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    • 专利摘要:
    CRYSTALLINE FORMS FOR SODIUM SALT OF 5-AMINO-2,3DI-HYDRO PHTALAZINE-1,4-DIONE, PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME AND PROCESS FOR THE PRODUCTION OF SAID FORMS. The invention relates to the provision of two new crystalline forms I and II for the sodium salt of 5-amino-2,3-dihydrophthalazine-1,4-dine. Surprisingly, form I and form II have been found to have different immunological effects. This advantageous property is useful for immunospecific applications. In editing, both forms have advantageous physicochemical properties, which are useful in the production, further processing and/or use of a pharmaceutical preparation of form I or form II or a mixture of both.
    公开号:BR112012021857B1
    申请号:R112012021857-3
    申请日:2011-03-01
    公开日:2021-06-22
    发明作者:Josef Breu；Wolfgang Brysch；Astrid Kaiser；Beate Ludescher；Gerrit Maass；Thomas Martin；Wolfgang Milius；Michael Niedermaier
    申请人:Metriopharm Ag；
    IPC主号:
    专利说明:

    Technical Field of the Invention
    [0001] The present invention relates to the provision of at least two new crystalline forms for the sodium salt of 5-amino-2,3-dihydrophthalazine-1,4-dione with advantageous properties, pharmaceutical preparations containing the same , and processes for producing them.
    [0002] The invention in particular relates to the provision of 2 new crystalline forms for 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt with immunostimulating and immunodepressive properties for medical purposes. Background of the Invention
    [0003] For some time, chemical compounds having immunomodulatory effects have been known in the art. To these compounds also belongs the sodium salt of 5-amino-2,3-dihydro phthalazine-1,4-dione, the compound of the present invention, which is known for example from EP 1 203 587 A and has the following basic structure (Na+ not shown):

    [0004] The basic structure above is also called luminol. It is known from the prior art that alkaline salts of 5-amino-2,3-dihydrophthalazine-1,4-dione crystallize as solid matter in different hydrate forms. In the prior art, in particular the sodium salt dihydrate (RU 2113222 C1) and a potassium salt trihydrate and their mixed forms (RU2211036 C2) are described.
    [0005] It is known in the art that crystalline forms of a substance can differ in their physical properties such as solubility, dissolution rate, stability, etc. (Haleblian and McCrone (1969): Journal of Pharmaceutical Sciences, 58:911- 929).
    [0006] Such properties can affect the pharmaceutical processing of the active ingredient as well as its biological availability and thus the biological efficacy (cf. Griesser (2006) in: Polymorphisms in the Pharmaceutical Industry. Hilfiker (Ed.) 211-234).
    [0007] For the production of medicines, it is important that the original substance is stable, not withdrawing water and controllable in its solid behavior during the complete production process. Furthermore, chemical stability and solid phase stability with long storage capacity of an active ingredient are extremely important (cf. Miller et al. (2006) in: Polymorphisms in the Pharma-ceutical Industry. Hilfiker (Ed.) 385-403 ). It is desirable that even over a longer storage time, the physical properties of the active ingredient will be maintained. This refers to, for example, the hygroscopicity, solubility or initial dissolution rate of the active ingredient.
    [0008] US 6 489 326 B1 describes a process for producing 5-amino-2,3-dihydro phthalazine-1,4-dione sodium salt to be used for medical purposes, which results in a di-form. hydrate. The disadvantage of this process is the use of a heavy metal catalyst that can leave residues in the product. Products with residues have allergenic potential and are generally judged critical for pharmaceutical use by the EMEA (cf. Guideline EMEA/CHMP/SWP/4446/2000).
    [0009] Very important for pharmaceutical processing and medical use are production processes, which allow reliably and reproducibly to produce the desired crystalline forms. When producing crystal forms, it must be considered that small deviations from the process parameters will already cause changes in the crystal structure of the products and can thus ultimately lead to different crystal forms or mixed forms. Properties so altered - for example, a biological efficacy modified by a different solubility - can lead to a rejection of whole batches, often not being possible to produce the desired shape (cf. Ulrich and Jones (2005): Nachrichten aus der Chemie 53:19-23). In addition to the degree of purity of the active ingredient and the resulting possible changes in efficacy, even important properties for pharmaceutical processing can be adversely affected, for example, the ability to be compressed into tablets through a deterioration in pourability. or crystal form flow rate. Alkaline salts of 5-amino-2,3-dihydro phthalazine-1,4-dione belong to the group of amino phthalhydrazides and are described in the prior art as immunomodulators with special anti-inflammatory, antioxidant and anti-toxic properties (cf. US 6,489,326 B1; EP 0617024, US 5,512,573, US 5,543,410 A, US 7,326,690 B2).
    [00010] Immunomodulatory substances are commonly grouped according to their effects on immunosuppressants and immunostimulants (cf. Rote Liste Service GmbH (2011): www.rote-liste.de).
    [00011] Corresponding preparations having exclusively immunodepressive or exclusively immunostimulating effect, such as, for example, immunodepressant TNF alpha blockers or interferon-beta immunostimulant preparations, often cause significant unwanted side effects in the body, precisely because of their very specific mechanism of action . Some known immunosuppressive substances, such as, for example, a TNF alpha blocker adalimumab, specifically inhibit certain inflammatory mediators. Such therapies are known to have serious side effects (cf. Descotes (2008): Expert Opin. Drug Metab. Toxicol., 4: 12: 1537-1549), since blocking individual inflammatory mediators is a severe system intervention complex immune. Consequently, the organism is no longer able to fulfill its functions, to react automatically and physiologically appropriately to exogenous or endogenous inflammatory stimuli, such as, for example, bacterial infections. Thus, for example, the application of TNF alpha blockers is contraindicated in the case of serious infections, this applies in particular to sepsis and tuberculosis. Before administration of a corresponding medication, such as, for example, for the treatment of rheumatoid arthritis, a TBS separation is strongly recommended (cf. Diel et al. (2009): Z Rheumatol 5:411-416). Hoffman (2005: Intensivmed 42:371-377) can clearly demonstrate that TNF alpha blockers are not suitable for clinical application in the case of septic conditions, but on the contrary they can even lead to an increase in mortality.
    [00012] The particular immunomodulatory properties of the alkaline salts of 5-amino-2,3-dihydro phthalazine-1,4-dione are, however, distinctly useful for the prevention of so-called cytokine storms (cf. Suntharalingam et al. (2006): N Engl J Med 355;1018-28) caused by excessive immune responses. Unlike so-called cytokine blockers, these salts are mostly free from side effects, as an inhibition of individual cytokines will not occur, but these are regulated to a physiological level, and thus an adequate body reaction to infectious germs is still assured. However, the prior art does not allocate any different immunospecific effects to individual crystalline forms of alkaline salts for 5-amino-2,3-dihydrophthalazine-1,4-dione. In particular, no statement can be found in the prior art as to whether individual crystalline forms can be used specifically and according to indication, i.e. according to their main specific, basic immunomodulating effect, preferably as immunodepressants or preferably as immunostimulants .
    [00013] A special medical application of 5-amino-2,3-dihydro phthalazine-1,4-dione sodium salt is described in US 2003/0195183 A1 with the "Correction of the immune system" by use of different doses (0.2 μg to 1000 mg) of alkaline salts of 5-amino-2,3-dihydrophthalazine-1,4-dione in different experimental runs. Effective doses within this range varied depending on the disease examined and individual parameters such as, for example, species, age, genus, and weight. For example, the application of different doses between 2 and 200 μg of 5-amino-2,3-dihydro phthalazine-1,4-dione sodium salt will lead to different consequences for the cellular immune response of induced mice through subcutaneous injection of erythrocytes (delayed hypersensitivity response - DHR). The lower the dose used, the higher the DHR index. In the more sensitive of the two mouse strains used, the higher dose will lead to an inhibition of DHR. This example and further in vivo, in vitro examples and also clinical examples in US 2003/0195183 A1 indicate that low doses of alkaline salts of 5-amino-2,3-dihydrophthalazine-1,4-dione act mainly in an immunostimulating manner, while higher doses of 5-amino-2,3-dihydro phthalazine-1,4-dione alkaline salts act primarily in an immunodepressive manner. Since the transition from immunostimulating dose to immunodepressive dose for different strains of mice is different high, the treatment of different species and individuals in human and veterinary medicine will also cause genetic effects in population, so that particular risks of this dose-dependent application will result.
    [00014] Therefore, for clinical practice, in particular for the prevention of severe diseases with acquired or congenital immune deficiency or with excessive immune responses, a process for specific control of immune modulation through the simple provision of different polymorphs of a substance can be advantageous.
    [00015] The property of a preferably stimulating immune modulator is desirable, for example, for the therapeutic treatment of patients having a weak immune defense, such as after an HIV infection or after a chemotherapeutic treatment.
    [00016] The property of a preferably depressive immune modulator is desirable, for example, for minimizing inflammatory processes, such as in the case of a surgical operation, autoimmune diseases and allergies.
    [00017] In clinical practice, for some indications, in particular recurrent inflammatory diseases, immunostimulants as well as immunodepressants are often therapeutically used simultaneously or alternately (cf. DMSG 2006: Aktuelle Therapieempfehlungen September 2006; Rote Liste Service GmbH (2011): www .rote-list.de). This will lead to an increased risk of interactions. Chemically similar substances from a class of substances that are capable of producing opposite effects may therefore offer an advantage to clinical practice, since it can be expected that they will cause, with simultaneous or time-shifted administration, fewer interactions caused pharmacologically in the organism than active ingredients of different classes of substances used for the same purposes.
    [00018] A disadvantage of the prior art is still that a dose-dependent application of an immunomodulator requires greater attention from the administering medical team or from the patients themselves and thus increases the risk of application errors. Therefore a non-only dose-dependent immunospecific application of an alkaline salt of 5-amino-2,3-dihydrophthalazine-1,4-dione is desirable for a practical and low-risk therapeutic application, which in addition exploits the medical advantages of this class of substance.
    [00019] It should be noted that interventions in the complex rules of the immune system can have serious consequences for the organism involved. The most important ones for medical application are therefore immunomodulators having as few side effects as possible and an immunologically defined effect, which makes possible a specific prophylaxis or therapy of immunologically caused diseases. Such immunomodulators can be of great importance to medicine. Brief Summary of the Invention
    [00020] The present invention was carried out on the background of the above prior art, the aim of the present invention being to provide new forms for the sodium salt of 5-amino-2,3-dihydro phthalazine-1,4-dione having specific, independent immunological effects, which can thus be used specifically for primarily immunodepressive or primarily immunostimulating purposes. As a particularly desirable property, these new forms are intended to have primarily immunostimulating or primarily immunodepressive effects, respectively, irrespective of dose. Furthermore, the forms provided are to have physical-chemical properties, which are advantageous for medications produced, stored and/or applied with them individually or in combination.
    [00021] This object was obtained through provision of two novel anhydrates of 5-amino-2,3-dihydro phthalazine-1,4-dione sodium salt (anhydrate forms I and II), which surprisingly and reliably contrast with the prior art, on the basis of experimental data on independent immunomodulatory and physicochemical properties, i.e. in particular for the known sodium salt of 5-amino-2,3-dihydrophthalazine-1,4-dione. Whereas the anhydrate form I according to the invention (^crystal form I) has immunomodulating properties, in particular mainly immunostimulating, the new anhydrate form II (^crystal form II) according to the invention has immunomodulatory properties, in particular mainly immunodepressive.
    [00022] The crystalline forms I and II are defined by 10 characteristic values each of interplanar spacing and 2-theta angles, expressed each in a powdered X-ray diffractogram (Figures 2 and 3).
    [00023] The inventors found that forms I and II have positive physical properties for pharmaceutical application and processing, including stability, storage capacity, non-hygroscopicity and solubility. These are advantageous for pharmaceutical production and further processing compared, for example, to dihydrates, where changes in water content and thus formulation problems can occur, for example, through changes in weight of the active ingredient during tablet pressing, encapsulation or sterilization. There are differences in physical properties between the forms according to the invention and the prior art, for example in solubility (cf. Table 6).
    [00024] Furthermore, the inventors set themselves the task of providing processes for making the new anhydrate forms for 5-amino-2,3-dihydro phthalazine-1,4-dione sodium salt according to the invention possible in a workable and reproducible way. The processes described are intended to be carried out without the use of heavy metal catalysts and to allow reproducible production of the new crystalline form II even for arbitrary batch sizes. Furthermore, the inventors set themselves the task of providing processes for producing crystalline forms I and II with advantageous properties with respect to pharmaceutical processing and different types of application.
    [00025] This object was obtained through at least one process to optionally produce crystalline form I or II, where sodium hydroxide and luminol are dissolved in water. Upon addition of a low molecular weight alcohol, preferably ethanol or 2-propanol, crystalline luminol sodium salt precipitates. The desired crystalline form I or II is obtained after isolation and repeated washing steps and maintaining a certain stirring time. Processes according to the invention can be used for arbitrary batch sizes.
    [00026] The starting product for producing both crystalline forms is luminol as pure as possible or a process for producing the same by reducing 3-nitrophthalic acid in an alkaline medium with an appropriate reducing agent over 3-nitrophthalic anhydride. Optional purification steps through recrystallization are carried out next.
    [00027] The present invention finally comprises pharmaceutical preparations of form I or II or a combination thereof, respectively alone or together with pharmaceutically suitable auxiliary substances. Brief Description of Figures:
    [00028] Figure 1 shows scanning electron microscope images of form I (top) and II (bottom).
    [00029] Figure 2 depicts a powdered diffractogram of crystalline form I.
    [00030] Figure 3 depicts a powdered diffractogram of crystalline form II.
    [00031] Figure 4 depicts the rate of dissolution of forms I and II in water as a function of time (20 minutes).
    [00032] Form I is shown by the line below the two lines, form II by the top line. Detailed Description
    [00033] Unless otherwise known, technical and scientific terms used in the present invention have the meaning that those skilled in the art will ascribe to them.
    [00034] An "organism" is a living entity, in particular human or animal, provided with a self-regulating immune system.
    [00035] The term "active ingredient" comprises crystalline form I or crystalline form II or a mixture of both.
    [00036] The term "pharmaceutical preparation" comprises the active ingredient in any pharmacologically appropriate defined dose and form of administration, such as, for example, a spray, suspension, emulsion and/or mixtures thereof. It comprises pharmaceutically appropriate auxiliary substances, and all substances, which are generated directly or indirectly as a combination, aggregation, complex formation of the ingredients, or as a consequence of other reactions or interactions, and still other active ingredients alone or in combination.
    [00037] Pharmaceutical preparations of the active ingredient according to the invention, individually or in combination with other adjuvants and standard therapies, can be formulated according to the invention in liquid and solid form and be administered in any medically acceptable manner, mainly, but not exclusively, intravenously, intramuscularly, topically (eg eye drops), subcutaneously, transdermally, vaginally, rectally or orally, including sublingually and buccally, as well as in the form of eluting implants - substance. Liquid forms can be: eg solutions (eg for injections and infusions), suspensions, emulsions, spreads, lotions and ointments. Solid forms can be: tablets, pills, capsules, powders or other forms being familiar and seeming appropriate to those skilled in the art, eg suppositories.
    [00038] The term "auxiliary substance" is used here to describe every constituent of a pharmaceutical preparation in addition to the active ingredient itself. The choice of an appropriate auxiliary substance depends on factors such as type of application and dose as well as the influence on the solubility and stability of the preparation by the auxiliary substance itself.
    [00039] Pharmaceutical "auxiliary substances" are substances that are known to those skilled in the art or can be found in standard pharmaceutical textbooks or official pharmacopoeias (eg European Pharmacopoeia). Such substances can, for example, influence the distribution of the active ingredient in different tissues and organs or change the duration of effectiveness or speed of action of drug forms, for example, by accelerating reabsorption (for example, through sulfoxide of dimethyl, nicotinic acid, hyaluronidase), or by the fact that the onset of its efficacy is delayed by appropriate delay preparations.
    [00040] Pharmaceutical auxiliary substances for use in the desired application form can be, for example: sodium citrate, calcium phosphate, calcium carbonate together with suitable tablet disintegrants, for example, for oral application. These can be, for example, substances that swell due to water intake (starch, cellulose derivatives, alginates, polysaccharides, dextrans, cross-linked polyvinyl pyrrolidone), substances that develop gas through a chemical reaction with water (hydrogen carbonate of sodium, citric and tartaric acid) or substances which improve, as a hydrophilizing agent, the wetting of crystallites and thus mediate their dissolution in water (eg polyethylene glycol sorbitan fatty acid ester).
    [00041] Auxiliary substances are also substances that can be used as binders, such as, for example, starch, gelatin, sugar substances, cellulose derivatives, or diluents, for example, sugar substances. Also, surface-active substances, for example, sodium lauryl sulfate, or polysorbate 80, or lubricants, such as, for example, magnesium stearate, sodium stearate and still flavoring agents, antioxidants, dyes and preserving agents that those skilled in the art can check appropriate.
    [00042] The term "substantially pure" means a degree of purity of the active ingredient of at least 95%, preferably 98%, more preferably 99% 5-amino-2,3-dihydrophthalazine-1 sodium salt, 4- dione.
    [00043] The term “immunospecific” designates the specific use of form I and/or form II for the treatment of diseases with an immunodeficient background or excessive immune system.
    [00044] The term "effect" describes the specific mechanism, here immunospecific, of action of an active ingredient for the purpose of this invention with mainly immunostimulating or mainly immunodepressive effect.
    [00045] New crystalline forms I and II for 5-amino-2,3-dihydro phthalazine-1,4-dione sodium salt
    [00046] The present invention includes a novel crystalline anhydrate I form of 5-amino-2,3-dihydro phthalazine-1,4-dione sodium salt characterized by a powdered X-ray diffractogram of a Bragg diffractometer. Brentano (Panalytical X'Pert Pro) provided with a lambda wavelength = 1.54187 Angstroms, and with an X'Celerator Scientific RTMS detector and using nickel-filtered CuK(α1) copper radiation, expressed as D or 2 values -theta, “D” being the interplanar spacings (Table 1) and “2-theta” being the 2-theta angles in degrees. I (rel) represents the relative intensities of the reflexes (Table 2): Table 1: D values of anhydrate form I:
    Table 2: 2-theta values of anhydrate form I and relative intensities I (rel):
    where: w = weak, m = medium, st = strong and vst = very strong
    [00047] The present invention further includes a novel crystalline anhydrate II form of 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt characterized by a powdered X-ray diffractogram of a diffractogram. Bragg-Brentano tomometer (Panalytical X'Pert Pro) provided with a lambda wavelength = 1.54187 Angstroms, and with an X'Celerator Scientific RTMS detector and using nickel-filtered Cu K (α1) copper radiation, expressed in D or 2-theta values, “D” being the interplanar spacings (Table 3) and “2-theta” being the 2-theta angles in degrees. I (rel) represents the relative intensities of the reflexes (Table 4): Table 3: D values of anhydrate form II:
    Table 4: 2-theta values of anhydrate form II and relative intensities I (rel):
    where: w = weak, m = medium, st = strong and vst = very strong. Advantageous physical properties:
    [00048] Both forms according to the invention can be distinguished by scanning electron microscope: Form II has mainly an octahedral structure of needle-shaped crystallite of several micrometers in length composed of layers, while in SEM of form I mainly morphologically non-uniform crystallites with rounded edges are shown which agglomerate in a pulverized-like manner (Figure 1). Advantageous properties for pharmaceutical processing of forms according to the invention result from its crystal forms: Form II has, compared to form I, due to its crystal particle form a greater pourability and thus an improved filterability, while form I is better suited, in particular because of its higher bulk density for tablet pressing, which is further promoted by its tendency to agglomeration, possibly due to the bonding of its laminar substructures.
    [00049] Both crystalline forms are stable for a time of at least two months at room temperature (25oC) and 40oC and will only disintegrate above 335oC +/- 10oC (form I) or 385oC +/- 10oC (form II), respectively , while in the dihydrate according to US 6 489 326 B1 an endothermic solid phase transformation can already be observed at 85°C (Table 5). The solid phase transformation of the dihydrate according to US 6 489 326 B1 was measured by means of simultaneous differential thermal analysis - thermogravimetry with a Linseis L81-077 coupled with mass spectroscopy measurement with a Netzsch STA 449 C thermal balance, with MS and FTIR coupling at 30 - 300oC under helium. The disintegration temperatures of forms I-II were determined with the same device at 30 - 500°C in synthetic air (4 N2 : 1 O2). Data were analyzed with the Proteus software factoryset. Table 5: Disintegration temperatures of forms I-II and determination of solid phase transformation of the dihydrate according to US 6 489 326 B1.

    [00050] The thermoanalytical data confirms the inventors' assumption that both crystalline forms have advantageous properties with respect to stability and storage capacity. These properties further promote the pharmaceutical processing capacity of crystalline forms I and II according to the invention compared to the dihydrate of US 6 489 326 B1 making them insensitive to steps with high energy input, for example sterilization or milling.
    [00051] Furthermore, both crystalline forms I and II are substantially stable with respect to a change in water content, so formulation problems due to changes in active ingredient weight during further pharmaceutical processing (eg tabletting , encapsulation, etc.) are reduced.
    [00052] Still, the solubility of crystalline forms in a saturated solution was determined. Accordingly, form II is more soluble than form I; both forms are in turn more soluble than the dihydrate according to US 6 489 326 B1. The new crystalline forms represent an advantage compared to the prior art, as a considerably higher maximum solubility for injection solutions allows for smaller injection volumes and offers significantly better processing capacity for topical preparations such as creams having a low water content. . Table 6: Survey of solubilities of form I and form II in water at room temperature compared to the dihydrate of US 6,489,326 B1 producible according to US 6,489,326 B1.

    [00053] The comparatively better solubility of form II is also supported by the initial dissolution rate data. These data originate from an in-situ ATR-IR measurement at measurement intervals of 15 s each, forms I and II having been added 5 minutes after the start of annotation. The complete dissolution of 0.25 g of form I or form II, respectively, in 10 mL of H2O VE was achieved under agitation (500 rpm) at 25oC. It was found that the dissolution rate of form II in the first minutes after addition to an aqueous solution is greater than that of form I which only in a delayed manner reaches its full equilibrium concentration. The different solubilities and initial dissolution rates of forms I and II (Figure 4) may be caused by their different surface structures (Figure 1). The morphologically non-uniform round crystallites of form I represent a more compact surface structure than the octahedral crystals of form II which, due to their shape, offer the solvents a larger accessible surface. The differences in the initial dissolution rates between form I and II are in particular important for the production of oral formulations, as a slower dissolution rate as for form I offers advantages where a delayed release of active ingredient is intended (formulations of delay). A faster dissolution rate as for form II is advantageous for the formulation of acute oral medications, where the fastest and greatest possible bioavailability is desired.
    [00054] The different thermal stabilities of forms I and II are caused by the different stoichiometric coordination of the sodium cation and the luminolate molecules. While in form I a sodium cation coordinates through intermolecular hydrogen bonds in a total of 6 luminolate molecules in a triagonal prism, there are only 4 luminolate molecules in form II, which are tetrahedrically arranged by intermolecular hydrogen bonds. This results in a thermally biased better and more stable form II than form I coordination. Medical Use:
    [00055] Surprisingly, the inventors found in in vitro experiments and in vivo studies a remarkably different immunological effect between crystalline forms I and II.
    [00056] Furthermore, it was found that forms I and II can be used, due to their different immunomodulatory effect, in a more specific way than the prior art: while form II has a mainly depressive immunomodulating effect on certain cytokines, form I shows a mainly immunostimulating effect on certain cytokines. Form II is therefore particularly suitable for therapeutic application under conditions with excessive immune responses, Form I is particularly suitable for therapeutic application under indications with an immunodeficient background.
    [00057] In particular for chronic diseases (eg multiple sclerosis, hepatitis C, chronic enteritis and colloids), the patient's immune status can always vary such that a change from immunostimulant to immunosuppressive or from immunosuppressive to immunostimulant therapy or an administration combined or time-shifted of both approaches seems reasonable (cf. DMSG 2006: Aktuelle Therapieempfehlungen September 2006). Therefore, the following listings may be exemplary only, designating a disease for conditions with excessive immune responses does not preclude its treatment with form II or with combinations of form I and form II, and designating a disease for conditions with an immunodeficient background does not exclude its treatment with form I or with combinations of form I and form II.
    [00058] Conditions with excessive immune responses are, for example, rejection responses after transplants, active autoimmune diseases (in particular active rheumatoid arthritis, recurrent multiple sclerosis, lupoid hepatitis, polyarteritis nodosa, Crohn's disease, ulcerative colitis, dermatomyositis, Behcet's disease, uveitis, thrombocytopenic purpura, myasthenia gravis, polymyositis, psoriasis, arthritis psoriasis, Bekhterev's disease, paroxysmal nocturnal hemoglobinuria, ankylosing spondylitis, autoimmune thyroiditis, etc.), aplastic anemia, pemphigus, exogenous pemphigus. , nephrotic syndrome and atopic dermatitis and particularly preferred septic conditions induced by bacterial infections with gram-negative or gram-positive pathogens, such as, for example, by MRSA (methicillin-resistant Staphylococcus aureus) and systemic inflammatory response syndrome (SIRS) induced by other (eg immunological or chemical) factors.
    [00059] Conditions with an immunodeficient background are, for example, recurrent respiratory tract infections, recurrent efferent urinary tract infections, fatigue, weakness, disposition to absence of unknown origin, reconvalescence, chronic virus infections (in particular HIV, hepatitis B, hepatitis C, encephalitis, herpes zoster, herpes simplex, inner ear infections, chickenpox, measles, cytomegaly, Epstein-Barr), different oncological diseases (in particular hairy cell leukemia, myeloid leukemia, multiple myeloma, follicular lymphomas , Kaposi's sarcoma, cutaneous T cell lymphoma, nasopharyngeal carcinoma, carcinoid, renal cell carcinoma, urinary bladder carcinoma, basal cell carcinomas, metastatic carcinomas and particularly preferred malignant melanoma), septic granulomatosis, neutropenia, warts genitals, keratoses, autoimmune diseases (in particular non-active stages, such as, for example, recurrent multiple sclerosis among exacerbations), radiogenic colitis, diverticulitis, allergies (in particular hay fever, mild polymorphic rash, eczema, neurodermitis), enteritis, colitis, as well as particularly preferred monitoring before, during and after chemotherapy and radiation therapies.
    [00060] Surprisingly, the inventors can show different effects by simply providing specific crystal forms of 5-amino-2,3-dihydro phthalazine-1,4-dione sodium salt, preferably of anhydrate polymorphs, particularly preferred form I and form II. These different effects allow a specific immunomodulatory application for mainly immunostimulation purposes (form I) or mainly immunosuppression (form II), both forms acting generically in a regulatory manner on the immune system. Thus, the inventors can prove in vitro and in vivo a surprising immunostimulating effect for form I.
    [00061] Form II in contrast has immunomodulatory properties that are advantageous for activated macrophages. The inventors can in particular substantiate mainly form II immunodepressive properties on the basis of in vitro tests with stimulated macrophages - LPS. By this means, a distinct reduction in IL-6 values was obtained. Through in vivo tests in mice (sepsis model with S. pyogenes), a considerable therapeutic efficacy of form II can also be verified.
    [00062] Furthermore, the inventors can show through weight development and liver enzyme values of healthy mice that the new forms I and II have no or only low toxicity. Both forms act in an immunomodulatory way, without being exclusively immunostimulating or exclusively immunodepressive. Form I as well as form II lead to higher survival rates in the sepsis model.
    [00063] The inventors assume that a combined application, preferably time-shifted application of form I and form II can also be successful, and that for certain indications, in particular but not exclusively autoimmune diseases, a combined application is advantageous over individual application. Example 1 - Effect of form I on stimulated murine macrophages - LPS in vitro
    [00064] In a test with isolated mouse macrophages, the immunomodulatory effect of form I was shown in vitro based on the concentration of TNF-alpha or IL-6 measured in the supernatants. For this purpose, macrophages were first treated with form I (20 or 200 μg/ml). After 1 hour the treated macrophages were stimulated with LPS (10, 100 or 1000 ng/ml). Supernatants were collected 24 hours later, and the concentration of TNF-alpha and IL-6 was measured. Unstimulated macrophages treated with 200 μg/mL of form I and macrophages stimulated with LPS (10, 100 or 1000 ng/mL LPS) were used as controls. Measured values are listed in Table 7.
    [00065] With single LPS administration (at concentrations of 1 μg/ml, 100 ng/ml and 10 ng/ml), the TNF-alpha measurements of Table 7 show a dose-dependent stimulation by LPS. Table 7:


    [00066] In the combination groups with LPS and macrophages treated with form I, in all LPS groups a dose-dependent immunodepressive effect of form I can be seen. This effect was more distinct in the combination with 100 ng/5 mL of LPS-stimulated macrophages treated with 200 μg/mL of form I, followed by a significant reduction in TNF-alpha values in the combination of 1 μg/mL of LPS with 200 μg/mL of form I.
    [00067] Furthermore, in the control group of unstimulated macrophages treated with 200 μg/mL of form I, a distinct immunomodulating effect, here immunostimulating, can be seen, as proven by the measured TNF-alpha values. Example 2 - Effect of form II on stimulated murine macrophages - LPS in vitro
    [00068] Still in an in vitro model with bone marrow macrophages (mouse), the effect of immunomodulatory treatment, mainly immunodepressant, form II can be confirmed. For this purpose, mouse bone marrow macrophages were first treated with form II at concentrations of 2, 20 or 200 μg/mL and stimulated 1 hour after treatment with 100 ng/mL or 10 ng/mL LPS. Supernatants were collected 24 hours later, and the concentration of TNF-alpha and IL-6 was measured. Unstimulated macrophages treated with 200 μg/ml of form II and macrophages stimulated with LPS (10 or 100 ng/ml LPS) were used as controls. The measured values are listed in Table 8. Table 8:

    [00069] A significant reduction in TNF-alpha concentration can be measured in the group of macrophages stimulated with 100 ng/mL LPS at all active ingredient concentrations. In the group of macrophages stimulated with 10 ng/ml of LPS a significant reduction of TNF-alpha at the highest concentration of active ingredient (200 μg/ml) could be seen.
    [00070] A form II immunodepressive effect on LPS-stimulated macrophages, furthermore, can be observed on the basis of significant reductions in IL-6 values. These were measured in the combination of 2 μg/ml of active ingredient with macrophages stimulated with 100 ng/ml of LPS as well as in the group of macrophages stimulated with 10 ng/ml at the concentration of active ingredient with 20 μg/ml. These results are in agreement with IL-6 values from a previous in vitro pilot test with macrophages, in which a different combination of active ingredient and LPS (1 μg/ml LPS with 100 μg/ml) was used and which also showed a form II immunodepressive effect on stimulated murine macrophages. An immunostimulating effect on macrophages not induced with LPS cannot be shown. Example 3 - Weight development of healthy mice.
    [00071] In a mouse model of Gram-positive sepsis (infection with S. pyogenes) the therapeutic use of crystal forms I and II of the sodium salt of 5-amino-2,3-dihydro phthalazine-1 ,4-dione was tested. The administration of active ingredient was done parenterally 6 after the occurrence of infection. A second active ingredient administration was made 24 hours after the first application. The test was completed 48 hours after infection. For both forms (groups of substances) three different doses were used. The mice obtained 2, 20 or 200 μg each of form I or form II per animal and application.
    [00072] In addition to substance groups (form I and form II) one group obtained a solution of common salt (NaCl) instead of the dissolved active substances, and one group does not receive any treatment. In parallel to the infected animals, groups comparable to uninfected animals were formed.
    [00073] The individual treatment groups comprised 5 animals each, and for the uninfected controls two replicates and for the infected controls and those groups that contained form II four replicates were made, so that in total 180 animals were in the test.
    [00074] It is known that the toxicity of substances in an animal test with growing mice or rats can influence weight development. The development of weight (g) of uninfected control animals over a two-day time period is summarized in Table 9. Table 9:

    [00075] There were no deaths among uninfected animals. Relevant differences in weight development between groups cannot be verified. Hence it can be assumed that form I as well as form II have no toxicity at all or at most very little. Example 4 - Weight development of infected mice
    [00076] In the sepsis model described in Example 3, the influence of crystal forms I and II of the sodium salt of 5-amino-2,3-dihydro phthalazine-1,4-dione on the weight development of mice infected with S. pyogenes was tested. The development of body weight during an acute infection can provide important predictive information. Some animals do not survive the second day until the end of the test. Incidentally, the subjects' body weight development during the first 24 hours after infection yielded a signal for the probability of survival until the end of the test after 48 hours, however, there was no significant correlation. Since there is no data on weight development over the entire test time for the animals killed during the second day, it is also shown in Table 10 below, in addition to the weight development over the entire test time, the weight development from the first day of testing. Table 10:


    [00077] Tendently, mice that obtained form I 5-amino-2,3-dihydro phthalazine-1,4-dione sodium salt showed less weight loss in the first 24 hours after infection than mice in control groups. This advantage is particularly significant for the 20 and 200 μg doses of form I. This indirect sign about a biased higher survival rate in the substance groups can no longer be found for animals that survived the second day. Example 5 - Probability of survival after infection with S. pyogenes
    [00078] In the sepsis model described in Example 3, the influence of crystal forms II and I of the sodium salt of 5-amino-2,3-dihydro phthalazine-1,4-dione on the probability of survival of mice infected with S. pyogenes was tested. Individual groups showed different probabilities for survival at least 48 hours after infection. Distributions of surviving animals are summarized in Table 11. Table 11:

    [00079] Form I and Form II both lead to an increased distribution of surviving animals compared to controls. Thus, a positive influence on septic behavior can be assumed for form I as well as form II, also independently of their respective specific effect. Example 6 - Cargo of germs in blood and liver
    [00080] In the sepsis model described in Example 3, the influence of crystal forms II and I of the sodium salt of 5-amino-2,3-dihydro phthalazine-1,4-dione on the germ load of mice infected with S. pyogenes in the blood and liver was tested. The test was completed 48 hours after infection, and the germ load (CFU) present in the blood and liver at this time was determined (see Table). Table 12:

    [00081] Form II as well as form II showed at the highest dose a biased reduction in blood germ count compared to controls. The inventors look at this as evidence of an improved ability to control infection by administering 5-amino-2,3-dihydro phthalazine-1,4-dione sodium salt, in particular form 2. However it should be noted that for animals having died before the end of the test, there are no germ count determinations. The inventors assume that for an early time germ count determination the germ load of animals having died later may have been particularly high, and that the effects induced by forms I and II may be even more apparent. Example 7 - Cytokines in healthy test animals
    [00082] When administering form I and form II to healthy mice, it was investigated for the animal model described in Example 3, whether and what influence the application has on certain cytokines, in particular IL-6 and TNF-alpha, in mice . Blood intake occurred after 48 hours at the end of the second day of application. For IL-6, neither the substance groups nor the control groups were seen to increase. The results for TNF-alpha are summarized in Table 13. Table 13:

    [00083 While form II and controls did not cause a relevant increase in TNF-alpha, distinct increases compared to the other groups occurred after administration of form I. This effect was more distinct for the 20 μg dose, this group was significantly different (p < 0.001) of the control groups as well as the groups that received form II. Here, a specific immunostimulating effect occurs for form I that cannot be detected for form II. Example 8 - Cytokines in the sepsis model
    [00084] In the sepsis model described in Example 3, it was also investigated, what influence the administration of form I and form II has on certain cytokines, in particular IL-6 and TNF-alpha, in mice infected with S. pyogenes. Blood draw occurred at the end of the test 48 hours after infection.
    [00085] Since it can be shown that the cytokine increases caused by the infection are significantly different, in some cases even within control groups (negative control and NaCl) between repeats, the repeat data cannot be amalgamated.
    [00086] It should also be noted that these values were only obtained for those animals that also survived the second day of testing to the end. The inventors further assume that animals that have died previously had very high prognostically unfavorable IL-6 values.
    [00087] Nevertheless, there were in part distinct trends of a reduction of IL-6 by form II, which unfortunately could not be confirmed in all repeats. Yet animal models which are better suited to absolutely prove the depressive effect of form II on cytokines even in vivo, are at present investigated by the inventors. Example 9 - liver enzymes / transaminases for healthy test animals
    [00088] When administering form I and form II to healthy mice, it was investigated, whether and what influence the application has on certain liver enzymes, in particular the GOT transaminases (AST) and GPT (ALT). Blood draw occurred at the end of the second day of application. Distinct differences between groups cannot be found here. This confirms the good compatibility shown in Example 3. Example 10 - Liver enzymes / transaminases in the sepsis model
    [00089] In the sepsis model described in Example 3, it was also investigated, what influence the administration of form I and form II has on certain liver enzymes, in particular GOT transaminase (AST) and GPT (ALT), in infected mice with S. pyogenes.
    [00090] Blood intake occurred 48 hours after infection. For an infection with a septic course, in some cases drastic increases in liver enzyme values may occur. In an analogous manner as for the cytokine values of the infected mice, significant differences within identical groups occurred here, too, between individual replicates, so that a full analysis of the data was not possible. Form II showed in some replicates tendencies to reduce liver enzyme values. These signs, however, cannot be seen in every repetition.
    [00091] Substantial differences between the groups, however, cannot be found. In an analogous manner as for the germ counts in Example 6 and the cytokine values in Example 8, there is a skewing through the missing data from animals having died prematurely. The inventors assume that a determination of transaminases after 24 hours may be a distinct advantage for mice treated with 5-amino-2,3-dihydro phthalazin-1,5-dione sodium salt, in particular form II. Production of crystalline anhydrate forms I and II according to the invention
    [00092] In what follows, the production of crystalline forms I and II is exemplary described.
    [00093] The starting point of synthesis for all production examples is luminol known from the prior art, which can, for example, be produced according to the following reaction scheme:

    [00094] Shown here is the synthesis of luminol (iii) through the reaction of 3-nitrophthalic acid (i) which can be reduced in an alkaline medium by hydrazine or one of its salts, or other suitable reducing agents, for example, sulfite of ammonium or triethylene glycol, to luminol via 3-nitrophthalic anhydride (ii). Appropriate production processes for luminol can be found in: Williamson, K.L. In: Macroscale and Microscale Organic Experiments; 2nd ed.; D.C. Heath: Lexington, MA, 1994. Another suitable process for producing luminol using a Raney nickel catalyst is, for example, found in US patent 6,489,326 B1.
    [00095] In a more specific process, the starting product luminol can also be produced as follows, and using the specified equivalents, arbitrary amounts of luminol can be produced: Example of luminol production 1st step: 3-nitrophthalic acid - 3 -nitrophthalhydrazide Batch sizes:


    [00096] In a first step, 3-nitrophthalic acid (200 g, 0.95 mol) and hydrazine hydrate (51 g, 1.02 mol) were provided and mixed with ethylene glycol (300 mL) in a reaction flask 2L bottle equipped with a combination of a reflux condenser (T = 110oC) and a Liebig condenser. The temperature was raised to 110oC, and the water was removed by distillation. Heating of the reaction mixture was continued until the ethylene glycol refluxed at approximately 200°C. After one hour water was no longer formed. The mixture was cooled to approximately 100°C, and water (1200 mL) was added. A slightly brownish precipitate was generated. The mixture was cooled by adding ice water to room temperature (25oC +/- 5oC) and stirred overnight. The precipitate was filtered and washed with water (3x300 ml). The wet product was dried in a rotary evaporator at 90oC/20 +/- 10 mbar until constant masses were obtained.
    [00097] The advantages of this process are that through the use of hydrazine hydrate instead of hydrazine sulfate, there will not be formed any disturbing inorganic material in the following steps, and that through the use of ethylene glycol with a boiling point of approx. . 196oC process control through reflux boiling can be handled better than through other solvents with higher boiling points, the use of which can lead to product contamination. 2nd step: 3-nitrophthalhydrazide - 5-amino-2,3-dihydrophthalazine-1,4-dione Batch sizes:

    [00098] In a second step, 3-nitrophthalhydrazide was reacted to 5-amino-2,3-dihydrophthalazine-1,4-dione whereby 3-nitrophthalhydrazide (100 g, 0.48 mol) 48.3 mmol)( ) is dissolved in 3 molar sodium hydroxide solution (1700 mL) while heating to approximately 50-60oC. To this solution sodium dithionite (300 g, 1.73 mol) is added in portions. Hence, the temperature of the reaction mixture will be raised to approximately 80°C. After complete addition of sodium dithionite, the reaction mixture is heated for approximately 4 hours to reflux. Acetic acid (200 mL, 1.73 mol) is added, and the reaction mixture is cooled overnight. The resulting precipitate is isolated and washed with water (3x170 ml). The product is dried in the rotary evaporator at approximately 80oC/20 +/10 mbar. Anhydrate form I I. Production example I - crystalline form I
    [00099] The subject matter of the invention is a process for the production of anhydrate form I by mixing 5-amino-2,3-dihydrophthalazine-1,4-dione (luminol) in sodium hydroxide solution and adding this drop solution to a low molecular weight liquid alcohol, preferably ethanol which decreases the product solubility of the sodium salt of luminol generated so that the latter will begin to precipitate. Alcohols should have a degree of purity of preferably >95%, particularly preferred >98%. According to the invention, the generated precipitate is dried at temperatures between 50 and a maximum of 90°C. Production example I - crystalline form I - realization I
    [000100] In a preferred embodiment of production example I, crystalline form I can be precipitated by mixing 500 - 750 ml of a 0.8-1.2 molar suspension of luminol with 500-750 ml of a solution 1, 0-1.3 molar soda, the mixture being added dropwise at 20-50 °C under stirring to 10-15 L of a low molecular weight alcohol, preferably ethanol, preferably with a degree of purity > 95%, particularly preferred > 98%, and the suspension is then stirred for 15-25 hours at 10-40oC. After isolation, the precipitate generated is then preferably air dried. After further drying at 50oC-80oC, the precipitate is dissolved in an amount of 10-20 times of a low molecular weight alcohol, preferably ethanol with a purity grade >95%, particularly preferred >98%, and the suspension is stirred and filtered for 15-25 h at 10-40oC. The filter cake is then air dried, again dried at 50oC-90oC, preferably 50oC, sprayed and dried to a water of crystallization content of <0.4%, preferably <0.3%, more preferably <0.2 %, be obtained. Production example I - crystalline form I - embodiment II a) In a particularly preferred embodiment of production example I, crystalline form I can be produced as follows: b) Provide 190-220 g of luminol in the 2 L beaker and dissolve the same under stirring at least at 20°C in 1.25 L of 1.01.1 molar solution of NaOH. c) Filter batch of solution through porcelain funnel with filter paper < ’ 70 mm (eg Schleicher & Schuell Type 1575), without washing again. d) Provide 12-14 L of ethanol (preferably >98%) in the 3-neck round flask. Add batch of solution in drops under stirring at 25°C +/- 10°C within 25 minutes +/- 10 minutes. Shake the suspension for 16 +/- 5 h at 20oC +/- 10oC. e) Filter precipitate through a porcelain funnel with filter paper and wash again with approximately 400-500 ml of a low molecular weight alcohol, preferably ethanol with a purity of >98%. f) Finely disperse the filter cake over a glass bowl and dry under the exhaust hood overnight. Then dry in the dryer compartment at 50-90oC, preferably 50-70oC, particularly preferred 50oC, until constant masses are obtained. g) Spray and weigh the precipitate. h) Provide 12-15 times the amount (12-15 mL/g) of the precipitate obtained from g) in a low molecular weight alcohol (eg methanol, ethanol, 2-propanol, preferably with a purity of > 98%) in a 4-L, 3-necked, round-bottomed flask. Suspend the precipitate there while stirring. Shake the suspension for 16 hours +/- 5 hours at 20oC +/- 10oC. Filter the suspension through a porcelain funnel with filter paper and wash again with approximately 500 ml of a low molecular weight alcohol. i) Finely disperse the filter cake over a glass bowl and dry it under the exhaust hood overnight. Then dry it in the dryer compartment for 2-6 hours at 50-70oC, preferably 50oC, until constant masses are obtained. Crush the substance using a mortar and weigh it. The water of crystallization content must be <0.4%, measured according to, for example, the Karl-Fischer titration process. If the water of crystallization content is >0.4%, repeat steps h) - i). j) Weigh the substance and determine the yield. Production example I - crystalline form I - embodiment III.
    [000101] In a more preferred embodiment, crystalline form I can be produced as follows: a) Provide 200 g of luminol in the 2 L beaker and dissolve under stirring at 30°C +/- 10°C in 1.25 liters of 1 molar solution of NaOH. b) Filter batch of solution through porcelain funnel with 0 70 mm filter paper (eg Schleicher &Schuell Type 1575) without further washing. c) Provide 12.5 L of ethanol, preferably >99% purity, into the round bottom flask, 3 neck, 20 L. Add the batch of solution in drops under stirring at 25oC +/- 5oC within 30 minutes +/- 5 minutes. Shake the suspension for 20 hours +/- 1 hour at 25oC +/- 5oC. d) Filter the suspension through a porcelain funnel with 0 185 mm filter paper (eg Schleicher & Schuell Type 575) and wash again with approx. 500 ml ethanol, preferably >99% pure. Finely disperse the filter cake over a glass bowl and dry it under the exhaust hood. Then dry in the dryer compartment at 50-70oC, preferably 50oC, until constant masses are obtained. e) Spray the precipitate and weigh it. f) Provide 12 times the amount (12 ml/g) of the ethanol precipitate obtained, preferably with a purity of >99%, into the 3-neck bottom flask. Suspend the substance there while stirring. Shake the suspension for 20 hours +/- 1 hour at 25oC +/- 5oC. Filter the suspension through a porcelain funnel with 0 185 mm filter paper (eg Schleicher & Schuell Type 1575) and wash again with approx. 500 ml ethanol, preferably >95% pure, preferably >98%. Finely disperse the filter cake over a glass bowl and dry it under the exhaust hood. Then dry in the dryer compartment at 50-70oC, preferably 50oC until constant masses are obtained. Crush the product using a mortar and weigh it. g) The water content of crystallization must be <0.4%, measured, for example, by Karl-Fischer titration. If the water of crystallization content is >0.4%, repeat steps f)-g). h) Weigh substance and determine yield. Production example II - crystal form I.
    [000102] Under aqueous conditions, starting from luminol, crystalline form I can be produced whereby a sodium hydroxide solution is prepared, to which luminol is added. Luminol is dissolved by stirring. Then ethanol is added within 10-40 minutes, the luminol precipitating as a salt. After complete addition and stirring for several hours, the suspension is filtered, the filter cake is washed and dried. Production example II - form I - realization II.
    [000103] In a preferred embodiment, crystalline form I is produced using the following equivalents of reagents: A solution of 1.01.4 equivalents of sodium hydroxide in 4-7 vol/m of water is prepared, to which 1 equivalent of luminol is added. The reaction mixture is stirred until complete dissolution is obtained. Then, ethanol (50-70 vol/m) is added dropwise at room temperature (25oC +/- 5oC) within approximately 10-40 minutes. The luminol sodium salt precipitates as a sediment.
    [000104] After complete addition, the reaction mixture is again stirred for several hours at room temperature (25oC +/- 5oC), and the suspension is filtered; the filter cake is washed with ethanol (approximately 10-15 vol/m) and optionally dried in the dryer compartment or in a rotary evaporator. Production example II - form I - realization III
    [000105] In a particularly preferred embodiment, crystalline form I is produced using the following equivalents of reagents:

    [000106] A solution of 1.0-1.4 equivalent of sodium hydroxide, preferably 1.2 equivalent of sodium hydroxide (22 g, 0.55 mol), in water (6 vol/m) is produced (reactor 10 L).
    [000107] 1 equivalent of luminol is added to the sodium hydroxide solution. The reaction mixture is stirred until complete dissolution is obtained. A light brown solution is obtained.
    [000108] Then, ethanol (60 vol/m) is added dropwise at room temperature (25oC +/- 5oC) within approximately 20 minutes. The luminol sodium salt precipitates as a sediment.
    [000109] After complete addition, the reaction mixture is again stirred for a maximum of 20 hours, preferably 2-8 hours, particularly preferred 8 hours at room temperature (25°C +/- 5°C), and the suspension is filtered; the filter cake is washed with ethanol (approximately 13 vol/m) and optionally dried in the vacuum dryer compartment at 50-90oC/1-3 mbar, preferably 50-70oC, particularly preferred 50oC, or in a rotary evaporator at 20+/ - 10 mbar and 50-90oC, preferably 50-70oC, particularly preferred 50oC. Production example III - form I - batch sizes that can be increased
    [000110] The inventors have found that these verified equivalent ratios are appropriate for arbitrary luminol batch sizes and allow for the production of the desired Form I in a reproducible manner. Anhydrate form II: Production example I for crystal form II
    [000111] The inventors have found a process for producing crystalline form II, where under aqueous conditions luminol is mixed with a solution of sodium hydroxide, and through addition of 2-propanol, the solubility product of the sodium salt of luminol is reduced so that the latter starts to precipitate. The precipitated luminol sodium salt is washed with 2-propanol and dried until constant masses are obtained. Production example I - crystalline form II - realization II
    [000112] In a preferred embodiment crystalline form II is produced using the following equivalents of reagents. A solution of 1.02.0 equivalent of sodium hydroxide, preferably 1.1-1.4 equivalent of sodium hydroxide, particularly preferred 1.2 equivalent of sodium hydroxide, is produced at 6-7.5 vol/m of water, to which 0.51 equivalent of luminol is added. The reaction mixture is stirred until complete dissolution is obtained. Then, 2-propanol (60-120 vol/m) is added dropwise at room temperature (25oC +/- 5oC) within approximately 10-40 minutes. The luminol sodium salt precipitates as a sediment. After complete addition, the reaction mixture is stirred at room temperature (25oC +/- 5oC). The product is filtered, washed with a low molecular weight alcohol, preferably 2-propanol (approximately 13-16 vol/m) and optionally dried in the vacuum compartment dryer at 85-120oC/1-3 mbar, preferably 90oC/1 -3 mbar, or in the rotary evaporator at 85-120oC/20 +/- 10 mbar. Production example I - crystalline form II - realization III
    [000113] In a particularly preferred embodiment, equivalents and batch sizes for crystalline form II production are presented, and this applies for arbitrary luminol batch sizes and is shown exemplarily in the following for a luminol batch size of 10 g:

    [000114] 1.2 equivalent of sodium hydroxide and 1 equivalent of luminol are dissolved in water (6 vol/m). A clear solution is formed. This solution must be processed immediately as it will darken. Then, 2-propanol (60 vol/m) is added at room temperature (25oC +/- 5oC) within approximately 20 minutes, and a pellet of luminol sodium salt is formed. The suspension is stirred at room temperature for 1-5 hours, preferably 2 hours, particularly preferred 3 hours. The product is filtered, washed with 2-propanol (approximately 15 vol/m) and optionally dried in the vacuum compartment dryer at 85-120oC/1-3 mbar, preferably 90oC/1-3 mbar or in the rotary evaporator at 85- 120oC/20 +/- 10 mbar, preferably 90oC/20 +/- 10 mbar until constant masses are obtained. Production example I for crystal form II - embodiment IV.
    [000115] The inventors further demonstrate a process which is suitable for batch sizes of luminol of at least 300 g, preferably 400 g, particularly preferred > 500 g, and which is described exemplarily for a batch size of 785 g:

    [000116] A solution of 212 g (5.32 mol, 1.2 eq.) of sodium hydroxide in 4700 ml of water is produced (80 L reactor. The luminol (785 g, 4.43 mol) is added to the sodium hydroxide solution and is stirred until its dissolution is obtained. A clear, brown solution results, to which 2-propanol (60 vol/m) is added in a time of 20-30 minutes, preferably 30 minutes. of luminol sodium precipitates as a sediment.After complete addition, the mixture is again stirred for at least 10 hours, preferably 12 hours, at room temperature (25oC +/- 5oC) The mixture is filtered, the filter cake is washed with 2-propanol (13 vol/m) and optionally dried in the vacuum compartment dryer at 85-120oC/1-3 mbar, preferably 90oC/1-3 mbar or in the rotary evaporator at 85-120oC/20 +/- 10 mbar, preferably 90°C/20 +/- 10 mbar until constant masses are obtained. Production example I - crystalline form II - batch sizes that can be increased
    [000117] The inventors have found that these verified equivalent ratios are appropriate for arbitrary batch sizes of luminol and allow for the production of the desired form II in a reproducible manner. When using larger amounts of luminol (> 500 g) and volumes, care must be taken that the stirring time is selected correspondingly long, in order to obtain the highest possible yield of the final product. Production example II for crystalline form II (recrystallization).
    [000118] The inventors have found that crystalline form II can be produced by recrystallization of crystalline form I using the following equivalents: 2-propanol (10 vol/m) with a purity grade of 70-90%, preferably 80-90% , particularly preferred 90%, is added to a solution of 1 equivalent of form I and stirred for at least 10-14 hours, preferably 10-12 hours, at room temperature (25°C +/-5°C). The mixture is filtered, and the filter cake is washed with 2-propanol (approximately 20 vol/m) and optionally dried in the vacuum compartment drier at 85-120oC/1-3 mbar, preferably 90oC/1-3 mbar, or in the rotary evaporator at 85oC-120oC/20 +/- 10 mbar until constant masses are obtained. Production example II for crystalline form II - recrystallization of form I - batch sizes that can be increased.
    [000119] A recrystallization process verified by the inventors can be used with the following equivalents for arbitrary batch sizes, exemplary described for a Form I batch size of 1 g:

    [000120] Crystalline form I (1 g) is suspended in aqueous 2-propanol (10-20% water) and stirred for at least 10 hours, preferably 10-14 hours, particularly preferred 10-12 hours at room temperature (25°C +/- 5oC). After filtering off the remaining solvents, the filter cake is washed with 2-propanol (2x10 mL) and dried on a rotary evaporator at 90°C/20 mbar until constant masses are obtained. List of Abbreviations: μg microgram ALT alanine amino transferase Approx. Approximately AST aspartate amino transferase CFU colony forming units DMSG German multiple sclerosis association e.g. EMEA European Medicine Agency g gram GOT glutamate oxalacete transaminase GPT glutamate pyruvate transaminase IL interleukin L liter loc.cit. at the cited site LPS lipopolysaccharide mL milliliter MW mean value ng nanogram pg picogram SEM scanning electron microscope STD standard deviation TNF tumor necrosis factor U international units vol/m unit volume per unit mass
    权利要求:
    Claims (10)
    [0001]
    1. Crystalline form I for sodium salt of 5-amino-2,3-dihydrophthalazine-1,4-dione, characterized by the fact that it presents crystallographic values determined by means of powder x-ray 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
    [0002]
    2. Crystalline form, according to claim 1, characterized in that it has a water content of crystallization < 0.4%.
    [0003]
    3. Process for producing crystalline form I, as defined in claim 1 or 2, characterized in that it comprises mixing 5-amino-2,3-dihydrophthalazine-1,4-dione with sodium hydroxide solution and addition of a low molecular weight liquid alcohol, preferably ethanol or 2-propanol, whereby the solubility product of the 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt generated is reduced so that the latter precipitates, the precipitated crystalline product being separated and dried, the crystalline form I can be suspended several times in ethanol, stirred, again washed with ethanol, and again dried.
    [0004]
    4. Process according to claim 3, characterized in that the ethanol alcohol of low molecular weight is added with a degree of purity > 98%, particularly preferred > 99%, and at room temperature within 10-40 minutes , preferably 20 minutes.
    [0005]
    5. Process for producing crystalline form I, as defined in claim 1 or 4, characterized in that it comprises the steps of: (a) production of a mixture of 1.0-1.4 equivalents of sodium hydroxide, preferably 1.2 equivalents, with 4-7 equivalents (vol/m) of water, preferably 6 equivalents (vol/m) of water; (b) adding 1 equivalent of luminol (5-amino-2,3-dihydrophthalazine-1,4-dione) to this mixture and stirring until complete dissolution is obtained; (c) addition of 50-70 equivalents, preferably 60 equivalents (vol/m) of ethanol with a purity of >98%, particularly preferred >99%, at room temperature (25oC +/- 5oC) within 10-40 minutes, preferably 20 minutes; (d) after complete addition of the ethanol, again stirring the reaction mixture at room temperature for a maximum of 20 hours, preferably 2-8 hours, particularly preferred 8 hours, and filtering this mixture; (e) filter cake washing with 10-15 equivalents (vol/m) of ethanol, preferably 13 equivalents (vol/m) of ethanol, having a purity of >98%, particularly preferred >99%; and (f) drying product in the vacuum compartment dryer at 50-90oC/1-3 mbar, preferably 70-90oC, particularly preferred 80-90oC, or in a rotary evaporator at 20 +/- 10 mbar and 50-90oC , preferably 70-90°C, particularly preferred 80-90°C, until constant masses are obtained.
    [0006]
    6. Pharmaceutical preparations, characterized in that they contain the crystalline form, as defined in claim 1 or 2.
    [0007]
    7. Pharmaceutical preparations according to claim 6, characterized in that they comprise the application or combination with other active ingredients, adjuvants and/or standard therapies.
    [0008]
    8. Pharmaceutical preparations according to claim 6 or 7, characterized in that pharmaceutically acceptable auxiliary substances can be included.
    [0009]
    9. Crystalline form according to claim 1 or 2 and/or the pharmaceutical preparations according to claim 7 or 8, characterized in that it is for use in a process for modulating the immune system.
    [0010]
    10. Process according to claim 9, characterized in that it is in the immunospecific application of the crystalline form for immunostimulation of the immune system.
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    同族专利:
    公开号 | 公开日
    IL221680A|2015-09-24|
    IL221680D0|2012-12-02|
    RU2585677C2|2016-06-10|
    HK1223836A1|2017-08-11|
    AU2011223226A1|2012-10-25|
    CN105859634A|2016-08-17|
    CH704794B1|2013-04-15|
    PL2542535T3|2014-10-31|
    WO2011107295A1|2011-09-09|
    KR20130019383A|2013-02-26|
    EP2542535B1|2014-05-07|
    KR101770011B1|2017-08-21|
    EP2774920A1|2014-09-10|
    ES2487221T3|2014-08-20|
    HRP20140752T1|2014-10-24|
    BR112012021857A2|2016-05-17|
    CY1115585T1|2017-01-04|
    CN105859634B|2019-06-28|
    US9079863B2|2015-07-14|
    JP6061081B2|2017-01-18|
    US20140303169A1|2014-10-09|
    JP2016196483A|2016-11-24|
    RS53492B1|2015-02-27|
    US20120329801A1|2012-12-27|
    JP6206689B2|2017-10-04|
    JP2013521239A|2013-06-10|
    CA2791327A1|2011-09-09|
    CN102971300B|2016-03-02|
    DK2542535T3|2014-07-28|
    PT2542535E|2014-08-25|
    AU2011223226B2|2015-04-23|
    CN102971300A|2013-03-13|
    SI2542535T1|2014-09-30|
    EP2542535A1|2013-01-09|
    RU2012141274A|2014-04-20|
    US8772294B2|2014-07-08|
    CN105726541A|2016-07-06|
    CA2791327C|2018-10-30|
    HK1223929A1|2017-08-11|
    NZ601689A|2014-11-28|
    ZA201206264B|2016-07-27|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CN1089086C|1988-03-31|2002-08-14|兰德尔·L·米尔斯|Luminide and macroluminide class of pharmaceuticals|
    CH683965A5|1993-02-19|1994-06-30|Limad Marketing Exp & Imp|Ftalidrazidici compounds of the class as an active substance in anti-inflammatory agents and anti-toxic.|
    CH683966A5|1993-02-19|1994-06-30|Limad Marketing Exp & Imp|Compounds of the ftalidrazidici class as active substances in anti-hypoxic agents and defense.|
    RU2113222C1|1997-09-30|1998-06-20|Закрытое акционерное общество "Центр современной медицины "Медикор"|Immunomodulating agent|
    RU2138264C1|1999-05-06|1999-09-27|Абидов Муса Тажудинович|Process of production of medicinal preparation galavit|
    CZ2002235A3|2000-03-28|2002-05-15|Pavlov Anatoliy Ivanovich|Medicament and process for preparing thereof|
    RU2167659C1|2000-08-02|2001-05-27|Закрытое акционерное общество "Центр современной медицины "Медикор"|Method of correction of immune system of living body|
    RU2169139C1|2000-08-02|2001-06-20|Закрытое акционерное общество "Центр современной медицины "Медикор"|Method of preparing alkali and alkali-earth salts of 5-amino-2,3-dihydro-1,4-phthalazinedione|
    RU2211036C2|2001-11-20|2003-08-27|Общество с ограниченной ответственностью "Абидофарма"|Medicinal preparation and method for its production|
    RU2222327C2|2002-03-22|2004-01-27|Общество с ограниченной ответственностью "Абидофарма"|Method for preparing medicinal preparation|
    US7326690B2|2002-10-30|2008-02-05|Bach Pharma, Inc.|Modulation of cell fates and activities by phthalazinediones|
    RU2238730C1|2003-02-17|2004-10-27|Абидов Муса Тажудинович|Medicinal preparation|
    RU2233161C1|2003-04-18|2004-07-27|Общество с ограниченной ответственностью "Абидофарма"|Medicinal preparation and method for its producing|
    CN1217193C|2003-07-30|2005-08-31|中国药科大学|Luminol chemiluminescence immunological analysis detecting method for cardiac muscle calcium protein|
    AU2003301513A1|2003-08-04|2005-02-15|Valery Khazhmuratovich Zhilov|Cyclic bioisosters of purine system derivatives and a pharmaceutical composition based thereon|
    PL231885B1|2009-01-16|2019-04-30|AbidopharmaSpolka Z Ograniczona Odpowiedzialnoscia|New method of manufacturing the 5-amino-2,3-dihydrophtalazine-1,4-dione salts with alkali metals and their application in medicine|
    US20100222584A1|2009-02-06|2010-09-02|Bach Pharma, Inc.|Pharmaceutical grade phthalazinediones, process for their preparation and pharmaceutical compositions containing them|
    PT2542535E|2010-03-01|2014-08-25|Metriopharm Ag|Crystalline forms for 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt, pharmaceutical preparations containing the same and method for the production of said forms|PT2542535E|2010-03-01|2014-08-25|Metriopharm Ag|Crystalline forms for 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt, pharmaceutical preparations containing the same and method for the production of said forms|
    ES2753577T3|2014-12-18|2020-04-13|Metriopharm Ag|Crystalline form of 5-amino-2,3-dihydroftalazine-1,4-dione sodium salt, the pharmaceutical preparations containing it and method of production|
    CA3011766A1|2016-02-16|2017-08-24|Metriopharm Ag|Method for producing a crystalline form of 5-amino-2,3-dihydrophthalazine-1,4-dione|
    CA3011767A1|2016-02-16|2017-08-24|Metriopharm Ag|Crystalline form of 5-amino-2,3-dihydrophthalazine-1,4-dione|
    EP3248602A1|2016-05-26|2017-11-29|MetrioPharm AG|Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of inflammatory and/or degenerative disorders of the tendons, ligaments of the joints, articular capsules and bursae|
    RU2625267C1|2016-09-22|2017-07-12|Общество с ограниченной ответственностью "АБИДАФАРМА"|Method for manufacture of non-sterile substances of non-aqueous "tamerit" and/or double-aqueous "galavit" - sodium salts of 5-amino-2,3-dihydrophthalazine-1,4-dioneand methods for further processing thereof to obtain sterile medicinal preparations|
    WO2018082814A1|2016-11-07|2018-05-11|Metriopharm Ag|Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of chronic progressive multiple sclerosis|
    CN106810501B|2017-01-23|2019-09-10|湖北新德晟材料科技有限公司|A method of utilizing one pot process luminol or different luminol|
    RU2635769C1|2017-02-08|2017-11-15|Адмир Мусаевич Абидов|Drug based on 5-amino-2,3-dihydrophthalazine-1,4-dione as quick-soluble film for transbuccal introduction|
    RU2673452C1|2017-08-15|2018-11-27|Межрегиональное общественное учреждение "Институт инженерной физики"|Method of obtaining active pharmaceutical substance, presenting aminodihydrophthalazinedione of sodium|
    EP3511325A1|2018-01-11|2019-07-17|MetrioPharm AG|Method for solubilizing 5-amino-2,3-dihydro-1,4-phthalazinedione|
    WO2020084348A1|2018-10-26|2020-04-30|Immunopharma Plus D.O.O.|Oral aminodihydrophthalazinedione compositions and their use the treatment of non-viral hepatitis|
    EP3858358A1|2020-01-31|2021-08-04|MetrioPharm AG|Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of rare chronic inflammatory pulmonary diseases|
    EP3858328A1|2020-01-31|2021-08-04|MetrioPharm AG|Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the inhalatory treatment of inflammatory pulmonary diseases|
    WO2021190783A1|2020-03-25|2021-09-30|Metriopharm Ag|5-amino-2,3-dihydro-1,4-phthalazinedione for treatment of acute lung injury|
    WO2021249667A1|2020-06-10|2021-12-16|Metriopharm Ag|Compound for the treatment of coronaviral infections|
    WO2022008093A1|2020-07-09|2022-01-13|Metriopharm Ag|Glucocorticoid-sparing agent|
    RU2756568C1|2021-03-24|2021-10-01|Акционерное общество "Щелково Агрохим"|Method for obtaining sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione in hydrated or anhydrous form|
    法律状态:
    2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-05-21| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-06-25| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2021-05-04| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-06-22| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 01/03/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, , QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |
    优先权:
    申请号 | 申请日 | 专利标题
    EP10002067.6|2010-03-01|
    EP10002067|2010-03-01|
    EP10075744|2010-11-25|
    EP10075744.2|2010-11-25|
    PCT/EP2011/001124|WO2011107295A1|2010-03-01|2011-03-01|Crystalline forms for 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt, pharmaceutical preparations containing the same and method for the production of said forms|
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