Combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione

Abstract

The present invention relates to a pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutical acceptable salts. This pharmaceutical combination is used for the treatment of chronic inflammatory diseases, particularly COPD, asthma, Crohn's disease, ulcerative colitis and autoimmune hepatitis. The present invention particularly relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in this combination. Pharmaceutical compositions, advantageous formulation techniques and methods of treatment are disclosed.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutical acceptable salts. This pharmaceutical combination is used for the treatment of chronic inflammatory diseases, particularly COPD, asthma, Crohn's disease, ulcerative colitis and autoimmune hepatitis. The present invention particularly relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in this combination. Pharmaceutical compositions, advantageous formulation techniques and methods of treatment are disclosed. [Background technology]

[0002] Glucocorticoids are widely used to treat inflammatory diseases, including rheumatoid arthritis, osteoarthritis, gouty arthritis, ulcerative colitis, multiple sclerosis, asthma, severe psoriasis, some tumors, cerebral edema, chemotherapy-induced nausea and vomiting, prevention of transplant rejection, and other indications requiring rapid and significant anti-inflammatory and immunosuppressive effects.

[0003] Over the past 40 years, budesonide has become one of the most prescribed glucocorticoids in various medical fields. Available dosage forms include inhalers, nebulized solutions, tablets, nasal sprays, and rectal dosage forms. Inhaled dosage forms are used for the long-term management of asthma and chronic obstructive pulmonary disease (COPD). Extended-release tablets and rectal tablets are used to treat inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, and microscopic colitis. Nasal sprays are used to treat allergic rhinitis and nasal polyps. Budesonide has shown good results in inhaled treatment of COVID-19 patients. [Prior art documents] [Patent documents]

[0004] In general, budesonide has a positive effect on the course of many diseases and conditions related to the immune system. On the other hand, long-term administration of budesonide is accompanied by a number of severe side effects, many of which are specific to glucocorticoids. Adverse reactions to the drug with inhaled formulations include respiratory infections, cough, and headache. Common side effects with oral formulations include increased risk of infections, decreased bone strength, and cataracts. Long-term use of budesonide can cause adrenal insufficiency (www.drugs.com / monograph / budesonide-systemic-oral-inhalation.html, as of September 17, 2021).

[0005] Thus, there is a medical need to provide a budesonide-sparing medication, ie, one that serves to reduce the required dosage of budesonide without reducing the desired effects of budesonide.

[0006] An object of the present invention is also to provide a medicinal product which makes it possible to avoid and / or reduce the adverse side effects of budesonide.

[0007] The problem is solved by a pharmaceutical combination with 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts.

[0008] The pharmaceutical combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt has been shown to be particularly effective.

[0009] Budesonide is a synthetic glucocorticoid with weak mineralocorticoid activity. It is used medicinally for the local treatment of bronchial asthma, COPD (chronic obstructive pulmonary disease), nasal polyps, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, eosinophilic esophagitis, and chronic liver diseases such as autoimmune hepatitis. Recently, it has also been shown that inhaled administration of budesonide can reduce the number of severe COVID-19 cases compared to controls (Yu et al. (2021) Lancet 398:843-855).

[0010] Budesonide is a diastereomeric mixture of (22R)- and (22S)-11β,21-dihydroxy-16α,17α-(butylidenebis(oxy)pregna-1,4-diene-3,20-dione. Its IUPAC name is (1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-propyl-5,7-dioxapentacyclo[10.8.0.0]. 2.9 .0 4.8 .0 13.18 ]icosa-14,17-dien-16-one. The (22R) isomer is also known as dexbudesonide. Within the scope of this disclosure, the term budesonide is intended to cover the diastereomeric mixture as well as the single isomers.

[0011] Budesonide is currently available in the following formulations: nasal drops, nasal spray, bronchial inhalation spray, capsules, tablets, creams, intravenous solutions, and enemas, but systemic administration is limited by its strong first-pass effect.

[0012] Like all glucocorticoids, budesonide has immunosuppressive effects and may increase the risk of infection. Common side effects include headache, dizziness, runny nose, sneezing, cough, nausea, indigestion, abdominal pain, gas, vomiting, fatigue, back pain, aches, itching, skin rash, fever, swelling of the face and neck, difficulty breathing, severe headache, acne, and bruising (see MedlinePlus, as of September 29, 2021). With inhaled budesonide, fungal infections of the mouth (e.g., candidiasis) and hoarseness may occur.

[0013] A number of drug-drug interactions must be considered when using budesonide. The most common interactions reported are with low-concentration acetylsalicylic acid, metoprolol, fluticasone / salmeterol, alformoterol, budesonide / formoterol, albuterol, and albuterol / ipratropium (see www.drugs.com / drug-interactions / budesonide.html, as of September 17, 2021). A presumed interaction is with voriconazole.

[0014] 5-Amino-2,3-dihydro-1,4-phthalazinedione (luminol) belongs to the pharmaceutical class of phthalazinedione. This class of compounds is known for its beneficial anti-inflammatory properties. 5-Amino-2,3-dihydro-1,4-phthalazinedione is also known by the name luminol. Luminol has excellent chemiluminescent properties. It is widely used in diagnostic assays as a means of detection and in forensic science, such as tracing bloodstains. In medicine, 5-Amino-2,3-dihydro-1,4-phthalazinedione has been developed in the form of its sodium salt. In some countries, it has been approved as a treatment for a wide range of acute and chronic inflammatory diseases, including acute infections, especially of the intestinal tract, caused by bacteria and viruses, inflammations such as hepatitis B and C, gastroenteritis, prostatitis, endometriosis, pharyngitis, bronchial asthma, pneumonia, periodontitis, pyelonephritis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, autoimmune diseases such as scleroderma. Furthermore, there is still a large body of scientific and patent literature for indications in which 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt has been tested for treatment or has been suggested to have beneficial use (see, e.g., WO2004 / 041169, WO2007 / 018546, WO2012 / 127441, WO2017 / 202496, WO2018 / 082814).

[0015] While most conventional immunomodulatory drugs exhibit severe side effects or, at the very least, are problematic in long-term treatment, 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharma- ceutical acceptable salts are well tolerated and have a high safety margin with respect to dosage.

[0016] To increase solubility and bioavailability, pharma- ceutically acceptable salts of 5-amino-2,3-dihydro-1,4-phthalazinedione are used. Sodium, potassium and lithium salts have been described for therapeutic use (see WO2010 / 082858). The crystal structures of lithium, sodium, potassium, rubidium and cesium salts are described in Guzei et al., Journal of Coordination Chemistry (2013, 66:3722-3739). Thus, this patent application also refers to the use of any pharma- ceutically acceptable salt of 5-amino-2,3-dihydro-1,4-phthalazinedione.

[0017] In particular, the present application discloses 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of muscular dystrophy, wherein the pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1,4-phthalazinedione is 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt.

[0018] 5-amino-2,3-dihydro-1,4-phthalazinedione is often used as a hydrate, for example as the sodium salt dihydrate. This patent application therefore also refers to the use of all hydrates and other solvates of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharma-ceutically acceptable salts. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma-ceutically acceptable salts may form a complex with a suitable ligand. This patent application therefore also refers to such a complex. For the purposes of this disclosure, all hydrates and solvates are intended to be included in the term "5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma-ceutically acceptable salts."

[0019] To ensure reproducible and standardized API manufacturing and to improve the stability properties of the active agent, anhydrous formulations are often preferred. The anhydrous forms of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt have been described as crystalline polymorphs in WO2011 / 107295 (form I, form II) and WO2016 / 096143 (form III). These crystalline polymorphs are substantially free of phase impurities and have been characterized by X-ray powder diffraction. This method provides a set of characteristic d values ​​indicating the interplanar spacing [Angstroms] and the corresponding 2-theta (2θ) angles [°] at which the Bragg reflections occur. This provides a unique and unambiguous fingerprint of each polymorph.

[0020] 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 2 Theta values: 6.5, 12.7, 16.9, 19.3, 22.8, 25.8, 26.6, 27.2, 28.7, 30.3.

[0021] 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 2 Theta values: 6.8, 11.2, 12.5, 13.7, 16.7, 22.4, 24.3, 24.9, 27.2, 27.8.

[0022] For Form III the following values ​​were obtained: 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 2 Theta 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.

[0023] The use of the anhydrous form I of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is preferred. 5-Amino-2,3-dihydro-1,4-phthalazinedione itself exhibits polymorphism: Form I (Paradise (1992) Ber. Bunsen-Ges. Phys. Chem 96:1027-1031) and Form II (WO2017 / 140430) have been disclosed.

[0024] Thus, this patent application also refers to the use of any crystalline form and polymorphic form of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharma- ceutically acceptable salts according to the disclosure. The use of Form II of 5-amino-2,3-dihydro-1,4-phthalazinedione is preferred.

[0025] Similar therapeutic effects are known for various phthalazinediones, which are derivatives of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharma-ceutically acceptable salts. One example is 6-amino-2,3-dihydrophthalazine-1,4-dione (isoluminol). A summary of suitable phthalazinediones is given in WO2007 / 018546. It is reasonable to assume that these compounds will show comparable effects when used for therapeutic purposes according to the present disclosure.

[0026] Tautomerism refers to the rapid internal transformation of organic compounds in which a hydrogen atom or proton formally migrates within the compound. This involves the switching of a single bond and an adjacent double bond. The single bond forms are called tautomers. For example, keto-enol tautomerism occurs in 5-amino-2,3-dihydro-1,4-phthalazinedione (Proescher and Moody (1939) J Lab Clin Med, 1183-1189). Therefore, this patent application also refers to the use of all tautomers of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharma-ceutically acceptable salts.

[0027] The term "5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts" as used throughout this application is intended to encompass all the aforementioned molecular variants of 5-amino-2,3-dihydro-1,4-phthalazinedione, i.e., 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, or a solvate, hydrate, crystalline polymorph, or tautomer thereof.

[0028] Various combinations of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt significantly inhibited stimulated CD19 + They were tested in a cell culture model including B cells and PBMCs (peripheral blood mononuclear cells). This is an established in vitro model for testing the effect of pharmaceuticals in inflammation (Kunkel et al. (2004) Assay Drug Dev Technol 2:431-441; Berg et al. (2010) J Pharmacol Toxicol Methods 61:3-15; Melton et al. (2013) PloS ONE 8:e58966). Because immunocompetent cells are involved, it is assumed that the results of this model are predictive not only for in vitro, but also for all chronic inflammatory diseases. The cytokines tested were TNF-α and IL-6, which are the main inflammatory cytokines, and IL-2, which stimulates the proliferation and differentiation of B and T lymphocytes (see Arenas Ramirez et al. (2015) Trends Immunol 36:763-777). A reduction in the release levels is thought to correlate with the anti-inflammatory effect of the drug.

[0029] A wide range of different combinations of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt significantly reduced the release of soluble fractions of TNF-α, IL-6, and IL-2 (see Example 1). Computer-based evaluation suggested an additive effect of the combination of the present invention for all three cytokines (see Example 2). It is therefore reasonable to assume that: a) 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt can enhance the anti-inflammatory effect of budesonide; b) 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt allows the dosage of budesonide to be reduced without reducing its therapeutic effect, thus preventing or at least significantly reducing the side effects of long-term treatment with budesonide.

[0030] To avoid ambiguity in the art, the terms drug-drug interaction are defined as follows. They are used in this sense throughout the disclosure. When at least two substances (e.g., pharmaceuticals) are administered and at least one of these substances affects the activity of at least one other substance, a so-called drug-drug interaction occurs. When said interaction leads to an exaggerated or increased effect of the drug substances, the effect is synergistic. The respective formulas 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 seen after co-administration, respectively. A net effect equal to the sum of the effects seen with the administration of the drugs alone is an additive synergistic effect. If the net effect is greater than the predicted effect, the term superadditivity is used. If the effect is smaller, it is subadditive. On the other hand, if an interaction between drugs reduces the effect of the drug components, the effect is not synergistic at all, but antagonistic.

[0031] Thus, within the scope of this disclosure, the terms "antagonism" and "antagonistic" are used for a decrease in drug effect induced by a drug-drug interaction, and the terms "synergy" and "synergistic" are used for an increase in drug effect induced by a drug-drug interaction. To describe and determine the degree of this synergy, the terms "subadditive," "additive," and "superadditive" and their respective nouns are used. Thus, the term superadditive is used to describe the effect of two or more combined drugs that is greater than the expected additive effect of the drugs alone.

[0032] The use of synergistic drug combinations can enhance both therapeutic efficacy and potency, the latter primarily serving to reduce off-target toxicity. The identification of drug-drug interactions relies on the null hypothesis of "no interaction", which is based on the observed drug response and not on a model of the mechanism. Thus, for two different drugs, their degree of additivity is based on a reference point of reading that depends on the chosen mathematical model. There are various methods for identifying such interactions, calculating the expected additive effect of two substances, and determining whether the actual synergistic effect observed is subadditive, additive, or superadditive. Various methods are advocated in the field. The most common methods are outlined below.

[0033] Basic methods such as constructing simple arithmetic sums or fractional products provide an easy way to gain initial insight into whether a particular combination has superadditivity.

[0034] The simple arithmetic sum method of additivity is based on the equation A+B=(A+B), where A and B are the percent or fractional effect seen when each substance is administered alone, and (A+B) is the percent or fractional effect seen after administering these substances in combination using the same doses as when administered alone. If A+B>(A+B), superadditivity is indicated. 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.

[0035] The fractional product method is based on the formula 1-(1-A)*(1-B)=(A+B), where A and B are the fractal effects seen when each substance is administered alone, and (A+B) is the fractal effect seen after co-administration of each substance at the same dose as when each substance was administered alone. Superadditivity is demonstrated when 1-(1-A)*(1-B)>(A+B).

[0036] A more sophisticated method is the use of so-called isobolograms. These are graphs constructed on a coordinate system defined by the individual drug doses, showing a "line of additivity" that allows to distinguish between subadditive, additive (effects along the line) and superadditive effects. The "line of additivity" connects single drug doses that show the same effect (e.g. 50% inhibition of a certain 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 line of additivity, i.e. close to any point, show the same effect and are considered superadditive. Dose combinations that lie outside the triangle are considered subadditive. Each diagram can be mapped using specific software such as CompuSyn (Chou TC, Martin N, ComboSyn, Inc. Paramus, NJ 2007 [www.combosyn.com]).

[0037] Also, further specific index values, such as, for example, the combination index (CI, formula from Chou and Talalay (1984) Adv Enzyme Reg 22:27-55) and the dose reduction index (DRI, formula from Chou, 1984), can be easily calculated using the specific software mentioned above. Both of these values ​​allow to determine whether drug substances act superadditively or synergistically when administered simultaneously. The CI is based on the principle of the law of mass action and can be applied to any kind of drug combination, regardless of the mechanism of action, the kinetic order, or the units of the amount used for each drug in the combination. The CI value defines the synergistic effect as superadditive if CI<1 and additive if CI=1. If CI>1, the effect is either subadditive or antagonistic. Therefore, CI=1 also refers to the "line of additivity". In the classical isobologram mentioned above. In a simplified approach, it can 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%, respectively, and A(x) and B(x) represent the proportion of each drug in the combination that also inhibits x%. 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 efficacy, compared to the dose of each drug alone. Thus, DRI=1 indicates additivity, while DRI>1 and <1 indicate superadditivity and subadditivity (or antagonism), respectively. For presentation purposes, isobolograms, i.e. isoeffectiveness curves at various concentrations or doses of the two aforementioned drugs, are a dose-oriented graphical approach based on a special case of the CI formula. However, a more convenient graphical approach is the effect-oriented so-called FaCI plot, which displays the combination index (CI) against the fractal effect (Fa), preferably for a specific dose combination.

[0038] Thus, it has been found that administration of 5-amino-2,3-dihydro-1,4-phthalazinedione, or one of its pharma- ceutically acceptable salts, in addition to budesonide therapy, allows for a reduction in the dosage of budesonide without reducing the efficacy of budesonide, and also reduces the undesirable effects associated with budesonide.

[0039] In particular, administration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in addition to budesonide allows for a reduction in the amount of budesonide administered, since 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and budesonide have been shown to act additively when administered simultaneously (see Examples 1 and 2).

[0040] Thus, the present application relates to a pharmaceutical combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts for use in glucocorticoid sparing.

[0041] In particular, administration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in addition to budesonide can reduce the undesirable side effects associated with budesonide, as coadministration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt with budesonide has been shown to reduce the undesirable side effects associated with budesonide.

[0042] Administration of 5-amino-2,3-dihydro-1,4-phthalazinedione or either of its pharma- ceutically acceptable salts to existing budesonide therapy can help avoid undesirable budesonide effects or can further reduce undesirable budesonide effects that are already present.

[0043] In particular, administration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in addition to budesonide therapy can avoid and / or reduce the undesirable effects of budesonide.

[0044] Thus, the present application relates to a pharmaceutical combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts for use in reducing or avoiding undesirable budesonide side effects.

[0045] These undesirable side effects of budesonide are similar to those of common glucocorticoids and include, but are not limited to, increased muscle tone, weight gain and obesity (especially trunk obesity, including the so-called "buffalo hump"), edema, facial puffiness (moon face), potassium wasting, muscle weakness, headaches, facial hair growth (in women), thinning of the skin, easy bruising and poor wound healing, glaucoma, cataracts, gastric and duodenal ulcers, menstrual irregularities, steroid-induced diabetes, loss of control of existing diabetes, osteoporosis (leading to fractures), adrenal joint necrosis (especially of the hip or knee), psychiatric disorders (e.g., depression, euphoria, insomnia, mood swings, personality changes), psychotic behavior, growth retardation in children, convulsions, increased infection rates, worsening of opportunistic infections (tuberculosis, shingles, pneumocystis, etc.), and reduced efficacy of antibiotics and vaccines, especially Cushing's syndrome. Cushing's syndrome is a general term for a set of signs and symptoms that occur with long-term exposure to glucocorticoids and include high blood pressure, abdominal obesity, striae, "moon face," corticosteroid-induced lipodystrophy (e.g., buffalo hump), muscle weakness, osteoporosis, fragile skin, acne, facial hair growth (in women), and menstrual irregularities.

[0046] The administration of either 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharma- ceutically acceptable salt thereof in combination with budesonide therapy to reduce the dose of budesonide also serves to avoid and / or reduce the undesirable effects associated with budesonide removal. Common undesirable effects associated with glucocorticoid removal, such as adrenal insufficiency and acute Addisonian attacks, including symptoms such as nausea, vomiting, and shock, can thus be avoided or at least reduced.

[0047] In particular, the present disclosure relates to a pharmaceutical combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts for use in medicine, with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt being preferred.

[0048] The term "chronic inflammatory disease" refers to any disease characterized by prolonged inflammation. Chronic inflammatory diseases are characterized by a gradual change in the types of cells present at the site of inflammation, such as mononuclear cells, and the simultaneous destruction and healing of tissues by the inflammatory process. Causes of chronic inflammation include failure to eliminate factors that cause acute inflammation, such as infectious microorganisms such as tuberculosis, protozoa, fungi, and other parasites that may resist host defenses and remain in tissues for long periods of time, or low-level exposure to certain irritants or foreign bodies that cannot be eliminated by enzymatic degradation or phagocytosis in the body, including substances or industrial chemicals (such as silica dust) that may be inhaled for long periods of time. Or it may be due to an autoimmune disease in which the immune system recognizes normal components of the body as foreign antigens and attacks healthy tissues, causing diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), or when there is a defect in the cells that mediate inflammation, causing persistent or recurrent inflammation, such as autoinflammatory diseases (familial Mediterranean fever), or when there are recurrent episodes of acute inflammation. The common denominator of chronic inflammation is oxidative stress and mitochondrial dysfunction due to inflammatory and biochemical triggers, resulting in increased production of free radical molecules, advanced glycation end products (AGEs), uric acid (urate) crystals, oxidized lipoproteins, homocysteine, etc. (See Pahwa et al. (2021) Chronic inflammatory. Stat Pearls, as of October 1, 2021).

[0049] Typical examples of chronic inflammatory diseases include: Autoimmune diseases 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 (e.g., from exposure to poison oak or poison ivy), hives, angioedema, anaphylaxis, or severe hypersensitivity reactions; Cancers such as leukemias including acute and chronic lymphocytic leukemia, acute and chronic myeloid leukemia, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, brain tumors, intracranial tumors; Side effects from cancer treatments such as chemotherapy and radiation therapy (including but not limited to fatigue, nausea, 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, herpes zoster, dermatomyositis, keloids, and lichens, such as lichen simplex chronicus, lichen planus, lichen sclerosus, and lichen sclerosus atrophicus; Inflammatory diseases of the respiratory system such as asthma, bronchitis, laryngitis, croup, severe tuberculosis, chronic obstructive pulmonary disease (COPD), prevention of exacerbations of COPD, cystic fibrosis, lipid pneumonia, acute respiratory distress syndrome (ARDS), prevention of infant respiratory distress syndrome (IRDS), and acute shock lung following trauma; Inflammatory diseases of the digestive 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, nephrotic syndrome, cystic fibrosis, and phimosis; Inflammatory diseases of the musculoskeletal system, such as bursitis, osteoarthritis, tendonitis, gouty arthritis, lateral epicondylitis, ataxia telangiectasia, plantar fasciitis, mixed connective tissue disease, dermatomyositis, juvenile chronic arthritis, and polymyalgia rheumatica; Muscular dystrophies, such as Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle dystrophies, dysferlinopathies, myotonic myopathies 1-3, hereditary inclusion body myopathy (HIBM), distal myopathy with rimmed vacuoles (DMRV), distal Nonaka myopathy, quadriceps-sparing myopathy, spinal-bulbar muscular atrophy (SMA), SMARD1, Werdnig-Hoffmann disease, Kugelberg-Welander disease, Charcot-Marie-Tooth disease, Curschmann-Steinerth disease, 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, myo-oculo-encephalopathies, Ullrich congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy (EMD), facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy and myofibrillar myopathy types 1 to 6; Inflammatory diseases of the nervous system and sensory organs, such as ophthalmitis, sympathetic ophthalmia, uveitis, meningitis, cluster headache, ataxia telangiectasia, Bell's palsy, herpes zoster, chronic inflammatory demyelinating polyneuropathy (CIPD), myasthenia gravis, Meniere's disease, acute idiopathic tinnitus, heart failure, pericarditis, orthostatic hypotension, rheumatic fever with carditis, vasculitis, polyarteritis nodosa, panarteritis nodosa, giant cell arteritis, temporal arteritis, granulomatosis with polyangiitis, and other inflammatory diseases of the cardiovascular system; Other systemic inflammatory diseases, such as sepsis (including but not limited to septic shock, bacteremia, viremia, fungemia, parasite-associated sepsis, Herxheimer reaction, SIRS (systemic inflammatory response syndrome)), and other inflammatory response syndromes such as acute respiratory distress syndrome (ARDS), Kawasaki syndrome, and pediatric inflammatory multisystem syndrome tentatively associated with SARS-CoV-2 (PIMS-TS); Serious infectious diseases such as tuberculosis, typhoid, and brucellosis; Many other conditions include 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. and prevention of transplant rejection.

[0050] The present application therefore also refers to a pharmaceutical combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts for use in the treatment of chronic inflammatory diseases. 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is preferred.

[0051] Chronic respiratory diseases of the lower respiratory tract are of particular interest for treatment with a combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts.

[0052] These diseases include, but are not limited to, bronchitis not specified as acute or chronic; simple and mucopurulent chronic bronchitis; chronic bronchitis; chronic bronchitis; chronic tracheitis; chronic tracheobronchitis; emphysema; chronic obstructive pulmonary disease (COPD); asthma; conditions such as asthma, bronchiectasis, pulmonary sarcoidosis, pulmonary fibrosis, croup, alveolar microlithiasis, and the like.

[0053] Such combined treatment of non-infectious rhinitis and nasal polyps is also of interest.

[0054] COPD is a progressive development of airflow limitation that is not completely reversible. Most COPD patients suffer from a triad of pathology: bronchitis, emphysema, and mucus plugging. The disease is characterized by a relatively preserved forced vital capacity (FVC) and a slowly progressive and irreversible decrease in forced forced expiratory volume in 1 second (FEV1). In both asthma and COPD, there is a significant and well-defined remodeling of the airways. Most of the airflow obstruction is due to two major components: destruction of alveoli (emphysema) and small airway obstruction (chronic obstructive bronchitis). COPD is primarily characterized by severe mucus cell hyperplasia. The main feature of COPD is neutrophil infiltration into the lungs of patients. Elevated levels of inflammatory cytokines such as TNF-α, and especially chemokines such as interleukin-8 (IL-8), play an important role in the development of COPD. Platelet thromboxane synthesis has been found to be enhanced in COPD patients. Most of the tissue damage is caused by neutrophil activation and subsequent release of matrix metalloproteinases and increased production of ROS and RNS.

[0055] Emphysema refers to the destruction of lung structure with enlargement of air spaces and reduction of alveolar surface area. Lung damage occurs when alveoli within the lungs weaken and rupture. Several adjacent alveoli may rupture, forming one large space instead of many small spaces. Large spaces may merge into even larger cavities called bullae. As a result, the lung tissue loses its natural elasticity and becomes overstretched and ruptures, minimizing lung compliance. It also reduces the pulling force on the small bronchi, which may collapse and obstruct airflow. Any air that is not exhaled before the next breathing cycle becomes trapped in the lungs, leading to difficulty breathing. The effort required to push air out of the lungs when exhaling can leave the patient exhausted.

[0056] The most common symptoms of COPD include shortness of breath, chronic cough, chest tightness, difficulty breathing, increased mucus secretion and frequent throat clearing. Patients are unable to carry out normal daily activities.

[0057] Long-term smoking is the most common cause of COPD, accounting for 80-90% of all cases. Other risk factors include genetics, passive smoking, air pollution, and a history of frequent respiratory infections during childhood. COPD is progressive, sometimes irreversible, and there is currently no cure.

[0058] The clinical progression of COPD is usually described in three stages: Stage 1: Lung function (measured by FEV1) is greater than 50% of predicted normal lung function. There is minimal impact on health-related quality of life. At this stage, symptoms may progress and the patient may begin to experience severe shortness of breath, necessitating evaluation by a pulmonologist. Stage 2: FEV1 lung function is 35-49% of predicted normal lung function, significantly impacting health-related quality of life. Stage 3: FEV1 lung function is less than 35% of predicted normal lung function, significantly impacting health-related quality of life.

[0059] Symptomatic pharmacotherapy includes the administration of bronchodilators, glucocorticoids, and PDE4 inhibitors. Suitable bronchodilators include short-acting beta-2 adrenergic agonists such as fenoterol or salbutamol, long-acting salmeterol or formoterol, muscarinic anticholinergics such as ipratropium bromide or tiotropium bromide, and methylxanthines such as theophylline.

[0060] Suitable glucocorticoids include inhaled glucocorticoids such as budesonide, beclomethasone, fluticasone, orally administered glucocorticoids such as prednisolone, and intravenously administered glucocorticoids such as prednisolone. A suitable PDE (phosphodiesterase) 4 inhibitor is roflumilast.

[0061] Asthma is also of particular interest within the scope of this application. Asthma is a chronic inflammatory disease of the lower airways. It is primarily characterized by recurrent episodes of reversible airflow obstruction and easily provoked bronchospasm. Symptoms include attacks of wheezing, coughing, chest tightness, and dyspnea.

[0062] Asthma is thought to be caused by a combination of genetic and environmental factors, including exposure to air pollution and allergens. Other potential triggers are iatrogenic.

[0063] Asthma is clinically classified as intermittent, mild persistent, moderate persistent, or severe persistent based on the frequency of symptoms. The most important parameters are FEV1 and peak expiratory flow rate.

[0064] Asthma cannot currently be cured. Long-term treatment involves avoiding triggers such as allergens and irritants, and preventing symptoms such as status asthmaticus pharmacologically with inhaled corticosteroids. Long-acting beta-2 agonists (LABAs) or anti-leukotrienes can be used in addition. The most common inhaled corticosteroids include beclomethasone, budesonide, fluticasone, mometasone, and ciclesonide. Suitable LABAs include salmeterol and formoterol. Leukotriene receptor antagonists such as montelukast, pranlukast, and zafirlukast are administered orally. Suitable 5-lipoxygenase (5-LOX) inhibitors include meclofenamate sodium and zileuton. In severe stages of asthma, intravenous corticosteroids such as prednisolone are recommended.

[0065] Acute asthma attacks (status asthmaticus) are best treated with inhaled short-acting beta2 agonists such as salbutamol, or inhaled ipratropium bromide. Intravenous corticosteroids can also be used. Inhaled administration is usually by metered dose inhaler or dry powder inhaler.

[0066] Pulmonary sarcoidosis is also of particular interest within the scope of this application. Pulmonary sarcoidosis (used interchangeably herein as pulmonary sarcoidosis, PS) is characterized by abnormal collections of inflammatory cells that form masses known as granulomas in the lungs. The cause of sarcoidosis is unknown. The disease usually begins in the lungs, skin, or lymph nodes and may appear throughout the body. The most common symptom is prolonged fatigue that continues even after disease activity has ceased. General malaise, shortness of breath, joint pain, elevated body temperature, weight loss, and skin pain may appear. In general, the prognosis is good. The acute form, in particular, usually causes few problems and symptoms gradually subside naturally. If sarcoidosis is present in the heart, kidneys, liver, and / or central nervous system, or if it is widespread in the lungs, the prognosis is less favorable. In general, sarcoidosis is classified into four stages by chest radiographs. However, these stages do not correlate with severity. 1. Bilateral hilar lymphadenopathy (lymph node granulomas) 2. Bilateral hilar lymphadenopathy and reticulonodular infiltrates (pulmonary granulomas) 3. Bilateral pulmonary infiltrates (pulmonary granulomas, no lymph node granulomas) 4. Fibrocystic sarcoidosis (irreversible scarring of the lungs typically with superior hilar depressions, cystic and bullous changes, i.e. pulmonary fibrosis). Patients in stages 2 and 3 often have a chronic progressive disease course.

[0067] Symptomatic treatment of pulmonary sarcoidosis includes administration of corticosteroids such as prednisone or prednisolone, TNF-α inhibitors (etanercept, adalimumab, golimumab, infliximab), immunosuppressants such as cyclophosphamide, cladribine, cyclosporine, chlorambucil, and chloroquine, IL-23 inhibitors such as tildrakizumab and guselkumab, and antimetabolites such as mycophenolate, leflunomide, azathioprine, and methotrexate. In subtypes such as Löfgren's syndrome, COX inhibitors such as acetylsalicylic acid, diclofenac, and ibuprofen are used. All of these active agents have been administered systemically to date.

[0068] Within the scope of this application, bronchiectasis is also of particular interest. Bronchiectasis is considered to be an idiopathic disease. Morphologically, it is characterized by a permanent enlargement of parts of the lower airways. Pathological conditions discussed include post-infection, immunodeficiency, exaggerated immune response, congenital anomalies, inflammatory pneumonia, fibrosis, and mechanical obstruction. Symptoms include chronic cough with daily mucus production. It thus resembles cystic fibrosis, but without the characteristic genetic mutation. Pulmonary function test results generally show airflow obstruction ranging from moderate to severe. Other symptoms include dyspnea, hemoptysis, chest pain, hemoptysis, fatigue, and weight loss.

[0069] Treatment of bronchiectasis aims to control infection and bronchial secretions, relieve airway obstruction, and remove diseased lung segments by surgery or arterial embolization. Antibiotics, particularly macrolides, are administered when indicated. Excessive mucus secretion can be managed with mucolytics. Bronchodilators are used to make breathing easier. Continuous inhalation of corticosteroids, such as budesonide, reduces sputum production, reduces airway narrowing, and has some benefit in preventing disease progression.

[0070] Pulmonary fibrosis is also of particular interest within the scope of this application. In this case, scarring occurs in the lung tissue, leading to severe respiratory problems. Scarring, i.e. the accumulation of excess fibrous connective tissue, leads to thickening of the walls and causes a reduction in the oxygen supply in the blood. The result is chronic progressive respiratory distress. Pulmonary fibrosis is often secondary to other lung diseases, such as interstitial lung disease, autoimmune diseases of the lungs, inhalation of environmental and occupational pollutants, or certain infections. Otherwise, it is classified as idiopathic pulmonary fibrosis.

[0071] Pulmonary fibrosis is a disease characterized by the gradual replacement of parenchyma with fibrotic tissue. Scar tissue irreversibly reduces oxygen diffusion capacity, leading to lung stiffness and reduced lung compliance. Pulmonary fibrosis is sustained by abnormalities in wound healing.

[0072] Currently, there is no general drug treatment for pulmonary fibrosis. Some subtypes respond to corticosteroids such as prednisone, antifibrotic agents such as pirfenidone or nintedanib, or immunosuppressants such as cyclophosphamide, azathioprine, methotrexate, penicillamine, or cyclosporine.

[0073] The present application therefore also refers to a pharmaceutical combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts for use in the treatment of a chronic respiratory disease selected from chronic obstructive pulmonary disease, asthma, croup, non-infectious rhinitis and nasal polyps. 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is preferred.

[0074] In the scope of the present disclosure, inflammatory bowel disease (IBD) is also of particular interest. IBD is a recurrent (relapsing) or continuously progressive inflammatory disease of the intestinal tract. The most common IBDs are Crohn's disease and ulcerative colitis. Less common are two forms of microscopic colitis: collagenous colitis and lymphocytic colitis.

[0075] Crohn's disease is generally considered an autoimmune disease. The typical symptoms are abdominal pain and diarrhea, which may be bloody. The pain occurs mainly in the right abdomen and often after meals. Other symptoms include fever, weight loss, anorexia, nausea, and vomiting. Anal fissures, fistulas, and abscesses may also develop. Laboratory tests usually reveal leukocytosis and anemia. The disease course is characterized by repeated relapses lasting several weeks. Approximately 20% of cases involve the colon, approximately 30% involve the ileum, and approximately 50% involve the ileocolon. Typically, granulomas are seen at the site of inflammation. A lead pipe pattern indicating strictures may develop in the colon. In approximately 10% of cases, inflammation does not occur. Extraintestinal manifestations such as joint pain, arthritis, erythema nodosum, and pyoderma gangrenosum are present in 50% of patients. The etiology of Crohn's disease has not been conclusively resolved. Some patients have a genetic predisposition. The most prominent genetic defect associated with Crohn's disease is a frameshift in the NOD2 gene. It is believed to be due to a dysfunction of the innate immune system. The disease develops when the adaptive immune system attempts to compensate for a defective innate immune system. Impaired cytokine secretion by macrophages has been reported, which contributes to impaired innate immunity and sustains a microbial-induced inflammatory response in the colon with a high bacterial load. Alternatively, it has been postulated that inflammation in Crohn's disease is caused by an overshoot of Th1 and Th17 cytokine responses.

[0076] Apart from symptomatic treatment, relapses are treated with drugs such as glucocorticoids such as budesonide and prednisone, sulfasalazine, and the anti-TNF-α antibodies infliximab, adalimumab, and certolizumab. Metronidazole and ciprofloxacin are used to treat fistulas. In severe cases, resection of the affected bowel segment may be necessary. In remission, immunosuppressants such as azathioprine, 6-mercaptopurine, mesalamine (mesalazine, 5-aminosalicylic acid (5-ASA)), and methotrexate (MTX) are used, as well as the anti-TNF-α antibodies infliximab, adalimumab, and certolizumab, the anti-IL-12 / IL-23 antibody ustekinumab, and the integrin antagonists vedolizumab and natalizumab.

[0077] Ulcerative colitis is a chronic inflammatory bowel disease that manifests exclusively in the large intestine. The incidence in developed countries is 160-250 per 100,000. Ulcerative colitis is an autoimmune disease characterized by T cell infiltration into the large intestine (Ko et al. (2010) Mol Ther 18:1365-1372). There may be a genetic cause. It is presumed that the transcription factor NF-κB, which controls the expression of proinflammatory proteins, is permanently activated. Inflammation is limited to the intestinal mucosa and submucosa. The disease is characterized by recurrent diarrhea, gastrointestinal bleeding, abdominal pain, and colic. Patients suffer from fecal incontinence, increased frequency of bowel movements, difficulty in defecation, and weakness. Frequent extraintestinal symptoms include erythema nodosum, osteopenia, and sacroiliitis. In milder forms of ulcerative colitis, edematous swelling of the intestinal mucosa occurs. Moderately severe disease is characterized by mild bleeding and ulceration. In severe disease, extensive ulceration leads to loss of mucosa. Hidden abscesses typically develop. Pseudopolyps are common. Ulcerative colitis progresses with repeated relapses and remissions. Long-term disease increases the risk of developing malignant tumors in the large intestine.

[0078] Pharmacological treatment during relapses includes glucocorticoids such as budesonide. Budesonide can be given rectally as an enema or foam, or systemically (orally and intravenously). In remission, mesalamine (5-ASA) is the primary treatment. In more severe cases, the anti-TNF-α antibodies infliximab, adalimumab, and golimumab, and the immunosuppressant azathioprine, are used. In severe cases, calcineurin inhibitors such as cyclosporine A and tacrolimus, and JAK kinase inhibitors such as tofacitinib, are also used. In very severe cases, colectomy may be required.

[0079] The present application therefore also refers to a pharmaceutical combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts for use in the treatment of an inflammatory bowel disease selected from Crohn's disease, ulcerative colitis and microscopic colitis. 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is preferred.

[0080] Autoimmune hepatitis is a rare acute or chronic inflammatory autoimmune disease. T cells attack antigens on liver cells, causing hepatitis. Environmental toxins, bacterial antigens (e.g., Salmonella), and viral infections (hepatitis A, B, C, and D, measles virus, and herpes virus) are thought to be triggers of autoimmune hepatitis. Typical symptoms include fatigue, nausea, loss of appetite, fever, joint pain, and jaundice. Extrahepatic manifestations are centered on autoimmune inflammation of the thyroid, blood vessels, colon, pleura, and skin. In addition, autoimmune anemia is common. In mild cases, leukocyte infiltration is limited to the portal vein, but in moderate to severe cases, the hepatic lobule is also affected. The infected tissue undergoes necrosis, and in later (or more severe) stages, fibrosis also occurs, eventually resulting in cirrhosis. The prevalence is 10–20 per 100,000 in Western countries. Interestingly, women are affected four times more often than men, and the disease usually begins before the age of 30.

[0081] Autoimmune hepatitis can be fatal if not properly treated. Drug therapy focuses on glucocorticoids such as prednisone and budesonide. Glucocorticoids are often combined with the immunosuppressant azathioprine to reduce the feared side effects of glucocorticoids. In the case of autoimmune hepatitis, these side effects are mainly osteoporosis and Cushing's syndrome. Second-line drugs include cyclophosphamide, tacrolimus, methotrexate (MTX), and mycophenolate mofetil. In most cases, drug therapy is lifelong. If all drugs fail, the last option is a liver transplant.

[0082] The present application therefore also refers to a pharmaceutical combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, for use in the treatment of autoimmune hepatitis. 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is preferred.

[0083] Unless otherwise defined, technical or scientific terms used herein have the meanings ascribed to them by experts in the relevant art.

[0084] The term "composition" or "pharmaceutical composition" includes at least one active ingredient in at least one pharmacologically acceptable defined dosage and administration form, and at least one pharma- ceutically acceptable excipient, as well as any pharmaceutical agents produced directly or indirectly in combination, as a deposit, complex or crystal, or as a result of other reactions or interactions, from the ingredients outlined below, and optionally at least one additional pharmaceutical agent listed below.

[0085] In this application, the term "excipient" is used to refer to an ingredient of a pharmaceutical composition other than the pharma- ceutical active ingredient. Selection of an appropriate excipient depends on a variety of factors, such as the dosage form, the dosage amount, the desired solubility, and the stability of the composition.

[0086] The terms "effect," "therapeutic effect," "action," "therapeutic action," "efficacy," and "effectiveness," with respect to a substance of the invention or other active agent described herein, refer to a beneficial result that occurs causally in an organism to which the substance has previously been administered.

[0087] According to the disclosure, the terms "effective amount" and "therapeutically effective amount" refer to an amount of a substance of the invention sufficient to effect a desired beneficial effect in a subject in need of such treatment.

[0088] The terms "treatment" and "therapy" include administration of at least an agent of the present invention alone or in combination with at least one other pharmaceutical agent, regardless of the chronological order of administration. Such administration is intended to significantly improve the disease course of congenital muscular dystrophy by halting or slowing the progression of impairment during the course of the disease.

[0089] The term "prevention" or "prophylactic treatment" includes administration of at least the substance of the invention alone or in combination with at least one further pharmaceutical agent, regardless of the chronological order of administration, to prevent or inhibit the manifestation of symptoms resulting from congenital muscular dystrophy. This particularly refers to a condition in a patient where the manifestation of such symptoms is expected to occur with a reasonable probability in the distant or near future.

[0090] The terms "subject" and "patient" include individuals suffering from, and having confirmed or suspected diagnosis of, a disease symptom or disorder associated with a congenital muscular dystrophy. The individual is a mammal, particularly a human.

[0091] In another aspect of the present invention, a pharmaceutical composition is disclosed comprising budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma-ceutically acceptable salts and at least one pharma-ceutically acceptable excipient.

[0092] In particular, the present application relates to a pharmaceutical composition comprising budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutical acceptable salts and at least one pharma-ceutical acceptable excipient for use in the treatment of chronic inflammatory diseases.

[0093] The above outlined application forms of the compositions according to the invention 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.

[0094] Pharmaceutical compositions according to the invention are preferred, said pharmaceutical compositions being suitable for intravenous, oral, sublingual, inhalation, rectal, topical or transdermal administration.

[0095] The term "pharmaceutical acceptable excipient" refers to natural or synthetic compounds added to pharmaceutical formulations along with the active pharmaceutical ingredient. They may help bulk the formulation, improve the desired pharmacokinetic properties or stability of the formulation, and are also beneficial to the manufacturing process. Advantageous classes of excipients according to the disclosure include carriers, binders, colorants, buffers, preservatives, antioxidants, coatings, sweeteners, thickeners, pH adjusters, acidity adjusters, acidifiers, solvents, tonicity agents, disintegrants, glidants, lubricants, emulsifiers, solubilizers, stabilizers, diluents, anti-caking agents (anti-adherents), penetration enhancers, adsorbents, foaming agents, antifoaming agents, opacifiers, fatliquoring agents, viscosity enhancers, hydrotropes, fragrances and flavorings.

[0096] Generally, one or more pharma- ceutically acceptable carriers are added to the pharma- ceutically active agent.All carriers known in the art and their combinations are suitable.For solid dosage forms, for example, vegetable and animal fats, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide, etc.For liquid dosage forms and emulsions, suitable carriers are, for example, solvents, solubilizers, 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 ester, polyethyl glycol, sorbitan fatty acid ester, etc. Suspensions according to the present invention may use carriers known in the art, such as diluents (e.g., water, ethanol or propylene glycol), ethoxylated isostearyl alcohol, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline cellulose, bentonite, agar, tragacanth, and the like.

[0097] The term binder refers to a substance that binds or adheres powders together and provides cohesion through granule formation. Binders act as the "glue" of the formulation. Binders enhance the cohesive strength of any diluent or filler that is provided.

[0098] Suitable binders include, for example, starches derived from wheat, corn, rice or potato, gelatin, natural sugars such as glucose, sucrose or beta-lactose, sweeteners derived 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, etc. The proportion of binder in the composition is in the range of 1-30% by weight, preferably 2-20% by weight, more preferably 3-10% by weight, most preferably 3-6% by weight.

[0099] Colorants are excipients that impart color to pharmaceutical formulations. These excipients may be food colorants. They may be adsorbed onto suitable adsorption means such as clay or aluminum oxide. A further advantage of colorants is that they can make aqueous solutions spilled on the nebulizer and / or mouthpiece visible to facilitate cleaning. The amount of colorant can vary in the range of 0.01-10% by weight of the pharmaceutical composition, preferably in the range of 0.05-6%, more preferably in the range of 0.1-4%, and most preferably in the range of 0.1-1%.

[0100] Suitable pharmaceutical colours include, for example, curcumin, riboflavin, riboflavin-5'-phosphate, tartrazine, alkannin, quinolion yellow WS, fast yellow AB, sodium riboflavin-5'-phosphate, yellow 2G, sunset yellow FCF, orange GGN, cochineal, carminic acid, citrus red 2, carmoisine, amaranth, ponceau 4R, ponceau SX, ponceau 6R, erythrosine, red 2G, allura red AC, indanthrene 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 sulphite caramel, ammoniacal caramel, ammoniacal sulphite caramel, black PN, carbon black, vegetable colours and the like. Carbon, Brown FK, Brown HT, α-carotene, β-carotene, γ-carotene, annatto, bixin, norbixin, paprika oleoresin, capsanthin, capsorubin, lycopene, β-apo-8'-carotenal, β-apo-8'-carotenoic acid ethyl ester, flavoxanthin, lutein, cryptoxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, zeaxanthin, citranaxanthin, astaxanthin, betanin, anthocyanin, saffron, calcium carbonate, titanium dioxide, iron oxide, iron hydroxide, aluminum, silver, gold, rubinic acid pigment, tannin, orcein, ferrous gluconate, ferrous lactate.

[0101] Furthermore, buffers are preferred for liquid formulations, especially pharmaceutical liquid formulations. The terms buffer, buffer system, and buffer, especially for aqueous solutions, refer to the ability of the system to resist pH changes due to the addition of acid or base, or dilution with a solvent. Preferred buffer systems include formic acid, lactic acid, benzoic acid, oxalic acid, fumaric acid, aniline, acetate buffer, citrate buffer, glutamate buffer, phosphate buffer, succinic acid, pyridine, phthalic acid, histidine, MES (2-(N-morpholino)ethanesulfonic acid), maleic acid, cacodylic acid (dimethylarsenic acid), carbonic acid, ADA (N-(2-acetamido)iminodiacetic acid), PIPES (4-piperazine-bis-ethanesulfonic acid), BIS-TRIS propane (1,3-bis[trimethylsilyl]phenyl)prop ... Examples of buffers that have a pKa between 3.8 and 7.7 include N-(2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid), ethylenediamine, ACES (2-[(amino-2-oxoethyl)amino]ethanesulfonic acid), imidazole, MOPS (3-(N-morpholino)propanesulfonic acid), diethylmalonate, TES (2-[tris(hydroxymethyl)methyl]aminoethanesulfonic acid), HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid), and other buffers with a pKa between 3.8 and 7.7.

[0102] Preferred are carbonate buffers such as acetate buffers, dicarboxylic acid buffers such as fumaric acid, tartaric acid, phthalic acid, and tricarboxylic acid buffers such as citric acid.

[0103] A further group of preferred buffers are inorganic buffers such as sulfate hydroxide, borate hydroxide, carbonate hydroxide, oxalate hydroxide, calcium hydroxide, phosphate buffers, etc. Another group of preferred buffers are nitrogen-containing buffers such as imidazole, diethylenediamine, piperazine, etc. 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), MOPS, and N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES). Another group of preferred buffers are glycine, glycyl-glycine, glycyl-glycyl-glycine, N,N-bis-(2-hydroxyethyl)glycine, and N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricine). Also preferred are amino acid buffers such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxyproline, N,N,N-trimethyllysine, 3-methylhistidine, 5-hydroxylysine, o-phosphoserine, γ-carboxyglutamic acid, [ε]-N-acetyllysine, [ω]-N-methylarginine, citrulline, ornithine, and derivatives thereof. Particularly preferred are KH 2 PO 4 It is a buffer solution.

[0104] Preservatives for liquid and / or solid dosage forms may be used as needed. These include sorbic acid, potassium sorbate, sodium sorbate, calcium sorbate, methylparaben, ethylparaben, methylethylparaben, propylparaben, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, heptyl parahydroxybenzoate, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, benzyl alcohol, benzalkonium chloride, phenylethyl alcohol, cresol, cetylpyridinium chloride, chlorobutanol, thiomersal (sodium 2-(ethylmercurithio)benzoate), sulfur dioxide, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, potassium sulfite, calcium sulfite, calcium bisulf ... ammonium, calcium bisulfite, potassium bisulfite, biphenyl, orthophenylphenol, sodium orthophenylphenol, thiabendazole, nisin, natamycin, formic acid, sodium formate, calcium formate, hexamine, formaldehyde, dimethyl dicarbonate, potassium nitrite, sodium nitrite, sodium nitrate, potassium nitrate, acetic acid, potassium acetate, sodium acetate, 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 of skill in the art.

[0105] Adding sufficient amounts of antioxidants is particularly preferred for liquid and topical dosage forms.Suitable examples of antioxidants include sodium metabisulfite, α-tocopherol, ascorbic acid, maleic acid, sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid or propyl gallic acid.The use of sodium metabisulfite, α-tocopherol and ascorbyl palmitate is preferred.A strong antioxidant is inhaled carbon monoxide (CO).

[0106] Tablets or pills are usually coated, i.e. the coating constitutes the outer layer. This can be a film coating, a sugar coating including sugars, and a compression coating. Pharmaceutically acceptable varnishes or waxes, HPMC (hydroxypropyl methylcellulose), MC (methylcellulose), or HPC (hydroxypropyl cellulose) can be used. Such coatings may help mask the taste and facilitate swallowing or identification. Coatings often contain plasticizers and pigments. Capsules usually have a gelatinous shell that encases the active ingredient. The specific composition and thickness of this gelatinous layer determine the rate at which the capsule is absorbed after ingestion. Of particular interest are sustained release formulations known in the art.

[0107] Suitable sweeteners may be selected from the group consisting of 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.

[0108] Suitable thickening agents may be selected from the group including, but not limited to, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, dextrin, polydextrose, modified starch, alkaline modified starch, bleached starch, oxidized starch, enzyme treated starch, monostarch phosphate, di-starch phosphate esterified with sodium trimetaphosphate or phosphorus oxychloride, di-starch phosphate, acetylated di-starch phosphate, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated di-starch adipate, acetylated di-starch glycerol, di-starch glycerin, hydroxypropyl starch, hydroxypropyl di-starch glycerin, hydroxypropyl di-starch phosphate, hydroxypropyl di-starch glycerol, sodium starch octenyl succinate, acetylated oxidized starch, hydroxyethyl cellulose.

[0109] Suitable pH adjusting agents for liquid dosage forms include, for example, buffer substances such as sodium hydroxide, hydrochloric acid, sodium dihydrogen phosphate or disodium hydrogen phosphate.

[0110] 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, adipic acid, citric ... Sodium adipate, potassium adipate, ammonium adipate, succinic acid, sodium fumarate, potassium fumarate, calcium fumarate, ammonium fumarate, 1,4-heptonolactone, triammonium citrate, ferric ammonium 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.

[0111] Oxidizing agents are inorganic chemicals that produce or become acids. Suitable examples include ammonium chloride and calcium chloride.

[0112] Suitable solvents may be selected from the group including, but not limited to, water, carbonated water, water for injection, water containing an isotonic agent, saline, isotonic saline, alcohol, particularly ethyl alcohol and n-butyl alcohol, and mixtures thereof.

[0113] Suitable isotonicity agents include, for example, pharma- ceutically acceptable salts, particularly sodium chloride and potassium chloride, sugars such as glucose or lactose, sugar alcohols such as mannitol and sorbitol, citrates, phosphates, borates, and mixtures thereof.

[0114] Suitable disintegrants may be selected from the group consisting of starch, cold water soluble starches such as carboxymethyl starch, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, crosslinked microcrystalline cellulose such as microcrystalline cellulose and croscarmellose sodium, natural and synthetic gums such as guar, agar, Karaya (Indian tragacanth), locust bean gum, tragacanth, clays such as bentonite, xanthan gum, alginates such as alginic acid and sodium alginate, effervescent compositions, etc. Moisture expansion is promoted by, for example, starch, cellulose derivatives, alginates, polysaccharides, dextran, crosslinked polyvinylpyrrolidone, etc. The amount of disintegrant in the composition may vary from 1 to 40% by weight, preferably from 3 to 20% by weight, most preferably from 5 to 10% by weight.

[0115] Glidants are substances that prevent seizing of the respective supplement and improve the flow properties of the granules 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 varies from 0.01 to 10% by weight, preferably from 0.1 to 7% by weight, more preferably from 0.2 to 5% by weight, and most preferably from 0.5 to 2% by weight.

[0116] The term "lubricant" refers to a substance added to a dosage form to facilitate the release of tablets, granules, etc. from a press die or exit nozzle. Lubricants reduce friction or wear. Lubricants are usually added just before pressing, as they need to be present on the surfaces of the granules and between the granules and the parts of the press die. The amount of lubricant in the composition can vary between 0.05-15% by weight, with 0.2-5% by weight being preferred, 0.3-3% by weight being more preferred, and 0.3-1.5% by weight being most preferred. Suitable lubricants are metal stearates such as sodium oleate, sodium stearate, calcium stearate, potassium stearate, magnesium stearate, stearic acid, sodium benzoate, sodium acetate, sodium chloride, boric acid, high melting point waxes, and polyethylene glycols.

[0117] The emulsifier can be chosen, for example, from the following anionic and nonionic emulsifiers: anionic emulsifier wax, cetyl alcohol, cetylstearyl alcohol, stearic acid, oleic acid, polyoxyethylene polyoxypropylene block polymers, addition products of 2 to 60 moles of ethylene oxide onto castor oil and / or hydrogenated castor oil, wool wax oil (lanolin), sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene stearate, polyvinyl alcohol, metatartaric acid, calcium tartrate, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, propane-1,2-diol alginate, carrageenan, modified eukema 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 yajin, disodium phosphate, trisodium phosphate, tetrasodium phosphate, dicalcium phosphate, dihydrogen calcium phosphate, trisodium phosphate, pentapotassium phosphate, sodium polyphosphate, calcium polyphosphate, ammonium polyphosphate, β-cyclodextrin, powdered cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylmethylcellulose, carboxymethylcellulose, calcium Sodium carboxymethylcellulose, ethyl hydroxyethylcellulose, croscarmellose, enzymatically hydrolyzed carboxymethylcellulose, mono- and diglycerides of fatty acids, glyceryl monostearate, glyceryl distearate, monoacetate esters of mono- and diglycerides of fatty acids, lactic acid esters of mono- and diglycerides of fatty acids, citric acid esters of mono- and diglycerides of fatty acids, tartaric acid esters of mono- and diglycerides of fatty acids, mono- and diacetyl tartaric acid esters of mono- and diglycerides of fatty acids, mixed acetate and tartaric acid esters of mono- and diglycerides of fatty acids, succinic acid monoglyceride, sucrose esters of fatty acids, sucroglycerides, polyglycerol esters of fatty acids, polyglycerol polyricinoleate, propane-1,2-Diol esters, propylene glycol esters of fatty acids, lactic acid fatty acid esters of glycerol and propane-1, thermo-oxidized soybean oil interacting with mono- and diglycerides of fatty acids, dioctyl sodium sulfosuccinate, sodium stearoyl-2-lactylate, calcium stearoyl-2-lactylate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, calcium stearoyl fumarate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, stearoyl fumarate Examples of suitable glyceryl phosphates include calcium phosphate, sodium lauryl sulfate, ethoxylated mono- and diglycerides, methylglucoside-coconut oil esters, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate, calcium sodium polyphosphate, calcium polyphosphate, ammonium polyphosphate, cholic acid, choline salts, distarch glycerol, sodium starch octenylsuccinate, acetylated oxidized starch. Preferred are phospholipids such as glycerol monooleate, stearic acid, and lecithin.

[0118] Suitable surface-active solubilizers include, for example, diethylene glycol monoethyl ester, polyethylene propylene glycol copolymers, cyclodextrins such as α- and β-cyclodextrin, glyceryl monostearates such as Solutol HS15 (BASF macrogol-15-hydroxystearate, PEG 660-15 hydroxystearate), sorbitan esters, polyoxyethylene glycols, polyoxyethylene sorbitan acid esters, polyoxyethylene sorbitan monooleate, polyoxyethylene oxystearic acid triglyceride, polyvinyl alcohol, sodium dodecyl sulfate, (anionic) glyceryl monooleate.

[0119] Stabilizers are substances that can be added to prevent undesirable changes. Stabilizers are not true emulsifiers, but they also contribute to the stability of an emulsion. Suitable examples of stabilizers include oxystearin, xanthan gum, agar, oat gum, guar gum, tara gum, polyoxyethylene stearate, aspartame acesulfame salt, amylase, protease, papain, bromelain, ficin, invertase, polydextrose, polyvinylpyrrolidone, polyvinylpolypyrrolidone, triethyl citrate, maltitol, maltitol syrup, etc.

[0120] Diluents or fillers are inert substances added to drugs to handle the minimum amount of active agent.Examples of suitable diluents include 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 methyl cellulose, polyethylene glycol, xanthan gum, gum arabic, or combinations thereof.

[0121] Anti-caking agents (anti-adherents) can be added to the supplement or the composition of the supplement 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 aluminosilicate, calcium aluminosilicate, bentonite, aluminosilicate, stearic acid, polydimethylsiloxane, etc.

[0122] Sorbents are substances that absorb oil from water. Suitable examples include natural sorbents such as peat moss, sawdust, feathers, and other natural substances containing carbon, and synthetic sorbents such as polyethylene and nylon. Sorbents are used to moisture-proof tablets / capsules by limited liquid adsorption (absorption of liquids or gases by adsorption or sorption) in dry conditions.

[0123] In some herbal formulations, it may be desirable to generate a foam when the liquid oral dosage form dissolves. Such an effect can be supported by the addition of effervescent agents that lower the surface tension of the liquid, promoting foam formation; or inhibiting bubble coalescence, thereby enhancing colloidal stability; or stabilizing the foam. Suitable examples include mineral oil, Quillaja extract, triethyl citrate, sodium lauryl ether sulfate, sodium lauryl sulfate, and ammonium lauryl sulfate.

[0124] Alternatively, some liquid oral dosage forms may foam slightly when prepared. While this does not prevent the intended use, it may affect patient compliance in the case of pharmaceuticals and commercial success in the case of dietary supplements. It may therefore be desirable to add a pharma- ceutically acceptable antifoaming agent (defoamer). Examples include polydimethylsiloxane or silicone oil in dietary supplements and simethicone in pharmaceuticals.

[0125] An opacifier is a substance that renders a liquid dose opaque when necessary. The opacifier must have a refractive index substantially different from that of the solvent (most often water). At the same time, it 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.

[0126] Suitable fatliquors include, for example, decyl oleate, hydrated castor oil, light mineral oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, and the like.

[0127] Examples of viscosity enhancers include cetyl alcohol, cetyl ester wax, hydrated castor oil, microcrystalline wax, non-ionic emulsifying wax, beeswax, paraffin, or stearyl alcohol.

[0128] Suitable hydrotropes are alcohols, such as ethanol, isopropyl alcohol, or polyols, such as glycerin.

[0129] Suitable aroma and flavoring substances include essential oils that can be used for this purpose. Generally, the term refers to volatile extracts from plants or plant parts that have their own characteristic odor. These can be extracted from the plants or plant parts by steam distillation.

[0130] Suitable examples include aromatic substances such as essential oils, achillea, sage, cedar, clove, chamomile, anise, anise seed, star anise, thyme, tea tree, peppermint, mint oil, menthol, cineole, borneol, gingerol, eucalyptus, mango, fig, lavender oil, chamomile flower, pine needles, cypress, orange, rose, rosewood, plum, currant, cherry, birch leaf, cinnamon, lime, grapefruit, tangerine, juniper, valerian, lemon, lemon balm, lemongrass, palmarosa, cranberry, pomegranate, rosemary, ginger, pineapple, guava, echinacea, ivy leaf extract, blueberry, persimmon, melon, α- or β-pinene, α-pinene oxide, α-camphorenic aldehyde, α-citronellol. α-Isoamylcinnamic acid, α-Cinnamic terpinene, α-Terpineol, α-Terpinene, Aldehyde C 16, alpha-phellandrene, amyl cinnamaldehyde, amyl salicylate, anisaldehyde, basil, anethole, bay, benzyl acetate, benzyl alcohol, bergamot, bitter orange peel, black pepper, calamus, camphor, cananga oil, cardamom, carnation, carvacrol, carveol, cassia, castor, cedarwood, cinnamaldehyde, cinnamaldehyde alcohol, cis-pinane, citral, citronella, citronellal, citronellol dextrose, citronellol, citronellyl acetate. Citronellyl nitrile, Satsuma mandarin, clary sage, clove bud, coriander, corn, cottonseed, d-dihydrocarvone, decyl aldehyde, diethyl phthalate, dihydroanethole, dihydrocarveol, dihydrolinalool, dihydromyrcene, dihydromyrcenol, dihydromyrcenyl acetate, dihydroterpineol, dimethylsalicylate, dimethyloctanal, dimethyloctanol, dimethyloctanyl acetate, diphenyl oxide, dipropylene glycol, d-limonene, d-pulegone, estragole, ethyl vanillin, eucalyptol. Eucalyptus citriodora, Eucalyptus globulus, Eugenol, Evening primrose, Fencol, Fennel, Ferniol, Fish, Florazone, Galaxolide, Geraniol, Geranium, Geranyl acetate, Geranyl nitrile, Guaiacol, Guaiacwood, Gurjun balsam, Heliotropin, Herbanate, Hiba, Hydroxycitronellal, i-Carvone, i-Methyl acetate, Ionone, Isobutyl quinolein, Isobornyl acetate, Isobornyl methyl ether, Isoeugenol, Isolongifolene, Jasmine, Lavender, Limone , linalool oxide, linalool, linalyl acetate, flaxseed, litseacubaba, I-methyl acetate, longifolene, mandarin, mentha, menthane hydroperoxide, menthol crystals, menthol laevo, menthone laevo, methyl anthranilic acid, methyl cedryl ketone, methyl chavicol, methyl hexyl ether, methyl ionone, methyl salicylic acid, minerals, mint, musk ambrette, musk ketone, musk xylol, myrcene, nerol, neryl acetate, nonyl aldehyde, nutmeg, orris root, paracymene,Parahydroxyphenylbutanone crystals, patchouli, p-cymene, pennyroyal oil, pepper, perilla aldehyde, petitgrain, phenylethyl alcohol, phenylethyl propionate, phenylethyl-2-methylbutyrate, pimento berry, pimento leaf, pinan hydroperoxide, pinanol, pine esters, pine, pinene, piperonal, piperonyl acetate, piperonyl alcohol, purinol, purinyl acetate, pseudo-ionone, rhodinol, rhodinyl acetate, rosalin, rue, sandalwood, sandenol, sassafras, sesame, soybean, spearmint, spice, spike rabender , spilanthol, star flower, tea seed, terpenoids, terpineol, terpinolene, terpinyl acetate, tert-butylcyclohexyl acetate, tetrahydrolinalool, tetrahydrolinalyl acetate, tetrahydromyrcenol, tulasi, thymol, tomato, trans-2-hexenol, trans-anethole, turmeric, turpentine, vanillin, vetiver, vitalizer, white cedar, white grapefruit, wintergreen, etc., or mixtures thereof, as well as menthol, peppermint, star anise oil, or mixtures of menthol and cherry flavor.

[0131] These aromatic or flavouring substances may be present in amounts ranging from 0.0001 to 10% by weight (particularly in the composition) of the total 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. It may be advantageous to use different amounts in relation to the application or individual case.

[0132] According to the disclosure, all of the aforementioned excipients and excipient classes can be used without limitation, alone or in any conceivable combination, as long as it does not interfere with the use of the invention, does not cause toxic effects, or violates the laws of the respective countries.

[0133] In accordance with the present invention, it is possible to administer a pharmaceutical combination of the present invention in which 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts is administered in addition to budesonide or in the same pharmaceutical composition as budesonide.

[0134] In another aspect of the present invention, the present application relates to a pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutical acceptable salts, i.e., a pharmaceutical composition according to the present disclosure for use in an oral administration formulation.

[0135] A pharmaceutical formulation suitable for an oral administration form of a pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, each pharmaceutical composition according to the present disclosure, can be administered in discrete units in the form of tablets, soft gelatin capsules, hard gelatin capsules, dragees or pills, powders or granules, juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids, edible foams or mousses, or oil-in-water or water-in-oil emulsions.

[0136] In oral dosage forms such as tablets and capsules, the active agent can be combined with a non-toxic, pharma- ceutically acceptable inert carrier, such as ethanol, glycerol, water, etc. Powders are produced by grinding the compound to a suitable small particle size and mixing in a similar manner with a pharmaceutical carrier, such as an edible carbohydrate, such as starch or mannitol. Flavoring, preservative, dispersing agent, or coloring agent can also be present.

[0137] Tablets are formulated by preparing, granulating or dry pressing a powder mixture, adding a lubricant and disintegrant, and compressing the mixture into tablets. The powder mixture is produced by mixing the compound, suitably comminuted, with the aforementioned diluents or bases, and, if applicable, with binders such as carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone, dissolution retarders such as paraffin, absorption enhancers such as quaternary salts, and / or absorbents 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 solutions 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 machine to produce lumps of non-uniform shape which are broken into granules. The granules can be lubricated with the addition of stearic acid, a stearate salt, talc, or mineral oil to prevent the granules from sticking to the tablet mold. The lubricated mixture is then compressed to give tablets. The compounds of the present invention can also be mixed with a free-flowing inert excipient and compressed directly to give tablets without going through the granulation or dry pressing steps.

[0138] In another aspect of the present invention, the pharmaceutical combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, i.e., the pharmaceutical composition according to the present disclosure, is provided in a hard gelatin capsule, respectively. These are produced by preparing a powder mixture as described above and filling it into a molded gelatin cover. Glidants and lubricants, such as highly dispersed silica, talc, magnesium stearate, calcium stearate, or polyethylene glycol, can be added as solids to the powder mixture. Disintegrants or solubilizers, such as agar-agar, calcium carbonate, or sodium carbonate, can be added as well to improve the availability of the drug after taking the capsule. Furthermore, suitable binders and / or coloring agents can be added to the mixture, if desired or necessary.

[0139] In another aspect of the invention, the pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, i.e., the pharmaceutical composition according to the disclosure, is encapsulated in soft gelatin capsules (SGCs). SGCs dissolve as they pass through the digestive tract. They consist mainly of gelatin enriched with various amounts of plasticizers such as glycerol and 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 the administration of active agents that are poorly soluble in water.

[0140] In another embodiment of the present invention, the pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, i.e. the pharmaceutical composition of the present invention, is contained in a chewable tablet or hard caramel, wherein the substances are integrated into the matrix of the tablet or caramel.

[0141] In another aspect of the invention, the pharmaceutical formulation of the invention is formulated in a delayed formulation, i.e. a formulation that provides delayed release of at least one of budesonide or 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharma- ceutical acceptable salt thereof. These are also known as sustained release (SR), extended release (ER, XR) or controlled / continuous release (CR) forms. Suitable formulations and carriers are known to those skilled in the art (Kleinsorge (1995) Retardformulierungen in der medikamentosen). Most commonly, at least one active agent is embedded in a matrix of insoluble material such as acrylic or chitin. Thus, the active agent must exit through the openings in the matrix. In some formulations, holes are drilled with a laser on one side and a porous membrane on the other side. Gastric fluid attacks and flows through this porous membrane, pushing the active agent out of the holes on the other side. In other formulations, the active agent dissolves and expands within the matrix, forming a gel. The active agent is then released from the pores of the gel. Other examples include specially coated tablets resistant to gastric juices, delayed capsules containing delayed pellets of active agent that are released after dissolution of the capsule casing, multi-unit pellet systems (MUPS), oral osmotic systems, resonators, coacervation, microencapsulation, etc. Such delayed formulations allow control of the site of release of the drug and its pharmacokinetics. For example, it is often desirable for a dosage form of an active agent not to dissolve before reaching a certain point in the intestine. Because of changes in pH on the way through the intestine, the dissolution process can be designed to be pH dependent. In therapeutic applications where it is necessary to facilitate absorption of the active agent through the intestinal mucosa to increase its bioavailability, it may be desirable to use a neutral form of the active agent rather than a salt.

[0142] In another aspect of the invention, the application relates to a pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutical acceptable salts, i.e., a pharmaceutical composition according to the present disclosure, for use in the treatment of chronic respiratory diseases of the lower respiratory tract, in a formulation for administration by inhalation.

[0143] For an effective inhalation therapy, it is advantageous that budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, the pharmaceutical composition according to the invention or the pharmaceutical combination according to the invention 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 pharma- ceutical active agents are so-called mesh nebulizers. Within the scope of this application, practically all mesh nebulizers known in the art can be used, from fairly simple disposable mesh nebulizers for cough and cold or decorative purposes to sophisticated high-end mesh nebulizers for clinical or home treatment of severe diseases or conditions of the lower respiratory tract.

[0144] Suitable commercially available mesh nebulizers, jet nebulizers, ultrasonic nebulizers, dry powder inhalers, and (pressurized) metered dose inhalers include PARI eFlow® rapid, PARI LC STAR®, PARI Velox, PARI Velox Junior (PARI GmbH, Starnberg, Germany), Philips Respironics I-neb, Philips InnoSpire Go (Koninklijke Philips NV, Eindhoven, The Netherlands), VENTA-NEB®-ir, OPTI-NEB®, M-neb® dose+ mesh nebulizer inhalation MN-300 / 8, M-Neb Flow+, M-neb® mesh nebulizer MN-300 / X (NEBU-TEC, Eisenfeld, Germany), Hcmed Deepro HCM-86C and HCM860 (HCmed Innovations Co., Ltd, Taipei, Taiwan), OMRON MicroAir U22 and U100 (Omron, Kyoto, Japan), Aerogen® Solo, Aerogen® Ultra and Aerogen® PRO (Aerogen, Galway, Ireland), KTMED NePlus NE-SM1 (KTMED Inc., Seoul, Korea), Vectura Bayer Breelib™ (Bayer AG, Leverkusen, Germany), Vectura Fox, MPV Truma and MicroDrop® Smarty (MPV MEDICAL GmbH, Kirchheim, Germany), MOBI MESH (APEX Medical, New Taipei City, Taiwan), B.Well WN-114, TH-134 and TH-135 (B.Well Swiss AG, Widnau, Switzerland), Babybelle Asia BBU01 (Babybelle Asia Ltd., Hong Kong), CA-MI Kiwi and others (CA-MI sri, Langhirano, Italy), Diagnosis PRO MESH (Diagnosis SA, Białystok, Poland), DIGIO2 (DigiO2 International Co., Ltd., New Taipei City, Taiwan), feellife AIR PLUS, AEROCENTRE+, AIR 360+, AIR GARDEN, AIRICU, AIR MASK, AIRGEL BOY, AIR ANGEL, AIRGEL GIRL, AIR PRO 4 (Feellife Health Inc., Shenzhen, China), Hannox MA-02 (Hannox International Corp., Taipei, Taiwan), Health and Life HL100 and HL100A (HEALTH&LIFE Co., Ltd., New Taipei City, Taiwan), Honsun NB-810B (Honsun Co., Ltd., Nantong, China), K-jump(R) KN-9100 (K-jump Health Co., Ltd., New Taipei City, Taiwan), microlife NEB-800 (Microlife AG, Widnau, Switzerland), OK Biotech Docspray(OK Biotech Co., Ltd., Hsinchu City, Taiwan), Prodigy Mini-Mist(R) (Prodigy Diabetes Care, LLC, Charlotte, USA), Quatek NM211, NE203, NE320, NE403 (Big Eagle Holding Ltd., Taipei, Taiwan), Simzo NBM-1 and NBM-2 (Simzo Electronic Technology Ltd., Dongguan, China), Mexus® BBU01 and BBU02 (Tai Yu International Manufactory Ltd., Dongguan, China), TaiDoc TD-7001 (TaiDoc Technology Co., New Taipei City, Taiwan), Vibralung® and HIFLO Miniheart CirculaireII (Westmed Medical Group, Purchase, USA), KEJIAN (Xuzhou Kejian Hi-Tech Co., Ltd., Xuzhou, China), YM-252, P&S-T45 and P&S-360 (TEKCELEO, Valbonne, France), Maxwell YS-31 (Maxwell India, Jaipur, India), Kernmed® JLN-MB001 (Kernmed, Durmersheim, Germany).

[0145] Preferred are mesh nebulizers with piezoelectric activation of the nebulization process, or vibrating mesh nebulizers.

[0146] Thus, in another aspect of the invention, the application relates to a pharmaceutical composition according to the present disclosure for use in a pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, i.e., a formulation for inhalation administration, the administration being by means of a vibrating mesh nebulizer.

[0147] Mesh nebulizers can be divided into two groups, depending on their interaction with the patient: continuous mode devices and trigger-activated devices. In continuous mode mesh nebulizers, nebulized aerosol is continuously released into the mouthpiece, and the patient must inhale the provided aerosol. In trigger-activated devices, a certain amount of aerosol is released only during active, deep inspiration. In this way, a much larger amount of active agent-containing aerosol is inhaled and reaches the lowermost airways than in continuous mode devices. In the latter, a large amount of active agent-containing aerosol is lost to the surroundings or in passing through the upper airways, since the release of the aerosol is not linked to the respiratory cycle.

[0148] Therefore, trigger-activated mesh nebulizers, and particularly vibrating mesh nebulizers, are preferred.

[0149] Particularly preferred are trigger-activated mesh sprayers with piezoelectric actuation of the spray process.

[0150] Recommended are 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®. and high-end models such as Philips Respironics I-neb, PARI Velox, Philips Respironics I-neb, M-neb® dose+mesh nebulizer inhalation MN-300 / 8, Aerogen® Solo, Vectura Fox, and Vectura Bayer Breelib®.

[0151] The average droplet size is usually characterized as MMAD (mass mean aerodynamic diameter). The individual droplet size is called MAD (mass mean aerodynamic diameter). This value indicates the diameter of 50% of the aerosolized particles (droplets) smaller or larger, respectively. Particles with MMAD >10 μm usually do not reach the lower respiratory tract and often get stuck in the throat. Particles with MMAD >5 μm and <10 μm usually reach the bronchi but not the alveoli. Particles with MMAD between 100 nm and 1 μm do not deposit in the alveoli and are quickly exhaled. Therefore, the optimal range is MMAD between 1 μm and 5 μm. Recent publications recommend a narrower range of 3.0 μm to 4.0 μm (cf. Amirav et al. (2010) J Allergy Clin Immunol 25:1206-1211; Haidl et al. (2012) Pulmonology 66:356-360).

[0152] Another commonly accepted quality parameter is the percentage of particles with a diameter between 1 μm and 5 μm in the generated aerosol (FPM, fine particle mass). FPM is a measure of particle distribution. It is calculated by subtracting the percentage of particles with a diameter less than 1 μm in the generated aerosol from the total percentage of particles with a diameter less than 5 μm in the generated aerosol (FPF, fine particle fraction).

[0153] In another aspect of the invention, the application also refers to a method for producing an aerosol according to the disclosure, comprising the following steps: a) filling the nebulization chamber of a mesh nebulizer with 0.1 ml to 5 ml of an aqueous solution containing a combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, and, optionally, at least one pharma- ceutically acceptable excipient; b) The mesh of the mesh nebulizer is vibrated at a frequency of 80 kHz to 200 kHz. c) The generated aerosol is discharged from the side of the mesh nebulizer opposite the spray chamber.

[0154] The vibration frequency of a vibrating mesh nebulizer is typically in the range of 80 kHz to 200 kHz, with 90 kHz to 180 kHz being preferred, 100 kHz to 160 kHz being more preferred, and 105 kHz to 130 kHz being most preferred (see Chen, The Aerosol Society: DDL 2019; Gardenshire et al. (2017) A Guide to Aerosol Delivery Devices for Respiratory Therapists, 4th ed.).

[0155] Therefore, the above method is also disclosed for said vibration frequency range.

[0156] The method of the present invention is therefore characterized in that at least 80%, preferably at least 85%, most preferably at least 90% by weight of the pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts contained in said aqueous solution is atomized into the aerosol generated.

[0157] The method of the present invention is particularly effective in nebulizing high concentrations of pharma- ceutical active agents from a provided aqueous solution in a short time, which is an important feature for patient compliance. A significant proportion of patients find the inhalation process unpleasant, tiring, and physically taxing. On the other hand, active patient cooperation is essential for effective and targeted inhalation application. It is therefore desirable to apply a therapeutically sufficient amount in as short a time as possible. Surprisingly, it has been shown that 95% of the substance provided in an aqueous solution can be nebulized in a time frame of 3 minutes, which is an ideal time frame for increasing patient compliance.

[0158] Thus, the methods of the present disclosure are characterized in that at least 80%, preferably at least 85%, and most preferably at least 90% of the aerosol generated is generated within 3 minutes after the start of nebulization with the mesh nebulizer.

[0159] Pharmaceutically active agents are usually provided in a single-dosage container for each nebulization procedure, whereas the nebulizer and / or mouthpiece can be used for a certain period of time and must be replaced at certain intervals. It is recommended that the nebulizer and mouthpiece be cleaned by default after each nebulization. However, in this case, patient compliance cannot be taken for granted. However, even after careful cleaning, aerosol deposits are always present in the nebulization chamber, outlet, and / or mouthpiece. As aerosols are generated from aqueous solutions, these deposits carry the risk of generating a bacterial bioburden that can contaminate the inhaled aerosol. Deposits can also block holes in the mesh membrane of mesh nebulizers. In general, the nebulizer and / or mouthpiece must be replaced every week or two. It is therefore convenient to provide the agent and nebulizer as a combined product.

[0160] Thus, in another aspect of the present invention, the application also refers to a kit comprising a mesh nebulizer and a pharma- ceutically acceptable container containing an aqueous solution comprising an effective amount of a combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, and, optionally, at least one pharma- ceutically acceptable excipient.

[0161] In an alternative kit, the pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, i.e., the pharmaceutical composition according to the present disclosure, is not provided in the form of an aqueous solution, but in two separate containers, one for the solid form of the active agent and one for the aqueous solution. The final aqueous solution is freshly prepared by dissolving the active agent in the final solution. The final aqueous solution is then filled into the nebulizing chamber of the mesh nebulizer. These two containers may be completely separate containers, for example two vials, or for example a dual chamber vial. To dissolve the active agent, for example a hole is made in the membrane between the two chambers, allowing the contents of both chambers to mix.

[0162] Accordingly, the present application also discloses a kit comprising a mesh nebulizer, a first pharma- ceutically acceptable container containing water for injection or saline, and a second pharma-ceutically acceptable container containing effective solid doses of budesonide and one of 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharma-ceutically acceptable salt thereof, each of which is a pharmaceutical composition according to the present disclosure, and optionally at least one pharma-ceutically acceptable excipient is included in the first pharma-ceutically acceptable container and / or the second pharma-ceutically acceptable container.

[0163] The aerosols produced by the methods according to the invention may be administered or self-administered via a mouthpiece, which may optionally be included in addition to the kits described above.

[0164] A common method is to transfer the provided or final aqueous solution to the nebulizer chamber by a syringe equipped with a needle. The aqueous solution is first drawn into the syringe and then injected into the nebulizer chamber. Optionally, such a syringe and / or needle can be additionally included in the aforementioned kit. Common syringes made of, but not limited to, polyethylene, polypropylene, or cyclic olefin copolymers can be used, and common gauges for stainless steel needles range from 14 to 27.

[0165] In yet another aspect of the present invention, a pharmaceutical combination, i.e. a pharmaceutical composition according to the present invention, consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma-ceutically acceptable salts is disclosed, said substance, composition or combination being applied in the form of liposomes, micelles, multilamellar vesicles or cyclodextrin complexes.

[0166] In yet another aspect of the present invention, the present application relates to a pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, i.e., a pharmaceutical composition of the present invention in liquid dosage form.

[0167] The present application also discloses a pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, i.e., parenteral administration of the pharmaceutical composition according to the present disclosure in the form of an intravenous, intraarterial or intraperitoneal injection.

[0168] These liquid dosage forms include solutions, suspensions, and emulsions, such as water and water / propylene glycol solutions for parenteral injection or oral solutions, suspensions, and emulsions containing sweeteners or opacifiers.

[0169] These liquid dosage forms can be stored in vials, IV bags, ampoules, cartridges, prefilled syringes, etc. Suitable excipients include solubilizers, stabilizers, buffers, tonicity adjusters, bulking agents, viscosity enhancers / reducers, surfactants, chelating agents, adjuvants, etc.

[0170] In yet another aspect of the present invention, a pharmaceutical combination, i.e. a pharmaceutical composition according to the present invention, consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma-ceutically acceptable salts is disclosed, said combination or said composition being formulated as a lyophilisate, which can be reconstituted with water for injection or saline or a water / ethanol solution and then administered by injection.

[0171] Common applications of intravenous injection include infusion pumps, hypodermic needles, drip chambers, peripheral cannulas (peripheral venous catheters), and pressure bags.

[0172] Generally, aqueous or saline solutions are preferred, although in the case of poorly soluble drugs according to the present invention, ethanol or ethanol / water mixtures may also be used.

[0173] Further suitable liquid dosage forms include drops, gels, and hydrogels. Gels are colloids in which a solid dispersed phase combines with a fluid continuous phase to form a network, resulting in a viscous semi-rigid sol. Gels vary in properties from soft and weak to hard and tough. Gels are defined as substantially dilute cross-linked systems that do not exhibit flow under steady state conditions. By weight, gels are mostly liquid, but behave like solids due to a three-dimensional cross-linked network within the liquid. It is the cross-links within the fluid that give gels their consistency and contribute to their cohesiveness. A gel is a dispersion of liquid molecules within a solid medium.

[0174] A hydrogel is a network of hydrophilic polymer chains, sometimes seen as a colloidal gel in which water is the dispersion medium. The hydrophilic polymer chains are linked together by crosslinks to form a three-dimensional solid. Due to the inherent crosslinks, the structural integrity of the hydrogel network is such that it cannot be dissolved by high concentrations of water. Hydrogels are highly absorbent (contains more than 90% water) natural or synthetic polymer networks. Hydrogels also have a high water content, giving them flexibility very similar to natural tissues. In medicine, hydrogels can encapsulate chemical systems and release certain pharmacologically active substances into the environment, most often by transitioning from a gel-sol to a liquid state, upon stimulation by an external factor such as a change in pH.

[0175] Suitable gel-forming agents may be selected from the group including, but not limited to, agar, algin, alginic acid, bentonite, carbomer, carrageenan, hectorite, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium carbomer.

[0176] In yet another aspect of the present invention, the present application relates to a pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, i.e., a pharmaceutical composition according to the present disclosure in the formulation of a sublingual tablet.

[0177] Sublingual administration is an alternative to oral administration because it avoids hepatic metabolism. For some drugs, especially those used to treat acute illnesses, a rapid onset of pharmacological effect is often desired. Sublingual tablets disintegrate rapidly, and the presence of small amounts of saliva is usually sufficient to achieve disintegration of the drug with better dissolution and increased bioavailability.

[0178] Drugs must be lipophilic enough to pass through the lipid bilayer, but not so lipophilic that once in, they cannot exit again. According to the diffusion model of absorption, the flux across the lipid bilayer is directly proportional to the concentration gradient. Thus, low solubility in saliva results in low absorption, and vice versa. In general, drugs formulated for sublingual administration should ideally have a molecular weight below 500 to facilitate diffusion. The pH range of the oral cavity is narrow, between 5.0 and 7.0. Including an appropriate buffer in the formulation of an ionizable drug can control the pH of aqueous saliva.

[0179] Taste masking is necessary to avoid unpleasant tastes and odors of medications. Sweeteners, flavors, and other taste masking agents are essential ingredients. Sugar-based excipients dissolve quickly in saliva and generate an endothermic heat of solution. They create a pleasant sensation in the mouth and, together with other flavors, are ideal for sublingual tablets.

[0180] Common 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).

[0181] If swallowing is avoided, administration of the active ingredient via a sublingual tablet can also reach the pharynx / throat locally. The majority of the active ingredient is absorbed via the pharyngeal mucosa.

[0182] For topical application comprising a pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, a pharmaceutical composition, cream, emulsion, lotion, gel, hydrogel, paste, powder, ointment, salve, film, liposome, skin patch, transdermal patch, transdermal spray or suspension according to the disclosure for use according to the present invention is suitable.

[0183] Penetration enhancer is often used in topical dosage form.Suitable penetration enhancer includes, but is not limited to, all pharmaceutically acceptable penetration enhancer known in the art, such as azones such as laurocapram, 1-dodecylazacycloheptan-2-one, sulfoxides such as dimethyl sulfoxide, DMAC, DMF, pyrrolidones such as 2-pyrrolidone, N-methyl-2-pyrrolidone, alcohols such as ethanol, 1,2-propanediol or decanol, glycols such as propylene glycol, diethylene glycol, tetraethylene glycol, fatty acids such as oleic acid, lauric acid, sodium lauryl sulfate, myristic acid, isopropyl myristic acid, capric acid, nonionic surfactants such as polyoxyethylene-2-oleyl ether, polyoxyethylene-2-stearyl ether, terpenes, terpenoids, oxazolidinones, urea. Ceramide analogues, azone analogues, menthol derivatives, etherified derivatives, esterified derivatives, transcarbamine, carbamate salts, TXA derivatives, DDAIP (dodecyl 2-(dimethylamino)propanoate), DDAK, natural essential oils (all of which are described in Chenetal. (2014) Asian J. Pharm. Sc. 9, 51-64), citrate esters (such as triethyl citrate), hydrophobin polypeptides, α-bisabolol, dimethyl isosorbide (Arlasolve), ethoxydiglycol, 1,2-propanediol are preferred.

[0184] Typical examples of preservatives suitable for topical application include, for example, benzyl benzoate, benzoic acid, benzyl alcohol, benzalkonium chloride, N-cetyl-NN-trimethylammonium bromide (cetrimide, Merck), chlorhexidine, chlorobutanol, chlorocresol, imidurea, parabens such as methyl, ethyl, propyl or butyl paraben, sodium methylparaben, sodium propylparaben, potassium sorbate, sodium benzoate, sodium propionate, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, sorbic acid or thiomersal (sodium methylmercurithiosalicylate). Methylparaben, propylparaben, and sodium methylparaben and sodium propylparaben are preferred.

[0185] In topical administration forms, the addition of antioxidants is particularly preferred.Suitable examples of antioxidants include sodium metabisulfite, alpha-tocopherol, ascorbic acid, maleic acid, sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, or propyl gallic acid.The use of sodium metabisulfite is preferred.

[0186] Suitable pH adjusting agents for topical administration forms include, for example, buffer substances such as sodium hydroxide, hydrochloric acid, sodium dihydrogen phosphate or disodium hydrogen phosphate.

[0187] Cream formulations may also contain other excipients or additives such as fatliquors to improve flowability, solvents, consistency improvers, hydrotropes, etc. In this case, not only a single substance from the same group of additive or excipient may be present, but several substances may be present in a mixture.

[0188] To prepare suppository dosage forms containing the pharmaceutical formulation of the present invention, a mixture of a low melting wax and fatty acid glyceride such as cocoa butter is first melted, and then the budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt are uniformly dispersed in the mixture by stirring or other mixing methods. The molten homogeneous mixture is transferred to suitable molds and allowed to cool until solid.

[0189] A particular form of topical application is an enema. An enema (enema device) is an injection of medical liquid into the lower intestine of the rectum. In the pharmaceutical combinations according to the present disclosure, they can be used to treat inflammatory bowel disease. Enemas containing budesonide can be prepared in dispersible tablets and solutions for rectal suspension (entocort enema). Dispersible tablets can include the following excipients: anhydrous lactose, riboflavin sodium phosphate, lactose monohydrate, polyvidone, colloidal anhydrous silica, and magnesium stearate. Vehicles can include sodium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, and purified water. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts can be mixed into the dispersible tablets of budesonide edema or administered simultaneously via another dosage form. 5-Amino-2,3-dihydro-1,4-phthalazinedione sodium salt Form I is preferred.

[0190] Another specific form of local application is the rectal form, especially in the treatment of inflammatory bowel disease. They are an alternative to suppositories and enemas. In this way, the undesirable systemic side effects of glucocorticoid therapy can be avoided, or at least reduced. The composition of the budesonide rectal form (UCERIS®) contains cetyl alcohol, citric acid monohydrate, disodium edetate, macrogol stearyl ether, emulsifying wax, polyoxyl(10) stearyl ether, propylene glycol, and purified water. As propellants for rectal application, butane, isobutane, propane, or mixtures thereof can be used (see: Budesonide 2 mg / dose rectal form - Summary of Product Characteristics (SmPC) - (emc) (medicines.org.uk), as of October 7, 2021). The 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts can be mixed with the budesonide rectal foam or administered simultaneously via a separate dosage form.

[0191] Surprisingly, co-administration of pharmaceutical combinations according to the present invention is shown not only to exhibit a general additive effect, but to exhibit this effect across a wide range of fixed ratios tested (see Examples 1 and 2).

[0192] The term "ratio" or "fixed ratio" herein refers to any kind of ratio between two ingredients, regardless of the units used. Such ratios are valid for weight, weight %, concentration specifications, and other units feasible in the pharmaceutical field. Thus, for example, a ratio of budesonide to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmacologically acceptable salts is 1:10, which can be implemented in, for example, 1mg:10mg, 1mg / kg:10mg / kg, 1mM / 10mM, 1%:10%, etc., or other units, as long as the ratio itself is 1:10.

[0193] The present patent application also relates to a budesonide-sparing agent or respective pharmaceutical combination comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmacologically acceptable salts, hydrates and solvates and budesonide for use in the prevention and / or treatment of conditions or diseases normally treated with budesonide, wherein the efficacy of the prevention and / or treatment is significantly improved compared to the respective treatment with budesonide alone.

[0194] Furthermore, the pharmaceutical combination according to the present invention may be used for the prevention and / or treatment of conditions or diseases which are normally treated with budesonide, wherein the components may be used in any ratio.

[0195] However, to achieve optimal efficacy, practical considerations must be taken into account, including the medical indication being treated, the potency of budesonide, the form of application, and the feasibility of the ratio, the latter especially in order to maintain patient compliance.

[0196] Thus, the pharmaceutical combination according to the present invention may be used for the prevention and / or treatment of conditions or diseases normally treated with budesonide, and the budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutical acceptable salts may be used in any ratio, preferably between 1:10 and 1:50,000, more preferably between 1:15 and 1:10,000, even more preferably between 1:20 and 1:5,000, and most preferably between 1:30 and 1:2,500.

[0197] 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.

[0198] Depending on the form of application, the indication for treatment, and the patient's personal risk profile, for example budesonide for oral administration is given in doses of up to 9 mg / day in severe and acute cases, while a typical maintenance dose in chronic disease is 6 mg / day. 5-Amino-2,3-dihydro-1,4-phthalazinedione sodium salt has been shown to be very safe, but for compliance reasons, the dose should not exceed 10 g / day for tablets or capsules.

[0199] Thus, the pharmaceutical combination according to the invention can be used for the prevention and / or treatment of conditions or diseases that are usually treated with budesonide, in which case budesonide is administered orally, characterized in that in severe acute cases the ratio of budesonide to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is 1:10 to 1:10,000, preferably 1:15 to 1:5,000, more preferably 1:20 to 1:2,000, most preferably 1:30 to 1:1,000, and in chronic cases the maintenance dose is characterized in that the ratio of budesonide to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is 1:15 to 1:10,000, preferably 1:20 to 1:5,000, more preferably 1:30 to 1:2,000, most preferably 1:50 to 1:1000.

[0200] Thus, the pharmaceutical formulation of the invention can be used for the prevention and / or treatment of conditions or diseases that are usually treated with budesonide, the pharmaceutical formulation of the invention being administered by inhalation and characterized in that in severe acute cases the ratio of budesonide to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is 1:30 to 1:2,000, preferably 1:50 to 1:1,000, more preferably 1:100 to 1:500, most preferably 1:100 to 1:200, and in chronic cases the maintenance dose is characterized in that the ratio of budesonide to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is 1:25 to 1:2,000, preferably 1:30 to 1:1,000, more preferably 1:50 to 1:500, most preferably 1:100 to 1:200.

[0201] Thus, the pharmaceutical combination of the present invention can be used for the prevention and / or treatment of symptoms or diseases that are usually treated with budesonide, and the pharmaceutical combination of the present invention is administered via a rectal foam characterized in that the ratio of budesonide to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is 1:25 to 1:5,000, preferably 1:40 to 1:2,000, more preferably 1:50 to 1:1,000, and most preferably 1:100 to 1:500, as a maintenance dose in chronic cases.

[0202] However, in the case of liquids, higher doses and / or volumes can be administered without adversely affecting patient compliance.

[0203] Due to the superadditive nature of the pharmaceutical combination of the present invention, the dosage of budesonide can be reduced depending on the individual patient, the indication, and the ratio of the ingredients used. In some cases, it may be necessary to adjust the dosage and ratio over time to achieve the best results.

[0204] Therefore, the dosage of budesonide in the pharmaceutical combination of the present invention can be reduced to 80%, preferably 50%, and most preferably 20% compared to the dosage when budesonide is administered alone.

[0205] The present application therefore relates to a 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts for use as a budesonide sparing agent in the prophylaxis and / or treatment of conditions normally treated with budesonide, characterized in that the dose of budesonide can be significantly reduced, such that a significant reduction means a reduction of the dose of budesonide to 80%, preferably 50%, most preferably 20% of the original dose.

[0206] The present patent application also relates to a pharmaceutical combination comprising 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and budesonide for use in the prevention and / or treatment of conditions or diseases that are normally treated with budesonide, where the dosage of budesonide can be significantly reduced compared to the respective treatment with budesonide alone, such significantly reduced meaning that the dosage of budesonide is reduced to 80%, preferably 50%, most preferably 20% of the original dosage.

[0207] In a further aspect, the present invention relates to a method of treatment comprising administering to a patient in need thereof an effective dose of a pharmaceutical combination consisting of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, or a pharmaceutical composition according to the present disclosure.

[0208] The present invention also relates to 5-amino-2,3-dihydro-1,4-phthalazinedione, or any one of its pharma- ceutically acceptable salts, hydrates or solvates, for use in a method for the treatment and / or prevention of a chronic inflammatory disease in a subject, the method comprising administering to the subject an effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione, or any one of its pharma- ceutically acceptable salts, hydrates or solvates, concomitantly or subsequently with an effective amount of budesonide, or any one of its pharma- ceutically acceptable salts.

[0209] The present invention also relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, hydrates or solvates for use in a method for the treatment and / or prevention of chronic inflammatory diseases in a subject, the method comprising administering to the subject an effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, hydrates or solvates, concomitantly or subsequently, an effective amount of budesonide or one of its pharma- ceutically acceptable salts, wherein the 5-amino-2,3-dihydro-1,4-phthalazinedione is a sodium salt.

[0210] The present invention also relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or any one of its pharma- ceutically acceptable salts, hydrates or solvates for use in a method for the treatment and / or prevention of a chronic inflammatory disease in a subject, the method comprising administering to the subject an effective amount of budesonide, or any one of its pharma- ceutically acceptable salts, concomitantly or subsequently with an effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione, or any one of its pharma- ceutically acceptable salts, hydrates or solvates.

[0211] The present invention also relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, hydrates or solvates for use in a method for the treatment and / or prevention of a chronic inflammatory disease in a subject, the method comprising administering to the subject an effective amount of budesonide or one of its pharma- ceutically acceptable salts, concomitantly or subsequently with an effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, hydrates or solvates, wherein the 5-amino-2,3-dihydro-1,4-phthalazinedione is a sodium salt. EXAMPLES

[0212] [Example 1] Effect of budesonide in combination with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in an in vitro cell system

[0213] Different combinations of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt were tested in a cell system to determine whether they had a greater than additive effect on cytokine release compared to either agent alone. +B cells were co-cultured with PBMCs (peripheral blood mononuclear cells). They were stimulated with α-IgM and TCR (T cell receptor) ligands (0.001x). B cells were cultured in 96-well plates until confluence, after which PBMCs were added. Budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I were provided by the applicant. Budesonide was prepared in DMSO and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in PBS (phosphate-buffered saline). These were added at the indicated concentrations 1 hour before stimulation and cultured for 72 hours. Each plate included positive and negative controls (unstimulated cells) and a vehicle control (buffer). Direct ELISA (enzyme-linked immunosorbent assay) was used to measure cytokine levels. Soluble factors from the supernatant were quantified using capture ELISA.

[0214] Cells were monitored by alamarBlue staining over a 42-hour period, during which no cytotoxic effects were observed for any of the substances or combinations (data not shown).

[0215] The following concentrations and combinations were tested: a) 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt alone: 1mM-0.5mM-0.25mM-0.125mM b) Budesonide alone: 5nM-2.5nM-1.25nM-0.625nM c) Combination: 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 5nM budesonide 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 2.5nM budesonide 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 1.25nM budesonide 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 0.625nM budesonide 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 5nM budesonide 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 2.5nM budesonide 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 1.25nM budesonide 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 0.625nM budesonide 0.25mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 5nM budesonide 0.25mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 2.5nM budesonide 0.25mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 1.25nM budesonide 0.25mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 0.625nM budesonide 0.125mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 5nM budesonide 0.125mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 2.5nM budesonide 0.125mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 1.25nM budesonide 0.125mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 0.625nM budesonide The following cytokines were determined: sTNF-a (soluble tumor necrosis factor alpha) sIL-6 (soluble interleukin 6) sIL-2 (soluble interleukin 2)

[0216] Cytokine measurements were performed in triplicate and the results were averaged and divided by the mean of the solvent control samples to calculate ratios, which were then transformed to log10. a) For sTNF-a, the results for 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, four concentrations of budesonide and their respective combinations are shown in FIG. 1A. For sTNF-α, the results for 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, four concentrations of budesonide, and their respective combinations are shown in FIG. 1B. b) For sIL-6, the results for 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, four concentrations of budesonide and their respective combinations are shown in FIG. 3A. For sIL-6, the results for 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, four concentrations of budesonide, and their respective combinations are shown in Figure 3B. c) For sIL-2, the results for 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, four concentrations of budesonide and their respective combinations are shown in FIG. 5A. For sIL-2, the results for 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, four concentrations of budesonide and their respective combinations are shown in FIG. 5B.

[0217] Each reduction in cytokine release is shown as the mean ± SEM (n = 3). Statistics were performed with unpaired Student's t-test. The results of each combination of budesonide concentration with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt were compared. a) For sTNF-α, three out of four combinations showed significant reductions in the panel using 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, and four out of four combinations showed significant reductions in the panel using 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt. b) For sIL-6, 4 out of 4 combinations showed a significant reduction in the panel when 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was used, and 4 out of 4 combinations showed a significant reduction in the panel when 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was used. c) For sIL-2, 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt resulted in a significant reduction in the panel in three of four combinations, and 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt resulted in a significant reduction in the panel in four of four combinations.

[0218] These results indicate that the addition of an effective concentration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt can significantly increase the reduction in proinflammatory cytokine release induced by the glucocorticoid budesonide. Thus, the addition of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt can enhance the anti-inflammatory effect of budesonide. Furthermore, this can be considered as evidence that 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt can be used as a glucocorticoid-sparing agent. Therefore, it is reasonable to assume that the adverse side effects of long-term glucocorticoid treatment are suppressed or at least significantly reduced by combined treatment with budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt.

[0219] [Example 2] CompuSyn software, which tests for additive effects, confirmed the supraadditive effect of the combination of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and budesonide.

[0220] As mentioned above, the CompuSyn software model for additive effects (www.combosyn.com) is a computer model for evaluating the additive effects of two substances in biological systems.By mathematical transformation, the results of each drug combination in Example 1 are related to the results of both single substances.For this purpose, the results in Example 1 are de-logarithmized.

[0221] Fa / CI plots for all drug combinations tested (non-constant ratios) The horizontal axis shows the fractal effect (Fa), i.e., the relative inhibition of proinflammatory cytokine release by each pharmaceutical combination of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and budesonide, between 0 and 1, where 1 means 100% inhibition and 0 means no inhibition. The vertical axis shows the combination index (CI) calculated by CompuSyn software, where a value of 1 indicates additivity, a value <1 indicates superadditivity, and a value >1 indicates subadditivity, no effect, or antagonism. The closer the value is to 0, the more pronounced the superadditivity.

[0222] Figure 2 shows that all 16 combinations show a significant additive effect on the release of sTNF-a. This computational evaluation supports the results of the evaluation in Example 1a).

[0223] Figure 4 shows that 12 combinations showed a significant superadditive effect on sIL-6 release, 1 combination showed an additive effect, and 3 combinations showed a subadditive effect. This computer evaluation supports the results of the evaluation in Example 1b).

[0224] Figure 6 shows that all 16 combinations show a significant superadditive effect on the release of sIL-2. This computational evaluation supports the results of the evaluation in Example 1c). [Brief description of the drawings]

[0225] L: 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt B: Budesonide *: p<0.05; **: p<0.01 ***: p<0.001 Figure 1: A: Bars for the reduction in sTNF-a release: 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 5nM budesonide 5nM budesonide + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 2.5nM budesonide 2.5 nM budesonide + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 1.25 μm budesonide 1.25 nM budesonide + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 0.625nM budesonide 0.625 nM budesonide + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt B: Bars showing reduction in sTNF-a release: 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 5nM budesonide 5nM budesonide + 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 2.5nM budesonide 2.5 nM budesonide + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 1.25 μm budesonide 1.25 nM budesonide + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 0.625nM budesonide 0.625 nM budesonide + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt Figure 2 Fa / CI diagram of the results of Example 1 of sTNF-a generated by CompuSyn software Fa: Fractal effect CI: Combination Index Figure 3: A: Bars for reduction in release of sIL-6: 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 5nM budesonide 5nM budesonide + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 2.5nM budesonide 2.5 nM budesonide + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 1.25 μm budesonide 1.25 nM budesonide + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 0.625nM budesonide 0.625 nM budesonide + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt B: Bars showing decreased release of sIL-6: 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 5nM budesonide 5nM budesonide + 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 2.5nM budesonide 2.5 nM budesonide + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 1.25 μm budesonide 1.25 nM budesonide + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 0.625nM budesonide 0.625 nM budesonide + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt Figure 4 Fa / CI diagram of the results of Example 1 of sIL-6 generated by CompuSyn software Fa: Fractal effect CI: Combination Index Figure 5 A: Bars for reduction in release of sIL-2: 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 5nM budesonide 5nM budesonide + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 2.5nM budesonide 2.5 nM budesonide + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 1.25 μm budesonide 1.25 nM budesonide + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 0.625nM budesonide 0.625 nM budesonide + 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt B: Bars showing decreased release of sIL-2: 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 5nM budesonide 5nM budesonide + 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 2.5nM budesonide 2.5 nM budesonide + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 1.25 μm budesonide 1.25 nM budesonide + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 0.625nM budesonide 0.625 nM budesonide + 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt Figure 6 Fa / CI diagram of the results of Example 1 of sIL-2 generated by CompuSyn software Fa: Fractal effect CI: Combination Index

Claims

1. A medicament comprising a combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1,4-phthalazinedione is 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt.

3. 3. The medicament of claim 2, wherein 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is provided as one of crystalline anhydrous polymorphic forms I, II or III characterized by the following crystallographic values ​​as determined by X-ray powder diagram: For Form I, d values: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1; 3.0 and / or 2-theta values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3, For Form II, d values: 12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and / or 2-theta values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8, and For Form III, 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 2-theta 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.

4. The pharmaceutical agent according to any one of claims 1 to 3, which is used to spare glucocorticoids.

5. The pharmaceutical agent according to any one of claims 1 to 3, which is used to reduce or avoid undesirable side effects of budesonide.

6. The pharmaceutical agent according to any one of claims 1 to 3 for treating a chronic inflammatory disease.

7. The pharmaceutical composition according to claim 6, wherein the chronic inflammatory disease is a chronic respiratory disease selected from chronic obstructive pulmonary disease, asthma, croup, non-infectious rhinitis, and nasal polyps.

8. The pharmaceutical composition according to claim 6, wherein the chronic inflammatory disease is an inflammatory bowel disease selected from Crohn's disease, ulcerative colitis, and microscopic colitis.

9. The pharmaceutical composition according to claim 6, wherein the chronic inflammatory disease is autoimmune hepatitis.

10. The pharmaceutical composition according to any one of claims 1 to 3, which contains at least one pharmaceutically acceptable excipient.

11. The medicament according to claim 10, wherein the medicament is for intravenous administration, oral administration, sublingual administration, inhalation administration, rectal administration, topical administration or dermal administration.

12. 12. A medicament according to claim 11 suitable for oral administration, wherein the dosage form is selected from tablets, soft gelatin capsules, hard gelatin capsules, dragees or pills; powders or granules; juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or oil-in-water or water-in-oil emulsions.

13. 11. The pharmaceutical composition of claim 10, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of carriers, binders, colorants, buffers, preservatives, antioxidants, coatings, sweeteners, thickeners, pH adjusters, acidity adjusters, acidifiers, solvents, isotonicity agents, disintegrants, glidants, lubricants, emulsifiers, solubilizers, stabilizers, diluents, anti-caking agents, permeation enhancers, adsorbents, foaming agents, anti-foaming agents, opacifiers, fatty agents, viscosity enhancers, hydrotropes, fragrances, and flavoring substances.

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