MXPA00002608A - A stable aqueous solution of em 12 - Google Patents

Abstract

An aqueous solution 3-(1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione (EM 12) is described which is suitable for parenteral administration, particularly for intravenous administration of EM 12 for treating immunological and haematological-oncological diseases, and a method of producing the corresponding solution of EM 12 is also described.

Description

In addition to the Patent Application of the patent - main DE 197 43 968.3 of Grünenthal GmbH, with address at D-52078 Aachen. (your reference G 29051) STABLE AQUEOUS SOLUTION OF EM 12 r ~ The invention relates to a form of oral application of the EM 12 derivative of thalidomide, as well as to a method for its preparation. This form of application can be applied for the therapy of inflammatory and hematological-oncological diseases. Excessive formation of proinflammatory cytokines TNF-a (tumor necrosis factor) and A 10 interleukin (IL) -12 by phagocytic cells (by • example, monocytes) is of paramount importance in the pathogenesis of various inflammatory diseases (Trinchieri 1995, Ann. Rev. Immunol, 13: 251). A point of attack for the therapy of these diseases consists in the channelized inhibition of the formation of these proinflammatory cytokines by the administration of immunomodulating active substances such as, for example, dexamethasone or thalidomide, or the EM derivative. • of thalidomide. While corticosteroids such as dexamethasone are available in injectable form, this is not currently the case for the immunomodulatively active EM 12 derivative. For thalidomide a parenteral application form was proposed in DE 197 43 968.3. 25 Thalidomide has been shown to be superior to classical immunosuppressants in the treatment of severe aphthous stomatitis. Other examples Or diseases in which thalidomide showed good activity without causing a general immunosuppression are 5 cutaneous lupus erythematosus, pyoderma gangrenosum and orogenital ulcer in the case of morbus Bequet, as well as in the case of ulcerations that do not deviate histologically from the ulcer foot-and-mouth disease in HIV-infected individuals, in whom no provocative agents could be proven microbial, unlike what happens with most mucocutaneous lesions associated with HIV. These lesions, which in part also acquire the size of major aphthous ulcers, in contrast to aphthous stomatitis, can occur in the entire intestinal tract and, in the case of being located in the region of the pharynx or esophagus, making it difficult to take food, but also oral intake, due to its effect that causes pain. In severe cases of ulcer of the pharynx or esophagus, in which oral administration can be difficult and even impossible, and in cases of pathologies associated with HIV, in which severe diarrheal symptoms cause oral administration to be unpredictable, parenteral administration of the active substance is offered. However, the reduced solubility in The water of thalidomide (Arch. Pharm., 321, 371 (1988)) is contrasted with the parenteral application of these active substances. Therefore, experiments were not lacking to develop water-soluble application forms. • Document DE 42 11 812 is known water soluble thalidomide derivatives, which in comparison with thalidomide have a remarkably higher solubility in water and, which are suitable for parenteral application. In addition, prodrugs of thalidomide were proposed for the application of parenteral átk, which can be applied in the range of physiological pH values dissolved in water and are toxicologically harmless (DE 196 13 976). The disadvantage is that both types of the compounds mentioned above are more complex in their preparation than the preparation of thalidomide. By virtue of the fact that the EM 12 derivative of thalidomide has properties similarly disadvantageous to those of thalidomide in terms of its solubility in # Aqueous media and its tendency to spontaneous hydrosis, the task on which the invention was based was to develop a water-soluble application form of this thalidomide derivative with immunomodulatory activity. In addition, the application form to be developed should be stable in the aqueous dissolved form and, toxicological effects due to physical-chemical anti-physiological properties should not occur. It was found that the preparation of aqueous solutions is not practicable due to the tendency of EM 12 to the • spontaneous hydrolysis. However, if the pH values of the aqueous solutions are within the range of pH less than or equal to 5.5 hydrolysis does not occur. Table 1 Structure of the substances thalidomide and EM 12 Therefore, an EM 12 solution suitable for parenteral application is the object of the invention, this solution being an aqueous solution with a pH value less than or equal to 5.5 and containing as glucose as a component. According to the invention, EM 12 is dissolved in isotonic glucose solution, either as a racemate or as one of the enantiomers. These solutions can be used for parenteral application, in particular for intravenous application. As injectable forms of EM 12 application are those that have a content of when • less 0.2 mg / ml of active substance. 5 Another additional object of the invention is a . process for the preparation of the aqueous solution of EM 12. For this purpose, in accordance with the invention, the EM 12 is added to an isotonic glucose solution with a pH value of 4 to 5 and, this mixture is stirred until the The complete dissolution of the EM 12, and / or is then treated with ultrasound to shorten the preparation time, and filtered under aseptic conditions. The method of application according to the invention is toxicologically harmless both in the case of a rapid infusion and in that of a slow infusion (10 ml / min). In addition to EM 12, the medicaments according to the invention also contain glucose. Eventually • Other auxiliary substances can be added to the EM solution 12. The choice of the other auxiliary substances, as well as the amounts to be used, depend on the exact form in which the medication should be applied. The amount to be administered to the patient, 25 which depends on the weight of the patient, the form of parenteral application, the indication and the severity of the disease, is generally between 0.1 and 1 mg / kg. Parenteral EM 12 solutions, as well as thalidomide solutions, can be applied for the therapy of diseases in which the pathogenesis is blamed on the excess production of TNF-a and IL-12 (inter alia, diseases of the intestine, of skin, mucous membranes, vessels as well as autoimmune diseases), furthermore, by virtue of the anti-angiogenic activity, also for the therapy of hematological diseases and other oncological diseases. Among the diseases of the previously mentioned morphological circumscriptions are among others cutaneous inflammations (for example atopic dermatitis, psoriasis, exema), inflammations of the respiratory tract (for example bronchitis, pneumonia, bronchial asthma, ARDS (respiratory insufficiency syndrome in adults). ), sarcoidosis (silicosa / fibrous), inflammations of the gastrointestinal tract (eg gastroduodenal ulcer, Crohn's morbus, ulcerative colitis), as well as diseases such as hepatitis, pancreatitis, appendicitis, peritonitis, nephritis, aphtosis, conjunctivitis, keratitis, uveitis, rhinitis. Autoimmune diseases include diseases of the arthritic morphological circumscription (for example, rheumatoid arthritis, diseases associated with HLA-B27), as well as multiple sclerosis, juvenile diabetes or • lupus erythematosus. 5 Other indications are septicemia, meningitis . bacterial, cachexia, rejection reactions to transplants, graft versus host reactions, as well as reperfusion syndrome and arteriosclerosis. Among the symptomatology are also the a ^ k 10 hematological diseases such as multiple myeloma and leukemias, as well as other oncological diseases such as glioblastoma, prostate cancer as well as breast cancer. Example 15 For the preparation of infusion solution in a concentration of 200 μg / ml, 70 mg of EM were added 12 racemic to 350 ml of a glucose solution for 5% infusions (pH 4 to 5) in an infusion glass bottle. The mixture was stirred thoroughly and treated for 15 minutes with ultrasound. Since the concentration of dissolved EM 12 that is obtained depends on the intensity of the agitation and the treatment with ultrasound, both steps were repeated until the total dissolution. The temperature of the water in the bathroom ultrasound reached 33 ° C maximum. The solution was filtered under aseptic conditions into a glass bottle for sterile infusions through a sterile Millex GS filter with 0.22 μm pore size (Millipore, S.A., Molsheim, • France) . The solution was stored at the temperature atmosphere. The pH value of the prepared solution was 5.5. Stability test Over a period of 2 weeks, partial quantities of the k-solutions were extracted several times for analysis. After 2 weeks the EM 12 was present with full biological activity. Immunomodulatory activity testing To investigate the immunomodulatory activity of the prepared solutions, human monocytes were isolated from peripheral blood mononuclear cells (PBMC) and activated with microbial LPS (lipopolysaccharide). The concentration of TNF-α and IL-12 in the supernatants of cell cultures was determined by sandwich ELISA 20 (Biosource Europe, Fleurus, Belgium).

Table 2 The influence of an EM 12 solution prepared according to the preceding example on the production of TNF-α and IL-12 of monocytes activated with LPS Table 2 • • % inh =% inhibition of TNF-a or IL-12 production of the control without inhibitors

Claims (3)

1. CLAIMS 1. Stable aqueous solution, containing EM 12 for parenteral administration, with EM 12 dissolved in an isotonic glucose solution and the pH value of the solution is less than or equal to 5.5.
2. 2. A stable aqueous solution according to claim 1, characterized in that it has an active substance content of at least 0.2 mg / ml. Method for the preparation of the stable aqueous solution according to claim 1, characterized in that EM 12 is added to an isotonic solution of glucose with a pH value of 4 to 5, and that this solution is stirred until dissolution total, and / or treated with ultrasound to shorten the preparation time, and filtered under aseptic conditions.