WO2001097635A2

WO2001097635A2 - Microcapsules containing arginine and the different uses thereof

Info

Publication number: WO2001097635A2
Application number: PCT/IL2001/000535
Authority: WO
Inventors: Yoseph Bornstein
Original assignee: Coraltis Ltd.
Priority date: 2000-06-20
Filing date: 2001-06-12
Publication date: 2001-12-27
Also published as: AU2001274457A1; IL136899A0; WO2001097635A3

Abstract

The present invention provides microcapsules comprising a core of arginine (Arg), preferably L-arginine, encapsulated by an external coating material comprising one or more of a polymer, a lipid or a waxy material combined with at least one fatty acid. The polymer is a pH-independent polymer or a mixture of such polymers. The arginine microcapsules of the invention are incorporated in suitable oral compositions characterized by improved taste.

Description

MICROCAPSULES CONTAINING ARGININE AND THE DIFFERENT USES THEREOF

FIELD OF THE INVENTION This invention relates to arginine (Arg) compositions having an improved taste.

BACKGROUND OF THE INVENTION

It is well known that the basic L-amino acids such as L-lysine, L-ornithine, L-arginine (hereinafter "L-Arg") are useful as a nutritive supplement or as a medicine. L-Arg was recognized in 1988 as the physiological precursor of nitric oxide (NO) (Nature 333:664-667 (1988)). NO has found its way into nearly every phase of biology and medicine ranging from its role as a critical endogenous regulator of blood flow and thrombosis to a principal neurotransmitter mediating erectile function and to a major pathophysiological mediator of inflammation and host defense.

L-Arg is one of the least toxic amino acids. It has been shown that a daily dose of 18-20 grams provides maximal benefit without significant side effects, while it is agreed between physicians that even a daily regime of 6-10 grams would suffice in order to achieve an adequate therapeutic effect. However, the maximal amount of L-Arg that can be administered today by one large capsule (1.7x0.6 cm) ranges from 500 to 1000 mg. Therefore, in order to reach satisfactory therapeutic effect in a patient in need, 12-20 capsules of 500 mg each will be required on a daily basis. Such an amount cannot be respected from a patient compliance point of view. Furthermore, another problem exists when administering L-Arg in oral solid form because of its extreme bitterness. This problem also exists when L-Arg is administered orally in liquid dosage form as dispersion or syrup and, in fact, no conveniently administrable oral formulation of L-Arg or salts thereof is available to date since there are no aromatic excipients able to mask its bitter taste.

Various ways have been attempted in the prior art to make wider use of L-Arg while substantially eliminating its bitter taste, and make it more pleasant upon oral administration. EP 567433 describes orally-ingestible nutrition compositions having improved taste and comprising a low pH form of an amino acid such as arginine, valine or ornithine.

SUMMARY OF THE INVENTION The present invention is based on the surprising finding that combining a coating agent with an organic acid and encapsulating an amino acid, e.g., Arg, therewith, reduces, if not eliminates, the bitter taste typically associated with the swallowing of basic amino acids and compositions containing them.

Thus, in accordance with a first aspect of the present invention there are provided microcapsules comprising an Arg core encapsulated by a coating material comprising one or more of a polymer, a lipid or a waxy material (the coating agent) combined with at least one fatty acid.

As known, the biologically active form of amino acids is the L form and in the case of Arg, L-Arg. Thus, the term "Arg" as used herein signifies either L-Arg, D-Arg or a racemic form thereof. Nevertheless, it preferably denotes an Arg composition in which the L form is at least about 50% of the total of L- and D-Arg. As known, in a naturally-derived Arg composition the Arg will be predominantly if not exclusively, the L form, nevertheless, according to the present invention, also synthetic Arg compositions may be employed, in which case, it may contain pure L-Arg or the racemic form thereof as defined above.

Thus, in accordance with the invention, the microcapsules contain a core of pure Arg or a core formed of an inert excipient coated with a formulation which comprises Arg. The inert excipient is made of an inert, pharmaceutically acceptable excipient, such as sugar, starch, mixtures thereof, etc.

The term "coating material" as used herein signifies any physiologically acceptable material which may be used for encapsulating one or more amino acids, the material being preferably a combination of two or more substances. In particular, the coating material of the invention comprises a coating agent, e.g. one or more of a polymer, lipid or waxy material and one or more fatty acids. The coating material forming the microcapsules should preferably have the property of substantially delaying the release of the amino acid from the microcapsule at least until the latter leaves the oral cavity. The polymeric constituent of the coating material is preferably a pH-independent polymer or a mixture of such polymers. Such polymers include in general polyacrylates, polymethacrylates (e.g. the different well known Eudragit^R polymers, including Eudragit RS), polyvinyl acetate, cellulose and cellulose derivatives. Particular pharmaceutically acceptable coating agents suitable for use in the invention include synthetic polymers such as methylcellulose, methylpropylcellulose, polyvinylpyrrolidone, hydroxyethylcellulose, polyvinyl alcohol, sodium carboxymethylcellulose, hydroxypropyhnethylcellulose, 2-methyl-5-vinylpyridine methacrylic acid methacrylate copolymer, ethylcellulose and the like and natural gums or resins such as gelatin, acacia, carragheen, alginic acid, tragacanth and certain of their hydrolysis products or the like.

Notwithstanding the above list, according to one embodiment of the invention, the polymer is a cellulose derivative, preferably, ethyl cellulose. The fatty acid forming part of the coating material is preferably an acid which is not substantially dissolved in water and may include various acids. Examples of fatty acids which may be employed are fumaric acid, adipic acid, stearic acid, oleic acid, linoleic acid, alpha-linoleic acid, palmitic acid or any mixture of these acids or of other organic acids exhibiting similar dissolution characteristics. Preferably, the fatty acid employed in the microcapsules of the present invention is stearic acid.

It should however be noted that the preceding lists of ingredients of the coating material are not exhaustive but merely illustrates the range of coating agents and acids which may be used to produce the microcapsules of the present invention.

Notwithstanding the above, one preferred coating material according to the invention is obtained from a combination of ethyl cellulose (such as ethyl cellulose N-10) and stearic acid. The coating material may alternatively or additionally comprise a lipid material or a waxy material. Examples for a lipid material include, but are not limited thereto, glyceryl palmitostearate, tristearin and tripalmitin, while example for waxy material include, inter alia, white paraffin, wax (e.g. beeswax), glycerol esters (e.g. tripalmitate, tristearate, palmito stearate, behenate) and cetyl alcohol, all of which are typically used in oral dosage formulations. The encapsulation of the Arg within the coating material, to form the microcapsules of the present invention may be carried out by various known methods, e.g. spray drying, spray coating, solvent emulsion evaporation or extraction. As may be recognized by those versed in the art, the spray coating technique is at times preferred since it is easily scaled-up and is well adapted to obtain microcapsules whose diameter ranges between 50 μm and 400 μm.

Thus, in accordance with a second aspect, the invention relates to a method of preparing the microcapsules of the present invention, i.e. which comprise Arg encapsulated by a coating material comprising one or more of a polymer, a lipid or a waxy material combined with at least one fatty acid, as defined hereinbefore, the method comprises the steps of: a. dissolving the coating material in an organic solvent; b. spraying said dissolved coating material onto Arg particles to induce solvent evaporation and coating material deposition, thereby forming said microcapsules.

The encapsulation method is based on the HS Wurster coating methodology, known in the art of microencapsulation.

According to a preferred manner of performing the above method, the organic solvent employed is acetone, methanol, ethanol, propanol or a mixture of the same and the spraying is performed under vacuum conditions, at a temperature of between 30°C to 60°C.

In accordance with a further aspect of the invention there is provided a dry powder comprising a mixture of: - microcapsules comprising Arg encapsulated by a coating material comprising one or more of a polymer, a lipid or a waxy material combined with at least one fatty acid;

- at least one physiologically acceptable wetting agent; and

- at least one physiologically acceptable water-soluble acid or salt thereof.

Evidently, having a dry formulation is advantageous over liquid ones as it typically increases the shelf-life of a formulation.

The microcapsules within the dry powder are as disclosed hereinbefore, while the wetting agent may be, inter alia, a non-ionic surfactant typically having a hydrophilic-lipophilic balance (HBL) of between about 6 and about 16. Such non-ionic surfactants are typically utilized as wetting agents in the preparation of pharmaceutical formulations. Example in general of wetting agents include polysorbates such as Tween 20, Tween 40, Tween 60 or Tween 80 or polypropylene glycol or glycerol.

The water-soluble acid is preferably an organic acid. Examples for such acids include, inter alia, tartaric, succinic, citric, phosphoric, acetic, fumaric, malic, lactic acid, a citrus-derived acid, or mixtures of said organic acids.

The dry powder may also include other additives, such as one or more flavoring and/or sweetening agents. An example for a flavoring agent is banana flavor while examples for sweetening agents are aspartame, sodium cyclomate, saccharin or their derivatives. According to one preferred embodiment, the dry powder comprises the following constituents :-

Arg-containing microcapsules - 7.5 gram

Lactic Acid - 1.5 gram

Flavoring agents - 0.75 gram

Aspartame - 0.04 gram

Propylene glycol - 0.1-0.2 gram

The above powder may be prepared with tartaric acid or malic acid instead of lactic acid. Alternatively, it may be prepared with citric acid or with a combination of citric acid and sodium citrate or a combination of citric acid and malic acid instead of lactic acid.

Formulations of the microcapsules of the invention into the suitable administration form may take place shortly after their production by spray coating or alternatively, the formulation may occur separately at a later time. Thus one further aspect of the invention comprises the processing of the powder into forms suitable for oral administration to animals including human.

Thus, the dry powder may be incorporated in a unit dose such as capsules, tablets, chewable tablets, effervescent tablets, effervescent powder, packaged granules, as a mixture in a sachet to be added to food products such as milk, yogurts, etc., or adapted to any other adequate nutritive form, for example bars, cereals, chocolate, etc.

The invention also relates to an oral aqueous composition containing:

- an effective amount of microcapsules comprising Arg encapsulated by a coating material comprising one or more of a polymer, a lipid or a waxy material combined with at least one fatty acid;

- at least one physiologically acceptable wetting agent;

- at least one physiologically acceptable water-soluble acid or salts thereof; and optionally additional physiologically acceptable additives, all of which are dissolved in an aqueous media to form the oral aqueous composition.

The Arg-containing microcapsules, the wetting agent and the water soluble acid within the oral composition are as defined above.

The term "effective amount" for purposes used herein is determined by those skilled in the art of pharmacy or medicine. The amount must be effective to achieve the effect known to be associated with treatment of subjects with Arg, including but not limited to improved survival rate or more rapid recovery, or improvement or elimination of symptoms and other indicated as are selected as appropriate measures by those skilled in the art.

The term "additional physiologically acceptable additives" signifies any physiologically acceptable excipient, however, preferably refers to food additives or ingredients including flavoring agents, disintegrants, lubricants, sweeteners etc. Examples of flavoring agents and sweetening agents are the banana flavor and aspartame, respectively, employed in the following specific Examples.

According to one preferred embodiment of the invention, the oral composition comprises from about 30% to about 90% Arg-containing microcapsules of the present invention, and from about 3% to about 35% physiologically acceptable water-soluble acid, and a remaining amount of the wetting agent. One special feature of the oral composition of the invention is that it lacks a bitter taste typically associated with pharmaceutical or nutritional formulations containing basic amino acids, such as Arg. The masking of the unpleasant taste is probably due to the combination of the fatty acid with the coating agent in the coating of the microcapsules which delays the Arg release from the microcapsule, resulting it that as long as the medicament is in the oral cavity, substantially no bitterness is tasted.

The invention further provides a method of preparing an oral composition containing:

- microcapsules comprising Arg encapsulated by a coating material comprising one or more of a polymer, a lipid or a waxy material combined with at least one fatty acid;

- at least one physiologically acceptable wetting agent; andat least one physiologically acceptable water soluble acid or salts thereof; the method comprising the steps of:

a. mixing the microcapsules, the at least one wetting agent and the at least one water-soluble acid, all of which being in a dry powder form;

b. dispersing the dry mixture obtained in (a) in an aqueous media to form an aqueous dispersion thereof. The aqueous dispersion obtained is then suitable for administration.

The aqueous media employed in preparing the oral composition may be of any type known to those skilled in the art of pharmaceutics and particularly those used for the preparation of compositions for oral administration. According to one embodiment, the aqueous media is water including taped water, distilled water or double-distilled water (DDW). Alternatively, the aqueous media may be a fruit juice in which the powder is dispersed. Evidently, the aqueous dispersion may be obtained by either pouring the dry mixture containing the microcapsules, the wetting agent and the water-soluble acid into the aqueous media or by pouring the aqueous media thereon.

Yet further, the invention relates to a kit comprising a package containing dry powder mixture containing (a) microcapsules comprising Arg encapsulated by a coating material comprising one or more of a polymer, a lipid or a waxy material combined with at least one fatty acid; (b) at least one physiologically acceptable wetting agent; and (c) at least one physiologically acceptable water-soluble acid or a salt thereof; the kit further comprising an aqueous solution for dispersing the dry powder to obtain an aqueous composition; and instructions for use of the dry powder and aqueous media to form the aqueous composition, said instructions prescribing the administration of the aqueous composition obtained to a subject in need of said composition.

The dry powder is as defined above whereas the aqueous media is preferably water (e.g. taped water, distilled water or double distilled water). According to one preferred embodiment, the aqueous composition obtained is intended for oral administration.

The instructions included in the kit provide the user of the kit, e.g. the subject in need of the resulting composition or the subject preparing the resulting composition for someone else (e.g. the physician, the nurse or a pharmacist), with detailed instructions on how to prepare the composition so as to contain an effective amount of the Arg ingredient and also instructions for administration to the subject the resulting composition.

The oral aqueous composition of the present invention (either a priori prepared and provided to the consumer as an aqueous composition or prepared from the above said kit) is administered and dosed in accordance with good medical practice, taking into account the clinical conditions of the subject treated, scheduling of administration, patient age, sex, body weight and other factors known to medical or pharmacy practitioners. Thus, the kit may be designed so as to enable preparation by the user of different formulations of the aqueous composition, i.e. having different Arg-effective amounts. The instructions for how to prepare the different formulations may then be prescribed in the accompanying instructions or be given by a person authorized to provide such instructions (e.g. physician, pharmacists etc.).

The kit may also comprise additional additives, such as flavoring and/or sweetening agents (e.g. fruit flavors) to make the swallowing even more pleasant. The additional additives may be included in the microcapsules containing package or be provided in a separate package. In addition, the kit may comprise a measuring device, such as a measuring spoon to facilitate preparation of the prescribed aqueous composition by the user.

Finally, the invention relates to a method of providing a subject with Arg containing composition, the method comprising the steps of: a. providing a powder mixture comprising:

(i) microcapsules comprising Arg encapsulated by a coating material comprising one or more of a polymer, a lipid or a waxy material combined with at least one fatty acid;

(ii) at least one physiologically acceptable wetting agent; and

(iii) at least one physiologically acceptable water-soluble acid or acid salts thereof;

wherein all of the above ingredients (i), (ii) and (iii) are as defined hereinbefore;

b. dispersing said powder mixture in an aqueous media to form an aqueous dispersion thereof; c. administering via the oral cavity (e.g. by swallowing) said Arg-containing aqueous composition to said subject.

The invention will now be described by the foregoing specific examples. However, it should be noted that these examples have been provided merely for the purpose of explanation and are in no way to be construed as limiting of the present invention. While the invention has been described with reference to a preferred embodiments, it is understood that the words which have been used herein are words of description and illustration, rather than words of limitation. Changes may be made, within the purview of the appended claims, as presently stated and without departing from the scope and spirit of the invention in its aspects. Although the invention has been described with reference to particular means, materials and embodiments, the invention is not intended to be limited to the particulars disclosed herein; rather, the invention extends to all functionally equivalent structures, methods and uses, such as are within the scope of the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be described below with reference to the accompanying drawings, in which:

Fig. 1 - a calibration graph for L-Arg in water

Fig. 2 - a graph showing the dissolution profile of Arg-containing microcapsules from batch HP75, in 0. IN HC1

Fig. 3 - a graph showing the dissolution profile of Arg-containing microcapsules from batch EC2

Fig. 4 - a graph showing the dissolution profile of Arg-containing microcapsules from batch EC2, in three different media: distilled water, 0.1N HC1, 0.001N NaOH.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

A. Analytical

Microcapsules preparation and characterization

The microcapsules employed were prepared according to standard technology using an HS Wurster coating system known in the art. In general, the microcapsules were prepared by dissolving a mixture of the indicated amounts of N-ethyl cellulose or hydroxypropylmethyl cellulose (the coating agents) and stearic acid or talc, in a mixture of acetone :methanol or acetone alone. Then, Arg particles were sprayed with the dissolved mixture under vacuum conditions, at a temperature ranging from 30°C to 60°C, whereby the solvent is evaporated and the coating material is deposited onto the Arg particles to form the described microcapsules.

The following Arg-containing microcapsules have been prepared, as showed in Table 1 below:

Table 1 - L-Arg containing microcapsules batches and their respective batch codes:

* HPMCP- Hydroxypropylmethyl cellulose phtalate (signified also by HP)

Microcapsules characterization

1. L-Arginine Assay (Ninhydrin test)

A solution of 10 mg L-Arg in 200 ml distilled water was prepared, yielding a 50 μg/ml concentration solution. From this mother solution (m.sol) several dilutions were prepared, using distilled water. Ten standard solutions with concentrations ranging from 10 to 50 μg/ml were prepared, as shown in Table 2 hereinafter. To 200 μl of each of the 10 standard solutions, 200 μl of Ninhydrin reagent solution (SIGMA Ltd. MO-USA) was added. The resulting solutions were stirred well and the tubes were closed, heated for 15 minutes in a boiling water bath and cooled immediately using ice. An aliquot of 1 ml of 50% ethanol was added to each tube and shacked well. The optical absorption of the resulting mixture was read at a wavelength of 570 nm against a respective blank for each of the samples prepared indicating the L-Arg concentration in each solution.

Table 2: L-Arg concentrations

2. L-Arginine content determination in microcapsules

L-Arg microcapsules (103.7 mg) from batch EC2, L-Arg microcapsules (101.4 mg) from batch HP70, L-Arg microcapsules (108.7 mg) from batch HP75, L-Arg microcapsules (109.2 mg) from batch HP 80, and L-Arg microcapsules (102.4 mg) from batch HP85 were each dispersed in a 200 ml volumetric flask, using distilled water. The solutions were mixed well and left overnight up to total dissolution of all the excipients, including L-Arg. A hundred micro-liters of each of these clear solutions were diluted with 900 μl of distilled water.

The concentration of L-Arg was calculated against two calibration curves constructed from known standard concentrations of L-Arg in distilled water shown in Fig. 1 and using the Ninhydrin test discussed hereinbefore.

3. In vitro release kinetics experiments L-Arg microcapsules (800 mg) from batches EC2 and HP75 were separately well mixed with 10.6 mg of propylene glycol (wetting agent). The mixtures of microcapsules and wetting agent were properly dispersed into each of the containers containing 800 ml 0.1N HC1 (pH=1.0).

At given time intervals, 0.5 ml samples were carefully withdrawn following filtration through 0.45 μ filters while avoiding any microcapsule separation from the solution. These samples were further diluted by adding

100 μl of 0.1N sodium hydroxide solution and 800 μl of distilled water to 100 μl of the samples.

The concentration of L-Arg at each given time interval, and for each of the samples was calculated against the two respective calibration curves constructed from known standard concentrations of L-Arg in distilled water (Fig. 1). The dissolution profiles are depicted in Figs. 2 and 3 respectively.

Fig. 4 describes the dissolution profiles for the EC2 microcapsules in three different media (distilled water, 0.1N HC1 and 0.00 IN NaOH). 800 mg of L-Arg microcapsules were mixed well with 10.6 mg of propylene glycol (wetting agent). The microcapsules-wetting agent mixture was properly dispersed into a container containing 800 ml medium. At given time intervals, 0.5 ml samples were carefully withdrawn following filtration through 0.45 μ filters, while avoiding any microcapsule separation from the solution. The samples which were poured into 0.1N HC1 medium, were further diluted by adding 100 μl solution of 0.1N sodium hydroxide and 800 μl of distilled water, while the samples poured into distilled water and 0.00 IN sodium hydroxide were further diluted by adding 900 μl of distilled water. The concentration of L-Arg in each sample was detected as explained above.

The dissolution process conditions were in accordance with USPXXII: 1. 100 rpm.

2. Dissolution medium temperature being 37°C .

3. Big paddles were placed 25 mm above the container's bottom. Results and Discussion

Most of the batches prepared presented an observed drug content close to the theoretical content.

Table 3: Observed L-Arg content in four microcapsule batches

Comparing Fig. 2 to Fig. 3 leads to the conclusion that the release of L-A from microcapsules of batch EC2 is slower (after 5 and 15 minutes: 17% and 52% release, respectively) than that from HP75 microcapsules (after 5 and 15 minutes, 38 and 70% release respectively). A slow release of L-Arg during the first five dissolution minutes is preferred in order to avoid the appearance of bitter taste during the swallowing of the composition.

In addition, it is shown in Fig. 4 that the fastest release rate of L-Arg, after 5 minutes dissolution, is at pH 8.5 (34%), followed by a slower release in distilled water (26%) and even slower at pH of 1 (18%).

B. Formulations for taste masking

Several attempts were made to further improve the taste of EC2 L-Arg microcapsules. The following formulations were prepared: Formula 1 - EC2

Formula3-EC2

Formula 4-EC2

Formula 5 - EC2

Formula 6 seems to be the most adequate composition for taste masking and pH stabilizing. This formula was repeated again with an enterocoating polymer Zein but the taste masking was poor irrespective of the coating thickness. In addition, formulations similar to formulations 1-6 above were prepared for microcapsules of batch HP80, as follows: Formula 1- HP80

Formula 2 - HP80

Formula3-HP80

Formula 4 - HP80

Formula 5 - HP80

Formula 6 - HP80

The above results show that when using ethyl cellulose as part of the coating material, as compared to HPMCP, which is a conventional entero-coating polymer (entero-soluble polymer), the taste was more pleasant and thus, compositions containing ethyl cellulose are advantageous. C. Formulation for chewable tablet

Claims

CLAIMS:

1. Microcapsules comprising a core comprising an effective amount of arginine (Arg), the core being encapsulated by an external coating material comprising one or more of a polymer, a lipid or a waxy material combined with at least one fatty acid.

2. Microcapsules according to Claim 1, wherein said Arg is L-Arg.

3. Microcapsules according to Claim 1 or 2, wherein said polymer is a pH-independent polymer or a mixture of such polymers.

4. Microcapsules according to Claim 3, wherein said polymer is selected from the group consisting of acrylates, methacrylates, polyvinyl acetate, cellulose and cellulose derivatives.

5. Microcapsules according to Claim 1, wherein said at least one fatty acid is selected from the group of acids consisting of fumaric, adipic, stearic, oleic, linoleic, alpha-linoleic, palmitic and any mixture of these acids.

6. Microcapsules according to any one of Claims 1 to 5, wherein said coating material comprises ethyl cellulose in combination with stearic acid.

7. A method of preparing microcapsules comprising Arg encapsulated by a coating material the method comprises the steps of: a. dissolving said coating material comprising one or more of a polymer, a lipid or a waxy material in combination with at least one fatty acid, in an organic solvent; b. spraying said dissolved coating material onto arginine core to induce solvent evaporation and coating material deposition, thereby forming said microcapsules.

8. A method according to Claim 7, wherein said Arg is L-Arg.

9. A method according to Claim 7 or 8, wherein said coating material comprises a pH-independent polymer.

10. A method according to Claim 9, wherein said polymer is selected from the group consisting of acrylates, methacrylates, polyvinyl acetate, cellulose and cellulose derivatives.

11. A method according to Claim 7, wherein said fatty acid is selected from the group consisting of fumaric, adipic, stearic, oleic, linoleic, alpha-linoleic, palmitic and any mixture of these acids.

12. A method according to any one of Claims 7 to 11, wherein said polymer is ethyl cellulose and said fatty acid is stearic acid.

13. A method according to Claim 7, wherein said organic solvent is acetone, methanol, ethanol, propanol or a mixture of the same.

14. A dry powder mixture comprising:

a. microcapsules comprising Arg core encapsulated by a coating material comprising one or more of a polymer, a lipid or a waxy material combined with at least one fatty acid;

b. at least one physiologically acceptable wetting agent; and

c. at least one physiologically acceptable water-soluble acid or salts thereof.

15. A powder according to Claim 14, further comprising one or more sweetening agents.

16. A powder according to Claim 14 or 15, wherein said polymer is a pH-independent polymer or a mixture of such polymers.

17. A powder according to Claim 16, wherein said polymer is selected from the group consisting of acrylates, methacrylates, polyvinyl acetate, cellulose and cellulose derivatives.

18. A powder according to Claim 14, wherein said fatty acid is selected from the group of acids consisting of fumaric, adipic, stearic, oleic, linoleic, alpha-linoleic, palmitic and any mixture of these acids.

19. A powder according to Claim 14, wherein said wetting agent is a non-ionic 5 surfactant, propylene glycol or glycerol.

20. A powder according to any one of Claims 14 to 19, wherein said polymer is ethyl cellulose and said fatty acid is stearic acid.

21. A powder according to any one of Claims 14 to 20, comprising the following constituents:-

Arg-containing microcapsules - 7.5 gram

Tartaric acid - 1.5 gram

Flavoring agents - 0.75 gram

Aspartame - 0.04 gram

Propylene glycol - 0.1 -0.2 gram

₁0

22. An oral aqueous composition containing:

a. an effective amount of microcapsules comprising Arg encapsulated by a coating material comprising one or more of a polymer, a lipid or a waxy material combined with at least one fatty acid;

b. at least one physiologically acceptable wetting agent;

₁5 c. at least one physiologically acceptable water-soluble acid or salts thereof; and

d. optionally, additional physiologically acceptable additives.

23. A composition according to Claim 22, wherein said Arg is L-Arg.

24. A composition according to Claim 22 or 23, further comprising one or more ₀ sweetening agents.

25. A composition according to Claim 22, wherein said polymer is a pH-independent polymer or a mixture of such polymers.

26. A composition according to Claim 25, wherein said polymer is selected from the group consisting of acrylates, methacrylates, polyvinyl acetate, cellulose and

5 cellulose derivatives.

27. A composition according to Claim 22, wherein said at least one fatty acid is selected from the group of acids consisting of adipic, stearic, oleic, linoleic, alpha-linoleic, palmitic or a mixture of these acids.

28. A composition according to Claim 22, wherein said wetting agent is a 10 non-ionic surfactant, propylene glycol or glycerol.

29. A composition according to any one of Claims 22 to 28, wherein said cellulose is ethyl cellulose and said fatty acid is stearic acid.

30. A composition according to Claim 22, wherein said water soluble acid is a water soluble organic acid.

15 31. A composition according to Claim 30, wherein said organic acid is selected from the group of acids consisting of tartaric, succinic, citric, phosphoric, acetic, fumaric, malic, lactic acid, a citrus-derived acid or a mixture of said acids.

32. A composition according to any one of Claims 22-31, comprising from about 30% to about 90% Arg-containing microcapsules, and from about 3% to about 35% 0 physiologically acceptable water soluble acid or salts thereof.

33. A composition according to any one of Claims 22-32 substantially lacking a bitter taste.

34. A method of preparing an oral composition containing:

i. microcapsules comprising Arg core encapsulated by a coating 5 material comprising one or more of a polymer, a lipid or a waxy material combined with at least one fatty acid;

ii. at least one physiologically acceptable wetting agent; and iii. at least one physiologically acceptable water-soluble acid or salts thereof;

the method comprising the steps of:

5 a. providing a mixture of said microcapsules, said at least wetting agent, and said at least one water-soluble acid or salt thereof, all of which being in a dry powder form;

b. dispersing the mixture obtained in (a) in an aqueous media to form an aqueous dispersion thereof.

10 35. A method according to Claim 34, further comprising the addition of one or more flavoring agents and/or sweetening agents.

36. A method according to Claim 34, wherein said dry mixture is dispersed in water.

37. A method according to Claim 34, wherein said dry mixture is dispersed in a 15 fruit juice.

38. A kit comprising: a. a dry powder mixture comprising: i. microcapsules comprising Arg core encapsulated by a coating material comprising one or more of a polymer, a lipid or a waxy material 0 combined with at least one fatty acid; ii. at least one physiologically acceptable wetting agent; and iii. at least one physiologically acceptable water-soluble acid or salts thereof; b. an aqueous solution for dispersing said dry powder to obtain an 5 aqueous composition; and c. instructions for use of said dry powder and aqueous dispersion, said instructions prescribing the administration of the aqueous composition obtained to a subject in need of said composition.

39. A kit according to Claim 38, further comprising one or more sweetening 5 agents.

40. A kit according to Claim 38, wherein said aqueous solution is distilled water.

41. A method of providing a subject with Arg-containing composition comprising the steps of: a. providing a dry powder mixture comprising:

10 (i) microcapsules comprising Arg core encapsulated by a coating material comprising one or more of a polymer, a lipid or a waxy material combined with at least one fatty acid;

(ii) at least one physiologically acceptable wetting agent; and

(iii) at least one physiologically acceptable water-soluble acid 15 or salts thereof;

b. dispersing an effective amount of said powder mixture in an aqueous media to form an aqueous composition thereof; and

c. orally administering said aqueous composition to said subject.

20 42. Microcapsules according to claim 1 wherein said core is formed of an inert pharmaceutically acceptable excipient, coated by an Arg formulation.

43. Microcapsules according to claim 42, wherein said Arg is L-Arg.

44. Microcapsules according to claim 42 or 43, wherein said inert excipient is selected from sugar, starch or mixtures thereof.

25 45. An oral composition comprising dry powder mixture according to claim 14, said composition being in the form of capsules, tablets, chewable tablets, effervescent tablets, effervescent powder, packaged granules, as a mixture in a sachet or adapted to any other adequate nutritive fonn.