizing agent that are stable over a hydrochlorides, acetates, citrates, salicylates, , phos longer period of time even when not stored under refrigera phates. Other suitable pharmaceutically acceptable salts tion. The stable compositions of tetrahydrobiopterin accord include, for example, acetic, citric, oxalic, tartaric, or man ing to the present invention thus provide desired amount of delic acids, hydrochloric acid, hydrobromic acid, sulfuric active over the entire shelf life of the product. acid orphosphoric acid, organic carboxylic, Sulfonic, Sulfo or phospho acids or N-Substituted Sulfamic acids, for example SUMMARY OF THE INVENTION acetic acid, propionic acid, glycolic acid, Succinic acid, 0015 The present invention relates to stable pharmaceu maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric tical compositions comprising tetrahydrobiopterin and at acid, malic acid, tartaric acid, lactic acid, oxalic acid, glu US 2013/0336945 A1 Dec. 19, 2013 conic acid, glucaric acid, glucuronic acid, citric acid, benzoic employed in the compositions of the present invention acid, cinnamic acid, mandelic acid, salicylic acid, 4-ami include, but are not limited to, antioxidants, chelating agents, nosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic disaccharides or higher polyols, cyclodextrins, moisture acid, embonic acid, nicotinic acid or isonicotinic acid; and retaining agents, hydrophobic agents and the like or any com amino acids. Such as the 20 alpha amino acids involved in the binations thereof. synthesis of proteins in nature, for example glutamic acid or 0024. In one embodiment the stabilizing agent employed aspartic acid, and also with phenylacetic acid, methane in the compositions of the present invention is at least one Sulfonic acid, ethanesulfonic acid, 2 hydroxyethanesulfonic antioxidant. Antioxidants are included in the compositions of acid, ethane 1.2 disulfonic acid, benzenesulfonic acid, 4 the present invention to prevent degradation of the active from methylbenzenesulfoc acid, naphthalene 2 sulfonic acid, oxidation. Antioxidants employed in the compositions of the naphthalene 1.5 disulfonic acid, 2 or 3 phosphoglycerate, present invention include, but are not limited to, organic anti glucose 6 , N cyclohexylsulfamic acid (with the oxidants and inorganic antioxidants or any combinations formation of cyclamates), or with other acid organic com thereof. pounds, Such as ascorbic acid. 0025. The organic antioxidants employed in the composi 0019. In one embodiment, tetrahydrobiopterin employed tions of the present invention include, but are not limited to, in the compositions of the present invention is in the form of butylated hydroxyanisole (BHA), butylated hydroxytoluene a dihydrochloride salt. In another embodiment, tetrahydro (BHT), tert-butyl-hydroquinone (TBHQ), 4-hydroxymethyl biopterin employed in the compositions of the present inven 2,6-di-tert-butylphenol (HMBP), 2,4,5-trihydroxybuty tion is sapropterin. In a further embodiment, tetrahydrobiop rophenone (THEP), alkylgallates, propyl gallate, octyl gal terin employed in the compositions of the present invention is late, dodecyl gallate, ethoxyquin, gallic acid, (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin dihydrochloride nordihydroguaiaretic acid, glycine, ascorbic acid, fatty acid or (6R)-2-amino-6-(1R,2S)-1,2-dihydroxypropyl-5,6,7,8- esters of ascorbic acid Such as ascorbyl palmitate and ascor tetrahydro-4(1H)-pteridinone dihydrochloride or sapropterin byl Stearate, and salts of ascorbic acid such as sodium, cal dihydrochloride. cium, or potassium ascorbate; erythorbic acid, L-, 0020. The present invention contemplates amorphous or acetyl L-carnitine, thioglycerol, thioglycolic acid (TGA), crystalline forms of sapropterin including, but not limited to, cysteine, N-acetyl cysteine, methionine, , citric all the polymorphs, Solvates, and hydrates. The various crys acid, tartaric acid, fumaric acid, Succinic acid, glycolic acid, talline polymorphic forms include, but are not limited to, oxalic acid, malic acid, ellagic acid, tocopherols such as, but Form A, B, C, D, E, F, G, H, I, J, K, L, M, N and O. Within the not limited to, alpha tocopherol, delta tocopherol; lipoic acid, purview of the present invention are all the crystal forms that thiolated polymers such as, but not limited to, polycarbophil can be used for the preparation of stable polymorph B. In one cysteine, polymethacrylic-SH, carboxy methylcellulose-cys embodiment, Form B of sapropterin dihydrochloride is teine, beta-carotene, carotenoids, flavonoids, flavones, isofla present in the compositions of the present invention. Vones, flavanones, , anthocyanidins, chalcones, 0021. The compositions of the present invention employ Vitamins, amino acids; enzymes such as, but not limited to, pharmaceutically effective amount of tetrahydrobiopterin. dismutase; and the like or any combinations The term “pharmaceutically effective amount” refers to an thereof. In one embodiment the organic antioxidant may be amount that is effective to achieve therapeutic and/or benefi acidic, non-acidic or any combination thereof. cial effect. In one embodiment the amount of tetrahydrobiop terin used in the composition varies from about 1 wt % to 0026. The inorganic antioxidants employed in the compo about 95 wt %, of the total weight of the composition. In sitions of the present invention include, but are not limited to, another embodiment the amount of tetrahydrobiopterin in the Sulfites, including but not limited to potassium and sodium composition varies from about 2 wt % to 90 wt % of the total salts of Sulphurous acid such as sodium metabisulfite, potas weight of the composition. In still another embodiment, the sium sulfite, Sodium Sulfite, sodium thiosulfate and sodium amount of tetrahydrobiopterin in the composition varies from bisulfite. about 5 wt % to about 85 wt % of the total weight of the 0027. In a further embodiment the stabilizing agent composition. In one embodiment the compositions of the employed in the compositions of the present invention is at present invention may administer a dose of about 1 mg to least one chelating agent. about 900 mg of tetrahydrobiopterin or higher. In another 0028 Chelating agents stabilize tetrahydrobiopterin and embodiment the compositions of the present invention may compositions thereof and/or enhance the action of antioxi administer a dose of about 5 mg to about 600 mg of tertrahy dants by reacting with heavy metal ions which catalyze oxi drobiopterin. Inafurther embodiment the compositions of the dation. Chelating agents such as, but not limited to, ethylene present invention may administer a dose of about 100 mg. diaminetetraacetic acid (EDTA), desferrioxamine B, defer 0022 Tetrahydrobiopterin may be employed in the formu oxamine, dithiocarb Sodium, penicillamine, pentetate cal lations of the present invention in the form of, but not limited cium, a sodium salt of pentetic acid, Succimer, trientine, to, powder, granules, pellets, beads, minitablets or the like. nitrilotriacetic acid, trans-diaminocyclohexanetetraacetic Granules of tetrahydrobiopterins may be prepared by meth acid (DCTA), diethylenetriaminepentaacetic acid, dihydroet ods such as, but not limited to, wet granulation, dry granula hylglycine, bis(aminoethyl)glycolether-N.N.N',N'-tetraace tion or roll compaction, melt granulation or the like. tic acid, iminodiacetic acid, poly(aspartic acid), citric acid, 0023 The compositions of the present invention com tartaric acid, fumaric acid, Succinic acid, glycolic acid, lactic prise, apart from active ingredient, one or more of stabilizing acid, oxalic acid, malic acid, lecithin or any salt thereof, and agents. The term “stabilizer and “stabilizing agent” for the the like or a combination thereof may be employed. purpose of the present invention has been used interchange 0029. In a further embodiment the stabilizing agent ably and refers to compounds that stabilize tetrahydrobiop employed in the compositions of the present invention is at terin and compositions thereof. The stabilizing agents least one disaccharide or higher polyol. US 2013/0336945 A1 Dec. 19, 2013

0030 "Disaccharide or higher polyol employed in the not limited to, hydrogenated palm kernel oil, hydrogenated compositions of the present invention refers to hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed disaccharide, oligosaccharide or polysaccharide or any oil, hydrogenated rice bran oil, hydrogenated Soybean oil, derivatives thereof. One or more disaccharide polyols that hydrogenated Sunflower oil, hydrogenated castor oil, hydro may be employed in the compositions of the present invention genated cottonseed oil, and the like, and mixtures thereof. include, but are not limited to, isomalt, hydrogenated maltu Other fatty acids that may be employed in the present inven lose, lactitol, maltitol, isomaltitol, or derivatives thereof. One tion include, but are not limited to, decenoic acid, docosanoic or more higher oligosaccharide or polysaccharide polyols acid, Stearic acid, palmitic acid, lauric acid, myristic acid, and that may be employed in the compositions of the present the like, and mixtures thereof. Long chain fatty alcohols invention include, but are not limited to, maltotriitol, mal include, but are not limited to, cetyl alcohol, stearyl alcohol or totetraitol or other hydrogenated oligo- and polysaccharides mixtures thereof. obtained by hydrolysis of starch followed by a hydrogena 0038 Waxes are esters of fatty acids with long chain alco tion, cellobiitol, cellotriitol, xylobiitol, Xylotriitol, inulotriitol hols. Waxes that may be employed in the present invention or other hydrogenated oligo- and polysaccharides obtained include, but are not limited to, natural waxes, such as animal by hydrolysis of cellulose, Xylans or fructans such as for waxes, vegetable waxes, and petroleum waxes (i.e., paraffin example inulin followed by hydrogenation; and the like or waxes, microcrystalline waxes, petrolatum waxes, combinations thereof. waxes), and synthetic waxes. Specific examples include, but 0031. In a further embodiment the stabilizing agent are not limited to, spermaceti wax, carnauba wax, Japan wax, employed in the compositions of the present invention is at bayberry wax, flax wax, beeswax, Chinese wax, shellac wax, least one cyclodextrin. lanolin wax, Sugarcane wax, candelilla wax, paraffin wax, 0032 Cyclodextrins are cyclic oligosaccharides formed microcrystalline wax, petrolatum wax, carbowax, and the from C-(1,4)-linked D-glucopyranose units. C. Band Y-cyclo like, or mixtures thereof. Mixtures of these waxes with the dextrins consist of six, seven and eight units respectively. fatty acids may also be used. Waxes are also monoglyceryl Suitable cyclodextrins for use in the compositions of the esters, diglyceryl esters, or triglyceryl esters (glycerides) and present invention include, but are not limited to, C, B and derivatives thereof formed from a fatty acid having from Y-cyclodextrins, or alkylated, hydroxyalkylated, esterified, about 10 to about 22 carbon atoms and glycerol, wherein one glycosylated or substituted derivatives thereof, such as (2,6- or more of the hydroxyl groups of glycerol are substituted by di-o-methyl)-f-cyclodextrin (DIMEB), randomly methy a fatty acid. Glycerides employed in the present invention lated-B-cyclodextrin (RAMEB), and hydroxypropyl-3-cy include, but are not limited to, glyceryl monostearate, glyc clodextrin (HPBCD), hydroxyethyl-3-cyclodextrin, eryl distearate, glyceryl tristearate, glyceryl dipalmitate, dihydroxypropyl-3-cyclodextrin, methyl-3-cyclodextrin, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl sulfobutyl ether cyclodextrin (SBE-CD), glucosyl-O-cyclo dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl dextrin, glucosyl-3-cyclodextrin, diglucosyl-3-cyclodextrin, didocosanoate, glyceryl tridocosanoate, glyceryl mon maltosyl-Y-cyclodextrin, maltosyl-Y-cyclodextrin, maltosyl odocosanoate, glyceryl monocaproate, glyceryl dicaproate, Y-cyclodextrin, maltotriosyl-3 cyclodextrin, maltotriosyl-y- glyceryl tricaproate, glyceryl monomyristate, glyceryl cyclodextrin, dimaltosyl-3-cyclodextrinand mixtures thereof dimyristate, glyceryl trimyristate, glyceryl monodecenoate, Such as maltosyl-3-cyclodextrin/dimaltosyl-3-cyclodextrin, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behen and the like or combinations thereof. ate, polyglyceryl diisoStearate, lauroyl macrogolglycerides, 0033. In a further embodiment the stabilizing agent oleyl macrogolglycerides, Stearoyl macrogolglycerides, and employed in the compositions of the present invention is at the like, or mixtures thereof. least one moisture retaining agent. 0039. In one embodiment the stabilizing agent is present 0034 Moisture retaining agents may be employed in the in the compositions of the present invention in an amount compositions of the present invention, to preferentially from about 0.001% to about 80% by weight of the composi absorb moisture and protect the active agent there from. Such tion. In another embodiment the stabilizing agent is present in agents include, but are not limited to, ethylene glycol, propy the compositions of the present invention in an amount from lene glycol, butylene glycol and glycerol and an aliphatic acid about 0.01% to about 75% by weight of the composition. In a ester or glycerol ester thereof; lactic acid and salts thereof further embodiment the stabilizing agent is present in the Such as, but not limited to Sodium lactate, calcium lactate, compositions of the present invention in an amount from magnesium lactate; colloidal silicon dioxide and the like or about 0.1% to about 70% by weight of the composition. In a any combinations thereof. further embodiment the weight ratio of stabilizing agent to 0035. In one embodiment the chelating agents, disaccha tetrahydrobiopterin in the compositions of the present inven rides or higher polyols, cyclodextrins, moisture retaining tion is in the range of about 0.001:1 to about 5:1. In another agents improve the action of antioxidants or preserve their embodiment the weight ratio of about 0.005:1 to about 4.5:1. action thereby increasing the stability of tetrahydrobiopterin In one embodiment the weight ratio of stabilizer to tetrahy and compositions thereof. drobiopterin in the compositions of the present invention is in 0036. In a further embodiment the stabilizing agent the range of about 0.001:1 to about 0.03:1. In one embodi employed in the compositions of the present invention is at ment the weight ratio of stabilizer to tetrahydrobiopterin in least one hydrophobic agent. the compositions of the present invention is in the range of 0037 Hydrophobic agents may be employed in the com about 0.2:1 to about 5:1. In one embodiment the weight ratio positions of the present invention, for providing protection of stabilizer to tetrahydrobiopterin in the compositions of the against moisture. Such agents include, but are not limited to, present invention is in the range of about 2:1 to about 5:1. fatty acids, long chain fatty alcohols, fats and oils, waxes, 0040. The stable pharmaceutical compositions of the phospholipids, terpenes, or combinations thereof. Fatty acids present invention may further comprise at least one pharma that may be employed in the present invention include, but are ceutically acceptable excipient. By “pharmaceutically US 2013/0336945 A1 Dec. 19, 2013 acceptable excipient' is meant a material which is not bio pectin, Xanthan, gellan, maltodextrin, galactomannan, logically or otherwise undesirable, i.e., the material can be pusstulan, laminarin, Scleroglucan, gum arabic, inulin, administered to an individual along with the active and sta karaya, whelan; polyols such as, but not limited to dipropy bilizing agent in a formulation without causing any undesir lene glycol, polypropylene glycol, propylene glycol, polyeth able biological effects or interacting in a deleterious manner ylene glycol (PEG), sorbitol and glycerol; carbopol, starch with any of the components of the formulation in which it is and starch-based polymers such as, but not limited to, prege contained. Pharmaceutically acceptable excipients ease the latinized starch, acrylic acid and methacrylic acid polymers, manufacturing process as well as improve the performance of and esters thereof, maleic anhydride polymers; polymaleic the dosage form. acid; poly(acrylamides); poly(olefinic alcohol)S. poly(N-vi 0041. The pharmaceutically acceptable excipients that nyl lactams); polyoxyethylated Saccharides; polyoxazolines; may be present in the stabilized pharmaceutical compositions polyvinylamines; polyvinylacetates; polyimines; poVidone, of the present invention include, but are not limited to, dilu vinylpyrrolidone/vinyl acetate copolymer and polyvinyl ents, binders, disintegrants, lubricants, colorants, flavors, pH acetate, mixture of polyvinyl acetate and polyvinylpyrroli adjusters, buffers, viscolizers, antiadherents, preservatives done, chitin, gelatin, chitosan and the like or any mixtures glidants, acidulants, artificial and natural Sweeteners, and the thereof. like. Diluents that may optionally be incorporated in the com positions of the present invention include, but are not limited 0043 Suitable sweetening agent includes, but is not lim to, talc, mannitol. Xylitol. Sucrose, Sorbitol, microcrystalline ited to, aspartame, Stevia extract, glycyrrhiza, Saccharine, cellulose, silicified microcrystalline cellulose dibasic cal saccharine Sodium, acesulfame. Sucralose, dipotassium gly cium phosphate, starch, maize starch, pregelatinized starch, cyrrhizinate. Sucrose, Sugar, maltose, partially hydrolyzed partially pregelatinized starch and the like, and combinations starch, corn syrup Solids, Sorbitol. Xylitol, mannitol and the thereof. Binders employed in the compositions of the present like or mixtures thereof. The compositions may comprise one invention include, but are not limited to, microcrystalline or more natural and/or artificial flavors such as, but not lim cellulose, calcium hydrogen phosphate, polyethylene glycol, ited to, mint flavour, orange flavour, lemon flavors, Strawberry polyvinylpyrrolidone, maize starch, pregelatinized starch, aroma, Vanilla flavour, raspberry aroma, cherry flavor, tutty partially pregelatinized starch, hydroxypropyl methylcellu frutty flavor, magnasweet 135, key lime flavor, grape flavor, lose, hydroxypropyl cellulose and the like, or combinations trusil art 511815, and fruit extracts and the like. Nonlimiting thereof. Disintegrants employed in the compositions of the examples of preservatives for use in a composition described present invention include, but are not limited to, sodium herein include, but are not limited to, methyl or propylpara starch glycolate, sodium carboxymethyl cellulose, croscar bens, Sorbic acid, chlorobutanol, phenol, thimerosal, sodium mellose sodium, crospovidone, polyvinylpyrrolidone, benzoate and the like or any combinations thereof. Suitable methyl cellulose, starch, pregelatinized starch, partially colorants include, but are not limited to, pigments and dyes pregelatinized starch and the like or combinations thereof. such as FD&C Red, riboflavin, carmine, FD&C Yellow, Lubricants that may be employed in the compositions of the FD&C Green, and FD&C Blue and the like or combinations present invention include, but are not limited to, magnesium thereof. Stearate, calcium Stearate, Zinc Stearate, Sodium Stearyl fuma 0044) The term “composition' or “formulation” or “dos rate and the like, or combinations thereof. Suitable glidants age form has been employed interchangeably for the pur include but are not limited to, colloidal silica, silica gel. pose of the present invention and mean that it is a pharma precipitated silica, and the like or combinations thereof. Suit ceutical composition which is suitable for administration to a able anti-adherents employed include, but are not limited to, patient. In one embodiment, the stable pharmaceutical com talc, magnesium Stearate or finely divided silica, and the like positions of tetrahydrobiopterin are for oral delivery. The or combinations thereof. Suitable pH adjuster or buffer compositions for oral delivery may be in any form, Such as, employed include, but are not limited to, Sodium citrate, citric but not limited to, liquid, Solid or semi-solid preparations and acid and the like or combinations thereof. Suitable acidulants the like. Liquid preparations for oral administration may be in employed include, but are not limited to, citric acid, malic any form including, but not limited to, Suspensions, syrups or acid, tartaric acid, fumaric acid, Succinic acid, glycolic acid, the like. Solid preparations for oral administration may be in oxalic acid, mandelic acid, phosphoric acid, aspartic acid, any form including, but not limited to, soluble tablets, dis glutamic acid and salts thereof and the like or combinations persible tablets, dry Suspension for reconstitution, powder or thereof. Further anti-caking agents that may be optionally granule for Solution or Suspension, granules, wafers, bite incorporated include, but are not limited to, colloidal silicon dispersion tablets capsules, tablets, caplets, orally disinte dioxide, tribasic calcium phosphate, powdered cellulose, grating tablets, and the like or any combinations thereof. In magnesium trisilicate, starch, and mixtures thereof. one embodiment the stable pharmaceutical composition of 0.042 Suitable viscolizers include, but are not limited to, tetrahydrobiopterin of the present invention is a soluble tab coprocessed microcrystalline cellulose such as but not lim let. As per the Ph. Eur, soluble tablets are uncoated or film ited to, microcrystalline cellulose and sodiumcarboxymeth coated tablets intended to be dissolved in water before admin ylcellulose sodium (Avicel RC591, Avicel CL-611); D-sor istration and are required to disintegrate within 3 minutes in bitol solution, polyalkylene oxides such as, but not limited to water at 15-25°C. In one embodiment, compositions of the polyethylene oxide; cellulose ethers such as, but not limited present invention are in the form of immediate release dosage to hydroxyethyl cellulose, hydroxypropylcellulose, hydrox form. In one embodiment the compositions of the present ypropyl methyl cellulose, methyl cellulose, ethyl cellulose, invention is a matrix type formulation. In another embodi Sodium carboxy methylcellulose, calcium carboxymethyl ment the compositions of the present invention is a multipar cellulose, microcrystalline cellulose, gums such as but not ticulate type formulation. Tablets of the present invention limited to gum arabic alginates, agar, sodium alginate, guar may vary in shape including, but not limited to, oval, triangle, gum, locust bean, carrageenan, tara, gum arabic, tragacanth, almond, peanut, parallelogram, pentagonal. It is contem US 2013/0336945 A1 Dec. 19, 2013 plated within the scope of the invention that the dosage form 0056 (b) blending the drug granules of step (a) with at can be encapsulated or coated. least one pharmaceutically acceptable excipient to form 0045. The stable formulations of the invention may be a blend; and provided, e.g. as tablets or pills or capsules in HDPE bottles 0057 (c) lubricating and compressing the blend of step provided with a desiccant capsule or pouch; or in foil-on-foil (b) to form tablets. blister packaging, or in blister packaging. 0.058 Inafurther embodiment is provided the use of stable 0046. The present invention also provides a process for the pharmaceutical compositions of tetrahydrobiopterin for the preparation of stable pharmaceutical composition compris manufacture of a medicament for the treatment of hyperphe ing tetrahydrobiopterin. Such a process comprises combining nylalaninemia. Further, the present invention provides a tetrahydrobiopterin with at least one stabilizing agent and at method of treating hyperphenyalaninemia, comprising least one pharmaceutically acceptable excipient. According administering to the Subject in need thereof stable pharma to the present invention tablets may be manufactured using ceutical compositions of tetrahydrobiopterin of the present conventional techniques known in the art such as direct com invention. pression, dry granulation and wet granulation extrusion/melt 0059. In another embodiment of the present invention the granulation and the like. In one embodiment, the stable Solid tetrahydrobiopterins may be combined with other active compositions of the present invention can be prepared by dry agents or pharmaceutically acceptable salts thereof includ blending the active and at least one stabilizing agent along ing, but not limited to, roflumilast; roflumilast-N-oxide. In a with other pharmaceutically acceptable excipients followed further embodiment the compositions comprising tetrahydro by compression into tablets. In a further embodiment of the biopterins or derivatives, precursors or analogs thereof may present invention granules of tetrahydrobiopterin may be pre be co-administered with organic nitrates such as glyceryl pared by any granulation method known to a person skilled in trinitrate; ; isosorbide-5-mononitrate; the art, including but not limited to, dry granulation, roll atorvastatin; and amoldipine. In an embodiment of the compaction, wet granulation, melt granulation and the like; present invention, the stable pharmaceutical compositions of without compromising on the stability of tetrahydrobiopter the present invention may further comprise , including ins and employed for preparation of pharmaceutical compo precursors, folic acids, or folate derivatives; and/or sitions. In another embodiment, granules, pellets and the like ; and/or vitamins, such as Cand/or vitamin B of stabilizing agent and other pharmaceutically acceptable 2 (riboflavin) and/or vitamin B12; and/or excipients may be prepared and used to formulate stable precursors such as L-dopa or carbidopa. pharmaceutical compositions of the present invention. In a 0060. While the present invention has been described in further embodiment, granules of tetrahydrobiopterin, stabi terms of its specific embodiments, certain modifications and lizing agent and other pharmaceutically acceptable excipients equivalents will be apparent to those skilled in the art and are may be prepared and used to formulate stable pharmaceutical intended to be included within the scope of the present inven compositions of the present invention. In case of wet granu tion. The invention is further illustrated by the following lation active agent is blended with a binder and granulation is examples, which are for illustrative purposes and should not carried out using a solvent. Alternatively a blend of active be construed as limiting the scope of the invention in any way. agent and other inactive excipients is granulated using a binder solution. Such granules are then blended with at least EXAMPLES one stabilizing agent and other excipients. 0047. In one embodiment, the process of preparing stable Example 1 compositions comprising tetrahydrobiopterin comprises the steps of: Soluble Tablet Composition of Sapropterin 0048 (a) blending the active with at least stabilizing Dihydrochloride agent, at least one pharmaceutically acceptable excipi 0061 Soluble tablet of sapropterin dihydrochloride was ent to form a blend; and prepared as per the composition of table 1 beneath: 0049 (b) lubricating and compressing the blend of step (a) to form tablets. TABLE 1 0050. In another embodiment, the process of preparing stable compositions comprising tetrahydrobiopterin com Composition of sapropterin dihydrochloride soluble tablet prises the steps of Ingredients mg tablet 0051 (a) granulating the active and at least one phar maceutically acceptable excipient with binder solution Sapropterin dihydrochloride 1OO Copovidone, USPNF 2O to form drug granules; D-Mannitol, USP 235.5 0.052 (b) blending the drug granules of step (a) with at Crospovidone, USPNF 35 least one stabilizer, and at least one pharmaceutically Sodium metabisulfite, USPNF 2.4 Carmine O.1 acceptable excipient to form a blend; and Mint flavor 2 0053 (c) lubricating and compressing the blend of step Sodium stearyl fumarate, USPNF 5 (b) to form tablets. 0054. In a further embodiment, the method of preparing Total 400 compositions comprising tetrahydrobiopterin comprises the steps of: 0062 Procedure: The active ingredient was dry mixed 0055 (a) granulating the active, at least one stabilizer, with all the excipients other than lubricant to form a blend. and at least one pharmaceutically acceptable excipient, The blend was then lubricated and compressed to form with binder Solution to form drug granules; soluble tablets of sapropterin dihydrochloride. US 2013/0336945 A1 Dec. 19, 2013

Example 2 0068. These soluble tablets were found to retain more than 99% of the initial amount of active after six months when Soluble Tablet Composition of Sapropterin stored at 40° C. and 75% relative humidity in HDPE con Dihydrochloride tainer. 0063 Soluble tablet of sapropterin dihydrochloride was Example 4 prepared as per the composition of table 2 beneath: Soluble Tablet Composition of Sapropterin TABLE 2 Dihydrochloride 0069. Soluble tablets of sapropterin dihydrochloride were Composition of sapropterin dihydrochloride soluble tablet prepared as per the composition of table 4 beneath: Ingredients mg tablet TABLE 4 Sapropterin dihydrochloride 100 Povidone, USPNF 12 Composition of soluble tablet of sapropterin dihydrochloride D-Mannitol, USP 258 Croscarmellose sodium, USPNF 2O Ingredients mg tablet Sodium metabisulfite, USPNF 2.4 EDTA tetrasodium, USP O.S Sapropterin dihydrochloride 1OO Riboflavin O.1 D-Mannitol, USP 155.6 Orange flavor 2 Copovidone, USP 15 Sodium stearyl fumarate, USPNF 5 Butylated hydroxy toluene, USPNF O.3 Beta cyclodextrin, USPNF 50 Total 400 Crospovidone, USPNF 22 Carmine O.1 Mint flavor 3 0064 Procedure: The active ingredient and part of D-man Sodium stearyl fumarate, USP 4 nitol, EDTA tetrasodium and sodium metabisulfite were Total 350 blended and the blend was kneaded with solution of povi done. The kneaded mass was granulated, dried and sized to obtain granules. These granules were blended with remaining 0070 Procedure: The active ingredient was dry mixed excipients except the lubricant, then lubricated and com with all the excipients other than lubricant to form a blend. pressed into soluble tablets of sapropterin dihydrochloride. The blend was then lubricated and compressed to form soluble tablets of sapropterin dihydrochloride. 0065. The soluble tablets had a disintegration time of less (0071. These soluble tablets were found to retain more than than 2 minutes in water at 15-25°C. 99% of the initial amount of active after six months when stored at 40° C. and 75% relative humidity in HDPE con Example 3 tainer. Soluble Tablet Composition of Sapropterin Example 5 Dihydrochloride Tablet Composition of Sapropterin Dihydrochloride 0066 Soluble tablets of sapropterin dihydrochloride were 0072 Tablets of sapropterin dihydrochloride were pre prepared as per the composition of table 3 beneath: pared as per the composition of table 5 beneath:

TABLE 3 TABLE 5 Composition of sapropterin dihydrochloride soluble tablet Composition of sapropterin dihydrochloride tablet Ingredients mg tablet Ingredients mg tablet Sapropterin dihydrochloride 100 Sapropterin dihydrochloride 100 Pregelatinized starch, USPNF 70 Microcrystalline cellulose, USP 184 Isomalt, Ph.Eur 150 Propyl gallate, USPNF 0.4 Crospovidone, USPNF 2O Ascorbic acid 55 Sodium ascorbate, USP 2.4 Oxalic acid 2 Citric acid, USP O.S Crospovidone, USPNF 22.5 Riboflavin O.1 Talc, USP 8 Orange flavor 2 Carmine O.1 Sodium stearyl fumarate, USPNF 5 Magnesium stearate, USP 3

Total 350 Total 375

0067 Procedure: The active ingredient, pregelatinized 0073 Procedure: The active ingredient was dry mixed starch, part of isomalt and Sodium ascorbate were blended with all the excipients other than lubricant to form a blend. and roll compacted. The compacted mass was sized to form The blend was lubricated and compressed to form tablets of granules that were blended with remaining excipients except saproterin dihydrochloride. the lubricant. The blend was then lubricated and compressed 1. A pharmaceutical composition comprising tetrahydro to form tablets of sapropterin dihydrochloride. biopterin and at least one stabilizing agent. US 2013/0336945 A1 Dec. 19, 2013

2. The composition of claim 1, wherein the tetrahydrobiop dextrin, dihydroxypropyl-3-cyclodextrin, methyl-3- terin is in the form of a free base, a free acid, a pharmaceuti cyclodextrin, Sulfobutyl ether cyclodextrin, glucosyl-C- cally acceptable salt, a , a precursor, an active cyclodextrin, glucosyl-3-cyclodextrin, diglucosyl-3- metabolite, a derivative, an analog, a polymorph, a Solvate, a cyclodextrin, maltosyl-Y-cyclodextrin, maltosyl-y- hydrate, an amorphous form, an enantiomer, an optical iso cyclodextrin, maltosyl-Y-cyclodextrin, maltotriosyl-B mer, a tautomer, a racemic mixture or any mixture thereof. cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-3-cy 3. The composition of claim 1, wherein the tetrahydrobiop clodextrin, maltosyl-3-cyclodextrin/dimaltosyl-3-cyclodex terin is sapropterin dihydrochloride. trin, or derivative thereof, or any mixture thereof. 4. The composition of claim 1, wherein the stabilizing 11. The composition of claim 4, wherein the moisture agent is an antioxidant, a chelating agent, a disaccharide or retaining agent is ethylene glycol, propylene glycol, butylene higher polyol, a cyclodextrin, a moisture retaining agent, a glycol, glycerol, glycerol ester, lactic acid, Sodium lactate, hydrophobic agent or any combination thereof. calcium lactate, magnesium lactate; colloidal silicon dioxide 5. The composition of claim 4, wherein the antioxidant is or any combination thereof. an organic antioxidant, an inorganic antioxidant or any com 12. The composition of claim 4, wherein the hydrophobic bination thereof. agent is a fatty acid, a long chain fatty alcohol, a fat, an oil, a 6. The composition of claim 5, wherein the organic anti wax, a phospholipid, a terpene, or any combination thereof. oxidant is butylated hydroxyanisole, butylated hydroxytolu 13. The composition of claim 1, wherein ratio of the stabi ene, tert-butyl-hydroquinone, 4-hydroxymethyl-2,6-di-tert lizing agent to tetrahydrobiopterin is about 0.001:1 to about butylphenol. 2,4,5-trihydroxybutyrophenone, alkylgallate, 5:1. propyl gallate, octyl gallate, dodecyl gallate, ethoxyquin, gal 14. The composition of claim 1, wherein ratio of the stabi lic acid, nordihydroguaiaretic acid, glycine, ascorbic acid, lizing agent to tetrahydrobiopterin is about 0.001:1 to about fatty acid ester of ascorbic acid, Salt of ascorbic acid, ascorbyl O.O3:1. palmitate, ascorbyl Stearate, sodium ascorbate, calcium 15. The composition of claim 1, wherein ratio of the stabi ascorbate, potassium ascorbate, erythorbic acid, L-carnitine, lizing agent to tetrahydrobiopterin is about 0.2:1 to about 5:1. acetyl L-carnitine, thioglycerol, thioglycolic acid, cysteine, 16. The composition of claim 1, wherein ratio of the stabi N-acetyl cysteine, methionine, glutathione, citric acid, tar lizing agent to tetrahydrobiopterin is about 2:1 to about 5:1. taric acid, fumaric acid, Succinic acid, glycolic acid, oxalic 17. The composition of claim 1, further comprises at least acid, malic acid, ellagic acid, tocopherol, lipoic acid, thi one pharmaceutically acceptable excipient, said excipient olated polymer, beta-carotene, carotenoid, flavonoid, flavone, being diluent, binder, disintegrant, lubricant, colorant, flavor, isoflavone, flavanone, , anthocyanidin, chalcone, pH adjuster, buffer, viscolizer, preservative, antiadherent, Vitamin, , enzyme or any combination thereof. glidant, acidulant, Sweetener, or any combination thereof. 7. The composition of claim 5, wherein the inorganic anti 18. The composition of claim 1, wherein the composition is oxidant is sodium metabisulfite, potassium sulfite, sodium in the form of liquid, Solid or semi-solid dosage form, said sulfite, sodium thiosulfate, sodium bisulfite or any combina solid dosage form being a soluble tablet, a dispersible tablet, tion thereof. a dry suspension for reconstitution, powder or granule for 8. The composition of claim 4, wherein the chelating agent Solution or Suspension, granule, wafer, a bite-dispersion tab is ethylene diaminetetraacetic acid, desferrioxamine B, def let, a capsule, a tablet, a caplet, or an orally disintegrating eroxamine, dithiocarb sodium, penicillamine, pentetate cal tablet. cium, a sodium salt of pentetic acid, Succimer, trientine, 19. The composition of claim 5 wherein the organic anti nitrilotriacetic acid, trans-diaminocyclohexanetetraacetic oxidant is butylated hydroxyanisole, butylated hydroxytolu acid, diethylenetriaminepentaacetic acid, dihydroethylgly ene, tert-butyl-hydroquinone, 4-hydroxymethyl-2,6-di-tert cine, bis(aminoethyl)glycolether-N.N.N',N'-tetraacetic acid, butylphenol. 2,4,5-trihydroxybutyrophenone, alkylgallate, iminodiacetic acid, poly(aspartic acid), citric acid, tartaric propyl gallate, octyl gallate, dodecyl gallate, ethoxyquin, gal acid, fumaric acid. Succinic acid, glycolic acid, oxalic acid, malic acid, ellagic acid, lactic acid, lecithin or any salt lic acid, nordihydroguaiaretic acid, glycine, erythorbic acid, thereof, or any combination thereof. L-carnitine, acetyl L-carnitine, thioglycerol, thioglycolic 9. The composition of claim 4, wherein the disaccharide or acid, methionine, glutathione, citric acid, tartaric acid, higher polyol is isomalt, hydrogenated maltulose, lactitol, fumaric acid, Succinic acid, glycolic acid, oxalic acid, malic maltitol, isomaltitol, maltotriitol, maltotetraitol, cellobiitol, acid, ellagic acid, lipoic acid, thiolated polymer, carotenoid, cellotriitol, xylobiitol, xylotriitol, inulotriitol, hydrogenated flavonoid, flavone, isoflavone, flavanone, catechin, anthocya oligo- and polysaccharide obtained by hydrolysis of starch nidin, chalcone, Vitamin, amino acid, enzyme or any combi followed by hydrogenation, hydrogenated oligo- and nation thereof. polysaccharides obtained by hydrolysis of cellulose, Xylan or 20. The composition of claim 5 wherein the organic anti fructan followed by hydrogenation, or a derivative, or any oxidant is ascorbic acid, fatty acid ester of ascorbic acid, salt combination thereof. of ascorbic acid, ascorbyl palmitate, ascorbyl Stearate, 10. The composition of claim 4, wherein the cyclodextrin is Sodium ascorbate, calcium ascorbate, potassium ascorbate, C-cyclodextrin, B-cyclodextrin, Y-cyclodextrin, hydroxypro cysteine, N-acetyl cysteine, tocopherol, beta-carotene, or any pyl-3-cyclodextrin, (2,6-di-O-methyl)-3-cyclodextrin, ran combination thereof. domly methylated-B-cyclodextrin, hydroxyethyl-3-cyclo