Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of congenital muscular dystrophies

Abstract

The present invention relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in the treatment of congenital muscular dystrophies, particularly Duchenne muscular dystrophy or Becker muscular dystrophy. The present invention particularly relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for said purpose. Also disclosed is a pharmaceutical combination of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts with a glucocorticoid for use in these indications. Pharmaceutical compositions, advantageous formulation techniques and methods of treatment are disclosed.

Description

[Technical field]

[0001] The present invention relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in the treatment of congenital muscular dystrophies, particularly Duchenne muscular dystrophy or Becker muscular dystrophy. The present invention particularly relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for said purpose. Also disclosed is a pharmaceutical combination of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts with a glucocorticoid for use in these indications. Pharmaceutical compositions, advantageous formulation techniques and methods of treatment are disclosed. [Background technology]

[0002] Congenital muscular dystrophies (CMDs) encompass a broad group of muscle disorders characterized by progressive skeletal muscle weakness. CMDs show histological muscle changes and abnormalities in muscle structure. The severity and course of the disease vary. Early onset of muscle weakness begins by 1 year of age. To date, more than 50 types of CMDs have been described. Most of them are due to mutations in genes that code for structural proteins in skeletal muscle cells (see Falsaperla et al. (2016) It J Pediat 42:78). These diseases are not very common. The most prominent and most feared of them is Duchenne muscular dystrophy (DMD). DMD is an X-linked recessive progressive wasting disease caused by loss-of-function mutations in the dystrophin gene. Therefore, the onset of DMD is almost exclusively limited to boys. DMD occurs in approximately 1 in 5,000 male births. Progressive muscle degeneration leads to the inability to walk at age 8 to 12 years. Respiratory and cardiac failure usually results in premature death at age 20-30 (see Guiraud and Davies. (2017) Current Opinion in Pharmacology 34:36-48). Pharmacological treatments can sometimes extend lifespan into the 30s. Treatment options are still very limited. The most promising approach has been gene therapy, which introduces a complete dystrophin gene into the genome. However, this has shown only marginal success, possibly due to an autoimmune response. Another approach is exon skipping. In this method, antisense oligonucleotides are administered that skip the defective part of the dystrophin gene, producing a semi-functional version of dystrophin, although the defect remains (see Dunckley et al. (1998) Human Mol Gen 7:1083-1090). Studies with ataluren have shown moderate clinical improvement, but eteplirsen is still in clinical trials. However, this method requires periodic re-administration into the muscle. Systemic routes of administration are still under investigation. Therefore, the standard approach remains symptomatic pharmacological treatment, attempting to slow muscle deterioration and extend the patient's lifespan as long as possible.The most commonly prescribed medications for DMD include glucocorticoids, particularly agonists such as prednisone, prednisolone, deflazacort, and salbutamol beta-2 agonists, anticonvulsants to control seizures, and immunosuppressants.

[0003] Another approach that is currently being investigated is the Na+ / Ca2 + These include exchange pump inhibitors, NF-κβ inhibitors, antioxidants, mitochondrial dysfunction regulators, HDAC (histone deacetylase) inhibitors, antifibrotic agents, myostatin inhibitors, TGF-β pathway antifibrotic agents, and PDE5 inhibitors for muscle ischemia (see Guiraud and Davies. (2017) Current Opinion in Pharmacology 34:36-48).

[0004] Currently, glucocorticoids are the best treatment, but they have a significant number of side effects that severely limit their long-term use. These include Cushing's syndrome, hypertonia, weight gain and obesity (especially of the trunk, including the so-called "buffalo hump"), edema, facial puffiness (moon face), potassium wasting, muscle weakness, headaches, thinning of the skin, easy bruising and poor wound healing, glaucoma, cataracts, gastric and duodenal ulcers, steroid-induced diabetes, loss of control of existing diabetes, osteoporosis (leading to fractures), adrenal joint necrosis (especially of the hip or knee joints), psychiatric disorders (e.g. depression, euphoria, insomnia, mood swings, personality changes), psychotic behavior, growth retardation in children, convulsions, increased susceptibility to infections, exacerbation of opportunistic infections (tuberculosis, shingles, Pneumocystis pneumonia, etc.), and reduced efficacy of antibiotics and vaccines.

[0005] This applies to all congenital muscular dystrophies.

[0006] Therefore, there is a great medical need to find new drugs that can alleviate the symptoms and improve the quality of life of patients with CMDs, especially Duchenne and Becker muscular dystrophy.Ideally, new drugs for these diseases should have the same therapeutic efficacy as glucocorticoids but without the harsh side effects that can replace glucocorticoid treatment or allow for a significant reduction in glucocorticoids when used in combination with glucocorticoid therapy.

[0007] Surprisingly, this problem is solved by 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharma- ceutically acceptable salt thereof. [Description of the Invention]

[0008] The sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione has been tested in the mdx mouse model. These mice carry a nonsense mutation in the dystrophin gene, thus mimicking a mutation similar to that in human Duchenne muscular dystrophy (and Becker muscular dystrophy), as seen in examples 1 and 2. Results from this model are thought to be predictive not only for DMD, but also for other congenital muscular dystrophies.

[0009] Administration of the sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione as a single agent significantly improves physiologically relevant parameters such as muscle contractile properties and weight gain compared to controls.

[0010] A comparison of therapeutic concentrations of two glucocorticoids commonly used to treat DMD, prednisolone and deflazacort, showed that the sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione was nearly as effective as prednisolone and significantly more effective than deflazacort.

[0011] 5-Amino-2,3-dihydro-1,4-phthalazinedione (luminol) belongs to the pharmaceutical class of phthalazinedione. This class of compounds is known for its beneficial anti-inflammatory properties. 5-Amino-2,3-dihydro-1,4-phthalazinedione is also known by the name luminol. Luminol has excellent chemiluminescent properties. It is widely used in diagnostic assays as a means of detection and in forensic science, such as tracing bloodstains. In medicine, 5-Amino-2,3-dihydro-1,4-phthalazinedione has been developed in the form of its sodium salt. In some countries, it has been approved as a treatment for a wide range of acute and chronic inflammatory diseases, including acute infections, especially of the intestinal tract, caused by bacteria and viruses, inflammations such as hepatitis B and C, gastroenteritis, prostatitis, endometriosis, pharyngitis, bronchial asthma, pneumonia, periodontitis, pyelonephritis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, autoimmune diseases such as scleroderma. Furthermore, there is still a large body of scientific and patent literature for indications in which 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt has been tested for treatment or has been suggested to have beneficial use (see, e.g., WO2004 / 041169, WO2007 / 018546, WO2012 / 127441, WO2017 / 202496, WO2018 / 082814).

[0012] While most conventional immunomodulatory drugs have serious side effects or, at the very least, problems with long-term treatment, 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmacologic acceptable salts are well tolerated and have a high safety margin with respect to dosage.

[0013] To increase solubility and bioavailability, pharma- ceutically acceptable salts of 5-amino-2,3-dihydro-1,4-phthalazinedione are used. Sodium, potassium and lithium salts have been described for therapeutic use (see WO2010 / 082858). The crystal structures of lithium, sodium, potassium, rubidium and cesium salts are described in Guzei et al., Journal of Coordination Chemistry (2013, 66:3722-3739). Thus, this patent application also refers to the use of any pharma- ceutically acceptable salt of 5-amino-2,3-dihydro-1,4-phthalazinedione.

[0014] In particular, the present application discloses 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of congenital muscular dystrophy, wherein the pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1,4-phthalazinedione is the sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione.

[0015] 5-amino-2,3-dihydro-1,4-phthalazinedione is often used as a hydrate, for example as the sodium salt dihydrate. This patent application therefore also refers to the use of all hydrates and other solvates of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharma-ceutically acceptable salts. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma-ceutically acceptable salts may form a complex with a suitable ligand. This patent application therefore also refers to such complexes. For the purposes of this disclosure, all hydrates and solvates are intended to be included in the term "5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma-ceutically acceptable salts."

[0016] To ensure reproducible and standardized API manufacturing and to improve the stability properties of the active agent, anhydrous formulations are often preferred. The anhydrous forms of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt have been described as crystalline polymorphs in WO2011 / 107295 (form I, form II) and WO2016 / 096143 (form III). These crystalline polymorphs are substantially free of phase impurities and have been characterized by X-ray powder diffraction. This method provides a set of characteristic d values ​​indicating the interplanar spacing [Angstroms] and the corresponding 2-theta (2θ) angles [°] at which the Bragg reflections occur. This provides a unique and unambiguous fingerprint of each polymorph.

[0017] For Form I the following values ​​were determined: d-values: 13.5, 6.9, 5.2, 4.6, 3.9, 3.5, 3.4, 3.3, 3.1, 3.0 and / or 2 Theta values: 6.5, 12.7, 16.9, 19.3, 22.8, 25.8, 26.6, 27.2, 28.7, 30.3.

[0018] Form II is characterized by the following values: d-values: 12.9, 7.9, 7.1, 6.5, 5.3, 4.0, 3.7, 3.6, 3.3, 3.2 and / or 2 Theta values: 6.8, 11.2, 12.5, 13.7, 16.7, 22.4, 24.3, 24.9, 27.2, 27.8.

[0019] For Form III the following values ​​were obtained: d-values: 13.131, 7.987, 7.186, 6.566, 6.512, 5.372, 3.994, 3.662, 3.406, 3.288, 3.283, 3.222, 3.215, 3.127, 2.889 and / or 2 Theta values: 6.73, 11.07, 12.31, 13.48, 13.59, 16.49, 22.24, 24.29, 26.14, 27.10, 27.14, 27.67, 27.72, 28.52, 30.93. The use of the anhydrous form I of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is preferred.

[0020] 5-Amino-2,3-dihydro-1,4-phthalazinedione itself exhibits polymorphism: Form I (Paradise (1992) Ber. Bunsen-Ges. Phys. Chem 96:1027-1031) and Form II (WO2017 / 140430) have been disclosed.

[0021] Thus, this patent application also refers to the use of any crystalline form and polymorphic form of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharma- ceutically acceptable salts according to the disclosure. The use of Form II of 5-amino-2,3-dihydro-1,4-phthalazinedione is preferred.

[0022] Similar therapeutic effects are known for various phthalazinediones, which are derivatives of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharma-ceutically acceptable salts. One example is 6-amino-2,3-dihydrophthalazine-1,4-dione (isoluminol). A summary of suitable phthalazinediones is given in WO2007 / 018546. It is reasonable to assume that these compounds will show comparable effects when used for therapeutic purposes according to the present disclosure.

[0023] Tautomerism refers to the rapid internal transformation of organic compounds in which a hydrogen atom or proton formally migrates within the compound. This involves the switching of a single bond and an adjacent double bond. The single bond forms are called tautomers. For example, keto-enol tautomerism occurs in 5-amino-2,3-dihydro-1,4-phthalazinedione (Proescher and Moody (1939) J Lab Clin Med, 1183-1189). Therefore, this patent application also refers to the use of all tautomers of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharma-ceutically acceptable salts.

[0024] The term "5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts" as used throughout this application is intended to encompass all the aforementioned molecular variants of 5-amino-2,3-dihydro-1,4-phthalazinedione, i.e., 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, or a solvate, hydrate, crystalline polymorph, or tautomer thereof.

[0025] Unless otherwise defined, technical or scientific terms used herein have the meanings ascribed to them by experts in the relevant art. The term "composition" or "pharmaceutical composition" includes at least one active ingredient in at least one pharmacologically acceptable defined dosage and administration form, and at least one pharma- ceutically acceptable excipient, as well as any pharmaceutical agents produced directly or indirectly in combination, as a deposit, complex or crystal, or as a result of other reactions or interactions, from the ingredients outlined below, and optionally at least one additional pharmaceutical agent listed below.

[0026] 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.

[0027] The terms "effect," "therapeutic effect," "action," "therapeutic action," "efficacy," and "effectiveness" with respect to a disclosed substance or pharmaceutical combination, or other active agent described herein, refer to a beneficial result that occurs causally in an organism to which the substance has previously been administered.

[0028] According to the disclosure, the terms "effective amount" and "therapeutically effective amount" refer to an amount of a substance of the invention sufficient to effect a desired beneficial effect in a subject in need of such treatment.

[0029] The terms "treatment" and "therapy" include administration of at least an agent of the present invention alone or in combination with at least one other pharmaceutical agent, regardless of the chronological order of administration. Such administration is intended to significantly improve the disease course of congenital muscular dystrophy by halting or slowing the progression of impairment during the course of the disease.

[0030] The terms "prevention" or "prophylactic treatment" include administration of at least the substance 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 manifestation of symptoms attributable to congenital muscular dystrophy, particularly in patients whose condition is expected to develop with a reasonable probability in the distant or near future.

[0031] The terms "subject" and "patient" include individuals suffering from, and having confirmed or suspected diagnosis of, a disease symptom or disorder associated with a congenital muscular dystrophy. The individual is a mammal, particularly a human.

[0032] The term "muscular dystrophy" is not always used precisely in the scientific and popular literature. Sometimes it is used to refer to general conditions of reduced muscle mass or significant weight loss, e.g. sarcopenia, cancer, chemotherapy, cachexia after excessive fasting, dexamethasone-induced muscle atrophy, and age-related muscle atrophy (e.g., Sakuma et al. (2014) Front Aging Neurosci 6:230; Saimithra et al. (2018) http: / / nopr.niscpr.res.in / handle / 123456789 / 44283). These conditions are better called "muscular atrophy". This disclosure is only concerned with muscular dystrophies in the stricter sense. To avoid ambiguity, the term "congenital muscular dystrophies" is used throughout this disclosure.

[0033] Congenital muscular dystrophies (CMDs) are a heterogeneous group of diseases that impair the function of various muscles and muscle groups. CMDs present with symptoms such as progressive muscle weakness, muscle atrophy, spasms, hypertonia, and muscle pain. Many CMDs present with cardiac and respiratory dysfunction, leading to premature death. Over 800 single gene mutations have been associated with human CMDs. Most of them are related to genes that code for structural muscle proteins (Chemello et al. (2020) J Clin Invest 130:2766-2776).

[0034] Duchenne muscular dystrophy (DMD) is the most common genetic muscle disorder. The prevalence is 1:3,600-1:6,000. Due to X-linked recessive inheritance, it affects almost exclusively boys. Muscle weakness begins around age 4 and disease progression is rapid. Muscle loss usually occurs first in the thighs and pelvis, then the arms. Most patients are unable to walk by age 12. Muscle wasting leads to painful joint malpositions and bone deformities. With proper disease management, patients can live into their 40s. In the end stage, severe cardiovascular and respiratory problems ultimately lead to death.

[0035] The disease is caused by mutations in the gene for the protein dystrophin. Dystrophin is important for maintaining the cell membrane of muscle fibers by linking it to the actin filaments of the cytoskeleton. The cellular pathophysiology includes mitochondrial dysfunction, reduced ATP levels, and increased Ca2+ influx due to damage to the sarcolemma. Damaged mitochondria are unable to buffer the surge in intracellular Ca2+. As a compensatory mechanism, pAMPK (phosphorylated AMP-activated protein kinase) is increased, as is the number of slow-twitch fibers and utrophin. Downregulation of nNOS (neuronal NO synthase) leads to a shortage of nitric oxide. This can lead to a lack of vasodilation and localized ischemia. (See Heydemann (2018) Nutrients 10:796).

[0036] So far, there is no effective causal treatment for DMD. Gene therapy approaches to introduce a functional dystrophin gene into the genome have been only moderately successful due to the occurrence of autoimmune reactions. Experiments with CRISPR / Cas genetic scissors are still in the very early stages. Moderate clinical improvement has been observed with exon skipping with ataluren. The antisense oligonucleotide skips the defective part of the dystrophin gene (here the stop codon). The result is a truncated but partially functional dystrophin (Dunckley et al. (1998) Human Mol Gen7:1083-1090). Until now, periodic re-administration into the affected muscles has been necessary, which is cumbersome and stressful for the patient.

[0037] Symptomatic pharmacological approaches are mainly based on glucocorticoids. Prednisone, prednisolone, and deflazacort are commonly prescribed. Vamorolone, a new synthetic glucocorticoid, is still in development for DMD. The aim is to slow down muscle degeneration. β2 agonists such as salbutamol are used as well as anticonvulsants and immunosuppressants to control seizures. Still in the experimental stage are Na+ / Ca2+ exchange pump inhibitors, NF-κβ inhibitors, antioxidants, mitochondrial dysfunction modulators, HDAC (histone deacetylase) inhibitors, antifibrotic agents, myostatin inhibitors, TGF-β pathway antifibrotic agents, and PDE5 inhibitors for muscle ischemia (see Guiraud and Davies (2017) Current Opinion in Pharmacology 34: 36-48).

[0038] A CMD similar to DMD is Becker muscular dystrophy (BMD, synonym: Becker-Kehner muscular dystrophy). It is also an inherited disorder of the dystrophin gene. The relevant point mutation in the dystrophin gene produces a truncated protein, but in contrast to DMD, this truncated dystrophin is still partially functional. The disease course is therefore milder than DMD. Patients are often able to maintain an active lifestyle. The prevalence of BMD is about 1.5-6 per 100,000 male births, making it less frequent than DMD. Symptoms usually appear around the age of 8-25. In an unfortunate disease course, patients may die at 40 years of age, while others reach normal age. Symptoms usually include progressive muscle weakness in the legs and pelvis, gradually making walking difficult. Other symptoms include upper limb weakness, toe walking, dyspnea, skeletal deformities such as scoliosis, pseudohypertrophy of calf muscles, muscle spasms, myocardial damage, and elevated blood creatine kinase levels (as of September 12, 2021, http: / / patient.info / doctor / beckers-musculardystrophy). There is no known cure for BMD. Physical therapy may help relieve symptoms. The glucocorticoid prednisone is administered to increase production of utrophin, a dystrophin-associated protein. Because the etiology is similar, the same medications are used as for DMD.

[0039] A group of limb-girdle dystrophies are associated with point mutations in autosomal genes encoding α-, β-, γ-, δ-, and e-sarcoglycans. Sarcoglycans are transmembrane proteins involved in a protein complex responsible for linking the musculoskeletal fiber to the extracellular matrix. The age of onset is usually between 10 and 30 years. Men and women are affected equally. The prevalence is approximately 1:14,500. Progressive muscle atrophy occurs, mainly affecting the hip and shoulder muscles. Symptoms include extreme difficulty walking, bending forward, and squatting. Other symptoms include pseudohypertrophy, muscle hypertrophy, respiratory muscle problems, palpitations, distal muscle problems, facial muscle weakness, and shoulder muscle weakness. Limb-girdle dystrophies do not usually have a fatal course. Physiotherapy may help alleviate symptoms. So far, there is no drug treatment. However, antioxidant therapy is recommended.

[0040] The group of dysferlinopathies includes myopathies caused by mutations in the gene DYSF, which codes for dysferlin, a protein associated with skeletal muscle repair. Examples of dysferlinopathies include Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal myopathy. These diseases usually become evident in the third of fourth decades. Typical symptoms are weakness and atrophy of voluntary skeletal muscles, such as the gastrocnemius and tibialis anterior. The epicenter of prevalence is the Middle East and the Indian subcontinent. To date, no curative treatment exists. Treatment options include synthesis of functional proteins after adeno-associated viral vector introduction, gene surgery (exon skipping, trans-splicing), and pharmacological and immunological approaches. Administration of dantrolene did not improve the phenotype. No clinical trials with intravascular immunoglobulin (IV-IG) were performed. A candidate substance is rituximab, a monoclonal antibody against CD20 positive B cells (see Barthelemy et al. (2011) Mol Med 17:875-882). Coenzyme Q10 and resveratrol have shown promising results in mice.

[0041] The group of N-acetylglucosamine 2-epimerase / N-acetylmannosamine kinase) myopathies includes hereditary inclusion body myopathy (HIBM), distal myopathy with rimmed vacuoles (DMRV), distal nonaka myopathy, and quadriceps-sparing myopathy. These mutations are most common in Iranian Jews. Muscle wasting begins around age 20-30 and disability occurs over a 10-15 year period. Symptoms include difficulty walking or running on heels, weakness of the index finger, and frequent loss of balance. So far, only symptomatic treatment is available, such as ankle braces.

[0042] The group of spinal-bulbar muscular atrophies (SMAs) includes SMARD1, Werdnig-Hoffmann disease, and Kugelberg-Welander disease. These diseases are characterized by degeneration of motor neurons in the anterior horn. This is due to mutations in the SMN1 gene, which codes for the so-called survival of the motor neuron protein. It is inherited in an autosomal recessive manner. Symptoms include areflexia, especially in the limbs, generalized muscle weakness, hypotonia, difficulty sitting, standing, and walking, weak cough and cry in infants, a bell-shaped body, fasciculations of the tongue, and difficulty sucking and swallowing. Drug treatment attempts include nusinersen, an antisense nucleotide that alters alternative splicing of the adjuvant SMN2 gene, recombinant therapy with onasemnogene, and risdiplam, a pyridazine derivative that also alters the SMN2 splicing pattern. Without treatment, most infantile patients do not survive to the age of 4 years. The disease is the leading cause of infant mortality due to genetic causes. In the absence of adequate drug treatment, SMA patients tend to deteriorate over time. The pathophysiology includes oxidative stress. In a transgenic mouse model, the curcumin derivative ASC-JM17, an Nrf2 activator, was shown to be beneficial.

[0043] Myotonic dystrophy is an autosomal inherited disease that causes progressive muscle loss and atrophy. Muscles often fail to relax after contraction. Other common symptoms are cataracts, intellectual disability, and cardiac conduction disorders. The prevalence is approximately 1:8,000 worldwide. The age of onset is usually in the 20s to 30s. The disease is caused by mutations in the DMPK gene, which codes for myotonin protein kinase (type 1, DM1), or mutations in the CNBP gene, which codes for cellular nucleic acid-binding protein (type 2, DM2). There is currently no cure for the disease. Treatments include braces or wheelchairs, pacemakers, and noninvasive positive pressure ventilation. Mexiletine or carbamazepine is prescribed for muscle relaxation. Pain can be treated with tricyclic antidepressants and NSAIDs (nonsteroidal anti-inflammatory drugs) (see Meola and Cardani (2015) Biochim Biophys Acta 1852:594-606).

[0044] Emery-Dreifuss muscular dystrophy (EMD) is caused by mutations in the gene encoding emerin. There are several types: EDMD1 to EDMD7. Symptoms include muscle weakness, especially in the shoulders and lower limbs, shortening of the Achilles tendon and elbow muscles, bradycardia, palpitations, and muscle contractures. During the course of the disease, patients may require orthopedic treatment (walkers, canes), physiotherapy, and respiratory support. Drug treatment is based on beta-blockers and ACE inhibitors.

[0045] Facioscapulohumeral muscular dystrophy (FSHD) is caused by mutations that lead to dysregulation of the gene encoding double homeobox 4 (DUX4). The disease primarily affects the skeletal muscles of the face, the muscles that position the scapula, and the muscles of the upper arm that cover the humerus (see Wagner (2019) Lifelong Learning in Neurology 25: 1662-1681). The prevalence ranges from 1:8,000 to 1:20,000. The disease typically develops between the ages of 15 and 30. Life expectancy is not usually shortened. To date, there is no treatment that can significantly slow the progression of the disease. Treatment includes physical and occupational therapy, as well as reconstructive surgery if necessary. Pharmacological treatment focuses on the glucocorticoid prednisone, the beta-2 agonist albuterol, the calcium channel blocker diltiazem, stamulumab (an antibody that inhibits myostatin), and the TGF-beta inhibitor ACE-083.

[0046] Oculopharyngeal muscular dystrophy (OPMD) is a disease characterized by autosomal mutations in the gene encoding polyadenylate-binding protein 2 (PABPN1). Onset is relatively late in life (40–50 years). Symptoms include ptosis, extraocular muscle weakness, dysphagia, aspiration pneumonia, and proximal limb weakness. Currently, there is no treatment to halt disease progression. Treatment attempts are targeted to specific diets and cricopharyngeal myotomy to reduce symptoms.

[0047] Myofibrillar myopathies (types 1-6, MFM1-6) are a clinically and genetically diverse group of skeletal muscle disorders with an age of onset after 40 years of age. Clinically, slowly progressive muscle weakness with different distribution of paralysis is typical. Distinct peripheral, scapuloperoneal, and limb-girdle phenotypes can be associated with cardiomyopathy, pulmonary involvement, and peripheral neuropathy. Morphologically, myofibril dissolution, deposition of myofibrillar breakdown products, abnormal expression of numerous intramuscular proteins, and intracellular desmin-positive protein aggregates are revealed. With management of cardiac and respiratory problems, patients with MFM can expect a normal life expectancy. The affected genes are DES (desmin), MYOT (myotilin), LDB3 (LIM domain binding 3, ZASP), FLNC (filamin C), CRYAB (alpha crystallin B), BAG3 (BAG family molecular chaperone regulatory factor 3), FHL1 (4.5 LIM domain protein 1), and DNAJB6 (DNaJ homolog subfamily B member 6). To date, there is no causal treatment for myofibrillar myopathy. Symptomatic treatment is given, if necessary, for cardiovascular problems, etc.

[0048] Additionally, CMD includes: Walker-Warburg syndrome (mutations in the O-mannosyltransferase 1 gene; POMT1, POMT2, FCMD, FKRP), Lamin A / C-associated congenital muscular dystrophy (lamin A / C gene mutation, LMNA), Fukuyama-type congenital muscular dystrophy (Fukutin gene mutation; FCMD) Congenital muscular dystrophy with partial merosin deficiency, Spinal muscular dystrophy (mutations in the selenoprotein N gene; SEPN1), Congenital muscular dystrophy associated with mutations in the A2 gene (LAMA2), LARGE-associated congenital muscular dystrophy (mutations in the acetylglucosaminyltransferase-like protein gene; LARGE), Myo-ophthalmopathy (mutations in the protein O-linked mannose beta 1 gene; POMGnT1), Ullrich congenital muscular dystrophy (= Bethlem myopathy), (mutations in the collagen VI gene; COL6A1-3), and Integrin alpha 7 dystrophy (ITGA7).

[0049] The present application therefore relates to a 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts for use in the treatment of a congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy.

[0050] In particular, the present application relates to 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for use in the treatment of congenital muscular dystrophy, especially Duchenne muscular dystrophy or Becker muscular dystrophy.

[0051] In another embodiment of the present invention, the application relates to a 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of a congenital muscular dystrophy selected from the group consisting of limb-girdle dystrophy, dysferlinopathy, GNE myopathy, spinal bulbar muscular atrophy, myotonic dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, myofibrillar myopathy, Walker-Warburg syndrome, lamin A / C-associated congenital muscular dystrophy, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy with partial merosin deficiency, spinal stenosis muscular dystrophy, congenital muscular dystrophy with primary laminin 2 deficiency, LARGE-associated congenital muscular dystrophy, myo-oculo-encephalopathies, Ullrich congenital muscular dystrophy and integrin alpha 7 dystrophy.

[0052] In another aspect of the invention, the application also refers to a pharmaceutical composition consisting of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts and at least one glucocorticoid, for use in the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy.

[0053] In particular, the present application relates to a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and at least one glucocorticoid for use in the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy.

[0054] In another embodiment of the present invention, the present application relates to a method for the treatment of a limb-girdle dystrophy, a dysferlinopathy, a GNE myopathy, a spinobulbar muscular atrophy, a myotonic dystrophy, an Emery-Dreifuss muscular dystrophy, a facioscapulohumeral muscular dystrophy, an oculopharyngeal muscular dystrophy, a myofibrillar myopathy, a Walker-Warburg syndrome, a lamin A / C-associated congenital muscular dystrophy, a Fukuyama congenital muscular dystrophy, a congenital muscular dystrophy with partial merosin deficiency, a spinal canal stenosis, The present invention relates to a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmacologic acceptable salts and at least one glucocorticoid for use in the treatment of a congenital muscular dystrophies selected from the group consisting of muscular dystrophy of the 1990s, congenital muscular dystrophy with primary laminin 2 deficiency, LARGE-associated congenital muscular dystrophy, muscle-eye-brain disease, Ullrich congenital muscular dystrophy, and integrin alpha 7 dystrophy, in which 5-amino-2,3-dihydro-1,4-phthalazinedione is preferably used.

[0055] Glucocorticoids suitable for such pharmaceutical compositions include prednisone, prednisolone, deflazacort, vamorolone, flumethasone, triamcinolone acetonide, betamethasone, dexamethasone, beclomethasone, betamethasone valerate, betamethasone dipropionate, budesonide, beclomethasone dipropionate, isoflupredone, fluocinonide, fluocinolone, methylprednisolone, halcinonide, desonide, deltasone, triamcinolone, triamcinolone acetonide, tixocortol pivalate, mometasone furoate, amcinonide, fluocortolone, halometazo These include fluocortolone, alclomethasone dipropionate, prednicarb, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, cortisol, hydrocortisone, hydrocortisone acetate, hydrocortisone-17-valerate, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, cortisone, and cortisone acetate.

[0056] Preferred are prednisone, prednisolone, deflazacort, and vamorolone.

[0057] In another aspect of the present invention, the present application relates to a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, or the aforementioned pharmaceutical combinations, and at least one pharma- ceutically acceptable excipient, for use in the treatment of congenital muscular dystrophy.

[0058] The pharmaceutical composition is preferably used for the treatment of Duchenne muscular dystrophy or Becker muscular dystrophy.

[0059] The term "pharmaceutical acceptable excipient" refers to natural or synthetic compounds added to pharmaceutical formulations along with the active pharmaceutical ingredient. They may help bulk the formulation, improve the desired pharmacokinetic properties or stability of the formulation, and are also beneficial to the manufacturing process. Advantageous classes of excipients according to the disclosure include carriers, binders, colorants, buffers, preservatives, antioxidants, coating agents, sweeteners, thickeners, pH adjusters, acidity adjusters, acidifiers, solvents, isotonicity agents, disintegrants, glidants, lubricants, emulsifiers, solubilizers, stabilizers, diluents, anti-caking agents (anti-adherents), adsorbents, penetration enhancers, foaming agents, antifoaming agents, opacifiers, fatliquoring agents, viscosity enhancers, hydrotropes, fragrances and flavorings.

[0060] Generally, one or more pharma- ceutically acceptable carriers are added to the pharma- ceutically active agent.All carriers known in the art and their combinations are suitable.For solid dosage forms, for example, vegetable and animal fats, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide, etc.For liquid dosage forms and emulsions, suitable carriers are, for example, solvents, solubilizers, emulsifiers, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, cottonseed oil, peanut oil, olive oil, castor oil, sesame oil, glycerol fatty acid ester, polyethyl glycol, sorbitan fatty acid ester, etc. Suspensions according to the 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.

[0061] The term binder refers to a substance that binds or adheres powders together and provides cohesion through granule formation. Binders act as the "glue" of the formulation. Binders enhance the cohesive strength of any diluent or filler that is provided.

[0062] Suitable binders include, for example, starches derived from wheat, corn, rice or potato, gelatin, natural sugars such as glucose, sucrose or beta-lactose, sweeteners derived from corn, natural and synthetic gums such as acacia, tragacanth or calcium ammonium alginate, sodium alginate, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl carboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, magnesium aluminum silicate, waxes, etc. The proportion of binder in the composition is in the range of 1-30% by weight, preferably 2-20% by weight, more preferably 3-10% by weight, most preferably 3-6% by weight.

[0063] Colorants are excipients that impart color to pharmaceutical formulations. These excipients may be food colorants. They may be adsorbed onto suitable adsorption means such as clay or aluminum oxide. A further advantage of colorants is that they can make aqueous solutions spilled on the nebulizer and / or mouthpiece visible to facilitate cleaning. The amount of colorant can vary in the range of 0.01-10% by weight of the pharmaceutical composition, preferably in the range of 0.05-6%, more preferably in the range of 0.1-4%, and most preferably in the range of 0.1-1%.

[0064] 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, carbon black, and the like. These include 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, flavoxanthin, 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.

[0065] Furthermore, buffers are preferred for liquid formulations, especially pharmaceutical liquid formulations. The terms buffer, buffer system, and buffer, especially for aqueous solutions, refer to the ability of the system to resist pH changes due to the addition of acid or base, or dilution with a solvent. Preferred buffer systems include formic acid, lactic acid, benzoic acid, oxalic acid, fumaric acid, aniline, acetate buffer, citrate buffer, glutamate buffer, phosphate buffer, succinic acid, pyridine, phthalic acid, histidine, MES (2-(N-morpholino)ethanesulfonic acid), maleic acid, cacodylic acid (dimethylarsenic acid), carbonic acid, ADA (N-(2-acetamido)iminodiacetic acid, PIPES (4-piperazine-bis-ethanesulfonic acid), BIS-TRIS propane (1,3-bis[tris(hydroxymethyl) The buffer may be selected from the group including N-(2-[(amino)methylamino]propane), ethylenediamine, ACES (2-[(amino-2-oxoethyl)amino]ethanesulfonic acid), imidazole, MOPS (3-(N-morpholino)propanesulfonic acid), diethylmalonate, TES (2-[tris(hydroxymethyl)methyl]aminoethanesulfonic acid), HEPES (N-2-hydroxyethylpiperazine-N'2-ethanesulfonic acid), and other buffers with a pKa between 3.8 and 7.7.

[0066] 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.

[0067] A further group of preferred buffers are inorganic buffers such as sulfate hydroxide, borate hydroxide, carbonate hydroxide, oxalate hydroxide, calcium hydroxide, phosphate buffers, etc. Another group of preferred buffers are nitrogen-containing buffers such as imidazole, diethylenediamine, piperazine, etc. Further preferred are sulfonic acid buffers such as TES, HEPES, ACES, PIPES, [(2-hydroxy-1,1-bis-(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid (TAPS), 4-(2-hydroxyethyl)piperazine-1-propanesulfonic acid (EEPS), MOPS, and N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES). Another group of preferred buffers are glycine, glycyl-glycine, glycyl-glycyl-glycine, N,N-bis-(2-hydroxyethyl)glycine, and N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricine). Also preferred are amino acid buffers such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxyproline, N,N,N-trimethyllysine, 3-methylhistidine, 5-hydroxylysine, o-phosphoserine, γ-carboxyglutamic acid, [ε]-N-acetyllysine, [ω]-N-methylarginine, citrulline, ornithine, and derivatives thereof. Particularly preferred is KH2PO4 buffer.

[0068] Preservatives for liquid and / or solid dosage forms may be used as needed. These include sorbic acid, potassium sorbate, sodium sorbate, calcium sorbate, methylparaben, ethylparaben, methylethylparaben, propylparaben, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, heptyl parahydroxybenzoate, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, benzyl alcohol, benzalkonium chloride, phenylethyl alcohol, cresol, cetylpyridinium chloride, chlorobutanol, thiomersal (sodium 2-(ethylmercurithio)benzoate), sulfur dioxide, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, potassium sulfite, calcium sulfite, calcium bisulfite, The additive may be selected from the group including, but not limited to, potassium bisulfite, biphenyl, orthophenylphenol, sodium orthophenylphenol, thiabendazole, nisin, natamycin, formic acid, sodium formate, calcium formate, hexamine, formaldehyde, dimethyl dicarbonate, potassium nitrite, sodium nitrite, sodium nitrate, potassium nitrate, acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, ammonium acetate, dehydroacetic acid, sodium dehydroacetate, lactic acid, propionic acid, sodium propionate, calcium propionate, potassium propionate, boric acid, sodium tetraborate, carbon dioxide, malic acid, fumaric acid, lysozyme, copper (II) sulfate, chlorine, chlorine dioxide, and other suitable substances or compositions known to those skilled in the art.

[0069] Adding sufficient amount of antioxidant is especially preferred for liquid and topical dosage forms.Suitable examples of antioxidant 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.

[0070] Tablets or pills are usually coated, i.e. the coating constitutes the outer layer. This can be a film coating, a sugar coating including sugars, and a compression coating. Pharmaceutically acceptable varnishes or waxes, HPMC (hydroxypropyl methylcellulose), MC (methylcellulose), or HPC (hydroxypropyl cellulose) can be used. Such coatings may help mask the taste and facilitate swallowing or identification. Coatings often contain plasticizers and pigments. Capsules usually have a gelatinous shell that encases the active ingredient. The specific composition and thickness of this gelatinous layer determine the rate at which the capsule is absorbed after ingestion. Of particular interest are sustained release formulations known in the art.

[0071] Suitable sweeteners may be selected from the group consisting of mannitol, glycerol, acesulfame potassium, aspartame, cyclamate, isomalt, isomaltitol, saccharin and its sodium, potassium and calcium salts, sucralose, alitame, thaumatin, glycyrrhizin, neohesperidin dihydrochalcone, steviol glycosides, neotame, aspartame, acesulfame salts, maltitol, maltitol syrup, lactitol, xylitol, erythritol.

[0072] Suitable thickening agents may be selected from the group including, but not limited to, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, dextrin, polydextrose, modified starch, alkaline modified starch, bleached starch, oxidized starch, enzyme treated starch, monostarch phosphate, di-starch phosphate esterified with sodium trimetaphosphate or phosphorus oxychloride, di-starch phosphate, acetylated di-starch phosphate, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated di-starch adipate, acetylated di-starch glycerol, di-starch glycerin, hydroxypropyl starch, hydroxypropyl di-starch glycerin, hydroxypropyl di-starch phosphate, hydroxypropyl di-starch glycerol, sodium starch octenyl succinate, acetylated oxidized starch, hydroxyethyl cellulose.

[0073] Suitable pH adjusting agents for liquid dosage forms include, for example, sodium hydroxide, hydrochloric acid, and buffer substances such as sodium dihydrogen phosphate or disodium hydrogen phosphate.

[0074] 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.

[0075] Oxidizing agents are inorganic chemicals that produce or become acids. Suitable examples include ammonium chloride and calcium chloride.

[0076] 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.

[0077] Suitable isotonicity agents include, for example, pharma- ceutically acceptable salts, particularly sodium chloride and potassium chloride, sugars such as glucose or lactose, sugar alcohols such as mannitol and sorbitol, citrates, phosphates, borates, and mixtures thereof.

[0078] Suitable disintegrants may be selected from the group consisting of starch, cold water soluble starches such as carboxymethyl starch, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, crosslinked microcrystalline cellulose such as microcrystalline cellulose and croscarmellose sodium, natural and synthetic gums such as guar, agar, Karaya (Indian tragacanth), locust bean gum, tragacanth, clays such as bentonite, xanthan gum, alginates such as alginic acid and sodium alginate, effervescent compositions, etc. Moisture expansion is promoted by, for example, starch, cellulose derivatives, alginates, polysaccharides, dextran, crosslinked polyvinylpyrrolidone, etc. The amount of disintegrant in the composition may vary from 1 to 40% by weight, preferably from 3 to 20% by weight, most preferably from 5 to 10% by weight.

[0079] 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.

[0080] The term "lubricant" refers to a substance added to a dosage form to facilitate the release of tablets, granules, etc. from a press die or exit nozzle. Lubricants reduce friction or wear. Lubricants are usually added just before pressing, as they need to be present on the surfaces of the granules and between the granules and the parts of the press die. The amount of lubricant in the composition can vary between 0.05-15% by weight, with 0.2-5% by weight being preferred, 0.3-3% by weight being more preferred, and 0.3-1.5% by weight being most preferred. Suitable lubricants are metal stearates such as sodium oleate, sodium stearate, calcium stearate, potassium stearate, magnesium stearate, stearic acid, sodium benzoate, sodium acetate, sodium chloride, boric acid, high melting point waxes, and polyethylene glycols.

[0081] The emulsifiers can be chosen, for example, from the following anionic and nonionic emulsifiers: anionic emulsifier wax, cetyl alcohol, cetylstearyl alcohol, stearic acid, oleic acid, polyoxyethylene polyoxypropylene block polymers, addition products of 2 to 60 moles of ethylene oxide onto castor oil and / or hydrogenated castor oil, wool wax oil (lanolin), sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethene sorbitan monolaurate, polyoxyethene sorbitan monooleate, polyoxyethene sorbitan monopalmitate, polyoxyethene sorbitan monostearate, polyoxyethene sorbitan tristearate, polyoxyethene stearate, polyvinyl alcohol, metatartaric acid, calcium tartrate, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, propane-1,2-diol alginate, carrageenan, modified eukema seaweed, locust bean gum, tragacanth, acacia gum, karaya gum, gellan gum, ghatti gum, 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, sodium calcium polyphosphate, calcium polyphosphate, ammonium polyphosphate, β-cyclodextrin, powdered cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylmethylcellulose, carboxymethylcellulose, methylcellulose, ethyl ... ethylcellulose, 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, citrate esters of mono- and diglycerides of fatty acids, tartrate esters of mono- and diglycerides of fatty acids, mono- and diacetyl tartarate esters of mono- and diglycerides of fatty acids, acetate and tartaric acid mixed esters of mono- and diglycerides of fatty acids, succinic acid monoglyceride, sucrose esters of fatty acids, sucroglycerides, polyglycerol esters of fatty acids, polyricinoleic acid polyglycerol, propane-1,2-Diol esters, propylene glycol fatty acid esters, lactate fatty acid esters of glycerol and propane-1, thermooxidized soybean oil interacted with mono- and diglycerides of fatty acids, sodium dioctyl sulfosuccinate, sodium stearoyl-2-lactylate, calcium stearoyl-2-lactylate, stearyl tartaric acid, stearyl citrate, sodium stearoyl fumarate, calcium stearoyl fumarate, stearyl tartaric acid, stearyl citrate, sodium stearoyl fumarate, stearoyl fumaric acid Calcium, sodium lauryl sulfate, ethoxylated mono- and diglycerides, methyl glucoside coconut oil esters, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate, calcium sodium polyphosphate, calcium polyphosphate, ammonium polyphosphate, cholic acid, choline salts, distarch glycerol, sodium starch octenylsuccinate, acetylated oxidized starch. Preferred are phospholipids such as glycerol monooleate, stearic acid, and lecithin.

[0082] Suitable surface-active solubilizers include, for example, diethylene glycol monoethyl ester, polyethylene propylene glycol copolymers, cyclodextrins such as α-cyclodextrin and β-cyclodextrin, glyceryl monostearates such as Solutol HS15 (BASF macrogol-15-hydroxystearate, PEG660-15 hydroxystearate), sorbitan esters, polyoxyethylene glycol, polyoxyethylene sorbitan acid esters, polyoxyethylene sorbitan monooleate, polyoxyethylene oxystearic acid triglyceride, polyvinyl alcohol, sodium dodecyl sulfate, and (anionic) glyceryl monooleate.

[0083] Stabilizers are substances that can be added to prevent undesirable changes. Stabilizers are not true emulsifiers, but they also contribute to the stability of an emulsion. Suitable examples of stabilizers include oxystearin, xanthan gum, agar, oat gum, guar gum, tara gum, polyoxyethylene stearate, aspartame acesulfame salt, amylase, protease, papain, bromelain, ficin, invertase, polydextrose, polyvinylpyrrolidone, polyvinylpolypyrrolidone, triethyl citrate, maltitol, maltitol syrup, etc.

[0084] Diluents or fillers are inert substances added to drugs to handle the minimum amount of active agent.Examples of suitable diluents include water, mannitol, pregelatinized starch, starch, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate dihydrate, calcium phosphate, calcium carbonate, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, xanthan gum, gum arabic, or combinations thereof.

[0085] Anti-caking agents (anti-adherents) can be added to the supplement or the composition of the supplement to prevent the formation of lumps and facilitate packaging, transportation, release from at least one chamber of the dispensing cap, and consumption.Suitable examples include tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talc powder, sodium aluminosilicate, potassium aluminosilicate, calcium aluminosilicate, bentonite, aluminosilicate, stearic acid, polydimethylsiloxane, etc.

[0086] 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.

[0087] Penetration enhancer is often used in topical dosage form.Suitable penetration enhancer includes, but is not limited to, all pharmaceutically acceptable penetration enhancer known in the art, such as azones such as laurocapram, 1-dodecylazacycloheptan-2-one, sulfoxides such as dimethyl sulfoxide, DMAC, DMF, pyrrolidones such as 2-pyrrolidone, N-methyl-2-pyrrolidone, alcohols such as ethanol, 1,2-propanediol or decanol, glycols such as propylene glycol, diethylene glycol, tetraethylene glycol, fatty acids such as oleic acid, lauric acid, sodium lauryl sulfate, myristic acid, isopropyl myristic acid, capric acid, nonionic surfactants such as polyoxyethylene-2-oleyl ether, polyoxyethylene-2-stearyl ether, terpenes, terpenoids, oxazolidinones, urea. Ceramide analogs, azone analogs, menthol derivatives, etherified derivatives, esterified derivatives, transcarbam, 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 (Arlasove® DMI), ethoxydiglycol, etc. 1,2-propanediol is preferred.

[0088] In some herbal formulations, it may be desirable to generate a foam when the liquid oral dosage form dissolves. Such an effect can be supported by the addition of effervescent agents that lower the surface tension of the liquid, promoting foam formation; or inhibiting bubble coalescence, thereby enhancing colloidal stability; or stabilizing the foam. Suitable examples include mineral oil, Quillaja extract, triethyl citrate, sodium lauryl ether sulfate, sodium lauryl sulfate, and ammonium lauryl sulfate.

[0089] 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 defoaming agent (defoamer). Examples include polydimethylsiloxane or silicone oil in dietary supplements and simethicone in pharmaceuticals.

[0090] An opacifier is a substance that renders a liquid dose opaque when necessary. The opacifier must have a refractive index substantially different from that of the solvent (most often water). At the same time, it must be inert to the other components of the composition. Suitable examples include titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof.

[0091] Suitable fatliquors include, for example, decyl oleate, hydrated castor oil, light mineral oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, and the like.

[0092] Examples of viscosity enhancers include cetyl alcohol, cetyl ester wax, hydrated castor oil, microcrystalline wax, non-ionic emulsifying wax, beeswax, paraffin, or stearyl alcohol.

[0093] Suitable hydrotropes are alcohols, such as ethanol, isopropyl alcohol, or polyols, such as glycerin.

[0094] Suitable aroma and flavoring substances include essential oils that can be used for this purpose. In general, the term refers to volatile extracts from plants or plant parts that have their characteristic odor. These can be extracted from plants or plant parts by steam distillation.

[0095] Suitable examples include essential oils, each of which is an aromatic substance from: achillea, sage, cedar, clove, chamomile, anise, anise seed, star anise, thyme, tea tree, peppermint, mint oil, menthol, cineole, borneol, gingerol, eucalyptus, mango, fig, lavender oil, chamomile flower, pine needles, cypress, orange, rose, rosewood, plum, currant, cherry, birch leaf, cinnamon, lime, grapefruit, tangerine, juniper, valerian, lemon, lemon balm, lemongrass, palmarosa, cranberry, pomegranate, rosemary, ginger, pineapple, guava, echinacea, ivy leaf extract, blueberry, persimmon, melon, thyme, thyme leaf extract ... cinnamyl, alpha- or beta-pinene, alpha-pinene oxide, alpha-camphorenic aldehyde, alpha-citronellol, alpha-isoamyl cinnamic acid, alpha-cinnamic terpinene, alpha-terpineol, alpha-terpinene, aldehyde C16, alpha-phellandrene, amyl cinnamic aldehyde, amyl salicylic acid, anisaldehyde, basil, anethole, bay leaf, benzyl acetate, benzyl alcohol, bergamot, bitter orange peel, black pepper, calamus, camphor, cananga oil, cardamom, carnation, carvacrol, carveol, cassia, castor, cedarwood, cinnamic aldehyde, cinnamic alcohol, cispinane, citral, citronella, citronellal, citronellol dextro, citronellol, citronellyl acetate. Citronellyl nitrile, Unshu mandarin orange, clary sage, clove bud, coriander, corn, cottonseed, d-dihydrocarvone, decyl aldehyde, diethyl phthalate, dihydroanethole, dihydrocarveol, dihydrolinalool, dihydromyrcene, dihydromyrcenol, dihydromyrcenyl acetate, dihydroterpineol, dimethylsalicylic acid, 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, isobutylquinolein, isobornyl acetate, isobornyl methyl ether, isoeugenol, isolongifolene, jasmine, lavender, limonene, linalool oxide, linalool, linalool, linalyl acetate, flaxseed, litseacube, i-methyl acetate, longifolene, mandarin, mint, mentha Droperoxide, Menthol Crystal, 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, Para-Cymene, Para-Hydroxyphenylbutanone Crystal, Patchouli, p-Cymene, Pennyroyal Oil, Pepper, Perillaldehyde, Petitgrain, Phenylethyl Alcohol , phenylethyl propionate, phenylethyl-2-methylbutyrate, pimento berry, pimento leaf, pinane hydroperoxide, pinanol, pine esters, pine, pinene, piperonal, piperonyl acetate, piperonyl alcohol, purinol, purinyl acetate, pseudoionone, rhodinol, rhodinyl acetate, rosalin, rue, sandalwood, sandenol, sassafras, sesame, soybean, spearmint, spice, spike lavender, spilanthol, starflower, tea seed, terpenoids, terpineol tallow, terpinolene, terpinyl acetate, tert-butylcyclohexyl acetate, tetrahydrolinalool, tetrahydrolinalyl acetate, tetrahydromyrcenol, tulasi, thymol, tomato, trans-2-hexenol, trans-anethole, turmeric, turpentine, vanillin, vetiver, vitalizer, white cedar, white grapefruit, wintergreen, etc., or mixtures thereof, as well as menthol, peppermint and star anise oils or menthol and cherry flavors.

[0096] These aromatic or flavouring substances may be present in amounts ranging from 0.0001 to 10% by weight (particularly in the composition) of the total composition, preferably from 0.001 to 6% by weight, more preferably from 0.001 to 4% by weight and most preferably from 0.01 to 1% by weight. It may be advantageous to use different amounts in relation to the application or individual case.

[0097] According to the disclosure, all of the aforementioned excipients and excipient classes can be used without limitation, alone or in any conceivable combination, as long as it does not interfere with the use of the invention, does not cause toxic effects, or violates the laws of the respective countries.

[0098] In another aspect of the invention, the application relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutical acceptable salts, a pharmaceutical composition according to the disclosure, or a pharmaceutical combination according to the disclosure, for use in an oral formulation in the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy.

[0099] A pharmaceutical formulation suitable for an oral dosage form of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, a pharmaceutical composition according to the present disclosure, or a pharmaceutical combination according to the present disclosure may be administered as a discrete unit in the form of a tablet, soft gelatin capsule, hard gelatin capsule, dragee or pill, powder or granule, juice, syrup, drip, tea, a solution or suspension in an aqueous or non-aqueous liquid, an edible foam or mousse, or an oil-in-water or water-in-oil emulsion.

[0100] In oral dosage forms such as tablets and capsules, the active agent can be combined with a non-toxic, pharma- ceutically acceptable inert carrier, such as ethanol, glycerol, water, etc. Powders are produced by grinding the compound to a suitable small particle size and mixing in a similar manner with a pharmaceutical carrier, such as an edible carbohydrate, such as starch or mannitol. Flavoring, preservative, dispersing agent, or coloring agent may also be present.

[0101] Tablets are formulated by preparing, granulating or dry pressing a powder mixture, adding a lubricant and disintegrant, and compressing the mixture into tablets. The powder mixture is produced by mixing the compound, suitably comminuted, with the aforementioned diluents or bases, and, if applicable, with binders such as carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone, dissolution retarders such as paraffin, absorption enhancers such as quaternary salts, and / or absorbents such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, acacia mucilage or solutions of cellulose or polymeric materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be passed through a tablet machine to produce lumps of non-uniform shape which are broken into granules. The granules can be lubricated with the addition of stearic acid, a stearate salt, talc, or mineral oil to prevent the granules from sticking to the tablet mold. The lubricated mixture is then compressed to give tablets. The compounds of the present invention can also be mixed with a free-flowing inert excipient and compressed directly to give tablets without going through the granulation or dry pressing steps.

[0102] In another aspect of the present invention, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, the pharmaceutical composition of the present invention, or the pharmaceutical combination of the present invention are provided in hard gelatin capsules. These are produced by preparing a powder mixture as described above and filling it into a molded gelatin cover. Glidants and lubricants such as highly dispersed silica, talc, magnesium stearate, calcium stearate, or polyethylene glycol can be added as solids to the powder mixture. Disintegrants or solubilizers such as agar-agar, calcium carbonate, or sodium carbonate can be added as well to improve the availability of the drug after taking the capsule. Furthermore, suitable binders and / or coloring agents can be added to the mixture if desired or necessary.

[0103] In another aspect of the invention, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, a pharmaceutical composition according to the disclosure, or a pharmaceutical combination according to the disclosure is contained in a soft gelatin capsule (SGC). SGCs dissolve as they pass through the gastrointestinal tract. They consist mainly of gelatin enriched 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 administration of active agents that are poorly soluble in water.

[0104] In another embodiment of the invention, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, the pharmaceutical composition of the invention, or the pharmaceutical combination of the invention is formulated into a chewable tablet or hard caramel, wherein the substance is incorporated into the matrix of the tablet or caramel.

[0105] In another aspect of the invention, the application relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, a pharmaceutical composition according to the disclosure, or a pharmaceutical combination according to the disclosure, in a formulation for inhaled administration, for use in the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy.

[0106] For an effective inhalation treatment of congenital muscular dystrophies that affect the respiratory tract at some stage of the disease course, it is advantageous that the 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, the pharmaceutical composition of the invention, or the pharmaceutical combination of the invention reach the alveoli of the patient. Therefore, the particle size must be small enough to reach the lowest part of the airways of the lung tissue. The best class of inhalation devices for the inhalation administration of pharma- ceutical active agents are the so-called mesh nebulizers. Within the scope of this application, virtually all mesh nebulizers known in the art can be used, from fairly simple disposable mesh nebulizers for cough and cold or decorative purposes to sophisticated high-end mesh nebulizers for clinical or home treatment of severe diseases or conditions of the lower respiratory tract.

[0107] Suitable commercially available mesh nebulizers, jet nebulizers, ultrasonic nebulizers, dry powder inhalers, and (pressurized) metered dose inhalers include PARI eFlow® rapid, PARI LC STAR®, PARI Velox, PARI Velox Junior (PARI GmbH, Starnberg, Germany), Philips Respironics I-neb, Philips InnoSpire Go (Koninklijke Philips NV, Eindhoven, The Netherlands), VENTA-NEB®-ir, OPTI-NEB®, M-neb® dose+ mesh nebulizer inhalation MN-300 / 8, M-Neb Flow+, M-neb® mesh nebulizer MN-300 / X (NEBU-TEC, Eisenfeld, Germany), Hcmed Deepro HCM-86C and HCM860 (HCmed Innovations Co., Ltd, Taipei, Taiwan), OMRON MicroAir U22 and U100 (Omron, Kyoto, Japan), Aerogen® Solo, Aerogen® Ultra and Aerogen® PRO (Aerogen, Galway, Ireland), KTMED NePlus NE-SM1 (KTMED Inc., Seoul, Korea), Vectura Bayer Breelib™ (Bayer AG, Leverkusen, Germany), Vectura Fox, MPV Truma and MicroDrop® Smarty (MPV MEDICAL GmbH, Kirchheim, Germany), MOBI MESH (APEX Medical, New Taipei City, Taiwan), B.Well WN-114, TH-134 and TH-135 (B.Well Swiss AG, Widnau, Switzerland), Babybelle Asia BBU01 (Babybelle Asia Ltd., Hong Kong), CA-MI Kiwi and others (CA-MI sri, Langhirano, Italy), Diagnosis PRO MESH (Diagnosis SA, Białystok, Poland), DIGIO2 (DigiO2 International Co., Ltd., New Taipei City, Taiwan), feellife AIR PLUS, AEROCENTRE+, AIR 360+, AIR GARDEN, AIRICU, AIR MASK, AIRGEL BOY, AIR ANGEL, AIRGEL GIRL, AIR PRO 4 (Feellife Health Inc., Shenzhen, China), Hannox MA-02 (Hannox International Corp., Taipei, Taiwan), Health and Life HL100 and HL100A (HEALTH&LIFE Co., Ltd., New Taipei City, Taiwan), Honsun NB-810B (Honsun Co., Ltd., Nantong, China), K-jump(R) KN-9100 (K-jump Health Co., Ltd., New Taipei City, Taiwan), microlife NEB-800 (Microlife AG, Widnau, Switzerland), OK Biotech Docspray(OK Biotech Co., Ltd., Hsinchu City, Taiwan), Prodigy Mini-Mist(R) (Prodigy Diabetes Care, LLC, Charlotte, USA), Quatek NM211, NE203, NE320, NE403 (Big Eagle Holding Ltd., Taipei, Taiwan), Simzo NBM-1 and NBM-2 (Simzo Electronic Technology Ltd., Dongguan, China), Mexus® BBU01 and BBU02 (Tai Yu International Manufactory Ltd., Dongguan, China), TaiDoc TD-7001 (TaiDoc Technology Co., New Taipei City, Taiwan), Vibralung® and HIFLO Miniheart CirculaireII (Westmed Medical Group, Purchase, USA), KEJIAN (Xuzhou Kejian Hi-Tech Co., Ltd., Xuzhou, China), YM-252, P&S-T45 and P&S-360 (TEKCELEO, Valbonne, France), Maxwell YS-31 (Maxwell India, Jaipur, India), Kernmed® JLN-MB001 (Kernmed, Durmersheim, Germany).

[0108] Preferred are mesh nebulizers with piezoelectric activation of the nebulization process, or vibrating mesh nebulizers.

[0109] Thus, in another aspect of the invention, the application relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutical acceptable salts, a pharmaceutical composition according to the present disclosure, or a pharmaceutical combination according to the present disclosure, in a formulation administered by inhalation using a vibrating mesh nebulizer, for the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy.

[0110] Mesh nebulizers can be divided into two groups, depending on their interaction with the patient: continuous mode devices and trigger-activated devices. In continuous mode mesh nebulizers, the nebulized aerosol is continuously released into the mouthpiece, and the patient must inhale the provided aerosol. In trigger-activated devices, the defined amount of aerosol is released only upon vigorous, deep inspiration. In this way, a much larger amount of active agent-containing aerosol is inhaled and reaches the lowermost airways than in continuous mode devices. In the latter, the release of the aerosol is not linked to the respiratory cycle, so a large amount of active agent-containing aerosol is lost to the surroundings or on passage through the upper airways.

[0111] Therefore, trigger-activated mesh nebulizers, and particularly vibrating mesh nebulizers, are preferred.

[0112] Particularly preferred are trigger-activated mesh sprayers with piezoelectric actuation of the spray process.

[0113] Recommended are mesh nebulizer models PARI eFlow® rapid, Philips Respironics I-neb, Philips InnoSpire Go, M-neb® dose+ mesh nebulizer inhalation MN-300 / 8, Hcmed Deepro HCM-86C and HCM860, OMRON MicroAir U100, Aerogen® Solo, KTMED NePlus NE-SM1, Vectura Fox, Vectura Bayer Breelib®.

[0114] Most preferred are high-end models such as PARI eFlow rapid®, PARI Velox, Philips Respironics I-neb, M-neb® dose+mesh nebulizer inhalation MN-300 / 8, Aerogen® Solo, Vectura Fox, Vectura Bayer Breelib™.

[0115] The average droplet size is usually characterized as MMAD (mass mean aerodynamic diameter). The individual droplet size is called MAD (mass mean aerodynamic diameter). This value indicates the diameter of 50% of the aerosolized particles (droplets) smaller or larger, respectively. Particles with MMAD >10 μm usually do not reach the lower respiratory tract and often get stuck in the throat. Particles with MMAD >5 μm and <10 μm usually reach the bronchi but not the alveoli. Particles with MMAD between 100 nm and 1 μm do not deposit in the alveoli and are quickly exhaled. Therefore, the optimal range is MMAD between 1 μm and 5 μm. Recent publications recommend a narrower range of 3.0 μm to 4.0 μm (cf. Amirav et al. (2010) J Allergy Clin Immunol 25:1206-1211; Haidl et al. (2012) Pulmonology 66:356-360).

[0116] Another commonly accepted quality parameter is the percentage of particles with a diameter between 1 μm and 5 μm in the generated aerosol (FPM, fine particle mass). FPM is a measure of particle distribution. It is calculated by subtracting the percentage of particles with a diameter less than 1 μm in the generated aerosol from the total percentage of particles with a diameter less than 5 μm in the generated aerosol (FPF, fine particle fraction).

[0117] In another aspect of the invention, the present application also refers to a method for producing an aerosol according to the disclosure for the treatment of congenital muscular dystrophy, the method comprising the steps of: a) filling the nebulization chamber of a mesh nebulizer with 0.1 ml to 5 ml of an aqueous solution containing a combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, and, optionally, at least one pharma- ceutically acceptable excipient; b) The mesh of the mesh nebulizer is vibrated at a frequency of 80 kHz to 200 kHz. c) The generated aerosol is discharged from the side of the mesh nebulizer opposite the spray chamber.

[0118] The vibration frequency of a vibrating mesh nebulizer is typically in the range of 80 kHz to 200 kHz, with 90 kHz to 180 kHz being preferred, 100 kHz to 160 kHz being more preferred, and 105 kHz to 130 kHz being most preferred (see Chen, The Aerosol Society: DDL 2019; Gardenshire et al. (2017) A Guide to Aerosol Delivery Devices for Respiratory Therapists, 4th ed.).

[0119] Therefore, the above method is also disclosed in said vibration frequency range.

[0120] Thus, the method according to the present disclosure is characterized in that at least 80% by weight, preferably at least 85% by weight, and most preferably at least 90% by weight of the 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, the pharmaceutical composition according to the present disclosure, or the pharmaceutical combination according to the present disclosure contained in said aqueous solution is sprayed into the aerosol generated.

[0121] The method of the present invention is particularly effective in nebulizing high concentrations of pharma- ceutical active agents from a provided aqueous solution in a short time, which is an important feature for patient compliance. A significant proportion of patients find the inhalation process unpleasant, tiring, and physically taxing. On the other hand, active patient cooperation is essential for effective and targeted inhalation application. It is therefore desirable to apply a therapeutically sufficient amount in as short a time as possible. Surprisingly, it has been shown that 95% of the substance provided in an aqueous solution can be nebulized in a time frame of 3 minutes, which is an ideal time frame for increasing patient compliance.

[0122] Thus, the methods of the present disclosure are characterized in that at least 80%, preferably at least 85%, and most preferably at least 90% of the aerosol generated is generated within 3 minutes after the start of nebulization with the mesh nebulizer.

[0123] Pharmaceutically active agents are usually provided in a single-dosage container for each nebulization procedure, whereas the nebulizer and / or mouthpiece can be used for a certain period of time and should be replaced at certain intervals. It is recommended that the nebulizer and mouthpiece be cleaned by default after each nebulization. However, in this case, patient compliance cannot be taken for granted. However, even after careful cleaning, aerosol deposits are always present in the nebulization chamber, outlet, and / or mouthpiece. As aerosols are generated from aqueous solutions, these deposits carry the risk of generating a bacterial bioburden that can contaminate the inhaled aerosol. The deposits can also block the holes in the mesh membrane of mesh nebulizers. In general, the nebulizer and / or mouthpiece should be replaced every week or two. It is therefore convenient to provide the agent and nebulizer as a combined product.

[0124] Therefore, in another aspect of the invention, the application also refers to a kit comprising a mesh nebulizer and a pharma- ceutically acceptable container containing an aqueous solution comprising an effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, a pharmaceutical composition according to the present disclosure, or a pharmaceutical combination according to the present disclosure for the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy, and optionally at least one pharma- ceutically acceptable excipient.

[0125] In an alternative kit, the pharmaceutical composition according to the present disclosure or the pharmaceutical combination according to the present disclosure is not provided in the form of an aqueous solution, but in two separate containers, one for the solid form of the active agent and one for the aqueous solution. The final aqueous solution is freshly prepared by dissolving the active agent in the final solution. The final aqueous solution is then filled into the nebulization chamber of the mesh nebulizer. These two containers may be, for example, two vials, or completely separate containers, such as, for example, a dual-chamber vial. To dissolve the active agent, for example, a hole is made in the membrane between the two chambers, allowing the contents of both chambers to mix.

[0126] Thus, the present application also discloses a kit comprising a mesh nebulizer, a first pharma- ceutically acceptable container containing water for injection or saline, and a second pharma- ceutically acceptable container containing an effective solid dose of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, a pharmaceutical composition according to the present disclosure, or a pharmaceutical combination according to the present disclosure, for the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy, and optionally comprising at least one pharma- ceutically acceptable excipient in the first pharma- ceutically acceptable container and / or the second pharma- ceutically acceptable container.

[0127] The aerosols produced by the methods according to the invention are administered or self-administered via a mouthpiece. Optionally, such a mouthpiece can be further included in the aforementioned kit.

[0128] A typical method for transferring the provided or final aqueous solution to the nebulizer chamber by a syringe with a needle is described below. The aqueous solution is first drawn into the syringe and then injected into the nebulizer chamber. Optionally, such a syringe and / or needle can be additionally included in the aforementioned kit. A typical syringe made of, but not limited to, polyethylene, polypropylene, or cyclic olefin copolymer can be used, and a typical gauge for stainless steel needles ranges from 14 to 27.

[0129] In yet another aspect of the present invention, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, the pharmaceutical composition according to the disclosure, or the pharmaceutical combination according to the disclosure is applied in the form of liposomes, micelles, multilamellar vesicles, or cyclodextrin complexes for use in the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy.

[0130] In yet another aspect of the invention, the application discloses 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, or a composition according to the invention, or a combination according to the invention, for use in the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy, which has been refractory to previous treatment with at least one other pharma- ceutically active agent.

[0131] In yet another aspect of the invention, the application discloses 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, or a composition according to the invention, or a combination according to the invention, for use in the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy, wherein said substance or said pharmaceutical composition is formulated as a suppository.

[0132] To prepare suppository forms of 5-amino-2,3-dihydro-1,4-phthalazinedione, a mixture of low melting wax and fatty acid glycerides, such as cocoa butter, is first melted and the 5-amino-2,3-dihydro-1,4-phthalazinedione is then dispersed homogeneously by stirring or other mixing methods, the molten homogeneous mixture is then transferred to suitable molds and allowed to cool until solid.

[0133] In yet another aspect of the invention, the application relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, a pharmaceutical composition according to the disclosure, or a pharmaceutical combination according to the disclosure, in a liquid dosage form, for use in the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy.

[0134] The present application also discloses the parenteral administration in the form of intravenous, intraarterial or intraperitoneal injection of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, a pharmaceutical composition according to the present disclosure, or a pharmaceutical combination according to the present disclosure, for the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy.

[0135] These liquid dosage forms include solutions, suspensions, and emulsions, such as water and water / propylene glycol solutions for parenteral injection or oral solutions, suspensions, and emulsions containing sweeteners or opacifiers.

[0136] These liquid dosage forms can be stored in vials, IV bags, ampoules, cartridges, prefilled syringes, etc. Suitable excipients include solubilizers, stabilizers, buffers, tonicity adjusters, bulking agents, viscosity enhancers / reducers, surfactants, chelating agents, adjuvants, etc.

[0137] Preferred dosage forms according to the invention are retard formulations, i.e. formulations with delayed release of at least one active agent. These are also known as sustained release (SR), extended release (ER, XR) or controlled / continuous release (CR) forms. Suitable formulations and carriers are known to those skilled in the art (Kleinsorge (1995) Retardformulierungen in der medikamentosen). Most commonly, at least one active agent is embedded in a matrix of insoluble substances such as acrylic or chitin. The active agent must therefore exit through openings in the matrix. In some formulations, holes are drilled with a laser on one side and a porous membrane on the other side. Gastric juice attacks and flows through this porous membrane, forcing the active agent out of the holes on the other side. In other formulations, the active agent dissolves and expands within the matrix, forming a gel. The active agent is then released from the pores of the gel. Other examples include specially coated tablets resistant to gastric juices, delayed capsules containing delayed pellets of active agent that are released after dissolution of the capsule casing, multi-unit pellet systems (MUPS), oral osmotic systems, resonators, coacervation, microencapsulation, etc. Such delayed formulations allow control of the site of release of the drug and its pharmacokinetics. For example, it is often desirable for a dosage form of an active agent not to dissolve before reaching a certain point in the intestine. Because of changes in pH on the way through the intestine, the dissolution process can be designed to be pH dependent. In therapeutic applications where it is necessary to facilitate absorption of the active agent through the intestinal mucosa to increase its bioavailability, it may be desirable to use a neutral form of the active agent rather than a salt.

[0138] The application therefore also refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts for use according to the invention, or to a pharmaceutical composition for use according to the invention, said substance or said pharmaceutical composition being formulated as a retardant.

[0139] In yet another embodiment of the present invention, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, the pharmaceutical composition according to the disclosure, or the pharmaceutical combination according to the disclosure is used for the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy, and said substance, composition, or combination is formulated as a lyophilizate. The lyophilizate can be reconstituted with water for injection, saline, or water / ethanol solution and administered by injection.

[0140] Common applications of intravenous injection include infusion pumps, hypodermic needles, drip chambers, peripheral cannulas (peripheral venous catheters), and pressure bags.

[0141] Generally, aqueous or saline solutions are preferred, although in the case of poorly soluble drugs according to the present invention, ethanol or ethanol / water mixtures can also be used.

[0142] Further suitable liquid dosage forms include drops, gels and hydrogels.

[0143] 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 under steady state conditions. 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.

[0144] A hydrogel is a network of hydrophilic polymer chains that may exist as a colloidal gel in which water is the dispersion medium. The hydrophilic polymer chains are linked together by crosslinks to form a three-dimensional solid. Due to the inherent crosslinks, the structural integrity of the hydrogel network is not 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 that gives them flexibility very similar to natural tissues. In medicine, hydrogels can encapsulate chemical systems and release certain pharmacologically active substances into the environment, most often by transitioning from a gel-sol to a liquid state, upon stimulation by an external factor such as a change in pH.

[0145] 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.

[0146] In yet another aspect of the present invention, the application relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutical acceptable salts, a pharmaceutical composition according to the present disclosure, or a pharmaceutical combination according to the present disclosure, for use in the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy, in the formulation of a sublingual tablet.

[0147] 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.

[0148] Drugs must be lipophilic enough to pass through the lipid bilayer, but not so lipophilic that once in, they cannot exit again. According to the diffusion model of absorption, the flux across the lipid bilayer is directly proportional to the concentration gradient. Thus, low solubility in saliva results in low absorption, and vice versa. In general, drugs formulated for sublingual administration should ideally have a molecular weight below 500 to facilitate diffusion. The pH range of the oral cavity is narrow, between 5.0 and 7.0. Including an appropriate buffer in the formulation of an ionizable drug can control the pH of aqueous saliva.

[0149] Taste masking is necessary to avoid unpleasant tastes and odors of medications. Sweeteners, flavors, and other taste masking agents are essential ingredients. Sugar-based excipients dissolve quickly in saliva and generate an endothermic heat of dissolution. They create a pleasant sensation in the mouth and, together with other flavorings, are ideal for sublingual tablets.

[0150] 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).

[0151] If swallowing is avoided, administration of the active ingredient via a sublingual tablet can also reach the pharynx / throat locally. The majority of the active ingredient is absorbed via the pharyngeal mucosa.

[0152] In yet another embodiment of the present invention, a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts for use in the treatment of congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy, is provided in a topical application form such as a cream, emulsion, lotion, gel, hydrogel, paste, powder, ointment, salve, film, liposome, skin patch, transdermal patch, transdermal spray or suspension.

[0153] In a further aspect of the present invention, a method for treating congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy, is disclosed, in which an effective dose of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, a pharmaceutical composition of the present invention, or a pharmaceutical combination of the present invention is administered to a patient in need thereof.

[0154] The present invention also relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, hydrates or solvates for use in a method for treating a congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy, 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, concomitantly with or subsequent to an effective amount of at least one glucocorticoid or one of its pharma-ceutically acceptable salts.

[0155] The present invention also relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharma- ceutically acceptable salts, hydrates or solvates for use in a method for treating a congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy, 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, concomitantly or subsequently, with an effective amount of at least one glucocorticoid or one of its pharma- ceutically acceptable salts, wherein the 5-amino-2,3-dihydro-1,4-phthalazinedione is the sodium salt.

[0156] The present invention also relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or any one of its pharma- ceutically acceptable salts, hydrates or solvates for use in a method for treating a congenital muscular dystrophy, in particular Duchenne muscular dystrophy or Becker muscular dystrophy, in a subject, the method comprising administering to the subject an effective amount of at least one glucocorticoid or any one of its pharma- ceutically acceptable salts, concomitantly or subsequently with an effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione or any one of its pharma- ceutically acceptable salts, hydrates or solvates.

[0157] The present invention also relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or any one of its pharma- ceutically acceptable salts, hydrates or solvates for use in a method for treating a congenital muscular dystrophy in a subject, in particular Duchenne muscular dystrophy or Becker muscular dystrophy, the method comprising administering to the subject an effective amount of at least one glucocorticoid or any one of its pharma- ceutically acceptable salts, hydrates or solvates, either simultaneously or subsequently, and an effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione or any one of its pharma- ceutically acceptable salts, hydrates or solvates, wherein 5-amino-2,3-dihydro-1,4-phthalazinedione is the sodium salt. example

[0158] The mdx mouse model has been the most widely used and studied animal model in Duchenne muscular dystrophy research since the early 1980s. These mice are characterized by muscle weakness, histological evidence of myopathy, and elevated serum levels of creatine kinase (CK) (see Bulfield et al. (1984) PNAS 81:1189-1192), where CK levels are a marker of destruction of CK-rich tissues such as skeletal muscle (rhabdomyolysis). The mutation in mdx mice is a nonsense mutation (C to T transition) in exon 23, which disrupts the expression of full-length dystrophin (see Sicinski et al. (1989) Science 244:1578-1580). Symptoms are moderate, and the average life span is shortened by approximately 25%. During the first 2 weeks of life, mdx mice are indistinguishable from wild-type mice. Skeletal muscle necrosis then begins until the sixth week of life, when the mice enter a plateau phase characterized by muscle hypertrophy. Only the diaphragm shows progressive deterioration. Severe dystrophic phenotypes, including muscle atrophy, scoliosis, and heart failure, do not develop until the mice are over 15 months old (see McGreevy et al. (2015) DisModelMech8:195-213). Many older mdx mice spontaneously develop sarcomas.

[0159] Four-week-old C57BL / 10ScSnJ (stock no. 000476) and C57BL / 10ScSn-Dmdmdx / J mice (stock no. 001801) were obtained from The Jackson Laboratory (Bar Harbor, USA). Animals were divided into two cohorts (n=49-56, 7-8 mice per group). Mice were divided into a total of five treatment groups. Mice in the control group were wild-type C57BL / 10ScSnJ and dmx strain C57BL / 10ScSn-Dmdmdx / J. Animals were allowed to acclimate for 7 days after arrival at the animal facility and were housed in cages with a maximum of five mice per cage. A 12-h light / 11-h dark cycle was maintained throughout the study. Room temperature was maintained between 20°C and 23°C. Food and water were available ad libitum throughout the study. Mice were identified by ear tags. Randomization was based on the average weight of the cages. These cages were randomly assigned to treatment groups. Animals were monitored daily for behavioral changes. If necessary, a veterinarian would determine whether the animal needed to be euthanized to relieve unnecessary pain and distress, in which case a decision would be made whether tissue sampling would still proceed.

[0160] Animal experiments were approved by the Dalhousie University Animal Committee in accordance with the regulations of the Canadian Council on Animal Care.

[0161] All therapeutic compounds were administered by intraperitoneal (IP) injection, except for prednisolone, which was administered by oral syrup. IP injections were performed by restraining the mouse and administering the therapeutic into either side of the abdomen, midway between the midline and the natural flexion of the knee. The needle was inserted at a 45° angle, bevel side up. Before administering the therapeutic, the syringe was slightly aspirated to ensure proper intraperitoneal positioning. Once the injection was administered, the mouse was monitored for several minutes to check for any side effects. Animals received injections on alternating days to reduce damage from repeated injections. Oral syrup containing prednisolone was administered to each mouse by filling a syringe (without a needle tip) with the desired therapeutic volume. The syringe was checked before administration to ensure there were no air bubbles in the syrup. Once the mouse was restrained, the syringe (without a needle tip) was placed over the mouse's mouth. The plunger of the syringe was slowly pressed to encourage the mouse to lick the syrup. Once all treatments were completed, the mice were returned to their cages and observed for a few minutes to see if there were any side effects.

[0162] The experiments were performed by AGADA Biosciences (Halifax, Canada) on behalf of the applicant. All treatment materials were provided by the applicant. All treatment groups were initiated with 15 mice. Treatments were blinded. [Table 1]

[0163] Example 1: In vitro effects of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt on the contractile properties of the extensor digitorum longus muscle of mdx mice (compared to deflazacort and prednisolone)

[0164] At the end of the study, the contractile properties of the right extensor digitorum longus (EDL) were measured in vitro. Mice were anesthetized with ketamine and xylamine. The EDL muscle of the right hindlimb was isolated from each mouse and immersed in an individual carbonated bath (95% O2, 5% CO2) containing Ringer's solution (pH 7.4) at 25 °C. Two electrodes were placed on either side of the muscle. Force was generated with the muscle held at 10 mN using fatigue-free twitch contractions. Maximum force was measured with the muscle held at 10 mN. The muscle was stimulated with electrodes to induce a tetanic contraction with a 2-min rest period. For each subsequent tetanic EDL, the stimulation frequency was increased by 20, 30, or 50 Hz until the force reached a plateau, which usually occurs around 250 Hz. This plateau was considered as the maximum force (mN) generated by the muscle. The cross-sectional area of ​​the muscle was measured based on muscle mass, muscle length, and tissue density. Finally, the muscle specific force (kN / m2) was calculated based on the muscle cross-sectional area and converted according to the individual body weight (nM / kg). The experimental setup is shown in Figure 1.

[0165] In this experiment, 15 mice from treatment groups 1 and 2, 14 mice from groups 3, 4, 6, and 7, and 12 mice from group 5 could be evaluated.

[0166] 5-Amino-2,3-dihydro-1,4-phthalazinedione sodium salt dose-dependently improved the maximal force produced by the muscle. The highest dose of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (5.0 mg / kg body weight) was nearly as effective as prednisolone (106.1 ± 8.0 mN / kg vs. 107.5 ± 7.2 mN / kg) but much more effective than deflazacort (96.8 ± 5.2 mN / kg). All data are mean ± SEM. In Figure 2A, these data are shown for all treatment groups. In Figure 2B, the same data are shown as the percentage improvement of the treatment group compared to the untreated mdx mouse control group, which was set at 100%. Here, the highest dose of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (5.0 mg / kg body weight) produced a 16.4% improvement compared with prednisolone (18.0%) and deflazacort (6.2%).

[0167] These data suggest that 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt may be an alternative to glucocorticoid treatment in patients with Duchenne and Becker muscular dystrophy, providing the same beneficial effects without the side effects of long-term glucocorticoid treatment. These data also suggest that the combination of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt and glucocorticoids may be beneficial in these patients.

[0168] Example 2: Effect of administration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt on the body weight of mdx mice (compared to deflazacort and prednisolone)

[0169] A known side effect of glucocorticoid treatment is weight loss in laboratory animals, which correlates with the effects of long-term glucocorticoid treatment in patients with Duchenne muscular dystrophy (and to some extent Becker muscular dystrophy), who often experience loss of muscle mass and growth retardation over the course of long-term treatment.

[0170] Body weights were measured weekly after the animals were acclimated to the facility and treatment began (at 5 weeks of age). At the beginning of each week, each mouse's body weight was measured on an OHAUS ScoutPro digital scale tared into an open 750 ml Tupperware container. Mice were individually confined to the container and placed on the scale.

[0171] As expected, the prednisolone and deflazacort treatment groups (groups F and G) showed a significant reduction in weight gain during the treatment period, beginning approximately 6 weeks after the start of treatment. The approximate difference was about 7%. The groups treated with the three concentrations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt showed no difference from untreated mdx mice and wild-type mice during the treatment period.

[0172] These data suggest that the commonly observed (and feared) side effects of treatment with 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, such as loss of muscle mass and growth retardation, are not to be expected, and in this respect 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt has been shown to be superior to prednisolone and deflazacort.

[0173] The changes in body weight during the treatment period are shown in Figure 3 for all groups. [Brief description of the drawings]

[0174] FIG. 1: Photograph of the experimental apparatus for measuring the contractile properties of the extensor digitorum longus muscle of mdx mice used in Example 1. Figure 2: A: Bar graph showing the effect of different treatment groups in measuring the contractile properties of the extensor digitorum longus muscle in mdx mice (example 1). B: Bar graph showing the percentage of treatment improvement for the different treatment groups, measuring the contractile properties of the extensor digitorum longus muscle in MDX mice compared to untreated MDX mice (example 1). [Table 2] Figure 3: Bar graph of the body weight of mice in the different treatment groups during the treatment period (5–10 weeks of age). [Table 3]

Claims

1. A pharmaceutical for monotherapy of congenital muscular dystrophy, comprising, as an active ingredient, 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, wherein the congenital muscular dystrophy is Duchenne muscular dystrophy or Becker muscular dystrophy.

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

3. The pharmaceutical according to claim 2, wherein the sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione is provided as one of crystalline anhydrous polymorphic forms I, II, or III characterized by the following crystallographic values ​​as determined by X-ray powder diagram: For Form I, d values: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1; 3.0 and / or 2-theta values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3, For Form II, d values: 12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and / or 2-theta values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8, and For Form III, d values: 13.131; 7.987; 7.186; 6.566; 6.512; 5.372; 3.994; 3.662; 3.406; 3.288; 3.283; 3.222; 3.215; 3.127; 2.889 and / or A drug with 2-theta values: 6.73; 11.07; 12.31; 13.48; 13.59; 16.49; 22.24; 24.29; 26.14; 27.10; 27.14; 27.67; 27.72; 28.52; 30.

93.

4. A pharmaceutical for monotherapy of muscular dystrophy, comprising a pharmaceutical composition containing the active ingredient 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient, wherein the muscular dystrophy is Duchenne muscular dystrophy or Becker muscular dystrophy.

5. 5. The method of claim 4, wherein the pharmaceutical composition is suitable for intravenous, oral, sublingual, inhaled, rectal, topical or dermal administration.

6. 6. The pharmaceutical composition of claim 4 or 5, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of carriers, binders, colorants, buffers, preservatives, antioxidants, coatings, sweeteners, thickeners, pH adjusters, acidity adjusters, acidifiers, solvents, isotonicity agents, disintegrants, glidants, lubricants, emulsifiers, solubilizers, stabilizers, diluents, anti-caking agents, adsorbents, permeation enhancers, foaming agents, anti-foaming agents, opacifiers, fatty agents, viscosity enhancers, hydrotropes, fragrances and flavoring substances.

7. A medicament according to claim 5, wherein the medicament is orally administered in the form of a tablet, soft gelatin capsule, hard gelatin capsule, dragee or pill; powder or granules; juice, syrup, drops, tea, solution or suspension in an aqueous or non-aqueous liquid; edible foam or mousse; or oil-in-water or water-in-oil emulsion.

8. The pharmaceutical described in claim 5, wherein the pharmaceutical is applied in the form of a sublingual tablet or lozenge.

9. The medicament of claim 5, wherein the medicament is administered by inhalation using a vibrating mesh nebulizer, a metered dose inhaler, a jet nebulizer, or a dry powder inhaler.

10. The pharmaceutical of claim 5, wherein the pharmaceutical is formulated as a sustained-release drug.

11. The pharmaceutical of claim 5, wherein the pharmaceutical is formulated as a freeze-dried drug.

12. The pharmaceutical according to claim 5, wherein the pharmaceutical is applied in the form of a liposome, a micelle, a multilamellar vesicle or a cyclodextrin complex.

13. The pharmaceutical composition of claim 5, for use in a patient with congenital muscular dystrophy who has been refractory to prior treatment with at least one other pharmaceutically active agent.

14. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is formulated as a suppository.

15. The pharmaceutical of claim 5, wherein the pharmaceutical is applied topically in the form of a cream, emulsion, lotion, gel, hydrogel, paste, powder, ointment, liniment, film, liposome, skin patch, transdermal patch, transdermal spray or suspension.

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