HK1018591B - Intravenous administration form of thalidomide for the therapy of immunologic diseases - Google Patents

Description

The invention relates to a parenteral application form of thalidomide and a method of its manufacture.

The excess production of the cytokine TNF-α (tumor necrosis factor α) plays a central role in the pathogenesis of graft-versus-host syndrome. aphthous stomatitis, erythema nodosum leprosum, Boeck' s disease, Crohn' s disease, rheumatoid arthritis and a number of other diseases that are accompanied by inflammatory symptoms.

Other examples of conditions in which thalidomide has shown good efficacy without leading to general immunosuppression include cutaneous lupus erythematosus, pyoderma gangrenosum and orogenital ulcers in Behcet' s disease, and ulcers not histologically different from aphthous ulcers in HIV-infected patients in which, unlike most HIV-associated mucocutaneous ulcers, no microbial locus can be detected. These changes in the size of the major lymph nodes may also affect the overall structure of the thyroid gland, unlike thalidomide, and may result in increased localized specialization or impaired development of the lymphatic system, which may be due to the presence of other factors such as the development of local and endogenous immune system, but may also be due to the presence of other pathogens such as adenocarcinoma and other local anticoagulants.

For severe pharyngeal or oesophageal ulcers, where oral administration may be difficult if not impossible, and for cases of HIV-associated pathology where severe diarrhoeal symptoms make oral administration unpredictable, parenteral administration is appropriate.

DE 42 11 812 water-soluble thalidomide derivatives are known which have a significantly higher water solubility than thalidomide and are suitable for parenteral application.

Furthermore, thalidomide products have been proposed for parenteral application which are water soluble and toxicologically safe in the physiological pH range (DE 196 13 976).

An aqueous solution of thalidomide mixed with hydroxypropyl-beta-cyclodextrin is known from Krenn et al. (J. Pharm. Sci. 81, 685-689 (1992)).

The purpose of the invention was to develop a water-soluble form of thalidomide application, which is stable in water and is not to produce toxicological effects due to non-physiological physicochemical properties.

It was found that the requirements for the application form to be developed are satisfied under certain conditions by the use of pure enantiomers of thalidomide.

The enantiomers of thalidomide have a water solubility up to a factor of 6 higher than that of racemate, but the tendency of thalidomide to spontaneously hydrolyze makes it impracticable to produce aqueous solutions.

According to current knowledge, the mode of action of thalidomide in immunological diseases cannot be attributed to a specific isomer. Pure enantiomers of thalidomide re-racemise in vitro and in vivo.

Accordingly, the subject matter of the invention is a solution of one of the two thalidomide antiomers suitable for parenteral application, where this solution is an aqueous solution with a pH of less than or equal to 5.5 and contains glucose as a component.

The definition of the invention covers both solutions of (+) - ((R) thalidomide and solutions of (-) - ((S) thalidomide which may be used individually or alternately for parenteral, particularly intravenous, applications.

Thalidomide injectable forms are suitable for use with a minimum active substance content of 0.2 mg/ ml.

The invention also relates to a method for the preparation of the aqueous thalidomide solution, in which (+) - ((R) - thalidomide or (-) - ((S) - thalidomide in pure form is added to an isotonic glucose solution with a pH of 4 to 5 and the mixture is shaken until the respective thalidomide anti-omer is completely dissolved, followed by ultrasonic treatment and aseptic filtration.

The application form of the invention is toxicologically safe for both rapid and slow infusion (10 ml/min)

The choice of additional excipients and the amounts to be used depend on the exact application of the product.

The dose to be administered to the patient, depending on the patient' s weight, parenteral route of administration, indication and severity of disease, is usually between 0.1 and 1 mg/ kg.

Examples Example 1

To prepare a solution for infusion at a concentration of 200 μg/ ml, 70 mg (+) - ((R) thalidomide was given in 350 ml of 5% glucose solution for infusion (pH 4 to 5) in a glass infusion bottle. The mixture was thoroughly shaken and treated with ultrasound for 15 minutes. Since the thalidomide concentration achieved depends on the intensity of the shaking and the ultrasound treatment, both steps were repeated until the solution was completely dissolved. The water temperature in the ultrasound bath reached a maximum of 33°C. The solution was filtered under aseptic conditions by a Millex sterile filter with a porosity of 0.22 μm (Millipore S.A., GS, France) and a glossy sterile solution was kept at room temperature.

The pH of the finished solution was 5.5.

The duration of ultrasonic treatment can be reduced by using a solution of the pure enantiomer in ethanol with a starting concentration 5 to 10 times higher.

Example 2

To prepare a solution for infusion at a concentration of 200 μg/ ml, 70 mg (-) - ((S) thalidomide was administered in 350 ml glucose solution for infusion (pH 4 to 5) in a glass infusion bottle as in example 1.

The pH of the finished solution was 5.5.

Stability testing

For 10 consecutive days, daily sub-categories of the solutions were taken for analysis.

After 10 days, the thalidomide antiomers were still completely intact and had not been hydrolysed. The thalidomide antiomers contained less than 1% of their optical antibodies after this period.

Claims (3)

1. Aqueous thalidomide solution having a pH value of less than or equal to 5.5, in which one of the two thalidomide enantiomers (+)-(R)-thalidomide or (-)-(S)-thalidomide in pure form is dissolved in isotonic glucose solution.
2. Aqueous thalidomide solution according to claim 1, characterised in that it has an active ingredient content of at least 0.2 mg/ml.
3. Process for the preparation of the aqueous thalidomide solution according to claim 1 or 2, characterised in that (+)-(R)-thalidomide or (-)-(S)-thalidomide in pure form is added to an isotonic glucose solution having a pH value of from 4 to 5 and the mixture is shaken until the thalidomide enantiomer in question has dissolved completely, and the solution is then treated with ultrasound and filtered under aseptic conditions.