Edible Formulations Based on Active Ingredients and Arginine

Abstract

The object of the present invention is the use of arginine and/or a salt thereof as a stabilizer of an acid active ingredient having a pKa of between 1 and 5 such as S-Adenosyl-L-methionine, and an edible formulation comprising an acid active ingredient, arginine and/or a pharmaceutically acceptable salt thereof, and at least one physiologically acceptable excipient.

Claims

1. Use of arginine and/or a pharmaceutically acceptable salt thereof as a stabilizer of an acid active ingredient having a pKa of between 1 and 5.

2. Use of arginine and/or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that said arginine is selected from L-arginine, D-arginine, and DL-arginine.

3. Use of arginine and/or a pharmaceutically acceptable salt thereof of claim 1, characterized in that said active ingredient is selected from S-Adenosyl-I-methionine or a salt thereof, ascorbic acid, acid amino acids, such as glutamic acid, N-acetyl-carnitine, L-acetyl-cysteine, acetyl-salicylic acid, salicylic acid, S-acetyl-l-glutathione, aspartic acid, lipoic acid, hydroxy-methyl-butyrate, carnitine, and acid botanical extracts, such as extracts of acerola and dog rose.

4. Use of arginine and/or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that said active ingredient is S-Adenosyl-I-methionine.

5. Edible formulation comprising an acid active ingredient having a pKa of between 1 and 5, arginine and/or a pharmaceutically acceptable salt thereof, and at least one physiologically acceptable excipient.

6. Edible formulation according to claim 5, characterized in that said active ingredient has a pKa of between 1 and 4.5.

7. Edible formulation according to claim 6, characterized in that said arginine is selected from L-arginine, D-arginine, and DL-arginine.

8. Edible formulation according to claim 6, characterized in that said active ingredient is selected from S-Adenosyl-l-methionine or a salt thereof, ascorbic acid, acid amino acids, such as glutamic acid, N-acetyl-carnitine, L-acetyl-cysteine, acetyl-salicylic acid, salicylic acid, S-acetyl-l-glutathione, aspartic acid, lipoic acid, hydroxy-methyl-butyrate, carnitine, or acid botanical extracts, such as extracts of acerola and dog rose.

9. Edible formulation according to claim 8, characterized in that said active ingredient is S-Adenosyl-l-methionine.

10. Edible formulation according to claim 5, characterized in that said at least one physiologically acceptable excipient is selected from diluents, lubricants, aggregating agents, disintegrating agents, film forming agents, coloring agents, sweeteners or flavoring agents and/or antioxidants-antimicrobials.

11. Edible formulation according to claim 10, characterized in that said at least one physiologically acceptable excipient is present in an amount of 5-80% by weight, with respect to the total weight of the formulation.

12. Edible formulation according to claim 5, characterized by being in the form of orosoluble formulations, preferably selected from orodispersible tablets, sublingual tablets, powders or granules for sachets or stick-packs; or in the form of swallowing formulations, preferably selected from chewable tablets, drinkable solutions, or syrups.

13. Edible formulation according to claim 5, characterized in that said active ingredient is present in an amount ranging from 5 to 70% by weight, with respect to the total weight of the formulation.

14. Edible formulation according to claim 5, characterized in that arginine or a pharmaceutical salt thereof is present in an amount ranging from 5% to 70% by weight, with respect to the total weight of the formulation.

15. Edible formulation according to claim 5, characterized in that it contains at least one further active ingredient.

16. Edible formulation according to claim 15, characterized in that said further active ingredient has a dietetic, alimentary, nutraceutical and/or phytotherapeutic activity and is selected from vitamins, such as vitamins A, D, E, K, vitamins of group B, pantothenic acid, minerals, such as magnesium, calcium, phosphorus, iron, zinc, copper, manganese, fluorine, selenium, chromium, molybdenum, iodine, boron, potassium, chlorine, sodium, silicon salts, phytotherapeutic agents, such as botanical extracts of Curcuma longa, Boswellia serrata, Silybum marianum, Ananas comosus, Griffonia simplicifolia, Camelia sinensis, Olea europea and other substances with a nutritional and/or physiological effect, such as essential amino acids, branched amino acids, hydroxy-isocaproic acid (HICA), hyaluronic acid, conjugated linoleic acid (CLA), nervonic acid, alpha-ketoisocaproate (KIC), arabinogalactan, arabinoxylan, arginine alpha-ketoglutarate (AAKG), astaxanthin, beta-alanine, betaine, beta-glucans, butyrate, caffeine, carnosine, chitosan, citicoline, chlorophyll, coenzyme Q10, ubiquinol, choline, collagen, colostrum, chondroitin sulfate, creatine, dimethylglycine, enzymes such as alpha-galactosidase, bromeline, enzymes from fermented maltodextrins, lactase, beta-galactosidase, papain or superoxide dismutase, epigallocathechingallate, phytosterols, flavonoids such as quercetin, quercitrin, rutin, spireoside, hesperidin, hesperitin or diosmin, phospholipids such as phosphatidylcholine, phosphatidylserine or phosphoserine, GABA, gamma oryzanol, glycero-phosphoryl-ethanolamine, glycocyamine, glucomannan, glucosamine, glucuronolactone, glutathione, guar gum, hydroxytyrosol/olive polyphenols, inositol, isoflavones, lactoferrin, lactulose, lycopene, lutein, melatonin, methylsulfonylmethane (MSM), monacolin K from fermented red rice (Monacus purpureus), N-acetyl-D-glucosamine, NADH, naringin, norvaline, nucleotides, fish oil (DHA-EPA), homotaurine, ornithine alpha-ketoglutarate (OKG), palmitoylethanolamide (PEA), PABA, pectin, pycnogenol, policosanol, polydatin, resveratrol, ribose, spermidine, squalene, taurine, theanine, zeaxanthin, or mesozeaxanthin.

Description

EXPERIMENTAL SECTION

Example 1

[0051] Some examples of formulations according to the present invention are reported in the following tables.

TABLE-US-00001 TABLE 1 Orosoluble granulate in sachet SAMe- ARGININE Mg SAMe TOSYLATE 400 L-ARGININE 300 XYLITOL 290 FLAVORING AGENT 5 SILICA GEL 5 1000

TABLE-US-00002 TABLE 2 Orosoluble granulate in sachet SAMe- ARGININE Mg SAMe TOSYLATE 400 L-ARGININE 300 INOSITOL 1000 MAGNESIUM 80 STEARIC ACID 10 XYLITOL 393 SUCRALOSE 2 FLAVORING AGENT 5 MAGNESIUM STEARATE 5 SILICA GEL 5 2200

TABLE-US-00003 TABLE 3 Orosoluble granulate in sachet SAMe- ARGININE- Mg SAMe TOSYLATE 400 L-ARGININE 300 GSH 250 MAGNESIUM 80 MANNITOL 503 ACESULFAME K 2 FLAVORING AGENT 5 MAGNESIUM STEARATE 5 SILICA GEL 5 1550

TABLE-US-00004 TABLE 4 Orosoluble Tablet SAMe- ARGININE - Mg SAMe TOSYLATE 400 DL-ARGININE 300 CITICOLINE BASE 500 MAGNESIUM 80 ISOMALT 400 ERYTHRITOL 405 FLAVORING AGENT 5 MAGNESIUM STEARATE 5 SILICA GEL 5 2100

TABLE-US-00005 TABLE 5 Orosoluble granulate in sachet ACETYLCYSTEINE- ARGININE - Mg ACETYLCYSTEINE 600 L-ARGININE 600 VITAMIN C 80 XYLITOL 253 MANNITOL 250 SUCRALOSE 2 FLAVORING AGENT 5 MAGNESIUM STEARATE 5 SILICA GEL 5 1800

TABLE-US-00006 TABLE 6 Chewable tablets LIPOIC ACID - ARGININE - Mg LIPOIC ACID 600 L-ARGININE 500 L-ACETYL-CARNITINE 150 ISOMALT 400 XYLITOL 395 STEARIC ACID 40 FLAVORING AGENT 5 MAGNESIUM STEARATE 5 SILICA GEL 5 2100

TABLE-US-00007 TABLE 7 Bottle containing syrup SAMe- ARGININE- Mg SAMe TOSYLATE 400 L-ARGININE 300 VITAMIN C 60 MELATONIN 1 FRUCTOSE 500 SUCRALOSE 2 SODIUM BENZOATE 5 FLAVORING AGENT 5 DISTILLED WATER 727 2000

TABLE-US-00008 TABLE 8 Swallowable tablet SAMe- ARGININE Mg SAME TOSYLATE 400 L-ARGININE 300 XYLITOL 290 MAGNESIUM STEARATE 5 SILICA GEL 5 1000

[0052] The formulations of Tables 2-8 may optionally contain any one of the optional active ingredients according to the present invention.

Example 2

[0053]

TABLE-US-00009 TABLE 8 pKa values of the active ingredients used in the compositions Active ingredient pKa Solubility in water (g/L) SAMe 1.7 1.19 Ascorbic Acid 4.36 245 N-Acetyl Cysteine 3.82 5.09 Acetylsalicylic acid 3.41 1.46 S-acetyl-L-glutatione 1.75 n.d. Aspartic Acid 1.7 142 Lipoic acid 4.52 0.224 Hydroxy-methyl-butyrate (3- 4.4 15 hydroxy-3-methylbutyric acid) Levocarnitine 4.2 5.33 L-Acetyl Carnitine 4.09 142 Glutamic acid 1.88 80.6

Example 3

Neutralization of an Aqueous Solution of SAM-e Tosylate (Salt)

[0054] To demonstrate that not all buffering agents may be used in commercial pharmaceutical forms in order to neutralize the acid pKa of the active ingredients, the following laboratory test was set up to find the exactly measured amount needed to neutralize a solution containing 400 mg of SAMe (salt). After measuring the pH, the solution was gradually added with buffering substance until neutralization and a pH 7 value were reached. As it can be seen from the table below (Table 9), the amount of Lysine and Potassium Citrate tribasic appear to be excessive to consider their use in commercial pharmaceutical forms. More precisely, from the table it can be noted that 15.4 g of Lysine fail to bring the SAMe solution to neutralization (the pH value remains 4).

[0055] SAMe tosilate concentration: 400 mg/100 mL

TABLE-US-00010 TABLE 9 Sam-e tosylate Neutralizing Neutralizing Neutralizing weight Volume Initial agents added Final Stabilization Agents agents Batch (mg) (mL) pH amount (mg) pH time 1 Arginine A18120073 400 100 2.08 375 7.0 <3 minutes 2 Lysine A18080075 400 100 2.08 15402 4.0 <3 minutes 3 Sodium A18110103 400 100 2.08 690 7.0 <3 minutes bicarbonate 4 Sodium A19010401 400 100 2.10 200 7.0 <3 minutes carbonate 5 Sodium 103\Re2016 400 100 2.09 510 7.0 <3 minutes phosphate tribasic 6 Potassium A19050053 400 100 2.10 14943 7.0 <3 minutes citrate tribasic 7 Light A19020294 400 100 2.08 44.91 7.1 60 minutes magnesium oxide
Neutralization of an Aqueous Solution Containing Other Acid Principles with L-Arginine.

[0056] Based on the excellent neutralization results obtained with L-Arginine, the same method was used to analyze the amount of L-Arginine necessary to neutralize a solution including other acid active ingredients (results below): [0057] An aqueous solution containing 1 g of N-Acetyl-Cysteine is neutralized with 1.086 g of L-Arginine [0058] An aqueous solution containing 1 g of L-Acetyl-Carnitine is neutralized with 0.736 g of L-Arginine

Example 4

Taste Test for Palatability of SAMe in the Presence of Different Buffering Agents.

[0059] To prove the excellent palatability of the invention, especially when compared with other neutralizing substances, the following experimental test was set up using as the active ingredient SAMe (S-adenosyl-l-methionine tosylate, para-toluenesulfonate), the active with the lowest pKa among those tested and certainly the most critical in terms of flavor and stability.

[0060] Single-dose sachets containing 400 mg of SAMe (S-adenosyl-l-methionine tosylate, para-toluenesulfonate) were prepared, in addition to a weighed amount of the various buffers in the table of Example 2, so as to have mixtures at pH 7.

[0061] Associations of SAMe with Lysine and Potassium citrate were excluded from the palatability test because the amounts of neutralizing agent required are considered excessive (Lysine does not neutralize the acid solution even at 15.4 g) for pharmaceutical forms for oral intake too.

[0062] All the sachets thus obtained were made to taste by 8 people, without them knowing what the neutralizing agent contained in each sachet was.

[0063] The volunteers were asked to express an evaluation from 0 to 5, where zero is the lowest score (unpleasant) and 5 the highest score (pleasant), with respect to the following parameters: first feeling, dissolution in the mouth, aftertaste after final dissolution, bitterness, acidity, exothermia, effervescence.

[0064] More specifically, scores were given as follow: [0065] First feeling: zero (Unpleasant)-five (Pleasant) [0066] Dissolution in the mouth: Zero (Slightly soluble—Unpleasant)-Five (Very soluble—Pleasant) [0067] Aftertaste after final dissolution: Zero (Unpleasant)-Five (Pleasant) [0068] Bitterness: Zero (Unpleasant—Very bitter)-Five (Pleasant—Slightly bitter) [0069] Acidity: Zero (Unpleasant—Very acid)-Five (Pleasant—Slightly acid) [0070] Exothermia: Zero (Strong exothermic feeling)-Five (Absence of exothermic feeling) [0071] Effervescence: NO (Absence of effervescence)-YES (Presence of effervescence)

[0072] The evaluation of the test 13919-4 (SAMe—Sodium Phosphate Tribasic) gave a result of zero (0) due to an intense caustic feeling when in contact with the oral mucosa which did not allow further evaluations.

[0073] The average of the scores obtained are reported in the table below.

TABLE-US-00011 TABLE 10 Legend of samples used TEST ID ACTIVE BUFFERING AGENT PR-13919-1 SAMe L-ARGININE PR-13919-2 SAMe SODIUM BICARBONATE PR-13919-3 SAMe SODIUM BICARBONATE PR-13919-4 SAMe SODIUM PHOSPHATE TRIBASIC PR-13919-5 SAMe MAGNESIUM OXIDE

TABLE-US-00012 TABLE 11 Palatable SAMe Taste test for samples described in Table 10 (average evaluation form 8 volunteers) PALATABLE SAMe EVALUATION FORM Taste tests PR-13919-1 PR-13919-2 PR-13919-3 PR-13919-4 PR-139191-5 FIRST FEELING 3.125 1 1 0 0.25 DISSOLUTION IN 4 3.25 2.5 0 0.5 THE MOUTH AFTERTASTE AFTER 3.75 1.375 1 0 0.625 FINAL DISSOLUTION BITTERNESS 3.125 1.5 1.25 0 0.625 ACIDITY 3.5 1.5 1.5 0 0.75 EXOTHERMIA 2.75 1.625 2 0 0.625 EFFERVESCENCE NO YESì YES NO NO

Example 5

Stability Test for Combinations SAMe+Buffering Agents.

[0074] To test the good stability of the association SAMe and L-Arginine, and compare it with the stability of the other buffering agents, the mixtures used in Example 3 were placed in a climatic chamber within heat-sealed aluminum bags, at climatic conditions of 50° C. for 5 days, to test the stability of the mixtures.

[0075] The control parameters were: [0076] Appearance [0077] % H.sub.2O determined by KF (Karl Fischer) method [0078] Active assay [0079] Degradation substances

[0080] Table 12 shows that not all buffering agents ensure proper stability of the active ingredient.

TABLE-US-00013 TABLE 12 BATCH: 13919-4 PR.1 BATCH: 13919-4 PR.2 BATCH: 13919-4 PR.3 BATCH: 13919-4 PR.4 BATCH: 13919-4 PR.5 TIME STEP 1: TIME STEP 1: TIME STEP 1: TIME STEP 1: TIME STEP 1: ANALYSIS ZERO 5 ZERO 5 days ZERO 5 days ZERO 5 days ZERO 5 days APPEARANCE White Unchanged White Unchanged White Unchanged White Unchanged White Unchanged powder powder powder powder powder % H.sub.2O K.F  1.581% 1.681% N.D * N.D* N.D* N.D*  3.934% 4.106%  2.030% N.D ASSAY 30.30% 29.29% 36.56% 30.53% 19.70% 14.07% 23.79% 21.53% 49.84% 48.39% (−3%) (−16%) (−28.6%) (−9%) (−2.9%) DEGRAD. 0.61% A 3.15% A 1.05% A 4.85% A 1.25% A 4.94% A 2.68% A 7.45% A 1.03% A 3.27% A SUBST. (0.05 P/P) (0.25 P/P) (0.11 P/P) (0.43 P/P) (0.07 P/P) (0.19 P/P) (0.21 P/P) (0.45 P/P) (0.14 P/P) (0.42 P/P) LOD 45° C. × — —  1.23% 1.00%  0.68% 0.45% — —  0.75% 0.80% 20′ STABILITY: STABILITY: STABILITY: STABILITY: STABILITY: NON- CRITICAL CRITICAL NON- NON- CRITICAL CRITICAL CRITICAL

Example 6

Stability Test on SAMe+Arginine Swallowable Tablet

[0081] To further confirm the stabilizing effect of Arginine on active ingredients with acid pKa, a stability test was performed on a swallowable tablet of SAMe and Arginine according to Example no. 8.

[0082] The tablet was obtained using standard equipment known to the person skilled in the art following a process of weighing, mixing, and pressing the mixture.

[0083] The tablets thus obtained in Example no. 8 were placed in a climatic chamber within heat-sealed aluminum bags, under climatic conditions of 50° C. for 5 days to test the tablets stability by monitoring the parameters at T0, T2, T5

[0084] The control parameters were: [0085] Appearance [0086] % H.sub.2O determined by KF (Karl Fischer) method [0087] Active assay [0088] Degradation substances

[0089] Table 13 demonstrates that tablets thus obtained show an excellent stability profile thanks to the presence of arginine as a stabilizer.

TABLE-US-00014 TABLE 13 BATCH: 3520-1B ANALYSIS TIME ZERO STEP 1: 5 STEP 1: 5 APPEARANCE White Tablet Unchanged Unchanged % H.sub.2O K.F 0.819% 0.799% 0.837% ASSAY 205.53 mg/cpr 197.13 mg/cpr 197.40 mg/cpr (−4.1%) (−4%) DEGRAD. SUBST. 1.08% A 2.92% A 6.04% A STABILITY: NON-CRITICAL