DE1493558A1 - New peptide complexes with adrenocorticotropic effects and processes for their preparation - Google Patents

Description

Additional patent to main patent No. 119b ööö -

H93558

CIBA AKTIENGESELLSCHAFT, BASEL (SWITZERLAND)

Germany

New peptide complexes with adrenocorticotropic effects and processes for their preparation.

The main patent No. II96 666 describes a process for the production of new tetracosapeptides with adrenocorticotropic action, namely L-seryl-L-tyrosyl-L-seryl-L-methionyl-L-glutamyl-L-histidyl-L-phenylalanyl-L-arginyl -L-tryptophyl-glycy1-L-lysyl-L-proly1-L-valyl-glycyl-L-lysy1-L-lysyl-L-arglnyl-L-arginyl-L-prolyl-L-valyl-L-lysyl-L -valyl-L-tyrosyl-L-pro-

1 -24
lins (ß-corticotropin) and the corresponding compound, which has the remainder of glutamine instead of the glutamyl residue, and their salts and heavy metal, in particular

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Zinc complexes. - ■ - -

It has now been found that the clinical application of the tetracosapeptide complexes can be significantly facilitated and improved if the complexes are formed with zinc pyrophosphate. The present invention therefore provides complexes of the tetracosapeptide of the formula t-seryl-L-tyrosyl-L-seryl- L-methionyl-L-glutamyl-L-histidyl-L-phenylalanyl-L-arginyl-L-tryptophyl-glycyl-L-ly ^ yl-L-prolyl-L-valylglycyl-L-lysyl-L-lysyl-L- arginyl-L-arginyl-L-proly1-L-valy1-L-lysyl-L-valyl-L-tyrosyl-L-proline or the corresponding compound which has the remainder of glutamine instead of the glutamyl radical, with zinc pyrosphat, in which per mole of Tefc racosapeptide- at least 20 gram equivalents of zinc are present. ^T Ieberraschenderweise is obtained of the sparingly water-soluble Tetracosapeptid-Zinkpyrophosphatkomplex in the form of a precipitate of a defined, uniform particle size, which allows the preparation of stable suspensions. For sterilization of suspensions (20 min. 12O ⁰ C) does not change the particle size.

Depending on the precipitation conditions (zinc salt concentration. Temperature, pH) the particle size can be varied, for example between 1 and 50μ particle diameter. Preferably one produces precipitations with a particle diameter between 2 and 20μ.

According to the process of the invention, the tetracoapeptide-zinc pyrophosphate complex in a watery

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Solution, preferably from pH 5 to 6.5, which is at least 20 Contains gram equivalents of a therapeutically usable soluble zinc salt per mole of tetraoosapeptide, with a therapeutically usable pyrophosphate ion-containing aqueous Solution, preferably with a small excess the stoichlometric amount of sodium pyrophosphate, precipitated. The excess is about £ 1-2. As soluble zinc salts Examples include t zinc chloride, zinc sulfate and zinc acetate. If the acetate is chosen as the soluble zinc salt, the sodium acetate produced during the precipitation acts as a buffer, the adjust the pH of the suspension to the above. 6.0 holds »This pH is also maintained during sterilization. If the solvable Zinc salt-containing solution has a pH above 6.5 adjusted to the desired pH by means of dilute mineral acid, preferably hydrochloric acid.

The zinc salt concentration is chosen so that the suspension per mole is at least 20, preferably 300-2000 Contains gram equivalents of zinc. The Tetraoosapeptide concentration is chosen according to the desired dose strength; 1 mg tetraoosapeptide, injected intramuscularly, corresponds to 100 I.U.

The precipitation is carried out at temperatures of 0-50 ⁰ C, preferably at room temperature, with stirring.

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^: - 4 - ■ U93558

The new complexes can be in pharmaceutical form Preparations «are preferably used as suspensions for intramuscular or subcutaneous injection. The suspensions can be stored in ampoules or vials. However, they can also be prepared from lyophilized complexes (trooken ampoules) before use. If the complexes are lyophilized, a carrier material, e.g. mannitol, is added to the suspension to be lyophilized as usual. to.

The suspensions can be sterilized in conventional catfish. You can also use them for the precipitation Filter solutions aseptically and fill the suspension into ampoules or vials under sterile conditions. The suspensions can also contain preservatives, stabilizers, Contain wetting or emulsifying agents or other therapeutically valuable substances.

The tetra oosapeptide contained in the complexes can be obtained according to the method described in the main patent no. (Annw no. C 26 ' 884 ivb / l2qu

Case 4823 / I + 2 / E) or in the additional patents no.

IVb / 12 qu (Note No. C 32 150 - Case 5246/1 + 2) or No.

IVb / 12 qu
(Note No. C 30 563- Case 5247/5123 / E)

getting produced. '

The invention is described in the following examples.

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Example 1 :

1-24 IjO ml of an aqueous solution containing O ₄ OOl g β -

Corticotropin, 0.02 g zinc acetate (Zn (CH, C00) ₂ «2HgO), 0.0015 g sodium chloride, 0.02 g benzyl alcohol and 0.005 ml 1-n. Contains hydrochloric acid, 1.0 ml of a 2.16 strength aqueous solution of sodium pyrophosphate (Na ^ PgO ™, 10 HgO) is added with stirring at room temperature.

The suspension of zinc pyrophosphate resulting from this reaction is isotonic and has a pH value of 6.0. The sterilized suspension also has a pH of 6.0. Most of the parts have a diameter from 3-4μ, spread: 2-6μ. The suspension contains 0.5 mg (50 IU) β-corticotropin, 6.94 mg zinc pyrophosphate, 7 »47 mg sodium acetate, 0.75 mg sodium chloride per ml and 10.0 mg benzyl alcohol.

Example 2;

1.0 ml of an aqueous solution containing 0.001 g ^ "^ - corticotropin, 0.05 g zinc sulfate (ZnSO ^, 7 H ₂ O) and 0.02 g benzyl alcohol is stirred with 1.0 ml of a 3, 95 # solution of sodium pyrophosphate 10 HgO) added.

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The zinc pyrophosphate suspension formed during this reaction has a pH of 5 * 5. The sterilized suspension has a pH of 6.0. The particles have an average diameter of 6-7μ, 1 ml suspension contains 50 IU ß ^x -corticotropin.

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Claims (1)

I tdOJJO .'Patent claims: 1. Process for the preparation of zinc complexes of the tetracosapeptide of the formula L-Seryl-L-tyrosyl-L-seryl-L-methionyl-L-glutamyl-L-histidyl-L-phenylalanyl-L-arginyl-Ir tryptophyl-glyoyl-L-lysyl-L-prolyl-L-valyl-glyoyl-L-lysyl-L-lysyl-L-arginyl-L-arginyl-L-prolyl-L-valyl-L-lysyl-L-valyl- L-tyrosyl-L-proline or the corresponding compound which instead of the Qlutamylrest the remainder of the glutamine has, daduroh; that one has a Tetraoosapeptide-Zlnk-Pyrophosphatkomplux. forms j by., one watery « ge solution containing at least 20 percent per Qrammol tetraoosapeptide Contains gram equivalents of a therapeutically usable soluble zinc salt, mixed with a therapeutically usable pyrophosphate ion-containing aqueous solution. 2. The method according to claim 1, characterized in that 300-2000 gram equivalents of zinc are used per mole of tetra oosapeptide. 3 · Method according to claims 1 and 2, daduroh characterized in that zinc acetate is used as the soluble zinc salt. 909820/13 20 -8- H93558 4. The method according to claims l-3 # characterized in that the complex is precipitated with sodium pyrophosphate. 5. The method according to claims 1-4, characterized in that with a small excess over the stoichiometric amount of pyrophosphate falls. 6. Process according to claims 1-5, characterized in that the precipitation is carried out at a pH of 5 to 6.5. 7. Process according to claims 1-6, characterized in that the precipitation is carried out in the presence of a buffer. 8. Complexes of the tetracosapeptide of the formula L-Seryl-L-tyrosyl-L-seryl -L-methionyl-L-glutamyl-L-histidyl'-L-phenylalanyl-L-arginyl-L-tryptophyl-glycyl-L-lysyl- L-prolyl-L-valylglycyl-L-lysyl-L-lysyl-L-arginyl-L-arginyl-L-prolyl-L-valyl-L-lysyl-L-valyl-L-tyrosyl-L-proline or the equivalent Compound - which instead of the glutamyl residue contains the remainder of the glutamine with zinc pyrophosphate, wherein per mole of tetracosapeptide at least. 20. Gram equivalents of zinc are present. 9. Complexes of the Tetracosapeptlds of the formula L-Seryl- 909820/1320 L-tyrosyl-L-seryl-L-methionyl-L-glutamyl-L-histidyl-L-phenylalanyl-L-arginyl-L-tryptophyl-glycyl-L-lysyl-L-prolyl-L-valylglycyl-L-lysyl- L-lysyl-L-arginyl-L-arginyl-L-propyl-L-valyl-L-lysyl-L-valyl-L-tyrosyl-L-proline or the corresponding compound which, instead of the glutamine residue, contains the remainder of the olutamine having, with zinc pyrophosphate, wherein per mole of tetracosapeptide There are 300-2000 gram equivalents of zinc present. 10. Pharmaceutical preparations containing complexes of tetracosapeptide of the formula L-Seryl-L-tyrosyl-L-seryl-L-methionyl -L-glutamyl-L-hi-stidyl -L-phenylanalyl - · -L-arglnyl-L-.tryptophyl-glycyl-L-lysyl-L-prolyl-L-valyl-glycyl-L-lysyl-L-lysyl -L-arginyl-L-arglnyl-L-prolyl-L-valyl-L-lysyl-L-valyl-L-tyrosyl-L-proline or the corresponding compound, which has the remainder of glutamine instead of the glutafnyl radical, with zinc pyrophosphate, wherein per mole of tetracosapeptide there is at least 20 gram equivalents of zinc, along with a pharmaceutical Support material included. 909820/13 20