Aqueous preparation containing oligopeptides and etherified cyclodextrin
The present invention relates to an aqueous pharmaceutical preparation of oligopeptides comprising an oligopeptide of the formula I, cyclo-(n-Arg-nGly-nAsp-nD-nE), and a partially etherified β-cyclodextrin having a water solubility of greater than 1.8 mg/ml of water, and to the preparation of the aqueous pharmaceutical preparation.
1. An aqueous pharmaceutical composition comprising: an oligopeptide of formula I
cyclo-(n-Arg-nGly-nAsp-nD-nE) (I)
in which
D and E each, independently of one another, denote Gly, Ala, β-Ala, Asn, Asp, Asp(OR), Arg, Cha, Cys, Gln, Glu, His, Ile, Leu, Lys, Lys(Ac), Lys(AcNH 2 ), Lys(AcSH), Met, Nal, NIe, Orn, Phe, 4-Hal-Phe, homoPhe, Phg, Pro, Pya, Ser, Thr, Tia, Tic, Trp, Tyr or Val;
R denotes alkyl having 1-18 C atoms;
Hal denotes F, Cl Br or I;
Ac denotes alkanoyl having 1-10 C atoms, aroyl having 7-11 C atoms or aralkanoyl having 8-12 C atoms; and
n denotes H, R, benzyl or aralkyl radical having 7-18 C atoms on the alpha-amino function of the corresponding amino acid, with the proviso that at least one amino acid has a substituent n, where n denotes R,
and where, if the amino acids are optically active, both the D and L forms are included,
and physiologically acceptable salts thereof;
and an etherified β-cyclodextrin having a water solubility of greater than 1.8 mg/ml in water.
2. An aqueous pharmaceutical composition according to claim 1 , wherein the etherified β-cyclodextrin present is a partially etherified β-cyclodextrin.
3. An aqueous pharmaceutical composition according to claim 1 , wherein the ether substituents in the etherified β-cyclodextrin are hydroxymethyl, hydroxypropyl, or combinations thereof.
4. An aqueous pharmaceutical composition according to claim 1 , wherein the etherified β-cyclodextrin has a molar degree of substitution of between 0.2 and 10, based on the ether substituents.
5. An aqueous pharmaceutical composition according to claim 4 , wherein the partially etherified β-cyclodextrin has a molar degree of substitution of between 0.2 and 2, based on the ether substituents.
6. An aqueous pharmaceutical composition according to claim 4 , wherein the partially etherified β-cyclodextrin has a molar degree of substitution of between 0.5 and 0.8, based on the ether substituents.
7. An aqueous pharmaceutical composition according to claim 1 , wherein the oligopeptide is cilengitide.
8. An aqueous pharmaceutical composition according to claim 1 , further comprising an isotonicity agent in an amount necessary for establishing isotonicity.
9. An aqueous pharmaceutical composition according to claim 1 , wherein said composition has a pH of from 5 to 8.
10. An aqueous pharmaceutical composition according to claim 9 , wherein said composition has a pH of from 6 to 7.2.
11. An aqueous pharmaceutical composition according to claim 1 , wherein said oligopeptide is cilengitide and said etherified β-cyclodextrin is a hydroxypropyl-β-cyclodextrin having a molar degree of substitution of from 0.5 to 0.8, and said composition contains from 20 to 120 mg/ml of cilengitide and from 15 to 25% by weight of said hydroxypropyl-β-cyclodextrin.
12. An aqueous pharmaceutical composition according to claim 11 , wherein said composition contains about 80 mg/ml of cilengitide and about 20% by weight of hydroxypropyl-β-cyclodextrin having a molar degree of substitution of about 0.58-0.73.
13. A process for the preparation of an aqueous pharmaceutical preparation according to claim 1 , said process comprising:
dissolving the β-cyclodextrin ether in water, and then subsequently adding the oligopeptide and any further adjuvants.
14. An aqueous pharmaceutical composition according to claim 1 , wherein said composition has a pH of from 5.6 to 7.4.
15. An aqueous pharmaceutical composition according to claim 1 , wherein said composition has a pH of from 6 to 7.2. and the osmolality is from 250 to 350 mOsmol/kg.
16. An aqueous pharmaceutical composition according to claim 2 , wherein the ether substituents in the etherified β-cyclodextrin are hydroxymethyl, hydroxypropyl, or combinations thereof.
17. An aqueous pharmaceutical composition according to claim 4 , wherein the partially etherified β-cyclodextrin has a molar degree of substitution of 0.58-0.73, based on the ether substituents.
18. An aqueous pharmaceutical composition according to claim 1 , wherein said oligopeptide is cyclo-(NMeArg-Gly-Asp-D-Phe-Val), cyclo-(Arg-Gly-Asp-DPhe-NMeVal), cyclo-(Arg-NMeGly-Asp-DPhe-Val), cyclo-(Arg-Gly-NMeAsp-DPhe-Val), or cyclo-(Arg-Gly-Asp-NMeDPhe-Val).
19. An aqueous pharmaceutical composition according to claim 8 , wherein said isotonicity agent is a physiologically tolerated salt, physiologically tolerated polyol, or a physiologically tolerated sugar.
20. An aqueous pharmaceutical composition according to claim 19 , wherein said isotonicity agent is sodium chloride, potassium chloride, glucose, glycerol or mannitol.
21. An aqueous pharmaceutical composition according to claim 1 , further comprising one or more physiologically tolerated adjuvants selected from antioxidants, preservatives, and further stabilisers, structure formers and solubilizers, wherein the stabilisers, structure formers and solubilizers are selected from the group consisting of polyethylene glycols and dextrans.
22. An aqueous pharmaceutical composition according to claim 1 , further comprising one or more physiologically tolerated buffers, present in a concentration of from 5 mmol/l to 50 mmol/l.
23. An aqueous pharmaceutical composition according to claim 1 , wherein the osmolality is from 250 to 350 mOsmol/kg.