Combination of 5-amino-2,3-dihydro-1,4-phthalazinedione and fumaric acid ester

Abstract

The present application relates to a combination of 5-amino-2,3-dihydro-1,4-phthalazinedione, or a pharma- ceutically acceptable salt thereof, and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof. In particular, the present invention relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in a pharmaceutical combination. Pharmaceutical compositions and advantageous formulation techniques are disclosed.

Description

[Technical field]

[0001] The present application relates to a combination of 5-amino-2,3-dihydro-1,4-phthalazinedione, or one of its pharmaceutically acceptable salts, with at least one fumaric acid ester, or one of its pharmaceutically acceptable salts. In particular, the present invention relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in said pharmaceutical combination. Pharmaceutical compositions and advantageous formulation techniques are disclosed. [Background technology]

[0002] Dimethyl fumarate (DMF) is the diester of fumaric acid and methanol. DMF and other fumarate esters are used as treatments for multiple sclerosis and psoriasis.

[0003] DMF is an oral medication indicated for the twice-daily treatment of multiple sclerosis (MS) and relapsing-remitting MS (RRMS). It has immunomodulatory and neuroprotective properties, both of which contribute to its efficacy (Deeks (2016) Drugs 76:243-254).

[0004] DMF is marketed as a single substance in the UK for the treatment of moderate to severe psoriasis. In Germany it is marketed for this indication as Fumaderm®.

[0005] Fumaric acid esters have excellent efficacy against these diseases. Although fumaric acid esters can alleviate the diseases, they cannot completely suppress each symptom of the diseases. Therefore, it would be desirable to improve the efficacy of fumaric acid esters.

[0006] Common side effects of fumarates include gastrointestinal upset (diarrhea, nausea, stomach cramps, epigastric pain, flatulence), facial flushing, skin redness, skin irritation, headache, and lymphopenia. Less common side effects in the treatment of psoriasis include progressive multifocal leukoencephalopathy and Fanconi syndrome. In the treatment of multiple sclerosis, anaphylaxis, angioedema, progressive multifocal leukoencephalopathy, and liver damage occur rarely (see Xu et al. (2015) The Cochrane Library Reviews 4 No. CD011076 and Gieselbach et al. (2017) J Neurol 264:1155-1164).

[0007] Furthermore, DMF was used as a biocide against mold, for example to protect leather furniture and shoes. Due to an increase in reports of allergic reactions, DMF has been banned in the European Union for this use. DMF therefore also has a significant allergenic potential.

[0008] Therefore, there is also a medical need to find formulations or compositions that allow for reduced dosages of fumaric acid esters while maintaining their therapeutic effect.

[0009] Surprisingly, these effects can be achieved by a pharmaceutical combination of 5-amino-2,3-dihydro-1,4-phthalazinedione, or one of its pharma- ceutically acceptable salts, solvates, or hydrates, and at least one fumarate ester, or one of its pharma- ceutically acceptable salts. The combination of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and DMF shows a greater than additive effect in terms of efficacy in reducing the release of the proinflammatory cytokine TNF-α and the proinflammatory immune biomarker IgG in an in vitro cell system, compared to DMF alone. Furthermore, this combination allows the dosage of DMF to be reduced, thus reducing the aforementioned adverse side effects.

[0010] Accordingly, the present application discloses a pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof.

[0011] In particular, a pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, for use in medicine is disclosed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] 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 for a wide range of acute and chronic inflammatory diseases, including inflammation of the intestinal tract, 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. 5-amino-2,3-dihydro-1,4-phthalazinedione can effectively prevent cytokine storm caused by excessive immune response. Moreover, there is still a large amount of scientific and patent literature on the testing of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt or indications for which beneficial use has been suggested (see WO 2004 / 041169, WO 2007 / 018546, WO 2012 / 127441, WO 2016 / 096143, WO 2017 / 202496, and WO 2018 / 082814).

[0013] While most conventional immunomodulatory drugs exhibit severe side effects or at least have problems with 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.

[0014] To increase solubility and bioavailability, 5-amino-2,3-dihydro-1,4-phthalazinedione pharmaceutically acceptable salts are used. Sodium, potassium and lithium salts have been described for therapeutic use (see WO 2010 / 082858). The crystal structures of lithium, sodium, potassium, rubidium and cesium salts are described in Guzei et al. (2013) Journal of Coordination Chemistry 66, 3722-3739. Therefore, this patent application also refers to the use of any pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1,4-phthalazinedione.

[0015] Fumaric acid esters (FAEs), also called fumarates, are ester derivatives of fumaric acid. Fumaric acid is an intermediate in the citric acid cycle, a fundamental cellular process that produces energy in mitochondria. Fumaric acid esters were developed as medicines because orally ingested fumaric acid is excessively irritating to the gastrointestinal tract (see Balak (2015) Psoriasis 5:9-23). ​​Dimethyl fumarate (DMF) is the most widely used fumaric acid ester to date. DMF is the methyl ester of fumaric acid. As an α,β-unsaturated carboxylic acid ester produced by reacting fumaric acid with methanol in the presence of sulfuric acid, DMF significantly stimulates mitochondrial tricarboxylic acid cycle activity and ATP production (Landeck et al. (2018) Arch Dermatol Res 310:475-483). Fumarate is poorly absorbed in the gastrointestinal tract, but DMF and its active metabolite, monomethyl fumarate (MMF), show strong bioavailability and exert beneficial effects on inflammation, neurodegeneration, and toxic oxidative stress (see Kourakis et al. (2020) Pharmaceuticals 13:306). Recently, diroximel fumarate (DRF) has been developed and shown to have comparable efficacy but fewer side effects (Naismith (2020) CNS Drugs 34:185-196). The mechanism of action of FAE appears to be mediated by activation of Nrf2 (nuclear erythroid 2-related factor), a transcription factor that upregulates the transcription of a set of antioxidant and phase II cytoprotective genes. The Nrf2 pathway is thought to be an important cellular defense system against potentially toxic stimuli. Another effect of FAE is its interaction with the anti-inflammatory hydroxycarboxylic acid receptor 2 (HCAR2) (Parodi et al. (2015) Acta Neuropathol 130:279-295 and Chen et al. (2014) J Clin Investig 124:2188-2194).

[0016] DMF is used to treat multiple sclerosis (MS) and relapsing-remitting MS (RRMS). For the treatment of moderate to severe psoriasis, DMF is used in the UK and a mixture of DMF and MMF salts (calcium, magnesium, zinc salts) is used in Germany. Ethyl hydrogen fumarate is a synonym of MMF.

[0017] A pharmaceutically acceptable salt should be considered in the context of this application as an active agent that contains a compound according to the invention in the form of a salt, especially when this salt provides specific or improved pharmacokinetic properties compared to the free form of the active agent or another salt of the active agent.A pharmaceutically acceptable salt of an active agent can also provide the active agent with pharmacokinetic properties that it does not have in its free form.Therefore, it can even positively affect the pharmacodynamics of the active agent with regard to its therapeutic effect in an organism.

[0018] Therefore, it is desirable to find an agent that can enhance the effect of fumaric acid esters, or pharma- ceutically acceptable salts thereof, in order to enhance the therapeutic effect in the treatment of multiple sclerosis, psoriasis and related diseases. A further desirable measure is to reduce the dosage of at least one of the fumaric acid esters or pharma- ceutically acceptable salts thereof, so that the adverse side effects associated therewith can be avoided or at least reduced. It is reasonable to assume that by reducing the dosage of at least one of the fumaric acid esters or pharma- ceutically acceptable salts thereof by the pharmaceutical combination according to the disclosure, those adverse side effects will also be reduced.

[0019] 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 simultaneously and at least one of these substances affects the activity of at least one other substance, a so-called drug-drug interaction occurs. When the 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. The final effect equal to the sum of the effects seen with the administration of the drugs alone is an additive synergistic effect. If the final effect is greater than the predicted effect, the term superadditivity is used. Smaller effects are less than additive. 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.

[0020] 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 an effect of two or more combined drugs that is greater than the expected additive effect of the drugs alone.

[0021] The use of synergistic drug combinations can enhance both therapeutic efficacy and potency, the latter primarily serving to reduce off-target toxicity.

[0022] The identification of drug-drug interactions relies on the null hypothesis of "no interaction", which is based on the observed drug responses and not on a model of 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 to identify such interactions, calculate the expected additive effect of two substances, and determine 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.

[0023] 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. The simple arithmetic sum method of additivity is based on the equation A+B=(A+B), where again A and B are the percent or fractional effect seen when each agent is administered alone, and (A+B) is the percent or fractional effect seen after administering these agents 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.

[0024] The fractional product law 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 given if 1-(1-A)*(1-B)>(A+B).

[0025] 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 the 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 and Martin N. ComboSyn, Inc. Paramus, NJ 2007 [www.combosyn.com]).

[0026] There are also further specific index values, such as, for example, the combination index (CI, equation of Chou and Talalay (1984) Adv Enzyme Reg 22:27-55) and the dose reduction index (DRI, Chou equation 1984), which can be easily calculated using the specific software mentioned above. Both of these values ​​allow to determine whether drug substances act 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 quantity 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. Thus, a CI of 1 also refers to the "additive line" of 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 or B alone that inhibit x%, respectively, and A(x) and B(x) represent the proportion of each drug that inhibits x% in combination as well. DRI is a measure of how many times the dose of each drug in a synergistic combination can be reduced at a given effect level 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) versus the fractal effect (Fa), preferably for a specific dose combination.

[0027] Multiple sclerosis (MS) is a collective term for the most frequent demyelinating diseases of the human central nervous system (CNS). Disease patterns vary widely among patients. However, there are two main variants with significantly different pathophysiology and clinical manifestations. The first variant is relapsing-remitting multiple sclerosis (RRMS), which accounts for approximately 80% of all cases, and the second variant is the chronic progressive form of multiple sclerosis, which is subdivided into primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS). In the International Classification of Diseases, 10th Revision (ICD-10-GM, German Modification, 2017 Edition, DIMDI 23 September 2016), RRMS, PPMS, and SPMS are classified as G35.1, G35.2, and G35.3, respectively. PPMS accounts for approximately 10-20% of all MS cases. There is ongoing controversy as to whether RRMS and PPMS / SPMS are two distinct disorders that coincidentally share some common pathophysiological features but are otherwise clearly distinct.

[0028] RRMS is characterized by unpredictable acute exacerbations (relapses) during the course of the disease, followed by a period of recovery to previous levels of underlying disease, often followed by complete recovery (remission). The time between relapses typically becomes shorter the longer the patient has had the disease. In most cases, RRMS begins with a clinically isolated syndrome (CIS). CIS represents an attack of one organ system, presumably due to demyelination. Between 30 and 70% of people who experience a CIS attack will later develop MS.

[0029] The beneficial effect of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt on RRMS has been postulated, for example, in WO 2011 / 107295 A1.

[0030] The clinical hallmark of PPMS is the accumulation of neurological disability without clear recovery (Cerda et al. (2016) Multiple Sclerosis and Demyelinating Disorders 1:9). Disease progression in PPMS is more insidious and subtle than in RRMS, where relapses are clearly defined. There is characteristic neuronal atrophy due to Wallerian degeneration caused by demyelination and neurodegenerative oxidative damage to the axons. The characteristic age of onset of clinical symptoms in PPMS patients is around 40 years of age. PPMS is disproportionately common in populations that are relatively resistant to MS (Africans, Orientals) and disproportionately common in men. The ratio of women to men affected by MS is generally about 3:1, but in PPMS it is about 1:1.

[0031] SPMS is diagnosed after a period of at least 3 months when the previous RRMS has ceased to cause relapses and clinical symptoms have continued to worsen. The symptoms of SPMS are similar to those of PPMS, but may differ quantitatively. Therefore, most clinicians consider SPMS and PPMS to be the same disease, and the only difference is whether or not there was a previous RRMS phase. The difference in the age of onset between RRMS and PPMS is usually about 10 years, but the transition from RRMS to SPMS occurs at about the same age as PPMS usually appears (Antel et al. (2012) Acta Neuropathol 123:627-638).

[0032] The beneficial effect of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt on PPMS and SPMS is shown in WO 2018 / 082814 A1.

[0033] Another group of neurodegenerative diseases associated with multiple sclerosis are the so-called white matter diseases (WMDs). Within the scope of this application, these are also called multiple sclerosis-associated WMDs, which affect the normal pattern of myelination and are a variety of congenital and acquired processes. They can be classified according to their cause into primary and secondary types. Primary demyelinating diseases have unknown etiology, such as multiple sclerosis. Secondary demyelinating diseases include a variety of known causes. The underlying condition is damage to the myelin sheath or myelin-producing cells, such as oligodendrocytes. The connecting link of the effect of the drug combination according to the present disclosure is the role of proinflammatory cytokines. Multiple sclerosis and WMDs share similar brain histology in the EAE (experimental autoimmune encephalomyelitis) model after the end of the experiment. It can therefore be reasonably assumed that drug combinations according to the present disclosure may similarly reduce the release of proinflammatory cytokines and the characteristic invasion / infiltration of leukocytes into the CNS in WMD, resulting in the formation of the typical cores of demyelinated axons (corresponding to white matter loss) identifiable either by staining or radiological methods, which is a common feature of WMD.

[0034] Typical WMDs include: - Acute disseminated encephalomyelitis (ADEM) is a rare autoimmune disease characterized by a sudden, widespread attack of inflammation in the central nervous system. It damages the myelin insulation and results in damage to the white matter. It is often caused by a viral infection (Garg (2003) Postgrad Med J 79 :11-17). - Neuromyelitis optica (NMO, synonym: Devic's disease) and Neuromyelitis optica spectrum disorder (NMOSD): characterized by acute inflammation mainly of the optic nerve. They are caused by immunoglobulin G autoantibodies against aquaporin 4 (anti-AQP4), the most abundant water channel protein in the central nervous system (Lana Peixoto et al. (2019) Biomedicines 7:42). - Idiopathic inflammatory demyelinating diseases are a type of multiple sclerosis. - Central pontine myelinolysis is a neurological disorder involving severe damage to the myelin sheaths of pontine neurons. It is primarily iatrogenic and is characterized by acute paralysis, dysarthria, and dysphagia (Yoon et al.(2008) Alcohol 43:647-649). - Tabes dorsalis (syphilitic myelopathy) is a sequela of neurosyphilis that is characterized by a delay in neurogenesis in the dorsal root ganglion. Patients experience stabbing neuralgia accompanied by coughing and sensory oculomotor ataxia. - Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal viral disease (infection with JC virus, human polyomavirus 2). PML is characterized by progressive damage or inflammation of the white matter of the CNS in multiple locations. PML occurs almost exclusively in severely immunocompromised patients, and these patients have a mortality rate of 30-50%. - Acute hemorrhagic leukoencephalopathy (AHL, Hurst disease) is a hyperacute, often fatal form of ADEM, characterized by venular necrotizing vasculitis, hemorrhage, and edema. - Toxic leukoencephalopathy is a rare disease in which progressive damage occurs to the white matter of the central nervous system due to drug use, environmental toxins, or exposure to chemotherapy drugs (Filley and Kleinschmidt-de Masters (2001) N Engl J Med 345:425-432). - Vanishing white matter disease (VWM disease) is an autosomal recessive neurological disorder. It is caused by mutations in the translation initiation factors eIF2B, EIF2B2, IF2B3, EIF2B4, or EIF2B5. Symptoms include cerebellar ataxia, spasticity, optic atrophy, epilepsy, loss of motor function, irritability, vomiting, and coma (van der Knaap et al. (2006) Lancet Neurology 5:413-423). - Leukoencephalopathy with neuroaxonal spheroids (LENAS) is a very rare idiopathic neurodegenerative leukoencephalopathy. LENAS causes severe, subacute dementia. Damage to the white matter occurs through swellings called spheroids. - Reversible posterior leukoencephalopathy syndrome (PRES) is a rare disorder in which parts of the brain become swollen, usually secondary to another condition such as severe high blood pressure, kidney failure, severe infection, or preeclampsia. Symptoms include headaches, visual disturbances, seizures, confusion, and limb weakness. - Megacephalic leukoencephalopathy with subcortical cysts (MLC, van der Knaap disease) is an inherited demyelinating disease of the central nervous system. It may be caused by mutations in the MLC1, MLC2A, or MLC2B genes (cf. van der Knaap et al. (1996) Acta neuropath 92:206-212). - Hypertensive leukoencephalopathy is a disease characterized by degeneration of the white matter of the central nervous system associated with a sudden increase in blood pressure. Other symptoms include acute confusion, headache, vomiting, seizures, and sometimes retinal hemorrhages and hard exudates. - Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder that affects sphingolipid metabolism. Leukodystrophies inhibit the growth and development of myelin. An autosomal recessive inheritance pattern has been identified in MLD. - Krabbe disease (KD, globular cell leukodystrophy, galactosylceramide lipidosis) is a rare, severe lysosomal storage disorder that causes progressive damage to the nervous system. Sphingolipoid metabolism is impaired. Inheritance is autosomal recessive. Symptoms include irritability, fever, limb rigidity, seizures, feeding problems, vomiting, staring episodes, and delayed cognitive and motor development (Wasserstein and Andriola (2016) Genetics in Medicine 18:1235-1243). - Canavan disease is a fatal autosomal recessive neurodegenerative disorder that results in the gradual loss of white matter in the central nervous system. The underlying cause is a deficiency of aminoacylase 2 (ASPA). Symptoms appear in early infancy and typically include intellectual disability, loss of previously acquired motor skills, feeding problems, abnormally low muscle tone, poor head control, macrocephaly, and occasionally paralysis, blindness, or seizures (Kumar et al. (2006) Mental Retardation and Developmental Disabilities Research Reviews 12:157-165). - Alexander disease is a very rare autosomal dominant leukodystrophy with abnormal myelin, especially seen in infants. Symptoms include delayed cognitive and physical development. Abnormal head size and seizures, as well as excessive vomiting, difficulty swallowing and speaking, loss of coordination and loss of motor control. The underlying cause is a defect in the GFAP (glial fibrillary acidic protein) gene. - Adrenomyeloneuropathy (ALD, X-linked adrenoleukodystrophy) is an X-linked disease (ABCD1 gene). It is caused by a defect in the chain of fatty acid transporters in peroxisomes, which leads to the accumulation of fatty acids and damage to the myelin sheath of nerve axons. Symptoms in early childhood include emotional lability, hyperactivity, and disruptive behavior. Typical symptoms in adulthood are muscle rigidity, paralysis, and sexual dysfunction (Moser et al.(2007) Nature Clin Pract Neurol 3:140-151). - Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive form of xanthomatosis caused by mutations in the CYP27A1 gene. It is characterized by cerebellar ataxia, juvenile cataracts, chronic diarrhea, neurological deficits, and tendon or tuberous xanthomas (Pilo de la Fuente et al. (2008) J Neurol 255:839-842). - Pelizaeus-Merzbacher disease is an X-linked neurological disorder that damages oligodendrocytes. It is caused by a mutation in the PLP1 (proteolipid protein 1) gene, which plays a key role in myelination. It is characterized by little or no movement of the limbs, difficulty breathing, and characteristic side-to-side eye movements. Early symptoms include nystagmus and decreased muscle tone (Hobson and Garbern (2012) Seminars in Neurology 32:62-67). - Hyperleukodystrophy type 7 (HLD7) is caused by autosomal recessive mutations in the POLR3A gene, leading to hypomyelination of axons. Symptoms include progressive motor decline, spasticity, ataxia, tremor, cerebellar symptoms, mild cognitive regression, and hypodontia (Wu et al. (2019) BMC pediatrics 19:289). - Refsum disease is an autosomal recessive disorder that results in excessive accumulation of phytanic acid in cells and tissues. The underlying cause is impaired alpha-oxidation of branched fatty acids due to mutations in the PEX7 gene. Patients present with nerve damage, cerebellar degeneration, and peripheral neuropathy. Other symptoms include ataxia, ichthyosis, hearing loss, and ophthalmological problems such as retinitis pigmentosa, cataracts, and night blindness (Masuhr (2013) Akt Neurol 40:58). - Tumor-like demyelinating disease occurs in individuals with demyelinating lesions that have atypical features of standard multiple sclerosis. - In Barrow's concentric sclerosis, damage to the brain's white matter appears in concentric layers, leaving the axial cylindrical area intact. This is a borderline form of multiple sclerosis. - Marburg multiple sclerosis (acute fulminant multiple sclerosis) is a borderline multiple sclerosis disease. The disease progresses so rapidly that it can cause severe disability within a few days and even death within a few months. - Schilder's disease (diffuse myelinating sclerosis) is a borderline form of multiple sclerosis characterized by pseudotumorous demyelinating lesions with plaques larger than 2 cm in diameter. - Sporadic sclerosis refers to discrete tumor-like demyelinating lesions larger than 2 cm that resemble intracranial tumors. - Myelocortical multiple sclerosis is a variant of multiple sclerosis in which demyelination occurs in the spinal cord and cerebral cortex, but not in the cerebral white matter. - Optospinal multiple sclerosis (OSMS) is a form of multiple sclerosis characterized by selective and severe damage to the optic nerves and spinal cord. (Fujiwara (2006) Clinical Neurology 46:866-868) - The features of pure spinal multiple sclerosis suggest spinal cord involvement due to multiple sclerosis, but other typical central nervous system manifestations are absent. - Multiple sclerosis associated with LHON (Leber's hereditary optic neuropathy) causes multiple sclerosis-like CNS damage. Demyelination leads to acute or subacute central vision loss. - Oligoclonal band-negative multiple sclerosis is a variant of multiple sclerosis in which there are no immunochemically stained IgG bands (Zeman et al. (1996) J Neurol Neurosurg Psych 60:27-30). - Oligoclonal IgM-positive multiple sclerosis is a variant of multiple sclerosis in which IgM is found intrathecally in addition to IgG (Monreal et al. (2021) Neurol Neuroimmun Neuroinflamm 8:5). - Lyme disease is a vector-borne disease caused by the Borrelia bacteria. It can cause a chronic encephalomyelitis similar to multiple sclerosis. It is progressive and can cause symptoms such as cognitive impairment, brain blurring, migraines, balance problems, leg weakness, awkward gait, facial paralysis, bladder problems, dizziness, and back pain. - Human immunodeficiency virus encephalopathy is a neurocognitive disorder due to HIV infection that is associated with metabolic encephalopathy and is caused by immune activation of macrophages and microglia (Gray et al. (2001) Clin Neuropathol 20:146-155).

[0035] In another aspect, the application relates to a method for treating a disease including relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, acute disseminated encephalomyelitis, neuromyelitis optica, idiopathic inflammatory demyelinating diseases, central pontine myelinolysis, tabes dorsalis, progressive multifocal leukoencephalopathy, acute hemorrhagic leukoencephalopathy, toxic leukoencephalopathy, vanishing white matter disease, leukoencephalopathy with neuroaxonal spheroids, reversible posterior leukoencephalopathy syndrome, macrocephalic leukoencephalopathy with subcortical cysts, hypertensive leukoencephalopathy, metachromatic leukodystrophy, Krabbe disease, Canavan disease, Alexander disease, cerebrotendinous xanthomatosis, Pelizaeus-Merzbacher disease, cerebral leukodysplasia type 7, Refsum disease, tumor-like demyelinating disease, The present invention relates to a pharmaceutical combination of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutical acceptable salts, hydrates or solvates, and at least one fumaric acid ester or a pharma- ceutical acceptable salt thereof, for use in the prophylaxis or treatment of myelocortical multiple sclerosis, Barro concentric sclerosis, Marburg multiple sclerosis, Schilder's disease, sporadic sclerosis, myelocortical multiple sclerosis, optic-spinal multiple sclerosis, pure spinal multiple sclerosis, LHON-associated multiple sclerosis, oligoclonal band-negative multiple sclerosis, oligoclonal IgM positive multiple sclerosis, Lyme disease, and human immunodeficiency virus encephalopathy.

[0036] Within the scope of this disclosure, these diseases are encompassed under the term "multiple sclerosis-type diseases" or "multiple sclerosis-related disorders."

[0037] Accordingly, the present disclosure provides a method and apparatus for treating acute disseminated encephalomyelitis, neuromyelitis optica, idiopathic inflammatory demyelinating disease, central pontine myelinolysis, tabes dorsalis, progressive multifocal leukoencephalopathy, acute hemorrhagic leukoencephalopathy, toxic leukoencephalopathy, vanishing white matter disease, leukoencephalopathy with neuroaxonal spheroids, reversible posterior leukoencephalopathy syndrome, macrocephalic leukoencephalopathy with subcortical cysts, hypertensive leukoencephalopathy, metachromatic leukodystrophy, Krabbe disease, Canavan disease, Alexander disease, cerebrotendinous xanthomatosis, Pelizaeus-Merzbacher disease, cerebral leukodysplasia type 7, Refsum disease, tumor-like demyelinating disease, Barrow concentric sclerosis, Marburg multiple sclerosis, Schilder disease, orphan The present invention also relates to 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt, a hydrate, or a solvate thereof, in the prophylaxis or treatment of a demyelinating disease selected from the group consisting of myelocortical multiple sclerosis, myelocortical multiple sclerosis, optic-spinal multiple sclerosis, pure spinal multiple sclerosis, LHON-associated multiple sclerosis, oligoclonal band-negative multiple sclerosis, oligoclonal IgM-positive multiple sclerosis, Lyme disease, and human immunodeficiency virus encephalopathy.

[0038] In other words, the present invention provides a method for treating acute disseminated encephalomyelitis, neuromyelitis optica, idiopathic inflammatory demyelinating disease, central pontine myelinolysis, tabes dorsalis, progressive multifocal leukoencephalopathy, acute hemorrhagic leukoencephalopathy, toxic leukoencephalopathy, vanishing white matter disease, leukoencephalopathy with neuroaxonal spheroids, reversible posterior leukoencephalopathy syndrome, macrocephalic leukoencephalopathy with subcortical cysts, hypertensive leukoencephalopathy, metachromatic leukodystrophy, Krabbe disease, Canavan disease, Alexander disease, cerebrotendinous xanthomatosis, Pelizaeus-Merzbacher disease, cerebral leukodysplasia type 7, Refsum disease, tumor-like demyelinating disease, Barrow concentric sclerosis, Marburg multiple sclerosis, Schilder disease, orphan The present invention also relates to 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt, a hydrate, or a solvate thereof, in the prophylaxis or treatment of a white matter disease selected from the group consisting of atopic dermatitis, myelopathy, rheumatoid arthritis ...

[0039] Psoriasis is a chronic, non-contagious autoimmune disease characterized by raised, abnormal skin. These areas are red or purple, dry, itchy, and above all scaly. These areas vary in size from small localized patches to covering the entire body (Boehncke, Schon (2015) Lancet 386:983-994). There is no known cure for psoriasis, but there are several symptomatic treatment options, including monoclonal antibodies and fumaric acid esters.

[0040] Plaque psoriasis typically appears as raised areas of inflamed skin covered with silvery-white scales. These areas, called plaques, are most commonly found on the elbows, knees, scalp, and back (Palfreeman et al. (2013) Drug Design Devel Ther 7:201-210).

[0041] Pustular psoriasis is characterized by raised, non-infectious pus-filled bumps. The skin under and around the pustules becomes red and painful. It is often localized to the hands and feet (Raychauduri et al. (2014) Autoimmun Rev 13;490-495).

[0042] Inverse psoriasis (flexural psoriasis) appears as smooth, inflamed patches of skin, often found in skin folds such as the genitals, armpits, fatty layers, between the buttocks, and in the inflamed folds under the breasts (Weigle and McBane (2013) Am Family Physician 87:627-633).

[0043] Diaper psoriasis typically occurs in infants, appearing as red, silvery-scaly bumps in the diaper area that may spread to the trunk and extremities.

[0044] Guttate psoriasis is characterized by numerous small, scaly, red or pink, droplet-like papules that appear over large areas of the trunk, as well as the hands, feet, and scalp. There may be an underlying streptococcal infection (Weigle and McBane (2013) Am Family Physician 87:627-633).

[0045] Erythrodermic psoriasis is characterized by widespread inflammation and peeling of the skin, often covering more than 90% of the body surface area. It is often an exacerbation of plaque psoriasis (Rendon and Schakel (2019) Int J Mol Sci 20:1475).

[0046] Seborrheic-like psoriasis is a type of psoriasis that combines symptoms of seborrheic dermatitis. It commonly occurs on the scalp, forehead, in the skin folds next to the nose, around the mouth, above the breastbone, and in skin folds.

[0047] Psoriatic arthritis is a chronic inflammatory autoimmune disease of the joints that belongs to the group of spondyloarthropathy. It often occurs in association with psoriasis of the skin and nails. Symptoms are painful inflammation of the joints and surrounding connective tissue, mainly of the fingers and toes (Goldenstein-Schainberg et al. (2012) Rev Brasil Reumatol 52:98-106). It shares various symptoms with rheumatoid arthritis, but also has some unique features. A form of psoriasis may occur at the same time. The etiology is currently unknown. Although any joint may be affected, typically the distal and interphalangeal joints of the hands and feet, the knee joint, and the sacroiliac joint are affected. The disease course is often asymmetric.

[0048] In another aspect, the present application relates to a pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt, a hydrate, or a solvate thereof 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt, a hydrate, or a solvate thereof, and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, for use in the prophylaxis or treatment of psoriasis, psoriasis vulgaris, pustular psoriasis, inverse psoriasis, diaper psoriasis, guttate psoriasis, erythrodermic psoriasis, seborrheic-like psoriasis, and psoriatic arthritis.

[0049] Within the scope of this disclosure, these diseases are encompassed under the term "psoriasis-type diseases" or "psoriasis-like disorders."

[0050] 5-amino-2,3-dihydro-1,4-phthalazinedione is often used as a hydrate, for example as the sodium salt dihydrate. Therefore, this patent application also relates to the use of all hydrates and other solvates of 5-amino-2,3-dihydro-1,4-phthalazinedione, or one of 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. Therefore, this patent application also relates to such complexes.

[0051] 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 WO 2011 / 107295 (form I, form II) and WO 2016 / 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 [Å] and the corresponding two-theta (2θ) angles [°] at which the Bragg reflections occur. This provides a unique and unambiguous fingerprint of each polymorph.

[0052] For Form I the following values ​​were determined: d-value: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1; 3.0 and / or 2Theta values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3.

[0053] Form II is characterized by the following values: d-value: 12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and / or 2Theta values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8.

[0054] For Form III the following values ​​were obtained: d value: 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 2Theta 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.

[0055] The use of the anhydrous form I of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is preferred.

[0056] 5-Amino-2,3-dihydro-1,4-phthalazinedione itself also exhibits polymorphism: Form I (Paradies (1992) Ber. Bunsen-Ges. Phys. Chem 96:1027-1031) and Form II (WO2017 / 140430) have been disclosed.

[0057] WO 2017 / 140430 also discloses that 5-amino-2,3-dihydro-1,4-phthalazinedione has great potential for the immunomodulatory treatment of inflammatory and autoimmune diseases. Crystalline Form II is particularly useful for the treatment of inflammatory and autoimmune respiratory diseases, such as upper and lower respiratory tract infections.

[0058] The present application therefore also relates to the use according to the invention of all crystalline forms of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharma- ceutically acceptable salts, hydrates and solvates, and of its polymorphs. The use of Form II of 5-amino-2,3-dihydro-1,4-phthalazinedione is preferred.

[0059] 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 WO 2007 / 018546. It is reasonable to assume that these compounds will show comparable effects when used in the therapeutic applications of the present invention.

[0060] 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 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). Thus, the present application also relates to the use of all tautomers of 5-amino-2,3-dihydro-1,4-phthalazinedione, and its pharma-ceutically acceptable salts, hydrates, and solvates.

[0061] Isomers are a general term for molecules with the same chemical formula but different chemical structures. They can be distinguished into constitutional (structural) isomers (where an exchange of atoms or functional groups occurs) and stereoisomers. Stereoisomers can be subdivided into enantiomers (non-superimposable mirror images of the same molecule) and diastereomers (the same molecule with different configurations at one or more stereocenters). Diastereomers can be subdivided into cis / trans isomers (referring to the relative orientation of functional groups in a molecule) and, on the other hand, into conformational isomers (rotation around a formally single bond) and rotamers (different rotation positions around a single bond). An example of a constitutional isomer of 5-amino-2,3-dihydro-1,4-phthalazinedione is 6-amino-2,3-dihydrophthalazine-1,4-dione (isoluminol). Stereoisomers may exist for phthalazinedione derivatives. Therefore, this patent application also relates to the use of all isomeric forms of 5-amino-2,3-dihydro-1,4-phthalazinedione, its derivatives, and its pharma- ceutically acceptable salts, hydrates, and solvates.

[0062] In some applications, for example for diagnostic purposes, it may be desirable to use isotopically enriched forms of the compounds of the invention, and therefore the present application also relates to such isotopically enriched forms of the compounds of the invention.

[0063] From a pharmacokinetic point of view or for manufacturing reasons, it may be preferable to use a prodrug as a dosage form. A prodrug is administered in a pharmacokinetically inactive form and is converted in the body by metabolism into an active form. This conversion can occur systemically or locally. Therefore, the present application also relates to prodrugs of the compounds of the present invention.

[0064] The term "5-amino-2,3-dihydro-1,4-phthalazinedione or a pharma- ceutically acceptable salt, hydrate, or solvate thereof" 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-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, a crystalline polymorph, a tautomer, or an isotopically enriched form.

[0065] Unless otherwise defined, technical or scientific terms used herein have the meanings ascribed to them by experts in the relevant art.

[0066] The term "composition" or "pharmaceutical composition" includes at least one active ingredient in at least one pharma- ceutically acceptable defined dosage and administration form, and at least one pharma- ceutically acceptable excipient, as well as any pharmaceutical agent 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.

[0067] 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.

[0068] The terms "effect," "therapeutic effect," "action," "therapeutic action," "efficacy," and "effectiveness" with respect to the disclosed pharmaceutical formulations or other active substances described herein refer to a beneficial result that occurs causally in an organism to which the substance has previously been administered.

[0069] According to the present invention, the terms "effective amount" and "therapeutically effective amount" refer to an amount of a substance of the present invention sufficient to bring about a desired beneficial effect in a subject in need of such treatment.

[0070] The terms "treatment" and "therapy" include administration of at least an agent of the invention alone or in combination with at least one other pharmaceutical agent, regardless of the chronological order of administration. Such administration is intended to substantially ameliorate the pathology of multiple sclerosis-type disease or psoriasis-type disease by either curing the disease entirely or by halting or slowing the progression of damage during the course of the disease.

[0071] The terms "prevention" or "prophylactic treatment" include administration of at least an agent of the invention alone or in combination with at least one other pharmaceutical agent, regardless of the chronological order of administration, to prevent or inhibit the onset of symptoms attributable to multiple sclerosis-type disease or psoriasis-type disease, particularly those conditions in a patient where the onset of such symptoms is expected to occur with a reasonable probability in the distant or near future.

[0072] The terms "subject" and "patient" include individuals with multiple sclerosis-type disease or psoriasis-type disease, either confirmed or suspected to be diagnosed with said disease. Individuals are mammals, particularly humans.

[0073] The pharmaceutical combination of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, hydrates or solvates and at least one fumaric acid ester or a pharma- ceutically acceptable salt thereof can be used as a monotherapy or can be further combined with at least one further active ingredient selected from the group comprising active ingredients used in the disease-modifying therapy of multiple sclerosis-type diseases or psoriasis-type diseases, their symptomatic treatment, and the treatment of complications.

[0074] 5-amino-23-dihydro-1,4-phthalazinedione, its pharma- ceutically acceptable salt, its hydrate, or its solvate. The pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, its pharma- ceutically acceptable salt, its hydrate, or its solvate, and at least one fumaric acid ester, or its pharma- ceutically acceptable salt, can be used simultaneously, separately, or sequentially to treat or prevent disease conditions. The at least two active agents can be provided in a single dosage form or as separate formulations, each formulation containing at least one of the two active agents. One or either active agent can be formulated as a bolus.

[0075] Disclosed is a pharmaceutical combination of 5-amino-2,3-dihydro-1,4-phthalazinedione, or one of its pharma- ceutical acceptable salts, and at least one fumaric acid ester, or one of its pharma- ceutical acceptable salts, for use in the treatment of multiple sclerosis-type disease or psoriasis-type disease that has been refractory to previous treatment with at least one other pharma- ceutical active agent.

[0076] The terms "medicine" or "healthcare" include veterinary medicine as well as human medicine.

[0077] The term "organism" refers to any living organism with an autoregulatory immune system, particularly a human or animal.

[0078] The term "active agent" in the present application, unless otherwise specified, refers to 5-amino-23-dihydro-1,4-phthalazinedione, its pharma- ceutically acceptable salts, its hydrates, or its solvates 5-amino-23-dihydro-1,4-phthalazinedione, its pharma- ceutically acceptable salts, its hydrates, or its solvates and at least one fumaric acid ester, or its pharma- ceutically acceptable salts. In addition, this term may include further agents known from the state of the art.

[0079] The terms "composition" and "pharmaceutical composition" include pharmaceutical combinations of 5-amino-23-dihydro-1,4-phthalazinedione, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, 5-amino-23-dihydro-1,4-phthalazinedione, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and at least one fumaric acid ester, or a pharmaceutically acceptable salt thereof, in any pharmaceutically suitable defined dose and dosage form, together with at least one suitable excipient and carrier material, as well as any material which may be produced directly or indirectly as a combination, accumulation, complex formation or crystallization of the aforementioned components, or which results from other reactions or interactions.

[0080] The term "excipient" is used in this application to describe each component of an excipient. A pharmaceutical composition includes an excipient in addition to an active agent. The selection of an appropriate excipient depends on factors such as the dosage form and dosage amount, and the effect of the excipient itself on the solubility and stability of the composition.

[0081] The term "action" describes the unique and specific mode of action of each drug within the scope of this application.

[0082] The terms "effect," "therapeutic effect," "action," and "therapeutic effect" with respect to at least one active agent according to the present invention refer to a beneficial outcome that causally occurs to an organism to which the at least one active agent is administered.

[0083] In this application, "therapeutically effective amount" means that a sufficient amount of the pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and at least one fumarate ester, or a pharma- ceutically acceptable salt thereof, is administered to an organism or patient in need of such treatment.

[0084] The terms "co-administration", "combined administration" or "simultaneous administration" of at least one agent according to the present invention and / or at least one agent according to the state of the art include administration of the mentioned agents at the same time or virtually close to each other, as well as administration of said agents at different times within a consistent experiment. The chronological order of administration of said agents is not limited by these terms. A person skilled in the art can easily deduce from his knowledge and experience the chronological or local order of the described administration.

[0085] The term "organism" refers to any animal, particularly a vertebrate animal, including humans. A "patient" in this application refers to an organism suffering from a definable and diagnosable disease and to which an appropriate active agent can be administered.

[0086] The terms "prevention", "treatment" and "therapy" include administration of a pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, or at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, to an organism in order to prevent the onset of a particular disease, suppress and alleviate the symptoms, or initiate the healing process of the respective disease.

[0087] 5-amino-23-dihydro-1,4-phthalazinedione, its pharmaceutically acceptable salt, its hydrate, or its solvate The pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, its pharmaceutically acceptable salt, its hydrate, or its solvate and at least one fumaric acid ester, or its pharmaceutically acceptable salt, can be administered by any medically acceptable route to a patient in need thereof for the prevention or treatment of multiple sclerosis-type disease or psoriasis-type disease. Such medically acceptable route of administration can be, for example, intravenous, oral, sublingual, topical, parenteral, intraperitoneal, intraarterial, intramuscular, dermal, transdermal, subcutaneous, intradermal, sublingual, intrathecal, or intracerebroventricular administration.

[0088] In particular, the present application relates to pharmaceutical combinations for use according to the disclosure, said pharmaceutical combinations being used in the prevention or treatment of conditions treatable with at least one fumaric acid ester.

[0089] A preferred oral formulation for use in the prevention or treatment of multiple sclerosis-type disease or psoriasis-type disease is a capsule or tablet containing 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof in an amount of 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg, preferably 100 mg, 150 mg, 200 mg, 300 mg, or 400 mg, most preferably 300 mg, and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof.

[0090] It is understood that within the scope of this disclosure, any combination of the above dosages of one of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, is disclosed.

[0091] In another aspect of the present invention, a pharmaceutical composition for use in the prevention or treatment of multiple sclerosis type disease or psoriasis type disease is disclosed, the pharmaceutical composition comprising 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, a carrier, and at least one pharma- ceutically acceptable excipient.

[0092] 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 present invention include carriers, binders, colorants, buffers, preservatives, antioxidants, coating agents, sweeteners, thickeners, pH adjusters, acidity adjusters, acidifiers, solvents, tonicity agents, disintegrants, glidants, lubricants, emulsifiers, solubilizers, stabilizers, diluents, anti-caking agents (anti-adherents), permeation enhancers, adsorbents, foaming agents, antifoaming agents, opacifiers, fatliquors, thickeners, hydrotropes, fragrances, and flavoring agents.

[0093] 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, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, 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 esters, polyethyl glycols, sorbitan fatty acid esters, 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.

[0094] The term binder refers to a substance that binds or glues 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.

[0095] 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 the binder in the composition is in the range of 1 to 30% by weight, preferably 2 to 20% by weight, more preferably 3 to 10% by weight, and most preferably 3 to 6% by weight.

[0096] 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 atomizer 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%.

[0097] Suitable pharmaceutical colorants 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 sulfite caramel, ammoniacal caramel, ammoniacal sulfite caramel, black PN, and the like. Carbon black, vegetable 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, flavaxanthin, lutein, cryptoxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, zeaxanthin, citranaxanthin, astaxanthin, betanin, anthocyanin, saffron, calcium carbonate, titanium dioxide, iron oxide, iron hydroxide, aluminum, silver, gold, rubin pigment, tannin, orcein, ferrous gluconate, and ferrous lactate.

[0098] Furthermore, buffers are suitable for liquid formulations, especially pharmaceutical liquid formulations. The terms buffer, buffer system, buffer, especially aqueous buffer, refer to the ability of a system to resist pH changes due to addition of acid or base, or dilution with a solvent. Preferred buffer systems include those containing 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[tris(hydroxymethyl)methylamino]propane), ethylenediamine, ACES (2-[(amino-2-oxoethyl)amino]ethanesulfonic acid), imidazole, MOPS (3-(N-morpholino)propanesulfonic acid), diethylmalonic acid, TES (2-[tris(hydroxymethyl)methyl]aminoethanesulfonic acid), HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid), and other buffers with pKa between 3.8 and 7.7.

[0099] 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.

[0100] 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, [epsilon]-N-acetyllysine, [omega]-N-methylarginine, citrulline, ornithine, and derivatives thereof. Particularly preferred is KH2PO4 buffer.

[0101] Preservatives for liquid and / or solid dosage forms may be used as needed, including 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, sulfite. The active ingredient is selected from the group including calcium hydrogen, potassium hydrogen sulfite, 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 skilled in the art.

[0102] 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.

[0103] 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 disclosed pharmaceutical composition. The specific composition and thickness of this gelatin layer determine how quickly absorption occurs after ingestion of the capsule. Of particular interest are sustained release formulations known in the art.

[0104] Suitable sweeteners may be selected from the group comprising mannitol, glycerol, acesulfame potassium, aspartame, cyclamate, isomalt, isomaltitol, saccharin and its sodium, potassium and calcium salts, sucralose, alitame, thaumatin, glycyrrhizin, neohesperidin dihydrochalcone, steviol glycosides, neotame, aspartame-acesulfame salt, maltitol, maltitol syrup, lactitol, xylitol, erythritol.

[0105] Suitable thickening agents may be selected from the group comprising polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, dextrin, polydextrose, modified starch, alkaline modified starch, bleached starch, oxidized starch, enzyme treated starch, monostarch phosphate, tert-butyl starch phosphate which is sodium trimetaphosphate or phosphorus oxychloride, phosphate di-starch phosphate, acetylated di-starch phosphate, tert-butyl starch acetate which is acetic anhydride, tert-butyl starch acetate which is 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.

[0106] Suitable pH adjusting agents for liquid dosage forms include, for example, sodium hydroxide, hydrochloric acid, buffer substances such as sodium dihydrogen phosphate or disodium hydrogen phosphate.

[0107] Suitable acidity regulators are acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, carbon dioxide, malic acid, fumaric acid, sodium lactate, potassium lactate, calcium lactate, ammonium lactate, magnesium lactate, citric acid, mono-, di-, trisodium citrate, mono-, di-, tripotassium citrate, mono-, di-, tricalcium citrate, tartaric acid, mono-, disodium tartrate, mono-, dipotassium tartrate, sodium potassium tartrate, orthophosphoric acid, lecithin citrate, magnesium citrate, ammonium malate, sodium malate, sodium hydrogen malate, calcium malate, calcium hydrogen malate, adipic acid, sodium adipate. , 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.

[0108] Oxidizing agents are inorganic chemicals that produce or become acids. Suitable examples include ammonium chloride and calcium chloride.

[0109] 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.

[0110] Suitable isotonicity agents include, for example, pharma- ceutically acceptable salts, in particular sodium chloride and potassium chloride, sugars such as glucose or lactose, sugar alcohols such as mannitol and sorbitol, citrates, phosphates, borates, and mixtures thereof.

[0111] 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. Moisture expansion is promoted by, for example, starch, cellulose derivatives, alginates, polysaccharides, dextran, crosslinked polyvinylpyrrolidone. 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.

[0112] 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.

[0113] 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, for example, 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, polyethylene glycols.

[0114] The emulsifier may 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 eukami seaweed, locust bean gum, tragacanth, acacia gum, karaya gum, gellan gum, gum ghatti, glucomannan, pectin, amidated pectin, ammonium phospholipids, brominated vegetable oil, sucrose acetate isobutyrate, glycerol ester of wood rosin, 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 sucrose, sodium carboxymethylcellulose, ethyl hydroxyethylcellulose, croscarmellose, enzymatically hydrolyzed carboxymethylcellulose, mono- and diglycerides of fatty acids, glyceryl monostearate, glyceryl distearate, acetate esters of mono- and diglycerides of fatty acids, lactate esters of mono- and diglycerides of fatty acids, 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, acetate and tartaric acid mixed esters of mono- and diglycerides of fatty acids, succinylated monoglycerides, sucrose esters of fatty acids, sucroglycerides, polyglycerol esters of fatty acids, polyglycerol polyricinoleate, propane-1,2-Diol esters, propylene glycol esters of fatty acids, lactate fatty acid esters of glycerol and propane-1, mono- and diglycerides of fatty acids, sodium dioctyl sulfosuccinate, sodium stearoyl-2-lactylate, calcium stearoyl-2-lactylate, stearyl tartaric acid, stearyl citric acid, sodium stearoyl fumarate, calcium stearoyl fumarate, stearyl tartaric acid, stearyl citric acid, sodium stearoyl fumarate, calcium stearoyl fumarate , sodium lauryl sulfate, ethoxylated mono- and diglycerides, methyl glucoside coconut oil esters, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate, sodium calcium polyphosphate, calcium polyphosphate, ammonium polyphosphate, cholic acid, choline salts, distarch glycerol, starch sodium octenylsuccinate, acetylated oxidized starch. Phospholipids such as glycerol monooleate, stearic acid, and lecithin are preferred.

[0115] Suitable surface-active solubilizers include, for example, diethylene glycol monoethyl esters, polyethylene propylene glycol copolymers, cyclodextrins such as α- and β-cyclodextrins, 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, and (anionic) glyceryl monooleate.

[0116] Stabilizers are substances that can be added to prevent undesirable changes. Stabilizers are not true emulsifiers, but they also contribute to the stability of emulsions. 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.

[0117] Diluents or fillers are inert substances added to a drug to handle a minimal 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.

[0118] Anti-caking agents (anti-adherents) can be added to the supplement or supplement composition to prevent the formation of lumps and facilitate packaging, shipping, 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.

[0119] 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 protect tablets / capsules from moisture by limited liquid adsorption (the absorption of liquids or gases by adsorption or sorption) in dry conditions.

[0120] 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. Alternatively, the foam can be stabilized. Suitable examples include mineral oil, Quillaja extract, triethyl citrate, sodium lauryl ether sulfate, sodium lauryl sulfate, and ammonium lauryl sulfate.

[0121] 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. Therefore, it may be desirable to add a pharma- ceutically acceptable antifoaming agent (defoamer). Examples include polydimethylsiloxane or silicone oil in dietary supplements and simethicone in pharmaceuticals.

[0122] 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, the opacifier 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.

[0123] Suitable fatliquors include, for example, decyl oleate, hydrated castor oil, light mineral oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, and the like.

[0124] Examples of thickening agents include cetyl alcohol, cetyl ester wax, hydrated castor oil, microcrystalline wax, non-ionic emulsifying wax, beeswax, paraffin, or stearyl alcohol.

[0125] Suitable hydrotropes are alcohols, such as ethanol, isopropyl alcohol, or polyols, such as glycerin.

[0126] Suitable aroma and flavoring substances include essential oils that can be used for this purpose. In general, this term refers to volatile extracts from plants or plant parts that have their respective characteristic odors. These can be extracted from plants or plant parts by steam distillation.

[0127] Suitable examples are 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. Phosphorus, 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-isoamyl cinnamic acid, α-terpinene cinnamate, 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 lavender, spi Ranthol, starflower, 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, and the like, or mixtures thereof, as well as menthol, peppermint, star anise oil, or a mixture of menthol and cherry flavor.

[0128] These aromatic or flavouring substances may be present in the range of 0.0001 to 10% by weight (particularly in the composition), preferably 0.001 to 6% by weight, more preferably 0.001 to 4% by weight and most preferably 0.01 to 1% by weight, based on the total composition. It may be advantageous to use different amounts in relation to the application or individual case.

[0129] According to the present invention, all the aforementioned excipients and excipient classes can be used without restriction, either 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 does not violate the laws of the respective countries.

[0130] In another aspect of the invention, the application relates to a pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, or 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, for use in an oral formulation in the prophylaxis or treatment of multiple sclerosis-type diseases or psoriasis-type diseases.

[0131] Pharmaceutical formulations suitable for oral administration of a pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, may 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.

[0132] 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 comminuting 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, or coloring agents may also be present.

[0133] 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 appropriately comminuted compound 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, cellulose, or a solution of polymeric material, 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 then broken into granules. The granules can also be lubricated with the addition of stearic acid, a stearate salt, talc, or mineral oil to prevent the tablets from sticking to the mold. The lubricated mixture is then compressed to produce tablets. The compounds of the present invention can also be mixed with a free-flowing inert excipient and compressed directly to give tablets without carrying out the granulation or dry-pressing steps.

[0134] In another aspect of the present invention, 5-amino-23-dihydro-1,4-phthalazinedione, its pharma- ceutically acceptable salt, its hydrate, or its solvate, and a pharmaceutical combination with at least one fumaric acid ester, or its pharma- ceutically acceptable salt, are provided in hard gelatin capsules. These are produced by preparing a powder mixture as described above and filling it into a formed 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 ingestion of the capsule. Furthermore, suitable binders and / or coloring agents can be added to the mixture if desired or necessary.

[0135] In another aspect of the invention, 5-amino-23-dihydro-1,4-phthalazinedione, its pharma- ceutically acceptable salt, its hydrate, or its solvate. 5-amino-23-dihydro-1,4-phthalazinedione, its pharma- ceutically acceptable salt, its hydrate, or its solvate, and at least one fumaric acid ester, or its pharma- ceutically acceptable salt, are contained in a soft gelatin capsule (SGC). SGCs dissolve as they pass through the digestive tract. They consist primarily of gelatin reinforced with various amounts of plasticizers such as glycerol or sorbitan. The release rate depends on the specific formulation of the SGC carrier material. They are also suitable for sustained release of active agents. SGCs are particularly useful for the administration of active agents that are poorly soluble in water.

[0136] In another aspect of the invention, the pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, is included in a chewable tablet or hard caramel, where the material is incorporated into the matrix of the tablet or caramel.

[0137] In yet another aspect of the invention there is provided a pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to the invention for use in the prevention or treatment of multiple sclerosis type diseases or psoriasis type diseases, wherein said pharmaceutical combination or pharmaceutical composition is applied in the form of liposomes, micelles, multilamellar vesicles or cyclodextrin complexes.

[0138] In yet another aspect of the invention, the present application relates to a pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, for use in the prophylaxis or treatment of multiple sclerosis-type diseases or psoriasis-type diseases in a sublingual tablet formulation.

[0139] In yet another aspect of the invention, the application relates to a pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, or 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to the invention for use in a liquid dosage form for the prophylaxis or treatment of multiple sclerosis type diseases, or psoriasis type diseases.

[0140] The present application also discloses the parenteral administration in the form of intravenous, intraarterial or intraperitoneal injection of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, a pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention, in the prophylaxis or treatment of multiple sclerosis type diseases or psoriasis type diseases.

[0141] These liquid dosage forms include solutions, suspensions, and emulsions. Examples include water and water / propylene glycol solutions for parenteral injection or oral solutions, suspensions, and emulsions with the addition of sweeteners or opacifiers. They can be stored in vials, IV bags, ampoules, cartridges, or prefilled syringes. Suitable excipients include solubilizers, stabilizers, buffers, tonicity adjusters, bulking agents, viscosity enhancers / reducers, surfactants, chelating agents, adjuvants, etc.

[0142] In yet another aspect of the present invention, the pharmaceutical combination of 5-amino-23-dihydro-1,4-phthalazinedione, its pharmaceutically acceptable salt, its hydrate, or its solvate, 5-amino-23-dihydro-1,4-phthalazinedione, its pharmaceutically acceptable salt, its hydrate, or its solvate, and at least one fumaric acid ester, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to the present invention is for use in the prevention or treatment of multiple sclerosis type disease or psoriasis type disease, said pharmaceutical combination or pharmaceutical composition is formulated as a lyophilizate.The lyophilizate can be reconstituted with water for injection or saline or water / ethanol solution and administered by injection.

[0143] Common applications of intravenous injections include infusion pumps, hypodermic needles, drop chambers, peripheral cannulas (peripheral venous catheters), and pressure bags.

[0144] Generally, aqueous or saline solutions are preferred, although in the case of poorly soluble drugs of the invention, ethanol or ethanol / water mixtures may also be used.

[0145] Another suitable liquid dosage form is a drop.

[0146] A gel is a colloid in which a solid dispersed phase combines with a fluid continuous phase to form a network, resulting in a viscous semi-rigid sol. Gels can vary in properties from soft and weak to hard and tough. A gel is defined as a substantially dilute cross-linked system that does not exhibit flow at steady state. By weight, a gel is mostly liquid, but behaves like a solid due to a three-dimensional cross-linked network within the liquid. It is the cross-links within the fluid that give the gel its viscosity and contribute to its stickiness. A gel is a dispersion of liquid molecules within a solid medium.

[0147] A hydrogel is a network of hydrophilic polymer chains, which may exist as a colloidal gel in which water is the dispersion medium. The hydrophilic polymer chains are linked 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, which gives them flexibility very similar to natural tissue. 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.

[0148] 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.

[0149] Sublingual administration is an alternative to oral administration because it bypasses hepatic metabolism. For some drugs, especially those used to treat acute diseases, 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.

[0150] Drugs must be lipophilic enough to pass through the lipid bilayer, but not so lipophilic that once inside, they cannot exit again. According to the diffusion model of absorption, the flow 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 use 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.

[0151] 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, generating an endothermic heat of solution. They create a pleasant sensation in the mouth and, together with other flavors, are ideal for sublingual tablets.

[0152] 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).

[0153] For topical administration comprising a combination of at least one fumaric acid ester, or one of its pharma- ceutically acceptable salts, and 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt, a hydrate, or a solvate thereof, a pharmaceutical composition according to the disclosure for use according to the present invention, a cream, emulsion, lotion, gel, hydrogel, paste, powder, ointment, liniment, film, liposome, skin patch, transdermal patch, transdermal spray or suspension is suitable.

[0154] Permeation enhancers are often used in topical dosage forms.Suitable permeation enhancers include, but are not limited to, all pharma- ceutically acceptable permeation enhancers known in the art, such as azones such as laurocapram, 1-dodecylazacycloheptan-2-one, sulfoxides such as dimethylsulfoxide, 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, non-ionic surfactants such as polyoxyethylene-2-oleyl ether, polyoxyethylene-2-stearyl ether, terpenes, terpenoids, oxazolidinones, urea, etc. 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 Chen et al. (2014) Asian J.Pharm.Sc. 9,51-64), citrate esters (such as triethyl citrate), hydrophobin polypeptides, α-bisabolol. 、 Dimethyl isosorbide (Arlasolve® DMI), ethoxydiglycol. 1,2-propanediol is preferred.

[0155] Typical examples of preservatives suitable for 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 methylmercuric thiosalicylate). Methylparaben, propylparaben, and sodium methylparaben and sodium propylparaben are preferred.

[0156] In topical administration forms, the addition of an antioxidant is particularly preferred.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 is preferred.

[0157] 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.

[0158] Cream formulations may also contain other excipients or additives such as fatliquors to improve flow, solvents, thickeners, 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.

[0159] Surprisingly, co-administration of pharmaceutical combinations according to the present invention is shown to not only exhibit a general additive effect, but to exhibit this effect across the broad range of fixed ratios tested.

[0160] The term "ratio" or "fixed ratio" herein refers to any kind of ratio between two components, 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 at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, and 5-amino-2,3-dihydro-1,4-phthalazinedione, or one of its pharma- ceutically acceptable salts, is 1:10, which can be implemented, for example, as 1 mg:10 mg, 1 mg / kg:10 mg / kg, 1 mM / 10 mM, or 1%:10%, or in any other units, as long as the ratio itself is 1:10.

[0161] The present patent application also relates to a pharmaceutical combination comprising 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof and at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition according to the invention, for use in the prevention or treatment of multiple sclerosis type diseases or psoriasis type diseases, the efficacy of which prevention or treatment is significantly improved compared to the respective treatment with said at least one fumaric acid ester alone.

[0162] Furthermore, the pharmaceutical combination according to the present disclosure may be used for the prevention or treatment of multiple sclerosis-type diseases or psoriasis-type diseases, wherein the components may be used in any ratio.

[0163] However, in order to obtain the best possible effect on the medical indication being treated, the feasibility of the efficacy, application forms and ratios of the pharmaceutical combinations disclosed herein must be considered from a practical point of view, the latter especially with a view to maintaining patient compliance.

[0164] 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.

[0165] Depending on the application form, the indication to be treated and the patient's personal risk status, at least one fumaric acid ester is administered, for example, as a capsule (Tecfidera®), a gastric acid-resistant tablet (Fumaderm®) or a tablet (Skilarence®).

[0166] Fumarates should be administered cautiously, starting at low doses for the first week and then gradually increasing the dose.

[0167] The typical dosage for Tecfidera® (dimethyl fumarate) is started with a single dose of 120 mg every 12 hours (q12hr), or 240 mg per day, increased to 240 mg every 12 hours (q12hr), or 480 mg per day.

[0168] A typical dosage for Fumaderm® (120 mg dimethyl fumarate, 87 mg calcium ethyl hydrogen fumarate (also known as monomethyl fumarate), 5 mg magnesium ethyl hydrogen fumarate, and 3 mg zinc ethyl hydrogen fumarate per tablet) in the treatment of severe psoriasis starts at 215 mg every 24 hours, which is increased successively to 2 tablets every 8 hours, i.e. 1290 mg per day.

[0169] A typical dosage for Skilarence® (dimethyl fumarate) begins at 30 mg every 24 hours, which is gradually increased over several weeks to two 120 mg tablets every 8 hours, or 720 mg per day.

[0170] 5-Amino-2,3-dihydro-1,4-phthalazinedione sodium salt has been shown to be very safe, however, for compliance reasons, the dosage should not exceed 10 g / day for tablets or capsules.

[0171] Thus, the pharmaceutical combination according to the present disclosure can be used for the prevention or treatment of multiple sclerosis-type disease or psoriasis-type disease, and can comprise at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, and 5-amino-2,3-dihydro-1,4-phthalazinedione, or one of its pharma- ceutically acceptable salts, hydrates, or solvates, preferably in any ratio of 1.5:1 to 1:40, more preferably 1:1 to 1:30, even more preferably 1:3 to 1:20, and most preferably 1:5 to 1:10.

[0172] Thus, the present application relates to the use of a pharmaceutical combination comprising at least one fumaric acid ester, or one of its pharma- ceutically acceptable salts, and 5-amino-23-dihydro-1,4-phthalazinedione, its pharma- ceutically acceptable salts, its hydrates, or its solvates in a weight ratio of dosages of 5-amino-23-dihydro-1,4-phthalazinedione, its pharma- ceutically acceptable salts, its hydrates, or its solvates in the range of 1.5:1 to 1:40.

[0173] However, higher doses and / or volumes may be administered in liquid form without adversely affecting patient compliance.

[0174] Further ratios for liquid or intravenous administration can be calculated based on the examples of the present disclosure.Accordingly, the present application relates to the use of a pharmaceutical combination in which the weight ratio of the dosage of at least one fumaric acid ester, or one of its pharmaceutically acceptable salts, to 5-amino-23-dihydro-1,4-phthalazinedione, its pharmaceutically acceptable salts, its hydrates, or its solvates ranges from 1:5 to 1:80, preferably 1:10 to 1:80, most preferably 1:20 to 1:80.

[0175] Due to the superadditive nature of the pharmaceutical formulation of the present invention, the dosage of at least one fumaric acid ester, or pharmaceutical salt thereof, 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 obtain optimal results.

[0176] Thus, the dosage of the at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, in the pharmaceutical combination of the present invention can be reduced by up to 80%, preferably by 50%, and most preferably by 20%, compared to the dosage when the at least one fumaric acid ester, or a pharma- ceutically acceptable salt thereof, is administered alone.

[0177] The present invention also relates to 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt, hydrate or solvate thereof for use in a method for the treatment and / or prevention of multiple sclerosis type disease in a subject, the method comprising administering to the subject an effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, and simultaneously or subsequently administering an effective amount of at least one fumaric acid ester, or one of its pharma- ceutically acceptable salts.

[0178] The present invention relates to 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt, hydrate or solvate thereof for use in a method for the treatment and / or prevention of psoriasis-type diseases, the method comprising administering to a subject an effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, and simultaneously or subsequently administering an effective amount of at least one fumaric acid ester, or one of its pharma- ceutically acceptable salts.

[0179] The present invention also relates to 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof for use in a method for the treatment and / or prevention of multiple sclerosis type diseases in a subject, the method comprising administering to the subject an effective amount of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, concomitantly or subsequently, an effective amount of at least one fumaric acid ester, or one of its pharma- ceutically acceptable salts, wherein the 5-amino-2,3-dihydro-1,4-phthalazinedione is a sodium salt.

[0180] The present invention also relates to 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof for use in a method for the treatment and / or prevention of a psoriasis-type disease in a subject, the method comprising administering to the subject an effective amount of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, concomitantly with or subsequent to the administration of an effective amount of at least one fumaric acid ester, or one of its pharma- ceutically acceptable salts, wherein the 5-amino-2,3-dihydro-1,4-phthalazinedione is a sodium salt.

[0181] The present invention also relates to 5-amino-23-dihydro-1,4-phthalazinedione, any one of its pharma- ceutically acceptable salts, hydrates, or solvates for use in a method for the treatment and / or prevention of multiple sclerosis type diseases in a subject, the method comprising administering to the subject an effective amount of at least one fumaric acid ester, or any one of its pharma- ceutically acceptable salts, concomitantly or subsequently with an effective amount of 5-amino-23-dihydro-1,4-phthalazinedione, any one of its pharma- ceutically acceptable salts, hydrates, or solvates.

[0182] The present invention also relates to 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof for use in a method for the treatment and / or prevention of a psoriasis-type disease in a subject, the method comprising administering to the subject an effective amount of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, concomitantly with or subsequent to an effective amount of at least one fumaric acid ester, or one of its pharma- ceutically acceptable salts.

[0183] The present invention also relates to 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof for use in a method for the treatment and / or prevention of multiple sclerosis-type diseases in a subject, the method comprising administering to the subject an effective amount of 5-amino-23-dihydro-1,4-phthalazinedione, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, concomitantly or subsequently with an effective amount of at least one fumaric acid ester, or one of its pharma- ceutically acceptable salts, wherein 5-amino-2,3-dihydro-1,4-phthalazinedione is the sodium salt.

[0184] The present invention also relates to 5-amino-23-dihydro-1,4-phthalazinedione, one of its pharma- ceutically acceptable salts, one of its hydrates, or one of its solvates for use in a method for the treatment and / or prevention of a psoriasis-type disease in a subject, the method comprising administering to the subject an effective amount of at least one fumaric acid ester, or one of its pharma- ceutically acceptable salts, concomitantly or subsequently, with an effective amount of 5-amino-23-dihydro-1,4-phthalazinedione, one of its pharma- ceutically acceptable salts, one of its hydrates, or one of its solvates, wherein the 5-amino-2,3-dihydro-1,4-phthalazinedione is a sodium salt.

[0185] In a further aspect of the invention, a method of treatment is disclosed comprising administering an effective amount of a pharmaceutical composition according to the present disclosure for use in treating a patient suffering from a multiple sclerosis-type disease or a psoriasis-type disease and in need of such treatment.

[0186] example In all experiments, solutions containing 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt are prepared using the anhydrous Form I of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt described above (provided by MetrioPharm).

[0187] Example 1: Effect of the combination of dimethyl fumarate and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt on in vitro cell systems

[0188] Various combinations of dimethyl fumarate and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt were tested in cell systems to determine whether they had greater than additive effects 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 to confluence in 96-well plates, after which PBMCs were added. Dimethyl fumarate and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I were provided by the applicant. Stock solutions of dimethyl fumarate were prepared in DMSO (dimethyl sulfoxide) and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in PBS (phosphate-buffered saline) and thawed before the experiment. They were added at the indicated concentrations 1 h before stimulation and incubated for 72 h. 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.

[0189] Cell proliferation was 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).

[0190] The following concentrations and combinations were tested: a) 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt as a single substance: 1mM-0.5mM-0.25mM b) As a single substance, dimethyl fumarate: 50μM-25μM-12.5μM c) Combination: 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 50μM dimethyl fumarate 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 25μM dimethyl fumarate 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 12.5μM dimethyl fumarate 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 50μM dimethyl fumarate 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 25μM dimethyl fumarate 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 12.5μM dimethyl fumarate 0.25mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 50μM dimethyl fumarate 0.25mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 25μM dimethyl fumarate 0.25mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + 12.5μM dimethyl fumarate The following physiological parameters were determined: a) sTNF-α (soluble tumor necrosis factor alpha) b) sIgG (secretory immunoglobulin G)

[0191] TNF-α is a major proinflammatory cytokine released primarily by macrophages in local and systemic inflammation. TNF-α can regulate the activity of several immune cell types and induce apoptosis, cell proliferation, cell differentiation, and the release of further cytokines. It is a prominent marker of inflammation in general, and in diseases such as multiple sclerosis and psoriasis in particular.

[0192] IgG is the most abundant antibody species in blood and extracellular fluids and contributes to humoral immunity. Besides its well-known anti-pathogen activity, IgG is an established biomarker of inflammation, especially in autoimmune diseases, and is widely used for early diagnosis and disease monitoring. In multiple sclerosis, oligoclonal bands (OCBs) and IgG index are valuable biomarkers for early diagnosis of disease and monitoring the course of disease across relapses and remissions. IgG is significantly increased in most patients (see Zheng et al. (2020) Front Immunol 11:1799). The same is true for psoriasis (see Ramessur et al. (2022) Br J Dermatol. 187:481-493).

[0193] Measurements were performed in triplicate and the results were averaged and then divided by the average of the solvent control samples to generate a ratio, then log 10 was converted to. a) For sTNF-α, the results for 0.25 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, three concentrations of dimethyl fumarate and their respective combinations are shown in FIG. 1A. For sTNF-α, the results for four concentrations of 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, dimethyl fumarate, and their respective combinations are shown in FIG. 1B. For sTNF-α, the results for 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, four concentrations of dimethyl fumarate and their respective combinations are shown in FIG. 1C. b) For sIgG, the results for four concentrations and their combinations of 0.25 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, dimethyl fumarate are shown in FIG. 3A. For sIgG, the results for four concentrations of 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and dimethyl fumarate and their respective combinations are shown in FIG. 3B. For sIgG, the results for 1 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, four concentrations of dimethyl fumarate and their respective combinations are shown in FIG. 3C.

[0194] Each reduction in cytokine release is shown as the mean ± SEM (n = 3). Statistics were performed by unpaired Student's t-test with Welch's correction. Comparisons were made between each combination of dimethyl fumarate concentration and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt. a) For sTNF-α, a concentration-dependent reduction in the panel was observed for all combinations of 0.25mM, 0.5mM and 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt. The effect was more pronounced with higher concentrations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and was significant (up to p<0.05). b) For sIgG, a concentration-dependent reduction in the panel was observed for all combinations of 0.25mM, 0.5mM, and 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt. The effect was more pronounced with higher concentrations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and was highly significant (up to p<0.001).

[0195] 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 dimethyl fumarate. Thus, the addition of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt can enhance the anti-inflammatory effect of dimethyl fumarate. Furthermore, this can be considered as evidence that 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt can be used for dose-sparing of dimethyl fumarate and / or other fumarate esters. Therefore, it is reasonable to assume that the adverse side effects of treatment with fumarate esters are suppressed or at least significantly reduced by combined treatment with dimethyl fumarate and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt.

[0196] Example 2: Examining additive effects CompuSyn software confirms the superadditive effect of the combination of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and dimethyl fumarate.

[0197] As mentioned above, the CompuSyn software model for additive effects (www.combosyn.com) is a computer modulating method for evaluating the additive effects of two substances in biological systems. Through 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 of Example 1 are de-logarithmized.

[0198] Fa / CI plots (non-constant ratios) for all drug combinations tested The horizontal axis shows the fractal effect (Fa), i.e., the relative inhibition of proinflammatory cytokine release by each drug combination of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and dimethyl fumarate, 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.

[0199] Figure 2 shows that all nine combinations show a significant additive effect on sTNF-α release. This computational evaluation confirms the results shown in Figures 1a)-c).

[0200] This computational evaluation confirms the results shown in Figure 3a)-c), showing a significant superadditive effect on sIgG release, with one combination showing a subadditive effect. [Brief description of the drawings]

[0201] L: 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt D: Dimethyl fumarate *:p<0.05; **:p<0.01 ***:p<0.001 Figure 1 A: Bars for reduction in release of sTNF-α: 0.25mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 50μM dimethyl fumarate 50μM dimethyl fumaric acid + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 25μM dimethyl fumarate 25μM dimethyl fumaric acid + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 12.5μM dimethyl fumarate 12.5μM dimethyl fumaric acid + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt B: Bars showing decreased sTNF-α release: 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 50μM dimethyl fumarate 50μM dimethyl fumaric acid + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 25μM dimethyl fumarate 25μM dimethyl fumaric acid + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 12.5μM dimethyl fumarate 12.5μM dimethyl fumaric acid + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt C: Bars showing the reduction in release of sTNF-α: 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 50μM dimethyl fumarate 50μM dimethyl fumaric acid + 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 25μM dimethyl fumarate 25μM dimethyl fumaric acid + 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 12.5μM dimethyl fumarate 12.5μM dimethyl fumaric acid + 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt Figure 2 Fa / CI diagram of the results of Example 1 for sTNF-α generated by CompuSyn software Fa: Fractal effect CI: Combination Index Figure 3 A: Bar to suppress release of sIgG 0.25mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 50μM dimethyl fumarate 50μM dimethyl fumaric acid + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 25μM dimethyl fumarate 25μM dimethyl fumaric acid + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 12.5μM dimethyl fumarate 12.5μM dimethyl fumaric acid + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt B: Bars showing the decrease in release of sIgG: 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 50μM dimethyl fumarate 50μM dimethyl fumaric acid + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 25μM dimethyl fumarate 25μM dimethyl fumaric acid + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 12.5μM dimethyl fumarate 12.5μM dimethyl fumaric acid + 0.5mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt C: Bars showing the decrease in release of sIgG: 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 50μM dimethyl fumarate 50μM dimethyl fumaric acid + 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 25μM dimethyl fumarate 25μM dimethyl fumaric acid + 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 12.5μM dimethyl fumarate 12.5μM dimethyl fumaric acid + 1mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt Figure 4 Fa / CI diagram of sIgG Example 1 results generated by CompuSyn software Fa: Fractal effect CI: Combination Index

Claims

1. 5-amino-2,3-dihydro-1,4-phthalazinedione, or a pharmaceutically acceptable salt thereof; and, Fumarate esters, or pharmaceutically acceptable salts thereof; The use of combinations of these in the manufacture of pharmaceuticals.

2. The use described in claim 1, The aforementioned pharmaceuticals are used for relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, acute disseminated encephalomyelitis, neuromyelitis optica, idiopathic inflammatory demyelinating disease, central pontine myelin lysis, tabes dorsalis, progressive multifocal leukoencephalopathy, acute hemorrhagic leukoencephalopathy, toxic leukoencephalopathy, white matter disappearance disease, leukoencephalopathy with nerve axonal spheroids, reversible posterior leukoencephalopathy syndrome, macrocephalic leukoencephalopathy with subcortical cysts, hypertensive leukoencephalopathy, and metachromatic Use as a prophylactic or therapeutic agent for leukodystrophy, Krabbe disease, Canavan disease, Alexander disease, adrenal spinal neuropathy, cerebral tendon xanthomatous encephalopathy, Pelizaeus-Merzbacher disease, cerebral white matter dysplasia type 7, Refsum disease, neoplastic demyelinating disease, Barlow concentric sclerosis, Marburg multiple sclerosis, Schilder's disease, sporadic sclerosis, myelocortic multiple sclerosis, neurospinal optic multiple sclerosis, pure spinal multiple sclerosis, LHON-associated multiple sclerosis, oligoclonal band-negative multiple sclerosis, oligoclonal IgM-positive multiple sclerosis, Lyme disease, and human immunodeficiency virus encephalopathy.

3. The use described in claim 1, The use of the aforementioned pharmaceutical product as a preventive or therapeutic agent for psoriasis, psoriasis vulgaris, pustular psoriasis, reverse psoriasis, diaper psoriasis, guttate psoriasis, erythrodermic psoriasis, seborrheic-like psoriasis, and psoriatic arthritis.

4. The use according to any one of claims 1 to 3, 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.

5. The use according to any one of claims 1 to 3, wherein the fumarate ester or a pharmaceutically acceptable salt thereof is selected from the group comprising dimethyl fumarate, monomethyl fumarate, diroximel fumarate, ethylcalcium hydrogen fumarate, ethylmagnesium hydrogen fumarate, ethylzinc hydrogen fumarate, and mixtures thereof.

6. The use according to any one of claims 1 to 3, wherein the 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharmaceutically acceptable salt thereof is used to reduce or avoid undesirable effects of the fumarate ester.

7. The use according to any one of claims 1 to 3, wherein the pharmaceutical product is a preventive or therapeutic agent for a condition treated with a fumarate ester.

8. The use according to any one of claims 1 to 3, wherein the route of administration of the pharmaceutical is selected from intravenous administration, oral administration, sublingual administration, local administration, parenteral administration, intraperitoneal administration, intra-arterial administration, intramuscular administration, transdermal administration, transdermal administration, subcutaneous administration, intradermal administration, intrathecal administration, or intraventricular administration.

9. The use according to claim 8, wherein the route of administration is oral administration, and the dosage form is selected from tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets, or pills; powder or granules; juice, syrup, drops, tea, solution, or suspension in aqueous or non-aqueous liquid; edible foam or mousse; or oil-in-water or water-in-oil emulsion.

10. The use according to claim 8, wherein the route of administration is local administration, and the dosage form is selected from cream, emulsion, lotion, gel, hydrogel, paste, powder, ointment, liniment, film, skin patch, transdermal patch, transdermal spray, or suspension.

11. The use according to any one of claims 1 to 3, wherein the pharmaceutical is a pharmaceutical composition comprising the combination, carrier, and at least one pharmaceutically acceptable excipient as defined in claim 1.

12. The use according to claim 11, wherein the at least one pharmaceutically acceptable excipient is selected from the group comprising carriers, binders, colorants, buffers, preservatives, antioxidants, coatings, sweeteners, thickeners, pH adjusters, acidity adjusters, acidifying agents, solvents, isotonic agents, disintegrants, glidants, lubricants, emulsifiers, solubilizers, stabilizers, diluents, anticaking agents (anti-adhesion agents), permeation enhancers, adsorbents, foaming agents, defoaming agents, opacifiers, fatliquoring agents, consistency enhancers, hydrotropes, fragrances, and flavoring agents.

13. The 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharmaceutically acceptable salt thereof; and, Fumarate esters, or pharmaceutically acceptable salts thereof; The use according to claim 11, wherein the formulation is in the form of liposomes, micelles, multilayer vesicles, or cyclodextrin complexes.

14. The 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharmaceutically acceptable salt thereof; and, Fumarate esters, or pharmaceutically acceptable salts thereof; The use according to claim 12, wherein the formulation is in the form of liposomes, micelles, multilayer vesicles, or cyclodextrin complexes.

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