Stable aqueous solution eat 12


(57) Abstract:

The invention relates to medicine. Describes an aqueous solution of a derivative of thalidomide, which can be used in a form for parenteral, especially intravenous, in the treatment of immunologic and hematologic diseases, as well as the method of preparation of the corresponding solution. The solution is stable and non-toxic. 2 AD. and 1 C.p. f-crystals, 2 tab.

The present invention relates to intended for parenteral dosage form containing a derivative of thalidomide EAT 12 and also to the way it was received. This dosage form can be used for the treatment of inflammatory and hematologic diseases.

Excessive education promotes inflammation cytokines TNF- (tumor necrosis factor) and interleukin IL-12 phagocytic cells (e.g. monocytes) plays a major role in the pathogenesis of various inflammatory diseases (Trinchieri 1995, Ann. Rev. Immunolog. 13: 251).

Fundamental to the treatment of such diseases is targeted suppression of the formation of these promote inflammation cytokines carried out by the introduction of immunome Edomite EAT 12. If corticoide, such as dexamethasone, to date, presented in injectable forms, in relation to possessing immunomodulatory effect derived EAT 12 of these so far not been practiced. In the application DE 19743968.3 prompted thalidomide parenteral.

In the treatment of severe forms of aphthous stomatitis thalidomide, has been found superior in its effectiveness classic immunosup-springs. As other examples of diseases, therapy thalidomide produces good results, without giving effect to any significant immunosuppression, can be called lupus erythematosus (Lupus erythematodes), creeping ulcer (Pyoderma gangranosum) and urogenital ulcers when illness behceta, and does not differ in principle in histological respect from aphthous ulcers ulceration in HIV-infected patients, in which unlike most of the skin and mucous lesions, HIV-infection, is unable to detect microbial agents. These partially expanding also to the size of a large ulcers damage unlike aphthous stomatitis (Stomatitis aphthosa) can occur throughout the digestive tract and localization in the pharynx or esophagus due on the Sabbath.">In severe cases pharyngealised and oesophageal ulcers, in which the oral intake may be difficult or impossible, and in cases with associated with HIV infection pathology, in which the symptoms, caused by a severe form of diarrhea, you can't accurately calculate for oral administration, almost the only acceptable method is parenteral administration of the active substance. However, such a method of introducing active substances prevents the low solubility of thalidomide (Arch. Pharm. 321, 371 (1988)). Therefore there was no shortage of attempts to develop water-soluble forms of administration.

From the application DE 4211812 known water-soluble derivative of thalidomide, has compared himself thalidomide significantly higher solubility and is suitable for parenteral administration.

In addition, for parenteral administration have been proposed thalidomidesee proletarienne tools that can be used dissolved in the physiological pH range and are toxicologically safe (see DE 19613976). The disadvantage of the above-mentioned compounds of both types is that for their production requires more significant logistical setratio in the aquatic environment and its tendency to spontaneous hydrolysis characteristic similar adverse properties, as for the thalidomide, the basis of the invention was used to develop water-soluble form use this with immunomodulatory action of a derivative of thalidomide. In addition, it was envisaged that the developed form of application, being dissolved in water, should be stable and non-physical physical-chemical properties should not cause any Toxicological effect.

As was established, obtaining aqueous solutions when used for these purposes, the propensity to EAT 12 to spontaneous hydrolysis of almost impractical. In cases where the pH values of aqueous solutions are in the range of 5.5, the hydrolysis is missing.

The object of the invention accordingly is suitable for injecting the solution is to EAT 12, he is an aqueous solution with pH value of less than or equal to 5.5, and contains as a component of glucose. According to the invention EAT 12 dissolved in isotonic glucose solution or in the form of the racemate or in the form of one of the enantiomers. Such solutions can be used for parenteral, especially intravenous, administration.

As intended for injection d 0.2 mg/ml

Another object of the invention is a method of obtaining an aqueous solution EAT 12. Thus according to the invention it is envisaged to add EAT 12 in isotonic glucose solution when the pH value of the last 4-5 and the mixture is shaken until complete dissolution EAT 12 and/or to reduce the duration of the process of obtaining, processing then ultrasound and filter under aseptic conditions. Proposed in the invention is a pharmaceutical form of toxicologically safe at fast and slow infusion (10 ml/min).

Medicinal product according to the invention along with EATING 12 contains in its composition and glucose. Optionally, the solution is to EAT 12 you can also add other excipients. The choice of such auxiliary substances, as well as the quantities used depend on the dosage and methods of administration of the drug. Assigned to the patient an amount of the active substance, depending on the weight of the patient, methods of parenteral administration, the indication and the severity of the disease, is usually from 0.1 to 1 mg/kg

Intended for parenteral solutions EAT 12, as well as thalidomidesee solutions can be used for the treatment of diseases, the pathogen is, mucosa, vascular, and autoimmune diseases); in addition, thanks to antiangiogenesis action (i.e. to prevent the development of blood vessels) can also be used for therapy of hematological and other cancers.

To diseases of the aforementioned types include, among other things, dermatitis (e.g. atopic dermatitis, psoriasis, eczema), inflammation of the respiratory tract (e.g., bronchitis, pneumonia, bronchial asthma, respiratory distress syndrome of adults, sarcoidosis, silicosis/fibrosis), inflammation of the gastrointestinal tract (e.g., duodenal ulcer, Crohn's disease, ulcerative colitis), then such diseases as hepatitis, pancreatitis, appendicitis, peritonitis, nephritis, Aptos, conjunctivitis, keratitis, uveitis, rhinitis.

Among the autoimmune diseases include, for example, arthritic disease nature (e.g., rheumatoid arthritis), diseases related to or caused by leukocyte antigen major histocompatibility complex human (HLA-B27), additionally, multiple sclerosis, juvenile diabetes, and lupus erythematosus.

Other indications are sepsis, bacterial meningitis, cachexia, rocklers.

The picture above diseases complement oncohematological diseases such as multiple myeloma and leukocytosis, as well as other cancers, such as glioblastoma, carcinoma of the prostate and carcinoma of the breast.


To prepare intended for intravenous infusion solution at a concentration of 200 μg/ml, 70 mg of racemic EAT 12 was added 350 ml of 5% glucose solution (pH 4-5), placed in a glass bottle. Then the mixture was intensively shaken and within 15 minutes was treated with ultrasound. Because the required concentration of dissolved EAT 12 depends on the intensity of shaking and ultrasonic treatment, both these operations were repeated to achieve complete dissolution of the active substance. Water temperature in the ultrasonic bath was most 33C. The solution is aseptically filtered through a sterilizing filter Millex GS with a pore size of 0.2 μm (Millipore S.A., Molsheim, France), directing in a sterile glass bottle. Then the solution was placed in storage at room temperature. The pH value of the prepared solution was 5.5.

Testing resistance

During dvojni two weeks EAT 12 fully retained its biological effectiveness.

Confirmation immunomodulatory efficacy

To study immune modulating the effectiveness of the obtained solutions was isolated human monocytes from mononuclear (mononuclear) cells in peripheral blood and activated by bacterial LPS (lipopolysaccharide). The concentration of TNF - and IL-12 in the supernatant of the cell culture was determined using the "sandwich" ELISA-assay (ELISA) (Biosource Europe, Fleurus, Belgium).

1. A stable aqueous solution of immunomodulator for parenteral administration, containing 3-(1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione and isotonic glucose solution, the pH value of which is less than or equal to 5.5.

2. Stable aqueous solution under item 1, characterized in that it contains the active substance in the amount of at least 0.2 mg/ml.

3. The method of obtaining a stable aqueous solution under item 1, characterized in that 3-(1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione add in isotonic glucose solution at pH 4-5 and the mixture shaken until complete dissolution of the active substance and/or to reduce the duration of the cooking process, process, then ultrasound and filter


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