RU2787999C2 - Method for solubilization of 5-amino-2,3-dihydro-1,4-phthalazinedione - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention relates to a method for solubilization of 5-amino-2,3-dihydro-1,4-phthalazinedione. The method includes following stages: a) provision of 5-amino-2,3-dihydro-1,4-phthalazinedione in the total range from 0.1% to 25% by wt., at a room temperature and pressure from 0.2 bar to 1 bar; b) addition, in any order, of solubilizing agents: at least one phosphatidylcholine in the total range from 20% to 80% by wt., at least one triglyceride with an average chain length in the total range from 10% to 70% by wt., at least one lysophosphatidylcholine in the total range from 1% to 15% by wt., at least one C2-C4 alcohol in the total range from 1% to 20% by wt., and at least one glyceryl stearate and/or saturated or unsaturated C14-C20 fatty acid in the total range from 0.5% to 10% by wt., respectively, while relative weight percentages of all ingredients amount to no more than 100%, and all solubilizing agents are independently of each other a food additive and/or pharmaceutically acceptable auxiliary substance; c) gentle heating of the resulting mixture by continuous increasing a temperature with continuous increment of the temperature of 0.5°C/min - 3°C/min for a period from 20 to 60 minutes; d) termination of temperature increasing in the temperature range from 30°C to 125°C as soon as a transparent solution is obtained; and e) cooling of solubilizate to a room temperature. The invention also discloses solubilizate of 5-amino-2,3-dihydro-1,4-phthalazinedione; solubilizate of sodium, potassium, or lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione, or a mixture thereof; preventive or therapeutic use of solubilizate as an immunomodulator for the treatment of conditions with an excessive immune reaction or conditions with immunodeficiency background, as well as a pharmaceutical composition containing 5-amino-2,3-dihydro-1,4-phthalazinedione and at least one pharmaceutically acceptable auxiliary substance.

EFFECT: ease of handling, absence of long time for development of a suitable composition, absence of the need for use of expensive equipment, cheap materials and production costs, absence of the need for addition of polysorbate solubilizers.

14 cl, 10 ex

Description

The present invention relates to a method for the solubilization of 5-amino-2,3-dihydro-1,4-phthalazinedione or salts thereof, a solubilisate obtained by this method, its applications, and a pharmaceutical composition containing said solubilisate.

For decades, forensic experts have been using 5-amino-2,3-dihydro-1,4-phthalazinedione (Luminol) to detect traces of blood, even if efforts have been made to purify or remove it (cf. Barni et al ., Talanta 2007, 72, 896-913). The intense luminescence during oxidation, catalyzed by hemoglobin iron, makes luminol a sensitive detection tool. In addition to forensic applications, since the first report on the synthesis of luminol, many other applications have appeared, from applications in the field of ecology to medicine (A. J. Schmitz, Über das Hydrazid der Trimesinsäure und der Hemimellithsäure, Heidelberg, 1902). For example, luminol is used for heavy metal detection or biosensor detection in bioanalytical chemistry (cf. Klopf and Nieman, Anal. Chem. 1983, 55, 1080-1083).

The alkali salts of luminol have only recently been structurally characterized (Guzei et al., J. Coord. Chem. 2013, 66, 3722-3739), as the sodium salt of luminol is again of interest due to its pharmaceutical activity. Na-luminolate shows great potential in the immunomodulatory treatment of inflammatory and autoimmune diseases. Moreover, Na-luminolate exhibits rich polymorphism in the form of three anhydrous crystal structures that have been characterized to date (cf. WO 2011/107295 A1; WO 2016/96143 A1). Also, two crystal forms have been disclosed for luminol itself (Paradies, Ber. Bunsen-Ges. Phys. Chem 1992, 96, 1027-1031; WO 2017/140430 A1). The general physicochemical properties of isomeric forms of luminol in aqueous solutions have been disclosed by Skripnikova et al. (2017; J Mol Struct 1154: 59-63). Specific therapeutic uses for these crystalline forms of Na-luminolate or luminol have been described in WO 2017/202496 A1.

It is known that crystalline forms of a compound may exhibit various physical characteristics such as solubility, dissolution rate and stability (cf. Haleblian und McCrone (1969): Journal of Pharmaceutical Sciences, 58:911-929). These properties can influence the pharmaceutical processing of a compound, as well as its bioavailability and pharmacokinetics and hence its biological efficacy (cf. Griesser (2006) in: Polymorphisms in the Pharmaceutical Industry. Hilfiker (Ed.) 211-234). A formulation for increasing the oral bioavailability of drugs by adding at least one piperine to a solution has been disclosed in WO 2013/108254 A1.

While the previously described luminol salts are readily soluble in water, luminol itself is poorly soluble in water. Moreover, the small amount that can be dissolved tends to precipitate after a few days. Sensitivity to light, heat, and metal cations has also been described. This makes it very difficult to use aqueous solutions of luminol. The problem can be overcome by using a stock solution or by using a diluent such as ethanol or DMSO. However, these diluents are not suitable for a wide range of pharmaceutical applications.

The use of the sodium salt of luminol is preferred in terms of aqueous solubility. However, for absorption in the gastrointestinal tract, topical application for transdermal delivery, or for transport across the blood-brain barrier, it would be preferable to administer the free acid to increase the bioavailability of luminol. Thus, sufficiently high plasma and intracellular concentrations can be achieved to maximize the therapeutic potential of luminol. Thus, there is a need to find a way to solubilize luminol in an aqueous medium.

There are many approaches to improve the solubility of lipophilic pharmaceutical agents and in many cases also their bioavailability using solubilization techniques. In this case, the solubility of the agent in the medium is increased by adding a third substance. These third substances are referred to as solubilizers (solubilizing agents), substances which can, for example, form a complex with the substance to be solubilized. Examples of such chelating agents are sodium benzoate and sodium salicylate. Another mechanism of action of solubilizers is to increase the dissolving power of the solvent, for example, by disrupting the cluster structure of water. Examples of such structure destroying substances are glycerol (glycerol) and macrogols (polyethylene glycol, PEG).

The third solubilization mechanism is the use of micelles and liposomes. They have gained wide attention over the past decades. In this case, the delivered substance is enclosed in a spherical aggregate of surfactant molecules. These molecules are characterized by a polar head group and a long non-polar chain ("tail"). When released into an aqueous environment, these molecules tend to bind by aggregation into spherical structures by orienting the polar head group towards the environment and the non-polar chain towards the interior of the spheres. When these spheres consist of only one layer of such amphiphilic molecules, they are called micelles. Depending on the nature of the amphiphilic molecule and the reaction conditions, it is also possible to form spheres with more than one layer. Here, the second layer is formed within the outer layer of the sphere, with the non-polar groups of this second layer oriented towards the non-polar groups of the outer layer, and the polar head groups oriented towards the inside of the sphere. Such aggregates are called liposomes. In their structure, they resemble the lipid bilayer of the cell membrane. There are also multilayer liposomes in which at least two liposomal spheres are formed concentrically around each other, thereby creating a multispherical aggregate. When introduced into a lipophilic medium, these substances tend to form inverted spherical structures, where the lipophilic chain is oriented towards the solution medium and the other layers are arranged accordingly.

Various uses for such loaded spheres have been described in the art, including use as a dosage form to apply lipophilic substances and/or to increase the bioavailability of the contained substance. In micelles, the enclosed nonpolar substance is concentrated in the inner space of the sphere, towards which the nonpolar chains of amphiphilic molecules are oriented. However, in liposomes, the internal space of the spheres is an aqueous, respectively, hydrophilic medium. It can serve to pack hydrophilic molecules. However, poorly soluble in water and, accordingly, lipophilic molecules are collected mainly between the lipophilic structures of the liposomal layers.

Micelle-based solubilization methods have been disclosed, for example, in WO 03/007907 A1 or WO2014/094921 A1. In this case, an emulsifier with an HLB value (hydrophilic-lipophilic balance) of 9-16 or 13-18, respectively, is used. Polysorbate (Tween) 20 or 80 is often used. The implementation of this process technology seems to be limited to the production of chewing gum.

Another approach is to add a glucuronidation inhibitor to the pharmaceutical composition. Surfactants such as poloxamers or polysorbate 20, polysorbate 60, polysorbate 80 are widely used. Another common inhibitor of glucuronidation is bioperine. Glucuronidation inhibitors, however, also inhibit the proper metabolism and therefore the elimination of other drugs or endogenous substances. Thus, their use is a "double-edged sword" and should depend on the drug therapy of each individual patient. Therefore, such a composition may cause difficulties in long-term drug administration, especially in polymorbid patients.

It is known from empirical pharmacokinetic measurements that the body can absorb micelles as well as liposomes in the gastrointestinal tract via the intestinal villi. However, their degree of absorption appears to be quite variable and therefore these methods have had mixed success in increasing the bioavailability of the entrapped compound. Transport, respectively the rate of uptake across the cell membrane, is a characteristic inherent in each substance, depending on many factors such as the size of the molecule, the degree of lipophilicity and the presence of suitable transport molecules within the cell membrane. For many compounds, these parameters are not known and must be determined first before searching for a suitable package for that particular compound.

The use of liposomes has been widely discussed in medicine and pharmacology, and several complex solutions have been developed for specific active agents. Their use, however, is not widely used. One reason is the relatively high production costs, another reason is possible side effects. A liposome-based self-emulsification method for poorly water-soluble nutritional supplements and pharmaceutical active agents has been disclosed in EP 3290026 A1. In particular, when administered parenterally, liposomes carry the risk of accumulation in the liver, spleen and/or bone marrow. Therefore, liposome formulations are often viewed with skepticism.

A nano-liposphere preparation method for increasing drug bioavailability has been disclosed in WO 2013/108254. While this method offers some improvements over the present state of the art, there are also some inherent disadvantages. High pressure homogenizers are required to obtain these solid lipid nanoparticles. However, high pressure degradation of drugs has been described for some drugs or dietary supplements. Lipid crystallization, gelation effects and the coexistence of several colloidal particles occur. Other limiting factors such as cytotoxic effects after phagocytosis, toxic effects of organic residues, and difficult scale-up under industrial conditions have limited their application to date (Mehnert and Mäder, Adv Drug Deliv Res 2001, 47, 165-196; Dudala et al., Int. J Pharm Investg 2014, 4, 149-155). Moreover, their drug capacity is relatively small and they exhibit low viscosity. Therefore, they are not very attractive for topical or transdermal formulations (Mukherjee et al., Indian J Pharm Sci 2009, 71, 349-358). In addition, WO 2013/108254 requires the use of an amphiphilic solvent such as lower alkyl esters of lactic acid or N-methylpyrrolidone. N-methylpyrrolidone is considered a substance of great concern due to its potential carcinogenicity and reproductive toxicity, methyl lactate is commonly hydrolyzed to lactate and methanol in the aquatic environment. Ethyl lactate and others are well tolerated. However, due to relatively high production costs, it is not a very attractive solvent.

A process for solubilizing ubiquinone Q ₁₀ with a triglyceride-containing light oil is described in WO 03/007907 A1.

Another method of solubilization is the formation of inclusion complexes of the substance to be solubilized with cyclodextrins such as α-, β- or γ-cyclodextrin or cyclodextrin derivatives such as 2-hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin or trimethyl -β-cyclodextrin. As a rule, cyclodextrins consist of 6-8 1,4-linked α-D-glucopyranosides forming macrocycles. Thus, a water-soluble toroidal (cone-shaped or bucket-shaped) structure is formed, capable of retaining hydrophobic substances in its interior. The interior space is substantially less hydrophilic than the exterior space in contact with the aquatic environment. Cyclodextrins are obtained from starch by enzymatic processing. They are loaded with a compound to be dissolved by dispersion. The compound to be dissolved can then be released by bringing these complexes into contact with water, by changing the pH or temperature, depending on the particular composition. However, the development of cyclodextrin is obviously difficult and relatively costly. This has limited its use to date. Another problem is that cyclodextrins interact with preservatives such as parabens.

Thus, all these methods have their advantages, but also some disadvantages.

Polysorbates find wide use in these solubilization processes. However, there is ongoing controversy regarding the harmful effects of polysorbates on health. Polysorbate-20 is believed to be contaminated with unreacted 1,4-dioxane and ethylene oxide (from at least some vendors). They are known skin carcinogens (cf. http://www.fda.gov/ohrms/dockets/98fr/060199a.txt, March 22, 2017). Polysorbate 80 has recently been found to have a deleterious effect on the mouse gut microbiota promoting colitis and metabolic syndrome, Nature, 2015, 519, 92- 96). This is of particular importance for patients with chronic inflammatory bowel disease (IBD) such as Crohn's disease (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 therapeutic indication for 5-amino-2,3-dihydro-1,4-phthalazinedione. Another problem with polysorbates such as Tween 80 is that they reduce the effectiveness of commonly used preservatives such as parabens by binding them (cf. Blanchard et al., Effect of sorbitol on interaction of phenolic preservatives with polysorbate 80, 1977, J Pharm Sci 66, pp. 1470-1473). However, the concentration of parabens should not be appropriately increased due to their estrogenic potential (cf. 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, pp. 1225-1232). Other well-known problems with polysorbates (particularly polysorbate 80) are hypersensitivity reactions in patients (cf. Steele et al., Hypersensitivity reactions to the polysorbate contained in recombinant erythropoietin and darbepoietin, Nephrology, 2005, 10, p. 317-320; Norris et al., Polysorbate 80 hypersensitivity reactions: a renewed call to action, Commun Oncol, 2010, 7, 425-428). Polysorbate 80 has also been associated with systemic hypotension in amiodarone formulations, where it can even lead to accidents (cf. 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).

The solubilization method for 5-amino-2,3-dihydro-1,4-phthalazinedione must meet the following criteria:

- ease of handling

- lack of a long time to develop a suitable composition

- no need for expensive equipment

- inexpensive materials and production costs

- no need to add polysorbate solubilizers (Tween).

Surprisingly, it was found that the method according to the present invention is able to solve this problem.

In the present invention, 5-amino-2,3-dihydro-1,4-phthalazinedione is solubilized by the method of the present invention, comprising the following steps:

a) Provide 5-amino-2,3-dihydro-1,4-phthalazinedione in the general range from 0.1% to 25% of the mass. at room temperature and pressure from 0.2 bar to 1 bar;

b) Solubilizing agents are added in any order, such as at least one phosphatidylcholine in the general range from 20% to 80% wt.,

at least one triglyceride with a medium chain length in the general range from 10% to 70% wt.,

at least one lysophosphatidylcholine in the general range from 1% to 15% wt.,

at least one alcohol With ₂ -C ₄ in the General range from 1% to 20% of the mass. and at least one glyceryl stearate and/or saturated or unsaturated fatty acid C ₁₄ -C ₂₀ in the general range from 0.5% to 10 wt%, respectively,

where the relative mass percentages of all ingredients are not more than 100%, and all solubilizing agents are pharmaceutically acceptable excipients;

c) Gently heat the resulting mixture by continuously raising the temperature in continuous temperature increments of 0.5 °C/min to 3 °C/min over a period of 20 to 60 minutes;

d) Stop raising the temperature in the temperature range from 30 °C to 125 °C as soon as a clear solution is obtained; and

e) Allow the solubilisate to cool to room temperature.

In a preferred embodiment, 5-amino-2,3-dihydro-1,4-phthalazinedione is solubilized by the method of the present invention, comprising the following steps:

a) Provide 5-amino-2,3-dihydro-1,4-phthalazinedione in a general range of 0.5% to 10% wt. at room temperature and pressure from 0.2 bar to 1 bar;

b) Solubilizing agents are added in any order, such as at least one phosphatidylcholine in the general range from 20% to 80% wt.,

at least one triglyceride with a medium chain length in the general range from 10% to 70% wt.,

at least one lysophosphatidylcholine in the general range from 1% to 15% wt.,

at least one alcohol With ₂ -C ₄ in the General range from 1% to 20% of the mass. and at least one glyceryl stearate and/or saturated or unsaturated fatty acid C ₁₄ -C ₂₀ in the general range from 0.5% to 10 wt%, respectively,

where the relative mass percentages of all ingredients are not more than 100%, and all solubilizing agents are pharmaceutically acceptable excipients;

c) Gently heat the resulting mixture by continuously raising the temperature in continuous temperature increments of 0.5 °C/min to 3 °C/min over a period of 20 to 60 minutes;

d) Stop raising the temperature in the temperature range from 30 °C to 125 °C as soon as a clear solution is obtained; and

e) Allow the solubilisate to cool to room temperature.

Another aspect of the present invention is that the method of the present invention does not require the use of polysorbates as solubilizers and/or emulsifiers. Therefore, 5-amino-2,3-dihydro-1,4-phthalazinedione can be solubilized by the method of the present invention, comprising the following steps:

a) Provide 5-amino-2,3-dihydro-1,4-phthalazinedione over a total range of 0.1% to 25% wt. at room temperature and pressure from 0.2 bar to 1 bar;

b) Solubilizing agents are added in any order, such as at least one phosphatidylcholine in the general range from 20% to 80% wt.,

at least one triglyceride with a medium chain length in the general range from 10% to 70% wt.,

at least one lysophosphatidylcholine in the general range from 1% to 15% wt.,

at least one alcohol With ₂ -C ₄ in the General range from 1% to 20% of the mass. and at least one glyceryl stearate and/or saturated or unsaturated fatty acid C ₁₄ -C ₂₀ in the general range from 0.5% to 10 wt%, respectively,

where the relative mass percentages of all ingredients are not more than 100%, and all solubilizing agents are pharmaceutically acceptable excipients;

c) Gently heat the resulting mixture by continuously raising the temperature in continuous temperature increments of 0.5 °C/min to 3 °C/min over a period of 20 to 60 minutes;

d) Stop raising the temperature in the temperature range from 30 °C to 125 °C as soon as a clear solution is obtained; and

e) Allow the solubilizate to cool to room temperature,

which is characterized in that the resulting solubilizate does not contain polysorbate.

In other embodiments, the solubilisates of the present invention may also be prepared from 5-amino-2,3-dihydro-1,4-phthalazinedione salts. Sodium, potassium and lithium salts have been described for therapeutic use (cf. WO 2010/082858). Crystal structures for lithium, sodium, potassium, rubidium and cesium salts have been described in Guzei et al. (2013, Journal of Coordination Chemistry 66, 3722-3739; see also WO 2011/107295 A1; WO 2016/96143 A1). As a rule, these salts are soluble in water and, therefore, it is not necessary to dissolve them in aqueous solutions. However, when used therapeutically, the solubilisates of the present invention are capable of extending the shelf life of liquid dosage forms. In liquid oral dosage forms, they can mask the taste of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt solutions, which is not attractive to many patients. Moreover, they improve the absorption of these 5-amino-2,3-dihydro-1,4-phthalazinedione salts from the gastrointestinal tract in terms of amount and time. In this case, bioavailability can be improved, which can lead to favorable pharmacokinetic properties. However, higher ion concentrations prevent the formation of multilamellar vesicles, which are believed to be necessary for dissolving the solubilisates of the present invention in aqueous solution. Therefore, the maximum relative amounts of 5-amino-2,3-dihydro-1,4-phthalazinedione salts are lower than for the free base.

It was found that a maximum of 2 wt. salts of 5-amino-2,3-dihydro-1,4-phthalazinedione can be dissolved in accordance with the method according to the present invention.

Thus, the salt of 5-amino-2,3-dihydro-1,4-phthalazinedione is solubilized by the method of the present invention, comprising the following steps:

a) providing a salt of 5-amino-2,3-dihydro-1,4-phthalazinedione in the general range from 0.1% to 2% wt. at room temperature and pressure from 0.2 bar to 1 bar;

where the salt is a sodium, potassium or lithium salt or mixtures thereof;

b) adding in any order solubilizing agents:

at least one phosphatidylcholine in the general range from 20% to 80% wt.,

at least one triglyceride with a medium chain length in the general range from 10% to 70% wt.,

at least one lysophosphatidylcholine in the general range from 1% to 15% wt.,

at least one alcohol With ₂ -C ₄ in the General range from 1% to 20% of the mass. and at least one glyceryl stearate and/or saturated or unsaturated fatty acid C ₁₄ -C ₂₀ in the general range from 0.5% to 10 wt%, respectively,

where the relative mass percentages of all ingredients are not more than 100%, and all solubilizing agents are pharmaceutically acceptable excipients;

c) gently heating the resulting mixture by continuously raising the temperature in continuous temperature increments of 0.5 °C/min to 3 °C/min over a period of 20 to 60 minutes;

d) stopping the temperature increase in the temperature range from 30 °C to 125 °C as soon as a clear solution is obtained; and

e) cooling the solubilizate to room temperature.

In preferred embodiments, also embodiments of these 5-amino-2,3-dihydro-1,4-phthalazinedione salts are characterized in that the resulting solubilisate does not contain polysorbate.

It is to be understood that the following descriptions and embodiments also apply to said 5-amino-2,3-dihydro-1,4-phthalazinedione salts as the free base.

Obscure and even conflicting definitions can be found in the art. To avoid any ambiguity, the solubilisate of 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 salts or mixtures thereof and the solubilizing agents defined in accordance with the present invention. Further addition of a solvent or diluent is not covered by this term. The solubilisate of the present invention is first prepared by the solubilization method of the present invention, then a specific pharmaceutical composition is obtained with said solubilisate, and finally, said pharmaceutical composition is packaged in a suitable pharmaceutically acceptable container for the respective dosage form.

The solubilizate according to the present invention is characterized by essentially complete solubilization of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its salts or a mixture thereof, thus being an almost ideal solution in which the molecules behave essentially as independent objects in solution and essentially obey the rules of distribution and thermodynamics of Brownian motion. Thus, the solubilisate is a clear solution containing 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its salts or a mixture thereof in high concentration. As a rule, the solubilisate is not intended for administration without dilution, respectively, for administration without preparation in the form of a pharmaceutically acceptable dosage form. In most cases, the portion of solubilizate is a few ml.

Within the scope of this patent application, the terms " solubilized aggregate " or " solubilized substance " should be used as synonyms for the term "solubilisate".

The solubilizate according to the present invention must be different from a suspension (colloidal suspension). This term defines a heterogeneous mixture containing solid particles, which will sooner or later be subjected to sedimentation. It is also different from an emulsion (a mixture of two liquids that do not normally mix).

To increase the bioavailability of a substance, complete solubilization is highly preferred.

The term solubilisate used in accordance with the present invention is to be distinguished from pharmaceutical composition . The pharmaceutical composition of the present invention is prepared by diluting the solubilisate of the present invention, preferably in an aqueous solution to form a liquid dosage form, or by mixing the solubilisate with a topical dosage form, capsule or suppository.

The diluent within the scope of this application is a diluting agent (diluent, diluent). It is not part of the solubilizate according to the present invention.

Within the scope of this application, the term " solubilizing agent " refers to any chemical that is added to 5-amino-2,3-dihydro-1,4-phthalazinedione, or one of its salts, or mixtures thereof, in order to solubilize it so that 5 -amino-2,3-dihydro-1,4-phthalazinedione or one of its salts or a mixture thereof were dissolved in the aqueous solution. The term " solubilizer " is used as a synonym.

In the scope of this application, the term "drug" includes a drug for humans and animals.

The great advantage of such a solubilizate lies in its small volume. Thus, it can be easily divided into patient-friendly units, or relatively large quantities of solubilized material can be transported at low cost. To obtain a dosage form, preparation can be easily carried out by medical personnel or patients.

The solubilizate of the present invention must also be distinguished from a concentrate . The concentrate is a compound, respectively a compound composition without a diluent. When the concentrate is released into the diluent, the concentrate completely dissolves in the diluent or forms a suspension or emulsion with the diluent. There is no need for interaction of the concentrate with solubilizing agents, since it is itself soluble in water or aqueous solution.

In a preferred embodiment of the process according to the present invention, 5-amino-2,3-dihydro-1,4-phthalazinedione is provided in a general range of 2% to 15% by weight, in a more preferred embodiment in a general range of 2% to 10% wt.

Phosphatidylcholines are a class of choline-related phospholipids. They are the main component of cell membranes and are, for example, obtained from egg yolk, ox liver, marine animals, krill oil or soybeans. In practice, it has been shown that the origin of phosphatidylcholines largely influences their biological and chemical effects. According to the present invention, at least one phosphatidylcholine (PC) may be selected from the group consisting of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), natural (non-hydrogenated) or hydrogenated soybean PC, natural or hydrogenated egg PC, dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC) or 1,2-dioleyl-SN-glycero-3-phosphocholine (DOPC), 1-oleoyl-palmitoyl phosphatidylcholine (OPPC), diastearoylphosphatidylcholine (DSPC), monostearoylphosphatidylcholine (MSPC), diarachidoylphosphatidylcholine (DAPC) and mixtures thereof. Preferred phosphatidylcholines are unhydrogenated soybean PC, DMPC, POPC and DOPC. Non-hydrogenated phosphatidylcholines are also preferred. Particularly preferred is non-hydrogenated soy PC.

For the solubilisate of the present invention for the preparation of topical dosage forms, non-hydrogenated phosphatidylcholines are particularly preferred.

Lecithin is commonly used as a synonym for phosphatidylcholines. It is a mixture of phosphatidylcholine and other compounds.

According to the method of the present invention, phosphatidylcholines are used in the general range from 20% to 80% by weight, preferably from 40% to 70% by weight, more preferably from 50% to 65% by weight. and most preferably 60% of the mass.

Medium chain triglycerides (MCTs) refer to triglycerides whose fatty acids have an aliphatic tail of 6-12 carbon atoms. The fatty acids included in MCTs are called Medium Chain Fatty Acids (MCFAs). In triglycerides, three fatty acid molecules are linked to the glycerol backbone. By definition, at least two of these three fatty acids must be MCFA in MCTs. According to the present invention, the MCFAs may be independently selected from the group consisting of caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, unsaturated derivatives thereof, and mixtures thereof. Preferred MCFAs are caproic acid, caprylic acid, capric acid and lauric acid.

In some embodiments of the present invention, it may be preferable to use triglycerides containing from 1 to 3 residues of myristic acid and/or palmitic acid, instead of MCFA. Therefore, these two fatty acids should be included in the term MCT according to the present invention.

MCT oils or MCT fats are oils or fats containing predominantly said MCT. These terms refer to an appropriate mixture of different MCTs, which may contain different MCFAs. According to the present invention, any acceptable mixing ratio should be covered by these conditions. MCT fats are often extracted from certain vegetable fats, while MCT oils do not occur naturally. MCT oils and MCT fats are sold in a wide range as a healthy dietary supplement, respectively, as a substitute for long chain fats for food use.

According to the method of the present invention, MCT is used in the general range from 10% to 70% by weight, preferably from 20% to 40% by weight, more preferably from 25% to 35% by weight. and most preferably 30 wt%.

Lysophosphatidylcholines (LPC, lysoPC, also: lysolecithins) are a class of derivatives of phosphatidylcholines resulting from their partial hydrolysis, in which one of the fatty acid groups is removed. In the body, this hydrolysis is carried out by the enzyme phospholipase A2. According to the present invention, the at least one lysophosphatidylcholine may be independently selected from the group consisting of all hydrolysed compounds of the phosphatidylcholines listed above, 1-lysophosphatidylcholines (2-acyl-sn-glycero-3-phosphocholines), 2-lysophosphinolidylcholines, L-alpha -lysophosphatidylcholine; and mixtures thereof.

According to the method of the present invention, lysophosphatidylcholines are used in the general range from 1% to 15% by weight, preferably from 3% to 8% by weight, more preferably from 5% to 7% by weight. and most preferably 6% of the mass.

Within the scope of the present application, said lysophosphatidylcholines are not a mere variant or replacement for phosphatidylcholines, but play an independent role. Surprisingly, it has been found that two solubilizing agents of similar but not identical chemical composition can significantly improve the solubilizing effect when used in unequal proportions. 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 .

According to the present invention, at least one C ₂ -C ₄ alcohol (lower alcohol) may 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.

According to the method of the present invention, C ₂ -C ₄ alcohols are used in the general range from 1% to 20% wt., preferably from 2% to 10% wt., more preferably from 3% to 8% wt. and most preferably 5 wt%.

Glyceryl stearate (glycerol monostearate, GMS) is an emulsifier. The flake powder is also hygroscopic. GMS is used as a thickening, emulsifying, anti-caking, staling inhibiting and preservative agent.

According to the present invention, at least one saturated or unsaturated fatty acid With ₁₄ -C ₂₀ can be used instead of or in combination with glyceryl stearate. It may be selected from the group consisting of myristic acid (14:0), pentadecanoic acid (15:0), palmitic acid (16:0), heptadecanoic acid (17:0), stearic acid (18:0), nonadecanoic acid (19:0), arachidonic 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 ), linolenic 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)), calenoic 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 ). C ₁₄ -C ₂₀ fatty acids with an even number of atoms are preferred. Especially preferred is oleic acid.

According to the method of the present invention, glyceryl stearate and/or saturated or unsaturated C ₁₄ -C ₂₀ fatty acids are used in the general range from 0.5% to 10% by weight, preferably from 1% to 8% by weight, more preferably from 2% to 6% % wt. and most preferably from 3% of the mass.

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

The method according to the present invention can be carried out at a pressure of 0.2 bar to 1 bar. However, it is preferable to use the method at a pressure of 1 bar (atmospheric pressure). For certain applications, it may be preferable to use a light vacuum. The technical equipment for applying, maintaining and controlling such a light vacuum is well known in the art.

According to the method of the present invention, the resulting mixture is gently heated in step c) by continuously raising the temperature for 20-60 minutes. In preferred embodiments, this period is 25-40 minutes, and most preferably 30-35 minutes.

An important feature of the method according to the present invention is temperature control (temperature increase over time and duration of heating). Despite the variability in the relative amounts of solubilizing agents, controlled temperature rise is important. There appears to be an optimal window for each substance to be solubilized, depending on the mixture of solubilizing agents used. The assumption of exact values is difficult, they should be clarified empirically.

The continuous temperature increment (temperature slope) can vary from 0.5°C/min to 3°C/min, preferably from 1°C/min to 2°C/min, and most preferably 2°C/min.

According to step d), the temperature increase is stopped in the temperature range from 30 to 125 °C as soon as a clear solution is obtained. This point is highly dependent on the solubilizing agents chosen and the reaction conditions. It does not appear to be possible to predict this "solubilization temperature" based on the particular components that will be used. Each composition of these components exhibits specific characteristics that must be discovered experimentally. Thus, the experimenter has to find out the optimal combination of these parameters.

It should be understood that the process of the present invention may be modified so that any of the solubilizing agents in step b) may be added first, and then 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its salts, or their mixture, as well as other solubilizing agents, may be added in any order. It is also possible to first prepare a mixture of solubilizing agents in step b) and then add 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its salts or a mixture thereof. It was found that this change is neutral with respect to the result of the method according to the present invention.

In a preferred embodiment, said mixture of solubilizing agents in step b) and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its salts or mixtures thereof is provided in a two part system. This may facilitate the solubilization process of the present invention, and each part may be sold separately. This may be advantageous in order to ensure stability and thus to ensure the shelf life of the dosage form according to the present invention.

The point at which the resulting solubilizate becomes a clear solution is determined by the experimenter by observation. Typically, this point is reached when the solution appears clear and does not show any sedimentation, sedimentation, turbidity, darkening, or zebra stripes.

In an alternative embodiment, the temperature range parameters according to the present invention, which were determined as described above, can be implemented using the setting of an automated or semi-automatic device. This may be advantageous, for example, when scaling up for industrial applications.

Solubilisates prepared according to the process of the present invention retain this clarity upon cooling and remain clear and storage stable. The achievable shelf life of a pharmaceutical dosage form containing said solubilisate (approximately corresponding to the shelf life of the product) appears to be unlimited. In a preliminary stability analysis, the minimum shelf life was never less than 6 months.

However, to increase the shelf life of these solubilisates of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its salts or mixtures thereof, at least one antioxidant may be added to the solubilisate. In preferred embodiments, at least one given antioxidant is a pharmaceutically acceptable excipient. Suitable antioxidants may be selected from the group consisting of lactic acid, ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbic acid fatty acid esters, ascorbyl palmitate, ascorbyl stearate, tocopherols, alpha tocopherol, beta tocopherol, gamma tocopherol, delta-tocopherol, alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, delta-tocotrienol, propyl gallate, octyl gallate, dodecyl gallate, ethyl gallate, guaiac gum, erythorbic acid, sodium erythorbate, erythorbic acid, sodium erythorbin, tert-butylhydroquinone , butylated hydroxyanisole, butylated hydroxytoluene, mono-, di-, trisodium phosphate, mono-, di-, tripotassium phosphate, anoxomer, ethoxyquin, potassium lactate, tin chloride, sodium thiosulfate, 4-hexylresorcinol, glucose oxidase. Preferred are ascorbyl palmitate and alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol. Particularly preferred is the combination of ascorbyl palmitate and at least one of alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol.

The term tocopherol(s) refers to any of the aforementioned tocopherols or mixtures thereof.

According to the method of the present invention, this at least one antioxidant can be optionally added to the specified solubilisate or its preferred implementation options in the general range from 0.01% to 10% wt., preferably from 0.1% to 5% wt., more preferably from 0.2% to 1% wt. and most preferably from 0.3% to 0.5% wt.

Thus, the present application also relates to the solubilizate obtained by the solubilization process according to the present invention:

The solubilizate contains 5-amino-2,3-dihydro-1,4-phthalazinedione in the range from 0.5% to 10% wt. and the following solubilizing agents:

a) at least one phosphatidylcholine in the general range from 20% to 80% by weight;

b) at least one triglyceride with an average chain length in the general range from 10% to 70% of the mass.

c) at least one lysophosphatidylcholine in the general range from 1% to 15% wt.;

d) at least one C ₂ -C ₄ alcohol in the general range from 1% to 20% by weight, and

e) and at least one of glyceryl stearate or saturated or unsaturated C ₁₄ -C ₂₀ fatty acid in the range from 0.5% to 10 wt%, respectively,

where the relative mass percentages of all ingredients are not more than 100%, and all solubilizing agents are independently pharmaceutically acceptable excipients.

In a preferred embodiment, the solubilizate according to the present invention contains 5-amino-2,3-dihydro-1,4-phthalazinedione in the range from 1% to 8% of the mass. and

a) at least one phosphatidylcholine in the general range from 40% to 70% by weight;

b) at least one triglyceride with an average chain length in the general range from 20% to 40% of the mass.

c) at least one lysophosphatidylcholine in the general range of 3% to 8% by weight;

d) at least one C ₂ -C ₄ alcohol in the general range of 2% to 10% by weight, and

e) and at least one of glyceryl stearate or saturated or unsaturated C ₁₄ -C ₂₀ fatty acids in the range from 0.5% to 5% wt., respectively,

where the relative mass percentages of all ingredients are not more than 100%, and all solubilizing agents are independently pharmaceutically acceptable excipients.

In another preferred embodiment, the solubilizate according to the present invention contains 5-amino-2,3-dihydro-1,4-phthalazinedione in the range from 2% to 5% wt. and

a) at least one phosphatidylcholine in the general range from 40% to 60% by weight;

b) at least one triglyceride with an average chain length in the general range from 25% to 35% of the mass.

c) at least one lysophosphatidylcholine in the general range of 5% to 7% by weight;

d) at least one C ₂ -C ₄ alcohol in the general range from 4% to 7% wt., and

e) and at least one of glyceryl stearate or saturated or unsaturated C ₁₄ -C ₂₀ fatty acids in the range from 0.5% to 5% wt., respectively,

where the relative mass percentages of all ingredients are not more than 100%, and all solubilizing agents are independently pharmaceutically acceptable excipients.

In alternative embodiments, the method of the present invention also relates to:

A solubilizate containing a salt of 5-amino-2,3-dihydro-1,4-phthalazinedione in the range from 0.1% to 2% wt. and the following solubilizing agents,

where the specified salt is a sodium, potassium or lithium salt or a mixture thereof;

a) at least one phosphatidylcholine in the general range from 20% to 80% by weight;

b) at least one triglyceride with an average chain length in the general range from 10% to 70% of the mass.

c) at least one lysophosphatidylcholine in the general range from 1% to 15% wt.;

d) at least one C ₂ -C ₄ alcohol in the general range from 1% to 20% by weight, and

e) and at least one of glyceryl stearate or saturated or unsaturated C ₁₄ -C ₂₀ fatty acid in the range from 0.5% to 10 wt%, respectively,

where the relative mass percentages of all ingredients are not more than 100%, and all solubilizing agents are independently pharmaceutically acceptable excipients.

According to the present invention, said solubilisate or its preferred embodiments may additionally contain an antioxidant as listed above, in the general range from 0.01% to 10% wt., preferably from 0.1% to 5% wt., more preferably from 0.2 % to 1% wt. and most preferably from 0.3% to 0.5% wt.

In a particularly preferred embodiment of this solubilisate, said at least one saturated or unsaturated C ₁₄ -C ₂₀ fatty acid is oleic acid.

In a particularly preferred embodiment of this solubilisate, said at least one C ₂ -C ₄ alcohol is ethanol.

In preferred embodiments, the implementation of at least one antioxidant in the general range from 0.01 to 10% of the mass. is further contained in the solubilisate according to the present invention, wherein said at least one antioxidant is a pharmaceutically acceptable excipient.

In particularly preferred embodiments, said at least one antioxidant is ascorbyl palmitate and/or at least one tocopherol.

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

Within the scope of this application, the term "drug" refers to a human drug as well as an animal drug.

In particular, the present application relates to a solubilisate according to the present invention for prophylactic or therapeutic use as an immunomodulator.

The present application also relates to the use of the solubilisate according to the present invention for the treatment of conditions with an excessive immune response or conditions with an immunodeficiency background.

The present application also relates to a pharmaceutical composition for the treatment of a medical condition, containing the solubilisate of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its salts or mixtures thereof according to the present invention.

As used herein, the term permeability refers to the degree of absorption of a drug in humans through the intestinal wall. According to the established definition, a drug is classified as highly permeable if 90% or more of an orally administered dose is absorbed in the gastrointestinal tract. Accordingly, a drug having an absorption rate of less than 90% is classified as low permeable.

Thus, solubility and permeability are properties inherent in a substance. However, absorption and bioavailability describe pharmaceutical parameters that can be improved with appropriate measures. Although resorption refers to the fraction of the amount of an orally administered substance that is absorbed from the gastrointestinal tract, the bioavailability of a substance depends not only on resorption, but also on species-specific protein binding in the blood and on pharmacokinetic parameters such as first pass metabolism.

Therefore, another aspect of the present invention is the prophylactic or therapeutic use of the solubilisate of the present invention to enhance the absorption and/or bioavailability of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its salts or mixtures thereof.

Thus, the present application also relates to a solubilisate according to the present invention for use in a pharmaceutical dosage form.

In addition, the present application also relates to the medical use of the solubilisate of the present invention in a pharmaceutical dosage form.

In most cases, the solubilizate of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its salts or mixtures thereof is not yet a pharmaceutical dosage form. To be ready for use in a liquid dosage form, said solubilisate must be dissolved in a diluent. The preferred diluent for liquid dosage forms is water. To do this, the solubilizate according to the present invention is added to the aqueous solution in a suitable container. The container may be selected from the group including, but not limited to, bottles, vials, flasks, glasses, cups, syringes, jars, pots, dispensers, boxes, tubes, lids, sachets, and custom made two or multiple piece containers. Preferred containers are bottles, vials and jars.

Preferably, the container with the aqueous solution and the solubilisate dissolved therein is mixed or agitated several times to ensure a homogeneous distribution of the solubilisate in the aqueous solution.

Thus, the present application also relates to a pharmaceutical dosage form in which the solubilisate according to the present invention is dissolved in an aqueous solution.

In another preferred embodiment of the present invention, the solubilizate of the present invention is included in soft gelatin capsules (SGC). SGCs dissolve as they pass through the gastrointestinal tract. They consist mainly of gelatin with the addition of various amounts of plasticizers such as glycerin or sorbitan. The release rate depends on the particular composition of the SGC carrier material. They are also suitable for sustained release of the active agent. SGCs are particularly suitable for the administration of poorly water-soluble active agents. They are excellently suited for placement in the cavity of 5-amino-2,3-dihydro-1,4-phthalazinedione solubilizate.

In another embodiment of the present invention, the solubilizate of the present invention is provided in the form of hard gelatin capsules. They are made up of gelatin, water, and usually a dye, but do not contain a plasticizer. The solubilizate according to the present invention may be incorporated during the manufacturing process. It will be released after the hard gelatin capsule dissolves.

In another preferred embodiment of the present invention, the solubilizate of the present invention is included in chewable tablets or hard candies. In this document, the solubilizate according to the present invention is integrated into the matrix of tablets or lozenges.

In another embodiment of the present invention, the solubilisate of the present invention is included in a suppository. In a typical process, low melting waxes as well as a mixture of fatty acid glycerides such as cocoa butter are first melted. Then the active agent, in this case the solubilizate of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its salts or mixtures thereof, is homogeneously dispersed with stirring or using other mixing methods. The molten homogeneous mixture is then transferred into suitable molds and cooled to solidify.

In yet another embodiment of the present invention, the solubilisate of the present invention is provided in a topical form such as creams, emulsions, lotions, gels, hydrogels, pastes, powders, ointments, liniment, films, liposomes, dermal patches, transdermal patches, transdermal sprays or suspensions.

In an additional aspect, the present application also relates to a pharmaceutical composition containing 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its salts or a mixture thereof, formulated as a dosage form as previously defined, and at least one pharmaceutically acceptable excipient.

The term "pharmaceutical excipients" refers to natural or synthetic compounds that are added to a pharmaceutical composition along with a pharmaceutically active agent. They can help increase the weight of the formulation, improve the desired pharmacokinetic properties or stability of the formulation, and be useful during the manufacturing process. Preferred classes of excipients according to the present invention include carriers, binders, lubricants, lubricants, disintegrants, colorants, buffers, preservatives, emulsifiers, penetration enhancers, antioxidants, diluents, pH adjusters, impregnating agents (fatiquors), solvents, consistency enhancers, hydrotropes, sweeteners, acidifiers, thickeners, anti-adherents, bulking agents, flavoring agents, sweeteners, opacifying agents, flavoring agents and aromatic agents.

It may be preferable, accordingly, mandatory to add one or more pharmaceutically acceptable carriers to the pharmaceutically active agent. All carriers known in the art and combinations thereof are acceptable. In solid dosage forms, they can be, for example, vegetable and animal fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicon dioxide, 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 glycols, sorbitan fatty acid esters. Carriers known in the art such as diluents (eg water, ethanol or propylene glycol), ethoxylated isostearyl alcohols, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline cellulose, bentonites, agar-agar, tragacanth can be used in the suspensions of the present invention.

The term "binders" refers to substances that bind powders or stick them together by binding them through the formation of granules. They serve as the "glue" for the composition. Binding agents increase the cohesive strength of the proposed diluent or filler.

Suitable binding agents are, for example, wheat, corn, rice or potato starch, gelatin, natural sugars such as glucose, sucrose or beta-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or alginate. ammonium calcium, sodium alginate, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcarboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, magnesium and aluminum silicate, waxes and others. The percentage of binder in the composition can be from 1 to 30 wt %, preferably from 2 to 20 wt %, more preferably from 3 to 10 wt %. and most preferably from 3 to 6% of the mass.

Coloring agents are excipients that impart color to the beverage composition or dosage form. These excipients may be food colorings. They can be adsorbed onto suitable adsorption media such as clay or alumina. The amount of dye can vary from 0.01 to 10 wt%. from the pharmaceutical composition, preferably from 0.05 to 6% wt., more preferably from 0.1 to 4% wt., most preferably from 0.1 to 1% wt.

Suitable pharmaceutical colors are, for example, curcumin, riboflavin, riboflavin-5'-phosphate, tartrazine, alcannin, quinoline yellow WS, strong yellow AB, sodium riboflavin-5'-phosphate, yellow 2G, sunset yellow FCF, orange GGN, cochineal , carminic acid, citrus red 2, carmoisine, amaranth, ponceau 4R, ponceau SX, ponceau 6R, erythrosin, red 2G, alluring red AC, indanthrene blue RS, patent blue V, indigo carmine, brilliant blue FCF, chlorophylls and chlorophyllins, copper complexes chlorophyllins and chlorophyllins, green S, strong green FCF, simple caramel, caustic sulfite caramel, ammonia caramel, ammonia sulfite caramel, black PN, carbon black, vegetable charcoal, brown FK, brown HT, alpha-carotene, beta-carotene, gamma- carotene, annatto, bixin, norbixin, pepper resin oil, capsanthin, capsorubin, lycopene, beta-apo-8'-carotene aldehyde, beta-apo-8'-carotene ethyl ester, flavoxanthin, lutein, cryptoxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, zeaxanthin, citranaxanthin, astaxanthin, betanin, anthocyanins, saffron, calcium carbonate, titanium dioxide, iron oxides, iron hydroxides, aluminum, silver, gold, ruby pigment, tannin, orcein, ferrous gluconate, ferrous lactate .

In addition, buffer solutions are preferred for liquid formulations, in particular for pharmaceutical liquid formulations. The terms buffer, buffer system, and buffer solution, in particular an aqueous solution, refer to the system's ability to withstand a change in pH when an acid or base is added, or when diluted with a solvent. Preferred buffer systems may be selected from the group consisting of formate, lactate, benzoic acid, oxalate, fumarate, aniline, acetate buffer, citrate buffer, glutamate buffer, phosphate buffer, succinate, pyridine, phthalate, histidine, MES (2-(N- morpholino) ethanesulfonic acid, maleic acid, cacodylate (dimethylarsenate), carbonic acid, ADA (N-(2-acetamido) iminodiacetic acid, PIPES (4-piperazine-bis-ethanesulfonic acid), BIS-TRIS propane (1,3-bis[ tris(hydroxymethyl)methylaminol]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 other buffers with pK _a from 3.8 to 7.7.

Carbonic acid buffers such as acetate buffer and dicarboxylic acid buffers such as fumarate, tartrate and phthalate as well as tricarboxylic acid buffers such as citrate are preferred.

Another group of preferred buffers are inorganic buffers such as hydroxide sulfate, hydroxide borate, hydroxide carbonate, hydroxide oxalate, calcium hydroxide and phosphate buffers. Another group of preferred buffers are nitrogen containing buffers such as imidazole, diethylenediamine and piperazine. Also preferred are sulfonic acid buffers such as TES, HEPES, ACES, PIPES, [(2-hydroxy-1,1-bis-(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid (TAPS), 4-( 2-hydroxyethyl)piperazine-1-propanesulfonic acid (EEPS), 4-morpholino-propanesulfonic acid (MOPS) and N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES). Another group of preferred buffers are glycine, glycyl-glycine, glycyl-glycyl-glycine, N,N-bis-(2-hydroxyethyl)glycine and N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricine ). 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-hydroxy-lysine, o-phosphoserine, gamma-carboxyglutamate, [epsilon]-N-acetyl lysine, [omega]-N-methyl arginine, citrulline, ornithine and its derivatives.

Preservatives for liquid dosage forms or additives can be used as needed. They may be selected from the group including, but not limited to, 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 alcohols, cresols, cetylpyridinium chloride, chlorobutanol, thiomersal (sodium 2-ethylmercurthio)benzoic acid, dioxide sulfur, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, potassium sulfite, calcium sulfite, calcium hydrosulfite, potassium hydrosulfite, biphenyl, orthophenylphenol, sodium orthophenylphenol, thiabendazole, nisin, natamycin, formic acid, sodium formate, calcium formate, hexamine, formaldehyde, dimethyl dicarbonate, potassium nitrite, sodium nitrite, sodium nitrate, potassium nitrate, acetic acid, potassium acetate, sodium acetate, di sodium acetate, 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 sulfate ( II), chlorine, chlorine dioxide and other suitable substances or compositions known to the person skilled in the art.

Additional emulsifiers may be selected, for example, from the following anionic and nonionic emulsifiers: anionic emulsifying waxes, cetyl alcohol, cetyl stearyl alcohol, stearic acid, oleic acid, polyoxyethylene-polyoxypropylene block polymers, addition products of 2 to 60 moles of ethylene oxide to castor oil, and /or hardened castor oil, wool fat (lanolin), sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene stearate, polyvinyl alcohol, calcium tartrate, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, propane-1,2-diol alginate, carrageenan, processed eucheuma algae, locust bean gum, tragacanth, gum arabic, c karaya gum, gellan gum, ghatti gum, glucomannan, pectin, amidated pectin, ammonium phosphatides, brominated vegetable oil, sucrose acetate isobutyrate, esters of glycerol and wood resins, disodium phosphate, trisodium diphosphate, tetrasodium diphosphate, dicalcium diphosphate, calcium dihydrogen phosphate, sodium triphosphate, pentapotassium triphosphate , sodium polyphosphates, calcium sodium polyphosphate, calcium polyphosphates, ammonium polyphosphate, beta-cyclodextrin, powdered cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylhydroxyethylcellulose, croscarmellose, enzymatically hydrolyzed carboxymethylcellulose, mono- and diglycerides of fatty acids , glyceryl monostearate, glyceryl distearate, esters of acetic acid and mono- and diglycerides of fatty acids, esters of lactic acid and mono- and diglycerides of fatty acids, esters of citric acid and mono- and fatty acid diglycerides, esters of tartaric acid and mono- and diglycerides of fatty acids, esters of mono- and diacetyltartaric acid and mono- and diglycerides of fatty acids, mixed esters of acetic and tartaric acids and mono- and diglycerides of fatty acids, succinylated monoglycerides, complex sucrose fatty acid esters, saccharoglycerides, polyglycerol fatty acid esters, polyglycerol polyricinoleate, propane-1,2-diol fatty acid esters, propylene glycol fatty acid esters, lactylated fatty acid esters of glycerol and propane-1, thermally oxidized soybean oils reacted with mono- and diglycerides of fatty acids, sodium dioctyl 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, stearoyl fumarate calcium, sodium lauryl sulfate, ethoxylated mono- and diglycerides, ester of methyl glucoside and coconut oil, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate, sodium calcium polyphosphate, calcium polyphosphate, ammonium polyphosphate, cholic acid, choline salts, distarchglycerol, starch and sodium octenyl succinic acid ester, acetylated oxidized starch.

Preferred are glycerol monooleate and stearic acid.

Stabilizers are substances that can be added to prevent unwanted changes. Although stabilizers are not true emulsifiers, they can also contribute to the stability of emulsions or solubilisates. Suitable examples of stabilizers are oxystearin, xanthan gum, agar, oat gum, guar gum, tara gum, polyoxyethylene stearate, aspartame-acesulfame salt, amylase, proteases, papain, bromelain, ficin, invertase, polydextrose, polyvinyl pyrrolidone, polyvinyl polypyrrolidone, triethyl citrate, maltite. syrup.

Suitable additional surface-active solubilizing agents (solubilizers) are, for example, diethylene glycol monoethyl ester, polyethylpropylene glycol copolymers, cyclodextrins such as α- and β-cyclodextrin, glyceryl monostearates such as Solutol HS 15 (macrogol-15-hydroxystearate from BASF , PEG 660-15 hydroxystearates), sorbitan esters, polyoxyethylene glycol, polyoxyethylene sorbitan acid esters, polyoxyethylene sorbitan monooleate, polyoxyethylene oxystearic acid triglyceride, polyvinyl alcohol, sodium dodecyl sulfate, (anionic) glyceryl monooleates, etc.

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

Suitable isotonizing agents are, for example, pharmaceutically acceptable salts, in particular sodium chloride and potassium chloride, sugars such as glucose or lactose, sugar alcohols such as mannitol and sorbitol, citrate, phosphate, borate and mixtures thereof.

Suitable thickeners may be selected from the group including, but not limited to, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, dextrins, polydextrose, modified starch, alkali modified starch, bleached starch, oxidized starch, enzyme-treated starch, monocramal phosphate, distarch phosphate esterified with trimetaphosphate sodium or phosphorus oxychloride, distarch phosphate, acetylated distarch phosphate, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated distarch adipate, acetylated distarch glycerol, distarch glycerol, hydroxypropyl starch, hydroxypropyl distarch glycerol, hydroxypropyl distarch ether phosphate, hydroxypropyl distarch glycerol salt , acetylated oxidized starch, hydroxyethyl cellulose.

Diluents or excipients are inactive substances added to medicinal products to process a minimum amount of active agents. They may be suitable for 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, hydroxypropyl methylcellulose, polyethylene glycol, xanthan gum, gum arabic, or any of them. combination.

Penetration enhancers are often used in topical dosage forms. Suitable penetration enhancers include all pharmaceutically acceptable penetration enhancers known in the art, such as, but not limited to, azones such as laurocapram, 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, sodium lauryl sulfate, myristic acid, isopropyl myristic acid, capric acid; nonionic (nonic) surfactants such as polyoxyethylene-2-oleyl ether, polyoxyethylene-2-stearyl ether; terpenes; terpenoids; oxazolidinones; urea; ceramide analogs, azone analogs, menthol derivatives, esterified derivatives, esterified derivatives, trans-carbamates (transkarbams), carbamate salts, TXA derivatives, DDAIP (dodecyl 2-(dimethylamino)propanoate), DDAK, natural essential oils (all listed in Chen et al (2014) Asian J Pharm Sc 9, 51-64); citric acid esters such as triethyl citrate; hydrophobin polypeptides; alpha-bisabolol; dimethyl isosorbide (Arlasolve® DMI); ethoxydiglycol. Preferred is 1,2-propanediol.

Typical examples of preservatives suitable for topical application are, for example, benzyl benzoate, benzoic acid, benzyl alcohol, benzalkonium chloride, N-cetyl-N-N-trimethylammonium bromide (Cetrimid, Merck), chlorhexidine, chlorobutanol, chlorocresol, imidourea, parabens such as methyl, ethyl, propyl or butylparaben, sodium methylparaben, sodium propylparaben, potassium sorbate, sodium benzoate, sodium propionate, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuriborate, phenylmercurinitrate, sorbic acid, or thiomersal (sodium methylmercurythiosalicylate). Preferred are methylparaben, propylparaben, as well as sodium methylparaben and sodium propylparaben.

The addition of sufficient antioxidants is particularly preferred in topical dosage forms. Suitable examples of antioxidants include sodium metabisulfite, alpha-tocopherol, ascorbic acid, maleic acid, sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, or propyl gallate. The use of sodium metabisulphite is preferred.

Suitable pH adjusters for topical dosage forms are, for example, sodium hydroxide, hydrochloric acid, buffering agents such as sodium dihydrogen phosphate or disodium hydrogen phosphate.

Cream formulations may also contain other auxiliaries and additives such as impregnation agents, solvents, consistency enhancers or hydrotropes to improve flow characteristics. In this case, from one group of additives or excipients, both one or several substances can be present in the mixture.

Suitable impregnating agents are, for example, oleic acid decyl ester, hydrated castor oil, light mineral oil, mineral oil, polyethylene glycol, sodium lauryl sulfate.

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.

Consistency enhancers are, for example, cetyl alcohol, cetyl ester wax, hydrated castor oil, microcrystalline waxes, non-ionic emulsifying waxes, beeswax, paraffin or stearyl alcohol.

Suitable hydrotropes are alcohols such as ethanol, isopropyl alcohol or polyols such as glycerol.

According to the present invention, all of the aforementioned excipients and classes of excipients can be used alone without limitation or in any possible combination thereof, provided that the use of the solubilisate according to the present invention is not hindered, toxic effects do not occur, or relevant national laws are not violated.

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

The present application also relates to a pharmaceutical composition according to the present invention for oral, parenteral or topical administration.

Conditions with an excessive immune response are, for example, without limitation, transplant rejection after transplantation, active autoimmune disorders, respectively, diseases with an autoimmune component, in particular active rheumatoid arthritis, relapsing-remitting multiple sclerosis, lupoid hepatitis, polyarteritis nodosa, Crohn's disease, ulcerative colitis, Behcet's disease, Behcet's uveitis, idiopathic thrombocytopenic purpura, myasthenia gravis, Lambert-Eaton syndrome, polymyositis, psoriasis, psoriatic arthritis, ankylosing spondylitis, nocturnal paroxysmal hemoglobinuria, autoimmune thyroid diseases such as Hashimoto's thyroiditis, Orda's thyroiditis or Graves' disease, lupus erythematosus, vitiligo, autoimmune encephalomyelitis, idiopathic optic neuritis, sympathetic ophthalmia, anterior uveitis, retinal degeneration, peripheral ulcerative keratitis, bullous pemphigoid, chronic urticaria, dermatitis herpetiformis, acquired epidermosis bullosa, alopecia areata, autoimmune enteropathy, autoimmune polyendocrine syndrome such as APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy), Schmidt syndrome and XPID (X-linked polyendocrinopathic immunodeficiency and diarrhea syndrome), chronic gastritis, dermatomyositis, type 1 diabetes, type 2 diabetes mellitus, Graves' ophthalmopathy, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Guillain-Barré syndrome, lichen sclerosus, lichen mucosa, linear IgA dermatosis, microscopic polyangiitis, myalgic encephalomyelitis, narcolepsy, PANS (pediatric acute neuropsychiatric syndrome), such as PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections), exfoliative pemphigus, seborrheic pemphigus, pemphigus vulgaris, polychondritis, polymyalgia rheumatica, rheumatic fever, SAPHO syndrome (synovitis, acne, empty ulcer, hyperostosis, osteitis), sarcoidosis, Sjögren's syndrome, scleroderma, muscle stiffness syndrome, Henoch-Schonlein purpura, celiac disease, acute disseminated encephalomyelitis, antiphospholipid syndrome, autoimmune cardiomyopathy, autoimmune hemolytic anemia, autoimmune inner ear disease, panautoimmune lymphoproliferative syndrome, autoimmune syndrome , autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic recurrent osteomyelitis multiplex, COPD (chronic obstructive pulmonary disease), Churg-Strauss syndrome, cold agglutination syndrome, painful lipomatosis, endometriosis, eosinophilic fasciitis, encephalopathy acne, interstitial cystitis, Kawasaki disease, Sharp's syndrome, neuromyotonia, opso-myoclonal 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 such as those caused by infections with gram-negative or gram-positive bacteria such as MRSA (methicillin-resistant Staphylococcus aureus) or mycotic pathogens, and systemic inflammatory response syndrome (SIRS) caused by other factors, such as immunological or chemical factors.

Conditions with an immunodeficiency background include, but are not limited to, frequent flu-like infections; recurrent respiratory tract infections; recurrent efferent urinary tract infections; fatigue; cachexia; disorders of concentration of unknown origin; convalescence; chronic viral infections, in particular human immunodeficiency viruses such as HIV-1 and HIV-2, hepatitis B, hepatitis C, encephalitis, herpes zoster, herpes simplex, inner ear infections, chickenpox, measles, cytomegaly, Epstein-Barr, adenoviruses, human papillomaviruses and parvoviruses such as amdoviruses, bocaviruses, dependoviruses, erythroviruses and parvoviruses, some cancers, 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; radiogenic colitis, diverticulitis; allergies, in particular hay fever, polymorphic photodermosis, eczema, neurodermatitis; enteritis; colitis; and before, during and after chemotherapy and radiation.

In conclusion, the 5-amino-2,3-dihydro-1,4-phthalazinedione solubilizate obtained by the method of the present invention is particularly suitable for the treatment of all inflammatory diseases showing a significant increase in the release of pro-inflammatory cytokines, in particular IL-6 and TNF-alpha. . In addition to the above examples, this also occurs in wound healing, for example after surgery, trauma or burns, in independent immune processes such as dry keratitis, or in acute or chronic inflammations of unknown origin, such as tendovaginitis or osteoarthritis.

The 5-amino-2,3-dihydro-1,4-phthalazinedione solubilizate prepared by the method of the present invention can also be administered in combination with at least one other known pharmaceutically active agent and/or standard therapy.

Thus, the present application also relates to the combination of the solubilisate according to the present invention and at least one pharmaceutically active agent.

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

Pharmaceutically active agents suitable for such a combination may be selected from the group consisting of steroidal and non-steroidal anti-inflammatory agents, immunomodulators, immunostimulatory agents, immunosuppressive agents, anti-infective agents, antibiotics, antiviral agents, antifungal agents, antiprotozoal agents, anthelmintics, analgesics, local anesthetics. , anticoagulants, antiplatelet drugs, muscle relaxants, tonic and anabolic agents. Such a combination of pharmaceutically active agents can be used for prophylactic and/or therapeutic use in a person in need thereof.

Suitable examples of steroidal anti-inflammatory agents include corticosteroids, glucocorticoids, cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, dexamethasone, betamethasone, prednisone, prednisolone, methylprednisolone, deltason, triamcinolone, thixocortol pivalate, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinonide, halcinolone , fluocortolone, hydrocortisone-17-valerate, halomethasone, alklomethasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-´butyrate, clobetasone-17-propionate, fluocortolone caproate, fluocortolone pivalate, flupredniden acetate, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, triamcinolone acetonide, beclomethasone dipropionate.

Suitable examples of non-steroidal 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, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celexoxib, rofecoxib, valdecoxib, parecoxib, etobroxyboxyb , nimesulide, clonixin, licofelone, H-harpagid, flunixin, thiaprofenic acid.

Suitable examples of immunomodulators include thalidomide, lenalidomide, pomalidomide and apremilast.

Suitable examples of immunostimulatory agents include interferons (alpha, beta, gamma, tau interferon), interleukins, CSF, PDGF, EGF, IGF, THF, levamisole, dimepranol, inosine.

Suitable examples of immunosuppressive agents include the group of glucocorticoids such as those described above; cytostatics such as alkylating agents (eg cyclophosphamide), antimetabolites such as methotrexate, azathioprine, mercaptopurine, fluorouracil, leflunomide, protein synthesis inhibitors and specific antibiotics such as dactinomycin, anthracyclines, mitomycin C, bleomycin and mithramycin, intercalating agents such as as mitoxantrone; antibodies such as muromonab-CD3, rituximab, ustekinumab, alemtuzumab, natalizumab, basiliximab, and daclizumab; agents acting on immunophilins such as cyclosporine, tacrolimus and sirolimus; and unclassified immunosuppressive agents such as interferon beta, interferon gamma, opioids, TNF binding proteins such as infliximab, etanercept, adalimumab; or curcumin, catechins, mycophenolic acid, fingolimod, myriocin, and fumaric acid dimethyl ester.

Anti-infective agents is a general term for compounds useful in the treatment of bacterial, viral, fungal, protozoal and helminthic infections and includes antibiotics, antiviral agents, antimycotics, antiprotozoal agents, anthelmintics and other antiparasitic drugs.

Suitable examples of antibiotics include imipenem, meropenem, ertapenem, cephalosporins, aztreonam, penicillins such as penicillin G and penicillin V, piperacillin, mezlocillin, ampicillin, amoxicillin, flucloxacillin, methicillin, oxacillin, clavulanic acid, sulbactam, tazobactam, sultamicillin, teicomycin, teicomycin, , vancomycin, bacitracin, colistin, gramicidin, polymyxin B, tyrothricin, teixobactin, fosmidomycin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, chloramphenicol, fusidic acid, cethromycin, narbomycin, telithromycin, clindamycin, daplincomycin, daplincomycin , quinupristin, azithromycin, clarithromycin, erythromycin, roxithromycin, linezolid, doxycycline, minocycline, tetracycline, oxytetracycline, tigecycline, norfloxacin, enoxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, metronidazole, tinidazole, aminocoumarin, sulfadiazine, sulfamethadocalasine, , trimethoprim, reef mpicin.

Suitable examples of antiviral agents include anquiviroc, aplaviroc, cenicriviroc, enfuvirtide, maraviroc, vikriviroc, amantadine, rimantadine, pleconaril, idoxuridine, aciclovir, brivudine, famciclovir, penciclovir, sorivudine, valaciclovir, cidofovir, ganciclovir, valganciclovir, sofosbuvir, foscarine, ribavitarine , filibuvir, nesbuvir, tegobuvir, fosdevirin, favipiravir, merimepodib, asunaprevir, balapiravir, boseprevir, ciluprevir, danoprevir, daclatasvir, narlaprevir, telaprevir, simeprevir, vaniprevir, rupintrivir, fomivirsen, amenamevir, alisporivir, bevirimat, letermovir, pereltami, oseltamirami , zanamivir.

Suitable examples of antifungal agents include abafungin, amphotericin B, candicidin, filipin, gamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, thioconazole, альбаконазол, эфинаконазол, эпоксиконазол, флуконазол, изавуконазол, итраконазол, посаконазол, пропиконазол, равуконазол, терконазол, вориконазол, аморолфин, бутенафин, нафтифин, тербинафин, анидулафунгин, каспофунгин, микафунгин, бензойную кислоту, циклопирокс, флуцитозин, гризеофульвин, галопрогин, толнафтат, ундециловую acid, crystal violet, balsam of Peru.

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, proguanine quinil, cyclonyl , mefloquine, pyrimethamine, artemether, artemisinin, artesunate, dihydroartemisinin, halofantrine, lumefantrine, sulfadoxine.

Suitable examples of anthelmintics include mebendazole, praziquantel, albendazole, diethylcarbamazine, flubendazole, ivermectin, levamisole, metrifonate, niclosamide, oxyclozanide, oxamniquine, oxantel, piperazine, pyrantel, pyrantel pamoate, monopantel (monopantel), derquantel, pelletierin sulfate, thiefenabendazole, pyrvinium , triclabendazole, abamectin, suramin, emodepside, pirvinium embonate, aminoacetonitrile.

Suitable examples of other antiparasitic drugs include meglumine antimonate, benznidazole, sodium stibogluconate, fumagillin, halofantrine, melarsoprol, nifurtimox, nitazoxanide, permethrin, lindane, malathion, carbaryl, pyrethrum, phenothrin, bioallethrin, imidacloprid, moxidectin, nitenpyram, fipronil, pyriprole, selamectin , dimpilate, spinosad, indoxacarb, methoprene, pyriproxyfen, lufenuron, neem tree oil, citronella oil, clove oil, peppermint oil, eucalyptus oil.

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

Suitable examples for local anesthetics include lidocaine, lignocaine, menthol, articaine, bupivacaine, ropivacaine, benzocaine, chlorprocaine, cocaine, cyclomethicaine, dimethocaine, larocaine, piperocaine, propoxycaine, procaine, novocaine, proparcaine, tetracaine, amethocaine, cinchocaine, dibucaine, etidocaine, levobupivacaine, meplavacaine, prilocaine, trimecaine, saxitoxin, neosaxitoxin, tetrodotoxin, eugenol.

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, otamixaban.

Suitable examples of antiplatelet drugs include abciximab, acetylsalicylic acid, dipyridamole, clopidogrel, eptifibatide, ilomedin, prostacyclin, prasugrel, ticagrelor, ticlopidine, tirofiban.

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, vecuronium , rapakuronium, dacuronium, duador, maluetin, dipyrandium, pipercuronium, chandonium (chandonium), HS-342, atracurium, mivacurium, doxacurium, d-tubocurarine, dimethyl tubocurarine, gallamine, alcuronium, anatruxonium, diadonium, fazadinium, tropeinic, cisatrucurium.

Tonic agents are a general term for agents that strengthen the body, increase tone or restore its physiological functions. They can be of plant or animal origin.

Anabolic agents can promote anabolic metabolism and strengthen the cellular collagen scaffold. However, their widespread misuse is known as doping in sports and bodybuilding. Therefore, the combination with the solubilisate according to the present invention is recommended only if the use is covered by the relevant national legislation.

One of ordinary skill in the art will readily recognize standard treatments for the aforementioned pharmaceutically active agents from the prior art. Preferably, the respective modes of administration and dosages of the aforementioned combinations of pharmaceutically active agents are oriented towards already established standard treatments for the combined active agent.

Examples

In the following examples, the relative amounts of solubilizing agents may be varied within the limits indicated for each component in the method of the present invention. The addition of glyceryl oleate and/or antioxidant is optional.

You can increase or decrease these amounts in accordance with the desired absolute amount of the agent to be dissolved in the solubilizate. The solubilisate can be divided into portions according to the desired final amount of the agent to be administered to the patient in need thereof.

In general, the obtained solubilisates obtained by the method according to the present invention had a specific gravity of 0.92-0.94 kN/m ³ .

In each example, the preparation of a dosage form for solubilisates according to the present invention is described for illustrative purposes. It should be understood that the solubilisates of the present invention may also be administered in any appropriate dosage form known in the art, for example as set forth in Remington: The Science and Practice of Pharmacy, ^22nd edition, Pharmaceutical Press, 2013, which shall be incorporated by reference. Standard reagents were purchased from Sigma-Aldrich, Darmstadt, Germany.

Example 1: Solubilization of 5-amino-2,3-dihydro-1,4-phthalazinedione - Embodiment 1

The following guidelines refer to the weight percentage of the mixture. Approximately 100 ml of solubilisate was obtained. 5-Amino-2,3-dihydro-1,4-phthalazinedione was provided, and then the solubilizing agents were mixed one by one with stirring for 5 minutes at room temperature (20±5°C) and atmospheric pressure.

5-amino-2,3-dihydro-1,4-phthalazinedione 2.0% Non-hydrogenated soy PC 46.0% MCT oil 45.6% A mixture of 1-lysophosphatidylcholine and 2-lysophosphatidylcholine 2.2% ethanol 1.9% Oleic acid 0.8% glyceryl stearate 1.2% glyceryl oleate 0.2% alpha tocopherol 0.1%

The composition was then gently heated with constant stirring at an approximate temperature increment of 1 °C/min. After about 20 minutes (about 40°C), the composition began to take on the form of a clear solution. This solubilization process was continued for about 16 minutes more. Thus, the solubilizate according to the present invention was obtained after about 36 minutes at about 56°C. Then heating and stirring were stopped and the resulting solubilizate was allowed to cool to room temperature. The solubilisate remained clear and stable during a follow-up period of at least 6 months.

Example 2: Solubilization of 5-amino-2,3-dihydro-1,4-phthalazinedione - Embodiment 2

The following guidelines refer to the weight percentage of the mixture. Approximately 100 ml of solubilisate was obtained. 5-Amino-2,3-dihydro-1,4-phthalazinedione was provided, and then the solubilizing agents were mixed one by one with stirring for 5 minutes at room temperature (20±5°C) and atmospheric pressure.

5-amino-2,3-dihydro-1,4-phthalazinedione 0.15% 1,2-dioleyl-SN-glycero-3-phosphocholine (DOPC) 60% MCT oil 32.45% 1-lysophosphatidylcholine 2.6% ethanol 2.2% oleic acid 1.1% glyceryl stearate 1.2% glyceryl oleate 0.2% beta-tocopherol 0.1%

The composition was then gently heated with constant stirring at an approximate temperature increment of 1.5 °C/min. After about 23 minutes (about 55°C), the composition began to take the form of a clear solution. This solubilization process was continued for about 10 more minutes. Thus, the solubilizate according to the present invention was obtained after about 33 minutes at about 70°C. Then heating and stirring were stopped and the resulting solubilizate was allowed to cool to room temperature. The solubilisate remained clear and stable during a follow-up period of at least 6 months.

Example 3: Solubilization of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt

The following guidelines refer to the weight percentage of the mixture. Approximately 100 ml of solubilisate was obtained. The sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione (as polymorph Form I as described in WO 2011/107295 A1) was provided and then the solubilizing agents were mixed one by one with stirring for 5 minutes at room temperature (20 ± 5 °С) and atmospheric pressure.

5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 1.0% non-hydrogenated soy PC 70.0% MCT oil 21.6% 2-lysophosphatidylcholine 2.6% ethanol 2.2% oleic acid 1.1% glyceryl stearate 1.2% glyceryl oleate 0.2% delta tocopherol 0.1%

The composition was then gently heated with constant stirring at an approximate temperature increment of 1 °C/min. After about 32 minutes (about 52°C), the composition began to take the form of a clear solution. This solubilization process was continued for about 8 minutes more. Thus, the solubilizate according to the present invention was obtained after about 40 minutes at about 60°C. Then heating and stirring were stopped and the resulting solubilizate was allowed to cool to room temperature. The solubilisate remained clear and stable during a follow-up period of at least 2 months.

Example 4: Preparation of a liquid dosage form for oral administration

In 45 ml of a liquid carrier containing the following composition (in wt.%)

Water for injection 99.3% Citrate buffer 0.5% Methylparaben + propylparaben (ratio 5:1) 0.1% Sodium Metabisulphite 0.1%

5 ml of the solubilisate from example 1 was dissolved. This solution (50 ml) can be placed in a suitable dropper bottle known in the art.

This composition does not need an additional emulsifier such as polysorbate.

Example 5: Obtaining a liquid dosage form for parenteral administration

In 245 ml of liquid carrier containing the following composition (in wt.%)

Water for injection 98.9% Sodium chloride 0.9% Methylparaben + propylparaben (10:1 ratio) 0.1% Sodium Metabisulphite 0.1%

5 ml of the solubilisate from example 1 was dissolved. This solution (250 ml) for parenteral administration can be placed in a suitable infusion bag known in the art.

This composition does not need an additional emulsifier such as polysorbate.

Example 6: Obtaining a solid dosage form in the form of a soft gelatin capsule

The composition of the soft gelatin capsule shell (wt.%)

gelatin 66.3% glycerol 33.0% Methylparaben + propylparaben (4:1 ratio) 0.1% carmoisine 0.1% titanium dioxide 0.5% dist water 1.3 x gelatin

A soft gelatin capsule containing 5-amino-2,3-dihydro-1,4-phthalazinedione solubilizate was prepared according to standard methods as set forth in: Mahato and Narang, Pharmaceutical Dosage Forms and Drug Delivery, 2 ^nd ed, chap . 18.3.5. Here, 1.25 ml of the solubilisate from Example 1 was introduced into the matrix cavity of the proposed gelatin capsule, which was then sealed.

Example 7: Obtaining a solid dosage form in the form of a hard gelatin capsule

The composition of the hard gelatin capsule shell (wt.%)

gelatin 85.0% water 14.3% Methylparaben + propylparaben (4:1 ratio) 0.1% sunny sunset 0.1% titanium dioxide 0.5%

Hard gelatin capsules (size "000", having a volume of 1.4 ml) were prepared by standard methods known in the art. 1.25 ml of the solubilisate obtained in Example 1 was placed in a capsule, respectively. Then collected two parts of hard gelatin capsules.

Example 8: Obtaining a dosage form for topical use in the form of a cream

The following ingredients were used (wt %):

5-amino-2,3-dihydro-1,4-phthalazinedione solubilisate as described in Example 1 3.00% Cetearyl alcohol (Lanette D®) 6.60% Glyceryl Stearate (Cutina MD®) 4.15% Ceteareth 20 (Eumulgin B2®) 0.40% Ceteareth 12 (Eumulgin B1®) 1.25% Decyloleate (Cetiol V®) 2.50% allantoin 0.15% Sodium stearyl sulfate (Lanette E®) 0.65% glycerol 20.70% phenoxyethanol, dehydroacetic acid, benzoic acid (Rokonsal ND®) 1.00% water 59.60%

In the first preparation, the solubilizate of 5-amino-2,3-dihydro-1,4-phthalazinedione, cetearyl alcohol, glyceryl stearate, ceteareth 20, ceteareth 12, sodium decyloleate, and sodium cetearyl sulfate was mixed and heated to 70°C. In the second preparation, allantoin, glycerin and water were mixed and heated to 70°C. Then the first preparation and the second preparation were slowly mixed and homogenized with a dispersant (Ultra-Turrax T-18®) for 2-3 minutes. While cooling to 35°C, a third preparation consisting of Rokonsal ND® was added and mixed homogeneously. The mixture was re-homogenized at a temperature of approximately 45°C for 1 min. The resulting mixture was then allowed to cool to room temperature while stirring while avoiding the inclusion of air. If necessary, the pH can be adjusted with NaOH or citric acid.

The pH of the cream is 5.40. The skin cream was stable for at least 6 months at 40°C. At this temperature, phase separation did not occur.

50 ml of the resulting cream was packaged in a suitable squeezable aluminum tube known in the art.

Example 9: Obtaining a dosage form for topical use in the form of a hydrogel

The hydrogel was obtained by slight modifications to the method disclosed in US 2010/0129448 A1.

A 3% solution of CMC (carboxymethyl cellulose) was prepared by mixing 5 ml of the solubilisate from example 1 with WFI (water for injection) followed by autoclaving until the CMC was completely dissolved in the solution, resulting in the formation of a CMC hydrogel. The suspension was obtained by adding the specified solubilizate dissolved in WFI to the CMC hydrogel. Stabilizers (TEA, citric acid) were added to the CMC hydrogel. The resulting combination was mixed under high shear conditions (paddle mixer and sonication) as described in US 2005/0175707 at elevated temperature (40 to 50°C). Glycerin and additional WFI were also added to the suspension. The amount of excipients added to the hydrogel was controlled to achieve the required concentration containing 5-amino-2,3-dihydro-1,4-phthalazinedione.

The 3% CMC hydrogel slurry was further agitated for 20 minutes, resulting in a volume of hydrogel slurry. The volume of the hydrogel suspension was observed in an optical microscope at a magnification of 100 times. The primary particle size of the suspended particles is less than about 10 microns, which allows the composition to be topically applied to open wounds or other tissues without scratching.

Example 10: Obtaining a solid dosage form in the form of a suppository

The composition of the base of the suppository (wt.%):

Cacao butter 97.9% Vitamin C 0.1% Aluminum monostearate 2.0%

1) For melting, the base of the suppository was heated to 50 - 52 °C. The melted fat base was then slowly cooled to 36°C.

2) For each suppository to be cast, an appropriate amount of 0.5 ml of the solubilisate from Example 3 was added to the fat base. A soft base was formed.

3) Said soft base was poured into a suppository mold designed to obtain rectal suppositories in the form of a torpedo 3 cm long, having a mass of about 2 g.

4) The suppositories were allowed to cool to room temperature and then collected.

The use of the solubilizate according to the present invention makes it possible to obtain suppositories without the use of an additional emulsifier and/or plasticizer. Thus, such a suppository according to the present invention does not contain polysorbate.

Claims (38)

1. Method for solubilizing 5-amino-2,3-dihydro-1,4-phthalazinedione, comprising the following steps: a) providing 5-amino-2,3-dihydro-1,4-phthalazinedione in the general range from 0.1% to 25% wt. at room temperature and pressure from 0.2 bar to 1 bar; b) adding in any order of solubilizing agents: at least one phosphatidylcholine in the general range from 20% to 80% wt., at least one triglyceride with a medium chain length in the general range from 10% to 70% wt., at least one lysophosphatidylcholine in the general range from 1% to 15% wt., at least one alcohol With ₂ -C ₄ in the General range from 1% to 20% of the mass. and at least one glyceryl stearate and/or saturated or unsaturated fatty acid C ₁₄ -C ₂₀ in the general range from 0.5% to 10 wt%, respectively, while the relative mass percentages of all ingredients are not more than 100%, and all solubilizing agents independently of each other are a food additive and/or a pharmaceutically acceptable excipient; c) gently heating the resulting mixture by continuously raising the temperature in continuous temperature increments of 0.5 °C/min to 3 °C/min over a period of 20 to 60 minutes; d) stopping the temperature increase in the temperature range from 30 °C to 125 °C as soon as a clear solution is obtained; and e) cooling the solubilizate to room temperature. 2. The method according to p. 1, in which 5-amino-2,3-dihydro-1,4-phthalazinedione provide in the form of sodium, potassium or lithium salts or mixtures thereof in the general range from 0.1% to 2% of the mass. at room temperature and pressure from 0.2 bar to 1 bar. 3. The method according to claim 1 or 2, wherein said at least one saturated or unsaturated C ₁₄ -C ₂₀ fatty acid is oleic acid. 4. The method according to any one of paragraphs. 1-3, wherein said at least one C ₂ -C ₄ alcohol is ethanol. 5. The method according to any one of paragraphs. 1-4, in which in addition at stage (b) at least one antioxidant is added in the general range from 0.01 to 10 wt. -%, and said at least one antioxidant is a pharmaceutically acceptable excipient. 6. The method of claim 5, wherein said at least one antioxidant is ascorbyl palmitate and/or at least one tocopherol. 7. Solubilizate of 5-amino-2,3-dihydro-1,4-phthalazinedione for use as an immunomodulator, containing: 5-amino-2,3-dihydro-1,4-phthalazinedione in the general range from 0.1% to 25% wt., at least one phosphatidylcholine in the general range from 20% to 80% wt., at least one triglyceride with a medium chain length in the general range from 10% to 70% wt., at least one lysophosphatidylcholine in the general range from 1% to 15% wt., at least one alcohol C ₂ -C ₄ in the general range from 1% to 20% wt., and at least glyceryl stearate and/or saturated or unsaturated fatty acid C ₁₄ -C ₂₀ in the general range from 0.5% to 10% wt., respectively, where the relative weight percentages of all ingredients are not more than 100%, and all solubilizing agents are independently a food additive and/or pharmaceutically acceptable excipients. 8. Solubilisate of sodium, potassium or lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione or a mixture thereof for use as an immunomodulator, containing: sodium, potassium or lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione in the general range from 0.1% to 25% wt., at least one phosphatidylcholine in the general range from 20% to 80% wt., at least one triglyceride with a medium chain length in the general range from 10% to 70% wt., at least one lysophosphatidylcholine in the general range from 1% to 15% wt., at least one alcohol C ₂ -C ₄ in the general range from 1% to 20% wt., and at least glyceryl stearate and/or saturated or unsaturated fatty acid C ₁₄ -C ₂₀ in the general range from 0.5% to 10% wt., respectively, where the relative weight percentages of all ingredients are not more than 100%, and all solubilizing agents are independently a food additive and/or pharmaceutically acceptable excipients. 9. Prophylactic or therapeutic use of the solubilizate according to claim 7 or 8 in medicine as an immunomodulator for the treatment of conditions with an excessive immune response or conditions with an immunodeficiency background. 10. Prophylactic or therapeutic use of the solubilizate according to claim 9 to increase the absorption and/or bioavailability of 5-amino-2,3-dihydro-1,4-phthalazinedione. 11. Pharmaceutical composition for use as an immunomodulator, containing 5-amino-2,3-dihydro-1,4-phthalazinedione, prepared as a solubilisate according to paragraph 7, and at least one pharmaceutically acceptable excipient. 12. A pharmaceutical composition according to claim 11, wherein said pharmaceutical composition is suitable for oral, parenteral or topical administration. 13. The pharmaceutical composition according to claim 12, wherein said at least one pharmaceutically acceptable excipient is selected from the group consisting of carriers, binders, lubricants, lubricants, disintegrants, colorants, buffers, preservatives, emulsifiers, penetration enhancers, antioxidants , diluents, pH adjusters, impregnation agents, solvents, consistency enhancers, hydrotropes, sweeteners, acidifiers, thickeners, release agents, bulking agents, flavoring agents, opacifying agents, flavoring agents and aromatic agents. 14. Pharmaceutical composition according to claim 12 or 13 for use in medicine as an immunomodulator.