Alpha keto acid compositions for treating hypo-albuminemia

Abstract

Provided herein are nutritional, or therapeutic, compositions and methods of use in primarily treating kidney patients suffering from low serum albumin. The compositions are divided into four formulations, comprising: 1) the magnesium salt and/or the calcium salt of the alpha keto acids of: α-leucine, α-valine, α-isoleucine, α-phenylalanine, α-hydroxy methionine; and/or α-tryptophan, and/or α-tyrosine; 2) L-lysine monoacetate, L-threonine; and/or 3) histidine, tryptophan, and tyrosine, as amino acids or base acids. The specific formulation administered depends in part upon which stage 2-5 of renal disease the patient has. The invention further comprises methods of treatment of disorders associated with low serum albumin using the composition as an over-the-counter pill. The patient's serum albumin is tested on a periodic basis and the selected composition and dose are adjusted accordingly. And the invention comprises method of making α-leucine, α-valine, α-isoleucine, a-tyrosine and α-tryptophan in a multi-step process.

Claims

1. A nutritional or therapeutic composition safe for oral consumption, comprising: a) at least three alpha keto analogue or acid of an amino acid of, or any combination thereof: 1) a magnesium salt; 2) a calcium salt; 3) a calcium salt and a magnesium salt; 4) wherein the at least three alpha keto analogue of the amino acid comprises: i) a α-leucine; ii) a α-valine; iii) a α-isoleucine; iv) a α-phenylalanine; v) a α-methionine or an α-hydroxy methionine; b) a L-lysine monoacetate, and a L-threonine; c) histidine amino acid, or a magnesium salt, or a calcium salt, or a calcium salt and a magnesium salt, of a keto analogue of a α-histidine; d) tryptophan amino acid, or a magnesium salt, or a calcium salt, or a calcium salt and a magnesium salt, of a keto analogue of a α-tryptophan; and e) wherein the oral composition comprises: a nitrogen load that does not exceed 3.8%; a calcium load that does not exceed 6.5%; a magnesium load that is at least 2.2%; and a sodium load that does not exceed 0.8%.

2. The nutritional or therapeutic composition of claim 1, further comprising a tyrosine amino acid, or a magnesium salt, or a calcium salt, or a calcium salt and a magnesium salt, of a keto analogue of a α-tyrosine.

3. The nutritional or therapeutic composition of claim 1, further comprising: about 8 to 31% wt/wt of the alpha keto analogue of leucine; about 5 to 21% wt/wt of the alpha keto analogue of valine; about 3 to 16% wt/wt of the alpha keto analogue of isoleucine; about 6 to 10% wt/wt of the alpha keto analogue of phenylalanine; about 3 to 5 wt/wt of the alpha keto analogue of hydroxy-methionine; about 9 to 13% wt/wt of L-lysine monoacetate; about 5 to 8% wt/wt of L-threonine; about 0 to 0.7% wt/wt of tyrosine or the magnesium salt of the alpha keto analogue of tyrosine; and/or about 0 to 0.4% wt/wt of tryptophan, or the alpha keto analogue of tryptophan; and/or about 2 to 4v % wt/wt of histidine amino acid, or a calcium or magnesium salt, or non-salt of the α keto analog of histidine.

4. The nutritional or therapeutic composition of claim 1, formulated as a tablet with an excipient comprising one or more of: microcrystalline cellulose, povidone K-30, crospovidone, and magnesium stearate.

5. The nutritional or therapeutic composition of claim 1, comprising: 1) the magnesium salt of the keto analogue of α-leucine, α-valine, α-isoleucine-α-phenylalanine, α-methionine; 2) a free amino acid of histidine, or a calcium or magnesium keto analogue of α-histidine; 3) a magnesium salt of the alpha keto analogue of tryptophan; or a base acid of tryptophan; 4) L-lysine monoacetate; 5) L-threonine; and 6) wherein said composition is to treat kidney disease.

6. The nutritional or therapeutic composition of claim 1, comprising: 1) the magnesium salt of the keto analogue of α-leucine, α-valine, α-isoleucine, α-tryptophan; 2) the calcium salt of the keto analogue of α-phenylalanine, α-methionine; 3) the free amino acid of histidine, or the calcium salt, or the magnesium salt, of the keto analogue of α-histidine; 4) L-lysine monoacetate; 5) L-threonine; and 6) wherein said composition is to treat kidney disease.

7. The nutritional or therapeutic composition of claim 1, comprising: 1) the calcium salt of the keto analogue of α-leucine, α-valine, α-isoleucine, α-phenylalanine, α-hydroxy methionine; 2) the magnesium salt of the keto analogue of α-tryptophan, α-leucine, α-valine, or α-isoleucine; 3) the free amino acid of histidine, or the calcium salt, or the magnesium salt, of the keto analogue of α-histidine; 4) magnesium salt of the keto analogue of tyrosine, or tyrosine amino acid; 5) L-lysine monoacetate; 6) L-threonine; and 7) wherein said composition is to treat stage 4 kidney disease.

8. The nutritional or therapeutic composition of claim 1, comprising: 1) the calcium salt of keto analogue of α-leucine, α-valine, α-isoleucine, α-phenylalanine, α-hydroxy methionine; 2) the magnesium salt of the keto analogue of α-tyrosine, or a tyrosine amino acid; 3) the free amino acid of histidine, or the calcium salt, or the magnesium salt, of the keto analogue of α-histidine; 4) the magnesium salt of the keto analogous of tryptophan or tryptophan amino acid; 5) L-lysine monoacetate; 6) L-threonine; and 7) wherein said composition is able to treat stage 5 kidney disease.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 illustrates the prior art chemical structure and formula for L-lysine monoacetate.

(2) FIG. 2 illustrates the prior art chemical structure and formula for keto-analogue α-leucine (calcium salt).

(3) FIG. 3 illustrates the chemical structure and formula for the keto-analogue of α-leucine (magnesium salt).

(4) FIG. 4 illustrates the chemical structure and formula for the keto-analogue of α-valine (magnesium salt).

(5) FIG. 5 illustrates the prior art chemical structure and formula for the keto-analogue of α-phenylalanine (calcium salt).

(6) FIG. 6 illustrates the chemical structure and formula for the keto-analogue of α-phenylalanine (magnesium salt).

(7) FIG. 7 illustrates the prior art chemical structure and formula for the keto-analogue of α-isoleucine (calcium salt).

(8) FIG. 8 illustrates the chemical structure and formula for the keto-analogue of α-isoleucine (magnesium salt).

(9) FIG. 9A illustrates the prior art chemical structure and formula for α-hydroxy methionine (calcium salt).

(10) FIG. 9B illustrates the chemical structure and formula for α-hydroxy methionine (magnesium salt).

(11) FIG. 10 illustrates the prior art chemical structure and formula for L-threonine (neutral).

(12) FIG. 11A illustrates the prior art chemical structure and formula for the keto-analogue of α-histidine.

(13) FIG. 11B illustrates the chemical structure and formula for the keto-analogue of α-histidine (magnesium salt).

(14) FIG. 11C illustrates the prior art chemical structure and formula for L-histidine.

(15) FIG. 12A illustrates the prior art chemical structure and formula for keto-analogue of α-tyrosine as a free acid without an NH2 group.

(16) FIG. 12B illustrates the chemical structure and formula for the keto-analogue of α-tyrosine (magnesium salt).

(17) FIG. 13A illustrates the prior art chemical structure and formula for α-tryptophan.

(18) FIG. 13B illustrates the chemical structure and formula for one embodiment of the keto-analogue of α-tryptophan (magnesium salt).

(19) FIG. 14 illustrates the chemical reactions for the manufacturing process of the magnesium salt of the alpha keto acid of leucine.

(20) FIG. 15 illustrates the chemical reactions for the manufacturing process of the magnesium salt of the alpha keto acid of isoleucine.

(21) FIG. 16 illustrates the chemical reactions for the manufacturing process of the magnesium salt of the alpha keto acid of valine.

(22) FIG. 17 illustrates the chemical reactions for the manufacturing process of the magnesium salt of the alpha keto acid of tyrosine, which does not comprise nitrogen.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

(23) Glossary of Terms

(24) As used herein, the term “load”, refers to the amount in grams or milligrams or grams/deciliters (g/dL) of nitrogen, calcium, sodium, and magnesium in the composition.

(25) As used herein, the term “optimal dosage” refers to as the smallest amount of amount of the composition to raise and then maintain serum albumin to normal levels of 4.6 or higher.

(26) As used herein, the term “about” refers to +/− five percent of the stated number or value.

(27) As used herein, the term “alpha keto acid” refers to the alpha (α) ketocarboxylic acid, which is the “ketoanalog” or “keto analogue” of an amino acid formed from the amino acid being substituted by a keto group. Keto acids or ketoacids are organic compounds that contain a carboxylic acid group and a ketone group—see FIGS. 1-17. It is also noted that “keto analogue of α-leucine, α-valine, α-isoleucine, α-phenylalanine, α-methionine, α-tryptophan” and so forth is equivalent to the alpha keto acid of leucine, valine, isoleucine, phenylalanine, tryptophan, and so forth.

(28) Magnesium Salts of Keto Acids:

(29) Described herein are compositions that are novel magnesium salts of alpha keto acids, including the magnesium salt of the keto analog of α-histidine, the magnesium salt of the keto analog of α-tyrosine, the magnesium salt of the keto analog of α-valine, the magnesium salt of the keto analog of α-tryptophan, the magnesium salt of the keto analog of α-leucine, the magnesium salt of the keto analog of α-isoleucine, the magnesium salt of the keto analog of α-hydroxy methionine, and the magnesium salt of the keto analog of α-phenylalanine. (These compounds are known in the prior art only as calcium and sodium salts).

(30) Novel Keto Acid—Magnesium Salt Compounds

(31) The present disclosure further comprises novel alpha (α) keto acids of EAA and/or non-EAA compounds, formulas, compositions comprising, compositions consisting essentially of, and/or compositions consisting at least one of the novel magnesium salts listed supra (#1-9), which are derived by reacting the amino acid with magnesium oxide or magnesium hydroxide—see figures disclosing their molecular formula, molar mass, and chemical structure, comprising:

(32) 1) the magnesium salt of the keto analog of α-leucine (FIG. 3);

(33) 2) the magnesium salt of the keto analog of α-valine (FIG. 4);

(34) 3) the magnesium salt of the keto analog of α-phenylalanine (FIG. 6);

(35) 4) the magnesium salt of the keto analog of α-isoleucine (FIG. 8);

(36) 5) the magnesium salt of the α-hydroxy methionine (FIG. 9B);

(37) 6) the magnesium salt of the keto analog of α-histidine (FIG. 11B);

(38) 7) the magnesium salt of the keto analog of α-tyrosine (FIG. 12B); and/or

(39) 8) the magnesium salt of the keto analog of α-tryptophan (FIG. 13B).

(40) Formulations Comprising Magnesium Salts:

(41) Several reasons exist for using magnesium salts instead of calcium salts. A pure calcium salt formula like current or past formulations can cause hypercalcemia in patients. Another group of patients may not meet the criteria for hypercalcemia but have calcium levels in or near the highest normal range. High calcium levels accelerate heart disease in kidney patients. Calcification of arteries is accelerated by high calcium levels. Calcification is also accelerated by calcium supplementation. Magnesium is used to stop this from occurring. Magnesium ameliorates and may prevent future phosphate induced calcification in vascular smooth muscle. Not only does adding magnesium reduce calcium content, it also reduces the effect of calcium. Low magnesium is a mortality indicator for kidney and heart patients. Magnesium nutrition is provided by the formulation. Previous formulas contain no magnesium. Magnesium is rarely a problem in kidney patients and is not restricted in most cases. By reducing calcium, patients get 0% to 65% of the RDA with the average dose. Patients can get over 80% to 160% of the RDA of calcium with the older formulas. The old approach assumes dietary sources of calcium do not exist and that high calcium is not an issue. By consuming less than 65% of the daily RDA's, dietary intake is accounted for. This increases safety for long term use.

(42) Formulations are described in herein that comprise at least one keto acid as a magnesium salt. In one embodiment, formulations comprise at least two alpha keto acids as their magnesium salts. In another embodiment, a formulation comprises at least three keto acids as their magnesium salts. In another embodiment, a formulation comprises at least four keto acids as their magnesium salts. In another embodiment, a formulation is described that comprises between one and eight keto acids as their magnesium salts.

(43) In one embodiment, a formulation is described herein that comprises at least one magnesium salt of a keto acid, wherein the keto acid is selected from the group comprising histidine or the keto analog of α-histidine, the keto analog of α-tyrosine, the keto analog of α-valine, the keto analog of α-tryptophan, the keto analog of α-leucine, the keto analog of α-isoleucine, the keto analog of α-hydroxy methionine, and the keto analog of α-phenylalanine.

(44) In another embodiment, a formulation is described herein that comprises at least two magnesium salts of keto acids, wherein the keto acids are selected from the group comprising histidine or the keto analog of α-histidine, the keto analog of α-tyrosine, the keto analog of α-valine, the keto analog of α-tryptophan, the keto analog of α-leucine, the keto analog of α-isoleucine, the keto analog of α-hydroxy methionine, and the keto analog of α-phenylalanine.

(45) In another embodiment, a formulation is described herein that comprises at least three magnesium salts of keto acids, wherein the keto acids are selected from the group comprising histidine or the keto analog of α-histidine, the keto analog of α-tyrosine, the keto analog of α-valine, the keto analog of α-tryptophan, the keto analog of α-leucine, the keto analog of α-isoleucine, the keto analog of α-hydroxy methionine, and the keto analog of α-phenyl alanine.

(46) In another embodiment, a formulation is described herein that comprises at least four magnesium salts of keto acids, wherein the keto acids are selected from the group comprising histidine or the keto analog of α-histidine, the keto analog of α-tyrosine, the keto analog of α-valine, the keto analog of α-tryptophan, the keto analog of α-leucine, the keto analog of α-isoleucine, the keto analog of α-hydroxy methionine, and the keto analog of α-phenylalanine.

(47) In another embodiment, a formulation is described herein that comprises at least five magnesium salts of keto acids, wherein the keto acids are selected from the group comprising the keto analog of α-histidine, the keto analog of α-tyrosine, the keto analog of α-valine, the keto analog of α-tryptophan, the keto analog of α-leucine, the keto analog of α-isoleucine, the keto analog of α-hydroxy methionine, and the keto analog of α-phenylalanine.

(48) In another embodiment, a formulation is described herein that comprises at least six magnesium salts of keto acids, wherein the keto acids are selected from the group comprising the keto analog of α-histidine, the keto analog of α-tyrosine, the keto analog of α-valine, the keto analog of α-tryptophan, the keto analog of α-leucine, the keto analog of α-isoleucine, the keto analog of α-hydroxy methionine, and the keto analog of α-phenylalanine.

(49) In another embodiment, a formulation is described herein that comprises at least seven magnesium salts of keto acids, wherein the keto acids are selected from the group comprising the keto analog of α-histidine, the keto analog of α-tyrosine, the keto analog of α-valine, the keto analog of α-tryptophan, the keto analog of α-leucine, the keto analog of α-isoleucine, the keto analog of α-hydroxy methionine, and the keto analog of α-phenylalanine.

(50) In another embodiment, a formulation is described herein that comprises at least eight magnesium salts of keto acids, wherein the keto acids are selected from the group comprising the keto analog of α-histidine, the keto analog of α-tyrosine, the keto analog of α-valine, the keto analog of α-tryptophan, the keto analog of α-leucine, the keto analog of α-isoleucine, the keto analog of α-hydroxy methionine, and the keto analog of α-phenylalanine.

(51) Tables 1-4 comprise four exemplary formulations, claimed herein, that are used to correctly supply protein nutrition, increase albumin levels and manage magnesium and calcium levels for each stage of kidney disease and current patient health while reducing the risk of vascular calcification/heart disease. The formulations used allow exact dosing and management of these conditions during different phases or stages of kidney disease progression.

(52) ALBUTRIX S2™ comprises a formula (composition) comprising 100% magnesium salts and three amino acids, no supplemental calcium or calcium salts for patients with persistent hypercalcemia or who can tolerate magnesium doses greater than the recommended daily amount of 400 mg. The targeted patient here is early stage kidney disease patient or stage 2 with a history or family history of heart disease.

(53) ALBUTRIX S3™ comprises a formula comprising magnesium and calcium salts that provide the recommended daily amount of magnesium and minimal calcium. The target patient is a stage three patient.

(54) ALBUTRIX S4™ comprises a formula comprising magnesium and calcium salts in which calcium and magnesium amounts are appreciably equal, and target patients who are in a stage four kidney patient.

(55) ALBUTRIX S5™ comprises a formula comprising very low magnesium and higher calcium salts levels for stage five or end stage renal disease patients who already have magnesium levels above the normal range.

(56) In the embodiments disclosed in Tables 1-4, the composition comprises the active ingredients of: about 8 to 31% wt/wt of the alpha keto analogue of leucine; about 5 to 21% wt/wt of the alpha keto analogue of valine; about 3 to 16% wt/wt of the alpha keto analogue of isoleucine; about 6 to 10% wt/wt of the alpha keto analogue of phenylalanine; about 3 to 5 wt/wt of the alpha keto analogue of methionine or hydroxy-methionine; about 9 to 13% wt/wt of L-lysine monoacetate; about 5 to 8% wt/wt of L-threonine; about 0 to 0.7% wt/wt of tyrosine or the Mg or salt of the alpha keto analogue of tyrosine; and about 0 to 0.4% wt/wt of tryptophan, or the alpha keto analogue of tryptophan without nitrogen; and/or about 2 to 4% wt/wt of histidine a.a., or a calcium or magnesium salt of the α keto analog of histidine.

(57) In an exemplary embodiment, Table 1 discloses a composition in tablet form comprising magnesium salts of six alpha keto analogues, and three amino acids, and L-lysine monoacetate.

(58) TABLE-US-00001 TABLE 1 ALBUTRIX S2 ™ % wt/wt % wt/wt Mg/ Active All Active Ingredients Tablet Ingredients Ingredients Mg salt α keto analog of leucine 236 30.37 24.97 Mg salt α keto analog of valine 156 20.08 16.50 Mg salt α keto analog of isoleucine 120 15.44 12.70 Mg salt α keto analog of 60 7.72 6.35 phenylalanine Mg salt α keto analog of hydroxy 30 3.86 3.17 methionine 0 0 0 Mg salt α keto analog Tryptophan; 2 .257 .212 or base acid Histidine amino acid., or Ca or 30 3.86 3.17 Mg salt, or non-salt α keto analog of histidine L-lysine monoacetate 90 11.58 9.52 L-threonine 48 6.18 5.08 Inactive Ingredients Microcrystalline cellulose 101.01 10.69 Povidone (K30) ™ 20.20 2.14 Crospovidone ™ 20.20 2.14 Magnesium Stearate 6.73 .712 Instacoat Aqueous film 20.20 2.14 coating-Readymix ™
Combination of Magnesium and Calcium Salts

(59) Tables 2 and 3 comprise compositions with a combination of magnesium and calcium salts of alpha keto analogues. The combination of magnesium and calcium reduces the possibility of exceeding RDAs. The combination of magnesium and calcium may be more effective, or as effective as, a phosphate binder than calcium salts alone. The combination is a safer way to reduce phosphorus than calcium alone.

(60) TABLE-US-00002 TABLE 2 ALBUTRIX S3 ™ % wt/wt % wt/wt Active All Active Ingredients Mg/Tablet Ingredients Ingredients Mg salt α keto analog of leucine 226 29.08 23.92 Mg salt α keto analog of valine 151 19.43 19.43 Mg salt α keto analog of isoleucine 123 15.83 15.83 Ca salt α keto analog of phenylalanine 77 9.91 9.91 Ca salt α keto analog of methionine 36 4.63 4.63 Mg salt α keto analog/keto 2 .257 .257 acid tryptophan Histidine amino acid 25 3.22 3.22 L-lysine monoacetate 90 11.58 11.58 L-threonine 47 6.05 6.05 Inactive Ingredients Microcrystalline cellulose 101.01 10.68 Povidone (K30) ™ 20.20 2.6 Crospovidone ™ 20.20 2.6 Magnesium Stearate 6.73 .867 Instacoat Aqueous 20.20 2.6

(61) TABLE-US-00003 TABLE 3 ALBUTRIX S4 ™ % wt/wt % wt/wt Active All Active Ingredients Mg/Tablet Ingredients Ingredients Ca salt α keto analog of leucine 71 9.14 7.51 Ca salt α keto analog of valine 47 6.05 4.97 Ca salt α keto analog of isoleucine 38 4.89 4.02 Ca salt α keto analog of phenylalanine 55 7.08 5.82 Ca salt α keto analog of hydroxy 28 3.60 2.96 methionine Mg salt α keto analog of leucine 160 20.59 16.93 Mg salt α keto analog of valine 115 14.80 12.17 Mg salt α keto analog of isoleucine 76 9.78 8.04 Mg salt α keto analog tryptophan 2 .257 .217 Histidine amino acid 30 3.86 3.17 L-lysine monoacetate 95 12.22 10.05 L-threonine 56 7.21 5.93 Mg salt α keto analog of tyrosine; 4 .515 .423 free or base acid Mg salt Inactive Ingredients Microcrystalline cellulose 101.01 10.69 Povidone (K-30) 20.20 2.14 Crospovidone 20.20 2.14 Magnesium Stearate 6.73 .713 Instacoat Aqueous 20.20 2.14

(62) TABLE-US-00004 TABLE 4 ALBUTRIX S5 ™ % wt/wt % wt/wt Active All Active Ingredients Mg/Tablet Ingredients Ingredients CA salt α keto analog of leucine 236 30.37 24.97 CA salt α keto analog of valine 156 20.08 16.50 CA salt α keto analog of isoleucine 120 15.44 12.70 CA salt α keto analog of 60 7.72 6.35 phenylalanine CA salt α keto analog of methionine 30 3.86 3.18 Mg salt α keto analog tryptophan 2 .257 Histidine amino acid 30 3.86 3.18 L-lysine monoacetate 90 11.58 9.52 L-threonine 48 6.18 5.08 Mg salt α keto analog of tyrosine; 5 .643 .529 free or base acid Mg salt Inactive Ingredients Microcrystalline cellulose 101.01 10.69 Povidone (K-30) 20.20 2.14 Crospovidone 20.20 2.14 Magnesium Stearate 6.73 .713 Instacoat Aqueous 20.20 2.14

(63) In one or more embodiments, the alpha keto acid of the non-EAA is: the keto analogue of alpha-tyrosine.

(64) And in one or more embodiments, the alpha keto acid of the EAA is: α-histidine, α-tyrosine, α-valine, α-tryptophan, α-leucine, α-isoleucine and α-phenylalanine.

(65) And the compositions may further comprise one or more of the following as a neutral compound, or as a calcium salt, or as a novel magnesium salt: L-lysine monoacetate, L-threonine, and/or α-hydroxy methionine.

(66) The histidine is a free amino acid, or it is a magnesium and/or a calcium salt of an alpha (α) keto acid, or a neutral amino acid (e.g. FIGS. 11A, 11B, and/or 11C).

(67) In one embodiment, a formulation comprises at least one magnesium salt; and/or a calcium salt and a magnesium salt of a keto acid, wherein the keto acid is selected from the group comprising the of: the keto analog of α-histidine, the keto analog of α-tyrosine, the keto analog of α-valine, the keto analog of α-tryptophan, the keto analog of α-leucine, the keto analog of α-isoleucine, the keto analog of α-hydroxy methionine, and the keto analog of α-phenylalanine.

(68) Table 5 discloses other non-magnesium and non-calcium formulations of the EAA's and tyrosine that may be used within the compositions disclosed herein.

(69) TABLE-US-00005 TABLE 5 of Free Acid (No Salt) EAA's and Tyrosine Keto-form Amino Acids Keto Form (no Mg or Ca salt) (CAS#) FIG. # Lysine N/A N/A Leucine α-Ketoisocaproic acid 816-66-0 Valine α-Ketoisovaleric acid 759-05-7 Phenylalanine β-Phenylpyruvic acid 156-06-9 Isoleucine α-Keto-β-methylvaleric acid 39748-49-7 Methionine 2-keto-4-methylthiobutyric acid 583-92-6 Threonine N/A N/A Histidine β-Imidazolyl pyruvic acid CAS: 2504-83-8 FIG. 11A L-Histidine CAS: 71-00-1 or 11C Tyrosine 4-Hydroxyphenylpyruvic acid 156-39-8 FIG. 12A Tryptophan β-Indolepyruvic acid 392-12-1 FIG. 13A
Nitrogen Load

(70) Compositions in the Appendix comprise reduced nitrogen loads as measured by the total nitrogen content (mg) per average daily dose of the formulation. In one embodiment, a formulation is described herein that comprises amino acids and keto acids with a nitrogen load that does not exceed 10%. In one embodiment, the nitrogen load does not exceed 7.5%. In one embodiment, the nitrogen load does not exceed 5%. In a preferred embodiment, the nitrogen load does not exceed 3.8%.

(71) Keto Acid: Amino Acid Content

(72) Prior art formulations have used a combination of five amino acids and five keto acids. One or more formulations described herein contain higher amounts of keto acids to amino acids as compared to the prior art, such as: two amino acids; and seven alpha keto acids of essential amino acids (6) and non-essential amino acids (1). This allows nitrogen content to be reduced. Nitrogen wastes incur a workload on the kidneys. Reducing nitrogen waste products allows patients with compromised kidneys to receive sufficient protein without increasing kidney workload. This formulation has the lowest nitrogen load of any formulation.

(73) Formulations comprising compositions in the Appendix comprise a mixture of amino acids and keto acids. In one embodiment, a formulation described herein comprises more keto acids than amino acids. In one embodiment, a formulation described herein comprises between 3 and 15 keto acids. In one embodiment, a formulation described herein comprises a maximum of 5 amino acids. In one embodiment, a formulation is described herein that comprise a maximum of 4 amino acids. In one embodiment, a formulation described herein comprises a maximum of 3 amino acids. In one embodiment, a formulation described herein comprises a maximum of 2 amino acids. In one embodiment, a formulation described herein comprises a maximum of 1 amino acid.

(74) In some embodiments, the ratio of keto acid:amino acid is equal to or greater than 2:1. In one embodiment, the ratio of keto acid:amino acid is equal to or greater than 3:1. In another embodiment, the ratio of keto acid:amino acid is equal to or greater than 4:1. In one embodiment, the ratio of keto acid:amino acid is equal to or greater than 5:1.

(75) Methionine Content

(76) Methionine content has been too high in past formulations. Methionine is the most toxic of essential amino acids. Methionine contributes to acidosis which in turn accelerates kidney and heart disease. In 2007, the World Health Organization (WHO) reduced the daily recommended daily allowance for methionine. Methionine toxicity can also cause heart problems at high levels. Methionine metabolism may be impaired in kidney patients, so methionine is reduced to diminish risk of acidosis while still providing protein nutrition. The formulations in compositions of the Appendix comprise significantly less methionine than older formulations. Supplemental methionine is reduced to 270 mg in an average dose of nine pills. The recommended daily amount is 800 to 950 mg. However, real intake of dietary methionine is estimated at 125 to 507 mg/kg per day, which well in excess of actual needs. For this reason, methionine is reduced to compensate for dietary methionine intake.

(77) Keto Acid Form of Tryptophan

(78) In the formulations in the compositions the present disclosure, the keto acid form of tryptophan is used instead of the amino acid as in past formulas. Tryptophan is related to the production of uremic toxins like indoxyl sulfate. This risk is reduced in three ways. No tryptophan is used, or the keto acid of tryptophan and a reduced amount of tryptophan is used. The keto acid of tryptophan reduces production of indoxyl sulfate. Tryptophan dosage is supplemented at 27 to 30 mg per day at an average dose.

(79) Keto Acid Form of Leucine

(80) One of the issues affecting kidney patients is protein energy wasting and or muscle wasting. The amino acid leucine is related to muscle protein synthesis. A higher amount of the keto acid of leucine is used in the compositions disclosed herein to promote muscle synthesis and reduce protein energy wasting with no increase in nitrogen load This is also a benefit to aging or elderly patients.

(81) Keto acid for of valine is one of the branched chain amino acids and supplied at a high dose to promote muscle synthesis and to compensate for reduced amino acid metabolism that is common in kidney patients

(82) Keto acid of iso-leucine is also one of the branched chain amino acids and is supplied at a higher does to promote muscle synthesis and to compensate for reduced amino acid metabolism that is common in kidney patients.

(83) EXEMPLIFICATIONS: Formulations with limitations on nitrogen load, calcium load, and sodium load, methionine content as well as the minimum magnesium content.

(84) In an embodiment, some of the compositions disclosed herein comprise amino acids and keto acids wherein at least one of the acids is present as a magnesium salt; or, as a magnesium and a calcium salt.

(85) And/or the total elemental composition of calcium does not exceed 6.5%. And/or the total elemental composition of magnesium is a minimum of 2.2%. And/or the total elemental composition of sodium does not exceed 0.8%. And/or the nitrogen load may not exceed 3.8%.

(86) Furthermore, the formulation may comprise: a magnesium salt of the keto analog of α-histidine as a magnesium salt; and/or a magnesium salt of the keto analog of α-tyrosine; and/or a magnesium salt of the keto analog of α-valine.

(87) Therapeutic and Nutritional Goals

(88) Treatment doses comprise the highest magnesium and the lowest calcium intake combined with the correct dosage of keto amino acid supplement based on severity of hypoalbuminemia. The treatment plan is based on three-month increment evaluations. As long as the patient is progressing, and serum levels are improving the diet continues. After a three-month evaluation with no improvement, a different set of decisions must be made. Patients are also encouraged to work on improving or curing comorbid conditions during each three-month period.

(89) The first part is determining the correct dosage of keto/amino acids. The second is determining the correct amount of magnesium or calcium/magnesium blend that is appropriate for patient's current health and serum magnesium and calcium. Patient's with impaired kidney function cannot manage calcium and magnesium metabolism compared with a healthily adult. The work is done for the kidneys by selecting the appropriate formulation from 100% magnesium to a to a 90% to 100% of calcium to magnesium. The supplement helps the patients keep these numbers in check without the risks of hypercalcemia, hypocalcemia, hypermagnesemia and hypomagnesemia. Risk are significantly diminished, but protein nutrition is still provided.

(90) Treatment plan takes place over a three-month period with monthly blood test. At the end of the three-month period, the highest magnesium formula that can be safely tolerated by the patient will be known. This dosage should be sustainable, well tolerated, safe and reduce inflammation and heart disease progression while providing the appropriate protein nutrition.

(91) As the diet and supplement treatment progresses over time albumin levels will rise. The end goal is a daily maintenance dose of 100% magnesium salts as keto acids. Ideally, kidney patients will not consume supplemental calcium only dietary calcium. Depending on the severity of the hypoalbuminemia, the recommended dosage may contain more magnesium that can be safely tolerated. Calcium magnesium blends are used initially to determine the dosage the patient can tolerate. Different patients will respond differently depending on other illnesses or health conditions, current stage of kidney disease and compliance with Kidney Factor diet.

(92) To raise serum albumin, inflammation and oxidative stress must be addressed. This diet ends up being a low protein diet Amino and keto acids are used to provide nutrition during the diet. The supplement and diet go hand and hand One can rarely be successful without the other. Both are required to raise albumin levels.

(93) The first part of the diet has the goal of stopping kidney disease and or going into remission. This will not be possible for all patients. It is unknown now why some patients respond to the diet and supplement and others do not respond or respond more slowing. This diet is very strict in terms of foods allowed. The second part of the diet is a maintenance diet to keep kidney disease progression slowed and to increase nutrition. The maintenance diet may be relaxed after it is determined if the patient has the potential to slow disease progression. The reason is the combination of a protein source of keto acids does not contribute to inflammation, oxidative stress, acidosis and other conditions that contribute to lower serum albumin. This is true for all patients. Treating low serum albumin without treating inflammation and oxidative stress is unlikely to work alone.

(94) The cycle for the diet is based on three-month increments. It will normally take up to four months on the diet and supplement for measurable changes to occur for patients with proteinuria. For this reason, the results are not evaluated until after 90 days on the diet and supplement. It takes this long for our bodies to start reducing oxidative stress or inflammation. At the end of three months, the effectiveness of the diet and supplement should be evaluated.

(95) TABLE-US-00006 TABLE 6 Successful treatment with diet and supplement will have the following characteristics: Increased serum albumin levels Improved Creatinine clearance Improved Blood Urea Nitrogen Decreased inflammation measured as C reactive protein Serum magnesium at the high end of the normal range Serum Calcium with in the normal range. Reduced proteinuria GFR near past GFR levels or slightly improved GFR *A standard accepted test for oxidative stress does not exist. Oxidative stress is not measured.

(96) If results are positive, continue with the diet for another three months. Repeat testing. If blood levels are increasing, continue the three-month cycle. At some point, patient's numbers will level out and continued treatment will not yield additional gains. The time frame for this is twelve to twenty-four months. Most patients can continue to see gains for twelve to fifteen months. The most severe patients may still be improving after 20 months.

(97) One three-month period of stable results and evaluation should be made to determine is kidney disease has significantly slowed progression or if patient may be in partial remission. Another three-month period is to verify that kidney disease has stopped progressing at a measurable rate.

(98) If results confirm disease progression has stopped or slowed dramatically, patient can choose to stay on the diet to try for further gains or move to the maintenance diet. Maintenance diet is designed to keep the gains made during the prior year; but be much easier to manage and allow more food choices. Maintenance diet will be lifelong for most patients, but their disease progression may be slowed dramatically. If diet is changed back to a diet that contributes to oxidative stress, acidosis and inflammation disease progression may continue. In addition, protein nutrition will be poor.

METHODS OF TREATMENT

(99) Disclosed herein are methods of treatment of the diseases, disorders, and conditions listed in Table 6, and using the steps illustrated in Table 7.

(100) It also comprises determining which formulation of Tables 1-4 to administer. This is based largely on the patient's type and severity of their medical condition. The range of formulas allows patients and doctors to do four things: 1. Provide protein nutrition 2. Control magnesium intake and serum magnesium levels 3. Control calcium intake and serum calcium levels 4. Specific nutrition for each stage of kidney disease to reduce the risk of heart disease and vascular calcification.

(101) The composition is in a tablet form, each tablet comprising: 1) 100% magnesium salts of the keto-acids; or 2) both magnesium and calcium salts for each keto-acid.

(102) TABLE-US-00007 TABLE 7 of Diseases, Disorders, and Conditions Treatable via the Administration of Compositions Kidney disease including dialysis Liver disease Age related kidney decline Pre-surgery to improve recovery times and decrease risk if albumin levels are below 4.6 Post-surgery to improve recovery times and decrease risk if albumin levels are below 4.6 Pre-hospitalization/pre-operative to decrease morbidity/morality rates and decrease risk to patient if albumin levels are below 4.6 Post hospitalization/Post-operative to decrease morbidity/mortality rates and decrease risks to patient if albumin levels are below 4.6 Cancer/Chemotherapy patients with impaired metabolism and albumin level below 46 Protein energy wasting (PEW) Sarcopenia Age related decline in muscle mass if albumin levels are below 4.6 Reduce recovery time for professional athletes who train or compete daily/frequently Acute and or chronic inflammation Malnutrition and or protein malnutrition if albumin levels are below 4.6 Crohn's disease if albumin levels are below 4.6 Burn patients if albumin levels are below 4.6 Sepsis if albumin levels are below 4.6 Heart failure if albumin levels are below 4.6 Ischemic Stroke if albumin levels are below 4.6 Transplant recipients if albumin levels are below 4.6

(103) Table 8 discloses the general steps with exemplified computations in an embodiment of computing the proper baseline dose for a patient to take of any one of the compositions of Tables 1-4. In step 1, the patient's body weight in kilograms is multiplied by 0.8 to determine their total daily protein requirement. In step 2, determine the current protein intake or proposed protein intake based on low or very low protein diet. In step 3, subtract dietary protein requirement from dietary protein restriction. In step 4, determine current protein intake, or proposed protein intake, based on a low or very low protein diet; and then solve for supplement protein requirement using body weight using shortfall. In step 5, use an estimate of one pill equals 4 grams of dietary protein to solve to correct dosage for equivalent of 60 grams of protein per day.

(104) This is the first step in calculating correct dosage. This approach allows the lowest amount of nitrogen and ammonia workload on the kidneys for the first ninety days. At this stage, Blood urea nitrogen levels and creatinine levels are higher than normal or outside the normal range. The smallest dose possible is used for the first ninety days to give the kidneys a chance to work off the excess ammonia and nitrogen waste products. Dosage will be corrected every 90 days going forward.

(105) TABLE-US-00008 TABLE 8 Step Exemplary Computation-Baseline dose 1 75 kg patient weight * .8 = 60 kgs of dietary protein 2 .4 kg for dietary protein restriction * 75 kg weight = 30 grams/day from dietary protein 3 .8-.4 = .4 grams per kg 4 75 kg *.4 = 30 grams; 30 grams/4 gram per pills = 7.5 pills per day 5 7.5 pills rounded up to 8 pills Second Dose Computation 6 Repeat steps 1-5 to ensure base dosage is correct. 7 4.5 g/dl − 3.5 g/gl = 1 g/dl shortfall 8 1 × 3 = 4 pills so new total is now 8 + 3 = 11 pills per day

(106) Second dosage computation: After the first ninety days, a serum albumin test should be done to determine if current dosage is sufficient to raise albumin levels and provide adequate protein nutrition. Using these test results the following calculation should be used to determine new dosage. In Table 8, step 6, repeat steps 1-5 to ensure base dosage is correct in case of body weight changes or dietary changes. If a lower or higher protein diet is used, then dosage must be recalculated.

(107) In step 7, the minimum albumin goal is 4.0 g/dl, and the optimal level is 4.5 g/dl or higher. If current albumin dosage is below 4.0 g/dl, use desired levels of 4.5 g/dl minus current albumin level to determine shortfall amount (as exemplified in Table 7). In step 8, the shortfall amount times 4 equals the number of pills that should be added to the baseline or base dosage.

(108) Alternatively, in step 7, if the albumin level is above 4.0 g/dl, but lower than 4.5 g/dl, the patient may stay on the same dosage for the next ninety day cycle, or may use the same formula to adjust dosage.

(109) Sarcopenia and protein energy wasting base dosage: for patients not on a low or very low protein diet, this low nitrogen protein food can be used to increase albumin, but dosage is different. The optimal level of 4.5 g/dl minus current aluminum levels equals shortfall (4.5 g/dl minus 3.5 g/dl). The shortfall amount times 5 equals the number of pills needed, and no base dosage is used (5×1=5 pills per day).

(110) Sarcopenia and protein energy wasting second dosage: continue to correct using same dosage at ninety-day increments. As albumin rises, dosage will automatically lower or increase based on current albumin levels. The formula is self-correcting. Once an albumin level of 4.0 g/dl is achieved, patient may continue on the same dosage, or may adjust again to increase the albumin levels closer to 4.5 g/dl.

(111) Method of Making the Magnesium Salts of the Alpha Keto Acids

(112) Table 9 discloses the specific method of manufacturing the magnesium salt of the alpha keto acids of: valine (FIG. 14), leucine (FIG. 15), and isoleucine (FIG. 16). In general, the process comprises combining the raw materials of: the calcium salt of the amino acid, water, hydrochloric acid, methyl tert-butyl ether, and magnesium carbonate; stirring the composition for about thirty minutes; allowing to settle into two layers, and collecting the top organic layer to which water and magnesium carbonate are added; heat for about one hour to about 60-65 degrees Celsius; remove solvent, cool, add methyl-tert-butyl ether; stir for about one hour at about 25-30 degrees Celsius; and filter, wash, dry under vacuum, store as powder. Convert powder into an orally consumable “low nitrogen” food product: e.g. food, beverage, tablet, etc.

(113) The manufacturing process disclosed herein does not involve the usage of the following ICH class −1 solvents i.e. Benzene, carbon tetrachloride, 1,2-Dichloroethane and 1,1,1-trichloroethane. And the solvents of class-2 and class-3 used in the manufacturing process are within the acceptance criteria of ICH requirements. And the compounds have tested safe for microbial levels: total microbial count; yeast and mold count; absence of bacterial strains comprising Escherichia coli, Salmonella, and Pseudomonas aeruginosa.

(114) TABLE-US-00009 TABLE 9 Method of Making Magnesium Salt of Alpha Keto Acid of Leucine, Isoleucine, and Valine Step Leucine Isoleucine Valine No. Qty. Qty. Qty. Procedure  1. Check the cleanliness of the reactor  2. 570.0 ml 2.39 L 280.0 ml Charge water to the reactor  3. 100.0 gm  418 ml  50.0 gm Charge Keto amino acid calcium salt  4. 480.0 ml 2.04 L 240.0 ml Charge methyl tert-butyl ether, stir for 15 min  5. Stir for 5 minutes  6.  60.0 ml 0.32 L  30.0 ml Add hydrochloric acid to pH-1-2  7. Stir for 30 min  8. Allowed to settle and separate the two layers  9. Separate the bottom aqueous layer 10. Collect the top organic layer separately 11. Transfer the organic layer back to reactor 12. 300.0 ml 1.25 L 150.0 ml Charge process water in the mass, stir for 15 min 13. Allowed to settle and separate the two layers 14. Separate the bottom Aqueous layer 15. Collect the top organic layer separately 16. Transfer the organic layer back to reactor 17. 800.0 ml 3.34 L 400.0 ml Charge water in to the organic layer 18.  25.2 gm 84.2 gm  12.6 gm Charge magnesium carbonate 19. Heat to 60-65° C. for 1 hour 20. After temperature maintains, distill of the solvent completely under vacuum at below 70° C. 21. Cool the residue to 25-30° C. 22. 300.0 ml 1.25 L 150.0 ml Add methyl-tert-butyl ether 23. Stir for 1 hour at 25-30° C. 24. 200.0 ml .836 L 100.0 ml Filter, wash with methyl tert-butyl ether 25. Dry the material at 70-75° C. under vacuum till specification meets 26.  52.0 gm  180 gm  32.0 gm Unload the material in to double polythene bag, store in HDPE containers

(115) The magnesium salt of the alpha keto acid of tyrosine is produced using the protocol of Appendix A and FIG. 17. It is a three-stage process comprising: the production of 5[4-hydroxyphenyl) methylidene] imidazolidine-2,4-dione (TYM-I) in stage 1 (Table 10); the production of 3-(4-hydroxyphenyl)-2-oxopropanoic acid (TYM-II) in stage 2 (Table 11); and the production of Tyrosine Keto magnesium (TYM) in stage 3 (Table 12).

(116) The tyrosine keto magnesium salt manufactured by the process of FIG. 17 meets the specifications of the heavy metals as per ICH guidelines. And the compounds have tested safe for microbial levels: total microbial count; yeast and mold count; absence of bacterial strains comprising Escherichia coli, Salmonella, and Pseudomonas aeruginosa.

(117) And the tyrosine keto magnesium salt manufactured by the process of Appendix A does not involve the usage of the following ICH class −1 solvents i.e. benzene, carbon tetrachloride, 1,2-Dichloroethane and 1,1,1-trichloroethane. And the following solvents class-2 and class-3 are involved in the manufacturing process of Tyrosine Keto Magnesium salt are within the acceptance criteria of ICH requirements.

(118) Pill Formulation

(119) The formulations in the compositions of the present disclosure may be administered orally in a pill or tablet form to improve patient compliance and control of dosage. It is also noted that they may be formulated into drink and/or food products, such as by way of non-limiting examples comprises: smoothies, shakes, yogurts; nutritional bars and baked goods; sports drinks and supplements; etc.

(120) Traditional medical foods, or amino acid supplements, for kidney patients are powders. Powders are difficult to measure and mix for many patients due to lifestyle and work constraints. For example, essential amino acids powders require a blender in many situations and taste is not pleasant. A pill containing 775 to 800 mg of essential amino acids—allows patients very precise control. Patient compliance is the holy grail of many treatments and this is no exception. Ease of use and consistency of dosage are key factors in patient compliance and success. Easy to remember dosages are required for long-term management of chronic diseases. Pills size may vary.

(121) Pill Coatings

(122) Pills comprising one each of the compositions of the present disclosure are coated to limit bitter taste and aftertaste. Keto amino acids have a very bitter taste and are very unpleasant. A coated pill, or a film coated pill, using natural ingredients to mask or cover the taste is required. If powders are used, artificial colors and flavorings are used to mask the taste. It takes an incredible amount of these ingredients to effectively mask the taste. Patients prefer and need supplements that do not increase artificial or chemical ingredients. This is especially true for kidney patients who have impaired metabolism of many ingredients. Adding ingredients to mask taste may contain restricted items like sodium, potassium and phosphorus. This version contains no sodium, potassium or phosphorus as a pill where powders may contain these restricted ingredients.

(123) Solid dosage forms for oral administration may include capsules, tablets, caplets, pills, troches, lozenges, powders, and granules. A capsule typically comprises a core material comprising a composition of the invention and a shell wall that encapsulates the core material. The core material may be solid, liquid, or an emulsion. The shell wall material may comprise soft gelatin, hard gelatin, or a polymer. Suitable polymers include, but are not limited to: cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ammonio methylacrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate (e.g., those copolymers sold under the trade name “Eudragit”); vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymers; and shellac (purified Iac). Some such polymers may also function as taste-masking agents.

(124) Tablets, pills, and the like may be compressed, multiply compressed, multiply layered, and/or coated. The coating may be single or multiple. In one embodiment, the coating material may comprise a polysaccharide or a mixture of saccharides and glycoproteins extracted from a plant, fungus, or microbe. Non-limiting examples include corn starch, wheat starch, potato starch, tapioca starch, cellulose, hemicellulose, dextrans, maltodextrin, cyclodextrins, inulins, pectin, mannans, gum arabic, locust bean gum, mesquite gum, guar gum, gum karaya, gum ghatti, tragacanth gum, funori, carrageenans, agar, alginates, chitosans, or gellan gum. In another embodiment, the coating material may comprise a protein. Suitable proteins include, but are not limited to, gelatin, casein, collagen, whey proteins, soy proteins, rice protein, and corn proteins. In an alternate embodiment, the coating material may comprise a fat or oil, and in particular, a high temperature melting fat or oil. The fat or oil may be hydrogenated or partially hydrogenated, and preferably is derived from a plant. The fat or oil may comprise glycerides, free fatty acids, fatty acid esters, or a mixture thereof. In still another embodiment, the coating material may comprise an edible wax. Edible waxes may be derived from animals, insects, or plants. Non-limiting examples include beeswax, lanolin, bayberry wax, carnauba wax, and rice bran wax. Tablets and pills may additionally be prepared with enteric coatings.

(125) Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tableting agents, lubricants, disintegrants, colorants, flavorings, and wetting agents. The tablets may be coated according to well-known methods in the art.

(126) Suitable fillers for use include, mannitol and other similar agents. Suitable disintegrants include starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate.

(127) These solid oral compositions may be prepared by conventional methods of blending, filling, tableting or the like. Repeated blending operations may be used to distribute the active agents throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.

CONCLUSION

(128) Other features that are considered as characteristic for the various embodiments are set forth in the appended claims.

(129) Although the various embodiments are illustrated and described herein as embodied in nutritional compositions and food products, it is nevertheless not intended to be limited to the details shown, since various modifications and structural changes may be made therein without departing from the spirit of the invention and within the scope and range of equivalents of the claims.

(130) The product names used in this document are for identification purposes only. All trademarks and registered trademarks are the property of their respective owners.

APPENDIX A

Manufacturing Process for Tyrosine Keto Magnesium Salt

(131) Stage-I: 5[(4-hydroxyphenyl)methylidene]imidazolidine-2,4-dione (TYM-I)

(132) TABLE-US-00010 S No. Raw Materials M. Wt. Wt. UOM Mole M.R. Make 1. P-hydroxy benzaldehyde 122.12 500 gm 4.09 1.0 LR Grade 2. Hydantoin 100.08 450 gm 4.49 1.1 LR Grade 3. Piperidine 85.15 820 mL 9.6 2.35 LR Grade 4. Process water — 16225 mL In house 5. Hydrochloric acid 36.46 1600 gm 14.04 2.86 LR Grade
Procedure:

(133) TABLE-US-00011 Step No. Qty UOM Procedure  1. Check for the cleanliness of the reactor  2.  450 g Charge hydantoin  3.  500 g Charge P-Hydroxy benzaldehyde  4.  820 mL Charge piperidine  5. Heat the mass to 125-130° C.  6. Stir the mass for 45 minutes at 130° C.  7. Check for completion of the reaction  8. After completion of reaction, cool the mass to room temperature  9. 16000 mL Charge process water to the cooled reaction mass 10. Stir for 30 minutes 11.  1600 g Add slowly concentrated hydrochloric acid to the mass at 15-20° C. till pH attains 2-3 12. Stir the mass for 1 hour at RT 13. Filter the precipitated product 14.  225 mL Wash the product with cold water 15.  670 g Dry the product to constant weight-TYM-1
Stage-II: 3-(4-hydroxyphenyl)-2-oxopropanoic acid (TYM-II) Raw materials:

(134) TABLE-US-00012 S No. Raw Materials M. Wt. Wt. UOM K. Mole M.R. Make 1. P-Hydroxy benzyl hydantoin 204.18 670 g 3.28 1.0 TYM-I 2. Process water — 19000 mL — — In house 3. Sodium hydroxide 40.00 3790 g 94.75 28.88 LR Grade 4. Hydrochloric acid 36.46 12000 g 105.32 32.11 LR Grade 5. Ethyl acetate — 10050 mL — — LR Grade 6. Hexane — 10050 mL — — LR Grade
Process:

(135) TABLE-US-00013 Step No. Qty UOM Procedure  1. Check for the cleanliness of the reactor  2. 19000 mL Charge process water to the reactor  3.  3790 g Charge sodium hydroxide flakes  4. Stir for 15 minutes, cool to 20-25° C.  5.  670 g Charge TYM-Stage I at 20-25° C.  6. Stir for 15 minutes  7. Heat the mass to 150-160° C.  8. Stir the mass for 4 hours at 150-160° C.  9. Check for the completion of the reaction 10. After completion reaction, cool the mass to 10-15° C. 11.  8000 g Add slowly hydrochloric acid at below 20° C. till pH attains 8-9 12.  3350 mL Charge hexane to the reaction mass 13. Stir for 15 minutes 14. Allow to separate the two layers. 15. Separate the product aqueous layer. 16. Collect tile top hexane layer separately 17. Charge back the aqueous layer to the reactor 18.  3350 mL Charge hexane 19. Stir for 15 mInutes 20. Allow to separate the two layers. 21. Separate the product aqueous layer. 22. collect the top hexane layer separately 23. Charge hack aqueous layer to the reactor 24.  4000 g Add hydrochloric acid slowly through addition funnel till pH attains 1-2 at below 20° C. 25. Stir the precipitated product for one hour at 10-20° C. 26.  5025 mL Add ethyl acetate to the acidified reaction mass 27. Stir the precipitated product for one hour at 10-20° C. 28. Separate the bottom aqueous layer 29. Collect the top product organic layer separately 30. Charge back the aqueous layer to the reactor 31.  5025 mL Add ethyl acetate to the aqueous layer 32. Stir for 15 min, allow to separate the two layers 33. Separate the bottom aqueous layer 34. Combine all the organic layers 35. Distill of the solvent completely under vacuum at below 50° C. 36.  2680 mL Add hexane to the residue 37. Stir for 30 min 38. Filter the precipitated product 39.  670 mL Wash with hexane 40. Dry the mass to constant weight at 50-60° C. under vacuum 41.  335 g Yield of TYM-II
Stage-III: Tyrosine Keto magnesium (TYM)

(136) TABLE-US-00014 S No. Raw Materials M. Wt. Wt. UOM K. Mole M.R. Make 1. TYM-II 180.15 335 g 0.055 1.0 In house 2. Methanol — 5025 mL — — Commercial 3. Process water — 3000 mL — — In house 4. Magnesium carbonate 84.31 693 g 0.027 0.50 Commercial 5. MTBE 1850 mL
Process:

(137) TABLE-US-00015 Step No. Qty UOM Procedure  1. Check the cleanliness of the reactor  2. 335 g Charge TYM-II  3. 5025 mL Charge methanol  4. Stir the mass for 15 minutes  5. 3000 mL Charge water  6. 693 g Charge Magnesium Carbonate  7. Heat the mass to 55-60° C. for 1 hour  8. Distilled the solvent completely under vacuum at below 70° C.  9. 1675 mL Charge MTBE to the residue 10. Stir for 30 minutes 11. 167.5 mL Filter the precipitated product 12. Wash the material with MTBE 13. Dry the product to constant weight under vacuumat below 70° C. 14. 188 g Yield of Tyrosine Keto Magnesium