KR20180013148A - Composition for injection having improved solubility and stability - Google Patents

Abstract

The present invention relates to a composition for injection comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, a cyclodextrin or a derivative thereof and an organic acid, and a process for preparing the same.

Description

[0001] The present invention relates to a composition for injecting improved stability and solubility,

The present invention relates to a process for the preparation of (S) -4 ((5,7-difluorochroman-4-yl) oxy) -N, N-2-trimethyl-1H- benzo [d] imidazole- A pharmaceutically acceptable salt thereof, and a process for producing the same.

In general, in order to develop a drug having a very low water solubility as a injectable composition, an excess amount of a solubilizing agent and an organic solvent base are required. However, in the case of a pharmaceutical composition containing a lot of solubilizing agent and organic solvent, there is a problem that hypersensitivity may occur when a high dose of the active ingredient is administered.

For example, docetaxel, a well-known poorly soluble drug, is solubilized using polysorbate having a high viscosity. In this case, the 0.22um filtration process, which is essential for the preparation of the injectable form, is not easy, There is also a problem that hypersensitive reaction occurs due to the use of polysorbate.

In International Patent No. WO 99/24073, the water solubility of docetaxel was increased using certain cyclodextrins. In the above patent, docetaxel is dissolved in a small amount of ethanol, and then acetyl gamma cyclodextrin (Ac-gamma-CD) or hydroxypropylbetacyclodextrin (HP-beta-CD) is added to dissolve the above mixture in an aqueous solvent Process. Further, it is known to remove the ethanol and then freeze-dry it to prepare a freeze-dried composition.

However, in the above patent, the ratio of docetaxel to cyclodextrin may be as high as 1: 400, so that the amount of cyclodextrin used for solubilizing 80 mg of docetaxel is very large, the volume of the lyophilized product becomes large, do. In addition, ethanol used to dissolve docetaxel is likely to remain.

(S) -4 ((5,7-difluorochroman-4-yl) oxy) -N, N-2-trimethyl-1H- benzo [d] imidazole- (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, gastritis, Helicobacter pylori infection, gastroesophageal reflux disease, gastroesophageal reflux disease, gastroesophageal reflux disease (Including, but not limited to, dyspepsia, functional dyspepsia, Kollinger-Ellison syndrome, NERD, visceral pain, heartburn, nausea, esophagitis, dysphagia, salivation, Lt; RTI ID = 0.0 > (I) < / RTI > acid pump antagonistic activity. The above compounds are insoluble in water and have a very low solubility under a pH environment of neutral or above, which makes them difficult to formulate and dissolve in an aqueous solution.

(S) -4 ((5,7-difluorochroman-4-yl) oxy) -N, N-2-trimethyl- The 1H-benzo [d] imidazole-6-carboxamide has an extremely poor chemical structural stability in an acidic environment, resulting in an increase in degradation products.

Therefore, there is a need for studies on the formulation of such compounds which are excellent in storage stability and which ensure solubility that can be used as injections and which do not use solubilizing agents such as ethanol or polysorbate which may have adverse effects as injections.

WO99 / 24073

It is an object of the present invention to provide a injectable composition comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, a cyclodextrin and an organic acid, and a process for producing the same.

[Chemical Formula 1]

.

.

As one aspect for solving the above problems, the present invention provides a injectable composition comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, a cyclodextrin and an organic acid.

[Chemical Formula 1]

In the present invention, the compound of Formula 1 is a novel substance that prevents and treats bleeding related to gastrointestinal diseases and gastrointestinal diseases by pharmacological mechanism of Potassium competitive acid blocker (P-CAB). The compound of formula (1) is insoluble or sparingly soluble in a neutral to basic environment and extremely poor in chemical structural stability in an acidic environment, resulting in an increase in degradation products.

In order to formulate the compound of formula (1) into the composition for injection, the compound of formula (1) must be dissolved and the stability of the dissolved composition should be ensured.

The present inventors have tried various formulations to develop a injectable composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof as a result of which a compound of the formula (I) or a pharmaceutically acceptable salt thereof It has been found that when the injectable composition contains cyclodextrin and organic acid, complete dissolution of the compound of formula (I) and excellent formulation stability are achieved.

In the present invention, the compound of Formula 1 may be a free base or a pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts of the compounds of formula (I) in the present invention include acid addition salts and base salts. The acid addition salts include, for example, acid addition salts such as acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, eddylate, Hydrobromide / bromide, hydroiodide / iodide, bromide, bromide, bromide, iodide, bromide, iodide, Salicylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, isoleuconate, isoleuconate, isoleuconate, / Hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, A Te-rate, succinate, burnt carbonate, tartrate, tosylate, trifluoro acetate, and has a fabric Gino benzoate salt.

In addition, base addition salts include alkali metal salts such as lithium salts, sodium salts and potassium salts; Alkaline earth metal salts such as calcium salts and magnesium salts; Ammonium salts; Organic base salts such as triethylamine salt, diisopropylamine salt and cyclohexylamine salt, and the like. Specifically, the salt is an alkali metal salt, more specifically, a sodium salt.

For a general description of suitable salts, see Stahl and Wermuth, Wiley-VCH, Wainheim, Germany, 2002, Handbook of Pharmaceutical Salts: Properties, Selection, and Use. If appropriate, the pharmaceutically acceptable salts of the compounds of formula I can be readily prepared by mixing together the desired acid or base with a solution of the compound of formula (I).

The injectable composition according to the present invention includes cyclodextrin or derivatives thereof. The cyclodextrin is a cyclic oligosaccharide in which 6 to 12 glucose molecules are alpha-1,4-glycosidic bonds. Alpha (alpha) -cyclodextrin to which 6 glucose molecules are linked, and 7 glucose molecules are linked Beta (beta) -cyclodextrin, gamma (gamma) -cyclodextrin to which 8 glucose molecules are linked, and the like.

Cyclodextrins are classified into alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and the like depending on the number of glucose molecules. The cyclodextrins usable in the present invention include all of the above-mentioned three kinds of cyclodextrin derivatives, and more specifically, betacyclodextrins or derivatives thereof in which seven glucose units are cyclic. Methyl and hydroxyethyl, hydroxypropyl betacyclodextrin and sulfobutyl ether betacyclodextrin derivatives are present depending on the alkyl group substituted in the glucose unit, and the composition of the present invention is preferably commercially available as an injection, Hydroxypropylbetacyclodextrin (HP-β-CD) or sulfobutyletherbetacyclodextrin (SBE-β-CD) can be used.

In the injectable composition of the present invention, the content of the cyclodextrin or its derivative may be 1 to 100 parts by weight, and preferably 2 to 40 parts by weight based on 1 part by weight of the compound of formula (1). If the injectable composition according to the present invention contains too much cyclodextrin or a derivative thereof, the viscosity of the injectable composition becomes too high and the filtration step is not easy. On the other hand, when the cyclodextrin or its derivative is contained in too small amount, Solubility and stability can not be secured.

The injectable composition of the present invention also includes an organic acid. The organic acid may be, for example, at least one selected from the group consisting of tartaric acid, pyroglutamic acid, malic acid, citric acid and lactic acid, but is not limited thereto.

The content of the organic acid may be 0.1 to 100 parts by weight, preferably 0.1 to 4.0 parts by weight based on 1 part by weight of the compound of formula (1). When the organic acid is contained in an amount of less than 0.1 part by weight, the active ingredient can not be sufficiently dissolved. When the organic acid is contained in an amount of more than 4.0 parts by weight, the stability is poor under severe conditions due to the unstable active ingredient.

The injectable composition according to the present invention may further comprise at least one water-soluble polymer in addition to the compound of formula (I) or a pharmaceutically acceptable salt thereof, cyclodextrin and organic acid. Examples of the water-soluble polymer include polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), hydroxymethylcellulose (HMC), hydroxyethyl Cellulose (HEC) and hydroxypropyl methylcellulose (HPMC) may be used. The content of the water-soluble polymer may be 0.1 to 100 parts by weight, specifically 0.1 to 4.0 parts by weight based on 1 part by weight of the compound of formula (1). If the water-soluble polymer is used in an amount of more than 4.0 parts by weight, the viscosity of the solution is excessively increased, and filtration after the dissolution is impossible.

The injectable composition of the present invention may be in the form of a liquid or a dry powder. The main-use dry powder may be reconstituted into injectable water, physiological saline solution, glucose solution, amino acid solution, etc. to be administered to a patient when administered to a patient.

The drying can be carried out by a conventional drying method, for example, freeze-drying, rotary evaporation drying, spray drying, or fluidized bed drying, and can be carried out by lyophilization.

The present invention also provides, in another aspect, a process for preparing a cyclodextrin or a derivative thereof, comprising the steps of: a) dissolving a cyclodextrin or a derivative thereof and an organic acid in an aqueous medium; b) mixing and dissolving the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof in the solution prepared in the step (a)

[Chemical Formula 1]

; 및

; And

And sterilizing the mixed solution prepared in the step (b) and freeze-drying the mixture.

The cyclodextrin or derivative thereof, the organic acid, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof are as described above.

More specifically, the preparation method of the present invention dissolves a cyclodextrin or a derivative thereof in an aqueous medium and dissolves a compound of the formula (1) or a pharmaceutically acceptable salt thereof therein. Wherein the aqueous medium may be distilled water, injectable water or physiological saline.

Thereafter, stabilization is induced by sufficiently stirring the mixture of the cyclodextrin or its derivative, the organic acid and the compound of formula (1) or a pharmaceutically acceptable salt thereof, and the mixture is filtered through sterilization filtration, for example, a 0.22um filter, .

At this time, the stirring is carried out at a temperature range of 5 to 50 ° C, specifically at 15 to 30 ° C. Further, the filtered mixture is frozen at a low temperature of -30 ° C or below for freeze-drying and then decompressed-dried in a frozen state to prepare a white or almost white freeze-dried composition.

Preferably, the cyclodextrin may be hydroxypropyl-beta cyclodextrin (HP-beta-CD) or sulfobutyl ether-beta cyclodextrin (SBE- beta -CD).

Also, preferably, the organic acid is any one selected from the group consisting of tartaric acid, pyroglutamic acid, malic acid, citric acid, and lactic acid.

Also, the aqueous medium of step (a) preferably further comprises at least one water-soluble polymer. Examples of the water-soluble polymer include polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), hydroxymethylcellulose (HMC), hydroxyethyl Cellulose (HEC) and hydroxypropyl methylcellulose (HPMC) may be used.

The lyophilized composition prepared above can be stored for a long period of time by securing an excellent stability against temperature and humidity, and is easily formulated with an injection. In addition, there is no additive to cause ethanol or hypersensitive side effects, so it is not harmful to use in human body.

The injectable composition according to the present invention not only completely dissolves the compound of formula (1) but also has excellent storage stability, and therefore is effective and can be used as an injection for long-term storage.

1 is a graph comparing the amounts of total flexible substances produced during storage under the harsh conditions (60 DEG C, 80% RH) while storing the freeze-dried composition for main use according to Examples 1 to 17 and Comparative Examples 3 to 6 to be.

Hereinafter, the present invention will be described in detail with reference to preferred embodiments thereof for better understanding of the present invention. However, the following examples are provided to further understand the present invention, and the present invention is not limited by the examples.

Example  1 to 6: hydroxypropyl-beta- Cyclodextrin  ≪ / RTI > and an organic acid.

(HP-β-CD), tartaric acid and polyethylene glycol (PEG) were weighed in the amounts shown in Table 1, and they were dissolved in distilled water for injection by stirring at room temperature, And then dissolved in the above solution by stirring. Then, the solution was filtered through a 0.22-μm filter and then lyophilized to prepare a freeze-dried composition for main use. The prepared freeze-dried composition was white or almost white. The specific ingredients and contents contained in the composition are the same as in Table 1 (unit: mg).

Example  7: Sulfobutyl ether -beta- Cyclodextrin  ≪ / RTI > and an organic acid.

(SBE-? -CD), tartaric acid and polyethylene glycol (PEG) were weighed in the amounts shown in Table 1, and after they were dissolved in distilled water for injection by stirring at room temperature, And then dissolved in the above solution by stirring. Then, the solution was filtered through a 0.22-μm filter and then lyophilized to prepare a freeze-dried composition for main use. The prepared freeze-dried composition was white or almost white. The specific ingredients and contents contained in the composition are the same as in Table 1 (unit: mg).

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 The compound of formula (1) 100 50 25 100 100 100 100 HP-β-CD 4000 600 300 2000 1000 500 SBE-β-CD 1674 Tartaric acid 50 25 12.5 50 50 100 25 PEG 400 200 100 50 200 200 200 200

Example  8 to 13: hydroxypropyl-beta- Cyclodextrin  ≪ / RTI > and an organic acid.

(HP-β-CD), tartaric acid or citric acid and polyethylene glycol (PEG) were weighed in the amounts shown in Table 2, and they were dissolved in distilled water for injection by stirring at room temperature. The compound was dissolved in the above solution by stirring. Then, the solution was filtered through a 0.22-μm filter and then lyophilized to prepare a freeze-dried composition for main use. The prepared freeze-dried composition was white or almost white. The specific ingredients and contents contained in the composition are as shown in Table 2 (unit: mg).

Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 The compound of formula (1) 100 100 100 100 100 100 HP-β-CD 1200 1200 1200 1600 2000 1600 Citric acid 50 100 Tartaric acid 50 100 200 50 PEG 400 200 50 100 400

Example  14 to 17: Hydroxypropyl-beta- Cyclodextrin  ≪ / RTI > and an organic acid.

Hydroxypropyl-β-cyclodextrin (HP-β-CD), 2-hydroxyglutaric acid-γ-lactone, pyroglutamic acid, malic acid and polyethylene glycol (PEG) , And they were dissolved in distilled water for injection by stirring at room temperature. Then, the compound of formula (I) was added to the above solution and dissolved by stirring. Then, the solution was filtered through a 0.22-μm filter and then lyophilized to prepare a freeze-dried composition for main use. The prepared freeze-dried composition was white or almost white. The specific ingredients and content contained in the composition are the same as in Table 3 (unit: mg).

Example 14 Example 15 Example 16 Example 17 The compound of formula (1) 100 100 100 100 HP-β-CD 2000 200 1600 250 Lactic acid 50 Pyroglutamic acid 70 35 Malian 70 PEG 400 200

Comparative Example  One

Was prepared by dissolving the compound of formula (1) in water for injection without adding other excipients. The specific ingredients and contents contained in the composition are as shown in Table 4 (unit: mg).

Comparative Example  2

The procedure of Example 4 was repeated except that no organic acid was used. The specific ingredients and contents contained in the composition are as shown in Table 4 (unit: mg).

Comparative Example 1 Comparative Example 2 The compound of formula (1) 100 100 HP-β-CD 2000 PEG400 200

Comparative Example  3 to 6

Beta-cyclodextrin (HP-beta-CD), D-mannitol, sorbitol and polyethylene glycol (PEG) were weighed in the composition and content shown in Table 5 below and stirred at room temperature with distilled water for injection After adding citric acid or phosphoric acid, the compound of formula (1) was added to the solution and stirred. Then, the solution was filtered through a 0.22-μm filter and then lyophilized to prepare a freeze-dried composition for main use. The specific ingredients and content contained in the composition are the same as in Table 5 (unit: mg).

Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 The compound of formula (1) 100 100 100 100 HP-β-CD 2000 D-mannitol 200 200 Sorbitol 200 Citric acid 150 150 Phosphoric acid 50 100 PEG 400 200 200

Test Example  1: Stability evaluation

The stability of the freeze-dried composition for injection-use obtained in Examples 1 to 17 and Comparative Examples 3 to 6 was evaluated under a harsh condition (60 ° C, 80% RH). Stability was evaluated by the amount of total flexible material produced during storage. The analytical conditions for measuring the content of the flexible substance are as follows.

Column: Column packed with octadecyl silica gel for liquid chromatography (4.6 mm x 15 cm x 2.7 um)

Column temperature: constant temperature around 30 ° C

Detector: Ultraviolet absorptiometer (measuring wavelength: 220 nm)

Flow rate: 0.8 mL / min

Mobile phase gradient condition

The results are shown in the following Table 6 as the total peak area% relative to the total content of the flexible substances.

Early 2 weeks 4 weeks Example 1 0.15 0.15 0.18 Example 2 0.16 0.17 0.16 Example 3 0.17 0.21 0.18 Example 4 0.11 0.17 0.15 Example 5 0.23 0.17 0.23 Example 6 0.27 0.25 0.30 Example 7 0.11 0.11 0.11 Example 8 0.17 0.18 0.18 Example 9 0.17 0.35 0.37 Example 10 0.18 0.23 0.24 Example 11 0.11 0.19 0.19 Example 12 0.12 0.22 0.22 Example 13 0.12 0.13 0.13 Example 14 0.12 0.12 0.12 Example 15 0.18 0.25 0.31 Example 16 0.18 0.19 0.21 Example 17 0.22 0.27 0.34 Comparative Example 3 0.45 4.37 8.19 Comparative Example 4 0.73 3.01 7.64 Comparative Example 5 0.24 2.52 4.90 Comparative Example 6 0.55 2.34 4.32

As shown in Table 6, in Examples 1 to 17, the amount of the total flexible material after storage for 4 weeks under severe conditions was 0.5% or less, while the amount of the flexible materials in Comparative Examples 3 to 6 was observed from 4.32 to 8.19% It was confirmed that the storage stability of the injectable composition according to the present invention was excellent.

Test Example  2: Evaluation of solubility

The water solubility of the compound of the formula (1) was measured by the comparative example 1 (the concentration of the compound of the formula (1): 10 mg / ml). Further, a solution containing the components described in Examples 1 to 17 and Comparative Example 2 was prepared at a concentration of 10 mg / ml, the solution was filtered through a 0.22-μm filter, and the properties of the solution before freeze- And the content of the compound was measured. The content was analyzed under the same conditions as in Test Example 1 and the results are shown in Table 7 (unit: mg / mL).

The compound < RTI ID = 0.0 > Solution property Example 1 10.04 Clear solution Example 2 10.01 Clear solution Example 3 10.05 Clear solution Example 4 10.04 Clear solution Example 5 10.02 Clear solution Example 6 10.06 Clear solution Example 7 10.02 Clear solution Example 8 10.11 Clear solution Example 9 10.07 Clear solution Example 10 10.12 Clear solution Example 11 10.02 Clear solution Example 12 10.05 Clear solution Example 13 10.09 Clear solution Example 14 10.01 Clear solution Example 15 10.03 Clear solution Example 16 10.21 Clear solution Example 17 10.14 Clear solution Comparative Example 1 0.02 Not transparent Comparative Example 2 1.82 Not transparent

As a result, as shown in Table 7, it was observed that the solutions of Examples 1 to 17 were completely dissolved and transparent to the compound of Formula 1, while the solutions of Comparative Examples 1 and 2 did not dissolve the compound of Formula 1 And it was possible to observe an unstructured image. In Examples 1 to 17, 10 mg / ml of the compound of Formula 1 was detected to show high solubility, whereas Comparative Examples 1 and 2 showed very low solubilities of 0.02 mg / ml and 1.82 mg / ml, respectively. As a result, it was confirmed that the injectable composition of the present invention exhibited far superior solubilization as compared with Comparative Example 1 which does not include both cyclodextrin and organic acid and Comparative Example 2 which does not include organic acid.

Test Example  3: Stability evaluation

After storing Examples 1 to 17 and Comparative Example 6 under harsh conditions (60 ° C, 80% RH), the content% of the compound of Chemical Formula 1 and changes in properties were confirmed. The content was analyzed under the same conditions as in Test Example 1 and the results are shown in Table 8.

content % Appearance Early 2 weeks 4 weeks Early 4 weeks Example 1 100.59 101.26 100.08 Clear solution Clear solution Example 2 103.52 102.28 102.76 Clear solution Clear solution Example 3 99.85 101.31 100.11 Clear solution Clear solution Example 4 101.20 100.87 98.31 Clear solution Clear solution Example 5 100.91 99.75 102.32 Clear solution Clear solution Example 6 103.19 102.35 98.37 Clear solution Clear solution Example 7 101.34 100.53 102.21 Clear solution Clear solution Example 8 100.21 99.88 101.14 Clear solution Clear solution Example 9 100.43 101.97 103.54 Clear solution Clear solution Example 10 97.56 100.18 100.32 Clear solution Clear solution Example 11 100.23 103.71 99.76 Clear solution Clear solution Example 12 102.35 98.13 100.35 Clear solution Clear solution Example 13 99.73 102.39 100.19 Clear solution Clear solution Example 14 102.35 100.69 103.49 Clear solution Clear solution Example 15 102.32 100.23 98.73 Clear solution Clear solution Example 16 101.56 99.53 100.04 Clear solution Clear solution Example 17 99.98 101.97 100.78 Clear solution Clear solution Comparative Example 6 99.50 96.71 93.37 Clear solution Sedimentation

As shown in Table 8, in Comparative Example 6, precipitation occurred during redispersion after 4 weeks under severe conditions, and it was confirmed that the content of the compound of Chemical Formula 1 was lowered. On the other hand, in Examples 1 to 17, there was no change in the content of the compound of Chemical Formula 1, and it was confirmed that the freeze-dried formulation remained in a transparent solution state even upon redispersion, so that the composition of the present invention had excellent stability and high solubility .

Claims (13)

A composition for injection comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, cyclodextrin and an organic acid:
[Chemical Formula 1]

. The injectable composition of claim 1, wherein the cyclodextrin is beta-cyclodextrin or a derivative thereof. The injectable composition according to claim 1, wherein the cyclodextrin is hydroxypropyl-beta-cyclodextrin (HP-beta -CD) or sulfobutyl ether-beta-cyclodextrin (SBE- beta -CD). The injectable composition according to claim 1, wherein the cyclodextrin content is 2 to 40 parts by weight based on 1 part by weight of the compound 1 represented by the formula (1) or a pharmaceutically acceptable salt thereof. The injectable composition according to claim 1, wherein the organic acid is at least one selected from the group consisting of tartaric acid, pyroglutamic acid, malic acid, citric acid and lactic acid. The injectable composition according to claim 1, wherein the content of the organic acid is 0.1 to 4 parts by weight based on 1 part by weight of the compound 1 represented by the formula (1) or a pharmaceutically acceptable salt thereof. The composition according to claim 1, further comprising at least one polymer selected from the group consisting of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), hydroxymethylcellulose HMC) and hydroxyethylcellulose (HEC). ≪ Desc / Clms Page number 13 > The injectable composition of claim 1, wherein the composition is in the form of a liquid or a dry powder. a) dissolving cyclodextrin or a derivative thereof and an organic acid in an aqueous medium;
b) mixing and dissolving the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof in the solution prepared in the step (a)
[Chemical Formula 1]

; And
The method according to claim 1, comprising the step of sterilizing and filtering the mixed solution prepared in step b), followed by lyophilization. The process according to claim 9, wherein the cyclodextrin is hydroxypropyl-beta cyclodextrin (HP-beta-CD) or sulfobutyl ether-beta cyclodextrin (SBE- beta -CD). 10. The method according to claim 9, wherein the organic acid is at least one selected from the group consisting of tartaric acid, pyroglutamic acid, malic acid, citric acid and lactic acid. 10. The method according to claim 9, wherein the aqueous medium is distilled water, injection water or physiological saline. The composition according to claim 9, which is selected from the group consisting of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), hydroxymethylcellulose HMC) and hydroxyethylcellulose (HEC) is further dissolved in the aqueous medium of step a).

Images