# US 10,500,180 B2 · Modified release orally administered amino acid formulations

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- Number: US 10,500,180 B2
- Document ID: US10500180B2
- Status: Granted
- Kind: B2
- Application number: 15/938,837
- Filed: 2018-03-28
- Published: 2018-11-08
- Granted: 2019-12-10
- Earliest claimed: 2015-09-28
- Assignees: APR Applied Pharma Research S.A.
- Applicants: Apr Applied Pharma Research S.A.
- Inventors: Alberto Reiner; Giorgio Reiner
- Web page: https://patentgrep.com/patent/US10500180B2

## CPC

- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A21D 2/245: {Amino acids, nucleic acids}
- A21D 13/80: Pastry not otherwise provided for elsewhere, e.g. cakes, biscuits or cookies
- A23L 33/15: Vitamins
- A23L 33/16: Inorganic salts, minerals or trace elements
- A23L 33/175: Amino acids
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/0056: {Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals}
- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/205: {Polysaccharides, e.g. alginate, gums; Cyclodextrin}
- A61K 9/5015: {Organic compounds, e.g. fats, sugars}
- A61K 9/5047: {Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose}
- A61K 9/5073: {having two or more different coatings optionally including drug-containing subcoatings}
- A61K 9/5115: {Inorganic compounds}
- A61K 9/5123: {Organic compounds, e.g. fats, sugars}
- A61K 9/5138: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/5161: {Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin}
- A61K 31/00: Medicinal preparations containing organic active ingredients
- A61K 31/401: Proline; Derivatives thereof, e.g. captopril
- A61K 31/405: Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
- A61K 31/4172: Imidazole-alkanecarboxylic acids, e.g. histidine
- A61K 33/00: Medicinal preparations containing inorganic active ingredients
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A23V 2002/00: Food compositions, function of food ingredients or processes for food or foodstuffs
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A21D: TREATMENT OF FLOUR OR DOUGH FOR BAKING, e.g. BY ADDITION OF MATERIALS; BAKING; BAKERY PRODUCTS (preservation of flour or dough before baking A23B40/00; preservation of bakery products A23B45/00)
- A23L: FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF (preservation thereof A23B)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A23V: INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION

## Abstract

Methods and formulations of modified release amino acids are provided for the treatment or management of diseases defined by impaired amino acid metabolism, with improved pharmacokinetics, metabolism and utilization.

## Claims

### Claim 1

An orally administered amino acid formulation comprising:
a) one or more modified release amino acids;
b) hydroxymethylpropyl cellulose or ethylcellulose or a combination thereof integrally mixed with said amino acids; or
c) a coating on said modified release amino acids comprising ethylcellulose or a combination of ethylcellulose and glyceryl dibehenate;
wherein the formulation comprising 2 g of the modified release amino acids comprises a release profile releasing no more than 70% of the modified release amino acids in 30 minutes of dissolution testing performed in a <711> USP 39 NF 34, paddle apparatus, at 37° C., in 450 or 500 mL, 0.1 N hydrochloric acid (pH 1.2), paddle speed 50 rpm, and said modified release is defined by said release profile.

### Claim 2 (depends on 1)

The formulation of claim 1, comprising five or more of the following amino acids as modified release amino acids in the recited weight parts:
Amino Acid
Weight Parts
L-Alanine
2.0-12.0
L-Arginine
3.0-10.5
L-Aspartic Acid
5.0-10.5
L-Cystine
1.5-4.0
L-Glutamic Acid +
7.0-25.0
Glutamine
Glycine
3.5-15.0
L-Histidine
2.0-6.5
L-Isoleucine
2.0-8.5
L-Leucine
8.0-15.0
L-Lysine
4.5-10.5
L-Methionine
1.0-3.0
L-Phenylalanine
4.0-7.5
L-Proline
3.5-15.0
L-Serine
2.0-8.5
L-Threonine
4.0-7.5
L-Tryptophan
1.0-4.0
L-Tyrosine
2.5-14.0
L-Valine
2.5-10.0
L-Carnitine
0.0-0.2
Taurine
0.05-1.0.

### Claim 3 (depends on 2)

The formulation of claim 2, comprising ten or more of the recited amino acids as modified release amino acids in the recited weight parts.

### Claim 4 (depends on 2)

The formulation of claim 2, comprising fifteen or more of the recited amino acids as modified release amino acids in the recited weight parts.

### Claim 5 (depends on 2)

The formulation of claim 2, comprising the recited essential amino acids, branched chain amino acids, and large neutral amino acids as modified release amino acids in the recited weight parts.

### Claim 6 (depends on 1)

The formulation of claim 1, comprising five or more of the following amino acids as modified release amino acids in the recited weight parts:
Amino Acid
Weight Parts
L-Alamine
2.0-12.0
L-Arginine
3.0-10.5
L-Aspartic Acid
5.0-10.5
L-Cystine
1.5-4.0
L-Glutamic Acid + Glutamine
7.0-25.0
Glycine
3.5-15.0
L-Histidine
2.0-6.5
L-Isoleucine
2.0-8.5
L-Leucine
8.0-15.0
L-Lysine
4.5-10.5
L-Methionine
1.0-3.0
L-Phenylalanine
4.0-7.5
L-Proline
3.5-15.0
L-Serine
2.0-8.5
L-Threonine
4.0-7.5
L-Tryptophan
1.0-4.0
L-Tyrosine
2.5-14.0
L-Valine
2.5-10.0
L-Carnitine
0.0-0.2
Taurine
0.05-1.0
comprising 0.0 weight parts L-phenylalanine.

### Claim 7 (depends on 1)

The formulation of claim 1, comprising five or more of the following amino acids as modified release amino acids in the recited weight parts
Amino Acid
Weight Parts
L-Alamine
2.0-12.0
L-Arginine
3.0-10.5
L-Aspartic Acid
5.0-10.5
L-Cystine
1.5-4.0
L-Glutamic Acid + Glutamine
7.0-25.0
Glycine
3.5-15.0
L-Histidine
2.0-6.5
L-Isoleucine
2.0-8.5
L-Leucine
8.0-15.0
L-Lysine
4.5-10.5
L-Methionine
1.0-3.0
L-Phenylalanine
4.0-7.5
L-Proline
3.5-15.0
L-Serine
2.0-8.5
L-Threonine
4.0-7.5
L-Tryptophan
1.0-4.0
L-Tyrosine
2.5-14.0
L-Valine
2.5-10.0
L-Carnitine
0.0-0.2
Taurine
0.05-1.0
comprising 0.0 weight parts L-phenylalanine and 0.0 weight parts L-tyrosine.

### Claim 8 (depends on 1)

The formulation of claim 1 wherein the formulation is a powder or granulate.

### Claim 9 (depends on 1)

The formulation of claim 1 in the form of a tablet, a pill, a soft or hard gelatin capsule, a powder, a granulate, a microsphere, a lozenge, a sachet of packaged powders or granulates or microspheres, an elixir, a suspension, an emulsion, a chewable tablet, or a syrup.

### Claim 10 (depends on 1)

The formulation of claim 1, wherein the formulation further comprises one or more additional ingredients selected from the group consisting of:
a) vitamins, minerals and carbohydrates; or
b) choline, inositol, vitamin A, vitamin D, vitamin E, vitamin K, vitamin C, thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, biotin, pantothenic acid, potassium, calcium, magnesium, iron, zinc, copper, manganese, selenium, chromium, molybdenum, iodine, sodium, sulfur, phosphorus, docosahexaenoic acid, eicosapentaenoic acid, arachidonic acid, and lutein, and salts, chelates, and esters thereof.

### Claim 11 (depends on 1)

The formulation of claim 1 wherein the formulation comprising 2 g of the modified release amino acids comprises a release profile releasing no more than 60% of the modified release amino acids in 30 minutes of dissolution testing performed in a <711> USP 39 NF 34, paddle apparatus, at 37° C., in 450 or 500 mL, 0.1 N hydrochloric acid (pH 1.2), paddle speed 50 rpm, and said modified release is defined by said release profile.

### Claim 12

An orally administered amino acid formulation comprising one or more modified release amino acids wherein the formulation comprising 2 g of the modified release amino acids comprises a release rate releasing no more than 70% of the modified release amino acids in 30 minutes of dissolution testing performed in a <711> USP 39 NF 34, paddle apparatus, at 37° C., in 450 or 500 mL, 0.1 N hydrochloric acid (pH 1.2), paddle speed 50 rpm, wherein said modified release is defined by said release profile, wherein the modified release amino acids are granulates coated by from 5 wt % to 25 wt % of one or more release modifying excipients based on the weight of the amino acids, wherein each of the granulates comprise a plurality of modified release amino acids, and wherein said formulation comprises:
a) hydroxymethylpropyl cellulose or ethylcellulose or a combination thereof integrally mixed with said amino acids; or
b) a coating on said modified release amino acids comprising ethylcellulose or a combination of ethylcellulose and glyceryl dibehenate.

### Claim 13 (depends on 12)

The formulation of claim 12 further comprising one or more release modifying excipients selected from ethylcellulose and a combination of ethylcellulose and glyceryl dibehenate.

### Claim 14 (depends on 12)

The formulation of claim 12 further comprising:
a) a bulking agent selected from lactose, sucrose, dextrose, sorbitol, fructose, and cellulose powder;
b) a disintegrating agent selected from microcrystalline cellulose, starches, crospovidone, sodium starch glycolate, and crosscarmellose sodium;
c) a glidant or lubricant selected from talc, corn starch, silicon dioxide, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, stearic acid, sodium stearyl fumarate, hydrogenated cotton seed oil, talc, waxes, cetyl alcohol, glyceryl stearate, glyceryl palmitate, glyceryl behenate, hydrogenated vegetable oils, and stearyl alcohol;
d) a taste-masking agent selected from cellulose hydroxypropyl ethers (HPC); low-substituted hydroxypropyl ethers (L-HPC); cellulose hydroxypropyl methyl ethers (HPMC); methylcellulose polymers; Ethylcelluloses (EC) and mixtures thereof; Polyvinyl alcohol (PVA); hydroxyethylcelluloses; carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC); polyvinyl alcohol and polyethylene glycol co-polymers; monoglycerides, triglycerides, polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers; cellulose acetate phthalate; sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures thereof;
e) a flavoring agent selected from acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate, maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, neotame, acesulfame potassium, mannitol, talin, xylitol, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or a combination thereof;
f) one or more release modifying excipients selected from the group consisting of ethylcellulose, glyceryl dibehenate, cellulose acetate, vinyl acetate/vinyl chloride copolymers, acrylate/methacrylate copolymers, polyethylene oxide, hydroxypropyl methylcellulose, carrageenan, alginic acid and salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya gum, acacia gum, tragacanth gum, locust bean gum, guar gum, sodium carboxymethyl cellulose, methyl cellulose, beeswax, carnauba wax, cetyl alcohol, hydrogenated vegetable oils, stearyl alcohol, acrylic acid copolymers, sodium alginate, carrageenan, alginic acid, pectin, sodium carboxymethyl cellulose, a starch derivative, or a combination thereof; or
g) a binder selected from polyvinyl pyrrollidone, starch, methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sucrose solution, dextrose solution, guar gum, xanthan gum, acacia, tragacanth, locust bean gum and sodium alginate, or an alginic acid salt.

### Claim 15 (depends on 12)

The formulation of claim 12 further comprising a binder selected from sodium alginate or an alginic acid salt.

### Claim 16 (depends on 1)

The formulation of claim 1, wherein tyrosine in the formulation is not coated by a modified release coating.

### Claim 17 (depends on 12)

A method of making a formulation of claim 12 comprising:
a) providing a first mixture comprising a plurality of amino acids;
b) contacting the mixture with a wetting agent and a binder to form a wet mixture;
c) optionally passing the wet mixture through a sieve to form a uniform wet granulate;
d) drying the uniform wet granulate to form a dry granulate;
e) optionally passing the dry granulate through a sieve to form a uniform dry granulate; and
f) coating the uniform dry granulate with a modified release composition.

### Claim 18

An orally administered amino acid formulation comprising one or more modified release amino acids wherein the formulation comprising 2 g of the modified release amino acids comprises a release profile releasing no more than 70% of the modified release amino acids in 30 minutes of dissolution testing performed in a <711> USP 39 NF 34, paddle apparatus, at 37° C., in 450 or 500 mL, 0.1 N hydrochloric acid (pH 1.2), paddle speed 50 rpm, wherein said modified release is defined by said release profile, wherein the modified release amino acids are granulates coated by from 5 wt % to 25 wt % of one or more release modifying excipients based on the weight of the amino acids, and wherein each of the granulates comprise a plurality of modified release amino acids, further comprising one or more release modifying excipients selected from ethylcellulose and a combination of ethylcellulose and glyceryl dibehenate.

### Claim 19 (depends on 18)

The formulation of claim 18 further comprising a binder selected from sodium alginate or an alginic acid salt.

### Claim 20 (depends on 18)

The formulation of claim 18, wherein tyrosine in the formulation is not coated by a modified release coating.

### Claim 21 (depends on 18)

The formulation of claim 18 comprising granulates having a size ranging from 0.1 to 1.5 mm.