United States Patent:  6,022,860

Assignee:  Asta Medica Aktiengesellschaft (Dresden, DE)

Filed:  March 26, 1998

In this invention, a release-delaying system is to be developed for LHRH antagonists, in particular for cetrorelix, which allows the active compound to be released in a controlled manner over several weeks by complexation with suitable biophilic carriers. The acidic polyamino acids polyglutamic acid and polyaspartic acid were selected for complexation with cetrorelix. The cetrorelix polyamino acid complexes are prepared from aqueous solutions by combination of the solutions and precipitation of the complexes, which are subsequently centrifuged off and dried over P₂ O₅ in vacuo. If complexes having a defined composition are to be obtained, lyophilization proves to be a suitable method. The cetrorelix-carboxylic acid complexes were also prepared from the aqueous solutions. In the random liberation system, the acidic polyamino acids poly-Glu and poly-Asp showed good release-delaying properties as a function of the hydrophobicity and the molecular mass of the polyamino acid. In animal experiments, it was possible to confirm the activity of the cetrorelix-polyamino acid complexes as a depot system in principle. It is thus possible by complexation of cetrorelix with polyamino acids to achieve testosterone suppression in male rats over 600 hours. The release of active compound here can be controlled by the nature and the molecular mass of the polymers.

SUMMARY OF THE INVENTION

The aim of the invention is to prepare depot preparations having improved and controllable release-delaying properties and increased stability against premature proteolytic degradation of LHRH antagonists for therapy in the areas known for this such as hormone-sensitive tumours, such as, for example, breast and prostate carcinoma, benign prostate hypertrophy, endometriosis, hysteroscopy and for the treatment of fertility disorders and to indicate an easily controllable and environmentally friendly process for the production of these preparations.

The object of the invention is to prepare novel depot preparations having improved and controllable release-delaying properties of LHRH antagonists such as antide, antarelix, azaline, A-75998, ganirelix, Nal-Glu antagonist, but preferably cetrorelix, with biodegradable polymers, and a process for their preparation.

According to the invention, the object is achieved by preparing immobilized and activity-stabilized, parenterally administerable peptide hormone preparations from complexes of LHRH antagonists with polyamino acids, in particular polyglutamic acid and polyaspartic acid by precipitating the polyamino acid-peptide hormone complex from aqueous solutions avoiding organic solvents. Advantageously, the polyamino acid-peptide hormone complexes can furthermore be prepared with a controllable hormone content by lyophilization of the aqueous solutions. By means of the nature and the molecular mass of the polyamino acids, by incorporation of hydrophobic amino acids into the polymer structure or by partial esterification, the release rate of the active compound can be controlled.

The complexes according to the invention are used in medicine for the therapy of hormone-sensitive tumours, in particular for the treatment of breast and prostate carcinomas, of benign prostate hypertrophy and in gynaecology for the induction of ovulation, in vitro fertilization and endometriosis and in connection with hysteroscopy.

The term "complex" in the context of this invention comprises the assembly of two or more components to give a poorly soluble system which is subject to no proven stoichiometry. In this case, a superposition of interactions occurs, mainly secondary valence bonds playing a part.

In the literature, poorly soluble peptide complexes are occasionally also described as a "salt". This description is likewise in many cases not exact, since they are not, as already mentioned, substances having a defined composition.

In peptides and proteins ionic interactions admittedly occur, but they are not responsible on their own for a structural or physical state change.

For peptides and proteins, the term "complex" and "salt" is to be taken in a wider sense on account of the large number of functional groups, since several interactions which lead to synthesis and structure of the peptides and proteins are superimposed.

Polyamine [sic] acids were used which are suitable as biophilic carrier materials for peptides. It is essential to the invention here that the active compounds are not bonded chemically to the polymer, but are only attached to the polymer by secondary valence bonds and hydrophobic interactions.

Unexpectedly, it is seen that the LHRH antagonist Cetrorelix especially has a very high binding affinity to polyamino acids, in particular to polyglutamic acid and polyaspartic acid. Such a high affinity of cetrorelix was not foreseeable on the basis of the literature up to now and was surprising on the basis of the structure of the peptide.

The spontaneously precipitating complexes have a defined, reproducible hormone content.

Should the hormone content in the complexes vary, however, and be defined exactly, lyophilization has turned out as a suitable method.

These preparation conditions are significantly milder than described in earlier patents and thus prevent possible inactivation of the hormone.

The interactions occurring between the molecules on mixing the solutions lead to stable complexes which have a controllable active compound release profile and an increased stability to proteolysis.

Polyamino acids thus affect not only the release-delaying behaviour, but simultaneously offer protection from undesired, premature proteolytic degradation. This aspect is especially of importance in view of the long-term use of such preparations.

The release-delaying behaviour of the complexes can be significantly affected by the nature and the molecular mass of the polyamino acids, the incorporation of amino acids having hydrophobic side chains into the polymer structure and by partial esterification of carboxyl groups present.

Claim 1 of 7 Claims

1. A complex of an LHRH antagonist selected from the group consisting of antide, antarelix, azaline, A-75998, ganirelix, Nal-Glu antagonist and cetrorelix with a polyamino acid selected from the group consisting of polyglutamic acid and polyaspartic acid.

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