Glucocorticoid-sparing agents

Abstract

Disclosed is 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use as a glucocorticoid-sparing agent and as a pharmaceutical combination comprising a glucocorticoid, for use in the prevention and / or treatment of conditions or diseases normally treated with glucocorticoids, as well as suitable application forms, pharmaceutical compositions and their prophylactic or therapeutic uses.

Description

[Background technology]

[0001] Corticosteroids are a class of steroid hormones synthesized in the adrenal glands and can be further subdivided into two groups, glucocorticoids and mineralocorticoids, according to their respective primary physiological and pharmacological actions.

[0002] Mineralocorticoids regulate salt and water metabolism, while glucocorticoids have strong anti-inflammatory effects. They suppress inflammation and immunity and are also involved in the breakdown of macronutrients such as fats, carbohydrates, and proteins. Therefore, both naturally occurring glucocorticoids, particularly cortisol (also known as hydrocortisone or 11β,17α,21-trihydroxypregn-4-ene-3,20-dione) and cortisone (also known as corticosterone or 17-hydroxy-11-dehydrocorticosterone), as well as their artificial derivatives (synthetic glucocorticoids), are widely used in medicines for the treatment of various medical conditions, especially those related to the immune system, such as inflammatory diseases and allergic reactions.

[0003] Glucocorticoids are used, for example, to treat rheumatoid arthritis, osteoarthritis, gouty arthritis, ulcerative colitis, multiple sclerosis, asthma, severe psoriasis, some tumors, cerebral edema, chemotherapy-induced nausea and vomiting, to prevent transplant rejection and any further indication requiring a rapid and significant anti-inflammatory and / or immunosuppressive effect.

[0004] Glucocorticoids are primarily available as injections, oral administration, ointments, eye drops, and inhalation formulations. Dosages and treatment regimens vary considerably depending on the specific glucocorticoid type, species, age, indication, acuteness, desired pharmacokinetics, and application form. Due to common serious adverse reactions and long-term effects, as outlined below, very strict treatment regimens must be followed when administering glucocorticoids. In most cases, treatment begins with a relatively high initial dose to achieve a favorable initial response. The dose is then reduced in small steps to the lowest possible dose that maintains an adequate clinical response. Both the initial and maintenance doses must be determined and controlled at regular intervals by a physician. Detailed overviews of different and indication-dependent dosing regimens for dexamethasone are provided in publicly available online databases, such as Drugs.com.

[0005] While it can generally be stated that glucocorticoids have a significant positive impact on the course of many diseases and conditions, particularly those related to the immune system, the administration of glucocorticoids to subjects in need thereof is also associated with a number of significant drawbacks.

[0006] Adverse drug reactions include, among others, swelling, muscle weakness, mood swings, and reduced effectiveness of antibiotics and vaccines. A more extensive list of adverse drug reactions is provided below.

[0007] Thereby, it should be considered that long-term use of glucocorticoids often leads to such serious conditions and adverse drug reactions.

[0008] Regardless of the adverse reactions and conditions already mentioned, the early or late long-term use of glucocorticoids inevitably leads to atrophy of the adrenal glands (adrenal insufficiency) and, consequently, the inability of the organism to produce cortisol. Therefore, after longer treatment with glucocorticoids, the dose must be gradually reduced and not suddenly discontinued due to the risk of the so-called adrenal (or Addisonian) crisis, which is accompanied by symptoms of nausea, vomiting, and shock.

[0009] There are also many drug-drug interactions that must be considered when using glucocorticoids. Some drugs (e.g., troleandomycin, erythromycin, clarithromycin) and estrogens reduce the liver's ability to metabolize glucocorticoids, thus increasing their plasma levels and thus increasing both the desired effects and adverse drug reactions. Other drugs reduce glucocorticoid plasma levels by increasing their degradation in the liver (e.g., phenobarbital, ephedrine, phenytoin, rifampicin) or by reducing the absorption of orally ingested glucocorticoids (e.g., cholestyramine). The effects of some other drugs (e.g., diuretics, amphotericin B, warfarin) are increased when glucocorticoids are administered concomitantly, potentially leading to life-threatening situations.

[0010] Due to all these risks, certain maximum residue limits and waiting periods must be observed in foods of animal origin, and some specific products may not be tolerated at all. Therefore, the veterinary application of glucocorticoids in livestock is further restricted by government regulations.

[0011] task

[0012] Due to these numerous drawbacks, current treatment regimens using glucocorticoids are often considered inadequate. There is a medical need for new agents and / or treatment regimens that can prevent and / or reduce the undesirable effects of glucocorticoid therapy, such as adverse drug reactions, drug-drug interactions, long-term effects, and habituation, while maintaining the therapeutic effect in subjects in need thereof.

[0013] It is therefore an object of the present invention to provide a glucocorticoid-sparing agent, such as a pharmaceutical, which makes it possible to reduce the required dosage of glucocorticoids without reducing the desired efficacy.

[0014] Another object of the present invention is to provide an agent such as a pharmaceutical product that makes it possible to avoid and / or reduce adverse reactions of glucocorticoids and conditions associated with the long-term use of glucocorticoids.

[0015] Therefore, most preferred are combinations of glucocorticoids with at least one additional agent that act synergistically in terms of efficacy, while at the same time reducing the frequency, severity and severity of glucocorticoid-associated adverse reactions and conditions associated with long-term use of glucocorticoids. Summary of the Invention

[0016] It has surprisingly been found that the administration of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in addition to glucocorticoid treatment allows for a reduction in the dosage of glucocorticoid treatment without reducing its effectiveness, as well as a reduction in the undesirable effects associated with glucocorticoids, as specified in detail in the Examples.

[0017] In particular, administration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in addition to glucocorticoid therapy allows for a reduction in the dose of the glucocorticoid, as 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and the glucocorticoid dexamethasone have been found to act superadditively when administered concomitantly (see Example 1).

[0018] In particular, administration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in addition to glucocorticoid therapy can reduce the undesirable effects associated with glucocorticoids, and further, co-administration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and dexamethasone can be shown to reduce the undesirable effects associated with dexamethasone (see Example 2).

[0019] The addition of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts to an already ongoing glucocorticoid therapy may also help to avoid undesired glucocorticoid effects and may even reduce undesired glucocorticoid effects that are already present.

[0020] In particular, by administering 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in addition to glucocorticoid therapy, undesirable glucocorticoid effects can be avoided and / or reduced.

[0021] These undesirable effects include, but are not limited to, increased muscle tone, weight gain and obesity (especially truncal obesity, including so-called "buffalo hump"), edema, facial swelling (moon face), potassium wasting, muscle weakness, headache, facial hair growth (in women), thinning of the skin, easy bruising and delayed wound healing, glaucoma, cataracts, gastric and duodenal ulcers, irregular menstrual cycles, steroid-induced diabetes, loss of control in existing diabetes, osteoporosis (leading to fractures), adrenal joint necrosis (especially in the hip or knee joints), psychiatric disorders (e.g., depression, euphoria, etc.), and These include: hypertension, insomnia, mood swings, personality changes), psychotic behavior, childhood growth retardation, seizures, increased infection rates, exacerbation of opportunistic infections (such as tuberculosis, shingles, and Pneumocystis pneumonia), decreased effectiveness of antibiotics and vaccines, and in particular Cushing's syndrome, the latter describing a collection of signs and symptoms resulting from long-term exposure to cortisol including, for example, high blood pressure, abdominal obesity, striae, "moon face," corticosteroid-induced lipodystrophy (e.g., buffalo hump), weak muscles, weak bones, fragile skin, acne, facial hair growth (in women), and irregular menstruation.

[0022] Providing the possibility of reducing the dosage of glucocorticoid therapy by adding 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts to the therapy also helps to avoid and / or reduce undesirable effects associated with glucocorticoid withdrawal. In particular, administering 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in addition to glucocorticoid therapy can reduce undesirable effects associated with glucocorticoid withdrawal, such as adrenal insufficiency, or even acute Addison's disease crisis, including symptoms such as nausea, vomiting, and shock.

[0023] In such cases of adrenal insufficiency, corticosteroids with mineralocorticoid potency must be parenterally administered in addition to glucocorticoids with anti-inflammatory potency to maintain regulation of salt and water metabolism. Therefore, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts can be considered a sparing agent for all corticosteroid drugs, especially glucocorticoids with additional mineralocorticoid potency.

[0024] 5-Amino-2,3-dihydro-1,4-phthalazinedione belongs to the pharmaceutical class of phthalazinedione. Compounds of this class are known for their beneficial anti-inflammatory properties. 5-Amino-2,3-dihydro-1,4-phthalazinedione is also known as luminol. Luminol has become known for its chemiluminescent properties. It has been widely applied in diagnostic assays as a detection tool and in forensic science, such as blood spot tracing. In medicine, 5-amino-2,3-dihydro-1,4-phthalazinedione has been developed in the form of its sodium salt, suitable for use in the prevention and treatment of a wide range of acute and chronic inflammatory disorders, including acute infections of bacterial and viral origin, particularly intestinal, hepatitis B and C, gastroenteritis, inflammations such as prostatitis, endometriosis, throat inflammation, bronchial asthma, pneumonia, periodontitis, pyelonephritis, and autoimmune diseases such as Crohn's disease, ulcerative colitis, lupus erythematosus, and scleroderma. Furthermore, the scientific and patent literature still contains a long list of therapeutic indications for which 5-amino-2,3-dihydro-1,4-phthalazinediones have been tested for allergenicity or for which beneficial use has been suggested (see, inter alia, WO 2004 / 041169; WO 2007 / 018546; WO 2012 / 127441).

[0025] However, the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts as a glucocorticoid-sparing agent in conditions treated with glucocorticoids, allowing a clear reduction in the required glucocorticoid dose, has not yet been described.

[0026] The present invention relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use as a glucocorticoid-sparing agent in the prevention and / or treatment of conditions normally treated with glucocorticoids. In particular, the present invention relates to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for such use.

[0027] While most conventional immunomodulatory agents exhibit severe adverse reactions or at least become problematic during long-term treatment, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is well tolerated and has a high safety margin relative to the administered dose (Schumann et al., Int. J. Mol. Sci. 2020, 21(22), 8803). In contrast, it has been found herein that 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts avoids and / or reduces the undesirable effects of glucocorticoids, such as adverse reactions and / or conditions associated with long-term use of glucocorticoids.

[0028] Such a use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in conditions treated with glucocorticoids to avoid and / or reduce undesirable effects associated with glucocorticoid treatment has also not yet been described.

[0029] The present invention also refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use as an agent for reducing or avoiding undesired glucocorticoid effects in conditions treated with glucocorticoids.

[0030] Furthermore, the present invention refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use as a glucocorticoid-sparing agent in the prevention and / or treatment of conditions that are normally treated with glucocorticoids, which is further characterized by its use as a medicament for reducing or avoiding undesired glucocorticoid effects. In particular, the present invention relates to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for such use.

[0031] Thus, disclosed herein is the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, particularly 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, as a glucocorticoid-sparing agent and as an agent for reducing undesired glucocorticoid effects.

[0032] Further disclosed are pharmaceutical combinations comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, particularly 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, as well as suitable application and treatment modes, methods of application and treatment regimens, and pharmaceutically acceptable dosage forms, including pharmaceutical compositions comprising both a glucocorticoid and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, particularly 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt.

[0033] Methods of treatment are also disclosed. [Brief explanation of the drawings]

[0034] [Figure 1] FIG. 1 shows FaCI non-constant ratio combinations—Example 1—Experimental Part 1. [Figure 2] FIG. 10: FaCI Non-Constant Ratio Combinations—Example 1—Experimental Part 2. [Figure 3] FIG. 10: FaCI fixed ratio combinations—Example 1—Experimental Part 2. DETAILED DESCRIPTION OF THE INVENTION

[0035] The invention described in the Summary of the Invention section is supported by detailed definitions and listings provided below.

[0036] To avoid ambiguity in the art, the following terms for drug-drug interactions are defined. They are used in this context throughout this disclosure. When at least two substances (e.g., pharmaceuticals) are administered simultaneously and at least one of these substances affects the activity of at least one other substance, a so-called drug-drug interaction is achieved. If the interaction results in an exaggerated or increased effect of the drug substance, the effect is synergistic. The respective equations can be expressed as (A + B) > A or (A + B) > B, where A and B are the percentage or fractional effect (i.e., values ​​between 0 and 1) seen when each substance is administered alone, and (A + B) is the percentage or fractional effect, respectively, seen after combined application. A net effect equal to the sum of the effects seen with the single drug applications is an additive synergistic effect. If the net effect is greater than the expected effect, the term superadditivity is used. A smaller effect is subadditivity. On the other hand, if a drug-drug interaction results in a decrease in the effect of the drug substance, the effect is not synergistic at all, but antagonistic.

[0037] Therefore, within the scope of this disclosure, the terms "antagonism" and "antagonistic" are used for any decreased drug effect induced by a drug-drug interaction, and the terms "synergy" and "synergistic" are used for any increased drug effect induced by a drug-drug interaction. To describe and determine the degree of such synergy, the terms "subadditivity," "additivity," and "superadditivity," and their respective nouns, are used. Thus, the term superadditivity is used to describe an effect of two or more combined drugs that is greater than the expected additive effect of a single drug.

[0038] The use of synergistic drug combinations can serve to increase both therapeutic efficacy and potency, the latter primarily serving to reduce off-target toxicity.

[0039] Identification of drug-drug interactions relies on a "no interaction" null hypothesis, which is based on observed drug responses and not on a mechanistic model. Therefore, for two different drugs, the grade of their additivity is based on a reference point for readout, which in turn depends on the mathematical model selected. There are various methods for identifying such interactions, calculating the expected additive effect of two substances, and thus determining whether the actual synergistic effect observed is subadditive, additive, or superadditive. Various methods are recommended in the art. The most common methods are outlined below.

[0040] Basic methods such as constructing simple arithmetic sums or fractional generation provide an easy way to gain initial insight into when a particular combination has superadditive potential.

[0041] The simple arithmetic sum method for additivity is based on the formula A+B=(A+B), where A and B are again the percent or fractional effect seen when each agent is administered alone, and (A+B) is the percent or fractional effect seen after the combined application of the agents using the same doses as in the single application. If A+B>(A+B), then superadditivity is given. An obvious and significant drawback of this method is that results with A+B≧100% cannot be analyzed for superadditivity. Therefore, this method is primarily used to interpret suboptimal dose combinations.

[0042] Fractional production is based on the formula 1-(1-A)*(1-B)=(A+B), where A and B are the fractual effects seen when each agent is administered alone, and (A+B) is the fractual effect seen after combined administration of the agents using the same dose as in the single administration. Supraadditivity is given when 1-(1-A)*(1-B)>(A+B).

[0043] More sophisticated methods include the use of so-called isobolograms, which are graphs constructed on a coordinate system defined by individual drug doses, showing a "line of additivity" that allows for the distinction between subadditive, additive, and supra-additive effects (along the line). The "line of additivity" connects those single drug doses that show the same effect (e.g., 50% inhibition of a specific marker). All possible dose combinations along this line are expected to show the same efficacy. Dose combinations that lie within the triangle constructed by the coordinates and the additivity line, i.e., closer to any point, and that show the same effect, are considered supra-additive. Dose combinations that lie outside the triangle are considered sub-additive.

[0044] Each diagram can be mapped using specific software, for example CompuSyn (Chou TC and Martin N. ComboSyn, Inc. Paramus, NJ 2007 [www.combosyn.com]).

[0045] In addition, further specific index values, such as the combination index (CI, Chou-Talalay 1984 formula) and dose reduction index (DRI, Chou 1984 formula), can be easily calculated using the specific software mentioned above. Both of these values ​​allow determining whether drug substances act synergistically or additively when administered simultaneously. CI is based on the principle of mass action and is applicable to any type of drug combination, regardless of the mechanism of action, kinetic sequence, or dosage units used for each drug in the combination. The CI value defines synergy as superadditive if CI<1 and additive if CI=1. If CI>1, the effect is either subadditive or antagonistic. Therefore, a CI of 1 also refers to the "line of additivity" in the classical isobologram mentioned above. In a simplified approach, it could be calculated as follows: CI=A(t) / A(x)+B(t) / B(x). where A(t) and B(t) are the doses of drugs A and B alone that inhibit x%, and A(x) and B(x) also represent the portions of each drug in combination that inhibit x%.

[0046] The DRI is a measure of how many times the dose of each drug in a synergistic combination can be reduced at a given level of effect compared to the dose of each drug alone. Thus, a DRI of 1 indicates additivity, while a DRI of >1 and <1 indicates supra-additivity and sub-additivity (or antagonism), respectively.

[0047] For display purposes, an isobologram, i.e., an isoeffect curve of two drugs at various concentrations or doses as described above, is a dose-oriented graphical approach based on a special case of the CI equation. However, a more convenient graphical technique is the effect-oriented so-called FaCI plot, which displays the combination index (CI) against the fractional effect (Fa), preferably for a particular dose combination (see Figures 1 and 2).

[0048] Some of the most commonly systemically applied corticosteroids are cortisone, hydrocortisone, prednisone, prednisolone, triamcinolone, methylprednisolone, betamethasone, dexamethasone, and fludrocortisone. They differ in their relative anti-inflammatory (glucocorticoid) and mineralocorticoid potency compared to naturally occurring cortisol, as well as in their duration of effect, which is not accurately reflected by their plasma half-life. Among the corticosteroids listed above, fludrocortisone is worth mentioning as the mineralocorticoid with the highest mineralocorticoid potency combined with a medium-duration effect of approximately 24 hours, while all other examples are glucocorticoids, with betamethasone and dexamethasone having the highest anti-inflammatory potency combined with a long-duration effect of 2 to 3 days.

[0049] Within the scope of this disclosure, the term "corticosteroid" includes any type of natural or synthetic corticosteroid administered to humans or animals to treat or prevent any type of condition or disease. The term "glucocorticoid" includes any "corticosteroid" that exhibits significant anti-inflammatory potency and affinity for the glucocorticoid receptor. Furthermore, the term "glucocorticoid" includes any pharmaceutically acceptable form of glucocorticoid, such as esters and salts.

[0050] In the sense of this patent application, unless expressly specified otherwise, the terms "condition" and "disease" refer to any kind of condition, disease or disorder that can be prevented and / or treated by the administration of glucocorticoids.

[0051] Preferably, the present invention relates to a corticosteroid having primarily anti-inflammatory properties, namely, but not limited to, flumethasone, triamcinolone acetonide, betamethasone, deflazacort, dexamethasone, beclomethasone, betamethasone valerate, betamethasone dipropionate, budesonide, beclomethasone dipropionate, isoflupredone, fluocinonide, fluocinolone, prednisone, prednisolone, methylprednisolone, halocinonide, desonide, deltasone, triamcinolone, triamcinolone acetonide, tixocortol pivalate, mometasone, amcinonide, flucortol, flumethasone dipropionate ... Glucocorticoids include fluocortolone, halometasone, alclometasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, cortisol, hydrocortisone, hydrocortisone acetate, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 17-aceponate, 17-hydrocortisone buteprate, cortisone and cortisone acetate.

[0052] The present invention most preferably relates to glucocorticoids selected from the group comprising cortisone, hydrocortisone, prednisone, prednisolone, triamcinolone, methylprednisolone, betamethasone and dexamethasone.

[0053] From a practical standpoint, different substances are used for different indications due to their glucocorticoid potency compared to cortisol: for example, cortisone is less potent than cortisol, whereas prednisone is four times more potent than cortisol, prednisolone and methylprednisolone are five times more potent, and dexamethasone is about 30 times more potent than cortisol.

[0054] A wide variety of glucocorticoid formulations are available for oral, parenteral, and various topical uses, such as cutaneous, transdermal, ocular, and intra-articular. The present invention relates to any suitable glucocorticoid formulation. Preferably, the present invention relates to formulations comprising at least one glucocorticoid for systemic or topical administration. Most preferably, the present invention relates to systemically or topically administered glucocorticoids, wherein the mode of administration is selected from the group consisting of intravenous, oral, sublingual, rectal, topical, and cutaneous administration.

[0055] As previously mentioned, the present invention relates to 5-amino-2,3-dihydro-1,4-phthalazinediones as corticoid-sparing agents.

[0056] To ensure better solubility and bioavailability, pharmaceutically acceptable salts of 5-amino-2,3-dihydro-1,4-phthalazinedione may be used. Sodium, potassium, and lithium salts have been described for therapeutic applications (see WO 2010 / 082858). Thus, the present invention relates to a pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1,4-phthalazinedione selected from the group consisting of sodium, potassium, and lithium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione. In particular, the present invention relates to the sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione.

[0057] The crystal structures of the lithium, sodium, potassium, rubidium and cesium salts are described in Guzel et al. (2013) Journal of Coordination Chemistry 66, 3722-3739. Therefore, this patent application also refers to the use of crystalline forms of all pharmaceutically acceptable salts of 5-amino-2,3-dihydro-1,4-phthalazinedione. 5-amino-2,3-dihydro-1,4-phthalazinedione is often used as a hydrate, for example, the sodium salt dihydrate. Therefore, this patent application also refers to the use of all hydrates and other solvates of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts. 5-amino-2,3-dihydro-1,4-phthalazinedione, its derivatives, or its pharmaceutically acceptable salts can be complexed with suitable ligands. Therefore, this patent application also refers to such complexes.

[0058] It is often desirable to ensure reproducible, standardized production of active pharmaceutical ingredients (APIs) and to provide improved stability characteristics for anhydrous formulations of active drugs. The anhydrous forms of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt are described as crystalline polymorphs in WO 2011 / 107295 (Form I, Form II) and WO 2016 / 096143 (Form III). These polymorphs are substantially free of phase impurities and have been characterized by X-ray powder diffraction. This method yields a set of characteristic d-values ​​indicating the interplanar spacings and corresponding 2-theta (2θ) angles at which Bragg reflections occur. Additionally, the relative intensities of the reflections (normalized to 100% for the highest peak) are shown. This provides a unique and unambiguous fingerprint for each polymorph.

[0059] For Form I, the following values ​​were determined: d values: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1; 3.0 and / or 2θ values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3.

[0060] Form II is characterized by the following values: d values: 12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and / or 2θ values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8.

[0061] Form III yielded the following values: d values: 13.131; 7.987; 7.186; 6.566; 6.512; 5.372; 3.994; 3.662; 3.406; 3.288; 3.283; 3.222; 3.215; 3.127; 2.889 and / or 2θ values: 6.73; 11.07; 12.31; 13.48; 13.59; 16.49; 22.24; 24.29; 26.14; 27.10; 27.14; 27.67; 27.72; 28.52; 30.93.

[0062] Therefore, this patent application also refers to the use of all crystalline forms of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts, and polymorphs thereof.

[0063] Similar therapeutic effects are known for various phthalazinediones, which are derivatives of 5-amino-2,3-dihydro-1,4-phthalazinedione, and their pharmaceutically acceptable salts. One example is 6-amino-2,3-dihydrophthalazine-1,4-dione (isoluminol). A summary of suitable phthalazinediones is given in WO 2007 / 018546. It is reasonable to assume that these compounds will exhibit similar effects when used in therapeutic applications according to the present invention.

[0064] Tautomerism refers to the rapid internal transformation of organic compounds in which a hydrogen atom or proton formally migrates to the interior of the compound. This involves switching of a single bond and an adjacent double bond. A single form is called a tautomer. For example, keto-enol tautomerism occurs in 5-amino-2,3-dihydro-1,4-phthalazinedione. Therefore, this patent application also refers to the use of all tautomers of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts.

[0065] As used throughout this application, the term "5-amino-2,3-dihydro-1,4-phthalazinedione" is intended to encompass all the aforementioned molecular variants of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts, unless otherwise specified, and in particular the term includes complexes, as well as solvates, hydrates, crystalline polymorphs and tautomers.

[0066] Within the scope of this application, the term "combination" or "pharmaceutical combination" refers to the administration of at least two different active substances within the same treatment scheme for a particular indication. The term "composition" or "pharmaceutical composition" refers to a single pharmaceutical preparation containing at least one active ingredient. Thus, the at least two active substances within a "pharmaceutical combination" can be administered separately or in the same single "composition."

[0067] Accordingly, the present patent application relates to a pharmaceutical combination comprising at least one 5-amino-2,3-dihydro-1,4-phthalazinedione and at least one glucocorticoid for use in the prevention and / or treatment of conditions or diseases that are normally treated with glucocorticoids, wherein the 5-amino-2,3-dihydro-1,4-phthalazinedione is administered as an add-on to the at least one glucocorticoid or in the same pharmaceutical composition as the at least one glucocorticoid.

[0068] Preferably, the present patent application relates to pharmaceutical combinations comprising at least one 5-amino-2,3-dihydro-1,4-phthalazinedione for use in the prevention and / or treatment of conditions or diseases that are usually treated with glucocorticoids, characterized by a lower dose of glucocorticoid compared to the respective treatment with glucocorticoid alone.

[0069] The present patent application also relates to a pharmaceutical combination comprising at least one 5-amino-2,3-dihydro-1,4-phthalazinedione and at least one glucocorticoid for use in the prevention and / or treatment of undesired glucocorticoid action, wherein the 5-amino-2,3-dihydro-1,4-phthalazinedione is administered as an add-on to the at least one glucocorticoid or in the same pharmaceutical composition as the at least one glucocorticoid.

[0070] As used herein, the terms "pharmaceutical" and "medical" include both human and veterinary medicine.

[0071] According to this application, unless otherwise specified, the terms "drug", "medicine", "compound", "active substance" or "active pharmaceutical ingredient" (API) refer to 5-amino-2,3-dihydro-1,4-phthalazinedione and / or glucocorticoid substances or compounds as defined above.

[0072] The term "composition" or "pharmaceutical composition" includes at least one active substance in any pharmacologically acceptable defined dosage form and dosage form, together with at least one pharmaceutically acceptable excipient, and any drug produced directly or indirectly from the above-mentioned components as a combination, accumulation, complex or crystal, or as a result of other reaction or interaction, and optionally at least one further pharmaceutical agent.

[0073] The term "excipient" is used in this application to describe any component of a pharmaceutical composition other than the active agent. The selection of an appropriate excipient depends on various factors, such as the dosage form of the composition, the dosage amount, and the desired solubility and stability.

[0074] The term "effect" or "action" with respect to an active substance, respectively a combination of the present invention, refers to a result that occurs causally in an organism to which the substance or combination has been previously administered. In the case of a beneficial result that occurs causally in an organism, the terms "therapeutic effect," "therapeutic action," or "efficacy" are used. The term "efficacy" refers to the degree of the desired therapeutic effect.

[0075] The term "undesirable glucocorticoid action" or "undesirable effects associated with glucocorticoids" also includes any undesirable effects associated with treatment with glucocorticoids, such as adverse reactions, long-term side effects, habituation, and effects associated with the sudden removal of glucocorticoids.

[0076] According to the present invention, the terms "effective amount" and "therapeutically effective amount" refer to an amount of a substance of the present invention that is large enough to bring about the desired beneficial effect in those in need of such prevention or treatment.

[0077] The term "synergy" or "synergistic effect" refers to the effect resulting from the combined application of at least two substances that exhibit comparable efficacy, in which the therapeutic effect of one of the substances is enhanced when at least one additional substance is added.

[0078] The terms "subadditivity," "additivity," and "superadditivity" refer to the grade of synergistic effect of substances administered in combination compared to the same substances administered as single agents.

[0079] The term "antagonism" or "antagonistic effect" refers to the effect resulting from the combined application of at least two substances that exhibit equivalent efficacy, such that the addition of at least one further substance weakens the therapeutic effect of one of the substances.

[0080] In the scope of the present invention, the term "co-administration" or "administered simultaneously" refers to the administration of at least two pharmaceutical agents within a specific time frame, the latter depending on the administration interval of the less frequently administered agent. For example, if the agent with a longer administration interval is administered daily, the second agent must be administered on the same day for co-administration. However, in the case of injections every two weeks, the administration of the second agent within these two weeks must be considered concomitant. The application form and administration site are independent, and therefore, although they may be completely different, the two agents may be provided in the same pharmaceutical composition.

[0081] The terms "prevention," "treatment," and "therapy" include the administration of at least any substance of the present invention, alone or in combination with at least one additional substance of the present invention and optionally one or more additional pharmaceutical agents, to a subject in need thereof, regardless of the chronological order of administration. Such administration is intended to prevent or inhibit any symptoms or undesirable effects associated with one of the disorders of the present invention or the treatment of such a disorder, and / or to alleviate the undesirable effects or symptoms, and / or to initiate the healing process of such a disorder.

[0082] Glucocorticoids are used to treat, for example, rheumatoid arthritis, bursitis, osteoarthritis, tendonitis, gouty arthritis, epicondylitis, ulcerative colitis, Crohn's disease, multiple sclerosis, asthma, bronchitis, skin rashes, allergies, severe hypersensitivity reactions, shock, systemic lupus erythematosus, severe psoriasis, alopecia, focal neurodermatitis, granuloma annulare, granulomatosis with polyangiitis, lichen planus, keloids, acute and chronic leukemia, lymphoma, multiple myeloma, brain tumors, intracranial tumors, cerebral edema, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, acute mountain sickness, acute idiopathic tinnitus, eczema, muscular dystrophy, Bell's palsy, cluster headache, chronic obstructive pulmonary disease (COPD), croup, chemotherapy-induced fatigue, nausea and vomiting, and to prevent transplant rejection.

[0083] Furthermore, early intervention with dexamethasone in septic shock, especially when used at low doses, could reduce mortality (Lian XJ et al. 2019, Hindawi, BioMed Res Int, Article ID 3175047, published June 10, 2019). More recently, the same effect could be demonstrated in patients with severe COVID-19 symptoms who required mechanical ventilation after developing acute respiratory stress syndrome due to an overreaction of the immune system (Tomazini et al. 2020, JAMA 324(13), 1307-1316; Horby et al. 2020, NEJM 384, 693-704). Therefore, glucocorticoid treatment may prove useful in critically ill patients at high risk for infection, or even when infection itself is the reason for treatment. Dosage is important, and any adverse reactions associated with glucocorticoids can be fatal for these patients. The pharmaceutical combination according to the present invention may help to further reduce the dose administered in such cases, thereby reducing the patient's risk of adverse reactions.

[0084] Glucocorticoids are well known for their success in treating cerebral edema, and therefore in the surgical field glucocorticoids are used to reduce inflammation in delicate tissues, for example in neurosurgery.

[0085] For example, various skin conditions such as eczema or reactions to contact toxins such as poison ivy are primarily treated by topical application. In pediatrics, glucocorticoids are primarily used to treat cerebral edema, meningitis, chemotherapy-induced nausea and vomiting, acute asthma, croup, acute mountain sickness, idiopathic thrombocytopenic purpura, and any additional indication requiring a rapid and reasonable anti-inflammatory and / or immunosuppressive effect.

[0086] Glucocorticoids are also used prophylactically, for example to prevent exacerbations of COPD or to prevent post-traumatic acute shock lung.

[0087] In veterinary medicine, glucocorticoids are also widely used to treat allergic and inflammatory diseases of the skin, lungs and gastrointestinal tract, but also to treat conditions such as cerebral edema and cardiogenic or septic shock.

[0088] The medicaments or pharmaceutical combinations according to the present invention may be used in the prevention and / or treatment of unwanted glucocorticoid action and / or in the treatment of conditions or diseases that are normally treated with glucocorticoids, including but not limited to: Autoimmune disorders, such as multiple sclerosis, rheumatoid arthritis, juvenile chronic arthritis, polymyalgia rheumatica, autoimmune hemolytic anemia, Sjogren's syndrome, autoimmune hepatitis, systemic lupus erythematosus, rheumatic fever, alopecia, pemphigus, bullous pemphigoid, dermatomyositis, psoriasis, pyoderma gangrenosum, autoimmune thyroiditis, and immune thrombocytopenia; Allergies, such as asthma, skin rashes, contact dermatitis, such as from exposure to poison oak or poison ivy, urticaria, angioedema, anaphylaxis, and severe hypersensitivity reactions; Cancers such as leukemias, including acute and chronic lymphocytic leukemia and acute and chronic myeloid leukemia, lymphomas, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, brain tumors and intracranial tumors; adverse reactions related to cancer treatments such as chemotherapy and radiation therapy, including but not limited to fatigue, nausea and vomiting; Inflammatory diseases of the skin, such as skin rash, eczema, dermatitis, contact dermatitis, atopic dermatitis, urticaria, systemic lupus erythematosus, alopecia, psoriasis, phimosis, granuloma annulare, pemphigus, bullous pemphigoid, pyoderma gangrenosum, shingles, dermatomyositis, keloids and lichens, such as localized neurodermatitis, lichen planus, lichen sclerosus and lichen sclerosus et atrophicus; Prevention of respiratory inflammatory diseases such as asthma, bronchitis, laryngitis, croup, severe tuberculosis, chronic obstructive pulmonary disease (COPD), prevention of COPD exacerbations, cystic fibrosis, lipid-containing interstitial pneumonia, acute respiratory distress syndrome (ARDS), infantile respiratory distress syndrome (IRDS), and acute shock lung after trauma; Inflammatory diseases of the gastrointestinal tract, such as inflammatory bowel disease, ulcerative colitis, cystic fibrosis, and Crohn's disease; Inflammatory diseases of the genitourinary system, such as acute interstitial nephritis, renal syndrome, cystic fibrosis and phimosis; Inflammatory diseases of the musculoskeletal system such as bursitis, osteoarthritis, tendonitis, gouty arthritis, epicondylitis, ataxia telangiectasia, plantar fasciitis, mixed connective tissue disease, dermatomyositis, juvenile chronic arthritis, and polymyalgia rheumatica; Muscular dystrophies, e.g., Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle dystrophies, dysferlin abnormalities, Miyoshi myopathy 1-3, hereditary inclusion body myopathy (HIBM), distal myopathy with rimmed vacuoles (DMRV), Nonaka distal myopathy, limb-sparing myopathy, spinal-bulbar muscular atrophy (SMA), SMARD1, Werdnig-Hoffmann disease, Kugelberg-Welander disease, Charcot-Marie-Tooth disease, Curschmann-Steinert disease, and proximal myotonic myopathy , PROMM (type 2), Walker-Warburg syndrome, lamin A / C-related congenital muscular dystrophy, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy with partial merosin deficiency, spinal rigid muscular dystrophy, congenital muscular dystrophy with primary laminin 2 deficiency, LARGE-related congenital muscular dystrophy, muscle-eye-brain disease, Ullrich congenital muscular dystrophy, Emery-Dreyfuss muscular dystrophy (EMD), facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy and myofibrillar myopathy types 1-6; Inflammatory diseases of the nervous system and sensory organs, such as ocular inflammation, sympathetic ophthalmia, uveitis, meningitis, cluster headache, ataxia-telangiectasia, Bell's palsy, herpes zoster, chronic inflammatory demyelinating polyneuropathy (CIPD), myasthenia gravis, Meniere's disease, and acute idiopathic tinnitus, Inflammatory diseases of the cardiovascular system, such as heart failure, pericarditis, postural hypotension, rheumatic fever with carditis, vasculitis, polyarteritis nodosa, panarteritis nodosa, giant cell arteritis, temporal arteritis, and granulomatosis with polyangiitis; Further systemic inflammatory diseases such as septic shock, bacteremia, viremia, fungemia, sepsis including but not limited to parasite-associated sepsis, Herxheimer reaction, and SIRS (systemic inflammatory response syndrome), as well as further inflammatory response syndromes such as acute respiratory distress syndrome (ARDS), Kawasaki syndrome, and temporarily, pediatric inflammatory multisystem syndrome associated with SARS-CoV-2 (PIMS-TS); severe infectious diseases such as tuberculosis, typhoid and brucellosis; and numerous additional conditions, such as cerebral edema, shock; post-traumatic shock syndrome, post-traumatic stress disorder, sarcoidosis, hypercalcemia, adrenal insufficiency (including primary, secondary and tertiary adrenal insufficiency), adrenogenital syndrome, thyroiditis, and acute mountain sickness; The medicament or pharmaceutical combination according to the present invention is capable of preventing transplant rejection.

[0089] Surprisingly, it can be shown that the simultaneous administration of pharmaceutical combinations according to the present invention not only exhibits a general supra-additive effect, but also exhibits this effect across a wide range of fixed ratios tested (see Example 1).

[0090] The term "ratio" or "fixed ratio" as used herein refers to any kind of ratio between two components, regardless of the units used. Such ratios are valid in weight, weight percent, concentration specifications, and any other feasible units in the pharmaceutical field. Thus, for example, a 1:10 ratio of glucocorticoid to 5-amino-2,3-dihydro-1,4-phthalazinedione can be expressed, for example, as 1 mg:10 mg, 1 mg / kg:10 mg / kg, 1 mM / 10 mM, or 1%:10%, or any other unit as long as the ratio itself is 1:10.

[0091] The present patent application also refers to a glucocorticoid-sparing agent or respective pharmaceutical combination comprising at least one 5-amino-2,3-dihydro-1,4-phthalazinedione and at least one glucocorticoid for use in the prevention and / or treatment of conditions or diseases that are normally treated with glucocorticoids, wherein the efficacy of the prevention and / or treatment is significantly improved compared to the respective treatment with glucocorticoid alone.

[0092] Furthermore, the glucocorticoid-sparing agent or the respective pharmaceutical combination according to the present invention can therefore be used for the prevention and / or treatment of conditions or diseases that are usually treated with glucocorticoids, and the components can be used in any ratio.

[0093] However, in order to obtain the best effect for the medical indication being treated, the practical feasibility of the potency, application form and ratio of the glucocorticoids used should be taken into account, the latter especially in order to maintain patient compliance.

[0094] Thus, the glucocorticoid-sparing agent or the respective pharmaceutical combination according to the present invention can be used for the prevention and / or treatment of conditions or diseases that are normally treated with glucocorticoids, and the components glucocorticoid and 5-amino-2,3-dihydro-1,4-phthalazinedione can be used in any ratio, preferably from 10:1 to 1:5000, more preferably from 4:1 to 1:1600, and most preferably from 1:5 to 1:400.

[0095] Below, some possible combinations and their respective ratios are provided, but the pharmaceutical combinations according to the present invention are not limited to these examples.

[0096] Depending on the dosage form, the indication being treated, and the patient's individual risk profile, oral dexamethasone is administered at doses of up to 100 mg per day in severe and acute cases, while maintenance doses in chronic conditions typically range from 4 to 8 mg per day. 5-Amino-2,3-dihydro-1,4-phthalazinedione has been shown to be very safe, but for compliance reasons, dosages should not exceed 10 grams per day, for example, in tablets or capsules.

[0097] Thus, the glucocorticoid-sparing agent or the respective pharmaceutical combination according to the present invention can be used for the prevention and / or treatment of conditions or diseases that are usually treated with glucocorticoids, wherein the component dexamethasone is administered orally and is characterized in a ratio of dexamethasone to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt of 4:1 to 1:100, preferably 2:1 to 1:50, more preferably 1:1 to 1:20, most preferably 1:2 to 1:10 for severe acute cases, and in a ratio of dexamethasone to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt of 1:5 to 1:800, preferably 1:10 to 1:400, more preferably 1:20 to 1:200, most preferably 1:50 to 1:100 for maintenance doses in chronic cases.

[0098] However, with liquid applications, higher doses and / or volumes can be administered without adversely affecting patient compliance.

[0099] Thus, the glucocorticoid-sparing agent or the respective pharmaceutical combination according to the present invention can be used for the prevention and / or treatment of conditions or diseases that are usually treated with glucocorticoids, wherein the components dexamethasone and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt are administered orally and are characterized by a low dose dexamethasone to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt ratio of 1:5 to 1:1600, preferably 1:10 to 1:800, more preferably 1:20 to 1:400, most preferably 1:50 to 1:200, in patients receiving any liquid form of these pharmaceuticals.

[0100] Injectable dexamethasone is administered in a similar manner to oral dexamethasone. However, in very severe cases, an acute initial dose of up to 200 mg is administered intravenously, and in these cases, maintenance doses are also higher. Doses for local infiltration and injection therapy typically range from 2 mg to 8 mg per injection.

[0101] Thus, the glucocorticoid-sparing agent or the respective pharmaceutical combination according to the present invention can be used for the prevention and / or treatment of conditions or diseases that are usually treated with glucocorticoids, wherein the component dexamethasone is administered intravenously and is characterized in a ratio of dexamethasone to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt of 10:1 to 1:100, preferably 4:1 to 1:50, more preferably 2:1 to 1:20, most preferably 1:1 to 1:10 in severe acute cases, and in chronic cases for maintenance doses of 1:1 to 1:400, preferably 1:2 to 1:200, more preferably 1:5 to 1:100, most preferably 1:10 to 1:50.

[0102] Thus, the glucocorticoid-sparing agent or the respective pharmaceutical combination according to the present invention can be used for the prevention and / or treatment of conditions or diseases that are usually treated with glucocorticoids, wherein the component dexamethasone is administered locally by infiltration or injection and is characterized by a ratio of dexamethasone to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt of 1:5 to 1:1600, preferably 1:10 to 1:800, more preferably 1:20 to 1:400, most preferably 1:50 to 1:200.

[0103] Oral prednisone is started at a low maintenance dose of 1 mg per day, up to 250 mg per day in severe acute cases.

[0104] Thus, the glucocorticoid-sparing agent or the respective pharmaceutical combination according to the present invention can be used for the prevention and / or treatment of conditions or diseases that are usually treated with glucocorticoids, wherein the component prednisone is administered orally and is characterized in a ratio of dexamethasone to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt of 10:1 to 1:100, preferably 4:1 to 1:50, more preferably 2:1 to 1:20, most preferably 1:1 to 1:10 for severe acute cases, and in chronic cases for the maintenance dose of 1:2 to 1:1600, preferably 1:5 to 1:800, more preferably 1:10 to 1:400, most preferably 1:20 to 1:200 for prednisone to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt.

[0105] In severe acute cases, prednisolone is administered as an injection in doses up to 1000 mg. Maintenance doses of 50 mg or more per day are not uncommon.

[0106] Thus, the glucocorticoid-sparing agent or the respective pharmaceutical combination according to the present invention can be used for the prevention and / or treatment of conditions or diseases that are usually treated with glucocorticoids, wherein the component prednisolone is administered orally and is characterized by a ratio of prednisolone to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt of 10:1 to 1:20, preferably 4:1 to 1:10, more preferably 2:1 to 1:5, most preferably 1:1 to 1:2 for severe acute cases, and by a ratio of dexamethasone to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt of 4:1 to 1:400, preferably 2:1 to 1:200, more preferably 1:1 to 1:100, most preferably 1:2 to 1:50 for maintenance doses.

[0107] For further glucocorticoid substances as well as further application forms, such as creams for topical treatment or inhalation preparations containing glucocorticoids, suitable ratios can be determined accordingly.

[0108] Due to the superadditivity demonstrated for the pharmaceutical combinations of the present invention, the glucocorticoid dosage can be reduced depending on the individual patient, the indication, and the ratio of the components used. In some cases, adaptation of the dosage and ratio over time may be necessary to achieve optimal results. As shown in Example 1 (see Table 2), the improvement of the combination compared to glucocorticoid alone reached 25% in almost all combinations investigated, with 50% or even 100% improvement being very common, and improvements of up to more than 500% were observed in single combinations.

[0109] Therefore, the dosage of the glucocorticoid in the pharmaceutical combination of the present invention can be reduced by 80%, preferably 50%, and most preferably 20% compared to the dosage when the glucocorticoid is administered alone.

[0110] Thus, the present application refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use as a glucocorticoid-sparing agent in the prevention and / or treatment of conditions that are normally treated with glucocorticoids, characterized in that it allows for a significant reduction in the dose of glucocorticoid, whereby such a significant reduction means a reduction of the glucocorticoid dose by 80%, preferably 50%, and most preferably 20% of the original dose.

[0111] The present patent application also relates to a pharmaceutical combination comprising at least one 5-amino-2,3-dihydro-1,4-phthalazinedione and at least one glucocorticoid for use in the prevention and / or treatment of conditions or diseases that are usually treated with glucocorticoids, wherein the dose of the glucocorticoid can be significantly reduced compared to the respective treatment with glucocorticoid alone, such a significant reduction meaning a reduction of the glucocorticoid dose by 80%, preferably 50%, most preferably 20% of the original dose.

[0112] By reducing the dose of glucocorticoid, each undesirable effect will occur less frequently and less severely. Furthermore, Example 2 provides a clear hint that the administration of the pharmaceutical combination of the present invention reduces the undesirable side effects of glucocorticoids, even without reducing the dose of glucocorticoid.

[0113] The present patent application also relates to a pharmaceutical combination comprising at least one 5-amino-2,3-dihydro-1,4-phthalazinedione and at least one glucocorticoid for use in the prevention and / or treatment of conditions or diseases that are normally treated with glucocorticoids, wherein the number and severity of glucocorticoid-associated side effects are significantly reduced compared to respective treatments with glucocorticoid alone.

[0114] Depending on the specific glucocorticoid used, high dosages can cause problems because, above a critical serum concentration, glucocorticoid receptors and, to a lesser extent, mineralocorticoid receptors are activated. In most cases, this is an undesirable side effect. By using a combination of a glucocorticoid with 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts according to the present invention, the effective dosage of the glucocorticoid can be reduced so that mineralocorticoid receptor activation does not occur, or at least to a much lesser extent. To achieve this effect, the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is particularly preferred.

[0115] This patent application relates to a method of treatment by providing a patient in need thereof with a pharmaceutical combination comprising at least one 5-amino-2,3-dihydro-1,4-phthalazinedione and at least one glucocorticoid for use in the prevention and / or treatment of conditions or diseases that are normally treated with glucocorticoids. The method comprises providing the pharmaceutical combination of the present invention by administering the combination to a patient in need thereof in effective amounts and ratios. Examples of such effective amounts and ratios are described above.

[0116] The present patent application also relates to a method of treatment by providing a pharmaceutical combination comprising at least one 5-amino-2,3-dihydro-1,4-phthalazinedione and at least one glucocorticoid to a patient in need thereof for use in the prevention and / or treatment of undesired glucocorticoid action. The method comprises providing the pharmaceutical combination of the present invention by administering the combination to a patient in need thereof in effective amounts and ratios. Examples of such effective amounts and ratios are described above.

[0117] The present application also refers to a pharmaceutical composition for use as an add-on in the prevention and / or treatment of conditions or diseases that are usually treated with glucocorticoids, said composition comprising at least one 5-amino-2,3-dihydro-1,4-phthalazinedione and at least one excipient.

[0118] The present application also refers to pharmaceutical compositions for use in the prevention and / or treatment of conditions or diseases that are normally treated with glucocorticoids, said compositions comprising at least one of 5-amino-2,3-dihydro-1,4-phthalazinedione or any of the aforementioned molecular variants of this compound, at least one glucocorticoid and at least one excipient.

[0119] The at least one excipient is selected from the group consisting of carriers, penetration enhancers, binders, solvents, solubilizers, buffers, preservatives, antioxidants, coatings, colorants, flavorings, aromatics, sweeteners, thickeners, disintegrants, glidants, lubricants, emulsifiers, stabilizers, diluents, anti-caking agents (anti-adherents), pH adjusters, acidifying agents, tonicity agents, foaming agents, anti-foaming agents, fat agents, consistency improvers, hydrotropes, adsorbents, and opacifiers.

[0120] Suitable carriers include all carriers known in the art and their combinations. For solid dosage forms, they can be, for example, vegetable and animal fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silica, talcum, and zinc oxide. For liquid dosage forms and emulsions, suitable carriers include, for example, solvents, solubilizers, and 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, polyethylene glycol, and fatty acid esters of sorbitan. For suspensions, carriers known in the art can be used, such as diluents (e.g., water, ethanol, or propylene glycol), ethoxylated isostearyl alcohol, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline cellulose, bentonite, agar, and tragacanth.

[0121] Penetration enhancers are often used in topical dosage forms.Suitable penetration enhancers include all pharmaceutically acceptable penetration enhancers known in the art, for example, but not limited to, azones such as laurocapran, 1-dodecylazacycloheptan-2-one; sulfoxides such as dimethyl sulfoxide, DMAC, DMF; pyrrolidones such as 2-pyrrolidone, N-methyl-2-pyrrolidone; alcohols such as ethanol, 1,2-propanediol or decanol; glycols such as propylene glycol, diethylene glycol, tetraethylene glycol; oleic acid, lauric acid, lauryl Examples of surfactants include sodium sulfate, fatty acids such as myristic acid, isopropyl myristate, and capric acid; nonionic surfactants such as polyoxyethylene-2-oleyl ether and polyoxyethylene-2-stearyl ether; terpenes; terpenoids; oxazolidinones; urea; ceramide analogs, azone analogs, menthol derivatives, etherified derivatives, esterified derivatives, transcarbamic acid, carbamate salts, TXA derivatives, DDAIP (dodecyl 2-(dimethylamino)propanoate), DDAK, and natural essential oils (all of which are listed in Chen et al. (2014) Asian J. Pharm. Sc. 9, 51-64); citrate esters such as triethyl citrate; hydrophobin polypeptides; α-bisabrole; dimethyl isosorbide (Arlasove® DMI); and ethoxydiglycol. 1,2-propanediol is preferred.

[0122] The term binder refers to substances that bind or glue powders together, making them cohesive through granulation. They function as the "glue" of the formulation. Binders increase the cohesive strength of the diluent or filler provided.

[0123] Suitable binders include starches from wheat, corn, rice or potato, gelatin, naturally occurring sugars such as glucose, sucrose or beta-lactose, sweeteners from corn, natural and synthetic gums such as acacia, tragacanth, or calcium ammonium alginate, sodium alginate, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl carboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, magnesium aluminum silicate, waxes and others. The percentage of binder in the composition may range from 1 to 30% by weight, preferably from 2 to 20% by weight, more preferably from 3 to 10% by weight, and most preferably from 3 to 6% by weight.

[0124] Suitable solvents may be selected from the group comprising water, carbonated water, water for injection, water containing an isotonic agent, saline, isotonic saline, alcohols, in particular ethyl and n-butyl alcohol, glycols, oleic and linoleic triglycerides, caprylic and capric mono-, di- and triglycerides, polyoxyethylene caprylic and capric glycerides, propylene glycol fatty acid esters, lower alkyl fatty acid esters, soybean oil, propylene glycol laurate, polyoxyethylene 35 (PEG-35) castor oil, polyoxyethylene glyceryl trioleate, ethyl butyrate, ethyl caprylate, ethyl oleate and mixtures thereof.

[0125] Suitable surface-active solubilizers (solubilizers) are, for example, diethylene glycol monoethyl ester, polyethylpropylene glycol copolymers, cyclodextrins, such as - and -cyclodextrin, glyceryl monostearate, for example Solutol HS15 (Macrogol-15-hydroxystearate, PEG 660-15 hydroxystearate from BASF), sorbitan esters, polyoxyethylene glycol, polyoxyethylene sorbitan acid esters, polyoxyethylene sorbitan monooleate, polyoxyethylene oxystearic acid triglyceride, polyvinyl alcohol, sodium dodecyl sulfate, (anionic) glyceryl monooleate, etc.

[0126] Additionally, one or more buffers are preferred for liquid formulations, particularly pharmaceutical liquid formulations. The terms buffer, buffer system, and buffer solution, particularly for aqueous solutions, refer to the system's ability to resist pH changes due to the addition of acid or base, or due to dilution with a solvent. Preferred buffer systems include formate, lactate, benzoate, oxalate, fumarate, aniline, acetate buffer, citrate buffer, glutamate buffer, phosphate buffer, succinate, pyridine, phthalate, histidine, MES (2-(N-morpholino)ethanesulfonic acid), maleic acid, cacodylate (dimethyl arsenate), carbonic acid, ADA (N-(2-acetamido)iminodiacetic acid), PIPES (4-piperazine-bis-ethanesulfonic acid), BIS-TRIS protease inhibitors, and the like. Pan (1,3-bis[tris(hydroxymethyl)methylamino]propane), ethylenediamine, ACES (2-[(amino-2-oxoethyl)amino]ethanesulfonic acid), imidazole, MOPS (3-(N-morphino)propanesulfonic acid), diethylmalonate, TES (2-[tris(hydroxymethyl)methyl]aminoethanesulfonic acid), and HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid), with pK values ​​between 3.8 and 7.7. a The buffer may be selected from the group including other buffers having the formula:

[0127] Carbonate buffers such as acetate buffers and dicarboxylic acid buffers such as fumarate, tartrate and phthalate, and tricarboxylic acid buffers such as citrate are preferred.

[0128] Another group of preferred buffers are inorganic buffers such as sulfate hydroxide, borate hydroxide, carbonate hydroxide, oxalate hydroxide, calcium hydroxide, and phosphate buffers. Another group of preferred buffers are nitrogen-containing buffers such as imidazole, diethylenediamine, and piperazine. Further preferred are sulfonic acid buffers such as TES, HEPES, ACES, PIPES, [(2-hydroxy-1,1-bis-(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid (TAPS), 4-(2-hydroxyethyl)piperazine-1-propanesulfonic acid (EEPS), 4-morpholino-propanesulfonic acid (MOPS), and N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES). Another group of preferred buffers is glycine, 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-hydroxylysine, o-phosphoserine, γ-carboxyglutamate, [epsilon]-N-acetyllysine, [omega]-N-methylarginine, citrulline, ornithine, and derivatives thereof.

[0129] Preservatives for liquid dosage forms may be used upon request, including 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 parahydroxybenzoate, sodium ethyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, benzyl alcohol, benzalkonium chloride, phenylethyl alcohol, cresol, cetylpyridinium chloride, chlorobutanol, thiomer (sodium 2-(ethylmercurithio)benzoate), sulfur dioxide, sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium metabisulfite, potassium metabisulfite, potassium sulfite, calcium sulfite. The additive may be selected from the group comprising sodium, calcium bisulfite, potassium bisulfite, biphenyl, orthophenylphenol, sodium orthophenylphenol, thiabendazole, herring, natamycin, formic acid, sodium formate, calcium formate, hexamine, formaldehyde, dimethyl bicarbonate, potassium nitrite, sodium nitrite, sodium nitrate, potassium nitrate, acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, ammonium acetate, dehydroacetic acid, sodium dehydroacetate, lactic acid, propionic acid, sodium propionate, calcium propionate, potassium propionate, boric acid, sodium tetraborate, carbon dioxide, malic acid, fumaric acid, lysozyme, copper-(II)-sulfate, chlorine, chlorine dioxide and other suitable substances or compositions known to those skilled in the art.

[0130] The addition of an antioxidant is particularly preferred in topical formulations. Suitable examples of antioxidants include sodium metabisulfite, α-tocopherol, ascorbic acid, maleic acid, sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, or propyl gallate. The use of sodium metabisulfite is preferred.

[0131] Tablets or pills are usually coated, i.e., the coating constitutes the outer layer. This can be a film coating, a sugar coating containing sugar, or a compression coating. Pharmaceutically acceptable varnishes or waxes, such as HPMC, MC, or HPC, can be used. Such coatings can help disguise the taste and make swallowing or identification easier. In many cases, plasticizers and pigments are included in the coating.

[0132] Capsules typically have a gelatinous envelope that encloses the active substance. The specific composition and thickness of this gelatinous layer determine how quickly absorption occurs after ingestion of the capsule. As is known in the art, sustained-release formulations are of particular interest.

[0133] Colorants are excipients that impart color to the beverage composition, respectively the dosage form. These excipients may be food colorants. They may be adsorbed onto suitable adsorption means such as clay or aluminum oxide. The amount of colorant may vary from 0.01 to 10% by weight of the composition, preferably from 0.05 to 6% by weight, more preferably from 0.1 to 4% by weight, and most preferably from 0.1 to 1% by weight. Suitable food colorants include curcumin, riboflavin, riboflavin-5'-phosphate, tartrazine, alkanine, quinolion yellow WS, fast yellow AB, riboflavin-5'-sodium phosphate, yellow 2G, sunset yellow FCF, orange GGN, cochineal, carminic acid, citrus red 2, carmoisine, amaranth, ponceau 4R, ponceau SX, ponceau 6R, erythrosine, red 2G, allura red AC, industrene blue RS, patent blue V, indigo carmine, brilliant blue FCF, chlorophyll and chlorophyllin, copper complexes of chlorophyll and chlorophyllin, green S, fast green FCF, plain caramel, caustic sulfite caramel, ammonia caramel, sulfite ammonia caramel, black PN, carbon black, vegetable carbon, brown FK, brown HT, α-carotene, β-carotene, γ-carotene, annatto, bixin, norbixin, paprika oleoleoresin, capsanthin, capsorubin, lycopene, β-apo-8'-carotenal, ethyl ester of β-apo-8'-carotenoic acid, flavoxanthin, lutein, cryptoxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, zeaxanthin, citranaxanthin, astaxanthin, betanin, anthocyanins, saffron, calcium carbonate, titanium dioxide, iron oxide, iron hydroxide, aluminum, silver, gold, pigment rubin, tannin, orcein, ferrous gluconate, and ferrous lactate.

[0134] Suitable aromatic and flavoring substances include all essential oils that can be used for this purpose. Generally, this term refers to volatile extracts from plants or plant parts that have their characteristic odor. They can be extracted from plants or plant parts by steam distillation. Examples include the individual aromatic substances from essential oils, sage, clove, chamomile, anise, star anise, thyme, tea tree, peppermint, mint oil, menthol, cineole, eucalyptus oil, mango, fig, lavender oil, chamomile flower, pine needles, cypress, orange, rosewood, plum, currant, cherry, birch leaf, cinnamon, lime, grapefruit, tangerine, juniper, valerian, lemon balm, lemongrass, palmarosa, cranberry, pomegranate, rosemary, ginger, pineapple, guava, echinacea, ivy leaf extract, blueberry, persimmon, melon, etc., or mixtures thereof, as well as mixtures of menthol, peppermint and star anise oil or menthol and cherry flavor. These aromatic or flavoring substances may be present in an amount ranging from 0.0001 to 10% by weight (particularly in the composition), preferably from 0.001 to 6% by weight, more preferably from 0.001 to 4% by weight, and most preferably from 0.01 to 1% by weight, relative to the total composition. Depending on the application or on a single occasion, it may be advantageous to use different amounts.

[0135] Suitable sweeteners may be selected from the group comprising mannitol, glycerol, acesulfame potassium, aspartame, cyclamate, isomalt, isomaltitol, saccharin and its sodium, potassium and calcium salts, sucralose, alitame, thaumatin, glycyrrhizin, neohesperidin dihydrochalcone, steviol glycosides, neotame, aspartame-acesulfame salt, maltitol, maltitol syrup, lactitol, xylitol, erythritol.

[0136] Suitable thickeners may be selected from the group comprising polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, dextrin, polydextrose, modified starch, alkali modified starch, bleached starch, oxidized starch, enzyme treated starch, monostarch phosphate, didarch phosphate esterified with sodium trimetaphosphate or phosphorus oxychloride, phosphatedistarch phosphate, acetylated didarch phosphate, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated didarch adipate, acetylated didarch glycerol, didarch glycerin, hydroxypropyl starch, hydroxypropyl didarch glycerin, hydroxypropyl didarch phosphate, hydroxypropyl didarch glycerin, starch sodium octenylsuccinate, acetylated oxidized starch, hydroxyethyl cellulose.

[0137] Suitable disintegrants can be selected from the group consisting of starch, cold-water-soluble starches such as carboxymethyl starch, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, cross-linked microcrystalline cellulose such as microcrystalline cellulose and croscarmellose sodium, natural and synthetic gums such as guar, agar, Karaya (Indian tragacanth), locust bean gum, and tragacanth, clays such as bentonite, xanthan gum, alginates such as alginic acid and sodium alginate, and effervescent compositions. Hydration is supported by, for example, starch, cellulose derivatives, alginates, polysaccharides, dextran, and cross-linked polyvinylpyrrolidone. The amount of disintegrant in the composition can vary from 1 to 40% by weight, preferably from 3 to 20% by weight, and most preferably from 5 to 10% by weight.

[0138] Glidants are materials that prevent seizing of the respective supplements and improve the flow characteristics of the granulation so that the flow is smooth and consistent. Suitable glidants include silicon dioxide, magnesium stearate, sodium stearate, starch, and talc. The amount of glidant in the composition can vary from 0.01 to 10% by weight, preferably 0.1 to 7% by weight, more preferably 0.2 to 5% by weight, and most preferably 0.5 to 2% by weight.

[0139] The term "lubricant" refers to substances added to dosage forms to facilitate the release of tablets, granules, etc. from the press die or exit nozzle. They reduce friction or wear. Lubricants are usually added just before pressing, since they must be present on the surface of the granules and between the granules and the press die parts. The amount of lubricant in the composition can vary from 0.05 to 15% by weight, preferably 0.2 to 5% by weight, more preferably 0.3 to 3% by weight, and most preferably 0.3 to 1.5% by weight. Suitable lubricants include metal stearates such as sodium oleate, sodium stearate, calcium stearate, potassium stearate, and magnesium stearate, stearic acid, sodium benzoate, sodium acetate, sodium chloride, boric acid, high-melting waxes, and polyethylene glycol, among others.

[0140] Examples of the emulsifier include the following anionic emulsifiers and nonionic emulsifiers, anionic emulsifier wax, cetyl alcohol, cetylstearyl alcohol, stearic acid, oleic acid, polyoxyethylene polyoxypropylene block polymers, addition products of 2 to 60 mol of ethylene oxide to castor oil and / or hydrogenated castor oil, wool wax oil (lanolin), sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethene sorbitan monolaurate, polyoxyethene sorbitan monooleate, polyoxyethene sorbitan monopalmitate, polyoxyethene sorbitan monostearate, polyoxyethene sorbitan tristearate, polyoxyethene stearate, polyvinyl alcohol, metatartaric acid, calcium tartrate, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, propane-1,2-diol alginate, carrageenan, modified Eucheuma seaweed, locust bean gum, tragacanth, acacia gum, karaya gum, gellan gum, ghatti gum, glucomannan, pectin, amidated pectin, ammonium phosphatide, brominated vegetable oil, sucrose acetate isobutyrate, glycerol ester of wood rosin, disodium phosphate, trisodium diphosphate, tetrasodium diphosphate, dicalcium diphosphate, dibasic calcium phosphate, sodium triphosphate, pentapotassium triphosphate, sodium polyphosphate, sodium calcium polyphosphate, calcium polyphosphate, ammonium polyphosphate, β-cyclodextrin, powdered cellulose, methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, ethylmethylcellulose, calcium Carboxymethylcellulose, sodium carboxymethylcellulose, ethylhydroxyethylcellulose, croscarmellose, enzymatically hydrolyzed carboxymethylcellulose, mono- and diglycerides of fatty acids, glyceryl monostearate, glyceryl distearate, acetate esters of mono- and diglycerides of fatty acids, lactate esters of mono- and diglycerides of fatty acids, citrate esters of mono- and diglycerides of fatty acids, tartrate esters of mono- and diglycerides of fatty acids, mono- and diacetyltartaric acid esters of mono- and diglycerides of fatty acids, mixed acetate and tartrate esters of mono- and diglycerides of fatty acids, succinylated monoglycerides, sucrose esters of fatty acids, sucrose esters of fatty acids, polyglycerol esters of fatty acids, polyglycerol polyricinoleate, propane-1,2-Diol esters, propylene glycol esters of fatty acids, lactylated fatty acid esters of glycerol and propane-1, thermally oxidized soybean oil interacting with mono- and diglycerides of fatty acids, sodium dioctyl sulfosuccinate, sodium stearoyl-2-lactylate, calcium stearoyl-2-lactylate, stearyl tartrate, stearyl citrate, sodium stearyl fumarate, calcium stearoyl fumarate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, calcium stearoyl fumarate The surfactant may be selected from the group consisting of sodium lauryl sulfate, ethoxylated monoglycerides and diglycerides, methyl glucoside-coconut oil ester, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate, sodium calcium polyphosphate, calcium polyphosphate, ammonium polyphosphate, choline acid, choline salts, didarch glycerol, starch sodium octenylsuccinate, and acetylated oxidized starch. Phospholipids such as glycerol monooleate, stearic acid, and lecithin are preferred.

[0141] Stabilizers are substances that can be added to prevent undesired changes in active substances or other auxiliary substances. While not actual emulsifiers, stabilizers can also contribute to emulsion stability. Examples of suitable stabilizers include oxystearin, xanthan gum, agar, oat gum, guar gum, tara gum, polyoxyethene stearate, aspartame acesulfame salt, amylase, protease, papain, bromelain, ficin, invertase, polydextrose, polyvinylpyrrolidone, polyvinylpolypyrrolidone, triethyl citrate, maltitol, and maltitol syrup.

[0142] Diluents or fillers are inert substances added to a drug to handle a minimal amount of active agent. 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 combination thereof.

[0143] Anti-caking agents (anti-adhesion agents) can be added to the supplement or supplement composition to prevent the formation of lumps and facilitate packaging, transportation, release from at least one chamber of the dispensing cap, and consumption. Suitable examples include tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talc powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, polydimethylsiloxane.

[0144] Suitable pH adjusting agents for liquid dosage forms are, for example, buffer substances such as sodium hydroxide, hydrochloric acid, sodium dihydrogen phosphate or disodium hydrogen phosphate.

[0145] Suitable acidity regulators include acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, carbon dioxide, malic acid, fumaric acid, sodium lactate, potassium lactate, calcium lactate, ammonium lactate, magnesium lactate, citric acid, mono-, di-, trisodium citrate, mono-, di-, tripotassium citrate, mono-, di-, tricalcium citrate, tartaric acid, mono-, disodium tartrate, mono-, dipotassium tartrate, sodium potassium tartrate, orthophosphoric acid, lecithin citrate, magnesium citrate, ammonium malate, sodium malate, sodium hydrogen malate, calcium malate, calcium hydrogen malate, adipic acid, sodium adipate. The surfactant may be selected from the group comprising sodium, potassium adipate, ammonium adipate, succinic acid, sodium fumarate, potassium fumarate, calcium fumarate, ammonium fumarate, 1,4-heptonolactone, triammonium citrate, ammonium ferrous citrate, calcium glycerophosphate, isopropyl citrate, potassium carbonate, potassium bicarbonate, ammonium carbonate, ammonium bicarbonate, magnesium carbonate, magnesium bicarbonate, ferrous carbonate, ammonium sulfate, potassium aluminum sulfate, ammonium aluminum sulfate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, magnesium hydroxide, gluconic acid.

[0146] Acidifying agents are used which are inorganic chemicals that generate or become acids. Suitable examples are ammonium chloride, calcium chloride.

[0147] Suitable isotonicity 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, citrates, phosphates, borates and mixtures thereof.

[0148] In some galenic preparations, it may be desirable for the liquid oral dosage form to generate some foam upon dissolution. Such an effect can be supported by the addition of foaming agents, which reduce the surface tension of the liquid and thus promote the formation of bubbles, or increase its colloidal stability by inhibiting the coalescence of bubbles. Alternatively, the foam can be stabilized. Suitable examples include mineral oil, Quillaja extract, triethyl citrate, sodium lauryl ether sulfate, sodium lauryl sulfate, and ammonium lauryl sulfate.

[0149] Alternatively, some liquid oral dosage forms may appear slightly foamy when prepared. While this does not prevent the desired use, it may affect patient compliance in the case of pharmaceuticals or commercial success in the case of dietary supplements. Therefore, it may be desirable to add a pharmaceutically acceptable anti-foaming agent (anti-foaming agent). Examples are polydimethylsiloxane or silicone oil in dietary supplements, or simethicone in pharmaceuticals.

[0150] Suitable fats are, for example, decyl oleate, hydrated castor oil, light mineral oil, mineral oil, polyethylene glycol, sodium lauryl sulfate.

[0151] Consistency improvers are, for example, cetyl alcohol, cetyl ester wax, hydrated castor oil, microcrystalline wax, nonionic emulsifier wax, beeswax, paraffin or stearyl alcohol.

[0152] Suitable hydrotropes are alcohols such as ethanol, isopropyl alcohol, or polyols such as glycerin.

[0153] Sorbents are materials that absorb oil from water. Suitable examples include natural sorbents such as peat moss, sawdust, feathers, and any natural sorbents containing carbon and synthetic sorbents such as polyethylene and nylon. Sorbents are used to protect tablets / capsules from moisture by limited fluid adsorption (the uptake of liquids or gases by adsorption or sorption) in a dry state.

[0154] Opacifiers are substances that, if necessary, make drinkable liquids opaque. They must have a refractive index substantially different from that of the solvent, in most cases water, herein. At the same time, they must be inert to the other components of the composition. Suitable examples include titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof.

[0155] In another aspect of the present invention, the present application relates to a pharmaceutical composition comprising a 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts according to the present disclosure and at least one glucocorticoid, for use in a formulation for oral administration in the prevention or treatment of diseases that are typically treated with glucocorticoids.

[0156] These pharmaceutical preparations suitable for oral dosage form may be administered as discrete units such as tablets, soft gelatin capsules, hard gelatin capsules, dragees or pills; as powders or granules; as juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids; as edible foams or mousses; or as oil-in-water or water-in-oil emulsions.

[0157] Thus, in oral dosage forms such as tablets or capsules, the active agent can be combined with a non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, or water.

[0158] Powders are prepared by comminuting the compound to a suitable small size and mixing them in a similar manner with a pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. A flavoring, preservative, dispersing agent, or coloring agent can also be present.

[0159] Tablets are formulated by preparing a powder mixture, granulating or dry-pressing it, adding a lubricant and disintegrant, and pressing the mixture into tablets. The powder mixture is prepared by mixing the appropriately comminuted compound with a diluent or base as described above, and, if applicable, with a binder such as carboxymethylcellulose, alginate, gelatin, or polyvinylpyrrolidone, a solution retarder such as paraffin, an absorption accelerator such as a quaternary salt, and / or an absorbent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, acacia mucilage, or a solution of cellulose or polymeric materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be passed through a tablet press, resulting in unevenly shaped lumps that are broken down to form granules. The granules can be lubricated with the addition of stearic acid, stearic phosphate, talc, or mineral oil to prevent adhesion to the tablet die. The lubricated mixture is then pressed to form tablets. The compounds according to the invention can also be combined with a flowable inert excipient and then pressed directly to give tablets without carrying out the granulation or dry-pressing steps.

[0160] In another aspect of the present invention, pharmaceutical compositions containing 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid are provided in hard gelatin capsules. They are produced by preparing a powder mixture as described above and filling a formed gelatin capsule with it. Glazing agents and lubricants such as highly dispersed silica, talcum, magnesium stearate, calcium stearate, or polyethylene glycol can be added as solids to the powder mixture. Disintegrants or solubilizers such as agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the drug after ingestion of the capsule. Furthermore, suitable binders and / or coloring agents can be added to the mixture as desired or necessary.

[0161] In another aspect of the present invention, a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid is contained in a soft gelatin capsule (SGC). SGCs dissolve as they pass through the digestive tract. They consist primarily of gelatin thickened with varying amounts of plasticizers, such as glycerol or sorbitan. The release rate depends on the specific formulation of the SGC carrier material. They are also suitable for sustained release of active agents. SGCs are particularly useful for administering poorly water-soluble active agents.

[0162] In another aspect of the invention, a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid is contained in a chewable tablet or hard caramel, wherein the substances are incorporated into the matrix of the tablet or caramel.

[0163] In another aspect of the invention, the present application relates to a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid for use in the prevention or treatment of diseases that are normally treated with glucocorticoids in a formulation for inhaled administration.

[0164] For effective prophylactic or therapeutic treatment of pulmonary diseases typically treated with glucocorticoids, it is advantageous for a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid to reach the patient's alveoli. Therefore, the particle size must be small enough to reach the lowest part of the airways of the lung tissue. The best class of inhalation devices for inhalation administration of pharmaceutically active agents are so-called mesh nebulizers. Within the scope of this application, virtually all mesh nebulizers known in the art can be used, from rather simple disposable mesh nebulizers for cough and cold or specialty purposes to sophisticated high-end mesh nebulizers for clinical or home treatment of serious diseases or conditions of the lower respiratory tract.

[0165] Suitable are all commercially available mesh nebulizers, jet nebulizers, ultrasonic nebulizers, dry powder inhalers and (pressurized) metered dose inhalers.

[0166] Mesh nebulizers with piezoelectric activation of the nebulization process, respectively vibrating mesh nebulizers, are preferred.

[0167] Thus, in another aspect of the present invention, the present application relates to a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid for use in the prevention or treatment of pulmonary diseases that are normally treated with glucocorticoids in a formulation for inhalation administration, wherein the inhalation administration is by means of a vibrating mesh nebulizer.

[0168] Mesh nebulizers can be divided into two groups based on their interaction with the patient: continuous-mode devices and trigger-activated devices. Continuous-mode mesh nebulizers continuously release nebulized aerosol into the mouthpiece, requiring the patient to inhale the aerosol. Trigger-activated devices release a defined amount of aerosol only during active, deep inspiration. Thus, a much larger volume of active-agent-containing aerosol is inhaled and reaches the lowest airways than continuous-mode devices. The latter lose a larger volume of active-agent-containing aerosol to either the periphery or the upper airway because the aerosol release is not coupled to the respiratory cycle.

[0169] Therefore, trigger-activated mesh nebulizers, and particularly vibrating mesh nebulizers, are preferred.

[0170] Particularly preferred are trigger-activated mesh nebulizers with piezoelectric activation of the nebulization process.

[0171] Mesh nebulizer models PARI eFlow® rapid, Philips Respironics I-neb, Philips InnoSpire Go, M-neb® dose + Mesh nebulizer inhalation MN-300 / 8, Hcmed Deepro HCM-86C and HCM860, OMRON MicroAir U100, Aerogen® Solo, KTMED NePlus NE-SM1, Vectura Fox, Vectura Bayer Breelib™ are preferred.

[0172] The most preferred vibrating mesh nebulizer models are the PARI eFlow® rapid, PARI Velox, Philips Respironics I-neb, and M-neb® dose. +High-end models include mesh nebulizer inhalation MN-300 / 8, Aerogen® Solo, Vectura Fox, and Vectura Bayer Breelib.

[0173] Yet another aspect of the present invention is a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid for use in the prevention or treatment of pulmonary diseases typically treated with glucocorticoids. The pharmaceutical composition is provided in the form of assisted ventilation, as an additive to the ventilation air of a cardiopulmonary bypass machine. As the condition of patients in intensive care units deteriorates, they often need to be ventilated indefinitely in such machines until their own breathing provides sufficient oxygen. Good results have been achieved using aerosols from a metered-dose inhaler combined with a Y-piece inhalation chamber. Alternatively, constant-output mesh or vibrating mesh nebulizers, ultrasonic nebulizers, or jet nebulizers may be used. The advantages and disadvantages of different types are known to those skilled in the art and are described in the scientific literature.

[0174] In these cases, a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid can be added to the intubation ventilation air in solid form (dry powder) or in liquid form (in an aqueous solution or as a nebulized aerosol, as described above).

[0175] In yet another aspect of the present invention, the present application relates to a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid for use in the prevention or treatment of diseases that are usually treated with glucocorticoids in a sublingual tablet formulation.

[0176] Sublingual dosage forms can be an alternative to oral drug delivery because they bypass hepatic metabolism.Fast onset of pharmacological effects is often desired for some drugs, especially those used to treat acute disorders.Sublingual tablets disintegrate quickly, and the small amount of saliva present is usually sufficient to achieve disintegration of the dosage form, which results in better dissolution and increased bioavailability.

[0177] Drugs must be sufficiently lipophilic to be able to partition through the lipid bilayer, but not so lipophilic that they redistribute once inside. According to the diffusion model of absorption, the flux across the lipid bilayer is directly proportional to the concentration gradient. Therefore, lower salivary solubility results in a lower absorption rate, and vice versa. In general, drugs formulated for sublingual use should ideally have a molecular weight below 500 to facilitate their diffusion. The oral cavity has a narrow pH range of 5.0 to 7.0. The inclusion of an appropriate buffer in the formulation of ionizable drugs allows for control of the pH of aqueous saliva.

[0178] Drug taste masking is necessary to avoid the possibility of unpleasant taste or odor. Sweeteners, flavoring agents, and other flavoring agents are essential ingredients. Sugar-based excipients dissolve rapidly in saliva, resulting in a dissolution endotherm. They create a pleasant sensation in the mouth and are best suited for sublingual tablets along with other flavors.

[0179] Typical techniques for manufacturing sublingual tablets include direct compression, compression molding, freeze-drying, and hot-melt extrusion (Khan et al. (2017) J Pharmaceut Res 16:257-267).

[0180] In yet another aspect of the present invention, the present application relates to a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid for use in the prevention or treatment of diseases that are normally treated with glucocorticoids in a liquid dosage form.

[0181] The present application also discloses the parenteral administration of pharmaceutical compositions comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid in the prevention or treatment of diseases that are normally treated with glucocorticoids in the form of intravenous, intraarterial or intraperitoneal injections.

[0182] These liquid dosage forms include solutions, suspensions, and emulsions. Examples are water and water / propylene glycol solutions for parenteral injection or addition of sweeteners or opacifiers for oral solutions, suspensions and emulsions.

[0183] These liquid dosage forms can be stored in vials, IV bags, ampoules, cartridges, and pre-filled syringes. Suitable excipients include solubilizers, stabilizers, buffers, tonicity adjusters, bulking agents, viscosity / reducing agents, surfactants, chelating agents, and adjuvants.

[0184] In yet another aspect of the present invention, a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid for use in the prevention or treatment of diseases typically treated with glucocorticoids is formulated as a lyophilizate, which can be reconstituted with water for injection, saline, or a water / ethanol solution, and then administered by injection. Typical applications for intravenous injection include infusion pumps, hypodermic needles, drip chambers, peripheral cannulas (peripheral intravenous catheters), and pressure bags.

[0185] Generally, aqueous or saline solutions are preferred. In the case of poorly soluble pharmaceuticals according to the invention, ethanol or ethanol / water mixtures can also be used.

[0186] Further suitable liquid dosage forms include drops, eye drops, and ear drops.

[0187] Common formulation types used in nasal spray products are solutions, suspensions, and emulsions. Nasal spray formulations can be aqueous, hydroalcoholic, or non-aqueous-based. Depending on the type of system, the formulation contains a range of functional excipients, including solvents and cosolvents; mucoadhesives; pH buffers; antioxidants; preservatives; osmolality and tonicity agents; penetration enhancers; suspending agents; and surfactants. The choice of formulation type and the excipients selected are determined by the solubility and stability of the pharmaceutical composition containing 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid, as well as the concentration required to deliver an effective dose in a typical 100 μl spray (see Kulkarni and Shaw (2016) in: Essential Chemistry for Formulators of Semisolid and Liquid Dosages, Elsevier). The aforementioned Carragelose® technology is also used in nasal sprays.

[0188] Nasal drops are administered in a similar formulation, but are dispensed by drops instead of by pressing a dispenser.

[0189] The present application also relates to a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid, the administration of which is by eye drops.

[0190] Eye drops are primarily aqueous solutions containing pharmaceutical active agents. The pH is usually adjusted to 7.1–7.5. Common buffers for eye drops are boric acid and monobasic sodium phosphate. Tonicity should be adjusted to an osmotic pressure (225–430 mosm / kg) isotonic with 0.9% saline (or another tonicity agent, such as potassium nitrate, boric acid, sodium acetate, sodium acetate phosphate buffer, or mannitol) to be isotonic with the corneal epithelium. Suitable preservatives include thiomersal, organic mercury compounds such as phenylmercury, benzalkonium chloride, chlorhexidine, and benzyl alcohol. To extend contact time, contact-time-increasing thickening agents (thickeners) such as cellulose derivatives (hypromellose, methylcellulose, hydroxypropylmethylcellulose), hyaluronic acid, cellulose acetate phthalate, polyethylene glycol, polyvinyl alcohol, or poloxamer can be added. Wetting agents or surfactants such as benzalkonium chloride, polysorbate 20, polysorbate 80, dioctyl sodium sulfosuccinate, etc. may be included. Several amino acids, alone or in combination with sodium hyaluronate, may help promote tissue remodeling as needed. Suitable amino acids are glycine, leucine, lysine, and proline.

[0191] In yet another embodiment of the present invention, a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid according to the present disclosure is provided in a topical application form such as a cream, emulsion, lotion, gel, hydrogel, paste, powder, ointment, paint, film, liposome, skin patch, transdermal patch, transdermal spray or suspension.

[0192] Specifically, for preparing a low-melting suppository wax, a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is then uniformly dispersed therein by stirring or other mixing methods. The molten homogeneous mixture is then transferred to suitable molds and allowed to cool until solidified.

[0193] All of the aforementioned substances and classes of substances can be used as excipients according to the present invention, either alone or in any conceivable combination thereof.

[0194] The present application also relates to compositions for use in the prevention and / or treatment of conditions or diseases that are typically treated with glucocorticoids, the compositions comprising at least one of 5-amino-2,3-dihydro-1,4-phthalazinedione or any of the aforementioned molecular variants of this compound, at least one excipient, and at least one additional non-steroidal active agent. Such pharmaceutical compositions optionally further comprise at least one glucocorticoid.

[0195] The at least one further active agent may be selected from the group comprising nonsteroidal anti-inflammatory drugs; immunomodulators; immunostimulants; immunosuppressants; antibiotics; anti-infectives; antivirals; antifungals; antiprotozoal agents; anthelmintics; analgesics; local anesthetics; anticoagulants; antiplatelet agents; muscle relaxants; bronchodilators; pulmonary vasodilators; mucolytics; pulmonary surfactants; antioxidants; ENaC activators; HMG-CoA reductase inhibitors; AT1 receptor antagonists; tonics; and anabolic agents.

[0196] Suitable examples of such nonsteroidal anti-inflammatory drugs (NSAIDs) include acetylsalicylic acid, salicylic acid and salicylates, acetaminophen (paracetamol), salsalate, diflunisal, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, benzodiazepine, benzocaine ... Includes phenac, aceclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolamic acid, celexoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, flocoxib, nimesulide, clonixin, licofelone, H-harpagide, flunixin, and tiaprofenic acid.

[0197] Suitable examples of such immunomodulatory drugs (IMIDs) include thalidomide, lenalidomide, pomalidomide and apremilast. Suitable examples of such antiviral agents include ancriviroc, aplaviroc, cenicriviroc, enfuvirtide, maraviroc, vicriviroc, amantadine, rimantadine, pleconaril, idoxuridine, acyclovir, brivudine, famciclovir, penciclovir, sorivudine, valacyclovir, cidofovir, ganciclovir, valganciclovir, sofosbusvir, foscarnet, ribavirin, talivirin, and fibrin. These include buvir, nesbuvir, tegobuvir, fosdevirine, favipiravir, merimeposib, asunaprevir, valapiravir, boceprivir, cilprevir, danoprevir, daclatasvir, naraprevir, telaprevir, simeprevir, vanipevir, rupintrivir, fomivirsen, amenamevir, alisporivir, bevirimate, letermovir, laninamavir, oseltamivir, peramivir, zanamivir, and remdesivir.

[0198] Suitable examples of such immunostimulants include interferon (α-, β-, γ-, and τ-interferon), interleukin, CSF, PDGF, EGF, IGF, THF, levamisole, dimepranol, and inosine.

[0199] Suitable examples of such immunosuppressants include cytostatics such as alkylating agents (such as cyclophosphamide), antimetabolites such as methotrexate, azathioprine, mercaptopurine, fluorouracil, leflunomide, protein synthesis inhibitors and certain antibiotics such as dactinomycin, anthracyclines, mitomycin C, bleomycin and mithramycin, intercalating agents such as mitoxantrone; muromonab-CD3, rituximab, ustekinumab, allergy Antibodies such as mutuzumab, natalizumab, basiliximab and daclizumab; drugs acting on immunophilins such as cyclosporine, tacrolimus and sirolimus, and non-classified immunosuppressants such as beta-interferon and gamma-interferon, opioids, TNF-binding proteins such as infliximab, etanercept and adalimumab; or curcumin, catechin, mycophenolic acid, fingolimod, myriocin and fumaric acid dimethyl ester.

[0200] Suitable examples of such 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, fosfomycin, teicoplanin, vancomycin, bacitracin, colistin, gramicidin, polymyxin B, tyrothricin, teixobactin, fosmidomycin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, chloramphenicol, fusidic acid, benzodiazepines ... These include benzodiazepines, cethromycin, narbomycin, telithromycin, clindamycin, lincomycin, daptomycin, dalfopristin, quinupristin, azithromycin, clarithromycin, erythromycin, roxithromycin, linezolid, doxycycline, minocycline, tetracycline, oxytetracycline, tigecycline, norfloxacin, enoxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, metronidazole, tinidazole, aminocoumarin, sulfadiazine, sulfadoxine, sulfamethoxazole, sulfasalazine, pyrimethamine, trimethoprim, and rifampin.

[0201] Anti-infectives is a general term for compounds useful in the treatment of bacterial, viral, fungal, protozoal and parasitic infections, and includes antibiotics, antivirals, antifungals and antiparasitic agents.

[0202] Suitable examples of such muscle relaxants include tercuronium, 1-ethylcarbamoyl-3-(3-trifluoromethylphenyl)pyrrolidine, metaxalone, methocarbamol, meprobamate, baclofen, carisoprodol, chlorzoxanzone, cyclobenzaprine, dantrolene, diazepam, orphenadrine, quinine, rocuronium, succinylcholine, decamethonium, pancuronium, beruronium, lapacuronium, dacuronium, duadol, marouetin, dipyranthium, pipercuronium, chandonium, HS-342, atracurium, mivacurium, doxacurium, d-tubocurarine, dimethyltubocurarine, gallamine, alcuronium, anatruxonium, diadonium, diazonium, fazadinium, tropeinium, and cisacurium.

[0203] Suitable examples of such antifungal agents are abafungin, amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clomitrazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxy Conazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, amorolfine, butenafine, naftifine, terbinafine, anidulafungin, caspafungin, micafungin, benzoic acid, ciclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, crystal violet, balsam of Peru

[0204] Suitable examples of such antiprotozoal agents include metronidazole, tinidazole, ornidazole, atovaquone, clioquinol, chlorquinaldol, emetine, pentamidine isethionate, eflornithine, nitrofural, halofuginone, miltefosine, chloroquine, hydroxychloroquine, mepacrine, primaquine, amodiaquine, pamaquine, piperaquine, proguanil, cyclohexanone, quinine, mefloquine, pyrimethamine, artemether, artemisinin, artesunate, dihydroartemisinin, halofantrine, lumantrine, and sulfadoxine.

[0205] Suitable examples of such anthelmintics include mebendazole, praziquantel, albendazole, diethylcarbamazine, flubendazole, ivermectin, levamisole, metrifonate, niclosamide, oxyclozanide, oxamniquine, oxantel, piperazine, pyrantel, pyrantel pamoate, monopantel, delquantel, pelletierin sulfate, pyrvinium, thiabendazole, fenbendazole, triclabendazole, abamectin, suramin, emodepside, pyrvinium embonate, aminoacetonitrile.

[0206] Suitable examples of further antiparasitic agents include meglumine antimoniate, benznidazole, sodium stibogluconate, fumagillin, halofantrine, melarsoprol, nifurtimox, nitazoxanide, permethrin, lindane, malathion, carbaryl, pyrethrim, fenothrin, bioallethrin, imidacloprid, moxidectin, nitenpyram, fipronil, pyriprol, selamectin, dimpyrate, spinosad, indoxacarb, methoprene, pyriproxyfen, lufenuron, neem oil, citronella oil, clove oil, peppermint oil, eucalyptus oil.

[0207] Suitable examples of such local anesthetics include lidocaine, lignocaine, menthol, articaine, bupivacaine, ropivacaine, benzocaine, chloroprocaine, cocaine, cyclomethicane, dimethocane, larocaine, piperocaine, propoxycaine, procaine, novocaine, proparacaine, tetracaine, amethocaine, cinchocaine, dibucaine, etidocaine, levobupivacaine, mepravacaine, prilocaine, trimecaine, saxitoxin, neosaxitoxin, tetrodotoxin, and eugenol.

[0208] Suitable examples of analgesics include opioid analgesics such as the above-mentioned NSAIDs, morphine, fentanyl, methadone, oxycodone, carfentanil, dihydroetorphine, omefentanil, etorphine, sufentanil, remifentanil, alfentanil, buprenorphine, hydromorphone, levomethadone, hydrocodone, piritramide, nalbuphine, tapentadol, pentazocine, dihydrocodeine, codeine, pethidine, tramadol, tilidine, meptazinol, naloxone, naltrexone, diprenorphine, loperamide, apomorphine, etc.; epibatidine; scopolamine; ziconit; cannabinoids such as tetrahydrocannabinol, cannabidiol, Marinol, etc.; flupirtine; ketamine, and the ketamine and local anesthetics listed above.

[0209] Suitable examples of such anticoagulants include heparin, coumarins such as phenprocoumon (marcumar) and warfarin, apixaban, rivaroxaban, edoxaban, dabigatran, betrixaban, ximelagatran, hirudin, lepirudin, bivalirudin, citrate, EDTA, fondaparinux, idraparinux, idrabiotaparinux, argatroban, otamixaban.

[0210] Suitable examples of such antiplatelet agents include abciximab, acetylsalicylic acid, dipyridamole, clopidogrel, eptifibatide, ilomedin, prostacyclin, prasugrel, ticagrelor, ticlopidine, tirofiban.

[0211] Suitable bronchodilators, such as beta-2 adrenergic receptor agonists, include short-acting beta-2 agonists (SABAs), such as salbutamol, albuterol, bitolterol, fenoterol, isoprenaline, levosalbutamol, levalbuterol, orciprenaline, pirbuterol, procaterol, ritodrine, and terbutaline; long-acting beta-2 agonists (LABAs), such as arformoterol, bambuterol, clenbuterol, formoterol, and salmeterol; ultra-long-acting beta-2 agonists (alone or in combination with umeclidinium bromide and / or fluticasone furoate), such as abesiterol, carmoterol, indacaterol, olodaterol, and vilanterol; and beta-2 agonists of unknown duration of action, such as isoxsuprine, mabuterol, or zilpaterol.

[0212] Suitable muscarinic anticholinergics (bronchodilatory M3 receptor antagonists) include ipratropium bromide, tiotropium bromide, oxitropium bromide, glycopyrronium bromide, aclidinium bromide, umeclidinium bromide, atropine, hyoscyamine, aclidinium bromide, 4-DAMP, darifenacin, DAU-5884, HL-031, HL-120, J-104, J-129, procyclidine, oxybutynin, tolterodine, and zamifenacin.

[0213] Further bronchodilators include epinephrine, ephedrine, theophylline and TSG12.

[0214] A potent pulmonary vasodilator is nitric oxide. Further suitable pulmonary vasodilators are prostacyclin (prostaglandin PGI2) analogues, such as iloprost, epoprostenol and treprostinil.

[0215] Suitable mucolytic agents include N-acetylcysteine ​​(NAC), ambroxol, bromhexine, carbocysteine, erdocysteine, mecysteine ​​and dornase alfa.

[0216] Suitable pulmonary surfactants include synthetic compositions such as colfosceril palmitate, Pumactant, KL-4, Venticute, and Lucinactant, as well as animal-derived surfactants such as Beractant, Calfactant, and Poractant alfa.

[0217] A powerful antioxidant is inhaled carbon monoxide (CO).

[0218] Suitable ENaC (epithelial sodium channel) activating peptides include AP301 and S3969.

[0219] Suitable HMG-CoA reductase inhibitors (statins) include atorvastatin, alone or in combination with amlodipine and / or perindopril, cerivastatin, fluvastatin, lovastatin, alone or in combination with niacin, mevastatin, pitavastatin, pravastatin, rosuvastatin, alone or in combination with ezetimibe, simvastatin, alone or in combination with ezetimibe or niacin.

[0220] Suitable AT1 antagonists (angiotensin II receptor blockers; sartans) include losartan, valsartan, candesartan, telmisartan, irbesatan, olmesartan, eprosartan, fimasartan, azilsartan, mirfasartan, pomisartan, pratosartan, lipisartan, tasosartan, saprosartan and EXP3174.

[0221] Tonics are a general term that refers to substances that invigorate, regulate, or restore the body and its physiological functions. They can be of herbal or animal origin.

[0222] Anabolic drugs can be useful for anabolism and strengthening of cellular collagen scaffolds. However, there has been widespread abuse of these substances for doping and body shaping in sports. Therefore, their use in combination is only encouraged if the national legal prohibition of these anabolic compounds is not violated.

[0223] Modes of application of the compositions according to the present invention as outlined above include, but are not limited to, oral, parenteral, intravenous, intraarterial, inhalation, intubation, intramuscular, topical, transdermal, subcutaneous, intradermal, transmucosal, sublingual, buccal, conjunctival, intravaginal, rectal or nasal administration.

[0224] Depending on the target tissue, systemic application may not always produce the desired results. In these cases, an alternative local route of administration may be desirable to avoid administering increased doses.

[0225] It has been found that direct injection of active agents into affected tissue, surrounding tissues or body fluids can result in improved results in terms of drug efficacy, safety and / or pharmacokinetics.

[0226] The present application therefore also refers to the use of a composition according to the invention, wherein parenteral application is carried out by injection of said composition into the affected tissue, the surrounding tissue or the surrounding body fluids.

[0227] Suitable examples include, but are not limited to, intraperitoneal, intraosseous, periosseous, intra-articular, peri-articular, epidural, peridural, intrathecal, intravitreal, intravesical, and intrapericardial injection.

[0228] If the affected tissue is part of the skin or is located near the surface of the skin, it may be preferable to use a topical application to the skin for the same reasons as above.

[0229] The present application therefore also relates to the use of a composition according to the invention, wherein the topical application is carried out by means of a cream, emulsion, lotion, gel, hydrogel, paste, powder, ointment, paint, film, liposome, skin patch, transdermal patch, transdermal spray or suspension.

[0230] Improved results in such topical applications with respect to efficacy, safety and / or pharmacokinetics may be achieved if a permeation enhancer is included in the topical dosage form. Suitable permeation enhancers are listed above. [Example]

[0231] Effects of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and dexamethasone on LPS-stimulated RAW264.7 cells: To test whether the combination of dexamethasone and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt exhibits synergistic effects and / or allows for a booster effect, the following experiment was performed using 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt corresponding to Form I as defined above in the Description. Raw264.7 cells (a leukemia-transformed monocyte-macrophage cell line derived from mouse ascites) were grown in Dulbecco's modified Eagle's medium enriched with glutamine and fetal bovine serum and maintained at 37°C and 5% CO2.

[0232] RAW264.7 cells were preincubated with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (dose range: 0.025 mM to 1 mM) and the following concentrations of dexamethasone (1, 0.1, and 0.01 μM, and serial two-fold dilutions ranging from 0.01 to 0.0003 μM at subthreshold concentrations) 1 hour before lipopolysaccharide (LPS) stimulation (100 ng / ml). After 24 hours, interleukin-6 (IL-6) levels in the supernatants were determined by ELISA and compared with those from cells treated with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt or dexamethasone alone.

[0233] Two experimental parts were performed. In Part 1 of the experiment, dexamethasone was used at three 10-fold scalar concentrations (1, 0.1, and 0.01 μM) and incubated with 2-fold scalar concentrations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (ranging from 1 to 0.025 mM). A complete summary of the percent reduction in IL-6 production for these combinations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and dexamethasone is shown in Table 1. Part 2 of the experiment was performed to further demonstrate the effect of the combination of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and dexamethasone on IL-6 levels when suboptimal doses of dexamethasone were used. Therefore, in experimental part 2, six serial two-fold dilutions of dexamethasone, starting at 0.01 μM as the highest concentration, were administered along with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt. A complete summary of the percent reduction in IL-6 production for these additional combinations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and dexamethasone is also shown in Table 1. [Table 1]

[0234] A-Synergy The general synergistic effect of the combination of dexamethasone and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt could be demonstrated in both experimental parts described above, both for 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt added to dexamethasone (see Table 2) and vice versa (not shown). [Table 2]

[0235] In Experimental Part 1, all combinations tested showed synergistic effects in this regard. This effect was more pronounced in combinations in which 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was added to low-dose dexamethasone. In Experimental Part 2, in which 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was added to suboptimal doses of dexamethasone, all other combinations tested, except for the four low-dose / low-dose combinations, also showed synergistic effects in this regard. The effect was highly pronounced in most combinations. The best synergistic effect was obtained when any concentration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was added to 0.0012 μM dexamethasone. When 0.05 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was added to 0.0012 μM dexamethasone, the efficacy of the combination was more than five times higher than predicted by pure additivity. These results confirmed the synergistic effect between 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and dexamethasone on IL-6 production from Raw264.7 cells. The synergistic effect observed works in both directions: dexamethasone can synergistically improve the effect of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt can synergistically improve the effect of dexamethasone.

[0236] B-Superadditive Synergy A cumulative effect greater than that predicted by the combination of two individual effects is considered a supra-additive effect. Based on simple arithmetic summation in Experimental Part 1, such a supra-additive effect on IL-6 levels was observed for the combination of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and dexamethasone at the lowest concentrations used. Indeed, 0.025 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and 0.01 μM dexamethasone inhibited IL-6 production by 17% and 34.7%, respectively, when administered as single drugs, whereas the combined effect reached a 59.4% inhibitory effect. Similarly, 0.05 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt inhibited IL-6 production by 25.8%, and the combined effect with 0.01 μM dexamethasone reached a 65.3% inhibitory effect (Table 1). In Experiment Part 2, which used subthreshold doses of dexamethasone, the majority of combinations showed such supra-additive effects. In Table 1, values ​​that demonstrate supra-additivity by this method are marked with an asterisk. Because inhibition greater than 100% is not possible, combinations with predicted sums greater than 100, which applies to most of the results gathered from Experiment Part 1, are not applicable to this method.

[0237] To allow interpretation of all combinations investigated, including those that theoretically sum to more than 100%, the decimal product method was also applied to these data. Table 3 shows the difference between the predicted and measured inhibition of IL-6 production for each combination of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and dexamethasone after this method.

[0238] Nearly all combinations in both Experimental Part 1 and Experimental Part 2 could be shown to be superadditive, including many uninterpretable combinations by arithmetic summation. [Table 3]

[0239] Furthermore, a combination index (CI) was calculated for all combinations received in Experiments 1 and 2 (combinations with non-constant ratios) using the specialized software CompuSyn.

[0240] In Experimental Part 1, the CI values ​​were less than 1 for all combinations investigated (Figure 1). Therefore, according to this parameter, all combinations tested in Experimental Part 1 must be considered supraadditive. In Experimental Part 2, the CI values ​​were again less than 1 for most combinations investigated, with only three exceptions: 0.0003 μg DEX / 0.025 mg 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, 0.0006 μg DEX / 0.025 mg 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, and 0.0006 μg DEX / 0.05 mg 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (Figure 2).

[0241] The results from both experimental parts allowed the calculation of CIs for various fixed ratio combinations of dexamethasone and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (4:1, 2:1, 1:1, 1:2, 5, 1:5, and 1:10 in experimental part 1, and 1:5, 1:10, 1:20, 1:40, 1:50, 1:100, 1:200, 1:400, 1:800, and 1:1600 in experimental part 2). Such fixed ratio approaches are based on different doses / concentrations of the active ingredients, but the ratio between the active ingredients remains fixed. Based on the received data, CIs are calculated along the increasing fractional effect. Calculation of a single part of the curve may result in a CI higher than 1, but in most cases, still gives clear superadditivity. In other words, the FaCI plots for all fixed ratio combinations in both experimental parts were either entirely, or at least a much larger portion of, in the superadditive region of the plot. Some of these fixed ratio curves from Experiment 2 are illustratively shown in Figure 3. [Example]

[0242] Weight loss in mice treated with dexamethasone It is a well-known phenomenon that laboratory animals, particularly mice and rats, experience slower weight gain or even weight loss when administered glucocorticoids, an effect that is induced and occurs independently of other conditions investigated in each trial.

[0243] In a pilot study of collagen-induced arthritis (CIA) of rheumatoid arthritis in mice, Applicant found that both the arithmetic mean and median body weight at the end of the study (day 45) were higher in the group administered a combination of dexamethasone and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt compared to the group administered dexamethasone alone (see Table 4).

[0244] Thus, there is a clear trend indicating that the additional application of 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt to a given amount of dexamethasone helps to prevent glucocorticoid-induced side effects. In this test, arthritis was induced by subcutaneous injection of 100 μg of chicken collagen type UU in Freund's adjuvant on day 0, followed by a respective boost of 50 μg on day 21. The test item (dexamethasone, 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt) was administered intraperitoneally daily after disease onset when an individual disease score higher than 2 was reached. Scoring was performed using a macroscopic assessment of the limbs ranging from 0 to 15, where 1 point was given for swollen or red toes, 1 point for swollen or red metatarsal toes or knuckles, and 5 points for swollen ankles, resulting in a maximum total score of 60 for each mouse. [Table 4] [Example]

[0245] Case report of rheumatoid arthritis A 53-year-old man was diagnosed with rheumatoid arthritis several months after experiencing his first symptoms. Because of the known NSAID (nonsteroidal anti-inflammatory drug), hypersensitivity treatment was initiated immediately with prednisone. Therefore, the patient was administered 10 mg of prednisone retard tablets once daily before bedtime. Both pain and inflammation improved within the next few months but did not completely disappear, and weight gain began. After 8 months of glucocorticoid treatment, 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was added to his ongoing treatment, beginning with 50 mg orally twice daily. Ten days after initiating combination therapy, the patient felt much better, pain nearly disappeared, and inflammation dramatically improved. After 4 to 12 weeks of combination therapy, the prednisone dose was gradually reduced to 5, 2, and 1 mg per day, respectively. The dose of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was gradually increased from 100 mg per day to 150 and 200 mg per day, to a maintenance dose of 250 mg per day, which was found to be a suitable dose for long-term treatment. [Example]

[0246] Dosing Scheme for Crohn's Disease Glucocorticoid treatment for patients experiencing acute Crohn's disease should begin with 60 mg of prednisolone per day, then gradually decrease to a maintenance dose of 5 mg to 10 mg per day within the next 8 to 12 weeks, followed by a fixed-ratio regimen for approximately 3 months.

[0247] Any feasible ratio would be applicable according to the results shown in Example 1. However, given that dexamethasone is approximately six times more potent than prednisolone, and that compliance places practical limitations on the amount of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt that can be administered orally to a patient for best results, the following fixed dose ratios are particularly useful:

[0248] Possible pairs of prednisolone and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for the initial daily dose are, for example, 60 mg / 400 mg, 40 mg / 800 mg and 20 mg / 1200 mg.

[0249] The respective maintenance doses are 4mg / 400mg, 2mg / 200mg and 1mg / 100mg.

[0250] DESCRIPTION OF THE DRAWINGS

[0251] Figure 1: FaCI Non-Constant Ratio Combinations - Example 1 - Experimental Part 1

[0252] The X-axis indicates the fractional effect (Fa), i.e., a value between 0 and 1 for the relative inhibition of IL-6 in LPS-stimulated RAW264.7 cells, with 1 meaning 100% inhibition and 0 meaning no inhibition. The Y-axis displays the combination index calculated via CompuSyn software, with a value of 1 indicating additivity, values ​​less than 1 indicating superadditivity, and values ​​greater than 1 indicating subadditivity or antagonism.

[0253] All dose combinations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and dexamethasone investigated are shown.

[0254] All CI values ​​were less than 1, thus indicating a supra-additive effect.

[0255] Figure 2: FaCI Non-Constant Ratio Combinations - Example 1 - Experimental Part 2

[0256] The X-axis indicates the fractional effect (Fa), i.e., a value between 0 and 1 for the relative inhibition of IL-6 in LPS-stimulated RAW264.7 cells, with 1 meaning 100% inhibition and 0 meaning no inhibition. The Y-axis displays the combination index calculated via CompuSyn software, with a value of 1 indicating additivity, values ​​less than 1 indicating superadditivity, and values ​​greater than 1 indicating subadditivity or antagonism.

[0257] All dose combinations of MP1032 and dexamethasone investigated are shown except for three values, for better graphical overview only values ​​with a CI of up to 2 are shown. All other CI values ​​are less than 1 and therefore indicate a supra-additive effect.

[0258] Figure 3: FaCI fixed ratio combinations - Example 1 - Experimental Part 2

[0259] The x-axis indicates the fractional effect (Fa), i.e., a value between 0 and 1 for the relative inhibition of IL-6 in LPS-stimulated RAW264.7 cells, with 1 meaning 100% inhibition and 0 meaning no inhibition. The y-axis displays the combination index calculated via CompuSyn software, with a value of 1 indicating additivity, values ​​less than 1 indicating superadditivity, and values ​​greater than 1 indicating subadditivity or antagonism. Calculated CI values ​​for the various fractional effects, including estimated standard deviations, are shown.

[0260] Calculations are shown for fixed dose combinations of dexamethasone and MP1032 as follows: A 1:10, B 1:40, C 1:100 and D 1:200.

Claims

1. A pharmaceutical for the combined administration of two drugs for the prevention or treatment of a condition or disease that can be prevented or treated by glucocorticoids, The pharmaceutical comprises 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and a glucocorticoid as active ingredients for administration of two drugs in combination.

2. The pharmaceutical according to claim 1, wherein the 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts functions as a glucocorticoid-sparing agent, thereby reducing the amount of glucocorticoid administered compared to when the glucocorticoid is administered alone.

3. The pharmaceutical composition according to claim 1, A medicine comprising 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt.

4. A pharmaceutical composition according to any one of claims 1 to 3, A pharmaceutical agent in which undesirable glucocorticoid effects are reduced or avoided.

5. The pharmaceutical composition according to claim 1, The glucocorticoid may be flumethasone, betamethasone, deflazacort, dexamethasone, beclomethasone, betamethasone valerate, betamethasone dipropionate, budesonide, beclomethasone dipropionate, isoflupredone, fluocinonide, fluocinolone, prednisone, prednisolone, methylprednisolone, halocinonide, desonide, triamcinolone, triamcinolone acetonide, tixocortol pivalate, mometasone, amcinonide, flucortolone, halometasone, alclometasone dipropionate, A pharmaceutical agent selected from the group comprising prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, cortisol, hydrocortisone, hydrocortisone acetate, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 17-aceponate, 17-hydrocortisone buteprate, cortisone and cortisone acetate.

6. The pharmaceutical composition according to claim 1, The condition or disease is selected from the group comprising autoimmune disorders, allergies, cancer, adverse reactions associated with cancer treatment, muscular dystrophies, severe infectious diseases, systemic inflammatory diseases and inflammatory diseases of the skin, respiratory system, gastrointestinal tract, genitourinary system, cardiovascular system, musculoskeletal system, nervous system and sensory organs, and further conditions such as cerebral edema, shock; sarcoidosis, hypercalcemia, adrenal insufficiency, adrenogenital syndrome and acute mountain sickness; and preventing transplant rejection.

7. The pharmaceutical composition according to claim 4, 10. The pharmaceutical composition of claim 1, wherein the undesirable glucocorticoid effect to be reduced or avoided is selected from the group consisting of muscle hypertonia, weight gain, obesity, truncal obesity, corticosteroid-induced lipodystrophy, edema, facial swelling, potassium wasting, muscle weakness, headache, facial hair growth in women, thinning of the skin, easy bruising, slow wound healing, glaucoma, cataracts, gastric and duodenal ulcers, acne, irregular menstrual cycles, steroid-induced diabetes, loss of control in existing diabetes, osteoporosis, adrenal joint necrosis, psychiatric disorders, psychotic behavior, growth retardation in children, convulsions, increased infection rate, worsening of opportunistic infections, reduced efficacy of antibiotics and vaccines, and Cushing's syndrome.

8. The pharmaceutical composition according to claim 1, A medicament wherein said glucocorticoid further exhibits mineralocorticoid efficacy.

9. The pharmaceutical composition according to claim 1, A medicament wherein 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is administered in the same pharmaceutical composition as said glucocorticoid.

10. The pharmaceutical composition according to claim 1, A medicament wherein the mode of administration of said medicament is selected from intravenous, oral, sublingual, rectal, topical and dermal administration.

11. The pharmaceutical composition according to claim 10, A pharmaceutical product, the dosage form of which is selected from: a tablet, a soft gelatin capsule, a hard gelatin capsule, a dragee or pill; a powder or granules; a juice, syrup, drops, tea, a solution or suspension in an aqueous or non-aqueous liquid; an edible foam or mousse; or an oil-in-water or water-in-oil emulsion.

12. The pharmaceutical composition according to claim 1, Inhaled medicine.

13. The pharmaceutical composition of claim 10, A medicament for topical application, wherein the dosage form is selected from a cream, emulsion, lotion, gel, hydrogel, paste, powder, ointment, liniment, film, liposome, skin patch, transdermal patch, transdermal spray or suspension.

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