Method for solubilizing 5-amino-2,3-dihydro-1,4-phthalazinedione

Abstract

To provide a method for solubilizing 5-amino-2,3-dihydro-1,4-phthalazinedione or salts thereof, and a solubilisate produced by this method.SOLUTION: A method comprises the following steps: providing 5-amino-2,3-dihydro-1,4-phthalazinedione in a range of 0.1 wt.% to 25 wt.% at a room temperature and a pressure of 0.2 bar to 1 bar; adding in any sequence at least one or more solubilization agents of phosphatidylcholine, medium-chained triglyceride, lysophosphatidylcholine, C2-C4 alcohol, and glyceryl stearate and / or a saturated or unsaturated C14-C20 fatty acid; heating the resulting mixture by continuously increasing the temperature with a continuous temperature increment of 0.5°C / min-3°C / min over a period of 20-60 minutes; stopping the temperature increase in a temperature range of 30°C to 125°C as soon as a clear solution is reached; and letting the resulting solubilisate cool down to the room temperature.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for solubilizing 5-amino-2,3-dihydro-1,4-phthalazinedione or various salts thereof, to the solubilizates produced by this method, their uses, and to pharmaceutical compositions containing said solubilizates. [Background technology]

[0002] For decades, 5-amino-2,3-dihydro-1,4-phthalazinedione (luminol) has been used by crime scene investigators to detect blood traces, even if someone has tried diligently to clean or remove them (see Barni et al., Talanta, 2007, 72, 896–913). Its intense luminescence upon oxidation catalyzed by iron in hemoglobin makes it a highly sensitive sensor. In addition to its forensic uses, numerous other applications, ranging from environmental to medical, have been established since the first report of luminol's synthesis was published (AJ Schmitz, Uber das Hydrazid der Trimesinsaure und der Hemimellithsaure, Heidelberg, 1902). For example, luminol is used in bioanalytical chemistry for heavy metal detection or biosensing (see Klopf and Nieman, Anal. Chem. 1983, 55, 1080-1083). [ka]

[0003] The sodium salt of luminol has rekindled interest in its pharmaceutical activity, and various alkali salts of luminol have only recently been structurally characterized (Guzei et al., J. Coord. Chem. 2013, 66, 3722-3739). Na-luminolate shows great potential in the immunomodulatory treatment of inflammatory and autoimmune diseases. Furthermore, Na-luminolate exhibits numerous polymorphic forms, with three anhydrous crystal structures characterized to date (see International Publication WO 2011 / 107295 A1; International Publication WO 2016 / 96143 A1). Luminol itself also has two published crystalline forms (Paradies, Ber. Bunsen-Ges. Phys. Chem. 1992, 96, 1027-1031; International Publication WO 2017 / 140430 A1). The general physicochemical properties of the isomeric forms of luminol in aqueous solution have been published by Skripnikova et al. (2017; J Mol Struct 1154:59-63). Specific therapeutic uses of these Na-luminolate or luminol crystalline forms are described in International Publication WO 2017 / 202496 A1.

[0004] It is known that crystalline forms of a compound can exhibit different physical properties, such as solubility, dissolution rate, and stability (see Haleblian and McCrone (1969): Journal of Pharmaceutical Sciences, 58:911-929). These properties may affect the compound's formulation processing, as well as its bioavailability and pharmacokinetics, and therefore its biological efficacy (see Griesser (2006), Polymorphisms in the Pharmaceutical Industry, Hilfiker (ed.), pp. 211-234). A formulation for increasing the oral bioavailability of a drug by adding at least one piperine-based compound to the solution was disclosed in International Publication WO 2013 / 108254 A1.

[0005] Although the luminol salts described so far are readily soluble in water, luminol itself has very poor water solubility. Furthermore, the small amount that can be dissolved tends to precipitate after a few days. It has also been described as sensitive to light, high temperatures, and metal cations. This significantly hinders the use of aqueous luminol solutions. This problem can sometimes be solved by using basic solutions or diluents such as ethanol or DMSO. However, these diluents are unacceptable for a wide variety of pharmaceutical applications.

[0006] The use of luminol sodium salt is advantageous in terms of solubility in aqueous environments. However, for absorption in the gastrointestinal tract, topical application for transdermal delivery, or transport across the blood-brain barrier, it would be preferable if the free acid could be administered to increase the bioavailability of luminol. Thus, sufficiently high plasma and intracellular concentrations could be achieved to maximize the therapeutic potential of luminol. Therefore, there is a need to find a method for solubilizing luminol in aqueous media.

[0007] There are various approaches to improve the solubility, and often also the bioavailability, of lipophilic pharmaceutical agents by using solubilization techniques. Herein, the solubility of the drug in the vehicle is enhanced by adding a third substance. These third substances are referred to as solubilizers (solubilizing agents), i.e., substances that may form complexes with the solubilized substance, for example. Examples of such chelating agents include sodium benzoate and sodium salicylate. Another mechanism of action of solubilizers is to enhance the dissolving ability of the solvent, for example, by disrupting the water cluster structure. Examples of such structure-disrupting agents include glycerol (glycerin) and macrogol (polyethylene glycol, PEG).

[0008] A third solubilization mechanism is the application of micelles and liposomes. Such techniques have attracted widespread attention over the past few decades. Here, the substance to be delivered is trapped in a spherical aggregate of surfactant molecules. These molecules are characterized by a polar head group and a long nonpolar chain ("tail"). When placed in an aqueous medium, these molecules tend to associate by assembling into a spherical structure with the polar head group orienting toward the surrounding medium and the nonpolar chain toward the interior of the sphere. When these spheres consist of only one layer of such amphiphilic molecules, they are called micelles. Depending on the nature of the amphiphilic molecules and the reaction conditions, it is also possible to form spheres with two or more layers. Here, a second layer is formed inside the outer layer of the sphere, with the nonpolar groups of this second layer facing toward the nonpolar groups of the outer layer and the polar head groups facing toward the interior of the sphere. Such aggregates are called liposomes. In their structure, liposomes resemble the lipid bilayer of a cell membrane. Multilamellar liposomes also exist, in which at least two liposome spheres are formed concentrically around one another, thus forming multispherical assemblies. When placed in a lipophilic medium, these substances tend to adopt an inverted spherical structure in which the lipophilic chains face toward the solution medium and the other layers are arranged accordingly.

[0009] Various uses of such loaded spheres have been described in the art, including as dosage forms for applying lipophilic substances and / or increasing the bioavailability of the entrapped substances. In micelles, the entrapped nonpolar substances are collected in the interior space of the sphere, where the nonpolar chains of the amphiphilic molecules are oriented. However, in liposomes, the interior space of the sphere is an aqueous, respectively hydrophilic medium. This interior space can serve to pack hydrophilic molecules. However, lipophilic molecules with poor water solubility are mostly collected between the lipophilic structures of the liposome layer.

[0010] Micellar solubilization techniques are disclosed, for example, in International Publication Nos. WO 03 / 007907 A1 and WO 2014 / 094921 A1. They use emulsifiers with HLB (hydrophilic-lipophilic balance) values ​​of 9-16 and 13-18, respectively. Polysorbate (Tween) 20 or 80 is often used. At first glance, the application of this technique appears to be limited to the production of chewing gum.

[0011] Another approach is to incorporate glucuronidation inhibitors into pharmaceutical compositions. Poloxamers or surfactants such as polysorbate 20, polysorbate 60, and polysorbate 80 are widely used. Another common glucuronidation inhibitor is bioperine. However, glucuronidation inhibitors also inhibit the intrinsic metabolism and, as a result, the elimination of other drugs or endogenous substances. Therefore, the use of glucuronidation inhibitors is a double-edged sword and must depend on the drug therapy of each individual patient. Therefore, such compositions may pose various problems for long-term drug therapy, especially in multimorbid patients.

[0012] Empirical pharmacokinetic measurements have shown that organisms can absorb micelles and liposomes in the gastrointestinal tract via the intestinal villi. However, their absorption rates appear to be quite variable, and therefore these methods have had mixed success in enhancing the bioavailability of encapsulated compounds. Transport across cell membranes, i.e., the rate of absorption across each cell membrane, is a unique property of each substance, depending on various factors (e.g., molecular size, degree of lipophilicity, presence of appropriate transporter molecules within the cell membrane, etc.). For many compounds, these parameters are unknown and will have to be first determined before finding a suitable packaging for the specific compound.

[0013] The various applications of liposomes have been extensively discussed in medicine and pharmacology, and several elegant solutions have been developed for specific active agents. However, their use is not very common. One reason is the relatively high production cost, and another is the potential harmful side effects. A liposome-based self-emulsifying method for poorly water-soluble active agents for dietary supplements and pharmaceuticals was disclosed in European Patent Publication EP3290026A1. In particular, when applied parenterally, liposomes run the risk of accumulating in the liver, spleen, and / or bone marrow. Therefore, liposome formulations are often viewed with skepticism.

[0014] A nanoliposphere-based formulation method for increasing drug bioavailability was disclosed in International Publication WO 2013 / 108254. While this method represents a significant advance over the state of the art, it also has several inherent drawbacks. A high-pressure homogenizer is required to produce these solid lipid nanoparticles. However, high-pressure-induced drug degradation has been reported for some drugs or dietary supplements. Lipid crystallization, gelation, and the coexistence of several colloidal species occur. Further limiting factors, such as the cytotoxic effect after phagocytosis, the toxic effects of organic residues, and difficult industrial scale-up, have limited their use to date (Mehnert and Mader, Adv Drug Deliv Res, 2001, 47, 165-196; Dudala et al., Int J Pharm Investg, 2014, 4, 149-155). Furthermore, the drug loading capacity of nanoliposphere-based formulations is relatively low, and they exhibit low viscosity. This makes them less attractive for topical or transdermal application forms (Mukherjee et al., Indian J Pharm Sci, 2009, 71, 349-358). Furthermore, the use of amphiphilic solvents, such as lower alkyl esters of lactic acid or N-methylpyrrolidone, is required in International Publication WO 2013 / 108254. N-methylpyrrolidone is listed as a substance of great concern for its potential carcinogenicity and reproductive toxicity. Methyl lactate is usually hydrolyzed to lactic acid and methanol in an aqueous environment. Ethyl lactate and other solvents are well tolerated. However, due to its relatively high production cost, ethyl lactate is not a very attractive solvent.

[0015] Ubiquinone Q with triglyceride-containing diesel fuel 10 Solubilization techniques for this purpose have been described in International Publication WO 03 / 007907 A1.

[0016] Another solubilization technique involves forming inclusion complexes of the substance to be solubilized with cyclodextrins (e.g., α-, β-, or γ-cyclodextrin) or cyclodextrin derivatives (e.g., 2-hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, or trimethyl-β-cyclodextrin). Typically, cyclodextrins consist of six to eight 1,4-linked α-D-glucopyranosides forming a macrocycle. This results in a water-soluble toroidal (cone- or bucket-shaped) structure that can accommodate hydrophobic substances. This interior space is significantly less hydrophilic than the exterior, which is in contact with the aqueous environment. Cyclodextrins are produced from starch by enzymatic processing. The cyclodextrin is loaded with the compound to be solubilized by dispersion. Depending on its specific composition, the compound to be solubilized can then be released by contacting these complexes with water or by changes in pH or temperature. However, the development of cyclodextrins is seemingly difficult and relatively expensive, which has limited their use to date. An additional problem is that cyclodextrins interact with preservatives (e.g., parabens).

[0017] Thus, all these techniques have their advantages, but also some disadvantages.

[0018] Various polysorbates are widely used in these solubilization techniques. However, controversy continues regarding the adverse health effects of polysorbates. Polysorbate-20 is controversially contaminated (at least by some suppliers) with unreacted 1,4-dioxane and ethylene oxide, which are known skin-penetrating carcinogens (see http: / / www.fda.gov / ohrms / dockets / 98fr / 060199a.txt (as of March 22, 2017)). Polysorbate 80 has recently been found to have adverse effects on the mouse gut microbiota, thereby promoting obesity and inflammatory bowel disease (Chassaing et al., Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome, Nature, 2015, 519, 92–96). This is particularly important for patients with chronic inflammatory bowel disease (IBD), such as Crohn's disease (see Roberts et al., "Translocation of Crohn's disease Escherichia coli across M-cells: contrasting effects of soluble plant fibers and emulsifiers," Gut, 2010, 59, pp. 1331-1339). IBD is a target indication for the therapeutic use of 5-amino-2,3-dihydro-1,4-phthalazinedione. A further problem with polysorbates (such as Tween 80) is that they reduce the efficacy of commonly used preservatives (such as parabens) by binding to the preservative (see Blanchard et al., "Effect of sorbitol on interaction of phenolic preservatives with polysorbate 80," 1977, J Pharm Sci, 66, pp. 1470-1473).However, due to the estrogenic potential of parabens, paraben concentrations should not be increased accordingly (see Okubo et al., "ER-dependent estrogenic activity of parabens assessed by proliferation of human breast cancer MCF-7 cells and expression of ERalpha and PR," Food Chem Toxicol, 39, pp. 1225-1232, 2001). Another well-known problem with polysorbates, particularly polysorbate 80, is hypersensitivity reactions in patients (see Steele et al., "Hypersensitivity reactions to the polysorbate contained in recombinant erythropoietin and darbepoietin," Nephrology, 2005, 10, pp. 317-320; Norris et al., "Polysorbate 80 hypersensitivity reactions: a renewed call to action," Commun Oncol, 2010, 7, pp. 425-428). Polysorbate 80 has also been associated with systemic hypotension, even death, in amiodarone formulations (see Cushing et al., PM 101: A cyclodextrin-based intravenous formulation of amiodarone devoid of adverse hemodynamic effects, Eur J Pharmacol, 2009, 607, pp. 167-172). [Prior art documents] [Patent documents]

[0019] [Patent Document 1] International Publication WO2011 / 107295A1 [Patent Document 2] International Publication WO2016 / 96143A1 [Patent Document 3] International Publication WO2017 / 140430A1 [Patent Document 4] International Publication WO2017 / 202496A1 [Patent Document 5] International Publication WO2013 / 108254A1 [Patent Document 6] International Publication WO03 / 007907A1 [Patent Document 7] International Publication WO2014 / 094921A1 [Patent Document 8] European Patent Publication EP3290026A1 [Patent Document 9] International Publication WO2013 / 108254 [Patent Document 10] International Publication WO03 / 007907A1 [Non-patent literature]

[0020] [Non-Patent Document 1] Barni et al., Talanta, 2007, 72, 896~913 [Non-patent document 2] AJ Schmitz, Uber das Hydrazid der Trimesinsaure und der Hemimellithsaure, Heidelberg, 1902 [Non-patent document 3] Klopf and Nieman, Anal.Chem.1983, 55, 1080-1083 [Non-patent document 4] Guzei et al., J.Coord.Chem.2013, 66, 3722~3739 [Non-patent document 5] Paradies, Ber.Bunsen-Ges.Phys.Chem, 1992, 96, 1027~1031 [Non-patent document 6] Skripnikova et al., 2017;J Mol Struct, 1154:59~63 [Non-Patent Document 7] Haleblian McCrone (1969): Journal of Pharmaceutical Sciences, 58:911~929 [Non-licensed Document 8] Griesser (2006), Polymorphisms in the Pharmaceutical Industry, Hilfiker (ed.), 211~234 [Non-licensed Document 9] Mehnert Mader, Adv Drug Deliv Res, 2001, 47, 165~196 [Non-licensed Document 10] Dudala, Int J Pharm Investg, 2014, 4, 149~155 [Non-licensed Document 11] Mukherjee, Indian J Pharm Sci, 2009, 71, 349~358 [Non-licensed Document 12] http: / / www.fda.gov / ohrms / dockets / 98fr / 060199a.txt (as of March 22, 2017) [Non-licensed Document 13] Chassaing him, Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome, Nature, 2015, 519, 92~96 [Non-licensed Document 14] Roberts, Translocation of Crohn's disease Escherichia coli across M-cells: contrasting effects of soluble plant fibers and emulsifiers, Gut, 2010, 59, p.1331~1339 [Non-licensed Document 15] Blanchard et al., Effect of sorbitol on interaction of phenolic preservatives with polysorbate 80, 1977, J Pharm Sci, 66, p.1470~1473 [Non-Patent Document 16] Okubo et al., ER-dependent estrogenic activity of parabens assessed by proliferation of human breast cancer MCF-7 cells and expression of ERalpha and PR, 2001, Food Chem Toxicol, 39, p.1225~1232 [Non-Patent Document 17] Steele et al., Hypersensitivity reactions to the polysorbate contained in recombinant erythropoietin and darbepoietin, Nephrology, 2005, 10, p.317~320 [Non-Patent Document 18] Norris et al., Polysorbate 80 hypersensitivity reactions: a renewed call to action, Commun Oncol, 2010, 7, 425–428 [Non-Patent Document 19] Cushing et al., PM 101:A cyclodextrin-based intravenous formulation of amiodarone devoid of adverse hemodynamic effects, Eur J Pharmacol, 2009, 607, p.167~172 Summary of the Invention [Problem to be solved by the invention]

[0021] The method for solubilizing 5-amino-2,3-dihydro-1,4-phthalazinedione must meet the following criteria: Easy to use -Low development time to find favorable compositions No need for expensive equipment Low material and manufacturing costs -No need to add polysorbate (Tween) solubilizer. [Means for solving the problem]

[0022] Surprisingly, it has been found that the method according to the invention is able to solve this problem.

[0023] As used herein, 5-amino-2,3-dihydro-1,4-phthalazinedione can be prepared by the following steps: a) providing 5-amino-2,3-dihydro-1,4-phthalazinedione in the range of 0.1% to 25% by weight at room temperature and a pressure of 0.2 bar to 1 bar; b) at least one phosphatidylcholine in the range of 20% to 80% by weight; at least one medium chain triglyceride in the overall range of 10% to 70% by weight; at least one lysophosphatidylcholine in the overall range of 1% to 15% by weight; At least one C2-C4 alcohol in the range of 1% to 20% by weight overall, and glyceryl stearate and / or saturated or unsaturated C 14 ~C 20 At least one of the fatty acids of solubilizing agents in any order, the relative weight percentages of all components total 100% and all solubilizing agents are pharmaceutically acceptable excipients; c) carefully heating the resulting mixture by successively increasing the temperature by successive temperature increments of 0.5°C / min to 3°C / min over a period of 20 minutes to 60 minutes; d) stopping the temperature increase in the temperature range of 30°C to 125°C as soon as a clear solution is reached; and e) cooling the solubilized product to room temperature The solubilized product is solubilized by a method according to the present invention, comprising:

[0024] In a preferred embodiment, 5-amino-2,3-dihydro-1,4-phthalazinedione can be prepared by the following process: a) providing 5-amino-2,3-dihydro-1,4-phthalazinedione in the range of 0.5% to 10% by weight at room temperature and a pressure of 0.2 bar to 1 bar; b) at least one phosphatidylcholine in the overall range of 20% to 80% by weight; at least one medium chain triglyceride in the overall range of 10% to 70% by weight; at least one lysophosphatidylcholine in the overall range of 1% to 15% by weight; At least one C2-C4 alcohol in the range of 1% to 20% by weight overall, and glyceryl stearate and / or saturated or unsaturated C 14 ~C 20 At least one of the fatty acids of solubilizing agents in any order, the relative weight percentages of all components total 100% and all solubilizing agents are pharmaceutically acceptable excipients; c) carefully heating the resulting mixture by successively increasing the temperature by successive temperature increments of 0.5°C / min to 3°C / min over a period of 20 minutes to 60 minutes; d) stopping the temperature increase in the temperature range of 30°C to 125°C as soon as a clear solution is reached; and e) cooling the solubilized product to room temperature The solubilized product is solubilized by a method according to the present invention, comprising:

[0025] Another aspect of the present invention is that the process according to the present invention does not require polysorbate as a solubilizer and / or emulsifier. Therefore, 5-amino-2,3-dihydro-1,4-phthalazinedione can be prepared by the following steps: a) providing 5-amino-2,3-dihydro-1,4-phthalazinedione in the range of 0.1% to 25% by weight at room temperature and a pressure of 0.2 bar to 1 bar; b) at least one phosphatidylcholine in the overall range of 20% to 80% by weight; at least one medium chain triglyceride in the overall range of 10% to 70% by weight; at least one lysophosphatidylcholine in the overall range of 1% to 15% by weight; At least one C2-C4 alcohol in the range of 1% to 20% by weight overall, and glyceryl stearate and / or saturated or unsaturated C 14 ~C 20 At least one of the fatty acids of solubilizing agents in any order, the relative weight percentages of all components total 100% and all solubilizing agents are pharmaceutically acceptable excipients; c) carefully heating the resulting mixture by successively increasing the temperature by successive temperature increments of 0.5°C / min to 3°C / min over a period of 20 minutes to 60 minutes; d) stopping the temperature increase in the temperature range of 30°C to 125°C as soon as a clear solution is reached; and e) cooling the solubilized product to room temperature Including, It can be solubilized by the method according to the invention, which is characterized in that the solubilizate obtained is free of polysorbates.

[0026] In a further embodiment, the solubilizer of the present invention can also be prepared from various salts of 5-amino-2,3-dihydro-1,4-phthalazinedione. Sodium, potassium, and lithium salts have been described for therapeutic applications (see International Publication WO2010 / 082858). The crystal structures of lithium, sodium, potassium, rubidium, and cesium salts have been described by Guzei et al. (2013, Journal of Coordination Chemistry, 66, 3722-3739) (see also International Publication WO2011 / 107295A1 and WO2016 / 96143A1). Generally, these salts are water-soluble and therefore do not need to be solubilized for aqueous solutions. However, when used therapeutically, the solubilizer of the present invention tends to extend the shelf life of liquid dosage forms. In liquid dosage forms for oral administration, these liquid dosage forms can mask the taste of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt solutions, which are unappealing to many patients. Furthermore, these liquid dosage forms improve the reabsorption of these salts of 5-amino-2,3-dihydro-1,4-phthalazinedione from the gastrointestinal tract in terms of quantity and time. This may result in favorable pharmacokinetic properties and can improve bioavailability. However, higher ionic concentrations prevent the formation of multilamellar vesicles, which are believed to be essential for dissolving the solubilized product of the present invention in aqueous solution. Therefore, the maximum relative amount of 5-amino-2,3-dihydro-1,4-phthalazinedione salt is lower than that of the free base.

[0027] It has been found that up to 2% by weight of 5-amino-2,3-dihydro-1,4-phthalazinedione salt can be dissolved according to the method of the present invention.

[0028] Thus, the salt of 5-amino-2,3-dihydro-1,4-phthalazinedione can be prepared by the following process: a) providing a salt of 5-amino-2,3-dihydro-1,4-phthalazinedione at room temperature and a pressure of 0.2 bar to 1 bar in the range of 0.1% to 2% overall, the salt is a sodium salt, a potassium salt, or a lithium salt or a mixture thereof; b) at least one phosphatidylcholine in the overall range of 20% to 80% by weight; at least one medium chain triglyceride in the overall range of 10% to 70% by weight; at least one lysophosphatidylcholine in the overall range of 1% to 15% by weight; At least one C2-C4 alcohol in the range of 1% to 20% by weight overall, and glyceryl stearate and / or saturated or unsaturated C 14 ~C 20 At least one of the fatty acids of solubilizing agents in any order, the relative weight percentages of all components total 100% and all solubilizing agents are pharmaceutically acceptable excipients; c) carefully heating the resulting mixture by successively increasing the temperature by successive temperature increments of 0.5°C / min to 3°C / min over a period of 20 minutes to 60 minutes; d) stopping the temperature increase in the temperature range of 30°C to 125°C as soon as a clear solution is reached; and e) cooling the solubilized product to room temperature The solubilized product is solubilized by a method according to the present invention, comprising:

[0029] In a preferred embodiment, these salt embodiments of 5-amino-2,3-dihydro-1,4-phthalazinedione are also characterized in that the resulting solubilizate is free of polysorbates.

[0030] It will be understood that in the following description and embodiments, the salts of 5-amino-2,3-dihydro-1,4-phthalazinedione will be referred to similarly as if they were the free base. DETAILED DESCRIPTION OF THE INVENTION

[0031] Confusing and even contradictory definitions can be found in the art. To avoid any ambiguity, the solubilisate according to the present invention is defined as follows: The solubilizate is a composition of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof and a solubilizing agent as defined in accordance with the present invention. The addition of a solvent or diluent is not intended to be encompassed by this term. The solubilizate according to the present invention is first prepared by the solubilization method according to the present invention, and then a specific pharmaceutical composition is prepared using the solubilizate, and finally the pharmaceutical composition is packaged in a suitable pharmaceutically acceptable container for each dosage form.

[0032] The solubilizate according to the present invention is characterized by the substantially complete solubilization of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof, and therefore by being an almost complete solution in which the molecules behave as substantially independent entities in the solution and are substantially subject to the distribution and thermodynamic rules of Brownian motion. Thus, the solubilizate according to the present invention is a clear solution containing a high concentration of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof. Generally, the solubilizate according to the present invention is not intended for administration without dilution, i.e., not intended to be administered individually without being formulated into a pharmaceutically acceptable dosage form. In most cases, the volume of the solubilizate divided into portions is several ml.

[0033] Within the scope of this patent application, the terms "solubilized aggregate" or "solubilized entity" shall be used synonymously with "solubilate".

[0034] The solubilisate according to the present invention must be distinguished from a suspension (colloidal suspension), which defines a heterogeneous mixture containing solid particles that will sooner or later settle. The solubilisate according to the present invention is also different from an emulsion (a mixture of two normally immiscible liquids).

[0035] Complete solubilization is highly preferred to increase the bioavailability of the substance.

[0036] The term solubilizate as used in accordance with the present invention must be distinguished from pharmaceutical compositions, which are prepared by diluting the solubilizate according to the present invention in a preferably aqueous solution to produce a liquid dosage form, or by incorporating the solubilizate according to the present invention into a topical dosage form (i.e., capsules or suppositories).

[0037] Diluents in the context of this application are diluting agents (dilutants, thinners) that are not part of the solubilisate according to the invention.

[0038] In the context of this application, the term "solubilizing agent" refers to any chemical substance that is added to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof in order to solubilize the 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof, so that the 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof can be dissolved in an aqueous solution. The term "solubilizer" is used synonymously.

[0039] Within the scope of this application, the term "medicine" is intended to include human medicine and veterinary medicine.

[0040] A major advantage of such solubilizates is their small volume, which allows them to be easily divided into patient-friendly units or to transport relatively large quantities of the solubilized material at low cost, and preparation can be easily performed by medical staff or the patient to produce a dosage form.

[0041] The solubilized product of the present invention must also be distinguished from a concentrate. A concentrate is a composite, i.e., a composition of compounds without a diluent. When a concentrate is released into a diluent, it either completely dissolves in the diluent or forms a suspension or emulsion with the diluent. Because concentrates are essentially soluble in water or aqueous solutions, they do not require interaction with a solubilizing agent.

[0042] In a preferred embodiment of the method according to the present invention, 5-amino-2,3-dihydro-1,4-phthalazinedione is provided in the range of 2% to 15% by weight overall, and in a more preferred embodiment, in the range of 2% to 10% by weight overall.

[0043] Phosphatidylcholine is a group of phospholipids linked to choline. Phosphatidylcholine is a major component of cell membranes, and can be obtained from, for example, egg yolk, bovine liver, marine animals, krill oil or soybean. In fact, it has been shown that the origin of phosphatidylcholine significantly affects its biological and chemical effects. According to the present invention, at least one phosphatidylcholine (PC) can be selected from the group consisting of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), natural (non-hydrogenated) soybean PC or hydrogenated soybean PC, natural egg PC or hydrogenated egg PC, dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC) or 1,2-dioleyl-SN-glycero-3-phosphocholine (DOPC), 1-oleoyl-palmitoylphosphatidylcholine (OPPC), diastereoylphosphatidylcholine (DSPC), monostearoylphosphatidylcholine (MSPC), diarachidoylphosphatidylcholine (DAPC), and mixtures thereof. Preferred phosphatidylcholines are non-hydrogenated soybean PC, DMPC, POPC, and DOPC. Non-hydrogenated phosphatidylcholines are also preferred. Particularly preferred is non-hydrogenated soybean PC.

[0044] Non-hydrogenated phosphatidylcholine is particularly preferred for topical dosage forms of the solubilisate according to the present invention.

[0045] Lecithin is commonly used as a synonym for phosphatidylcholine. Lecithin is a mixture of phosphatidylcholine and other compounds.

[0046] According to the method of the present invention, phosphatidylcholine is used in the range of 20% to 80% by weight, preferably in the range of 40% to 70% by weight, more preferably in the range of 50% to 65% by weight, and most preferably in the range of 60% by weight.

[0047] Medium-chain triglycerides (MCTs) refer to triglycerides in which the fatty acids have an aliphatic tail of 6 to 12 carbon atoms. The fatty acids incorporated into MCTs are called medium-chain fatty acids (MCFAs). In triglycerides, three fatty acid molecules are attached to a glycerol backbone. By definition, in MCTs, at least two of these three fatty acids must be MCFAs. According to the present invention, the MCFAs can be independently selected from the group including caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, their unsaturated derivatives, and mixtures thereof. Preferred MCFAs are caproic acid, caprylic acid, capric acid, and lauric acid.

[0048] It may be advantageous in some embodiments of the present invention to use triglycerides containing one to three myristic and / or palmitic acid residues instead of MCFAs, and these two fatty acids are therefore intended to be encompassed by the term MCT according to the present invention.

[0049] MCT oil or MCT fat is the oil or fat that mainly contains the MCT.These terms refer to the mixture of different MCTs, which may contain various MCFAs.According to the present invention, any reasonable mixture ratio is encompassed by these terms.MCT fat is often extracted from certain plant fats, while MCT oil does not exist in nature.MCT oil and MCT fat are widely sold as health supplements, that is, as substitutes for long-chain fats in nutrition, respectively.

[0050] According to the method of the present invention, MCT is used throughout the range of 10% to 70% by weight, preferably throughout the range of 20% to 40% by weight, more preferably throughout the range of 25% to 35% by weight, and most preferably 30% by weight.

[0051] Lysophosphatidylcholine (LPC, lysoPC, also lysolecithin) is a group of derivatives of phosphatidylcholine resulting from its partial hydrolysis, in which one of the fatty acid groups is removed. In living organisms, this hydrolysis is caused by the enzyme phospholipase A2. According to the present invention, at least one lysophosphatidylcholine can be independently selected from the group including all hydrolyzed compounds of phosphatidylcholine listed above, 1-lysophosphatidylcholine (2-acyl-sn-glycero-3-phosphocholine), 2-lysophosphatidylcholine, L-alpha-lysophosphatidylcholine, and mixtures thereof.

[0052] According to the method of the present invention, lysophosphatidylcholine is used in an amount ranging from 1% to 15% by weight, preferably from 3% to 8% by weight, more preferably from 5% to 7% by weight, and most preferably at 6% by weight.

[0053] In the present application, the lysophosphatidylcholine is not merely a variant or substitute for phosphatidylcholine, but plays an independent role. Surprisingly, it has been found that the solubilizing effect can be significantly improved if two solubilizing agents with similar but not identical chemical structures are used in different ratios. According to the present invention, the ratio of phosphatidylcholine to lysophosphatidylcholine is 80:1 to 1.33:1, preferably 40:1 to 3:1, more preferably 25:1 to 5:1, and most preferably 20:1 to 8:1.

[0054] According to the present invention, the at least one C2-C4 alcohol (lower alcohol) can be selected from the group consisting of ethanol, propanol, isopropanol, butan-1-ol, butan-2-ol, isobutanol (2-methyl-1-propanol), ethylene glycol (ethane-1,2-diol), α-propylene glycol (propane-1,2-diol), β-propylene glycol (propane-1,3-diol), 1,2-butylene glycol (butane-1,2-diol), 1,3-butylene glycol (butane-1,3-diol), 1,4-butylene glycol (butane-1,4-diol) and diethylene glycol. Ethanol is preferred.

[0055] According to the method of the present invention, the C2-C4 alcohol is used in an amount ranging from 1% to 20% by weight, preferably from 2% to 10% by weight, more preferably from 3% to 8% by weight, and most preferably from 5% by weight.

[0056] Glyceryl stearate (glycerol monostearate, GMS) is an emulsifier. The flake powder is also hygroscopic. GMS is used as a thickener, emulsifier, anticaking agent, anti-aging agent, and preservative.

[0057] According to the present invention, at least one saturated or unsaturated C 14 ~C 20 Fatty acids can be used in place of or in combination with glyceryl stearate. At least one saturated or unsaturated C 14 ~C 20 The fatty acids are myristic acid (14:0), pentadecanoic acid (15:0), palmitic acid (16:0), heptadecanoic acid (17:0), stearic acid (18:0), nonadecanoic acid (19:0), arachidic acid (20:0), myristoleic acid (14:1, cis-Δ 9 ), palmitoleic acid (16:1, cis-Δ 9 ), sapienic acid (16:1, cis-Δ 6), hexadecatrienoic acid (16:3, (n-3), oleic acid (18:1, cis-Δ 9 ), elaidic acid (18:1, trans-Δ 9 ), vaccenic acid (18:1, trans-Δ 11 ), linoleic acid (18:2; cis, cis-Δ 9 ,Δ 12 ), linoleadic acid (18:2, trans,trans-Δ 9 ,Δ 12 ), α-linolenic acid (18:3, cis,cis,cis-Δ 9 ,Δ 12 ,Δ 15 ), γ-linolenic acid (18:3, (ω-3)), calendic acid (8E,10E,12Z-octadecatrienoic acid), stearidonic acid (18:4(n-3)), dihomo-γ-linolenic acid (20:3; (ω-6)), eicosadienoic acid (20:2, (n-6)), eicosatrienoic acid (20:3, (n-3)), eicosatetraenoic acid (20:4, (n-3)), arachidonic acid (20:4, cis,cis,cis,cis-Δ 5 ,Δ 8 ,Δ 11 ,Δ 14 ), eicosapentaenoic acid (20:5, cis,cis,cis,cis,cis-Δ 5 ,Δ 8 ,Δ 11 ,Δ 14 ,Δ 17 ) can be selected from the group including. 14 ~C 20 Fatty acids are preferred, with oleic acid being particularly preferred.

[0058] According to the method of the present invention, glyceryl stearate and / or saturated or unsaturated C 14 ~C 20 The fatty acids are used throughout the range of 0.5% to 10% by weight, preferably throughout the range of 1% to 8% by weight, more preferably throughout the range of 2% to 6% by weight, and most preferably 3% by weight.

[0059] The process according to the invention is usually started at room temperature. However, in an alternative embodiment, it may also be possible to preheat the 5-amino-2,3-dihydro-1,4-phthalazinedione and / or any solubilizing agent to be added in step b) of the process of the invention, provided that the preheating temperature does not exceed 28° C.

[0060] The process according to the invention can be carried out at a pressure of 0.2 bar to 1 bar. However, it is preferred that the process according to the invention is carried out at 1 bar (atmospheric pressure). For certain applications, it may be preferable to use a slight vacuum. Industrial equipment for applying, maintaining, and controlling such slight vacuums is widely known in the art.

[0061] According to the method of the present invention, the resulting mixture is carefully heated in step c) by continuously increasing the temperature over a period of 20 to 60 minutes, in a preferred embodiment this period is 25 to 40 minutes, most preferably 30 to 35 minutes.

[0062] An essential feature of the method according to the invention is the temperature control (temperature increment per time and duration of heating). Although there is variability in the relative amounts of solubilizing agents, a controlled temperature increase is essential. Obviously, there is an optimum operating range for each substance to be solubilized, depending on the mixture of solubilizing agents used. The exact values ​​are difficult to predict and must be found empirically.

[0063] The continuous temperature increment (steepness of the temperature gradient) can be varied between 0.5°C / min and 3°C / min, preferably between 1°C / min and 2°C / min, and most preferably 2°C / min.

[0064] According to step d), the temperature increase is stopped as soon as a clear solution is reached, in the temperature range of 30°C to 125°C. This time depends greatly on the solubilizing agent selected and the reaction conditions. Obviously, it is not possible to predict this "solubilization temperature" based on the specific components to be used. Each composition of these components exhibits specific properties that must be found experimentally. Therefore, it is up to the experimenter to find the optimal combination of these parameters.

[0065] It is understood that the method according to the present invention can be modified in such a way that any of the solubilizing agents of step b) can be provided first, and then 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof, as well as other solubilizing agents, can be added in any order. It is also possible to provide a mixture of solubilizing agents of step b) first, and then add 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof. Such variations have been found to be neutral to the results of the method according to the present invention.

[0066] In a preferred embodiment, the mixture of solubilizing agent of step b) and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof is provided in a two-compartment system, which may facilitate the solubilization process according to the invention and each compartment can be sold separately, which may be advantageous for the stability and therefore the shelf life of the dosage form according to the invention.

[0067] The point at which the resulting solubilisate becomes a clear solution is determined by observation by the experimenter, and is generally reached when the solution appears clear and does not exhibit any sedimentation, precipitate, slur, smear or streaks (zebra effect).

[0068] In an alternative embodiment, the parameters for the temperature gradient according to the present invention determined as described above can be performed in an automated or semi-automated device setup, which may be advantageous, for example, in high-end, high-quality industrial applications.

[0069] The solubilizate produced according to the method of the present invention maintains this clarity when cooled and remains clear and stable when stored. The achievable shelf life of pharmaceutical dosage forms containing said solubilizate (which roughly corresponds to the shelf life of the product) appears seemingly unlimited. In preliminary stability analyses, the minimum shelf life was greater than 6 months.

[0070] However, to increase the shelf life of these solubilizates of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof, at least one antioxidant can be added to the solubilizate, which in a preferred embodiment is a pharmaceutically acceptable excipient. Suitable antioxidants include lactic acid, ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, fatty acid esters of ascorbic acid, ascorbyl palmitate, ascorbyl stearate, tocopherol, alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, delta-tocotrienol, propyl gallate, octyl gallate, dodecyl gallate, ethyl gallate, guaiac resin, erythorbic acid, sodium erythorbate, erythorbic acid The additives may be selected from the group consisting of ascorbyl palmitate, sodium erythorbine, tert-butylhydroquinone, butylated hydroxyanisole, butylated hydroxytoluene, monosodium phosphate, disodium phosphate, trisodium phosphate, monopotassium phosphate, dipotassium phosphate, tripotassium phosphate, anoxomer, ethoxyquin, potassium lactate, stannous chloride, sodium thiosulfate, 4-hexylresorcinol, and glucose oxidase. Preferred are ascorbyl palmitate and alpha-tocopherol, beta-tocopherol, gamma-tocopherol, and delta-tocopherol. Particularly preferred is a combination of ascorbyl palmitate with at least one of alpha-tocopherol, beta-tocopherol, gamma-tocopherol, and delta-tocopherol.

[0071] The term tocopherol refers to any of the aforementioned tocopherols or mixtures thereof.

[0072] According to the method of the present invention, the at least one antioxidant may be added, if necessary, to the solubilisate or preferred embodiments thereof in an amount ranging from 0.01% to 10% by weight, preferably from 0.1% to 5% by weight, more preferably from 0.2% to 1% by weight, and most preferably from 0.3% to 0.5% by weight.

[0073] Therefore, the present application also refers to the solubilisate resulting from the solubilisation method according to the invention, i.e. 5-amino-2,3-dihydro-1,4-phthalazinedione in the range of 0.5% to 10% by weight and a solubilizing agent such as: a) at least one phosphatidylcholine in the overall range of 20% to 80% by weight; b) at least one medium chain triglyceride in the overall range of 10% to 70% by weight; c) at least one lysophosphatidylcholine in the overall range of 1% to 15% by weight; d) at least one C2-C4 alcohol in the overall range of 1% to 20% by weight, and e) and glyceryl stearate or saturated or unsaturated C in the range of 0.5% by weight to 10% by weight, respectively 14 ~C 20 At least one of the fatty acids A solubilized product comprising: A solubilizate in which the relative weight percentages of all components total 100% by weight and in which all solubilizing agents, independently of one another, are pharmaceutically acceptable excipients.

[0074] In a preferred embodiment, the solubilisate according to the invention is 5-amino-2,3-dihydro-1,4-phthalazinedione in the range of 1% by weight to 8% by weight; a) at least one phosphatidylcholine in the overall range of 40% to 70% by weight; b) at least one medium chain triglyceride in the overall range of 20% to 40% by weight; c) at least one lysophosphatidylcholine in the overall range of 3% to 8% by weight; d) at least one C2-C4 alcohol in the overall range of 2% to 10% by weight, and e) and glyceryl stearate or saturated or unsaturated C in the range of 0.5% by weight to 5% by weight, respectively 14 ~C 20 At least one of the fatty acids and provided that the relative weight percentages of all components total 100% and that all solubilizing agents, independently of one another, are pharmaceutically acceptable excipients.

[0075] In a further preferred embodiment, the solubilisate according to the invention comprises 5-amino-2,3-dihydro-1,4-phthalazinedione in the range of 2% by weight to 5% by weight; a) at least one phosphatidylcholine in the overall range of 40% to 60% by weight; b) at least one medium chain triglyceride in the overall range of 25% to 35% by weight; c) at least one lysophosphatidylcholine in the overall range of 5% to 7% by weight; d) at least one C2-C4 alcohol in the overall range of 4% to 7% by weight, and e) and glyceryl stearate or saturated or unsaturated C in the range of 0.5% by weight to 5% by weight, respectively 14 ~C 20 At least one of the fatty acids and provided that the relative weight percentages of all components total 100% and that all solubilizing agents, independently of one another, are pharmaceutically acceptable excipients.

[0076] In an alternative embodiment, the method according to the invention also refers to the following solubilisates: 5-amino-2,3-dihydro-1,4-phthalazinedione salt in the range of 0.1% to 2% by weight wherein the salt is a sodium salt, a potassium salt, or a lithium salt, or a mixture thereof; and a) at least one phosphatidylcholine in the overall range of 20% to 80% by weight; b) at least one medium chain triglyceride in the overall range of 10% to 70% by weight; c) at least one lysophosphatidylcholine in the overall range of 1% to 15% by weight; d) at least one C2-C4 alcohol in the overall range of 1% to 20% by weight, and e) and glyceryl stearate or saturated or unsaturated C in the range of 0.5% by weight to 10% by weight, respectively 14 ~C 20 At least one of the fatty acids A solubilized product comprising: A solubilizate in which the relative weight percentages of all components add up to 100% and in which all solubilizing agents, independently of one another, are pharmaceutically acceptable excipients.

[0077] According to the present invention, the solubilisate or preferred embodiments thereof may further contain an antioxidant as listed above in an amount ranging from 0.01% to 10% by weight overall, preferably from 0.1% to 5% by weight overall, more preferably from 0.2% to 1% by weight overall, and most preferably from 0.3% to 0.5% by weight overall.

[0078] In a particularly preferred embodiment of this solubilisate, the at least one saturated or unsaturated C 14 ~C 20 The fatty acid is oleic acid.

[0079] In a particularly preferred embodiment of this solubilisate, said at least one C2-C4 alcohol is ethanol.

[0080] In a preferred embodiment, the solubilisate according to the present invention further comprises at least one antioxidant in the overall range of 0.01% to 10% by weight, provided that said at least one antioxidant is a pharmaceutically acceptable excipient.

[0081] In a particularly preferred embodiment, the at least one antioxidant is ascorbyl palmitate and / or at least one tocopherol.

[0082] Another aspect of the present application is the solubilisate according to the invention for prophylactic or therapeutic use in medicine, as well as the prophylactic or therapeutic use of said solubilisate in medicine.

[0083] Within the scope of this application, the term "medicine" is intended to denote human medicine as well as veterinary medicine.

[0084] In particular, the present application refers to the solubilisate according to the invention for prophylactic or therapeutic use as an immunomodulator.

[0085] The present application also refers to the use of the lysate according to the invention for treating conditions involving an excessive immune response or having an immunodeficiency background.

[0086] The present application also refers to a pharmaceutical composition for treating a medical condition, comprising a solubilisate according to the invention of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof.

[0087] In this specification, the term permeability refers to the degree to which a drug is absorbed through the intestinal wall in humans.According to the established definition, if 90% or more of the orally administered dose of a drug is reabsorbed in the gastrointestinal tract, the drug is classified as having high permeability.Correspondingly, if the absorption rate is less than 90%, the drug is classified as having low permeability.

[0088] Thus, solubility and permeability are inherent substance properties. However, absorption and bioavailability represent pharmaceutical parameters that can be improved by appropriate strategies. Resorption indicates the proportion of an orally administered substance that is absorbed from the gastrointestinal tract, while the bioavailability of a substance depends not only on absorption but also on species-specific protein binding in the blood and pharmacokinetic parameters (e.g., first-pass metabolism).

[0089] Therefore, another aspect of the present invention is the prophylactic or therapeutic use of the solubilisate according to the invention to increase the absorption and / or bioavailability of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof.

[0090] The present application therefore also refers to a solubilisate according to the invention for use in a pharmaceutical dosage form.

[0091] Moreover, the present application also refers to the medical use of the solubilisate according to the invention in pharmaceutical dosage forms.

[0092] In most cases, the solubilized product of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof is not yet in a pharmaceutical dosage form. To be immediately used for ingestion in a liquid dosage form, the solubilized product must be dissolved in a diluent. A preferred diluent for liquid dosage forms is water. Therefore, the solubilized product according to the present invention is added to an aqueous solution in a suitable container. The container can be selected from the group including, but not limited to, bottles, vials, bottles, glasses, cups, syringes, jars, pots, dispensers, boxes, tubes, caps, sachets, and custom-made two-compartment or multi-compartment containers. Preferred containers are bottles, vials, and jars.

[0093] The container containing the aqueous solution and the solubilizate dissolved therein is preferably shaken or stirred several times to ensure uniform distribution of the solubilizate in the aqueous solution.

[0094] The present application therefore also refers to pharmaceutical dosage forms in which the solubilisate according to the invention is dissolved in an aqueous solution.

[0095] In another preferred embodiment of the present invention, the solubilized product of the present invention is contained in a soft gelatin capsule (SGC). The SGC dissolves as it passes through the gastrointestinal tract. The SGC is mainly composed of gelatin enriched with various amounts of plasticizers (e.g., glycerol or sorbitan). The release rate depends on the specific formulation of the SGC carrier material. The SGC is also suitable for the sustained release of active agents. The SGC is particularly useful for administering active agents with poor water solubility. The SGC is well suited for receiving the solubilized product of 5-amino-2,3-dihydro-1,4-phthalazinedione into its cavity.

[0096] In another embodiment of the present invention, the solubilizate according to the present invention is provided in a hard gelatin capsule. The hard gelatin capsule consists of gelatin, water, and usually a colorant, but does not contain a plasticizer. The solubilizate according to the present invention can be included during the manufacturing process. The solubilizate according to the present invention will be released when the hard gelatin capsule dissolves.

[0097] In another preferred embodiment of the invention, the solubilizate according to the invention is included in a chewable tablet or hard caramel, where the solubilizate according to the invention is integrated into the matrix of the tablet or caramel.

[0098] In another embodiment of the present invention, the solubilizer of the present invention is incorporated into suppositories. In a typical manufacturing method, a low-melting wax and a mixture of fatty acid glycerides (e.g., cocoa butter) are first melted. Then, the solubilizer of the active agent, herein 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof, is dispersed uniformly by stirring or other mixing methods. The molten homogeneous mixture is then transferred to a suitable mold and cooled until solidified.

[0099] In yet another embodiment of the present invention, the solubilisate according to the present invention is provided as a topical application form, such as a cream, emulsion, lotion, gel, hydrogel, paste, powder, ointment, liniment, film, liposome, skin patch, transdermal patch, transdermal spray or suspension.

[0100] In a further aspect, the present application also refers to a pharmaceutical composition containing 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its various salts or a mixture thereof, formulated into a dosage form as defined above, and at least one pharmaceutically acceptable excipient.

[0101] The term "pharmaceutical excipient" refers to a natural or synthetic compound that is added to a pharmaceutical formulation along with a pharmaceutical active agent. Pharmaceutical excipients may serve to increase the formulation's bulk, enhance the formulation's desired pharmacokinetic properties or stability, as well as be beneficial in the manufacturing process. Advantageous classes of excipients according to the present invention include carriers, binders, lubricants, glidants, disintegrants, colorants, buffers, preservatives, emulsifiers, penetration enhancers, antioxidants, diluents, pH adjusters, fatiquors, solvents, consistency enhancers, hydrotopes, sweeteners, acidifiers, thickeners, anti-adherents, fillers, flavors, sweeteners, opacifiers, flavorings, and aromas.

[0102] It may be convenient to add one or more pharmaceutically acceptable carriers to the pharmaceutically active agent, and each may be necessary.All carriers known in this technical field and their combinations are suitable.For solid dosage forms, carriers can be, for example, plant and animal fats, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide.For liquid dosage forms and emulsions, suitable carriers are, for example, solvents, solubilizing agents, emulsifiers, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, cottonseed oil, peanut oil, olive oil, castor oil, sesame oil, glycerol fatty acid esters, polyethyl glycol, fatty acid esters of sorbitan, etc. Suspensions according to the invention may use carriers known in the art, such as diluents (e.g., water, ethanol, or propylene glycol), ethoxylated isostearyl alcohol, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline cellulose, bentonite, agar, tragacanth, and the like.

[0103] The term binder refers to a substance that binds or glues powders together, thereby making them cohesive through granule formation. Binders act as the "glue" of the formulation. Binders increase the binding strength of the diluent or filler provided.

[0104] Suitable binders are, for example, starch obtained from wheat, corn, rice or potato, gelatin, naturally occurring sugars (such as glucose, sucrose or beta-lactose), sweeteners obtained from corn, natural and synthetic gums (such as gum arabic, tragacanth or calcium ammonium alginate), sodium alginate, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl carboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, magnesium aluminum silicate, waxes, etc. The proportion of binder in the composition can range from 1% to 30% by weight, preferably from 2% to 20% by weight, more preferably from 3% to 10% by weight, and most preferably from 3% to 6% by weight.

[0105] Colorants are excipients that impart color to the beverage composition, respectively the dosage form. These excipients can be food colorants. The colorants can be adsorbed onto a suitable adsorption means (e.g., clay or aluminum oxide). The amount of colorant can vary between 0.01% and 10% by weight of the pharmaceutical composition, preferably between 0.05% and 6%, more preferably between 0.1% and 4%, and most preferably between 0.1% and 1%.

[0106] Suitable pharmaceutical colorants are, for example, curcumin, riboflavin, riboflavin-5'-phosphate, tartrazine, alkanine, quinolione yellow WS, fast yellow AB, riboflavin-5'-phosphate sodium, yellow 2G, sunset yellow FCF, orange GGN, cochineal, carminic acid, citrus red 2, carmoisine, amaranth, ponceau 4R, ponceau SX, ponceau 6R, erythrosine, red 2G, allura red AC, indathrene blue RS, patent blue V, indigo carmine, brilliant blue FCF, chlorophyll and chlorophyllin, copper complexes of chlorophyll and chlorophyllin, green S, fast green FCF, plain caramel, caustic sulfite caramel, and Caramel, sulfite ammonia caramel, black PN, carbon black, vegetable carbon, brown FK, brown HT, alpha-carotene, beta-carotene, gamma-carotene, annatto, bixin, norbixin, paprika oleoresin, capsanthin, capsorubin, lycopene, beta-apo-8'-carotenal, ethyl ester of beta-apo-8'-carotenoic acid, flavoxanthin, lutein, cryptoxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, zeaxanthin, citranaxanthin, astaxanthin, betanin, anthocyanin, saffron, calcium carbonate, titanium dioxide, iron oxide, iron hydroxide, aluminum, silver, gold, pigment rubin, tannin, orcein, ferrous gluconate, ferrous lactate.

[0107] Moreover, buffer solutions are preferred for liquid formulations, especially pharmaceutical liquid formulations. The terms buffer, buffer system, and buffer solution (especially those in aqueous solutions) refer to the ability of the system to resist pH changes due to the addition of acid or base or due to solvent dilution. Preferred buffer systems include formate, lactate, benzoate, oxalate, fumarate, aniline, acetate buffer, citrate buffer, glutamate buffer, phosphate buffer, succinate, pyridine, phthalate, histidine, MES (2-(N-morpholino)ethanesulfonic acid, maleic acid, cacodylate (dimethylarsenate), carbonic acid, ADA (N-(2-acetamido)iminodiacetic acid), PIPES (4-piperazine-bis-ethanesulfonic acid), BIS-TRIS Propane (1,3-bis[tris(hydroxymethyl)methylamino]propane), ethylenediamine, ACES (2-[(amino-2-oxoethyl)amino]ethanesulfonic acid), imidazole, MOPS (3-(N-morphino)-propanesulfonic acid), diethylmalonic acid, TES (2-[tris(hydroxymethyl)methyl]aminoethanesulfonic acid), HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid), as well as pK a The buffer may be selected from the group including other buffers having a pH between 3.8 and 7.7.

[0108] Preferred are carbonate buffers (such as acetate buffers), and dicarboxylic acid buffers (such as fumarate, tartrate and phthalate), as well as tricarboxylic acid buffers (such as citrate).

[0109] Another group of preferred buffers is inorganic buffers, such as sulfate hydroxide buffers, borate hydroxide buffers, carbonate hydroxide buffers, oxalate hydroxide buffers, calcium hydroxide buffers, and phosphate buffers. Another group of preferred buffers is nitrogen-containing buffers, such as imidazole, diethylenediamine, and piperazine. More preferred are sulfonic acid buffers, such as TES, HEPES, ACES, PIPES, [(2-hydroxy-1,1-bis-(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid (TAPS), 4-(2-hydroxyethyl)piperazine-1-propanesulfonic acid (EEPS), 4-morpholino-propanesulfonic acid (MOPS), and N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES). Another group of preferred buffers is glycine, glycylglycine, glycylglycylglycine, N,N-bis-(2-hydroxyethyl)glycine, and N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricine). Also preferred are amino acid buffers, such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxyproline, N,N,N-trimethyllysine, 3-methylhistidine, 5-hydroxylysine, o-phosphoserine, gamma-carboxyglutamate, [epsilon]-N-acetyllysine, [omega]-N-methylarginine, citrulline, ornithine, and derivatives thereof.

[0110] Preservatives for liquid dosage forms or supplements can be used as needed, such as sorbic acid, potassium sorbate, sodium sorbate, calcium sorbate, methylparaben, ethylparaben, methylethylparaben, propylparaben, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, heptyl p-hydroxybenzoate, sodium methyl para-hydroxybenzoate, sodium ethyl para-hydroxybenzoate, sodium propyl para-hydroxybenzoate, benzyl alcohol, benzalkonium chloride, phenylethyl alcohol, cresols, cetylpyridinium chloride, chlorobutanol, thiomersal (sodium 2-(ethylmercurithio)benzoate), sulfur dioxide, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, potassium sulfite, calcium sulfite, and potassium bisulfite. The surfactant may be selected from the group including, but not limited to, potassium, potassium bisulfite, biphenyl, orthophenylphenol, orthophenylphenol sodium, thiabendazole, nisin, natamycin, formic acid, sodium formate, calcium formate, hexamine, formaldehyde, dimethyl bicarbonate, potassium nitrite, sodium nitrite, sodium nitrate, potassium nitrate, acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, ammonium acetate, dehydroacetic acid, sodium dehydroacetate, lactic acid, propionic acid, sodium propionate, calcium propionate, potassium propionate, boric acid, sodium tetraborate, carbon dioxide, malic acid, fumaric acid, lysozyme, copper (II) sulfate, chlorine, chlorine dioxide, and other suitable substances or compositions known to those skilled in the art.

[0111] Further emulsifiers can be selected, for example, from the following anionic and nonionic emulsifiers: anionic emulsifier waxes, cetyl alcohol, cetylstearyl alcohol, stearic acid, oleic acid, polyoxyethylene polyoxypropylene block polymers, addition products of 2 mol to 60 mol of ethylene oxide to castor oil and / or hydrogenated castor oil, wool wax oil (lanolin), sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethene sorbitan monolaurate, polyoxyethene sorbitan monooleate, polyoxyethene sorbitan monopalmitate, polyoxyethene sorbitan monostearate, polyoxyethene sorbitan tristearate, polyoxyethene stearate, polyvinyl alcohol, metatartaric acid, calcium tartrate, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, propane-1 alginate,2-diol, carrageenan, modified eucheuma algae, locust bean gum, tragacanth, gum arabic, karaya gum, gellan gum, gum ghatti, glucomannan, pectin, amidated pectin, ammonium phosphatide, brominated vegetable oil, sucrose acetate isobutyrate, glycerol ester of wood rosin, disodium phosphate, trisodium diphosphate, tetrasodium diphosphate, dicalcium diphosphate, dihydrogen calcium diphosphate, sodium triphosphate, pentapotassium triphosphate, sodium polyphosphate, sodium calcium polyphosphate, calcium polyphosphate, ammonium polyphosphate, beta-cyclodextrin, powdered cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylhydroxyethylcellulose, croscarmellose cellulose, enzyme hydrolyzed carboxymethylcellulose, mono- and diglycerides of fatty acids, glyceryl monostearate, glyceryl distearate, acetate esters of mono- and diglycerides of fatty acids, lactate esters of mono- and diglycerides of fatty acids, citrate esters of mono- and diglycerides of fatty acids, tartrate esters of mono- and diglycerides of fatty acids, monoacetyltartaric acid and diacetyltartaric acid esters of mono- and diglycerides of fatty acids, mixed acetate tartaric acid esters of mono- and diglycerides of fatty acids, succinylated monoglycerides, sucrose esters of fatty acids, sucroglycerides, polyglycerol esters of fatty acids, polyglycerol polyricinoleate, propane-1,2-Diol esters, propylene glycol esters of fatty acids, lactylated fatty acid esters of glycerol and propane-1, thermally oxidized soybean oil interacted with mono- and diglycerides of fatty acids, dioctyl sodium sulfosuccinate, sodium stearoyl-2-lactylate, calcium stearoyl-2-lactylate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, calcium stearoyl fumarate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, calcium Sodium stearoyl fumarate, sodium lauryl sulfate, ethoxylated mono- and diglycerides, methyl glucoside-coconut oil ester, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate, sodium calcium polyphosphate, calcium polyphosphate, ammonium polyphosphate, cholic acid, choline salt, glycerol cross-linked starch, starch sodium octenylsuccinate, acetylated oxidized starch.

[0112] Preferred are glyceryl monooleate and stearic acid.

[0113] Stabilizers are substances that can be added to prevent undesired changes. Although stabilizers are not true emulsifiers, they may also contribute to the stability of emulsions and solubilizers, respectively. Suitable examples of stabilizers include oxystearin, xanthan gum, agar, oat gum, guar gum, tara gum, polyoxyethene stearate, aspartame-acesulfame salt, amylase, protease, papain, bromelain, ficin, invertase, polydextrose, polyvinylpyrrolidone, polyvinylpolypyrrolidone, triethyl citrate, maltitol, and maltitol syrup.

[0114] Suitable further surface-active solubilizing agents (solubilizers) are, for example, diethylene glycol monoethyl ester, polyethylpropylene glycol copolymers, cyclodextrins (such as, for example, α-cyclodextrin and β-cyclodextrin), glyceryl monostearate (such as, for example, Solutol HS15 (macrogol-15-hydroxystearate, PEG660-15 hydroxystearate, available from BASF)), sorbitan esters, polyoxyethylene glycol, polyoxyethylene sorbitan acid esters, polyoxyethylene sorbitan monooleate, polyoxyethyleneoxystearic acid triglyceride, polyvinyl alcohol, sodium dodecyl sulfate, (anionic) glyceryl monooleate, etc.

[0115] Suitable further solvents may be selected from the group including, but not limited to, water, carbonated water, water for injection, water containing an isotonic agent, saline, isotonic saline, alcohol (especially ethyl alcohol and n-butyl alcohol), glycol, oleic and linoleic triglycerides, mono-, di- and triglycerides of caprylic and capric acid, polyoxyethylene caprylic and capric glycerides, propylene glycol fatty acid esters, lower alkyl fatty acid esters, soybean oil, propylene glycol laurate, polyoxyethylene (35) castor oil, polyoxyethylene glyceryl trioleate, ethyl butyrate, ethyl caprylate, ethyl oleate and mixtures thereof.

[0116] Suitable isotonicity agents are, for example, pharmaceutically acceptable salts (especially sodium chloride and potassium chloride), sugars (such as glucose or lactose), sugar alcohols (such as mannitol and sorbitol), citrates, phosphates, borates and mixtures thereof.

[0117] Suitable thickening agents may be selected from the group including, but not limited to, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, dextrin, polydextrose, modified starch, alkali-modified starch, bleached starch, oxidized starch, enzyme-treated starch, phosphate-modified starch esterified with sodium trimetaphosphate or phosphorus oxychloride, phosphate distarch phosphate, acetylated phosphate-modified starch, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated adipate-modified starch, acetylated glycerol-modified starch, glycerin-modified starch, hydroxypropyl starch, hydroxypropyl glycerin-modified starch, hydroxypropyl phosphate-modified starch, hydroxypropyl glycerol-modified starch, starch sodium octenyl succinate, acetylated oxidized starch, hydroxyethyl cellulose.

[0118] Diluents or fillers are inactive substances added to drugs to minimize the amount of active agent.Diluents or fillers can be useful in the solubilization process.Examples of suitable diluents are water, mannitol, pregelatinized starch, starch, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate dihydrate, calcium phosphate, calcium carbonate, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, polyethylene glycol, xanthan gum, gum arabic, or any combination thereof.

[0119] Penetration enhancers are often used in topical dosage forms. Suitable penetration enhancers include all pharmaceutically acceptable penetration enhancers known in the art, including, but not limited to, azones such as laurocapran, 1-dodecylazacycloheptan-2-one, sulfoxides such as dimethyl sulfoxide, DMAC, DMF, pyrrolidones such as 2-pyrrolidone, N-methyl-2-pyrrolidone, alcohols such as ethanol, 1,2-propanediol or decanol, glycols such as propylene glycol, diethylene glycol, tetraethylene glycol, fatty acids such as oleic acid, lauric acid, lauric acid, glycerin, glycerol ... Examples of surfactants include sodium uryl sulfate, myristic acid, isopropyl myristate, and capric acid; nonic surfactants, such as polyoxyethylene-2-oleyl ether and polyoxyethylene-2-stearyl ether; terpenes; terpenoids; oxazolidinones; urea; ceramide analogs, azone analogs, menthol derivatives, etherified derivatives, esterified derivatives, various transcarbams, carbamate salts, TXA derivatives, DDAIP (2-(dimethylamino)propanoic acid dodecyl), DDAK, and natural essential oils (all of which are listed in Chen et al. (2014), Asian J. Pharm. Sc., 9, 51-64); citrate esters, such as triethyl citrate; hydrophobin polypeptides; alpha-bisabolol; dimethyl isosorbide (Arlasolve® DMI); and ethoxydiglycol. 1,2-propanediol is preferred.

[0120] Typical examples of preservatives suitable for topical application are, for example, benzyl benzoate, benzoic acid, benzyl alcohol, benzalkonium chloride, N-cetyl-NN-trimethylammonium bromide (Cetrimid, Merck), chlorhexidine, chlorbutanol, chlorcresol, imidurea, parabens (such as methylparaben, ethylparaben, propylparaben or butylparaben), sodium methylparaben, sodium propylparaben, potassium sorbate, sodium benzoate, sodium propionate, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuriacetate, phenylmercuriborate, phenylmercurinitrate, sorbic acid or thiomersal (sodium methylmercurithiosalicylate).Preferred are methylparaben, propylparaben, as well as sodium methylparaben and sodium propylparaben.

[0121] Adding a sufficient amount of antioxidant is particularly preferred for topical dosage forms.Suitable examples of antioxidants include sodium metabisulfite, α-tocopherol, ascorbic acid, maleic acid, sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid or propyl gallate.Preferably, sodium metabisulfite is used.

[0122] Suitable pH adjusting agents for topical dosage forms are, for example, sodium hydroxide, hydrochloric acid, buffer substances such as sodium dihydrogen phosphate or disodium hydrogen phosphate.

[0123] Cream preparations may also contain other excipients and additives to improve flow properties, such as fats, solvents, consistency enhancers or hydrotropes. Here, only one substance from the same group of additives or excipients may be present, as well as several substances in a mixture.

[0124] Suitable fatty acids are, for example, decyl oleate, hydrated castor oil, light mineral oil, mineral oil, polyethylene glycol, sodium lauryl sulfate.

[0125] Suitable solvents are corn oil, cottonseed oil, peanut oil, sesame oil, soybean oil, ethyl oleate, glycerin, isopropyl myristate, isopropyl palmitate, polyethylene glycol or polypropylene glycol.

[0126] Consistency enhancers are, for example, cetyl alcohol, cetyl ester wax, hydrated castor oil, microcrystalline wax, nonionic emulsifier wax, beeswax, paraffin or stearylic alcohol.

[0127] Suitable hydrotropes are alcohols (eg, ethanol, isopropyl alcohol, etc.) or polyols (eg, glycerin, etc.).

[0128] According to the present invention, all of the aforementioned excipients and excipient classes may be used, without limitation, alone or in any of their envisaged combinations, as long as the inventive use of the solubilisate is not hindered, or toxic effects may occur, or the respective national legislation is violated.

[0129] Therefore, the present application also refers to a pharmaceutical composition according to the invention for use in medicine.

[0130] The present application also refers to pharmaceutical compositions according to the invention for oral, parenteral or topical administration.

[0131] Conditions involving an excessive immune response include, but are not limited to, post-transplant graft rejection, active autoimmune disorders, diseases each with an autoimmune component (particularly active rheumatoid arthritis), relapsing-remitting multiple sclerosis, lupoid hepatitis, polyarteritis nodosa, Crohn's disease, ulcerative colitis, Behçet's disease, Behçet's uveitis, idiopathic thrombocytopenic purpura, myasthenia gravis, Lambert-Eaton syndrome, polymyositis, psoriasis, psoriatic arthritis, ankylosing spondylitis, paroxysmal nocturnal hemoglobinuria, autoimmune thyroid disorders (such as Hashimoto's thyroiditis, Ord's thyroiditis, or Graves' disease), lupus erythematosus, vitiligo, autoimmune encephalomyelitis, idiopathic thyroid ... Optic neuritis, sympathetic ophthalmia, anterior uveitis, retinal degeneration, peripheral ulcerative keratitis, bullous pemphigoid, chronic urticaria, dermatitis herpetiformis, epidermolysis bullosa acquisita, alopecia areata, autoimmune enteropathy, autoimmune polyendocrine syndromes (e.g., APECED (autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy), Schmidt syndrome, and XPID (X-linked polyendocrinopathy immunodeficiency and diarrhea syndrome)), chronic gastritis, dermatomyositis, type 1 diabetes, type 2 diabetes, Graves' ophthalmopathy, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Guillain-Barré syndrome, lichen sclerosus, lichen mucosa (Lichen ruber syndrome)mucosae), linear IgA dermatosis, microscopic polyangiitis, myalgic encephalomyelitis, narcolepsy, PANS (pediatric acute-onset neuropsychiatric syndromes) (e.g., PANDAS (pediatric autoimmune streptococcal neuropsychiatric disorders)), pemphigus foliaceus, seborrheic pemphigus, pemphigus vulgaris, polychondritis, polymyalgia rheumatica, rheumatic fever, SAPHO syndrome (synovitis, acne, pustulosis, osteophytosis, osteitis), sarcoidosis sis, Sjögren's syndrome, scleroderma, stiff-man syndrome, Henoch-Schönlein purpura, celiac disease, acute disseminated encephalomyelitis, antiphospholipid syndrome, autoimmune cardiomyopathy, autoimmune hemolytic anemia, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic renal failure These include multiple myelitis, chronic obstructive pulmonary disease (COPD), Churg-Strauss syndrome, cold agglutinin disease, painful lipomatosis, endometriosis, eosinophilic fasciitis, Hashimoto's encephalopathy, acne inversus, interstitial cystitis, Kawasaki disease, Sharp syndrome, neuromyotonia, opsoclonus-myoclonus syndrome, primary biliary cirrhosis, Raynaud's phenomenon, restless legs syndrome, transverse myelitis and vasculitis, aplastic anemia, pemphigus, pemphigoid, endogenous uveitis; nephrotic syndrome and atopic dermatitis; as well as septic conditions (e.g., those induced by infection with gram-negative or gram-positive bacteria (e.g., MRSA (methicillin-resistant Staphylococcus aureus)) or fungal pathogens), and systemic inflammatory response syndrome (SIRS) induced by other factors, such as immunological or chemical factors.

[0132] Conditions with a background of immunodeficiency include, but are not limited to, frequent influenza-like infections; recurrent respiratory tract infections; recurrent infections of the efferent urinary tract; fatigue; cachexia; congestive heart failure of unknown origin; reconvalescence; chronic viral infections, particularly human immunodeficiency viruses (e.g., HIV-1 and HIV-2), hepatitis B, hepatitis C, encephalitis, shingles, herpes simplex, inner ear infections, chickenpox, measles, cytomegaly, Epstein-Barr, adenovirus, human papillomavirus, and parvoviruses (e.g., amdovirus, bocavirus, dependovirus, erythrovirus and parvovirus spec.), some neoplastic diseases, in particular hairy cell leukemia, myeloid leukemia, multiple myeloma, follicular lymphoma, Kaposi's sarcoma, cutaneous T-cell lymphoma, nasopharyngeal carcinoma, carcinoid, renal carcinoma, bladder carcinoma, basal cell carcinoma, metastatic carcinoma and malignant melanoma; septic granulomatosis, neutropenia; genital warts; keratosis; autoimmune diseases, in particular inactive stages, such as relapsing-remitting multiple sclerosis between relapses; radiation-related colitis, diverticulitis; allergies, in particular hay fever, polymorphous light eruption, eczema, neurodermatitis; enteritis; colitis; as well as before, during and after chemotherapy and radiation.

[0133] In summary, the solubilized 5-amino-2,3-dihydro-1,4-phthalazinedione prepared by the method of the present invention is particularly suitable for treating all inflammatory diseases that show a substantial increase in the release of pro-inflammatory cytokines, in particular IL-6 and TNF-α. In addition to the aforementioned examples, this also applies during wound healing, for example after surgical intervention, trauma or burns, in unrelated immune processes such as keratitis sicca, or in acute or chronic inflammation of unknown origin (for example, tenosynovitis or osteoarthritis).

[0134] The solubilized 5-amino-2,3-dihydro-1,4-phthalazinedione produced by the methods of the present invention can also be administered in combination with at least one other known pharmaceutically active agent and / or standard of care treatment.

[0135] The present application therefore also refers to the combination of a solubilisate according to the invention with at least one pharmaceutically active agent.

[0136] The present application also refers to the combination of the solubilisate according to the invention with at least one pharmaceutically active agent for use in the prevention and / or treatment of conditions involving an excessive immune response or conditions with a background of immunodeficiency.

[0137] Pharmaceutically active agents suitable for such combinations can be selected from the group including steroidal and nonsteroidal anti-inflammatory agents, immunomodulators, immunostimulants, immunosuppressants, anti-infectives, antibiotics, antivirals, antifungals, antiprotozoal agents, anthelmintics, analgesics, local anesthetics, anticoagulants, antiplatelet agents, muscle relaxants, tonics, and anabolic agents. Such combinations of pharmaceutically active agents can be used for prophylactic and / or therapeutic applications in persons in need thereof.

[0138] Suitable examples of steroidal anti-inflammatory agents include corticosteroids, glucocorticoids, cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, dexamethasone, betamethasone, prednisone, prednisolone, methylprednisolone, deltasone, triamcinolone, tixocortol pivalate, mometasone, amcinonide, budesonide, desonide, fluociconide, fluocinolone, halcinonide, fluocortolone, hydrocortisone-17-valerate, and halometasone. , alclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarb, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, triamcinolone acetonide, and beclomethasone dipropionate. Suitable examples of nonsteroidal anti-inflammatory drugs (NSAIDs) include acetylsalicylic acid, salicylic acid and salicylates, paracetamol (acetaminophen), salsalate, diflunisal, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, These include piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celexoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib, nimesulide, clonixin, licofelone, H-harpagide, flunixin, and tiaprofenic acid.

[0139] Suitable examples of immunomodulatory agents include thalidomide, lenalidomide, pomalidomide and apremilast.

[0140] Suitable examples of immune stimulants include interferons (alpha-interferon, beta-interferon, gamma-interferon, tau-interferon), interleukins, CSF, PDGF, EGF, IGF, THF, levamisole, dimepranol, inosine.

[0141] Suitable examples of immunosuppressants include glucocorticoids, such as those mentioned above; cytostatics, such as alkylating agents (e.g., cyclophosphamide); antimetabolites, such as methotrexate, azathioprine, mercaptopurine, fluorouracil, leflunomide; protein synthesis inhibitors; and certain antibiotics, such as dactinomycin, anthracycline antibiotics, mitomycin C, bleomycin, and mithramycin; intercalating agents, such as mitoxantrone; antibodies, such as muromonas anti-CD3, rituximab, ustekinumab, alemtuzumab, natalizumab, basiliximab, and daclizumab; immunophilin-acting drugs, such as cyclosporine, tacrolimus, and sirolimus; unclassified immunosuppressants, such as beta-interferon, gamma-interferon, opioids, TNF-binding proteins, such as infliximab, etanercept, and adalimumab; or curcumin, catechins, mycophenolic acid, fingolimod, myriocin, and fumaric acid dimethyl ester.

[0142] Anti-infective is a general term for compounds that can be used in the treatment of bacterial, viral, fungal, protozoal and helminthic infections and includes antibiotics, antivirals, antifungals, antiprotozoal agents, antihelminthic agents and further antiparasitic agents.

[0143] Suitable examples of antibiotics include imipenem, meropenem, ertapenem, cephalosporin antibiotics, aztreonam, penicillin antibiotics (such as penicillin G and penicillin V), piperacillin, mezlocillin, ampicillin, amoxicillin, flucloxacillin, methicillin, oxacillin, clavulanic acid, sulbactam, tazobactam, sultamicillin, fosfomycin, teicoplanin, vancomycin, bacitracin, colistin, gramicidin, polymyxin B, tyrothricin, teixobactin, fosmidomycin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin ... clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, clostridium nitrite, These include loramphenicol, fusidic acid, cethromycin, narbomycin, telithromycin, clindamycin, lincomycin, daptomycin, dalfopristin, quinupristin, azithromycin, clarithromycin, erythromycin, roxithromycin, linezolid, doxycycline, minocycline, tetracycline, oxytetracycline, tigecycline, norfloxacin, enoxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, metronidazole, tinidazole, aminocoumarin, sulfadiazine, sulfadoxine, sulfamethoxazole, sulfasalazine, pyrimethamine, trimethoprim, and rifampin.

[0144] Suitable examples of antiviral agents include ancriviroc, aplaviroc, cenicriviroc, enfuvirtide, maraviroc, vicriviroc, amantadine, rimantadine, pleconaril, idoxuridine, acyclovir, brivudine, famciclovir, penciclovir, sorivudine, valacyclovir, cidofovir, ganciclovir, valganciclovir, sofosbusvir, foscarnet, ribavirin, taribavirin, thiazolinone ... These include fluprevir, filibusterin, nesbuvir, tegoviravir, fosdevirine, favipiravir, merimepodib, asunaprevir, valapiravir, boceprevir, cilprevir, danoprevir, daclatasvir, narulaprevir, telaprevir, simeprevir, vaniprevir, rupintrivir, fomivirsen, amenamevir, alisporivir, bevirimat, letermovir, laninamivir, oseltamivir, peramivir, and zanamivir.

[0145] Suitable examples of antifungal agents include abafungin, amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxiconazole, These include epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, amorolfine, butenafine, nafitifine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, undecylic acid, crystal violet, and balsam of Peru.

[0146] Suitable examples of antiprotozoal agents include metronidazole, tinidazole, ornidazole, atovaquone, clioquinol, chlorquinaldol, emetine, pentamidine isethionate, eflornithine, nitrofural, halofuginone, miltefosine, chloroquine, hydroxychloroquine, mepacrine, primaquine, amodiaquine, pamaquine, piperaquine, proguanil, cycloguanil embonate, quinine, mefloquine, pyrimethamine, artemether, artemisinin, artesunate, dihydroartemisinin, halofantrine, lumefantrine, and sulfadoxine.

[0147] Suitable examples of anthelmintics include mebendazole, praziquantel, albendazole, diethylcarbamazine, flubendazole, ivermectin, levamisole, metrifonate, niclosamide, oxyclozanide, oxamniquine, oxantel, piperazine, pyrantel, pyrantel pamoate, monopantel, delquantel, pelletierin sulfate, pyrvinium, thiabendazole, fenbendazole, triclabendazole, abamectin, suramin, emodepside, pyrvinium embonate, aminoacetonitrile.

[0148] Suitable examples of further antiparasitic agents include meglumine antimoniate, benznidazole, sodium stibogluconate, fumagillin, halofantrine, melarsoprol, nifurtimox, nitazoxanide, permethrin, lindane, malathion, carbaryl, pyrethrum, fenothrin, bio-allethrin, imidacloprid, moxidectin, nitenpyram, fipronil, pyriprole, selamectin, dimpirate, spinosad, indoxacarb, methoprene, pyriproxyfen, lufenuron, neem oil, citronella oil, clove oil, peppermint oil, eucalyptus oil.

[0149] Suitable examples of analgesics include the NSAIDs listed above; opioid analgesics such as morphine, fentanyl, methadone, oxycodone, carfentanil, dihydroetorphine, ohmefentanyl, etorphine, sufentanil, remifentanil, alfentanil, buprenorphine, hydromorphone, levomethadone, hydrocodone, pintramide, nalbuphine, tapentadol, pentazocine, dihydrocodeine, codeine, pethidine, tramadol, tilidine, meptazinol, naloxone, naltrexone, diprenorphine, loperamide, apomorphine, and the like; epibatidine; scopolamine; ziconitide; cannabinoids such as tetrahydrocannabinol, cannabidiol, marinol, and the like; flupirtine; ketamine, and the local anesthetics listed above.

[0150] Suitable examples of local anesthetics include lidocaine, lignocaine, menthol, articaine, bupivacaine, ropivacaine, benzocaine, chloroprocaine, cocaine, cyclomethicaine, dimethocaine, larocaine, piperocaine, propoxycaine, procaine, novocaine, proparacaine, tetracaine, amethocaine, cinchocaine, dibucaine, etidocaine, levobupivacaine, meplavacaine, prilocaine, trimecaine, saxitoxin, neosaxitoxin, tetrodotoxin, and eugenol.

[0151] Suitable examples of anticoagulants include heparins, coumarins (such as phenprocoumon (Marcumar) and warfarin), apixaban, rivaroxaban, edoxaban, dabigatran, ximelagatran, hirudin, lepirudin, bivalirudin, citrate, EDTA, fondaparinux, argatroban, and otamixaban.

[0152] Suitable examples of antiplatelet agents include abciximab, acetylsalicylic acid, dipyridamole, clopidogrel, eptifibatide, ilomedine, prostacyclin, prasugrel, ticagrelor, ticlopidine, and tirofiban.

[0153] Suitable examples of muscle relaxants include tercuronium, 1-ethylcarbamoyl-3-(3-trifluoromethylphenyl)pyrrolidine, metaxalone, methocarbamol, meprobamate, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, diazepam, orphenadrine, quinine, rocuronium, succinylcholine, decamethonium, pancuronium, veruronium, rapacuronium, dacuronium, duador, and maloflurane. These include malouetine, dipyrandium, pipercuronium, chandonium, HS-342, atracurium, mivacurium, doxacurium, d-tubocurarine, dimethyltubocurarine, gallamine, alcuronium, anatruxonium, diadonium, fazadinium, tropeinium, and cisatrucurium.

[0154] A tonic is a general term for an agent that strengthens the body, increases tone, or restores its physiological functions. Tonics can be of herbal or animal origin.

[0155] Anabolic agents can promote anabolic metabolism and strengthen the collagen scaffolding of cells. However, widespread abuse is known as doping in sports and bodybuilding. Therefore, the combination with the solubilisate according to the present invention is only recommended insofar as its use is covered by the respective national legislation.

[0156] Those skilled in the art will readily identify standard treatments for the above-mentioned pharmaceutically active agents from the state of the art. The mode of administration and dosage of each of the above-mentioned combinations of pharmaceutically active agents is preferably consistent with the already established standard treatment for the combined active agents. [Example]

[0157] In the examples that follow, the relative amounts of solubilizing agents can be varied within the limits shown for each component in the methods according to the invention. The addition of glyceryl oleate and / or antioxidants is optional.

[0158] The amounts shown can be upscaled or downscaled according to the desired absolute amount of drug to be solubilized in the solubilizer, which can be dispensed according to the desired final amount of drug to be administered to a patient in need thereof.

[0159] Generally, the resulting solubilisate produced according to the method of the present invention has a specific density of 0.92 to 0.94 kN / m 3 It was.

[0160] In each example, the preparation of a dosage form for the solubilisate according to the present invention is described for illustrative purposes. It is understood that the solubilisate according to the present invention can also be used in any corresponding dosage form known in the art, for example, as described in Remington: The Science and Practice of Pharmacy (22nd Edition, Pharmaceutical Press, 2013; which is incorporated by reference).

[0161] Standard chemicals were purchased from Sigma-Aldrich (Darmstadt, Germany). [Example]

[0162] Solubilization of 5-amino-2,3-dihydro-1,4-phthalazinedione—Embodiment 1

[0163] The following notations indicate the weight percentages of the mixture: Approximately 100 ml of solubilisate is made: 5-amino-2,3-dihydro-1,4-phthalazinedione is provided, and then the solubilising agent is mixed one by one under stirring at room temperature (20±5°C) and atmospheric pressure for 5 minutes.

[0164] [Table 1]

[0165] The composition is then carefully heated with continuous stirring at a temperature increment of approximately 1°C / min. After about 20 minutes (about 40°C), the composition begins to become a clear solution. This solubilization process continues for about 16 minutes or more. Thus, a solubilizate according to the present invention is obtained after about 36 minutes at about 56°C. Thereafter, heating and stirring are stopped, and the solubilizate obtained is cooled to room temperature. The solubilizate remains clear and stable for an observation period of at least 6 months. [Example]

[0166] Solubilization of 5-amino-2,3-dihydro-1,4-phthalazinedione—Embodiment 2

[0167] The following notations indicate the weight percentages of the mixture: Approximately 100 ml of solubilisate is made: 5-amino-2,3-dihydro-1,4-phthalazinedione is provided, and then the solubilising agent is mixed one by one under stirring at room temperature (20±5°C) and atmospheric pressure for 5 minutes.

[0168] [Table 2]

[0169] The composition is then carefully heated with continuous stirring at a temperature increment of approximately 1.5°C / min. After about 23 minutes (about 55°C), the composition begins to become a clear solution. This solubilization process continues for about 10 minutes or more. Thus, a solubilizate according to the present invention is obtained after about 33 minutes at about 70°C. Thereafter, heating and stirring are stopped, and the solubilizate obtained is cooled to room temperature. The solubilizate remains clear and stable for an observation period of at least 6 months. [Example]

[0170] Solubilization of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt

[0171] The following notations indicate the weight percentages of the mixture: Approximately 100 ml of solubilized material is produced: 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (the salt in the form of polymorph I as described in International Publication WO 2011 / 107295 A1) is provided, and then the solubilizing agent is mixed one by one under stirring at room temperature (20±5°C) and atmospheric pressure for 5 minutes.

[0172] [Table 3]

[0173] The composition is then carefully heated with continuous stirring at a temperature increment of approximately 1°C / min. After about 32 minutes (about 52°C), the composition begins to become a clear solution. This solubilization process continues for about 8 minutes or more. Thus, a solubilizate according to the present invention is obtained after about 40 minutes at about 60°C. Thereafter, heating and stirring are stopped, and the solubilizate obtained is cooled to room temperature. The solubilizate remains clear and stable for an observation period of at least 2 months. [Example]

[0174] Preparation of Liquid Dosage Forms for Oral Administration

[0175] In 45 ml of liquid carrier having the following composition (by weight):

[0176] [Table 4]

[0177] Dissolve 5 ml of the solubilisate from Example 1. This solution (50 ml) can be filled into a suitable dropper bottle known in the art.

[0178] This formulation does not require additional emulsifiers (such as polysorbates). [Example]

[0179] Preparation of liquid dosage forms for parenteral administration

[0180] In 245 ml of liquid carrier having the following composition (by weight):

[0181] [Table 5]

[0182] Dissolve 5 ml of the solubilisate of Example 1. This parenteral solution (250 ml) can be filled into suitable infusion bags known in the art.

[0183] This formulation does not require additional emulsifiers (such as polysorbates). [Example]

[0184] Preparation of solid dosage forms as soft gelatin capsules

[0185] Soft gelatin capsule shell composition (wt%): [Table 6]

[0186] Soft gelatin capsules containing the solubilizate of 5-amino-2,3-dihydro-1,4-phthalazinedione are prepared according to standard methods as described in Mahato and Narang, Pharmaceutical Dosage Forms and Drug Delivery (2nd Edition, Chapter 18.3.5), wherein 1.25 ml of the solubilizate of Example 1 is injected into the mold cavity of the provided soft gelatin capsule, and then the soft gelatin capsule is sealed. [Example]

[0187] Preparation of solid dosage forms as hard gelatin capsules

[0188] Hard gelatin capsule shell composition (wt%): [Table 7]

[0189] Hard gelatin capsules (size "000", with a capacity of 1.4 ml) are prepared by standard methods known in the art. Each capsule is filled with 1.25 ml of the solubilizate as prepared in Example 1. Immediately thereafter, the two pieces of the hard gelatin capsule are joined together. [Example]

[0190] Preparation of a topical dosage form as a cream

[0191] The following ingredients are used (% by weight): [Table 8]

[0192] In the first preparation, 5-amino-2,3-dihydro-1,4-phthalazinedione solubilizer, cetearyl alcohol, glyceryl stearate, ceteareth 20, ceteareth 12, decyl oleate, and sodium cetearyl sulfate are mixed and heated to 70°C. In the second preparation, allantoin, glycerin, and water are mixed and heated to 70°C. The first and second preparations are then slowly mixed and homogenized for 2 to 3 minutes using a disperser (Ultra-Turrax T-18®). Once cooled to 35°C, the third preparation consisting of Rokonsal ND® is added and stirred uniformly. The mixture is again homogenized at approximately 45°C for 1 minute. The resulting mixture is then cooled to room temperature while stirring, avoiding the inclusion of air. If necessary, the pH can be adjusted with NaOH or citric acid.

[0193] The pH of the cream is 5.40. The stability of this skin cream is at least 6 months at 40° C. At this temperature, no phase separation occurs.

[0194] 50 ml of the resulting cream is packaged in suitable collapsible aluminium tubes known in the art. [Example]

[0195] Preparation of topical dosage forms as hydrogels

[0196] The hydrogel is made by a slight modification of the method disclosed in US Patent Application Publication No. 2010 / 0129448 A1.

[0197] A 3% CMC (carboxymethylcellulose) solution is prepared by mixing 5 ml of the solubilizate from Example 1 with WFI (water for injection), followed by autoclaving to completely dissolve the CMC into the solution, thereby forming a CMC hydrogel. A suspension is prepared by adding the solubilizate dissolved in WFI to the CMC hydrogel. Stabilizers (TEA, citric acid) are added to the CMC hydrogel. The resulting combination is mixed at elevated temperatures (40-50°C) under high shear conditions (paddle mixer and sonication) as described in U.S. Patent Application Publication No. 2005 / 0175707. Glycerol and additional WFI are also added to the suspension. The amount of excipients added to the hydrogel is controlled to achieve the desired concentration of 5-amino-2,3-dihydro-1,4-phthalazinedione.

[0198] The 3% CMC hydrogel suspension is mixed for another 20 minutes, thereby forming a bulk hydrogel suspension. The bulk hydrogel suspension is observed under an optical microscope at 100x magnification. The primary particle size of the suspended particles is less than about 10 μm, which allows the composition to be applied topically to open wounds or other tissues without abrasion. [Example]

[0199] Preparation of solid dosage forms as suppositories

[0200] Suppository base composition (wt%): [Table 9]

[0201] 1) To melt the suppository base, heat it to 50-52°C. Then, slowly cool the melted fatty base to 36°C. 2) For each suppository to be cast, a respective amount of 0.5 ml of the solubilisate of Example 3 is added to the fatty base. A soft base is formed. 3) The soft base is filled into a suppository mold configured to produce 3 cm long, torpedo-shaped rectal suppositories weighing approximately 2 g. 4) Cool the suppositories to room temperature and collect. The use of the solubilisate according to the invention allows the production of suppositories without the use of additional emulsifiers and / or plasticisers, and therefore such suppositories according to the invention are polysorbate-free.

Claims

1. 1. A method for solubilizing 5-amino-2,3-dihydro-1,4-phthalazinedione, comprising the steps of: a) providing 5-amino-2,3-dihydro-1,4-phthalazinedione at 0.1% to 2% by weight at room temperature and a pressure of 0.2 bar to 1 bar; b) 20% to 80% by weight of at least one phosphatidylcholine; 10% to 70% by weight of at least one medium chain triglyceride; 1% to 15% by weight of at least one lysophosphatidylcholine, 1% to 20% by weight of at least one C ２ ~C ４ Alcohol, and 0.5% to 10% by weight of each glyceryl stearate and / or saturated or unsaturated C １４ ~C ２０ adding, in any order, at least one solubilizing agent for fatty acids; the relative weight percentages of said ingredients add up to 100% by weight and all solubilizing agents are, independently of one another, food additives and / or pharmaceutically acceptable excipients; c) heating the resulting mixture by successively increasing the temperature by successive temperature increments of 0.5°C / min to 3°C / min over a period of 20 minutes to 60 minutes; d) stopping the temperature increase in the temperature range of 30°C to 125°C as soon as a clear solution is reached; and e) cooling the solubilized product to room temperature; The resulting solubilisate is clear, polysorbate-free and emulsion-free. method.

2. At least one of the saturated or unsaturated C １４ ~C ２０ The fatty acid is oleic acid The method of claim 1.

3. The at least one C ２ ~C ４ The alcohol is ethanol 3. The method according to claim 1 or 2.

4. Further, in step b), 0.01% to 10% by weight of at least one antioxidant is added, wherein said at least one antioxidant is a pharmaceutically acceptable excipient, and the relative weight percentages of said ingredients also include the relative weight percentage of said at least one antioxidant. The method according to any one of claims 1 to 3.

5. The at least one antioxidant is ascorbyl palmitate and / or at least one tocopherol. The method of claim 4.

6. A solubilized product of 5-amino-2,3-dihydro-1,4-phthalazinedione, 0.1% by weight to 2% by weight of 5-amino-2,3-dihydro-1,4-phthalazinedione; As a solubilizing agent, 20% to 80% by weight of at least one phosphatidylcholine; 10% to 70% by weight of at least one medium chain triglyceride; 1% to 15% by weight of at least one lysophosphatidylcholine, 1% to 20% by weight of at least one C ２ ~C ４ Alcohol, and 0.5% to 10% by weight of each glyceryl stearate and / or saturated or unsaturated C １４ ~C ２０ It consists of fatty acids the relative weight percentages of said ingredients add up to 100% by weight and all solubilizing agents, independently of one another, are food additives and / or pharmaceutically acceptable excipients; The solubilizate is clear, polysorbate-free, and not an emulsion.

7. The solubilized product according to claim 6, which is for medical use and is used in preventive medicine or treatment.

8. The solubilized product according to claim 6 or 7, Solubilisates that are immunomodulators for treating conditions involving an excessive immune response or conditions with a background of immunodeficiency.

9. A pharmaceutical composition comprising the solubilized product of claim 6, which comprises 5-amino-2,3-dihydro-1,4-phthalazinedione, and at least one pharmaceutically acceptable excipient.

10. 10. The pharmaceutical composition of claim 9 for oral, parenteral or topical administration.

11. A medicament comprising the solubilisate of claim 6 and at least one pharmaceutically active agent, the at least one pharmaceutically active agent is at least one pharmaceutically active agent selected from the group comprising steroidal and non-steroidal anti-inflammatory drugs; immunomodulators; immunostimulants; immunosuppressants; antibiotics; anti-infectives; antivirals; antifungals; antiprotozoal agents; anthelmintics; analgesics; local anesthetics; anticoagulants; antiplatelet agents; muscle relaxants; tonics; and anabolic agents; Medications used in the prevention and / or treatment of conditions involving an excessive immune response or conditions with a background of immunodeficiency.

12. The at least one pharmaceutically acceptable excipient is selected from the group comprising carriers, binders, lubricants, glidants, disintegrants, colorants, buffers, preservatives, emulsifiers, penetration enhancers, antioxidants, diluents, pH adjusters, solvents, consistency enhancers, hydrotopes, sweeteners, acidifiers, thickeners, anti-adherents, fillers, flavors, sweeteners, opacifiers, flavorings and fragrances. The pharmaceutical composition of claim 9.

13. 13. A pharmaceutical composition according to claim 9 or 12 for use in medicine.

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