US-12616695-B2 - Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of rare chronic inflammatory pulmonary diseases

US12616695B2US 12616695 B2US12616695 B2US 12616695B2US-12616695-B2

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 rare chronic inflammatory pulmonary diseases. The invention in particular relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for said purposes.

Inventors

Wolfgang Brysch
Astrid Kaiser
Petra Schulz
Sara Schumann
Jörg von Wegerer

Assignees

METRIOPHARM AG

Dates

Publication Date: 20260505
Application Date: 20210129
Priority Date: 20200131

Claims (20)

1 . A method of treating an individual having a postprocedural or related lower respiratory disease selected from a group consisting of chronic pulmonary insufficiency following surgery, host-versus-graft disease after lung transplantation, graft-versus-host disease after lung transplantation, chronic lung allograft dysfunction, chronic lung allograft dysfunction—bronchiolitis obliterans syndrome, lung ischemia reperfusion injury, primary graft dysfunction after lung transplantation, Mendelson's syndrome, pulmonary collapse, atelectasis, interstitial emphysema, mediastinal emphysema, compensatory emphysema, mediastinitis and disorders of diaphragm by administering to such individual a pharmaceutically effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts.
2 . The method of claim 1 , wherein said pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1,4-phthalazinedione is 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt.
3 . The method of claim 2 , wherein 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is provided as one of crystalline anhydrate polymorph forms I, II or III characterized by crystallography values determined by means of x-ray powder diagrams: 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 I, 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 for form II, and 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 for form III.
4 . The method of claim 1 , wherein 5-amino-2,3-dihydro-1,4-phthalazinedione is provided in a composition containing 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a carrier and at least one pharmaceutically acceptable excipient.
5 . The method of claim 4 , wherein the at least one pharmaceutically acceptable excipient is selected from a group comprising binding agents, colorants, buffers, preservatives, antioxidants, coatings, sweeteners, thickening agents, pH-regulators, acidity regulators acidifiers, solvents, isotonizing agents, penetration enhancers, disintegrants, glidants, lubricants, emulsifiers, solubilizing agents, stabilizers, diluents, anti-caking agents, sorbents, foaming agents, anti-foaming agents, opacifiers, fatliquors, consistency enhancers, hydrotropes, aromatic and flavoring substances.
6 . The method of claim 1 , wherein 5-amino-2,3-dihydro-1,4-phthalazinedione is provided in a combination of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one further active agent selected from a group comprising steroidal and non-steroidal anti-inflammatory drugs, immunomodulators, immunostimulatory agents, immunosuppressive agents, antibiotics, antiviral agents, antifungal agents, antiprotozoal agents, analgesics, anticoagulants, antiplatelet drugs, bronchodilators, pulmonary vasodilators, mucolytic agents, pulmonary surfactants, antioxidants, ENaC-activating agents, HMG-CoA reductase inhibitors, calcium antagonists or AT 1 receptor antagonists.
7 . The method of claim 1 , wherein 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is applied by inhalation, by intubation, orally, parenterally, intraperitoneally, intravenously, intraarterially, intramuscularly, topically, transdermally, subcutaneously, intradermally, sublingually, conjunctivally, intravaginally, rectally, intrathecally, pharyngeally or nasally.
8 . The method of claim 4 , wherein said composition is applied by inhalation, by intubation, orally, parenterally, intraperitoneally, intravenously, intraarterially, intramuscularly, topically, transdermally, subcutaneously, intradermally, sublingually, conjunctivally, intravaginally, rectally, intrathecally, pharyngeally or nasally.
9 . The method of claim 1 , wherein 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is applied orally in the form of tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets, pills, powders, granulates, juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids, edible foams, mousses, oil-in-water lotions or water-in-oil lotions.
10 . The method of claim 4 , wherein said composition is applied orally in the form of tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets, pills, powders, granulates, juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids, edible foams, mousses, oil-in-water lotions or water-in-oil lotions.
11 . The method of claim 1 , wherein 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is applied in the form of sublingual tablets or lozenges.
12 . The method of claim 4 , wherein said composition is applied in the form of sublingual tablets or lozenges.
13 . The method of claim 1 , wherein 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is applied by inhalation by using a vibrant mesh nebulizer, metered dose-inhaler, jet nebulizer, ultrasonic nebulizer or dry-powder inhaler.
14 . The method of claim 4 , wherein said composition is applied by inhalation by using a vibrant mesh nebulizer, metered dose-inhaler, jet nebulizer, ultrasonic nebulizer or dry-powder inhaler.
15 . The method of claim 1 , wherein 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is added to the ventilation air of a cardiopulmonary bypass device.
16 . The method of claim 4 , wherein said composition is added to the ventilation air of a cardiopulmonary bypass device.
17 . The method of claim 1 , wherein 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is formulated as a retard drug.
18 . The method of claim 4 , wherein said composition is formulated as a retard drug.
19 . The method of claim 1 , wherein 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is formulated as a lyophilizate.
20 . The method of claim 4 , wherein said composition is formulated as a lyophilizate.

Description

The present invention relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or its pharmaceutically acceptable salts in the treatment of rare chronic inflammatory pulmonary diseases. The invention in particular relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for said purposes. BACKGROUND OF THE INVENTION Pulmonary diseases cover a plethora of diseases of the lower airways of the respiratory system, in particular of the lungs. While for common pulmonary diseases such as pneumonia, asthma or chronic obstructive pulmonary disease (COPD) pharmaceutical therapies are available there is a broad spectrum of rare chronic pulmonary diseases for which no effective or only a poorly effective medication has been developed yet. Because of economic prospects these rare diseases are not in the focus of the pharmaceutical industry. Thus, there is a medical need to provide pharmaceutical medications for the treatment of these rare chronic pulmonary diseases for patients in need thereof. Most of these rare chronic pulmonary diseases are classified in the ICD-10 Chapter X: Diseases of the respiratory system (J00-J99), Version 2016, as of Jan. 10, 2020. The terms rare disease and orphan disease are often used synonymously. However, rare disease refers rather to the epidemiologic prevalence of a disease in a population. Orphan disease refers to the regulatory classification of a disease by the respective medical authorities. An orphan disease must be a rare disease and no effective medication is available due to a lack of economic incentive for the pharmaceutical industry (cf. Orphan Drug Act, USA; European Organization for Rare Diseases (EURORDIS)). The term prevalence refers to the overall percentage of a population suffering from this specific disease. The term incidence refers to the number of new patients that become diseased with this specific disorder in the course of one year. The frequency for such a classification may differ between countries, regions and ethnic groups. The frequency may also vary over time. For example, in the European Union a prevalence of 1:2000 or less is required, while in the USA a frequency of 1:1500 or less is required and in Japan a frequency of 1:2500 or less. In the scope of the present application the term rare disease(s) shall thus refer to a worldwide prevalence of 1:1500 or less. The term pulmonary disease(s) encompasses pathological conditions that impair the gas exchange in the lungs or bronchi in mammals. In general, they are differentiated into obstructive and restrictive pulmonary diseases. Obstructive pulmonary diseases are characterized by airway obstruction. This limits the amount of air that is able to enter the alveoli because of constriction of the bronchial tree, due to inflammation. Restrictive pulmonary diseases are characterized by a loss of lung compliance, causing incomplete lung expansion and increased lung stiffness. They can be also categorized as airway diseases, lung tissue diseases, lung infectious diseases and lung proliferative diseases. Airway diseases affect the tubes that carry oxygen and other gases into and out of the lungs. They usually cause a narrowing or blockage of the airways. Typical airway diseases include asthma, chronic obstructive pulmonary disease (COPD) and bronchiectasis. Lung tissue diseases affect the structure of the lung tissue. Scarring or inflammation of the tissue makes the lungs unable to expand fully. This complicates the gas exchange. As a result, these patients can't breathe deeply. Pulmonary fibrosis and sarcoidosis are typical examples thereof. Lung infectious diseases refer to disorders caused by an infection of the lower airways, e.g. pneumonia. Lung proliferative diseases include all tumors or neoplasms of the lower airways. Most of the airway diseases are caused by an underlying inflammation or at least include an inflammatory component. Lung tissue diseases often also have an inflammatory component, unless they are caused by direct physical impairment of the respiratory tract. Infectious and proliferative diseases of the lungs may also have an inflammatory component, often secondary to the infection or the underlying malignancy. Thus, these inflammatory pulmonary diseases have in common that they could be pharmacologically treated by anti-inflammatory drugs. While there are established medications for the treatment of acute inflammatory pulmonary diseases, e.g. for bacterial and viral infections, and of tumors there is still a need for pharmaceutical treatment of chronic inflammatory pulmonary diseases, in particular for the rare diseases of this group. Thus, there is a medical need to find a pharmaceutical agent that shows a high efficacy in the treatment of rare chronic inflammatory pulmonary diseases. Surprisingly, this task is solved by the administration of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts or solvates, hydrates, crystalline polymo