Aqueous preparation containing oligopeptides and etherified cyclodextrin

• US 20050239692A1
• Filed: 05/19/2003
• Published: 10/27/2005
• Est. Priority Date: 06/24/2002
• Status: Active Grant

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Lindenblatt, Hiltrud, Zobel, Hans-Peter
• Granted Patent: US 7,262,165 B2
• Time in Patent Office: Days
• US Class Current: 514/19.100
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

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.

Claims

1. Aqueous pharmaceutical preparation of oligopeptides, comprising an oligopeptide of the 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(AcNH₂), Lys(AcSH), Met, Nal, Nle, Orn, Phe, 4-Hal-Phe, homoPhe, Phg, Pro, Pya, Ser, Thr, Tia, Tic, Trp, Tyr or Val, where the said amino acid radicals may also be derivatised,

R denotes alkyl having 1-18 C atoms,

Hal denotes F, Cl, Br, I,

Ac denotes alkanoyl having 1-10 C atoms, aroyl having 7-11 carbon atoms or aralkanoyl having 8-12 C atoms,

n denotes a hydrogen atom or an alkyl radical R, benzyl or an aralkyl radical having 7-18 C atoms on the alpha-amino function of the corresponding amino acid radical,

with the proviso that at least one amino acid radical has a substituent n, where n denotes R,

and where, if they are radicals of optically active amino acids and amino acid derivatives, 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 of water

2. Aqueous pharmaceutical preparation according to claim 1, characterised in that the etherified β

-cyclodextrin present is partially etherified β

-cyclodextrin

3. Aqueous pharmaceutical preparation according to claim 1, characterised in that the ether substituents in the etherified β

-cyclodextrin are hydroxyethyl and/or hydroxypropyl groups

4. Aqueous pharmaceutical preparation according to claim 1, characterised in that the etherified β

-cyclodextrin has a molar degree of substitution of between 0.2 and 10

5. Aqueous pharmaceutical preparation according to claim 4, characterised in that the partially etherified β

-cyclodextrin has a molar degree of substitution of between 0.2 and 2, based on the ether substituents

6. Aqueous pharmaceutical preparation according to claim 4, characterised in that the partially etherified β

-cyclodextrin has a molar degree of substitution of between 0.5 and 0.8, based on the ether substituents

7. Aqueous pharmaceutical preparation according to claim 1, characterised in that the oligopeptide is cilengitide

8. Aqueous pharmaceutical preparation according to claim 1, characterised in that an isotonicity agent is furthermore present in an amount necessary for establishing isotonicity

9. Aqueous pharmaceutical preparation according to claim 1, characterised in that it has a pH of from 5 to 8, preferably a pH of from 5.6 to 7.4.

10. Aqueous pharmaceutical preparation according to claim 9, characterised in that it has a pH of from 6 to 7.2

11. Aqueous pharmaceutical preparation according to claim 1, characterised in that it comprises from 20 to 120 mg/ml of cilengitide and from 15 to 25% by weight of hydroxypropyl-β

-cyclodextrin having a molar degree of substitution of from 0.5 to 0.8

12. Aqueous pharmaceutical preparation according to claim 11, characterised in that it comprises 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. Process for the preparation of an aqueous pharmaceutical preparation according to claim 1, characterised in that firstly the β

-cyclodextrin ether is dissolved in water, and the active ingredient and any further adjuvants are subsequently added