CZ20001164A3 - Stable aqueous solutions of Thalidomide EM 12 derivative and process of their preparation - Google Patents

Abstract

An aqueous solution of Thalidomide EM 12 derivative is disclosed it is suitable as a parenteral, especially intravenous, application the form of the Thalidomide EM 12 derivative for immunological therapy and hematological and oncological diseases as well as the method producing a corresponding solution of the Thalidomide EM EM derivative 12.

Description

Technical field

The present invention relates to a parenteral dosage form of a Thalidomide EM 12 derivative and a process for its preparation. This dosage form can be used to treat inflammatory and hematologic-oncological diseases.

BACKGROUND OF THE INVENTION

The predominant production of the proinflammatory cytokone TNF-α (tumor-necrosis factor) and interleukin IL- (12) by phagocyter cells (for example monocytes) plays a central role in the pathogenesis of various inflammatory diseases (Trinchieri 1995, Ann. Rev. Immunol. 13: 251).

The use for the treatment of these diseases consists in the targeted suppression of the production of these proinflammatory cytokines by the administration of immunomodulatory active substances such as Dexamathasone or Thalidomide or a derivative of Thalidomide EM12. not yet. DE 197 43 968 proposes a parenteral dosage form for Thalidomide.

Thalidomide has been shown to be more advantageous in the treatment of severe affinity stomatitis compared to classical immunosuppressants. Other examples of diseases in which Thalidomide shows good efficacy without leading to general immunosuppression

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resi, Lutus erythematosus, pyoderma gangrenosum, and urogenital ulcer in Morbus Behcet, as well as histotologically non-affective ulceration in HIV-positive ulcers, which, unlike most HIV-associated mucocutaneous organisms, have no microbial agents.

Unlike stomatitis aftosa, these lesions, which are partially increasing in size and in size, may occur throughout the digestive tract and, when located in the throat and esophagus, their pain makes it difficult to accept nutrition but also oral medications.

For severe cases of pharyngealer or osophagealer ulcers in which oral administration is more difficult, if not completely excluded, as well as in cases of HIV-associated pathology in which severe diarrhea symptoms prevent oral administration, parenteral administration of the active ingredient is offered. However, the low solubility of Thalidomide in water (Arch.Pharm. 321, 371 (1998)), however, excludes parenteral administration. Therefore, many attempts have been made to develop a water-soluble dosage form.

DE-A 42 11 812 discloses water-soluble derivatives of Thalidomide which have a considerably higher water-solubility than Thalidomide and are suitable for parenteral applications.

In addition, thalidomide prodrugs have been proposed for parenteral administration, which can be dissolved toxic in water in the physiological pH range (DE 196 13 976). It is disadvantageous that both types of the above compounds are more expensive to manufacture than Thalidomide.

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Since the Thalidomide EM-12 derivative exhibits similar negative properties to Thalidomide in terms of its solubility in aqueous media and its propensity for spontaneous hydrolysis, the development of the water-soluble dosage form of this immunomodulatory Thalidomide derivative has been the primary objective of the invention. In addition, the dosage form to be developed should be stable in aqueous solution and, by virtue of its non-physiological physicochemical properties, should not produce any toxicological effects.

SUMMARY OF THE INVENTION

It has been found that the production of aqueous solutions is not viable due to EM 12's tendency to spontaneous hydrolysis. However, if the pH values of the aqueous solutions are less than or equal to 5.5, the hydrolysis does not occur.

Table 1

Structure of Thalidomide and EM 12 substances

Substance structure name Thalidomide 0 0 H 2- (2,6-Dioxo- piperidin-3-yl) isoindole-1,3-dione EM 12 ... 3- (1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione

9.... 9

Accordingly, the present invention provides an EM 12 solution suitable for parenteral administration, wherein the solution is aqueous with a pH of less than or equal to 5.5 and contains glucose as a component. According to the invention, EM 12 in the form of a racemate or as one of the enantiomers is dissolved in an isotonic glucose solution. Such solutions can be used for parenteral, especially intravenous applications.

Suitable injectable dosage forms of EM 12 are those in which the active substance content is at least 0.2 mg / ml.

A further object of the invention is a process for the manufacture of aqueous solutions of EM 12. According to the invention, EM 12 is added to an isotonic glucose solution having a pH of 4-5 and this mixture is shaken until EM 12 is completely dissolved, and / ultrasound and filtered under aseptic conditions.

The dosage form according to the invention is toxicologically harmless both at a faster infusion and at a slower infusion (10 ml / min).

In addition to EM 12, the medicament according to the invention also contains glucose. Optionally, additional excipients may be added to the EM 12 solution. The choice of other excipients as well as the amount thereof depends on how precisely the drug is to be administered.

The amount of active ingredient administered to a patient depends on the weight of the patient, the mode of parenteral administration, the indication and the severity of the disease, and is usually between 0.1 and 1 mg / kg.

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EM 12 parenteral solutions may be used in the same way as Thalidomide solutions for the treatment of diseases whose pathogenesis is due to excess TNF-α and IL-12 production (including, but not limited to, intestinal, skin, mucosal, vascular and autoimmune diseases). -angiogenetic effect also for the treatment of hematological diseases and other oncological diseases.

Diseases of the aforementioned species include, but are not limited to, skin inflammation (e.g., atopic dermatitis, psoriasis, eczema), airway inflammation (e.g., bronchitis, pneumonia, bronchial asthma, ARDS (Distress Syndrome Respirators), sarcoidosis, silicosis / fibrosis), gastrointestinal inflammation tract (e.g. gastroduodenal ulcer, Morbus Crohn, ulcerative colitis), as well as diseases such as hepatitis, pancreatitis, appendicitis, peritonilis, nephritis, aftosis, conjunctivitis, keratitis, uveitis, rhinitis.

Autoimmune diseases include, for example, diseases of the arthritic species (for example, rheumatoid arthritis, diseases associated with HLA-B27), multiple sclerosis, juvenile diabetes or Lupus erythematosus.

Other indications are sepsis, bacterial meningitis, cachexia, graft versus recipient graft rejection reactions, as well as reperfusion syndrome and atherosclerosis.

It also includes hematological diseases such as myeloma multiples and leukemia, as well as other oncological diseases such as glioblastoma, prostate cancer and breast cancer.

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DETAILED DESCRIPTION OF THE INVENTION

Example

To produce a 200 gg / ml solution for infusion, 70 mg of racemic EM 12 is added to 350 ml of a 5% glucose solution for infusion (pH 4-5) in a glass infusion bottle. The mixture was shaken vigorously and sonicated for 15 minutes. Since the concentration of dissolved EM 12 reached depends on the intensity of shaking and ultrasonic treatment, both steps are repeated until complete dissolution. The water in the ultrasonic bath is at most 33 ° C. The solution is aseptically filtered through a 0.22 µm Millex GS sterile filter (Millipore S.A., Molsheim, France) into a sterile glass infusion bottle. The solution was stored at room temperature.

The pH of the final solution is 5.5.

Stability tests

Subsequent amounts were removed repeatedly from the solutions for analysis for 2 weeks.

After two weeks, EM 12 maintained full biological activity.

Demonstration of immunmodulatory efficacy

To test the immunmodulatory efficacy of the solutions produced, human monocytes from peripheral blood mononuclear cells (PBMCs) are isolated and activated with bacterial LPS. (Lipopolysaccharide). TNF-α and IL-12 concentrations in cell culture residues were determined by Sandwich-Elisa (Biosource Europe, Fleurus, Belgium).

Table 2

Effect of EM 12 solution produced according to the above example on TNF-α and IL-12 production of LPS-activated monocytes

*% Inh.

% inhibition of TNF-α and IL-12 production without inhibitors

Claims (3)

PATENT CLAIMS Stable aqueous solutions according to DE 197 43 968.3 comprising EM 12 for parenteral administration, wherein the EM 12 is dissolved in isotonic glucose solution and the pH of the solution is less than or equal to 5. Stable aqueous solutions according to claim 1, characterized in that they have an active substance content of at least 0.2 mg / ml. Method for producing stable aqueous solutions according to claim 1, characterized in that the EM 12 is placed in an isotonic glucose solution having a pH of 4-5 and the mixture is shaken until completely dissolved and / or subsequently reduced sonicated and filtered under aseptic conditions.