WO2020244798A1 - Method for taste/odor masking of a product for chronic kidney disease patients - Google Patents

Abstract

The present invention relates to a method for taste/odor masking of a product for chronic kidney disease patients, in particular of compositions containing essential amino acids and/or alpha-ketoanalogues of essential amino acids and/or alpha-hydroxyanalogues of essential amino acids, to corresponding pharmaceutical compositions and their nutritional, therapeutic or prophylactic uses. A phosphatidylcholine-based method is disclosed.

Description

Method for taste/odor masking of a product for chronic kidney disease patients

The present invention relates to a method for taste/odor masking of a product for chronic kidney disease patients, in particular of compositions containing essential amino acids and/or alpha-ketoanalogues of essential amino acids and/or alpha-hydroxyanalogues of essential amino acids, to corresponding pharmaceutical compositions and their nutritional, therapeutic or prophylactic uses. A phosphatidylcholine-based method is disclosed.

It has been known for decades that a low-protein diet (LPD) is beneficial for patients with advanced chronic kidney disease, respectively end-stage renal disease (CKD, respectively ESRD). LPD is thought to ameliorate the uremic symptoms and to slow the progression of renal dysfunction. Nitrogen from nitrogen-containing substances such as amino acids is eliminated from the organism mostly via the formation of urea as product of the urea cycle. In CKD patients the urea elimination is increasingly impaired. Therefore, the rationale is to reduce the protein amount of the food intake for keeping the urea load low. However, LPD often leads to a deficiency of certain essential amino acids. This is even more pronounced in specific dietary variants such as very low-protein diet (VLPD). To overcome this deficiency LPD or VLPD can be complemented by supplementation of alpha-ketoanalogues (KA) of these deficient essential amino acids. It could be shown that these alpha-ketoanalogues are converted into the respective essential amino acids by transaminases. These transaminases transfer the amino group of endogenous amino acids to the alpha-ketoanalogues by replacing their alpha-keto group, while said endogenous amino acids are converted to the respective alpha-keto acids. In an advanced variant of KA diet some of the scarcest essential amino acids (EAA) are supplemented additionally to said alpha-ketoanalogues for compensating their deficiency due to LPD or VLPD. Such a dietary combination (KA/EAA diet) showed to be successful during CKD stages II, III and IV (cf. Clinical Practice

Guidelines. For Chronic Kidney Disease: Evaluation, Classification and Stratification (2002) National Kidney Foundation. Table 3). The time of initiation when CKD patients are forced to undergo regular dialysis treatment, respectively to wait for a kidney transplant, due to continuously aggravating CKD can be deferred by LPD or VLPD by 1 to 1.5 years. This is valuable time for these patients during which they are not subjected to a strict dialysis regimen and during which they have a chance that a suitable donor for a kidney transplant is found. In the end, they may win over 1 year of life time. The critical parameter below which dialysis treatment becomes mandatory is a glomerular filtration rate (GFR) < 15 ml/min (CKD stage V). In comparison, a healthy subject with normal blood pressure has a GFR of 120 ml/min. While a CKD patient is already under hemodialysis, a larger daily interval between dialysis sessions can be upheld for some time with KA/EAA diet.

A further positive effect of LPD or VLPD is that it helps to keep the dialysis shunt open.

Preferably, a native arteriovenous fistula (AVF) is used as dialysis shunt. This is not always possible due to AVF maturation failure and a continuously deteriorating shunt stenosis. A shunt stenosis is a major reason why in CKD patients hemodialysis must be discontinued after ca. 5 years. If no kidney transplantation is possible these patients face a poor survival rate. ESRD predialysis patients under a VLPD regime with KA/EAA were found to show an improved AVF maturation and vascular wall elasticity. This enables the AVF to dilate easily upon increased flow and shear stress due to hemodialysis and to delay shunt stenosis (David et al. (2016) BMC Nephrology 17: 131 ).

A problem for the patient in KA/EAA diet is the daily dosage. 100 mg / kg body weight, respectively 1 tablet / 5 kg body weight are recommended in average (cf. http://de.remedv- info.com/ketosteril.html, as of November 6^th 2018). Since this is a permanent medication oral dosage forms are strongly preferred. This means that an average 70 kg person should ingest about 4 - 8 large-size capsules or film-coated tablets thrice daily. For the patients this is very cumbersome and uncomfortable, in particular for children, the elderly, persons with cognitive impairment or persons with swallowing problems. Consequently, patient compliance is rather low. Thus, there is a medical need for a water-soluble liquid oral formulation for KA/EAA diet. The alpha-ketoanalogues and the essential amino acids are perfectly water-soluble. The problem is their strongly repugnant and disgusting taste, scientifically more precisely their odor. Even if they are released from a formulation only after passing through the buccal cavity there is regularly a strong emanation that strikes back through the esophagus via regurgitation. This foul smell is due to the high content of primary amines. The taste, respectively odor is described as a mixture of ammonia and of rotting meat or fish and other unidentifiable disgusting components. Many people claim that this is one of the most disgusting tastes (odors) they have ever experienced. There were a number of efforts to cover, respectively to mask this taste (odor), but hitherto without a satisfactory outcome. Some methods known in the art add good tasting or scenting ingredients without masking the KA/EAA odor, other methods of the art can mask only partially the aversive odor. Therefore, such a liquid oral formulation is not available on the market.

This problem does not affect only humans but also animals with chronic kidney diseases, such as cats and dogs. While herbivores are not so much affected by uremia because of their habitual low-protein food it is a major problem for carnivores. The feeding habits from dogs can be partially shifted to a rather low-protein diet. But this is a serious problem in cats because of their natural need of exogenous amino acid supply by meat-based staples. Therefore, both have a need for KA/EAA supplementation. The aversive taste and odor of liquid KA/EAA solutions added to their food, however, causes them to avoid such food.

Therefore, it was the task of the present invention to provide a method by which a KA and/or EAA composition can be provided in a liquid oral formulation, wherein this aversive taste (odor) is masked or at least strongly reduced so that the sensual impairment becomes bearable for the patients.

Surprisingly, this task could be solved by the method of the invention.

This method for taste/odor masking of a product for chronic kidney disease patients comprises the following steps: a) Providing a first composition comprising at least one essential amino acid and/or at least one alpha-ketoanalogue of an essential amino acid and/or at least one alpha-hydroxyanalogue of an essential amino acid,

and mixing said first composition;

b) Providing a second composition comprising

at least one non-hydrogenated phosphatidylcholine in the overall range of 20 % to 80 % per weight,

at least one medium-chained triglyceride in the overall range of 10 % to 70 % per weight,

at least one non-hydrogenated lysophosphatidylcholine in the overall range of 1 % to 15 % per weight,

at least one C2 to C₄ alcohol in the overall range of 1 % to 20 % per weight, and at least one of glyceryl stearate and/or a saturated or unsaturated C₁₄ to C₂₀ fatty acid in the overall range of 0.5 % to 10 % per weight, respectively,

wherein the relative weight percentages of all ingredients add up to 100 % and all taste/odor masking agents are independently from one another a food additive and/or a pharmaceutically acceptable excipient,

and mixing said second composition;

c) Providing an aqueous solution;

d) Mixing said first composition and said second composition,

thus generating a third composition;

e) Mixing said third composition to said aqueous solution by application of force, thus generating a final solution; wherein the method is carried out at room temperature, the weight ratio of non-hydrogenated phosphatidylcholines to non-hydrogenated lysophosphatidylcholines in the second composition is in the range of 5:1 to 20:1 , the weight ratio of the first composition to the second composition is in the range of 4:1 to 12:1 , and the volume ratio of the aqueous solution to the third composition is in the range of 30:1 to 350:1.

In another embodiment of the method of the invention said steps d) and e) are varied: d) Mixing said first composition and said aqueous solution, thus generating a third composition;

e) Mixing said third composition with said second composition by application of force, thus generating a final solution;

In yet another embodiment of the method of the invention said steps d) and e) are varied: d) Mixing said second composition and said aqueous solution, thus generating a third composition;

e) Mixing said third composition with said first composition by application of force, thus generating a final solution;

Preferred is the first of these three embodiments. It showed the best results (see Examples).

According to the invention, the term“first composition” refers to a composition that comprises all substances intended to apply for a KA/EAA diet to a person in need thereof. In specific embodiments this term may further include all food additives and/or pharmaceutically acceptable excipients provided together with the KA/EAA substances in form of a dry powder.

According to the invention, the term“second composition” refers to a composition that comprises all substances intended for the taste/odor masking of the KA/EAA substances. In specific embodiments this term may further include all food additives and/or pharmaceutically acceptable excipients provided together with the taste/odor masking substances in liquid form or solubilized in the liquid taste/odor masking agents.

According to the invention, the term“aqueous solution” refers to any aqueous solution with a weight percentage of H2O > 90%, preferred > 95%, more preferred > 98%, most preferred > 99%. It is understood that all other agents should be either food additives or

pharmaceutically acceptable. In general, the aqueous solution according to the invention is tap water or mineral water, with or without gas. In further embodiments, it could be also purified water, water for injection, a soft drink, fruit juice, coffee, tea, hot chocolate or light alcoholic beverages or other common beverages. According to the invention, the term“third composition” refers to a mixture of the first composition according to the invention with the second composition according to the invention in any ratio disclosed in the scope of the present application.

According to the invention, the term“final solution” refers to a mixture of the third composition according to the invention with the aqueous solution according to the invention in any ratio disclosed in the scope of the present application. The final solution is the liquid dosage form that a person in need thereof will imbibe. The final solution corresponds to the product of the method according to the invention.

According to the invention, the term“mixing it by application of force” refers to any standard mixing procedure that goes beyond a simple blending and stirring. In general, said mixing procedure generating the final solution takes place in a drinking bottle. In such a case the mixing by application of force is effected by vigorously shaking the bottle for a few seconds until a clear solution is reached. However, the dissolution can also be effected by vigorously stirring the mixture by hand or with a mixer, with a magnetic stirrer, by application of ultrasound or by any mixing method known in the art.

A worldwide leading product for the supplementation of LPD / VLPD with a composition of essential amino acids, alpha-ketoanalogues of essential amino acids and an alpha- hydroxyanalogue of essential amino acids is Ketosteril^® from Fresenius Kabi, Bad Homburg, Germany. The composition is provided as film-coated tablets.

One film-coated tablet contains the following amounts of essential amino acids and alpha- ketoanalogues of essential amino acids:

(RS)-3-methyl-2-oxovaleric acid calcium salt 67 mg (= alpha-ketoanalogue to DL-isoleucine)

4-methyl-2-oxovaleric acid calcium salt 101 mg (= alpha-ketoanalogue to leucine)

2-oxo-3-phenylpropionic acid calcium salt 68 mg (= alpha-ketoanalogue to phenylalanine)

3-methyl-2-oxobutyric acid calcium salt 86 mg (= alpha-ketoanalogue to valine)

(RS)-2-hydroxy-4-methylthio-butyric acid calcium salt 59 mg (= alpha-hydroxyanalogue to DL-methionine)

L-lysine acetate 105 mg

L-threonine 53 mg

L-tryptophan 23 mg

L-histidine 38 mg L-tyrosine 30 mg

A similar product is Shire’s Alfa Kappa^® which is available in Italy only. The KA/EAA composition of their pills differs only in that L-tryptophan is waived. The amounts of all other KA/EAA per pill are the same as in Ketosteril^®.

Further KA known in the art for LPD supplementation are, without being limiting: Alpha- ketoanalogue of ornithine, alpha-ketoanalogue of lysine, alpha-ketoanalogue of histidine.

A further amino acid known in the art for LPD supplementation is, without being limiting, L- ornithine.

More useful applications of Ketosteril^® are amino acid deficiency, incontinence, allergies, depression, asthma, paracetamol poisoning, paracetamol overdosage, copper poisoning, radiation side effects, alcoholism, diaper rashes (https://www.tabletwise.com/ketosteril-tablet: as of October 26^th 2018).

Further beneficial uses for KA, KA/EAA or amino acid diet supplementation of various composition are, without being limiting, chronic liver disease and hepatic encephalopathy (branched chain amino acids (BCCA) such as alpha-ketoanalogues of leucine, isoleucine and valine (O’Keefe et al. (1987) J Parenter Enteral Nutr 11 : 447-453; Amino Acids:

Chemistry, Biology and Medicine (1990) ed. Lubec and Rosenthal, Springer) and certain muscle dystrophies such as Duchenne muscular dystrophy and Becker muscular dystrophy (DMD; BCAA supplementation; cf. Stewart et al. (1982) Muscle & Nerve 5: 197-201 ).

Different supplemental amino acid compositions are used in a diet for phenylketonuria (phenylalanine-free amino acid diet; cf. MacLeod and Ney (2010) Ann Nestle 68: 58-69) and homocystinuria (low-methionine diet, cysteine supplementation; cf, Tϋzϋh (2010) J Turk Acad Dermatol 4: 041021 r).

In cats, taurine is an essential non-proteinogenic amino acid. It is a natural constituent of meat and fish and thus included in a usual cat staple. However, when a low-protein diet is fed to a cat taurine needs to be substituted. Therefore, a specific embodiment for cats includes also taurine in the first composition according to the invention.

In humans, taurine is a popular dietary supplement, e.g. in energy drinks or specific dietary supplement compositions where it serves as a nervous system depressant in order to counterbalance some overshooting effects of caffeine, to generate anxiolytic, cytoprotective and neuroprotective effects and is thought to be beneficial in cardiovascular disorders, inflammatory diseases, diabetes and muscle dystrophies such as Duchenne muscle dystrophy (cf. Schaffer and Kim (2018) Biomol Ther 26: 225-241 ). Taurine absorption by food is 200 - 400 mg/d in a healthy human. However, dietary supplements provide up to 2,000 mg / serving. Therefore, in a further embodiment taurine is included in the first composition.

Therefore, the ingredients of the first composition are selected from a group comprising the aforementioned at least one essential amino acid and/or at least one alpha-ketoanalogue of an essential amino acid and/or at least one alpha-hydroxyanalogue of an essential amino acid.

The term“mixing said first composition” refers to a simple blending of the selected ingredients for the first composition according to the invention. These substances use to be easily miscible. Said first composition is usually a dry powder at room temperature.

Phosphatidylcholines are a class of phospholipids linked to choline. They are a major component of cell membranes and are for example obtained from egg yolk, ox liver, marine animals, krill oil or soybeans. In practice, it showed that the origin of phosphatidylcholines influences their biological and chemical effects considerably. According to the invention the at least one phosphatidylcholine (PC) can be selected from the group comprising 1-palmitoyl- 2-oleoyl-sn-glycero-3-phosphocholine (POPC), natural (non-hydrogenated) soy bean PC, natural egg PC, dipalmitoyl phosphatidylcholine (DPPC), dimyristoyl phosphatidylcholine (DMPC) or 1 ,2-dioleyl-SN-glycero-3-phosphocholine (DOPC), 1-oleoyl-palmitoyl

phosphatidylcholine (OPPC), diasteroyl phosphatidylcholine (DSPC),

monostearoylphosphatidylcholine (MSPC), diarachidoylphosphatidylcholine (DAPC), corn lecithin, cottonseed oil lecithin, rapeseed lecithin, phosphatidylethanolamine,

phosphatidylserine, phosphatidylinositol, phosphatidylinositol polyphosphates,

phosphatidylglycerol, phosphatidic acid, phosphatidylinositolamine, diphosphatidylglycerol (cardiolipin), sphingomyelin, ceramide aminoethylphosphonic acid, ceramide

phosphorylglycerol, dicetylphosphoric acid, stearylamine, and mixtures thereof. Preferred are non-hydrogenated phosphatidylcholines. Also preferred are non-hydroxylated

phosphatidylcholines. Particularly preferred are non-hydrogenated and non-hydroxylated phosphatidylcholines. Thus, particularly preferred phosphatidylcholines are non- hydrogenated soybean PC, DMPC, POPC and DOPC. Most preferred is non-hydrogenated soybean PC.

Lecithin is a common generic term for phosphatidylcholines. It is a mixture of

phosphatidylcholine and other compounds.

According to the method of the invention phosphatidylcholines are used in the overall range of 20 % to 80 % per weight of the second composition, preferred 40 % to 70 % per weight of the second composition, more preferred 50 % to 65 % per weight of the second composition and most preferred 60 % per weight of the second composition. Medium-chained triglycerides (MCT) refer to triglycerides whose fatty acids have an aliphatic tail of 6 - 12 carbon atoms. Fatty acids incorporated in MCT are called medium-chain fatty acids (MCFA). In triglycerides three fatty acid molecules are bound to a glycerol backbone. Per definition, in MCT at least two of these three fatty acids must be MCFAs. According to the invention MCFA can be selected independently from one another from the group comprising caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecilyc acid, lauric acid, their unsaturated derivatives, and mixtures thereof. Preferred MCFA are caproic acid, caprylic acid, capric acid, and lauric acid.

It can be advantageous in some embodiments of the invention to use triglycerides containing 1 to 3 myristic acid and/or palmitic acid residues instead of MCFAs. Hence, these two fatty acids shall be subsumed under the term MCT according to the invention too.

MCT oils or MCT fats are oils or fats containing predominantly said MCT. These terms refer to a respective mixture of different MCT that may contain a variety of MCFA. According to the invention any reasonable mixing ratio shall be covered by these terms. MCT fats are often extracted from specific plants, while MCT oils do not occur naturally. MCT oils and MCT fats are broadly marketed as healthy dietary supplements, respectively as a surrogate for long- chain fats in nutrition.

According to the method of the invention MCT are used in the overall range of 10 % to 70 % per weight of the first composition, preferred 20 % to 40 % per weight of the second composition, more preferred 25 % to 35 % per weight of the second composition and most preferred 30 % per weight of the second composition.

Lysophosphatidylcholines (LPC, lysoPC, also: lysolecithins) are a class of derivatives of phosphatidylcholines, resulting of their partial hydrolysis in which one of the fatty acid groups is removed. In the organism this hydrolysis is catalyzed by the enzyme phospholipase A2. According to the invention the at least one lysophosphatidylcholine added can be selected independently from one another from the group comprising all hydrolyzed compounds of the phosphatidylcholines listed above, 1 -lysophosphatidylcholines (2-acyl-sn-glycero-3- phosphocholines), 2-lysophosphatidylcholines, L-alpha-lysophosphatidylcholine, the respective lysoPC derivatives from natural lecithins such as soybean lecithin, egg-yolk lecithin, corn lecithin, cottonseed oil lecithin, and rapeseed lecithin, as well as

phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylinositol polyphosphate, phosphatidylglycerol, phosphatidic acid, phosphatidylinositolamine, diphosphatidylglycerol (cardiolipin), and mixtures thereof. Preferred are non-hydrogenated lysophosphatidylcholines. Also preferred are non-hydroxylated lysophosphatidylcholines. Particularly preferred are non-hydrogenated and non-hydroxylated lysophosphatidylcholines. According to the method of the invention lysophosphatidylcholines are used in the overall range of 1 % to 15 % per weight of the first composition, preferred 3 % to 8 % per weight of the second composition, more preferred 5 % to 7 % per weight of the second composition and most preferred 6 % per weight of the second composition.

According to the invention the at least one C₂ to C₄ alcohol (lower alcohol) can be selected from the group comprising ethanol, propanol, isopropanol, butane-1 -ol, butane-2-ol, isobutanol (2-methyl-1 -propanol), ethylene glycol (ethane-1 ,2-diol), alpha-propylene glycol (propane-1 ,2-diol), beta-propylene glycol (propane-1 -3-diol), 1 ,2-butylene glycol (butane-1 ,2- diol), 1 ,3-butylene glycol (butane-1 , 3-diol), 1 ,4-butylene glycol (butane-1 , 4-diol), and diethylene glycol. Preferred is ethanol.

According to the method of the invention C₂ to C₄ alcohols are used in the overall range of 1 % to 20 % per weight of the second composition, preferred 2 % to 10 % per weight of the second composition, more preferred 3 % to 8 % per weight of the second composition and most preferred 5 % per weight of the second composition.

Glyceryl stearate (glycerol monostearate, GMS) is an emulsifier that helps to stabilize the oily components in the second composition. The flaky powder is also hygroscopic. GMS is also used as thickening, emulsifying, anti-caking, anti-staling and preservative agent.

According to the invention the at least one saturated or unsaturated C₁₄ to C₂₀ fatty acid can be used instead of or in combination with glyceryl stearate. It can be selected from the group comprising myristic acid (14:0), pentadecanoic acid (15:0), palmitic acid (16:0),

heptadecanoic acid (17:0), stearic acid (18:0), nonadecanoic acid (19:0), arachidic acid (20:0), myristoleic acid (14:1 ,cis-A⁹), palmitoleic acid (16:1 , cis-D⁹), sapienic acid (16:1 , cis- D⁶), hexadecatrienoic acid (16:3, (n-3), oleic acid (18:1 , cis-D⁹), elaidic acid (18:1 , trans-D⁹), vaccenic acid (18:1 , trans-D¹¹), linoleic acid (18:2; cis,cis-A⁹,A¹²), linoleadic acid (18:2, trans,trans-A⁹,A¹²), oc-linolenic acid (18:3, cis,cis,cis-A⁹,A¹² ,A¹⁵), g-linolenic acid (18:3, (co-3)), calendic acid (8E,10E,12Z-octadecatrienoic acid), stearidonic acid (18:4 (n-3)), dihomo-g- linolenic acid (20:3; (co-6)), eicosadienoic acid (20:2, (n-6)), eicosatrienoic acid (20:3, (n-3)), eicosatetraenoic acid (20:4, (n-3)), arachidonic acid (20:4, cis,cis,cis,cis-A⁵, D⁸,D¹¹,D¹⁴), eicosapentaenoic acid (20:5, cis,cis,cis,cis,cis-A⁵, D⁸,D¹¹,D¹⁴,D¹⁷). Preferred are even- numbered Ci4 to C₂₀ fatty acids. Particularly preferred is oleic acid.

According to the method of the invention glyceryl stearate and/or a saturated or unsaturated Ci4 to C2₀ fatty acid are used in the overall range of 0.5 % to 10 % per weight of the second composition, preferred 1 % to 8 % per weight of the second composition, more preferred 2 % to 6 % per weight of the second composition and most preferred 3 % per weight of the second composition. Therefore, the ingredients of the second composition according to the invention are selected independently from one another from the groups listed above.

The term“mixing said second composition” refers to a simple blending and stirring of the selected ingredients for the first composition according to the invention. These substances use to be easily miscible. Said second composition is usually a clear solution at room temperature.

In the scope of the present application said lysophpsphatidylcholines are not a mere variant or substitute for phosphatidylcholines but fulfill an independent role. Surprisingly, it was found that two self-emulsifying agents of similar but not identical chemical constitution can significantly improve the taste/odor masking effect, if used in an uneven ratio. Control experiments without lysophosphatidylcholines in which their relative weight percentage was substituted by a correspondingly higher amount of phosphatidylcholines only led to second compositions according to the method of the invention having a higher viscosity. They had an appearance of a greasy stodge and could not be properly mixed with the second or third composition according to the method of the invention. Thus, the lysophosphatidylcholines act as a co-masking agent in the scope of the method of the invention. According to the invention the weight ratio phosphatidylcholine to lysophosphatidylcholine in the first composition according to the method of the invention is from 5:1 to 20:1 , more preferred 7:1 to 15: 1 , most preferred 10:1.

An advantage of the method of the invention is that it can be carried out at room

temperature. This allows for example an instant mixing of the respective compositions according to the invention at room temperature by medical staff or the patients themselves.

The weight ratio of the first composition according to the invention to the second composition according to the invention is in the range of 4:1 to 12:1 , preferred 6.1 to 10:1 , most preferred 8:1.

While the first composition according to the invention is a dry powder the second composition according to the invention is a clear solution at room temperature. The relative density of the second composition according to the invention is in the range of 0.92 to 0.94. Thus, the relative density of a specific second composition according to the invention can be easily determined by a person skilled in the art. Based on this result a person skilled in the art can easily convert a volume into a weight for setting said weight ratio disclosed above.

According to the invention, the volume ratio of the third composition to the aqueous solution is in the range of 30:1 to 350:1 , preferred 35:1 to 150:1 , most preferred 40:1 to 75:1. A minimum range of 30:1 is needed for generating a final solution in which the aversive taste/odor of the KA/EAA is masked. It is obvious to a person skilled in the art that the maximum range (maximum dissolution) is only limited by the volume a person in need thereof is able to imbibe during a single administration, respectively per day.

The method according to the invention is usually carried out at room temperature. However, in alternative embodiments it may be also possible to heat any of the compositions or solutions according to the invention mildly, provided that the heating temperature does not exceed 28°C.

All embodiments of the method according to the invention can be performed at a pressure of 0.2 bar to 1 bar. It is preferred, however, to run the method at 1 bar (atmospheric pressure). For certain applications it may be preferable to use a light vacuum. The technical equipment for applying, maintaining and controlling such a light vacuum is well known in the art.

The second composition according to the method of the invention maintains its clearness and stability over a period of minimum 4 months. It can be stored over this time and used on demand. The first composition according to the method of the invention is usually a dry powder, respectively a granulate. It can be stored over a minimum period of 6 months.

However, it is preferred that it is stored in an air-insulated manner and protected against heat and/or UV radiation. The final solution according to the method of the invention stays stable over a minimum of one day, often longer. During this time frame it can be consumed by a patient in need thereof, all at once or in portions. The taste/odor masking effect of the method of the invention is maintained over this minimum period.

However, for augmenting the shelf life, respectively the time frame for consumption of the compositions, respectively the aqueous solution produced by the method of the invention at least one antioxidant can be added to the respective compositions or solutions. In preferred embodiments this at least one antioxidant is a food additive and/or a pharmaceutically acceptable excipient. Suitable antioxidants can be selected from the group comprising lactic acid, ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, fatty acid esters of ascorbic acid, ascorbyl palmitate, ascorbyl stearate, tocopherols, alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, delta-tocotrienol, propyl gallate, octyl gallate, dodecyl gallate, ethyl gallate, guaiac resin, erythorbic acid, sodium erythorbate, tert-butylhydroquinone, butylated hydroxyanisole, butylated hydroxytoluene, mono-, di-, trisodium phosphate, mono-, di-, tripotassium phosphate, anoxomer, ethoxyquin, potassium lactate, stannous chloride, sodium thiosulfate, 4-hexylresorcinol, glucose oxidase. Preferred are ascorbyl palmitate and alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol. Particularly preferred is a combination of ascorbyl palmitate and at least one of alpha-tocopherol, beta- tocopherol, gamma-tocopherol, delta-tocopherol. According to the method of the invention this at least one antioxidant can be optionally included or added to any of the compositions or solutions according to the method of the invention in the overall range of 0.01 % to 10 % per weight, preferred 0.1 % to 5 % per weight, more preferred 0.2 % to 1% per weight and most preferred 0.3 % to 0.5 % per weight. In a preferred embodiment this at least one antioxidant is added to the mixture of the taste/odor masking agents of the second composition according to the method of the invention.

With the method of the invention it is possible to generate a final solution according to the invention that has a neutral taste or evokes only a slight taste/odor impairment in a person in need of a KA/EAA diet. This depends on the individual taste/odor sensitivity, the volume of the aqueous solution according to the invention and the specific ingredients of the first composition according to the invention and of the second composition according to the invention and their relative weight ratio.

Even better results in respect of taste/odor masking can be achieved when at least one flavoring agent is added either to the first composition according to the invention, the second composition according to the invention, the aqueous solution according to the invention, the third composition according to the invention and/or the final solution according to the invention. This at least one flavoring agent should be a food additive and/or a

pharmaceutically acceptable excipient.

Suitable flavoring agents comprise above all essential oil that can be used for this purpose.

In general, this term refers to volatile extracts from plants or parts of plants with the respective characteristic smell. They can be extracted from plants or parts of plants by steam distillation.

Examples are: Essential oils, respectively aromatic substances from sage, cloves, chamomile, anise, star anise, thyme, tea tree, peppermint, mint oil, menthol, cineol, eucalyptus oil, mango, figs, lavender oil, chamomile blossoms, pine needles, cypress, oranges, rosewood, plum, currant, cherry, birch leaves, cinnamon, limes, lemons, grapefruit, tangerine, banana, juniper, valerian, lemon balm, lemon grass, palmarosa, cranberry, pomegranate, rosemary, ginger, pineapple, guava, echinacea, ivy leave extract, blueberry, kaki, melons etc. or mixtures thereof, as well as mixtures of menthol, peppermint and star anise oil or menthol and cherry flavor.

These aromatic or flavoring substances can be included in the range of 0.0001 to 10 % per weight, preferred 0.001 to 6% per weight, more preferred 0.001 to 4% per weight, most preferred 0.01 to 1% per weight, with regard to any of the compositions or solutions according to the invention. Application- or single case-related it may be advantageous to use differing quantities.

A further advantage of the method of the invention consists in the small volumes needed.

The first composition according to the method of the invention and/or the second composition according to the method of the invention can be easily portioned to patient-friendly units, or relatively huge numbers of these packed compositions can be shipped and/or stored at low costs.

In another aspect the present application refers also to the final solution resulting from the taste/odor masking method according to the invention:

A final solution comprising a first composition of at least one essential amino acid, at least one alpha-ketoanalogue of an essential amino acid and/or at least one alpha-hydroxyanalogue of an essential amino acid as defined above, comprising:

at least one essential amino acid and/or at least one alpha-ketoanalogue of an essential amino acid and/or at least one alpha-hydroxyanalogue of an essential amino acid and the following taste/odor masking agents of the second composition:

a) at least one non-hydrogenated phosphatidylcholine in the overall range of 5 % to 60 % per weight;

b) at least one medium-chained triglyceride in the overall range of 2.5 % to 53 % per weight;

c) at least one non-hydrogenated lysophosphatidylcholine in the overall range of 0.25 % to 12 % per weight;

d) at least one C2 to C4 alcohol in the overall range of 0.25 % to 15 % per weight, and e) and at least one of glyceryl stearate or a saturated or unsaturated C14 to C20 fatty acid in the range of 0.1 % to 7.5 % per weight, respectively,

wherein the relative weight percentages of all ingredients refer to the second composition according to the method of the invention, the relative weight percentages of all ingredients add up to 100 %, all taste/odor masking agents are independently from one another a food additive and/or a pharmaceutically acceptable excipient and the weight ratio of non- hydrogenated phosphatidylcholines to non-hydrogenated lysophosphatidylcholines is in the range of 5:1 to 20:1 and an aqueous solution as defined above, wherein the weight ratio of the first composition to the second composition is in the range of 4:1 to 12:1 , and the volume ratio of the third composition to the second composition is in the range of 30:1 to 350:1. In a preferred embodiment the weight ratio of the first composition according to the invention to the second composition according to the invention is in the range of 6:1 to 20:1. In a more preferred embodiment the weight ratio of the first composition according to the invention to the second composition according to the invention is 8:1.

In a preferred embodiment the volume ratio of the third composition according to the invention to the second composition according to the invention is in the range of 35:1 to 150:1. In a more preferred embodiment the weight ratio of the third composition according to the invention to the second composition according to the invention is in the range of 40:1 to 75:1.

In a preferred embodiment the second composition according to the invention comprises the following taste/odor masking agents:

a) at least one non-hydrogenated phosphatidylcholine in the overall range of 1 0 % to 55 % per weight;

b) at least one medium-chained triglyceride in the overall range of 5 % to 30 % per weight;

c) at least one non-hydrogenated lysophosphatidylcholine in the overall range of 0.75 % to 7 % per weight;

d) at least one C2 to C4 alcohol in the overall range of 0.5 % to 7.5 % per weight, and e) and at least one of glyceryl stearate or a saturated or unsaturated C14 to C20 fatty acids in the range of 0.1 % to 4 % per weight, respectively,

wherein the relative weight percentages of all ingredients refer to the second composition according to the invention, the relative weight percentages of all ingredients add up to 100 %, all taste/odor masking agents are independently from one another a food additive and/or a pharmaceutically acceptable excipient and the weight ratio of non-hydrogenated

phosphatidylcholines to non-hydrogenated lysophosphatidylcholines is in the range of 7:1 to 15:1.

In a further preferred embodiment the second composition according to the invention comprises the following taste/odor masking agents:

a) at least one non-hydrogenated phosphatidylcholine in the overall range of 10 % to 50 % per weight;

b) at least one medium-chained triglyceride in the overall range of 6 % to 25 % per weight;

c) at least one non-hydrogenated lysophosphatidylcholine in the overall range of 2 % to 7 % per weight;

d) at least one C2 to C4 alcohol in the overall range of 1 % to 7 % per weight, and e) and at least one of glyceryl stearate or a saturated or unsaturated C to C₂o fatty acids in the range of 0.1 % to 5 % per weight, respectively,

wherein the relative weight percentages of all ingredients refer to the second composition according to the invention, the relative weight percentages of all ingredients add up to 100 %, all taste/odor masking agents are independently from one another a food additive and/or a pharmaceutically acceptable excipient and the weight ratio of non-hydrogenated

phosphatidylcholines to non-hydrogenated lysophosphatidylcholines is in the range of 7:1 to 15:1.

Particularly good results could be obtained when glyceryl stearate is used in a method according to the invention, respectively comprised in a composition according to the invention. Glyceryl stearate showed to be the best agent to significantly reduce the turbidity of a composition produced by a method according to the invention, respectively of a liquid dosage form upon generating an aqueous solution from said composition. Concomitantly, its refractive index is lowered. With the use of glyceryl stearate crystal clear solutions can be generated. This is a key factor for patient compliance. A further advantage of the use of glyceryl stearate is that upon storing a composition of the invention over a longer period of time crystallization can be widely avoided.

Therefore, the present application refers also to a final solution produced by the method according to the invention, wherein the second composition comprises glyceryl stearate.

The term food additive refers to substances that are added to food to preserve the flavor or enhance its taste and appearance. They bestow chemical, physical or physiological effects to the food for controlling its consistency, taste, color, chemical and microbiological durability, for regulating their practical and nutritional value or for ensuring efficient food production. They can be synthetic compounds or of natural origin. In virtually all countries they are strictly regulated. Each approved additive is assigned a unique number. In Europe this number is preceded by the prefix E.

According to the invention any of the compositions to the inventions or solutions according to the invention or its preferred embodiments may additionally contain an antioxidant as listed before in the overall range of 0.01 % to 10 % per weight, preferred 0.1 % to 5 % per weight, more preferred 0.2 % to 1 % per weight and most preferred 0.3 % to 0.5 % per weight.

In a particularly preferred embodiment of the final solution according to the invention said at least one saturated or unsaturated C_M to C20 fatty acid of the second composition according to the invention is oleic acid.

In a particularly preferred embodiment of the final solution according to the invention said at least one C₂ to C4 alcohol of the second composition according to the invention is ethanol. In the scope of the present application the term“medicine” shall comprise human and/or veterinary medicine.

The present application refers also to a final solution according to the invention for use in a pharmaceutical dosage form.

Moreover, the present application refers also to the use in medicine or veterinary medicine of a final solution according to the invention. In a preferred embodiment said final solution comprises glyceryl stearate.

In regulatory aspects a KA/EAA diet is classified differently by the authorities in various countries. For example, in Germany it is regarded as a supplement balanced diet. In the USA it is regarded as a dietary supplement. In China it is a medication. Therefore, different regulatory standards apply to such a product. There might be also a reclassification of such a product in the future.

Therefore, the present application refers also to the use of a final solution according to the invention as a medication, as a medical product, as a therapeutic nutritional, as a dietary supplement or as a supplement balanced diet.

In another aspect the present application refers also to the use of the final solution according to the invention, wherein the final solution is administered orally.

In another aspect the present application refers also to the use of the final solution according to the invention, wherein the orally administered final solution is a liquid dosage form.

In a further aspect the present application refers also to the use of the final solution according to the invention for delaying dialysis initiation in a patient in need thereof.

In yet another aspect the present application refers also to the use of the final solution produced by a method according to the invention for the manufacture of a therapeutic nutritional for a patient suffering from chronic kidney disease or amino acid deficiency.

In yet another aspect the present application refers also to the use of the final solution produced by a method according to the invention for the manufacture of a composition for treatment and/or prophylaxis of chronic kidney disease, amino acid deficiency, incontinence, allergies, depression, asthma, paracetamol poisoning, paracetamol overdosage, copper poisoning, radiation side effects, alcoholism, diaper rashes, chronic liver disease, hepatic encephalopathy, Duchenne muscular dystrophy, Becker muscular dystrophy, phenylketonuria or homocystinuria.

In yet another aspect the present application refers also to the use of the final solution produced by a method according to the invention for the preparation of a drinkable aqueous solution by adding said final solution according to the invention dropwise to a further pharmaceutically acceptable aqueous solution.

Moreover, the present application refers also to a pharmaceutical composition comprising a final solution according to the invention and at least one pharmaceutically acceptable excipient.

Thus, the present application refers also to a pharmaceutical composition according to the invention for use in medicine.

The term“pharmaceutical excipients” refers to natural or synthetic compounds that are added to a pharmaceutical formulation alongside the first composition according to the invention. They may help to bulk up the formulation, to enhance the desired pharmacokinetic properties or the stability of the formulation, as well as be beneficial in the manufacturing process. Advantageous classes of excipients according to the invention include carriers, binding agents, lubricants, glidants, colorants, buffers, preservatives, diluents, sweeteners, thickening agents, antiadherents, fillers and flavor enhancers.

It can be advantageous, respectively mandatory to add one or more pharmaceutically acceptable carrier to the first composition according to the invention. Eligible are all carriers known in the art and combinations thereof. They can be for example plant and animal fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talcum, zinc oxide. For liquid dosage forms and emulsions suitable carriers are for example solvents, solubilizing agents, emulsifiers such as water, ethanol,

isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butyl glycol, cotton seed oil, peanut oil, olive oil, castor oil, sesame oil, glycerol fatty acid esters, polyethyl glycols, fatty acid esters of sorbitan. Suspensions according to the invention may use carriers known in the art such as diluents (e.g. water, ethanol or propylene glycol), ethoxylized isostearyl alcohols, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline cellulose, bentonites, agar agar, tragacanth.

The term binding agents refers to substances that bind powders or glue them together, rendering them cohesive through granule formation. They serve as a“glue” of the

formulation. Binding agents increase the cohesive strength of the provided diluent or filler.

Suitable binding agents are for example starch from wheat, corn, rice or potato, gelatin, naturally occurring sugars such as glucose, sucrose or beta-lactose, sweeteners from corn, natural and synthetic gums such as acacia, tragacanth or ammonium calcium alginate, sodium alginate, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl carboxymethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, magnesium aluminum silicate, waxes and others. The percentage of the binding agent in a first composition according to the invention can range from 1 - 30 % by weight, preferred 2 - 20 % by weight, more preferred 3 - 10 % by weight and most preferred 3 - 6 % by weight.

Colorants are excipients that bestow a colorization to the composition of the drink, respectively the dosage form. These excipients can be food colorants. They can be adsorbed on a suitable adsorption means such as clay or aluminum oxide. The amount of the colorant may vary between 0.01 and 10 % per weight of the first composition, preferred between 0.05 and 6 % per weight, more preferred between 0.1 and 4 % per weight, most preferred between 0.1 and 1 % per weight.

Suitable food or pharmaceutical colorants are for example curcumin, riboflavin, riboflavin-5’- phosphate, tartrazine, alkannin, quinolone yellow WS, Fast Yellow AB, riboflavin-5’-sodium phosphate, yellow 2G, Sunset yellow FCF, orange GGN, cochineal, carminic acid, citrus red 2, carmoisine, amaranth, Ponceau 4R, Ponceau SX, Ponceau 6R, erythrosine, red 2G, Allura red AC, Indathrene blue RS, Patent blue V, indigo carmine, Brilliant blue FCF, chlorophylls and chlorophyllins, copper complexes of chlorophylls and chlorophyllins, Green S, Fast Green FCF, Plain caramel, Caustic sulphite caramel, ammonia caramel, sulphite ammonia caramel, Black PN, Carbon black, vegetable carbon, Brown FK, Brown HT, alpha-carotene, beta-carotene, gamma-carotene, annatto, bixin, norbixin, paprika oleoresin, capsanthin, capsorubin, lycopene, beta-apo-8’-carotenal, ethyl ester of beta-apo-8’-carotenic acid, flavoxanthin, lutein, cryptoxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, zeaxanthin, citranaxanthin, astaxanthin, betanin, anthocyanins, saffron, calcium carbonate, titanium dioxide, iron oxides, iron hydroxides, aluminum, silver, gold, pigment rubine, tannin, orcein, ferrous gluconate, ferrous lactate.

Flavor enhancers are widely used for liquid oral dosage forms. Suitable examples are glutamic acid, monosodium glutamate, monopotassium glutamate, calcium diglutamate, monoammonium glutamate, magnesium diglutamate, guanylic acid, sodium guanylate, disodium guanylate, dipotassium guanylate, calcium guanylate, inosinic acid, disodium inosinate, dipotassium inosinate, calcium inosinate, calcium 5’-ribonucleotides, disodium 5’- ribonucleotides, glycine, sodium glycinate, zinc acetate, gum benzoic, thaumatin,

glycyrrhizin, neohesperidine dihydrochalcone, glyceryl monoacetate, glyceryl diacetate.

Moreover, buffer solutions are preferred for liquid formulations, in particular for

pharmaceutical liquid formulations. The terms buffer, buffer system and buffer solution, in particular of an aqueous solution, refer to the capacity of the system to resist a pH change by the addition of an acid or a base, or by dilution with a solvent. Preferred buffer systems may be selected from the group comprising formate, lactate, benzoic acid, oxalate, fumarate, aniline, acetate buffer, citrate buffer, glutamate buffer, phosphate buffer, succinate, pyridine, phthalate, histidine, MES (2-(N-morpholino) ethanesulfonic acid, maleic acid, cacodylate (dimethyl arsenate), carbonic acid, ADA (N-(2-acetamido)imino diacetic acid, PIPES (4- piperazine-bis-ethanesulfonic acid), BIS-TRIS propane (1 ,3- bis[tris(hydroxymethyl)methylamino] propane), ethylene diamine, ACES (2-[(amino-2- oxoethyl)amino]ethanesulfonic acid), imidazole, MOPS (3-(N-morphino)-propanesulfonic acid, diethyl malonic acid, TES (2-[tris(hydroxymethyl)methyl]aminoethanesulfonic acid, HEPES (N-2-hydroxyethylpiperazine-N’-2-ethanesulfonic acid), as well as other buffers with a pKa between 3.8 and 7.7.

A further group of preferred buffers are inorganic buffers such as sulfate hydroxide, borate hydroxide, carbonate hydroxide, oxalate hydroxide, calcium hydroxide and phosphate buffers. Another group of preferred buffers are nitrogen-containing puffers such as imidazol, diethylene diamine and piperazine. Furthermore preferred are sulfonic acid buffers such as TES, HEPES, ACES, PIPES, [(2-hydroxy-1 ,1-bis-(hydroxymethyl)ethyl)amino]-1- propanesulfonic acid (TAPS), 4-(2-hydroxyethyl)piperazine-1 -propanesulfonic acid (EEPS), 4-morpholino-propanesulfonic acid (MOPS) and N,N-bis-(2-hydroxyethyl)-2- aminoethanesulfonic acid (BES). Another group of preferred buffers are glycine, glycyl- glycine, glycyl-glycyl-glycine, N,N-bis-(2-hydroxyethyl)glycine and N-[2-hydroxy-1 ,1- bis(hydroxymethyl)ethyl]glycine (tricine). Preferred are also amino acid buffers such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxy proline, N,N,N-trimethyllysine, 3-methyl histidine, 5-hydroxy- lysine, o-phosphoserine, gamma-carboxyglutamate, [epsilon]-N-acetyl lysine, [omega]-N- methyl arginine, citrulline, ornithine and their derivatives.

Preservatives for liquid oral dosage forms can be used on demand. They may be selected from the group comprising, but not limited to, sorbic acid, potassium sorbate, sodium sorbate, calcium sorbate, methyl paraben, ethyl paraben, methyl ethyl paraben, propyl paraben, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, heptyl p- hydroxybenzoate, sodium methyl para-hydroxybenzoate, sodium ethyl parahydroxybenzoate, sodium propyl para-hydroxybenzoate, benzyl alcohol, benzalkonium chloride, phenylethyl alcohols, cresols, cetylpyridinium chloride, chlorbutanol, thiomersal (sodium 2-(ethylmercurithio) benzoic acid), sulfur dioxide, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, potassium sulfite, calcium sulfite, calcium hydrogen sulfite, potassium hydrogen sulfite, biphenyl, orthophenyl phenol, sodium orthophenyl phenol, thiabendazole, nisin, natamycin, formic acid, sodium formate, calcium formate, hexamine, formaldehyde, dimethyl dicarbonate, potassium nitrite, sodium nitrite, sodium nitrate, potassium nitrate, acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, ammonium acetate, dehydroacetic acid, sodium dehydroacetate, lactic acid, propionic acid, sodium propionate, calcium propionate, potassium propionate, boric acid, sodium tetraborate, carbon dioxide, malic acid, fumaric acid, lysozyme, copper- (ll)-sulfate, chlorine, chlorine dioxide and other suitable substances or compositions known to the person skilled in the art.

Suitable sweeteners can be selected from the group comprising, but not limited to, mannitol, glycerol, acesulfame potassium, aspartame, cyclamate, isomalt, isomaltitol, saccharin and its sodium, potassium and calcium salts, sucralose, alitame, thaumatin, glycyrrhizin,

neohesperidine dihydrochalcone, neotame, aspartame-acesulfame salt, maltitol, maltitol syrup, lactitol, xylitol, erythritol.

Suitable thickening agents can be selected from the group comprising, but not limited to, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, dextrins, polydextrose, modified starch, alkaline modified starch, bleached starch, oxidized starch, enzyme-treated starch, monostarch phosphate, distarch phosphate esterified with sodium trimetaphosphate or phosphorus oxychloride, phosphate distarch phosphate, acetylated distarch phosphate, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated distarch adipate, acetylated distarch glycerol, distarch glycerin, hydroxypropyl starch, hydroxy propyl distarch glycerin, hydroxypropyl distarch phosphate, hydroxypropyl distarch glycerol, starch sodium octenyl succinate, acetylated oxidized starch, hydroxyethyl cellulose.

Diluents or fillers are inactive substances added to drugs in order to handle minimal amounts of active agents. Examples for suitable diluents are water, mannitol, pre-gelatinized starch, starch, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate dihydrate, calcium phosphate, calcium carbonate, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, xanthum gum, gum arabic or any combination thereof.

Antiadherents (anti-caking agents) can be added to the first composition according to the invention in order to prevent the formation of lumps and for easing packaging, transport and release from forms or molds and for consumption. Suitable examples include tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, polydimethyl siloxane. Glidants are materials that prevent a baking of the respective supplements and improve the flow characteristics of granulations so that the flow is smooth and constant. Suitable glidants comprise silicon dioxide, magnesium stearate, sodium stearate, starch and talcum. The amount of the glidant in the first composition according to the invention may vary between 0.01 and 10% per weight, preferred between 0.1 and 7% per weight, more preferred between 0.2 and 5% per weight, most preferred between 0.5 and 2% per weight.

The term lubricants refers to substances that are added in order to facilitate tablets, granulates etc. to be released from the press mold or the outlet nozzle. They diminish friction or abrasion. Lubricants are usually added shortly before pressing, as they should be present on the surface of the granules and between them and the parts of the press mold. They may be useful when the ingredients of the first composition according to the method of the invention are provided in a granulated form. The amount of the lubricant in the

pharmaceutical composition may vary between 0.05 and 15% per weight, preferred between 0.2 and 5% per weight, more preferred between 0.3 and 3% per weight, most preferred between 0.3 and 1.5% per weight. Suitable lubricants are a.o. sodium oleate, metal stearates such as sodium stearate, calcium stearate, potassium stearate and magnesium stearate, stearic acid, sodium benzoate, sodium acetate, sodium chloride, boric acid, waxes having a high melting point, polyethylene glycol.

According to the invention all of the aforementioned excipients and classes of excipients can be used without limitation alone or in any conceivable combination thereof, as long as the inventive use of the pharmaceutical composition is not thwarted, toxic actions may occur or the respective national legislations are infracted.

The second composition according to the invention can be combined with a variety of additives, as laid out in the following:

Suitable vitamins are for example vitamin C (L-ascorbic acid, sodium L-ascorbate, calcium L- ascorbate, potassium L-ascorbate, L-ascorbyl 6-palmitate), vitamin A (retinol, retinyl acetate, retinyl palmitate, beta-carotene), vitamin D (cholecalciferol, ergocalciferol), vitamin E (D- alpha-tocopherol, DL-alpha-tocopherol, D-alpha-tocopheryl acetate, DL-alpha-tocopheryl acetate, D-alpha-tocopheryl succinate), vitamin K (phylloquinone), vitamin B1 (thiamin hydrochloride, thiamin mononitrate), vitamin B2 (riboflavin, sodium riboflavin 5’-phosphate), niacin (nicotinic acid, nicotinamide), pantothenic acid (calcium D-pantothenate, sodium D- pantothenate, D-panthenol), vitamin B6 (pyridoxine hydrochloride, pyridoxine 5’-phosphate), folic acid (pteroyl monoglutaminic acid), vitamin B12 (cyanocobalamin, hydroxocobalamin), biotin (D-biotin). Suitable minerals to be included are for example calcium (calcium carbonate, calcium chloride, citric acid calcium salt, calcium gluconate, calcium glycerophosphate, calcium lactate, ortho-phosphoric acid calcium salt, calcium hydroxide, calcium oxide), magnesium (magnesium acetate, magnesium carbonate, magnesium chloride, citric acid magnesium salt, magnesium gluconate, magnesium glycerophosphate, ortho-phosphoric acid

magnesium salt, magnesium lactate, magnesium hydroxide, magnesium oxide, magnesium sulfate), iron (iron carbonate, iron citrate, iron ammonium citrate, iron gluconate, iron fumarate, iron sodium diphosphate, iron lactate, iron sulfate, iron diphosphate, ferric saccharate, elemental iron), copper (copper carbonate, copper citrate, copper gluconate, copper sulfate, copper lysine complex), iodine (sodium iodide, sodium iodate, potassium iodide, potassium iodate), zinc (zinc acetate, zinc chloride, zinc citrate, zinc gluconate, zinc lactate, zinc oxide, zinc carbonate, zinc sulfate), manganese (manganese carbonate, manganese chloride, manganese citrate, manganese gluconate, manganese

glycerophosphate, manganese sulfate), sodium (sodium bicarbonate, sodium carbonate, sodium chloride, sodium citrate, sodium gluconate, sodium lactate, sodium hydroxide, ortho- phosphoric acid sodium salt), potassium (potassium bicarbonate, potassium carbonate, potassium chloride, potassium citrate, potassium gluconate, potassium glycerophosphate, potassium lactate, potassium hydroxide, ortho-phosphoric acid potassium salt), selenium (sodium selenite, sodium hydrogen selenite, sodium selenite), chrome (chrome-(lll)-chloride, chrome-(lll)-sulfate), molybdenum (ammonium molybdate (molybdenum (VI), sodium molybdate (molybdenum (VI)), fluorine (sodium fluoride, potassium fluoride), chlorine, phosphor.

Trace elements are dietary minerals that are needed by the organism in very small amounts for growth, development and physiology, for example as co-enzymes. Some of them are virtually always present in the organism in sufficient quantities, others have to be substituted in persons in need thereof. They can be selected from the group comprising, but not limited to, chrome, cobalt, iron, iodine, copper, manganese, molybdenum, selenium, zinc, fluoride, silicon, arsenic, nickel, rubidium, tin, vanadium. They can be substituted either as a pure element or in any of the mineral forms mentioned above.

In a first embodiment of the disclosure the first composition according to the invention is provided in a bottle, preferably a transparent plastic bottle. The preferred volume of said bottle is 150 ml to 500 ml, more preferred 200 ml to 400 ml, most preferred 250 ml to 300 ml. The second composition according to the invention is provided in a dispensing cap. Typical suitable dispensing caps are disclosed for example in WO 2018/188797 which is

incorporated herein by reference. The preferred filling volume of such a dispensing cap is 3 ml to 20 ml, preferred 4 ml to 10 ml. This dispensing cap is mounted by a standard screw cap onto the bottle filled with the first composition. The patient in need thereof (respectively the medical staff acting instead of him) screws off the dispensing cap and fills the bottle with an adequate amount of the aqueous solution according to the invention. The first composition is easily solved in the aqueous solution by slight agitation. Then the dispensing cap is mounted again on the filled bottle. By acting the release mechanism, the liquid second composition is released from the dispensing cap into the third composition in the bottle. By vigorously shaking the bottle for about five seconds the final solution is generated and ready to be imbibed by the patient in need thereof.

In a second embodiment of the disclosure the first composition is provided in a dispensing cap as described before. The second composition is provided in a bottle as described before. The patient in need thereof screws off the dispensing cap and fills the bottle with an adequate amount of the aqueous solution according to the invention. The second

composition is solved in the aqueous solution by slight agitation. Then the dispensing cap is mounted again on the filled bottle. By acting the release mechanism, the dry first composition is released from the dispensing cap into the bottle. By vigorously shaking the bottle for about five seconds the final solution is generated and ready to be imbibed by the patient in need thereof.

In a third embodiment of the disclosure the first composition is provided in a bottle as described before. The second composition is provided in a dispensing cap as described before. By acting the release mechanism, the liquid second composition is released from the dispensing cap into the bottle. The patient in need thereof screws off the dispensing cap and fills the bottle with an adequate amount of the aqueous solution according to the invention. Then the dispensing cap is mounted again on the filled bottle. By vigorously shaking the bottle for about five seconds the final solution is generated and ready to be imbibed by the patient in need thereof.

In a fourth embodiment of the disclosure the first composition is provided in a dispensing cap as described before. The second composition is provided in a bottle as described before. By acting the release mechanism, the dry first composition is released from the dispensing cap into the bottle. The patient in need thereof screws off the dispensing cap and fills the bottle with an adequate amount of the aqueous solution according to the invention. Then the dispensing cap is mounted again on the filled bottle. By vigorously shaking the bottle for about five seconds the final is generated and ready to be imbibed by the patient in need thereof.

In a fifth embodiment of the disclosure the first composition is provided in a first chamber of a dual-chamber dispensing cap and the second composition is provided in a second chamber of a dual-chamber dispensing cap. Numerous types of dual-chamber dispensing caps are known in the art. Examples are disclosed, without being limiting, in US 2005/018490, US 5873494, US 6481571 , US 6550647. By acting the respective release mechanism, the first composition and the second composition are released from their respective chamber in the dispensing cap into the bottle. It is possible to release the first composition first and thereupon the second composition, or to release the second composition first and thereupon the first composition, or to release the first composition and the second composition concomitantly. The patient in need thereof screws off the dispensing cap and fills the bottle with an adequate amount of the aqueous solution according to the invention. Then the dispensing cap is mounted again on the filled bottle. By vigorously shaking the bottle for about five seconds the final is generated and ready to be imbibed by the patient in need thereof.

In a sixth embodiment of the disclosure the first composition is provided in a first chamber of a dual-chamber dispensing cap and the second composition is provided in a second chamber of a dual-chamber dispensing cap as described before. The patient in need thereof screws off the dispensing cap and fills the bottle with an adequate amount of the aqueous solution according to the invention. Then the dispensing cap is mounted again on the filled bottle. By acting the respective release mechanism, the first composition and the second composition are released from their respective chamber in the dispensing cap into the bottle. It is possible to release the first composition first and thereupon the second composition, or to release the second composition first and thereupon the first composition, or to release the first composition and the second composition concomitantly. By vigorously shaking the bottle for about five seconds the final is generated and ready to be imbibed by the patient in need thereof.

In a seventh embodiment of the disclosure the first composition is provided in a first chamber of a dual-chamber dispensing cap and the second composition is provided in a second chamber of a dual-chamber dispensing cap as described before. An adequate amount of the aqueous solution according to the invention is already provided in the bottle as described before. By acting the respective release mechanism, the first composition and the second composition are released from their respective chamber in the dispensing cap into the bottle. It is possible to release the first composition first and thereupon the second composition, or to release the second composition first and thereupon the first composition, or to release the first composition and the second composition concomitantly. By vigorously shaking the bottle for about five seconds the final is generated and ready to be imbibed by the patient in need thereof.

A final solution according to the invention is also particularly useful in veterinary medicine. Until now, it was difficult to impossible to administer regularly a KA/EAA diet to a dog or a cat suffering from chronic kidney disease, respectively one of the further diseases mentioned before. The dog or cat would consequently refrain from drinking a KA/EAA formulation, respectively from eating it when mixed under the food because of the repulsive taste/odor. With a final solution according to the invention - either in the drinking water or in the food - the dog or cat does not notice the KA/EAA ingredients and shows no refusing attitude to this treatment. By the method of the invention a KA/EAA treatment becomes available for dogs and cats.

EXAMPLES

The weight percentages refer to the second composition. Phosphatidylcholine and the lysophosphatidylcholines were purchased from Lipoid GmbH, Ludwigshafen, Germany, the MCT oil from Azelis, Moers, Germany, all other agents from Sigma-Aldrich, Germany.

Example 1 :

The first composition according to the invention comprises 4.41 g of the Ketosteril^® composition described before. This corresponds to the content of 7 tablets. This corresponds to 50% of the recommended daily dosage (1 tablet per 5 kg body weight for an average 70 kg person).

The second composition according to the invention comprises 0.44 g of the following solubilizing agents: non-hydrogenated soybean

200 mg 45.5 %

phosphatidylcholine

MCT oil 205 mg 46.6 %

mixture of 1- lysophosphatidylcholine and

17 mg 3.9 %

2-lysophosphatidylcholine

(1 :1 )

ethanol 8 mg 1.8 %

oleic acid 4 mg 0.9 %

glyceryl stearate 5 mg 1.1 %

alpha-tocopherol 1 mg 0.2 %

The first composition is provided in a 250 ml bottle. The second composition is provided in a dispensing cap as described before that is mounted on said bottle. The second composition is released into the bottle by triggering the release mechanism of the dispensing cap (room temperature, atmospheric pressure). The resulting third composition is mixed by slightly agitating the bottle. Then the user twists the dispensing cap off and fills the bottle up ad 200 ml with mineral water. The dispensing cap is mounted again. Then the bottle is vigorously shaken for 5 seconds. The preparation is ready for consumption. It is a clear solution and has a neutral taste.

Example 2:

The first composition is the same as in Example 1.

The second composition according to the invention comprises 0.631 g of the following solubilizing agents:

1 ,2-dioleyl-SN-glycero-3-

378 mg 60.0 %

phosphocholine (DOPC)

MCT oil 200 mg 31.7 %

1 -lysophosphatidylcholine 22 mg 3.5 %

ethanol 14 mg 2.2 %

oleic acid 7 mg 1.1 %

glyceryl stearate 9 mg 1.4 %

beta-tocopherol 1 mg 0.1 %

The first composition is provided in a dispensing cap as described before that is mounted on said bottle. The second composition is provided in a 250 ml bottle. The first composition is released into the bottle by triggering the release mechanism of the dispensing cap (room temperature, atmospheric pressure). The resulting third composition is mixed by slightly agitating the bottle. Then the user twists the dispensing cap off and fills the bottle up ad 200 ml with mineral water. The dispensing cap is mounted again. Then the bottle is vigorously shaken for 5 seconds. The preparation is ready for consumption. It is a clear solution and has a neutral taste.

Example 3:

The first composition is the same as in Example 1.

The second composition according to the invention comprises 0.371 g of the following solubilizing agents:

1 -palmitoyl-2-oleoyl-sn- glycero-3-phosphocholine 259 mg 70.0 %

(POPC) MCT oil 80 mg 21.7 %

2-lysophosphatidylcholine 13 mg 3.6 %

ethanol 8 mg 2.2 %

oleic acid 4 mg 1.1 %

glyceryl stearate 5 mg 1.2 %

ascorbyl palmitate 1 mg 0.2 %

The first composition is provided in a first chamber of a dual-chamber dispensing cap as described before. The second composition is provided in a second chamber of said dualchamber dispensing cap. The first composition and the second composition are released into the bottle by triggering the release mechanism of the dispensing cap (room temperature, atmospheric pressure). The resulting third composition is mixed by slightly agitating the bottle. Then the user twists the dispensing cap off and fills the bottle up ad 200 ml with mineral water. The dispensing cap is mounted again. Then the bottle is vigorously shaken for 5 seconds. The preparation is ready for consumption. It is a clear solution and has a neutral taste.

Example 4:

The first composition of Example 2 is varied in that 1 g taurine is additionally added. The preparation method is the same as in Example 2. From the final solution 20 ml are added to the diluted milk of a cat (female, 11 years old, 4 kg) suffering from chronic kidney disease. The cat accepts to drink the milk with no repulsive behavior.

Claims

Claims

1. Method for taste/odor masking of a product for chronic kidney disease patients,

comprising the following steps:

a) Providing a first composition comprising at least one essential amino acid and/or at least one alpha-ketoanalogue of an essential amino acid and/or at least one alpha-hydroxyanalogue of an essential amino acid,

and mixing said first composition;

b) Providing a second composition comprising

at least one non-hydrogenated phosphatidylcholine in the overall range of 20 % to 80 % per weight,

at least one medium-chained triglyceride in the overall range of 10 % to 70 % per weight,

at least one non-hydrogenated lysophosphatidylcholine in the overall range of 1 % to 15 % per weight,

at least one C₂ to C₄ alcohol in the overall range of 1 % to 20 % per weight, and at least one of glyceryl stearate and/or a saturated or unsaturated C14 to C20 fatty acid in the overall range of 0.5 % to 10 % per weight, respectively,

wherein the relative weight percentages of all ingredients add up to 100 % and all taste/odor masking agents are independently from one another a food additive and/or a pharmaceutically acceptable excipient,

and mixing said second composition;

c) Providing an aqueous solution;

d) Mixing said first composition and said second composition,

thus generating a third composition;

e) Mixing said third composition to said aqueous solution by application of force, thus generating a final solution; wherein the method is carried out at room temperature, the weight ratio of non-hydrogenated phosphatidylcholines to non-hydrogenated lysophosphatidylcholines in the second composition is in the range of 5:1 to 20:1 , the weight ratio of the first composition to the second composition is in the range of 4:1 to 12:1 , and the volume ratio of the aqueous solution to the third composition is in the range of 30:1 to 350:1.

2. The method according to claim 1 , wherein at least one flavoring agent being a food additive and/or a pharmaceutically acceptable excipient is added to the first composition and/or the second composition and/or the third composition and/or the aqueous solution and/or the final solution.

3. The method according to any of claims 1 or 2, wherein said at least one essential amino acid and/or at least one ketoanalogue of an essential amino acid and/or at least one alpha-hydroxyanalogue of an essential amino acid of said first composition is selected from the group comprising (RS)-3-methyl-2-oxovaleric acid calcium salt, 4- methyl-2-oxovaleric acid calcium salt, 2-oxo-3-phenylpropionic acid calcium salt, 3- methyl-2-oxobutyric acid calcium salt, (RS)-2-hydroxy-4-methylthio-butyric acid calcium salt, L-lysine acetate, L-threonine, L-tryptophan, L-histidine, L-tyrosine and taurine.

4. The method according to any one of claims 1 to 3, wherein said at least one saturated or unsaturated CM to C20 fatty acid of said second composition is oleic acid.

5. The method according to any of claims 1 to 4, wherein said at least one C2 to C4 alcohol of said second composition is ethanol.

6. The method according to any one of claims 1 to 5, wherein at least one antioxidant in the overall range of 0.01 to 10% per weight is added to the first composition and/or the second composition and/or the aqueous solution and/or the third composition and/or the final solution, said at least one antioxidant being a food additive and/or a pharmaceutically acceptable excipient.

7. The final solution produced by a method as defined in any one of claims 1 to 6.

8. Use of the final solution as defined in claim 7 in medicine or veterinary medicine.

9. Use of the final solution as defined in claim 7 as a medication, as a medical product, as a therapeutic nutritional, as a dietary supplement or as a supplement balanced diet.

10. Use of the final solution according to any of claims 8 or 9, wherein the final solution is administered orally.

11. Use of the final solution according to claim 10, wherein the orally administered final solution is a liquid dosage form.

12. Use of the final solution according to any one of claims 8 to 11 for delaying dialysis initiation in a patient in need thereof.

13. Use of the final solution produced by a method as defined in any one of claims 1 to 6 for the manufacture of a therapeutic nutritional for a patient suffering from chronic kidney disease or amino acid deficiency.

14. Use of the final solution produced by a method as defined in any one of claims 1 to 6 for the manufacture of a composition for treatment and/or prophylaxis of chronic kidney disease, amino acid deficiency, incontinence, allergies, depression, asthma, paracetamol poisoning, paracetamol overdosage, copper poisoning, radiation side effects, alcoholism, diaper rashes, chronic liver disease, hepatic encephalopathy, Duchenne muscular dystrophy, Becker muscular dystrophy, phenylketonuria or homocystinuria.

15. Use of the final solution produced by a method as defined in any one of claims 1 to 6 for the preparation of a drinkable aqueous solution by adding said final solution dropwise to a further pharmaceutically acceptable aqueous solution.