Crystalline complex of oxidized glutathione trisulfide and amino acid

Abstract

PROBLEM TO BE SOLVED: To provide oxidized glutathione trisulfide having improved solubility in aqueous solvents and a method for producing the same. Another purpose of the present invention is to provide a method for improving the solubility of oxidized glutathione trisulfide in aqueous solvents. SOLUTION: The solubility of oxidized glutathione trisulfide in aqueous solvents can be improved by making the oxidized glutathione trisulfide and an amino acid into a crystalline complex. Also, a liquid composition which can be handled stably can be obtained by dissolving the crystalline complex in an appropriate aqueous solvent.

Description

Crystalline Complex of Oxidized Glutathione Trisulfide and an Amino Acid

[0001] The present invention relates to a crystalline complex of oxidized glutathione trisulfide and an amino acid.

[0002] In recent years, persulfides (also referred to as active sulfur compounds, supersulfur compounds, or supersulfur molecules) have attracted attention as glutathione-related substances and N-acetylcysteine-related substances, and their high reactivity and physiological activity are expected. However, it is known that persulfides of oxidized glutathione have high reactivity, that is, low stability, and furthermore, problems have been posed by their low solubility in water and tendency to precipitate compared to reduced glutathione (GSH) and oxidized glutathione (GSSG).

[0003] Heretofore, oxidized glutathione trisulfide dihydrate crystals obtained by purifying oxidized glutathione trisulfide, which is a type of oxidized glutathione persulfide, have been reported (Patent Document 1). This is considered to precipitate as persulfide hydrate crystals over time due to low solubility. In fact, when oxidized glutathione trisulfide dihydrate crystals are dissolved in water at room temperature and then left to stand at room temperature for a long time, they precipitate via recrystallization. Therefore, the concentration of an aqueous solution that does not form crystals is about 0.1%. Although persulfides of oxidized glutathione can be dissolved in strong acids such as hydrochloric acid to form high-concentration solutions, when intended for use as an external composition or oral composition, low-pH solutions are considered to have irritation to the skin and mucous membranes. For this reason, it is necessary to adjust to a usable pH after dissolution, or to use the solution diluted to a low concentration. On the other hand, although partial improvement in solubility is observed by increasing the pH through adding a basic solvent or compound, it has been known that decomposition of persulfides progresses under basic conditions.

[0004] As described above, it has been difficult to handle persulfides as stable liquid compositions due to their low stability caused by high reactivity and their property of easily precipitating.

[0005] On the other hand, a method for dissolving poorly soluble compounds is known, which involves using 1,2-diol compounds having a cyclohexane ring and an alkylene group (Patent Document 2). However, when using persulfides in cosmetics and topical preparations, there is often resistance to incorporating compounds that do not exist in nature or compounds that have not been used in existing products for stabilization purposes, and there has been a tendency to prefer products that use as many naturally derived ingredients as possible.

[0006] In addition, in terms of transportation costs and efficiency in general distribution, solid forms such as powders and granules were preferred over liquids.

[0007] Therefore, there was a need for an oxidized glutathione trisulfide with improved solubility, using existing naturally derived compounds that could be handled as solids such as powders or granules.

[0008] WO2018 / 117186 Pamphlet, Japanese Patent Publication No. 2022-031761

[0009] Br J Pharmacol., 176(4):671-683 (2019)

[0010] The object of the present invention is to provide an oxidized glutathione trisulfide with improved solubility in aqueous solvents, and a method for producing the same. Furthermore, the object is to provide a method for improving the solubility of oxidized glutathione trisulfide in aqueous solvents.

[0011] As a result of diligent research into the above-mentioned problems, the inventors of the present invention discovered that the solubility of oxidized glutathione trisulfide is improved by forming a crystalline complex of a specific amino acid with oxidized glutathione trisulfide, and thus completed the present invention.

[0012] In other words, the present invention relates to the following (1) to (11): (1) A crystalline complex of oxidized glutathione trisulfide and an amino acid. (2) The crystalline complex according to (1), wherein the amino acid is glycine, alanine, and serine. (3) The crystalline complex according to (1) or (2), wherein in powder X-ray diffraction using CuKα as an X-ray source, the diffraction angle (2θ) has peaks at 20.2°±0.2°, 28.1°±0.2°, 34.1°±0.2°, and 36.1°±0.2°. (4) The crystalline complex according to (3), wherein in powder X-ray diffraction using CuKα as an X-ray source, the diffraction angle (2θ) further has peaks at 16.6°±0.2°, 17.5°±0.2°, and 30.2°±0.2°. (5) A method for producing the crystalline complex described in (1), comprising the steps of obtaining a solution by coexisting oxidized glutathione trisulfide and an amino acid in a solvent, and removing the solvent from the solution. (6) A method for producing the crystalline complex described in (5), wherein the amount of amino acid is 4.5 to 20 parts by weight per 1 part by weight of oxidized glutathione trisulfide. (7) A method for producing the crystalline complex described in (5) or (6), wherein the step of removing the solvent is freeze-drying. (8) A method for producing an oxidized glutathione trisulfide solution, comprising the step of dissolving the crystalline complex described in (1) in a solvent. (9) A method for improving the solubility of oxidized glutathione trisulfide, characterized by forming a crystalline complex with an amino acid. (10) A topical composition containing the crystalline complex described in (1). (11) An oral composition containing the crystalline complex described in (1).

[0013] According to the present invention, the solubility of oxidized glutathione trisulfide in aqueous solvents can be improved by forming a crystalline complex of oxidized glutathione trisulfide and an amino acid. Furthermore, by dissolving the crystalline complex in a suitable aqueous solvent, a liquid composition that can be handled stably can be provided.

[0014] Powder X-ray diffraction spectrum of the crystalline composite of the present invention Powder X-ray diffraction spectrum of a mixture of the crystalline composite of the present invention and its freeze-dried product Infrared spectroscopic analysis spectrum of the crystalline composite of the present invention and a comparative sample Comparison of infrared spectroscopic analysis spectra of the crystalline composite of the present invention and a comparative sample Differential calorimetry spectrum of the crystalline composite of the present invention and a comparative sample

[0015] The crystalline complex of the present invention is a crystalline complex comprising oxidized glutathione trisulfide and a specific amino acid.

[0016] Here, the oxidized glutathione trisulfide (hereinafter sometimes referred to as GSSSG) in the present invention is the compound indicated by CAS number: 32607-79-7. Oxidized glutathione trisulfide can be produced using generally available oxidized glutathione (hereinafter sometimes referred to as GSSSG) as a starting material, based on previously published papers (Non-Patent Literature 1). For example, by reacting oxidized glutathione with peracetic acid on ice for 30 minutes, adding a solvent mixture of equal parts ethanol and THF (tetrahydrofuran), and then centrifuging the resulting precipitate, and further reacting the precipitate with sodium hydrogen sulfide at room temperature, an oxidized glutathione persulfide can be obtained in which one or more sulfur atoms are added to the disulfide bond of oxidized glutathione. By purifying this oxidized glutathione persulfide, oxidized glutathione trisulfide can be produced, and it can be obtained in crystalline, amorphous, solution, suspension, or other states. The amount of oxidized glutathione trisulfide can be determined using a common quantitative analysis method involving HPLC.

[0017] Furthermore, in the present invention, amino acids refer to compounds containing one or more amino groups and one or more carboxyl groups in a single molecule. Examples include glycine, alanine, valine, leucine, isoleucine, aspartic acid, glutamic acid, asparagine, glutamine, proline, phenylalanine, tryptophan, lysine, cysteine, methionine, tyrosine, arginine, histidine, serine, threonine, homoserine, and salts thereof. The amino acids included in the crystalline complex of the present invention can be those that are generally available, preferably one or more amino acids selected from the group consisting of glycine, alanine, and serine, more preferably two or more, and even more preferably glycine, alanine, and serine. Each amino acid can be quantified by analysis according to general methods, and for example, the amount of amino acids contained in the analytical sample can be determined from a calibration curve created from standards of known concentration using HPLC.

[0018] The weight ratio of oxidized glutathione trisulfide to the total amount of amino acids in the crystalline complex of the present invention is preferably 4.5 parts by weight or more, and more preferably 5 parts by weight or more, of oxidized glutathione trisulfide per 1 part by weight of amino acids. Furthermore, it is preferably 20 parts by weight or less, and more preferably 10 parts by weight or more, of amino acids per 1 part by weight of oxidized glutathione trisulfide.

[0019] The weight ratio of oxidized glutathione trisulfide to at least one amino acid in the crystalline complex of the present invention is preferably 1.5 parts by weight or more, and more preferably 1.66 parts by weight or more, of one amino acid per 1 part by weight of oxidized glutathione trisulfide. Furthermore, the weight ratio of oxidized glutathione trisulfide to at least one amino acid in the crystalline complex of the present invention is preferably 6.67 parts by weight or less, and more preferably 3.34 parts by weight or less, of one amino acid per 1 part by weight of oxidized glutathione trisulfide. Moreover, if the crystalline complex of the present invention contains multiple amino acids, it is preferably 6.67 parts by weight or less, and more preferably 3.34 parts by weight or less, of each amino acid per 1 part by weight of oxidized glutathione trisulfide.

[0020] The crystalline composite of the present invention is preferably one in which, in powder X-ray diffraction using CuKα as the X-ray source, the diffraction angles (hereinafter sometimes denoted as 2θ or 2Th.) have peaks at 20.2°±0.2°, preferably 0.1°, 28.1°±0.2°, preferably 0.1°, 34.1°±0.2°, preferably 0.1°, and 36.1°±0.2°, preferably 0.1°. The crystalline composite of the present invention is more preferably one in which, in powder X-ray diffraction using CuKα as the X-ray source, the diffraction angles (2θ) have peaks at 16.6°±0.2°, preferably 0.1°, 17.5°±0.2°, preferably 0.1°, and 30.2°±0.2°, preferably 0.1°. Such diffraction angle patterns are different from those of oxidized glutathione trisulfide dihydrate crystals reported to date. Powder X-ray diffraction using CuKα as the X-ray source can be performed using general techniques.

[0021] The crystalline composite of the present invention exhibits excellent solubility in aqueous solvents. Here, the aqueous solvent that can be used to dissolve the crystalline composite of the present invention refers to water, solvents that mix with water in any ratio, such as ethanol used in food and beverages, pharmaceuticals, and cosmetics, and buffer solutions, with water being a preferred aqueous solvent. The pH of the aqueous solvent in this case is preferably 2 to 7, more preferably 2.5 to 6.5, and even more preferably 3 to 6. The pH of the liquid composition may be adjusted by general methods.

[0022] The crystalline composite of the present invention dissolves when added to an aqueous solvent as described above and stirred at room temperature, making it easy to obtain a solution containing oxidized glutathione trisulfide. On the other hand, when the same procedure is performed on known oxidized glutathione trisulfide dihydrate crystals or lyophilized products, they do not dissolve completely and remain in the solution. An oxidized glutathione trisulfide solution can then be obtained by stirring while heating at about 60°C. Thus, because the crystalline composite of the present invention has superior solubility compared to known crystals, an oxidized glutathione trisulfide solution can be easily prepared.

[0023] The crystalline complex of the present invention can be produced by removing a solvent from a solution containing oxidized glutathione trisulfide and an amino acid. Specifically, it can be produced by a method comprising the steps of obtaining a solution by coexisting oxidized glutathione trisulfide and an amino acid in an aqueous solvent, and removing the solvent from the solution.

[0024] The method for obtaining a solution in which oxidized glutathione trisulfide and amino acids coexist in a solvent is not particularly limited; they may be added to the solvent simultaneously, or one may be added first. Alternatively, solutions of oxidized glutathione trisulfide and amino acids may be prepared separately and then mixed to bring them together in the solution. When using two or more types of amino acids, the order and timing of addition can be set as appropriate. Furthermore, the method may include a step of concentration after the oxidized glutathione trisulfide and amino acids have coexisted in the solution.

[0025] Furthermore, in the production of the crystalline composite of the present invention, a general drying process can be used to remove the solvent from the solution containing oxidized glutathione trisulfide and amino acids, but spray drying or freeze-drying is preferred, and freeze-drying is more preferred.

[0026] Furthermore, the present invention relates to a method for improving the solubility of oxidized glutathione trisulfide in aqueous solvents. The method for improving the solubility of oxidized glutathione trisulfide in aqueous solvents is to form a crystalline complex between oxidized glutathione trisulfide and an amino acid. The method for forming the crystalline complex can be achieved by the method described above.

[0027] The crystalline complex of the present invention can be used as is in the form of an oral composition or a topical composition as a pharmaceutical, supplement, food or beverage, or cosmetic. Furthermore, an oxidized glutathione trisulfide solution obtained by dissolving the crystalline complex of the present invention in an aqueous solvent can be used as a topical composition applicable to the skin or mucous membranes, or as an orally ingestible pharmaceutical, food or beverage, or cosmetic.

[0028] In addition, mixtures with other materials may be used, as long as they do not hinder the effects of the present invention. The form of compositions containing materials other than the crystalline composite of the present invention is not limited as long as they can be taken orally, applied to the skin, or used as injections. They can be prepared in the form of solutions, dispersions, powders, granules, capsules, tablets, pastes, gels, or sheets according to conventional methods using solvents and base materials commonly used in foods, supplements, cosmetic compositions, pharmaceutical compositions, topical skin preparations, and injections, or they may be prepared as kits for on-demand preparation.

[0029] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

[0030] The persulfide was prepared by the following method based on a previously published paper (Non-Patent Literature 1). Commercially available oxidized glutathione was dissolved in ultrapure water to prepare a 170 mM aqueous solution of oxidized glutathione. 4 mL of 32 wt% peracetic acid solution was added to 2.5 mL of this aqueous solution and reacted on ice for 30 minutes. 30 mL of a solvent mixture of equal parts ethanol and tetrahydrofuran was added to the resulting reaction mixture and the mixture was centrifuged at 10,000 rpm for 10 minutes at 4°C. The recovered precipitate was dried under reduced pressure for 1 hour. 2.5 mL of ultrapure water was added to the dried product and dissolved. An equal volume of sodium hydrogen sulfide solution, prepared to 60 mM with 0.3 M aqueous sodium hydroxide solution, was added and reacted at room temperature for 1 hour to obtain oxidized glutathione persulfide. The obtained oxidized glutathione persulfide was purified using a synthetic adsorption resin, concentrated, and dried to obtain oxidized glutathione trisulfide (GSSG) powder.

[0031] (Preparation of Crystalline Complex) To 1 part by weight of the obtained GSSSG, GSSSG and amino acids were added to water so that each amount was 3 parts by weight of commercially available reagent-grade glycine, alanine, and serine (all manufactured by Fujifilm Wako Pure Chemical Industries), and a solution containing GSSSG and amino acids in a weight ratio of 1:9 was prepared. At this time, the concentration of GSSSG was adjusted to 0.05% by weight. This solution was concentrated until the GSSSG concentration reached 2% by weight, passed through a 0.2 μm filter, and then freeze-dried to obtain a crystalline complex containing GSSSG and amino acids. This crystalline complex was designated as Sample 1 of the present invention. In addition, a solution was prepared and concentrated containing 3% by weight of GSSSG, glycine, alanine, and serine in a ratio of 1:1:1, and the total amount of the three types of amino acids per 1 part by weight of GSSSG was 5 parts by weight. This solution was freeze-dried to obtain a crystalline complex containing GSSSG and amino acids. This crystalline complex was designated as Sample 2 of the present invention.

[0032] In addition, an attempt was made to produce a crystalline complex by preparing a solution containing 3% by weight of GSSSG, glycine, alanine, and serine in a 1:1:1 ratio, and with 4 parts by weight of amino acids per 1 part by weight of GSSSG, using a similar method. However, precipitation of GSSSG was observed, and a crystalline complex could not be obtained.

[0033] (Confirmation of solubility of crystalline complex) When sample 1 of the present invention was added to water at a concentration of 1% by weight (0.1% by weight in terms of oxidized glutathione trisulfide dihydrate) and stirred at room temperature, it dissolved completely and a clear solution was obtained. Similarly, when sample 2 was added to water at a concentration of 0.6% by weight (0.1% by weight in terms of oxidized glutathione trisulfide dihydrate) and the same procedure was performed, it dissolved completely and a clear solution was obtained. On the other hand, when oxidized glutathione trisulfide dihydrate crystals were added to water at a concentration of 0.1% by weight and stirred at room temperature, they did not dissolve completely, and a suspension was obtained in which some dihydrate crystals were observed in the liquid. When this suspension was heated to 60°C, it dissolved completely and a clear solution was obtained. From this, it was clear that the crystalline complex of the present invention exhibits excellent solubility. Furthermore, it was shown that the solubility of oxidized glutathione trisulfide in aqueous solvents is improved by forming a crystalline complex with an amino acid.

[0034] (Powder X-ray diffraction of crystalline complexes) Sample 1, a crystalline complex of oxidized glutathione trisulfide (GSSSG) and an amino acid, was subjected to powder X-ray diffraction several times using CuKα as the X-ray source. For comparison, crystalline oxidized glutathione trisulfide dihydrate (Sample 3) was similarly subjected to powder X-ray diffraction. In addition, as a comparison for Sample 2, a crystalline complex of oxidized glutathione trisulfide (GSSSG) and an amino acid, a mixture of lyophilized oxidized glutathione trisulfide (GSSSG) and lyophilized glycine, alanine, and serine (mixing date was the same as for Sample 2; Sample 4) was similarly subjected to powder X-ray diffraction.

[0035] (Measurement conditions for powder X-ray diffraction) Measurement device Aeris Research edition (Malvern Panalogical) X-ray output setting 15 mA, 40 kV Goniometer radius [mm] 145.00 Scan axis Gonio Start position [°2Th.] 5.0407 End position [°2Th.] 69.9707 Step size [°2Th.] 0.0430 Scan step time [s] 96.3900 Scan type Continuous PSD mode Scan PSD distance [°2Th.] 5.54 Offset [°2Th.] 0.0000 Divergent slit (DS) type Fixed divergent slit (DS) size [°] 0.1146 Sample width [mm] 10.00 Measurement temperature [°C] 25.00 Target: Cu Intended Wavelength Type: K-α1 Distance between focus and DS [mm]: 95.00 Incident monochromator: None

[0036] (Results of Powder X-ray Diffraction) Table 1 shows the diffraction angles (2Th.) with a relative intensity ratio of 10 or more from the powder X-ray diffraction results of Sample 1. Figure 1 shows the XRD (powder X-ray diffraction) chart of Sample 1. For Sample 3, only characteristic peaks are shown in the figure. From these results, it was confirmed that there are peaks common to Sample 1 and Sample 3, while peaks specific to Sample 1 were also observed. In other words, it became clear that Sample 1 and Sample 3 give different diffraction angles. Furthermore, in the powder X-ray diffraction of the freeze-dried oxidized glutathione trisulfide solution, a broad chart was obtained, and clear diffraction angles and diffraction patterns could not be obtained. In addition, Figure 2 shows the XRD (powder X-ray diffraction) charts of Sample 2 and Sample 4. As a result, it was shown that Sample 2, which was freeze-dried with freeze-dried oxidized glutathione trisulfide (GSSSG) and three types of amino acids, and Sample 4, which was a mixture of the freeze-dried products, give different spectra. Furthermore, although not shown in the diagram, when oxidized glutathione trisulfide dihydrate crystals were used instead of the freeze-dried product and mixed with three freeze-dried amino acids, and subjected to powder X-ray diffraction, it was found that a different spectrum from that of sample 2 was obtained.

[0037]

[0038] (Infrared Spectroscopic Analysis of Crystalline Complexes) Infrared spectroscopy was performed on the crystalline complex of the present invention, which consists of oxidized glutathione trisulfide (GSSSG) and an amino acid (Sample 1), oxidized glutathione trisulfide dihydrate crystals (Sample 3), and a mixture of oxidized glutathione trisulfide dihydrate crystals and glycine, alanine, and serine crystals in the same proportion as Sample 1 (Sample 5), using an FT / IR-6100 (manufactured by JASCO Corporation). In addition, infrared spectroscopy was performed on the sample containing only glycine, alanine, and serine used in Sample 4 (Sample 6). Prior to the infrared spectroscopy, the infrared spectral spectra of the glycine, alanine, and serine crystals and lyophilized products were examined, and no significant differences were observed between the crystals and the lyophilized products. Furthermore, when the infrared spectral spectra of a freeze-dried solution containing three types of amino acids and a sample (sample 6) containing a mixture of crystals of each amino acid were examined, no significant differences were observed between the freeze-dried product and the crystalline mixture.

[0039] (Results of Infrared Spectroscopic Analysis) Figure 3 shows the results of infrared spectroscopic analysis of samples 1, 3, 5, and 6. Figure 4 shows the superimposed spectra of samples 1 and 3. Comparing sample 1 and sample 3, it became clear that they yielded infrared spectroscopic spectra with different peak patterns. Furthermore, when comparing sample 1 with a sample (sample 5) which was a mixture of oxidized glutathione trisulfide dihydrate and glycine, alanine, and serine crystals, the peaks in the infrared spectroscopic spectra showed different patterns. It also showed a different peak pattern when compared with sample 6, which was a mixture of crystalline amino acids. From the above results of infrared spectroscopic analysis, it is suggested that the crystalline complex of the present invention has a different structure from oxidized glutathione trisulfide dihydrate crystals. It is also suggested that it has a different structure from a sample which was a mixture of oxidized glutathione trisulfide dihydrate and amino acid crystals.

[0040] (Differential Calorimetry of Crystalline Complexes) Differential calorimetry (DSC) was performed on Sample 1, a crystalline complex of oxidized glutathione trisulfide (GSSG) and an amino acid; Sample 3, crystals of oxidized glutathione trisulfide dihydrate; Sample 5, a mixture of oxidized glutathione trisulfide dihydrate crystals and glycine, alanine, and serine crystals; and Sample 6, a mixture of equal amounts of glycine, alanine, and serine, using a DSC-60A Plus (Shimadzu Corporation). Differential calorimetry was performed by heating the samples to 300°C with a starting temperature of 0°C and a heating rate of 10°C / min, and analyzing them with a sampling interval of 1.0 second.

[0041] (DSC Results) The results are shown in Figure 5. Comparing Sample 1 and Sample 3, Sample 1, which is the crystalline composite of the present invention, showed peaks at 197.24°C, 247.62°C, and 274.53°C, while Sample 3, which is an oxidized glutathione trisulfide dihydrate crystal, showed a peak at 187.19°C. Furthermore, in Sample 5, which was a mixture of oxidized glutathione trisulfide dihydrate crystals and glycine, alanine, and serine crystals, peaks were observed at 210.74°C, 243.98°C, and 265.89°C. When a sample (Sample 6), which was a mixture of equal amounts of glycine, alanine, and serine, was analyzed, peaks were observed at 222.64°C, 251.76°C, and 279.14°C. The results above suggest that the crystalline complex of the present invention has a structure different from a mixture of amino acids alone, oxidized glutathione trisulfide dihydrate crystals, and mixtures thereof.

[0042] From the above, it was revealed that the crystalline complex containing oxidized glutathione trisulfide and amino acids exhibits superior solubility compared to known oxidized glutathione trisulfide dihydrate crystals. Furthermore, results from powder X-ray diffraction, infrared spectroscopy, and differential calorimetry suggested that it has a different structure from existing crystal mixtures. Since the amino acids used in this invention can be used in cosmetics and food products, the crystalline complex of this invention can be used in general food and beverage products, cosmetics, pharmaceuticals, etc.

Claims

A crystalline complex of oxidized glutathione trisulfide and an amino acid. The crystalline complex according to claim 1, wherein the amino acids are glycine, alanine, and serine. The crystalline composite according to claim 1 or 2, wherein, in powder X-ray diffraction using CuKα as an X-ray source, it has peaks at diffraction angles (2θ) of 20.2°±0.2°, 28.1°±0.2°, 34.1°±0.2°, and 36.1°±0.2°. The crystalline composite according to claim 3, wherein, in powder X-ray diffraction using CuKα as an X-ray source, it further has peaks at diffraction angles (2θ) of 16.6°±0.2°, 17.5°±0.2°, and 30.2°±0.2°. A method for producing a crystalline complex according to claim 1, comprising the steps of obtaining a solution by coexisting oxidized glutathione trisulfide and an amino acid in a solvent, and removing the solvent from the solution. The manufacturing method according to claim 5, wherein the amount of amino acids is 4.5 to 20 parts by weight per 1 part by weight of oxidized glutathione trisulfide. The manufacturing method according to claim 5 or 6, wherein the step of removing the solvent is freeze-drying. A method for producing an oxidized glutathione trisulfide solution, comprising the step of dissolving the crystalline complex described in claim 1 in a solvent. A method for improving the solubility of oxidized glutathione trisulfide, characterized by forming a crystalline complex with an amino acid. A topical composition comprising the crystalline complex described in claim 1. An oral composition comprising the crystalline complex described in claim 1.

Images